Title 21 Food and Drugs Parts 200 to 299

Revised as of April 1, 2019

Containing a codification of documents of general applicability and future effect

As of April 1, 2019

Published by the Office of the Federal Register National Archives and Records Administration as a Special Edition of the Federal Register

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00001 Fmt 8091 Sfmt 8091 Y:\SGML\247073.XXX 247073 U.S. GOVERNMENT OFFICIAL EDITION NOTICE

Legal Status and Use of Seals and Logos The seal of the National Archives and Records Administration (NARA) authenticates the Code of Federal Regulations (CFR) as the official codification of Federal regulations established under the Federal Register Act. Under the provisions of 44 U.S.C. 1507, the contents of the CFR, a special edition of the Federal Register, shall be judicially noticed. The CFR is prima facie evidence of the original documents published in the Federal Register (44 U.S.C. 1510). It is prohibited to use NARA’s official seal and the stylized Code of Federal Regulations logo on any republication of this material without the express, written permission of the Archivist of the United States or the Archivist’s designee. Any person using NARA’s official seals and logos in a manner inconsistent with the provisions of 36 CFR part 1200 is subject to the penalties specified in 18 U.S.C. 506, 701, and 1017.

Use of ISBN Prefix This is the Official U.S. Government edition of this publication and is herein identified to certify its authenticity. Use of the 0–16 ISBN prefix is for U.S. Government Publishing Office Official Edi- tions only. The Superintendent of Documents of the U.S. Govern- ment Publishing Office requests that any reprinted edition clearly be labeled as a copy of the authentic work with a new ISBN.

U.S. GOVERNMENT PUBLISHING OFFICE U.S. Superintendent of Documents • Washington, DC 20402–0001 http://bookstore.gpo.gov Phone: toll-free (866) 512-1800; DC area (202) 512-1800

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00002 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 e:\seals\archives.ai e:\seals\gpologo2.eps Table of Contents

Page Explanation ...... v

Title 21:

Chapter I—Food and Drug Administration, Department of Health and Human Services (Continued) ...... 3

Finding Aids:

Table of CFR Titles and Chapters ...... 217

Alphabetical List of Agencies Appearing in the CFR ...... 237

List of CFR Sections Affected ...... 247

iii

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00003 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Cite this Code: CFR

To cite the regulations in this volume use title, part and section number. Thus, 21 CFR 200.5 refers to title 21, part 200, section 5.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00004 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Explanation

The Code of Federal Regulations is a codification of the general and permanent rules published in the Federal Register by the Executive departments and agencies of the Federal Government. The Code is divided into 50 titles which represent broad areas subject to Federal regulation. Each title is divided into chapters which usually bear the name of the issuing agency. Each chapter is further subdivided into parts covering specific regulatory areas. Each volume of the Code is revised at least once each calendar year and issued on a quarterly basis approximately as follows: Title 1 through Title 16...... as of January 1 Title 17 through Title 27 ...... as of April 1 Title 28 through Title 41 ...... as of July 1 Title 42 through Title 50...... as of October 1 The appropriate revision date is printed on the cover of each volume. LEGAL STATUS The contents of the Federal Register are required to be judicially noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie evidence of the text of the original documents (44 U.S.C. 1510). HOW TO USE THE CODE OF FEDERAL REGULATIONS The Code of Federal Regulations is kept up to date by the individual issues of the Federal Register. These two publications must be used together to determine the latest version of any given rule. To determine whether a Code volume has been amended since its revision date (in this case, April 1, 2019), consult the ‘‘List of CFR Sections Affected (LSA),’’ which is issued monthly, and the ‘‘Cumulative List of Parts Affected,’’ which appears in the Reader Aids section of the daily Federal Register. These two lists will identify the Federal Register page number of the latest amendment of any given rule. EFFECTIVE AND EXPIRATION DATES Each volume of the Code contains amendments published in the Federal Reg- ister since the last revision of that volume of the Code. Source citations for the regulations are referred to by volume number and page number of the Federal Register and date of publication. Publication dates and effective dates are usually not the same and care must be exercised by the user in determining the actual effective date. In instances where the effective date is beyond the cut- off date for the Code a note has been inserted to reflect the future effective date. In those instances where a regulation published in the Federal Register states a date certain for expiration, an appropriate note will be inserted following the text. OMB CONTROL NUMBERS The Paperwork Reduction Act of 1980 (Pub. L. 96–511) requires Federal agencies to display an OMB control number with their information collection request.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00005 Fmt 8008 Sfmt 8092 Y:\SGML\247073.XXX 247073 Many agencies have begun publishing numerous OMB control numbers as amendments to existing regulations in the CFR. These OMB numbers are placed as close as possible to the applicable recordkeeping or reporting requirements. PAST PROVISIONS OF THE CODE Provisions of the Code that are no longer in force and effect as of the revision date stated on the cover of each volume are not carried. Code users may find the text of provisions in effect on any given date in the past by using the appropriate List of CFR Sections Affected (LSA). For the convenience of the reader, a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume. For changes to the Code prior to the LSA listings at the end of the volume, consult previous annual editions of the LSA. For changes to the Code prior to 2001, consult the List of CFR Sections Affected compilations, published for 1949- 1963, 1964-1972, 1973-1985, and 1986-2000. ‘‘[RESERVED]’’ TERMINOLOGY The term ‘‘[Reserved]’’ is used as a place holder within the Code of Federal Regulations. An agency may add regulatory information at a ‘‘[Reserved]’’ location at any time. Occasionally ‘‘[Reserved]’’ is used editorially to indicate that a portion of the CFR was left vacant and not accidentally dropped due to a printing or computer error. INCORPORATION BY REFERENCE What is incorporation by reference? Incorporation by reference was established by statute and allows Federal agencies to meet the requirement to publish regulations in the Federal Register by referring to materials already published elsewhere. For an incorporation to be valid, the Director of the Federal Register must approve it. The legal effect of incorporation by reference is that the material is treated as if it were published in full in the Federal Register (5 U.S.C. 552(a)). This material, like any other properly issued regulation, has the force of law. What is a proper incorporation by reference? The Director of the Federal Register will approve an incorporation by reference only when the requirements of 1 CFR part 51 are met. Some of the elements on which approval is based are: (a) The incorporation will substantially reduce the volume of material published in the Federal Register. (b) The matter incorporated is in fact available to the extent necessary to afford fairness and uniformity in the administrative process. (c) The incorporating document is drafted and submitted for publication in accordance with 1 CFR part 51. What if the material incorporated by reference cannot be found? If you have any problem locating or obtaining a copy of material listed as an approved incorporation by reference, please contact the agency that issued the regulation containing that incorporation. If, after contacting the agency, you find the material is not available, please notify the Director of the Federal Register, National Archives and Records Administration, 8601 Adelphi Road, College Park, MD 20740-6001, or call 202-741-6010. CFR INDEXES AND TABULAR GUIDES A subject index to the Code of Federal Regulations is contained in a separate volume, revised annually as of January 1, entitled CFR INDEX AND FINDING AIDS. This volume contains the Parallel Table of Authorities and Rules. A list of CFR titles, chapters, subchapters, and parts and an alphabetical list of agencies publishing in the CFR are also included in this volume.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00006 Fmt 8008 Sfmt 8092 Y:\SGML\247073.XXX 247073 An index to the text of ‘‘Title 3—The President’’ is carried within that volume. The Federal Register Index is issued monthly in cumulative form. This index is based on a consolidation of the ‘‘Contents’’ entries in the daily Federal Reg- ister. A List of CFR Sections Affected (LSA) is published monthly, keyed to the revision dates of the 50 CFR titles. REPUBLICATION OF MATERIAL There are no restrictions on the republication of material appearing in the Code of Federal Regulations. INQUIRIES For a legal interpretation or explanation of any regulation in this volume, contact the issuing agency. The issuing agency’s name appears at the top of odd-numbered pages. For inquiries concerning CFR reference assistance, call 202–741–6000 or write to the Director, Office of the Federal Register, National Archives and Records Administration, 8601 Adelphi Road, College Park, MD 20740-6001 or e-mail [email protected]. SALES The Government Publishing Office (GPO) processes all sales and distribution of the CFR. For payment by credit card, call toll-free, 866-512-1800, or DC area, 202-512-1800, M-F 8 a.m. to 4 p.m. e.s.t. or fax your order to 202-512-2104, 24 hours a day. For payment by check, write to: US Government Publishing Office – New Orders, P.O. Box 979050, St. Louis, MO 63197-9000. ELECTRONIC SERVICES The full text of the Code of Federal Regulations, the LSA (List of CFR Sections Affected), The United States Government Manual, the Federal Register, Public Laws, Public Papers of the Presidents of the United States, Compilation of Presi- dential Documents and the Privacy Act Compilation are available in electronic format via www.govinfo.gov. For more information, contact the GPO Customer Contact Center, U.S. Government Publishing Office. Phone 202-512-1800, or 866- 512-1800 (toll-free). E-mail, [email protected]. The Office of the Federal Register also offers a free service on the National Archives and Records Administration’s (NARA) World Wide Web site for public law numbers, Federal Register finding aids, and related information. Connect to NARA’s web site at www.archives.gov/federal-register. The e-CFR is a regularly updated, unofficial editorial compilation of CFR material and Federal Register amendments, produced by the Office of the Federal Register and the Government Publishing Office. It is available at www.ecfr.gov.

OLIVER A. POTTS, Director, Office of the Federal Register April 1, 2019.

vii

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00007 Fmt 8008 Sfmt 8092 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00008 Fmt 8008 Sfmt 8092 Y:\SGML\247073.XXX 247073 THIS TITLE

Title 21—FOOD AND DRUGS is composed of nine volumes. The parts in these volumes are arranged in the following order: Parts 1–99, 100–169, 170–199, 200–299, 300–499, 500–599, 600–799, 800–1299 and 1300 to end. The first eight volumes, containing parts 1–1299, comprise Chapter I—Food and Drug Administration, Depart- ment of Health and Human Services. The ninth volume, containing part 1300 to end, includes Chapter II—Drug Enforcement Administration, Department of Jus- tice, and Chapter III—Office of National Drug Control Policy. The contents of these volumes represent all current regulations codified under this title of the CFR as of April 1, 2019.

For this volume, Susannah C. Hurley was Chief Editor. The Code of Federal Regulations publication program is under the direction of John Hyrum Martinez, assisted by Stephen J. Frattini.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00009 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00010 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 21—Food and Drugs

(This book contains parts 200 to 299)

Part

CHAPTER I—Food and Drug Administration, Department of Health and Human Services (Continued) ...... 200

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00011 Fmt 8008 Sfmt 8008 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00012 Fmt 8008 Sfmt 8008 Y:\SGML\247073.XXX 247073 CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED)

EDITORIAL NOTE: Nomenclature changes to chapter I appear at 59 FR 14366, Mar. 28, 1994, and 66 FR 56035, Nov. 6, 2001.

SUBCHAPTER C—DRUGS: GENERAL

Part Page 200 General ...... 5 201 Labeling ...... 8 202 Prescription drug advertising ...... 107 203 Prescription drug marketing ...... 116 205 Guidelines for State licensing of wholesale prescription drug distributors ...... 129 206 Imprinting of solid oral dosage form drug products for human use ...... 134 207 Requirements for foreign and domestic establishment registration and listing for human drugs, including drugs that are regulated under a biologics license application, and animal drugs, and the national drug code ...... 135 208 Medication Guides for prescription drug products .. 151 209 Requirement for authorized dispensers and pharmacies to distribute a side effects statement ...... 154 210 Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general ...... 156 211 Current good manufacturing practice for finished pharmaceuticals ...... 158 212 Current good manufacturing practice for positron emission tomography drugs ...... 179 216 Human drug compounding ...... 188 225 Current good manufacturing practice for medicated feeds ...... 191 226 Current good manufacturing practice for Type A medicated articles ...... 198 250 Special requirements for specific human drugs ...... 203 3

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00013 Fmt 8008 Sfmt 8008 Y:\SGML\247073.XXX 247073 21 CFR Ch. I (4–1–19 Edition)

Part Page 290 Controlled drugs...... 211 299 Drugs; official names and established names ...... 212

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00014 Fmt 8008 Sfmt 8008 Y:\SGML\247073.XXX 247073 SUBCHAPTER C—DRUGS: GENERAL

PART 200—GENERAL use the distinctive envelopes for ordinary mail. Subpart A—General Provisions (a) Use first class mail and No. 10 white envelopes. Sec. 200.5 Mailing of important information (b) The name and address of the agen- about drugs. cy or the drug manufacturer or dis- 200.7 Supplying pharmacists with indica- tributor is to appear in the upper left tions and dosage information. corner of the envelope. 200.10 Contract facilities (including con- (c) The following statements are to sulting laboratories) utilized as extramural facilities by pharmaceutical man- appear in the far left third of the enve- ufacturers. lope front, in the type and size indi- 200.11 Use of octadecylamine in steam lines cated, centered in a rectangular space of drug establishments. approximately 3 inches wide and 21⁄4 200.15 Definition of term ‘‘insulin’’. inches high with an approximately 3⁄8 inch-wide border in the color indicated: Subpart B [Reserved] (1) When the information concerns a Subpart C—Requirements for Specific significant hazard to health, the state- Classes of Drugs ment: 200.50 Ophthalmic preparations and dis- IMPORTANT pensers. 200.51 Aqueous-based drug products for oral DRUG inhalation. WARNING Subpart D [Reserved] Subpart E—Prescription Drug Consumer The statement shall be in three lines, Price Listing all capitals, and centered. ‘‘Important’’ shall be in 36 point Gothic Bold type. 200.200 Prescription drugs; reminder adver- ‘‘Drug’’ and ‘‘Warning’’ shall be in 36 tisements and reminder labeling to pro- point Gothic Condensed type. The rec- vide price information to consumers. tangle’s border and the statement AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, therein shall be red. 355, 358, 360e, 371, 374, 375. (2) When the information concerns SOURCE: 40 FR 13996, Mar. 27, 1975, unless important changes in drug package la- otherwise noted. beling, the statement:

Subpart A—General Provisions IMPORTANT

§ 200.5 Mailing of important informa- PRESCRIBING tion about drugs. Manufacturers and distributors of INFORMATION drugs and the Food and Drug Adminis- tration occasionally are required to The statement shall be in three lines, mail important information about all capitals, and centered. ‘‘Important’’ drugs to physicians and others respon- shall be in 36 point Gothic Bold type. sible for patient care. In the public in- ‘‘Prescribing’’ and ‘‘Information’’ shall terest, such mail should be distinctive be in 36 point Gothic Condensed type. in appearance so that it will be The rectangle’s border and the state- promptly recognized and read. The ment therein shall be blue. Food and Drug Administration will (3) When the information concerns a make such mailings in accordance with correction of prescription drug adver- the specifications set forth in this sec- tising or labeling, the statement: tion. Manufacturers and distributors of drugs are asked to make such mailings as prescribed by this section and not to

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00015 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 200.7 21 CFR Ch. I (4–1–19 Edition)

IMPORTANT tion (NDA) or to the sponsor of an In- vestigational New Drug (IND) Applica- CORRECTION tion, any information obtained during OF DRUG the inspection of an extramural facility having a specific bearing on the INFORMATION compliance of the manufacturer’s, applicant’s, or sponsor’s product with the The statement shall be in four lines, all Federal Food, Drug, and Cosmetic Act. capitals, and centered. ‘‘Important’’ The Food and Drug Administration’s shall be in 36 point Gothic Bold type. ‘‘Correction,’’ ‘‘Of Drug,’’ and ‘‘Infor- position is that by the acceptance of mation’’ shall be in 36 point Gothic such contract work, the extramural fa- Condensed type. The rectangle’s border cility authorizes such disclosures. and the statement therein shall be (d) The Food and Drug Administra- brown. tion does not consider results of validation studies of analytical and assay § 200.7 Supplying pharmacists with in- methods and control procedures to be dications and dosage information. trade secrets that may be withheld There are presently no regulations from the drug manufacturer by the under the Federal Food, Drug, and Cos- contracted extramural facility. metic Act that prevent a manufacturer [40 FR 13996, Mar. 27, 1975, as amended at 55 of prescription drugs from sending the FR 11576, Mar. 29, 1990] pharmacist data he needs on indications and dosage in exercising his im- § 200.11 Use of octadecylamine in portant professional function of check- steam lines of drug establishments. ing against possible mistakes in a pre- The Food and Drug Administration scription. The Food and Drug Adminis- will not object to the use of tration believes manufacturers should octadecylamine in steam lines where be encouraged to supply such printed the steam may be used for autoclaving matter to the pharmacist for his pro- surgical instruments and gauze if the fessional information. Obviously, such octadecylamine in the steam is not printed matter should not be displayed more than 2.4 parts per million. to prospective purchasers to promote over-the-counter sale of prescription § 200.15 Definition of term ‘‘insulin.’’ drugs. For purposes of sections 801 and 802 of § 200.10 Contract facilities (including the act and this title, the term insulin consulting laboratories) utilized as means the active principle of the pan- extramural facilities by pharma- creas that affects the metabolism of ceutical manufacturers. carbohydrates in the animal body and (a) Section 704(a) of the Federal which is of value in the treatment of Food, Drug, and Cosmetic Act specifi- diabetes mellitus. The term includes cally authorizes inspection of con- synthetic and biotechnologically de- sulting laboratories as well as any fac- rived products that are the same as, or tory, warehouse, or establishment in similar to, naturally occurring insulins which prescription drugs are manufac- in structure, use, and intended effect tured, processed, packed, or held. and are of value in the treatment of di- (b) The Food and Drug Administra- abetes mellitus. tion is aware that many manufacturers [63 FR 26698, May 13, 1998] of pharmaceutical products utilize extramural independent contract facilities, such as testing laboratories, con- Subpart B [Reserved] tract packers or labelers, and custom grinders, and regards extramural facili- Subpart C—Requirements for ties as an extension of the manufactur- Specific Classes of Drugs er’s own facility. (c) The Food and Drug Administra- § 200.50 Ophthalmic preparations and tion reserves the right to disclose to dispensers. the pharmaceutical manufacturer, or (a)(1) Informed medical opinion is in to the applicant of a new drug applica- agreement that all preparations offered

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00016 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 200.200

or intended for ophthalmic use, includ- sterile. These articles, which are regu- ing preparations for cleansing the eyes, lated as drugs if packaged with the should be sterile. It is further evident drugs with which they are to be used, that such preparations purport to be of should be packaged so as to maintain such purity and quality as to be suit- sterility until the package is opened able for safe use in the eye. and be labeled, on or within the retail (2) The Food and Drug Administra- package, so as to afford adequate direction concludes that all such preparations and necessary warnings to mini- tions, if they are not sterile, fall below mize the hazard of injury resulting their professed standard of purity or from contamination during use. quality and may be unsafe. In a state- [40 FR 13996, Mar. 27, 1975, as amended at 47 ment of policy issued on September 1, FR 50455, Nov. 5, 1982] 1964, the Food and Drug Administra- tion ruled that liquid preparations of- § 200.51 Aqueous-based drug products fered or intended for ophthalmic use for oral inhalation. that are not sterile may be regarded as (a) All aqueous-based drug products adulterated within the meaning of sec- for oral inhalation must be manufac- tion 501(c) of the Federal Food, Drug, tured to be sterile. and Cosmetic Act (the act), and, fur- (b) Manufacturers must also comply ther, may be deemed misbranded with- with the requirements in § 211.113(b) of in the meaning of section 502(j) of the this chapter. act. This ruling is extended to affect all preparations for ophthalmic use. By [65 FR 34089, May 26, 2000] this regulation, this ruling is applicable to ophthalmic preparations that Subpart D [Reserved] are regulated as drugs. By the regulation in § 800.10 of this chapter, this rul- Subpart E—Prescription Drug ing is applicable to ophthalmic prep- Consumer Price Listing arations that are regulated as medical devices. § 200.200 Prescription drugs; reminder (3) The containers of ophthalmic advertisements and reminder label- preparations shall be sterile at the ing to provide price information to time of filling and closing, and the con- consumers. tainer or individual carton shall be so (a) Prescription drug reminder adver- sealed that the contents cannot be used tisements and reminder labeling in- without destroying the seal. The pack- tended to provide price information to aging and labeling of ophthalmic prep- consumers are exempt from the re- arations that are over-the-counter quirements of §§ 201 .100 and 202.1 of this drugs shall also comply with § 211.132 of chapter if all of the following condi- this chapter on tamper-resistant pack- tions are met: aging requirements. (1) The only purpose of the reminder (b) Liquid ophthalmic preparations advertisement or reminder labeling is packed in multiple-dose containers to provide consumers with information should: concerning the price charged for a pre- (1) Contain one or more suitable and scription for a particular drug product, harmless substances that will inhibit and the reminder advertisement or re- the growth of microorganisms; or minder labeling contains no represen- (2) Be so packaged as to volume and tation or suggestion concerning the type of container and so labeled as to drug product’s safety, effectiveness, or duration of use and with such nec- indications for use. essary warnings as to afford adequate (2) The reminder advertisement or re- protection and minimize the hazard of minder labeling contains the propri- injury resulting from contamination etary name of the drug product, if any; during use. the established (generic) name of the (c) Eye cups, eye droppers, and other drug product, if any; the drug product’s dispensers intended for ophthalmic use strength if the product contains a sin- should be sterile, and may be regarded gle active ingredient or if the product as falling below their professed stand- contains more than one active ingre- ard of purity or quality if they are not dient and a relevant strength can be

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00017 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Pt. 201 21 CFR Ch. I (4–1–19 Edition)

associated with the product without in- 201.15 Drugs; prominence of required label dicating each active ingredient (the es- statements. tablished name and quantity of each 201.16 Drugs; Spanish-language version of active ingredient are not required); the certain required statements. 201.17 Drugs; location of expiration date. dosage form; and the price charged for 201.18 Drugs; significance of control num- a prescription for a specific quantity of bers. the drug product. 201.19 Drugs; use of term ‘‘infant’’. (3) The reminder advertisement or re- 201.20 Declaration of presence of FD&C Yel- minder labeling may also include other low No. 5 and/or FD&C Yellow No. 6 in written, printed, or graphic matter, certain drugs for human use. e.g., identification of professional or 201.21 Declaration of presence of convenience services provided by the phenylalanine as a component of aspar- pharmacy: Provided, That such infor- tame in over-the-counter and prescription drugs for human use. mation is neither false nor misleading 201.22 Prescription drugs containing sul- and contains no representation or sug- fites; required warning statements. gestion concerning the drug product’s 201.23 Required pediatric studies. safety, effectiveness, or indications for 201.24 Labeling for systemic antibacterial use. drug products. (4) The price stated in the reminder 201.25 Bar code label requirements. advertisement or reminder labeling as 201.26 Exceptions or alternatives to labeling that charged for a prescription shall in- requirements for human drug products held by the Strategic National Stockpile. clude all charges to the consumer including, but not limited to, the cost of Subpart B—Labeling Requirements for the drug product, professional fees, and Prescription Drugs and/or Insulin handling fees, if any. Mailing fees and delivery fees, if any, may be stated sep- 201.50 Statement of identity. arately and without repetition. 201.51 Declaration of net quantity of contents. (b) This exemption from §§ 201.100 and 201.55 Statement of dosage. 202.1 of this chapter is applicable to all 201.56 Requirements on content and format prescription drug reminder labeling of labeling for human prescription drug and reminder advertisements solely in- and biological products. tended to provide consumers with in- 201.57 Specific requirements on content and formation regarding the price charged format of labeling for human prescrip- for prescriptions including price lists, tion drug and biological products de- catalogs, and other promotional mate- scribed in § 201.56(b)(1). 201.58 Waiver of labeling requirements. rial, whether mailed, posted in a pharmacy, placed in a newspaper, or aired Subpart C—Labeling Requirements for on radio or television. Over-the-Counter Drugs (c) Any reminder advertisement or reminder labeling intended to provide 201.60 Principal display panel. consumers with prescription price in- 201.61 Statement of identity. formation which is not in compliance 201.62 Declaration of net quantity of contents. with this section shall be the subject of 201.63 Pregnancy/breast-feeding warning. appropriate regulatory action. Such ac- 201.64 Sodium labeling. tion may be taken against the product 201.66 Format and content requirements for and/or the responsible person. over-the-counter (OTC) drug product labeling. [40 FR 58799, Dec. 18, 1975] 201.70 Calcium labeling. 201.71 Magnesium labeling. PART 201—LABELING 201.72 Potassium labeling. 201.80 Specific requirements on content and Subpart A—General Labeling Provisions format of labeling for human prescription drug and biological products; older Sec. drugs not described in § 201.56(b)(1). 201.1 Drugs; name and place of business of manufacturer, packer, or distributor. Subpart D—Exemptions From Adequate 201.2 Drugs and devices; National Drug Code Directions for Use numbers. 201.5 Drugs; adequate directions for use. 201.100 Prescription drugs for human use. 201.6 Drugs; misleading statements. 201.105 Veterinary drugs. 201.10 Drugs; statement of ingredients. 201.115 New drugs or new animal drugs.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00018 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.1

201.116 Drugs having commonly known di- 201.316 Drugs with thyroid hormone activity rections. for human use; required warning. 201.117 Inactive ingredients. 201.317 Digitalis and related cardiotonic 201.119 In vitro diagnostic products. drugs for human use in oral dosage 201.120 Prescription chemicals and other forms; required warning. prescription components. 201.319 Water-soluble gums, hydrophilic 201.122 Drugs for processing, repacking, or gums, and hydrophilic mucilloids (in- manufacturing. cluding, but not limited to agar, alginic 201.125 Drugs for use in teaching, law en- acid, calcium polycarbophil, forcement, research, and analysis. carboxymethylcellulose sodium, carra- 201.127 Drugs; expiration of exemptions. geenan, chondrus, glucomannan ((B-1,4 201.128 Meaning of ‘‘intended uses’’. linked) polymannose acetate), guar gum, 201.129 Drugs; exemption for radioactive karaya gum, kelp, methylcellulose, drugs for research use. plantago seed (psyllium), polycarbophil tragacanth, and xanthan gum) as active Subpart E—Other Exemptions ingredients; required warnings and directions. 201.150 Drugs; processing, labeling, or re- 201.320 Warning statements for drug prod- packing. ucts containing or manufactured with 201.161 Medical gases. chlorofluorocarbons or other ozone-depleting substances. Subpart F—Labeling Claims for Drugs in 201.323 Aluminum in large and small vol- Drug Efficacy Study ume parenterals used in total parenteral nutrition. 201.200 Disclosure of drug efficacy study 201.325 Over-the-counter drugs for vaginal evaluations in labeling and advertising. contraceptive and spermicide use containing nonoxynol 9 as the active ingre- Subpart G—Specific Labeling dient; required warnings and labeling in- Requirements for Specific Drug Products formation. 201.326 Over-the-counter drug products con- 201.300 Notice to manufacturers, packers, taining internal analgesic/antipyretic ac- and distributors of glandular prepara- tive ingredients; required warnings and tions. other labeling. 201.301 Notice to manufacturers, packers, 201.327 Over-the-counter sunscreen drug and distributors of estrogenic hormone products; required labeling based on ef- preparations. fectiveness testing. 201.302 Notice to manufacturers, packers, 201.328 Labeling of medical gas containers. and distributors of drugs for internal use APPENDIX A TO PART 201—EXAMPLES OF which contain mineral oil. GRAPHIC ENHANCEMENTS USED BY FDA 201.303 Labeling of drug preparations containing significant proportions of winter- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, green oil. 355, 358, 360, 360b, 360gg–360ss, 371, 374, 379e; 42 201.304 Tannic acid and barium enema prep- U.S.C. 216, 241, 262, 264. arations. SOURCE: 40 FR 13998, Mar. 27, 1975, unless 201.305 Isoproterenol inhalation prepara- otherwise noted. tions (pressurized aerosols, nebulizers, powders) for human use; warnings. EDITORIAL NOTE: Nomenclature changes to 201.306 Potassium salt preparations in- part 201 appear at 69 FR 13717, Mar. 24, 2004. tended for oral ingestion by man. 201.307 Sodium phosphates; package size Subpart A—General Labeling limitation, warnings, and directions for Provisions over-the-counter sale. 201.308 Ipecac syrup; warnings and direc- § 201.1 Drugs; name and place of busi- tions for use for over-the-counter sale. ness of manufacturer, packer, or 201.309 Acetophenetidin (phenacetin)-con- distributor. taining preparations; necessary warning statement. (a) A drug or drug product (as defined 201.310 Phenindione; labeling of drug prep- in § 320.1 of this chapter) in finished arations intended for use by man. package form is misbranded under sec- 201.311 [Reserved] tion 502 (a) and (b)(1) of the act if its 201.312 Magnesium sulfate heptahydrate; label does not bear conspicuously the label declaration on drug products. name and place of business of the man- 201.313 Estradiol labeling. 201.314 Labeling of drug preparations con- ufacturer, packer, or distributor. This taining salicylates. paragraph does not apply to any drug 201.315 Over-the-counter drugs for minor or drug product dispensed in accord- sore throats; suggested warning. ance with section 503(b)(1) of the act.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00019 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.1 21 CFR Ch. I (4–1–19 Edition)

(b) As used in this section, and for tice in the drug industry to contract purposes of section 502 (a) and (b)(1) of out the performance of certain manu- the act, the manufacturer of a drug facturing operations listed in para- product is the person who performs all graph (b) of this section. These oper- of the following operations that are re- ations include: (1) Soft-gelatin encap- quired to produce the product: (1) Mix- sulating, (2) aerosol filling, (3) steri- ing, (2) granulating, (3) milling, (4) lizing by irradiation, (4) lyophilizing, molding, (5) lyophilizing, (6) tableting, and (5) ethylene oxide sterilization. (7) encapsulating, (8) coating, (9) steri- (e) A person performs an operation lizing, and (10) filling sterile, aerosol, listed in paragraph (b) of this section or gaseous drugs into dispensing con- only if the operation is performed, in- tainers. cluding the performance of the appro- (c) If no person performs all of the priate in-process quality control oper- applicable operations listed in para- ations, except laboratory testing of graph (b) of this section, no person may samples taken during processing, as be represented as manufacturer except follows: as follows: (1) By individuals, a majority of (1) If the person performs more than whom are employees of the person and, one half of the applicable operations throughout the performance of the op- listed in paragraph (b) of this section eration, are subject to the person’s di- and acknowledges the contribution of rection and control; other persons who have performed the (2) On premises that are continuously remaining applicable operations by owned or leased by the person and sub- stating on the product label that ‘‘Cer- ject to the person’s direction and contain manufacturing operations have trol; and been performed by other firms.’’; or (3) On equipment that is continu- (2) If the person performs at least one ously owned or leased by the person. As applicable operation listed in para- used in this paragraph, person, when it graph (b) of this section and identifies identifies a corporation, includes a par- by appropriate designation all other ent, subsidiary, or affiliate company persons who have performed the re- where the related companies are under maining applicable operations, e.g., common ownership and control. ‘‘Made by (Person A), Filled by (Person (f) The name of the person rep- B), Sterilized by (Person C)’’; or resented as manufacturer under para- (3) If the person performs at least one graph (b) or (c) of this section must be applicable operation listed in para- the same as either (1) the name of the graph (b) of this section and the person establishment (as defined in § 207.1 of is listed along with all other persons this chapter) under which that person who have performed the remaining ap- is registered at the time the labeled plicable operations as ‘‘joint manufac- product is produced or (2) the reg- turers.’’ A list of joint manufacturers istered establishment name of a par- shall be qualified by the phrase ent, subsidiary, or affiliate company ‘‘Jointly Manufactured By where the related companies are under llllll,’’ and the names of all of common ownership and control. In ad- the manufacturers shall be printed to- dition, the name shall meet the re- gether in the same type size and style; quirements of paragraph (g) of this sec- or tion. (4) If the person performs all applica- (g) The requirement for declaration ble operations listed in paragraph (b) of of the name of the manufacturer, pack- this section except for those operations er, or distributor shall be deemed to be listed in paragraph (d) of this section. satisfied, in the case of a corporate per- For purposes of this paragraph, person, son, only by the actual corporate when it identifies a corporation, in- name, except that the corporate name cludes a parent, subsidiary, or affiliate may be the name of a parent, sub- company where the related companies sidiary, or affiliate company where the are under common ownership and con- related companies are under common trol. ownership and control. The corporate (d) The Food and Drug Administra- name may be preceded or followed by tion finds that it is the common prac- the name of the particular division of

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00020 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.5

the corporation. ‘‘Company,’’ ‘‘Incor- a current city directory or telephone porated,’’ etc., may be abbreviated or directory. The requirement for inclu- omitted and ‘‘The’’ may be omitted. In sion of the ZIP Code shall apply to con- the case of an individual, partnership, sumer commodity labels developed or or association, the name under which revised after July 1, 1969. In the case of the business is conducted shall be used. nonconsumer packages, the ZIP Code (h)(1) Except as provided in this sec- shall appear either on the label or the tion, no person other than the manu- labeling (including the invoice). facturer, packer, or distributor may be (j) If a person manufactures, packs, identified on the label of a drug or drug or distributes a drug or drug product at product. a place other than the person’s prin- (2) The appearance on a drug product cipal place of business, the label may label of a person’s name without quali- state the principal place of business in fication is a representation that the lieu of the actual place where such named person is the sole manufacturer drug or drug product was manufactured of the product. That representation is or packed or is to be distributed, unless false and misleading, and the drug such statement would be misleading. product is misbranded under section (k) Paragraphs (b), (c), (d), (e), and (f) 502(a) of the act, if the person is not of this section, do not apply to the la- the manufacturer of the product in ac- beling of drug components. cordance with this section. (l) A drug product is misbranded (3) If the names of two or more per- under section 502(a) of the act if its la- sons appear on the label of a drug or beling identifies a person as manufac- drug product, the label may identify which of the persons is to be contacted turer, packer, or distributor, and that for further information about the prod- identification does not meet the re- uct. quirements of this section. (4) If a trademark appears on the (m) This section does not apply to bi- drug or drug product label or appears ological drug products that are subject as a mark directly on the drug product to the requirements of section 351 of (e.g., tablet or capsule), the label may the Public Health Service Act, 42 identify the holder or licensee of the U.S.C. 262. trademark. The label may also state [45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. whether the person identified holds the 31, 1980, as amended at 48 FR 37620, Aug. 19, trademark or is licensee of the trade- 1983; 81 FR 60212, Aug. 31, 2016] mark. (5) If the distributor is named on the § 201.2 Drugs and devices; National label, the name shall be qualified by Drug Code numbers. one of the following phrases: ‘‘Manu- The National Drug Code (NDC) num- factured for llllll’’, ‘‘Distributed ber is requested but not required to ap- by llllll’’, ‘‘Manufactured by pear on all drug labels and in all drug llllll for llllll’’, ‘‘Manu- labeling, including the label of any pre- factured for lllllby lllll’’, scription drug container furnished to a ‘‘Distributor: llllll’’, ‘‘Marketed consumer. by llllll’’. The qualifying phrases may be abbreviated. [40 FR 52002, Nov. 7, 1975, as amended at 81 (6) If the packer is identified on the FR 60212, Aug. 31, 2016] label, the name shall be qualified by the phrase ‘‘Packed by llllll’’ or § 201.5 Drugs; adequate directions for use. ‘‘Packaged by llllll’’. The qualifying phrases may be abbreviated. Adequate directions for use means di- (i) The statement of the place of busi- rections under which the layman can ness shall include the street address, use a drug safely and for the purposes city, State, and ZIP Code. For a foreign for which it is intended. (Section manufacturer, the statement of the 201.128 defines ‘‘intended use.’’) Direc- place of business shall include the tions for use may be inadequate be- street address, city, country, and any cause, among other reasons, of omis- applicable mailing code. The street ad- sion, in whole or in part, or incorrect dress may be omitted if it is shown in specification of:

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00021 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.6 21 CFR Ch. I (4–1–19 Edition)

(a) Statements of all conditions, pur- pear together, without any intervening poses, or uses for which such drug is in- written, printed, or graphic matter, extended, including conditions, purposes, cept the proprietary names of ingredi- or uses for which it is prescribed, rec- ents, which may be included with the ommended, or suggested in its oral, listing of established names, and such written, printed, or graphic adver- statements that are specifically re- tising, and conditions, purposes, or quired for certain ingredients by the uses for which the drug is commonly act or regulations in this chapter. used; except that such statements shall (b) The term ingredient applies to any not refer to conditions, uses, or pur- substance in the drug, whether added poses for which the drug can be safely to the formulation as a single sub- used only under the supervision of a stance or in admixture with other sub- practitioner licensed by law and for stances. which it is advertised solely to such (c) The labeling of a drug may be practitioner. misleading by reason (among other rea- (b) Quantity of dose, including usual sons) of: quantities for each of the uses for (1) The order in which the names of which it is intended and usual quan- the ingredients present in the drug ap- tities for persons of different ages and pear in the labeling, or the relative different physical conditions. prominence otherwise given such (c) Frequency of administration or names. application. (2) Failure to reveal the proportion (d) Duration of administration or ap- of, or other fact with respect to, an in- plication. gredient present in such drug, when (e) Time of administration or appli- such proportion or other fact is mate- cation (in relation to time of meals, rial in the light of the representation time of onset of symptoms, or other that such ingredient is present in such time factors). drug. (f) Route or method of administra- (3) The employment of a fanciful pro- tion or application. prietary name for a drug or ingredient (g) Preparation for use, i.e., shaking, in such a manner as to imply that the dilution, adjustment of temperature, drug or ingredient has some unique ef- or, other manipulation or process. fectiveness or composition when, in fact, the drug or ingredient is a com- [41 FR 6908, Feb. 13, 1976] mon substance, the limitations of § 201.6 Drugs; misleading statements. which are readily recognized when the drug or ingredient is listed by its es- (a) Among representations in the la- tablished name. beling of a drug which render such drug (4) The featuring in the labeling of misbranded is a false or misleading inert or inactive ingredients in a man- representation with respect to another ner that creates an impression of value drug or a device or a food or cosmetic. greater than their true functional role (b) The labeling of a drug which con- in the formulation. tains two or more ingredients may be (5) Designation of a drug or ingre- misleading by reason, among other rea- dient by a proprietary name that, be- sons, of the designation of such drug in cause of similarity in spelling or pro- such labeling by a name which includes nunciation, may be confused with the or suggests the name of one or more proprietary name or the established but not all such ingredients, even name of a different drug or ingredient. though the names of all such ingredi- (d)(1) If the drug is in tablet or cap- ents are stated elsewhere in the label- sule form or other unit dosage form, ing. any statement of the quantity of an in- [41 FR 6908, Feb. 13, 1976] gredient contained therein shall express the quantity of such ingredient in § 201.10 Drugs; statement of ingredi- each such unit. If the drug is not in ents. unit dosage form, any statement of the (a) The ingredient information re- quantity of an ingredient contained quired by section 502(e) of the Federal therein shall express the amount of Food, Drug, and Cosmetic Act shall ap- such ingredient in a specified unit of

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00022 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.10

weight or measure of the drug, or the in association with such proprietary percentage of such ingredient in such name or designation and in the same drug. Such statements shall be in type size used in such running text: terms that are informative to licensed Provided, however, That if the propri- practitioners, in the case of a prescrip- etary name or designation is used in tion drug, and to the layman, in the the running text in larger size type, case of a nonprescription drug. the established name shall be used at (2) A statement of the percentage of least once in association with, and in an ingredient in a drug shall, if the type at least half as large as the type term percent is used without qualifica- used for, the most prominent presen- tion, mean percent weight-in-weight, if tation of the proprietary name or des- the ingredient and the drug are both ignation in such running text. If any solids, or if the ingredient is a liquid labeling includes a column with run- and the drug is a solid; percent weight ning text containing detailed informa- ° ° in volume at 68 F. (20 C.), if the ingre- tion as to composition, prescribing, dient is a solid and the drug is a liquid; side effects, or contraindications and ° and percent volume in volume at 68 F. the proprietary name or designation is ° (20 C.), if both the ingredient and the used in such column but is not featured drug are liquids, except that alcohol above or below the column, the estab- shall be stated in terms of percent vol- ° lished name shall be used at least once ume of absolute alcohol at 60 F. (15.56 in such column of running text in asso- °C.). ciation with such proprietary name or (e) A derivative or preparation of a designation and in the same type size substance named in section 502(e) of used in such column of running text: the act is an article derived or prepared Provided, however, That if the propri- from such substance by any method, etary name or designation is used in including actual or theoretical chemical action. such column of running text in larger (f) If an ingredient is a derivative or size type, the established name shall be preparation of a substance specifically used at least once in association with, named in section 502(e) of the act and and in type at least half as large as the the established name of such ingre- type used for, the most prominent pres- dient does not indicate that it is a de- entation of the proprietary name or rivative or preparation of the parent designation in such column of running substance named in section 502(e) of text. Where the established name is re- the act, the labeling shall, in conjunc- quired to accompany or to be used in tion with the listing of the established association with the proprietary name name of such ingredient, declare that or designation, the established name such article is a derivative or prepara- shall be placed in direct conjunction tion of such parent substance. with the proprietary name or designa- (g)(1) If the label or labeling of a pre- tion, and the relationship between the scription drug bears a proprietary proprietary name or designation and name or designation for the drug or the established name shall be made any ingredient thereof, the established clear by use of a phrase such as ‘‘brand name, if such there be, corresponding of’’ preceding the established name, by to such proprietary name or designa- brackets surrounding the established tion shall accompany such proprietary name, or by other suitable means. name or designation each time it is (2) The established name shall be featured on the label or in the labeling printed in letters that are at least half for the drug; but, except as provided in as large as the letters comprising the this subparagraph, the established proprietary name or designation with name need not be used with the propri- which it is joined, and the established etary name or designation in the run- name shall have a prominence com- ning text of the label or labeling. On mensurate with the prominence with any label or page of labeling in which which such proprietary name or des- the proprietary name or designation is ignation appears, taking into account not featured but is used in the running all pertinent factors, including typog- text, the established name shall be raphy, layout, contrast, and other used at least once in the running text printing features.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00023 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.15 21 CFR Ch. I (4–1–19 Edition)

(h)(1) In the case of a prescription § 201.15 Drugs; prominence of required drug containing two or more active in- label statements. gredients, if the label bears a propri- (a) A word, statement, or other infor- etary name or designation for such mation required by or under authority mixture and there is no established of the act to appear on the label may name corresponding to such propri- lack that prominence and conspicuous- etary name or designation, the quan- ness required by section 502(c) of the titative ingredient information re- act by reason, among other reasons, of: quired on the label by section 502(e) of (1) The failure of such word, state- the act shall be placed in direct con- ment, or information to appear on the junction with the most prominent dis- part or panel of the label which is pre- play of the proprietary name or des- sented or displayed under customary ignation. The prominence of the quan- conditions of purchase; titative ingredient information shall (2) The failure of such word, state- bear a reasonable relationship to the ment, or information to appear on two prominence of the proprietary name. or more parts or panels of the label, (2) If the drug is packaged in a con- each of which has sufficient space tainer too small to bear the quan- therefor, and each of which is so de- titative ingredient information on the signed as to render it likely to be, main display panel, the quantitative under customary conditions of pur- ingredient information required by sec- chase, the part or panel displayed; tion 502(e) of the act may appear else- (3) The failure of the label to extend where on the label, even though the over the area of the container or pack- proprietary name or designation ap- age available for such extension, so as pears on the main display panel of the to provide sufficient label space for the label; but side- or back-panel place- prominent placing of such word, statement shall in this case be so arranged ment, or information; and printed as to provide size and (4) Insufficiency of label space for the prominence of display reasonably re- prominent placing of such word, state- lated to the size and prominence of the ment, or information, resulting from front-panel display. the use of label space for any word, (i) A drug packaged in a container statement, design, or device which is too small or otherwise unable to ac- not required by or under authority of commodate a label with sufficient the act to appear on the label; space to bear the information required (5) Insufficiency of label space for the for compliance with section 502(e)(1) prominent placing of such word, state- (A)(ii) and (B) of the act shall be ex- ment, or information, resulting from empt from compliance with those the use of label space to give materi- clauses: Provided, That: ally greater conspicuousness to any (1) The label bears: other word, statement, or information, (i) The proprietary name of the drug; or to any design or device; or (ii) The established name, if such (6) Smallness or style of type in there be, of the drug; which such word, statement, or infor- (iii) An identifying lot or control mation appears, insufficient back- number; and ground contrast, obscuring designs or vignettes, or crowding with other writ- (iv) The name of the manufacturer, ten, printed, or graphic matter. packer, or distributor of the drug; and (b) No exemption depending on insuf- (2) All the information required to ficiency of label space, as prescribed in appear on the label by the act and the regulations promulgated under section regulations in this chapter appears on 502 (b) or (e) of the act, shall apply if the carton or other outer container or such insufficiency is caused by: wrapper if such carton, outer con- (1) The use of label space for any tainer, or wrapper has sufficient space word, statement, design, or device to bear such information, or such com- which is not required by or under au- plete label information appears on a thority of the act to appear on the leaflet with the package. label; [40 FR 13998, Mar. 27, 1975, as amended at 67 (2) The use of label space to give FR 4906, Feb. 1, 2002] greater conspicuousness to any word,

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00024 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.20

statement, or other information than § 201.17 Drugs; location of expiration is required by section 502(c) of the act; date. or When an expiration date of a drug is (3) The use of label space for any rep- required, e.g., expiration dating of drug resentation in a foreign language. products required by § 211.137 of this (c)(1) All words, statements, and chapter, it shall appear on the imme- other information required by or under diate container and also the outer authority of the act to appear on the package, if any, unless it is easily leg- label or labeling shall appear thereon ible through such outer package. How- in the English language: Provided, however, when single-dose containers are ever, That in the case of articles dis- packed in individual cartons, the expi- tributed solely in the Commonwealth ration date may properly appear on the of Puerto Rico or in a Territory where individual carton instead of the imme- the predominant language is one other diate product container. than English, the predominant lan- [43 FR 45076, Sept. 29, 1978] guage may be substituted for English. (2) If the label contains any represen- § 201.18 Drugs; significance of control tation in a foreign language, all words, numbers. statements, and other information re- The lot number on the label of a drug quired by or under authority of the act should be capable of yielding the com- to appear on the label shall appear plete manufacturing history of the thereon in the foreign language. package. An incorrect lot number may (3) If the labeling contains any rep- be regarded as causing the article to be resentation in a foreign language, all misbranded. words, statements, and other information required by or under authority of § 201.19 Drugs; use of term ‘‘infant’’. the act to appear on the label or label- The regulations affecting special die- ing shall appear on the labeling in the tary foods (§ 105.3(e) of this chapter) de- foreign language. fine an infant as a child not more than 12 months old. Apart from this, the [41 FR 6908, Feb. 13, 1976] Food and Drug Administration has not established any definition of the term § 201.16 Drugs; Spanish-language infant. Some question has arisen version of certain required state- whether, for the purposes of drug label- ments. ing, an infant means a child up to 1 An increasing number of medications year of age or a child up to 2 years of restricted to prescription use only are age. Until the term is more precisely being labeled solely in Spanish for dis- defined by legislation or formal regula- tribution in the Commonwealth of tion, where the exact meaning of the Puerto Rico where Spanish is the pre- term is significant, manufacturers dominant language. Such labeling is should qualify any reference to ‘‘in- authorized under § 201.15(c). One re- fant’’ to indicate whether it refers to a quired warning, the wording of which is child who is not more than 1 year of fixed by law in the English language, age, or a child not more than 2 years of could be translated in various ways, age. from literal translation to loose inter- [40 FR 13998, Mar. 27, 1975, as amended at 42 pretation. The statutory nature of this FR 14091, Mar. 15, 1977; 44 FR 16006, Mar. 16, warning requires that the translation 1979] convey the meaning properly to avoid confusion and dilution of the purpose § 201.20 Declaration of presence of of the warning. Section 503(b)(4) of the FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for Federal Food, Drug, and Cosmetic Act human use. requires, at a minimum, that the label bear the statement ‘‘Rx only.’’ The (a) The label for over-the-counter and prescription drug products intended for Spanish-language version of this must human use administered orally, na- be ‘‘Solamente Rx’’. sally, rectally, or vaginally, or for use [67 FR 4906, Feb. 1, 2002] in the area of the eye, containing

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00025 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.21 21 CFR Ch. I (4–1–19 Edition)

FD&C Yellow No. 5 as a color additive § 201.21 Declaration of presence of using the names FD&C Yellow No. 5 phenylalanine as a component of and tartrazine. The labeling for over- aspartame in over-the-counter and the-counter and prescription drug prod- prescription drugs for human use. ucts shall bear a statement such as (a) Aspartame is the methylester of a ‘‘Contains FD&C Yellow No. 5 dipeptide composed of two amino acids, (tartrazine) as a color additive’’ or phenylalanine and aspartic acid. When ‘‘Contains color additives including FD&C Yellow No. 5 (tartrazine)’’. The these two amino acids are so combined labels of certain drug products subject to form aspartame (1-methyl N-L-a- to this labeling requirement that are aspartyl-L-phenylalanine), they also cosmetics, such as antibacterial produce an intensely sweet-tasting sub- mouthwashes and fluoride toothpastes, stance, approximately 180 times as need not comply with this requirement sweet as sucrose. The Food and Drug provided they comply with the require- Administration has determined that ments of § 701.3 of this chapter. aspartame when used at a level no (b) For prescription drugs for human higher than reasonably required to per- use containing FD&C Yellow No. 5 that form its intended technical function is are administered orally, nasally, safe for use as an inactive ingredient in vaginally, or rectally, or for use in the human drug products, provided persons area of the eye, the labeling required with phenylketonuria, who must re- by § 201.100(d) shall bear the warning strict carefully their phenylalanine in- statement ‘‘This product contains take, are alerted to the presence of FD&C Yellow No. 5 (tartrazine) which phenylalanine in the drug product and may cause allergic-type reactions (in- the amount of the ingredient in each cluding bronchial asthma) in certain dosage unit. susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (b) The label and labeling of all over- (tartrazine) sensitivity in the general the-counter human drug products con- population is low, it is frequently seen taining aspartame as an inactive ingre- in patients who also have aspirin dient shall bear a statement to the fol- hypersensitivity.’’ This warning state- lowing effect: Phenylketonurics: Con- ment shall appear in the ‘‘Precautions’’ tains Phenylalanine (l)mg Per (Dos- section of the labeling. age Unit). (c) The label for over-the-counter (c) The package labeling and other drug products intended for human use labeling providing professional use in- administered orally, nasally, rectally, formation concerning prescription or vaginally containing FD&C Yellow drugs for human use containing aspar- No. 6 shall specifically declare the tame as an inactive ingredient shall presence of FD&C Yellow No. 6 by list- bear a statement to the following ef- ing the color additive using the name fect under the ‘‘Precautions’’ section of FD&C Yellow No. 6. The labeling for the labeling, as required in § 201.57(f)(2): over-the-counter and prescription drug Phenylketonurics: Contains products containing FD&C Yellow No. Phenylalanine (l)mg Per (Dosage 6 shall declare the presence of FD&C Unit). Yellow No. 6. The labels of certain drug (d) Holders of approved new drug ap- products subject to this labeling re- plications who reformulate their drug quirement that are also cosmetics, such as antibacterial mouthwashes and products under the provisions of this fluoride toothpastes, need not comply section shall submit supplements under with this requirement provided they § 314.70 of this chapter to provide for comply with the requirements of § 701.3 the new composition and the labeling of this chapter. changes. [45 FR 60422, Sept. 12, 1980, as amended at 51 (Approved by the Office of Management and FR 41783, Nov. 19, 1986; 52 FR 21509, June 8, Budget under control number 0910–0242) 1987; 59 FR 60898, Nov. 29, 1994] [52 FR 2111, Jan. 20, 1987; 52 FR 12152, Apr. 15, EFFECTIVE DATE NOTE: At 53 FR 49138, Dec. 1987; 53 FR 4135, Feb. 12, 1988] 6, 1988, § 201.20(c) was suspended pending further agency action.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00026 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.23

§ 201.22 Prescription drugs containing epinephrine in a life-threatening situa- sulfites; required warning state- tion may not be satisfactory. The pres- ments. ence of a sulfite(s) in this product (a) Sulfites are chemical substances should not deter administration of the that are added to certain drug products drug for treatment of serious allergic to inhibit the oxidation of the active or other emergency situations.’’ This drug ingredient. Oxidation of the ac- statement shall appear in the ‘‘Warn- tive drug ingredient may result in in- ings’’ section of the labeling. stability and a loss of potency of the [51 FR 43904, Dec. 5, 1986] drug product. Examples of specific sulfites used to inhibit this oxidation § 201.23 Required pediatric studies. process include sodium bisulfite, sodium metabisulfite, sodium sulfite, po- (a) A manufacturer of a marketed tassium bisulfite, and potassium drug product, including a biological metabisulfite. Recent studies have drug product, that is used in a substan- demonstrated that sulfites may cause tial number of pediatric patients, or allergic-type reactions in certain sus- that provides a meaningful therapeutic ceptible persons, especially asthmatics. benefit over existing treatments for pe- The labeling for any prescription drug diatric patients, as defined in product to which sulfites have been §§ 314.55(c)(5) and 601.27(c)(5) of this added as an inactive ingredient, regard- chapter, but whose label does not pro- less of the amount added, must bear vide adequate information to support the warning specified in paragraph (b) its safe and effective use in pediatric or (c) of this section. populations for the approved indica- (b) The labeling required by §§ 201.57 tions may be required to submit an ap- and 201.100(d) for prescription drugs for plication containing data adequate to human use containing a sulfite, except assess whether the drug product is safe epinephrine for injection when in- and effective in pediatric populations. tended for use in allergic or other The application may be required to emergency situations, shall bear the contain adequate evidence to support warning statement ‘‘Contains (insert dosage and administration in some or the name of the sulfite, e.g., sodium all pediatric subpopulations, including metabisulfite), a sulfite that may cause neonates, infants, children, and adoles- allergic-type reactions including cents, depending upon the known or ap- anaphylactic symptoms and life- propriate use of the drug product in threatening or less severe asthmatic such subpopulations. The applicant episodes in certain susceptible people. may also be required to develop a pedi- The overall prevalence of sulfite sensi- atric formulation for a drug product tivity in the general population is un- that represents a meaningful thera- known and probably low. Sulfite sensi- peutic benefit over existing therapies tivity is seen more frequently in asth- for pediatric populations for whom a matic than in nonasthmatic people.’’ pediatric formulation is necessary, un- This statement shall appear in the less the manufacturer demonstrates ‘‘Warnings’’ section of the labeling. that reasonable attempts to produce a (c) The labeling required by §§ 201.57 pediatric formulation have failed. and 201.100(d) for sulfite-containing epi- (b) The Food and Drug Administra- nephrine for injection for use in aller- tion (FDA) may by order, in the form gic emergency situations shall bear the of a letter, after notifying the manu- warning statement ‘‘Epinephrine is the facturer of its intent to require an as- preferred treatment for serious allergic sessment of pediatric safety and effec- or other emergency situations even tiveness of a pediatric formulation, and though this product contains (insert the after offering an opportunity for a name of the sulfite, e.g., sodium written response and a meeting, which metabisulfite), a sulfite that may in may include an advisory committee other products cause allergic-type re- meeting, require a manufacturer to actions including anaphylactic symp- submit an application containing the toms or life-threatening or less severe information or request for approval of asthmatic episodes in certain suscep- a pediatric formulation described in tible persons. The alternatives to using paragraph (a) of this section within a

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00027 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.24 21 CFR Ch. I (4–1–19 Edition)

time specified in the order, if FDA of the grounds for waiver specified in finds that: paragraphs (c)(2) or (c)(3) of this sec- (1) The drug product is used in a sub- tion have been met. If a waiver is stantial number of pediatric patients granted on the ground that it is not for the labeled indications and the ab- possible to develop a pediatric formula- sence of adequate labeling could pose tion, the waiver will cover only those significant risks to pediatric patients; pediatric age groups requiring that for- or mulation. If a waiver is granted be- (2) There is reason to believe that the cause there is evidence that the prod- drug product would represent a mean- uct would be ineffective or unsafe in ingful therapeutic benefit over existing pediatric populations, this information treatments for pediatric patients for will be included in the product’s label- one or more of the claimed indications, ing. and the absence of adequate labeling (d) If a manufacturer fails to submit could pose significant risks to pedi- a supplemental application containing atric patients. the information or request for approval (c)(1) An applicant may request a full of a pediatric formulation described in waiver of the requirements of para- paragraph (a) of this section within the graph (a) of this section if the appli- time specified by FDA, the drug prod- cant certifies that: uct may be considered misbranded or (i) Necessary studies are impossible an unapproved new drug or unlicensed or highly impractical because, e.g., the biologic. number of such patients is so small or geographically dispersed, or [63 FR 66668, Dec. 2, 1998] (ii) There is evidence strongly suggesting that the product would be inef- § 201.24 Labeling for systemic anti- fective or unsafe in all pediatric age bacterial drug products. groups. The labeling of all systemic drug (2) An applicant may request a par- products intended for human use indi- tial waiver of the requirements of para- cated to treat a bacterial infection, ex- graph (a) of this section with respect to cept a mycobacterial infection, must a specified pediatric age group, if the bear the following statements: applicant certifies that: (a) At the beginning of the label, (i) The product: under the product name, the labeling (A) Does not represent a meaningful must state: therapeutic benefit over existing therapies for pediatric patients in that age To reduce the development of drug-resist- group, and ant bacteria and maintain the effectiveness (B) Is not likely to be used in a sub- of (insert name of antibacterial drug product) stantial number of patients in that age and other antibacterial drugs, (insert name of group, and antibacterial drug product) should be used only to treat or prevent infections that are (C) The absence of adequate labeling proven or strongly suspected to be caused by could not pose significant risks to pedi- bacteria. atric patients; or (ii) Necessary studies are impossible (b) In the ‘‘Indications and Usage’’ or highly impractical because, e.g., the section, the labeling must state: number of patients in that age group is To reduce the development of drug-resist- so small or geographically dispersed, or ant bacteria and maintain the effectiveness (iii) There is evidence strongly sug- of (insert name of antibacterial drug product) gesting that the product would be inef- and other antibacterial drugs, (insert name of fective or unsafe in that age group, or antibacterial drug product) should be used (iv) The applicant can demonstrate only to treat or prevent infections that are that reasonable attempts to produce a proven or strongly suspected to be caused by pediatric formulation necessary for susceptible bacteria. When culture and sus- ceptibility information are available, they that age group have failed. should be considered in selecting or modi- (3) FDA shall grant a full or partial fying antibacterial therapy. In the absence waiver, as appropriate, if the agency of such data, local epidemiology and suscep- finds that there is a reasonable basis tibility patterns may contribute to the em- on which to conclude that one or more piric selection of therapy.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00028 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.25

(c) In the ‘‘Precautions’’ section, (E) Radiopharmaceuticals; and under the ‘‘General’’ subsection, the la- (F) Low-density polyethylene form beling must state: fill and seal containers that are not packaged with an overwrap. Prescribing (insert name of antibacterial drug product) in the absence of a proven or (ii) The bar code requirement does strongly suspected bacterial infection or a not apply to prescription drugs sold by prophylactic indication is unlikely to pro- a manufacturer, repacker, relabeler, or vide benefit to the patient and increases the private label distributor directly to pa- risk of the development of drug-resistant tients, but versions of the same drug bacteria. product that are sold to or used in hos- (d) In the ‘‘Precautions’’ section, pitals are subject to the bar code re- under the ‘‘Information for Patients’’ quirements. subsection, the labeling must state: (2) Biological products; and (3) OTC drug products that are dis- Patients should be counseled that anti- pensed pursuant to an order and are bacterial drugs including (insert name of antibacterial drug product) should only be used to commonly used in hospitals. For pur- treat bacterial infections. They do not treat poses of this section, an OTC drug viral infections (e.g., the common cold). product is ‘‘commonly used in hos- When (insert name of antibacterial drug prod- pitals’’ if it is packaged for hospital uct) is prescribed to treat a bacterial infec- use, labeled for hospital use (or uses tion, patients should be told that although it similar terms), or marketed, promoted, is common to feel better early in the course or sold to hospitals. of therapy, the medication should be taken (c) What does the bar code look like? exactly as directed. Skipping doses or not completing the full course of therapy may (1) Where does the bar code go? (1) Each decrease the effectiveness of the immediate drug product described in paragraph (b) treatment and (2) increase the likelihood of this section must have a bar code that bacteria will develop resistance and will that contains, at a minimum, the ap- not be treatable by (insert name of anti- propriate National Drug Code (NDC) bacterial drug product) or other antibacterial number in a linear bar code that meets drugs in the future. European Article Number/Uniform [68 FR 6081, Feb. 6, 2003] Code Council (EAN/UCC) or Health In- dustry Business Communications § 201.25 Bar code label requirements. Council (HIBCC) standards or another (a) Who is subject to these bar code re- standard or format that has been ap- quirements? Manufacturers, repackers, proved by the relevant Food and Drug relabelers, and private label distribu- Administration Center Director. Addi- tors of a human prescription drug prod- tionally, the bar code must: uct or an over-the-counter (OTC) drug (i) Be surrounded by sufficient blank product that is regulated under the space so that the bar code can be Federal Food, Drug, and Cosmetic Act scanned correctly; and or the Public Health Service Act are (ii) Remain intact under normal con- subject to these bar code requirements ditions of use. unless they are exempt from the reg- (2) The bar code must appear on the istration and drug listing requirements drug’s label as defined by section 201(k) in section 510 of the Federal Food, of the Federal Food, Drug, and Cos- Drug, and Cosmetic Act. metic Act. (b) What drugs are subject to these bar (d) Can a drug be exempted from the bar code requirements? The following drug code requirement? (1) On our own initia- products are subject to the bar code tive, or in response to a written relabel requirements: quest from a manufacturer, repacker, (1) Prescription drug products, how- relabeler or private label distributor, ever: we may exempt a drug product from (i) The bar code requirement does not the bar code label requirements set apply to the following entities: forth in this section. The exemption re- (A) Prescription drug samples; quest must document why: (B) Allergenic extracts; (i) compliance with the bar code re- (C) Intrauterine contraceptive de- quirement would adversely affect the vices regulated as drugs; safety, effectiveness, purity or potency (D) Medical gases; of the drug or not be technologically

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00029 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.26 21 CFR Ch. I (4–1–19 Edition)

feasible, and the concerns underlying (ii) The Center Director may grant the request could not reasonably be ad- an exception or alternative described dressed by measures such as package in paragraph (a) of this section on his redesign or use of overwraps; or or her own initiative. (ii) an alternative regulatory pro- (2) A written request for an exception gram or method of product use renders or alternative described in paragraph the bar code unnecessary for patient (a) of this section must: safety. (i) Identify the specified lots, (2) Requests for an exemption should batches, or other units of the human be sent to the Office of Compliance, drug product that would be subject to Center for Drug Evaluation and Re- the exception or alternative; search, Food and Drug Administration, (ii) Identify the labeling provision(s) 10903 New Hampshire Ave., Bldg. 51, listed in paragraph (f) of this section Silver Spring, MD 20993–0002 (requests that are the subject of the exception or involving a drug product or biological alternative request; product regulated by the Center for (iii) Explain why compliance with Drug Evaluation and Research) or to such labeling provision(s) could ad- the Food and Drug Administration, versely affect the safety, effectiveness, Center for Biologics Evaluation and or availability of the specified lots, Research, Document Control Center, batches, or other units of a human drug 10903 New Hampshire Ave., Bldg. 71, product that are or will be held in the Rm. G112, Silver Spring, MD 20993–0002 Strategic National Stockpile; (requests involving a biological prod- (iv) Describe any proposed safeguards uct regulated by the Center for Bio- or conditions that will be implemented logics Evaluation and Research). so that the labeling of the product includes appropriate information nec- [69 FR 9170, Feb. 26, 2004, as amended at 76 essary for the safe and effective use of FR 12847, Mar. 9, 2011; 80 FR 18090, Apr. 3, the product, given the anticipated cir- 2015; 81 FR 60212, Aug. 31, 2016] cumstances of use of the product; (v) Provide a draft of the proposed la- § 201.26 Exceptions or alternatives to beling of the specified lots, batches, or labeling requirements for human other units of the human drug product drug products held by the Strategic National Stockpile. subject to the exception or alternative; and (a) The appropriate FDA Center Di- (vi) Provide any other information rector may grant an exception or alter- requested by the Center Director in native to any provision listed in para- support of the request. graph (f) of this section and not explic- (c) The Center Director must respond itly required by statute, for specified in writing to all requests under this lots, batches, or other units of a human section. drug product, if the Center Director de- (d) A grant of an exception or alter- termines that compliance with such la- native under this section will include beling requirement could adversely af- any safeguards or conditions deemed fect the safety, effectiveness, or avail- appropriate by the Center Director so ability of such product that is or will that the labeling of product subject to be included in the Strategic National the exception or alternative includes Stockpile. the information necessary for the safe (b)(1)(i) A Strategic National Stock- and effective use of the product, given pile official or any entity that manu- the anticipated circumstances of use. factures (including labeling, packing, (e) If you are a sponsor receiving a relabeling, or repackaging), distrib- grant of a request for an exception or utes, or stores a human drug product alternative to the labeling require- that is or will be included in the Stra- ments under this section: tegic National Stockpile may submit, (1) You need not submit a supplement with written concurrence from a Stra- under § 314.70(a) through (c) or tegic National Stockpile official, a § 601.12(f)(1) through (f)(2) of this chap- written request for an exception or alter; however, ternative described in paragraph (a) of (2) You must report any grant of a re- this section to the Center Director. quest for an exception or alternative

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00030 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.51

under this section as part of your an- measure. The statement of quantity of nual report under §§ 314.70(d) or drugs in tablet, capsule, ampule, or 601.12(f)(3) of this chapter. other unit dosage form shall be ex- (f) The Center Director may grant an pressed in terms of numerical count; exception or alternative under this sec- the statement of quantity for drugs in tion to the following provisions of this other dosage forms shall be in terms of chapter, to the extent that the require- weight if the drug is solid, semi-solid, ments in these provisions are not ex- or viscous, or in terms of fluid measure plicitly required by statute: if the drug is liquid. When the drug (1) § 201.1(h)(1) through (h)(2), (h)(5) quantity statement is in terms of the through (h)(6), and (i); numerical count of the drug units, it (2) § 201.10(a), (d)(2), (f), (g)(1), and shall be augmented to give the weight (h)(1); or measure of the drug units or the (3) § 201.17; quantity of each active ingredient in (4) § 201.18; each drug unit or, when quantity does (5) § 201.19; not accurately reflect drug potency, a (6) § 201.20; statement of the drug potency. (7) § 201.21; (b) Statements of weight of the con- (8) § 201.22; tents shall in the case of prescription (9) § 201.24; and drugs be expressed in terms of avoirdu- (10) § 312.6. pois pound, ounce, and grain or of kilo- [72 FR 73599, Dec. 28, 2007] gram, gram, and subdivisions thereof. A statement of liquid measure of the Subpart B—Labeling Requirements contents shall in the case of prescrip- for Prescription Drugs and/or tion drugs be expressed in terms of the Insulin U.S. gallon of 231 cubic inches and quart, pint, fluid-ounce, and fluid-dram § 201.50 Statement of identity. subdivisions thereof, or of the liter and (a) The label of prescription and insu- milliliter, or cubic centimeter, and ° lin-containing drugs in package form shall express the volume at 68 F. (20 ° shall bear as one of its principal fea- C.). A statement of the liquid measure tures a statement of the identity of the of the contents in the case of insulin- drug. containing drugs shall be expressed in (b) Such statement of identity shall terms of the liter and milliliter, or be in terms of the established name of cubic centimeter, and shall express the the drug. In the case of a prescription volume at 68 °F. (20 °C.). drug that is a mixture and that has no (c) The declaration shall contain only established name, the requirement for such fractions as are generally used in statement of identity shall be deemed expressing the quantity of the drug. A to be satisfied by a listing of the quan- common fraction shall be reduced to titative ingredient information as pre- its lowest terms; a decimal fraction scribed by § 201.10. shall not be carried out to more than (c) The statement of identity of a three places, except in the case of a prescription drug shall also comply statement of the quantity of an active with the placement, size and promi- ingredient in a unit of a drug. nence requirements of § 201.10. (d) The declaration shall appear as a [40 FR 13998, Mar. 27, 1975, as amended at 63 distinct item on the label and, in the FR 26698, May 13, 1998] case of large volume parenterals, may be embossed on the glass. § 201.51 Declaration of net quantity of (e) The declaration shall accurately contents. reveal the quantity of drug in the (a) The label of a prescription or in- package exclusive of wrappers and sulin-containing drug in package form other material packed therewith. shall bear a declaration of the net (f) A statement of the quantity of a quantity of contents. This shall be ex- prescription or insulin-containing drug pressed in the terms of weight, meas- in terms of weight or measure applica- ure, numerical count, or a combination ble to such drug, under the provisions of numerical count and weight or of paragraph (a) of this section, shall

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00031 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.55 21 CFR Ch. I (4–1–19 Edition)

express with prominence and conspicu- for dosage information’’, where the de- ousness the number of the largest tailed information is contained in such whole unit, as specified in paragraph insert. However, if an informative, re- (b) of this section, that are contained alistic, recommended or usual dosage in the package. Any remainder shall be can readily be set forth on the label, it expressed in terms of common or dec- should appear thereon. imal fractions of such unit or in terms of the next smaller whole unit and § 201.56 Requirements on content and common or decimal fractions thereof. format of labeling for human pre- (g) The declaration of net quantity of scription drug and biological prod- contents shall express an accurate ucts. statement of the quantity of contents (a) General requirements. Prescription of the package. Reasonable variations drug labeling described in § 201.100(d) caused by loss or gain of moisture dur- must meet the following general re- ing the course of good distribution quirements: practice or by unavoidable deviations (1) The labeling must contain a sum- in good manufacturing practice will be mary of the essential scientific infor- recognized. Variations from stated mation needed for the safe and effec- quantity of contents shall not be un- tive use of the drug. reasonably large. In the case of a liquid (2) The labeling must be informative drug in ampules or vials, intended for and accurate and neither promotional injection, the declaration shall be con- in tone nor false or misleading in any sidered to express the minimum quan- particular. In accordance with §§ 314.70 tity and the variation above the stated and 601.12 of this chapter, the labeling measure shall comply with the excess must be updated when new information volume prescribed by the National For- becomes available that causes the la- mulary or the U.S. Pharmacopeia for beling to become inaccurate, false, or filling of ampules. In the case of a solid misleading. drug in ampules or vials, the declara- (3) The labeling must be based when- tion shall be considered to express the ever possible on data derived from accurate net weight. Variations shall human experience. No implied claims comply with the limitations provided or suggestions of drug use may be made in the U.S. Pharmacopeia or the Na- if there is inadequate evidence of safe- tional Formulary. ty or a lack of substantial evidence of (h) A drug shall be exempt from com- effectiveness. Conclusions based on pliance with the net quantity declara- animal data but necessary for safe and tion required by this section if it is an effective use of the drug in humans ointment labeled ‘‘sample’’, ‘‘physi- must be identified as such and included cian’s sample’’, or a substantially simi- with human data in the appropriate lar statement and the contents of the section of the labeling. package do not exceed 8 grams. (b) Categories of prescription drugs subject to the labeling content and format re- § 201.55 Statement of dosage. quirements in §§ 201.56(d) and 201.57. (1) Section 201.100(b)(2) requires that la- The following categories of prescrip- bels for prescription drugs bear a state- tion drug products are subject to the ment of the recommended or usual dos- labeling requirements in paragraph (d) age. Since the dosage for some pre- of this section and § 201.57 in accord- scription drugs varies within extremely ance with the implementation schedule wide limits, depending upon the condi- in paragraph (c) of this section: tions being treated, it may not be pos- (i) Prescription drug products for sible in all cases to present an inform- which a new drug application (NDA), ative or useful statement of the rec- biologics license application (BLA), or ommended or usual dosage in the space efficacy supplement was approved by available on the label or carton of the the Food and Drug Administration package. It is the view of the Food and (FDA) between June 30, 2001 and June Drug Administration that when such a 30, 2006; situation prevails, compliance with (ii) Prescription drug products for this requirement would be met by a which an NDA, BLA, or efficacy supple- statement such as ‘‘See package insert ment is pending on June 30, 2006; or

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00032 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.56

(iii) Prescription drug products for (d) Labeling requirements for new and which an NDA, BLA, or efficacy supple- more recently approved prescription drug ment is submitted anytime on or after products. This paragraph applies only June 30, 2006. to prescription drug products described (2) Prescription drug products not de- in paragraph (b)(1) of this section and scribed in paragraph (b)(1) of this sec- must be implemented according to the tion are subject to the labeling require- schedule specified in paragraph (c) of ments in paragraph (e) of this section this section. and § 201.80. (1) Prescription drug labeling de- (c) Schedule for implementing the label- scribed in § 201.100(d) must contain the ing content and format requirements in specific information required under §§ 201.56(d) and 201.57. For products de- § 201.57(a), (b), and (c) under the fol- scribed in paragraph (b)(1) of this sec- lowing headings and subheadings and tion, labeling conforming to the re- in the following order: quirements in paragraph (d) of this sec- Highlights of Prescribing Information tion and § 201.57 must be submitted ac- Product Names, Other Required Informa- cording to the following schedule: tion (1) For products for which an NDA, Boxed Warning BLA, or efficacy supplement is sub- Recent Major Changes mitted for approval on or after June 30, Indications and Usage 2006, proposed conforming labeling Dosage and Administration must be submitted as part of the appli- Dosage Forms and Strengths cation. Contraindications (2) For products for which an NDA, Warnings and Precautions BLA, or efficacy supplement is pending Adverse Reactions Drug Interactions on June 30, 2006, or that has been ap- Use in Specific Populations proved any time from June 30, 2005, up Full Prescribing Information: Contents to and including June 30, 2006, a supple- Full Prescribing Information ment with proposed conforming label- Boxed Warning ing must be submitted no later than 1 Indications and Usage June 30, 2009. 2 Dosage and Administration (3) For products for which an NDA, 3 Dosage Forms and Strengths BLA, or efficacy supplement has been 4 Contraindications approved anytime from June 30, 2004, 5 Warnings and Precautions up to and including June 29, 2005, a sup- 6 Adverse Reactions 7 Drug Interactions plement with proposed conforming la- 8 Use in Specific Populations beling must be submitted no later than 8.1 Pregnancy June 30, 2010. 8.2 Lactation (4) For products for which an NDA, 8.3 Females and Males of Reproductive BLA, or efficacy supplement has been Potential approved anytime from June 30, 2003, 8.4 Pediatric use up to and including June 29, 2004, a sup- 8.5 Geriatric use plement with proposed conforming la- 9 Drug Abuse and Dependence beling must be submitted no later than 9.1 Controlled substance June 30, 2011. 9.2 Abuse 9.3 Dependence (5) For products for which an NDA, 10 Overdosage BLA, or efficacy supplement has been 11 Description approved anytime from June 30, 2002, 12 Clinical Pharmacology up to and including June 29, 2003, a sup- 12.1 Mechanism of action plement with proposed conforming la- 12.2 Pharmacodynamics beling must be submitted no later than 12.3 Pharmacokinetics June 30, 2012. 13 Nonclinical Toxicology (6) For products for which an NDA, 13.1 Carcinogenesis, mutagenesis, impair- BLA, or efficacy supplement has been ment of fertility 13.2 Animal toxicology and/or pharma- approved anytime from June 30, 2001, cology up to and including June 29, 2002, a sup- 14 Clinical Studies plement with proposed conforming la- 15 References beling must be submitted no later than 16 How Supplied/Storage and Handling June 30, 2013. 17 Patient Counseling Information

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00033 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

(2) Additional nonstandard sub- Warnings headings that are used to enhance la- Precautions beling organization, presentation, or Adverse Reactions ease of use (e.g., for individual warn- Drug Abuse and Dependence ings or precautions, or for each drug Overdosage interaction) must be assigned a dec- Dosage and Administration How Supplied imal number that corresponds to their placement in labeling. The decimal (2) The labeling may contain the fol- numbers must be consistent with the lowing additional section headings if standardized identifying numbers list- appropriate and if in compliance with ed in paragraph (d)(1) of this section § 201.80(l) and (m): (e.g., subheadings added to the ‘‘Warn- Animal Pharmacology and/or Animal Toxi- ings and Precautions’’ section must be cology numbered 5.1, 5.2, and so on). Clinical Studies (3) Any reference in Highlights to in- References formation appearing in the full prescribing information must be accom- (3) Omit clearly inapplicable sec- panied by the identifying number (in tions, subsections, or specific informa- parentheses) corresponding to the location. tion of the information in the full pre- (4) The labeling may contain a scribing information. ‘‘Product Title’’ section preceding the (4) Omit clearly inapplicable sec- ‘‘Description’’ section and containing tions, subsections, or specific informa- only the information required by tion. If sections or subsections required § 201.80(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and under paragraph (d)(1) of this section (a)(1)(iv) and § 201.100(e). The informa- are omitted from the full prescribing tion required by § 201.80(a)(1)(i) through information, the heading ‘‘Full Pre- (a)(1)(iv) must appear in the ‘‘Descrip- scribing Information: Contents’’ must tion’’ section of the labeling, whether be followed by an asterisk and the fol- or not it also appears in a ‘‘Product lowing statement must appear at the Title.’’ end of Contents: ‘‘* Sections or sub- (5) The labeling must contain the sections omitted from the full pre- date of the most recent revision of the scribing information are not listed.’’ labeling, identified as such, placed (5) Any risk information that is re- prominently immediately after the last quired under § 201.57(c)(9)(iv) is consid- section of the labeling. ered ‘‘appropriate pediatric contra- (6) The requirement in § 201.80(f)(2) to indications, warnings, or precautions’’ reprint any FDA-approved patient la- within the meaning of section 505A(l)(2) beling at the end of prescription drug of the Federal Food, Drug, and Cos- labeling or accompany the prescription metic Act (the act) (21 U.S.C. drug labeling must be implemented no 355A(l)(2)), whether such information later than June 30, 2007. appears in the ‘‘Contraindications,’’ [71 FR 3986, Jan. 24, 2006, as amended at 79 ‘‘Warnings and Precautions,’’ or ‘‘Use FR 72101, Dec. 4, 2014] in Specific Populations’’ section of labeling. § 201.57 Specific requirements on con- (e) Labeling requirements for older pre- tent and format of labeling for scription drug products. This paragraph human prescription drug and bio- applies only to approved prescription logical products described in drug products not described in para- § 201.56(b)(1). graph (b)(1) of this section. The requirements in this section (1) Prescription drug labeling de- apply only to prescription drug prod- scribed in § 201.100(d) must contain the ucts described in § 201.56(b)(1) and must specific information required under be implemented according to the § 201.80 under the following section schedule specified in § 201.56(c), except headings and in the following order: for the requirement in paragraph (c)(18) Description of this section to reprint any FDA-ap- Clinical Pharmacology proved patient labeling at the end of Indications and Usage prescription drug labeling or accom- Contraindications pany the prescription drug labeling,

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00034 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

which must be implemented no later (c)(2), (c)(3), (c)(5), and (c)(6) of this sec- than June 30, 2007. tion, that contain(s) substantive label- (a) Highlights of prescribing informa- ing changes that have been approved tion. The following information must by FDA or authorized under appear in all prescription drug label- § 314.70(c)(6) or (d)(2), or § 601.12(f)(1) ing: through (f)(3) of this chapter. The head- (1) Highlights limitation statement. The ing(s) and, if appropriate, the sub- verbatim statement ‘‘These highlights heading(s) of the labeling section(s) af- do not include all the information fected by the change must be listed to- needed to use (insert name of drug prod- gether with each section’s identifying uct) safely and effectively. See full pre- number and the date (month/year) on scribing information for (insert name which the change was incorporated in of drug product).’’ labeling. These labeling sections must (2) Drug names, dosage form, route of be listed in the order in which they ap- administration, and controlled substance pear in the full prescribing informa- symbol. The proprietary name and the tion. A changed section must be listed established name of the drug, if any, as under this heading in Highlights for at defined in section 502(e)(3) of the Fed- eral Food, Drug, and Cosmetic Act (the least 1 year after the date of the label- act) or, for biological products, the ing change and must be removed at the proper name (as defined in § 600.3 of this first printing subsequent to the 1 year chapter) including any appropriate period. descriptors. This information must be (6) Indications and usage. A concise followed by the drug’s dosage form and statement of each of the product’s indi- route of administration. For controlled cations, as required under paragraph substances, the controlled substance (c)(2) of this section, with any appro- symbol designating the schedule in priate subheadings. Major limitations which the controlled substance is listed of use (e.g., lack of effect in particular must be included as required by subsets of the population, or second § 1302.04 of this chapter. line therapy status) must be briefly (3) Initial U.S. approval. The verbatim noted. If the product is a member of an statement ‘‘Initial U.S. Approval’’ fol- established pharmacologic class, the lowed by the four-digit year in which concise statement under this heading FDA initially approved a new molec- in Highlights must identify the class in ular entity, new biological product, or the following manner: ‘‘(Drug) is a new combination of active ingredients. (name of class) indicated for (indica- The statement must be placed on the tion(s)).’’ line immediately beneath the estab- (7) Dosage and administration. A con- lished name or, for biological products, cise summary of the information re- proper name of the product. quired under paragraph (c)(3) of this (4) Boxed warning. A concise sum- section, with any appropriate sub- mary of any boxed warning required by headings, including the recommended paragraph (c)(1) of this section, not to dosage regimen, starting dose, dose exceed a length of 20 lines. The sum- range, critical differences among popu- mary must be preceded by a heading, in lation subsets, monitoring rec- upper-case letters, containing the word ‘‘WARNING’’ and other words that are ommendations, and other clinically appropriate to identify the subject of significant clinical pharmacologic in- the warning. The heading and the sum- formation. mary must be contained within a box (8) Dosage forms and strengths. A con- and bolded. The following verbatim cise summary of the information re- statement must be placed immediately quired under paragraph (c)(4) of this following the heading of the boxed section, with any appropriate sub- warning: ‘‘See full prescribing informa- headings (e.g., tablets, capsules, tion for complete boxed warning.’’ injectable, suspension), including the (5) Recent major changes. A list of the strength or potency of the dosage form section(s) of the full prescribing infor- in metric system (e.g., 10-milligram mation, limited to the labeling sec- tablets) and whether the product is tions described in paragraphs (c)(1), scored.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00035 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

(9) Contraindications. A concise state- (14) Patient counseling information ment of each of the product’s contra- statement. The verbatim statement indications, as required under para- ‘‘See 17 for Patient Counseling Infor- graph (c)(5) of this section, with any mation’’ or, if the product has FDA-ap- appropriate subheadings. proved patient labeling, the verbatim (10) Warnings and precautions. A con- statement ‘‘See 17 for Patient Coun- cise summary of the most clinically seling Information and (insert either significant information required under FDA-approved patient labeling or paragraph (c)(6) of this section, with Medication Guide).’’ any appropriate subheadings, including (15) Revision date. The date of the information that would affect decisions most recent revision of the labeling, about whether to prescribe a drug, rec- identified as such, placed at the end of ommendations for patient monitoring Highlights. that are critical to safe use of the drug, (b) Full prescribing information: Con- and measures that can be taken to pre- tents. Contents must contain a list of vent or mitigate harm. each heading and subheading required (11) Adverse reactions. (i) A list of the in the full prescribing information most frequently occurring adverse re- under § 201.56(d)(1), if not omitted under actions, as described in paragraph (c)(7) § 201.56(d)(4), preceded by the identi- of this section, along with the criteria fying number required under used to determine inclusion (e.g., inci- § 201.56(d)(1). Contents must also con- dence rate). Adverse reactions impor- tain any additional subheading(s) in- tant for other reasons (e.g., because cluded in the full prescribing informa- they are serious or frequently lead to tion preceded by the identifying num- discontinuation or dosage adjustment) ber assigned in accordance with must not be repeated under this head- § 201.56(d)(2). ing in Highlights if they are included (c) Full prescribing information. The full prescribing information must con- elsewhere in Highlights (e.g., Warnings tain the information in the order re- and Precautions, Contraindications). quired under paragraphs (c)(1) through (ii) For drug products other than vac- (c)(18) of this section, together with the cines, the verbatim statement ‘‘To re- headings, subheadings, and identifying port SUSPECTED ADVERSE REAC- numbers required under § 201.56(d)(1), TIONS, contact (insert name of manu- unless omitted under § 201.56(d)(4). If facturer) at (insert manufacturer’s phone additional subheadings are used within number) or FDA at (insert current FDA a labeling section, they must be pre- phone number and Web address for vol- ceded by the identifying number as- untary reporting of adverse reactions).’’ signed in accordance with § 201.56(d)(2). (iii) For vaccines, the verbatim state- (1) Boxed warning. Certain contra- ment ‘‘To report SUSPECTED AD- indications or serious warnings, par- VERSE REACTIONS, contact (insert ticularly those that may lead to death name of manufacturer) at (insert manu- or serious injury, may be required by facturer’s phone number) or VAERS at the FDA to be presented in a box. The (insert the current VAERS phone number boxed warning ordinarily must be and Web address for voluntary reporting based on clinical data, but serious ani- of adverse reactions).’’ mal toxicity may also be the basis of a (iv) For manufacturers with a Web boxed warning in the absence of clin- site for voluntary reporting of adverse ical data. The box must contain, in up- reactions, the Web address of the direct percase letters, a heading inside the link to the site. box that includes the word ‘‘WARN- (12) Drug interactions. A concise sum- ING’’ and conveys the general focus of mary of the information required under the information in the box. The box paragraph (c)(8) of this section, with must briefly explain the risk and refer any appropriate subheadings. to more detailed information in the (13) Use in specific populations. A con- ‘‘Contraindications’’ or ‘‘Warnings and cise summary of the information re- Precautions’’ section, accompanied by quired under paragraph (c)(9) of this the identifying number for the section section, with any appropriate sub- or subsection containing the detailed headings. information.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00036 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

(2) 1 Indications and usage. This sec- drug in a short term trial in a given pa- tion must state that the drug is indi- tient), a statement of the conditions; cated for the treatment, prevention, or, if the indications for long term use mitigation, cure, or diagnosis of a rec- are different from those for short term ognized disease or condition, or of a use, a statement of the specific indica- manifestation of a recognized disease tions for each use. or condition, or for the relief of symp- (ii) If there is a common belief that toms associated with a recognized dis- the drug may be effective for a certain ease or condition. use or if there is a common use of the (i) This section must include the fol- drug for a condition, but the prepon- lowing information when the condi- derance of evidence related to the use tions listed are applicable: or condition shows that the drug is in- (A) If the drug is used for an indica- effective or that the therapeutic bene- tion only in conjunction with a pri- fits of the product do not generally mary mode of therapy (e.g., diet, sur- outweigh its risks, FDA may require gery, behavior changes, or some other that this section state that there is a drug), a statement that the drug is in- lack of evidence that the drug is effec- dicated as an adjunct to that mode of tive or safe for that use or condition. therapy. (iii) Any statements comparing the (B) If evidence is available to support safety or effectiveness of the drug with the safety and effectiveness of the drug other agents for the same indication or biological product only in selected must, except for biological products, be subgroups of the larger population supported by substantial evidence de- (e.g., patients with mild disease or pa- rived from adequate and well-con- tients in a special age group), or if the trolled studies as defined in § 314.126(b) indication is approved based on a sur- of this chapter unless this requirement rogate endpoint under § 314.510 or is waived under § 201.58 or § 314.126(c) of § 601.41 of this chapter, a succinct de- this chapter. For biological products, scription of the limitations of useful- such statements must be supported by ness of the drug and any uncertainty substantial evidence. about anticipated clinical benefits, with reference to the ‘‘Clinical Stud- (iv) For drug products other than bio- ies’’ section for a discussion of the logical products, all indications listed available evidence. in this section must be supported by (C) If specific tests are necessary for substantial evidence of effectiveness selection or monitoring of the patients based on adequate and well-controlled who need the drug (e.g., microbe sus- studies as defined in § 314.126(b) of this ceptibility tests), the identity of such chapter unless the requirement is tests. waived under § 201.58 or § 314.126(c) of (D) If information on limitations of this chapter. Indications or uses must use or uncertainty about anticipated not be implied or suggested in other clinical benefits is relevant to the rec- sections of the labeling if not included ommended intervals between doses, to in this section. the appropriate duration of treatment (v) For biological products, all indi- when such treatment should be lim- cations listed in this section must be ited, or to any modification of dosage, supported by substantial evidence of ef- a concise description of the informa- fectiveness. Indications or uses must tion with reference to the more de- not be implied or suggested in other tailed information in the ‘‘Dosage and sections of the labeling if not included Administration’’ section. in this section. (E) If safety considerations are such (3) 2 Dosage and administration. (i) that the drug should be reserved for This section must state the rec- specific situations (e.g., cases refrac- ommended dose and, as appropriate: tory to other drugs), a statement of the (A) The dosage range, information. (B) An upper limit beyond which (F) If there are specific conditions safety and effectiveness have not been that should be met before the drug is established, or beyond which increas- used on a long term basis (e.g., dem- ing the dose does not result in increas- onstration of responsiveness to the ing effectiveness,

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00037 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

(C) Dosages for each indication and tration, whenever solution and con- subpopulation, tainer permit.’’) (D) The intervals recommended be- (4) 3 Dosage forms and strengths. This tween doses, section must contain information on (E) The optimal method of titrating the available dosage forms to which dosage, the labeling applies and for which the (F) The usual duration of treatment manufacturer or distributor is respon- when treatment duration should be sible, including: limited, (i) The strength or potency of the (G) Dosing recommendations based dosage form in metric system (e.g., 10 on clinical pharmacologic data (e.g., milligram tablets), and, if the apothe- clinically significant food effects), cary system is used, a statement of the (H) Modification of dosage needed be- strength in parentheses after the met- cause of drug interactions or in special ric designation; and patient populations (e.g., in children, (ii) A description of the identifying in geriatric age groups, in groups de- characteristics of the dosage forms, in- fined by genetic characteristics, or in cluding shape, color, coating, scoring, patients with renal or hepatic disease), and imprinting, when applicable. The (I) Important considerations con- National Drug Code number(s) for the cerning compliance with the dosage drug product must not be included in regimen, this section. (J) Efficacious or toxic concentration (5) 4 Contraindications. This section ranges and therapeutic concentration must describe any situations in which windows of the drug or its metabolites, the drug should not be used because if established and clinically signifi- the risk of use (e.g., certain potentially cant. Information on therapeutic drug fatal adverse reactions) clearly out- concentration monitoring (TDM) must weighs any possible therapeutic ben- also be included in this section when efit. Those situations include use of the TDM is necessary. drug in patients who, because of their (ii) Dosing regimens must not be im- particular age, sex, concomitant ther- plied or suggested in other sections of apy, disease state, or other condition, the labeling if not included in this sec- have a substantial risk of being harmed tion. by the drug and for whom no potential (iii) Radiation dosimetry information benefit makes the risk acceptable. must be stated for both the patient re- Known hazards and not theoretical pos- ceiving a radioactive drug and the per- sibilities must be listed (e.g., if severe son administering it. hypersensitivity to the drug has not (iv) This section must also contain been demonstrated, it should not be specific direction on dilution, prepara- listed as a contraindication). If no con- tion (including the strength of the final traindications are known, this section dosage solution, when prepared accord- must state ‘‘None.’’ ing to instructions, in terms of milli- (6) 5 Warnings and precautions. (i) grams of active ingredient per milli- General. This section must describe liter of reconstituted solution, unless clinically significant adverse reactions another measure of the strength is (including any that are potentially more appropriate), and administration fatal, are serious even if infrequent, or of the dosage form, if needed (e.g., the can be prevented or mitigated through rate of administration of parenteral appropriate use of the drug), other po- drug in milligrams per minute; storage tential safety hazards (including those conditions for stability of the reconsti- that are expected for the pharma- tuted drug, when important; essential cological class or those resulting from information on drug incompatibilities drug/drug interactions), limitations in if the drug is mixed in vitro with other use imposed by them (e.g., avoiding drugs or diluents; and the following certain concomitant therapy), and verbatim statement for parenterals: steps that should be taken if they ‘‘Parenteral drug products should be occur (e.g., dosage modification). The inspected visually for particulate mat- frequency of all clinically significant ter and discoloration prior to adminis- adverse reactions and the approximate

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00038 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

mortality and morbidity rates for pa- events observed during use of a drug, tients experiencing the reaction, if only those adverse events for which known and necessary for the safe and there is some basis to believe there is a effective use of the drug, must be ex- causal relationship between the drug pressed as provided under paragraph and the occurrence of the adverse (c)(7) of this section. In accordance event. with §§ 314.70 and 601.12 of this chapter, (i) Listing of adverse reactions. This the labeling must be revised to include section must list the adverse reactions a warning about a clinically significant that occur with the drug and with hazard as soon as there is reasonable drugs in the same pharmacologically evidence of a causal association with a active and chemically related class, if drug; a causal relationship need not applicable. The list or lists must be have been definitely established. A specific warning relating to a use not pro- preceded by the information necessary vided for under the ‘‘Indications and to interpret the adverse reactions (e.g., Usage’’ section may be required by for clinical trials, total number ex- FDA in accordance with sections 201(n) posed, extent and nature of exposure). and 502(a) of the act if the drug is com- (ii) Categorization of adverse reactions. monly prescribed for a disease or con- Within a listing, adverse reactions dition and such usage is associated must be categorized by body system, with a clinically significant risk or by severity of the reaction, or in order hazard. of decreasing frequency, or by a com- (ii) Other special care precautions. This bination of these, as appropriate. With- section must contain information re- in a category, adverse reactions must garding any special care to be exer- be listed in decreasing order of fre- cised by the practitioner for safe and quency. If frequency information can- effective use of the drug (e.g., pre- not be reliably determined, adverse re- cautions not required under any other actions must be listed in decreasing specific section or subsection). order of severity. (iii) Monitoring: Laboratory tests. This (A) Clinical trials experience. This sec- section must identify any laboratory tion must list the adverse reactions tests helpful in following the patient’s identified in clinical trials that oc- response or in identifying possible ad- curred at or above a specified rate ap- verse reactions. If appropriate, infor- propriate to the safety database. The mation must be provided on such factors as the range of normal and abnor- rate of occurrence of an adverse reac- mal values expected in the particular tion for the drug and comparators (e.g., situation and the recommended fre- placebo) must be presented, unless such quency with which tests should be per- data cannot be determined or presen- formed before, during, and after ther- tation of comparator rates would be apy. misleading. If adverse reactions that (iv) Interference with laboratory tests. occurred below the specified rate are This section must briefly note informa- included, they must be included in a tion on any known interference by the separate listing. If comparative rates product with laboratory tests and ref- of occurrence cannot be reliably deter- erence the section where the detailed mined (e.g., adverse reactions were ob- information is presented (e.g., ‘‘Drug served only in the uncontrolled trial Interactions’’ section). portion of the overall safety database), (7) 6 Adverse reactions. This section adverse reactions must be grouped must describe the overall adverse reac- within specified frequency ranges as tion profile of the drug based on the en- appropriate to the safety database for tire safety database. For purposes of the drug (e.g., adverse reactions occur- prescription drug labeling, an adverse ring at a rate of less than 1/100, adverse reaction is an undesirable effect, rea- reactions occurring at a rate of less sonably associated with use of a drug, than 1/500) or descriptively identified, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00039 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

if frequency ranges cannot be deter- (i) 8.1 Pregnancy. This subsection of mined. For adverse reactions with sig- the labeling must contain the following nificant clinical implications, the list- information in the following order ings must be supplemented with addi- under the subheadings ‘‘Pregnancy Ex- tional detail about the nature, fre- posure Registry,’’ ‘‘Risk Summary,’’ quency, and severity of the adverse re- ‘‘Clinical Considerations,’’ and ‘‘Data’’: action and the relationship of the ad- (A) Pregnancy exposure registry. If verse reaction to drug dose and demo- there is a scientifically acceptable graphic characteristics, if data are pregnancy exposure registry for the available and important. drug, contact information needed to (B) Postmarketing experience. This sec- enroll in the registry or to obtain in- tion of the labeling must list the ad- formation about the registry must be verse reactions, as defined in paragraph provided following the statement: (c)(7) of this section, that are identified ‘‘There is a pregnancy exposure reg- from domestic and foreign spontaneous istry that monitors pregnancy out- reports. This listing must be separate comes in women exposed to (name of from the listing of adverse reactions drug) during pregnancy.’’ identified in clinical trials. (B) Risk summary. The Risk Summary (iii) Comparisons of adverse reactions must contain risk statement(s) based between drugs. For drug products other on data from all relevant sources than biological products, any claim (human, animal, and/or pharmacologic) comparing the drug to which the label- that describe, for the drug, the risk of ing applies with other drugs in terms of adverse developmental outcomes (i.e., frequency, severity, or character of ad- structural abnormalities, embryo-fetal verse reactions must be based on ade- and/or infant mortality, functional im- quate and well-controlled studies as de- pairment, alterations to growth). When fined in § 314.126(b) of this chapter un- multiple data sources are available, less this requirement is waived under the statements must be presented in § 201.58 or § 314.126(c) of this chapter. the following order: Human, animal, For biological products, any such claim pharmacologic. The source(s) of the must be based on substantial evidence. data must be stated. The labeling must (8) 7 Drug interactions. (i) This section state the percentage range of live must contain a description of clinically births in the United States with a significant interactions, either ob- major birth defect and the percentage served or predicted, with other pre- range of pregnancies in the United scription or over-the-counter drugs, States that end in miscarriage, regard- classes of drugs, or foods (e.g., dietary less of drug exposure. If such informa- supplements, grapefruit juice), and spe- tion is available for the population(s) cific practical instructions for pre- for which the drug is labeled, it must venting or managing them. The mecha- also be included. When use of a drug is nism(s) of the interaction, if known, contraindicated during pregnancy, this must be briefly described. Interactions information must be stated first in the that are described in the ‘‘Contra- Risk Summary. When applicable, risk indications’’ or ‘‘Warnings and Pre- statements as described in paragraphs cautions’’ sections must be discussed in (c)(9)(i)(B)(1) and (2) of this section more detail under this section. Details must include a cross-reference to addi- of drug interaction pharmacokinetic tional details in the relevant portion of studies that are included in the ‘‘Clin- the ‘‘Data’’ subheading in the ‘‘Preg- ical Pharmacology’’ section that are nancy’’ subsection of the labeling. If pertinent to clinical use of the drug data demonstrate that a drug is not must not be repeated in this section. systemically absorbed following a par- (ii) This section must also contain ticular route of administration, the practical guidance on known inter- Risk Summary must contain only the ference of the drug with laboratory following statement: ‘‘(Name of drug) is tests. not absorbed systemically following (9) 8 Use in specific populations. This (route of administration), and mater- section must contain the following sub- nal use is not expected to result in sections: fetal exposure to the drug.’’

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00040 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

(1) Risk statement based on human formation, to the extent it is available, data. When human data are available under the headings ‘‘Disease-associated that establish the presence or absence maternal and/or embryo/fetal risk,’’ of any adverse developmental out- ‘‘Dose adjustments during pregnancy come(s) associated with maternal use and the postpartum period,’’ ‘‘Maternal of the drug, the Risk Summary must adverse reactions,’’ ‘‘Fetal/Neonatal summarize the specific developmental adverse reactions,’’ and ‘‘Labor or de- outcome(s); their incidence; and the ef- livery’’: fects of dose, duration of exposure, and (1) Disease-associated maternal and/or gestational timing of exposure. If embryo/fetal risk. If there is a serious human data indicate that there is an known or potential risk to the preg- increased risk for a specific adverse de- nant woman and/or the embryo/fetus velopmental outcome in infants born to women exposed to the drug during associated with the disease or condi- pregnancy, this risk must be quan- tion for which the drug is indicated to titatively compared to the risk for the be used, the labeling must describe the same outcome in infants born to risk. women who were not exposed to the (2) Dose adjustments during pregnancy drug but who have the disease or condi- and the postpartum period. If there are tion for which the drug is indicated to pharmacokinetic data that support be used. When risk information is not dose adjustment(s) during pregnancy available for women with the disease or and the postpartum period, a summary condition for which the drug is indi- of this information must be provided. cated, the risk for the specific outcome (3) Maternal adverse reactions. If use of must be compared to the rate at which the drug is associated with a maternal the outcome occurs in the general pop- adverse reaction that is unique to preg- ulation. The Risk Summary must state nancy or if a known adverse reaction when there are no human data or when occurs with increased frequency or se- available human data do not establish verity in pregnant women, the labeling the presence or absence of drug-associ- must describe the adverse reaction and ated risk. available intervention(s) for moni- (2) Risk statement based on animal toring or mitigating the reaction. The data. When animal data are available, labeling must describe, if known, the the Risk Summary must summarize effect of dose, timing, and duration of the findings in animals and based on these findings, describe, for the drug, exposure on the risk to the pregnant the potential risk of any adverse devel- woman of experiencing the adverse re- opmental outcome(s) in humans. This action. statement must include: The number (4) Fetal/Neonatal adverse reactions. If and type(s) of species affected, timing it is known or anticipated that treat- of exposure, animal doses expressed in ment of the pregnant woman increases terms of human dose or exposure or may increase the risk of an adverse equivalents, and outcomes for pregnant reaction in the fetus or neonate, the la- animals and offspring. When animal beling must describe the adverse reac- studies do not meet current standards tion, the potential severity and revers- for nonclinical developmental toxicity ibility of the adverse reaction, and studies, the Risk Summary must so available intervention(s) for moni- state. When there are no animal data, toring or mitigating the reaction. The the Risk Summary must so state. labeling must describe, if known, the (3) Risk statement based on pharma- effect of dose, timing, and duration of cology. When the drug has a well-under- exposure on the risk. stood mechanism of action that may (5) Labor or delivery. If the drug is ex- result in adverse developmental out- pected to affect labor or delivery, the come(s), the Risk Summary must ex- labeling must provide information plain the mechanism of action and the about the effect of the drug on the potential associated risks. (C) Clinical considerations. Under the pregnant woman and the fetus or subheading ‘‘Clinical Considerations,’’ neonate; the effect of the drug on the the labeling must provide relevant in-

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00041 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

duration of labor and delivery; any in- not be included unless the animal creased risk of adverse reactions, in- model is specifically known to be pre- cluding their potential severity and re- dictive for humans. When use of a drug versibility; and must provide informa- is contraindicated during tion about available intervention(s) breastfeeding, this information must that can mitigate these effects and/or be stated first in the Risk Summary. adverse reactions. The information de- (1) Drug not absorbed systemically. If scribed under this heading is not re- data demonstrate that the drug is not quired for drugs approved for use only systemically absorbed by the mother, during labor and delivery. the Risk Summary must contain only (D) Data—(1) ‘‘Data’’ subheading. the following statement: ‘‘(Name of Under the subheading ‘‘Data,’’ the la- drug) is not absorbed systemically by beling must describe the data that are the mother following (route of admin- the basis for the Risk Summary and istration), and breastfeeding is not ex- Clinical Considerations. pected to result in exposure of the (2) Human and animal data headings. child to (name of drug).’’ Human and animal data must be pre- (2) Drug absorbed systemically. If the sented separately, beneath the head- drug is absorbed systemically, the Risk ings ‘‘Human Data’’ and ‘‘Animal Summary must describe the following Data,’’ and human data must be pre- to the extent relevant information is sented first. available: (3) Description of human data. For (i) Presence of drug in human milk. The human data, the labeling must describe Risk Summary must state whether the adverse developmental outcomes, ad- drug and/or its active metabolite(s) are verse reactions, and other adverse ef- present in human milk. If there are no fects. To the extent applicable, the la- data to assess this, the Risk Summary beling must describe the types of stud- must so state. If studies demonstrate ies or reports, number of subjects and that the drug and/or its active metabo- the duration of each study, exposure lite(s) are not detectable in human information, and limitations of the milk, the Risk Summary must state data. Both positive and negative study the limits of the assay used. If studies findings must be included. demonstrate the presence of the drug (4) Description of animal data. For ani- and/or its active metabolite(s) in mal data, the labeling must describe human milk, the Risk Summary must the following: Types of studies, animal state the concentration of the drug species, dose, duration and timing of and/or its active metabolite(s) in exposure, study findings, presence or human milk and the actual or esti- absence of maternal toxicity, and limi- mated daily dose for an infant fed ex- tations of the data. Description of ma- clusively with human milk. The actual ternal and offspring findings must in- or estimated amount of the drug and/or clude dose-response and severity of ad- its active metabolite(s) ingested by the verse developmental outcomes. Animal infant must be compared to the labeled doses or exposures must be described in infant or pediatric dose, if available, or terms of human dose or exposure to the maternal dose. If studies dem- equivalents and the basis for those cal- onstrate the presence of the drug and/ culations must be included. or its active metabolite(s) in human (ii) 8.2 Lactation. This subsection of milk but the drug and/or its active me- the labeling must contain the following tabolite(s) are not expected to be sys- information in the following order temically bioavailable to the breast-fed under the subheadings ‘‘Risk Sum- child, the Risk Summary must describe mary,’’ ‘‘Clinical Considerations,’’ and the disposition of the drug and/or its ‘‘Data’’: active metabolite(s). If only animal (A) Risk summary. When relevant lactation data are available, the Risk human and/or animal lactation data Summary must state only whether or are available, the Risk Summary must not the drug and/or its active metabo- include a cross-reference to the ‘‘Data’’ lite(s) were detected in animal milk subheading in the ‘‘Lactation’’ sub- and specify the animal species. section of the labeling. When human (ii) Effects of drug on the breast-fed data are available, animal data must child. The Risk Summary must include

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00042 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

information, on the known or predicted data that are the basis for the Risk effects on the child from exposure to Summary and Clinical Considerations. the drug and/or its active metabolite(s) (iii) 8.3 Females and males of reproduc- through human milk or from contact tive potential. When pregnancy testing with breast or nipple skin (for topical and/or contraception are required or products). The Risk Summary also recommended before, during, or after must include information on systemic drug therapy and/or when there are and/or local adverse reactions. If there human and/or animal data that suggest are no data to assess the effects of the drug-associated fertility effects, this drug and/or its active metabolite(s) on subsection of labeling must contain the breast-fed child, the Risk Summary this information under the subheadings must so state. ‘‘Pregnancy Testing,’’ ‘‘Contracep- (iii) Effects of drug on milk production. tion,’’ and ‘‘Infertility,’’ in that order. The Risk Summary must describe the (iv) 8.4 Pediatric use. (A) Pediatric effects of the drug and/or its active me- population(s)/pediatric patient(s): For tabolite(s) on milk production. If there the purposes of paragraphs (c)(9)(iv)(B) are no data to assess the effects of the through (c)(9)(iv)(H) of this section, the drug and/or its active metabolite(s) on terms pediatric population(s) and pedi- milk production, the Risk Summary atric patient(s) are defined as the pedi- must so state. atric age group, from birth to 16 years, (3) Risk and benefit statement. For including age groups often called neo- drugs absorbed systemically, unless nates, infants, children, and adoles- breastfeeding is contraindicated during cents. drug therapy, the following risk and (B) If there is a specific pediatric in- benefit statement must appear at the dication different from those approved end of the Risk Summary: ‘‘The devel- for adults that is supported by ade- opmental and health benefits of quate and well-controlled studies in breastfeeding should be considered the pediatric population, it must be de- along with the mother’s clinical need scribed under the ‘‘Indications and for (name of drug) and any potential ad- Usage’’ section, and appropriate pedi- verse effects on the breast-fed child atric dosage information must be given from (name of drug) or from the under- under the ‘‘Dosage and Administra- lying maternal condition.’’ tion’’ section. The ‘‘Pediatric use’’ sub- (B) Clinical considerations. Under section must cite any limitations on ‘‘Clinical Considerations,’’ the fol- the pediatric indication, need for spe- lowing information must be provided cific monitoring, specific hazards asso- to the extent it is available and rel- ciated with use of the drug in any sub- evant: sets of the pediatric population (e.g., (1) Minimizing exposure. The labeling neonates), differences between pedi- must describe ways to minimize expo- atric and adult responses to the drug, sure in the breast-fed child if: The drug and other information related to the and/or its active metabolite(s) are safe and effective pediatric use of the present in human milk in clinically drug. Data summarized in this sub- relevant concentrations; the drug does section should be discussed in more de- not have an established safety profile tail, if appropriate, under the ‘‘Clinical in infants; and the drug is used either Pharmacology’’ or ‘‘Clinical Studies’’ intermittently, in single doses, or for section. As appropriate, this informa- short courses of therapy. When application must also be contained in the ble, the labeling must also describe ‘‘Contraindications’’ and/or ‘‘Warnings ways to minimize a breast-fed child’s and Precautions’’ section(s). oral intake of topical drugs applied to (C) If there are specific statements on the breast or nipple skin. pediatric use of the drug for an indica- (2) Monitoring for adverse reactions. tion also approved for adults that are The labeling must describe available based on adequate and well-controlled intervention(s) for monitoring or miti- studies in the pediatric population, gating the adverse reaction(s) pre- they must be summarized in the ‘‘Pe- sented in the Risk Summary. diatric use’’ subsection and discussed (C) Data. Under the subheading in more detail, if appropriate, under ‘‘Data,’’ the labeling must describe the the ‘‘Clinical Pharmacology’’ and

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00043 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

‘‘Clinical Studies’’ sections. Appro- (E) If the requirements for a finding priate pediatric dosage must be given of substantial evidence to support a pe- under the ‘‘Dosage and Administra- diatric indication or a pediatric use tion’’ section. The ‘‘Pediatric use’’ sub- statement have not been met for a par- section of the labeling must also cite ticular pediatric population, the ‘‘Pe- any limitations on the pediatric use diatric use’’ subsection must contain statement, need for specific moni- an appropriate statement such as toring, specific hazards associated with ‘‘Safety and effectiveness in pediatric use of the drug in any subsets of the patients below the age of (ll) have pediatric population (e.g., neonates), not been established.’’ If use of the differences between pediatric and adult drug in this pediatric population is as- responses to the drug, and other infor- sociated with a specific hazard, the mation related to the safe and effective hazard must be described in this sub- pediatric use of the drug. As appropriate, this information must also be section, or, if appropriate, the hazard contained in the ‘‘Contraindications’’ must be stated in the ‘‘Contraindica- and/or ‘‘Warnings and Precautions’’ tions’’ or ‘‘Warnings and Precautions’’ section(s). section and this subsection must refer (D)(1) When a drug is approved for pe- to it. diatric use based on adequate and well- (F) If the requirements for a finding controlled studies in adults with other of substantial evidence to support a pe- information supporting pediatric use, diatric indication or a pediatric use the ‘‘Pediatric use’’ subsection of the statement have not been met for any labeling must contain either the fol- pediatric population, this subsection lowing statement or a reasonable alter- must contain the following statement: native: ‘‘Safety and effectiveness in pediatric The safety and effectiveness of (drug name) patients have not been established.’’ If have been established in the age groups use of the drug in premature or neo- lll to lll (note any limitations, e.g., no data for pediatric patients under 2, or only natal infants, or other pediatric sub- applicable to certain indications approved in groups, is associated with a specific adults). Use of (drug name) in these age hazard, the hazard must be described in groups is supported by evidence from ade- this subsection, or, if appropriate, the quate and well-controlled studies of (drug hazard must be stated in the ‘‘Contra- name) in adults with additional data (insert indications’’ or ‘‘Warnings and Pre- wording that accurately describes the data submitted to support a finding of substantial evi- cautions’’ section and this subsection dence of effectiveness in the pediatric popu- must refer to it. lation). (G) If the sponsor believes that none (2) Data summarized in the preceding of the statements described in para- prescribed statement in this subsection graphs (c)(9)(iv)(B) through (c)(9)(iv)(F) must be discussed in more detail, if ap- of this section are appropriate or rel- propriate, under the ‘‘Clinical Pharma- evant to the labeling of a particular cology’’ or the ‘‘Clinical Studies’’ sec- drug, the sponsor must provide reasons tion. For example, pediatric pharmaco- for omission of the statements and kinetic or pharmacodynamic studies may propose alternative statement(s). and dose response information should FDA may permit use of an alternative be described in the ‘‘Clinical Pharma- statement if FDA determines that no cology’’ section. Pediatric dosing in- statement described in those para- structions must be included in the ‘‘Dosage and Administration’’ section. graphs is appropriate or relevant to the Any differences between pediatric and drug’s labeling and that the alternative adult responses, need for specific moni- statement is accurate and appropriate. toring, dosing adjustments, and any (H) If the drug product contains one other information related to safe and or more inactive ingredients that effective use of the drug in pediatric present an increased risk of toxic ef- patients must be cited briefly in the fects to neonates or other pediatric ‘‘Pediatric use’’ subsection and, as ap- subgroups, a special note of this risk propriate, in the ‘‘Contraindications,’’ must be made, generally in the ‘‘Con- ‘‘Warnings and Precautions,’’ and traindications’’ or ‘‘Warnings and Pre- ‘‘Dosage and Administration’’ sections. cautions’’ section.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00044 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

(v) 8.5 Geriatric use. (A) A specific and over to determine whether elderly geriatric indication, if any, that is sup- subjects respond differently from ported by adequate and well-controlled younger subjects, and other reported studies in the geriatric population clinical experience has not identified must be described under the ‘‘Indica- such differences, the ‘‘Geriatric use’’ tions and Usage’’ section, and appro- subsection must include the following priate geriatric dosage must be stated statement: under the ‘‘Dosage and Administra- Clinical studies of (name of drug) did tion’’ section. The ‘‘Geriatric use’’ sub- not include sufficient numbers of subsection must cite any limitations on jects aged 65 and over to determine the geriatric indication, need for spe- whether they respond differently from cific monitoring, specific hazards asso- younger subjects. Other reported clin- ciated with the geriatric indication, and other information related to the ical experience has not identified dif- safe and effective use of the drug in the ferences in responses between the el- geriatric population. Unless otherwise derly and younger patients. In general, noted, information contained in the dose selection for an elderly patient ‘‘Geriatric use’’ subsection must per- should be cautious, usually starting at tain to use of the drug in persons 65 the low end of the dosing range, re- years of age and older. Data summa- flecting the greater frequency of de- rized in this subsection must be dis- creased hepatic, renal, or cardiac func- cussed in more detail, if appropriate, tion, and of concomitant disease or under ‘‘Clinical Pharmacology’’ or the other drug therapy. ‘‘Clinical Studies’’ section. As appro- (2) If clinical studies (including stud- priate, this information must also be ies that are part of marketing applica- contained in the ‘‘Warnings and Pre- tions and other relevant studies avail- cautions’’ and/or ‘‘Contraindications’’ able to the sponsor that have not been section(s). submitted in the sponsor’s applica- (B) Specific statements on geriatric tions) included enough elderly subjects use of the drug for an indication ap- to make it likely that differences in proved for adults generally, as distin- safety or effectiveness between elderly guished from a specific geriatric indi- and younger subjects would have been cation, must be contained in the detected, but no such differences (in ‘‘Geriatric use’’ subsection and must safety or effectiveness) were observed, reflect all information available to the and other reported clinical experience sponsor that is relevant to the appropriate use of the drug in elderly pa- has not identified such differences, the tients. This information includes de- ‘‘Geriatric use’’ subsection must con- tailed results from controlled studies tain the following statement: that are available to the sponsor and Of the total number of subjects in clinical pertinent information from well-docu- studies of (name of drug), ll percent were 65 mented studies obtained from a lit- and over, while ll percent were 75 and over. (Alternatively, the labeling may state the erature search. Controlled studies in- total number of subjects included in the clude those that are part of the mar- studies who were 65 and over and 75 and keting application and other relevant over.) No overall differences in safety or ef- studies available to the sponsor that fectiveness were observed between these sub- have not been previously submitted in jects and younger subjects, and other re- the investigational new drug applica- ported clinical experience has not identified tion, new drug application, biologics li- differences in responses between the elderly cense application, or a supplement or and younger patients, but greater sensitivity amendment to one of these applica- of some older individuals cannot be ruled tions (e.g., postmarketing studies or out. adverse drug reaction reports). The (3) If evidence from clinical studies ‘‘Geriatric use’’ subsection must con- and other reported clinical experience tain the following statement(s) or rea- available to the sponsor indicates that sonable alternative, as applicable, tak- use of the drug in elderly patients is ing into account available information: associated with differences in safety or (1) If clinical studies did not include effectiveness, or requires specific moni- sufficient numbers of subjects aged 65 toring or dosage adjustment, the

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00045 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

‘‘Geriatric use’’ subsection must con- for omission of the statements and tain a brief description of observed dif- may propose an alternative statement. ferences or specific monitoring or dos- FDA may permit omission of the state- age requirements and, as appropriate, ments if FDA determines that no state- must refer to more detailed discussions ment described in those paragraphs is in the ‘‘Contraindications,’’ ‘‘Warnings appropriate or relevant to the drug’s and Precautions,’’ ‘‘Dosage and Admin- labeling. FDA may permit use of an al- istration,’’ or other sections. ternative statement if the agency de- (C)(1) If specific pharmacokinetic or termines that such statement is accu- pharmacodynamic studies have been rate and appropriate. carried out in the elderly, they must be (vi) Additional subsections. Additional described briefly in the ‘‘Geriatric use’’ subsections may be included, as appro- subsection and in detail under the priate, if sufficient data are available ‘‘Clinical Pharmacology’’ section. The concerning the use of the drug in other ‘‘Clinical Pharmacology’’ and ‘‘Drug specified subpopulations (e.g., renal or Interactions’’ sections ordinarily con- hepatic impairment). tain information on drug/disease and (10) 9 Drug abuse and dependence. This drug/drug interactions that is particu- section must contain the following in- larly relevant to the elderly, who are formation, as appropriate: more likely to have concomitant ill- (i) 9.1 Controlled substance. If the drug ness and to use concomitant drugs. is controlled by the Drug Enforcement (2) If a drug is known to be substan- Administration, the schedule in which tially excreted by the kidney, the it is controlled must be stated. ‘‘Geriatric use’’ subsection must in- (ii) 9.2 Abuse. This subsection must clude the statement: state the types of abuse that can occur This drug is known to be substantially excreted by the kidney, and the risk of adverse with the drug and the adverse reac- reactions to this drug may be greater in pa- tions pertinent to them, and must tients with impaired renal function. Because identify particularly susceptible pa- elderly patients are more likely to have de- tient populations. This subsection creased renal function, care should be taken must be based primarily on human in dose selection, and it may be useful to data and human experience, but perti- monitor renal function. nent animal data may also be used. (D) If use of the drug in the elderly (iii) 9.3 Dependence. This subsection appears to cause a specific hazard, the must describe characteristic effects re- hazard must be described in the ‘‘Geri- sulting from both psychological and atric use’’ subsection, or, if appro- physical dependence that occur with priate, the hazard must be stated in the drug and must identify the quan- the ‘‘Contraindications’’ or ‘‘Warnings tity of the drug over a period of time and Precautions’’ section, and the that may lead to tolerance or depend- ‘‘Geriatric use’’ subsection must refer ence, or both. Details must be provided to those sections. on the adverse effects of chronic abuse (E) Labeling under paragraphs and the effects of abrupt withdrawal. (c)(9)(v)(A) through (c)(9)(v)(C) of this Procedures necessary to diagnose the section may include statements, if dependent state and the principles of they are necessary for safe and effec- treating the effects of abrupt with- tive use of the drug, and reflect good drawal must be described. clinical practice or past experience in a (11) 10 Overdosage. This section must particular situation, e.g., for a sedating be based on human data. If human data drug, it could be stated that: are unavailable, appropriate animal Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients and in vitro data may be used. The fol- generally should be started on low doses of lowing specific information must be (name of drug) and observed closely. provided: (F) If the sponsor believes that none (i) Signs, symptoms, and laboratory of the requirements described in para- findings associated with an overdosage graphs (c)(9)(v)(A) through (c)(9)(v)(E) of the drug; of this section are appropriate or rel- (ii) Complications that can occur evant to the labeling of a particular with the drug (for example, organ tox- drug, the sponsor must provide reasons icity or delayed acidosis);

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00046 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

(iii) Concentrations of the drug in (ii) If appropriate, other important biologic fluids associated with toxicity chemical or physical information, such or death; physiologic variables influ- as physical constants or pH, must be encing excretion of the drug, such as stated. urine pH; and factors that influence (13) 12 Clinical pharmacology. (i) This the dose response relationship of the section must contain information re- drug, such as tolerance. The pharmaco- lating to the human clinical pharma- kinetic data given in the ‘‘Clinical cology and actions of the drug in hu- Pharmacology’’ section also may be mans. Pharmacologic information referenced here, if applicable to based on in vitro data using human overdoses; biomaterials or pharmacologic animal (iv) The amount of the drug in a sin- models, or relevant details about in gle dose that is ordinarily associated vivo study designs or results (e.g., drug with symptoms of overdosage and the interaction studies), may be included amount of the drug in a single dose in this section if essential to under- that is likely to be life threatening; stand dosing or drug interaction infor- (v) Whether the drug is dialyzable; mation presented in other sections of and the labeling. This section must include (vi) Recommended general treatment the following subsections: procedures and specific measures for (A) 12.1 Mechanism of action. This sub- support of vital functions (e.g., proven section must summarize what is known antidotes, gastric lavage, forced diure- about the established mechanism(s) of sis, or as per Poison Control Center). the drug’s action in humans at various Such recommendations must be based levels (e.g., receptor, membrane, tis- on data available for the specific drug sue, organ, whole body). If the mecha- or experience with pharmacologically nism of action is not known, this sub- related drugs. Unqualified rec- section must contain a statement ommendations for which data are lack- about the lack of information. ing for the specific drug or class of drugs must not be stated. (B) 12.2 Pharmacodynamics. This sub- (12) 11 Description. (i) This section section must include a description of must contain: any biochemical or physiologic phar- (A) The proprietary name and the es- macologic effects of the drug or active tablished name, if any, as defined in metabolites related to the drug’s clin- section 502(e)(2) of the act, of the drug ical effect in preventing, diagnosing, or, for biological products, the proper mitigating, curing, or treating disease, name (as defined in § 600.3 of this chap- or those related to adverse effects or ter) and any appropriate descriptors; toxicity. Exposure-response relation- (B) The type of dosage form(s) and ships (e.g., concentration-response, the route(s) of administration to which dose-response) and time course of the labeling applies; pharmacodynamic response (including (C) The same qualitative and/or quan- short-term clinical response) must be titative ingredient information as re- included if known. If this information quired under § 201.100(b) for drug labels is unknown, this subsection must con- or §§ 610.60 and 610.61 of this chapter for tain a statement about the lack of in- biological product labels; formation. Detailed dosing or moni- (D) If the product is sterile, a state- toring recommendations based on ment of that fact; pharmacodynamic information that (E) The pharmacological or thera- appear in other sections (e.g., ‘‘Warn- peutic class of the drug; ings and Precautions’’ or ‘‘Dosage and (F) For drug products other than bio- Administration’’) must not be repeated logical products, the chemical name in this subsection, but the location of and structural formula of the drug; and such recommendations must be ref- (G) If the product is radioactive, a erenced. statement of the important nuclear (C) 12.3 Pharmacokinetics. This sub- physical characteristics, such as the section must describe the clinically principal radiation emission data, ex- significant pharmacokinetics of a drug ternal radiation, and physical decay or active metabolites, (i.e., pertinent characteristics. absorption, distribution, metabolism,

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00047 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.57 21 CFR Ch. I (4–1–19 Edition)

and excretion parameters). Informa- safe and effective use may be included tion regarding bioavailability, the ef- in this section only if a waiver is fect of food, minimum concentration granted under § 201.58 or § 314.126(c) of (Cmin), maximum concentration (Cmax), this chapter. time to maximum concentration (Tmax), (14) 13 Nonclinical toxicology. This sec- area under the curve (AUC), pertinent tion must contain the following sub- half-lives (t1/2), time to reach steady sections as appropriate: state, extent of accumulation, route(s) (i) 13.1 Carcinogenesis, mutagenesis, im- of elimination, clearance (renal, he- pairment of fertility. This subsection patic, total), mechanisms of clearance must state whether long term studies (e.g., specific enzyme systems), drug/ in animals have been performed to drug and drug/food (e.g., dietary sup- evaluate carcinogenic potential and, if plements, grapefruit juice) pharmaco- so, the species and results. If results kinetic interactions (including inhibi- from reproduction studies or other tion, induction, and genetic character- data in animals raise concern about istics), and volume of distribution (Vd) must be presented if clinically signifi- mutagenesis or impairment of fertility cant. Information regarding nonlin- in either males or females, this must earity in pharmacokinetic parameters, be described. Any precautionary state- changes in pharmacokinetics over ment on these topics must include time, and binding (plasma protein, practical, relevant advice to the pre- erythrocyte) parameters must also be scriber on the significance of these ani- presented if clinically significant. This mal findings. Human data suggesting section must also include the results of that the drug may be carcinogenic or pharmacokinetic studies (e.g., of me- mutagenic, or suggesting that it im- tabolism or interaction) that establish pairs fertility, as described in the the absence of an effect, including per- ‘‘Warnings and Precautions’’ section, tinent human studies and in vitro data. must not be included in this subsection Dosing recommendations based on of the labeling. clinically significant factors that (ii) 13.2 Animal toxicology and/or phar- change the product’s pharmacokinetics macology. Significant animal data nec- (e.g., age, gender, race, hepatic or renal essary for safe and effective use of the dysfunction, concomitant therapy) drug in humans that is not incor- that appear in other sections (e.g., porated in other sections of labeling ‘‘Warnings and Precautions,’’ ‘‘Dosage must be included in this section (e.g., and Administration’’ or ‘‘Use in Spe- specifics about studies used to support cific Populations’’) must not be re- approval under § 314.600 or § 601.90 of peated in this subsection, but the loca- this chapter, the absence of chronic tion of such recommendations must be animal toxicity data for a drug that is referenced. administered over prolonged periods or (ii) Data that demonstrate activity is implanted in the body). or effectiveness in in vitro or animal tests and that have not been shown by (15) 14 Clinical studies. This section adequate and well-controlled clinical must discuss those clinical studies that studies to be pertinent to clinical use facilitate an understanding of how to may be included under this section use the drug safely and effectively. Or- only under the following cir- dinarily, this section will describe the cumstances: studies that support effectiveness for (A) In vitro data for anti-infective the labeled indication(s), including dis- drugs may be included if the data are cussion of study design, population, immediately preceded by the state- endpoints, and results, but must not in- ment ‘‘The following in vitro data are clude an encyclopedic listing of all, or available but their clinical significance even most, studies performed as part of is unknown.’’ the product’s clinical development pro- (B) For other classes of drugs, in gram. If a specific important clinical vitro and animal data that have not study is mentioned in any section of been shown by adequate and well-con- the labeling required under §§ 201.56 and trolled studies, as defined in § 314.126(b) 201.57 because the study is essential to of this chapter, to be necessary for the an understandable presentation of the

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00048 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.57

information in that section of the la- (iv) Special handling and storage beling, any detailed discussion of the conditions. study must appear in this section. (18) 17 Patient counseling information. (i) For drug products other than bio- This section must contain information logical products, any clinical study necessary for patients to use the drug that is discussed in prescription drug safely and effectively (e.g., precautions labeling that relates to an indication concerning driving or the concomitant for or use of the drug must be adequate use of other substances that may have and well-controlled as described in harmful additive effects). Any FDA-ap- § 314.126(b) of this chapter and must not proved patient labeling must be ref- imply or suggest indications or uses or erenced in this section and the full text dosing regimens not stated in the ‘‘In- of such patient labeling must be re- dications and Usage’’ or ‘‘Dosage and printed immediately following this sec- Administration’’ section. For biologi- tion or, alternatively, accompany the cal products, any clinical study that is prescription drug labeling. Any FDA- discussed that relates to an indication approved patient labeling printed im- for or use of the biological product mediately following this section or ac- must constitute or contribute to sub- companying the labeling is subject to stantial evidence and must not imply the type size requirements in para- or suggest indications or uses or dosing graph (d)(6) of this section, except for a regimens not stated in the ‘‘Indications Medication Guide to be detached and and Usage’’ or ‘‘Dosage and Adminis- distributed to patients in compliance tration’’ section. with § 208.24 of this chapter. Medication (ii) Any discussion of a clinical study Guides for distribution to patients are that relates to a risk from the use of subject to the type size requirements the drug must also refer to the other set forth in § 208.20 of this chapter. sections of the labeling where the risk (d) Format requirements. All labeling is identified or discussed. information required under paragraphs (16) 15 References. When prescription (a), (b), and (c) of this section must be drug labeling must summarize or oth- printed in accordance with the fol- erwise rely on a recommendation by an lowing specifications: authoritative scientific body, or on a standardized methodology, scale, or (1) All headings and subheadings re- technique, because the information is quired by paragraphs (a) and (c) of this important to prescribing decisions, the section must be highlighted by bold labeling may include a reference to the type that prominently distinguishes source of the information. the headings and subheadings from other labeling information. Reverse (17) 16 How supplied/storage and han- type is not permitted as a form of high- dling. This section must contain information on the available dosage forms lighting. to which the labeling applies and for (2) A horizontal line must separate which the manufacturer or distributor the information required by paragraphs is responsible. The information must (a), (b), and (c) of this section. include, as appropriate: (3) The headings listed in paragraphs (i) The strength or potency of the (a)(5) through (a)(13) of this section dosage form in metric system (e.g., 10 must be presented in the center of a milligram tablets) and, if the apothe- horizontal line. cary system is used, a statement of the (4) If there are multiple subheadings strength in parentheses after the met- listed under paragraphs (a)(4) through ric designation; (a)(13) of this section, each subheading (ii) The units in which the dosage must be preceded by a bullet point. form is ordinarily available for pre- (5) The labeling information required scribing by practitioners (e.g., bottles by paragraphs (a)(1) through (a)(4), of 100); (a)(11)(ii) through (a)(11)(iv), and (a)(14) (iii) Appropriate information to fa- of this section must be in bold print. cilitate identification of the dosage (6) The letter height or type size for forms, such as shape, color, coating, all labeling information, headings, and scoring, imprinting, and National Drug subheadings set forth in paragraphs (a), Code number; and (b), and (c) of this section must be a

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00049 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.58 21 CFR Ch. I (4–1–19 Edition)

minimum of 8 points, except for label- in writing by the Director or the Direc- ing information that is on or within tor’s designee. the package from which the drug is to [71 FR 3996, Jan. 24, 2006, as amended at 74 be dispensed, which must be a min- FR 13112, Mar. 26, 2009; 80 FR 18090, Apr. 3, imum of 6 points. 2015] (7) The identifying numbers required by § 201.56(d) and paragraphs (c)(1) through (c)(18) of this section must be Subpart C—Labeling Require- presented in bold print and must pre- ments for Over-the-Counter cede the heading or subheading by at Drugs least two square em’s (i.e., two squares of the size of the letter ‘‘m’’ in 8 point SOURCE: 41 FR 6908, Feb. 13, 1976, unless type). otherwise noted. (8) The information required by paragraph (a) of this section, not including § 201.60 Principal display panel. the information required under para- The term principal display panel, as it graph (a)(4) of this section, must be applies to over-the-counter drugs in limited in length to an amount that, if package form and as used in this part, printed in 2 columns on a standard means the part of a label that is most sized piece of typing paper (81⁄2 by 11 likely to be displayed, presented, inches), single spaced, in 8 point type shown, or examined under customary with 1⁄2-inch margins on all sides and conditions of display for retail sale. between columns, would fit on one-half The principal display panel shall be of the page. large enough to accommodate all the (9) Sections or subsections of labeling mandatory label information required that are identified as containing recent to be placed thereon by this part with major changes under paragraph (a)(5) clarity and conspicuousness and with- of this section must be highlighted in out obscuring designs, vignettes, or the full prescribing information by the crowding. Where packages bear alter- inclusion of a vertical line on the left nate principal display panels, informa- edge of the new or modified text. tion required to be placed on the prin- (10) For the information required by cipal display panel shall be duplicated paragraph (b) of this section, each sec- on each principal display panel. For tion heading must be in bold print. the purpose of obtaining uniform type Each subheading within a section must size in declaring the quantity of con- be indented and not bolded. tents for all packages of substantially [71 FR 3988, Jan. 24, 2006, as amended at 79 the same size, the term area of the prin- FR 72101, Dec. 4, 2014] cipal display panel means the area of the side or surface that bears the prin- § 201.58 Waiver of labeling require- cipal display panel, which area shall ments. be: An applicant may ask the Food and (a) In the case of a rectangular pack- Drug Administration to waive any re- age where one entire side properly can quirement under §§ 201.56, 201.57, and be considered to be the principal dis- 201.80. A waiver request must be sub- play panel side, the product of the mitted in writing to the Director (or height times the width of that side; the Director’s designee), Center for (b) In the case of a cylindrical or Drug Evaluation and Research, Food nearly cylindrical container, 40 percent and Drug Administration, Central Doc- of the product of the height of the con- ument Room, 5901–B Ammendale Rd., tainer times the circumference; and Beltsville, MD 20705–1266, or, if applica- (c) In the case of any other shape of ble, the Director (or the Director’s des- container, 40 percent of the total sur- ignee), Food and Drug Administration, face of the container: Provided, how- Center for Biologics Evaluation and ever, That where such container pre- Research, Document Control Center, sents an obvious ‘‘principal display 10903 New Hampshire Ave., Bldg. 71, panel’’ such as the top of a triangular Rm. G112, Silver Spring, MD 20993–0002. or circular package, the area shall con- The waiver must be granted or denied sist of the entire top surface.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00050 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.62

In determining the area of the prin- § 201.62 Declaration of net quantity of cipal display panel, exclude tops, bot- contents. toms, flanges at the tops and bottoms (a) The label of an over-the-counter of cans, and shoulders and necks of bot- drug in package form shall bear a dec- tles or jars. In the case of cylindrical laration of the net quantity of con- or nearly cylindrical containers, infor- tents. This shall be expressed in the mation required by this part to appear terms of weight, measure, numerical on the principal display panel shall ap- count, or a combination or numerical pear within that 40 percent of the cir- count and weight, measure, or size. The cumference which is most likely to be statement of quantity of drugs in tab- displayed, presented, shown, or exam- let, capsule, ampule, or other unit form ined under customary conditions of dis- and the quantity of devices shall be ex- play for retail sale. pressed in terms of numerical count; the statement of quantity for drugs in § 201.61 Statement of identity. other dosage forms shall be in terms of weight if the drug is solid, semisolid, or (a) The principal display panel of an viscous, or in terms of fluid measure if over-the-counter drug in package form the drug is liquid. The drug quantity shall bear as one of its principal fea- statement shall be augmented when tures a statement of the identity of the necessary to give accurate information commodity. as to the strength of such drug in the (b) Such statement of identity shall package; for example, to differentiate be in terms of the established name of between several strengths of the same the drug, if any there be, followed by drug ‘‘100 tablets, 5 grains each’’ or an accurate statement of the general ‘‘100 capsules, 125 milligrams each’’ or pharmacological category(ies) of the ‘‘100 capsules, 250 milligrams each’’: drug or the principal intended action(s) Provided, That: of the drug. In the case of an over-the- (1) In the case of a firmly established, counter drug that is a mixture and that general consumer usage and trade cus- has no established name, this require- tom of declaring the quantity of a drug in terms of linear measure or measure ment shall be deemed to be satisfied by of area, such respective term may be a prominent and conspicuous state- used. Such term shall be augmented ment of the general pharmacological when necessary for accuracy of infor- action(s) of the mixture or of its prin- mation by a statement of the weight, cipal intended action(s) in terms that measure, or size of the individual units are meaningful to the layman. Such or of the entire drug; for example, the statements shall be placed in direct net quantity of adhesive tape in pack- conjunction with the most prominent age form shall be expressed in terms of display of the proprietary name or des- linear measure augmented by a state- ignation and shall employ terms de- ment of its width. scriptive of general pharmacological (2) Whenever the Commissioner de- category(ies) or principal intended ac- termines for a specific packaged drug tion(s); for example, ‘‘antacid,’’ ‘‘an- that an existing practice of declaring algesic,’’ ‘‘decongestant,’’ ‘‘antihis- net quantity of contents by weight, taminic,’’ etc. The indications for use measure, numerical count, or a com- shall be included in the directions for bination of these does not facilitate use of the drug, as required by section value comparisons by consumers, he 502(f)(1) of the act and by the regula- shall by regulation designate the ap- tions in this part. propriate term or terms to be used for (c) The statement of identity shall be such article. presented in bold face type on the prin- (b) Statements of weight of the contents shall be expressed in terms of av- cipal display panel, shall be in a size oirdupois pound and ounce. A state- reasonably related to the most promi- ment of liquid measure of the contents nent printed matter on such panel, and shall be expressed in terms of the U.S. shall be in lines generally parallel to gallon of 231 cubic inches and quart, the base on which the package rests as pint, and fluid-ounce subdivisions it is designed to be displayed. thereof, and shall express the volume

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00051 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.62 21 CFR Ch. I (4–1–19 Edition)

at 68 °F (20 °C). See also paragraph (p) (2) In the case of a drug that is mar- of this section. keted with both outer and inner retail (c) The declaration may contain com- containers bearing the mandatory label mon or decimal fractions. A common information required by this part and fraction shall be in terms of halves, the inner container is not intended to quarters, eights, sixteenths, or thirty- be sold separately, the net quantity of seconds; except that if there exists a contents placement requirement of this firmly established, general consumer section applicable to such inner con- usage and trade custom of employing tainer is waived. different common fractions in the net (3) The principal display panel of a quantity declaration of a particular drug marketed on a display card to commodity, they may be employed. A which the immediate container is af- common fraction shall be reduced to fixed may be considered to be the dis- its lowest terms; a decimal fraction play panel of the card, and the type shall not be carried out to more than size of the net quantity of contents two places. A statement that includes statement is governed by the dimen- small fractions of an ounce shall be sions of the display card. deemed to permit smaller variations (f) The declaration shall accurately than one which does not include such reveal the quantity of drug or device in fractions. the package exclusive of wrappers and (d) The declaration shall be located other material packed therewith: Pro- on the principal display panel of the vided, That in the case of drugs packed in containers designed to deliver the label, and with respect to packages drug under pressure, the declaration bearing alternate principal panels it shall state the net quantity of the con- shall be duplicated on each principal tents that will be expelled when the in- display panel. structions for use as shown on the con- (e) The declaration shall appear as a tainer are followed. The propellant is distinct item on the principal display included in the net quantity declara- panel, shall be separated, by at least a tion. space equal to the height of the let- (g) The declaration shall appear in tering used in the declaration, from conspicuous and easily legible boldface other printed label information appear- print or type in distinct contrast (by ing above or below the declaration and, typography, layout, color, embossing, by at least a space equal to twice the or molding) to other matter on the width of the letter ‘‘N’’ of the style of package; except that a declaration of type used in the quantity of contents net quantity blown, embossed, or mold- statement, from other printed label ined on a glass or plastic surface is per- formation appearing to the left or right missible when all label information is of the declaration. It shall not include so formed on the surface. Requirements any term qualifying a unit of weight, of conspicuousness and legibility shall measure, or count, such as ‘‘giant pint’’ include the specifications that: and ‘‘full quart’’, that tends to exag- (1) The ratio of height to width of the gerate the amount of the drug in the letter shall not exceed a differential of container. It shall be placed on the 3 units to 1 unit, i.e., no more than 3 principal display panel within the bot- times as high as it is wide. tom 30 percent of the area of the label (2) Letter heights pertain to upper panel in lines generally parallel to the case or capital letters. When upper and base on which the package rests as it is lower case or all lower case letters are designed to be displayed: Provided, used, it is the lower case letter ‘‘o’’ or That: its equivalent that shall meet the min- (1) On packages having a principal imum standards. display panel of 5 square inches or less (3) When fractions are used, each the requirement for placement within component numeral shall meet one- the bottom 30 percent of the area of the half the minimum height standards. label panel shall not apply when the (h) The declaration shall be in letters declaration of net quantity of contents and numerals in a type size established meets the other requirements of this in relationship to the area of the prin- part; and cipal display panel of the package and

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00052 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.62

shall be uniform for all packages of (2) The declaration may appear in substantially the same size by com- more than one line. The term net plying with the following type speci- weight shall be used when stating the fications: net quantity of contents in terms of (1) Not less than one-sixteenth inch weight. Use of the terms net or net con- in height on packages the principal dis- tents in terms of fluid measure or nu- play panel of which has an area of 5 merical count is optional. It is suffi- square inches or less. cient to distinguish avoirdupois ounce (2) Not less than one-eighth inch in from fluid ounce through association of height on packages the principal dis- terms; for example, ‘‘Net wt. 6 oz’’ or play panel of which has an area of more ‘‘6 oz net wt.,’’ and ‘‘6 fl oz’’ or ‘‘net than five but not more than 25 square contents 6 fl oz’’. inches. (j) On packages containing 4 pounds (3) Not less than three-sixteenths or 1 gallon or more and labeled in inch in height on packages the prin- terms of weight or fluid measure, the cipal display panel of which has an declaration shall be expressed in area of more than 25 but not more than pounds for weight units with any re- 100 square inches. mainder in terms of ounces or common (4) Not less than one-fourth inch in or decimal fractions of the pound; in height on packages the principal dis- the case of fluid measure, it shall be play panel of which has an area of more expressed in the largest whole unit than 100 square inches, except not less (gallons, followed by common or dec- than one-half inch in height if the area imal fractions of a gallon or by the is more than 400 square inches. next smaller whole unit or units (quarts or quarts and pints)) with any Where the declaration is blown, em- remainder in terms of fluid ounces or bossed, or molded on a glass or plastic common or decimal fractions of the surface rather than by printing, typ- pint or quart; see paragraph (k)(5) of ing, or coloring, the lettering sizes this section. specified in paragraphs (h) (1) through (k) Examples: (4) of this section shall be increased by (1) A declaration of 11⁄2 pounds weight one-sixteenth of an inch. shall be expressed as ‘‘Net wt. 24 oz (1 (i) On packages containing less than lb 8 oz),’’ or ‘‘Net wt. 24 oz (11⁄2 lb)’’ or 4 pounds or 1 gallon and labeled in ‘‘Net wt. 24 oz (1.5 lb)’’. terms of weight or fluid measure: (2) A declaration of three-fourths (1) The declaration shall be expressed pound avoirdupois weight shall be ex- both in ounces, with identification by pressed as ‘‘Net wt. 12 oz’’. weight or by liquid measure and, if ap- (3) A declaration of 1 quart liquid plicable (1 pound or 1 pint or more) fol- measure shall be expressed as ‘‘Net lowed in parentheses by a declaration contents 32 fl oz (1 qt)’’ or ‘‘32 fl oz (1 in pounds for weight units, with any re- qt)’’. mainder in terms of ounces or common (4) A declaration of 13⁄4 quarts liquid or decimal fractions of the pound (see measure shall be expressed as ‘‘Net examples set forth in paragraphs (k) (1) contents 56 fl oz (1 qt 1 pt 8 oz)’’ or and (2) of this section), or in the case of ‘‘Net contents 56 fl oz (1 qt 1.5 pt),’’ but liquid measure, in the largest whole not in terms of quart and ounce such as units (quarts, quarts and pints, or ‘‘Net 56 fl oz (1 qt 24 oz).’’ pints, as appropriate) with any remain- (5) A declaration of 21⁄2 gallons liquid der in terms of fluid ounces or common measure shall be expressed as ‘‘Net or decimal fractions of the pint or contents 2 gal 2 qt,’’ ‘‘Net contents 2.5 quart (see examples set forth in para- gallons,’’ or ‘‘Net contents 21⁄2 gal’’ but graphs (k) (3) and (4) of this section). If not as ‘‘2 gal 4 pt’’. the net weight of the package is less than 1 ounce avoirdupois or the net (l) For quantities, the following ab- fluid measure is less than 1 fluid ounce, breviations and none other may be em- the declaration shall be in terms of ployed. Periods and plural forms are common or decimal fractions of the re- optional: spective ounce and not in terms of Gallon gal pint pt drams. quart qt ounce oz

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00053 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.63 21 CFR Ch. I (4–1–19 Edition)

pound lb yard yd (p) A separate statement of net quan- grain gr feet or foot ft tity of contents in terms of the metric kilogram kg inch in system of weight or measure is not re- gram g meter m garded as a supplemental statement milligram mg centimeter cm microgram mcg millimeter mm and an accurate statement of the net liter l fluid fl quantity of contents in terms of the milliliter ml square sq metric system of weight or measure cubic centimeter cc weight wt may also appear on the principal dis- (m) On packages labeled in terms of play panel or on other panels. linear measure, the declaration shall (q) The declaration of net quantity of be expressed both in terms of inches contents shall express an accurate and, if applicable (1 foot or more), the statement of the quantity of contents largest whole units (yards, yards and of the package. Reasonable variations feet, feet). The declaration in terms of caused by loss or gain of moisture dur- the largest whole units shall be in pa- ing the course of good distribution rentheses following the declaration in practice or by unavoidable deviations terms of inches and any remainder in good manufacturing practice will be shall be in terms of inches or common recognized. Variations from stated or decimal fractions of the foot or quantity of contents shall not be un- yard; if applicable, as in the case of ad- reasonably large. hesive tape, the initial declaration in (r) A drug shall be exempt from com- linear inches shall be preceded by a pliance with the net quantity declara- statement of the width. Examples of tion required by this section if it is an linear measure are ‘‘86 inches (2 yd 1 ft ointment labeled ‘‘sample,’’ ‘‘physi- 2 in),’’ ‘‘90 inches (21⁄2 yd),’’ ‘‘30 inches cian’s sample,’’ or a substantially simi- (2.5 ft),’’ ‘‘ 3⁄4 inch by 36 in (1 yd),’’ etc. lar statement and the contents of the (n) On packages labeled in terms of package do not exceed 8 grams. area measure, the declaration shall be expressed both in terms of square § 201.63 Pregnancy/breast-feeding warning. inches and, if applicable (1 square foot or more), the largest whole square unit (a) The labeling for all over-the- (square yards, square yards and square counter (OTC) drug products that are feet, square feet). The declaration in intended for systemic absorption, un- terms of the largest whole units shall less specifically exempted, shall con- be in parentheses following the dec- tain a general warning under the head- laration in terms of square inches and ing ‘‘Warning’’ (or ‘‘Warnings’’ if it ap- any remainder shall be in terms of pears with additional warning state- square inches or common or decimal ments) as follows: ‘‘If pregnant or fractions of the square foot or square breast-feeding, ask a health profes- yard; for example, ‘‘158 sq inches (1 sq sional before use.’’ [first four words of ft 14 sq in).’’ this statement in bold type] In addi- (o) Nothing in this section shall pro- tion to the written warning, a symbol hibit supplemental statements at loca- that conveys the intent of the warning tions other than the principal display may be used in labeling. panel(s) describing in nondeceptive (b) Where a specific warning relating terms the net quantity of contents, to use during pregnancy or while nurs- provided that such supplemental state- ing has been established for a par- ments of net quantity of contents shall ticular drug product in a new drug ap- not include any term qualifying a unit plication (NDA) or for a product cov- of weight, measure, or count that tends ered by an OTC drug final monograph to exaggerate the amount of the drug in part 330 of this chapter, the specific contained in the package; for example, warning shall be used in place of the ‘‘giant pint’’ and ‘‘full quart.’’ Dual or warning in paragraph (a) of this sec- combination declarations of net quan- tion, unless otherwise stated in the tity of contents as provided for in para- NDA or in the final OTC drug monographs (a) and (i) of this section are not graph. regarded as supplemental net quantity (c) The following OTC drugs are ex- statements and shall be located on the empt from the provisions of paragraph principal display panel. (a) of this section:

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00054 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.64

(1) Drugs that are intended to benefit (c) The labeling of OTC drug products the fetus or nursing infant during the intended for oral ingestion shall con- period of pregnancy or nursing. tain the following statement under the (2) Drugs that are labeled exclusively heading ‘‘Warning’’ (or ‘‘Warnings’’ if for pediatric use. it appears with additional warning (d) The Food and Drug Administra- statements) if the amount of sodium tion will grant an exemption from present in the labeled maximum daily paragraph (a) of this section where ap- dose of the product is more than 140 propriate upon petition under the pro- milligrams: ‘‘Ask a doctor before use if visions of § 10.30 of this chapter. Deci- you have [in bold type] [bullet] 1 a so- sions with respect to requests for ex- dium-restricted diet’’. The warnings in emptions shall be maintained in a per- §§ 201.64(c), 201.70(c), 201.71(c), and manent file for public review by the Di- 201.72(c) may be combined, if applica- vision of Dockets Management (HFA– ble, provided the ingredients are listed 305), Food and Drug Administration, in alphabetical order, e g., a calcium or 5630 Fishers Lane, rm. 1061, Rockville, sodium restricted diet. MD 20852. (d) The term sodium free may be used (e) The labeling of orally or rectally in the labeling of OTC drug products administered OTC aspirin and aspirin- intended for oral ingestion if the containing drug products must bear a amount of sodium in the labeled max- warning that immediately follows the imum daily dose is 5 milligrams or less general warning identified in para- and the amount of sodium per dosage graph (a) of this section. The warning unit is 0 milligram (when rounded-off shall be as follows: in accord with paragraph (b) of this section). ‘‘It is especially important not to use’’ (select ‘‘aspirin’’ or ‘‘carbaspirin calcium,’’ as (e) The term very low sodium may be appropriate) ‘‘during the last 3 months of used in the labeling of OTC drug prod- pregnancy unless definitely directed to do so ucts intended for oral ingestion if the by a doctor because it may cause problems in amount of sodium in the labeled max- the unborn child or complications during de- imum daily dose is 35 milligrams or livery.’’ less. [47 FR 54757, Dec. 3, 1982, as amended at 55 (f) The term low sodium may be used FR 27784, July 5, 1990; 59 FR 14364, Mar. 28, in the labeling of OTC drug products 1994; 64 FR 13286, Mar. 17, 1999; 68 FR 24879, intended for oral ingestion if the May 9, 2003] amount of sodium in the labeled maximum daily dose is 140 milligrams or § 201.64 Sodium labeling. less. (a) The labeling of over-the-counter (g) The term salt is not synonymous (OTC) drug products intended for oral with the term sodium and shall not be ingestion shall contain the sodium con- used interchangeably or substituted for tent per dosage unit (e.g., tablet, tea- the term sodium. spoonful) if the sodium content of a (h) The terms sodium free, very low so- single maximum recommended dose of dium, and low sodium shall be in print the product (which may be one or more size and style no larger than the prod- dosage units) is 5 milligrams or more. uct’s statement of identity and shall OTC drug products intended for oral in- not be unduly prominent in print size gestion include gum and lozenge dosage or style compared to the statement of forms, but do not include dentifrices, identity. mouthwashes, or mouth rinses. (i) Any product subject to this para- (b) The sodium content shall be ex- graph that contains sodium bicarbon- pressed in milligrams per dosage unit ate, sodium phosphate, or sodium and shall include the total amount of biphosphate as an active ingredient for sodium regardless of the source, i.e., oral ingestion and that is not labeled from both active and inactive ingredi- as required by this paragraph and that ents. The sodium content shall be is initially introduced or initially de- rounded-off to the nearest whole num- livered for introduction into interstate ber. The sodium content per dosage unit shall follow the heading ‘‘Other 1 See § 201 .66(b)(4) of this chapter for defini- information’’ as stated in § 201.66(c)(7). tion of bullet symbol.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00055 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.66 21 CFR Ch. I (4–1–19 Edition)

commerce after April 22, 1997, is mis- § 201.66 Format and content require- branded under sections 201(n) and 502 ments for over-the-counter (OTC) (a) and (f) of the Federal Food, Drug, drug product labeling. and Cosmetic Act (the act). (a) Scope. This section sets forth the (j) Any product subject to paragraphs content and format requirements for (a) through (h) of this section that is the labeling of all OTC drug products. not labeled as required and that is ini- Where an OTC drug product is the sub- tially introduced or initially delivered ject of an applicable monograph or reg- for introduction into interstate com- ulation that contains content and for- merce after the following dates is mis- mat requirements that conflict with branded under sections 201(n) and 502(a) this section, the content and format re- and (f) of the Federal Food, Drug, and quirements in this section must be fol- Cosmetic Act. lowed unless otherwise specifically pro- (1) As of the date of approval of the vided in the applicable monograph or application for any single entity and regulation. combination products subject to drug (b) Definitions. The following defini- marketing applications approved on or tions apply to this section: after April 23, 2004. (1) Act means the Federal Food, Drug, (2) Septemeber 24, 2005, for all OTC and Cosmetic Act (secs. 201 et seq. (21 drug products subject to any OTC drug U.S.C. 321 et seq.)). monograph, not yet the subject of any (2) Active ingredient means any com- OTC drug monograph, or subject to ponent that is intended to furnish drug marketing applications approved pharmacological activity or other di- before April 23, 2004. rect effect in the diagnosis, cure, mitigation, treatment, or prevention of dis- (k) The labeling of OTC drug prod- ease, or to affect the structure or any ucts intended for rectal administration function of the body of humans. The containing dibasic sodium phosphate term includes those components that and/or monobasic sodium phosphate may undergo chemical change in the shall contain the sodium content per manufacture of the drug product and delivered dose if the sodium content is be present in the drug product in a 5 milligrams or more. The sodium con- modified form intended to furnish the tent shall be expressed in milligrams specified activity or effect. or grams. If less than 1 gram, milli- (3) Approved drug application means a grams should be used. The sodium con- new drug (NDA) or abbreviated new tent shall be rounded-off to the nearest drug (ANDA) application approved whole number if expressed in milli- under section 505 of the act (21 U.S.C. grams (or nearest tenth of a gram if ex- 355). pressed in grams). The sodium content (4) Bullet means a geometric symbol per delivered dose shall follow the that precedes each statement in a list heading ‘‘Other information’’ as stated of statements. For purposes of this sec- in § 201.66(c)(7). Any product subject to tion, the bullet style is limited to solid this paragraph that contains dibasic squares or solid circles, in the format sodium phosphate and/or monobasic so- set forth in paragraph (d)(4) of this sec- dium phosphate as an active ingredient tion. intended for rectal administration and (5) Established name of a drug or in- that is not labeled as required by this gredient thereof means the applicable paragraph and that is initially intro- official name designated under section duced or initially delivered for intro- 508 of the act (21 U.S.C. 358), or, if there duction into interstate commerce after is no designated official name and the November 29, 2005, is misbranded under drug or ingredient is recognized in an sections 201(n) and 502(a) and (f) of the official compendium, the official title act. of the drug or ingredient in such compendium, or, if there is no designated [61 FR 17806, Apr. 22, 1996, as amended at 62 official name and the drug or ingre- FR 19925, Apr. 24, 1997; 64 FR 13286, Mar. 17, dient is not recognized in an official 1999; 69 FR 13724, Mar. 24, 2004; 69 FR 69280, compendium, the common or usual Nov. 29, 2004] name of the drug or ingredient.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00056 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.66

(6) FDA means the Food and Drug application, products marketed with- Administration. out discrete dosage units (e.g., (7) Heading means the required state- topicals) shall state the proportion ments in quotation marks listed in (rather than the quantity) of each ac- paragraphs (c)(2) through (c)(9) of this tive ingredient. section, excluding subheadings (as de- (3) ‘‘Purpose’’ or ‘‘Purposes’’, fol- fined in paragraph (a)(9) of this sec- lowed by the general pharmacological tion). category(ies) or the principal intended (8) Inactive ingredient means any com- action(s) of the drug or, where the drug ponent other than an active ingredient. consists of more than one ingredient, (9) Subheading means the required the general pharmacological categories statements in quotation marks listed or the principal intended actions of in paragraphs (c)(5)(ii) through each active ingredient. When an OTC (c)(5)(vii) of this section. drug monograph contains a statement (10) Drug facts labeling means the of identity, the pharmacological action title, headings, subheadings, and infor- described in the statement of identity mation required under or otherwise de- shall also be stated as the purpose of scribed in paragraph (c) of this section. the active ingredient. (11) Title means the heading listed at (4) ‘‘Use’’ or ‘‘Uses’’, followed by the the top of the required OTC drug prod- indication(s) for the specific drug product labeling, as set forth in paragraph uct. (c)(1) of this section. (5) ‘‘Warning’’ or ‘‘Warnings’’, fol- (12) Total surface area available to bear lowed by one or more of the following, labeling means all surfaces of the out- if applicable: side container of the retail package or, if there is no such outside container, (i) ‘‘For external use only’’ [in bold all surfaces of the immediate container type] for topical drug products not in- or container wrapper except for the tended for ingestion, or ‘‘For’’ (select flanges at the tops and bottoms of cans one of the following, as appropriate: and the shoulders and necks of bottles ‘‘rectal’’ or ‘‘vaginal’’) ‘‘use only’’ [in and jars. bold type]. (c) Content requirements. The outside (ii) All applicable warnings listed in container or wrapper of the retail paragraphs (c)(5)(ii)(A) through package, or the immediate container (c)(5)(ii)(G) of this section with the ap- label if there is no outside container or propriate subheadings highlighted in wrapper, shall contain the title, head- bold type: ings, subheadings, and information set (A) Reye’s syndrome warning for forth in paragraphs (c)(1) through (c)(8) drug products containing salicylates of this section, and may contain the in- set forth in § 201.314(h)(1). This warning formation under the heading in para- shall follow the subheading ‘‘Reye’s graph (c)(9) of this section, in the order syndrome:’’ listed. (B) Allergic reaction and asthma alert (1) (Title) ‘‘Drug Facts’’. If the drug warnings. Allergic reaction warnings facts labeling appears on more than set forth in any applicable OTC drug one panel, the title ‘‘Drug Facts (con- monograph or approved drug applica- tinued)’’ shall appear at the top of each tion for any product that requires a subsequent panel containing such in- separate allergy warning. This warning formation. shall follow the subheading ‘‘Allergy (2) ‘‘Active ingredient’’ or ‘‘Active in- alert:’’ The asthma alert warning set gredients’’ ‘‘(in each [insert the dosage forth in §§ 341.76(c)(5) and 341.76(c)(6) of unit stated in the directions for use this chapter. This warning shall follow (e.g., tablet, 5 mL teaspoonful) or in the subheading ‘‘Asthma alert:’’ each gram as stated in §§ 333.110 and (C) Flammability warning, with ap- 333.120 of this chapter])’’, followed by propriate flammability signal word(s) the established name of each active in- (e.g., §§ 341.74(c)(5)(iii), 344.52(c), gredient and the quantity of each ac- 358.150(c), and 358.550(c) of this chap- tive ingredient per dosage unit. Unless ter). This warning shall follow a sub- otherwise provided in an applicable heading containing the appropriate OTC drug monograph or approved drug flammability signal word(s) described

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00057 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.66 21 CFR Ch. I (4–1–19 Edition)

in an applicable OTC drug monograph drug-drug and drug-food interaction or approved drug application. warnings. (D) Water soluble gums warning set (vi) ‘‘When using this product’’ [in forth in § 201.319. This warning shall bold type], followed by the side effects follow the subheading ‘‘Choking:’’ that the consumer may experience, and (E) Liver warning set forth in the substances (e.g., alcohol) or activi- § 201.326(a)(1)(iii) and/or stomach bleed- ties (e.g., operating machinery, driving ing warning set forth in a car, warnings set forth in § 369.21 of § 201.326(a)(2)(iii). The liver warning this chapter for drugs in dispensers shall follow the subheading ‘‘Liver pressurized by gaseous propellants) to warning:’’ and the stomach bleeding avoid while using the product. warning shall follow the subheading (vii) ‘‘Stop use and ask a doctor if’’ ‘‘Stomach bleeding warning:’’ [in bold type], followed by any signs of (F) Sore throat warning set forth in toxicity or other reactions that would § 201.315. This warning shall follow the necessitate immediately discontinuing subheading ‘‘Sore throat warning:’’ use of the product. For all OTC drug (G) Warning for drug products con- products under an approved drug appli- taining sodium phosphates set forth in cation whose packaging does not in- § 201.307(b)(2)(i) or (b)(2)(ii). This warn- clude a toll-free number through which ing shall follow the subheading ‘‘Dos- consumers can report complaints to age warning:’’ the manufacturer or distributor of the (H) Sexually transmitted diseases drug product, the following text shall (STDs) warning for vaginal contracep- immediately follow the subheading: tive and spermicide drug products con- ‘‘[Bullet] side effects occur. You may taining nonoxynol 9 set forth in report side effects to FDA at 1–800– § 201.325(b)(2). This warning shall follow FDA–1088.’’ The telephone number the subheading ‘‘Sexually transmitted must appear in a minimum 6–point diseases (STDs) alert:’’ bold letter height or type size. (iii) ‘‘Do not use’’ [in bold type], fol- (viii) Any required warnings in an ap- lowed by all contraindications for use plicable OTC drug monograph, other with the product. These contraindica- OTC drug regulations, or approved drug tions are absolute and are intended for application that do not fit within one situations in which consumers should of the categories listed in paragraphs not use the product unless a prior diag- (c)(5)(i) through (c)(5)(vii), (c)(5)(ix), nosis has been established by a doctor and (c)(5)(x) of this section. or for situations in which certain con- (ix) The pregnancy/breast-feeding sumers should not use the product warning set forth in § 201.63(a); the under any circumstances regardless of third trimester warning set forth in whether a doctor or health professional § 201.63(e) for products containing aspi- is consulted. rin or carbaspirin calcium; the third (iv) ‘‘Ask a doctor before use if you trimester warning set forth in ap- have’’ [in bold type] or, for products la- proved drug applications for products beled only for use in children under 12 containing ketoprofen, naproxen so- years of age, ‘‘Ask a doctor before use dium, and ibuprofen (not intended ex- if the child has’’ [in bold type], fol- clusively for use in children). lowed by all warnings for persons with (x) The ‘‘Keep out of reach of chil- certain preexisting conditions (exclud- dren’’ warning and the accidental over- ing pregnancy) and all warnings for dose/ingestion warning set forth in persons experiencing certain symp- § 330.1(g) of this chapter. toms. The warnings under this heading (6) ‘‘Directions’’, followed by the di- are those intended only for situations rections for use described in an appli- in which consumers should not use the cable OTC drug monograph or approved product until a doctor is consulted. drug application. (v) ‘‘Ask a doctor or pharmacist be- (7) ‘‘Other information’’, followed by fore use if you are’’ [in bold type] or, additional information that is not infor products labeled only for use in cluded under paragraphs (c)(2) through children under 12 years of age, ‘‘Ask a (c)(6), (c)(8), and (c)(9) of this section, doctor or pharmacist before use if the but which is required by or is made op- child is’’ [in bold type], followed by all tional under an applicable OTC drug

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00058 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.66

monograph, other OTC drug regulation, on OTC drug products in accordance or is included in the labeling of an ap- with the following specifications. In proved drug application. the interest of uniformity of presen- (i) Required information about cer- tation, FDA strongly reccommends tain ingredients in OTC drug products that the Drug Facts labeling be pre- (e.g., sodium in § 201.64(b), calcium in sented using the graphic specifications § 201.70(b), magnesium in § 201.71(b), and set forth in appendix A to part 201. potassium in § 201.72(b)) shall appear as (1) The title ‘‘Drug Facts’’ or ‘‘Drug follows: ‘‘each (insert appropriate dos- Facts (continued)’’ shall use uppercase age unit) contains:’’ [in bold type (in- letters for the first letter of the words sert name(s) of ingredient(s) (in alpha- ‘‘Drug’’ and ‘‘Facts.’’ All headings and betical order) and the quantity of each subheadings in paragraphs (c)(2) ingredient). This information shall be through (c)(9) of this section shall use the first statement under this heading. an uppercase letter for the first letter (ii) The phenylalanine/aspartame in the first word and lowercase letters content required by § 201.21(b), if applicable, shall appear as the next item of for all other words. The title, headings, information. and subheadings in paragraphs (c)(1), (iii) Additional information that is (c)(2), and (c)(4) through (c)(9) of this authorized to appear under this head- section shall be left justified. ing shall appear as the next item(s) of (2) The letter height or type size for information. There is no required order the title ‘‘Drug Facts’’ shall appear in for this subsequent information. a type size larger than the largest type (8) ‘‘Inactive ingredients’’, followed size used in the Drug Facts labeling. by a listing of the established name of The letter height or type size for the each inactive ingredient. If the product title ‘‘Drug Facts (continued)’’ shall be is an OTC drug product that is not also no smaller than 8-point type. The let- a cosmetic product, then the inactive ter height or type size for the headings ingredients shall be listed in alphabet- in paragraphs (c)(2) through (c)(9) of ical order. If the product is an OTC this section shall be the larger of ei- drug product that is also a cosmetic ther 8-point or greater type, or 2-point product, then the inactive ingredients sizes greater than the point size of the shall be listed as set forth in § 701.3(a) text. The letter height or type size for or (f) of this chapter, the names of cos- the subheadings and all other informa- metic ingredients shall be determined tion described in paragraphs (c)(2) in accordance with § 701.3(c) of this through (c)(9) of this section shall be chapter, and the provisions in § 701.3(e), no smaller than 6-point type. (g), (h), (l), (m), (n), and (o) of this (3) The title, heading, subheadings, chapter and § 720.8 of this chapter may and information in paragraphs (c)(1) also apply, as appropriate. If there is a through (c)(9) of this section shall be difference in the labeling provisions in legible and clearly presented, shall this § 201.66 and §§ 701.3 and 720.8 of this have at least 0.5-point leading (i.e., chapter, the labeling provisions in this space between two lines of text), and § 201.66 shall be used. (9) ‘‘Questions?’’ or ‘‘Questions or shall not have letters that touch. The comments?’’, followed by the telephone type style for the title, headings, sub- number of a source to answer questions headings, and all other required infor- about the product. It is recommended mation described in paragraphs (c)(2) that the days of the week and times of through (c)(9) of this section shall be the day when a person is available to any single, clear, easy-to-read type respond to questions also be included. style, with no more than 39 characters A graphic of a telephone or telephone per inch. The title and headings shall receiver may appear before the head- be in bold italic, and the subheadings ing. The telephone number must ap- shall be in bold type, except that the pear in a minimum 6-point bold type. word ‘‘(continued)’’ in the title ‘‘Drug (d) Format requirements. The title, Facts (continued)’’ shall be regular headings, subheadings, and information type. The type shall be all black or one set forth in paragraphs (c)(1) through color printed on a white or other con- (c)(9) of this section shall be presented trasting background, except that the

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00059 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.66 21 CFR Ch. I (4–1–19 Edition)

title and the headings may be pre- information required under paragraph sented in a single, alternative, con- (c)(3) of this section. The active ingre- trasting color unless otherwise pro- dients and purposes shall be aligned vided in an approved drug application, under the appropriate headings such OTC drug monograph (e.g., current re- that the heading and information requirements for bold print in §§ 341.76 quired under paragraph (c)(2) of this and 341.80 of this chapter), or other section shall be left justified and the OTC drug regulation (e.g., the require- heading and information required ment for a box and red letters in under paragraph (c)(3) of this section § 201.308(c)(1)). shall be right justified. If the OTC drug (4) When there is more than one product contains more than one active statement, each individual statement ingredient, the active ingredients shall listed under the headings and sub- be listed in alphabetical order. If more headings in paragraphs (c)(4) through than one active ingredient has the (c)(7) of this section shall be preceded same purpose, the purpose need not be by a solid square or solid circle bullet repeated for each active ingredient, of 5-point type size. Bullets shall be provided the information is presented presented in the same shape and color in a manner that readily associates throughout the labeling. The first each active ingredient with its purpose bulleted statement on each horizontal (i.e., through the use of brackets, dot line of text shall be either left justified leaders, or other graphical features). or separated from an appropriate head- The information described in para- ing or subheading by at least two graphs (c)(4) and (c)(6) through (c)(9) of square ‘‘ems’’ (i.e., two squares of the this section may start on the same line size of the letter ‘‘M’’). If more than as the required headings. None of the one bulleted statement is placed on the information described in paragraph same horizontal line, the end of one (c)(5) of this section shall appear on the bulleted statement shall be separated same line as the ‘‘Warning’’ or ‘‘Warn- from the beginning of the next bulleted ings’’ heading. statement by at least two square ‘‘ems’’ and the complete additional (7) Graphical images (e.g., the UPC bulleted statement(s) shall not con- symbol) and information not described tinue to the next line of text. Addi- in paragraphs (c)(1) through (c)(9) of tional bulleted statements appearing this section shall not appear in or in on each subsequent horizontal line of any way interrupt the required title, text under a heading or subheading headings, subheadings, and information shall be vertically aligned with the in paragraphs (c)(1) through (c)(9) of bulleted statements appearing on the this section. Hyphens shall not be used previous line. except to punctuate compound words. (5) The title, headings, subheadings, (8) The information described in and information set forth in para- paragraphs (c)(1) through (c)(9) of this graphs (c)(1) through (c)(9) of this sec- section shall be set off in a box or simi- tion may appear on more than one lar enclosure by the use of a barline. A panel on the outside container of the distinctive horizontal barline extend- retail package, or the immediate con- ing to each end of the ‘‘Drug Facts’’ tainer label if there is no outside con- box or similar enclosure shall provide tainer or wrapper. The continuation of separation between each of the head- the required content and format onto ings listed in paragraphs (c)(2) through multiple panels must retain the re- (c)(9) of this section. When a heading quired order and flow of headings, sub- listed in paragraphs (c)(2) through headings, and information. A visual (c)(9) of this section appears on a subse- graphic (e.g., an arrow) shall be used to quent panel immediately after the signal the continuation of the Drug ‘‘Drug Facts (continued)’’ title, a hori- Facts labeling to the next adjacent zontal hairline shall follow the title panel. and immediately precede the heading. (6) The heading and information re- A horizontal hairline extending within quired under paragraph (c)(2) of this two spaces on either side of the ‘‘Drug section shall appear immediately adja- Facts’’ box or similar enclosure shall cent and to the left of the heading and immediately follow the title and shall

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00060 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.66

immediately precede each of the sub- quired uses reflected in the applicable headings set forth in paragraph (c)(5) of monograph, as provided in § 330.1(c)(2) this section, except the subheadings in of this chapter. paragraphs (c)(5)(ii)(A) through (i) Paragraphs (d)(1), (d)(5), (d)(6), and (c)(5)(ii)(G) of this section. (d)(7) of this section shall apply. (9) The information set forth in para- (ii) Paragraph (d)(2) of this section graph (c)(6) of this section under the shall apply except that the letter heading ‘‘Directions’’ shall appear in a height or type size for the title ‘‘Drug table format when dosage directions Facts (continued)’’ shall be no smaller are provided for three or more age than 7-point type and the headings in groups or populations. The last line of paragraphs (c)(2) through (c)(9) of this the table may be the horizontal barline section shall be the larger of either 7- immediately preceding the heading of point or greater type, or 1-point size the next section of the labeling. greater than the point size of the text. (10) If the title, headings, sub- (iii) Paragraph (d)(3) of this section headings, and information in para- shall apply except that less than 0.5- graphs (c)(1) through (c)(9) of this sec- point leading may be used, provided tion, printed in accordance with the the ascenders and descenders do not specifications in paragraphs (d)(1) touch. through (d)(9) of this section, and any (iv) Paragraph (d)(4) of this section other FDA required information for shall apply except that if more than drug products, and, as appropriate, cos- one bulleted statement is placed on the metic products, other than information same horizontal line, the additional required to appear on a principle dis- bulleted statements may continue to play panel, requires more than 60 per- the next line of text, and except that cent of the total surface area available the bullets under each heading or sub- to bear labeling, then the Drug Facts heading need not be vertically aligned. labeling shall be printed in accordance (v) Paragraph (d)(8) of this section with the specifications set forth in shall apply except that the box or simi- paragraphs (d)(10)(i) through (d)(10)(v) lar enclosure required in paragraph of this section. In determining whether (d)(8) of this section may be omitted if more than 60 percent of the total sur- the Drug Facts labeling is set off from face area available to bear labeling is the rest of the labeling by use of color required, the indications for use listed contrast. under the ‘‘Use(s)’’ heading, as set (11)(i) The following labeling outlines forth in paragraph (c)(4) of this section, the various provisions in paragraphs (c) shall be limited to the minimum re- and (d) of this section:

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00061 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.66 21 CFR Ch. I (4–1–19 Edition)

(ii) The following sample label illus- trates the provisions in paragraphs (c) and (d) of this section:

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00062 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17MR99.003 Food and Drug Administration, HHS § 201.66

(iii) The following sample label illus- graph (d)(10) of this section, which per- trates the provisions in paragraphs (c) mits modifications for small packages: and (d) of this section, including para-

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00063 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17MR99.004 § 201.66 21 CFR Ch. I (4–1–19 Edition)

(iv) The following sample label illus- and (d) of this section for a drug prod- trates the provisions in paragraphs (c) uct marketed with cosmetic claims:

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00064 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17MR99.005 Food and Drug Administration, HHS § 201.66

(e) Exemptions and deferrals. FDA on drug product. Sponsors of a product its own initiative or in response to a marketed under an approved drug ap- written request from any manufac- plication shall also submit a single turer, packer, or distributor, may ex- copy of the exemption request to their empt or defer, based on the cir- application. Decisions on exemptions cumstances presented, one or more spe- and deferrals will be maintained in a cific requirements set forth in this sec- permanent file in this docket for public tion on the basis that the requirement review. Exemption and deferral re- is inapplicable, impracticable, or con- quests shall: trary to public health or safety. Re- (1) Document why a particular requests for exemptions shall be sub- quirement is inapplicable, impracti- mitted in three copies in the form of an cable, or is contrary to public health or ‘‘Application for Exemption’’ to the safety; and Food and Drug Administration, 5630 (2) Include a representation of the Fishers Lane, rm. 1061, Rockville, MD proposed labeling, including any 20852. The request shall be clearly iden- outserts, panel extensions, or other tified on the envelope as a ‘‘Request for graphical or packaging techniques in- Exemption from 21 CFR 201.66 (OTC La- tended to be used with the product. beling Format)’’ and shall be directed (f) Interchangeable terms and con- to Docket No. 98N–0337. A separate re- necting terms. The terms listed in quest shall be submitted for each OTC § 330.1(i) of this chapter may be used

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00065 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17MR99.006 § 201.70 21 CFR Ch. I (4–1–19 Edition)

interchangeably in the labeling of OTC (c) The labeling of OTC drug products drug products, provided such use does intended for oral ingestion shall con- not alter the meaning of the labeling tain the following statement under the that has been established and identi- heading ‘‘Warning’’ (or ‘‘Warnings’’ if fied in an applicable OTC drug mono- it appears with additional warning graph or by regulation. The terms list- statements) if the amount of calcium ed in § 330.1(j) of this chapter may be present in the labeled maximum daily deleted from the labeling of OTC drug dose of the product is more than 3.2 products when the labeling is revised grams: ‘‘Ask a doctor before use if you to comply with this section, provided have [in bold type] [bullet] 1 kidney such deletion does not alter the mean- stones [bullet] a calcium-restricted ing of the labeling that has been estab- diet’’. The warnings in §§ 201.64(c), lished and identified in an applicable 201.70(c), 201.71(c), and 201.72(c) may be OTC drug monograph or by regulation. combined, if applicable, provided the The terms listed in § 330.1(i) and (j) of ingredients are listed in alphabetical this chapter shall not be used to order, e.g., a calcium or sodium re- change in any way the specific title, stricted diet. headings, and subheadings required (d) Any product subject to this para- under paragraphs (c)(1) through (c)(9) graph that is not labeled as required by of this section. this paragraph and that is initially introduced or initially delivered for in- (g) Regulatory action. An OTC drug troduction into interstate commerce product that is not in compliance with after the following dates is misbranded the format and content requirements under sections 201(n) and 502(a) and (f) in this section is subject to regulatory of the Federal Food, Drug, and Cos- action. metic Act. [64 FR 13286, Mar. 17, 1999, as amended at 65 (1) As of the date of approval of the FR 8, Jan. 3, 2000; 65 FR 48904, Aug. 10, 2000; application for any single entity and 69 FR 13733, Mar. 24, 2004; 72 FR 71785, Dec. 19, combination products subject to drug 2007; 73 FR 403, Jan. 3, 2008; 74 FR 19407, Apr. marketing applications approved on or 29, 2009; 76 FR 44487, July 26, 2011] after April 23, 2004. (2) September 24, 2005, for all OTC § 201.70 Calcium labeling. drug products subject to any OTC drug (a) The labeling of over-the-counter monograph, not yet the subject of any (OTC) drug products intended for oral OTC drug monograph, or subject to ingestion shall contain the calcium drug marketing applications approved content per dosage unit (e.g., tablet, before April 23, 2004. teaspoonful) if the calcium content of a [69 FR 13733, Mar. 24, 2004] single maximum recommended dose of the product (which may be one or more § 201.71 Magnesium labeling. dosage units) is 20 milligrams or more. (a) The labeling of over-the-counter OTC drug products intended for oral in- (OTC) drug products intended for oral gestion include gum and lozenge dosage ingestion shall contain the magnesium forms, but do not include dentifrices, content per dosage unit (e.g., tablet, mouthwashes, or mouth rinses. teaspoonful) if the magnesium content (b) The calcium content shall be ex- of a single maximum recommended pressed in milligrams or grams per dos- dose of the product (which may be one age unit and shall include the total or more dosage units) is 8 milligrams amount of calcium regardless of the or more. OTC drug products intended source, i.e., from both active and inac- for oral ingestion include gum and loz- tive ingredients. If the dosage unit con- enge dosage forms, but do not include tains less than 1 gram of calcium, mil- dentifrices, mouthwashes, or mouth ligrams should be used. The calcium rinses. content per dosage unit shall be round- (b) The magnesium content shall be ed-off to the nearest 5 milligrams (or expressed in milligrams or grams per nearest tenth of a gram if over 1 gram). dosage unit and shall include the total The calcium content per dosage unit shall follow the heading ‘‘Other infor- 1 See § 201.66(b)(4) of this chapter for defini- mation’’ as stated in § 201.66(c)(7). tion of bullet symbol.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00066 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.72

amount of magnesium regardless of the of a single maximum recommended source, i.e., from both active and inac- dose of the product (which may be one tive ingredients. If the dosage unit con- or more dosage units) is 5 milligrams tains less than 1 gram of magnesium, or more. OTC drug products intended milligrams should be used. The magne- for oral ingestion include gum and loz- sium content shall be rounded-off to enge dosage forms, but do not include the nearest 5 milligrams (or nearest dentifrices, mouthwashes, or mouth tenth of a gram if over 1 gram). The rinses. magnesium content per dosage unit (b) The potassium content shall be shall follow the heading ‘‘Other infor- expressed in milligrams or grams per mation’’ as stated in § 201.66(c)(7). dosage unit and shall include the total (c) The labeling of OTC drug products amount of potassium regardless of the intended for oral ingestion shall con- source, i.e., from both active and inac- tain the following statement under the tive ingredients. If the dosage unit con- heading ‘‘Warning’’ (or ‘‘Warnings’’ if tains less than 1 gram of potassium, it appears with additional warning milligrams should be used. The potas- statements) if the amount of magnesium content shall be rounded-off to sium present in the labeled maximum the nearest 5 milligrams (or nearest daily dose of the product is more than tenth of a gram if over 1 gram). The po- 600 milligrams: ‘‘Ask a doctor before tassium content per dosage unit shall use if you have [in bold type] [bullet] 1 follow the heading ‘‘Other informa- kidney disease [bullet] a magnesium- tion’’ as stated in § 201.66(c)(7). restricted diet’’. The warnings in (c) The labeling of OTC drug products §§ 201.64(c), 201.70(c), 201.71(c), and intended for oral ingestion shall con- 201.72(c) may be combined, if applica- tain the following statement under the ble, provided the ingredients are listed heading ‘‘Warning’’ (or ‘‘Warnings’’ if in alphabetical order, e.g., a magne- it appears with additional warning sium or potassium-restricted diet. statements) if the amount of potassium (d) Any product subject to this para- present in the labeled maximum daily graph that is not labeled as required by dose of the product is more than 975 this paragraph and that is initially in- milligrams: ‘‘Ask a doctor before use if troduced or initially delivered for in- you have [in bold type] [bullet] 1 kidney troduction into interstate commerce disease [bullet] a potassium-restricted after the following dates is misbranded diet’’. The warnings in §§ 201.64(c), under sections 201(n) and 502(a) and (f) 201.70(c), 201.71(c), and 201.72(c) may be of the Federal Food, Drug, and Cos- combined, if applicable, provided the metic Act. ingredients are listed in alphabetical (1) As of the date of approval of the order, e.g., a magnesium or potassium- application for any single entity and restricted diet. combination products subject to drug (d) Any product subject to this para- marketing applications approved on or graph that is not labeled as required by after April 23, 2004. this paragraph and that is initially in- (2) September 24. 2005, for all OTC troduced or initially delivered for in- drug products subject to any OTC drug troduction into interstate commerce monograph, not yet the subject of any after the following dates is misbranded OTC drug monograph, or subject to under sections 201(n) and 502(a) and (f) drug marketing applications approved of the Federal Food, Drug, and Cos- before April 23, 2004. metic Act. [69 FR 13734, Mar. 24, 2004] (1) As of the date of approval of the application for any single entity and § 201.72 Potassium labeling. combination products subject to drug (a) The labeling of over-the-counter marketing applications approved on or (OTC) drug products intended for oral after April 23, 2004. ingestion shall contain the potassium (2) September 24, 2005, for all OTC content per dosage unit (e.g., tablet, drug products subject to any OTC drug teaspoonful) if the potassium content monograph, not yet the subject of any

1 See § 201.66(b)(4) of this chapter for defini- 1 See § 201.66(b)(4) of this chapter for definition of bullet symbol. tion of bullet symbol.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00067 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.80 21 CFR Ch. I (4–1–19 Edition)

OTC drug monograph, or subject to lites, rate or half-time of elimination, drug marketing applications approved concentration in body fluids associated before April 23, 2004. with therapeutic and/or toxic effects, [69 FR 13734, Mar. 24, 2004] degree of binding to plasma proteins, degree of uptake by a particular organ § 201.80 Specific requirements on con- or in the fetus, and passage across the tent and format of labeling for blood brain barrier. Inclusion of phar- human prescription drug and bio- macokinetic information is restricted logical products; older drugs not to that which relates to clinical use of described in § 201.56(b)(1). the drug. If the pharmacological mode Each section heading listed in of action of the drug is unknown or if § 201.56(d), if not omitted under important metabolic or pharmaco- § 201.56(d)(3), shall contain the fol- kinetic data in humans are unavail- lowing information in the following able, the labeling shall contain a state- order: ment about the lack of information. (a) Description. (1) Under this section (2) Data that demonstrate activity or heading, the labeling shall contain: effectiveness in in vitro or animal tests (i) The proprietary name and the es- and that have not been shown by ade- tablished name, if any, as defined in quate and well-controlled clinical stud- section 502(e)(2) of the act, of the drug; ies to be pertinent to clinical use may (ii) The type of dosage form and the be included under this section of the la- route of administration to which the beling only under the following cir- labeling applies; cumstances: (iii) The same qualitative and/or (i) In vitro data for anti-infective quantitative ingredient information as drugs may be included if the data are required under § 201.100(b) for labels; immediately preceded by the state- (iv) If the product is sterile, a statement ‘‘The following in vitro data are ment of that fact; available but their clinical significance (v) The pharmacological or thera- is unknown.’’ peutic class of the drug; (vi) The chemical name and struc- (ii) For other classes of drugs, in tural formula of the drug; vitro and animal data that have not (vii) If the product is radioactive, a been shown by adequate and well-con- statement of the important nuclear trolled clinical studies, as defined in physical characteristics, such as the § 314.126(b) of this chapter, to be perti- principal radiation emission data, ex- nent to clinical use may be used only if ternal radiation, and physical decay a waiver is granted under § 201.58 or characteristics. § 314.126(c) of this chapter. (2) If appropriate, other important (c) Indications and Usage. (1) Under chemical or physical information, such this section heading, the labeling shall as physical constants, or pH, shall be state that: stated. (i) The drug is indicated in the treat- (b) Clinical Pharmacology. (1) Under ment, prevention, or diagnosis of a rec- this section heading, the labeling shall ognized disease or condition, e.g., peni- contain a concise factual summary of cillin is indicated for the treatment of the clinical pharmacology and actions pneumonia due to susceptible of the drug in humans. The summary pneumococci; and/or may include information based on in (ii) The drug is indicated for the vitro and/or animal data if the infor- treatment, prevention, or diagnosis of mation is essential to a description of an important manifestation of a dis- the biochemical and/or physiological ease or condition, e.g., chlorothiazide mode of action of the drug or is other- is indicated for the treatment of edema wise pertinent to human therapeutics. in patients with congestive heart fail- Pharmacokinetic information that is ure; and/or important to safe and effective use of (iii) The drug is indicated for the re- the drug is required, if known, e.g., de- lief of symptoms associated with a dis- gree and rate of absorption, pathways ease or syndrome, e.g., of biotransformation, percentage of chlorpheniramine is indicated for the dose as unchanged drug and metabo- symptomatic relief of nasal congestion

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00068 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.80

in patients with vasomotor rhinitis; (ii) If safety considerations are such and/or that the drug should be reserved for (iv) The drug, if used for a particular certain situations, e.g., cases refrac- indication only in conjuction with a tory to other drugs, this information primary mode of therapy, e.g., diet, shall be stated in this section. surgery, or some other drug, is an ad- (iii) If there are specific conditions junct to the mode of therapy. that should be met before the drug is (2)(i) For drug products other than used on a long-term basis, e.g., dem- biological products, all indications list- onstration of responsiveness to the ed in this section must be supported by drug in a short-term trial, the labeling substantial evidence of effectiveness shall identify the conditions; or, if the based on adequate and well-controlled indications for long-term use are dif- studies as defined in § 314.126(b) of this ferent from those for short-term use, chapter unless the requirement is the labeling shall identify the specific waived under § 201.58 or § 314.126(c) of indications for each use. this chapter. Indications or uses must (iv) If there is a common belief that not be implied or suggested in other the drug may be effective for a certain sections of labeling if not included in use or if there is a common use of the this section. drug for a condition, but the prepon- (ii) For biological products, all indi- derance of evidence related to the use or condition shows that the drug is in- cations listed in this section must be effective, the Food and Drug Adminis- supported by substantial evidence of ef- tration may require that the labeling fectiveness. Indications or uses must state that there is a lack of evidence not be implied or suggested in other that the drug is effective for that use sections of labeling if not included in or condition. this section. (v) Any statements comparing the (3) This section of the labeling shall safety or effectiveness, either greater also contain the following additional or less, of the drug with other agents information: for the same indication shall be sup- (i) If evidence is available to support ported by adequate and well-controlled the safety and effectiveness of the drug studies as defined in § 314.126(b) of this only in selected subgroups of the larger chapter unless this requirement is population with a disease, syndrome, waived under § 201.58 or § 314.126(c) of or symptom under consideration, e.g., this chapter. patients with mild disease or patients (d) Contraindications. Under this sec- in a special age group, the labeling tion heading, the labeling shall de- shall describe the available evidence scribe those situations in which the and state the limitations of usefulness drug should not be used because the of the drug. The labeling shall also risk of use clearly outweighs any pos- identify specific tests needed for selec- sible benefit. These situations include tion or monitoring of the patients who administration of the drug to patients need the drug, e.g., microbe suscepti- known to have a hypersensitivity to it; bility tests. Information on the approx- use of the drug in patients who, be- imate kind, degree, and duration of im- cause of their particular age, sex, con- provement to be anticipated shall be comitant therapy, disease state, or stated if available and shall be based other condition, have a substantial on substantial evidence derived from risk of being harmed by it; or contin- adequate and well-controlled studies as ued use of the drug in the face of an un- defined in § 314.126(b) of this chapter acceptably hazardous adverse reaction. unless the requirement is waived under Known hazards and not theoretical pos- § 201.58 or § 314.126(c) of this chapter. If sibilities shall be listed, e.g., if hyper- the information is relevant to the rec- sensitivity to the drug has not been ommended intervals between doses, the demonstrated, it should not be listed as usual duration of treatment, or any a contraindication. If no contraindica- modification of dosage, it shall be stat- tions are known, this section of the la- ed in the ‘‘Dosage and Administration’’ beling shall state ‘‘None known.’’ section of the labeling and referenced (e) Warnings. Under this section head- in this section. ing, the labeling shall describe serious

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00069 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.80 21 CFR Ch. I (4–1–19 Edition)

adverse reactions and potential safety of such patient labeling must be re- hazards, limitations in use imposed by printed immediately following the last them, and steps that should be taken if section of labeling or, alternatively, they occur. The labeling shall be re- accompany the prescription drug label- vised to include a warning as soon as ing. The type size requirement for the there is reasonable evidence of an asso- Medication Guide set forth in § 208.20 of ciation of a serious hazard with a drug; this chapter does not apply to the a causal relationship need not have Medication Guide that is reprinted in been proved. A specific warning relat- or accompanying the prescription drug ing to a use not provided for under the labeling unless such Medication Guide ‘‘Indications and Usage’’ section of the is to be detached and distributed to pa- labeling may be required by the Food tients in compliance with § 208.24 of and Drug Administration if the drug is this chapter. commonly prescribed for a disease or (3) Laboratory tests. This subsection of condition, and there is lack of substan- the labeling shall identify any labora- tial evidence of effectivenes for that tory tests that may be helpful in fol- disease or condition, and such usage is lowing the patient’s response or in associated with serious risk or hazard. identifying possible adverse reactions. Special problems, particularly those If appropriate, information shall be that may lead to death or serious in- provided on such factors as the range jury, may be required by the Food and of normal and abnormal values ex- Drug Administration to be placed in a pected in the particular situation and prominently displayed box. The boxed the recommended frequency with warning ordinarily shall be based on which tests should be done before, dur- clinical data, but serious animal tox- ing, and after therapy. icity may also be the basis of a boxed warning in the absence of clinical data. (4)(i) Drug interactions. This sub- If a boxed warning is required, its loca- section of the labeling shall contain tion will be specified by the Food and specific practical guidance for the phy- Drug Administration. The frequency of sician on preventing clinically signifi- these serious adverse reactions and, if cant drug/drug and drug/food inter- known, the approximate mortality and actions that may occur in vivo in pa- morbidity rates for patients sustaining tients taking the drug. Specific drugs the reaction, which are important to or classes of drugs with which the drug safe and effective use of the drug, shall to which the labeling applies may be expressed as provided under the interact in vivo shall be identified, and ‘‘Adverse Reactions’’ section of the la- the mechanism(s) of the interaction beling. shall be briefly described. Information (f) Precautions. Under this section in this subsection of the labeling shall heading, the labeling shall contain the be limited to that pertaining to clin- following subsections as appropriate ical use of the drug in patients. Drug for the drug: interactions supported only by animal (1) General. This subsection of the la- or in vitro experiments may not ordi- beling shall contain information re- narily be included, but animal or in garding any special care to be exer- vitro data may be used if shown to be cised by the practitioner for safe and clinically relevant. Drug incompati- effective use of the drug, e.g., pre- bilities, i.e., drug interactions that cautions not required under any other may occur when drugs are mixed in specific section or subsection of the la- vitro, as in a solution for intravenous beling. administration, shall be discussed (2) Information for patients. This sub- under the ‘‘Dosage and Administra- section must contain information nec- tion’’ section of the labeling rather essary for patients to use the drug safe- than under this subsection of the label- ly and effectively (e.g., precautions ing. concerning driving or the concomitant (ii) Drug/laboratory test interactions. use of other substances that may have This subsection of the labeling shall harmful additive effects). Any FDA-ap- contain practical guidance on known proved patient labeling must be ref- interference of the drug with labora- erenced in this section and the full text tory tests.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00070 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.80

(5) Carcinogenesis, mutagenesis, impair- demonstrate a risk to the fetus, the la- ment of fertility. This subsection of the beling shall also state: ‘‘Reproduction labeling shall state whether long-term studies have been performed in (kinds studies in animals have been performed of animal(s)) at doses up to (x) times the to evaluate carcinogenic potential and, human dose and have revealed no evi- if so, the species and results. If repro- dence of impaired fertility or harm to duction studies or other data in ani- the fetus due to (name of drug).’’ The mals reveal a problem or potential labeling shall also contain a descrip- problem concerning mutagenesis or im- tion of available data on the effect of pairment of fertility in either males or the drug on the later growth, develop- females, the information shall be de- ment, and functional maturation of the scribed. Any precautionary statement child. on these topics shall include practical, (b) If animal reproduction studies relevant advice to the physician on the have failed to demonstrate a risk to significance of these animal findings. If the fetus and there are no adequate and there is evidence from human data that well-controlled studies in pregnant the drug may be carcinogenic or muta- women, the labeling shall state: ‘‘ Re- genic or that it impairs fertility, this production studies have been per- information shall be included under the formed in (kind(s) of animal(s)) at doses ‘‘Warnings’’ section of the labeling. up to (x) times the human dose and Also, under ‘‘Precautions,’’ the label- have revealed no evidence of impaired ing shall state: ‘‘See ‘Warnings’ section fertility or harm to the fetus due to for information on carcinogenesis, ( ). There are, however, no mutagenesis, and impairment of fer- name of drug tility.’’ adequate and well-controlled studies in (6) Pregnancy. This subsection of the pregnant women. Because animal relabeling may be omitted only if the production studies are not always pre- drug is not absorbed systemically and dictive of human response, this drug the drug is not known to have a poten- should be used during pregnancy only tial for indirect harm to the fetus. For if clearly needed.’’ If animal reproduc- all other drugs, this subsection of the tion studies have shown an adverse ef- labeling shall contain the following in- fect (other than decrease in fertility), formation: but adequate and well-controlled stud- (i) Teratogenic effects. Under this ies in pregnant women have failed to heading the labeling shall identify one demonstrate a risk to the fetus during of the following categories that applies the first trimester of pregnancy (and to the drug, and the labeling shall bear there is no evidence of a risk in later the statement required under the cat- trimesters), the labeling shall state: egory: ‘‘Reproduction studies in (kind(s) of (a) If adequate and well-controlled animal(s)) have shown (describe findings) studies in pregnant women have failed at (x) times the human dose. Studies in to demonstrate a risk to the fetus in pregnant women, however, have not the first trimester of pregnancy (and shown that (name of drug) increases the there is no evidence of a risk in later risk of abnormalities when adminis- trimesters), the labeling shall state: tered during the first (second, third, or ‘‘Studies in pregnant women have not all) trimester(s) of pregnancy. Despite shown that (name of drug) increases the the animal findings, it would appear risk of fetal abnormalities if adminis- that the possibility of fetal harm is re- tered during the first (second, third, or mote, if the drug is used during preg- all) trimester(s) of pregnancy. If this nancy. Nevertheless, because the stud- drug is used during pregnancy, the pos- ies in humans cannot rule out the possibility of fetal harm appears remote. sibility of harm, (name of drug) should Because studies cannot rule out the be used during pregnancy only if clear- possibility of harm, however, (name of ly needed.’’ The labeling shall also con- drug) should be used during pregnancy tain a description of the human studies only if clearly needed.’’ The labeling and a description of available data on shall also contain a description of the the effect of the drug on the later human studies. If animal reproduction growth, development, and functional studies are available and they fail to maturation of the child.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00071 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.80 21 CFR Ch. I (4–1–19 Edition)

(c) If animal reproduction studies risk based on adverse reaction reports have shown an adverse effect on the from investigational or marketing ex- fetus, if there are no adequate and perience, or both, and the risk of the well-controlled studies in humans, and use of the drug in a pregnant woman if the benefits from the use of the drug clearly outweighs any possible benefit in pregnant women may be acceptable (for example, safer drugs or other despite its potential risks, the labeling forms of therapy are available), the la- shall state: ‘‘ (Name of drug) has been beling shall state: ‘‘ See ‘Contraindica- shown to be teratogenic (or to have an tions’ section.’’ Under ‘‘Contraindica- embryocidal effect or other adverse ef- tions,’’ the labeling shall state: ‘‘(Name fect) in (name(s) of species) when given of drug) may (can) cause fetal harm in doses (x) times the human dose. when administered to a pregnant There are no adequate and well-con- woman. (Describe the human data and trolled studies in pregnant women. any pertinant animal data.) (Name of (Name of drug) should be used during drug) is contraindicated in women who pregnancy only if the potential benefit are or may become pregnant. If this justifies the potential risk to the drug is used during pregnancy, or if the fetus.’’ The labeling shall contain a de- patient becomes pregnant while taking scription of the animal studies. If there this drug, the patient should be ap- are no animal reproduction studies and prised of the potential hazard to the no adequate and well-controlled studies fetus.’’ in humans, the labeling shall state: (ii) Nonteratogenic effects. Under this ‘‘Animal reproduction studies have not heading the labeling shall contain been conducted with (name of drug). It other information on the drug’s effects is also not known whether (name of on reproduction and the drug’s use dur- drug) can cause fetal harm when ad- ing pregnancy that is not required spe- ministered to a pregnant woman or can cifically by one of the pregnancy cat- affect reproduction capacity. (Name of egories, if the information is relevant drug) should be given to a pregnant to the safe and effective use of the woman only if clearly needed.’’ The la- drug. Information required under this beling shall contain a description of heading shall include nonteratogenic any available data on the effect of the drug on the later growth, development, effects in the fetus or newborn infant and functional maturation of the child. (for example, withdrawal symptoms or (d) If there is positive evidence of hypoglycemia) that may occur because human fetal risk based on adverse reac- of a pregnant woman’s chronic use of tion data from investigational or mar- the drug for a preexisting condition or keting experience or studies in hu- disease. mans, but the potential benefits from (7) Labor and delivery. If the drug has the use of the drug in pregnant women a recognized use during labor or deliv- may be acceptable despite its potential ery (vaginal or abdominal delivery), risks (for example, if the drug is needed whether or not the use is stated in the in a life-threatening situation or seri- indications section of the labeling, this ous disease for which safer drugs can- subsection of the labeling shall de- not be used or are ineffective), the la- scribe the available information about beling shall state: ‘‘ See ‘Warnings’ sec- the effect of the drug on the mother tion.’’ Under the ‘‘Warnings’’ section, and the fetus, on the duration of labor the labeling states: ‘‘(Name of drug) can or delivery, on the possibility that for- cause fetal harm when administered to ceps delivery or other intervention or a pregnant woman. (Describe the human resuscitation of the newborn will be data and any pertinent animal data.) If necessary, and the effect of the drug on this drug is used during pregnancy, or the later growth, development, and if the patient becomes pregnant while functional maturation of the child. If taking this drug, the patient should be any information required under this apprised of the potential hazard to the subsection is unknown, this subsection fetus.’’ of the labeling shall state that the in- (e) If studies in animals or humans formation is unknown. have demonstrated fetal abnormalities (8) Nursing mothers. (i) If a drug is ab- or if there is positive evidence of fetal sorbed systemically, this subsection of

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00072 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.80

the labeling shall contain, if known, in- cised when (name of drug) is adminis- formation about excretion of the drug tered to a nursing woman.’’ in human milk and effects on the nurs- (9) Pediatric use. (i) Pediatric popu- ing infant. Pertinent adverse effects lation(s)/pediatric patient(s): For the observed in animal offspring shall be purposes of paragraphs (f)(9)(ii) described. through (f)(9)(viii) of this section, the (ii) If a drug is absorbed systemically terms pediatric population(s) and pedi- and is known to be excreted in human atric patient(s) are defined as the pedi- milk, this subsection of the labeling atric age group, from birth to 16 years, shall contain one of the following including age groups often called neo- statements, as appropriate. If the drug nates, infants, children, and adoles- is associated with serious adverse reac- cents. tions or if the drug has a known (ii) If there is a specific pediatric in- tumorigenic potential, the labeling dication (i.e., an indication different shall state: ‘‘Because of the potential from those approved for adults) that is for serious adverse reactions in nursing supported by adequate and well-con- infants from (name of drug) (or, ‘‘Be- trolled studies in the pediatric popu- cause of the potential for lation, it shall be described under the ‘‘Indications and Usage’’ section of the tumorigenicity shown for (name of labeling, and appropriate pediatric dos- drug) in (animal or human) studies), a age information shall be given under decision should be made whether to the ‘‘Dosage and Administration’’ sec- discontinue nursing or to discontinue tion of the labeling. The ‘‘Pediatric the drug, taking into account the im- use’’ subsection shall cite any limita- portance of the drug to the mother.’’ If tions on the pediatric indication, need the drug is not associated with serious for specific monitoring, specific haz- adverse reactions and does not have a ards associated with use of the drug in known tumorigenic potential, the la- any subsets of the pediatric population beling shall state: ‘‘Caution should be (e.g., neonates), differences between pe- exercised when (name of drug) is admin- diatric and adult responses to the drug, istered to a nursing woman.’’ and other information related to the (iii) If a drug is absorbed system- safe and effective pediatric use of the ically and information on excretion in drug. Data summarized in this sub- human milk is unknown, this subsection of the labeling should be dis- section of the labeling shall contain cussed in more detail, if appropriate, one of the following statements, as ap- under the ‘‘Clinical Pharmacology’’ or propriate. If the drug is associated with ‘‘Clinical Studies’’ section. As appro- serious adverse reactions or has a priate, this information shall also be known tumorigenic potential, the la- contained in the ‘‘Contraindications,’’ beling shall state: ‘‘It is not known ‘‘Warnings,’’ and elsewhere in the whether this drug is excreted in human ‘‘Precautions’’ sections. milk. Because many drugs are excreted (iii) If there are specific statements in human milk and because of the po- on pediatric use of the drug for an indi- tential for serious adverse reactions in cation also approved for adults that are nursing infants from (name of drug) (or, based on adequate and well-controlled ‘‘Because of the potential for studies in the pediatric population, tumorigenicity shown for (name of they shall be summarized in the ‘‘Pe- drug) in (animal or human) studies), a diatric use’’ subsection of the labeling decision should be made whether to and discussed in more detail, if appro- discontinue nursing or to discontinue priate, under the ‘‘Clinical Pharma- the drug, taking into account the im- cology’’ and ‘‘Clinical Studies’’ sec- portance of the drug to the mother.’’ If tions. Appropriate pediatric dosage the drug is not associated with serious shall be given under the ‘‘Dosage and adverse reactions and does not have a Administration’’ section of the label- known tumorigenic potential, the la- ing. The ‘‘Pediatric use’’ subsection of beling shall state: ‘‘It is not known the labeling shall also cite any limita- whether this drug is excreted in human tions on the pediatric use statement, milk. Because many drugs are excreted need for specific monitoring, specific in human milk, caution should be exer- hazards associated with use of the drug

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00073 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.80 21 CFR Ch. I (4–1–19 Edition)

in any subsets of the pediatric popu- be discussed in more detail, if appro- lation (e.g., neonates), differences be- priate, under the ‘‘Clinical Pharma- tween pediatric and adult responses to cology’’ or the ‘‘Clinical Studies’’ sec- the drug, and other information related tion. For example, pediatric pharmaco- to the safe and effective pediatric use kinetic or pharmacodynamic studies of the drug. As appropriate, this infor- and dose-response information should mation shall also be contained in the be described in the ‘‘Clinical Pharma- ‘‘Contraindications,’’ ‘‘Warnings,’’ and cology’’ section. Pediatric dosing in- elsewhere in the ‘‘Precautions’’ sec- structions shall be included in the tions. ‘‘Dosage and Administration’’ section (iv) FDA may approve a drug for pe- of the labeling. Any differences be- diatric use based on adequate and well- tween pediatric and adult responses, controlled studies in adults, with other need for specific monitoring, dosing ad- information supporting pediatric use. justments, and any other information In such cases, the agency will have related to safe and effective use of the concluded that the course of the dis- drug in pediatric patients shall be cited ease and the effects of the drug, both briefly in the ‘‘Pediatric use’’ sub- beneficial and adverse, are sufficiently section and, as appropriate, in the similar in the pediatric and adult popu- ‘‘Contraindications,’’ ‘‘Warnings,’’ lations to permit extrapolation from ‘‘Precautions,’’ and ‘‘Dosage and Ad- the adult efficacy data to pediatric pa- ministration’’ sections. tients. The additional information sup- (v) If the requirements for a finding porting pediatric use must ordinarily of substantial evidence to support a pe- include data on the pharmacokinetics diatric indication or a pediatric use of the drug in the pediatric population statement have not been met for a par- for determination of appropriate dos- ticular pediatric population, the ‘‘Pe- age. Other information, such as data diatric use’’ subsection of the labeling from pharmacodynamic studies of the shall contain an appropriate statement drug in the pediatric population, data such as ‘‘Safety and effectiveness in pe- from other studies supporting the safe- diatric patients below the age of (l) ty or effectiveness of the drug in pedi- have not been established.’’ If use of atric patients, pertinent premarketing the drug in this pediatric population is or postmarketing studies or experi- associated with a specific hazard, the ence, may be necessary to show that hazard shall be described in this sub- the drug can be used safely and effec- section of the labeling, or, if appro- tively in pediatric patients. When a priate, the hazard shall be stated in the drug is approved for pediatric use based ‘‘Contraindications’’ or ‘‘Warnings’’ on adequate and well-controlled studies section of the labeling and this sub- in adults with other information sup- section shall refer to it. porting pediatric use, the ‘‘Pediatric (vi) If the requirements for a finding use’’ subsection of the labeling shall of substantial evidence to support a pe- contain either the following statement, diatric indication or a pediatric use or a reasonable alternative: ‘‘The safe- statement have not been met for any ty and effectiveness of (drug name) have pediatric population, this subsection of been established in the age groups l to the labeling shall contain the following l (note any limitations, e.g., no data statement: ‘‘Safety and effectiveness in for pediatric patients under 2, or only pediatric patients have not been estab- applicable to certain indications ap- lished.’’ If use of the drug in premature proved in adults). Use of (drug name) in or neonatal infants, or other pediatric these age groups is supported by evi- subgroups, is associated with a specific dence from adequate and well-con- hazard, the hazard shall be described in trolled studies of (drug name) in adults this subsection of the labeling, or, if with additional data (insert wording appropriate, the hazard shall be stated that accurately describes the data sub- in the ‘‘Contraindications’’ or ‘‘Warn- mitted to support a finding of substan- ings’’ section of the labeling and this tial evidence of effectiveness in the pe- subsection shall refer to it. diatric population).’’ Data summarized (vii) If the sponsor believes that none in the preceding prescribed statement of the statements described in para- in this subsection of the labeling shall graphs (f)(9)(ii) through (f)(9)(vi) of this

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00074 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.80

section is appropriate or relevant to that are available to the sponsor and the labeling of a particular drug, the pertinent information from well-docu- sponsor shall provide reasons for omis- mented studies obtained from a lit- sion of the statements and may pro- erature search. Controlled studies in- pose alternative statement(s). FDA clude those that are part of the mar- may permit use of an alternative state- keting application and other relevant ment if FDA determines that no state- studies available to the sponsor that ment described in those paragraphs is have not been previously submitted in appropriate or relevant to the drug’s the investigational new drug applica- labeling and that the alternative state- tion, new drug application, biological ment is accurate and appropriate. license application, or a supplement or (viii) If the drug product contains one amendment to one of these applica- or more inactive ingredients that tions (e.g., postmarketing studies or present an increased risk of toxic ef- adverse drug reaction reports). The fects to neonates or other pediatric ‘‘Geriatric use’’ subsection shall con- subgroups, a special note of this risk tain the following statement(s) or rea- shall be made, generally in the ‘‘Con- sonable alternative, as applicable, tak- traindications,’’ ‘‘Warnings,’’ or ‘‘Pre- ing into account available information: cautions’’ section. (A) If clinical studies did not include (10) Geriatric use. (i) A specific geri- sufficient numbers of subjects aged 65 atric indication, if any, that is sup- and over to determine whether elderly ported by adequate and well-controlled subjects respond differently from studies in the geriatric population younger subjects, and other reported shall be described under the ‘‘Indica- clinical experience has not identified tions and Usage’’ section of the label- such differences, the ‘‘Geriatric use’’ ing, and appropriate geriatric dosage subsection shall include the following shall be stated under the ‘‘Dosage and statement: Administration’’ section of the label- ‘‘Clinical studies of (name of drug) did not ing. The ‘‘Geriatric use’’ subsection include sufficient numbers of subjects aged shall cite any limitations on the geri- 65 and over to determine whether they re- atric indication, need for specific moni- spond differently from younger subjects. toring, specific hazards associated with Other reported clinical experience has not identified differences in responses between the geriatric indication, and other in- the elderly and younger patients. In general, formation related to the safe and effec- dose selection for an elderly patient should tive use of the drug in the geriatric be cautious, usually starting at the low end population. Unless otherwise noted, in- of the dosing range, reflecting the greater formation contained in the ‘‘Geriatric frequency of decreased hepatic, renal, or car- use’’ subsection of the labeling shall diac function, and of concomitant disease or pertain to use of the drug in persons 65 other drug therapy.’’ years of age and older. Data summa- (B) If clinical studies (including stud- rized in this subsection of the labeling ies that are part of marketing applica- shall be discussed in more detail, if ap- tions and other relevant studies avail- propriate, under ‘‘Clinical Pharma- able to the sponsor that have not been cology’’ or the ‘‘Clinical Studies’’ sec- submitted in the sponsor’s application. As appropriate, this information tions) included enough elderly subjects shall also be contained in ‘‘Contra- to make it likely that differences in indications,’’ ‘‘Warnings,’’ and else- safety or effectiveness between elderly where in ‘‘Precautions.’’ and younger subjects would have been (ii) Specific statements on geriatric detected, but no such differences (in use of the drug for an indication ap- safety or effectiveness) were observed, proved for adults generally, as distin- and other reported clinical experience guished from a specific geriatric indi- has not identified such differences, the cation, shall be contained in the ‘‘Geriatric use’’ subsection shall con- ‘‘Geriatric use’’ subsection and shall tain the following statement: reflect all information available to the Of the total number of subjects in clinical sponsor that is relevant to the appro- studies of (name of drug), l percent were 65 priate use of the drug in elderly pa- and over, while l percent were 75 and over. tients. This information includes de- (Alternatively, the labeling may state the tailed results from controlled studies total number of subjects included in the

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00075 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.80 21 CFR Ch. I (4–1–19 Edition)

studies who were 65 and over and 75 and of the labeling, and the ‘‘Geriatric use’’ over.) No overall differences in safety or ef- subsection shall refer to those sections. fectiveness were observed between these sub- (v) Labeling under paragraphs jects and younger subjects, and other reported clinical experience has not identified (f)(10)(i) through (f)(10)(iii) of this sec- differences in responses between the elderly tion may include statements, if they and younger patients, but greater sensitivity would be useful in enhancing safe use of some older individuals cannot be ruled of the drug, that reflect good clinical out. practice or past experience in a particular situation, e.g., for a sedating (C) If evidence from clinical studies drug, it could be stated that: and other reported clinical experience available to the sponsor indicates that ‘‘Sedating drugs may cause confusion and use of the drug in elderly patients is over-sedation in the elderly; elderly patients associated with differences in safety or generally should be started on low doses of effectiveness, or requires specific moni- (name of drug) and observed closely.’’ toring or dosage adjustment, the (vi) If the sponsor believes that none ‘‘Geriatric use’’ subsection of the label- of the requirements described in para- ing shall contain a brief description of graphs (f)(10)(i) through (f)(10)(v) of observed differences or specific moni- this section is appropriate or relevant toring or dosage requirements and, as to the labeling of a particular drug, the appropriate, shall refer to more de- sponsor shall provide reasons for omis- tailed discussions in the ‘‘Contra- sion of the statements and may pro- indications,’’ ‘‘Warnings,’’ ‘‘Dosage and pose an alternative statement. FDA Administration,’’ or other sections of may permit omission of the statements the labeling. if FDA determines that no statement (iii)(A) If specific pharmacokinetic or described in those paragraphs is appro- pharmacodynamic studies have been priate or relevant to the drug’s label- carried out in the elderly, they shall be ing. FDA may permit use of an alter- described briefly in the ‘‘Geriatric use’’ native statement if the agency deter- subsection of the labeling and in detail mines that such statement is accurate under the ‘‘Clinical Pharmacology’’ and appropriate. section. The ‘‘Clinical Pharmacology’’ (g) Adverse Reactions. An adverse re- section and ‘‘Drug interactions’’ sub- action is an undesirable effect, reason- section of the ‘‘Precautions’’ section ably associated with the use of the ordinarily contain information on drug, that may occur as part of the drug-disease and drug-drug inter- pharmacological action of the drug or actions that is particularly relevant to may be unpredictable in its occurrence. the elderly, who are more likely to (1) This section of the labeling shall have concomitant illness and to utilize list the adverse reactions that occur concomitant drugs. with the drug and with drugs in the (B) If a drug is known to be substan- same pharmacologically active and tially excreted by the kidney, the chemically related class, if applicable. ‘‘Geriatric use’’ subsection shall in- (2) In this listing, adverse reactions clude the statement: may be categorized by organ system, ‘‘This drug is known to be substantially ex- by severity of the reaction, by fre- creted by the kidney, and the risk of toxic quency, or by toxicological mecha- reactions to this drug may be greater in pa- nism, or by a combination of these, as tients with impaired renal function. Because appropriate. If frequency information elderly patients are more likely to have de- from adequate clinical studies is avail- creased renal function, care should be taken able, the categories and the adverse re- in dose selection, and it may be useful to actions within each category shall be monitor renal function.’’ listed in decreasing order of frequency. (iv) If use of the drug in the elderly An adverse reaction that is signifi- appears to cause a specific hazard, the cantly more severe than the other re- hazard shall be described in the ‘‘Geri- actions listed in a category, however, atric use’’ subsection of the labeling, shall be listed before those reactions, or, if appropriate, the hazard shall be regardless of its frequency. If frequency stated in the ‘‘Contraindications,’’ information from adequate clinical ‘‘Warnings,’’ or ‘‘Precautions’’ section studies is not available, the categories

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00076 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.80

and adverse reactions within each cat- logical and physical dependence that egory shall be listed in decreasing occur with the drug and shall identify order of severity. The approximate fre- the quantity of the drug over a period quency of each adverse reaction shall of time that may lead to tolerance or be expressed in rough estimates or or- dependence, or both. Details shall be ders of magnitude essentially as fol- provided on the adverse effects of lows: ‘‘The most frequent adverse reac- chronic abuse and the effects of abrupt tion(s) to (name of drug) is (are) (list re- withdrawal. Procedures necessary to actions). This (these) occur(s) in about diagnose the dependent state shall be (e.g., one-third of patients; one in 30 provided, and the principles of treating patients; less than one-tenth of pa- the effects of abrupt withdrawal shall tients). Less frequent adverse reactions be described. are (list reactions), which occur in ap- (i) Overdosage. Under this section proximately (e.g., one in 100 patients). heading, the labeling shall describe the Other adverse reactions, which occur signs, symptoms, and laboratory find- rarely, in approximately (e.g., one in ings of acute overdosage and the gen- 1,000 patients), are (list reactions).’’ Per- eral principles of treatment. This sec- cent figures may not ordinarily be used tion shall be based on human data, unless they are documented by ade- when available. If human data are un- quate and well-controlled studies as de- available, appropriate animal and in fined in § 314.126(b) of this chapter, they vitro data may be used. Specific infor- are shown to reflect general experi- mation shall be provided about the fol- ence, and they do not falsely imply a lowing: greater degree of accuracy than actu- (1) Signs, symptoms, and laboratory ally exists. findings associated with an overdosage (3) The ‘‘Warnings’’ section of the la- of the drug. beling or, if appropriate, the ‘‘Contra- (2) Complications that can occur with indications’’ section of the labeling the drug (for example, organ toxicity shall identify any potentially fatal ad- or delayed acidosis). verse reaction. (4) Any claim comparing the drug to (3) Oral LD50 of the drug in animals; which the labeling applies with other concentrations of the drug in biologic drugs in terms of frequency, severity, fluids associated with toxicity and/or or character of adverse reactions shall death; physiologic variables influ- be based on adequate and well-con- encing excretion of the drug, such as trolled studies as defined in § 314.126(b) urine pH; and factors that influence of this chapter unless this requirement the dose response relationship of the is waived under § 201.58 or § 314.126(c) of drug, such as tolerance. The pharmaco- this chapter. kinetic data given in the ‘‘Clinical (h) Drug Abuse and Dependence. Under Pharmacology’’ section also may be this section heading, the labeling shall referenced here, if applicable to contain the following subsections, as overdoses. appropriate for the drug: (4) The amount of the drug in a single (1) Controlled Substance. If the drug is dose that is ordinarily associated with controlled by the Drug Enforcement symptoms of overdosage and the Administration, the schedule in which amount of the drug in a single dose it is controlled shall be stated. that is likely to be life-threatening. (2) Abuse. This subsection of the la- (5) Whether the drug is dialyzable. beling shall be based primarily on (6) Recommended general treatment human data and human experience, but procedures and specific measures for pertinent animal data may also be support of vital functions, such as used. This subsection shall state the proven antidotes, gastric lavage, and types of abuse that can occur with the forced diuresis. Unqualified rec- drug and the adverse reactions perti- ommendations for which data are lack- nent to them. Particularly susceptible ing with the specific drug or class of patient populations shall be identified. drugs, especially treatment using an- (3) Dependence. This subsection of the other drug (for example, central nerv- labeling shall describe characteristic ous system stimulants, respiratory effects resulting from both psycho- stimulants) may not be stated unless

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00077 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.80 21 CFR Ch. I (4–1–19 Edition)

specific data or scientific rationale ex- is used, a statement of the strength is ists to support safe and effective use. placed in parentheses after the metric (j) Dosage and Administration. This designation; section of the labeling shall state the (2) The units in which the dosage recommended usual dose, the usual form is ordinarily available for pre- dosage range, and, if appropriate, an scribing by practitioners, e.g., bottles upper limit beyond which safety and ef- of 100; fectiveness have not been established; (3) Appropriate information to facili- dosages shall be stated for each indica- tate identification of the dosage forms, tion when appropriate. Dosing regi- such as shape, color, coating, scoring, mens must not be implied or suggested and National Drug Code; and in other sections of labeling if not in- (4) Special handling and storage concluded in this section. This section ditions. shall also state the intervals rec- (l) Animal Pharmacology and/or Animal ommended between doses, the optimal Toxicology. In most cases, the labeling method of titrating dosage, the usual need not include this section. Signifi- duration of treatment, and any modi- cant animal data necessary for safe and fication of dosage needed in special pa- effective use of the drug in humans tient populations, e.g., in children, in shall ordinarily be included in one or geriatric age groups, or in patients more of the other sections of the label- with renal or hepatic disease. Specific ing, as appropriate. Commonly for a tables or monographs may be included drug that has been marketed for a long to clarify dosage schedules. Radiation time, and in rare cases for a new drug, dosimetry information shall be stated chronic animal toxicity studies have for both the patient receiving a radio- not been performed or completed for a active drug and the person admin- drug that is administered over pro- istering it. This section shall also con- longed periods or is implanted in the tain specific direction on dilution, body. The unavailability of such data preparation (including the strength of shall be stated in the appropriate sec- the final dosage solution, when pre- tion of the labeling for the drug. If the pared according to instructions, in pertinent animal data cannot be appro- terms of milligrams active ingredient priately incorporated into other sec- per milliliter of reconstituted solution, tions of the labeling, this section may unless another measure of the strength be used. is more appropriate), and administra- (m) ‘‘Clinical Studies’’ and ‘‘Ref- tion of the dosage form, if needed, e.g., erences’’. These sections may appear in the rate of administration of paren- labeling in the place of a detailed dis- teral drug in milligrams per minute; cussion of a subject that is of limited storage conditions for stability of the interest but nonetheless important. A drug or reconstituted drug, when im- reference to a specific important clin- portant; essential information on drug ical study may be made in any section incompatibilities if the drug is mixed of the format required under §§ 201.56 in vitro with other drugs; and the fol- and 201.57 if the study is essential to an lowing statement for parenterals: understandable presentation of the ‘‘Parenteral drug products should be available information. References may inspected visually for particulate mat- appear in sections of the labeling for- ter and discoloration prior to adminis- mat, other than the ‘‘Clinical Studies’’ tration, whenever solution and con- or ‘‘References’’ section, in rare cir- tainer permit.’’ cumstances only. A clinical study or (k) How Supplied. This section of the reference may be cited in prescription labeling shall contain information on drug labeling only under the following the available dosage forms to which conditions: the labeling applies and for which the (1)(i) If the clinical study is cited in manufacturer or distributor is respon- the labeling in place of a detailed dis- sible. The information shall ordinarily cussion of data and information con- include: cerning an indication for use of the (1) The strength of the dosage form, drug, the clinical study must con- e.g., 10-milligram tablets, in metric stitute an adequate and well-controlled system and, if the apothecary system study as described in § 314.126(b) of this

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00078 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.100

chapter, except for biological products, (3) The route of administration, if it and must not imply or suggest indica- is not for oral use; and tions or uses or dosing regimens not (4) The quantity or proportion of stated in the ‘‘Indications and Usage’’ each active ingredient, as well as the or ‘‘Dosage and Administration’’ sec- information required by section 502 (d) tion. and (e); and (ii) When prescription drug labeling (5) If it is for other than oral use, the must summarize or otherwise rely on a names of all inactive ingredients, ex- recommendation by an authoritative cept that: scientific body, or on a standardized (i) Flavorings and perfumes may be methodology, scale, or technique, because the information is important to designated as such without naming prescribing decisions, the labeling may their components. include a reference to the source of the (ii) Color additives may be des- information. ignated as coloring without naming (2) If the clinical study or reference is specific color components unless the cited in the labeling in the place of a naming of such components is required detailed discussion of data and infor- by a color additive regulation pre- mation concerning a risk or risks from scribed in subchapter A of this chapter. the use of the drug, the risk or risks (iii) Trace amounts of harmless sub- shall also be identified or discussed in stances added solely for individual the appropriate section of the labeling product identification need not be for the drug. named. If it is intended for administra- [44 FR 37462, June 26, 1979, as amended at 55 tion by parenteral injection, the quan- FR 11576, Mar. 29, 1990; 59 FR 64249, Dec. 13, tity or proportion of all inactive ingre- 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396, dients, except that ingredients added Dec. 1, 1998. Redesignated and amended at 71 to adjust the pH or to make the drug FR 3988, 3996, Jan. 24, 2006; 79 FR 72103, Dec. isotonic may be declared by name and 4, 2014] a statement of their effect; and if the vehicle is water for injection it need Subpart D—Exemptions From not be named. Adequate Directions for Use (6) An identifying lot or control num- § 201.100 Prescription drugs for ber from which it is possible to deter- human use. mine the complete manufacturing his- A drug subject to the requirements of tory of the package of the drug. section 503(b)(1) of the act shall be ex- (7) A statement directed to the phar- empt from section 502(f)(1) if all the macist specifying the type of container following conditions are met: to be used in dispensing the drug prod- (a) The drug is: uct to maintain its identity, strength, (1)(i) In the possession of a person (or quality, and purity. Where there are his agents or employees) regularly and standards and test procedures for de- lawfully engaged in the manufacture, termining that the container meets the transportation, storage, or wholesale requirements for specified types of con- distribution of prescription drugs; or tainers as defined in an official com- (ii) In the possession of a retail, hos- pendium, such terms may be used. For pital, or clinic pharmacy, or a public example, ‘‘Dispense in tight, light-re- health agency, regularly and lawfully sistant container as defined in the Na- engaged in dispensing prescription tional Formulary’’. Where standards drugs; or and test procedures for determining (iii) In the possession of a practi- the types of containers to be used in tioner licensed by law to administer or dispensing the drug product are not in- prescribe such drugs; and cluded in an official compendium, the (2) It is to be dispensed in accordance specific container or types of con- with section 503(b) (b) The label of the drug bears: tainers known to be adequate to main- (1) The statement ‘‘Rx only’’ and tain the identity, strength, quality, (2) The recommended or usual dosage and purity of the drug products shall and be described. For example, ‘‘Dispense

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00079 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.100 21 CFR Ch. I (4–1–19 Edition)

in containers which (statement of spec- ommends, or suggests a dosage for the ifications which clearly enable the dis- use of the drug (other than dose infor- pensing pharmacist to select an ade- mation required by paragraph (b)(2) of quate container)’’: Provided, however, this section and § 201.105(b)(2) contains: That in the case of containers too (1) Adequate information for such small or otherwise unable to accommo- use, including indications, effects, dos- date a label with sufficient space to ages, routes, methods, and frequency bear all such information, but which and duration of administration and any are packaged within an outer container relevant warnings, hazards, contra- from which they are removed for dis- indications, side effects, and pre- pensing or use, the information re- cautions, under which practitioners li- quired by paragraph (b) (2), (3), (5), and censed by law to administer the drug (7) of this section may be contained in can use the drug safely and for the pur- other labeling on or within the package poses for which it is intended, includ- from which it is to be dispensed; the in- ing all conditions for which it is adver- formation referred to in paragraph tised or represented; and if the article (b)(1) of this section may be placed on is subject to section 505 of the act, the such outer container only; and the in- parts of the labeling providing such information required by paragraph (b)(6) formation are the same in language of this section may be on the crimp of and emphasis as labeling approved or the dispensing tube. The information permitted, under the provisions of sec- required by this paragraph (b)(7) is not tion 505, and any other parts of the la- required for prescription drug products beling are consistent with and not con- packaged in unit-dose, unit-of-use, on trary to such approved or permitted la- other packaging format in which the beling; and manufacturer’s original package is de- (2) The same information concerning signed and intended to be dispensed to the ingredients of the drug as appears patients without repackaging. on the label and labeling on or within (c)(1) Labeling on or within the pack- the package from which the drug is to age from which the drug is to be dis- be dispensed. pensed bears adequate information for (3) The information required, and in its use, including indications, effects, the format specified, by §§ 201.56, 201.57, dosages, routes, methods, and fre- and 201.80. quency and duration of administration, (e) All labeling described in para- and any relevant hazards, contra- graph (d) of this section bears con- indications, side effects, and pre- spicuously the name and place of busi- cautions under which practitioners liness of the manufacturer, packer, or censed by law to administer the drug distributor, as required for the label of can use the drug safely and for the pur- the drug under § 201.1. poses for which it is intended, includ- (f) Reminder labeling which calls ating all purposes for which it is adver- tention to the name of the drug prod- tised or represented; and uct but does not include indications or (2) If the article is subject to section dosage recommendations for use of the 505 of the act, the labeling bearing such drug product is exempted from the pro- information is the labeling authorized visions of paragraph (d) of this section. by the approved new drug application This reminder labeling shall contain or required as a condition for the cer- only the proprietary name of the drug tification or the exemption from cer- product, if any; the established name of tification requirements applicable to the drug product, if any; the estab- preparations of insulin or antibiotic lished name of each active ingredient drugs. in the drug product; and, optionally, (d) Any labeling, as defined in section information relating to quantitative 201(m) of the act, whether or not it is ingredient statements, dosage form, on or within a package from which the quantity of package contents, price, drug is to be dispensed, distributed by the name and address of the manufac- or on behalf of the manufacturer, pack- turer, packer, or distributor or other er, or distributor of the drug, that fur- written, printed, or graphic matter nishes or purports to furnish informa- containing no representation or sug- tion for use or which prescribes, rec- gestion relating to the drug product. If

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00080 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.105

the Commissioner finds that there is lawfully engaged in the manufacture, evidence of significant incidence of fa- transportation, storage, or wholesale talities or serious injury associated distribution of drugs that are to be with the use of a particular prescrip- used only by or on the prescription or tion drug, he may withdraw this ex- other order of a licensed veterinarian; emption by so notifying the manufac- or turer, packer, or distributor of the (ii) In the possession of a retail, hos- drug by letter. Reminder labeling, pital, or clinic pharmacy, or other per- other than price lists and catalogs sole- son authorized under State law to dis- ly intended to convey price informa- pense veterinary prescription drugs, tion including, but not limited to, who is regularly and lawfully engaged those subject to the requirements of in dispensing drugs that are to be used § 200.200 of this chapter, is not per- only by or on the prescription or other mitted for a prescription drug product order of a licensed veterinarian; or whose labeling contains a boxed warn- (iii) In the possession of a licensed ing relating to a serious hazard associ- veterinarian for use in the course of his ated with the use of the drug product. professional practice; and Reminder labeling which is intended to provide consumers with information (2) To be dispensed in accordance concerning the price charged for a pre- with section 503(f) of the act. scription for a particular drug product (b) The label of the drug bears: shall meet all of the conditions con- (1) The statement ‘‘Caution: Federal tained in § 200.200 of this chapter. Re- law restricts this drug to use by or on minder labeling, other than that sub- the order of a licensed veterinarian’’; ject to the requirements of § 200.200 of and this chapter, is not permitted for a (2) The recommended or usual dos- drug for which an announcement has age; and been published pursuant to a review of (3) The route of administration, if it the labeling claims for the drug by the is not for oral use; and National Academy of Sciences/National (4) The quantity or proportion of Research Council (NAS/NRC), Drug Ef- each active ingredient as well as the ficacy Study Group, and for which no information required by section 502(e) claim has been evaluated as higher of the act; and than ‘‘possibly effective.’’ If the Com- (5) If it is for other than oral use, the missioner finds the circumstances are names of all inactive ingredients, ex- such that reminder labeling may be cept that: misleading to prescribers of drugs sub- (i) Flavorings and perfumes may be ject to NAS/NRC evaluation, such redesignated as such without naming minder labeling will not be allowed and their components. the manufacturer, packer, or dis- (ii) Color additives may be des- tributor will be notified either in the ignated as coloring without naming publication of the conclusions on the specific color components unless the effectiveness of the drug or by letter. naming of such components is required [40 FR 13998, Mar. 27, 1975, as amended at 40 by a color additive regulation pre- FR 58799, Dec. 18, 1975; 42 FR 15674, Mar. 22, scribed in subchapter A of this chapter. 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659, (iii) Trace amounts of harmless sub- Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR stances added solely for individual 25777, Apr. 15, 1980; 63 FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999; 67 FR 4906, Feb. 1, 2002; product identification need not be 71 FR 3996, Jan. 24, 2006] named. If it is intended for administration by § 201.105 Veterinary drugs. parenteral injection, the quantity or A drug subject to the requirements of proportion of all inactive ingredients, section 503(f)(1) of the act shall be ex- except that ingredients added to adjust empt from section 502(f)(1) of the act if the pH or to make the drug isotonic all the following conditions are met: may be declared by name and a state- (a) The drug is: ment of their effect; and if the vehicle (1)(i) In the possession of a person (or is water for injection, it need not be his agents or employees) regularly and named.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00081 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.105 21 CFR Ch. I (4–1–19 Edition)

(6) An identifying lot or control num- er, or distributor of the drug, that fur- ber from which it is possible to deter- nishes or purports to furnish informa- mine the complete manufacturing his- tion for use or which prescribes, rec- tory of the package of the drug; ommends, or suggests a dosage for the Provided, however, That in the case of use of the drug (other than dose infor- containers too small or otherwise un- mation required by paragraph (b)(2) of able to accommodate a label with suffi- this section and § 201.100(b)(2)) contains: cient space to bear all such informa- (1) Adequate information for such tion, but which are packaged within an use, including indications, effects, dos- outer container from which they are ages, routes, methods, and frequency removed for dispensing or use, the in- and duration of administration, and formation required by paragraphs (b) any relevant warnings, hazards, con- (2), (3), and (5) of this section may be traindications, side effects, and pre- contained in other labeling on or with- cautions, and including information in the package from which it is to be so relevant to compliance with the new dispensed, and the information referred animal drug provisions of the act, to in paragraph (b)(1) of this section under which veterinarians licensed by may be placed on such outer container law to administer the drug can use the only, and the information required by drug safely and for the purposes for paragraph (b)(6) of this section may be which it is intended, including all con- on the crimp of the dispensing tube. ditions for which it is advertised or (c)(1) Labeling on or within the pack- represented; and if the article is sub- age from which the drug is to be dis- ject to section 512 or 572 of the act, the pensed bears adequate information for parts of the labeling providing such in- its use, including indications, effects, formation are the same in language dosages, routes, methods, and fre- and emphasis as labeling approved, per- quency and duration of administration, and any relevant hazards, contra- mitted, or indexed under the provisions indications, side effects, and pre- of section 512 or 572, and any other cautions under which veterinarians li- parts of the labeling are consistent censed by law to administer the drug with and not contrary to such ap- can use the drug safely and for the pur- proved, permitted, or indexed labeling; poses for which it is intended, includ- and ing all purposes for which it is adver- (2) The same information concerning tised or represented; and the ingredients of the drug as appears (2) If the article is subject to section on the label and labeling on or within 512 or 572 of the act, the labeling bear- the package from which the drug is to ing such information is the labeling au- be dispensed; thorized by the approved new animal Provided, however, That the informa- drug application or contained in the tion required by paragraphs (d) (1) and index listing: Provided, however, That (2) of this section is not required on the the information required by paragraph so-called reminder-piece labeling which (c)(1) of this section may be omitted calls attention to the name of the drug from the dispensing package if, but but does not include indications or dos- only if, the article is a drug for which age recommendations for use of the directions, hazards, warnings, and use drug. information are commonly known to (e) All labeling, except labels and veterinarians licensed by law to admin- cartons, bearing information for use of ister the drug. Upon written request, the drug also bears the date of the stating reasonable grounds therefore, issuance or the date of the latest revi- the Commissioner will offer an opinion sion of such labeling. on a proposal to omit such information from the dispensing package under this (f) A prescription drug intended for proviso. both human and veterinary use shall (d) Any labeling, as defined in section comply with paragraphs (e) and (f) of 201(m) of the act, whether or not it is this section and § 201.100. on or within a package from which the [40 FR 13998, Mar. 27, 1975, as amended at 42 drug is to be dispensed, distributed by FR 15674, Mar. 22, 1977; 57 FR 54300, Nov. 18, or on behalf of the manufacturer, pack- 1992; 72 FR 69119, Dec. 6, 2007]

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00082 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.120

§ 201.115 New drugs or new animal tively, of the Federal Food, Drug, and drugs. Cosmetic Act (the act) or are a com- A new drug shall be exempt from sec- bination of drugs and devices, and may tion 502(f)(1) of the act: also be a biological product subject to (a) To the extent to which such ex- section 351 of the Public Health Service emption is claimed in an approved ap- Act. plication with respect to such drug (b) A product intended for use in the under section 505 or 512 of the act or an diagnosis of disease and which is an in index listing with respect to such drug vitro diagnostic product as defined in under section 572 of the act; or paragraph (a) of this section shall be (b) If no application under section 505 deemed to be in compliance with the or 512 of the act is approved and no re- requirements of this section and sec- quest for addition to the index is grant- tion 502(f)(1) of the act if it meets the ed under section 572 with respect to requirements of § 809.10 of this chapter. such drug but it complies with section 505(i), 512(j), or 572(g) of the act and [41 FR 6910, Feb. 13, 1976] regulations thereunder. No exemption shall apply to any other § 201.120 Prescription chemicals and drug which would be a new drug if its other prescription components. labeling bore representations for its in- A drug prepared, packaged, and pri- tended uses. marily sold as a prescription chemical [40 FR 13998, Mar. 27, 1975, as amended at 72 or other component for use by reg- FR 69119, Dec. 6, 2007] istered pharmacists in compounding prescriptions or for dispensing in dos- § 201.116 Drugs having commonly age unit form upon prescriptions shall known directions. be exempt from section 502(f)(1) of the A drug shall be exempt from section act if all the following conditions are 502(f)(1) of the act insofar as adequate met: directions for common uses thereof are (a) The drug is an official liquid acid known to the ordinary individual. or official liquid alkali, or is not a liq- [41 FR 6910, Feb. 13, 1976] uid solution, emulsion, suspension, tablet, capsule, or other dosage unit form; § 201.117 Inactive ingredients. and A harmless drug that is ordinarily (b) The label of the drug bears: used as an inactive ingredient, such as (1) The statement ‘‘For prescription a coloring, emulsifier, excipient, fla- compounding’’; and voring, lubricant, preservative, or sol- (2) If in substantially all dosage vent, in the preparation of other drugs forms in which it may be dispensed it shall be exempt from section 502(f)(1) of is subject to section 503(b)(1) of the act, the act. This exemption shall not apply the statement ‘‘Rx only’’; or to any substance intended for a use which results in the preparation of a (3) If it is not subject to section new drug, unless an approved new-drug 503(b)(1) of the act and is by custom application provides for such use. among retail pharmacists sold in or from the interstate package for use by § 201.119 In vitro diagnostic products. consumers, ‘‘adequate directions for (a) ‘‘In vitro diagnostic products’’ are use’’ in the conditions for which it is so those reagents, instruments and sys- sold. tems intended for use in the diagnosis Provided, however, That the informa- of disease or in the determination of tion referred to in paragraph (b)(3) of the state of health in order to cure, this section may be contained in the mitigate, treat, or prevent disease or labeling on or within the package from its sequelae. Such products are in- which it is to be dispensed. tended for use in the collection, preparation and examination of specimens (c) This exemption shall not apply to taken from the human body. These any substance intended for use in products are drugs or devices as defined compounding which results in a new in section 201(g) and 201(h), respec-

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00083 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.122 21 CFR Ch. I (4–1–19 Edition)

drug, unless an approved new-drug ap- (c) A new drug application or new plication covers such use of the drug in animal drug application or a request compounding prescriptions. for addition to the index covering the use of the drug substance in the pro- [40 FR 13998, Mar. 27, 1975, as amended at 67 duction and marketing of a finished FR 4906, Feb. 1, 2002] drug product has been submitted but § 201.122 Drugs for processing, repack- not yet approved, disapproved, granted, ing, or manufacturing. or denied, the bulk drug is not exported, and the finished drug product is A drug in a bulk package, except tab- not further distributed after it is man- lets, capsules, or other dosage unit ufactured until after the new drug ap- forms, intended for processing, repack- plication or new animal drug applica- ing, or use in the manufacture of an- tion is approved or the request for ad- other drug shall be exempt from sec- dition to the index is granted. tion 502(f)(1) of the act if its label bears the statement ‘‘Caution: For manufac- [41 FR 6911, Feb. 13, 1976, as amended at 41 FR 15844, Apr. 15, 1976; 50 FR 7492, Feb. 22, turing, processing, or repacking’’; and 1985; 55 FR 11576, Mar. 29, 1990; 57 FR 54301, if in substantially all dosage forms in Nov. 18, 1992; 67 FR 4906, Feb. 1, 2002; 72 FR which it may be dispensed it is subject 69119, Dec. 6, 2007] to section 503(b)(1) of the act, the statement ‘‘Rx only’’, or if in substantially § 201.125 Drugs for use in teaching, all dosage forms in which it may be law enforcement, research, and dispensed it is subject to section analysis. 503(f)(1) of the act, the statement A drug subject to § 201.100 or § 201.105, ‘‘Caution: Federal law restricts this shall be exempt from section 502(f)(1) of drug to use by or on the order of a li- the act if shipped or sold to, or in the censed veterinarian’’. This exemption possession of, persons regularly and and the exemption under § 201.120 may lawfully engaged in instruction in be claimed for the same article. How- pharmacy, chemistry, or medicine not ever, the exemption shall not apply to involving clinical use, or engaged in a substance intended for a use in manu- law enforcement, or in research not in- facture, processing, or repacking which volving clinical use, or in chemical causes the finished article to be a new analysis, or physical testing, and is to drug or new animal drug, unless: be used only for such instruction, law (a) An approved new drug application enforcement, research, analysis, or or new animal drug application or a testing. new animal drug index listing covers [41 FR 6911, Feb. 13, 1976] the production and delivery of the drug substance to the application or index § 201.127 Drugs; expiration of exemp- listing holder by persons named in the tions. application or in the request for deter- (a) If a shipment or delivery, or any mination of eligibility for indexing, part thereof, of a drug which is exempt and, for a new drug substance, the ex- under the regulations in this section is port of it by such persons under made to a person in whose possession § 314.410 of this chapter; or the article is not exempt, or is made (b) If no application is approved with for any purpose other than those speci- respect to such new drug or new animal fied, such exemption shall expire, with drug, and it is not listed in the index, respect to such shipment or delivery or the label statement ‘‘Caution: For part thereof, at the beginning of that manufacturing, processing, or repack- shipment or delivery. The causing of an ing’’ is immediately supplemented by exemption to expire shall be considered the words ‘‘in the preparation of a new an act which results in such drug being drug or new animal drug limited by misbranded unless it is disposed of Federal law to investigational use’’, under circumstances in which it ceases and the delivery is made for use only in to be a drug or device. the manufacture of such new drug or (b) The exemptions conferred by new animal drug limited to investiga- §§ 201.117, 201.119, 201.120, 201.122, and tional use as provided in part 312 or 201.125 shall continue until the drugs § 511.1 or § 516.125 of this chapter; or are used for the purposes for which

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00084 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.129

they are exempted, or until they are 14319, Mar. 20, 2017. At 83 FR 11639, Mar. 16, relabeled to comply with section 2018, the effective date for this revision was 502(f)(1) of the act. If, however, the delayed indefinitely. For the convenience of drug is converted, compounded, or the user, the revised text is set forth as follows: manufactured into a dosage form limited to prescription dispensing, no ex- § 201.128 Meaning of ‘‘intended uses’’. emption shall thereafter apply to the The words intended uses or words of similar article unless the dosage form is la- import in §§ 201.5, 201.115, 201.117, 201.119, beled as required by section 503(b) and 201.120, 201.122, and 1100.5 of this chapter refer §§ 201.100 or 201.105. to the objective intent of the persons legally responsible for the labeling of drugs. The in- [41 FR 6911, Feb. 13, 1976] tent is determined by such persons’ expressions or may be shown by the circumstances § 201.128 Meaning of ‘‘intended uses’’. surrounding the distribution of the article. The words intended uses or words of This objective intent may, for example, be similar import in §§ 201.5, 201.115, shown by labeling claims, advertising mat- 201.117, 201.119, 201.120, and 201.122 refer ter, or oral or written statements by such to the objective intent of the persons persons or their representatives. It may be legally responsible for the labeling of shown, for example, by circumstances in which the article is, with the knowledge of drugs. The intent is determined by such persons or their representatives, offered such persons’ expressions or may be and used for a purpose for which it is neither shown by the circumstances sur- labeled nor advertised. The intended uses of rounding the distribution of the arti- an article may change after it has been in- cle. This objective intent may, for ex- troduced into interstate commerce by its ample, be shown by labeling claims, ad- manufacturer. If, for example, a packer, dis- vertising matter, or oral or written tributor, or seller intends an article for dif- statements by such persons or their ferent uses than those intended by the per- representatives. It may be shown by son from whom he received the drug, such packer, distributor, or seller is required to the circumstances that the article is, supply adequate labeling in accordance with with the knowledge of such persons or the new intended uses. And if the totality of their representatives, offered and used the evidence establishes that a manufacturer for a purpose for which it is neither la- objectively intends that a drug introduced beled nor advertised. The intended uses into interstate commerce by him is to be of an article may change after it has used for conditions, purposes, or uses other been introduced into interstate com- than ones for which it is approved (if any), merce by its manufacturer. If, for ex- he is required, in accordance with section ample, a packer, distributor, or seller 502(f) of the Federal Food, Drug, and Cos- metic Act, or, as applicable, duly promul- intends an article for different uses gated regulations exempting the drug from than those intended by the person from the requirements of section 502(f)(1), to pro- whom he received the drug, such pack- vide for such drug adequate labeling that ac- er, distributor, or seller is required to cords with such other intended uses. supply adequate labeling in accordance with the new intended uses. But if a § 201.129 Drugs; exemption for radio- manufacturer knows, or has knowledge active drugs for research use. of facts that would give him notice, A radioactive drug intended for ad- that a drug introduced into interstate ministration to human research sub- commerce by him is to be used for con- jects during the course of a research ditions, purposes, or uses other than project intended to obtain basic re- the ones for which he offers it, he is research information regarding metabo- quired to provide adequate labeling for lism (including kinetics, distribution, such a drug which accords with such and localization) of a radioactively la- other uses to which the article is to be beled drug or regarding human physi- put. ology, pathophysiology, or bio- [41 FR 6911, Feb. 13, 1976] chemistry (but not intended for immediate therapeutic, diagnostic, or simi- EFFECTIVE DATE NOTE: At 82 FR 2217, Jan. 9, 2017, § 201.128 was revised, effective Feb. 8, lar purposes), under the conditions set 2017. This effective date was delayed to Mar. forth in § 361.1 of this chapter, shall be 21, 2017, at 82 FR 9501, Feb. 7, 2017, and was exempt from section 502(f)(1) of the act then further delayed to Mar. 19, 2018 at 82 FR if the packaging, label, and labeling

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00085 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.150 21 CFR Ch. I (4–1–19 Edition)

are in compliance with § 361.1(f) of this is adulterated or misbranded within chapter. the meaning of the act when so removed. [41 FR 6911, Feb. 13, 1976] (c) An exemption of a shipment or other delivery of a drug under para- Subpart E—Other Exemptions graph (a)(2) of this section shall become void ab initio with respect to the § 201.150 Drugs; processing, labeling, or repacking. person who introduced such shipment or delivery into interstate commerce (a) Except as provided by paragraphs upon refusal by such person to make (b) and (c) of this section, a shipment available for inspection a copy of the or other delivery of a drug which is, in agreement, as required by such para- accordance with the practice of the graph (a)(2) of this section. trade, to be processed, labeled, or re- (d) An exemption of a shipment or packed in substantial quantity at an other delivery of a drug under para- establishment other than that where graph (a)(2) of this section shall expire: originally processed or packed, shall be (1) At the beginning of the act of re- exempt, during the time of introduc- moving such shipment or delivery, or tion into and movement in interstate any part thereof, from such establish- commerce and the time of holding in ment if the drug comprising such ship- such establishment, from compliance ment, delivery, or part is adulterated with the labeling and packaging re- or misbranded within the meaning of quirements of sections 501(b) and 502 the act when so removed; or (b), (d), (e), (f), and (g) of the act if: (2) Upon refusal by the operator of (1) The person who introduced such the establishment where such drug is shipment or delivery into interstate to be processed, labeled, or repacked, commerce is the operator of the estab- to make available for inspection a copy lishment where such drug is to be proc- of the agreement, as required by such essed, labeled, or repacked; or clause. (2) In case such person is not such operator, such shipment or delivery is [41 FR 6911, Feb. 13, 1976, as amended at 64 made to such establishment under a FR 400, Jan. 5, 1999] written agreement, signed by and con- § 201.161 Medical gases. taining the post-office addresses of such person and such operator, and (a) Oxygen, nitrogen, carbon dioxide, containing such specifications for the helium, and nitrous oxide gases in- processing, labeling, or repacking, as tended for drug use, and medically ap- the case may be, of such drug in such propriate combinations of any of these establishment as will insure, if such gases intended for drug use, are ex- specifications are followed, that such empted from the requirements of drug will not be adulterated or mis- § 201.100(b)(2) and (3), and (c)(1), pro- branded within the meaning of the act vided that, where applicable, the re- upon completion of such processing, la- quirements of §§ 201.328 and 211.94(e)(2) beling, or repacking. Such person and of this chapter are met and the label- such operator shall each keep a copy of ing bears, in addition to any other in- such agreement until 2 years after the formation required by the Federal final shipment or delivery of such drug Food, Drug, and Cosmetic Act, the fol- from such establishment, and shall lowing: make such copies available for inspec- (1)(i) In the case of oxygen, a warning tion at any reasonable hour to any offi- statement providing that uninter- cer or employee of the Department who rupted use of high concentrations of requests them. oxygen over a long duration, without (b) An exemption of a shipment or monitoring its effect on oxygen con- other delivery of a drug under para- tent of arterial blood, may be harmful; graph (a)(1) of this section shall, at the that oxygen should not be used on pa- beginning of the act of removing such tients who have stopped breathing un- shipment or delivery, or any part less used in conjunction with thereof, from such establishment, be- resuscitative equipment; and, in the come void ab initio if the drug com- case of oxygen that may be provided prising such shipment, delivery, or part without a prescription for use in the

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00086 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.200

event of depressurization or other envi- been uniquely extensive in scope and ronmental oxygen deficiency, or for ox- uniquely intensive in time’’ and is ap- ygen deficiency or for use in emer- plicable to more than 80 percent of the gency resuscitation when administered currently marketed drugs. The report by properly trained personnel, a warn- further notes that the quality of the ing statement providing that oxygen evidence of efficacy, as well as the may be used for emergency use only quality of the labeling claims, is poor. when administered by properly trained Labeling and other promotional claims personnel for oxygen deficiency and re- have been evaluated as ‘‘effective,’’ suscitation, and that for all other med- ‘‘probably effective,’’ ‘‘possibly effec- ical applications a prescription is re- tive,’’ ‘‘ineffective,’’ ‘‘ineffective as a quired. fixed combination,’’ and ‘‘effective (ii) In the case of nitrogen, carbon di- but,’’ and a report for each drug in the oxide, helium, nitrous oxide, and medically appropriate combinations of any study has been submitted to the Com- of the gases listed in paragraph (a) of missioner. this section, a warning statement pro- (2) The Food and Drug Administra- viding that the administration of the tion is processing the reports, seeking gas or gas combination (as applicable) voluntary action on the part of the may be hazardous or contraindicated; drug manufacturers and distributors in and that the gas or gas combination (as the elimination or modification of un- applicable) should be used only by or supported promotional claims, and ini- under the supervision of a licensed tiating administrative actions as nec- practitioner who is experienced in the essary to require product and labeling use and administration of the gas or changes. gas combination (as applicable) and is (3) Delays have been encountered in familiar with the indications, effects, bringing to the attention of the pre- dosages, methods, and frequency and scribers of prescription items the con- duration of administration, and with clusions of the expert panels that re- the hazards, contraindications, and viewed the promotional claims. side effects and the precautions to be (b) The Commissioner of Food and taken. Drugs concludes that: (2) Any needed directions concerning the conditions for storage and warn- (1) The failure to disclose in the la- ings against the inherent dangers in beling of a drug and in other pro- the handling of the specific compressed motional material the conclusions of gas. the Academy experts that a claim is (b) [Reserved] ‘‘ineffective,’’ ‘‘possibly effective,’’ ‘‘probably effective,’’ or ‘‘ineffective as [81 FR 81696, Nov. 18, 2016] a fixed combination,’’ while labeling and promotional material bearing any Subpart F—Labeling Claims for such claim are being used, is a failure Drugs in Drug Efficacy Study to disclose facts that are material in light of the representations made and § 201.200 Disclosure of drug efficacy study evaluations in labeling and causes the drug to be misbranded. advertising. (2) The Academy classification of a (a)(1) The National Academy of drug as other than ‘‘effective’’ for a Sciences—National Research Council, claim for which such drug is rec- Drug Efficacy Study Group, has com- ommended establishes that there is a pleted an exhaustive review of labeling material weight of opinion among claims made for drugs marketed under qualified experts contrary to the rep- new-drug and antibiotic drug proce- resentation made or suggested in the dures between 1938 and 1962. The results labeling, and failure to reveal this fact are compiled in ‘‘Drug Efficacy Study, causes such labeling to be misleading. A Report to the Commissioner of Food (c) Therefore, after publication in the and Drugs from the National Academy FEDERAL REGISTER of a Drug Efficacy of Sciences (1969).’’ As the report notes, Study Implementation notice on a pre- this review has made ‘‘an audit of the scription drug, unless exempted or oth- state of the art of drug usage that has erwise provided for in the notice, all

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00087 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.200 21 CFR Ch. I (4–1–19 Edition)

package labeling (other than the im- shall be at least of the same size and mediate container or carton label, un- color and degree of prominence as less such labeling contains information other printing in the labeling and shall required by § 201.100(c)(1) in lieu of a be presented in a prominent box using package insert), promotional labeling, one of the following formats and proce- and advertisements shall include, as dures: part of the information for practi- (1) In drug labeling the box state- tioners under which the drug can be ment may entirely replace the indica- safely and effectively used, an appro- tions section and be in the following priate qualification of all claims evalu- format: ated as other than ‘‘effective’’ by a panel of the National Academy of INDICATIONS Sciences—National Research Council, Based on a review of this drug by the Na- Drug Efficacy Study Group, if such tional Academy of Sciences—National Re- claims continue to be included in ei- search Council and/or other information, ther the labeling or advertisements. FDA has classified the indication(s) as fol- However, this qualifying information lows: will be required in advertisements only Effective: (list or state in paragraph form). if promotional material is included ‘‘Probably’’ effective: (list or state in paragraph form). therein for claims evaluated as less ‘‘Possibly’’ effective: (list or state in para- than ‘‘effective’’ or if such claims are graph form). included in the indications section of Final classification of the less-than-effec- the portion of the advertisement con- tive indications requires further investiga- taining the information required in tion. brief summary by § 202.1(e)(1) of this chapter. When, however, the Food and (2) Or the indication(s) for which the Drug Administration classification of drug has been found effective may ap- such claim is ‘‘effective’’ (for example, pear outside the boxed statement and on the basis of revision of the language be followed immediately by the fol- of the claim or submission or existence lowing boxed statement: of adequate data), such qualification is Based on a review of this drug by the not necessary. When the Food and Drug National Academy of Sciences—Na- Administration classification of the tional Research Council and/or other claim, as stated in the implementation information, FDA has classified the notice, differs from that of the Acad- other indication(s) as follows: emy but is other than ‘‘effective,’’ the ‘‘Probably’’ effective: (list or state in qualifying statement shall refer to this paragraph form). classification in lieu of the Academy’s ‘‘Possibly’’ effective: (list or state in classification. paragraph form). (d) For new drugs and antibiotics, Final classification of the less-than- supplements to provide for revised la- effective indications requires further beling in accord with paragraph (c) of investigation. this section shall be submitted under (3) In drug labeling (other than that the provisions of § 314.70 and § 514.8 of which is required by § 201.100(c)(1)) this chapter within 90 days after publi- which may contain a promotional mes- cation of the implementation notice in sage, the promotional message shall be the FEDERAL REGISTER or by May 15, keyed to the boxed statement by the 1972, for those drugs for which notices same means as those provided for ad- have been published and such labeling vertisements in paragraph (f)(2) of this shall be put into use as soon as possible section. but not later than the end of the time (f) Qualifying information required in period allowed for submitting supple- prescription drug advertising by para- ments to provide for revised labeling. graph (c) of this section shall contain a (e) Qualifying information required prominent boxed statement of the ad- in drug labeling by paragraph (c) of vertised indication(s) and of the limita- this section in order to advise pre- tions of effectiveness using the same scribers of a drug of the findings made format, language, and emphasis as that by a panel of the Academy in evalu- required in labeling by paragraph (e) of ating a claim as other than ‘‘effective’’ this section.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00088 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.300

(1) The boxed statement shall appear ations in direct correspondence with in (or next to) the information required the drug promoters, after which the in brief summary by § 202.1(e)(1) of this failure to make the disclosure will be chapter and shall have prominence at regarded as misleading and appropriate least equal to that provided for other action will be taken. information presented in the brief sum- [40 FR 13998, Mar. 27, 1975, as amended at 55 mary and shall have type size, cap- FR 11576, Mar. 29, 1990] tions, color, and other physical characteristics comparable to the informa- Subpart G—Specific Labeling Re- tion required in the brief summary. (2) Less-than-effective indication(s) quirements for Specific Drug in the promotional message of an ad- Products vertisement which is a single page or § 201.300 Notice to manufacturers, less shall be keyed to the boxed state- packers, and distributors of glan- ment by asterisk, by an appropriate dular preparations. statement, or by other suitable means (a) Under date of December 4, 1941, in providing adequate emphasis on the a notice to manufacturers of glandular boxed statement. On each page where preparations, the Food and Drug Ad- less-than-effective indication(s) appear ministration expressed the opinion in a mutiple page advertisement, an as- that preparations of inert glandular terisk shall be placed after the most materials intended for medicinal use prominent mention of the indi- should, in view of the requirement of cation(s); if the degree of prominence section 201(n) of the Federal Food, does not vary, an asterisk shall be Drug, and Cosmetic Act (52 Stat. 1041; placed after the first mention of the in- 21 U.S.C. 321(n)), be labeled with a dication. The asterisk shall refer to a statement of the material fact that notation at the bottom of the page there is no scientific evidence that the which shall state ‘‘This drug has been articles contain any therapeutic or evaluated as probably effective (or pos- physiologically active constituents. sibly effective whichever is appro- Numerous preparations of such inert priate) for this indication’’ and ‘‘See glandular materials were subsequently Brief Summary’’ or ‘‘See Prescribing marketed with disclaimers of the type Information,’’ the latter legend to be suggested. The term inert glandular ma- used only if the advertisement carries terials means preparations incapable of the required information for profes- exerting an action or effect of some sional use as set forth in § 201.100(c)(1). significant or measurable benefit in (3) For less-than-effective indications one way or another, i.e., in the diag- which are included in the advertise- nosis, cure, mitigation, treatment, or ment only as a part of the information prevention of disease, or in affecting required in brief summary, the disclo- the structure or any function of the sure information shall appear in this body. portion of the advertisement in the (b) Manufacturers have heretofore same manner as is specified for label- taken advantage of § 201.100 permitting ing in paragraph (e) of this section. omission of directions for use when the (g) The Commissioner may find cir- label bears the prescription legend. cumstances are such that, while the Section 201.100(c) requires that the la- elimination of claims evaluated as beling of the drug, which may include other than effective will generally brochures readily available to licensed eliminate the need for disclosure about practitioners, bear information as to such claims, there will be instances in the use of the drug by practitioners li- which the change in the prescribing or censed by law to administer it. Obvi- promotional profile of the drug is so ously, information adequate for the use substantial as to require a disclosure of of an inert glandular preparation is not the reason for the change so that the available to practitioners licensed by purchaser or prescriber is not misled law. by being left unaware through the (c) The Department of Health and sponsor’s silence that a basic change Human Services is of the opinion that has taken place. The Food and Drug inert glandular materials may not be Administration will identify these situ- exempted from the requirements of

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00089 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.301 21 CFR Ch. I (4–1–19 Edition)

section 502(f)(1) of the act that they terms of international units of estrone bear adequate directions for use; and, activity is therefore considered mis- accordingly, that their labeling must leading, within the meaning of 21 include among other things, represen- U.S.C. 352(a). The declaration of the es- tations as to the conditions for which tradiol content of an estrogenic hor- such articles are intended to be used or mone preparation in terms of weight is as to the structure or function of the considered appropriate. human body that they are intended to affect. Since any such representations § 201.302 Notice to manufacturers, offering these articles for use as drugs packers, and distributors of drugs would be false or misleading, such arti- for internal use which contain min- cles will be considered to be mis- eral oil. branded if they are distributed for use (a) In the past few years research as drugs. studies have altered medical opinion as (d) The amended regulations provide to the usefulness and harmfulness of also that in the case of drugs intended mineral oil in the human body. These for parenteral administration there studies have indicated that when min- shall be no exemption from the require- eral oil is used orally near mealtime it ment that their labelings bear ade- interferes with absorption from the di- quate directions for use. Such inert gestive tract of provitamin A and the glandular materials for parenteral use fat-soluble vitamins A, D, and K, and are therefore subject to the same com- consequently interferes with the utili- ment as applies to those intended for zation of calcium and phosphorus, with oral administration. the result that the user is left liable to deficiency diseases. When so used in § 201.301 Notice to manufacturers, pregnancy it predisposes to hemor- packers, and distributors of estrogenic hormone preparations. rhagic disease of the newborn. (b) There is accumulated evidence Some drug preparations fabricated that the indiscriminate administration wholly or in part from estradiol and la- of mineral oil to infants may be fol- beled as to potency in terms of inter- lowed by aspiration of the mineral oil national units or in terms of inter- and subsequent ‘‘lipoid pneumonia.’’ national units of estrone activity have been marketed. The international unit (c) In view of these facts, the Depart- of the estrus-producing hormone was ment of Health and Human Services established by the International Con- will regard as misbranded under the ference on the Standardization of Sex provisions of the Federal Food, Drug, Hormones at London, England, on Au- and Cosmetic Act a drug for oral ad- gust 1, 1932. This unit was defined as ministration consisting in whole or in ‘‘the specific estrus-producing activity part of mineral oil, the labeling of contained in 0.1 gamma ( = 0.0001 mg.) which encourages its use in pregnancy of the standard’’ hydroxyketonic hor- or indicates or implies that such drug mone found in urine (estrone). The is for administration to infants. International Conference declared that (d) It is also this Department’s view it did not recommend the determina- that the act requires the labelings of tion of the activity of such drugs to bear a warning against nonhydroxyketonic forms of estrogenic consumption other than at bedtime hormones in units of estrone because of and against administration to infants. the varying ratios between the activity The following form of warning is sug- of such nonhydroxyketonic estrogenic gested: ‘‘Caution: To be taken only at hormones and estrone, when measured bedtime. Do not use at any other time by different methods on test animals. or administer to infants, except upon There is no international unit for the advice of a physician.’’ measuring the activity of estradiol and (e) This statement of interpretation no accepted relationship between its does not in any way exempt mineral oil activity and that of estrone, either in or preparations containing mineral oil test animals or in humans. The dec- from complying in all other respects laration of potency of estradiol in with the requirements of the Federal terms of international units or in Food, Drug, and Cosmetic Act.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00090 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.305

§ 201.303 Labeling of drug prepara- (b) In view of the hazards involved tions containing significant propor- when tannic acid is used in barium en- tions of wintergreen oil. emas, any shipments of tannic acid la- (a) Because methyl salicylate (win- beled to come within the exemptions tergreen oil) manifests no toxicity in under 502(f) of the Act containing such the minute amounts in which it is used phrases as: ‘‘Caution: For manufac- as a flavoring, it is mistakenly re- turing, processing, or repackaging,’’ garded by the public as harmless even ‘‘For prescription compounding,’’ or when taken in substantially larger ‘‘Diagnostic reagent—For professional amounts. Actually, it is quite toxic use only’’ will be regarded by the Com- when taken in quantities of a teaspoon- missioner of Food and Drugs as mis- ful or more. Wintergreen oil and prep- branded within the meaning of section arations containing it have caused a 502(f) of the Federal Food, Drug, and number of deaths through accidental Cosmetic Act unless the label and the labeling bear conspicuously a warning misuse by both adults and children. to the effect: ‘‘Warning— Not for use in Children are particularly attracted by enemas.’’ the odor and are likely to swallow these products when left within reach. (c) Any tannic acid intended for use by man and found within the jurisdic- (b) To safeguard against fatalities tion of the Federal Food, Drug, and from this cause, the Department of Cosmetic Act labeled contrary to this Health and Human Services will regard section after 60 days from the date of as misbranded under the provisions of its publication in the FEDERAL REG- the Federal Food, Drug, and Cosmetic ISTER may be made the subject of regu- Act any drug containing more than 5 latory proceedings. percent methyl salicylate (wintergreen oil), the labeling of which fails to warn § 201.305 Isoproterenol inhalation that use otherwise than as directed preparations (pressurized aerosols, therein may be dangerous and that the nebulizers, powders) for human article should be kept out of reach of use; warnings. children to prevent accidental poi- (a) Accumulating reports have been soning. received by the Food and Drug Admin- (c) This statement of interpretation istration and have appeared in the in no way exempts methyl salicylate medical literature of severe paradox- (wintergreen oil) or its preparations ical bronchoconstriction associated from complying in all other respects with repeated, excessive use of with the requirements of the Federal isoproterenol inhalation preparations Food, Drug, and Cosmetic Act. in the treatment of bronchial asthma and other chronic bronchopulmonary § 201.304 Tannic acid and barium disorders. The cause of this paradoxical enema preparations. reaction is unknown; it has been ob- (a) It has become a widespread prac- served, however, that patients have not tice for tannic acid to be added to bar- responded completely to other forms of ium enemas to improve X-ray pictures. therapy until use of the isoproterenol Tannic acid is capable of causing di- inhalation preparation was discon- minished liver function and severe tinued. In addition, sudden unexpected liver necrosis when absorbed in suffi- deaths have been associated with the cient amounts. The medical literature excessive use of isoproterenol inhala- reports a number of deaths associated tion preparations. The mechanism of with the addition of tannic acid to bar- these deaths and their relationship, if ium enemas. There is a lack of sci- any, to the cases of severe paradoxical entific evidence to establish the condi- bronchospasm are not clear. Cardiac tions, if any, under which tannic acid arrest was noted in several of these is safe and effective for use in enemas. cases of sudden death. Tannic acid for rectal use to enhance (b) On the basis of the above informa- X-ray visualization is regarded as a tion and after discussion with and con- new drug within the meaning of section currence of the Respiratory and Anes- 201(p) of the Federal Food, Drug, and thetic Drugs Advisory Committee for Cosmetic Act. Food and Drug Administration, the

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00091 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.306 21 CFR Ch. I (4–1–19 Edition)

Commissioner of Food and Drugs con- (ii) The holder of an approved new- cludes that in order for the labeling of drug application for such preparation such drugs to bear adequate informa- submits a supplement to his new-drug tion for their safe use, as required by application to provide for appropriate § 201.100, such labeling must include the labeling changes as described in para- following: graphs (b) and (c) of this section. (2) Within 90 days following the date Warning: Occasional patients have been re- of publication of this section in the ported to develop severe paradoxical airway FEDERAL REGISTER, the manufacturer, resistance with repeated, excessive use of isoproterenol inhalation preparations. The packer, or distributor of any drug con- cause of this refractory state is unknown. It taining isoproterenol intended for in- is advisable that in such instances the use of halation for which a new-drug approval this preparation be discontinued imme- is not in effect submits a new-drug ap- diately and alternative therapy instituted, plication containing satisfactory infor- since in the reported cases the patients did mation of the kinds required by § 314.50 not respond to other forms of therapy until of this chapter, including appropriate the drug was withdrawn. labeling as described in paragraphs (b) Deaths have been reported following exces- and (c) of this section. sive use of isoproterenol inhalation prepara- (3) The applicant submits additional tions and the exact cause is unknown. Car- information required for the approval diac arrest was noted in several instances. of the application as may be specified (c)(1) The Commissioner also con- in a written communication from the cludes that in view of the manner in Food and Drug Administration. which these preparations are self-ad- (e) After 270 days following expira- ministered for relief of attacks of bron- tion of said 90 days, regulatory pro- chial asthma and other chronic bron- ceedings based on section 505(a) of the chopulmonary disorders, it is necessary Federal Food, Drug, and Cosmetic Act for the protection of users that warn- may be initiated with regard to any ing information to patients be included such drug shipped within the jurisdic- as a part of the label and as part of any tion of the act for which an approved instructions to patients included in the new-drug application is not in effect. package dispensed to the patient as fol- [40 FR 13998, Mar. 27, 1975, as amended at 55 lows: FR 11576, Mar. 29, 1990]

Warning: Do not exceed the dose prescribed § 201.306 Potassium salt preparations by your physician. If difficulty in breathing intended for oral ingestion by man. persists, contact your physician immediately. (a) The Food and Drug Administra- tion will initiate no regulatory action (2) The warning on the label may be with respect to the continued mar- accomplished (i) by including it on the keting of coated tablets containing po- immediate container label with a tassium chloride or other potassium statement directed to pharmacists not salts which supply 100 milligrams or to remove the label or (ii) by including more of potassium per tablet provided in the package a printed warning with all the following conditions are met: instructions to pharmacists to place (1) Within 30 days from the date of the warning on the container prior to publication of this statement of policy dispensing. in the FEDERAL REGISTER: (d) The marketing of isoproterenol (i) The labeling of the drug bears the inhalation preparations may be contin- prescription caution statement quoted ued if all the following conditions are in section 503(b)(4) of the Federal Food, met: Drug, and Cosmetic Act; (1) Within 30 days following the date (ii) The labeling on or within the of publication of this section in the package from which the drug is to be FEDERAL REGISTER: dispensed bears adequate information (i) The label and labeling of such for its use by practitioners in accord preparations shipped within the juris- with the ‘‘full disclosure’’ labeling re- diction of the act are in accordance quirements of § 201.100 of this chapter, with paragraphs (b) and (c) of this sec- including the following warning state- tion. ment:

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00092 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.307

Warning—There have been several reports, sium per milliliter, labeled or intended published and unpublished, concerning non- for human use, unless all the following specific small-bowel lesions consisting of ste- conditions are met: nosis, with or without ulceration, associated (1) The labeling of the drug bears the with the administration of enteric-coated thiazides with potassium salts. These lesions prescription statement quoted in sec- may occur with enteric-coated potassium tion 503(b)(4) of the Federal Food, tablets alone or when they are used with Drug, and Cosmetic Act; and nonenteric-coated thiazides, or certain other (2) The labeling on or within the oral diuretics. These small-bowel lesions package from which the drug is to be have caused obstruction, hemorrhage, and dispensed bears adequate information perforation. Surgery was frequently required for its use by practitioners in accord and deaths have occurred. Based on a large survey of physicians and hospitals, both with the ‘‘full disclosure’’ labeling re- United States and foreign, the incidence of quirements of § 201.100 of this chapter, these lesions is low, and a causal relation- including a recommendation that pa- ship in man has not been definitely estab- tients be directed to dissolve any such lished. Available information tends to impli- tablets in an appropriate amount of cate enteric-coated potassium salts, al- liquid and to dilute any such liquid though lesions of this type also occur spon- preparations adequately to assure taneously. Therefore, coated potassium-containing formulations should be administered against gastrointestinal injury associ- only when indicated, and should be discon- ated with the oral ingestion of continued immediately if abdominal pain, dis- centrated potassium salt preparations. tention, nausea, vomiting, or gastro- [40 FR 13998, Mar. 27, 1975, as amended at 55 intestinal bleeding occur. Coated potassium FR 11576, Mar. 29, 1990; 67 FR 4906, Feb. 1, tablets should be used only when adequate 2002] dietary supplementation is not practicable. (Although the warning statement in- § 201.307 Sodium phosphates; package cludes references to enteric-coated po- size limitation, warnings, and directions for over-the-counter sale. tassium salt preparations, it applies to any capsule or coated tablet of a potas- (a) Reports in the medical literature sium salt intended for oral ingestion and data accumulated by the Food and without prior dilution with an ade- Drug Administration indicate that quate volume of liquid to preclude gas- multiple container sizes of sodium trointestinal injury.) phosphates oral solution available in (iii) Any other labeling or additional the marketplace have caused consumer advertising for the drug conforms to confusion and appear to have been in- the labeling described in paragraph volved in several consumer deaths. So- (a)(1)(ii) of this section, in accordance dium phosphates oral solution has been with §§ 202.1 and 201.100 of this chapter. marketed in 45-milliliter (mL), 90-mL, (2) Within 90 days from the date of and 240-mL container sizes. The 45-mL publication of this statement of policy and 90-mL container sizes of sodium in the FEDERAL REGISTER, the manu- phosphates oral solution are often rec- facturer, packer, or distributor of the ommended and prescribed by physi- drug shall submit a new-drug applica- cians for bowel cleansing prior to sur- tion containing satisfactory informa- gery and diagnostic procedures of the tion of the kind required by § 314.50 of colon. Sodium phosphates oral solution this chapter, with appropriate labeling (adult dose 20 mL to 45 mL) is also used as described in this paragraph. as an over-the-counter (OTC) laxative (b) The Food and Drug Administra- for the relief of occasional constipa- tion may initiate regulatory pro- tion. Accidental overdosing and deaths ceedings after 30 days from the date of have occurred because the 240-mL con- publication of this section, with re- tainer was mistakenly used instead of spect to the marketing of uncoated the 45-mL or 90-mL container. The tablets containing potassium chloride Food and Drug Administration is lim- or other potassium salts which supply iting the amount of sodium phosphates 100 milligrams or more of potassium oral solution to not more than 90 mL (3 per tablet or with respect to liquid ounces (oz)) per OTC container because preparations containing potassium of the serious health risks associated chloride or other potassium salts which with the ingestion of larger than in- supply 20 milligrams or more of potas- tended doses of this product. Further,

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00093 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.308 21 CFR Ch. I (4–1–19 Edition)

because an overdose of either oral or spoonfuls) in a 24-hour period.’’ Chil- rectal enema sodium phosphates can dren 5 to 9 years of age: Oral dosage is cause an electrolyte imbalance, addi- dibasic sodium phosphate 0.86 to 1.89 g tional warning and direction state- and monobasic sodium phosphate 2.2 to ments are required for the safe use of 5.05 g (5 to 10 mL dibasic sodium phos- any OTC laxative drug product con- phate/monobasic sodium phosphate taining sodium phosphates. oral solution) as a single daily dose. (b) Any OTC drug product for lax- ‘‘Do not take more than 10 mL (2 tea- ative or bowel cleansing use containing spoonfuls) in a 24-hour period.’’ Chil- sodium phosphates as an active ingre- dren under 5 years of age: ask a doctor. dient when marketed as described in (c) After June 22, 1998, for package paragraph (a) of this section is mis- size limitation and September 18, 1998, branded within the meaning of section for labeling in accord with paragraph 502 of the Federal Food, Drug, and Cos- (b) of this section, any such OTC drug metic Act unless packaged and labeled product initially introduced or ini- as follows: tially delivered for introduction into (1) Package size limitation for so- interstate commerce, or any such drug dium phosphates oral solution: Con- product that is repackaged or relabeled tainer shall not contain more than 90 after these dates regardless of the date mL (3 oz). the product was manufactured, ini- (2) Warnings. The following sentences tially introduced, or initially delivered shall appear in boldface type as the for introduction into interstate com- first statement under the heading merce, that is not in compliance with ‘‘Warnings.’’ this section is subject to regulatory ac- (i) Oral dosage forms. ‘‘Taking more tion. than the recommended dose in 24 hours [63 FR 27843, May 21, 1998] can be harmful.’’ (ii) Rectal enema dosage forms. § 201.308 Ipecac syrup; warnings and ‘‘Using more than one enema in 24 directions for use for over-the- hours can be harmful.’’ counter sale. (3) Directions—(i) The labeling of all (a) It is estimated that each year orally or rectally administered OTC about 500,000 accidental poisonings drug products containing sodium occur in the United States and result phosphates shall contain the following in approximately 1,500 deaths, of which directions in boldface type imme- over 400 are children. In the emergency diately preceding the dosage informa- treatment of these poisonings, ipecac tion: ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) syrup is considered the emetic of ‘‘more unless directed by a doctor. See choice. The immediate availability of Warnings.’’ this drug for use in such situations is (ii) For products containing dibasic critical, since rapid treatment may be sodium phosphate/monobasic sodium the difference between life and death. phosphate identified in § 334.16(d) mar- The restriction of this drug to prescrip- keted as a solution. Adults and chil- tion sale limits its availability in dren 12 years of age and over: Oral dos- emergencies. On the other hand, it is age is dibasic sodium phosphate 3.42 to the consensus of informed medical 7.56 grams (g) and monobasic sodium opinion that ipecac syrup should be phosphate 9.1 to 20.2 g (20 to 45 mL di- used only under medical supervision in basic sodium phosphate/monobasic so- the emergency treatment of dium phosphate oral solution) as a sin- poisonings. In view of these facts, the gle daily dose. ‘‘Do not take more than question of whether ipecac syrup la- 45 mL (9 teaspoonfuls or 3 tablespoon- beled as an emergency treatment for fuls) in a 24-hour period.’’ Children 10 use in poisonings should be available and 11 years of age: Oral dosage is diba- over the counter has been controver- sic sodium phosphate 1.71 to 3.78 g and sial. monobasic sodium phosphate 4.5 to 10.1 (b) In connection with its study of g (10 to 20 mL dibasic sodium phos- this problem, the Food and Drug Ad- phate/monobasic sodium phosphate ministration has obtained the views of oral solution) as a single daily dose. medical authorities. It is the unani- ‘‘Do not take more than 20 mL (4 tea- mous recommendation of the American

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00094 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.310

Academy of Pediatrics, the American Drugs, in December 1963, appointed an Association of Poison Control Centers, ad hoc Advisory Committee of Inquiry the American Medical Association, and on Possible Nephrotoxicity Associated the Medical Advisory Board of the With the Abuse of Acetophenetidin Food and Drug Administration that ip- (Phenacetin)-Containing Preparations. ecac syrup in 1 fluid ounce containers This committee, composed of scientists be permitted to be sold without pre- in the fields of pharmacology and med- scription so that it will be readily icine, on April 23, 1964, submitted its available in the household for emer- findings and conclusions in the matter gency treatment of poisonings, under and recommended that all acetophe- medical supervision, and that the drug netidin (phenacetin)-containing prep- be appropriately packaged and labeled arations bear a warning as provided in for this purpose. section 502(f)(2) of the Federal Food, (c) In view of the above recommenda- Drug, and Cosmetic Act. tions, the Commissioner of Food and (b) On the basis of the studies made Drugs has determined that it is in the by the Food and Drug Administration interest of the public health for ipecac and the report of the Advisory Com- syrup to be available for sale without mittee, the Commissioner of Food and prescription, provided that it is pack- Drugs has concluded that it is nec- aged in a quantity of 1 fluid ounce (30 essary for the protection of users that milliliters), and its label bears, in addi- the label and labeling of all acetophe- tion to other required label informa- netidin (phenacetin)-containing prep- tion, the following, in a prominent and arations bear a warning statement to conspicuous manner: the following effect: ‘‘Warning—This (1) A statement conspicuously boxed medication may damage the kidneys and in red letters, to the effect: ‘‘For when used in large amounts or for a emergency use to cause vomiting in long period of time. Do not take more poisoning. Before using, call physician, than the recommended dosage, nor the Poison Control Center, or hospital take regularly for longer than 10 days emergency room immediately for ad- without consulting your physician.’’ vice.’’ (2) A warning to the effect: ‘‘Warn- § 201.310 Phenindione; labeling of ing—Keep out of reach of children. Do drug preparations intended for use not use in unconscious persons. Ordi- by man. narily, this drug should not be used if (a) Reports in the medical literature strychnine, corrosives such as alkalies and data accumulated by the Food and (lye) and strong acids, or petroleum Drug Administration indicate that distillates such as kerosine, gasoline, phenindione, a synthetic anticoagulant coal oil, fuel oil, paint thinner, or drug, has caused a number of cases of cleaning fluid have been ingested.’’ agranulocytosis (with two fatalities). (3) Usual dosage: 1 tablespoon (15 mil- There are also reports implicating the liliters) in persons over 1 year of age. drug in cases of hepatitis and hypersensitivity reactions. In view of the po- § 201.309 Acetophenetidin (phen- tentially serious effects found to be as- acetin)-containing preparations; sociated with preparations of this drug necessary warning statement. intended for use by man, the Commis- (a) In 1961, the Food and Drug Admin- sioner of Food and Drugs will regard istration, pursuant to its statutory re- such preparations as misbranded with- sponsibility for the safety and effec- in the meaning of section 502(f) (1) and tiveness of drugs shipped in interstate (2) of the Federal Food, Drug, and Cos- commerce, began an active investiga- metic Act, unless the label and label- tion of reports of possible toxic effects ing on or within the package from and renal damage due to misuse of the which the drug is to be dispensed, and drug acetophenetidin. This study led to any other labeling furnishing or pur- the decision that there was probable porting to furnish information for use cause to conclude that misuse and pro- of the drug, bear a conspicuous warn- longed use of the drug were in fact re- ing statement to the following effect: sponsible for kidney lesions and dis- ‘‘Warning: Agranulocytosis and hepa- ease. The Commissioner of Food and titis have been associated with the use

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00095 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.311 21 CFR Ch. I (4–1–19 Edition)

of phenindione. Patients should be in- In case of overdose, get medical help or structed to report promptly prodromal contact a Poison Control Center right symptoms such as marked fatigue, away,’’ or ‘‘Keep out of reach of chil- chill, fever, and sore throat. Periodic dren [highlighted in bold type],’’ except blood studies and liver function tests that if the article is an aspirin prepara- should be performed. Use of the drug tion, it shall bear the first of these should be discontinued if leukopenia warning statements. Such a warning occurs or if evidence of hyper- statement is required for compliance sensitivity, such as dermatitis or fever, with section 502(f)(2) of the Federal appears.’’ Food, Drug, and Cosmetic Act and is (b) Regulatory action may be initi- intended to guard against accidental ated with respect to preparations of poisonings. Safety closures that pre- phenindione intended for use by man vent access to the drug by young chil- found within the jurisdiction of the act dren are also recommended to guard on or after November 25, 1961, unless against accidental poisonings. such preparations are labeled in ac- (b) Effervescent preparations and cordance with paragraph (a) of this sec- preparations containing para- tion. aminosalicylate as the only salicylate ingredient are exempted from this la- § 201.311 [Reserved] beling requirement. (c) Aspirin tablets sold as such and § 201.312 Magnesium sulfate heptahy- containing no other active ingredients, drate; label declaration on drug except tablets which cannot be readily products. subdivided into a child’s dose because Magnesium sulfate heptahydrate of their coating or size, should always should be listed on the label of a drug bear dosage directions for each age product as epsom salt, which is its group down to 3 years of age, with a common or usual name. statement such as ‘‘For children under 3 years of age, consult your physician.’’ § 201.313 Estradiol labeling. It is recommended that: The article presently recognized in (1) Aspirin tablets especially made The National Formulary under the for pediatric use be produced only in heading ‘‘Estradiol’’ and which is said 11⁄4-grain size to reduce the hazard of to be ‘‘17-cis-beta estradiol’’ is the errors in dosage; same substance formerly recognized in (2) By June 1, 1967, manufacturers the United States Pharmacopeia under and distributors of 11⁄4-grain size aspi- the designation ‘‘Alpha Estradiol.’’ The rin tablets discontinue the distribution substance should no longer be referred of such tablets in retail containers con- to in drug labeling as ‘‘Alpha Estra- taining more than 36 tablets, to reduce diol.’’ The Food and Drug Administra- the hazard of accidental poisoning; tion would not object to label ref- (3) The flavoring of 5-grain aspirin erences to the article as simply ‘‘Es- tablets or other ‘‘adult aspirin tablets’’ tradiol’’; nor would it object if the be discontinued; and label of a preparation containing this (4) Labeling giving undue emphasis substance referred to the presence of to the pleasant flavor of flavored aspi- ‘‘Estradiol (formerly known as Alpha rin tablets be discontinued. Estradiol).’’ (d) Salicylate preparations other than aspirin tablets sold as such may, § 201.314 Labeling of drug prepara- at the option of the distributor, be lations containing salicylates. beled for use by adults only. If their la- (a) The label of any oral drug prepa- beling and advertising clearly offer ration intended for sale without pre- them for administration to adults only. scription and which contains any salic- (e)(1) It is the obligation of the dis- ylate ingredient (including aspirin, sal- tributor who labels a salicylate prepa- icylamide, other salicylates, and com- ration for administration to children binations) must conspicuously bear, on to make certain that the article is a clearly contrasting background, the suitable for such use and labeled with warning statement: ‘‘Keep out of reach adequate directions for use in the age of children [highlighted in bold type]. group for which it is offered, but in no

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00096 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.314

case should such an article bear direc- bear a caution such as, ‘‘Caution: Dis- tions for use in children under 3 years continue use if excessive irritation of of age. If the directions provide for ad- the skin develops. Avoid getting into ministration to children as young as 3 the eyes or on mucous membranes.’’ years of age, the label should bear the (See also § 201.303.) statement, ‘‘For children under 3 years (h)(1) The labeling of orally or rec- of age consult your physician.’’ How- tally administered over-the-counter ever, if the directions provide for ad- drug products containing aspirin or ministration to children only of an age nonaspirin salicylates as active ingre- greater than 3 years (for example, the dients subject to this paragraph is re- dosage instructions provide for admin- quired to prominently bear the fol- istration of the article to children only lowing warning: ‘‘Reye’s syndrome down to age 6), the label should bear a [subheading in bold type]: Children and statement such as, ‘‘For younger chil- teenagers who have or are recovering dren consult your physician.’’ from chicken pox or flu-like symptoms (2) A statement such as, ‘‘For chil- should not use this product. When dren under 3 years of age consult your using this product, if changes in behav- physician’’ or ‘‘For younger children ior with nausea and vomiting occur, consult your physician’’ is not required consult a doctor because these symp- on the label of an article clearly of- toms could be an early sign of Reye’s fered for administration to adults only. syndrome, a rare but serious illness.’’ (f) If the labeling or advertising of a (2) This warning statement shall ap- salicylate preparation offers it for use pear on the immediate container label- in arthritis or rheumatism, the label ing. In cases where the immediate con- and labeling should clearly state that tainer is not the retail package, the re- the beneficial effects claimed are lim- tail package also must bear the warn- ited to: ‘‘For the temporary relief of ing statement. In addition, the warning minor aches and pains of arthritis and statement shall appear on any labeling rheumatism.’’ The qualifying phrase that contains warnings and, in such ‘‘for the temporary relief of minor cases, the warning statement shall be aches and pains’’ should appear with the first warning statement under the the same degree of prominence and heading ‘‘Warnings.’’ conspicuousness as the phrase ‘‘arthritis and rheumatism’’. The label and la- (3) Over-the-counter drug products beling should bear in juxtaposition subject to this paragraph and labeled with such directions for use con- solely for use by children (pediatric spicuous warning statements to the ef- products) shall not recommend the fect: ‘‘Caution: If pain persists for more product for use in treating flu or chick- than 10 days, or redness is present, or en pox. in conditions affecting children under (4) Any product subject to paragraphs 12 years of age, consult a physician im- (h)(1), (h)(2), and (h)(3) of this section mediately.’’ The salicylate dosage that is not labeled as required by these should not exceed 60 grains in a 24-hour paragraphs and that is initially intro- period or 10 grains in a 4-hour period. If duced or initially delivered for intro- the article contains other analgesics, duction into interstate commerce after the salicylate dosage should be appro- the following dates is misbranded priately reduced. under sections 201(n) and 502(a) and (f) (g)(1) The label of any drug con- of the Federal Food, Drug, and Cos- taining more than 5 percent methyl sa- metic Act. licylate (wintergreen oil) should bear a (i) Compliance by October 18, 2004, for conspicuous warning such as: ‘‘Do not OTC drug products containing aspirin use otherwise than as directed.’’ These and nonaspirin salicylates as an active drug products must also include the ingredient and marketed under a new ‘‘Keep out of reach of children’’ warn- drug application or abbreviated new ing and the accidental ingestion warn- drug application. ing as required in § 330.1(g) of this chap- (ii) Compliance by April 19, 2004, for ter. OTC antidiarrheal and overindulgence (2) If the preparation is a counter- drug products that contain bismuth irritant or rubefacient, it should also subsalicylate as an active ingredient

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00097 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.315 21 CFR Ch. I (4–1–19 Edition)

and have annual sales greater than tinue to be dispensed and prescribed $25,000. for, use in the treatment of obesity, al- (iii) Compliance by April 18, 2005, for though their safety and effectiveness OTC antidiarrheal and overindulgence for that use have never been estab- drug products that contain bismuth lished. subsalicylate as an active ingredient (b) Drugs for human use with thyroid and have annual sales less than $25,000. hormone activity are misbranded with- (iv) Compliance dates for all other in the meaning of section 502 of the OTC drug products containing aspirin Federal Food, Drug, and Cosmetic Act and nonaspirin salicylates as an active unless their labeling bears the fol- ingredient and marketed under an OTC lowing boxed warning at the beginning drug monograph (for internal analge- of the ‘‘Warnings’’ section: sic, antipyretic, and antirheumatic drug products, or for menstrual drug products) will be established when the Drugs with thyroid hormone activity, final monographs for those products alone or together with other therapeutic are published in a future issue of the agents, have been used for the treatment of obesity. In euthyroid patients, doses FEDERAL REGISTER. In the interim, within the range of daily hormonal re- these products should continue to be quirements are ineffective for weight relabeled with the previous Reye’s syn- duction. Larger doses may produce seri- drome warning that appears in para- ous or even life-threatening manifesta- graph (h)(1) of this section. tions of toxicity, particularly when given in association with sympatho- [40 FR 13998, Mar. 27, 1985, as amended at 51 mimetic amines such as those used for FR 8182, Mar. 7, 1986; 53 FR 21637, June 9, their anorectic effects. 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR 18869, Apr. 17, 2003] [43 FR 22009, May 23, 1978] § 201.315 Over-the-counter drugs for minor sore throats; suggested warn- § 201.317 Digitalis and related ing. cardiotonic drugs for human use in oral dosage forms; required warn- The Food and Drug Administration ing. has studied the problem of the labeling of lozenges or troches containing a (a) Digitalis and related cardiotonic local anesthetic, chewing gum con- drugs for human use in oral dosage taining aspirin, various mouth washes forms have been promoted for, and con- and gargles and other articles sold over tinue to be dispensed and prescribed the counter for the relief of minor irri- for, use in the treatment of obesity, al- tations of the mouth or throat. It will though their safety and effectiveness not object to the labeling of suitable for that use have never been estab- articles of this type ‘‘For the tem- lished. porary relief of minor sore throats’’, (b) Digitalis and related cardiotonic provided this is immediately followed drugs for human use in oral dosage in the labeling with a warning state- forms are misbranded within the mean- ment in prominent type essentially as ing of section 502 of the Federal Food, follows: ‘‘Warning—Severe or per- Drug, and Cosmetic Act unless their la- sistent sore throat or sore throat ac- beling bears the following boxed warn- companied by high fever, headache, ing at the beginning of the ‘‘Warnings’’ nausea, and vomiting may be serious. section: Consult physician promptly. Do not use more than 2 days or administer to children under 3 years of age unless di- Digitalis alone or with other drugs has rected by physician.’’ been used in the treatment of obesity. This use of digoxin or other digitalis § 201.316 Drugs with thyroid hormone glycosides is unwarranted. Moreover, activity for human use; required since they may cause potentially fatal warning. arrhythmias or other adverse effects, the use of these drugs in the treatment (a) Drugs with thyroid hormone ac- of obesity is dangerous. tivity have been promoted for, and con-

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00098 Fmt 8010 Sfmt 8006 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.320

(c) This section does not apply to dig- this chapter) and may not be marketed oxin products for oral use, which shall without an approved new drug applica- be labeled according to the require- tion because the warnings and direc- ments of § 310.500 of this chapter. tions in paragraph (b) of this section have been found inadequate for these [43 FR 22009, May 23, 1978] products. § 201.319 Water-soluble gums, hydro- (b) Any drug products for human use philic gums, and hydrophilic containing a water-soluble gum, hydro- mucilloids (including, but not lim- philic gum, or hydrophilic mucilloid as ited to agar, alginic acid, calcium an active ingredient in an oral dosage polycarbophil, form when marketed in a dry or incom- carboxymethylcellulose sodium, pletely hydrated form as described in carrageenan, chondrus, paragraph (a) of this section are mis- glucomannan ((B-1,4 linked) branded within the meaning of section polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, 502 of the Federal Food, Drug, and Cos- plantago seed (psyllium), metic Act unless their labeling bears polycarbophil tragacanth, and xan- the following warnings (under the sub- than gum) as active ingredients; re- heading ‘‘Choking’’) and directions: quired warnings and directions. ‘‘ ‘Choking’ [highlighted in bold (a) Reports in the medical literature type]: Taking this product without and data accumulated by the Food and adequate fluid may cause it to swell Drug Administration indicate that and block your throat or esophagus and esophageal obstruction and asphyxia- may cause choking. Do not take this tion have been associated with the in- product if you have difficulty in swal- gestion of water-soluble gums, hydro- lowing. If you experience chest pain, philic gums, and hydrophilic vomiting, or difficulty in swallowing or mucilloids including, but not limited breathing after taking this product, to, agar, alginic acid, calcium seek immediate medical attention;’’ polycarbophil, carboxymethylcellulose and sodium, carrageenan, chondrus, ‘‘ ‘Directions’ [highlighted in bold glucomannan ((B–1,4 linked) type]:’’ (Select one of the following, as polymannose acetate), guar gum, appropriate: ‘‘Take’’ or ‘‘Mix’’) ‘‘this karaya gum, kelp, methylcellulose, product (child or adult dose) with at plantago seed (psyllium), least 8 ounces (a full glass) of water or polycarbophil, tragacanth, and xan- other fluid. Taking this product with- than gum. Esophageal obstruction and out enough liquid may cause choking. asphyxiation due to orally-adminis- See choking warning.’’ tered drug products containing water- (c) After February 28, 1994, any such soluble gums, hydrophilic gums, and OTC drug product initially introduced hydrophilic mucilloids as active ingre- or initially delivered for introduction dients are significant health risks into interstate commerce, or any such when these products are taken without drug product that is repackaged or re- adequate fluid or when they are used labeled after this date regardless of the by individuals with esophageal nar- date the product was manufactured, rowing or dysfunction, or with dif- initially introduced, or initially deliv- ficulty in swallowing. Additional label- ered for introduction into interstate ing is needed for the safe and effective commerce, that is not in compliance use of any OTC drug product for human with this section is subject to regu- use containing a water-soluble gum, latory action. hydrophilic gum, or hydrophilic [58 FR 45201, Aug. 26, 1993, as amended at 64 mucilloid as an active ingredient when FR 13292, Mar. 17, 1999; 72 FR 14674, Mar. 29, marketed in a dry or incompletely hy- 2007] drated form to include, but not limited to, the following dosage forms: Cap- § 201.320 Warning statements for drug sules, granules, powders, tablets, and products containing or manufac- wafers. Granular dosage forms con- tured with chlorofluorocarbons or taining psyllium are not generally rec- other ozone-depleting substances. ognized as safe and effective as OTC (a)(1) All drug products containing or laxatives (see § 310.545(a)(12)(i)(B) of manufactured with

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00099 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.323 21 CFR Ch. I (4–1–19 Edition)

chlorofluorocarbons, halons, carbon scribes special handling and storage tetrachloride, methyl chloride, or any conditions on the physician labeling: other class I substance designated by NOTE: The indented statement below is re- the Environmental Protection Agency quired by the Federal government’s Clean (EPA) shall, except as provided in para- Air Act for all products containing or manu- graph (b) or (c) of this section, bear the factured with chlorofluorocarbons (CFC’s) following warning statement: [or name of other class I substance, if applicable]: Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a sub- WARNING: Contains [or Manufactured with, stance which harms public health and the if applicable] [insert name of substance], a sub- environment by destroying ozone in the stance which harms public health and the upper atmosphere. environment by destroying ozone in the upper atmosphere. (2) The warning statement shall be A notice similar to the above WARNING clearly legible and conspicuous on the has been placed in the information for the product, its immediate container, its patient [or patient information leaflet, if ap- outer packaging, or other labeling in plicable] of this product under the Environ- accordance with the requirements of 40 mental Protection Agency’s (EPA’s) regula- CFR part 82 and appear with such tions. The patient’s warning states that the patient should consult his or her physician if prominence and conspicuousness as to there are questions about alternatives. render it likely to be read and under- stood by consumers under normal con- (c)(1) For over-the-counter drug prod- ditions of purchase. ucts for human use, the following al- (b)(1) For prescription drug products ternative warning statement may be for human use, the following alter- used: native warning statement may be used: NOTE: The indented statement below is required by the Federal government’s Clean NOTE: The indented statement below is re- Air Act for all products containing or manu- quired by the Federal government’s Clean factured with chlorofluorocarbons (CFC’s) Air Act for all products containing or manu- [or other class I substance, if applicable]: factured with chlorofluorocarbons (CFC’s) [or name of other class I substance, if appli- WARNING: Contains [or Manufactured with, cable]: if applicable] [insert name of substance], a substance which harms public health and envi- This product contains [or is manufactured ronment by destroying ozone in the upper at- with, if applicable] [insert name of substance], mosphere. a substance which harms the environment by CONSULT WITH YOUR PHYSICIAN OR destroying ozone in the upper atmosphere. HEALTH PROFESSIONAL IF YOU HAVE Your physician has determined that this ANY QUESTION ABOUT THE USE OF THIS product is likely to help your personal PRODUCT. health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE (2) The warning statement shall be BY YOUR PHYSICIAN. If you have any ques- clearly legible and conspicuous on the tions about alternatives, consult with your product, its immediate container, its physician. outer packaging, or other labeling in (2) The warning statement shall be accordance with the requirements of 40 clearly legible and conspicuous on the CFR part 82 and appear with such product, its immediate container, its prominence and conspicuousness as to outer packaging, or other labeling in render it likely to be read and under- accordance with the requirements of 40 stood by consumers under normal con- CFR part 82 and appear with such ditions of purchase. prominence and conspicuousness as to (d) This section does not replace or render it likely to be read and under- relieve a person from any requirements stood by consumers under normal con- imposed under 40 CFR part 82. ditions of purchase. [61 FR 20100, May 3, 1996] (3) If the warning statement in paragraph (b)(1) of this section is used, the § 201.323 Aluminum in large and small following warning statement must be volume parenterals used in total placed on the package labeling in- parenteral nutrition. tended to be read by the physician (a) The aluminum content of large (physician package insert) after the volume parenteral (LVP) drug products ‘‘How supplied’’ section, which de- used in total parenteral nutrition

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00100 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.325

(TPN) therapy must not exceed 25 WARNING: This product contains alu- micrograms per liter (μg/L). minum that may be toxic. Aluminum may (b) The package insert of LVP’s used reach toxic levels with prolonged parenteral administration if kidney function is im- in TPN therapy must state that the paired. Premature neonates are particularly drug product contains no more than 25 at risk because their kidneys are immature, μg/L of aluminum. This information and they require large amounts of calcium must be contained in the ‘‘Pre- and phosphate solutions, which contain alu- cautions’’ section of the labeling of all minum. large volume parenterals used in TPN Research indicates that patients with im- therapy. paired kidney function, including premature (c) Except as provided in paragraph neonates, who receive parenteral levels of aluminum at greater than 4 to 5 μg/kg/day (d) of this section, the maximum level accumulate aluminum at levels associated of aluminum present at expiry must be with central nervous system and bone tox- stated on the immediate container icity. Tissue loading may occur at even label of all small volume parenteral lower rates of administration. (SVP) drug products and pharmacy bulk packages (PBPs) used in the prep- (f) Applicants and manufacturers aration of TPN solutions. The alu- must use validated assay methods to minum content must be stated as fol- determine the aluminum content in parenteral drug products. The assay lows: ‘‘Contains no more than ll μg/L of aluminum.’’ The immediate con- methods must comply with current tainer label of all SVP’s and PBP’s good manufacturing practice requirements. Applicants must submit to the that are lyophilized powders used in Food and Drug Administration valida- the preparation of TPN solutions must tion of the method used and release contain the following statement: data for several batches. Manufactur- ‘‘When reconstituted in accordance ers of parenteral drug products not with the package insert instructions, subject to an approved application the concentration of aluminum will be must make assay methodology avail- no more than ll μg/L.’’ This max- able to FDA during inspections. Hold- imum level of aluminum must be stat- ers of pending applications must sub- ed as the highest of: mit an amendment under § 314.60 or (1) The highest level for the batches § 314.96 of this chapter. produced during the last 3 years; (2) The highest level for the latest [65 FR 4110, Jan. 26, 2000, as amended at 67 five batches, or FR 70691, Nov. 26, 2002; 68 FR 32981, June 3, 2003] (3) The maximum historical level, but only until completion of produc- § 201.325 Over-the-counter drugs for tion of the first five batches after July vaginal contraceptive and 26, 2004. spermicide use containing (d) If the maximum level of alu- nonoxynol 9 as the active ingre- minum is 25 μg/L or less, instead of dient; required warnings and label- stating the exact amount of aluminum ing information. as required in paragraph (c) of this sec- (a) Studies indicate that use of vag- tion, the immediate container label inal contraceptive drug products con- may state: ‘‘Contains no more than 25 taining nonoxynol 9 does not protect μg/L of aluminum.’’ If the SVP or PBP against infection from the human im- is a lyophilized powder, the immediate munodeficiency virus (HIV), the virus container label may state: ‘‘When re- that causes acquired immunodeficiency constituted in accordance with the syndrome (AIDS), or against the trans- package insert instructions, the con- mission of other sexually transmitted centration of aluminum will be no diseases (STDs). Studies also indicate more than 25 μg/L’’. that use of vaginal contraceptive drug (e) The package insert for all LVP’s, products containing nonoxynol 9 can all SVP’s, and PBP’s used in TPN must increase vaginal irritation, such as the contain a warning statement. This disruption of the vaginal epithelium, warning must be contained in the and also can cause epithelial disruption ‘‘Warnings’’ section of the labeling. when used in the rectum. These effects The warning must state: may increase the risk of transmission

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00101 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.326 21 CFR Ch. I (4–1–19 Edition)

of the AIDS virus (HIV) from an in- the retail package, under the ‘‘Other fected partner. Therefore, consumers information’’ section of the Drug Facts should be warned that these products labeling in accordance with do not protect against the trans- § 201.66(c)(7), or in a package insert: mission of the AIDS virus (HIV) or (1) ‘‘[bullet] studies have raised safe- other STDs, that use of these products ty concerns that products containing can increase vaginal and rectal irrita- the spermicide nonoxynol 9 can irritate tion, which may increase the risk of the vagina and rectum. Sometimes this getting the AIDS virus (HIV) from an irritation has no symptoms. This irri- HIV infected partner, and that the tation may increase the risk of getting products are not for rectal use. Con- HIV/AIDS from an infected partner’’. sumers should also be warned that (2) ‘‘[bullet] you can use nonoxynol 9 these products should not be used by for birth control with or without a dia- persons who have HIV/AIDS or are at phragm or condom if you have sex with high risk for HIV/AIDS. only one partner who is not infected (b) The labeling of OTC vaginal con- with HIV and who has no other sexual traceptive and spermicide drug prod- partners or HIV risk factors’’. ucts containing nonoxynol 9 as the ac- (3) ‘‘[bullet] use a latex condom with- tive ingredient, whether subject to the out nonoxynol 9 if you or your sex ongoing OTC drug review or an ap- partner has HIV/AIDS, multiple sex proved drug application, must contain partners, or other HIV risk factors’’. the following warnings under the head- (4) ‘‘[bullet] ask a health professional ing ‘‘Warnings,’’ in accordance with 21 if you have questions about your best CFR 201.66. birth control and STD prevention (1) ‘‘[bullet] For vaginal use only methods’’. [bullet] Not for rectal (anal) use’’ [both (e) Any drug product subject to this warnings in bold type]. section that is not labeled as required (2) ‘‘Sexually transmitted diseases and that is initially introduced or ini- (STDs) alert [in bold type]: This prod- tially delivered for introduction into uct does not [word ‘‘not’’ in bold type] interstate commerce after June 19, protect against HIV/AIDS or other 2008, is misbranded under section 502 of STDs and may increase the risk of get- the Federal Food, Drug, and Cosmetic ting HIV from an infected partner’’. Act (the act) (21 U.S.C. 352), is a new (3) ‘‘Do not use’’ [in bold type] if you drug under section 505 of the act (21 or your sex partner has HIV/AIDS. If U.S.C. 355), and is subject to regulatory you do not know if you or your sex action. partner is infected, choose another form of birth control’’. [72 FR 71785, Dec. 19, 2007] (4) ‘‘When using this product [in bold type] [optional, bullet] you may get § 201.326 Over-the-counter drug prod- vaginal irritation (burning, itching, or ucts containing internal analgesic/ a rash)’’. antipyretic active ingredients; re- (5) ‘‘Stop use and ask a doctor if [in quired warnings and other labeling. bold type] [optional, bullet] you or (a) Labeling. The labeling for all over- your partner get burning, itching, a the-counter (OTC) drug products con- rash, or other irritation of the vagina taining any internal analgesic/anti- or penis’’. pyretic active ingredients (including, (c) The labeling of this product states but not limited to, acetaminophen, as- under the ‘‘Other information’’ section pirin, carbaspirin calcium, choline sa- of the Drug Facts labeling in accord- licylate, ibuprofen, ketoprofen, magne- ance with § 201.66(c)(7), ‘‘[bullet] when sium salicylate, naproxen sodium, and used correctly every time you have sex, sodium salicylate) alone or in combina- latex condoms greatly reduce, but do tion must bear the following labeling not eliminate, the risk of catching or in accordance with §§ 201.60, 201.61, and spreading HIV, the virus that causes 201.66. AIDS. (1) Acetaminophen—(i) Statement of (d) The labeling of this product in- identity. The statement of identity ap- cludes the following statements either pears in accord with §§ 201.61 and 299.4 on the outside container or wrapper of of this chapter. The ingredient name

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00102 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.326

‘‘acetaminophen’’ must appear high- an outer and immediate container of a lighted (e.g., fluorescent or color con- retail package, this warning must ap- trast) or in bold type, be in lines gen- pear on both the outer and immediate erally parallel to the base on which the containers. If the immediate container package rests as it is designed to be is a blister card, the warning must ap- displayed, and be in one of the fol- pear on the blister card and remain in- lowing sizes, whichever is greater: tact and readable when drug product is (A) At least one-quarter as large as removed from the blister card. The the size of the most prominent printed warning does not need to be included matter on the principal display panel on each blister unit. (PDP), or (B) ‘‘Do not use with any other drug (B) At least as large as the size of the containing acetaminophen (prescrip- ‘‘Drug Facts’’ title, as required in tion or nonprescription). If you are not § 201.66(d)(2). The presence of acetami- sure whether a drug contains acetaminophen must appear as part of the es- nophen, ask a doctor or pharmacist.’’ tablished name of the drug, as defined (C) ‘‘Ask a doctor before use if you in § 299.4 of this chapter. Combination have liver disease’’. products containing acetaminophen (D) ‘‘Ask a doctor or pharmacist be- and a nonanalgesic ingredient(s) (e.g., fore use if you are taking the blood cough-cold) must include the name thinning drug warfarin’’ except on the ‘‘acetaminophen’’ and the name(s) of labeling of combination products that the other active ingredient(s) in the contain acetaminophen and NSAID(s). product on the PDP in accord with this paragraph. Only the name ‘‘acetami- (iv) For products labeled only for chil- nophen’’ must appear highlighted or in dren under 12 years of age. bold type, and in a prominent print (A) Warnings. The labeling of the size, as described in this paragraph. product states the following warnings (ii) Active Ingredient and Purpose under the heading ‘‘Warnings’’: Headings. The information required (1) The liver warning states ‘‘Liver under § 201.66(c)(2) and (c)(3) of this warning [heading in bold type]: This chapter must be included under these product contains acetaminophen. Se- headings. The information under these vere liver damage may occur if your headings, but not the headings, may child takes [bullet] more than 5 doses appear highlighted. in 24 hours, which is the maximum (iii) For products labeled for adults daily amount [optional: ‘for this prod- only. The labeling of the product states uct’] [bullet] with other drugs con- the following warnings under the head- taining acetaminophen’’. This ‘‘Liver’’ ing ‘‘Warnings’’: warning must be the first warning (A) The liver warning states ‘‘Liver under the ‘‘Warnings’’ heading. If there warning [heading in bold type]: This is an outer and immediate container of product contains acetaminophen. Se- a retail package, this warning must ap- vere liver damage may occur if you pear on both the outer and immediate take [bullet] more than [insert max- containers. If the immediate container imum number of daily dosage units] in is a blister card, the warning must ap- 24 hours, which is the maximum daily pear on the blister card and remain in- amount [optional: ‘for this product’] tact and readable when drug product is [bullet] with other drugs containing ac- removed from the blister card. The etaminophen [bullet] 3 or more alco- warning is not required to be included holic drinks every day while using this on each blister unit. product’’. This ‘‘Liver’’ warning must (2) ‘‘Do not use with any other drug be the first warning under the ‘‘Warn- containing acetaminophen (prescrip- ings’’ heading. For products that con- tion or nonprescription). If you are not tain both acetaminophen and aspirin, sure whether a drug contains acetami- this ‘‘Liver’’ warning must appear after nophen, ask a doctor or pharmacist.’’ the ‘‘Reye’s syndrome’’ and ‘‘Allergy (3) ‘‘Ask a doctor before use if your alert’’ warnings in § 201.66(c)(5)(ii)(A) child has liver disease’’. and (c)(5)(ii)(B) and before the ‘‘Stom- (4) ‘‘Ask a doctor or pharmacist be- ach bleeding’’ warning in paragraph fore use if your child is taking the (a)(2)(iii)(A) of this section. If there is blood thinning drug warfarin’’ except

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00103 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.326 21 CFR Ch. I (4–1–19 Edition)

on the labeling of combination prod- (i) Statement of identity. The state- ucts that contain acetaminophen and ment of identity appears in accord with NSAID(s). §§ 201.61 and 299.4 of this chapter. The (B) Directions. The labeling of the word ‘‘(NSAID)’’ must appear high- product contains the following infor- lighted (e.g., fluorescent or color con- mation under the heading ‘‘Direc- trast) or in bold type, be in lines gen- tions’’: ‘‘this product does not contain erally parallel to the base on which the directions or complete warnings for package rests as it is designed to be adult use’’ [in bold type]. displayed, and be in one of the fol- (v) For products labeled for adults and lowing sizes, whichever is greater: children under 12 years of age. The label- (A) At least one-quarter as large as ing of the product states all of the the size of the most prominent printed warnings in paragraphs (a)(1)(iii)(A), matter on the PDP, or (a)(1)(iii)(B), and (a)(1)(iii)(C) of this (B) At least as large as the size of the section with the following modifica- ‘‘Drug Facts’’ title, as required in tions: § 201.66(d)(2). The word ‘‘(NSAID)’’ must (A) The liver warning states ‘‘Liver appear as part of the established name warning [heading in bold type]: This of the drug, as defined in § 299.4 of this product contains acetaminophen. Se- chapter, or after the general pharma- vere liver damage may occur if [bullet] cological (principal intended) action of adult takes more than [insert max- the NSAID ingredient. Combination imum number of daily dosage units] in products containing an NSAID and a 24 hours, which is the maximum daily nonanalgesic ingredient(s) (e.g., cough- amount [optional: ‘for this product’] cold) must include the name of the [bullet] child takes more than 5 doses NSAID ingredient and the word in 24 hours [bullet] taken with other ‘‘(NSAID)’’ in accordance with this drugs containing acetaminophen [bul- paragraph, and the name(s) of the let] adult has 3 or more alcoholic other active ingredient(s) in the prod- drinks everyday while using this product on the PDP. Only the word uct.’’ If there is an outer and imme- ‘‘(NSAID)’’ needs to appear highlighted diate container of a retail package, or in bold type, and in a prominent this warning must appear on both the print size, as described in this para- outer and immediate containers. If the graph. immediate container is a blister card, (ii) Active Ingredient and Purpose the warning must appear on the blister Headings. The information required card and remain intact and readable under § 201.66(c)(2) and (c)(3) of this when drug product is removed from the chapter must be included under these blister card. The warning is not re- headings. The active ingredient(s) sec- quired to be included on each blister tion of the product’s labeling, as de- unit. fined in § 201.66(c)(2), contains the term (B) ‘‘Ask a doctor before use if the ‘‘(NSAID*)’’ after the NSAID active in- user has liver disease.’’ gredient with an asterisk statement at (C) ‘‘Do not use with any other drug the end of the active ingredient(s) sec- containing acetaminophen (prescription that defines the term ‘‘NSAID’’ tion or nonprescription). If you are not and states ‘‘* nonsteroidal anti-inflam- sure whether a drug contains acetami- matory drug.’’ The information under nophen, ask a doctor or pharmacist.’’ these headings may appear highlighted. (D) ‘‘Ask a doctor or pharmacist be- However, the headings ‘‘Active Ingre- fore use if the user is taking the blood dient’’ and ‘‘Purpose’’ may not appear thinning drug warfarin’’ except on the highlighted. labeling of combination products that (iii) For products labeled for adults contain acetaminophen and NSAID(s). only. The labeling of the product states (2) Nonsteroidal anti-inflammatory an- the following warnings under the head- algesic/antipyretic active ingredients—in- ing ‘‘Warnings’’: cluding, but not limited to, aspirin, (A) The stomach bleeding warning carbaspirin calcium, choline salicylate, states ‘‘Stomach bleeding warning ibuprofen, ketoprofen, magnesium salicy- [heading in bold type]: This product late, naproxen sodium, and sodium salicy- contains an NSAID, which may cause late. severe stomach bleeding. The chance is

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00104 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.326

higher if you [bullet] are age 60 or older [bullet] takes a blood thinning (anti- [bullet] have had stomach ulcers or coagulant) or steroid drug [bullet] bleeding problems [bullet] take a blood takes other drugs containing prescrip- thinning (anticoagulant) or steroid tion or nonprescription NSAIDs (aspi- drug [bullet] take other drugs con- rin, ibuprofen, naproxen, or others) taining prescription or nonprescription [bullet] takes more or for a longer time NSAIDs (aspirin, ibuprofen, naproxen, than directed’’. The ‘‘Stomach bleed- or others) [bullet] have 3 or more alco- ing’’ warning must appear after the holic drinks every day while using this ‘‘Reye’s syndrome’’ and ‘‘Allergy product [bullet] take more or for a alert’’ warnings in § 201.66(c)(5)(ii)(A) longer time than directed’’. This and (c)(5)(ii)(B). If there is an outer and ‘‘Stomach bleeding’’ warning must ap- immediate container of a retail pack- pear after the ‘‘Reye’s syndrome’’ and age, this warning must appear on both ‘‘Allergy alert’’ warnings in the outer and immediate containers. If § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For the immediate container is a blister products that contain both acetamino- card, the warning must appear on the phen and aspirin, the acetaminophen blister card and remain intact and ‘‘Liver’’ warning in paragraph (a)(1)(iii) readable when drug product is removed of this section must appear before the from the blister card. The warning is ‘‘Stomach bleeding’’ warning in this not required to be included on each paragraph. If there is an outer and im- blister unit. mediate container of a retail package, (2) ‘‘Ask a doctor before use if [bul- this warning must appear on both the let] stomach bleeding warning applies outer and immediate containers. If the to your child [bullet] child has a his- immediate container is a blister card, tory of stomach problems, such as the warning must appear on the blister heartburn [bullet] child has not been card and remain intact and readable drinking fluids [bullet] child has lost a when drug product is removed from the lot of fluid due to vomiting or diarrhea blister card. The warning is not re- [bullet] child has high blood pressure, quired to be included on each blister heart disease, liver cirrhosis, or kidney unit. disease [bullet] child is taking a diu- (B) ‘‘Ask a doctor before use if [bul- retic’’. let] stomach bleeding warning applies (3) ‘‘Stop use and ask a doctor if [bul- to you [bullet] you have a history of let] child experiences any of the fol- stomach problems, such as heartburn lowing signs of stomach bleeding:’’ [add [bullet] you have high blood pressure, the following as second level of state- heart disease, liver cirrhosis, or kidney ments: [bullet] feels faint [bullet] vom- disease [bullet] you are taking a diu- its blood [bullet] has bloody or black retic’’. stools [bullet] has stomach pain that (C) ‘‘Stop use and ask a doctor if does not get better’’]. [bullet] you experience any of the fol- (B) Directions. The labeling of the lowing signs of stomach bleeding:’’ [add product contains the following infor- the following as second level of state- mation under the heading ‘‘Direc- ments: ‘‘[bullet] feel faint [bullet] tions’’: ‘‘this product does not contain vomit blood [bullet] have bloody or directions or complete warnings for black stools [bullet] have stomach pain adult use’’ [in bold type]. that does not get better’’]. (v) For products labeled for adults and (iv) For products labeled only for chil- children under 12 years of age. The label- dren under 12 years of age. ing of the product states all of the (A) Warnings. The labeling of the warnings in paragraphs (a)(2)(iii)(A) product states the following warnings through (a)(2)(iii)(C) of this section under the heading ‘‘Warnings’’: with the following modifications: (1) The stomach bleeding warning (A) The Stomach bleeding warning states ‘‘Stomach bleeding warning states ‘‘Stomach bleeding warning [heading in bold type]: This product [heading in bold type]: This product contains an NSAID, which may cause contains an NSAID, which may cause severe stomach bleeding. The chance is severe stomach bleeding. The chance is higher if your child [bullet] has had higher if the user [bullet] has had stomach ulcers or bleeding problems stomach ulcers or bleeding problems

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00105 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.327 21 CFR Ch. I (4–1–19 Edition)

[bullet] takes a blood thinning (anti- (1) At least one-quarter as large as coagulant) or steroid drug [bullet] the size of the most prominent printed takes other drugs containing prescrip- matter on the PDP, or tion or nonprescription NSAIDs (aspi- (2) At least as large as the size of the rin, ibuprofen, naproxen, or others) ‘‘Drug Facts’’ title, as required in [bullet] takes more or for a longer time § 201.66(d)(2). The new warnings infor- than directed [bullet] is age 60 or older mation statement must remain on the [bullet] has 3 or more alcoholic drinks PDP of the drug product for at least 1 everyday while using this product’’. year from the date the product is ini- The ‘‘Stomach bleeding’’ warning must tially introduced into interstate com- appear after the ‘‘Reye’s syndrome‘‘ merce. and ‘‘Allergy alert’’ warnings in (c) Requirements to supplement ap- § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If proved application. Holders of approved there is an outer and immediate con- applications for OTC drug products tainer of a retail package, this warning that contain internal analgesic/anti- must appear on both the outer and im- pyretic active ingredients that are sub- mediate containers. If the immediate ject to the requirements of paragraph container is a blister card, the warning (a) of this section must submit supple- must appear on the blister card and re- ments under § 314.70(c) of this chapter main intact and readable when drug to include the required information in product is removed from the blister the product’s labeling. Such labeling card. The warning is not required to be may be put into use without advance included on each blister unit. approval of FDA provided it includes at (B) The labeling states ‘‘Ask a doctor least the exact information included in before use if [bullet] stomach bleeding paragraph (a) of this section. warning applies to user [bullet] user has history of stomach problems, such [74 FR 19407, Apr. 29, 2009, as amended at 74 as heartburn [bullet] user has high FR 31180, June 30, 2009; 74 FR 61514, Nov. 25, blood pressure, heart disease, liver cir- 2009] rhosis, or kidney disease [bullet] user takes a diuretic [bullet] user has not § 201.327 Over-the-counter sunscreen drug products; required labeling been drinking fluids [bullet] user has based on effectiveness testing. lost a lot of fluid due to vomiting or diarrhea’’. The following provisions apply to (C) The labeling states ‘‘Stop use and sunscreen products containing amino- ask a doctor if [bullet] user experiences benzoic acid, avobenzone, cinoxate, any of the following signs of stomach dioxybenzone, ensulizole, homosalate, bleeding:’’ [add the following as second meradimate, octinoxate, octisalate, level of statements: [bullet] feels faint octocrylene, oxybenzone, padimate O, [bullet] vomits blood [bullet] has sulisobenzone, titanium dioxide, bloody or black stools [bullet] has trolamine salicylate, or zinc oxide, stomach pain that does not get bet- alone or in combination. The provi- ter’’]. sions do not apply to sunscreen prod- (b) New warnings information state- ucts marketed under approved new ment. The labeling of any drug product drug applications or abbreviated new subject to this section that is initially drug applications. introduced or initially delivered for in- (a) Principal display panel. In addition troduction into interstate commerce to the statement of identity in para- before or on April 29, 2010, must bear on graph (b) of this section, the following its PDP, as defined in § 201.60, the labeling shall be prominently placed on statement ‘‘See new warnings informa- the principal display panel: tion’’. This statement must appear (1) Effectiveness claim—(i) For products highlighted (e.g., fluorescent or color that pass the broad spectrum test in para- contrast) or in bold type, be in lines graph (j) of this section. (A) The labeling generally parallel to the base on which states ‘‘Broad Spectrum SPF [insert the package rests as it is designed to be numerical SPF value resulting from displayed, and be in one of the fol- testing under paragraph (i) of this sec- lowing sizes, whichever is greater: tion]’’.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00106 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 201.327

(B) Prominence. The Broad Spectrum ment in addition to the indication in SPF statement shall appear as contin- § 201.327(c)(1): ‘‘[Bullet] if used as di- uous text with no intervening text or rected with other sun protection meas- graphic. The entire text shall appear in ures (see Directions [in bold italic the same font style, size, and color font]), decreases the risk of skin cancer with the same background color. and early skin aging caused by the (ii) For sunscreen products that do not sun’’. pass the broad spectrum test in paragraph (3) Any labeling or promotional ma- (j) of this section. The labeling states terials that suggest or imply that the ‘‘SPF [insert numerical SPF value re- use, alone, of any sunscreen reduces sulting from testing under paragraph the risk of or prevents skin cancer or (i) of this section]’’. The entire text early skin aging will cause the product shall appear in the same font style, to be misbranded under section 502 of size, and color with the same back- the FD&C Act (21 U.S.C. 352). ground color. (d) Warnings. The labeling of the (2) Water resistance statements—(i) For product contains the following warn- products that provide 40 minutes of water resistance according to the test in para- ings under the heading ‘‘Warnings’’. graph (i)(7)(i) of this section. The label- (1) For all sunscreen products. (i) The ing states ‘‘Water Resistant (40 min- labeling states ‘‘Do not use [bullet] on utes)’’. damaged or broken skin’’. (ii) For products that provide 80 min- (ii) The labeling states ‘‘When using utes of water resistance according to the this product [bullet] keep out of eyes. test in paragraph (i)(7)(ii) of this section. Rinse with water to remove.’’ The labeling states ‘‘Water Resistant (iii) The labeling states ‘‘Stop use (80 minutes)’’. and ask a doctor if [bullet] rash oc- (b) Statement of identity. The labeling curs’’. of the product contains the established (2) For sunscreen products that are name of the drug, if any, and identifies broad spectrum with SPF values of at the drug as a ‘‘sunscreen.’’ least 2 but less than 15 according to the (c) Indications. The labeling of the SPF test in paragraph (i) of this section or product states, under the heading that do not pass the broad spectrum test ‘‘Uses,’’ the phrases listed in this para- in paragraph (j) of this section. The first graph (c), as appropriate. Other truth- statement under the heading ‘‘Warn- ful and nonmisleading statements, de- ings’’ states ‘‘Skin Cancer/Skin Aging scribing only the uses that have been Alert [in bold font]; Spending time in established and listed in this paragraph the sun increases your risk of skin can- (c), may also be used, as provided in cer and early skin aging. This product § 330.1(c)(2) of this chapter, subject to has been shown only to help prevent the provisions of section 502 of the Fed- sunburn, not [in bold font] skin cancer eral Food, Drug, and Cosmetic Act (the or early skin aging.’’ FD&C Act) relating to misbranding and (e) Directions. The labeling of the the prohibition in section 301(d) of the product contains the following state- FD&C Act against the introduction or ments, as appropriate, under the head- delivery for introduction into inter- ing ‘‘Directions.’’ More detailed direc- state commerce of unapproved new tions applicable to a particular product drugs in violation of section 505(a) of formulation may also be included. the FD&C Act. (1) For all sunscreen products, the (1) For all sunscreen products. (i) As an following indication statement must be option, the labeling may state ‘‘For included under the heading ‘‘Uses’’: sunscreen use:’’. ‘‘[Bullet] helps prevent sunburn’’. See (ii) The labeling states ‘‘[bullet] § 201.66(b)(4) of this chapter for defini- apply [select one of the following: ‘Lib- tion of bullet. erally’ or ‘generously’] [and, as an op- (2) For sunscreen products with a tion: ‘And evenly’] 15 minutes before Broad Spectrum SPF value of 15 or sun exposure’’. higher according to the tests in para- (iii) As an option, the labeling may graphs (i) and (j) of this section, the la- state ‘‘[bullet] apply to all skin ex- beling may include the following state- posed to the sun’’.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00107 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.327 21 CFR Ch. I (4–1–19 Edition)

(iv) The labeling states ‘‘[bullet] chil- § 347.50(e) of this chapter shall not dren under 6 months of age: Ask a doc- apply to these products. tor’’. (i) SPF test procedure—(1) UV source (2) For sunscreen products with a Broad (solar simulator). (i) Emission spectrum. A Spectrum SPF value of 15 or higher ac- single port or multiport solar simu- cording to the tests in paragraphs (i) and lator should be filtered so that it pro- (j) of this section. The labeling states vides a continuous emission spectrum ‘‘[bullet] Sun Protection Measures. [in from 290 to 400 nanometers (nm) with a bold font] Spending time in the sun in- limit of 1,500 Watts per square meter creases your risk of skin cancer and (W/m2) on total irradiance for all wave- early skin aging. To decrease this risk, lengths between 250 and 1,400 nm. regularly use a sunscreen with a Broad (A) The solar simulator should have Spectrum SPF value of 15 or higher the following percentage of erythema- and other sun protection measures ineffective radiation in each specified cluding: [Bullet] limit time in the sun, range of wavelengths: especially from 10 a.m.–2 p.m. [bullet] wear long-sleeved shirts, pants, hats, SOLAR SIMULATOR EMISSION SPECTRUM and sunglasses’’. Wavelength range (nm) Percent erythemal (3) For products that satisfy the water contribution 1 resistance test in paragraph (i)(7) of this section. The labeling states ‘‘[bullet] re- <290 ...... <0.1 apply: [Bullet] after [select one of the 290–300 ...... 1.0–8.0 following determined by water resist- 290–310 ...... 49.0–65.0 290–320 ...... 85.0–90.0 ance test: ‘40 minutes of’ or ‘80 minutes 290–330 ...... 91.5–95.5 of’] swimming or sweating [bullet] im- 290–340 ...... 94.0–97.0 mediately after towel drying [bullet] at 290–400 ...... 99.9–100.0 least every 2 hours’’. 1 Calculation of erythema action spectrum described in (4) For products that do not satisfy the § 201.327(i)(1)(ii) of this section. water resistance test in paragraph (i)(7) of (B) In addition, UVA II (320–340 nm) this section. The labeling states ‘‘[bul- irradiance should equal or exceed 20 let] reapply at least every 2 hours [bul- percent of the total UV (290–400 nm) ir- let] use a water resistant sunscreen if radiance. UVA I (340–400 nm) irradiance swimming or sweating’’. should equal or exceed 60 percent of the (f) Other information. The labeling of total UV irradiance. the product contains the following (ii) Erythema action spectrum. (A) Cal- statement under the heading ‘‘Other culate the erythema action spectrum information:’’ ‘‘[bullet] protect the weighting factor (Vi) at each wave- product in this container from exces- length λ: sive heat and direct sun’’. (1) Vi (λ) = 1.0 (250 <λ ≤298 nm) (g) False and misleading claims. There 0.094 298·λ) (2) Vi (λ) = 10 * ( (298 <λ ≤328 are claims that would be false and/or nm) misleading on sunscreen products. (3) V (λ) = 100.015* (140·λ) (328 <λ ≤400 These claims include but are not lim- i nm) ited to the following: ‘‘Sunblock,’’ (B) Calculate the erythema-effective ‘‘sweatproof,’’ and ‘‘waterproof.’’ These UV dose (E) delivered by a solar simu- or similar claims will cause the prod- lator as follows: uct to be misbranded under section 502 of the FD&C Act (21 U.S.C. 352). (h) Labeling of products containing a combination of sunscreen and skin pro- Where Vi(λ) = erythema action spectrum tectant active ingredients. Statements of weighting factor at each wavelength λ identity, indications, warnings, and di- I(λ) = irradiance (Watts per square meter) at rections for use, respectively, applica- each wavelength λ ble to each ingredient in the product t = exposure time (seconds) may be combined to eliminate duplica- tive words or phrases so that the re- Erythema-effective dose (E) is ex- sulting information is clear and under- pressed as effective Joules per square standable. Labeling provisions in meter (J/m2-eff).

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00108 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17JN11.002 Food and Drug Administration, HHS § 201.327

(C) The emission spectrum must be is any change in the lamp bulb or the determined using a handheld radiom- optical filtering components (i.e., fil- eter with a response weighted to match ters, mirrors, lenses, collimating de- the spectrum in ISO 17166 CIE S 007/E vices, or focusing devices). Daily solar entitled ‘‘Erythemal reference action simulator radiation intensity should be spectrum and standard erythema monitored with a broadband radiom- dose,’’ dated 1999 (First edition, 1999– eter with a response weighted to match 12–15; corrected and reprinted 2000–11– the erythema action spectrum in ISO 15), which is incorporated by reference 17166 CIE S 007/E entitled ‘‘Erythemal in accordance with 5 U.S.C. 552(a) and 1 reference action spectrum and standard CFR part 51. You may obtain a copy erythema dose,’’ which is incorporated from the ISO Copyright Office, Case by reference in paragraph (i)(1)(ii)(C) of Postale 56, CH–1211, Geneva 20, Switzer- this section. If a lamp must be replaced land, telephone +41–22–749–01–11 or fax due to failure or aging during a +41–22–74–09–47. http://www.iso.org. You phototest, broadband device readings may inspect a copy at the Center for consistent with those obtained for the Drug Evaluation and Research, 10903 original calibrated lamp will suffice New Hampshire Ave., Bldg. 22, Silver until measurements can be performed Spring, MD 20993, call 301–796–2090, or with the spectroradiometer at the ear- at the National Archives and Records liest possible opportunity. Administration (NARA). For informa- (2) SPF standard—(i) Preparation. The tion on the availability of this mate- SPF standard should be a formulation rial at NARA, call 202–741–6030, or go containing 7-percent padimate O and 3- to: http://www/archives.gov/ percent oxybenzone. federallregister/ codeloflfederallregulations/ COMPOSITION OF THE PADIMATE O/OXYBENZONE ibrllocations.html. The solar simulator SPF STANDARD output should be measured before and Percent by after each phototest or, at a minimum, Ingredients weight at the beginning and end of each test day. This radiometer should be cali- Part A: Lanolin ...... 4.50 brated using side-by-side comparison Cocoa butter ...... 2.00 with the spectroradiometer (using the Glyceryl monostearate ...... 3.00 weighting factors determined accord- Stearic acid ...... 2.00 ing to paragraph (i)(1)(ii)(A) of this sec- Padimate O ...... 7.00 Oxybenzone ...... 3.00 tion) at the time of the annual Part B: spectroradiometric measurement of Purified water USP ...... 71.60 the solar simulator as described in Sorbitol solution ...... 5.00 Triethanolamine, 99 percent ...... 1.00 paragraph (i)(1)(iv) of this section. Methylparaben ...... 0.30 (iii) Operation. A solar simulator Propylparaben ...... 0.10 should have no significant time-related Part C: fluctuations (within 20 percent) in radi- Benzyl alcohol ...... 0.50 Part D: ation emissions after an appropriate Purified water USP ...... QS 1 warm-up time and demonstrate good 1 beam uniformity (within 20 percent) in Quantity sufficient to make 100 grams. the exposure plane. The delivered dose Step 1. Add the ingredients of Part A to the UV exposure site must be within into a suitable stainless steel kettle 10 percent of the expected dose. equipped with a propeller agitator. Mix (iv) Periodic measurement. To ensure at 77 to 82 °C until uniform. that the solar simulator delivers the Step 2. Add the water of Part B into appropriate spectrum of UV radiation, a suitable stainless steel kettle the emission spectrum of the solar sim- equipped with a propeller agitator and ulator should be measured at least an- begin mixing at 77 to 82 °C. Add the re- nually with an appropriate and accu- maining ingredients of Part B and mix rately calibrated spectroradiometer until uniform. system (results should be traceable to Step 3. Add the batch of Step 1 to the the National Institute for Standards batch of Step 2 and mix at 77 to 82 °C and Technology). In addition, the solar until smooth and uniform. Slowly cool simulator must be recalibrated if there the batch to 49 to 54 °C.

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00109 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.327 21 CFR Ch. I (4–1–19 Edition)

Step 4. Add the benzyl alcohol of Part (C) HPLC system suitability. (1) Make C to the batch of Step 3 at 49 to 54 °C. three replicate 10-microliter injections Mix until uniform. Continue to cool of the HPLC reference standard (de- batch to 35 to 41 °C. scribed in paragraph (i)(2)(ii)(B) of this Step 5. Add sufficient water of Part D section). The relative standard devi- to the batch of Step 4 at 35 to 41 °C to ation in peak areas should not be more obtain 100 grams of SPF standard. Mix than 2.0 percent for either oxybenzone until uniform. Cool batch to 27 to 32 °C. or padimate O. (ii) HPLC assay. Use the following (2) Calculate the resolution (R) be- high performance liquid chroma- tween the oxybenzone and padimate O tography (HPLC) procedure to verify peaks from one chromatogram as fol- the concentrations of padimate O and lows: oxybenzone in the SPF standard: (A) Instrumentation. (1) Equilibrate a suitable liquid chromatograph to the following or equivalent conditions:

(i) Column .. C–18, 250 millimeters Where to = retention time for oxybenzone (mm) length, 4.6 mm tp = retention time for padimate O W = oxybenzone peak width at baseline inner diameter (5 mi- o W = padimate O peak width at baseline crons) p (ii) Mobile 85:15:0.5 methanol: If the resolution (R) is less than 3.0, ad- Phase. water: acetic acid just the mobile phase or replace the (iii) Flow 1.5 milliliters (mL) per column. Rate. minute (D) SPF standard assay—(1) The SPF (iv) Tem- Ambient standard is diluted to the same con- perature. centration as the HPLC reference (v) Detector UV spectrophotometer standard according to the following at 308 nanometers steps: (vi) Attenu- As needed ation. (i) Step 1. Weigh 1.0 g of the SPF standard (described in paragraph (i)(2)(i) of this section) into a 50-mL (2) Use HPLC grade reagents for mo- volumetric flask. bile phase. (B) Preparation of the HPLC reference (ii) Step 2. Add approximately 30 mL standard. (1) Weigh 0.50 gram (g) of of isopropanol and heat with swirling oxybenzone USP reference standard until contents are evenly dispersed. into a 250-mL volumetric flask. Dis- (iii) Step 3. Cool to room temperature solve and dilute to volume with (15 to 30 °C) and dilute to volume with isopropanol. Mix well. isopropanol. Mix well. (2) Weigh 0.50 g of padimate O USP (iv) Step 4. Pipet 5.0 mL of the prepa- reference standard into a 250-mL volu- ration into a 50-mL volumetric flask metric flask. Dissolve and dilute to and dilute to volume with isopropanol. volume with isopropanol. Mix well. Mix well. (3) Pipet 3.0 mL of the oxybenzone so- (2)(i) Inject 10-microliter of diluted lution and 7.0 mL of the padimate O so- SPF standard from paragraph lution into a 100-mL volumetric flask. (i)(2)(D)(1) of this section and calculate Dilute to volume with isopropanol and the amount of oxybenzone and mix well. padimate O as follows:

100

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00110 Fmt 8010 Sfmt 8006 Y:\SGML\247073.XXX 247073 ER17JN11.003 ER17JN11.004 Food and Drug Administration, HHS § 201.327

(ii) The percent of oxybenzone and corneum and temporarily alter the padimate O in the SPF standard should skin’s response to UV radiation. be between 95 and 105. (iv) Informed consent. Obtain legally (3) Test subjects—(i) Number of subjects. effective written informed consent A test panel should include enough from all test subjects. subjects to produce a minimum of 10 (4) Sunscreen application. (i) Test site. valid test results. A maximum of three Test sites are locations on each sub- subjects may be rejected from this ject’s back, between the beltline and panel based on paragraph (i)(5)(v)) of the shoulder blades (scapulae) and lat- this section. eral to the midline, where skin re- (ii) Medical history. (A) Obtain a med- sponses to UV radiation are deter- ical history from each subject with em- mined. Responses on unprotected skin phasis on the effects of sunlight on the (no test material applied) and pro- subject’s skin. Determine that each tected skin (sunscreen test product(s) subject is in good general health with or SPF standard applied) are deter- skin type I, II, or III as follows: mined at separate unprotected and pro- (1) Always burns easily; never tans tected test sites, respectively. Test (sensitive). sites should be randomly located in a (2) Always burns easily; tans mini- blinded manner. Each test site should mally (sensitive). be a minimum of 30 square centimeters (3) Burns moderately; tans gradually and outlined with indelible ink. (light brown) (normal). (ii) Test subsite. Test subsites are the (4) Burns minimally; always tans locations to which UV radiation is ad- well (moderate brown) (normal). ministered within a test site. At least (5) Rarely burns; tans profusely (dark five test subsites should receive UV brown) (insensitive). doses within each test site. Test (6) Never burns; deeply pigmented subsites should be at least 0.5 square (insensitive). centimeters (cm2) in area and should be (B) Skin type is based on first 30 to 45 separated from each other by at least minutes of sun exposure after a winter 0.8 cm. Each test subsite should be out- season of no sun exposure. Determine lined with indelible ink. that each subject is not taking topical (iii) Applying test materials. Apply the or systemic medication that is known sunscreen test product and the SPF to alter responses to UV radiation. De- standard at 2 milligrams per square termine that each subject has no his- centimeter (mg/cm2) to their respective tory of sensitivities to topical products test sites. Use a finger cot compatible and/or abnormal responses to sunlight, with the sunscreen to spread the prod- such as a phototoxic or photoallergic uct as evenly as possible. response. (iv) Waiting period. Wait at least 15 (iii) Physical examination. Conduct a minutes after applying a sunscreen physical examination to determine the product before exposing the test sites presence of sunburn, suntan, scars, ac- to UV radiation as described in para- tive dermal lesions, and uneven skin graph (i)(5)) of this section. For water tones on the areas of the back to be resistant sunscreen products, proceed tested. A suitable source of low power with the water resistance testing pro- UVA, such as a Woods lamp, is helpful cedure described in paragraph (i)(7) of in this process. If any of these condi- this section after waiting at least 15 tions are present, the subject is not minutes. qualified to participate in the study. (5) UV exposure—(i) Definition of mini- The presence of nevi, blemishes, or mal erythema dose (MED). The minimal moles will be acceptable if, in the phy- erythema dose (MED) is the smallest sician’s judgment, they will neither UV dose that produces perceptible red- compromise the study nor jeopardize a ness of the skin (erythema) with clear- subject’s safety. Subjects with ly defined borders at 16 to 24 hours dysplastic nevi should not be enrolled. after UV exposure. The MED for unpro- Excess hair on the back is acceptable if tected skin (MEDu) is determined on a the hair is clipped. Shaving is unac- test site that does not have sunscreen ceptable because it may remove a sig- applied. The MED for protected skin nificant portion of the stratum (MEDp) is determined on a test site 101

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00111 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.327 21 CFR Ch. I (4–1–19 Edition)

that has sunscreen applied. An MEDp is which fades in 30 to 60 minutes. After determined for the SPF standard the immediate responses are noted, (ssMEDp). An MEDp is determined for each subject should shield the exposed the sunscreen test product (tpMEDp). area from further UV radiation until (ii) UV exposure for initial MEDu. For the MED is determined. Determine the each test subject, administer a series of MED 16 to 24 hours after UV exposure. UV radiation doses expressed as J/m2- Because erythema is evaluated 16 to 24 eff (as determined according to para- hours after UV exposure, the final graph (a)(2) of this section) to the test MEDu, ssMEDp, and tpMEDp are typi- subsites within an unprotected test cally determined the day following de- site using an accurately calibrated termination of the initial MEDu. Evalu- solar simulator. Select doses that are a ate the erythema responses of each test geometric series represented by 1.25n subsite using either tungsten or warm (i.e., each dose is 25 percent greater white fluorescent lighting that pro- than the previous dose). vides at least 450 lux of illumination at (iii) UV exposure for final MEDu, the test site. For the evaluation, the ssMEDp, and tpMEDp. For each subject, test subject should be in the same posi- determine the final MEDu, ssMEDp, and tion as when the test site was irradi- tpMEDp by administering a series of ated. five UV doses to the appropriate test (v) Invalid test data. Reject test data sites. The middle dose (X) in each of for a test subject if erythema is not these dose series (i.e., the third dose) present on either the unprotected or should equal the initial MEDu times protected test sites; or erythema is the expected SPF. Note that the ex- present at all subsites; or the responses pected SPF equals 1 and 16.3 for the are inconsistent with the series of UV final MEDu and ssMEDp, respectively. doses administered; or the subject was The remaining UV doses in the series noncompliant (e.g., the subject with- depend upon the expected SPF value of draws from the test due to illness or the sunscreen test product(s). work conflicts or does not shield the For products with an expected SPF exposed testing sites from further UV less than 8, administer UV doses that radiation until the MED is deter- increase by 25 percent with each suc- mined). cessive dose (i.e., 0.64X, 0.80X, 1.00X, (6) Determination of SPF. (i) Calculate 1.25X, and 1.56X). For products with an an SPF value for each test subject expected SPF from 8 to 15, administer (SPFi) as follows: UV doses that increase by 20 percent with each successive dose (i.e., 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X). For products with an expected SPF higher than 15, administer UV doses that increase (ii) Calculate the mean by 15 percent with each successive dose (i.e., 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X). and the standard deviation (s) from the (iv) Evaluation of test subsites. In SPFi values. Calculate the standard order that the person who evaluates error (SE), which equals s/√n (where n the test subsites is not biased, he/she equals the number of subjects who pro- should not be the same person who ap- vided valid test results). Obtain the t plied the sunscreen drug product to the value from Student’s t distribution test site or administered the UV doses. table corresponding to the upper 5-per- After UV doses are administered, all cent point with n—1 degrees of free- immediate responses should be re- dom. Determine the labeled SPF value, corded. These may include an imme- which equals the largest whole number diate darkening or tanning, typically less than grayish or purplish in color, which fades in 30 to 60 minutes; an immediate reddening at the subsite, due to heating of the skin, which fades rapidly; In order for the SPF determination of and an immediate generalized heat re- a test product to be considered valid, sponse, spreading beyond the subsite, the SPF value of the SPF standard

102

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00112 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17JN11.005 ER17JN11.009 ER17JN11.012 Food and Drug Administration, HHS § 201.327

should fall within the standard devi- (K) Step 11: Expose test sites to UV ation range of the expected SPF (i.e., doses as described in paragraph (e) of 16.3 ±3.43). this section. (7) Determination of water resistance. (j) Broad spectrum test procedure—(1) The following procedure should be per- UV Spectrometry. (i) Plate. Use optical- formed in an indoor fresh water pool, grade polymethylmethacrylate whirlpool, and/or hot tub maintained (PMMA) plates suitable for UV trans- at 23 to 32 °C. Fresh water is clean mittance measurements. The plate drinking water that meets the stand- should be roughened on one side to a ards in 40 CFR part 141. The pool and three dimensional surface topography air temperature and the relative hu- measure (Sa) between 2 and 7 microm- midity should be recorded. eters and must have a rectangular ap- (i) Water resistance (40 minutes). The plication area of at least 16 square cen- labeled SPF should be determined after timeters (with no side shorter than 4 40 minutes of water immersion using cm). the following procedure: (ii) Sample holder. The sample holder (A) Step 1: Apply the sunscreen as de- should hold the PMMA plate in a hori- scribed in paragraph (d) of this section. zontal position to avoid flowing of the sunscreen drug product from one edge (B) Step 2: Perform moderate activ- of the PMMA plate to the other. It ity in water for 20 minutes. should be mounted as close as possible (C) Step 3: Rest out of water for 15 to the input optics of the spectrometer minutes. Do not towel test site(s). to maximize capture of forward scat- (D) Step 4: Perform moderate activ- tered radiation. The sample holder ity in water for 20 minutes. should be a thin, flat plate with a suit- (E) Step 5: Allow test sites to dry able aperture through which UV radi- completely without toweling. ation can pass. The PMMA plate should (F) Step 6: Apply the SPF standard be placed on the upper surface of the as described in paragraph (d) of this sample holder with the roughened side section. facing up. Step 1. Expose test sites to UV doses (iii) Light source. The light source as described in paragraph (e) of this should produce a continuous spectral section. distribution of UV radiation from 290 (ii) Water resistance (80 minutes). The to 400 nanometers. labeled SPF should be determined after (iv) Input optics. Unless the spectrom- 80 minutes of water immersion using eter is equipped with an integrating the following procedure: sphere, an ultraviolet radiation dif- (A) Step 1: Apply the sunscreen as de- fuser should be placed between the scribed in paragraph (d) of this section. sample and the input optics of the (B) Step 2: Perform moderate activ- spectrometer. The diffuser will be con- ity in water for 20 minutes. structed from any UV radiation trans- ® (C) Step 3: Rest out of water for 15 parent material (e.g., Teflon or minutes. Do not towel test site(s). quartz). The diffuser ensures that the radiation received by the spectrometer (D) Step 4: Perform moderate activ- is not collimated. The spectrometer ity in water for 20 minutes. input slits should be set to provide a (E) Step 5: Rest out of water for 15 bandwidth that is less than or equal to minutes. Do not towel test site(s). 1 nanometer. (F) Step 6: Perform moderate activ- (v) Dynamic range of the spectrometer. ity in water for 20 minutes. The dynamic range of the spectrometer (G) Step 7: Rest out of water for 15 should be sufficient to measure trans- minutes. Do not towel test site(s). mittance accurately through a highly (H) Step 8: Perform moderate activ- absorbing sunscreen product at all ter- ity in water for 20 minutes. restrial solar UV wavelengths (290 to (I) Step 9: Allow test sites to dry 400 nm). completely without toweling. (2) Sunscreen product application to (J) Step 10: Apply the SPF standard PMMA plate. The accuracy of the test as described in paragraph (d) of this depends upon the application of a pre- section. cisely controlled amount of sunscreen

103

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00113 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 201.327 21 CFR Ch. I (4–1–19 Edition)

product with a uniform distribution over the PMMA plate. The product is applied at 0.75 mg per square centimeter to the roughened side of the PMMA plate. The sunscreen product should be applied in a series of small Where n ≥5 dots over the entire PMMA plate and then spread evenly using a gloved fin- (5) Calculation of mean absorbance val- ger. Spreading should be done with a ues. (i) Mean transmittance values, very light spreading action for approximately 30 seconds followed by spreading with greater pressure for approximately 30 seconds. The plate should are converted into mean absorbance then be allowed to equilibrate for 15 values, minutes in the dark before the pre-irradiation described in paragraph (c) of this section. at each wavelength by taking the nega- (3) Sunscreen product pre-irradiation. tive logarithm of the mean transmit- To account for lack of photostability, tance value as follows: apply the sunscreen product to the PMMA plate as described in paragraph (b) of this section and then irradiate with a solar simulator described in sec- (ii) The calculation yields 111 tion 352.70(b) of this chapter. The irra- monochromatic absorbance values in 1 diation dose should be 4 MEDs which is nanometer increments from 290 to 400 equivalent to an erythemal effective nanometers. dose of 800 J/m2 (i.e., 800 J/m2-eff). (6) Number of plates. For each sun- (4) Calculation of mean transmittance screen product, mean absorbance val- values. After pre-irradiation described ues should be determined from at least in paragraph (c) of this section, mean three individual PMMA plates. Because transmittance values should be deter- paragraph (d) of this section requires mined for each wavelength λ over the at least 5 measurements per plate, full UV spectrum (290 to 400 nano- there should be a total of at least 15 meters). The transmittance values measurements. should be measured at 1 nanometer in- (7) Calculation of the critical wave- tervals. Measurements of spectral irra- length. The critical wavelength is iden- diance transmitted for each wave- tified as the wavelength at which the length λ through control PMMA plates integral of the spectral absorbance coated with 15 microliters of glycerin curve reaches 90 percent of the integral (no sunscreen product) should be ob- over the UV spectrum from 290 to 400 tained from at least 5 different loca- nm. The following equation defines the tions on the PMMA plate [C1(λ), C2(λ), critical wavelength: C3(λ), C4(λ), and C5(λ)]. In addition, a minimum of 5 measurements of spectral irradiance transmitted for each wavelength λ through the PMMA plate covered with the sunscreen product will be similarly obtained after pre-irradiation of the sunscreen product Where λc = critical wavelength [P1(λ), P2(λ), P3(λ), P4(λ), and P5(λ)]. A(λ) = mean absorbance at each wavelength The mean transmittance for each dλ = wavelength interval between measure- wavelength, ments A mean critical wavelength of 370 nm or greater is classified as broad spec- is the ratio of the mean of the C(λ) val- trum protection. ues to the mean of the P(λ) values, as [76 FR 35660, June 17, 2011, as amended at 76 follows: FR 38975, July 5, 2011]

104

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00114 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17JN11.010 ER17JN11.006 ER17JN11.010 ER17JN11.011 ER17JN11.008 ER17JN11.007 Food and Drug Administration, HHS Pt. 201, App. A

§ 201.328 Labeling of medical gas con- paragraph (a)(1) of this section or a tainers. separate label) must include, in con- (a) Portable cryogenic medical gas conspicuous lettering, the phrase ‘‘For tainers. For the purposes of this section Medical Use’’, ‘‘Medical Gas,’’ or some a ‘‘portable cryogenic medical gas con- similar phrase that indicates the gas is tainer’’ is one that is capable of being for medical use. transported and is intended to be at- (b) High-pressure medical gas cylinders. tached to a medical gas supply system Each high-pressure medical gas cyl- within a hospital, health care entity, inder must be colored on the shoulder nursing home, other facility, or home portion of the cylinder in the color or health care setting, or is a base unit colors designated in paragraph (c) of used to fill small cryogenic gas con- this section. The color or colors must tainers for use by individual patients. be visible when viewed from the top of The term does not include cryogenic cylinder. containers that are not designed to be (c) Medical gas colors. The colors re- connected to a medical gas supply sys- quired to identify medical gases under tem, e.g., tank trucks, trailers, rail paragraph (a) and (b) of this section cars, or small cryogenic gas containers are: for use by individual patients (includ- Medical gas Color ing portable liquid oxygen units as defined at § 868.5655 of this chapter). Medical Air ...... Yellow. Carbon Dioxide ...... Gray. (1) Each portable cryogenic medical Helium ...... Brown. gas container must be conspicuously Nitrogen ...... Black. marked with a 360° wraparound label Nitrous Oxide ...... Blue. identifying its contents. Such label Oxygen ...... Green. Mixture or Blend ...... Colors corresponding to each must meet the requirements of component gas. § 211.94(e)(2) of this chapter and the following additional requirements. [81 FR 81696, Nov. 18, 2016] (i) If the container holds a single gas, the name of the gas held in the con- APPENDIX A TO PART 201—EXAMPLES OF tainer must be printed on the label in GRAPHIC ENHANCEMENTS USED BY FDA one of the following ways: (A) Using lettering that appears in I. SECTION 201.66 STANDARD LABELING FORMAT the color designated for the gas in A. Overall paragraph (c) of this section and that is printed against a white background, or 1. The ‘‘Drug Facts’’ labeling is set off in a (B) Using lettering that appears in box or similar enclosure by the use of a barline with all black type printed on a white against a background that is white, color contrasting background. painted in the color for the gas designated in paragraph (c) of this section. B. Typeface and size (ii) The lettering for the name of the 1. ‘‘Drug Facts’’ is set in 14 point Helvetica gas on the label must be at least 2 Bold Italic, left justified. inches high. 2. ‘‘Drug Facts (continued)’’ is set in 8 (iii) The name of the gas must be point Helvetica Bold Italic for the words printed continuously around the label ‘‘Drug Facts’’ and 8 point Helvetica Regular and be capable of being read around the for the word ‘‘(continued)’’ and is left justi- entire container. fied. 3. The headings (e.g., ‘‘Directions’’) are set (iv) The label must be on the sidewall in 8 point Helvetica Bold Italic, left justified. of the container, as close to the top of 4. The subheadings (e.g., ‘‘Ask a doctor or the container as possible but below the pharmacist before use if you are’’) are set in top weld seam. 6 point Helvetica Bold, left justified. (v) A portable cryogenic medical gas 5. The information is set in 6 point container may only be colored in the Helvetica Regular with 6.5 point leading, left color or colors designated in paragraph justified. (c) of this section if the gas or gases 6. The heading ‘‘Purpose’’ is right justified. 7. The bullet is a 5-point solid square. held within the container correspond 8. Two em spacing separates bullets when to that color or those colors. more than one bullet is on the same line. (2) A label on the container (either 9. A table format is used for 3 or more dos- the 360° wraparound label required in age directions.

105

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00115 Fmt 8010 Sfmt 8002 Y:\SGML\247073.XXX 247073 Pt. 201, App. A 21 CFR Ch. I (4–1–19 Edition)

10. A graphic appears at the bottom of the 2. The headings (e.g., ‘‘Directions’’) are set first panel leading the reader to the next in 8 point Helvetica Bold Italic, left justified. panel. 3. The subheadings (e.g., ‘‘Ask a doctor or pharmacist before use if you are’’) are set in C. Barlines and hairlines 6 point Helvetica Bold, left justified. 1. A 2.5-point horizontal barline extends to 4. The information is set in 6 point each end of the ‘‘Drug Facts’’ box (or similar Helvetica Regular with 6.5 point leading, left enclosure), providing separation between justified. each of the headings. 5. The heading ‘‘Purpose’’ is right justified. 2. A 0.5-point horizontal hairline extends 6. The bullet is a 5-point solid square. within 2 spaces on either side of the ‘‘Drug Facts’’ box (or similar enclosure), imme- 7. Bulleted information may start on same diately following the title and immediately line as headings (except for the ‘‘Warnings’’ preceding the subheadings. heading) and subheadings, with 2 em spacing 3. A 0.5-point horizontal hairline follows separating bullets, and need not be vertically the title, immediately preceding the head- aligned. ing, when a heading appears on a subsequent panel immediately after the ‘‘Drug Facts C. Barlines and hairlines (continued)’’ title. 1. A 2.5-point horizontal barline extends to D. Box or Enclosure each end of the ‘‘Drug Facts’’ box (or similar enclosure), providing separation between 1. All information is enclosed by a 2.5-point each of the headings. barline. 2. A 0.5-point horizontal hairline extends II. SECTION 201.66 MODIFIED LABELING within 2 spaces on either side of the ‘‘Drug FORMAT Facts’’ box (or similar enclosure), immediately following the title and immediately A. Overall preceding the subheadings. 1. The ‘‘Drug Facts’’ labeling is presented in all black type printed on a white color D. Box or Enclosure contrasting background. 1. All information is set off by color contrast. No barline is used. B. Typeface and size 1. ‘‘Drug Facts’’ is set in 9 point Helvetica III. EXAMPLES OF § 201.66 STANDARD LABELING Bold Italic, left justified. AND MODIFIED LABELING FORMATS

106

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00116 Fmt 8010 Sfmt 8002 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 202.1

A. SECTION 201.66 STANDARD LABELING FORMAT

B. SECTION 201.66 MODIFIED LABELING FORMAT

PART 202—PRESCRIPTION DRUG § 202.1 Prescription-drug advertise- ADVERTISING ments. (a)(1) The ingredient information required by section 502(n) of the Federal AUTHORITY: 21 U.S.C. 321, 331, 352, 355, 360b, 371. Food, Drug, and Cosmetic Act shall appear together, without any intervening

107

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00117 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 ER17MR99.007 ER17MR99.008 § 202.1 21 CFR Ch. I (4–1–19 Edition)

written, printed, or graphic matter, ex- ning text in larger size type, the estab- cept the proprietary names of ingredi- lished name shall be used at least once ents, which may be included with the in association with, and in type at listing of established names. least half as large as the type used for, (2) The order of listing of ingredients the most prominent presentation of the in the advertisement shall be the same proprietary name or designation in as the order of listing of ingredients on such running text. If any advertise- the label of the product, and the infor- ment includes a column with running mation presented in the advertisement text containing detailed information as concerning the quantity of each such to composition, prescribing, side ef- ingredient shall be the same as the cor- fects, or contraindications and the pro- responding information on the label of prietary name or designation is used in the product. such column but is not featured above (3) The advertisement shall not em- or below the column, the established ploy a fanciful proprietary name for name shall be used at least once in the drug or any ingredient in such a such column of running text in associa- manner as to imply that the drug or in- tion with such proprietary name or gredient has some unique effectiveness designation and in the same type size or composition, when, in fact, the drug used in such column of running text: or ingredient is a common substance, Provided, however, That if the propri- the limitations of which are readily etary name or designation is used in recognized when the drug or ingredient such column of running text in larger is listed by its established name. size type, the established name shall be (4) The advertisement shall not fea- used at least once in association with, ture inert or inactive ingredients in a and in type at least half as large as the manner that creates an impression of type used for, the most prominent pres- value greater than their true func- entation of the proprietary name or tional role in the formulation. designation in such column of running (5) The advertisement shall not des- text. Where the established name is re- ignate a drug or ingredient by a propri- quired to accompany or to be used in etary name that, because of similarity association with the proprietary name in spelling or pronunciation, may be confused with the proprietary name or or designation, the established name the established name of a different shall be placed in direct conjunction drug or ingredient. with the proprietary name or designa- (b)(1) If an advertisement for a pre- tion, and the relationship between the scription drug bears a proprietary proprietary name or designation and name or designation for the drug or the established name shall be made any ingredient thereof, the established clear by use of a phrase such as ‘‘brand name, if such there be, corresponding of’’ preceding the established name, by to such proprietary name or designa- brackets surrounding the established tion shall accompany such proprietary name, or by other suitable means. name or designation each time it is (2) The established name shall be featured in the advertisement for the printed in letters that are at least half drug; but, except as provided below in as large as the letters comprising the this subparagraph, the established proprietary name or designation with name need not be used with the propri- which it is joined, and the established etary name or designation in the run- name shall have a prominence com- ning text of the advertisement. On any mensurate with the prominence with page of an advertisement in which the which such proprietary name or des- proprietary name or designation is not ignation appears, taking into account featured but is used in the running all pertinent factors, including typog- text, the established name shall be raphy, layout, contrast, and other used at least once in the running text printing features. in association with such proprietary (c) In the case of a prescription drug name or designation and in the same containing two or more active ingredi- type size used in the running text: Pro- ents, if the advertisement bears a provided, however, That if the proprietary prietary name or designation for such name or designation is used in the run- mixture and there is no established

108

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00118 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 202.1

name corresponding to such propri- ments described in paragraph (e)(2) of etary name or designation, the quan- this section, shall present a true state- titative ingredient information re- ment of information in brief summary quired in the advertisement by section relating to side effects, contraindica- 502(n) of the act shall be placed in ditions (when used in this section ‘‘side rect conjunction with the most promi- effects, contraindications’’ include side nent display of the proprietary name or effects, warnings, precautions, and con- designation. The prominence of the traindications and include any such in- quantitative ingredient information formation under such headings as cau- shall bear a reasonable relationship to tions, special considerations, impor- the prominence of the proprietary tant notes, etc.) and effectiveness. Ad- name. vertisements broadcast through media (d)(1) If the advertisement employs such as radio, television, or telephone one proprietary name or designation to communications systems shall include refer to a combination of active ingre- information relating to the major side dients present in more than one prepa- effects and contraindications of the ad- ration (the individual preparations dif- vertised drugs in the audio or audio fering from each other as to quantities and visual parts of the presentation of active ingredients and/or the form of and unless adequate provision is made the finished preparation) and there is for dissemination of the approved or no established name corresponding to permitted package labeling in connec- such proprietary name or designation, tion with the broadcast presentation a listing showing the established shall contain a brief summary of all names of the active ingredients shall necessary information related to side be placed in direct conjunction with effects and contraindications. the most prominent display of such (2) Exempt advertisements. The fol- proprietary name or designation. The lowing advertisements are exempt prominence of this listing of active in- from the requirements of paragraph gredients shall bear a reasonable rela- (e)(1) of this section under the condi- tionship to the prominence of the pro- tions specified: prietary name and the relationship be- (i) Reminder advertisements. Reminder tween such proprietary name or des- advertisements are those which call at- ignation, and the listing of active intention to the name of the drug prod- gredients shall be made clear by use of uct but do not include indications or such phrase as ‘‘brand of’’, preceding dosage recommendations for use of the the listing of active ingredients. drug product. These reminder adver- (2) The advertisement shall promi- tisements shall contain only the pro- nently display the name of at least one prietary name of the drug product, if specific dosage form and shall have the any; the established name of the drug quantitative ingredient information re- product, if any; the established name of quired by section 502(n) of the act in di- each active ingredient in the drug rect conjunction with such display. If product; and, optionally, information other dosage forms are listed in the ad- relating to quantitative ingredient vertisement, the quantitative ingre- statements, dosage form, quantity of dient information for such dosage package contents, price, the name and forms shall appear in direct conjunc- address of the manufacturer, packer, or tion and in equal prominence with the distributor or other written, printed, most prominent listing of the names of or graphic matter containing no rep- such dosage forms. resentation or suggestion relating to (e) True statement of information in the advertised drug product. If the brief summary relating to side effects, Commissioner finds that there is evi- contraindications, and effectiveness: dence of significant incidence of fatali- (1) When required. All advertisements ties or serious injury associated with for any prescription drug (‘‘prescrip- the use of a particular prescription tion drug’’ as used in this section drug, he may withdraw this exemption means drugs defined in section 503(b)(1) by so notifying the manufacturer, of the act and § 201.105, applicable to packer, or distributor of the drug by drugs for use by man and veterinary letter. Reminder advertisements, other drugs, respectively), except advertise- than those solely intended to convey

109

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00119 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 202.1 21 CFR Ch. I (4–1–19 Edition)

price information including, but not (i) The requirement of a true statement limited to, those subject to the require- of information relating to side effects, ments of § 200.200 of this chapter, are contraindications, and effectiveness not permitted for a prescription drug applies to the entire advertisement. product whose labeling contains a Untrue or misleading information in boxed warning relating to a serious any part of the advertisement will not hazard associated with the use of the be corrected by the inclusion in an- drug product. Reminder advertise- other distinct part of the advertisements which are intended to provide ment of a brief statement containing consumers with information con- true information relating to side ef- cerning the price charged for a pre- fects, contraindications, and effective- scription for a drug product are exempt ness of the drug. If any part or theme from the requirements of this section if of the advertisement would make the they meet all of the conditions con- advertisement false or misleading by tained in § 200.200 of this chapter. Re- reason of the omission of appropriate minder advertisements, other than qualification or pertinent information, those subject to the requirements of that part or theme shall include the § 200.200 of this chapter, are not per- appropriate qualification or pertinent mitted for a drug for which an an- information, which may be concise if it nouncement has been published pursu- is supplemented by a prominent ref- ant to a review on the labeling claims erence on each page to the presence for the drug by the National Academy and location elsewhere in the adver- of Sciences/National Research Council tisement of a more complete discussion (NAS/NRC), Drug Efficacy Study of such qualification or information. Group, and for which no claim has been (ii) The information relating to effec- evaluated as higher than ‘‘possibly ef- tiveness is not required to include infective.’’ If the Commissioner finds the formation relating to all purposes for circumstances are such that a re- which the drug is intended but may op- minder advertisement may be mis- tionally be limited to a true statement leading to prescribers of drugs subject of the effectiveness of the drug for the to NAS/NRC evaluation, such adver- selected purpose(s) for which the drug tisements will not be allowed and the is recommended or suggested in the ad- manufacturer, packer, or distributor vertisement. The information relating will be notified either in the publica- to effectiveness shall include specific tion of the conclusions on the effec- indications for use of the drug for pur- tiveness of the drug or by letter. poses claimed in the advertisement; for (ii) Advertisements of bulk-sale drugs. example, when an advertisement con- Advertisements of bulk-sale drugs that tains a broad claim that a drug is an promote sale of the drug in bulk pack- antibacterial agent, the advertisement ages in accordance with the practice of shall name a type or types of infections the trade solely to be processed, manu- and microorganisms for which the drug factured, labeled, or repackaged in sub- is effective clinically as specifically as stantial quantities and that contain no required, approved, or permitted in the claims for the therapeutic safety or ef- drug package labeling. fectiveness of the drug. (iii) The information relating to side (iii) Advertisements of prescription- effects and contraindications shall dis- compounding drugs. Advertisements of close each specific side effect and con- prescription-compounding drugs that traindication (which include side ef- promote sale of a drug for use as a pre- fects, warnings, precautions, and con- scription chemical or other compound traindications and include any such infor use by registered pharmacists in formation under such headings as cau- compounding prescriptions if the drug tions, special considerations, impor- otherwise complies with the conditions tant notes, etc.; see paragraph (e)(1) of for the labeling exemption contained in this section) contained in required, ap- § 201.120 and the advertisement con- proved, or permitted labeling for the tains no claims for the therapeutic advertised drug dosage form(s): Pro- safety or effectiveness of the drug. vided, however, (3) Scope of information to be included; (a) The side effects and contraindica- applicability to the entire advertisement. tions disclosed may be limited to those

110

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00120 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 202.1

pertinent to the indications for which (2) Additional uses contained in la- the drug is recommended or suggested beling in commercial use on October 9, in the advertisement to the extent that 1962, to the extent that such uses did such limited disclosure has previously not cause the drug to be an unapproved been approved or permitted in drug la- ‘‘new drug’’ as ‘‘new drug’’ was defined beling conforming to the provisions of in section 201(p) of the act as then in §§ 201.100 or 201.105; and force, and to the extent that such uses (b) The use of a single term for a would be permitted were the drug sub- group of side effects and contraindica- ject to paragraph (e)(4)(iii) of this sections (for example, ‘‘blood dyscrasias’’ tion. for disclosure of ‘‘leukopenia,’’ (3) Additional uses contained in la- ‘‘agranulocytosis,’’ and ‘‘neutropenia’’) beling in current commercial use to is permitted only to the extent that the extent that such uses do not cause the use of such a single term in place of the drug to be an unapproved ‘‘new disclosure of each specific side effect drug’’ as defined in section 201(p) of the and contraindication has been pre- act as amended or a ‘‘new animal drug’’ viously approved or permitted in drug as defined in section 201(v) of the act as labeling conforming to the provisions amended. of §§ 201.100 or 201.105. The advertisement shall present infor- (4) Substance of information to be in- mation from labeling required, ap- cluded in brief summary. (i)(a) An adver- proved, or permitted in a new-drug ap- tisement for a prescription drug cov- plication relating to each specific side ered by a new-drug application ap- effect and contraindication in such la- proved pursuant to section 505 of the beling that relates to the uses of the act after October 10, 1962, or a prescrip- advertised drug dosage form(s) or shall tion drug covered by a new animal drug otherwise conform to the provisions of application approved pursuant to sec- paragraph (e)(3)(iii) of this section. tion 512 of the act after August 1, 1969, (ii) In the case of an advertisement or any approved supplement thereto, or for a prescription drug other than a for a prescription drug listed in the drug the labeling of which causes it to index pursuant to section 572 of the be an unapproved ‘‘new drug’’ and act, or any granted modification there- other than drugs covered by paragraph to, shall not recommend or suggest any (e)(4)(i) of this section, an advertise- use that is not in the labeling accepted ment may recommend and suggest the in such approved new-drug application drug only for those uses contained in or supplement, new animal drug appli- the labeling thereof: cation or supplement, or new animal (a) For which the drug is generally drug index listing or modification. The recognized as safe and effective among advertisement shall present informa- experts qualified by scientific training tion from labeling required, approved, and experience to evaluate the safety permitted, or granted in a new-drug or and effectiveness of such drugs; or new animal drug application or new (b) For which there exists substantial animal drug index listing relating to evidence of safety and effectiveness, each specific side effect and contra- consisting of adequate and well-con- indication in such labeling that relates trolled investigations, including clin- to the uses of the advertised drug dos- ical investigations (as used in this sec- age form(s) or shall otherwise conform tion ‘‘clinical investigations,’’ ‘‘clin- to the provisions of paragraph (e)(3)(iii) ical experience,’’ and ‘‘clinical signifi- of this section. cance’’ mean in the case of drugs in- (b) If a prescription drug was covered tended for administration to man, in- by a new-drug application or a supple- vestigations, experience, or signifi- ment thereto that became effective cance in humans, and in the case of prior to October 10, 1962, an advertise- drugs intended for administration to ment may recommend or suggest: other animals, investigations, experi- (1) Uses contained in the labeling ac- ence, or significance in the specie or cepted in such new-drug application species for which the drug is adver- and any effective, approved, or per- tised), by experts qualified by scientific mitted supplement thereto. training and experience to evaluate the

111

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00121 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 202.1 21 CFR Ch. I (4–1–19 Edition)

safety and effectiveness of the drug in- (iii) It fails to reveal facts material volved, on the basis of which it can in the light of its representations or fairly and responsibly be concluded by material with respect to consequences such experts that the drug is safe and that may result from the use of the effective for such uses; or drug as recommended or suggested in (c) For which there exists substantial the advertisement. clinical experience (as used in this sec- (6) Advertisements that are false, lack- tion this means substantial clinical ex- ing in fair balance, or otherwise mis- perience adequately documented in leading. An advertisement for a pre- medical literature or by other data (to scription drug is false, lacking in fair be supplied to the Food and Drug Ad- balance, or otherwise misleading, or ministration, if requested)), on the otherwise violative of section 502(n) of basis of which it can fairly and respon- the act, among other reasons, if it: sibly be concluded by qualified experts (i) Contains a representation or sug- that the drug is safe and effective for gestion, not approved or permitted for such uses; or use in the labeling, that a drug is bet- (d) For which safety is supported ter, more effective, useful in a broader under any of the preceding clauses in range of conditions or patients (as used paragraphs (e)(4)(iii) (a), (b), and (c) of in this section patients means humans this section and effectiveness is sup- and in the case of veterinary drugs, ported under any other of such clauses. other animals), safer, has fewer, or less incidence of, or less serious side effects The advertisement shall present infor- or contraindications than has been mation relating to each specific side ef- demonstrated by substantial evidence fect and contraindication that is re- or substantial clinical experience (as quired, approved, or permitted in the described in paragraphs (e)(4)(ii) (b) and package labeling by §§ 201.100 or 201.105 (c) of this section) whether or not such of this chapter of the drug dosage representations are made by compari- form(s) or shall otherwise conform to son with other drugs or treatments, the provisions of paragraph (e)(3)(iii) of and whether or not such a representa- this section. tion or suggestion is made directly or (5) ‘‘True statement’’ of information. An through use of published or unpub- advertisement does not satisfy the re- lished literature, quotations, or other quirement that it present a ‘‘true references. statement’’ of information in brief (ii) Contains a drug comparison that summary relating to side effects, con- represents or suggests that a drug is traindications, and effectiveness if: safer or more effective than another (i) It is false or misleading with re- drug in some particular when it has spect to side effects, contraindications, not been demonstrated to be safer or or effectiveness; or more effective in such particular by (ii) It fails to present a fair balance substantial evidence or substantial between information relating to side clinical experience. effects and contraindications and infor- (iii) Contains favorable information mation relating to effectiveness of the or opinions about a drug previously re- drug in that the information relating garded as valid but which have been to effectiveness is presented in greater rendered invalid by contrary and more scope, depth, or detail than is required credible recent information, or con- by section 502(n) of the act and this in- tains literature references or formation is not fairly balanced by a quotations that are significantly more presentation of a summary of true in- favorable to the drug than has been formation relating to side effects and demonstrated by substantial evidence contraindications of the drug; Provided, or substantial clinical experience. however, That no advertisement shall (iv) Contains a representation or sug- be considered to be in violation of this gestion that a drug is safer than it has section if the presentation of true in- been demonstrated to be by substantial formation relating to side effects and evidence or substantial clinical experi- contraindications is comparable in ence, by selective presentation of infor- depth and detail with the claims for ef- mation from published articles or other fectiveness or safety. references that report no side effects or

112

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00122 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 202.1

minimal side effects with the drug or (xiii) Uses a study on normal individ- otherwise selects information from any uals without disclosing that the sub- source in a way that makes a drug ap- jects were normal, unless the drug is pear to be safer than has been dem- intended for use on normal individuals. onstrated. (xiv) Uses ‘‘statistics’’ on numbers of (v) Presents information from a patients, or counts of favorable results study in a way that implies that the or side effects, derived from pooling study represents larger or more general data from various insignificant or dis- experience with the drug than it actu- similar studies in a way that suggests ally does. either that such ‘‘statistics’’ are valid (vi) Contains references to literature if they are not or that they are derived or studies that misrepresent the effec- from large or significant studies sup- tiveness of a drug by failure to disclose porting favorable conclusions when that claimed results may be due to such is not the case. concomitant therapy, or by failure to (xv) Uses erroneously a statistical disclose the credible information avail- finding of ‘‘no significant difference’’ able concerning the extent to which to claim clinical equivalence or to claimed results may be due to placebo deny or conceal the potential existence effect (information concerning placebo of a real clinical difference. effect is not required unless the adver- (xvi) Uses statements or representa- tisement promotes the drug for use by tions that a drug differs from or does man). not contain a named drug or category (vii) Contains favorable data or con- of drugs, or that it has a greater po- clusions from nonclinical studies of a tency per unit of weight, in a way that drug, such as in laboratory animals or suggests falsely or misleadingly or in vitro, in a way that suggests they without substantial evidence or sub- have clinical significance when in fact stantial clinical experience that the no such clinical significance has been advertised drug is safer or more effec- demonstrated. tive than such other drug or drugs. (viii) Uses a statement by a recog- (xvii) Uses data favorable to a drug nized authority that is apparently fa- derived from patients treated with dos- vorable about a drug but fails to refer ages different from those recommended to concurrent or more recent unfavor- in approved or permitted labeling if the able data or statements from the same drug advertised is subject to section 505 authority on the same subject or sub- of the act, or, in the case of other jects. drugs, if the dosages employed were (ix) Uses a quote or paraphrase out of different from those recommended in context to convey a false or misleading the labeling and generally recognized idea. as safe and effective. This provision is (x) Uses literature, quotations, or ref- not intended to prevent citation of re- erences that purport to support an ad- ports of studies that include some pa- vertising claim but in fact do not sup- tients treated with dosages different port the claim or have relevance to the from those authorized, if the results in claim. such patients are not used. (xi) Uses literature, quotations, or (xviii) Uses headline, subheadline, or references for the purpose of recom- pictorial or other graphic matter in a mending or suggesting conditions of way that is misleading. drug use that are not approved or per- (xix) Represents or suggests that mitted in the drug package labeling. drug dosages properly recommended for (xii) Offers a combination of drugs for use in the treatment of certain classes the treatment of patients suffering of patients or disease conditions are from a condition amenable to treat- safe and effective for the treatment of ment by any of the components rather other classes of patients or disease con- than limiting the indications for use to ditions when such is not the case. patients for whom concomitant ther- (xx) Presents required information apy as provided by the fixed combina- relating to side effects or contraindication drug is indicated, unless such con- tions by means of a general term for a dition is included in the uses permitted group in place of disclosing each spe- under paragraph (e)(4) of this section. cific side effect and contraindication

113

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00123 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 202.1 21 CFR Ch. I (4–1–19 Edition)

(for example employs the term blood and ordinate so that the graph creates dyscrasias instead of ‘‘leukopenia,’’ a misleading impression. ‘‘agranulocytosis,’’ ‘‘neutropenia,’’ (v) Uses reports or statements rep- etc.) unless the use of such general resented to be statistical analyses, in- term conforms to the provisions of terpretations, or evaluations that are paragraph (e)(3)(iii) of this section. inconsistent with or violate the estab- Provided, however, That any provision lished principles of statistical theory, of this paragraph shall be waived with methodology, applied practice, and in- respect to a specified advertisement as ference, or that are derived from clin- set forth in a written communication ical studies the design, data, or con- from the Food and Drug Administra- duct of which substantially invalidate tion on a petition for such a waiver the application of statistical analyses, from a person who would be adversely interpretations, or evaluations. affected by the enforcement of such (vi) Contains claims concerning the provision on the basis of a showing mechanism or site of drug action that that the advertisement is not false, are not generally regarded as estab- lacking in fair balance, or otherwise lished by scientific evidence by experts misleading, or otherwise violative of qualified by scientific training and ex- section 502(n) of the act. A petition for perience without disclosing that the such a waiver shall set forth clearly claims are not established and the lim- and concisely the petitioner’s interest itations of the supporting evidence. in the advertisement, the specific pro- (vii) Fails to provide sufficient em- vision of this paragraph from which a phasis for the information relating to waiver is sought, a complete copy of side effects and contraindications, the advertisement, and a showing that when such information is contained in the advertisement is not false, lacking a distinct part of an advertisement, be- in fair balance, or otherwise mis- cause of repetition or other emphasis leading, or otherwise violative of sec- in that part of the advertisement of tion 502(n) of the act. claims for effectiveness or safety of the (7) Advertisements that may be false, drug. lacking in fair balance, or otherwise mis- (viii) Fails to present information re- leading. An advertisement may be false, lacking in fair balance, or otherwise lating to side effects and contraindica- misleading or otherwise violative of tions with a prominence and read- section 502(n) of the act if it: ability reasonably comparable with the (i) Contains favorable information or presentation of information relating to conclusions from a study that is inad- effectiveness of the drug, taking into equate in design, scope, or conduct to account all implementing factors such furnish significant support for such in- as typography, layout, contrast, head- formation or conclusions. lines, paragraphing, white space, and (ii) Uses the concept of ‘‘statistical any other techniques apt to achieve significance’’ to support a claim that emphasis. has not been demonstrated to have (ix) Fails to provide adequate empha- clinical significance or validity, or sis (for example, by the use of color fails to reveal the range of variations scheme, borders, headlines, or copy around the quoted average results. that extends across the gutter) for the (iii) Uses statistical analyses and fact that two facing pages are part of techniques on a retrospective basis to the same advertisement when one page discover and cite findings not soundly contains information relating to side supported by the study, or to suggest effects and contraindications. scientific validity and rigor for data (x) In an advertisement promoting from studies the design or protocol of use of the drug in a selected class of pa- which are not amenable to formal sta- tients (for example, geriatric patients tistical evaluations. or depressed patients), fails to present (iv) Uses tables or graphs to distort with adequate emphasis the significant or misrepresent the relationships, side effects and contraindications or trends, differences, or changes among the significant dosage considerations, the variables or products studied; for when dosage recommendations are in- example, by failing to label abscissa cluded in an advertisement, especially

114

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00124 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 202.1

applicable to that selected class of pa- antibiotic, or to recommend any regu- tients. latory action. (xi) Fails to present on a page facing (2) Within a reasonable time after in- another page (or on another full page) formation concerning the possibility of an advertisement on more than one that a drug may cause fatalities or se- page, information relating to side ef- rious damage has been widely pub- fects and contraindications when such licized in medical literature, the Food information is in a distinct part of the and Drug Administration shall notify advertisement. the sponsor of the drug by mail that (xii) Fails to include on each page or prior approval of advertisements for spread of an advertisement the infor- the drug is no longer necessary. mation relating to side effects and con- (3) Dissemination of an advertise- traindications or a prominent ref- ment not in compliance with this para- erence to its presence and location graph shall be deemed to be an act that when it is presented as a distinct part causes the drug to be misbranded under of an advertisement. section 502(n) of the act. (xiii) Contains information from pub- (4) Any advertisement may be sub- lished or unpublished reports or opin- mitted to the Food and Drug Adminis- ions falsely or misleadingly rep- tration prior to publication for com- resented or suggested to be authentic ment. If the advertiser is notified that or authoritative. the submitted advertisement is not in (f)–(i) [Reserved] violation and, at some subsequent (j)(1) No advertisement concerning a time, the Food and Drug Administra- particular prescription drug may be tion changes its opinion, the advertiser disseminated without prior approval by will be so notified and will be given a the Food and Drug Administration if: reasonable time for correction before any regulatory action is taken under (i) The sponsor or the Food and Drug this section. Notification to the adver- Administration has received informa- tiser that a proposed advertisement is tion that has not been widely pub- or is not considered to be in violation licized in medical literature that the shall be in written form. use of the drug may cause fatalities or (5) The sponsor shall have an oppor- serious damage; tunity for a regulatory hearing before (ii) The Commissioner (or in his ab- the Food and Drug Administration pur- sence the officer acting as Commis- suant to part 16 of this chapter with re- sioner), after evaluating the reliability spect to any determination that prior of such information, has notified the approval is required for advertisements sponsor that the information must be a concerning a particular prescription part of the advertisements for the drug, or that a particular advertise- drug; and ment is not approvable. (iii) The sponsor has failed within a (k) An advertisement issued or reasonable time as specified in such no- caused to be issued by the manufac- tification to present to the Food and turer, packer, or distributor of the Drug Administration a program, ade- drug promoted by the advertisement quate in light of the nature of the in- and which is not in compliance with formation, for assuring that such infor- section 502(n) of the act and the appli- mation will be publicized promptly and cable regulations thereunder shall adequately to the medical profession in cause stocks of such drug in possession subsequent advertisements. of the person responsible for issuing or If the Commissioner finds that the pro- causing the issuance of the advertise- gram presented is not being followed, ment, and stocks of the drug distrib- he will notify the sponsor that prior uted by such person and still in the approval of all advertisements for the channels of commerce, to be mis- particular drug will be required. Noth- branded under section 502(n) of the act. ing in this paragraph is to be construed (l)(1) Advertisements subject to sec- as limiting the Commissioner’s or the tion 502(n) of the act include advertise- Secretary’s rights, as authorized by ments in published journals, maga- law, to issue publicity, to suspend any zines, other periodicals, and news- new-drug application, to decertify any papers, and advertisements broadcast

115

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00125 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Pt. 203 21 CFR Ch. I (4–1–19 Edition)

through media such as radio, tele- trolled studies is waived as provided in vision, and telephone communication § 314.111(a)(5)(ii) of this chapter. systems. (2) Brochures, booklets, mailing * * * * * pieces, detailing pieces, file cards, bul- (vii) Suggests, on the basis of favorable letins, calendars, price lists, catalogs, data or conclusions from nonclinical studies house organs, letters, motion picture of a prescription drug, such as studies in lab- films, film strips, lantern slides, sound oratory animals or in vitro, that the studies recordings, exhibits, literature, and re- have clinical significance, if clinical signifi- prints and similar pieces of printed, cance has not been demonstrated. Data that audio, or visual matter descriptive of a demonstrate activity or effectiveness for a prescription drug in animal or in vitro tests drug and references published (for ex- and have not been shown by adequate and ample, the ‘‘Physicians Desk Ref- well-controlled clinical studies to pertain to erence’’) for use by medical practi- clinical use may be used in advertising ex- tioners, pharmacists, or nurses, concept that (a), in the case of anti-infective taining drug information supplied by drugs, in vitro data may be included in the the manufacturer, packer, or dis- advertisement, if data are immediately pre- tributor of the drug and which are dis- ceded by the statement ‘‘The following in seminated by or on behalf of its manu- vitro data are available but their clinical significance is unknown’’ and (b), in the case facturer, packer, or distributor are of other drug classes, in vitro and animal hereby determined to be labeling as de- data that have not been shown to pertain to fined in section 201(m) of the act. clinical use by adequate and well-controlled clinical studies as defined in § 314.111(a)(5)(ii) [40 FR 14016, Mar. 27, 1975, as amended at 40 of this chapter may not be used unless the FR 58799, Dec. 18, 1975; 41 FR 48266, Nov. 2, requirement for adequate and well-con- 1976; 42 FR 15674, Mar. 22, 1977; 60 FR 38480, trolled studies is waived as provided in July 27, 1995; 72 FR 69119, Dec. 6, 2007] § 314.111(a)(5)(ii) of this chapter. EFFECTIVE DATE NOTE: At 44 FR 37467, June 26, 1979, § 202.1(e)(6) (ii) and (vii) were revised. * * * * * At 44 FR 74817, Dec. 18, 1979, paragraphs (e)(6) (ii) and (vii) were stayed indefinitely. At 64 FR 400, Jan. 5, 1999, these paragraphs were PART 203—PRESCRIPTION DRUG amended. For the convenience of the user, MARKETING paragraphs (e)(6) (ii) and (vii), published at 44 FR 37467, are set forth below: Subpart A—General Provisions § 202.1 Prescription-drug advertisements. Sec. 203.1 Scope. * * * * * 203.2 Purpose. 203.3 Definitions. (e) * * * (6) * * * Subpart B—Reimportation (ii) Represents or suggests that a prescrip- 203.10 Restrictions on reimportation. tion drug is safer or more effective than an- 203.11 Applications for reimportation to other drug in some particular when the dif- provide emergency medical care. ference has not been demonstrated by sub- 203.12 An appeal from an adverse decision stantial evidence. An advertisement for a by the district office. prescription drug may not, either directly or by implication, e.g., by use of comparative Subpart C—Sales Restrictions test data or reference to published reports, represent that the drug is safer or more ef- 203.20 Sales restrictions. fective than another drug, nor may an adver- 203.22 Exclusions. tisement contain a quantitative statement 203.23 Returns. of safety or effectiveness (a) unless the representation has been approved as part of the Subpart D—Samples labeling in a new drug application or biologic license, or (b) if the drug is not a new 203.30 Sample distribution by mail or com- drug or biologic, unless the representation of mon carrier. safety or effectiveness is supported by sub- 203.31 Sample distribution by means other stantial evidence derived from adequate and than mail or common carrier (direct de- well-controlled studies as defined in livery by a representative or detailer). § 314.111(a)(5)(ii) of this chapter, or unless the 203.32 Drug sample storage and handling re- requirement for adequate and well-con- quirements.

116

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00126 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 203.3

203.33 Drug sample forms. wholesale distributors (see part 205 of 203.34 Policies and procedures; administra- this chapter), to protect the public tive systems. health, and to protect the public 203.35 Standing requests. 203.36 Fulfillment houses, shipping and against drug diversion by establishing mailing services, comarketing agree- procedures, requirements, and min- ments, and third-party recordkeeping. imum standards for the distribution of 203.37 Investigation and notification re- prescription drugs and prescription quirements. drug samples. 203.38 Sample lot or control numbers; labeling of sample units. § 203.3 Definitions. 203.39 Donation of drug samples to charitable institutions. (a) The act means the Federal Food, Drug, and Cosmetic Act, as amended Subpart E—Wholesale Distribution (21 U.S.C. 301 et seq.). (b) Authorized distributor of record 203.50 Requirements for wholesale distribution of prescription drugs. means a distributor with whom a manufacturer has established an ongoing Subpart F—Request and Receipt Forms, relationship to distribute such manu- Reports, and Records facturer’s products. (c) Blood means whole blood collected 203.60 Request and receipt forms, reports, from a single donor and processed ei- and records. ther for transfusion or further manu- Subpart G—Rewards facturing. (d) Blood component means that part 203.70 Application for a reward. of a single-donor unit of blood sepa- AUTHORITY: 21 U.S.C. 331, 333, 351, 352, 353, rated by physical or mechanical means. 360, 371, 374, 381. (e) Bulk drug substance means any SOURCE: 64 FR 67756, Dec. 3, 1999, unless substance that is represented for use in otherwise noted. a drug and that, when used in the manufacturing, processing, or packaging of Subpart A—General Provisions a drug, becomes an active ingredient or a finished dosage form of the drug, but § 203.1 Scope. the term does not include intermedi- This part sets forth procedures and ates used in the synthesis of such sub- requirements pertaining to the re- stances. importation and wholesale distribution (f) Charitable institution or charitable of prescription drugs, including both organization means a nonprofit hos- bulk drug substances and finished dos- pital, health care entity, organization, age forms; the sale, purchase, or trade institution, foundation, association, or of (or the offer to sell, purchase, or corporation that has been granted an trade) prescription drugs, including exemption under section 501(c)(3) of the bulk drug substances, that were pur- Internal Revenue Code of 1954, as chased by hospitals or health care enti- amended. ties, or donated to charitable organiza- (g) Common control means the power tions; and the distribution of prescrip- to direct or cause the direction of the tion drug samples. Blood and blood management and policies of a person or components intended for transfusion an organization, whether by ownership are excluded from the restrictions in of stock, voting rights, by contract, or and the requirements of the Prescrip- otherwise. tion Drug Marketing Act of 1987 and (h) Distribute means to sell, offer to the Prescription Drug Amendments of sell, deliver, or offer to deliver a drug 1992. to a recipient, except that the term ‘‘distribute’’ does not include: § 203.2 Purpose. (1) Delivering or offering to deliver a The purpose of this part is to imple- drug by a common carrier in the usual ment the Prescription Drug Marketing course of business as a common carrier; Act of 1987 and the Prescription Drug or Amendments of 1992, except for those (2) Providing of a drug sample to a sections relating to State licensing of patient by:

117

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00127 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 203.3 21 CFR Ch. I (4–1–19 Edition)

(i) A practitioner licensed to pre- drugs that will be used for routine of- scribe such drug; fice procedures. (ii) A health care professional acting (n) FDA means the U.S. Food and at the direction and under the super- Drug Administration. vision of such a practitioner; or (o) Group purchasing organization (iii) The pharmacy of a hospital or of means any entity established, main- another health care entity that is act- tained, and operated for the purchase ing at the direction of such a practi- of prescription drugs for distribution tioner and that received such sample in exclusively to its members with such accordance with the act and regula- membership consisting solely of hos- tions. pitals and health care entities bound (i) Drug sample means a unit of a pre- by written contract with the entity. scription drug that is not intended to (p) Handwritten signature means the be sold and is intended to promote the scripted name or legal mark of an indi- sale of the drug. vidual handwritten by that individual (j) Drug coupon means a form that and executed or adopted with the may be redeemed, at no cost or at represent intention to authenticate a duced cost, for a drug that is prescribed writing in a permanent form. The act in accordance with section 503(b) of the of signing with a writing or marking act. instrument such as a pen or stylus is (k) Electronic record means any com- preserved. The scripted name or legal bination of text, graphics, data, audio, mark, while conventionally applied to pictorial, or other information rep- paper, may also be applied to other de- resentation in digital form that is cre- vices that capture the name or mark. ated, modified, maintained, archived, (q) Health care entity means any per- retrieved, or distributed by a computer son that provides diagnostic, medical, system. surgical, or dental treatment, or chron- (l) Electronic signature means any ic or rehabilitative care, but does not computer data compilation of any sym- include any retail pharmacy or any bol or series of symbols executed, wholesale distributor. Except as pro- adopted, or authorized by an individual vided in § 203.22(h) and (i), a person can- to be the legally binding equivalent of not simultaneously be a ‘‘health care the individual’s handwritten signature. entity’’ and a retail pharmacy or (m) Emergency medical reasons in- wholesale distributor. clude, but are not limited to, transfers (r) Licensed practitioner means any of a prescription drug between health person licensed or authorized by State care entities or from a health care en- law to prescribe drugs. tity to a retail pharmacy to alleviate a (s) Manufacturer means any person temporary shortage of a prescription who is a manufacturer as defined by drug arising from delays in or interrup- § 201.1 of this chapter. tion of regular distribution schedules; (t) Nonprofit affiliate means any not- sales to nearby emergency medical for-profit organization that is either services, i.e., ambulance companies and associated with or a subsidiary of a fire fighting organizations in the same charitable organization as defined in State or same marketing or service section 501(c)(3) of the Internal Rev- area, or nearby licensed practitioners, enue Code of 1954. of drugs for use in the treatment of (u) Ongoing relationship means an as- acutely ill or injured persons; provision sociation that exists when a manufac- of minimal emergency supplies of turer and a distributor enter into a drugs to nearby nursing homes for use written agreement under which the dis- in emergencies or during hours of the tributor is authorized to distribute the day when necessary drugs cannot be manufacturer’s products for a period of obtained; and transfers of prescription time or for a number of shipments. If drugs by a retail pharmacy to another the distributor is not authorized to dis- retail pharmacy to alleviate a tem- tribute a manufacturer’s entire prod- porary shortage; but do not include uct line, the agreement must identify regular and systematic sales to li- the specific drug products that the dis- censed practitioners of prescription tributor is authorized to distribute.

118

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00128 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 203.10

(v) PDA means the Prescription Drug health care entities that are under Amendments of 1992. common control; (w) PDMA means the Prescription (5) The sale, purchase, or trade of a Drug Marketing Act of 1987. drug or an offer to sell, purchase, or (x) Person includes any individual, trade a drug for emergency medical partnership, corporation, or associa- reasons; tion. (6) The sale, purchase, or trade of a (y) Prescription drug means any drug drug, an offer to sell, purchase, or (including any biological product, ex- trade a drug, or the dispensing of a cept for blood and blood components drug under a prescription executed in intended for transfusion or biological accordance with section 503(b) of the products that are also medical devices) act; required by Federal law (including Fed- eral regulation) to be dispensed only by (7) The distribution of drug samples a prescription, including finished dos- by manufacturers’ and authorized dis- age forms and bulk drug substances tributors’ representatives; subject to section 503(b) of the act. (8) The sale, purchase, or trade of (z) Representative means an employee blood or blood components intended for or agent of a drug manufacturer or dis- transfusion; tributor who promotes the sale of pre- (9) Drug returns, when conducted by scription drugs to licensed practi- a hospital, health care entity, or chari- tioners and who may solicit or receive table institution in accordance with written requests for the delivery of § 203.23; or drug samples. A detailer is a represent- (10) The sale of minimal quantities of ative. drugs by retail pharmacies to licensed (aa) Sample unit means a packet, practitioners for office use. card, blister pack, bottle, container, or (dd) Wholesale distributor means any other single package comprised of one person engaged in wholesale distribu- or more dosage units of a prescription tion of prescription drugs, including, drug sample, intended by the manufac- but not limited to, manufacturers; re- turer or distributor to be provided by a packers; own-label distributors; pri- licensed practitioner to a patient in an vate-label distributors; jobbers; bro- unbroken or unopened condition. kers; warehouses, including manufac- (bb) Unauthorized distributor means a turers’ and distributors’ warehouses, distributor who does not have an ongo- chain drug warehouses, and wholesale ing relationship with a manufacturer drug warehouses; independent whole- to sell or distribute its products. sale drug traders; and retail phar- (cc) Wholesale distribution means distribution of prescription drugs to per- macies that conduct wholesale dis- sons other than a consumer or patient, tributions. but does not include: [64 FR 67756, Dec. 3, 1999, as amended at 73 (1) Intracompany sales; FR 59500, Oct. 9, 2008] (2) The purchase or other acquisition by a hospital or other health care enti- Subpart B—Reimportation ty that is a member of a group purchasing organization of a drug for its § 203.10 Restrictions on reimportation. own use from the group purchasing organization or from other hospitals or No prescription drug or drug com- health care entities that are members posed wholly or partly of insulin that of such organizations; was manufactured in a State and ex- (3) The sale, purchase, or trade of a ported from the United States may be drug or an offer to sell, purchase, or reimported by anyone other than its trade a drug by a charitable organiza- manufacturer, except that FDA may tion to a nonprofit affiliate of the orga- grant permission to a person other nization to the extent otherwise per- than the manufacturer to reimport a mitted by law; prescription drug or insulin-containing (4) The sale, purchase, or trade of a drug if it determines that such re- drug or an offer to sell, purchase, or importation is required for emergency trade a drug among hospitals or other medical care.

119

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00129 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 203.11 21 CFR Ch. I (4–1–19 Edition)

§ 203.11 Applications for reimportation nization or from other hospitals or to provide emergency medical care. health care entities that are members (a) Applications for reimportation for of the organization. emergency medical care shall be sub- (b) The sale, purchase, or trade of a mitted to the director of the FDA Dis- drug or an offer to sell, purchase, or trict Office in the district where re- trade a drug by a charitable organiza- importation is sought (addresses found tion to a nonprofit affiliate of the orga- in part 5, subpart M of this chapter). nization to the extent otherwise per- (b) Applications for reimportation to mitted by law. provide emergency medical care shall (c) The sale, purchase, or trade of a be reviewed and approved or dis- drug or an offer to sell, purchase, or approved by each district office. trade a drug among hospitals or other [64 FR 67756, Dec. 3, 1999, as amended at 69 health care entities that are under FR 17292, Apr. 2, 2004] common control. (d) The sale, purchase, or trade of a § 203.12 An appeal from an adverse de- drug or an offer to sell, purchase, or cision by the district office. trade a drug for emergency medical An appeal from an adverse decision reasons. by the district office involving insulin- (e) The sale, purchase, or trade of a containing drugs or human prescrip- drug, an offer to sell, purchase, or tion drugs or biological products regu- trade a drug, or the dispensing of a lated by the Center for Drug Evalua- drug under a valid prescription. tion and Research may be made to the (f) The sale, purchase, or trade of a Office of Compliance, Center for Drug Evaluation and Research, Food and drug or the offer to sell, purchase, or Drug Administration, 10903 New Hamp- trade a drug by hospitals or health care shire Ave., Silver Spring, MD 20993– entities owned or operated by Federal, 0002. An appeal from an adverse deci- State, or local governmental units to sion by the district office involving other hospitals or health care entities human prescription biological products owned or operated by Federal, State, or regulated by the Center for Biologics local governmental units. Evaluation and Research may be made (g) The sale, purchase, or trade of, or to the Food and Drug Administration, the offer to sell, purchase, or trade Center for Biologics Evaluation and blood or blood components intended for Research, Document Control Center, transfusion. 10903 New Hampshire Ave., Bldg. 71, (h) The sale, purchase, or trade of, or Rm. G112, Silver Spring, MD 20993–0002. the offer to sell, purchase, or trade, by [80 FR 18090, Apr. 3, 2015] a registered blood establishment that qualifies as a health care entity any: Subpart C—Sales Restrictions (1) Drug indicated for a bleeding or clotting disorder, or anemia; § 203.20 Sales restrictions. (2) Blood collection container ap- Except as provided in § 203.22 or proved under section 505 of the act; or § 203.23, no person may sell, purchase, (3) Drug that is a blood derivative (or or trade, or offer to sell, purchase, or a recombinant or synthetic form of a trade any prescription drug that was: blood derivative); as long as all of the (a) Purchased by a public or private health care services that the establish- hospital or other health care entity; or ment provides are related to its activi- (b) Donated or supplied at a reduced ties as a registered blood establishment price to a charitable organization. or the health care services consist of collecting, processing, storing, or ad- § 203.22 Exclusions. ministering human hematopoietic Section 203.20 does not apply to: stem/progenitor cells or performing di- (a) The purchase or other acquisition agnostic testing of specimens provided of a drug for its own use by a hospital that these specimens are tested to- or other health care entity that is a gether with specimens undergoing rou- member of a group purchasing organi- tine donor testing. Blood establish- zation from the group purchasing orga- ments relying on the exclusion in this

120

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00130 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 203.30

paragraph must satisfy all other re- Subpart D—Samples quirements of the act and this part applicable to a wholesale distributor or § 203.30 Sample distribution by mail or retail pharmacy. common carrier. (i) The sale, purchase, or trade of, or (a) Requirements for drug sample dis- the offer to sell, purchase, or trade, by tribution by mail or common carrier. A a comprehensive hemophilia diagnostic manufacturer or authorized distributor treatment center that is receiving a of record may distribute a drug sample grant under section 501(a)(2) of the So- to a practitioner licensed to prescribe cial Security Act and that qualifies as the drug that is to be sampled or, at a health care entity, any drug indi- the written request of a licensed prac- cated for a bleeding or clotting dis- titioner, to the pharmacy of a hospital order, or anemia, or any drug that is a or other health care entity, by mail or blood derivative (or a recombinant or common carrier, provided that: synthetic form of a blood derivative). Comprehensive hemophilia diagnostic (1) The licensed practitioner executes treatment centers relying on the exclu- and submits a written request to the sion in this paragraph must satisfy all manufacturer or authorized distributor other requirements of the act and this of record, as set forth in paragraph (b) part applicable to a wholesale dis- of this section, before the delivery of tributor or retail pharmacy. the drug sample; (2) The manufacturer or authorized [64 FR 67756, Dec. 3, 1999, as amended at 73 distributor of record verifies with the FR 59500, Oct. 9, 2008] appropriate State authority that the § 203.23 Returns. practitioner requesting the drug sample is licensed or authorized under The return of a prescription drug State law to prescribe the drug prod- purchased by a hospital or health care uct; entity or acquired at a reduced price by (3) The recipient executes a written or donated to a charitable institution receipt, as set forth in paragraph (c) of is exempt from the prohibitions in this section, when the drug sample is § 203.20, provided that: delivered; and (a) The hospital, health care entity, (4) The receipt is returned to the or charitable institution documents manufacturer or distributor from the return by filling out a credit memo which the drug sample was received. specifying: (b) Contents of the written request form (1) The name and address of the hos- for delivery of samples by mail or common pital, health care entity, or charitable carrier. (1) A written request for a drug institution; (2) The name and address of the man- sample to be delivered by mail or com- ufacturer or wholesale distributor from mon carrier to a licensed practitioner which it was acquired; is required to contain the following: (3) The product name and lot or con- (i) The name, address, professional trol number; title, and signature of the practitioner (4) The quantity returned; and making the request; (5) The date of the return. (ii) The practitioner’s State license (b) The hospital, health care entity, or authorization number or, where a or charitable institution forwards a scheduled drug product is requested, copy of each credit memo to the manu- the practitioner’s Drug Enforcement facturer and retains a copy of each Administration number. credit memo for its records; (iii) The proprietary or established (c) Any drugs returned to a manufac- name and the strength of the drug sam- turer or wholesale distributor are kept ple requested; under proper conditions for storage, (iv) The quantity requested; handling, and shipping, and written (v) The name of the manufacturer documentation showing that proper and the authorized distributor of conditions were maintained is provided record, if the drug sample is requested to the manufacturer or wholesale dis- from an authorized distributor of tributor to which the drugs are re- record; and turned. (vi) The date of the request.

121

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00131 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 203.31 21 CFR Ch. I (4–1–19 Edition)

(2) A written request for a drug sam- pharmacy of a hospital or other health ple to be delivered by mail or common care entity, provided that: carrier to the pharmacy of a hospital (1) The manufacturer or authorized or other health care entity is required distributor of record receives from the to contain, in addition to all of the in- licensed practitioner a written request formation in paragraph (b)(l) of this signed by the licensed practitioner be- section, the name and address of the fore the delivery of the drug sample; pharmacy of the hospital or other (2) The manufacturer or authorized health care entity to which the drug distributor of record verifies with the sample is to be delivered. appropriate State authority that the (c) Contents of the receipt to be com- practitioner requesting the drug sam- pleted upon delivery of a drug sample. ple is licensed or authorized under The receipt is to be on a form des- State law to prescribe the drug prod- ignated by the manufacturer or dis- uct; tributor, and is required to contain the (3) A receipt is signed by the recipi- following: ent, as set forth in paragraph (c) of this (1) If the drug sample is delivered to section, when the drug sample is deliv- the licensed practitioner who requested ered; it, the receipt is required to contain (4) The receipt is returned to the the name, address, professional title, manufacturer or distributor; and and signature of the practitioner or the (5) The requirements of paragraphs practitioner’s designee who acknowl- (d) through (e) of this section are met. edges delivery of the drug sample; the (b) Contents of the written request proprietary or established name and forms for delivery of samples by a rep- strength of the drug sample and the resentative. (1) A written request for de- quantity of the drug sample delivered; livery of a drug sample by a represent- and the date of the delivery. ative to a licensed practitioner is re- (2) If the drug sample is delivered to quired to contain the following: the pharmacy of a hospital or other (i) The name, address, professional health care entity at the request of a title, and signature of the practitioner licensed practitioner, the receipt is re- making the request; quired to contain the name and address (ii) The practitioner’s State license of the requesting licensed practitioner; or authorization number, or, where a the name and address of the hospital or scheduled drug product is requested, health care entity pharmacy des- the practitioner’s Drug Enforcement ignated to receive the drug sample; the Administration number; name, address, professional title, and (iii) The proprietary or established signature of the person acknowledging name and the strength of the drug sam- delivery of the drug sample; the propri- ple requested; etary or established name and strength (iv) The quantity requested; of the drug sample; the quantity of the (v) The name of the manufacturer drug sample delivered; and the date of and the authorized distributor of the delivery. record, if the drug sample is requested from an authorized distributor of § 203.31 Sample distribution by means record; and other than mail or common carrier (vi) The date of the request. (direct delivery by a representative (2) A written request for delivery of a or detailer). drug sample by a representative to the (a) Requirements for drug sample dis- pharmacy of a hospital or other health tribution by means other than mail or care entity is required to contain, in common carrier. A manufacturer or au- addition to all of the information in thorized distributor of record may dis- paragraph (b) of this section, the name tribute by means other than mail or and address of the pharmacy of the common carrier, by a representative or hospital or other health care entity to detailer, a drug sample to a practi- which the drug sample is to be deliv- tioner licensed to prescribe the drug to ered. be sampled or, at the written request of (c) Contents of the receipt to be com- such a licensed practitioner, to the pleted upon delivery of a drug sample.

122

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00132 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 203.31

The receipt is to be on a form des- or established name, dosage strength, ignated by the manufacturer or dis- and number of units. tributor, and is required to contain the (2) The reconciliation report is re- following: quired to include: (1) If the drug sample is received at (i) The inventory record for the most the address of the licensed practitioner recently completed prior inventory; who requested it, the receipt is re- (ii) A record of each drug sample quired to contain the name, address, shipment received since the most re- professional title, and signature of the cently completed prior inventory, in- practitioner or the practitioner’s des- cluding the sender and date of the ship- ignee who acknowledges delivery of the ment, and the proprietary or estab- drug sample; the proprietary or established name, dosage strength, and num- lished name and strength of the drug ber of sample units received; sample; the quantity of the drug sam- (iii) A record of drug sample distribu- ple delivered; and the date of the deliv- tions since the most recently com- ery. pleted inventory showing the name and (2) If the drug sample is received by address of each recipient of each sam- the pharmacy of a hospital or other ple unit shipped, the date of the ship- health care entity at the request of a ment, and the proprietary or estab- licensed practitioner, the receipt is re- lished name, dosage strength, and num- quired to contain the name and address ber of sample units shipped. For the of the requesting licensed practitioner; purposes of this paragraph and paragraph (d)(2)(v) of this section, ‘‘dis- the name and address of the hospital or tributions’’ includes distributions to health care entity pharmacy des- health care practitioners or designated ignated to receive the drug sample; the hospital or health care entity phar- name, address, professional title, and macies, transfers or exchanges with signature of the person acknowledging other firm representatives, returns to delivery of the drug sample; the propri- the manufacturer or authorized dis- etary or established name and strength tributor, destruction of drug samples of the drug sample; the quantity of the by a sales representative, and other drug sample delivered; and the date of types of drug sample dispositions. The the delivery. specific type of distribution must be (d) Inventory and reconciliation of drug specified in the record; samples of manufacturers’ and distribu- (iv) A record of drug sample thefts or tors’ representatives. Each drug manu- significant losses reported by the rep- facturer or authorized distributor of resentative since the most recently record that distributes drug samples by completed prior inventory, including means of representatives shall conduct, the approximate date of the occurrence at least annually, a complete and accu- and the proprietary or established rate physical inventory of all drug name, dosage strength, and number of samples. All drug samples in the pos- sample units stolen or lost; and session or control of each manufactur- (v) A record summarizing the infor- er’s and distributor’s representatives mation required by paragraphs (d)(2)(ii) are required to be inventoried and the through (d)(2)(iv) of this section. The results of the inventory are required to record must show, for each type of be recorded in an inventory record, as sample unit (i.e., sample units having specified in paragraph (d)(1) of this sec- the same established or proprietary tion. In addition, manufacturers and name and dosage strength), the total distributors shall reconcile the results number of sample units received, dis- of the physical inventory with the tributed, lost, or stolen since the most most recently completed prior physical recently completed prior inventory. inventory and create a report docu- For example, a typical entry in this menting the reconciliation process, as record may read ‘‘50 units risperidone specified in paragraph (d)(2) of this sec- (1 mg) returned to manufacturer’’ or tion. simply ‘‘Risperidone (1 mg)/50/returned (1) The inventory record is required to manufacturer.’’ to identify all drug samples in a rep- (3) Each drug manufacturer or au- resentative’s stock by the proprietary thorized distributor of record shall

123

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00133 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 203.32 21 CFR Ch. I (4–1–19 Edition)

take appropriate internal control § 203.34 Policies and procedures; ad- measures to guard against error and ministrative systems. possible fraud in the conduct of the Each manufacturer or authorized dis- physical inventory and reconciliation, tributor of record that distributes drug and in the preparation of the inventory samples shall establish, maintain, and record and reconciliation report. adhere to written policies and proce- (4) A manufacturer or authorized dis- dures describing its administrative sys- tributor of record shall carefully evalu- tems for the following: ate any apparent discrepancy or sig- (a) Distributing drug samples by mail nificant loss revealed through the in- or common carrier, including method- ventory and reconciliation process and ology for reconciliation of requests and shall fully investigate any such dis- receipts; crepancy or significant loss that can- (b) Distributing drug samples by not be justified. means other than mail or common car- (e) Lists of manufacturers’ and distribu- rier including the methodology for: tors’ representatives. Each drug manu- (1) Reconciling requests and receipts, facturer or authorized distributor of identifying patterns of nonresponse, record who distributes drug samples by and the manufacturer’s or distributor’s response when such patterns are found; means of representatives shall main- (2) Conducting the annual physical tain a list of the names and addresses inventory and preparation of the rec- of its representatives who distribute onciliation report; drug samples and of the sites where (3) Implementing a sample distribu- drug samples are stored. tion security and audit system, including conducting random and for-cause § 203.32 Drug sample storage and han- audits of sales representatives by per- dling requirements. sonnel independent of the sales force; (a) Storage and handling conditions. and Manufacturers, authorized distributors (4) Storage of drug samples by rep- of record, and their representatives resentatives; shall store and handle all drug samples (c) Identifying any significant loss of under conditions that will maintain drug samples and notifying FDA of the their stability, integrity, and effective- loss; and ness and ensure that the drug samples (d) Monitoring any loss or theft of are free of contamination, deteriora- drug samples. tion, and adulteration. (b) Compliance with compendial and la- § 203.35 Standing requests. beling requirements. Manufacturers, au- Manufacturers or authorized dis- thorized distributors of record, and tributors of record shall not distribute their representatives can generally drug samples on the basis of open- comply with this section by following ended or standing requests, but shall the compendial and labeling require- require separate written requests for ments for storage and handling of a each drug sample or group of samples. particular prescription drug in han- An arrangement by which a licensed dling samples of that drug. practitioner requests in writing that a specified number of drug samples be de- § 203.33 Drug sample forms. livered over a period of not more than 6 months, with the actual delivery A sample request or receipt form dates for parts of the order to be set by may be delivered by mail, common car- subsequent oral communication or rier, or private courier or may be electronic transmission, is not consid- transmitted photographically or elec- ered to be a standing request. tronically (i.e., by telephoto, wire- photo, radiophoto, facsimile trans- § 203.36 Fulfillment houses, shipping mission (FAX), xerography, or elec- and mailing services, comarketing tronic data transfer) or by any other agreements, and third-party record- system, provided that the method for keeping. transmission meets the security re- (a) Responsibility for creating and quirements set forth in § 203.60(c). maintaining forms, reports, and records.

124

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00134 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 203.37

Any manufacturer or authorized dis- (3) Provide FDA with a complete tributor of record that uses a fulfill- written report, including the reason for ment house, shipping or mailing serv- and the results of the investigation, ice, or other third party, or engages in not later than 30 days after the date of a comarketing agreement with another the initial notification in paragraph manufacturer or distributor to dis- (b)(1) of this section. tribute drug samples or to meet any of (c) Conviction of a representative. (1) A the requirements of PDMA, PDA, or manufacturer or authorized distributor this part, remains responsible for cre- of record that distributes drug samples ating and maintaining all requests, re- shall notify FDA, by telephone or in ceipts, forms, reports, and records re- writing, within 30 days of becoming quired under PDMA, PDA, and this aware of the conviction of one or more part. (b) Responsibility for producing re- of its representatives for a violation of quested forms, reports, or records. A man- section 503(c)(1) of the act or any State ufacturer or authorized distributor of law involving the sale, purchase, or record that contracts with a third trade of a drug sample or the offer to party to maintain some or all of its sell, purchase, or trade a drug sample. records shall produce requested forms, (2) A manufacturer or authorized dis- reports, records, or other required doc- tributor of record shall provide FDA uments within 2 business days of a re- with a complete written report not quest by an authorized representative later than 30 days after the date of the of FDA or another Federal, State, or initial notification. local regulatory or law enforcement of- (d) Selection of individual responsible ficial. for drug sample information. A manufacturer or authorized distributor of § 203.37 Investigation and notification record that distributes drug samples requirements. shall inform FDA in writing within 30 (a) Investigation of falsification of drug days of selecting the individual respon- sample records. A manufacturer or au- sible for responding to a request for in- thorized distributor of record that has formation about drug samples of that reason to believe that any person has individual’s name, business address, falsified drug sample requests, receipts, and telephone number. or records, or is diverting drug samples, shall: (e) Whom to notify at FDA. Notifica- (1) Notify FDA, by telephone or in tions and reports concerning human writing, within 5 working days; prescription drugs or biological prod- (2) Immediately initiate an investiga- ucts regulated by the Center for Drug tion; and Evaluation and Research shall be made (3) Provide FDA with a complete to the Division of Compliance Risk written report, including the reason for Management and Surveillance, Office and the results of the investigation, of Compliance, Center for Drug Evalua- not later than 30 days after the date of tion and Research, Food and Drug Ad- the initial notification in paragraph ministration, 10903 New Hampshire (a)(1) of this section. Ave., Silver Spring, MD 20993–0002. No- (b) Significant loss or known theft of tifications and reports concerning drug samples. A manufacturer or au- human prescription biological products thorized distributor of record that dis- regulated by the Center for Biologics tributes drug samples or a charitable Evaluation and Research shall be made institution that receives donated drug to the Food and Drug Administration, samples from a licensed practitioner Center for Biologics Evaluation and shall: Research, Document Control Center, (1) Notify FDA, by telephone or in 10903 New Hampshire Ave., Bldg. 71, writing, within 5 working days of be- Rm. G112, Silver Spring, MD 20993–0002. coming aware of a significant loss or known theft; [64 FR 67756, Dec. 3, 1999, as amended at 69 (2) Immediately initiate an investiga- FR 48775, Aug. 11, 2004; 70 FR 14981, Mar. 24, tion into the significant loss or known 2005; 74 FR 13112, Mar. 26, 2009; 80 FR 18090, theft; and Apr. 3, 2015]

125

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00135 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 203.38 21 CFR Ch. I (4–1–19 Edition)

§ 203.38 Sample lot or control num- (b) Delivery of a donated drug sample bers; labeling of sample units. to a recipient charitable institution (a) Lot or control number required on shall be completed by mail or common drug sample labeling and sample unit carrier, collection by an authorized label. The manufacturer or authorized agent or employee of the recipient distributor of record of a drug sample charitable institution, or personal de- shall include on the label of the sample livery by a licensed practitioner or an unit and on the outside container or agent or employee of the donating packaging of the sample unit, if any, charitable institution. Donated drug an identifying lot or control number samples shall be placed by the donor in that will permit the tracking of the a sealed carton for delivery to or col- distribution of each drug sample unit. lection by the recipient charitable in- (b) Records containing lot or control stitution. numbers required for all drug samples dis- (c) A donated drug sample shall not tributed. A manufacturer or authorized be dispensed to a patient or be distrib- distributor of record shall maintain for uted to another charitable institution all samples distributed records of drug until it has been examined by a li- sample distribution containing lot or censed practitioner or registered phar- control numbers that are sufficient to macist at the recipient charitable in- permit the tracking of sample units to stitution to confirm that the donation the point of the licensed practitioner. record accurately describes the drug (c) Labels of sample units. Each sample sample delivered and that no drug sam- unit shall bear a label that clearly de- ple is adulterated or misbranded for notes its status as a drug sample, e.g., any reason, including, but not limited ‘‘sample,’’ ‘‘not for sale,’’ ‘‘professional to, the following: courtesy package.’’ (1) The drug sample is out of date; (1) A drug that is labeled as a drug (2) The labeling has become muti- sample is deemed to be a drug sample lated, obscured, or detached from the within the meaning of the act. drug sample packaging; (2) A drug product dosage unit that (3) The drug sample shows evidence bears an imprint identifying the dosage of having been stored or shipped under form as a drug sample is deemed to be conditions that might adversely affect a drug sample within the meaning of its stability, integrity, or effectiveness; the act. (4) The drug sample is for a prescrip- (3) Notwithstanding paragraphs (c)(1) tion drug product that has been re- and (c)(2) of this section, any article called or is no longer marketed; or that is a drug sample as defined in sec- (5) The drug sample is otherwise pos- tion 503(c)(1) of the act and § 203.3(i) sibly contaminated, deteriorated, or that fails to bear the label required in adulterated. this paragraph (c) is a drug sample. (d) The recipient charitable institution shall dispose of any drug sample § 203.39 Donation of drug samples to found to be unsuitable by destroying it charitable institutions. or by returning it to the manufacturer. A charitable institution may receive The charitable institution shall main- a drug sample donated by a licensed tain complete records of the disposi- practitioner or another charitable in- tion of all destroyed or returned drug stitution for dispensing to a patient of samples. the charitable institution, or donate a (e) The recipient charitable institu- drug sample to another charitable in- tion shall prepare at the time of collec- stitution for dispensing to its patients, tion or delivery of a drug sample a provided that the following require- complete and accurate donation ments are met: record, a copy of which shall be re- (a) A drug sample donated by a li- tained by the recipient charitable in- censed practitioner or donating chari- stitution for at least 3 years, con- table institution shall be received by a taining the following information: charitable institution in its original, (1) The name, address, and telephone unopened packaging with its labeling number of the licensed practitioner (or intact. donating charitable institution);

126

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00136 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 203.60

(2) The manufacturer, brand name, volving the drug, starting with the quantity, and lot or control number of manufacturer; and the drug sample donated; and (7) The date of each previous trans- (3) The date of the donation. action. (f) Each recipient charitable institu- (b) The drug origin statement is sub- tion shall maintain complete and accu- ject to the record retention require- rate records of donation, receipt, in- ments of § 203.60 and must be retained spection, inventory, dispensing, redis- by all wholesale distributors involved tribution, destruction, and returns suf- in the distribution of the drug product, ficient for complete accountability and whether authorized or unauthorized, auditing of drug sample stocks. for 3 years. (g) Each recipient charitable institu- (c) Identifying statement not required tion shall conduct, at least annually, when additional manufacturing processes an inventory of prescription drug sam- A manufacturer that sub- ple stocks and shall prepare a report are completed. reconciling the results of each inven- jects a drug to any additional manufac- tory with the most recent prior inven- turing processes to produce a different tory. Drug sample inventory discrep- drug is not required to provide to a ancies and reconciliation problems purchaser a statement identifying the shall be investigated by the charitable previous sales of the component drug institution and reported to FDA. or drugs. (h) A recipient charitable institution (d) List of authorized distributors of shall store drug samples under condi- record. Each manufacturer shall main- tions that will maintain the sample’s tain at the corporate offices a current stability, integrity, and effectiveness, written list of all authorized distribu- and will ensure that the drug samples tors of record. will be free of contamination, deterio- (1) Each manufacturer’s list of au- ration, and adulteration. thorized distributors of record shall (i) A charitable institution shall no- specify whether each distributor listed tify FDA within 5 working days of be- thereon is authorized to distribute the coming aware of a significant loss or manufacturer’s full product line or known theft of prescription drug sam- only particular, specified products. ples. (2) Each manufacturer shall update its list of authorized distributors of Subpart E—Wholesale Distribution record on a continuing basis. (3) Each manufacturer shall make its § 203.50 Requirements for wholesale list of authorized distributors of record distribution of prescription drugs. available on request to the public for (a) Identifying statement for sales by inspection or copying. A manufacturer unauthorized distributors. Before the may impose reasonable copying completion of any wholesale distribu- charges for such requests from mem- tion by a wholesale distributor of a bers of the public. prescription drug for which the seller is not an authorized distributor of record to another wholesale distributor or re- Subpart F—Request and Receipt tail pharmacy, the seller shall provide Forms, Reports, and Records to the purchaser a statement identifying each prior sale, purchase, or § 203.60 Request and receipt forms, reports, and records. trade of such drug. This identifying statement shall include: (a) Use of electronic records, electronic (1) The proprietary and established signatures, and handwritten signatures name of the drug; executed to electronic records. (1) Pro- (2) Dosage; vided the requirements of part 11 of (3) Container size; this chapter are met, electronic (4) Number of containers; records, electronic signatures, and (5) The drug’s lot or control num- handwritten signatures executed to ber(s); electronic records may be used as an (6) The business name and address of alternative to paper records and hand- all parties to each prior transaction in- written signatures executed on paper

127

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00137 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 203.70 21 CFR Ch. I (4–1–19 Edition)

to meet any of the record and signa- or transmitted in a form that provides ture requirements of PDMA, PDA, or reasonable assurance of being: this part. (1) Resistant to tampering, revision, (2) Combinations of paper records and modification, fraud, unauthorized use, electronic records, electronic records or alteration; and handwritten signatures executed (2) Preserved in accessible and re- on paper, or paper records and elec- trievable fashion; and tronic signatures or handwritten signa- (3) Available to permit copying for tures executed to electronic records, purposes of review, analysis, may be used to meet any of the record verification, authentication, and repro- and signature requirements of PDMA, duction by the person who executed the PDA, or this part, provided that: form or created the record, by the man- (i) The requirements of part 11 of this ufacturer or distributor, and by au- chapter are met for the electronic thorized personnel of FDA and other records, electronic signatures, or hand- regulatory and law enforcement agen- written signatures executed to elec- cies. tronic records; and (d) Retention of request and receipt (ii) A reasonably secure link between forms, reports, lists, records, and other the paper-based and electronic compo- documents. Any person required to cre- nents exists such that the combined ate or maintain reports, lists, or other records and signatures are trustworthy records under PDMA, PDA, or this and reliable, and to ensure that the part, including records relating to the signer cannot readily repudiate the distribution of drug samples, shall re- signed records as not genuine. tain them for at least 3 years after the (3) For the purposes of this paragraph date of their creation. (a), the phrase ‘‘record and signature (e) Availability of request and receipt requirements of PDMA, PDA, or this forms, reports, lists, and records. Any part’’ includes drug sample request and person required to create or maintain receipt forms, reports, records, and request and receipt forms, reports, other documents, and their associated lists, or other records under PDMA, signatures required by PDMA, PDA, PDA, or this part shall make them and this part. available, upon request, in a form that (b) Maintenance of request and receipt permits copying or other means of du- forms, reports, records, and other docu- plication, to FDA or other Federal, ments created on paper. Request and re- State, or local regulatory and law en- ceipt forms, reports, records, and other forcement officials for review and re- documents created on paper may be production. The records shall be made maintained on paper or by photo- available within 2 business days of a re- graphic imaging (i.e., photocopies or quest. microfiche), provided that the security and authentication requirements de- Subpart G—Rewards scribed in paragraph (c) of this section are followed. Where a required docu- § 203.70 Application for a reward. ment is created on paper and electroni- (a) Reward for providing information cally scanned into a computer, the re- leading to the institution of a criminal sulting record is an electronic record proceeding against, and conviction of, a that must meet the requirements of person for the sale, purchase, or trade of part 11 of this chapter. a drug sample. A person who provides (c) Security and authentication require- information leading to the institution ments for request and receipt forms, re- of a criminal proceeding against, and ports, records, and other documents cre- conviction of, a person for the sale, ated on paper. A request or receipt purchase, or trade of a drug sample, or form, report, record, or other docu- the offer to sell, purchase, or trade a ment, and any signature appearing drug sample, in violation of section thereon, that is created on paper and 503(c)(1) of the act, is entitled to one- that is maintained by photographic im- half the criminal fine imposed and col- aging, or transmitted electronically lected for such violation, but not more (i.e., by facsimile) shall be maintained than $125,000.

128

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00138 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 205.3

(b) Procedure for making application distribution of human prescription for a reward for providing information drugs in interstate commerce. leading to the institution of a criminal proceeding against, and conviction of, a § 205.2 Purpose. person for the sale, purchase, or trade of The purpose of this part is to imple- a drug sample. A person who provides ment the Prescription Drug Marketing information leading to the institution Act of 1987 by providing minimum of a criminal proceeding against, and standards, terms, and conditions for conviction of, a person for the sale, the licensing by State licensing au- purchase, or trade of a drug sample, or thorities of persons who engage in the offer to sell, purchase, or trade a wholesale distributions in interstate drug sample, in violation of section commerce of prescription drugs. 503(c)(1) of the act, may apply for a reward by making written application to: § 205.3 Definitions. (1) Director, Office of Compliance, (a) Blood means whole blood collected Center for Drug Evaluation and Re- from a single donor and processed ei- search, Food and Drug Administration, ther for transfusion or further manu- 10903 New Hampshire Ave., Silver facturing. Spring, MD 20993–0002; or (b) Blood component means that part (2) Food and Drug Administration, of blood separated by physical or me- Center for Biologics Evaluation and chanical means. Research, Office of Compliance and Biologics Quality (ATTN: Director), (c) Drug sample means a unit of a pre- Document Control Center, 10903 New scription drug that is not intended to Hampshire Ave., Bldg. 71, Rm. G112, be sold and is intended to promote the Silver Spring, MD 20993–0002, as appro- sale of the drug. priate. (d) Manufacturer means anyone who is engaged in manufacturing, pre- [64 FR 67756, Dec. 3, 1999, as amended at 69 paring, propagating, compounding, FR 48775, Aug. 11, 2004; 74 FR 13112, Mar. 26, processing, packaging, repackaging, or 2009; 80 FR 18091, Apr. 3, 2013] labeling of a prescription drug. (e) Prescription drug means any PART 205—GUIDELINES FOR STATE human drug required by Federal law or LICENSING OF WHOLESALE PRE- regulation to be dispensed only by a SCRIPTION DRUG DISTRIBUTORS prescription, including finished dosage forms and active ingredients subject to Sec. section 503(b) of the Federal Food, 205.1 Scope. Drug, and Cosmetic Act. 205.2 Purpose. (f) Wholesale distribution and wholesale 205.3 Definitions. distribution means distribution of pre- 205.4 Wholesale drug distributor licensing scription drugs to persons other than a requirement. 205.5 Minimum required information for li- consumer or patient, but does not in- censure. clude: 205.6 Minimum qualifications. (1) Intracompany sales; 205.7 Personnel. (2) The purchase or other acquisition 205.8 Violations and penalties. by a hospital or other health care enti- 205.50 Minimum requirements for the stor- ty that is a member of a group pur- age and handling of prescription drugs chasing organization of a drug for its and for the establishment and mainte- own use from the group purchasing or- nance of prescription drug distribution records. ganization or from other hospitals or health care entities that are members AUTHORITY: 21 U.S.C. 351, 352, 353, 371, 374. of such organizations; SOURCE: 55 FR 38023, Sept. 14, 1990, unless (3) The sale, purchase, or trade of a otherwise noted. drug or an offer to sell, purchase, or trade a drug by a charitable organiza- § 205.1 Scope. tion described in section 501(c)(3) of the This part applies to any person, part- Internal Revenue Code of 1954 to a non- nership, corporation, or business firm profit affiliate of the organization to in a State engaging in the wholesale the extent otherwise permitted by law;

129

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00139 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 205.4 21 CFR Ch. I (4–1–19 Edition)

(4) The sale, purchase, or trade of a a ‘‘health care entity’’ and a retail drug or an offer to sell, purchase, or pharmacy or wholesale distributor. trade a drug among hospitals or other [55 FR 38023, Sept. 14, 1990, as amended at 64 health care entities that are under FR 67762, Dec. 3, 1999, 73 FR 59501, Oct. 9, common control; for purposes of this 2008] section, common control means the power to direct or cause the direction § 205.4 Wholesale drug distributor li- of the management and policies of a censing requirement. person or an organization, whether by Every wholesale distributor in a ownership of stock, voting rights, by State who engages in wholesale dis- contract, or otherwise; tributions of prescription drugs in (5) The sale, purchase, or trade of a interstate commerce must be licensed drug or an offer to sell, purchase, or by the State licensing authority in ac- trade a drug for emergency medical cordance with this part before engag- reasons; for purposes of this section, ing in wholesale distributions of pre- emergency medical reasons includes scription drugs in interstate com- transfers of prescription drugs by a re- merce. tail pharmacy to another retail pharmacy to alleviate a temporary short- § 205.5 Minimum required information age; for licensure. (6) The sale, purchase, or trade of a (a) The State licensing authority drug, an offer to sell, purchase, or shall require the following minimum trade a drug, or the dispensing of a information from each wholesale drug drug pursuant to a prescription; distributor as part of the license de- (7) The distribution of drug samples scribed in § 205.4 and as part of any re- by manufacturers’ representatives or newal of such license: distributors’ representatives; or (1) The name, full business address, (8) The sale, purchase, or trade of and telephone number of the licensee; blood and blood components intended (2) All trade or business names used for transfusion. by the licensee; (9) Drug returns, when conducted by (3) Addresses, telephone numbers, a hospital, health care entity, or chari- and the names of contact persons for table institution in accordance with all facilities used by the licensee for § 203.23 of this chapter; or the storage, handling, and distribution (10) The sale of minimal quantities of of prescription drugs; drugs by retail pharmacies to licensed (4) The type of ownership or oper- practitioners for office use. ation (i.e., partnership, corporation, or (g) Wholesale distributor means any sole proprietorship); and one engaged in wholesale distribution (5) The name(s) of the owner and/or of prescription drugs, including, but operator of the licensee, including: not limited to, manufacturers; re- (i) If a person, the name of the per- packers; own-label distributors; prison; vate-label distributors; jobbers; bro- (ii) If a partnership, the name of each kers; warehouses, including manufac- partner, and the name of the partner- turers’ and distributors’ warehouses, ship; chain drug warehouses, and wholesale (iii) If a corporation, the name and drug warehouses; independent whole- title of each corporate officer and di- sale drug traders; and retail phar- rector, the corporate names, and the macies that conduct wholesale dis- name of the State of incorporation; and tributions. (iv) If a sole proprietorship, the full (h) Health care entity means any per- name of the sole proprietor and the son that provides diagnostic, medical, name of the business entity. surgical, or dental treatment, or chron- (b) The State licensing authority ic or rehabilitative care, but does not may provide for a single license for a include any retail pharmacy or any business entity operating more than wholesale distributor. Except as pro- one facility within that State, or for a vided in § 203.22(h) and (i) of this chap- parent entity with divisions, subsidi- ter, a person cannot simultaneously be aries, and/or affiliate companies within

130

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00140 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 205.50

that State when operations are con- § 205.7 Personnel. ducted at more than one location and The State licensing authority shall there exists joint ownership and con- require that personnel employed in trol among all the entities. wholesale distribution have appro- (c) Changes in any information in priate education and/or experience to paragraph (a) of this section shall be submitted to the State licensing au- assume responsibility for positions re- thority as required by such authority. lated to compliance with State licensing requirements. (Approved by the Office of Management and Budget under control number 0910–0251) § 205.8 Violations and penalties. § 205.6 Minimum qualifications. (a) State licensing laws shall provide for the suspension or revocation of li- (a) The State licensing authority censes upon conviction of violations of shall consider, at a minimum, the fol- Federal, State, or local drug laws or lowing factors in reviewing the quali- regulations, and may provide for fines, fications of persons who engage in imprisonment, or civil penalties. wholesale distribution of prescription (b) State licensing laws shall provide drugs within the State: for suspension or revocation of li- (1) Any convictions of the applicant censes, where appropriate, for viola- under any Federal, State, or local laws tions of its provisions. relating to drug samples, wholesale or retail drug distribution, or distribution § 205.50 Minimum requirements for of controlled substances; the storage and handling of pre- (2) Any felony convictions of the ap- scription drugs and for the estab- plicant under Federal, State, or local lishment and maintenance of pre- laws; scription drug distribution records. (3) The applicant’s past experience in The State licensing law shall include the manufacture or distribution of pre- the following minimum requirements scription drugs, including controlled for the storage and handling of pre- substances; scription drugs, and for the establish- (4) The furnishing by the applicant of ment and maintenance of prescription false or fraudulent material in any ap- drug distribution records by wholesale plication made in connection with drug drug distributors and their officers, manufacturing or distribution; agents, representatives, and employees: (5) Suspension or revocation by Fed- (a) Facilities. All facilities at which eral, State, or local government of any prescription drugs are stored, license currently or previously held by warehoused, handled, held, offered, the applicant for the manufacture or marketed, or displayed shall: distribution of any drugs, including controlled substances; (1) Be of suitable size and construc- (6) Compliance with licensing re- tion to facilitate cleaning, mainte- quirements under previously granted nance, and proper operations; licenses, if any; (2) Have storage areas designed to (7) Compliance with requirements to provide adequate lighting, ventilation, maintain and/or make available to the temperature, sanitation, humidity, State licensing authority or to Fed- space, equipment, and security condi- eral, State, or local law enforcement tions; officials those records required under (3) Have a quarantine area for stor- this section; and age of prescription drugs that are out- (8) Any other factors or qualifica- dated, damaged, deteriorated, mis- tions the State licensing authority branded, or adulterated, or that are in considers relevant to and consistent immediate or sealed, secondary con- with the public health and safety. tainers that have been opened; (b) The State licensing authority (4) Be maintained in a clean and or- shall have the right to deny a license derly condition; and to an applicant if it determines that (5) Be free from infestation by in- the granting of such a license would sects, rodents, birds, or vermin of any not be in the public interest. kind.

131

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00141 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 205.50 21 CFR Ch. I (4–1–19 Edition)

(b) Security. (1) All facilities used for (2) Each outgoing shipment shall be wholesale drug distribution shall be se- carefully inspected for identity of the cure from unauthorized entry. prescription drug products and to en- (i) Access from outside the premises sure that there is no delivery of pre- shall be kept to a minimum and be scription drugs that have been dam- well-controlled. aged in storage or held under improper (ii) The outside perimeter of the conditions. premises shall be well-lighted. (3) The recordkeeping requirements (iii) Entry into areas where prescrip- in paragraph (f) of this section shall be tion drugs are held shall be limited to followed for all incoming and outgoing authorized personnel. prescription drugs. (2) All facilities shall be equipped (e) Returned, damaged, and outdated with an alarm system to detect entry prescription drugs. (1) Prescription after hours. drugs that are outdated, damaged, de- (3) All facilities shall be equipped teriorated, misbranded, or adulterated with a security system that will pro- shall be quarantined and physically vide suitable protection against theft separated from other prescription and diversion. When appropriate, the drugs until they are destroyed or re- security system shall provide protec- turned to their supplier. tion against theft or diversion that is (2) Any prescription drugs whose im- facilitated or hidden by tampering with mediate or sealed outer or sealed sec- computers or electronic records. ondary containers have been opened or (c) Storage. All prescription drugs used shall be identified as such, and shall be stored at appropriate tempera- shall be quarantined and physically tures and under appropriate conditions separated from other prescription in accordance with requirements, if drugs until they are either destroyed any, in the labeling of such drugs, or or returned to the supplier. with requirements in the current edi- (3) If the conditions under which a tion of an official compendium, such as prescription drug has been returned the United States Pharmacopeia/Na- cast doubt on the drug’s safety, iden- tional Formulary (USP/NF). tity, strength, quality, or purity, then (1) If no storage requirements are es- the drug shall be destroyed, or re- tablished for a prescription drug, the drug may be held at ‘‘controlled’’ room turned to the supplier, unless examina- temperature, as defined in an official tion, testing, or other investigation compendium, to help ensure that its proves that the drug meets appropriate identity, strength, quality, and purity standards of safety, identity, strength, are not adversely affected. quality, and purity. In determining (2) Appropriate manual, whether the conditions under which a electromechanical, or electronic tem- drug has been returned cast doubt on perature and humidity recording equip- the drug’s safety, identity, strength, ment, devices, and/or logs shall be uti- quality, or purity, the wholesale drug lized to document proper storage of distributor shall consider, among other prescription drugs. things, the conditions under which the (3) The recordkeeping requirements drug has been held, stored, or shipped in paragraph (f) of this section shall be before or during its return and the con- followed for all stored drugs. dition of the drug and its container, (d) Examination of materials. (1) Upon carton, or labeling, as a result of stor- receipt, each outside shipping con- age or shipping. tainer shall be visually examined for (4) The recordkeeping requirements identity and to prevent the acceptance in paragraph (f) of this section shall be of contaminated prescription drugs or followed for all outdated, damaged, de- prescription drugs that are otherwise teriorated, misbranded, or adulterated unfit for distribution. This examina- prescription drugs. tion shall be adequate to reveal con- (f) Recordkeeping. (1) Wholesale drug tainer damage that would suggest pos- distributors shall establish and main- sible contamination or other damage tain inventories and records of all to the contents. transactions regarding the receipt and

132

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00142 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 205.50

distribution or other disposition of pre- tration or other Federal, State, or scription drugs. These records shall in- local law enforcement or other govern- clude the following information: ment agency, including the State li- (i) The source of the drugs, including censing agency; the name and principal address of the (ii) Any voluntary action by the seller or transferor, and the address of manufacturer to remove defective or the location from which the drugs were potentially defective drugs from the shipped; market; or (ii) The identity and quantity of the (iii) Any action undertaken to pro- drugs received and distributed or dis- mote public health and safety by re- posed of; and placing of existing merchandise with (iii) The dates of receipt and distribu- an improved product or new package tion or other disposition of the drugs. design. (2) Inventories and records shall be (3) A procedure to ensure that whole- made available for inspection and sale drug distributors prepare for, pro- photocopying by authorized Federal, tect against, and handle any crisis that State, or local law enforcement agency affects security or operation of any fa- officials for a period of 3 years after the cility in the event of strike, fire, flood, date of their creation. or other natural disaster, or other situ- (3) Records described in this section ations of local, State, or national that are kept at the inspection site or emergency. that can be immediately retrieved by (4) A procedure to ensure that any computer or other electronic means shall be readily available for author- outdated prescription drugs shall be ized inspection during the retention pe- segregated from other drugs and either riod. Records kept at a central location returned to the manufacturer or de- apart from the inspection site and not stroyed. This procedure shall provide electronically retrievable shall be for written documentation of the dis- made available for inspection within 2 position of outdated prescription drugs. working days of a request by an au- This documentation shall be main- thorized official of a Federal, State, or tained for 2 years after disposition of local law enforcement agency. the outdated drugs. (g) Written policies and procedures. (h) Responsible persons. Wholesale Wholesale drug distributors shall es- drug distributors shall establish and tablish, maintain, and adhere to writ- maintain lists of officers, directors, ten policies and procedures, which managers, and other persons in charge shall be followed for the receipt, secu- of wholesale drug distribution, storage, rity, storage, inventory, and distribu- and handling, including a description tion of prescription drugs, including of their duties and a summary of their policies and procedures for identifying, qualifications. recording, and reporting losses or (i) Compliance with Federal, State, and thefts, and for correcting all errors and local law. Wholesale drug distributors inaccuracies in inventories. Wholesale shall operate in compliance with appli- drug distributors shall include in their cable Federal, State, and local laws written policies and procedures the fol- and regulations. lowing: (1) Wholesale drug distributors shall (1) A procedure whereby the oldest permit the State licensing authority approved stock of a prescription drug and authorized Federal, State, and product is distributed first. The proce- local law enforcement officials to enter dure may permit deviation from this and inspect their premises and delivery requirement, if such deviation is tem- vehicles, and to audit their records and porary and appropriate. written operating procedures, at rea- (2) A procedure to be followed for sonable times and in a reasonable man- handling recalls and withdrawals of ner, to the extent authorized by law. prescription drugs. Such procedure (2) Wholesale drug distributors that shall be adequate to deal with recalls deal in controlled substances shall reg- and withdrawals due to: ister with the appropriate State con- (i) Any action initiated at the re- trolled substance authority and with quest of the Food and Drug Adminis- the Drug Enforcement Administration

133

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00143 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Pt. 206 21 CFR Ch. I (4–1–19 Edition)

(DEA), and shall comply with all appli- Imprinted means marked with an cable State, local, and DEA regula- identification code by means of em- tions. bossing, debossing, engraving, or print- (j) Salvaging and reprocessing. Whole- ing with ink. sale drug distributors shall be subject Manufacturer means the manufac- to the provisions of any applicable Fed- turer as described in §§ 201.1 and 600.3(t) eral, State, or local laws or regulations of this chapter. that relate to prescription drug prod- Solid oral dosage form means capsules, uct salvaging or reprocessing, includ- tablets, or similar drug products in- ing parts 207, 210, and 211 of this chap- tended for oral use. ter. (Approved by the Office of Management and § 206.7 Exemptions. Budget under control number 0910–0251) (a) The following classes of drug [55 FR 38023, Sept. 14, 1990, as amended at 64 products are exempt from requirements FR 67763, Dec. 3, 1999] of this part: (1) Drug products intended for use in PART 206—IMPRINTING OF SOLID a clinical investigation under section ORAL DOSAGE FORM DRUG 505(i) of the act, but not including PRODUCTS FOR HUMAN USE drugs distributed under a treatment IND under part 312 of this chapter or distributed as part of a nonconcur- Sec. 206.1 Scope. rently controlled study. Placebos in- 206.3 Definitions. tended for use in a clinical investiga- 206.7 Exemptions. tion are exempt from the requirements 206.10 Code imprint required. of this part if they are designed to copy AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, the active drug products used in that 371; 42 U.S.C. 262. investigation. (2) Drugs, other than reference listed SOURCE: 58 FR 47958, Sept. 13, 1993, unless otherwise noted. drugs, intended for use in bioequiva- lence studies. § 206.1 Scope. (3) Drugs that are extemporaneously This part applies to all solid oral dos- compounded by a licensed pharmacist, age form human drug products, includ- upon receipt of a valid prescription for ing prescription drug products, over- an individual patient from a practi- the-counter drug products, biological tioner licensed by law to prescribe or drug products, and homeopathic drug administer drugs, to be used solely by products, unless otherwise exempted the patient for whom they are pre- under § 206.7. scribed. (4) Radiopharmaceutical drug prod- § 206.3 Definitions. ucts. The following definitions apply to (b) Exemption of drugs because of this part: size or unique physical characteristics: The act means the Federal Food, (1) For a drug subject to premarket Drug, and Cosmetic Act (21 U.S.C. 301 approval, FDA may provide an exemp- et seq.). tion from the requirements of § 206.10 Debossed means imprinted with a upon a showing that the product’s size, mark below the dosage form surface. shape, texture, or other physical char- Drug product means a finished dosage acteristics make imprinting techno- form, e.g., a tablet or capsule that con- logically infeasible or impossible. tains a drug substance, generally, but (i) Exemption requests for products not necessarily, in association with one with approved applications shall be or more other ingredients. made in writing to the appropriate re- Embossed means imprinted with a view division in the Center for Drug mark raised above the dosage form sur- Evaluation and Research (CDER), Food face. and Drug Administration, 5901–B Engraved means imprinted with a Ammendale Rd., Beltsville, MD 20705– code that is cut into the dosage form 1266 or the Food and Drug Administra- surface after it has been completed. tion, Center for Biologics Evaluation

134

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00144 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS Pt. 207

and Research, Document Control Cen- (b) A holder of an approved applica- ter, 10903 New Hampshire Ave., Bldg. tion who has, under § 314.70 (b) of this 71, Rm. G112, Silver Spring, MD 20993– chapter, supplemented its application 0002. If FDA denies the request, the to provide for a new imprint is not re- holder of the approved application will quired to bring its product into compli- have 1 year after the date of an agency ance with this section during the pend- denial to imprint the drug product. ency of the agency’s review. Once the (ii) Exemption requests for products review is complete, the drug product is that have not yet received approval subject to the requirements of the rule. shall be made in writing to the appro- (c) A solid oral dosage form drug priate review division in CDER or product that does not meet the require- CBER. ment for imprinting in paragraph (a) of (2) Any product not subject to pre- this section and is not exempt from the market approval is exempt from the re- requirement may be considered adul- quirement of § 206.10 if, based on the terated and misbranded and may be an product’s size, shape, texture, or other unapproved new drug. physical characteristics, the manufac- (d) For purposes of this section, code turer or distributor of the product is imprint means any single letter or num- prepared to demonstrate that imprint- ber or any combination of letters and ing the dosage form is technologically numbers, including, e.g., words, com- infeasible or impossible. pany name, and National Drug Code, or (c) For drugs that are administered a mark, symbol, logo, or monogram, or solely in controlled health care set- a combination of letters, numbers, and tings and not provided to patients for marks or symbols, assigned by a drug self-administration, sponsors may sub- firm to a specific drug product. mit requests for exemptions from the [58 FR 47958, Sept. 13, 1993, as amended at 60 requirements of this rule. Controlled FR 19846, Apr. 21, 1995; 69 FR 18763, Apr. 8, settings include physicians’ offices and 2004] other health care facilities. Exemption requests should be submitted in writ- PART 207—REQUIREMENTS FOR ing to the appropriate review division FOREIGN AND DOMESTIC ESTAB- in CDER or CBER. LISHMENT REGISTRATION AND [58 FR 47958, Sept. 13, 1993, as amended at 70 LISTING FOR HUMAN DRUGS, IN- FR 14981, Mar. 24, 2005; 74 FR 13112, Mar. 26, CLUDING DRUGS THAT ARE REG- 2009; 80 FR 18091, Apr. 3, 2015] ULATED UNDER A BIOLOGICS LI- § 206.10 Code imprint required. CENSE APPLICATION, AND ANI- MAL DRUGS, AND THE NATIONAL (a) Unless exempted under § 206.7, no DRUG CODE drug product in solid oral dosage form may be introduced or delivered for in- Subpart A—General troduction into interstate commerce unless it is clearly marked or im- Sec. printed with a code imprint that, in 207.1 What definitions and interpretations conjunction with the product’s size, of terms apply to this part? shape, and color, permits the unique 207.3 Bulk drug substance. identification of the drug product and 207.5 What is the purpose of this part? the manufacturer or distributor of the 207.9 Who does this part cover? 207.13 Who is exempt from the registration product. Identification of the drug and listing requirements? product requires identification of its active ingredients and its dosage Subpart B—Registration strength. Inclusion of a letter or number in the imprint, while not required, 207.17 Who must register? is encouraged as a more effective 207.21 When must initial registration infor- means of identification than a symbol mation be provided? 207.25 What information is required for reg- or logo by itself. Homeopathic drug istration? products are required only to bear an 207.29 What are the requirements for re- imprint that identifies the manufac- viewing and updating registration infor- turer and their homeopathic nature. mation?

135

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00145 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.1 21 CFR Ch. I (4–1–19 Edition)

Subpart C—National Drug Code Active pharmaceutical ingredient means any substance that is intended 207.33 What is the National Drug Code (NDC), how is it assigned, and what are for incorporation into a finished drug its requirements? product and is intended to furnish 207.35 What changes require a new NDC? pharmacological activity or other di- 207.37 What restrictions pertain to the use rect effect in the diagnosis, cure, miti- of the NDC? gation, treatment, or prevention of disease, or to affect the structure or any Subpart D—Listing function of the body. Active pharma- 207.41 Who must list drugs and what drugs ceutical ingredient does not include must they list? intermediates used in the synthesis of 207.45 When, after initial registration of an the substance. establishment, must drug listing infor- Bulk drug substance, as referenced in mation be submitted? 207.49 What listing information must a reg- sections 503A(b)(1)(A) and 503B(a)(2) of istrant submit for a drug that it manu- the Federal Food, Drug, and Cosmetic factures? Act, means the same as ‘‘active phar- 207.53 What listing information must a reg- maceutical ingredient’’ as defined in istrant submit for a drug that it repacks § 207.1(b). or relabels? Commercial distribution means any dis- 207.54 What listing information must a registrant submit for a drug that it tribution of a human drug, except for salvages? investigational use under part 312 of 207.55 What additional drug listing informa- this chapter, and any distribution of an tion may FDA require? animal drug or an animal feed bearing 207.57 What information must registrants or containing an animal drug, except submit when updating listing informa- for investigational use under part 511 tion and when? of this chapter. The term does not in- Subpart E—Electronic Format for clude internal or interplant transfer Registration and Listing between registered establishments under common ownership and control, 207.61 How is registration and listing infor- including a parent, subsidiary, or affil- mation provided to FDA? iate company. For foreign establish- 207.65 How can a waiver of the electronic ments that manufacture, repack, submission requirement be obtained? relabel, or salvage, or for foreign pri- Subpart F—Miscellaneous vate label distributors, the term ‘‘commercial distribution’’ has the 207.69 What are the requirements for an of- same meaning except the term does not ficial contact and a United States agent? include distribution of any drug that is 207.77 What legal status is conferred by registration and listing? neither imported nor offered for import 207.81 What registration and listing infor- into the United States. mation will FDA make available for pub- Content of labeling means: lic disclosure? (1) For human prescription drugs AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, that are subject to section 505 of the 360, 360b, 371, 374, 381, 393; 42 U.S.C. 262, 264, Federal Food, Drug, and Cosmetic Act 271. or section 351 of the Public Health SOURCE: 81 FR 60212, Aug. 31, 2016, unless Service Act: The content of the pre- otherwise noted. scription drug labeling (as specified in §§ 201.56, 201.57, and 201.80 of this chap- Subpart A—General ter), including all text, tables, and figures. § 207.1 What definitions and interpre- (2) For human prescription drugs tations of terms apply to this part? that are not subject to section 505 of The definitions and interpretations the Federal Food, Drug, and Cosmetic of terms in sections 201 and 510 of the Act or section 351 of the Public Health Federal Food, Drug, and Cosmetic Act Service Act: The labeling equivalent to apply to the terms used in this part, if the content of the prescription drug la- not otherwise defined in this section. beling (as specified in §§ 201.56, 201.57, The following definitions apply to this and 201.80 of this chapter), including all part: text, tables, and figures.

136

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00146 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.1

(3) For human over-the-counter tion with other ingredients in finished (OTC) drugs: All text, tables, and fig- package form suitable for distribution ures including the drug facts labeling to pharmacies, hospitals, or other sell- required by § 201.66 of this chapter. ers or dispensers of the drug product to (4) For animal drugs (including, but patients or consumers. not limited to, drugs that are subject Foreign for the purposes of registra- to section 512 of the Federal Food, tion and listing under this part: Drug, and Cosmetic Act): The content (1) When used to modify the term of the labeling that accompanies the ‘‘manufacturer,’’ ‘‘repacker,’’ ‘‘re- drug that is necessary to enable safe labeler,’’ or ‘‘salvager,’’ refers to a and proper administration of the drug manufacturer, repacker, relabeler, or (e.g., the labeling applicable to veteri- salvager, who is located in a foreign nary drugs specified in part 201 of this country and who manufactures, re- chapter), including all text, tables, and packs, relabels, or salvages a drug, or figures. an animal feed bearing or containing a Domestic for purposes of registration new animal drug, that is imported or and listing under this part, when used offered for import into the United to modify the term ‘‘registrant,’’ States. ‘‘manufacturer,’’ ‘‘repacker,’’ ‘‘re- (2) When used to modify the term labeler,’’ ‘‘salvager,’’ ‘‘private label ‘‘establishment’’ refers to an establish- distributor,’’ or ‘‘establishment,’’ re- ment that is located in a foreign coun- fers to a registrant, manufacturer, re- try and is engaged in the manufacture, packer, relabeler, salvager, private repackaging, relabeling, or salvaging of label distributor, or establishment any drug, or any animal feed bearing or within any State or Territory of the containing a new animal drug, that is United States, the District of Colum- imported or offered for import into the bia, or the Commonwealth of Puerto United States. Rico. Importer means, for purposes of this Drug, for the purposes of registration part, a person in the United States that and listing under this part, has the is an owner, consignee, or recipient, at meaning given in section 201(g)(1) of the time of entry, of a foreign estab- the Federal Food, Drug, and Cosmetic lishment’s drug, or an animal feed Act. bearing or containing a new animal Establishment means a place of busi- drug, that is imported into the United ness under one management at one States. general physical location. The term in- Manufacture means each step in the cludes, among others, independent lab- manufacture, preparation, propagation, oratories that engage in control activi- compounding, or processing of a drug ties for a registered drug establishment or an animal feed bearing or containing (e.g., consulting laboratories), manu- a new animal drug. Manufacture in- facturers of medicated feeds and of vi- cludes the making by chemical, phys- tamin products that are drugs in ac- ical, biological, or other procedures or cordance with section 201(g) of the Fed- manipulations of a drug, or an animal eral Food, Drug, and Cosmetic Act, feed bearing or containing a new ani- human blood donor centers, and animal mal drug, including control procedures facilities used for the production or applied to the final product or to any control testing of licensed biologicals, part of the process. Manufacture in- and establishments engaged in sal- cludes manipulation, sampling, testing, vaging. or control procedures applied to the Establishment registration number final product or to any part of the means the number assigned to the es- process, including, for example, analyt- tablishment, as identified by FDA, ical testing of drugs for another reg- after the establishment registration re- istered establishment’s drug. For pur- quired in this part. poses of this part, and in order to clar- Finished drug product means a fin- ify the responsibilities of the entities ished dosage form (e.g., tablet, capsule, engaged in different operations, the or solution) that contains at least one term manufacture is defined and used active pharmaceutical ingredient, gen- separately from the terms relabel, re- erally, but not necessarily, in associa- package, and salvage, although the

137

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00147 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.1 21 CFR Ch. I (4–1–19 Edition)

term ‘‘manufacture, preparation, prop- United States by international mail or agation, compounding, or processing,’’ other private delivery service, but it as used in section 510 of the Federal does not include carriers who merely Food, Drug, and Cosmetic Act, includes transport the drug. relabeling, repackaging, and salvaging Private label distribution means com- activities. mercial distribution of a drug under Manufacturer means a person who the label or trade name of a person who owns or operates an establishment that did not manufacture, repack, relabel, manufactures a drug or an animal feed or salvage that drug. bearing or containing a new animal Private label distributor means, with drug. This term includes, but is not respect to a particular drug, a person limited to, control laboratories, con- who did not manufacture, repack, tract laboratories, contract manufac- relabel, or salvage the drug but under turers, contract packers, contract la- whose label or trade name the drug is belers, and other entities that manu- commercially distributed. facture a drug, or an animal feed bear- Registrant means any person that ing or containing a new animal drug, owns or operates an establishment that as defined in this paragraph. For pur- manufactures, repacks, relabels, or poses of this part, and in order to clar- salvages a drug, and is not otherwise ify the responsibilities of the entities exempt from establishment registra- engaged in different operations, the tion requirements under section 510 of term manufacturer is defined and used the Federal Food, Drug, and Cosmetic separately from the terms relabeler, Act or this part. repacker, and salvager, although the term ‘‘manufacture, preparation, prop- Relabel means to change the existing agation, compounding, or processing,’’ label or labels on a drug or drug pack- as used in section 510 of the Federal age, or change or alter the existing la- Food, Drug, and Cosmetic Act, includes beling for a drug or drug package, the activities of relabelers, repackers, without repacking the drug or drug and salvagers. Repackers, relabelers, package. This term does not include and salvagers are subject to the provi- the addition or modification of infor- sions of this part that are applicable to mation affixed solely for purposes of repackers, relabelers, and salvagers, delivery to a customer, customer iden- but are not subject to the provisions of tification, and/or inventory manage- this part that are applicable to manu- ment. facturers. When not modified by ‘‘do- Relabeler means a person who owns or mestic’’ or ‘‘foreign,’’ the term in- operates an establishment that relabels cludes both domestic manufacturers a drug. When not modified by ‘‘domes- and foreign manufacturers. tic’’ or ‘‘foreign,’’ the term includes Material change means any change in both domestic relabelers and foreign any drug listing information, as re- relabelers. quired under §§ 207.49, 207.53, 207.54, Repack or repackage means the act of 207.55, or 207.57 except changes in for- taking a finished drug product or un- mat of labeling, labeling changes of an finished drug from the container in editorial nature, or inclusion of a bar which it was placed in commercial dis- code or initial inclusion of an NDC on tribution and placing it into a different the label. container without manipulating, Outsourcing facility means a changing, or affecting the composition compounder that has elected to reg- or formulation of the drug. ister with FDA under section 503B of Repacker means a person who owns or the Federal Food, Drug, and Cosmetic operates an establishment that repacks Act and that meets all of the condi- a drug or drug package. When not tions of section 503B. modified by ‘‘domestic’’ or ‘‘foreign,’’ Person who imports or offers for import the term includes both domestic re- means, for purposes of this part, the packers and foreign repackers. owner or exporter of a drug who con- Representative sampling of advertise- signs and ships a drug from a foreign ments means typical advertising mate- country to the United States. This in- rial (including the promotional mate- cludes persons who send a drug to the rial described in § 202.1(l)(1) of this

138

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00148 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.9

chapter, but excluding labeling as de- Cosmetic Act and are used for many termined in § 202.1(l)(2) of this chapter), important public health purposes. that gives a balanced picture of the promotional claims used for the drug. § 207.9 Who does this part cover? Representative sampling of any other (a) Except as provided in paragraph labeling means typical labeling mate- (b) of this section, this part applies to: rial (including the labeling material (1) Domestic manufacturers, domes- described in § 202.1(l)(2) of this chapter, tic repackers, domestic relabelers and but excluding labels and package in- domestic salvagers, not exempt under serts) that gives a balanced picture of section 510(g) of the Federal Food, the promotional claims used for the Drug, and Cosmetic Act or § 207.13, re- drug. gardless of whether their drugs enter Salvage means the act of segregating interstate commerce; out those finished drug products that (2) Foreign manufacturers, foreign may have been subjected to improper repackers, foreign relabelers and for- storage conditions (such as extremes in eign salvagers, not exempt under sec- temperature, humidity, smoke, fumes, tion 510(g) of the Federal Food, Drug, pressure, age, or radiation) for the pur- and Cosmetic Act or § 207.13; pose of returning the products to the (3) Private label distributors, because marketplace and includes applying they must have labeler codes; manufacturing controls such as those (4) Establishments engaged in the required by current good manufac- manufacture, repacking, relabeling, or turing practice in parts 210 and 211 of salvaging of human drugs regulated this chapter. under a biologics license application Salvager means a person who owns or (BLA). These establishments are sub- operates an establishment that engages ject to the requirements of this part in salvaging. When not modified by unless they are required to register and ‘‘domestic’’ or ‘‘foreign,’’ the term in- list such drugs as human blood or blood cludes both domestic and foreign sal- products under part 607 of this chapter vagers. and do not engage in activities that Unfinished drug means an active would otherwise require them to reg- pharmaceutical ingredient either alone ister and list under this part. or together with one or more other in- (5) Establishments engaged in the gredients but does not include finished manufacture (as defined in § 1271.3(e) of drug products. this chapter) of human cells, tissues, and cellular and tissue-based products § 207.3 Bulk drug substance. (HCT/Ps) (as defined in § 1271.3(d) of this Bulk drug substance, as referenced in chapter) that, under § 1271.20 of this sections 503A(b)(1)(A) and 503B(a)(2) of chapter, are also drugs regulated under the Federal Food, Drug, and Cosmetic section 351 of the Public Health Service Act, previously defined in § 207.3(a)(4), Act or section 505 of the Federal Food, means the same as ‘‘active pharma- Drug, and Cosmetic Act. These estab- ceutical ingredient’’ as defined in lishments must register and list those § 207.1(b). HCT/Ps following the procedures described in this part. § 207.5 What is the purpose of this (b) This part does not apply to own- part? ers and operators of establishments Establishment registration informa- that collect or process human whole tion helps FDA identify who is manu- blood and blood products unless the es- facturing, repacking, relabeling, and tablishment also manufactures, re- salvaging drugs and where those oper- packs, or relabels other drugs. For pur- ations are performed. Drug listing in- poses of this paragraph (b), human formation gives FDA a current inven- whole blood and blood products do not tory of drugs manufactured, repacked, include plasma derivatives such as al- relabeled, or salvaged for commercial bumin, Immune Globulin, Factor VIII distribution. Both types of information and Factor IX, and recombinant facilitate implementation and enforce- versions of plasma derivatives or ani- ment of the Federal Food, Drug, and mal derived plasma derivatives, or

139

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00149 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.13 21 CFR Ch. I (4–1–19 Edition)

bulk product substances such as frac- of the Federal Food, Drug, and Cos- tionation intermediates or pastes. Es- metic Act. tablishments that collect or process (b)(1) Hospitals, clinics, other health human whole blood and blood products care entities, and public health agen- as well as establishments involved in cies that: testing of human whole blood and (i) Operate establishments in con- blood products must register and list formance with all applicable local laws under part 607 of this chapter. Manu- regulating the practice of pharmacy facturers of licensed devices and manu- and medicine, including all applicable facturers of licensed biological prod- local laws regulating the dispensing of ucts used in a licensed device must reg- prescription drugs; ister and list under part 607 of this (ii) Regularly engage in dispensing chapter. prescription drugs, other than human (c) This part does not apply to estab- whole blood or blood products, upon a lishments that solely manufacture, valid order or prescription by practi- prepare, propagate, compound, assem- tioners licensed by law to administer ble, or process medical devices. Reg- these drugs to patients under their pro- istration and listing regulations for fessional care; and such establishments are codified in (iii) Do not manufacture, repack, part 807 of this chapter. relabel, or salvage drugs other than in the regular course of their practice of § 207.13 Who is exempt from the reg- pharmacy, including dispensing. istration and listing requirements? (2) The exemption in this paragraph (b) is limited to hospitals, clinics, Except as provided in § 207.13(l), the other health care entities, and public following classes of persons are exempt health agencies located in any State as from registration and drug listing in defined in section 201(a)(1) of the Fed- accordance with section 510(g) of the eral Food, Drug, and Cosmetic Act. Federal Food, Drug, and Cosmetic Act (c) Individuals or establishments or because FDA has determined, under under contract, agreement, or other ar- section 510(g)(5) of the Federal Food, rangement with a registered establish- Drug, and Cosmetic Act, that their reg- ment and engaged solely in recovering istration is not necessary for the pro- cells or tissues and sending the recov- tection of the public health. This ex- ered cells or tissues to the registered emption is limited to establishment establishment to become components registration and drug listing require- of a biological product are exempt from ments and does not relieve a person registration and listing under this part from other statutory or regulatory ob- unless FDA determines that drug es- ligations. tablishment registration and listing is (a)(1) Pharmacies that: necessary for the protection of the pub- (i) Operate in conformance with all lic health. applicable local laws regulating the (d) Practitioners who are licensed by practice of pharmacy and medicine, in- law to prescribe or administer drugs cluding all applicable local laws regu- and who manufacture, repack, relabel, lating the dispensing of prescription or salvage drugs solely for use in their drugs; professional practice. (ii) Regularly engage in dispensing (e) Manufacturers, repackers, re- prescription drugs upon a valid pre- labelers, or salvagers who manufac- scription by practitioners licensed by ture, repack, relabel, or salvage drugs law to administer these drugs to pa- solely for use in research, teaching, or tients under their professional care; chemical analysis and not for sale. and (f) Manufacturers, repackers, and re- (iii) Do not manufacture, repack, labelers of harmless inactive ingredi- relabel, or salvage drugs other than in ents such as excipients, colorings, the regular course of their business of flavorings, emulsifiers, lubricants, pre- dispensing or selling drugs at retail. servatives, or solvents that become (2) The exemption in this paragraph components of drugs. (a) is limited to pharmacies located in (g) Manufacturers, repackers, re- any State as defined in section 201(a)(1) labelers, or salvagers of Type B or Type

140

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00150 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.21

C medicated feeds, except for persons (1) Manufacture (as defined in who manufacture, repack, relabel, or § 207.1(b)), repack, relabel, or salvage salvage Type B or Type C medicated compounded positron emission tomog- feeds starting from Category II, Type A raphy drugs as defined in section 201(ii) medicated articles for which a medi- of the Federal Food, Drug, and Cos- cated feed mill license approved under metic Act; part 515 of this chapter is required. (2) Manufacture (as defined in This exemption also does not apply to § 600.3(u) of this chapter) a human bio- persons that would otherwise be re- logical product subject to licensing quired to register (such as manufactur- under section 351 of the Public Health ers, repackers, relabelers, or salvagers Service Act; or of certain free-choice feeds, as defined (3) Engage in activities that would in § 510.455 of this chapter, or certain otherwise require them to register liquid feeds, as defined in § 558.5 of this under this part. chapter, where the specifications and/ or formulas are not published and a medicated feed mill license is re- Subpart B—Registration quired). All manufacturers, repackers, relabelers, or salvagers of Type B or § 207.17 Who must register? Type C medicated feeds are exempt (a) Unless exempt under section from listing. 510(g) of the Federal Food, Drug, and (h) Any manufacturer, repacker, re- Cosmetic Act or this part, all manufac- labeler, or salvager of a virus, serum, turers, repackers, relabelers, and sal- toxin, or analogous product intended vagers must register each domestic es- for the treatment of domestic animals tablishment that manufactures, re- who holds an unsuspended and packs, relabels, or salvages a drug, or unrevoked license issued by the Sec- an animal feed bearing or containing a retary of Agriculture under the animal new animal drug, and each foreign es- virus-serum-toxin law of March 4, 1913 tablishment that manufactures, re- (37 Stat. 832 (21 U.S.C. 151 et seq.)), pro- packs, relabels, or salvages a drug, or vided that this exemption from reg- an animal feed bearing or containing a istration applies only to the manufac- new animal drug, that is imported or turer, repacker, relabeler, or salvager offered for import into the United of that animal virus, serum, toxin, or States. When operations are conducted analogous product. at more than one establishment and (i) Carriers, in their receipt, carriage, common ownership and control among holding, or delivery of drugs in the all the establishments exists, the par- usual course of business as carriers. ent, subsidiary, or affiliate company (j) Foreign establishments whose may submit registration information drugs are imported or offered for im- for all establishments. port into the United States must com- (b) Private label distributors who do ply with the establishment registration and listing requirements of this part not also manufacture, repack, relabel, unless exempt under this section or un- or salvage drugs are not required to less: register under this part. FDA will ac- (1) Their drugs enter a foreign trade cept registration or listing information zone and are re-exported without hav- submitted by a private label dis- ing entered U.S. commerce, or tributor only if it is acting as an au- (2) Their drugs are imported in con- thorized agent for and submitting in- formance with section 801(d)(3) of the formation that pertains to an estab- Federal Food, Drug, and Cosmetic Act. lishment that manufactures, repacks, (k) Entities that are registered with relabels, or salvages drugs. FDA as outsourcing facilities and that compound drugs in conformance with § 207.21 When must initial registration section 503B of the Federal Food, Drug, information be provided? and Cosmetic Act. (a) Registrants must register each (l) The exemptions provided in para- domestic establishment no later than 5 graphs (a) through (k) of this section calendar days after beginning to manu- do not apply to such persons if they: facture, repack, relabel, or salvage a

141

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00151 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.25 21 CFR Ch. I (4–1–19 Edition)

drug or an animal feed bearing or con- § 207.29 What are the requirements for taining a new animal drug at such es- reviewing and updating registra- tablishment. tion information? (b) Registrants must register each (a) Expedited updates. Registrants foreign establishment before a drug or must update their registration infor- an animal feed bearing or containing a mation no later than 30 calendar days new animal drug manufactured, re- after: packed, relabeled, or salvaged at the (1) Closing or selling an establish- establishment is imported or offered ment; for import into the United States. (2) Changing an establishment’s name or physical address; or § 207.25 What information is required (3) Changing the name, mailing ad- for registration? dress, telephone number, or email address of the official contact or the Registrants must provide the fol- United States agent. A registrant, offi- lowing information: cial contact, or United States agent (a) Name of the owner or operator of may notify FDA about a change of in- each establishment; if a partnership, formation for the designated official the name of each partner; if a corpora- contact or United States agent, but tion, the name of each corporate offi- only a registrant is permitted to des- cer and director, and the place of incor- ignate a new official contact or United poration; States agent. (b) Each establishment’s name, phys- (b) Annual review and update of reg- ical address, and telephone number(s); istration information. Registrants must (c) All name(s) of the establishment, review and update all registration in- including names under which the es- formation required under § 207.25 for tablishment conducts business or each establishment. names by which the establishment is (1) The first review and update must known; occur during the period beginning on October 1 and ending December 31 of (d) Registration number of each es- the year of initial registration, if the tablishment, if previously assigned by initial registration occurs prior to Oc- FDA; tober 1. Subsequent reviews and up- (e) A Unique Facility Identifier in ac- dates must occur annually, during the cordance with the system specified period beginning on October 1 and end- under section 510 of the Federal Food, ing December 31 of each calendar year. Drug, and Cosmetic Act. (2) The updates must reflect all (f) All types of operations performed changes that have occurred since the at each establishment; last annual review and update. (g) Name, mailing address, telephone (3) If no changes have occurred since number, and email address of the offi- the last registration, registrants must cial contact for the establishment, as certify that no changes have occurred. provided in § 207.69(a); and (h) Additionally, with respect to for- Subpart C—National Drug Code eign establishments subject to registration, the name, mailing address, § 207.33 What is the National Drug Code (NDC), how is it assigned, and telephone number, and email address what are its requirements? must be provided for: (a) What is the NDC for a drug and (1) The United States agent, as pro- what products must have unique NDCs? vided in § 207.69(b); The NDC for a drug is a numeric code. (2) Each importer in the United Each finished drug product or unfin- States of drugs manufactured, re- ished drug subject to the listing repacked, relabeled, or salvaged at the quirements of this part must have a establishment that is known to the es- unique NDC to identify its labeler, tablishment; and product, and package size and type. (3) Each person who imports or offers (b) What is the format of an NDC? (1) for import such drug to the United Except as described in paragraph (b)(4) States. of this section, the NDC must consist

142

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00152 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.33

of 10 or 11 digits, divided into three seg- (c) Who must obtain an NDC labeler ments as follows: code and how is the code assigned and (i) The first segment of the NDC is updated? (1) Each person who engages the labeler code and consists of 4, 5, or in manufacturing, repacking, re- 6 digits. The labeler code is assigned by labeling, or private label distribution FDA. of a drug subject to listing under this (ii) The second segment of the NDC is part must apply for an NDC labeler the product code and consists of 3 or 4 code, by providing the following infor- digits, as specified in paragraphs (b)(2) mation: and (3) of this section. (i) The name, physical address, email (iii) The third segment of the NDC is address, and other contact information the package code and consists of 1 or 2 FDA may request, of the person for digits as specified in paragraphs (b)(2) whom the NDC labeler code is re- and (3) of this section. The package quested; code identifies the package size and (ii) The type(s) of activities (e.g., type of the drug and differentiates be- manufacture or repacking) in which tween different quantitative and quali- the person requesting the NDC labeler tative attributes of the product pack- code engages with respect to human aging. drugs; and (2) The following combinations of la- (iii) The type(s) of drug(s) (human, beler code, product code and package animal, or both, and prescription, non- code character lengths are permissible: prescription, or both) to which the (i) If a labeler code is either 5 or 6 NDC labeler code will be applied. digits in length, it may be combined (2) Each person who is assigned an with: NDC labeler code must update the in- (A) A product code consisting of 4 formation submitted under paragraph digits and a package code consisting of (c)(1)of this section within 30 calendar 1 digit for a total NDC length of 10 or days after any change to that informa- 11 digits (5–4–1 or 6–4–1), or tion. (B) A product code consisting of 3 (d) How is an NDC proposed for assign- digits and a package code consisting of ment by FDA, when is an NDC assigned 2 digits for a total NDC length of 10 or by FDA, and how can a proposed NDC be 11 digits (5–3–2 or 6–3–2). reserved? (1) An NDC is proposed for as- (ii) If a labeler code is 4 digits in signment by FDA when it is submitted length, it may be combined only with a for the first time with listing informa- product code consisting of 4 digits and tion in accordance with § 207.49 or a package code consisting of 2 digits § 207.53, as applicable. for a total NDC length of 10 digits (4–4– (i) Each manufacturer, repacker, or 2). relabeler must propose for assignment (3) A registrant or private label dis- by FDA an NDC that includes its own tributor with a given labeler code must labeler code for each package size and use only one Product-Package Code type of drug that it manufactures, re- configuration (e.g., a 3-digit product packs, or relabels for commercial dis- code combined with a 2-digit package tribution. code or a 4-digit product code combined (ii) In addition, if a drug is distrib- with a 1-digit package code). This sin- uted under the trade name or label of a gle configuration must be used in all private label distributor, the manufac- NDCs that include the given labeler turer, repacker, or relabeler must also code that are reserved in accordance propose for assignment by FDA an NDC with § 207.33(d)(3) or listed in accord- that includes the labeler code of the ance with § 207.49 or § 207.53. private label distributor under whose (4) An alternatively formatted NDC trade name or label the drug is distrib- that is approved for use by the relevant uted, for each package size and type so Center Director may be used for the distributed. following HCT/Ps if they are minimally (2) If a proposed NDC conforms to the manipulated: Hematopoietic stem/pro- requirements of this section and is not genitor cells derived from peripheral reserved for a different drug or was not and cord blood, and lymphocytes col- previously assigned to a different drug, lected from peripheral blood. FDA will assign the NDC to a drug

143

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00153 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.35 21 CFR Ch. I (4–1–19 Edition)

when it receives listing information re- (3) The dosage form; quired for that drug under § 207.49 or (4) A change in the drug’s status, be- § 207.53. tween prescription and nonprescrip- (3) A manufacturer, repacker, re- tion, or for animal drugs, between pre- labeler, or private label distributor scription, nonprescription, or veteri- may voluntarily reserve a proposed nary feed directive (VFD) status; NDC for a drug, before the drug is list- (5) A change in the drug’s intended ed, by submitting the following infor- use between human and animal; or mation: (6) The drug’s distinguishing charac- (i) A proposed NDC that conforms to teristics such as size, shape, color, code the requirements of this section; (ii) The established name of the ac- imprint, flavor, and scoring (if any). tive ingredient(s) and the strength of (c) When there is a change only to each active ingredient in the drug; and the package size or type, including the (iii) In the case of a finished drug immediate unit-of-use container, if product, the dosage form, and route of any, the proposed new NDC must in- administration. clude only a new package code and re- (4) If the required information is sub- tain the existing product code unless mitted and the proposed NDC is prop- all available package codes have al- erly formatted and not already as- ready been combined with the existing signed or reserved, FDA will reserve product code in NDCs assigned by FDA. the proposed NDC for a period of 2 years from the date of submission. If § 207.37 What restrictions pertain to the drug for which the proposed NDC is the use of the NDC? reserved is not listed in accordance (a) A product may be deemed to be with § 207.49 or § 207.53 during such 2- misbranded if an NDC is used: year period, the reservation of the pro- (1) To represent a different drug than posed NDC will lapse. FDA may also the drug for which the NDC has been cancel the reservation of a proposed assigned, as described in § 207.33; NDC at any time on the request of the (2) To denote or imply FDA approval person whose labeler code is included in the proposed NDC. of a drug; or (e) How must the information be sub- (3) On products that are not subject mitted to us? The information described to parts 207, 607 of this chapter, or 1271 in paragraphs (c) and (d) of this section of this chapter, such as dietary supple- must be submitted electronically un- ments and medical devices. less FDA grants a waiver under § 207.65. (b) If marketing is resumed for a discontinued drug, and no changes have § 207.35 What changes require a new been made to the drug that would re- NDC? quire a new NDC under § 207.35, the (a) Once an NDC has been assigned by drug must have the same NDC that was FDA, the registrant must propose a assigned to it as described in § 207.33, new and unique NDC for a drug when before marketing was discontinued. there is a change, after the drug is initially marketed, to any of the information identified in paragraphs (b) and (c) Subpart D—Listing of this section. A new NDC must be § 207.41 Who must list drugs and what proposed to FDA for assignment drugs must they list? through an updated listing in accordance with § 207.57. (a) Each registrant must list each (b) The proposed new NDC must in- drug that it manufactures, repacks, re- clude a new product code when there is labels, or salvages for commercial dis- a change to any of the following infor- tribution. Each domestic registrant mation: must list each such drug regardless of (1) The drug’s established name or whether the drug enters interstate proprietary name, if any; (2) Any active pharmaceutical ingredient or the strength of any active pharmaceutical ingredient;

144

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00154 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.49

commerce. When operations are con- package code variations. In the case of ducted at more than one establish- human drugs, the appropriate NDC(s) ment, and common ownership and con- submitted under this paragraph include trol exists among all the establish- the registrant’s labeler code. In the ments, the parent, subsidiary, or affil- case of animal drugs, the appropriate iate company may submit listing infor- NDC(s) submitted under this paragraph mation for any drug manufactured, re- include the registrant’s labeler code, packed, relabeled, or salvaged at any except that when the drug is manufac- such establishment. A drug manufactured for commercial distribution tured, repacked, or relabeled for pri- under the trade name or label of a private label distribution must be listed vate label distributor, the appropriate in accordance with paragraph (c) of NDC(s) for animal drugs include the this section. private label distributor’s labeler code; (b) Registrants must provide listing (2) Package type and volume infor- information for each drug in accord- mation corresponding to the package ance with the listing requirements de- code segment of the NDC; scribed in §§ 207.49, 207.53, and 207.54 (3) The listed drug’s established name that correspond to the activity or ac- and proprietary name, if any; tivities they engage in for that drug. (4) The name and quantity of each ac- (c)(1) For both animal and human tive pharmaceutical ingredient in the drugs, each registrant must list each listed drug; drug it manufactures, repacks, or re- (5) The name of each inactive ingre- labels for commercial distribution dient in the listed drug, along with any under the trade name or label of a pri- assertions of confidentiality associated vate label distributor using an NDC with individual inactive ingredients; that includes such private label dis- (6) The dosage form; tributor’s labeler code. (7) The drug’s approved U.S. applica- (2) Additionally, in the case of human tion number, if any; drugs, each registrant must list each (8) The drug type (e.g., as applicable, human drug it manufactures, repacks, finished vs. unfinished, human vs. ani- or relabels using an NDC that includes mal, prescription vs. nonprescription); the registrant’s own labeler code, re- (9) In the case of an unfinished drug, gardless of whether the drug is com- the number assigned to the Drug Mas- mercially distributed under the reg- ter File or Veterinary Master File, if istrant’s own label or trade name or any, that describes the manufacture of under the label or trade name of a pri- the drug; vate label distributor. (10) For each drug that is subject to the imprinting requirements of part 206 § 207.45 When, after initial registration of this chapter including products that of an establishment, must drug list- are exempted under § 206.7(b), the ing information be submitted? drug’s size, shape, color, scoring, and For each drug being manufactured, code imprint (if any); repacked, relabeled, or salvaged for (11) The route or routes of adminis- commercial distribution at an estab- tration of the drug; lishment at the time of initial registra- (12) For each drug bearing an NDC: tion, drug listing information must be (i) The name and Unique Facility submitted no later than 3 calendar Identifier of the establishment where days after the initial registration of the registrant who lists the drug manu- the establishment. factures it and the type of operation performed on the drug at that estab- § 207.49 What listing information must lishment, and a registrant submit for a drug it (ii) The name and Unique Facility manufactures? Identifier of every other establishment (a) Each registrant must provide the where manufacturing is performed for following listing information for each the drug and the type of operation per- drug it manufactures for commercial formed at each such establishment. distribution. This includes all establishments in- (1) The appropriate NDC(s), as de- volved in the production of each unfin- scribed in § 207.33, that include all ished drug received by the registrant

145

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00155 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.49 21 CFR Ch. I (4–1–19 Edition)

for use in the production of the drug the content of labeling, as defined in being listed. The names, Unique Facil- § 207.1(b). ity Identifiers, and type of operations (B) For each human nonprescription for establishments involved in produc- drug not subject to section 505 of the tion of each unfinished drug received Federal Food, Drug, and Cosmetic Act by the registrant for use in the produc- or section 351 of the Public Health tion of the drug being listed may be Service Act, the current label (except provided by including the properly as- that only one representative container signed and listed NDC for such unfin- or carton label need be submitted ished drug. where differences exist only in the (13) The schedule of the drug under quantity of contents statement or the section 202 of the Controlled Sub- bar code), the package insert (if any), stances Act, if applicable; and a representative sampling of any (14) Advertisements: other labeling. This labeling submis- (i) A representative sampling of ad- sion must include the content of label- vertisements for a human prescription ing as defined in section § 207.1(b). drug that is not subject to section 505 (iii) Animal drugs. (A) For each ani- of the Federal Food, Drug, and Cos- mal drug that is subject to section 512 metic Act or section 351 of the Public of the Federal Food, Drug, and Cos- Health Service Act; metic Act, which includes, but is not (ii) If FDA requests it, for good limited to, new animal drugs that have cause, a copy of all advertisements for been approved, conditionally approved, a human prescription drug that is not or indexed under sections 512, 571, or subject to section 505 of the Federal 572 of the Federal Food, Drug, and Cos- Food, Drug, and Cosmetic Act or sec- metic Act, a copy of all current label- tion 351 of the Public Health Service ing (except that only one representa- Act, including those advertisements tive container or carton label need be described in § 202.1(l)(1) of this chapter. submitted where differences exist only Such advertisements must be sub- in the quantity of contents statement), mitted within 30 calendar days after including the content of labeling as de- FDA’s request. fined in § 207.1(b); (15) For drugs bearing the NDC(s) re- (B) For all other animal drugs, a ported under paragraph (a)(1) of this copy of the current label (except that section, except those drugs manufac- only one representative container or tured exclusively for private label dis- carton label need be submitted where tribution and not distributed under the differences exist only in the quantity registrant’s own name and label, pro- of contents statement), the package in- vide the following labeling, as applica- sert, the content of labeling as defined ble: in § 207.1(b), and a representative sam- (i) Human prescription drugs. All cur- pling of any other labeling; rent labeling except that only one rep- (iv) All other listed drugs. For all other resentative container or carton label listed drugs, including unfinished need be submitted where differences drugs, the label (if any), except that exist only in the quantity of contents only one representative label need be statement or the bar code. This label- submitted where differences exist only ing submission must include the con- in the quantity of contents statement. tent of labeling, as defined in § 207.1(b). (16) Listing submissions described in (ii) Human nonprescription drugs. (A) § 207.41(c)(2) for human drugs manufac- For each human nonprescription drug tured for private label distribution subject to section 505 of the Federal must include all information specified Food, Drug, and Cosmetic Act or sec- in § 207.49(a)(2) through (14) and: tion 351 of the Public Health Service (i) The appropriate NDC(s) (as de- Act, all current labeling, except that scribed in § 207.33) that include the pri- only one representative container or vate label distributor’s labeler code carton label need be submitted where and all package code variations; differences exist only in the quantity (ii) The name, mailing address, tele- of contents statement or the bar code. phone number, and email address of the This labeling submission must include private label distributor; and

146

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00156 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.53

(iii) For drugs bearing the NDC(s) re- tent of labeling, as defined in section ported under paragraph (a)(16)(i) of this § 207.1(b). section, labeling as described in para- (2) Human nonprescription drugs. (i) graph (a)(15) of this section that ac- For each human nonprescription drug companies the private label distribu- subject to section 505 of the Federal tor’s product. Food, Drug, and Cosmetic Act or sec- (b) Additionally, each registrant is tion 351 of the Public Health Service requested, but not required, to provide Act, all current labeling, except that the following information for each only one representative container or human drug it manufactures for com- carton label need be submitted where mercial distribution: differences exist only in the quantity (1) The drug’s over-the-counter of contents statement or the bar code. monograph reference, if any; and This labeling submission must include (2) The date on which the drug was or the content of labeling, as defined in will be introduced into commercial dis- § 207.1(b). tribution. (ii) For each human nonprescription drug not subject to section 505 of the § 207.53 What listing information must Federal Food, Drug, and Cosmetic Act a registrant submit for a drug that or section 351 of the Public Health it repacks or relabels? Service Act, the current label (except Each registrant must provide the fol- that only one representative container lowing listing information for each or carton label need be submitted drug it repacks or relabels: where differences exist only in the (a) NDC. The appropriate NDC(s), as quantity of contents statement or the described in § 207.33, that include the bar code), the package insert (if any), registrant’s labeler code and all pack- and a representative sampling of any age code variations; other labeling. This labeling submis- (b) Source NDC. The NDC assigned to sion must include the content of label- each finished drug received by the reg- ing as defined in § 207.1(b). istrant for repacking or relabeling, (3) Animal drugs. (i) For each animal with the exception of medical gases. drug that is subject to section 512 of Each such NDC must be associated the Federal Food, Drug, and Cosmetic with the corresponding NDC(s) for re- Act, which includes but is not limited packed or relabeled drugs, reported to, new animal drugs that have been under paragraph (a) of this section. approved, conditionally approved, or (c) Name and Unique Facility Identi- indexed under sections 512, 571, or 572 of fier. For each drug identified by an the Federal Food, Drug, and Cosmetic NDC reported under paragraph (a) of Act, a copy of all current labeling (ex- this section, the name and Unique Fa- cept that only one representative con- cility Identifier of every establishment tainer or carton label need be sub- where repacking or relabeling is permitted where differences exist only in formed for the drug and the type of op- the quantity of contents statement), eration (repacking vs. relabeling) per- including the content of labeling as de- formed at each such establishment. fined in § 207.1(b); (d) Labeling. For each drug identified (ii) For all other animal drugs, a by an NDC reported under paragraph copy of the current label (except that (a) of this section, except those human only one representative container or drugs repacked or relabeled exclusively carton label need be submitted where for private label distribution and not differences exist only in the quantity distributed under the registrant’s own of contents statement), the package in- name and label, provide the following: sert, the content of labeling as defined (1) Human prescription drugs. All cur- in § 207.1(b), and a representative sam- rent labeling for the repacked or re- pling of any other labeling; labeled drug except that only one rep- (4) All other. For all other listed resentative container or carton label drugs, including unfinished drugs, the need be submitted where differences label (if any), except that only one rep- exist only in the quantity of contents resentative label need be submitted statement or the bar code. This label- where differences exist only in the ing submission must include the con- quantity of contents statement.

147

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00157 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.54 21 CFR Ch. I (4–1–19 Edition)

(e) Advertisements. (1) A representa- § 207.55 What additional drug listing tive sampling of advertisements for a information may FDA require? human prescription drug that is not For a particular listed drug, upon our subject to section 505 of the Federal request, the registrant must briefly Food, Drug, and Cosmetic Act or sec- state the basis for its belief that the tion 351 of the Public Health Service drug is not subject to section 505 or 512 Act; of the Federal Food, Drug, and Cos- (2) If we request it for good cause, a metic Act or section 351 of the Public copy of all advertisements for a par- Health Service Act. ticular drug described in paragraph (e)(1) of this section, including adver- § 207.57 What information must reg- tisements described in § 202.1(l)(1) of istrants submit when updating list- this chapter. Such advertisements ing information and when? must be submitted within 30 calendar Registrants must review and update days after our request. listing information at a minimum, as (f) Private label distributor products. A follows: listing submission for a human drug (a) Registrants must provide listing distributed by a private label dis- information at the time of annual es- tributor described in § 207.41(c)(2) must tablishment registration for any drug include information specified in manufactured, repacked, relabeled, or § 207.53(b) through (e) as applicable and: salvaged by them for commercial dis- (1) The appropriate NDC(s) (as de- tribution that has not been listed prescribed in § 207.33) that include the pri- viously. vate label distributor’s labeler code (b) Registrants must review and up- and all package code variations; date their drug listing information (2) The name, mailing address, tele- each June and December. When doing phone number, and email address of the so, registrants must: private label distributor; and (1)(i) Provide listing information, in (3) For drugs bearing the NDC(s) re- accordance with §§ 207.49, 207.53, and ported under paragraph (f)(1) of this 207.54, for any drug manufactured, re- section, labeling as described in para- packed, relabeled, or salvaged by them graphs (d)(1) through (4) of this section, for commercial distribution that has as applicable, that accompanies the not been previously listed; private label distributor’s product. (ii) Submit the date that they discontinued the manufacture, repacking, re- § 207.54 What listing information must labeling or salvaging for commercial a registrant submit for a drug that distribution of a listed drug and pro- it salvages? vide the expiration date of the last lot A registrant who also relabels or re- manufactured, repacked, relabeled, or packs a drug that it salvages must list salvaged; the drug it relabels or repacks in ac- (iii) Submit the date that they re- cordance with § 207.53 rather than in ac- sumed the manufacture, repacking, or cordance with this section. A reg- relabeling for commercial distribution istrant who performs only salvaging of a drug previously discontinued, and with respect to a drug must provide the provide any required listing informa- following listing information for that tion not previously submitted; and drug. (iv) Submit any material changes in any information previously submitted (a) The NDC assigned to the drug im- pursuant to §§ 207.49, 207.53, 207.54, or mediately before the drug is received other relevant sections of this part; or by the registrant for salvaging; (2) For each listed drug, certify that (b) The lot number and expiration no changes subject to reporting under date of the salvaged drug product; and paragraph (b)(1)(iv) of this section have (c) The name and Unique Facility occurred if no such changes have oc- Identifier for each establishment where curred since the last review and up- the registrant salvages the drug. date. If a drug is discontinued and FDA has received the information required

148

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00158 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 207.69

under paragraph (b)(1)(ii) of this sec- ing must be provided at a minimum in tion, no further certifications are nec- the English language. Where § 201.15(c) essary for the discontinued drug. After of this chapter permits product label- initial electronic listing, registrants ing solely in a foreign language, the may satisfy the listing update require- content of labeling must be submitted ment with respect to unchanged listing in that language along with an accu- information by making a single ‘‘no rate English translation. changes’’ certification during the annual registration update under § 207.65 How can a waiver of the elec- § 207.29(b) applicable to all of the reg- tronic submission requirement be istrant’s listed drugs for which no obtained? changes have been made since the pre- (a) All information submitted under vious annual registration update. this part must be transmitted to FDA (c) Registrants are encouraged to electronically in accordance with submit listing information for every § 207.61(a) unless FDA has granted a re- drug subject to listing under this part quest for waiver of this requirement prior to commercial distribution and prior to the date on which submission are encouraged to update listing infor- of such information is due. Submission mation at the time of any change af- of a request for waiver does not excuse fecting information previously sub- timely compliance with the registra- mitted. tion and listing requirements. FDA will grant a waiver request if FDA de- Subpart E—Electronic Format for termines that the use of electronic Registration and Listing means for submission of registration and listing information is not reason- § 207.61 How is registration and listing able for the registrant making the information provided to FDA? waiver request. (a) Electronic format. (1) Except as (b) Waiver requests under this sec- provided in § 207.65, all information sub- tion must be submitted in writing and mitted under this part must be trans- must include the specific reasons why mitted to FDA in electronic format by electronic submission is not reasonable using our electronic drug registration for the registrant and a U.S. telephone and listing system, in a form that we number and mailing address where can process, review, and archive. We FDA can contact the registrant. All may periodically issue guidance on how waiver requests must be sent to: SPL to provide registration and listing in- Coordinator, U.S. Food and Drug Ad- formation in electronic format (speci- ministration, 10903 New Hampshire fying for example method of trans- Ave., Bldg. 32, Silver Spring, MD 20993. mission, media, file formats, prepara- (c) If FDA grants the waiver request, tion, and organization of files). FDA may limit its duration and will (2) Information provided in electronic specify terms of the waiver and provide format must comply with part 11 of information on how to submit estab- this chapter, except as follows: lishment registration, drug listings, (i) Advertisements and labeling, in- other information, and updates, as ap- cluding the content of labeling, re- plicable. quired under this part are exempt from the requirements in § 11.10(a), (c) through (h), and (k) of this chapter and Subpart F—Miscellaneous the corresponding requirements in § 11.30 of this chapter. § 207.69 What are the requirements for (ii) All other information submitted an official contact and a United States agent? under this part is exempt from the requirements in § 11.10(b), (c), and (e) of (a) Official contact. Registrants sub- this chapter and the corresponding reject to the registration requirements of quirements in § 11.30 of this chapter. this part must designate an official (b) English language. Drug establish- contact for each establishment. The of- ment registration and drug listing in- ficial contact is responsible for: formation must be provided in the (1) Ensuring the accuracy of registra- English language. The content of label- tion and listing information; and

149

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00159 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 207.77 21 CFR Ch. I (4–1–19 Edition)

(2) Reviewing, disseminating, rout- our database of drugs, has been as- ing, and responding to all communica- signed or displays an NDC, or the es- tions from FDA including emergency tablishment has been assigned an es- communications. tablishment registration number or (b) United States agent. Registrants of Unique Facility Identifier is mis- foreign establishments subject to this leading and constitutes misbranding. part must designate a single United Failure to comply with § 207.37 may States agent. The United States agent also constitute misbranding. must reside or maintain a place of (c) Neither registration nor listing business in the United States and may constitutes a determination by FDA not be a mailbox, answering machine that a product is a drug as defined by or service, or other place where a per- section 201(g)(1) of the Federal Food, son acting as the United States agent Drug, and Cosmetic Act. Registration is not physically present. The United or listing may, however, be evidence States agent is responsible for: that a facility intends to or does manu- (1) Reviewing, disseminating, rout- ing, and responding to all communica- facture, repack, relabel, distribute, or tions from FDA including emergency salvage drugs or that a product is in- communications; tended to be a drug. (2) Responding to questions con- § 207.81 What registration and listing cerning those drugs that are imported information will FDA make avail- or offered for import to the United able for public disclosure? States; (3) Assisting FDA in scheduling in- (a) Except as provided in paragraphs spections; and (b) and (c) of this section, the following (4) If FDA is unable to contact a for- information will be available for public eign registrant directly or expedi- disclosure, upon request or at FDA’s tiously, FDA may provide the informa- discretion: tion and/or documents to the United (1) All establishment registration in- States agent. FDA’s providing informa- formation, and tion and/or documents to the United (2) After a drug is marketed, informa- States agent is equivalent to providing tion obtained under § 207.33, § 207.49, the same information and/or docu- § 207.53, § 207.54, or § 207.57. ments to the foreign registrant. (b) Unless such information is publicly available or FDA finds that con- § 207.77 What legal status is conferred fidentiality would be inconsistent with by registration and listing? protection of the public health, FDA (a) Registration of an establishment will not make publicly available: or listing of a drug does not denote ap- (1) Any information submitted under proval of the establishment, the drug, § 207.55 as the basis upon which it has or other drugs of the establishment, been determined that a particular drug nor does it mean that a product may be is not subject to section 505 or 512 of legally marketed. Any representation the Federal Food, Drug, and Cosmetic that creates an impression of official Act or section 351 of the Public Health approval or that a drug is approved or Service Act, is legally marketable because of registration or listing is misleading and (2) The names of any inactive ingre- constitutes misbranding. dients submitted under § 207.49(a)(4) for (b) FDA’s acceptance of registration which the registrant makes a valid as- and listing information, inclusion of a sertion of confidentiality under § 20.61 drug in our database of drugs, or as- of this chapter or other provision of signment of an NDC does not denote law, or approval of the establishment or the (3) Drug listing information obtained drug or any other drugs of the estab- under § 207.33(d)(3), § 207.49(a)(9) and (12), lishment, nor does it mean that the § 207.53(b) and (c), or § 207.54(a) or (c). drug may be legally marketed. Any (c) FDA may determine, in limited representation that creates the impres- circumstances and on a case-by-case sion that a drug is approved or is le- basis, that it would be consistent with gally marketable because it appears in the protection of the public health and

150

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00160 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 208.3

the Freedom of Information Act to ex- (2) The drug product is one that has empt from public disclosure specific in- serious risk(s) (relative to benefits) of formation identified in paragraph (a) of which patients should be made aware this section. because information concerning the risk(s) could affect patients’ decision PART 208—MEDICATION GUIDES to use, or to continue to use, the prod- FOR PRESCRIPTION DRUG PROD- uct. (3) The drug product is important to UCTS health and patient adherence to directions for use is crucial to the drug’s ef- Subpart A—General Provisions fectiveness. Sec. 208.1 Scope and purpose. § 208.3 Definitions. 208.3 Definitions. For the purposes of this part, the following definitions shall apply: Subpart B—General Requirements for a (a) Authorized dispenser means an in- Medication Guide dividual licensed, registered, or other- 208.20 Content and format of a Medication wise permitted by the jurisdiction in Guide. which the individual practices to pro- 208.24 Distributing and dispensing a Medica- vide drug products on prescription in tion Guide. the course of professional practice. 208.26 Exemptions and deferrals. (b) Dispense to patients means the act AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, of delivering a prescription drug prod- 355, 356, 357, 360, 371, 374; 42 U.S.C. 262. uct to a patient or an agent of the patient either: SOURCE: 63 FR 66396, Dec. 1, 1998, unless (1) By a licensed practitioner or an otherwise noted. agent of a licensed practitioner, either directly or indirectly, for self-adminis- Subpart A—General Provisions tration by the patient, or the patient’s agent, or outside the licensed practi- § 208.1 Scope and purpose. tioner’s direct supervision; or (a) This part sets forth requirements (2) By an authorized dispenser or an for patient labeling for human pre- agent of an authorized dispenser under scription drug products, including bio- a lawful prescription of a licensed prac- logical products, that the Food and titioner. Drug Administration (FDA) determines (c) Distribute means the act of deliv- pose a serious and significant public ering, other than by dispensing, a drug health concern requiring distribution product to any person. of FDA-approved patient information. (d) Distributor means a person who It applies primarily to human prescrip- distributes a drug product. tion drug products used on an out- (e) Drug product means a finished dos- patient basis without direct super- age form, e.g., tablet, capsule, or solu- vision by a health professional. This tion, that contains an active drug in- part shall apply to new prescriptions gredient, generally, but not nec- and refill prescriptions. essarily, in association with inactive (b) The purpose of patient labeling ingredients. For purposes of this part, for human prescription drug products drug product also means biological required under this part is to provide product within the meaning of section information when the FDA determines 351(a) of the Public Health Service Act. in writing that it is necessary to pa- (f) Licensed practitioner means an in- tients’ safe and effective use of drug dividual licensed, registered, or other- products. wise permitted by the jurisdiction in (c) Patient labeling will be required which the individual practices to pre- if the FDA determines that one or scribe drug products in the course of more of the following circumstances professional practice. exists: (g) Manufacturer means for a drug (1) The drug product is one for which product that is not also a biological patient labeling could help prevent se- product, both the manufacturer as de- rious adverse effects. scribed in § 201.1 and the applicant as

151

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00161 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 208.20 21 CFR Ch. I (4–1–19 Edition)

described in § 314.3(b) of this chapter, U.S. Food and Drug Administration’’ and for a drug product that is also a bi- shall appear at the bottom of a Medica- ological product, the manufacturer as tion Guide. described in § 600.3(t) of this chapter. (7) The brand and established or prop- (h) Medication Guide means FDA-ap- er name of the drug product shall approved patient labeling conforming to pear immediately below the words the specifications set forth in this part ‘‘Medication Guide.’’ The established and other applicable regulations. or proper name shall be no less than (i) Packer means a person who pack- one-half the height of the brand name. ages a drug product. (b) A Medication Guide shall contain (j) Patient means any individual with those of the following headings rel- respect to whom a drug product is in- evant to the drug product and to the tended to be, or has been, used. need for the Medication Guide in the (k) Serious risk or serious adverse effect specified order. Each heading shall con- means an adverse drug experience, or tain the specific information as fol- the risk of such an experience, as that lows: term is defined in §§ 310.305, 312.32, (1) The brand name (e.g., the trade- 314.80, and 600.80 of this chapter. mark or proprietary name), if any, and established or proper name. Those Subpart B—General Requirements products not having an established or for a Medication Guide proper name shall be designated by their active ingredients. The Medica- § 208.20 Content and format of a Medi- cation Guide. tion Guide shall include the phonetic spelling of either the brand name or (a) A Medication Guide shall meet all the established name, whichever is of the following conditions: used throughout the Medication Guide. (1) The Medication Guide shall be (2) The heading, ‘‘What is the most written in English, in nontechnical, important information I should know understandable language, and shall not about (name of drug)?’’ followed by a be promotional in tone or content. statement describing the particular se- (2) The Medication Guide shall be scientifically accurate and shall be based rious and significant public health con- on, and shall not conflict with, the ap- cern that has created the need for the proved professional labeling for the Medication Guide. The statement drug product under § 201.57 of this chap- should describe specifically what the ter, but the language of the Medication patient should do or consider because Guide need not be identical to the sec- of that concern, such as, weighing par- tions of approved labeling to which it ticular risks against the benefits of the corresponds. drug, avoiding particular behaviors (3) The Medication Guide shall be (e.g., activities, drugs), observing cer- specific and comprehensive. tain events (e.g., symptoms, signs) that (4) The letter height or type size could prevent or mitigate a serious ad- shall be no smaller than 10 points (1 verse effect, or engaging in particular point = 0.0138 inches) for all sections of behaviors (e.g., adhering to the dosing the Medication Guide, except the man- regimen). ufacturer’s name and address and the (3) The heading, ‘‘What is (name of revision date. drug)?’’ followed by a section that iden- (5) The Medication Guide shall be tifies a drug product’s indications for legible and clearly presented. Where use. The Medication Guide may not appropriate, the Medication Guide identify an indication unless the indi- shall also use boxes, bold or underlined cation is identified in the indications print, or other highlighting techniques and usage section of the professional to emphasize specific portions of the labeling for the product required under text. § 201.57 of this chapter. In appropriate (6) The words ‘‘Medication Guide’’ circumstances, this section may also shall appear prominently at the top of explain the nature of the disease or the first page of a Medication Guide. condition the drug product is intended The verbatim statement ‘‘This Medica- to treat, as well as the benefit(s) of tion Guide has been approved by the treating the condition.

152

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00162 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 208.20

(4) The heading, ‘‘Who should not (vi) A statement of special pre- take (name of drug)?’’ followed by in- cautions, if any, that apply to the safe formation on circumstances under and effective use of the drug product in which the drug product should not be other identifiable patient populations. used for its labeled indication (its con- (7) The heading, ‘‘What are the pos- traindications). The Medication Guide sible or reasonably likely side effects shall contain directions regarding what of (name of drug)?’’ followed by: to do if any of the contraindications (i) A statement of the adverse reac- apply to a patient, such as contacting tions reasonably likely to be caused by the licensed practitioner or dis- the drug product that are serious or continuing use of the drug product. occur frequently. (5) The heading, ‘‘How should I take (ii) A statement of the risk, if there (name of drug)?’’ followed by informa- is one, of patients’ developing depend- tion on the proper use of the drug product, such as: ence on the drug product. (i) A statement stressing the impor- (iii) For drug products approved tance of adhering to the dosing instruc- under section 505 of the act, the fol- tions, if this is particularly important; lowing verbatim statement: ‘‘Call your (ii) A statement describing any spe- doctor for medical advice about side ef- cial instructions on how to administer fects. You may report side effects to the drug product, if they are important FDA at 1–800–FDA–1088.’’ to the drug’s safety or effectiveness; (8) General information about the (iii) A statement of what patients safe and effective use of prescription should do in case of overdose of the drug products, including: drug product; and (i) The verbatim statement that (iv) A statement of what patients ‘‘Medicines are sometimes prescribed should do if they miss taking a sched- for purposes other than those listed in uled dose(s) of the drug product, where a Medication Guide’’ followed by a there are data to support the advice, statement that patients should ask and where the wrong behavior could health professionals about any con- cause harm or lack of effect. cerns, and a reference to the avail- (6) The heading ‘‘What should I avoid ability of professional labeling; while taking (name of drug)?’’ followed (ii) A statement that the drug prod- by a statement or statements of spe- uct should not be used for a condition cific, important precautions patients other than that for which it is pre- should take to ensure proper use of the scribed, or given to other persons; drug, including: (iii) The name and place of business (i) A statement that identifies activi- of the manufacturer, packer, or dis- ties (such as driving or sunbathing), tributor of a drug product that is not and drugs, foods, or other substances also a biological product, or the name (such as tobacco or alcohol) that pa- and place of business of the manufac- tients should avoid when using the turer or distributor of a drug product medication; that is also a biological product, and in (ii) A statement of the risks to moth- any case the name and place of busi- ers and fetuses from the use of the drug ness of the dispenser of the product during pregnancy, if specific, important risks are known; may also be included; and (iii) A statement of the risks of the (iv) The date, identified as such, of drug product to nursing infants, if spe- the most recent revision of the Medica- cific, important risks are known; tion Guide placed immediately after (iv) A statement about pediatric the last section. risks, if the drug product has specific (9) Additional headings and sub- hazards associated with its use in pedi- headings may be interspersed through- atric patients; out the Medication Guide, if appro- (v) A statement about geriatric risks, priate. if the drug product has specific hazards [63 FR 66396, Dec. 1, 1998, as amended at 73 associated with its use in geriatric pa- FR 404, Jan. 3, 2008] tients; and

153

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00163 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 208.24 21 CFR Ch. I (4–1–19 Edition)

§ 208.24 Distributing and dispensing a (f) An authorized dispenser or whole- Medication Guide. saler is not subject to section 510 of the (a) The manufacturer of a drug prod- Federal Food, Drug, and Cosmetic Act, uct for which a Medication Guide is re- which requires the registration of pro- ducers of drugs and the listing of drugs quired under this part shall obtain in commercial distribution, solely be- FDA approval of the Medication Guide cause of an act performed by the au- before the Medication Guide may be thorized dispenser or wholesaler under distributed. this part. (b) Each manufacturer who ships a container of drug product for which a § 208.26 Exemptions and deferrals. Medication Guide is required under this part is responsible for ensuring (a) FDA on its own initiative, or in that Medication Guides are available response to a written request from an for distribution to patients by either: applicant, may exempt or defer any (1) Providing Medication Guides in Medication Guide content or format re- sufficient numbers to distributors, quirement, except those requirements packers, or authorized dispensers to in § 208.20 (a)(2) and (a)(6), on the basis permit the authorized dispenser to pro- that the requirement is inapplicable, vide a Medication Guide to each pa- unnecessary, or contrary to patients’ tient receiving a prescription for the best interests. Requests from appli- drug product; or cants should be submitted to the director of the FDA division responsible for (2) Providing the means to produce reviewing the marketing application Medication Guides in sufficient num- for the drug product, or for a biological bers to distributors, packers, or au- product, to the application division in thorized dispensers to permit the au- the office with product responsibility. thorized dispenser to provide a Medica- tion Guide to each patient receiving a (b) If the licensed practitioner who prescription for the drug product. prescribes a drug product subject to this part determines that it is not in a (c) Each distributor or packer that particular patient’s best interest to re- receives Medication Guides, or the ceive a Medication Guide because of means to produce Medication Guides, significant concerns about the effect of from a manufacturer under paragraph a Medication Guide, the licensed prac- (b) of this section shall provide those titioner may direct that the Medica- Medication Guides, or the means to tion Guide not be provided to the par- produce Medication Guides, to each au- ticular patient. However, the author- thorized dispenser to whom it ships a ized dispenser of a prescription drug container of drug product. product subject to this part shall pro- (d) The label of each container or vide a Medication Guide to any patient package, where the container label is who requests information when the too small, of drug product for which a drug product is dispensed regardless of Medication Guide is required under any such direction by the licensed this part shall instruct the authorized practitioner. dispenser to provide a Medication Guide to each patient to whom the drug product is dispensed, and shall PART 209—REQUIREMENT FOR AU- state how the Medication Guide is pro- THORIZED DISPENSERS AND vided. These statements shall appear PHARMACIES TO DISTRIBUTE A on the label in a prominent and con- SIDE EFFECTS STATEMENT spicuous manner. (e) Each authorized dispenser of a Subpart A—General Provisions prescription drug product for which a Medication Guide is required under Sec. this part shall, when the product is dis- 209.1 Scope and purpose. pensed to a patient (or to a patient’s 209.2 Definitions. agent), provide a Medication Guide di- Subpart B—Requirements rectly to each patient (or to the patient’s agent) unless an exemption ap- 209.10 Content and format of the side effects plies under § 208.26. statement.

154

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00164 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 209.11

209.11 Dispensing and distributing the side Side effects statement means the fol- effects statement. lowing verbatim statement: ‘‘Call your AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, doctor for medical advice about side ef- 355, 360, 371; 42 U.S.C. 241. fects. You may report side effects to SOURCE: 73 FR 404, Jan. 3, 2008, unless oth- FDA at 1–800–FDA–1088.’’ erwise noted. Subpart B—Requirements Subpart A—General Provisions § 209.10 Content and format of the side § 209.1 Scope and purpose. effects statement. (a) This part sets forth requirements (a) Content. The side effects state- for human prescription drug products ment provided with each prescription approved under section 505 of the Fed- drug product approved under section eral Food, Drug, and Cosmetic Act and 505 of the act must read: ‘‘Call your dispensed by authorized dispensers and doctor for medical advice about side ef- pharmacies to consumers. This part re- fects. You may report side effects to quires distribution of a side effects FDA at 1–800–FDA–1088.’’ statement and applies to new and refill (b) Format. The side effects statement prescriptions. This part is not intended must be in a single, clear, easy-to-read to apply to authorized dispensers dis- type style. The letter height or type pensing or administering prescription size used for the side effects statement drug products to inpatients in a hos- in accordance with paragraphs (b)(1) pital or health care facility under an and (b)(2) of § 209.11 must be no smaller order of a licensed practitioner, or as than 6 points (1 point = 0.0138 inch). part of supervised home health care. The letter height or type size for the (b) The purpose of providing the side side effects statement under para- effects statement is to enable con- graphs (b)(3), (b)(4), and (b)(5) of § 209.11 sumers to report side effects of pre- must be no smaller than 10 points. scription drug products to FDA. § 209.11 Dispensing and distributing § 209.2 Definitions. the side effects statement. For the purposes of this part, the fol- (a) Each authorized dispenser or lowing definitions apply: pharmacy must distribute the side ef- Act means the Federal Food, Drug, fects statement with each prescription and Cosmetic Act (sections 201–907 (21 drug product approved under section U.S.C. 301–397)). 505 of the act and dispensed. The side Authorized dispenser means an indi- effects statement must be distributed vidual licensed, registered, or other- with new and refill prescriptions. wise permitted by the jurisdiction in (b) An authorized dispenser or phar- which the individual practices to pro- macy must choose one or more of the vide drug products on prescription in following options to distribute the side the course of professional practice. effects statement: Consumer medication information means written information voluntarily (1) Distribute the side effects state- provided to consumers by dispensing ment on a sticker attached to the unit pharmacists as part of patient medica- package, vial, or container of the drug tion counseling activities. product; Medication Guide means FDA-ap- (2) Distribute the side effects state- proved patient labeling conforming to ment on a preprinted pharmacy pre- the specifications set forth in part 208 scription vial cap; of this chapter and other applicable (3) Distribute the side effects state- regulations. ment on a separate sheet of paper; Pharmacy includes, but is not limited (4) Distribute the side effects state- to, a retail, mail order, Internet, hos- ment in consumer medication informa- pital, university, or clinic pharmacy, tion; or or a public health agency, regularly (5) Distribute the appropriate FDA- and lawfully engaged in dispensing pre- approved Medication Guide that con- scription drugs. tains the side effects statement.

155

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00165 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Pt. 210 21 CFR Ch. I (4–1–19 Edition)

PART 210—CURRENT GOOD MAN- tion to the regulations in this part and UFACTURING PRACTICE IN MAN- in parts 211, 225, and 226 of this chapter. UFACTURING, PROCESSING, Failure to comply with any applicable regulation set forth in this part, in PACKING, OR HOLDING OF parts 211, 225, and 226 of this chapter, in DRUGS; GENERAL part 1271 subpart C of this chapter, or in part 1271 subpart D of this chapter Sec. with respect to the manufacture, proc- 210.1 Status of current good manufacturing essing, packing or holding of a drug, practice regulations. 210.2 Applicability of current good manu- renders an HCT/P adulterated under facturing practice regulations. section 501(a)(2)(B) of the act. Such 210.3 Definitions. HCT/P, as well as the person who is responsible for the failure to comply, is AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264. subject to regulatory action. SOURCE: 43 FR 45076, Sept. 29, 1978, unless [43 FR 45076, Sept. 29, 1978, as amended at 69 otherwise noted. FR 29828, May 25, 2004; 74 FR 65431, Dec. 10, 2009] § 210.1 Status of current good manufacturing practice regulations. § 210.2 Applicability of current good manufacturing practice regulations. (a) The regulations set forth in this part and in parts 211, 225, and 226 of (a) The regulations in this part and this chapter contain the minimum cur- in parts 211, 225, and 226 of this chapter rent good manufacturing practice for as they may pertain to a drug; in parts methods to be used in, and the facili- 600 through 680 of this chapter as they ties or controls to be used for, the man- may pertain to a biological product for ufacture, processing, packing, or hold- human use; and in part 1271 of this ing of a drug to assure that such drug chapter as they are applicable to a meets the requirements of the act as to human cell, tissue, or cellular or tis- safety, and has the identity and sue-based product (HCT/P) that is a strength and meets the quality and pu- drug (subject to review under an appli- rity characteristics that it purports or cation submitted under section 505 of is represented to possess. the act or under a biological product li- (b) The failure to comply with any cense application under section 351 of regulation set forth in this part and in the Public Health Service Act); shall parts 211, 225, and 226 of this chapter in be considered to supplement, not super- the manufacture, processing, packing, sede, each other, unless the regulations or holding of a drug shall render such explicitly provide otherwise. In the drug to be adulterated under section event of a conflict between applicable 501(a)(2)(B) of the act and such drug, as regulations in this part and in other well as the person who is responsible parts of this chapter, the regulation for the failure to comply, shall be sub- specifically applicable to the drug ject to regulatory action. product in question shall supersede the (c) Owners and operators of establish- more general. ments engaged in the recovery, donor (b) If a person engages in only some screening, testing (including donor operations subject to the regulations in testing), processing, storage, labeling, this part, in parts 211, 225, and 226 of packaging, or distribution of human this chapter, in parts 600 through 680 of cells, tissues, and cellular and tissue- this chapter, and in part 1271 of this based products (HCT/Ps), as defined in chapter, and not in others, that person § 1271.3(d) of this chapter, that are need only comply with those regula- drugs (subject to review under an appli- tions applicable to the operations in cation submitted under section 505 of which he or she is engaged. the act or under a biological product li- (c) An investigational drug for use in cense application under section 351 of a phase 1 study, as described in the Public Health Service Act), are § 312.21(a) of this chapter, is subject to subject to the donor-eligibility and ap- the statutory requirements set forth in plicable current good tissue practice 21 U.S.C. 351(a)(2)(B). The production of procedures set forth in part 1271 sub- such drug is exempt from compliance parts C and D of this chapter, in addi- with the regulations in part 211 of this

156

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00166 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 210.3

chapter. However, this exemption does (7) Active ingredient means any com- not apply to an investigational drug ponent that is intended to furnish for use in a phase 1 study once the in- pharmacological activity or other di- vestigational drug has been made rect effect in the diagnosis, cure, miti- available for use by or for the sponsor gation, treatment, or prevention of dis- in a phase 2 or phase 3 study, as de- ease, or to affect the structure or any scribed in § 312.21(b) and (c) of this function of the body of man or other chapter, or the drug has been lawfully animals. The term includes those com- marketed. If the investigational drug ponents that may undergo chemical has been made available in a phase 2 or change in the manufacture of the drug phase 3 study or the drug has been law- product and be present in the drug fully marketed, the drug for use in the phase 1 study must comply with part product in a modified form intended to 211. furnish the specified activity or effect. (8) Inactive ingredient means any com- [69 FR 29828, May 25, 2004, as amended at 73 ponent other than an active ingredient. FR 40462, July 15, 2008; 74 FR 65431, Dec. 10, 2009] (9) In-process material means any material fabricated, compounded, blended, § 210.3 Definitions. or derived by chemical reaction that is (a) The definitions and interpreta- produced for, and used in, the preparations contained in section 201 of the act tion of the drug product. shall be applicable to such terms when (10) Lot means a batch, or a specific used in this part and in parts 211, 225, identified portion of a batch, having and 226 of this chapter. uniform character and quality within (b) The following definitions of terms specified limits; or, in the case of a apply to this part and to parts 211, 225, drug product produced by continuous and 226 of this chapter. process, it is a specific identified (1) Act means the Federal Food, Drug, amount produced in a unit of time or and Cosmetic Act, as amended (21 quantity in a manner that assures its U.S.C. 301 et seq.). having uniform character and quality (2) Batch means a specific quantity of within specified limits. a drug or other material that is in- (11) Lot number, control number, or tended to have uniform character and batch number means any distinctive quality, within specified limits, and is combination of letters, numbers, or produced according to a single manu- symbols, or any combination of them, facturing order during the same cycle of manufacture. from which the complete history of the (3) Component means any ingredient manufacture, processing, packing, intended for use in the manufacture of holding, and distribution of a batch or a drug product, including those that lot of drug product or other material may not appear in such drug product. can be determined. (4) Drug product means a finished dos- (12) Manufacture, processing, packing, age form, for example, tablet, capsule, or holding of a drug product includes solution, etc., that contains an active packaging and labeling operations, drug ingredient generally, but not nec- testing, and quality control of drug essarily, in association with inactive products. ingredients. The term also includes a (13) The term medicated feed means finished dosage form that does not con- any Type B or Type C medicated feed tain an active ingredient but is in- as defined in § 558.3 of this chapter. The tended to be used as a placebo. feed contains one or more drugs as de- (5) Fiber means any particulate con- fined in section 201(g) of the act. The taminant with a length at least three manufacture of medicated feeds is sub- times greater than its width. ject to the requirements of part 225 of (6) Nonfiber releasing filter means any this chapter. filter, which after appropriate pretreatment such as washing or flush- (14) The term medicated premix means ing, will not release fibers into the a Type A medicated article as defined component or drug product that is in § 558.3 of this chapter. The article being filtered. contains one or more drugs as defined

157

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00167 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Pt. 211 21 CFR Ch. I (4–1–19 Edition)

in section 201(g) of the act. The manu- on which more than one item of label- facture of medicated premixes is sub- ing is printed. ject to the requirements of part 226 of [43 FR 45076, Sept. 29, 1978, as amended at 51 this chapter. FR 7389, Mar. 3, 1986; 58 FR 41353, Aug. 3, 1993; (15) Quality control unit means any 73 FR 51931, Sept. 8, 2008; 74 FR 65431, Dec. 10, person or organizational element des- 2009] ignated by the firm to be responsible for the duties relating to quality con- PART 211—CURRENT GOOD MAN- trol. (16) Strength means: UFACTURING PRACTICE FOR FIN- (i) The concentration of the drug sub- ISHED PHARMACEUTICALS stance (for example, weight/weight, weight/volume, or unit dose/volume Subpart A—General Provisions basis), and/or Sec. (ii) The potency, that is, the thera- 211.1 Scope. peutic activity of the drug product as 211.3 Definitions. indicated by appropriate laboratory tests or by adequately developed and Subpart B—Organization and Personnel controlled clinical data (expressed, for example, in terms of units by reference 211.22 Responsibilities of quality control unit. to a standard). 211.25 Personnel qualifications. (17) Theoretical yield means the quan- 211.28 Personnel responsibilities. tity that would be produced at any ap- 211.34 Consultants. propriate phase of manufacture, processing, or packing of a particular drug Subpart C—Buildings and Facilities product, based upon the quantity of components to be used, in the absence 211.42 Design and construction features. of any loss or error in actual produc- 211.44 Lighting. 211.46 Ventilation, air filtration, air heating tion. and cooling. (18) Actual yield means the quantity 211.48 Plumbing. that is actually produced at any appro- 211.50 Sewage and refuse. priate phase of manufacture, proc- 211.52 Washing and toilet facilities. essing, or packing of a particular drug 211.56 Sanitation. product. 211.58 Maintenance. (19) Percentage of theoretical yield means the ratio of the actual yield (at Subpart D—Equipment any appropriate phase of manufacture, 211.63 Equipment design, size, and location. processing, or packing of a particular 211.65 Equipment construction. drug product) to the theoretical yield 211.67 Equipment cleaning and mainte- (at the same phase), stated as a per- nance. centage. 211.68 Automatic, mechanical, and elec- (20) Acceptance criteria means the tronic equipment. product specifications and acceptance/ 211.72 Filters. rejection criteria, such as acceptable quality level and unacceptable quality Subpart E—Control of Components and level, with an associated sampling Drug Product Containers and Closures plan, that are necessary for making a 211.80 General requirements. decision to accept or reject a lot or 211.82 Receipt and storage of untested com- batch (or any other convenient sub- ponents, drug product containers, and groups of manufactured units). closures. (21) Representative sample means a 211.84 Testing and approval or rejection of sample that consists of a number of components, drug product containers, units that are drawn based on rational and closures. criteria such as random sampling and 211.86 Use of approved components, drug product containers, and closures. intended to assure that the sample ac- 211.87 Retesting of approved components, curately portrays the material being drug product containers, and closures. sampled. 211.89 Rejected components, drug product (22) Gang-printed labeling means la- containers, and closures. beling derived from a sheet of material 211.94 Drug product containers and closures.

158

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00168 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.1

Subpart F—Production and Process Subpart A—General Provisions Controls § 211.1 Scope. 211.100 Written procedures; deviations. 211.101 Charge-in of components. (a) The regulations in this part con- 211.103 Calculation of yield. tain the minimum current good manu- 211.105 Equipment identification. facturing practice for preparation of 211.110 Sampling and testing of in-process drug products (excluding positron materials and drug products. 211.111 Time limitations on production. emission tomography drugs) for admin- 211.113 Control of microbiological contami- istration to humans or animals. nation. (b) The current good manufacturing 211.115 Reprocessing. practice regulations in this chapter as they pertain to drug products; in parts Subpart G—Packaging and Labeling 600 through 680 of this chapter, as they Control pertain to drugs that are also biologi- 211.122 Materials examination and usage cal products for human use; and in part criteria. 1271 of this chapter, as they are appli- 211.125 Labeling issuance. cable to drugs that are also human 211.130 Packaging and labeling operations. cells, tissues, and cellular and tissue- 211.132 Tamper-evident packaging require- based products (HCT/Ps) and that are ments for over-the-counter (OTC) human drugs (subject to review under an appli- drug products. cation submitted under section 505 of 211.134 Drug product inspection. the act or under a biological product li- 211.137 Expiration dating. cense application under section 351 of Subpart H—Holding and Distribution the Public Health Service Act); supplement and do not supersede the regula- 211.142 Warehousing procedures. tions in this part unless the regula- 211.150 Distribution procedures. tions explicitly provide otherwise. In the event of a conflict between applica- Subpart I—Laboratory Controls ble regulations in this part and in 211.160 General requirements. other parts of this chapter, or in parts 211.165 Testing and release for distribution. 600 through 680 of this chapter, or in 211.166 Stability testing. part 1271 of this chapter, the regulation 211.167 Special testing requirements. specifically applicable to the drug 211.170 Reserve samples. product in question shall supersede the 211.173 Laboratory animals. more general. 211.176 Penicillin contamination. (c) Pending consideration of a pro- Subpart J—Records and Reports posed exemption, published in the FED- ERAL REGISTER of September 29, 1978, 211.180 General requirements. the requirements in this part shall not 211.182 Equipment cleaning and use log. be enforced for OTC drug products if 211.184 Component, drug product container, the products and all their ingredients closure, and labeling records. 211.186 Master production and control are ordinarily marketed and consumed records. as human foods, and which products 211.188 Batch production and control may also fall within the legal defini- records. tion of drugs by virtue of their in- 211.192 Production record review. tended use. Therefore, until further no- 211.194 Laboratory records. tice, regulations under parts 110 and 211.196 Distribution records. 117 of this chapter, and where applica- 211.198 Complaint files. ble, parts 113 through 129 of this chap- Subpart K—Returned and Salvaged Drug ter, shall be applied in determining Products whether these OTC drug products that are also foods are manufactured, proc- 211.204 Returned drug products. essed, packed, or held under current 211.208 Drug product salvaging. good manufacturing practice. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, [43 FR 45077, Sept. 29, 1978, as amended at 62 371, 374; 42 U.S.C. 216, 262, 263a, 264. FR 66522, Dec. 19, 1997; 69 FR 29828, May 25, SOURCE: 43 FR 45077, Sept. 29, 1978, unless 2004; 74 FR 65431, Dec. 10, 2009; 80 FR 56168, otherwise noted. Sept. 17, 2015]

159

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00169 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.3 21 CFR Ch. I (4–1–19 Edition)

§ 211.3 Definitions. turing practice shall be conducted by qualified individuals on a continuing The definitions set forth in § 210.3 of basis and with sufficient frequency to this chapter apply in this part. assure that employees remain familiar with CGMP requirements applicable to Subpart B—Organization and them. Personnel (b) Each person responsible for supervising the manufacture, processing, § 211.22 Responsibilities of quality packing, or holding of a drug product control unit. shall have the education, training, and (a) There shall be a quality control experience, or any combination there- unit that shall have the responsibility of, to perform assigned functions in and authority to approve or reject all such a manner as to provide assurance components, drug product containers, that the drug product has the safety, closures, in-process materials, pack- identity, strength, quality, and purity aging material, labeling, and drug that it purports or is represented to products, and the authority to review possess. production records to assure that no (c) There shall be an adequate num- errors have occurred or, if errors have ber of qualified personnel to perform occurred, that they have been fully in- and supervise the manufacture, proc- vestigated. The quality control unit essing, packing, or holding of each drug shall be responsible for approving or re- product. jecting drug products manufactured, processed, packed, or held under con- § 211.28 Personnel responsibilities. tract by another company. (a) Personnel engaged in the manu- (b) Adequate laboratory facilities for facture, processing, packing, or holding the testing and approval (or rejection) of a drug product shall wear clean of components, drug product con- clothing appropriate for the duties tainers, closures, packaging materials, they perform. Protective apparel, such in-process materials, and drug products as head, face, hand, and arm coverings, shall be available to the quality con- shall be worn as necessary to protect trol unit. drug products from contamination. (c) The quality control unit shall (b) Personnel shall practice good have the responsibility for approving sanitation and health habits. or rejecting all procedures or specifica- (c) Only personnel authorized by su- tions impacting on the identity, pervisory personnel shall enter those strength, quality, and purity of the areas of the buildings and facilities drug product. designated as limited-access areas. (d) The responsibilities and proce- (d) Any person shown at any time (ei- dures applicable to the quality control ther by medical examination or super- unit shall be in writing; such written visory observation) to have an appar- procedures shall be followed. ent illness or open lesions that may adversely affect the safety or quality of § 211.25 Personnel qualifications. drug products shall be excluded from (a) Each person engaged in the manu- direct contact with components, drug facture, processing, packing, or holding product containers, closures, in-process of a drug product shall have education, materials, and drug products until the training, and experience, or any com- condition is corrected or determined by bination thereof, to enable that person competent medical personnel not to to perform the assigned functions. jeopardize the safety or quality of drug Training shall be in the particular op- products. All personnel shall be in- erations that the employee performs structed to report to supervisory per- and in current good manufacturing sonnel any health conditions that may practice (including the current good have an adverse effect on drug prod- manufacturing practice regulations in ucts. this chapter and written procedures required by these regulations) as they re- § 211.34 Consultants. late to the employee’s functions. Consultants advising on the manu- Training in current good manufac- facture, processing, packing, or holding

160

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00170 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.46

of drug products shall have sufficient (7) Quarantine storage before release education, training, and experience, or of drug products; any combination thereof, to advise on (8) Storage of drug products after re- the subject for which they are retained. lease; Records shall be maintained stating (9) Control and laboratory oper- the name, address, and qualifications ations; of any consultants and the type of (10) Aseptic processing, which in- service they provide. cludes as appropriate: (i) Floors, walls, and ceilings of Subpart C—Buildings and Facilities smooth, hard surfaces that are easily cleanable; § 211.42 Design and construction fea- (ii) Temperature and humidity con- tures. trols; (iii) An air supply filtered through (a) Any building or buildings used in high-efficiency particulate air filters the manufacture, processing, packing, under positive pressure, regardless of or holding of a drug product shall be of whether flow is laminar or nonlaminar; suitable size, construction and location (iv) A system for monitoring environ- to facilitate cleaning, maintenance, mental conditions; and proper operations. (v) A system for cleaning and dis- (b) Any such building shall have ade- infecting the room and equipment to quate space for the orderly placement produce aseptic conditions; of equipment and materials to prevent (vi) A system for maintaining any mixups between different components, equipment used to control the aseptic drug product containers, closures, la- conditions. beling, in-process materials, or drug (d) Operations relating to the manu- products, and to prevent contamina- facture, processing, and packing of pen- tion. The flow of components, drug icillin shall be performed in facilities product containers, closures, labeling, separate from those used for other drug in-process materials, and drug products products for human use. through the building or buildings shall be designed to prevent contamination. [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995] (c) Operations shall be performed within specifically defined areas of ade- § 211.44 Lighting. quate size. There shall be separate or Adequate lighting shall be provided defined areas or such other control sys- in all areas. tems for the firm’s operations as are necessary to prevent contamination or § 211.46 Ventilation, air filtration, air mixups during the course of the fol- heating and cooling. lowing procedures: (a) Adequate ventilation shall be pro- (1) Receipt, identification, storage, vided. and withholding from use of compo- (b) Equipment for adequate control nents, drug product containers, clo- over air pressure, micro-organisms, sures, and labeling, pending the appro- dust, humidity, and temperature shall priate sampling, testing, or examina- be provided when appropriate for the tion by the quality control unit before manufacture, processing, packing, or release for manufacturing or pack- holding of a drug product. aging; (c) Air filtration systems, including (2) Holding rejected components, prefilters and particulate matter air drug product containers, closures, and filters, shall be used when appropriate labeling before disposition; on air supplies to production areas. If (3) Storage of released components, air is recirculated to production areas, drug product containers, closures, and measures shall be taken to control relabeling; circulation of dust from production. In (4) Storage of in-process materials; areas where air contamination occurs (5) Manufacturing and processing op- during production, there shall be ade- erations; quate exhaust systems or other sys- (6) Packaging and labeling oper- tems adequate to control contami- ations; nants.

161

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00171 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.48 21 CFR Ch. I (4–1–19 Edition)

(d) Air-handling systems for the man- (c) There shall be written procedures ufacture, processing, and packing of for use of suitable rodenticides, insecti- penicillin shall be completely separate cides, fungicides, fumigating agents, from those for other drug products for and cleaning and sanitizing agents. human use. Such written procedures shall be designed to prevent the contamination of § 211.48 Plumbing. equipment, components, drug product (a) Potable water shall be supplied containers, closures, packaging, label- under continuous positive pressure in a ing materials, or drug products and plumbing system free of defects that shall be followed. Rodenticides, insecti- could contribute contamination to any cides, and fungicides shall not be used drug product. Potable water shall meet unless registered and used in accord- the standards prescribed in the Envi- ance with the Federal Insecticide, Fun- ronmental Protection Agency’s Pri- gicide, and Rodenticide Act (7 U.S.C. mary Drinking Water Regulations set 135). forth in 40 CFR part 141. Water not (d) Sanitation procedures shall apply meeting such standards shall not be to work performed by contractors or permitted in the potable water system. temporary employees as well as work (b) Drains shall be of adequate size performed by full-time employees dur- and, where connected directly to a ing the ordinary course of operations. sewer, shall be provided with an air break or other mechanical device to § 211.58 Maintenance. prevent back-siphonage. Any building used in the manufac- [43 FR 45077, Sept. 29, 1978, as amended at 48 ture, processing, packing, or holding of FR 11426, Mar. 18, 1983] a drug product shall be maintained in a good state of repair. § 211.50 Sewage and refuse. Sewage, trash, and other refuse in Subpart D—Equipment and from the building and immediate premises shall be disposed of in a safe § 211.63 Equipment design, size, and and sanitary manner. location. § 211.52 Washing and toilet facilities. Equipment used in the manufacture, processing, packing, or holding of a Adequate washing facilities shall be drug product shall be of appropriate de- provided, including hot and cold water, soap or detergent, air driers or single- sign, adequate size, and suitably lo- service towels, and clean toilet facili- cated to facilitate operations for its in- ties easily accesible to working areas. tended use and for its cleaning and maintenance. § 211.56 Sanitation. § 211.65 Equipment construction. (a) Any building used in the manufacture, processing, packing, or holding of (a) Equipment shall be constructed so a drug product shall be maintained in a that surfaces that contact components, clean and sanitary condition, Any such in-process materials, or drug products building shall be free of infestation by shall not be reactive, additive, or ab- rodents, birds, insects, and other sorptive so as to alter the safety, iden- vermin (other than laboratory ani- tity, strength, quality, or purity of the mals). Trash and organic waste matter drug product beyond the official or shall be held and disposed of in a time- other established requirements. ly and sanitary manner. (b) Any substances required for oper- (b) There shall be written procedures ation, such as lubricants or coolants, assigning responsibility for sanitation shall not come into contact with com- and describing in sufficient detail the ponents, drug product containers, clo- cleaning schedules, methods, equip- sures, in-process materials, or drug ment, and materials to be used in products so as to alter the safety, iden- cleaning the buildings and facilities; tity, strength, quality, or purity of the such written procedures shall be fol- drug product beyond the official or lowed. other established requirements.

162

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00172 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.72

§ 211.67 Equipment cleaning and main- checks and inspections shall be maintenance. tained. (a) Equipment and utensils shall be (b) Appropriate controls shall be ex- cleaned, maintained, and, as appro- ercised over computer or related sys- priate for the nature of the drug, sani- tems to assure that changes in master tized and/or sterilized at appropriate production and control records or other records are instituted only by author- intervals to prevent malfunctions or ized personnel. Input to and output contamination that would alter the from the computer or related system of safety, identity, strength, quality, or formulas or other records or data shall purity of the drug product beyond the be checked for accuracy. The degree official or other established require- and frequency of input/output ments. verification shall be based on the com- (b) Written procedures shall be estab- plexity and reliability of the computer lished and followed for cleaning and or related system. A backup file of data maintenance of equipment, including entered into the computer or related utensils, used in the manufacture, system shall be maintained except processing, packing, or holding of a where certain data, such as calcula- drug product. These procedures shall tions performed in connection with lab- include, but are not necessarily limited oratory analysis, are eliminated by to, the following: computerization or other automated (1) Assignment of responsibility for processes. In such instances a written cleaning and maintaining equipment; record of the program shall be main- (2) Maintenance and cleaning sched- tained along with appropriate valida- ules, including, where appropriate, tion data. Hard copy or alternative sys- sanitizing schedules; tems, such as duplicates, tapes, or (3) A description in sufficient detail microfilm, designed to assure that of the methods, equipment, and mate- backup data are exact and complete rials used in cleaning and maintenance and that it is secure from alteration, operations, and the methods of dis- inadvertent erasures, or loss shall be assembling and reassembling equip- maintained. ment as necessary to assure proper (c) Such automated equipment used cleaning and maintenance; for performance of operations ad- (4) Removal or obliteration of pre- dressed by §§ 211.101(c) or (d), 211.103, vious batch identification; 211.182, or 211.188(b)(11) can satisfy the (5) Protection of clean equipment requirements included in those sec- from contamination prior to use; tions relating to the performance of an (6) Inspection of equipment for clean- operation by one person and checking liness immediately before use. by another person if such equipment is (c) Records shall be kept of mainte- used in conformity with this section, nance, cleaning, sanitizing, and inspec- and one person checks that the equip- tion as specified in §§ 211.180 and 211.182. ment properly performed the oper- [43 FR 45077, Sept. 29, 1978, as amended at 73 ation. FR 51931, Sept. 8, 2008] [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995; 73 FR 51932, Sept. 8, § 211.68 Automatic, mechanical, and 2008] electronic equipment. (a) Automatic, mechanical, or elec- § 211.72 Filters. tronic equipment or other types of Filters for liquid filtration used in equipment, including computers, or re- the manufacture, processing, or pack- lated systems that will perform a func- ing of injectable drug products in- tion satisfactorily, may be used in the tended for human use shall not release manufacture, processing, packing, and fibers into such products. Fiber-releas- holding of a drug product. If such ing filters may be used when it is not equipment is so used, it shall be rou- possible to manufacture such products tinely calibrated, inspected, or checked without the use of these filters. If use according to a written program de- of a fiber-releasing filter is necessary, signed to assure proper performance. an additional nonfiber-releasing filter Written records of those calibration having a maximum nominal pore size

163

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00173 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.80 21 CFR Ch. I (4–1–19 Edition)

rating of 0.2 micron (0.45 micron if the the area shall conform to the require- manufacturing conditions so dictate) ments of § 211.80. shall subsequently be used to reduce [43 FR 45077, Sept. 29, 1978, as amended at 73 the content of particles in the FR 51932, Sept. 8, 2008] injectable drug product. The use of an asbestos-containing filter is prohibited. § 211.84 Testing and approval or rejection of components, drug product [73 FR 51932, Sept. 8, 2008] containers, and closures. (a) Each lot of components, drug Subpart E—Control of Compo- product containers, and closures shall nents and Drug Product Con- be withheld from use until the lot has tainers and Closures been sampled, tested, or examined, as appropriate, and released for use by the § 211.80 General requirements. quality control unit. (a) There shall be written procedures (b) Representative samples of each describing in sufficient detail the re- shipment of each lot shall be collected ceipt, identification, storage, handling, for testing or examination. The num- sampling, testing, and approval or re- ber of containers to be sampled, and jection of components and drug prod- the amount of material to be taken uct containers and closures; such writ- from each container, shall be based ten procedures shall be followed. upon appropriate criteria such as sta- (b) Components and drug product tistical criteria for component varia- containers and closures shall at all bility, confidence levels, and degree of times be handled and stored in a man- precision desired, the past quality history of the supplier, and the quantity ner to prevent contamination. needed for analysis and reserve where (c) Bagged or boxed components of required by § 211.170. drug product containers, or closures (c) Samples shall be collected in ac- shall be stored off the floor and suit- cordance with the following proce- ably spaced to permit cleaning and in- dures: spection. (1) The containers of components se- (d) Each container or grouping of lected shall be cleaned when necessary containers for components or drug in a manner to prevent introduction of product containers, or closures shall be contaminants into the component. identified with a distinctive code for (2) The containers shall be opened, each lot in each shipment received. sampled, and resealed in a manner de- This code shall be used in recording the signed to prevent contamination of disposition of each lot. Each lot shall their contents and contamination of be appropriately identified as to its other components, drug product con- status (i.e., quarantined, approved, or tainers, or closures. rejected). (3) Sterile equipment and aseptic sampling techniques shall be used when § 211.82 Receipt and storage of untest- necessary. ed components, drug product containers, and closures. (4) If it is necessary to sample a component from the top, middle, and bot- (a) Upon receipt and before accept- tom of its container, such sample sub- ance, each container or grouping of divisions shall not be composited for containers of components, drug prod- testing. uct containers, and closures shall be (5) Sample containers shall be identi- examined visually for appropriate la- fied so that the following information beling as to contents, container dam- can be determined: name of the mate- age or broken seals, and contamina- rial sampled, the lot number, the con- tion. tainer from which the sample was (b) Components, drug product con- taken, the date on which the sample tainers, and closures shall be stored was taken, and the name of the person under quarantine until they have been who collected the sample. tested or examined, whichever is appro- (6) Containers from which samples priate, and released. Storage within have been taken shall be marked to

164

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00174 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.94

show that samples have been removed released for use. Any lot of such mate- from them. rial that does not meet such specifica- (d) Samples shall be examined and tions shall be rejected. tested as follows: (1) At least one test shall be con- [43 FR 45077, Sept. 29, 1978, as amended at 63 ducted to verify the identity of each FR 14356, Mar. 25, 1998; 73 FR 51932, Sept. 8, 2008] component of a drug product. Specific identity tests, if they exist, shall be § 211.86 Use of approved components, used. drug product containers, and clo- (2) Each component shall be tested sures. for conformity with all appropriate written specifications for purity, Components, drug product con- strength, and quality. In lieu of such tainers, and closures approved for use testing by the manufacturer, a report shall be rotated so that the oldest ap- of analysis may be accepted from the proved stock is used first. Deviation supplier of a component, provided that from this requirement is permitted if at least one specific identity test is such deviation is temporary and appro- conducted on such component by the priate. manufacturer, and provided that the manufacturer establishes the reli- § 211.87 Retesting of approved compo- ability of the supplier’s analyses nents, drug product containers, and through appropriate validation of the closures. supplier’s test results at appropriate Components, drug product con- intervals. tainers, and closures shall be retested (3) Containers and closures shall be or reexamined, as appropriate, for iden- tested for conformity with all appro- tity, strength, quality, and purity and priate written specifications. In lieu of approved or rejected by the quality such testing by the manufacturer, a control unit in accordance with § 211.84 certificate of testing may be accepted as necessary, e.g., after storage for from the supplier, provided that at long periods or after exposure to air, least a visual identification is con- heat or other conditions that might ad- ducted on such containers/closures by versely affect the component, drug the manufacturer and provided that product container, or closure. the manufacturer establishes the reliability of the supplier’s test results § 211.89 Rejected components, drug through appropriate validation of the product containers, and closures. supplier’s test results at appropriate intervals. Rejected components, drug product (4) When appropriate, components containers, and closures shall be iden- shall be microscopically examined. tified and controlled under a quar- (5) Each lot of a component, drug antine system designed to prevent product container, or closure that is their use in manufacturing or proc- liable to contamination with filth, in- essing operations for which they are sect infestation, or other extraneous unsuitable. adulterant shall be examined against established specifications for such con- § 211.94 Drug product containers and tamination. closures. (6) Each lot of a component, drug (a) Drug product containers and clo- product container, or closure with po- sures shall not be reactive, additive, or tential for microbiological contamina- absorptive so as to alter the safety, tion that is objectionable in view of its identity, strength, quality, or purity of intended use shall be subjected to the drug beyond the official or estab- microbiological tests before use. lished requirements. (e) Any lot of components, drug prod- (b) Container closure systems shall uct containers, or closures that meets the appropriate written specifications provide adequate protection against of identity, strength, quality, and pu- foreseeable external factors in storage rity and related tests under paragraph and use that can cause deterioration or (d) of this section may be approved and contamination of the drug product.

165

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00175 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.100 21 CFR Ch. I (4–1–19 Edition)

(c) Drug product containers and clo- containers must be reasonably resist- sures shall be clean and, where indi- ant to fading, durable when exposed to cated by the nature of the drug, steri- atmospheric conditions, and not read- lized and processed to remove ily soluble in water. pyrogenic properties to assure that they are suitable for their intended [43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008; 81 FR 81697, Nov. 18, use. Such depyrogenation processes 2016] shall be validated. (d) Standards or specifications, methods of testing, and, where indicated, Subpart F—Production and methods of cleaning, sterilizing, and Process Controls processing to remove pyrogenic properties shall be written and followed for § 211.100 Written procedures; devi- drug product containers and closures. ations. (e) Medical gas containers and closures (a) There shall be written procedures must meet the following requirements—(1) for production and process control de- Gas-specific use outlet connections. Port- signed to assure that the drug products able cryogenic medical gas containers have the identity, strength, quality, that are not manufactured with perma- and purity they purport or are rep- nent gas use outlet connections (e.g., resented to possess. Such procedures those that have been silver-brazed) shall include all requirements in this must have gas-specific use outlet con- subpart. These written procedures, in- nections that are attached to the valve cluding any changes, shall be drafted, body so that they cannot be readily re- reviewed, and approved by the appro- moved or replaced (without making the priate organizational units and re- valve inoperable and preventing the viewed and approved by the quality containers’ use) except by the manu- control unit. facturer. For the purposes of this para- (b) Written production and process graph, the term ‘‘manufacturer’’ in- control procedures shall be followed in cludes any individual or firm that fills the execution of the various production high-pressure medical gas cylinders or and process control functions and shall cryogenic medical gas containers. For be documented at the time of perform- the purposes of this section, a ‘‘portance. Any deviation from the written able cryogenic medical gas container’’ procedures shall be recorded and justi- is one that is capable of being trans- fied. ported and is intended to be attached to a medical gas supply system within § 211.101 Charge-in of components. a hospital, health care entity, nursing home, other facility, or home health Written production and control pro- care setting, or is a base unit used to cedures shall include the following, fill small cryogenic gas containers for which are designed to assure that the use by individual patients. The term drug products produced have the iden- does not include cryogenic containers tity, strength, quality, and purity they that are not designed to be connected purport or are represented to possess: to a medical gas supply system, e.g., (a) The batch shall be formulated tank trucks, trailers, rail cars, or with the intent to provide not less than small cryogenic gas containers for use 100 percent of the labeled or established by individual patients (including port- amount of active ingredient. able liquid oxygen units as defined at (b) Components for drug product § 868.5655 of this chapter). manufacturing shall be weighed, meas- (2) Label and coloring requirements. ured, or subdivided as appropriate. If a The labeling specified at § 201.328(a) of component is removed from the origi- this chapter must be affixed to the con- nal container to another, the new container in a manner that does not inter- tainer shall be identified with the fol- fere with other labeling and such that lowing information: it is not susceptible to becoming worn (1) Component name or item code; or inadvertently detached during nor- (2) Receiving or control number; mal use. Each such label as well as ma- (3) Weight or measure in new con- terials used for coloring medical gas tainer;

166

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00176 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.110

(4) Batch for which component was manufacture of each batch of a drug dispensed, including its product name, product. In cases where only one of a strength, and lot number. particular type of equipment exists in (c) Weighing, measuring, or subdi- a manufacturing facility, the name of viding operations for components shall the equipment may be used in lieu of a be adequately supervised. Each con- distinctive identification number or tainer of component dispensed to man- code. ufacturing shall be examined by a second person to assure that: § 211.110 Sampling and testing of in- (1) The component was released by process materials and drug prod- the quality control unit; ucts. (2) The weight or measure is correct (a) To assure batch uniformity and as stated in the batch production integrity of drug products, written pro- records; cedures shall be established and fol- (3) The containers are properly iden- lowed that describe the in-process con- tified. If the weighing, measuring, or trols, and tests, or examinations to be subdividing operations are performed conducted on appropriate samples of by automated equipment under § 211.68, in-process materials of each batch. only one person is needed to assure Such control procedures shall be estab- paragraphs (c)(1), (c)(2), and (c)(3) of lished to monitor the output and to this section. validate the performance of those man- (d) Each component shall either be ufacturing processes that may be re- added to the batch by one person and sponsible for causing variability in the verified by a second person or, if the characteristics of in-process material components are added by automated and the drug product. Such control equipment under § 211.68, only verified procedures shall include, but are not by one person. limited to, the following, where appropriate: [43 FR 45077, Sept. 29, 1978, as amended at 73 (1) Tablet or capsule weight vari- FR 51932, Sept. 8, 2008] ation; § 211.103 Calculation of yield. (2) Disintegration time; (3) Adequacy of mixing to assure uni- Actual yields and percentages of the- formity and homogeneity; oretical yield shall be determined at (4) Dissolution time and rate; the conclusion of each appropriate (5) Clarity, completeness, or pH of so- phase of manufacturing, processing, lutions. packaging, or holding of the drug prod- (6) Bioburden testing. uct. Such calculations shall either be (b) Valid in-process specifications for performed by one person and independ- such characteristics shall be consistent ently verified by a second person, or, if with drug product final specifications the yield is calculated by automated and shall be derived from previous ac- equipment under § 211.68, be independ- ceptable process average and process ently verified by one person. variability estimates where possible [73 FR 51932, Sept. 8, 2008] and determined by the application of suitable statistical procedures where § 211.105 Equipment identification. appropriate. Examination and testing (a) All compounding and storage con- of samples shall assure that the drug tainers, processing lines, and major product and in-process material con- equipment used during the production form to specifications. of a batch of a drug product shall be (c) In-process materials shall be test- properly identified at all times to indi- ed for identity, strength, quality, and cate their contents and, when nec- purity as appropriate, and approved or essary, the phase of processing of the rejected by the quality control unit, batch. during the production process, e.g., at (b) Major equipment shall be identi- commencement or completion of sig- fied by a distinctive identification nificant phases or after storage for number or code that shall be recorded long periods. in the batch production record to show (d) Rejected in-process materials the specific equipment used in the shall be identified and controlled under

167

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00177 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.111 21 CFR Ch. I (4–1–19 Edition)

a quarantine system designed to pre- of labeling and packaging materials; vent their use in manufacturing or such written procedures shall be fol- processing operations for which they lowed. Labeling and packaging mate- are unsuitable. rials shall be representatively sampled, and examined or tested upon receipt [43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008] and before use in packaging or labeling of a drug product. § 211.111 Time limitations on produc- (b) Any labeling or packaging mate- tion. rials meeting appropriate written spec- When appropriate, time limits for the ifications may be approved and re- completion of each phase of production leased for use. Any labeling or pack- shall be established to assure the qual- aging materials that do not meet such ity of the drug product. Deviation from specifications shall be rejected to pre- established time limits may be accept- vent their use in operations for which able if such deviation does not com- they are unsuitable. promise the quality of the drug prod- (c) Records shall be maintained for uct. Such deviation shall be justified each shipment received of each dif- and documented. ferent labeling and packaging material indicating receipt, examination or § 211.113 Control of microbiological testing, and whether accepted or re- contamination. jected. (a) Appropriate written procedures, (d) Labels and other labeling mate- designed to prevent objectionable rials for each different drug product, microorganisms in drug products not strength, dosage form, or quantity of required to be sterile, shall be estab- contents shall be stored separately lished and followed. with suitable identification. Access to (b) Appropriate written procedures, the storage area shall be limited to au- designed to prevent microbiological thorized personnel. contamination of drug products pur- (e) Obsolete and outdated labels, la- porting to be sterile, shall be estab- beling, and other packaging materials lished and followed. Such procedures shall be destroyed. shall include validation of all aseptic (f) Use of gang-printed labeling for and sterilization processes. different drug products, or different strengths or net contents of the same [43 FR 45077, Sept. 29, 1978, as amended at 73 drug product, is prohibited unless the FR 51932, Sept. 8, 2008] labeling from gang-printed sheets is § 211.115 Reprocessing. adequately differentiated by size, shape, or color. (a) Written procedures shall be estab- (g) If cut labeling is used for imme- lished and followed prescribing a sys- diate container labels, individual unit tem for reprocessing batches that do cartons, or multiunit cartons con- not conform to standards or specifica- taining immediate containers that are tions and the steps to be taken to in- not packaged in individual unit car- sure that the reprocessed batches will tons, packaging and labeling oper- conform with all established standards, ations shall include one of the fol- specifications, and characteristics. lowing special control procedures: (b) Reprocessing shall not be per- (1) Dedication of labeling and pack- formed without the review and ap- aging lines to each different strength proval of the quality control unit. of each different drug product; (2) Use of appropriate electronic or Subpart G—Packaging and electromechanical equipment to con- Labeling Control duct a 100-percent examination for correct labeling during or after comple- § 211.122 Materials examination and tion of finishing operations; or usage criteria. (3) Use of visual inspection to con- (a) There shall be written procedures duct a 100-percent examination for cor- describing in sufficient detail the re- rect labeling during or after comple- ceipt, identification, storage, handling, tion of finishing operations for hand- sampling, examination, and/or testing applied labeling. Such examination

168

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00178 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.132

shall be performed by one person and of labeling; such written procedures independently verified by a second per- shall be followed. son. [43 FR 45077, Sept. 29, 1978, as amended at 58 (4) Use of any automated technique, FR 41354, Aug. 3, 1993; 81 FR 81697, Nov. 18, including differentiation by labeling 2016] size and shape, that physically prevents incorrect labeling from being § 211.130 Packaging and labeling operations. processed by labeling and packaging equipment. There shall be written procedures de- (h) Printing devices on, or associated signed to assure that correct labels, la- with, manufacturing lines used to im- beling, and packaging materials are used for drug products; such written print labeling upon the drug product procedures shall be followed. These unit label or case shall be monitored to procedures shall incorporate the fol- assure that all imprinting conforms to lowing features: the print specified in the batch produc- (a) Prevention of mixups and cross- tion record. contamination by physical or spatial [43 FR 45077, Sept. 29, 1978, as amended at 58 separation from operations on other FR 41353, Aug. 3, 1993; 77 FR 16163, Mar. 20, drug products. 2012] (b) Identification and handling of filled drug product containers that are § 211.125 Labeling issuance. set aside and held in unlabeled condition for future labeling operations to (a) Strict control shall be exercised preclude mislabeling of individual con- over labeling issued for use in drug tainers, lots, or portions of lots. Identi- product labeling operations. fication need not be applied to each in- (b) Labeling materials issued for a dividual container but shall be suffi- batch shall be carefully examined for cient to determine name, strength, identity and conformity to the labeling quantity of contents, and lot or control specified in the master or batch pro- number of each container. duction records. (c) Identification of the drug product (c) Procedures shall be used to rec- with a lot or control number that per- oncile the quantities of labeling issued, mits determination of the history of used, and returned, and shall require the manufacture and control of the evaluation of discrepancies found be- batch. tween the quantity of drug product fin- (d) Examination of packaging and la- ished and the quantity of labeling beling materials for suitability and issued when such discrepancies are out- correctness before packaging oper- side narrow preset limits based on his- ations, and documentation of such ex- torical operating data. Such discrep- amination in the batch production ancies shall be investigated in accord- record. (e) Inspection of the packaging and ance with § 211.192. Labeling reconcili- labeling facilities immediately before ation is waived for cut or roll labeling use to assure that all drug products if a 100-percent examination for correct have been removed from previous oper- labeling is performed in accordance ations. Inspection shall also be made to with § 211.122(g)(2). Labeling reconcili- assure that packaging and labeling ma- ° ation is also waived for 360 wrap- terials not suitable for subsequent op- around labels on portable cryogenic erations have been removed. Results of medical gas containers. inspection shall be documented in the (d) All excess labeling bearing lot or batch production records. control numbers shall be destroyed. (e) Returned labeling shall be main- [43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993] tained and stored in a manner to prevent mixups and provide proper identi- § 211.132 Tamper-evident packaging fication. requirements for over-the-counter (f) Procedures shall be written de- (OTC) human drug products. scribing in sufficient detail the control (a) General. The Food and Drug Ad- procedures employed for the issuance ministration has the authority under

169

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00179 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.132 21 CFR Ch. I (4–1–19 Edition)

the Federal Food, Drug, and Cosmetic this section must be sealed using an ac- Act (the act) to establish a uniform na- ceptable tamper-evident technology. tional requirement for tamper-evident (c) Labeling. (1) In order to alert con- packaging of OTC drug products that sumers to the specific tamper-evident will improve the security of OTC drug feature(s) used, each retail package of packaging and help assure the safety an OTC drug product covered by this and effectiveness of OTC drug products. section (except ammonia inhalant in An OTC drug product (except a der- crushable glass ampules, containers of matological, dentifrice, insulin, or loz- compressed medical oxygen, or aerosol enge product) for retail sale that is not products that depend upon the power of packaged in a tamper-resistant pack- a liquefied or compressed gas to expel age or that is not properly labeled the contents from the container) is re- under this section is adulterated under quired to bear a statement that: section 501 of the act or misbranded (i) Identifies all tamper-evident fea- under section 502 of the act, or both. ture(s) and any capsule sealing tech- (b) Requirements for tamper-evident nologies used to comply with para- package. (1) Each manufacturer and graph (b) of this section; packer who packages an OTC drug (ii) Is prominently placed on the product (except a dermatological, den- package; and tifrice, insulin, or lozenge product) for (iii) Is so placed that it will be unaf- retail sale shall package the product in fected if the tamper-evident feature of a tamper-evident package, if this prod- the package is breached or missing. uct is accessible to the public while held for sale. A tamper-evident pack- (2) If the tamper-evident feature cho- age is one having one or more indica- sen to meet the requirements in para- tors or barriers to entry which, if graph (b) of this section uses an identi- breached or missing, can reasonably be fying characteristic, that char- expected to provide visible evidence to acteristic is required to be referred to consumers that tampering has oc- in the labeling statement. For exam- curred. To reduce the likelihood of suc- ple, the labeling statement on a bottle cessful tampering and to increase the with a shrink band could say ‘‘For your likelihood that consumers will discover protection, this bottle has an im- if a product has been tampered with, printed seal around the neck.’’ the package is required to be distinc- (d) Request for exemptions from pack- tive by design or by the use of one or aging and labeling requirements. A man- more indicators or barriers to entry ufacturer or packer may request an ex- that employ an identifying char- emption from the packaging and label- acteristic (e.g., a pattern, name, reg- ing requirements of this section. A re- istered trademark, logo, or picture). quest for an exemption is required to For purposes of this section, the term be submitted in the form of a citizen ‘‘distinctive by design’’ means the petition under § 10.30 of this chapter packaging cannot be duplicated with and should be clearly identified on the commonly available materials or envelope as a ‘‘Request for Exemption through commonly available processes. from the Tamper-Evident Packaging A tamper-evident package may involve Rule.’’ The petition is required to con- an immediate-container and closure tain the following: system or secondary-container or car- (1) The name of the drug product or, ton system or any combination of sys- if the petition seeks an exemption for a tems intended to provide a visual indi- drug class, the name of the drug class, cation of package integrity. The tam- and a list of products within that class. per-evident feature shall be designed to (2) The reasons that the drug prod- and shall remain intact when handled uct’s compliance with the tamper-evi- in a reasonable manner during manu- dent packaging or labeling require- facture, distribution, and retail dis- ments of this section is unnecessary or play. cannot be achieved. (2) In addition to the tamper-evident (3) A description of alternative steps packaging feature described in para- that are available, or that the peti- graph (b)(1) of this section, any two- tioner has already taken, to reduce the piece, hard gelatin capsule covered by likelihood that the product or drug

170

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00180 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.142

class will be the subject of malicious tion for both the reconstituted and adulteration. unreconstituted drug products. (4) Other information justifying an (d) Expiration dates shall appear on exemption. labeling in accordance with the re- (e) OTC drug products subject to ap- quirements of § 201.17 of this chapter. proved new drug applications. Holders of (e) Homeopathic drug products shall approved new drug applications for be exempt from the requirements of OTC drug products are required under this section. § 314.70 of this chapter to provide the (f) Allergenic extracts that are la- agency with notification of changes in beled ‘‘No U.S. Standard of Potency’’ packaging and labeling to comply with are exempt from the requirements of the requirements of this section. Changes in packaging and labeling re- this section. quired by this regulation may be made (g) New drug products for investiga- before FDA approval, as provided under tional use are exempt from the require- § 314.70(c) of this chapter. Manufac- ments of this section, provided that turing changes by which capsules are they meet appropriate standards or to be sealed require prior FDA approval specifications as demonstrated by sta- under § 314.70(b) of this chapter. bility studies during their use in clin- (f) Poison Prevention Packaging Act of ical investigations. Where new drug 1970. This section does not affect any products for investigational use are to requirements for ‘‘special packaging’’ be reconstituted at the time of dis- as defined under § 310.3(l) of this chap- pensing, their labeling shall bear expi- ter and required under the Poison Pre- ration information for the reconsti- vention Packaging Act of 1970. tuted drug product. (Approved by the Office of Management and (h) Pending consideration of a pro- Budget under OMB control number 0910–0149) posed exemption, published in the FED- [54 FR 5228, Feb. 2, 1989, as amended at 63 FR ERAL REGISTER of September 29, 1978, 59470, Nov. 4, 1998] the requirements in this section shall not be enforced for human OTC drug § 211.134 Drug product inspection. products if their labeling does not bear (a) Packaged and labeled products dosage limitations and they are stable shall be examined during finishing op- for at least 3 years as supported by ap- erations to provide assurance that con- propriate stability data. tainers and packages in the lot have [43 FR 45077, Sept. 29, 1978, as amended at 46 the correct label. FR 56412, Nov. 17, 1981; 60 FR 4091, Jan. 20, (b) A representative sample of units 1995] shall be collected at the completion of finishing operations and shall be visually examined for correct labeling. Subpart H—Holding and (c) Results of these examinations Distribution shall be recorded in the batch production or control records. § 211.142 Warehousing procedures. Written procedures describing the § 211.137 Expiration dating. warehousing of drug products shall be (a) To assure that a drug product established and followed. They shall in- meets applicable standards of identity, clude: strength, quality, and purity at the (a) Quarantine of drug products be- time of use, it shall bear an expiration fore release by the quality control date determined by appropriate sta- unit. bility testing described in § 211.166. (b) Storage of drug products under (b) Expiration dates shall be related appropriate conditions of temperature, to any storage conditions stated on the humidity, and light so that the iden- labeling, as determined by stability tity, strength, quality, and purity of studies described in § 211.166. the drug products are not affected. (c) If the drug product is to be reconstituted at the time of dispensing, its labeling shall bear expiration informa-

171

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00181 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.150 21 CFR Ch. I (4–1–19 Edition)

§ 211.150 Distribution procedures. procedures shall also require appropriate retesting of any component, Written procedures shall be estab- drug product container, or closure that lished, and followed, describing the dis- is subject to deterioration. tribution of drug products. They shall (2) Determination of conformance to include: written specifications and a descrip- (a) A procedure whereby the oldest tion of sampling and testing procedures approved stock of a drug product is dis- for in-process materials. Such samples tributed first. Deviation from this re- shall be representative and properly quirement is permitted if such devi- identified. ation is temporary and appropriate. (3) Determination of conformance to (b) A system by which the distribu- written descriptions of sampling proce- tion of each lot of drug product can be dures and appropriate specifications readily determined to facilitate its re- for drug products. Such samples shall call if necessary. be representative and properly identified. Subpart I—Laboratory Controls (4) The calibration of instruments, apparatus, gauges, and recording de- § 211.160 General requirements. vices at suitable intervals in accord- (a) The establishment of any speci- ance with an established written pro- fications, standards, sampling plans, gram containing specific directions, test procedures, or other laboratory schedules, limits for accuracy and pre- control mechanisms required by this cision, and provisions for remedial ac- subpart, including any change in such tion in the event accuracy and/or preci- specifications, standards, sampling sion limits are not met. Instruments, plans, test procedures, or other labora- apparatus, gauges, and recording de- tory control mechanisms, shall be vices not meeting established specifica- drafted by the appropriate organizations shall not be used. tional unit and reviewed and approved [43 FR 45077, Sept. 29, 1978, as amended at 73 by the quality control unit. The re- FR 51932, Sept. 8, 2008] quirements in this subpart shall be followed and shall be documented at the § 211.165 Testing and release for dis- time of performance. Any deviation tribution. from the written specifications, stand- (a) For each batch of drug product, ards, sampling plans, test procedures, there shall be appropriate laboratory or other laboratory control mecha- determination of satisfactory conform- nisms shall be recorded and justified. ance to final specifications for the drug (b) Laboratory controls shall include product, including the identity and the establishment of scientifically strength of each active ingredient, sound and appropriate specifications, prior to release. Where sterility and/or standards, sampling plans, and test pyrogen testing are conducted on spe- procedures designed to assure that cific batches of shortlived radio- components, drug product containers, pharmaceuticals, such batches may be closures, in-process materials, labeling, released prior to completion of ste- and drug products conform to appro- rility and/or pyrogen testing, provided priate standards of identity, strength, such testing is completed as soon as quality, and purity. Laboratory con- possible. trols shall include: (b) There shall be appropriate labora- (1) Determination of conformity to tory testing, as necessary, of each applicable written specifications for batch of drug product required to be the acceptance of each lot within each free of objectionable microorganisms. shipment of components, drug product (c) Any sampling and testing plans containers, closures, and labeling used shall be described in written proce- in the manufacture, processing, pack- dures that shall include the method of ing, or holding of drug products. The sampling and the number of units per specifications shall include a descrip- batch to be tested; such written proce- tion of the sampling and testing procedure shall be followed. dures used. Samples shall be represent- (d) Acceptance criteria for the sam- ative and adequately identified. Such pling and testing conducted by the

172

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00182 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.167

quality control unit shall be adequate available and are being conducted. to assure that batches of drug products Where data from accelerated studies meet each appropriate specification are used to project a tentative expira- and appropriate statistical quality con- tion date that is beyond a date sup- trol criteria as a condition for their ap- ported by actual shelf life studies, proval and release. The statistical there must be stability studies con- quality control criteria shall include ducted, including drug product testing appropriate acceptance levels and/or at appropriate intervals, until the ten- appropriate rejection levels. tative expiration date is verified or the (e) The accuracy, sensitivity, speci- appropriate expiration date deter- ficity, and reproducibility of test mined. methods employed by the firm shall be (c) For homeopathic drug products, established and documented. Such validation and documentation may be ac- the requirements of this section are as complished in accordance with follows: § 211.194(a)(2). (1) There shall be a written assess- (f) Drug products failing to meet es- ment of stability based at least on test- tablished standards or specifications ing or examination of the drug product and any other relevant quality control for compatibility of the ingredients, criteria shall be rejected. Reprocessing and based on marketing experience may be performed. Prior to acceptance with the drug product to indicate that and use, reprocessed material must there is no degradation of the product meet appropriate standards, specifica- for the normal or expected period of tions, and any other relevant criteria. use. (2) Evaluation of stability shall be § 211.166 Stability testing. based on the same container-closure (a) There shall be a written testing system in which the drug product is program designed to assess the sta- being marketed. bility characteristics of drug products. (d) Allergenic extracts that are la- The results of such stability testing beled ‘‘No U.S. Standard of Potency’’ shall be used in determining appro- are exempt from the requirements of priate storage conditions and expira- this section. tion dates. The written program shall be followed and shall include: [43 FR 45077, Sept. 29, 1978, as amended at 46 (1) Sample size and test intervals FR 56412, Nov. 17, 1981] based on statistical criteria for each attribute examined to assure valid esti- § 211.167 Special testing requirements. mates of stability; (a) For each batch of drug product (2) Storage conditions for samples re- purporting to be sterile and/or pyrogen- tained for testing; free, there shall be appropriate labora- (3) Reliable, meaningful, and specific tory testing to determine conformance test methods; to such requirements. The test proce- (4) Testing of the drug product in the dures shall be in writing and shall be same container-closure system as that followed. in which the drug product is marketed; (b) For each batch of ophthalmic (5) Testing of drug products for re- ointment, there shall be appropriate constitution at the time of dispensing (as directed in the labeling) as well as testing to determine conformance to after they are reconstituted. specifications regarding the presence of (b) An adequate number of batches of foreign particles and harsh or abrasive each drug product shall be tested to de- substances. The test procedures shall termine an appropriate expiration date be in writing and shall be followed. and a record of such data shall be (c) For each batch of controlled-re- maintained. Accelerated studies, com- lease dosage form, there shall be appro- bined with basic stability information priate laboratory testing to determine on the components, drug products, and conformance to the specifications for container-closure system, may be used the rate of release of each active ingre- to support tentative expiration dates dient. The test procedures shall be in provided full shelf life studies are not writing and shall be followed.

173

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00183 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.170 21 CFR Ch. I (4–1–19 Edition)

§ 211.170 Reserve samples. least once a year for evidence of dete- (a) An appropriately identified re- rioration unless visual examination serve sample that is representative of would affect the integrity of the re- each lot in each shipment of each ac- serve sample. Any evidence of reserve tive ingredient shall be retained. The sample deterioration shall be inves- reserve sample consists of at least tigated in accordance with § 211.192. twice the quantity necessary for all The results of the examination shall be tests required to determine whether recorded and maintained with other the active ingredient meets its estab- stability data on the drug product. Re- lished specifications, except for ste- serve samples of compressed medical rility and pyrogen testing. The reten- gases need not be retained. The retention time is as follows: tion time is as follows: (1) For an active ingredient in a drug (1) For a drug product other than product other than those described in those described in paragraphs (b) (2) paragraphs (a) (2) and (3) of this sec- and (3) of this section, the reserve sam- tion, the reserve sample shall be re- ple shall be retained for 1 year after tained for 1 year after the expiration the expiration date of the drug prod- date of the last lot of the drug product uct. containing the active ingredient. (2) For a radioactive drug product, (2) For an active ingredient in a ra- except for nonradioactive reagent kits, dioactive drug product, except for non- the reserve sample shall be retained radioactive reagent kits, the reserve for: sample shall be retained for: (i) Three months after the expiration (i) Three months after the expiration date of the drug product if the expira- date of the last lot of the drug product tion dating period of the drug product containing the active ingredient if the is 30 days or less; or expiration dating period of the drug product is 30 days or less; or (ii) Six months after the expiration (ii) Six months after the expiration date of the drug product if the expira- date of the last lot of the drug product tion dating period of the drug product containing the active ingredient if the is more than 30 days. expiration dating period of the drug (3) For an OTC drug product that is product is more than 30 days. exempt for bearing an expiration date (3) For an active ingredient in an under § 211.137, the reserve sample must OTC drug product that is exempt from be retained for 3 years after the lot or bearing an expiration date under batch of drug product is distributed. § 211.137, the reserve sample shall be re- [48 FR 13025, Mar. 29, 1983, as amended at 60 tained for 3 years after distribution of FR 4091, Jan. 20, 1995] the last lot of the drug product containing the active ingredient. § 211.173 Laboratory animals. (b) An appropriately identified re- Animals used in testing components, serve sample that is representative of each lot or batch of drug product shall in-process materials, or drug products be retained and stored under conditions for compliance with established speci- consistent with product labeling. The fications shall be maintained and con- reserve sample shall be stored in the trolled in a manner that assures their same immediate container-closure sys- suitability for their intended use. They tem in which the drug product is mar- shall be identified, and adequate keted or in one that has essentially the records shall be maintained showing same characteristics. The reserve sam- the history of their use. ple consists of at least twice the quantity necessary to perform all the re- § 211.176 Penicillin contamination. quired tests, except those for sterility If a reasonable possibility exists that and pyrogens. Except for those for drug a non-penicillin drug product has been products described in paragraph (b)(2) exposed to cross-contamination with of this section, reserve samples from penicillin, the non-penicillin drug prod- representative sample lots or batches uct shall be tested for the presence of selected by acceptable statistical pro- penicillin. Such drug product shall not cedures shall be examined visually at be marketed if detectable levels are

174

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00184 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.182

found when tested according to proce- tion. Records that can be immediately dures specified in ‘Procedures for De- retrieved from another location by tecting and Measuring Penicillin Con- computer or other electronic means tamination in Drugs,’ which is incor- shall be considered as meeting the re- porated by reference. Copies are avail- quirements of this paragraph. able from the Division of Research and (d) Records required under this part Testing (HFD–470), Center for Drug may be retained either as original Evaluation and Research, Food and records or as true copies such as photo- Drug Administration, 5001 Campus Dr., copies, microfilm, microfiche, or other College Park, MD 20740, or available for accurate reproductions of the original inspection at the National Archives records. Where reduction techniques, and Records Administration (NARA). such as microfilming, are used, suit- For information on the availability of able reader and photocopying equip- this material at NARA, call 202–741– ment shall be readily available. 6030, or go to: http://www.archives.gov/ (e) Written records required by this federallregister/ part shall be maintained so that data codeloflfederallregulations/ therein can be used for evaluating, at ibrllocations.html. least annually, the quality standards of each drug product to determine the [43 FR 45077, Sept. 29, 1978, as amended at 47 FR 9396, Mar. 5, 1982; 50 FR 8996, Mar. 6, 1985; need for changes in drug product speci- 55 FR 11577, Mar. 29, 1990; 66 FR 56035, Nov. 6, fications or manufacturing or control 2001; 69 FR 18803, Apr. 9, 2004; 81 FR 49897, procedures. Written procedures shall be July 29, 2016] established and followed for such evaluations and shall include provisions Subpart J—Records and Reports for: (1) A review of a representative num- § 211.180 General requirements. ber of batches, whether approved or re- (a) Any production, control, or dis- jected, and, where applicable, records tribution record that is required to be associated with the batch. maintained in compliance with this (2) A review of complaints, recalls, part and is specifically associated with returned or salvaged drug products, a batch of a drug product shall be re- and investigations conducted under tained for at least 1 year after the expi- § 211.192 for each drug product. ration date of the batch or, in the case (f) Procedures shall be established to of certain OTC drug products lacking assure that the responsible officials of expiration dating because they meet the firm, if they are not personally in- the criteria for exemption under volved in or immediately aware of such § 211.137, 3 years after distribution of actions, are notified in writing of any the batch. investigations conducted under (b) Records shall be maintained for §§ 211.198, 211.204, or 211.208 of these reg- all components, drug product con- ulations, any recalls, reports of tainers, closures, and labeling for at inspectional observations issued by the least 1 year after the expiration date Food and Drug Administration, or any or, in the case of certain OTC drug regulatory actions relating to good products lacking expiration dating be- manufacturing practices brought by cause they meet the criteria for exemp- the Food and Drug Administration. tion under § 211.137, 3 years after dis- [43 FR 45077, Sept. 29, 1978, as amended at 60 tribution of the last lot of drug product FR 4091, Jan. 20, 1995] incorporating the component or using the container, closure, or labeling. § 211.182 Equipment cleaning and use (c) All records required under this log. part, or copies of such records, shall be A written record of major equipment readily available for authorized inspec- cleaning, maintenance (except routine tion during the retention period at the maintenance such as lubrication and establishment where the activities de- adjustments), and use shall be included scribed in such records occurred. These in individual equipment logs that show records or copies thereof shall be sub- the date, time, product, and lot number ject to photocopying or other means of of each batch processed. If equipment reproduction as part of such inspec- is dedicated to manufacture of one

175

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00185 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.184 21 CFR Ch. I (4–1–19 Edition)

product, then individual equipment § 211.186 Master production and con- logs are not required, provided that trol records. lots or batches of such product follow (a) To assure uniformity from batch in numerical order and are manufac- to batch, master production and con- tured in numerical sequence. In cases trol records for each drug product, in- where dedicated equipment is em- cluding each batch size thereof, shall ployed, the records of cleaning, main- be prepared, dated, and signed (full sig- tenance, and use shall be part of the nature, handwritten) by one person and batch record. The persons performing independently checked, dated, and and double-checking the cleaning and signed by a second person. The prepara- maintenance (or, if the cleaning and tion of master production and control maintenance is performed using auto- records shall be described in a written mated equipment under § 211.68, just procedure and such written procedure the person verifying the cleaning and shall be followed. maintenance done by the automated equipment) shall date and sign or ini- (b) Master production and control tial the log indicating that the work records shall include: was performed. Entries in the log shall (1) The name and strength of the be in chronological order. product and a description of the dosage form; [73 FR 51933, Sept. 8, 2008] (2) The name and weight or measure of each active ingredient per dosage § 211.184 Component, drug product container, closure, and labeling unit or per unit of weight or measure records. of the drug product, and a statement of the total weight or measure of any dos- These records shall include the fol- age unit; lowing: (a) The identity and quantity of each (3) A complete list of components shipment of each lot of components, designated by names or codes suffi- drug product containers, closures, and ciently specific to indicate any special labeling; the name of the supplier; the quality characteristic; supplier’s lot number(s) if known; the (4) An accurate statement of the receiving code as specified in § 211.80; weight or measure of each component, and the date of receipt. The name and using the same weight system (metric, location of the prime manufacturer, if avoirdupois, or apothecary) for each different from the supplier, shall be component. Reasonable variations may listed if known. be permitted, however, in the amount (b) The results of any test or exam- of components necessary for the prepa- ination performed (including those per- ration in the dosage form, provided formed as required by § 211.82(a), they are justified in the master produc- § 211.84(d), or § 211.122(a)) and the con- tion and control records; clusions derived therefrom. (5) A statement concerning any cal- (c) An individual inventory record of culated excess of component; each component, drug product con- (6) A statement of theoretical weight tainer, and closure and, for each com- or measure at appropriate phases of ponent, a reconciliation of the use of processing; each lot of such component. The inven- (7) A statement of theoretical yield, tory record shall contain sufficient in- including the maximum and minimum formation to allow determination of percentages of theoretical yield beyond any batch or lot of drug product associ- which investigation according to ated with the use of each component, § 211.192 is required; drug product container, and closure. (8) A description of the drug product (d) Documentation of the examina- containers, closures, and packaging tion and review of labels and labeling materials, including a specimen or for conformity with established speci- copy of each label and all other label- fications in accord with §§ 211.122(c) and ing signed and dated by the person or 211.130(c). persons responsible for approval of (e) The disposition of rejected compo- such labeling; nents, drug product containers, clo- (9) Complete manufacturing and con- sure, and labeling. trol instructions, sampling and testing

176

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00186 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 211.194

procedures, specifications, special no- § 211.192 Production record review. tations, and precautions to be followed. All drug product production and con- § 211.188 Batch production and control trol records, including those for pack- records. aging and labeling, shall be reviewed and approved by the quality control Batch production and control records unit to determine compliance with all shall be prepared for each batch of drug established, approved written proce- product produced and shall include dures before a batch is released or dis- complete information relating to the tributed. Any unexplained discrepancy production and control of each batch. (including a percentage of theoretical These records shall include: yield exceeding the maximum or min- (a) An accurate reproduction of the imum percentages established in mas- appropriate master production or con- ter production and control records) or trol record, checked for accuracy, the failure of a batch or any of its com- dated, and signed; ponents to meet any of its specifica- (b) Documentation that each signifi- tions shall be thoroughly investigated, cant step in the manufacture, proc- whether or not the batch has already essing, packing, or holding of the batch been distributed. The investigation was accomplished, including: shall extend to other batches of the (1) Dates; same drug product and other drug products that may have been associ- (2) Identity of individual major ated with the specific failure or dis- equipment and lines used; crepancy. A written record of the in- (3) Specific identification of each vestigation shall be made and shall in- batch of component or in-process mate- clude the conclusions and followup. rial used; (4) Weights and measures of compo- § 211.194 Laboratory records. nents used in the course of processing; (a) Laboratory records shall include (5) In-process and laboratory control complete data derived from all tests results; necessary to assure compliance with (6) Inspection of the packaging and established specifications and stand- labeling area before and after use; ards, including examinations and as- (7) A statement of the actual yield says, as follows: and a statement of the percentage of (1) A description of the sample re- theoretical yield at appropriate phases ceived for testing with identification of of processing; source (that is, location from where (8) Complete labeling control records, sample was obtained), quantity, lot including specimens or copies of all la- number or other distinctive code, date beling used; sample was taken, and date sample was (9) Description of drug product con- received for testing. tainers and closures; (2) A statement of each method used (10) Any sampling performed; in the testing of the sample. The state- (11) Identification of the persons per- ment shall indicate the location of forming and directly supervising or data that establish that the methods checking each significant step in the used in the testing of the sample meet operation, or if a significant step in the proper standards of accuracy and reli- operation is performed by automated ability as applied to the product tested. equipment under § 211.68, the identifica- (If the method employed is in the cur- tion of the person checking the signifi- rent revision of the United States cant step performed by the automated Pharmacopeia, National Formulary, AOAC INTERNATIONAL, Book of equipment. Methods, 1 or in other recognized stand- (12) Any investigation made accord- ard references, or is detailed in an ap- ing to § 211.192. proved new drug application and the (13) Results of examinations made in accordance with § 211.134. 1 Copies may be obtained from: AOAC [43 FR 45077, Sept. 29, 1978, as amended at 73 INTERNATIONAL, 481 North Frederick Ave., FR 51933, Sept. 8, 2008] suite 500, Gaithersburg, MD 20877.

177

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00187 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 211.196 21 CFR Ch. I (4–1–19 Edition)

referenced method is not modified, a (e) Complete records shall be main- statement indicating the method and tained of all stability testing per- reference will suffice). The suitability formed in accordance with § 211.166. of all testing methods used shall be [43 FR 45077, Sept. 29, 1978, as amended at 55 verified under actual conditions of use. FR 11577, Mar. 29, 1990; 65 FR 18889, Apr. 10, (3) A statement of the weight or 2000; 70 FR 40880, July 15, 2005; 70 FR 67651, measure of sample used for each test, Nov. 8, 2005] where appropriate. § 211.196 Distribution records. (4) A complete record of all data se- cured in the course of each test, includ- Distribution records shall contain ing all graphs, charts, and spectra from the name and strength of the product laboratory instrumentation, properly and description of the dosage form, identified to show the specific compo- name and address of the consignee, nent, drug product container, closure, date and quantity shipped, and lot or control number of the drug product. in-process material, or drug product, For compressed medical gas products, and lot tested. distribution records are not required to (5) A record of all calculations per- contain lot or control numbers. formed in connection with the test, including units of measure, conversion (Approved by the Office of Management and factors, and equivalency factors. Budget under control number 0910–0139) (6) A statement of the results of tests [49 FR 9865, Mar. 16, 1984] and how the results compare with established standards of identity, § 211.198 Complaint files. strength, quality, and purity for the (a) Written procedures describing the component, drug product container, handling of all written and oral com- closure, in-process material, or drug plaints regarding a drug product shall product tested. be established and followed. Such pro- (7) The initials or signature of the cedures shall include provisions for review by the quality control unit, of any person who performs each test and the complaint involving the possible fail- date(s) the tests were performed. ure of a drug product to meet any of its (8) The initials or signature of a sec- specifications and, for such drug prod- ond person showing that the original ucts, a determination as to the need for records have been reviewed for accu- an investigation in accordance with racy, completeness, and compliance § 211.192. Such procedures shall include with established standards. provisions for review to determine (b) Complete records shall be main- whether the complaint represents a se- tained of any modification of an estab- rious and unexpected adverse drug ex- lished method employed in testing. perience which is required to be re- Such records shall include the reason ported to the Food and Drug Adminis- for the modification and data to verify tration in accordance with §§ 310.305 that the modification produced results and 514.80 of this chapter. that are at least as accurate and reli- (b) A written record of each com- able for the material being tested as plaint shall be maintained in a file des- the established method. ignated for drug product complaints. (c) Complete records shall be main- The file regarding such drug product tained of any testing and standardiza- complaints shall be maintained at the tion of laboratory reference standards, establishment where the drug product reagents, and standard solutions. involved was manufactured, processed, or packed, or such file may be main- (d) Complete records shall be maintained at another facility if the written tained of the periodic calibration of records in such files are readily avail- laboratory instruments, apparatus, able for inspection at that other facil- gauges, and recording devices required ity. Written records involving a drug by § 211.160(b)(4). product shall be maintained until at least 1 year after the expiration date of the drug product, or 1 year after the date that the complaint was received,

178

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00188 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS Pt. 212

whichever is longer. In the case of cer- turn, quantity returned, date of dis- tain OTC drug products lacking expira- position, and ultimate disposition of tion dating because they meet the cri- the returned drug product. If the rea- teria for exemption under § 211.137, such son for a drug product being returned written records shall be maintained for implicates associated batches, an ap- 3 years after distribution of the drug propriate investigation shall be con- product. ducted in accordance with the require- (1) The written record shall include ments of § 211.192. Procedures for the the following information, where holding, testing, and reprocessing of re- known: the name and strength of the turned drug products shall be in writ- drug product, lot number, name of complainant, nature of complaint, and ing and shall be followed. reply to complainant. § 211.208 Drug product salvaging. (2) Where an investigation under § 211.192 is conducted, the written Drug products that have been sub- record shall include the findings of the jected to improper storage conditions investigation and followup. The record including extremes in temperature, hu- or copy of the record of the investiga- midity, smoke, fumes, pressure, age, or tion shall be maintained at the estab- radiation due to natural disasters, lishment where the investigation oc- fires, accidents, or equipment failures curred in accordance with § 211.180(c). shall not be salvaged and returned to (3) Where an investigation under the marketplace. Whenever there is a § 211.192 is not conducted, the written question whether drug products have record shall include the reason that an been subjected to such conditions, sal- investigation was found not to be nec- vaging operations may be conducted essary and the name of the responsible only if there is (a) evidence from lab- person making such a determination. oratory tests and assays (including ani- [43 FR 45077, Sept. 29, 1978, as amended at 51 mal feeding studies where applicable) FR 24479, July 3, 1986; 68 FR 15364, Mar. 31, that the drug products meet all appli- 2003] cable standards of identity, strength, quality, and purity and (b) evidence Subpart K—Returned and from inspection of the premises that Salvaged Drug Products the drug products and their associated § 211.204 Returned drug products. packaging were not subjected to improper storage conditions as a result of Returned drug products shall be iden- the disaster or accident. Organoleptic tified as such and held. If the condi- examinations shall be acceptable only tions under which returned drug prod- as supplemental evidence that the drug ucts have been held, stored, or shipped products meet appropriate standards of before or during their return, or if the identity, strength, quality, and purity. condition of the drug product, its container, carton, or labeling, as a result Records including name, lot number, of storage or shipping, casts doubt on and disposition shall be maintained for the safety, identity, strength, quality drug products subject to this section. or purity of the drug product, the returned drug product shall be destroyed PART 212—CURRENT GOOD MAN- unless examination, testing, or other UFACTURING PRACTICE FOR investigations prove the drug product POSITRON EMISSION TOMOG- meets appropriate standards of safety, identity, strength, quality, or purity. A RAPHY DRUGS drug product may be reprocessed provided the subsequent drug product Subpart A—General Provisions meets appropriate standards, specifica- Sec. tions, and characteristics. Records of 212.1 What are the meanings of the tech- returned drug products shall be main- nical terms used in these regulations? tained and shall include the name and 212.2 What is current good manufacturing label potency of the drug product dos- practice for PET drugs? age form, lot number (or control num- 212.5 To what drugs do the regulations in ber or batch number), reason for the re- this part apply?

179

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00189 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 212.1 21 CFR Ch. I (4–1–19 Edition)

Subpart B—Personnel and Resources AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371, 374; Sec. 121, Pub. L. 105–115, 111 Stat. 2296. 212.10 What personnel and resources must I have? SOURCE: 74 FR 65431, Dec. 10, 2009, unless otherwise noted. Subpart C—Quality Assurance Subpart A—General Provisions 212.20 What activities must I perform to ensure drug quality? § 212.1 What are the meanings of the technical terms used in these regu- Subpart D—Facilities and Equipment lations? 212.30 What requirements must my facili- The following definitions apply to ties and equipment meet? words and phrases as they are used in this part. Other definitions of these Subpart E—Control of Components, words may apply when they are used in Containers, and Closures other parts of this chapter. 212.40 How must I control the components I Acceptance criteria means numerical use to produce PET drugs and the con- limits, ranges, or other criteria for tainers and closures I package them in? tests that are used for or in making a decision to accept or reject a unit, lot, Subpart F—Production and Process or batch of a PET drug product. Controls Act means the Federal Food, Drug, 212.50 What production and process controls and Cosmetic Act, as amended (21 must I have? U.S.C. 321 et seq.). Active pharmaceutical ingredient Subpart G—Laboratory Controls means a substance that is intended for 212.60 What requirements apply to the lab- incorporation into a finished PET drug oratories where I test components, in- product and is intended to furnish process materials, and finished PET drug pharmacological activity or other di- products? rect effect in the diagnosis or moni- 212.61 What must I do to ensure the sta- toring of a disease or a manifestation bility of my PET drug products through of a disease in humans, but does not in- expiry? clude intermediates used in the syn- Subpart H—Finished Drug Product Controls thesis of such substance. Batch means a specific quantity of and Acceptance Criteria PET drug intended to have uniform 212.70 What controls and acceptance cri- character and quality, within specified teria must I have for my finished PET limits, that is produced according to a drug products? single production order during the 212.71 What actions must I take if a batch same cycle of production. of PET drug product does not conform to Batch production and control record specifications? means a unique record that references Subpart I—Packaging and Labeling an accepted master production and control record and documents specific 212.80 What are the requirements associated details on production, labeling, and with labeling and packaging PET drug quality control for a single batch of a products? PET drug. Subpart J—Distribution Component means any ingredient intended for use in the production of a 212.90 What actions must I take to control PET drug, including any ingredients the distribution of PET drug products? that may not appear in the final PET drug product. Subpart K—Complaint Handling Conditional final release means a final 212.100 What do I do if I receive a complaint release made prior to completion of a about a PET drug product produced at required finished-product test because my facility? of a malfunction involving analytical equipment. Subpart L—Records Final release means the authoritative 212.110 How must I maintain records of my decision by a responsible person in a production of PET drugs? PET production facility to permit the

180

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00190 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 212.1

use of a batch of a PET drug in hu- not in association with one or more mans. other ingredients. Inactive ingredient means any in- PET drug production facility means a tended component of the PET drug facility that is engaged in the produc- other than the active pharmaceutical tion of a PET drug. ingredient. Production means the manufacturing, In-process material means any mate- compounding, processing, packaging, rial fabricated, compounded, blended, labeling, reprocessing, repacking, re- or derived by chemical reaction that is labeling, and testing of a PET drug. produced for, and is used in, the prepa- Quality assurance means a system for ration of a PET drug. ensuring the quality of active ingredi- Lot means a batch, or a specifically ents, PET drugs, intermediates, compo- identified portion of a batch, having nents that yield an active pharma- uniform character and quality within ceutical ingredient, analytical sup- specified limits. In the case of a PET plies, and other components, including drug produced by continuous process, a container-closure systems and in-proc- lot is a specifically identified amount ess materials, through procedures, produced in a unit of time or quantity tests, analytical methods, and accept- in a manner that ensures its having ance criteria. uniform character and quality within Receiving facility means any hospital, specified limits. institution, nuclear pharmacy, imaging Lot number, control number, or batch facility, or other entity or part of an number means any distinctive combina- entity that accepts a PET drug product tion of letters, numbers, or symbols that has been given final release, but from which the complete history of the does not include a common or contract production, processing, packing, hold- carrier that transports a PET drug ing, and distribution of a batch or lot product from a PET production facility of a PET drug can be determined. to a receiving facility. Master production and control record Specifications means the tests, analyt- means a compilation of instructions ical procedures, and appropriate ac- containing the procedures and speci- ceptance criteria to which a PET drug, fications for the production of a PET PET drug product, component, con- drug. tainer-closure system, in-process mate- Material release means the authori- rial, or other material used in PET tative decision by a responsible person drug production must conform to be in a PET production facility to permit considered acceptable for its intended the use of a component, container and use. Conformance to specifications closure, in-process material, packaging means that a PET drug, PET drug material, or labeling in the production product, component, container-closure of a PET drug. system, in-process material, or other PET means positron emission tomog- material used in PET drug production, raphy. when tested according to the described PET drug means a radioactive drug analytical procedures, meets the listed that exhibits spontaneous disintegra- acceptance criteria. tion of unstable nuclei by the emission Strength means the concentration of of positrons and is used for providing the active pharmaceutical ingredient dual photon positron emission tomo- (radioactivity amount per volume or graphic diagnostic images. The defini- weight at the time of calibration). tion includes any nonradioactive rea- Sub-batch means a quantity of PET gent, reagent kit, ingredient, nuclide drug having uniform character and generator, accelerator, target mate- quality, within specified limits, that is rial, electronic synthesizer, or other produced during one succession of mul- apparatus or computer program to be tiple irradiations, using a given syn- used in the preparation of a PET drug. thesis and/or purification operation. ‘‘PET drug’’ includes a ‘‘PET drug Verification means confirmation that product’’ as defined in this section. an established method, process, or sys- PET drug product means a finished tem meets predetermined acceptance dosage form of a PET drug, whether or criteria.

181

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00191 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 212.2 21 CFR Ch. I (4–1–19 Edition)

§ 212.2 What is current good manufac- brary, 10903 New Hampshire Ave., Sil- turing practice for PET drugs? ver Spring, MD, 20993–0002, 301–796–3504, Current good manufacturing practice or at the National Archives and for PET drugs is the minimum require- Records Administration (NARA). For ments for the methods to be used in, information on the availability of this and the facilities and controls used for, material at NARA, call 202–741–6030, or the production, quality assurance, go to http://www.archives.gov/ holding, or distribution of PET drugs federallregister/ intended for human use. Current good codeloflfederallregulations/ manufacturing practice is intended to ibrllocations.html. ensure that each PET drug meets the requirements of the act as to safety Subpart B—Personnel and and has the identity and strength, and Resources meets the quality and purity characteristics, that it is supposed to have. § 212.10 What personnel and resources must I have? § 212.5 To what drugs do the regula- You must have a sufficient number of tions in this part apply? personnel with the necessary edu- (a) Application solely to PET drugs. cation, background, training, and expe- The regulations in this part apply only rience to perform their assigned func- to the production, quality assurance, tions. You must have adequate re- holding, and distribution of PET drugs. sources, including facilities and equip- Any human drug that does not meet ment, to enable your personnel to per- the definition of a PET drug must be form their functions. manufactured in accordance with the current good manufacturing practice Subpart C—Quality Assurance requirements in parts 210 and 211 of this chapter. § 212.20 What activities must I perform (b) Investigational and research PET to ensure drug quality? drugs. For investigational PET drugs (a) Production operations. You must for human use produced under an in- oversee production operations to en- vestigational new drug application in sure that each PET drug meets the re- accordance with part 312 of this chap- quirements of the act as to safety and ter, and PET drugs produced with the has the identity and strength, and approval of a Radioactive Drug Re- meets the quality and purity charac- search Committee in accordance with teristics, that it is supposed to have. part 361 of this chapter, the require- (b) Materials. You must examine and ment under the act to follow current approve or reject components, con- good manufacturing practice is met by tainers, closures, in-process materials, complying with the regulations in this packaging materials, labeling, and fin- part or by producing PET drugs in ac- ished dosage forms to ensure compli- cordance with Chapter 823, ‘‘Radio- ance with procedures and specifica- pharmaceuticals for Positron Emission tions affecting the identity, strength, Tomography—Compounding,’’ May 1, quality, or purity of a PET drug. 2009, pp. 365–369, 32d ed. of the United (c) Specifications and processes. You States Pharmacopeia (USP) National must approve or reject, before imple- Formulary (NF) (USP 32/NF 27) (2009). mentation, any initial specifications, The Director of the Federal Register methods, processes, or procedures, and approves this incorporation by ref- any proposed changes to existing speci- erence in accordance with 5 U.S.C. fications, methods, processes, or proce- 552(a) and 1 CFR part 51. You may ob- dures, to ensure that they maintain tain a copy from the United States the identity, strength, quality, and pu- Pharmacopeial Convention, Inc., 12601 rity of a PET drug. You must dem- Twinbrook Pkwy., Rockville, MD 20852, onstrate that any change does not ad- Geeta M. Tirumalai, 301–816–8352, e- versely affect the identity, strength, mail: [email protected], Internet address: quality, or purity of any PET drug. http://www.usp.org/USPNF/notices. You (d) Production records. You must re- may inspect a copy at the Food and view production records to determine Drug Administration Biosciences Li- whether errors have occurred. If errors

182

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00192 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 212.40

have occurred, or a production batch or tion of components and drug product any component of the batch fails to containers and closures. The proce- meet any of its specifications, you dures must be adequate to ensure that must determine the need for an inves- the components, containers, and clo- tigation, conduct investigations when sures are suitable for their intended necessary, and take appropriate correc- use. tive actions. (b) Written specifications. You must (e) Quality assurance. You must es- establish appropriate written specifica- tablish and follow written quality as- tions for the identity, quality, and pu- surance procedures. rity of components and for the identity and quality of drug product containers Subpart D—Facilities and and closures. Equipment (c) Examination and testing. Upon receipt, each lot of components and con- § 212.30 What requirements must my tainers and closures must be uniquely facilities and equipment meet? identified and tested or examined to (a) Facilities. You must provide ade- determine whether the lot complies quate facilities to ensure the orderly with your specifications. You must not handling of materials and equipment, use in PET drug production any lot the prevention of mix-ups, and the pre- that does not meet its specifications, vention of contamination of equipment including any expiration date if appli- or product by substances, personnel, or cable, or that has not yet received its environmental conditions that could material release. Any incoming lot reasonably be expected to have an ad- must be appropriately designated as verse effect on product quality. quarantined, accepted, or rejected. You (b) Equipment procedures. You must must use a reliable supplier as a source implement procedures to ensure that of each lot of each component, con- all equipment that could reasonably be tainer, and closure. expected to adversely affect the iden- (1)(i) If you conduct finished-product tity, strength, quality, or purity of a testing of a PET drug product that in- PET drug, or give erroneous or invalid cludes testing to ensure that the cor- test results when improperly used or rect components have been used, you maintained, is clean, suitable for its in- must determine that each lot of incom- tended purposes, properly installed, ing components used in that PET drug maintained, and capable of repeatedly product complies with written speci- producing valid results. You must doc- fications by examining a certificate of ument your activities in accordance analysis provided by the supplier. You with these procedures. are not required to perform a specific (c) Equipment construction and mainte- identity test on any of those compo- nance. Equipment must be constructed nents. and maintained so that surfaces that (ii) If you do not conduct finished- contact components, in-process mate- product testing of a PET drug product rials, or PET drugs are not reactive, that ensures that the correct compo- additive, or absorptive so as to alter nents have been used, you must con- the quality of PET drugs. duct identity testing on each lot of a component that yields an active ingre- Subpart E—Control of Compo- dient and each lot of an inactive ingre- nents, Containers, and Clo- dient used in that PET drug product. sures This testing must be conducted using tests that are specific to each compo- § 212.40 How must I control the com- nent that yields an active ingredient ponents I use to produce PET drugs and each inactive ingredient. For any and the containers and closures I other component, such as a solvent or package them in? reagent, that is not the subject of fin- (a) Written procedures. You must es- ished-product testing, you must deter- tablish, maintain, and follow written mine that each lot complies with writ- procedures describing the receipt, ten specifications by examining a cer- login, identification, storage, handling, tificate of analysis provided by the sup- testing, and acceptance and/or rejec- plier; if you use such a component to

183

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00193 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 212.50 21 CFR Ch. I (4–1–19 Edition)

prepare an inactive ingredient on site, control records must include the fol- you must perform an identity test on lowing information: the components used to make the inac- (1) The name and strength of the PET tive ingredient before the components drug; are released for use. However, if you (2) If applicable, the name and radio- use as an inactive ingredient a product activity or other measurement of each that is approved under section 505 of active pharmaceutical ingredient and the act (21 U.S.C. 355) and is marketed each inactive ingredient per batch or as a finished drug product intended for per unit of radioactivity or other meas- intravenous administration, you need urement of the drug product, and a not perform a specific identity test on statement of the total radioactivity or that ingredient. other measurement of any dosage unit; (2) You must examine a representa- (3) A complete list of components tive sample of each lot of containers designated by names and codes suffi- and closures for conformity to its writ- ciently specific to indicate any special ten specifications. You must perform quality characteristic; at least a visual identification of each (4) Identification of all major pieces lot of containers and closures. of equipment used in production; (d) Handling and storage. You must (5) An accurate statement of the handle and store components, containers, and closures in a manner that weight or measurement of each compo- prevents contamination, mix-ups, and nent, using the same weight system deterioration and ensures that they are (metric, avoirdupois, or apothecary) for and remain suitable for their intended each component. Reasonable variations use. are permitted in the amount of compo- (e) Records. You must keep a record nent necessary if they are specified in for each shipment of each lot of compo- the master production and control nents, containers, and closures that records; you receive. The record must include (6) A statement of action limits on the identity and quantity of each ship- radiochemical yield, i.e., the minimum ment, the supplier’s name and lot num- percentage of yield beyond which in- ber, the date of receipt, the results of vestigation and corrective action are any testing performed, the disposition required; of rejected material, and the expiration (7) Complete production and control date (where applicable). instructions, sampling and testing procedures, specifications, special nota- Subpart F—Production and tions, and precautions to be followed; Process Controls and (8) A description of the PET drug § 212.50 What production and process product containers, closures, and pack- controls must I have? aging materials, including a specimen You must have adequate production or copy of each label and all other la- and process controls to ensure the con- beling. sistent production of a PET drug that (c) Batch production and control meets the applicable standards of iden- records. Each time a batch of a PET tity, strength, quality, and purity. drug is produced, a unique batch pro- (a) Written control procedures. You duction and control record must be cre- must have written production and ated. The batch production record process control procedures to ensure must include the following informa- and document that all key process pa- tion: rameters are controlled and that any (1) Name and strength of the PET deviations from the procedures are jus- drug; tified. (2) Identification number or other (b) Master production and control unique identifier of the specific batch records. You must have master produc- that was produced; tion and control records that document (3) The name and radioactivity or all steps in the PET drug production other measure of each active pharma- process. The master production and ceutical ingredient and each inactive

184

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00194 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 212.60

ingredient per batch or per unit of ra- Subpart G—Laboratory Controls dioactivity or other measurement of the drug product; § 212.60 What requirements apply to (4) Each major production step (ob- the laboratories where I test com- tained from the approved appropriate ponents, in-process materials, and master production and control record); finished PET drug products? (5) Weights (or other measure of (a) Testing procedures. Each labora- quantity) and identification codes of tory used to conduct testing of compo- components; nents, in-process materials, and fin- (6) Dates of production steps and ished PET drug products must have times of critical production steps; and follow written procedures for the (7) Identification of major pieces of conduct of each test and for the docu- equipment used in production of the mentation of the results. batch; (b) Specifications and standards. Each (8) Testing results; laboratory must have sampling and (9) Labeling; testing procedures designed to ensure (10) Initials or signatures of persons that components, in-process materials, performing or checking each signifi- and PET drug products conform to ap- cant step in the operation; and propriate standards, including estab- (11) Results of any investigations lished standards of identity, strength, conducted. quality, and purity. (d) Area and equipment checks. The (c) Analytical methods. Laboratory an- production area and all equipment in alytical methods must be suitable for the production area must be checked to their intended use and must be suffi- ensure cleanliness and suitability im- ciently sensitive, specific, accurate, mediately before use. A record of these and reproducible. checks must be kept. (d) Materials. The identity, purity, (e) In-process materials controls. Proc- and quality of reagents, solutions, and ess controls must include control of in- supplies used in testing procedures process materials to ensure that the must be adequately controlled. All so- materials are controlled until required lutions that you prepare must be prop- tests or other verification activities erly labeled to show their identity and have been completed or necessary ap- expiration date. provals are received and documented. (e) Equipment. All equipment used to (f) Process verification. (1) For a PET perform the testing must be suitable drug for which each entire batch under- for its intended purposes and capable of goes full finished-product testing to en- producing valid results. sure that the product meets all speci- (f) Equipment maintenance. Each lab- fications, process verification, as de- oratory must have and follow written scribed in paragraph (f)(2) of this sec- procedures to ensure that equipment is tion, is not required. routinely calibrated, inspected, (2) When the results of the produc- checked, and maintained, and that tion of an entire batch of a PET drug these activities are documented. are not fully verified through finished- (g) Test records. Each laboratory per- product testing or when only the ini- forming tests related to the production tial sub-batch in a series is tested, the of a PET drug must keep complete PET drug producer must demonstrate records of all tests performed to ensure that the process for producing the PET compliance with established specifica- drug is reproducible and is capable of tions and standards, including exami- producing a drug product that meets nations and assays, as follows: the predetermined acceptance criteria. (1) A suitable identification of the Process verification activities and re- sample received for testing. sults must be documented. Documenta- (2) A description of each method used tion must include the date and signa- in the testing of the sample, a record of ture of the individual(s) performing the all calculations performed in connec- verification, the monitoring and con- tion with each test, and a statement of trol methods and data, and the major the weight or measurement of the sam- equipment qualified. ple used for each test.

185

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00195 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 212.61 21 CFR Ch. I (4–1–19 Edition)

(3) A complete record of all data ob- (c) Conformance to specifications. Be- tained in the course of each test, in- fore final release, you must conduct an cluding the date and time the test was appropriate laboratory determination conducted, and all graphs, charts, and to ensure that each batch of a PET spectra from laboratory instrumenta- drug product conforms to specification, properly identified to show the tions, except for sterility. For a PET specific component, in-process mate- drug product produced in sub-batches, rial, or drug product for each lot test- before final release, you must conduct ed. an appropriate laboratory determina- (4) A statement of the results of tests tion to ensure that each sub-batch con- and how the results compare with es- forms to specifications, except for ste- tablished acceptance criteria. rility. (5) The initials or signature of the (d) Final release procedures. Except as person performing the test and the conditional final release is permitted date on which the test was performed. in accordance with paragraph (f) of this section, you must establish and follow § 212.61 What must I do to ensure the procedures to ensure that each batch of stability of my PET drug products a PET drug product is not given final through expiry? release until the following are done: (a) Stability testing program. You must (1) An appropriate laboratory deter- establish, follow, and maintain a writ- mination under paragraph (c) of this ten testing program to assess the sta- section is completed; bility characteristics of your PET drug (2) Associated laboratory data and products. The test methods must be re- documentation are reviewed and they liable, meaningful, and specific. The demonstrate that the PET drug prod- samples tested for stability must be uct meets specifications, except for representative of the lot or batch from sterility; and which they were obtained and must be (3) A designated qualified individual stored under suitable conditions. authorizes final release by dated signa- (b) Storage conditions and expiration ture. dates. The results of such stability test- (e) Sterility testing. Sterility testing ing must be documented and used in need not be completed before final re- determining appropriate storage condi- lease but must be started within 30 tions and expiration dates and times hours after completion of production. for each PET drug product you The 30-hour requirement may be ex- produce. ceeded due to a weekend or holiday. If the sample for sterility testing is held longer than 30 hours, you must dem- Subpart H—Finished Drug Product onstrate that the longer period does Controls and Acceptance not adversely affect the sample and the test results obtained will be equivalent § 212.70 What controls and acceptance to test results that would have been criteria must I have for my finished obtained if the test had been started PET drug products? within the 30-hour time period. Tested (a) Specifications. You must establish samples must be from individual specifications for each PET drug prod- batches and not pooled. If the product uct, including criteria for determining fails to meet a criterion for sterility, identity, strength, quality, purity, and, you must immediately notify all facili- if appropriate, sterility and pyrogens. ties that received the product of the (b) Test procedures. Before you imple- test results and provide any appro- ment a new test procedure in a speci- priate recommendations. The notifica- fication, you must establish and docu- tion must be documented. Upon comment the accuracy, sensitivity, speci- pletion of an investigation into the ficity, and reproducibility of the proce- failure to meet a criterion for sterility, dure. If you use an established you must notify all facilities that re- compendial test procedure in a speci- ceived the product of the findings from fication, you must first verify and doc- the investigation. ument that the test works under the (f) Conditional final release. (1) If you conditions of actual use. cannot complete one of the required

186

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00196 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 212.80

finished-product tests for a batch of a fications. You must have and follow PET drug product because of a mal- procedures to identify and segregate function involving analytical equip- the product to avoid mix-ups. You ment, you may approve the conditional must have and follow procedures to in- final release of the product if you meet vestigate the cause(s) of the noncon- the following conditions: forming product. The investigation (i) You have data documenting that must include, but is not limited to, ex- preceding consecutive batches, pro- amination of processes, operations, duced using the same methods used for records, complaints, and any other rel- the conditionally released batch, dem- evant sources of information con- onstrate that the conditionally re- cerning the nonconforming product. leased batch will likely meet the estab- (b) Investigation. You must document lished specifications; the investigation of a PET drug prod- (ii) You determine that all other acceptance criteria are met; uct that does not meet specifications, (iii) You retain a reserve sample of including the results of the investiga- the conditionally released batch of tion and what happened to the rejected drug product; PET drug product. (iv) You promptly correct the mal- (c) Correction of problems. You must function of analytical equipment, com- take action to correct any identified plete the omitted test using the reserve problems to prevent recurrence of a sample after the malfunction is cor- nonconforming product or other qual- rected, and document that reasonable ity problem. efforts have been made to prevent re- (d) Reprocessing. If appropriate, you currence of the malfunction; may reprocess a batch of a PET drug (v) If you obtain an out-of-specifica- product that does not conform to speci- tion result when testing the reserve fications. If material that does not sample, you immediately notify the re- meet acceptance criteria is reproc- ceiving facility; and essed, you must follow procedures stat- (vi) You document all actions regarded in the product’s approved applica- ing the conditional final release of the tion and the finished product must con- drug product, including the justifica- form to specifications, except for ste- tion for the release, all followup ac- rility, before final release. tions, results of completed testing, all notifications, and corrective actions to prevent recurrence of the malfunction Subpart I—Packaging and involving analytical equipment. Labeling (2) Even if the criteria in paragraph (f)(1) of this section are met, you may § 212.80 What are the requirements as- not approve the conditional final re- sociated with labeling and pack- lease of the product if the malfunction aging PET drug products? involving analytical equipment pre- (a) A PET drug product must be suit- vents the performance of a ably labeled and packaged to protect radiochemical identity/purity test or the product from alteration, contami- prevents the determination of the prod- nation, and damage during the estab- uct’s specific activity. lished conditions of shipping, distribu- (3) You may not release another tion, handling, and use. batch of the PET drug product until (b) Labels must be legible and applied you have corrected the problem con- so as to remain legible and affixed dur- cerning the malfunction of analytical ing the established conditions of proc- equipment and completed the omitted essing, storage, handling, distribution, finished-product test. and use. § 212.71 What actions must I take if a (c) All information stated on each batch of PET drug product does not label must also be contained in each conform to specifications? batch production record. (a) Rejection of nonconforming product. (d) Labeling and packaging oper- You must reject a batch of a PET drug ations must be controlled to prevent product that does not conform to speci- labeling and product mix-ups.

187

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00197 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 212.90 21 CFR Ch. I (4–1–19 Edition)

Subpart J—Distribution include the findings of any investigation and followup. § 212.90 What actions must I take to (d) Returned products. A PET drug control the distribution of PET product that is returned because of a drug products? complaint or for any other reason may (a) Written distribution procedures. You not be reprocessed and must be de- must establish, maintain, and follow stroyed in accordance with applicable written procedures for the control of Federal and State law. distribution of PET drug products shipped from the PET drug production Subpart L—Records facility to ensure that the method of shipping chosen will not adversely af- § 212.110 How must I maintain records fect the identity, purity, or quality of of my production of PET drugs? the PET drug product. (b) Distribution records. You must (a) Record availability. Records must maintain distribution records for each be maintained at the PET drug produc- PET drug product that include or refer tion facility or another location that is to the following: reasonably accessible to responsible of- (1) The name, address, and telephone ficials of the production facility and to number of the receiving facility that employees of FDA designated to per- received each batch of a PET drug form inspections. product; (b) Record quality. All records, includ- (2) The name and quantity of the ing those not stored at the inspected PET drug product shipped; establishment, must be legible, stored (3) The lot number, control number, to prevent deterioration or loss, and or batch number for the PET drug readily available for review and copy- product shipped; and ing by FDA employees. (4) The date and time you shipped the (c) Record retention period. You must PET drug product. maintain all records and documentation referenced in this part for a period Subpart K—Complaint Handling of at least 1 year from the date of final release, including conditional final re- § 212.100 What do I do if I receive a lease, of a PET drug product. complaint about a PET drug product produced at my facility? PART 216—HUMAN DRUG (a) Written complaint procedures. You COMPOUNDING must develop and follow written procedures for the receipt and handling of Subpart A—General Provisions [Reserved] all complaints concerning the quality or purity of, or possible adverse reac- Subpart B—Compounded Drug Products tions to, a PET drug product. (b) Complaint review. The procedures Sec. must include review by a designated 216.23 Bulk drug substances that can be person of any complaint involving the used to compound drug products in ac- possible failure of a PET drug product cordance with section 503A of the Federal to meet any of its specifications and an Food, Drug, and Cosmetic Act. investigation to determine the cause of 216.24 Drug products withdrawn or removed the failure. from the market for reasons of safety or effectiveness. (c) Complaint records. A written record of each complaint must be AUTHORITY: 21 U.S.C. 351, 352, 353a, 353b, maintained in a file designated for PET 355, and 371. drug product complaints. The record SOURCE: 64 FR 10944, Mar. 8, 1999, unless must include the name and strength of otherwise noted. the PET drug product, the batch number, the name of the complainant, the date the complaint was received, the Subpart A—General Provisions nature of the complaint, and the re- [Reserved] sponse to the complaint. It must also

188

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00198 Fmt 8010 Sfmt 8006 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 216.24

Subpart B—Compounded Drug tablish general recognition of the safe- Products ty or effectiveness of any such drug product. Any person who represents § 216.23 Bulk drug substances that can that a compounded drug made with a be used to compound drug products bulk drug substance that appears on in accordance with section 503A of this list is FDA approved, or otherwise the Federal Food, Drug, and Cos- endorsed by FDA generally or for a metic Act. particular indication, will cause the (a) The following bulk drug sub- drug to be misbranded under section stances can be used in compounding 502(a) and/or 502(bb) of the Federal under section 503A(b)(1)(A)(i)(III) of the Food, Drug, and Cosmetic Act. Federal Food, Drug, and Cosmetic Act. [84 FR 4710, Feb. 19, 2019] (1) Brilliant Blue G, also known as Coomassie Brilliant Blue G–250. § 216.24 Drug products withdrawn or (2) Cantharidin (for topical use only). removed from the market for rea- (3) Diphenylcyclopropenone (for top- sons of safety or effectiveness. ical use only). The following drug products were (4) N-acetyl-D-glucosamine (for top- withdrawn or removed from the mar- ical use only). ket because such drug products or com- (5) Squaric acid dibutyl ester (for ponents of such drug products have topical use only). been found to be unsafe or not effec- (6) Thymol iodide (for topical use tive. The following drug products may only). not be compounded under the exemp- (b) After balancing the criteria set tions provided by section 503A(a) or forth in paragraph (c) of this section, section 503B(a) of the Federal Food, FDA has determined that the following Drug, and Cosmetic Act: bulk drug substances will not be in- Adenosine phosphate: All drug products concluded on the list of substances that taining adenosine phosphate. can be used in compounding set forth Adrenal cortex: All drug products containing in paragraph (a) of this section: adrenal cortex. (1) Oxitriptan. Alatrofloxacin mesylate: All drug products (2) Piracetam. containing alatrofloxacin mesylate. (3) Silver Protein Mild. Aminopyrine: All drug products containing (4) Tranilast. aminopyrine. Astemizole: All drug products containing (c) FDA will use the following cri- astemizole. teria in evaluating substances consid- Azaribine: All drug products containing ered for inclusion on the list set forth azaribine. in paragraph (a) of this section: Benoxaprofen: All drug products containing (1) The physical and chemical charac- benoxaprofen. terization of the substance; Bithionol: All drug products containing (2) Any safety issues raised by the bithionol. Bromfenac sodium: All drug products con- use of the substance in compounded taining bromfenac sodium (except oph- drug products; thalmic solutions). (3) The available evidence of the ef- Bromocriptine mesylate: All drug products fectiveness or lack of effectiveness of a containing bromocriptine mesylate for pre- drug product compounded with the sub- vention of physiological lactation. stance, if any such evidence exists; and Butamben: All parenteral drug products con- (4) Historical use of the substance in taining butamben. Camphorated oil: All drug products con- compounded drug products, including taining camphorated oil. information about the medical condi- Carbetapentane citrate: All oral gel drug prod- tion(s) the substance has been used to ucts containing carbetapentane citrate. treat and any references in peer-re- Casein, iodinated: All drug products con- viewed medical literature. taining iodinated casein. (d) Based on evidence currently Cerivastatin sodium: All drug products con- available, there are inadequate data to taining cerivastatin sodium. Chloramphenicol: All oral drug products con- demonstrate the safety or efficacy of taining chloramphenicol. any drug product compounded using Chlorhexidine gluconate: All tinctures of any of the drug substances listed in chlorhexidine gluconate formulated for use paragraph (a) of this section, or to es- as a patient preoperative skin preparation.

189

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00199 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 216.24 21 CFR Ch. I (4–1–19 Edition)

Chlormadinone acetate: All drug products con- Nitrofurazone: All drug products containing taining chlormadinone acetate. nitrofurazone (except topical drug products Chloroform: All drug products containing formulated for dermatologic application). chloroform. Nomifensine maleate: All drug products con- Cisapride: All drug products containing taining nomifensine maleate. cisapride. Novobiocin sodium: All drug products con- Cobalt: All drug products containing cobalt taining novobiocin sodium. salts (except radioactive forms of cobalt Ondansetron hydrochloride: All intravenous and its salts and cobalamin and its deriva- drug products containing greater than a 16 tives). milligram single dose of ondansetron hy- Dexfenfluramine hydrochloride: All drug prod- drochloride. ucts containing dexfenfluramine hydro- Oxyphenisatin: All drug products containing chloride. oxyphenisatin. All drug products con- Diamthazole dihydrochloride: All drug prod- Oxyphenisatin acetate: ucts containing diamthazole taining oxyphenisatin acetate. Pemoline: All drug products containing dihydrochloride. pemoline. Dibromsalan: All drug products containing Pergolide mesylate: All drug products con- dibromsalan. taining pergolide mesylate. Diethylstilbestrol: All oral and parenteral drug Phenacetin: All drug products containing products containing 25 milligrams or more phenacetin. of diethylstilbestrol per unit dose. Phenformin hydrochloride: All drug products Dihydrostreptomycin sulfate: All drug products containing phenformin hydrochloride. containing dihydrostreptomycin sulfate. Phenylpropanolamine: All drug products con- Dipyrone: All drug products containing taining phenylpropanolamine. dipyrone. Pipamazine: All drug products containing Encainide hydrochloride: All drug products pipamazine. containing encainide hydrochloride. Polyethylene glycol 3350, sodium chloride, so- Esmolol hydrochloride: All parenteral dosage dium bicarbonate, potassium chloride, and form drug products containing esmolol hy- bisacodyl: All drug products containing pol- drochloride that supply 250 milligrams/mil- yethylene glycol 3350, sodium chloride, so- liliter of concentrated esmolol per 10-milli- dium bicarbonate, and potassium chloride liter ampule. for oral solution, and 10 milligrams or Etretinate: All drug products containing more of bisacodyl delayed-release tablets. etretinate. Potassium arsenite: All drug products con- Fenfluramine hydrochloride: All drug products taining potassium arsenite. containing fenfluramine hydrochloride. Potassium chloride: All solid oral dosage form Flosequinan: All drug products containing drug products containing potassium chlo- flosequinan. ride that supply 100 milligrams or more of Gatifloxacin: All drug products containing potassium per dosage unit (except for con- gatifloxacin (except ophthalmic solutions). trolled-release dosage forms and those Gelatin: All intravenous drug products con- products formulated for preparation of so- taining gelatin. lution prior to ingestion). Glycerol, iodinated: All drug products con- Povidone: All intravenous drug products containing iodinated glycerol. taining povidone. Gonadotropin, chorionic: All drug products Propoxyphene: All drug products containing containing chorionic gonadotropins of ani- propoxyphene. mal origin. Rapacuronium bromide: All drug products containing rapacuronium bromide. Grepafloxacin: All drug products containing Reserpine: All oral dosage form drug products grepafloxacin. containing more than 1 milligram of reser- Mepazine: All drug products containing pine. mepazine hydrochloride or mepazine ace- Rofecoxib: All drug products containing tate. rofecoxib. Metabromsalan: All drug products containing Sibutramine hydrochloride: All drug products metabromsalan. containing sibutramine hydrochloride. Methamphetamine hydrochloride: All paren- Sparteine sulfate: All drug products con- teral drug products containing meth- taining sparteine sulfate. amphetamine hydrochloride. Sulfadimethoxine: All drug products con- Methapyrilene: All drug products containing taining sulfadimethoxine. methapyrilene. Sulfathiazole: All drug products containing Methopholine: All drug products containing sulfathiazole (except for those formulated methopholine. for vaginal use). Methoxyflurane: All drug products containing Suprofen: All drug products containing methoxyflurane. suprofen (except ophthalmic solutions). Mibefradil dihydrochloride: All drug products Sweet spirits of nitre: All drug products con- containing mibefradil dihydrochloride. taining sweet spirits of nitre.

190

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00200 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 225.1

Tegaserod maleate: All drug products con- Subpart E—Records and Reports taining tegaserod maleate. Temafloxacin hydrochloride: All drug products 225.102 Master record file and production containing temafloxacin hydrochloride. records. Terfenadine: All drug products containing 225.110 Distribution records. terfenadine. 225.115 Complaint files. 3,3′,4′,5-tetrachlorosalicylanilide: All drug products containing 3,3′,4′,5-tetrachlorosalicyl- Subpart F—Facilities and Equipment anilide. 225.120 Buildings and grounds. Tetracycline: All liquid oral drug products 225.130 Equipment. formulated for pediatric use containing 225.135 Work and storage areas. tetracycline in a concentration greater than 25 milligrams/milliliter. Subpart G—Product Quality Assurance Ticrynafen: All drug products containing ticrynafen. 225.142 Components. Tribromsalan: All drug products containing 225.158 Laboratory assays. tribromsalan. 225.165 Equipment cleanout procedures. Trichloroethane: All aerosol drug products intended for inhalation containing trichloro- Subpart H—Labeling ethane. Troglitazone: All drug products containing 225.180 Labeling. troglitazone. Trovafloxacin mesylate: All drug products con- Subpart I—Records taining trovafloxacin mesylate. 225.202 Formula, production, and distribu- Urethane: All drug products containing ure- tion records. thane. Valdecoxib: All drug products containing AUTHORITY: 21 U.S.C. 351, 352, 360b, 371, 374. valdecoxib. SOURCE: 41 FR 52618, Nov. 30, 1976, unless Vinyl chloride: All aerosol drug products con- otherwise noted. taining vinyl chloride. Zirconium: All aerosol drug products containing zirconium. Subpart A—General Provisions Zomepirac sodium: All drug products containing zomepirac sodium. § 225.1 Current good manufacturing practice. [81 FR 69676, Oct. 7, 2016, as amended at 83 FR (a) Section 501(a)(2)(B) of the Federal 63573, Dec. 11, 2018] Food, Drug, and Cosmetic Act provides that a drug (including a drug contained PART 225—CURRENT GOOD MAN- in a medicated feed) shall be deemed to UFACTURING PRACTICE FOR be adulterated if the methods used in, MEDICATED FEEDS or the facilities or controls used for, its manufacture, processing, packing, or Subpart A—General Provisions holding do not conform to or are not operated or administered in conformity Sec. with current good manufacturing prac- 225.1 Current good manufacturing practice. 225.10 Personnel. tice to assure that such drug meets the requirement of the act as to safety and Subpart B—Construction and Maintenance has the identity and strength, and of Facilities and Equipment meets the quality and purity characteristics, which it purports or is rep- 225.20 Buildings. resented to possess. 225.30 Equipment. (b)(1) The provisions of this part set 225.35 Use of work areas, equipment, and forth the criteria for determining storage areas for other manufacturing whether the manufacture of a medi- and storage purpose. cated feed is in compliance with cur- Subpart C—Product Quality Control rent good manufacturing practice. These regulations shall apply to all 225.42 Components. types of facilities and equipment used 225.58 Laboratory controls. in the production of medicated feeds, 225.65 Equipment cleanout procedures. and they shall also govern those instances in which failure to adhere to Subpart D—Packaging and Labeling the regulations has caused nonmedi- 225.80 Labeling. cated feeds that are manufactured,

191

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00201 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 225.10 21 CFR Ch. I (4–1–19 Edition)

processed, packed, or held to be adul- Subpart B—Construction and terated. In such cases, the medicated Maintenance of Facilities and feed shall be deemed to be adulterated Equipment within the meaning of section 501(a)(2)(B) of the act, and the non- § 225.20 Buildings. medicated feed shall be deemed to be (a) The location, design, construc- adulterated within the meaning of section, and physical size of the buildings tion 402(a)(2)(C)(ii) of the act. and other production facilities are fac- (2) The regulations in §§ 225.10 tors important to the manufacture of through 225.115 apply to facilities man- medicated feed. The features of facili- ufacturing one or more medicated feeds ties necessary for the proper manufac- for which an approved medicated feed ture of medicated feed include provi- mill license is required. The regula- sion for ease of access to structures tions in §§ 225.120 through 225.202 apply and equipment in need of routine main- to facilities manufacturing solely tenance; ease of cleaning of equipment medicated feeds for which an approved and work areas; facilities to promote license is not required. personnel hygiene; structural condi- (c) In addition to the recordkeeping tions for control and prevention of requirements in this part, Type B and vermin and pest infestation; adequate Type C medicated feeds made from space for the orderly receipt and stor- Type A articles or Type B feeds under age of drugs and feed ingredients and approved NADAs or indexed listings the controlled flow of these materials and a medicated feed mill license are through the processing and manufacturing operations; and the equipment subject to the requirements of § 510.301 for the accurate packaging and deliv- of this chapter. ery of a medicated feed of specified la- [41 FR 52618, Nov. 30, 1976, as amended at 51 beling and composition. FR 7389, Mar. 3, 1986; 64 FR 63203, Nov. 19, (b) The construction and mainte- 1999; 72 FR 69120, Dec. 6, 2007; 79 FR 3739, Jan. nance of buildings in which medicated 23, 2014] feeds are manufactured, processed, packaged, labeled, or held shall con- § 225.10 Personnel. form to the following: (a) Qualified personnel and adequate (1) The building grounds shall be ade- personnel training and supervision are quately drained and routinely main- essential for the proper formulation, tained so that they are reasonably free manufacture, and control of medicated from litter, waste, refuse, uncut weeds feeds. Training and experience leads to or grass, standing water, and improp- proper use of equipment, maintenance erly stored equipment. of accurate records, and detection and (2) The building(s) shall be main- prevention of possible deviations from tained in a reasonably clean and or- current good manufacturing practices. derly manner. (3) The building(s) shall be of suitable (b)(1) All employees involved in the construction to minimize access by ro- manufacture of medicated feeds shall dents, birds, insects, and other pests. have an understanding of the manufac- (4) The buildings shall provide ade- turing or control operation(s) which quate space and lighting for the proper they perform, including the location performance of the following medi- and proper use of equipment. cated feed manufacturing operations: (2) The manufacturer shall provide an (i) The receipt, control, and storage on-going program of evaluation and su- of components. pervision of employees in the manufac- (ii) Component processing. ture of medicated feeds. (iii) Medicated feed manufacturing. [41 FR 52618, Nov. 30, 1976, as amended at 42 (iv) Packaging and labeling. FR 12426, Mar. 4, 1977] (v) Storage of containers, packaging materials, labeling and finished products. (vi) Routine maintenance of equipment.

192

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00202 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 225.42

§ 225.30 Equipment. proved drugs, indexed drugs, or ap- (a) Equipment which is designed to proved food additives intended for use perform its intended function and is in the manufacture of medicated feed. properly installed and used is essential [41 FR 52618, Nov. 30, 1976, as amended at 72 to the manufacture of medicated feeds. FR 69120, Dec. 6, 2007] Such equipment permits production of feeds of uniform quality, facilitates cleaning, and minimizes spillage of Subpart C—Product Quality drug components and finished product. Control (b)(1) All equipment shall possess the capability to produce a medicated feed § 225.42 Components. of intended potency, safety, and purity. (a) A medicated feed, in addition to (2) All equipment shall be maintained providing nutrients, is a vehicle for the in a reasonably clean and orderly man- administration of a drug, or drugs, to ner. animals. To ensure proper safety and (3) All equipment, including scales effectiveness, such medicated feeds and liquid metering devices, shall be of must contain the labeled amounts of suitable size, design, construction, pre- drugs. It is necessary that adequate cision, and accuracy for its intended procedures be established for the re- purpose. ceipt, storage, and inventory control (4) All scales and metering devices for all such drugs to aid in assuring shall be tested for accuracy upon in- their identity, strength, quality, and stallation and at least once a year thereafter, or more frequently as may purity when incorporated into prod- be necessary to insure their accuracy. ucts. (5) All equipment shall be so con- (b) The receipt, storage, and inven- structed and maintained as to prevent tory of drugs, including undiluted drug lubricants and coolants from becoming components, medicated premixes, and unsafe additives in feed components or semiprocessed (i.e., intermediate pre- medicated feed. mixes, inplant premixes and con- (6) All equipment shall be designed, centrates) intermediate mixes con- constructed, installed and maintained taining drugs, which are used in the so as to facilitate inspection and use of manufacture and processing of medi- cleanout procedure(s). cated feeds shall conform to the following: § 225.35 Use of work areas, equipment, (1) Incoming shipments of drugs shall and storage areas for other manufacturing and storage purpose. be visually examined for identity and damage. Drugs which have been sub- (a) Many manufacturers of medicated jected to conditions which may have feeds are also involved in the manufacture, storage, or handling of products adversely affected their identity, which are not intended for animal feed strength, quality, or purity shall not use, such as fertilizers, herbicides, in- be accepted for use. secticides, fungicides, rodenticides, and (2) Packaged drugs in the storage other pesticides. Manufacturing, stor- areas shall be stored in their original age, or handling of nonfeed and feed closed containers. products in the same facilities may (3) Bulk drugs shall be identified and cause adulteration of feed products stored in a manner such that their with toxic or otherwise unapproved identity, strength, quality, and purity feed additives. will be maintained. (b) Work areas and equipment used (4) Drugs in the mixing areas shall be for the manufacture or storage of medi- properly identified, stored, handled, cated feeds or components thereof shall and controlled to maintain their integ- not be used for, and shall be physically rity and identity. Sufficient space shall separated from, work areas and equip- be provided for the location of each ment used for the manufacture of fer- drug. tilizers, herbicides, insecticides, fungicides, rodenticides, and other pesticides unless such articles are ap-

193

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00203 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 225.58 21 CFR Ch. I (4–1–19 Edition)

(5) A receipt record shall be prepared cific lot number or feed manufacturer’s and maintained for each lot of drug re- shipment identification number. ceived. The receipt record shall accurately indicate the identity and quan- § 225.58 Laboratory controls. tity of the drug, the name of the sup- (a) The periodic assay of medicated plier, the supplier’s lot number or an feeds for drug components provides a identifying number assigned by the measure of performance of the manu- feed manufacturer upon receipt which facturing process in manufacturing a relates to the particular shipment, the uniform product of intended potency. date of receipt, the condition of the (b) The following assay requirements drug when received, and the return of shall apply to medicated feeds: any damaged drugs. (1) For feeds requiring a medicated (6) A daily inventory record for each drug used shall be maintained and shall feed mill license (Form FDA 3448) for list by manufacturer’s lot number or their manufacture and marketing, at the feed manufacturer’s shipment iden- least three representative samples of tification number at least the fol- medicated feed containing each drug or lowing information: drug combination used in the establish- (i) The quantity of drug on hand at ment shall be collected and assayed by the beginning and end of the work day approved official methods, at periodic (the beginning amount being the same intervals during the calendar year, un- as the previous day’s closing inventory less otherwise specified in this chapter. if this amount has been established to At least one of these assays shall be be correct); the quantity shall be deter- performed on the first batch using the mined by weighing, counting, or meas- drug. If a medicated feed contains a uring, as appropriate. combination of drugs, only one of the (ii) The amount of each drug used, drugs need be subject to analysis each sold, or otherwise disposed of. time, provided the one tested is dif- (iii) The batches or production runs ferent from the one(s) previously test- of medicated feed in which each drug ed. was used. (2) [Reserved] (iv) When the drug is used in the (c) The originals or copies of all re- preparation of a semiprocessed inter- sults of assays, including those from mediate mix intended for use in the State feed control officials and any manufacture of medicated feed, any ad- other governmental agency, shall be ditional information which may be re- maintained on the premises for a pe- quired for the purpose of paragraph riod of not less than 1 year after dis- (b)(7) of this section. tribution of the medicated feed. The re- (v) Action taken to reconcile any dis- sults of assays performed by State feed crepancies in the daily inventory control officials may be considered to- record. ward fulfillment of the periodic assay (7) Drug inventory shall be main- requirements of this section. tained of each lot or shipment of drug (d) Where the results of assays indi- by means of a daily comparison of the cate that the medicated feed is not in actual amount of drug used with the accord with label specifications or is theoretical drug usage in terms of the not within permissible assay limits as semiprocessed, intermediate and fin- specified in this chapter, investigation ished medicated feeds manufactured. and corrective action shall be imple- Any significant discrepancy shall be in- mented and an original or copy of the vestigated and corrective action taken. The medicated feed(s) remaining on the record of such action maintained on premises which are affected by this dis- the premises. crepancy shall be detained until the (e) Corrective action shall include discrepancy is reconciled. provisions for discontinuing distribu- (8) All records required by this section where the medicated feed fails to tion shall be maintained on the prem- meet the labeled drug potency. Dis- ises for at least one year after com- tribution of subsequent production of plete use of a drug component of a spe- the particular feed shall not begin

194

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00204 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 225.102

until it has been determined that prop- adhered to, will assure that the article er control procedures have been estab- is safe and effective for its intended lished. purposes. (b)(1) Labels and labeling, including [41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 55 FR 11577, Mar. 29, placards, shall be received, handled, 1990; 64 FR 63203, Nov. 19, 1999] and stored in a manner that prevents labeling mixups and assures that cor- § 225.65 Equipment cleanout proce- rect labeling is employed for the medi- dures. cated feed. (a) Adequate cleanout procedures for (2) Labels and labeling, including all equipment used in the manufacture placards, upon receipt from the printer and distribution of medicated feeds are shall be proofread against the Master essential to maintain proper drug po- Record File to verify their suitability tency and avoid unsafe contamination and accuracy. The proofread label shall of feeds with drugs. Such procedures be dated, initialed by a responsible in- may consist of cleaning by physical dividual, and kept for 1 year after all means, e.g., vacuuming, sweeping, the labels from that batch have been washing, etc. Alternatively, flushing or used. sequencing or other equally effective (3) In those instances where medi- techniques may be used whereby the cated feeds are distributed in bulk, equipment is cleaned either through complete labeling shall accompany the use of a feed containing the same shipment and be supplied to the con- drug(s) or through use of drug free signee at the time of delivery. Such la- feedstuffs. beling may consist of a placard or (b) All equipment, including that other labels attached to the invoice or used for storage, processing, mixing, delivery ticket, or manufacturer’s in- conveying, and distribution that comes voice that identifies the medicated feed in contact with the active drug compo- and includes adequate information for nent, feeds in process, or finished medi- the safe and effective use of the medicated feed shall be subject to all rea- cated feed. sonable and effective procedures to pre- (4) Label stock shall be reviewed pe- vent unsafe contamination of manufac- riodically and discontinued labels shall tured feed. The steps used to prevent be discarded. unsafe contamination of feeds shall include one or more of the following, or Subpart E—Records and Reports other equally effective procedures: (1) Such procedures shall, where ap- § 225.102 Master record file and pro- propriate, consist of physical means duction records. (vacuuming, sweeping, or washing), (a) The Master Record File provides flushing, and/or sequential production the complete procedure for manufac- of feeds. turing a specific product, setting forth (2) If flushing is utilized, the flush the formulation, theoretical yield, material shall be properly identified, manufacturing procedures, assay re- stored, and used in a manner to pre- quirements, and labeling of batches or vent unsafe contamination of other production runs. The production feeds. record(s) includes the complete history (3) If sequential production of medi- of a batch or production run. This cated feeds is utilized, it shall be on a record includes the amounts of drugs predetermined basis designed to pre- used, the amount of medicated feed vent unsafe contamination of feeds manufactured, and provides a check for with residual drugs. the daily inventory record of drug components. Subpart D—Packaging and (b) The Master Record File and pro- Labeling duction records shall comply with the following provisions: § 225.80 Labeling. (1) A Master Record File shall be pre- (a) Appropriate labeling identifies pared, checked, dated, and signed or the medicated feed, and provides the initialed by a qualified person and user with directions for use which, if shall be retained for not less than 1

195

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00205 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 225.110 21 CFR Ch. I (4–1–19 Edition)

year after production of the last batch records or of copies of the customer’s or production run of medicated feed to purchase orders and the manufactur- which it pertains. The Master Record er’s invoices bearing the information File or card shall include at least the required by this section. When a cus- following: tom order is received by telephone, the (i) The name of the medicated feed. manufacturer shall prepare the re- (ii) The name and weight percentage quired production records. or measure of each drug or drug com- (4) Batch production records shall be bination and each nondrug ingredient checked by a responsible individual at to be used in manufacturing a stated the end of the working day in which weight of the medicated feed. the product was manufactured to de- (iii) A copy or description of the label termine whether all required produc- or labeling that will accompany the tion steps have been performed. If sig- medicated feed. nificant discrepancies are noted, an in- (iv) Manufacturing instructions or vestigation shall be instituted imme- reference thereto that have been deter- diately, and the production record mined to yield a properly mixed medi- shall describe the corrective action cated feed of the specified formula for taken. each medicated feed produced on a (5) Each batch or production run of batch or continuous operation basis, medicated feed shall be identified with including mixing steps, mixing times its own individual batch or production and, in the case of medicated feeds pro- run number, code, date, or other suit- duced by continuous production run, able identification applied to the label, any additional manufacturing direc- package, invoice or shipping document. tions including, when indicated, the This identification shall permit the settings of equipment. tracing of the complete and accurate (v) Appropriate control directions or manufacturing history of the product reference thereto, including the man- by the manufacturer. ner and frequency of collecting the required number of samples for specified § 225.110 Distribution records. laboratory assay. (a) Distribution records permit the (2) The original production record or manufacturer to relate complaints to copy thereof shall be prepared by quali- specific batches and/or production runs fied personnel for each batch or run of of medicated feed. This information medicated feed produced and shall be may be helpful in instituting a recall. retained on the premises for not less (b) Distribution records for each ship- than 1 year. The production record ment of a medicated feed shall comply shall include at least the following: with the following provisions: (i) Product identification, date of (1) Each distribution record shall in- production, and a written endorsement clude the date of shipment, the name in the form of a signature or initials by and address of purchaser, the quantity a responsible individual. shipped, and the name of the medicated (ii) The quantity and name of drug feed. A lot or control number, or date components used. of manufacture or other suitable iden- (iii) The theoretical quantity of tification shall appear on the distribu- medicated feed to be produced. tion record or the label issued with (iv) The actual quantity of medicated each shipment. feed produced. In those instances where (2) The originals or copies of the dis- the finished feed is stored in bulk and tribution records shall be retained on actual yield cannot be accurately de- the premises for not less than one year termined, the firm shall estimate the after the date of shipment of the medi- quantity produced and provide the cated feed. basis for such estimate in the Master Record File. § 225.115 Complaint files. (3) In the case of a custom formula (a) Complaints and reports of experi- feed made to the specifications of a ences of product defects relative to the customer, the Master Record File and drug’s efficacy or safety may provide production records required by this an indicator as to whether or not medi- section shall consist either of such cated feeds have been manufactured in

196

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00206 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 225.142

conformity with current good manufac- § 225.130 Equipment. turing practices. These complaints and Equipment shall be capable of pro- experiences may reveal the existence of ducing a medicated feed of intended po- manufacturing problems not otherwise tency and purity, and shall be main- detected through the normal quality tained in a reasonably clean and or- control procedures. Timely and appro- derly manner. Scales and liquid meter- priate follow-up action can serve to ing devices shall be accurate and of correct a problem and minimize future problems. suitable size, design, construction, precision, and accuracy for their intended (b) The medicated feed manufacturer purposes. All equipment shall be de- shall maintain on the premises a file signed, constructed, installed, and which contains the following informa- maintained so as to facilitate inspection: tion and use of cleanout procedure(s). (1) The original or copy of a record of each oral and written complaint re- § 225.135 Work and storage areas. ceived relating to the safety and effectiveness of the product produced. The Work areas and equipment used for record shall include the date of the the production or storage of medicated complaint, the complainant’s name and feeds or components thereof shall not address, name and lot or control num- be used for, and shall be physically sep- ber or date of manufacture of the medi- arated from, work areas and equipment cated feed involved, and the specific de- used for the manufacture and storage tails of the complaint. This record of fertilizers, herbicides, insecticides, shall also include all correspondence fungicides, rodenticides, and other pes- from the complainant and/or memo- ticides unless such articles are ap- randa of conversations with the com- proved or index listed for use in the plainant, and a description of all inves- manufacture of animal feed. tigations made by the manufacturer [72 FR 69120, Dec. 6, 2007] and of the method of disposition of the complaint. (2) For medicated feeds whose manu- Subpart G—Product Quality facture require a medicated feed mill Assurance license (Form FDA 3448), records and reports of clinical and other experience SOURCE: 51 FR 7390, Mar. 3, 1986, unless oth- with the drug shall be maintained and erwise noted. reported, under § 510.301 of this chapter. § 225.142 Components. [41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 57 FR 6475, Feb. 25, 1992; Adequate procedures shall be estab- 64 FR 63203, Nov. 19, 1999] lished and maintained for the identification, storage, and inventory control Subpart F—Facilities and (receipt and use) of all Type A medicated articles and Type B medicated Equipment feeds intended for use in the manufacture of medicated feeds to aid in assur- SOURCE: 51 FR 7390, Mar. 3, 1986, unless oth- ing the identity, strength, quality, and erwise noted. purity of these drug sources. Packaged Type A medicated articles and Type B § 225.120 Buildings and grounds. medicated feeds shall be stored in des- Buildings used for production of ignated areas in their original closed medicated feed shall provide adequate containers. Bulk Type A medicated ar- space for equipment, processing, and ticles and bulk Type B medicated feeds orderly receipt and storage of medi- shall be identified and stored in a man- cated feed. Areas shall include access ner such that their identity, strength, for routine maintenance and cleaning quality, and purity will be maintained. of equipment. Buildings and grounds All Type A medicated articles and shall be constructed and maintained in Type B medicated feeds shall be used in a manner to minimize vermin and pest accordance with their labeled mixing infestation. directions.

197

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00207 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 225.158 21 CFR Ch. I (4–1–19 Edition)

§ 225.158 Laboratory assays. PART 226—CURRENT GOOD MAN- Where the results of laboratory as- UFACTURING PRACTICE FOR says of drug components, including as- TYPE A MEDICATED ARTICLES says by State feed control officials, indicate that the medicated feed is not in Subpart A—General Provisions accord with the permissible limits Sec. specified in this chapter, investigation 226.1 Current good manufacturing practice. and corrective action shall be imple- 226.10 Personnel. mented immediately by the firm and such records shall be maintained on Subpart B—Construction and Maintenance the premises for a period of 1 year. of Facilities and Equipment 226.20 Buildings. § 225.165 Equipment cleanout proce- 226.30 Equipment. dures. Adequate procedures shall be estab- Subpart C—Product Quality Control lished and used for all equipment used 226.40 Production and control procedures. in the production and distribution of 226.42 Components. medicated feeds to avoid unsafe con- 226.58 Laboratory controls. tamination of medicated and nonmedi- cated feeds. Subpart D—Packaging and Labeling 226.80 Packaging and labeling. Subpart H—Labeling Subpart E—Records and Reports § 225.180 Labeling. 226.102 Master-formula and batch-produc- Labels shall be received, handled, and tion records. stored in a manner that prevents label 226.110 Distribution records. mixups and assures that the correct la- 226.115 Complaint files.

bels are used for the medicated feed. AUTHORITY: 21 U.S.C. 351, 352, 360b, 371, 374. All deliveries of medicated feeds, whether bagged or in bulk, shall be SOURCE: 40 FR 14031, Mar. 27, 1975, unless otherwise noted. adequately labeled to assure that the feed can be properly used. Subpart A—General Provisions [51 FR 7390, Mar. 3, 1986] § 226.1 Current good manufacturing Subpart I—Records practice. (a) The criteria in §§ 226.10 through § 225.202 Formula, production, and 226.115, inclusive, shall apply in deter- distribution records. mining whether the methods used in, Records shall be maintained identi- or the facilities and controls used for fying the formulation, date of mixing, the manufacture, processing, packing, and if not for own use, date of ship- or holding of a Type A medicated article(s) conform to or are operated or ad- ment. The records shall be adequate to ministered in conformity with current facilitate the recall of specific batches good manufacturing practice to assure of medicated feed that have been dis- that a Type A medicated article(s) tributed. Such records shall be retained meets the requirements of the act as to on the premises for 1 year following the safety, and has the identity and date of last distribution. strength, and meets the quality and (Approved by the Office of Management and purity characteristics which it pur- Budget under control number 0910–0152) ports or is represented to possess, as required by section 501(a)(2)(B) of the [51 FR 7390, Mar. 3, 1986] act. The regulations in this part 226 permit the use of precision, automatic, mechanical, or electronic equipment in the production of a Type A medicated article(s) when adequate inspection

198

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00208 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 226.30

and checking procedures or other qual- (4) Storage of containers, packaging ity control procedures are used to as- materials, labeling, and finished prod- sure proper performance. ucts. (b) In addition to maintaining (5) Control laboratory operations. records and reports required in this (b) Provide adequate lighting and part, Type A medicated articles requir- ventilation, and when necessary for the ing approved NADAs are subject to the intended production or control pur- requirements of § 514.80 of this chapter. poses, adequate screening, dust and Similarly, Type A medicated articles temperature controls, to avoid con- listed in the index are subject to the tamination of Type A medicated arti- requirements of § 516.165 of this chap- cle(s), and to avoid other conditions ter. unfavorable to the safety, identity, strength, quality, and purity of the raw [40 FR 14031, Mar. 27, 1975, as amended at 68 materials and Type A medicated arti- FR 15364, Mar. 31, 2003; 72 FR 69120, Dec. 6, cle(s) before, during, and after produc- 2007] tion. § 226.10 Personnel. (c) Provide for adequate washing, cleaning, toilet, and locker facilities. The key personnel and any consultants involved in the manufacture and Work areas and equipment used for the control of the Type A medicated arti- production of Type A medicated article(s) shall have a background of ap- cle(s) or for the storage of the compo- propriate education or appropriate ex- nents of Type A medicated article(s) perience or combination thereof for as- shall not be used for the production, suming responsibility to assure that mixing or storage of finished or unfin- the Type A medicated article(s) has the ished insecticides, fungicides, proper labeling and the safety, iden- rodenticides, or other pesticides or tity, strength, quality, and purity that their components unless such mate- it purports to possess. rials are recognized as approved drugs intended for use in animal feeds.

Subpart B—Construction and § 226.30 Equipment. Maintenance of Facilities and Equipment used for the manufacture, Equipment processing, packaging, bulk shipment, labeling, holding, or control of Type A § 226.20 Buildings. medicated article(s) or their compo- Buildings in which Type A medicated nents shall be maintained in a clean article(s) are manufactured, processed, and orderly manner and shall be of packaged, labeled, or held shall be suitable design, size, construction, and maintained in a clear and orderly man- location to facilitate maintenance and ner and shall be of suitable size, con- operation for its intended purpose. The struction and location in relation to equipment shall: surroundings to facilitate maintenance (a) Be so constructed that any sur- and operation for their intended pur- faces that come into contact with Type pose. The building shall: A medicated article(s) are suitable, in (a) Provide adequate space for the or- that they are not reactive, additive, or derly placement of equipment and ma- absorptive to an extent that signifi- terials used in any of the following op- cantly affects the identity, strength, erations for which they are employed quality, or purity of the Type A medi- to minimize risk of mixups between cated article(s) or its components. different Type A medicated article(s), (b) Be so constructed that any sub- their components, packaging, or label- stance required for the operation of the ing: equipment, such as lubricants, cool- (1) The receipt, sampling, control, ants, etc., may be employed without and storage of components. hazard of becoming an unsafe additive (2) Manufacturing and processing op- to the Type A medicated article(s). erations performed on the Type A (c) Be constructed to facilitate ad- medicated article(s). justment, cleaning, and maintenance, (3) Packaging and labeling oper- and to assure uniformity of production ations. and reliability of control procedures

199

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00209 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 226.40 21 CFR Ch. I (4–1–19 Edition)

and to assure the exclusion from Type any significant discrepancies, key per- A medicated article(s) of contamina- sonnel shall prevent distribution of the tion, including cross-contamination batch in question and other associated from manufacturing operations. batches of Type A medicated article(s) (d) Be suitably grounded electrically that may have been involved in a to prevent lack of uniform mixing due mixup with it. to electrically charged particles. (e) Adequate procedures for cleaning (e) Be of suitable size and accuracy of those parts of storage, mixing con- for use in any intended measuring, veying and other equipment coming in mixing, or weighing operations. contact with the drug component of the Type A medicated article(s) shall Subpart C—Product Quality be used to avoid contamination of Type Control A medicated article(s). § 226.40 Production and control proce- (f) If there is sequential production of dures. batches of a Type A medicated article(s) containing the same drug compo- Production and control procedures nent (or components) at the same or shall include all reasonable precautions, including the following, to lower levels, there shall be sufficient assure that the Type A medicated arti- safeguards to avoid any buildup above cle(s) produced have the identity, the specified levels of the drug compo- strength, quality, and purity they pur- nents in any of the batches of the Type port to possess: A medicated article(s). (a) Each critical step in the process, (g) Production and control proce- such as the selection, weighing, and dures shall include provision for dis- measuring of components; the addition continuing distribution of any Type A of drug components during the process; medicated article(s) found by the assay weighing and measuring during various procedures, or other controls per- stages of the processing; and the deter- formed to fail to conform to appro- mination of the finished yield, shall be priate specifications. Distribution of performed by one or more competent, subsequent production of such Type A responsible individuals. If such steps in medicated article(s) shall not begin the processing are controlled by preci- until it has been determined that prop- sion, automatic, mechanical, or elec- er control procedures have been estab- tronic equipment, their proper per- lished. formance shall be adequately checked by one or more competent, responsible § 226.42 Components. individuals. (a) Drug components, including undi- (b) All containers to be used for undiluted drugs and any intermediate luted drugs, drug components, inter- mixes containing drugs used in the mediate mixtures thereof, and Type A manufacture and processing of Type A medicated article(s) shall be received, medicated article(s), shall be received, adequately identified, and properly stored and handled in a manner ade- examined or tested, stored, handled, quate to avoid mixups and contamina- and otherwise controlled in a manner tion. to maintain the integrity and identi- (c) Equipment, including dust-con- fication of such articles. Appropriate trol and other equipment, such as that receipt and inventory records shall be used for holding and returning recov- maintained for 2 years, and such ered or flush-out materials back into records shall show the origin of any production, shall be maintained and drug components, the manufacturer’s operated in a manner to avoid contami- control number (if any), the dates and nation of the Type A medicated arti- batches in which they were used, and cle(s) and to insure the integrity of the the results of any testing of them. finished product. (b) Nondrug components shall be (d) Competent and responsible per- stored and otherwise handled in a man- sonnel shall check actual against theo- ner to avoid contamination, including retical yield of a batch of Type A medi- cross-contamination from manufac- cated article(s), and, in the event of turing operations.

200

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00210 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 226.80

§ 226.58 Laboratory controls. standards of identity, strength, quality, and purity at the time of use. Laboratory controls shall include the (e) Adequate provision to check the establishment of adequate specifica- reliability, accuracy, and precision of tions and test procedures to assure any laboratory test procedure used. that the drug components and the Type The official methods in ‘‘Methods of A medicated article(s) conform to ap- Analysis of the Association of Official propriate standards of identity, Analytical Chemists,’’ 1 methods de- strength, quality, and purity. Labora- scribed in an official compendium, and tory controls shall include: any method submitted as a part of a (a) The establishment of master food additive petition or new-drug ap- records containing appropriate speci- plication that has been accepted by the fications and a description of the test Food and Drug Administration shall be procedures used to check them for each regarded as meeting this provision. kind of drug component used in the (f) Provisions for the maintenance of manufacture of Type A medicated arti- the results of any assays, including cle(s). This may consist of the manu- dates and endorsement of analysts. facturer’s or supplier’s statement of Such records shall be retained in the specifications and methods of analyses. possession of the manufacturer and (b) The establishment of specifica- shall be maintained for a period of at tions for Type A medicated article(s) least 2 years after distribution by the and a description of necessary labora- manufacturer of the Type A medicated tory test procedures to check such article(s) has been completed. specifications. (c) Assays which shall be made of [40 FR 14031, Mar. 27, 1975, as amended at 55 representative samples of finished FR 11577, Mar. 29, 1990; 55 FR 23703, June 12, Type A medicated article(s) in accord- 1990; 70 FR 40880, July 15, 2005; 70 FR 67651, Nov. 8, 2005] ance with the following schedule: (1) Each batch of a Type A medicated article(s) manufactured from an undi- Subpart D—Packaging and luted drug shall be assayed for its drug Labeling component(s). § 226.80 Packaging and labeling. (2) In the case of Type A medicated article(s) which are manufactured by (a) Packaging and labeling oper- dilution of Type A medicated article(s) ations shall be adequately controlled: assayed in accordance with paragraph (1) To assure that only those Type A (c)(1) of this section, each batch shall medicated article(s) that have met the be assayed for its drug component(s) specifications established in the mas- with the first five consecutive batches ter-formula records shall be distrib- assaying within the limitations, fol- uted. lowed thereafter by assay of represent- (2) To prevent mixups during the ative samples of not less than 5 percent packaging and labeling operations. of all batches produced. When any (3) To assure that correct labeling is batch does not assay within limita- employed for each Type A medicated tions, each batch should again be as- article(s). sayed until five consecutive batches (4) To identify Type A medicated ar- are within limitations. ticle(s) with lot or control numbers (d) A determination establishing that that permit determination of the his- the drug components remain uniformly tory of the manufacture and control of dispersed and stable in the Type A the batch of Type A medicated arti- medicated article(s) under ordinary cle(s). conditions of shipment, storage, and (b) Packaging and labeling oper- use. This may consist of a determina- ations shall provide: tion on a Type A medicated article(s) (1) For storage of labeling in a man- of substantially the same formula and ner to avoid mixups. characteristics. Suitable expiration dates shall appear on the labels of the 1 Copies may be obtained from: AOAC Type A medicated article(s) to assure INTERNATIONAL, 481 North Frederick Ave., that the articles meet the appropriate suite 500, Gaithersburg, MD 20877.

201

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00211 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 226.102 21 CFR Ch. I (4–1–19 Edition)

(2) For careful checking of labeling directions including, when indicated, for identity and conformity to the la- the settings of equipment that have beling specified in the batch-produc- been determined to yield an adequately tion records. mixed Type A medicated article(s) of (3) For adequate control of the quan- the specified formula. tities of labeling issued for use with (5) Control instructions, procedures, the Type A medicated article(s). specifications, special notations, and (c) Type A medicated article(s) shall precautions to be followed. be distributed in suitable containers to (b) A separate batch-production and insure the safety, identity, strength, control record shall be prepared for and quality of the finished product. each batch or run of Type A medicated article(s) produced and shall be re- Subpart E—Records and Reports tained for at least 2 years after distribution by the manufacturer has been § 226.102 Master-formula and batch- completed. The batch-production and production records. control record shall include: (a) For each Type A medicated arti- (1) Product identification, date of cle(s) master-formula records shall be production, and endorsement by a com- prepared, endorsed, and dated by a petent and responsible individual. competent and responsible individual (2) Records of each step in the manu- and shall be independently checked, facturing, packaging, labeling, and reconciled, endorsed, and dated by a controlling of the batch, including second competent and responsible indi- dates, specific identification of drug vidual. The record shall include: components used, weights or measures (1) The name of the Type A medi- of all components, laboratory-control cated article(s) and a specimen copy of results, mixing times, and the endorse- its label. ments of the individual actively per- (2) The weight or measure of each in- forming or the individual actively su- gredient, adequately identified, to be pervising or checking each step in the used in manufacturing a stated weight operation. of the Type A medicated article(s). (3) A batch number that permits de- (3) A complete formula for each termination of all laboratory-control batch size, or of appropriate size in the procedures and results on the batch case of continuous systems to be pro- and all lot or control numbers appear- duced from the master-formula record, ing on the labels of the Type A medi- including a complete list of ingredients cated article(s). designated by names or codes sufficiently specific to indicate any special § 226.110 Distribution records. quality characteristics; an accurate Complete records shall be maintained statement of the weight or measure of for each shipment of Type A medicated each ingredient, except that reasonable article(s) in a manner that will facili- variations may be permitted in the tate the recall, diversion, or destruc- amount of ingredients necessary in the tion of the Type A medicated article(s), preparation of the Type A medicated if necessary. Such records shall be re- article(s), provided that the variations tained for at least 2 years after the are stated in the master formula; an date of the shipment by the manufac- appropriate statement concerning any turer and shall include the name and calculated excess of an ingredient; and address of the consignee, the date and a statement of the theoretical yield. quantity shipped, and the manufac- (4) Manufacturing instructions for turing dates, control numbers, or each type of Type A medicated arti- marks identifying the Type A medi- cle(s) produced on a batch or contin- cated article(s) shipped. uous operation basis, including mixing steps and mixing times that have been § 226.115 Complaint files. determined to yield an adequately Records shall be maintained for a pe- mixed Type A medicated article(s); and riod of 2 years of all written or verbal in the case of Type A medicated arti- complaints concerning the safety or ef- cle(s) produced by continuous produc- ficacy of each Type A medicated arti- tion run, any additional manufacturing cle(s). Complaints shall be evaluated

202

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00212 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 250.12

by competent and responsible per- containing thyroid or thyrogenic sub- sonnel and, where indicated, appro- stances in combination with central priate action shall be taken. The nervous system stimulants, with or record shall indicate the evaluation without one or more additional drug and the action. substances such as barbiturates or laxatives, are being marketed for or as ad- PART 250—SPECIAL REQUIREMENTS juncts to the treatment, control, or FOR SPECIFIC HUMAN DRUGS management of obesity in humans. The Commissioner of Food and Drugs finds Subpart A—Drugs Regarded as that the administration of such com- Misbranded binations for said purposes is without medical rationale except possibly in Sec. those relatively uncommon instances 250.11 Thyroid-containing drug preparations where the condition is directly related intended for treatment of obesity in hu- to hypothyroidism and there exists a mans. 250.12 Stramonium preparations labeled concurrent need for appetite control with directions for use in self-medication (in such instances the safety and effec- regarded as misbranded. tiveness of such combinations are not generally recognized). In particular, Subpart B—New Drug or Prescription Status the Commissioner of Food and Drugs of Specific Drugs finds that neither the consensus of informed medical opinion nor clinical ex- 250.100 Amyl nitrite inhalant as a prescription drug for human use. perience justifies any representation 250.101 Amphetamine and methamphet- that such combinations are safe and ef- amine inhalers regarded as prescription fective in connection with the treat- drugs. ment, control, or management of obe- 250.102 Drug preparations intended for sity in patients having normal thyroid human use containing certain ‘‘coronary function. vasodilators’’. (b) Combinations of thyroid or other 250.103–250.104 [Reserved] 250.105 Gelsemium-containing preparations thyrogenic drugs with central nervous regarded as prescription drugs. system stimulants with or without 250.106–250.107 [Reserved] other drug substances when offered for 250.108 Potassium permanganate prepara- or as adjuncts to the treatment, con- tions as prescription drugs. trol, or management of obesity not related to hypothyroidism are regarded Subpart C—Requirements for Drugs and as misbranded. Such combinations Foods when offered for obesity in humans di- 250.201 Preparations for the treatment of rectly attributable to established pernicious anemia. hypothyroidism are regarded as new drugs within the meaning of section Subpart D—Requirements for Drugs and 201(p) of the Federal Food, Drug, and Cosmetics Cosmetic Act. 250.250 Hexachlorophene, as a component of drug and cosmetic products. § 250.12 Stramonium preparations labeled with directions for use in self- AUTHORITY: 21 U.S.C. 321, 336, 342, 352, 353, medication regarded as mis- 355, 361(a), 362(a) and (c), 371, 375(b). branded. SOURCE: 40 FR 14033, Mar. 27, 1975, unless (a) Stramonium products for inhala- otherwise noted. tion have been offered for use in the therapy of the acute attacks of bron- Subpart A—Drugs Regarded as chial asthma for many years although Misbranded their reliability and effectiveness are questionable. Recently, a significantly § 250.11 Thyroid-containing drug prep- increased number of reports have come arations intended for treatment of to the attention of the Food and Drug obesity in humans. Administration showing that such (a) Investigation by the Food and products have been subject to abuse Drug Administration has revealed that and misuse on a fairly large scale, a large number of drug preparations mostly by young people, through oral

203

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00213 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 250.100 21 CFR Ch. I (4–1–19 Edition)

ingestion for the purpose of producing Food and Drugs received reports of the hallucinations. Reports of such use abuse of this drug by those who do not have been received from physicians and require it for medical purposes. Addi- police and other law enforcement au- tionally, comment included a great thorities. Reports have also appeared deal of concern expressed by individual in the public press and in medical jour- physicians, medical associations, phar- nals. maceutical associations, manufactur- (b) Labeling these products with a ers, and State and local health authori- warning that they are not for oral in- ties. Based on the information avail- gestion has not been effective in pro- able, it is the opinion of the Commis- tecting the public. Misuse of stramo- sioner of Food and Drugs, concurred in nium preparations can cause serious by the Food and Drug Administration toxic effects including toxic delirium, Medical Advisory Board, that amyl ni- visual disturbances, fever, and coma. A trite inhalant is a drug with a poten- number of serious reactions have al- tiality for harmful effect and that it ready occurred from the oral ingestion should be removed from over-the- of such products. counter status and restricted to sale on (c) On the basis of this information, the prescription of a practitioner li- the Commissioner of Food and Drugs censed by law to administer such drug. has concluded that such articles have a (b) Therefore, amyl nitrite inhalant potentiality for harmful effect through will be regarded as misbranded unless misuse and are not safe for use except the labeling on or within the package under the supervision of a physician. In from which the drug is to be dispensed the interest of public health protec- bears adequate information for its safe tion, therefore, the Food and Drug Ad- and effective use by physicians, in ac- ministration adopts the following policy: cordance with § 201.100(c) of this chap- (1) Preparations containing stramo- ter, and its label bears the statement nium supplied from the leaves, seeds, ‘‘Rx only.’’ or any other part of the plant in the (c) Regulatory proceedings may be form of a powder, pipe mixture, ciga- initiated with regard to the interstate rette, or any other form, with or with- shipment of amyl nitrite inhalant that out admixture of other ingredients, is labeled, advertised, or dispensed con- will be regarded as misbranded if they trary to this statement of policy if are labeled with directions for use in such act occurs after July 1, 1969. self-medication. [40 FR 14033, Mar. 27, 1975, as amended at 67 (2) The Food and Drug Administra- FR 4906, Feb. 1, 2002] tion will, on request, furnish comment on proposed labeling limiting any such § 250.101 Amphetamine and meth- preparation to prescription sale. amphetamine inhalers regarded as (d) The labeling or dispensing of stra- prescription drugs. monium preparations contrary to this (a) Recurring reports of abuse and statement after 60 days following the misuse of methamphetamine (also date of its publication in the FEDERAL known as desoxyephedrine) inhalers REGISTER may be made the subject of show that they have a potentiality for regulatory proceedings. harmful effect and that they should not be freely available to the public Subpart B—New Drug or Prescrip- through over-the-counter sale. From tion Status of Specific Drugs complaints by law-enforcement officials, health officials, individual physi- § 250.100 Amyl nitrite inhalant as a cians, parents, and others as well as prescription drug for human use. from Food and Drug Administration in- (a) Amyl nitrite inhalant has been vestigations, it is evident that the available over-the-counter for emer- wicks from these inhalers are being re- gency use by the patient in the man- moved and the methamphetamine they agement of angina pectoris for a num- contain is being used as a substitute ber of years. As a result of a proposed for amphetamine tablets. Amphet- policy statement published August 25, amine tablets and amphetamine inhal- 1967 (32 FR 12404), the Commissioner of ers have been restricted to prescription

204

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00214 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 250.105

sale because of their potentiality for cept angina pectoris present after coro- harm to the user. nary occlusion and myocardial infarc- (b) It is the considered opinion of the tion. Food and Drug Administration that, in (c) Any preparation containing such order to adequately protect the public drugs that is labeled or advertised for health, inhalers containing meth- any use other than management of an- amphetamine or methamphetamine gina pectoris, or that is represented to salts (d-desoxyephedrine, or dl-desoxy- be efficacious for any other purpose by ephedrine, or their salts), as well as reason of its containing such drug, will amphetamine inhalers should be re- be regarded by the Food and Drug Ad- stricted to prescription sale and should ministration as misbranded and subject be labeled with the statement ‘‘Rx to regulatory proceedings, unless such only.’’ recommendations are covered by the [40 FR 14033, Mar. 27, 1975, as amended at 67 approval of a new-drug application FR 4906, Feb. 1, 2002] based on a showing of safety and effectiveness. § 250.102 Drug preparations intended for human use containing certain (d) Any such drug in long-acting dos- ‘‘coronary vasodilators’’. age form is regarded as a new drug that (a)(1) The Food and Drug Administra- requires an approved new-drug application finds that the following ‘‘coronary tion before marketing. vasodilators’’ are extensively regarded (e) Any of the drugs listed in para- by physicians as safe and useful as em- graph (a)(2) of this section is regarded ployed under medical supervision for as a new drug that requires an ap- the management of angina pectoris in proved new-drug application. Articles some patients: for which new-drug approvals are now in effect should be covered by supple- Amyl nitrite. Erythrityl tetranitrate. mental new-drug applications as nec- Mannitol hexanitrate. essary to provide for labeling revisions Nitroglycerin. consistent with this policy statement. Potassium nitrite. Sodium nitrite. §§ 250.103–250.104 [Reserved] (2) Additionally, new-drug applica- § 250.105 Gelsemium-containing prep- tions have been approved for products arations regarded as prescription containing: drugs. Inositol hexanitrate. It is the consensus of informed med- Isosorbide dinitrate. ical opinion that the margin of safety Octyl nitrite. Pentaerythritol tetranitrate. between the therapeutic and toxic con- Triethanolamine trinitrate biphosphate centration of gelsemium is narrow and (trolnitrate phosphate). it is difficult to predict the point at (b) The Food and Drug Administra- which the dose will be toxic. Very tion also finds that there is neither small doses may cause toxic symptoms. substantial evidence of effectiveness It is therefore the view of the Food and nor a general recognition by qualified Drug Administration that gelsemium experts that such drugs are effective is not a proper ingredient in any prod- for any of the other purposes for which uct that is to be sold without prescrip- some such drugs are promoted to the tion. Accordingly, any drug containing medical profession in labeling and ad- gelsemium will be regarded as mis- vertising. In particular, neither clin- branded under section 503(b)(4) of the ical investigations nor clinical experi- Federal Food, Drug, and Cosmetic Act ence justify any representations that if its label fails to bear in a prominent such drugs are effective in the manage- and conspicuous fashion the statement ment of hypertension; in the manage- ‘‘Rx only.’’ ment of coronary insufficiency or coronary artery disease, except for their [40 FR 14033, Mar. 27, 1975, as amended at 67 anginal manifestations; or in the man- FR 4906, Feb. 1, 2002] agement of the post coronary state, ex-

205

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00215 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 §§ 250.106–250.107 21 CFR Ch. I (4–1–19 Edition)

§§ 250.106–250.107 [Reserved] label fails to bear the statement ‘‘Rx only.’’ § 250.108 Potassium permanganate (2) Potassium permanganate labeled preparations as prescription drugs. for use as a prescription component in (a) There have been a number of re- human drugs under the exemption pro- ports in the medical literature of seri- vided in § 201.120 of this chapter or la- ous injuries to women resulting from beled for manufacturing use under the the misuse of potassium permanganate exemption provided in § 201.122 of this in an effort to induce abortion. Reports chapter will be regarded as misbranded from physicians who have treated such unless the label bears the statement, cases show that the injuries are com- ‘‘Rx only.’’ monly caused by introducing tablets or (3) These drugs will be regarded as crystals of potassium permanganate misbranded when intended for veteri- into the vagina. Experience with these nary use unless the label bears the leg- cases shows that such use of potassium end, ‘‘Caution: Federal law restricts permanganate is not effective in pro- this drug to sale by or on the order of ducing abortion, but that instead the a licensed veterinarian’’; Provided, how- drug produces serious and painful in- ever, That this shall not apply to a drug jury to the walls of the vagina, causing labeled and marketed for veterinary ulcers, massive hemorrhage, and infec- use if such drug contains not more tion. Such dangerous and useless em- than 50 percent of potassium per- ployment of potassium permanganate manganate and includes other ingredi- is apparently encouraged among the ents which make it unsuitable for misinformed by the mistaken idea that human use and unlikely that the arti- the vaginal bleeding caused by the cor- cle would be used in an attempt to in- rosive action of the drug indicates a duce abortion. termination of pregnancy, which it (4) Any preparation of potassium per- does not. manganate intended for over-the- (b) Potassium permanganate is a counter sale for human use internally strong oxidizing agent, a highly caus- or by application to any mucous mem- tic, tissue-destroying chemical, and a branes or for use in the vagina will be poison. There are no circumstances regarded as misbranded under the pro- under which crystals and tablets of po- visions of section 502(f) (1) and (2) and tassium permanganate constitute safe section 502(j) of the act. dosage forms for use in self-medica- (5) Any other preparation of potas- tion. It is the consensus of informed sium permanganate intended for over- medical opinion that the only dosage the-counter sale for human use will be forms of potassium permanganate regarded as misbranded under section known to be safe for use in self-medica- 502(f) (1) and (2) and section 502(j) of the tion are aqueous solutions containing act unless, among other things, all of not more than 0.04 percent potassium the following conditions are met: permanganate. Such solutions are safe (i) It is an aqueous solution con- for use in self-medication only by ex- taining not more than 0.04 percent po- ternal application to the skin. tassium permanganate. (c) In view of the very real poten- (ii) The label and labeling bear, in tiality for harmful effect, and the ac- juxtaposition with adequate directions tual injuries caused by the misuse of for use, clear warning statements des- potassium permanganate, the Food and ignated as ‘‘Warning,’’ and to the ef- Drug Administration believes that in fect: ‘‘Warning—For external use on order adequately to protect the public the skin only. Severe injury may result health: from use internally or as a douche. (1) Potassium permanganate and po- Avoid contact with mucous mem- tassium permanganate tablets intended branes.’’ for human use are drugs subject to sec- (d) The labeling or dispensing of any tion 503(b)(1) of the Federal Food, potassium permanganate preparations Drug, and Cosmetic Act and should be intended for drug use within the juris- restricted to prescription sale. Such diction of the Federal Food, Drug, and drugs will be regarded as misbranded if Cosmetic Act contrary to this state- at any time prior to dispensing the ment after 60 days from the date of its

206

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00216 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 250.201

publication in the FEDERAL REGISTER as pernicious anemia cannot be re- may be made the subject of regulatory garded as safe in all cases. proceedings. (4) The development of the classical [40 FR 14033, Mar. 27, 1975, as amended at 67 symptoms of pernicious anemia that FR 4906, Feb. 1, 2002] would cause a person to seek medical attention may in some cases be delayed Subpart C—Requirements for by oral ingestion of intrinsic factor. Drugs and Foods Pernicious anemia is a disease that is associated, among other things, with a § 250.201 Preparations for the treat- higher than normal incidence of cancer ment of pernicious anemia. of the stomach and that for the safety (a) The ninth announcement of the of the patient, requires continuous ex- Anti-anemia Preparations Advisory pert medical supervision. Board of the United States Pharma- (5) With inadequate treatment there copeia is concerned with the status of may be markedly deleterious effects on the treatment of pernicious anemia. It the nervous system. It is well estab- clearly presents the following facts: lished that whereas the development of (1) The Sixteenth Revision of the anemia is completely reversible with Pharmacopeia of the United States, adequate treatment, the involvement which became official on October 1, of the nervous system may not be com- 1960, does not include preparations in- pletely reversible and thus may result tended for the treatment of pernicious in permanent damage. anemia by oral administration. (6) Some hematologists prescribe oral (2) The U.S.P. unit for anti-anemia preparations no longer has any signifi- preparations of vitamin B12 in the cance. treatment of pernicious-anemia pa- (3) The U.S.P. Anti-anemia Prepara- tients. tions Advisory Board was disbanded. (7) Intrinsic factor and intrinsic fac- (b) On the basis of the scientific evi- tor concentrate serve no known useful dence and conclusions summarized in therapeutic or nutritive purpose except the statement of the U.S.P. Anti-ane- to the extent that they do increase the mia Preparations Advisory Board as gastrointestinal absorption of vitamin well as pertinent information from B12 in patients with a deficiency or ab- other sources, the Commissioner of sence of intrinsic factor, which may Food and Drugs finds it is the con- eventually lead to pernicious anemia. sensus of well informed medical opin- This conclusion does not apply to diag- ion that: nostic procedures using radioactive (1) The parenteral administration of cyanocobalamin. cyanocobalamin or vitamin B12 is gen- (8) Medical expertise is required for erally recognized as a fully effective the diagnosis as well as the manage- treatment of pernicious anemia. Paren- ment of pernicious anemia. teral cyanocobalamin preparations (c) The Eleventh Edition of The Na- have not been and are not authorized tional Formulary and its first Interim for use except by or on the prescription Revision include monographs for oral of a duly licensed medical practitioner. (2) Some patients afflicted with per- preparations of vitamin B12 with in- nicious anemia do not respond to oral- trinsic factor concentrate, establish a ly ingested products. There is no unit of vitamin B12 with intrinsic fac- known way to predict which patients tor concentrate, and provide for a Na- will fail to respond or will cease to re- tional Formulary Anti-anemia Prep- spond to the treatment of pernicious arations Advisory Board to assign the anemia with orally ingested prepara- potency of such preparations. This pro- tions. vides for the availability of such oral (3) The substitution of a possibly in- preparations, standardized within the adequate treatment, such as the inges- meaning of the broad limits char- tion of oral preparations of vitamin B12 acteristic of the evaluation of such with intrinsic factor concentrate, in preparations. place of parenteral vitamin B12 prod- (d) Any drug that is offered for or ucts for a disease condition as serious purports to contain intrinsic factor or

207

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00217 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 250.250 21 CFR Ch. I (4–1–19 Edition)

intrinsic factor concentrate will be re- Subpart D—Requirements for garded as misbranded within the mean- Drugs and Cosmetics ing of section 503(b) of the Federal Food, Drug, and Cosmetic Act unless it § 250.250 Hexachlorophene, as a com- is labeled with the statement ‘‘Rx ponent of drug and cosmetic prod- only.’’ ucts. (e) Any drug for oral ingestion in- (a) Antibacterial component. The use of tended, represented, or advertised for hexachlorophene as an antibacterial the prevention or treatment of per- component in drug and cosmetic prod- nicious anemia or which purports to ucts has expanded widely in recent contain any substance or mixture of years. It is used in such products be- substances described in paragraph (d) cause of its bacteriostatic action of this section (other than diagnostic against gram-positive organisms, espe- drugs containing radioactive cyano- cially against strains of staphy- cobalamin) will be regarded as mis- lococcus; however, hexachlorophene of- branded under sections 502 (f)(2) and (j) fers no protection against gram-nega- of the act unless its labeling bears a tive infections. In addition the anti- statement to the effect that some pa- bacterial activity depends largely on tients afflicted with pernicious anemia repeated use. A notice published in the may not respond to the orally ingested FEDERAL REGISTER of April 4, 1972 (37 product and that there is no known FR 6775), invited data on OTC anti- way to predict which patients will re- microbial ingredients, including spond or which patients may cease to hexachlorophene, for review by an OTC respond to the orally ingested prod- Drug Advisory Review Panel to be con- ucts. The labeling shall also bear a vened under the procedures set forth in statement that periodic examinations the FEDERAL REGISTER of May 11, 1972 and laboratory studies of pernicious (37 FR 9464). This statement of policy anemia patients are essential and rec- will remain in effect unless and until ommended. replaced by a monograph resulting (f) Under section 409 of the Federal from the OTC Drug Advisory Review Food, Drug, and Cosmetic Act, intrin- Panel. sic factor and intrinsic factor con- (b) Adverse effects. Though considered centrate are regarded as food additives. safe for many years, recent informa- No food additive regulation nor exist- tion has become available associating ing extension of the effective date of hexachlorophene with toxic effects, in- section 409 of the act authorizes these cluding deaths. Studies have shown additives in foods, including foods for that toxic amounts of hexachlorophene special dietary uses. Any food con- can be absorbed through the skin of hu- taining added intrinsic factor or intrin- mans, especially the skin of premature sic factor concentrate will be regarded babies or damaged skin. Human tox- as adulterated within the meaning of icity reports include data on symp- section 402(a)(2)(C) of the act. tomatology, blood and tissue levels of (g) Regulatory action may be initi- hexachlorophene, and descriptions of ated with respect to any article neuropathologic lesions. Recent infant shipped within the jurisdiction of the deaths due to use of baby powder acci- act contrary to the provisions of this dentally contaminated with 6 percent hexachlorophene have occurred. The policy statement after the 180th day accumulated evidence of toxicity is following publication of this statement sufficient to require that continued in the FEDERAL REGISTER. marketing of hexachlorophene con- [40 FR 14033, Mar. 27, 1975, as amended at 67 taining products be carefully defined in FR 4906, Feb. 1, 2002] order to protect consumers. (c) Prescription drugs. (1) Because of their potential for harmful effect, drugs containing hexachlorophene, other than as a preservative as described below, are not considered to

208

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00218 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 250.250

have been shown to be safe and effec- or the dermatitis of Letterer-Siwe’s syn- tive, are regarded as new drugs requir- drome or other generalized dermatologic ing approved new drug applications, conditions. Application to burns has also and would be misbranded for over-the- produced neurotoxicity and death. counter distribution. In the interest of Infants have developed dermatitis, irrita- public health protection, bility, generalized clonic muscular contrac- hexachlorophene containing drugs will tions and decerebrate rigidity following application of a 6 percent hexachlorophene be regarded as misbranded and subject powder. Examination of brainstems of those to regulatory proceedings unless the infants revealed vacuolization like that label bears the statement ‘‘Rx only,’’ which can be produced in newborn experi- and the labeling on or within the pack- mental animals following repeated topical age from which the drug is to be dis- application of 3 percent hexachlorophene. pensed bears adequate information for Moreover, a study of histologic sections of its safe and effective use by practi- premature infants who died of unrelated tioners, in accord with § 201.100(c) of causes has shown a positive correlation be- this chapter. tween hexachlorophene baths and lesions in (2) The Food and Drug Administra- white matter of brains. tion recognizes that hexachlorophene (ii) On the immediate container label is useful as a bacteriostatic skin prominently displayed and in bold cleanser. It further concludes that the print: margin of safety is such that products containing hexachlorophene may ap- ‘‘Special Warning: This compound may be propriately be used within clearly de- toxic if used other than as directed. Rinse lineated conditions of use. thoroughly after use. Monitor patients close- (3) In order for such drugs to bear ly for toxicity symptoms.’’ adequate information for safe and ef- (4) Marketing of products for the infective use the following statements dications listed in paragraph (c)(3) of are representative of the type of label- this section may be continued without ing for products shown to be effective an approved new drug application (or bacteriostatic skin cleansers. Labeling required supplement thereto) either for products other than bacteriostatic until a notice of opportunity for hear- skin cleansers will be determined ing is issued on a proposal by the Di- through the new drug procedures based rector of the Center for Drug Evalua- on the available data. tion and Research to refuse to approve (i) In the labeling other than on the such new drug application (or required immediate container label. supplement) or until January 31, 1978, whichever comes first, if all the fol- INDICATIONS lowing conditions were met after Sep- 1. Bacteriostatic skin cleanser for surgical tember 27, 1972: scrubbing or handwashing as part of patient (i) The product is labeled with the care. 2. For topical application to control an statement ‘‘Rx only’’ and adequate in- outbreak of gram-positive infection where formation for safe and effective use as other infection control procedures have been set forth in paragraph (c)(3) of this sec- unsuccessful. Use only as long as necessary tion. for infection control. (ii) Within 30 days, or by (10–27–72) CONTRAINDICATIONS the holder of an approved new drug application submits a supplement to pro- 1. Not for use on burned or denuded skin or on mucous membranes. vide for the revised label and full dis- 2. Not for routine prophylactic total body closure labeling. As the label and label- bathing. ing will have been put into use, the supplement should be submitted under WARNINGS the provision of § 314.70(c)(6)(iii) of this Rinse thoroughly after use. Patients chapter. should be closely monitored and use should (iii) Within 30 days, or by (10–27–72) be immediately discontinued at the first sign the holder of an approved new drug ap- of any of the symptoms described below. Hexachlorophene is rapidly absorbed and plication submits a supplement to pro- may produce toxic blood levels when applied vide for a revised formulation where to skin lesions such as ichthyosis congenita appropriate to comply with this order.

209

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00219 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 § 250.250 21 CFR Ch. I (4–1–19 Edition)

(iv) Within 90 days, or by (12–26–72) alternative preservative has not yet the holder of an approved new drug ap- been shown to be as effective or where plication submits a supplement con- adequate integrity and stability data taining blood level data obtained from for the reformulated product are not use of the drug as recommended, unless yet available. The component of a pre- such information is a part of the new servative system whether drug application file. hexachlorophene or other anti- (v) Within 90 days, or by (12–26–72), microbial agent, should be selected on the manufacturer or distributor of such the basis of the effect on the total mi- a drug for which a new drug approval is crobial ecology of the product, not not in effect submits a new drug appli- merely on gram-positive bacteria. cation in accord with § 314.50 of the new (1) Adequate safety data do not pres- drug regulations (21 CFR 314.50), including blood level data obtained from ently exist to justify wider use of use of the drug as recommended. hexachlorophene in cosmetics. (5) Prescription drug products may (2) Antibacterial ingredients used as contain hexachlorophene as part of an substitutes for hexachlorophene in cos- effective preservative system only metic products, and finished cosmetic under the conditions and limitations products containing such ingredients, provided for under paragraph (d) of this shall be adequately tested for safety section. prior to marketing. Any such ingre- (d) Over-the-counter (OTC) drugs. dient or product whose safety is not Over-the-counter drug products, other adequately substantiated prior to mar- than those which in normal use may be keting may be adulterated and will in applied to mucous membranes or which any event be deemed misbranded unless are intended to be used on mucous it contains a conspicuous front panel membranes, may contain statement that the product has not hexachlorophene only as part of an ef- been adequately tested for safety and fective preservative system, at a level may be hazardous. that is no higher than necessary to (f) Content statement. All reference to achieve the intended preservative func- hexachlorophene limit in this order is tion, and in no event higher than 0.1 on a weight-in-weight (w/w) basis. percent. Such use of hexachlorophene Quantitative declaration of shall be limited to situations where an hexachlorophene content on the label- alternative preservative has not yet been shown to be as effective or where ing of the products, where required, adequate integrity and stability data shall be on a w/w basis. for the reformulated product are not (g) Shipments of products. Shipments yet available. This use of of products falling within the scope of hexachlorophene will not, by itself, re- paragraphs (c), (d), or (e) of this section quire an approved new drug applica- which are not in compliance with the tion. Use of hexachlorophene as a pre- guidelines stated herein shall be the servative at a level higher than 0.1 per- subject of regulatory proceedings after cent is regarded as a new drug use re- the effective date of the final order. quiring an approved new drug applica- (h) Prior notices. This order preempts tion, which must be submitted within any conditions for marketing products the time set out in paragraph (c)(4) of set forth in the following prior notices. this section. (e) Cosmetics. Hexachlorophene may 1. DESI No. 4749 (34 FR 15389, October 2, 1969), be used as a preservative in cosmetic ‘‘Certain OTC Drugs for Topical Use.’’ products other than those which in 2. DESI No. 2855 (35 FR 12423, August 4, 1970), normal use may be applied to mucous ‘‘Certain Mouthwash and Gargle Prepara- tions.’’ membranes or which are intended to be 3. DESI No. 8940 (36 FR 14510, August 6, 1971), used on mucous membranes, at a level ‘‘Topical Cream Containing Pyrilamine that is no higher than necessary to Maleate, Benzocaine, Hexachlorophene, achieve the intended preservative func- and Cetrimonium Bromide.’’ tion, and in no event higher than 0.1 4. DESI No. 6615 (36 FR 18022, September 8, percent. Such use of hexachlorophene 1971), ‘‘Deodorant/Antiperspirant.’’ shall be limited to situations where an

210

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00220 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 290.10

5. DESI No. 6270 (36 FR 23330, December 8, other than those possessed by codeine 1971), ‘‘Certain Preparations Containing alone. Hexachlorophene’’. [67 FR 4907, Feb. 1, 2002] [40 FR 14033, Mar. 27, 1975, as amended at 42 FR 63773, Dec. 20, 1977; 55 FR 11577, Mar. 29, § 290.5 Drugs; statement of required 1990; 67 FR 4906, Feb. 1, 2002; 69 FR 18763, Apr. 8, 2004] warning. The label of any drug listed as a PART 290—CONTROLLED DRUGS ‘‘controlled substance’’ in schedule II, III, or IV of the Federal Controlled Subpart A—General Provisions Substances Act shall, when dispensed to or for a patient, contain the fol- Sec. lowing warning: ‘‘Caution: Federal law 290.1 Controlled substances. prohibits the transfer of this drug to 290.2 Exemption from prescription require- any person other than the patient for ments. whom it was prescribed.’’ This state- 290.5 Drugs; statement of required warning. ment is not required to appear on the 290.6 Spanish-language version of required warning. label of a controlled substance dis- 290.10 Definition of emergency situation. pensed for use in clinical investigations which are ‘‘blind.’’ Subpart B [Reserved] § 290.6 Spanish-language version of re- Subpart C—Requirements for Specific quired warning. Controlled Drugs [Reserved] By direction of section 305(c) of the Federal Controlled Substances Act, AUTHORITY: 21 U.S.C. 352, 353, 355, 371. § 290.5, promulgated under section SOURCE: 40 FR 14040, Mar. 27, 1975, unless 503(b) of the Federal Food, Drug, and otherwise noted. Cosmetic Act, requires the following warning on the label of certain drugs Subpart A—General Provisions when dispensed to or for a patient: ‘‘Caution: Federal law prohibits the § 290.1 Controlled substances. transfer of this drug to any person Any drug that is a controlled sub- other than the patient for whom it was stance listed in schedule II, III, IV, or prescribed.’’ The Spanish version of V of the Federal Controlled Substances this is: ‘‘Precaucion: La ley Federal Act or implementing regulations must prohibe el transferir de esta droga a be dispensed by prescription only as re- otra persona que no sea el paciente quired by section 503(b)(1) of the Fed- para quien fue recetada.’’ eral Food, Drug, and Cosmetic Act unless specifically exempted in § 290.2. § 290.10 Definition of emergency situation. [67 FR 4906, Feb. 1, 2002] For the purposes of authorizing an § 290.2 Exemption from prescription oral prescription of a controlled sub- requirements. stance listed in schedule II of the Fed- eral Controlled Substances Act, the The prescription-dispensing require- term emergency situation means those ments of section 503(b)(1) of the Fed- eral Food, Drug, and Cosmetic Act are situations in which the prescribing not necessary for the protection of the practitioner determines: public health with respect to a com- (a) That immediate administration of pound, mixture, or preparation con- the controlled substance is necessary, taining not more than 200 milligrams for proper treatment of the intended of codeine per 100 milliliters or per 100 ultimate user; and grams that also includes one or more (b) That no appropriate alternative nonnarcotic active medicinal ingredi- treatment is available, including ad- ents in sufficient proportion to confer ministration of a drug which is not a upon the compound, mixture, or prepa- controlled substance under schedule II ration valuable medicinal qualities of the Act, and

211

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00221 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Pt. 299 21 CFR Ch. I (4–1–19 Edition)

(c) That it is not reasonably possible clusion of any other nonproprietary for the prescribing practitioner to pro- name (except the applicable systematic vide a written prescription to be pre- chemical name or the chemical for- sented to the person dispensing the mula) and, if the drug is fabricated substance, prior to the dispensing. from two or more ingredients, the established name of each active ingre- Subpart B [Reserved] dient. (b) The term established name is de- Subpart C—Requirements for Spe- fined in section 502(e)(3) of the act as (1) an official name designated pursu- cific Controlled Drugs [Re- ant to section 508 of the act; (2) if no served] such official name has been designated for the drug and the drug is an article PART 299—DRUGS; OFFICIAL recognized in an official compendium, NAMES AND ESTABLISHED NAMES then the official title thereof in such compendium; and (3) if neither para- Subpart A—General Provisions graphs (b) (1) or (2) of this section applies, then the common or usual name Sec. 299.3 Definitions and interpretations. of the drug. 299.4 Established names for drugs. (c) The Food and Drug Administra- 299.5 Drugs; compendial name. tion recognizes the skill and experience of the U.S. Adopted Names Council AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 358, 360b, 371. (USAN) in deriving names for drugs. The U.S. Adopted Names Council is a SOURCE: 40 FR 14041, Mar. 27, 1975, unless private organization sponsored by the otherwise noted. American Medical Association, the United States Pharmacopeia, and the Subpart A—General Provisions American Pharmaceutical Association, and has been engaged in the assign- § 299.3 Definitions and interpretations. ment of names to drugs since January (a) As used in this part 299, act means 1964. The Council negotiates with man- the Federal Food, Drug, and Cosmetic ufacturing firms in the selection of Act, sections 201–902, 52 Stat. 1040 (21 nonproprietary names for drugs. U.S.C. 321–392), with all amendments (d) The Food and Drug Administra- thereto. tion cooperates with and is represented (b) The definitions and interpreta- on the USAN Council. In addition, the tions contained in section 201 of the act Food and Drug Administration agrees shall be applicable to such terms when with ‘‘Guiding Principles for Coining used in this part 299. U.S. Adopted Names for Drugs,’’ pub- (c) The term official name means, lished in USAN and the USP Dictionary with respect to a drug or ingredient of Drug Names (USAN 1985 ed., 1961–1984 thereof, the name designated in this cumulative list), which is incorporated part 299 under section 508 of the act as by reference. Copies are available from: the official name. U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, § 299.4 Established names for drugs. MD 20852, or are available for inspec- (a) Section 508 of the Federal Food, tion at the National Archives and Drug, and Cosmetic Act (added by the Records Administration (NARA). For Kefauver-Harris Drug Amendments of information on the availability of this 1962; Pub. L. 87–781) authorizes the material at NARA, call 202–741–6030, or Commissioner of Food and Drugs to go to: http://www.archives.gov/ designate an official name for any drug federallregister/ if he determines that such action is codeloflfederallregulations/ necessary or desirable in the interest of ibrllocations.html. All applicants for usefulness and simplicity. Section new-drug applications and sponsors for 502(e) of the act (as amended by said ‘‘Investigational New Drug Applica- Drug Amendments) prescribes that the tions’’ (IND’s) are encouraged to con- labeling of a drug must bear its estab- tact the USAN Council for assistance lished name, if there is one, to the ex- in selection of a simple and useful

212

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00222 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 Food and Drug Administration, HHS § 299.5

name for a new chemical entity. Ap- tially identical in strength, quality, proval of a new-drug application pro- and purity; or viding for the use of a new drug sub- (3) No USAN or other official or com- stance may be delayed if a simple and mon or usual name has been applied to useful nonproprietary name does not a medically useful drug. Any official exist for the substance and if one is not name published under section 508 of the proposed in the application that meets act will be the established name of the the above-cited guidelines. Prior use of drug. a name in the medical literature or (f) A cumulative list of U.S. adopted otherwise will not commit the Food names selected and released since June and Drug Administration to adopting 15, 1961, is published yearly by the U.S. such terminology as official. Pharmacopeial Convention, Inc., in (e) The Food and Drug Administra- USAN and the USP Dictionary of Drug Names. Copies may be purchased from tion will not routinely designate offi- the U.S. Pharmacopeial Convention, cial names under section 508 of the act. Inc., 12601 Twinbrook Parkway, Rock- As a result, the established name under ville, MD 20852. section 502(e) of the act will ordinarily be either the compendial name of the [40 FR 14041, Mar. 27, 1975, as amended at 49 drug or, if there is no compendial FR 37575, Sept. 25, 1984; 53 FR 5369, Feb. 24, name, the common and usual name of 1988; 55 FR 11577, Mar. 29, 1990; 64 FR 401, Jan. 5, 1999; 69 FR 18803, Apr. 9, 2004] the drug. Interested persons, in the absence of the designation by the food § 299.5 Drugs; compendial name. and Drug Administration of an official (a) The name by which a drug is des- name, may rely on as the established ignated shall be clearly distinguishing name for any drug the current and differentiating from any name rec- compendial name or the USAN adopted ognized in an official compendium un- name listed in USAN and the USP Dic- less such drug complies in identity tionary of Drug Names. The Food and with the identity prescribed in an offi- Drug Administration, however, will cial compendium under such recog- continue to publish official names nized name. under the provisions of section 508 of (b) The term drug defined in an official the act when the agency determines compendium means a drug having the that: identity prescribed for a drug in an of- (1) The USAN or other official or ficial compendium. common or usual name is unduly com- (c) A statement that a drug defined plex or is not useful for any other rea- in an official compendium differs in son; strength, quality, or purity from the (2) Two or more official names have standard of strength, quality, or purity been applied to a single drug, or to two set forth for such drug in an official or more drugs that are identical in compendium shall show all the respects chemical structure and pharma- in which such drug so differs, and the cological action and that are substan- extent of each such difference.

213

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00223 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00224 Fmt 8010 Sfmt 8010 Y:\SGML\247073.XXX 247073 FINDING AIDS

A list of CFR titles, subtitles, chapters, subchapters and parts and an alphabetical list of agencies publishing in the CFR are included in the CFR Index and Finding Aids volume to the Code of Federal Regulations which is published separately and revised annually. Table of CFR Titles and Chapters Alphabetical List of Agencies Appearing in the CFR List of CFR Sections Affected

215

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00225 Fmt 8008 Sfmt 8008 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00226 Fmt 8008 Sfmt 8008 Y:\SGML\247073.XXX 247073 Table of CFR Titles and Chapters (Revised as of April 1, 2019)

Title 1—General Provisions

I Administrative Committee of the Federal Register (Parts 1—49) II Office of the Federal Register (Parts 50—299) III Administrative Conference of the United States (Parts 300—399) IV Miscellaneous Agencies (Parts 400—599) VI National Capital Planning Commission (Parts 600—699)

Title 2—Grants and Agreements

SUBTITLE A—OFFICE OF MANAGEMENT AND BUDGET GUIDANCE FOR GRANTS AND AGREEMENTS I Office of Management and Budget Governmentwide Guidance for Grants and Agreements (Parts 2—199) II Office of Management and Budget Guidance (Parts 200—299) SUBTITLE B—FEDERAL AGENCY REGULATIONS FOR GRANTS AND AGREEMENTS III Department of Health and Human Services (Parts 300—399) IV Department of Agriculture (Parts 400—499) VI Department of State (Parts 600—699) VII Agency for International Development (Parts 700—799) VIII Department of Veterans Affairs (Parts 800—899) IX Department of Energy (Parts 900—999) X Department of the Treasury (Parts 1000—1099) XI Department of Defense (Parts 1100—1199) XII Department of Transportation (Parts 1200—1299) XIII Department of Commerce (Parts 1300—1399) XIV Department of the Interior (Parts 1400—1499) XV Environmental Protection Agency (Parts 1500—1599) XVIII National Aeronautics and Space Administration (Parts 1800— 1899) XX United States Nuclear Regulatory Commission (Parts 2000—2099) XXII Corporation for National and Community Service (Parts 2200— 2299) XXIII Social Security Administration (Parts 2300—2399) XXIV Department of Housing and Urban Development (Parts 2400— 2499) XXV National Science Foundation (Parts 2500—2599) XXVI National Archives and Records Administration (Parts 2600—2699)

217

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00227 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 2—Grants and Agreements—Continued Chap.

XXVII Small Business Administration (Parts 2700—2799) XXVIII Department of Justice (Parts 2800—2899) XXIX Department of Labor (Parts 2900—2999) XXX Department of Homeland Security (Parts 3000—3099) XXXI Institute of Museum and Library Services (Parts 3100—3199) XXXII National Endowment for the Arts (Parts 3200—3299) XXXIII National Endowment for the Humanities (Parts 3300—3399) XXXIV Department of Education (Parts 3400—3499) XXXV Export-Import Bank of the United States (Parts 3500—3599) XXXVI Office of National Drug Control Policy, Executive Office of the President (Parts 3600—3699) XXXVII Peace Corps (Parts 3700—3799) LVIII Election Assistance Commission (Parts 5800—5899) LIX Gulf Coast Ecosystem Restoration Council (Parts 5900—5999)

Title 3—The President

I Executive Office of the President (Parts 100—199)

Title 4—Accounts

I Government Accountability Office (Parts 1—199)

Title 5—Administrative Personnel

I Office of Personnel Management (Parts 1—1199) II Merit Systems Protection Board (Parts 1200—1299) III Office of Management and Budget (Parts 1300—1399) IV Office of Personnel Management and Office of the Director of National Intelligence (Parts 1400—1499) V The International Organizations Employees Loyalty Board (Parts 1500—1599) VI Federal Retirement Thrift Investment Board (Parts 1600—1699) VIII Office of Special Counsel (Parts 1800—1899) IX Appalachian Regional Commission (Parts 1900—1999) XI Armed Forces Retirement Home (Parts 2100—2199) XIV Federal Labor Relations Authority, General Counsel of the Fed- eral Labor Relations Authority and Federal Service Impasses Panel (Parts 2400—2499) XVI Office of Government Ethics (Parts 2600—2699) XXI Department of the Treasury (Parts 3100—3199) XXII Federal Deposit Insurance Corporation (Parts 3200—3299) XXIII Department of Energy (Parts 3300—3399) XXIV Federal Energy Regulatory Commission (Parts 3400—3499) XXV Department of the Interior (Parts 3500—3599) XXVI Department of Defense (Parts 3600—3699)

218

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00228 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 5—Administrative Personnel—Continued Chap.

XXVIII Department of Justice (Parts 3800—3899) XXIX Federal Communications Commission (Parts 3900—3999) XXX Farm Credit System Insurance Corporation (Parts 4000—4099) XXXI Farm Credit Administration (Parts 4100—4199) XXXIII Overseas Private Investment Corporation (Parts 4300—4399) XXXIV Securities and Exchange Commission (Parts 4400—4499) XXXV Office of Personnel Management (Parts 4500—4599) XXXVI Department of Homeland Security (Parts 4600—4699) XXXVII Federal Election Commission (Parts 4700—4799) XL Interstate Commerce Commission (Parts 5000—5099) XLI Commodity Futures Trading Commission (Parts 5100—5199) XLII Department of Labor (Parts 5200—5299) XLIII National Science Foundation (Parts 5300—5399) XLV Department of Health and Human Services (Parts 5500—5599) XLVI Postal Rate Commission (Parts 5600—5699) XLVII Federal Trade Commission (Parts 5700—5799) XLVIII Nuclear Regulatory Commission (Parts 5800—5899) XLIX Federal Labor Relations Authority (Parts 5900—5999) L Department of Transportation (Parts 6000—6099) LII Export-Import Bank of the United States (Parts 6200—6299) LIII Department of Education (Parts 6300—6399) LIV Environmental Protection Agency (Parts 6400—6499) LV National Endowment for the Arts (Parts 6500—6599) LVI National Endowment for the Humanities (Parts 6600—6699) LVII General Services Administration (Parts 6700—6799) LVIII Board of Governors of the Federal Reserve System (Parts 6800— 6899) LIX National Aeronautics and Space Administration (Parts 6900— 6999) LX United States Postal Service (Parts 7000—7099) LXI National Labor Relations Board (Parts 7100—7199) LXII Equal Employment Opportunity Commission (Parts 7200—7299) LXIII Inter-American Foundation (Parts 7300—7399) LXIV Merit Systems Protection Board (Parts 7400—7499) LXV Department of Housing and Urban Development (Parts 7500— 7599) LXVI National Archives and Records Administration (Parts 7600—7699) LXVII Institute of Museum and Library Services (Parts 7700—7799) LXVIII Commission on Civil Rights (Parts 7800—7899) LXIX Tennessee Valley Authority (Parts 7900—7999) LXX Court Services and Offender Supervision Agency for the District of Columbia (Parts 8000—8099) LXXI Consumer Product Safety Commission (Parts 8100—8199) LXXIII Department of Agriculture (Parts 8300—8399)

219

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00229 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 5—Administrative Personnel—Continued Chap.

LXXIV Federal Mine Safety and Health Review Commission (Parts 8400—8499) LXXVI Federal Retirement Thrift Investment Board (Parts 8600—8699) LXXVII Office of Management and Budget (Parts 8700—8799) LXXX Federal Housing Finance Agency (Parts 9000—9099) LXXXIII Special Inspector General for Afghanistan Reconstruction (Parts 9300—9399) LXXXIV Bureau of Consumer Financial Protection (Parts 9400—9499) LXXXVI National Credit Union Administration (Parts 9600—9699) XCVII Department of Homeland Security Human Resources Manage- ment System (Department of Homeland Security—Office of Personnel Management) (Parts 9700—9799) XCVIII Council of the Inspectors General on Integrity and Efficiency (Parts 9800—9899) XCIX Military Compensation and Retirement Modernization Commis- sion (Parts 9900—9999) C National Council on Disability (Parts 10000—10049) CI National Mediation Board (Part 10101)

Title 6—Domestic Security

I Department of Homeland Security, Office of the Secretary (Parts 1—199) X Privacy and Civil Liberties Oversight Board (Parts 1000—1099)

Title 7—Agriculture

SUBTITLE A—OFFICE OF THE SECRETARY OF AGRICULTURE (PARTS 0—26) SUBTITLE B—REGULATIONS OF THE DEPARTMENT OF AGRICULTURE I Agricultural Marketing Service (Standards, Inspections, Mar- keting Practices), Department of Agriculture (Parts 27—209) II Food and Nutrition Service, Department of Agriculture (Parts 210—299) III Animal and Plant Health Inspection Service, Department of Ag- riculture (Parts 300—399) IV Federal Crop Insurance Corporation, Department of Agriculture (Parts 400—499) V Agricultural Research Service, Department of Agriculture (Parts 500—599) VI Natural Resources Conservation Service, Department of Agri- culture (Parts 600—699) VII Farm Service Agency, Department of Agriculture (Parts 700— 799) VIII Grain Inspection, Packers and Stockyards Administration (Fed- eral Grain Inspection Service), Department of Agriculture (Parts 800—899)

220

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00230 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 7—Agriculture—Continued Chap.

IX Agricultural Marketing Service (Marketing Agreements and Or- ders; Fruits, Vegetables, Nuts), Department of Agriculture (Parts 900—999) X Agricultural Marketing Service (Marketing Agreements and Or- ders; Milk), Department of Agriculture (Parts 1000—1199) XI Agricultural Marketing Service (Marketing Agreements and Or- ders; Miscellaneous Commodities), Department of Agriculture (Parts 1200—1299) XIV Commodity Credit Corporation, Department of Agriculture (Parts 1400—1499) XV Foreign Agricultural Service, Department of Agriculture (Parts 1500—1599) XVI Rural Telephone Bank, Department of Agriculture (Parts 1600— 1699) XVII Rural Utilities Service, Department of Agriculture (Parts 1700— 1799) XVIII Rural Housing Service, Rural Business-Cooperative Service, Rural Utilities Service, and Farm Service Agency, Depart- ment of Agriculture (Parts 1800—2099) XX Local Television Loan Guarantee Board (Parts 2200—2299) XXV Office of Advocacy and Outreach, Department of Agriculture (Parts 2500—2599) XXVI Office of Inspector General, Department of Agriculture (Parts 2600—2699) XXVII Office of Information Resources Management, Department of Agriculture (Parts 2700—2799) XXVIII Office of Operations, Department of Agriculture (Parts 2800— 2899) XXIX Office of Energy Policy and New Uses, Department of Agri- culture (Parts 2900—2999) XXX Office of the Chief Financial Officer, Department of Agriculture (Parts 3000—3099) XXXI Office of Environmental Quality, Department of Agriculture (Parts 3100—3199) XXXII Office of Procurement and Property Management, Department of Agriculture (Parts 3200—3299) XXXIII Office of Transportation, Department of Agriculture (Parts 3300—3399) XXXIV National Institute of Food and Agriculture (Parts 3400—3499) XXXV Rural Housing Service, Department of Agriculture (Parts 3500— 3599) XXXVI National Agricultural Statistics Service, Department of Agri- culture (Parts 3600—3699) XXXVII Economic Research Service, Department of Agriculture (Parts 3700—3799) XXXVIII World Agricultural Outlook Board, Department of Agriculture (Parts 3800—3899) XLI [Reserved] XLII Rural Business-Cooperative Service and Rural Utilities Service, Department of Agriculture (Parts 4200—4299)

221

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00231 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 8—Aliens and Nationality Chap.

I Department of Homeland Security (Immigration and Naturaliza- tion) (Parts 1—499) V Executive Office for Immigration Review, Department of Justice (Parts 1000—1399)

Title 9—Animals and Animal Products

I Animal and Plant Health Inspection Service, Department of Ag- riculture (Parts 1—199) II Grain Inspection, Packers and Stockyards Administration (Packers and Stockyards Programs), Department of Agri- culture (Parts 200—299) III Food Safety and Inspection Service, Department of Agriculture (Parts 300—599)

Title 10—Energy

I Nuclear Regulatory Commission (Parts 0—199) II Department of Energy (Parts 200—699) III Department of Energy (Parts 700—999) X Department of Energy (General Provisions) (Parts 1000—1099) XIII Nuclear Waste Technical Review Board (Parts 1300—1399) XVII Defense Nuclear Facilities Safety Board (Parts 1700—1799) XVIII Northeast Interstate Low-Level Radioactive Waste Commission (Parts 1800—1899)

Title 11—Federal Elections

I Federal Election Commission (Parts 1—9099) II Election Assistance Commission (Parts 9400—9499)

Title 12—Banks and Banking

I Comptroller of the Currency, Department of the Treasury (Parts 1—199) II Federal Reserve System (Parts 200—299) III Federal Deposit Insurance Corporation (Parts 300—399) IV Export-Import Bank of the United States (Parts 400—499) V (Parts 500—599) [Reserved] VI Farm Credit Administration (Parts 600—699) VII National Credit Union Administration (Parts 700—799) VIII Federal Financing Bank (Parts 800—899) IX Federal Housing Finance Board (Parts 900—999) X Bureau of Consumer Financial Protection (Parts 1000—1099) XI Federal Financial Institutions Examination Council (Parts 1100—1199) XII Federal Housing Finance Agency (Parts 1200—1299) XIII Financial Stability Oversight Council (Parts 1300—1399)

222

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00232 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 12—Banks and Banking—Continued Chap.

XIV Farm Credit System Insurance Corporation (Parts 1400—1499) XV Department of the Treasury (Parts 1500—1599) XVI Office of Financial Research (Parts 1600—1699) XVII Office of Federal Housing Enterprise Oversight, Department of Housing and Urban Development (Parts 1700—1799) XVIII Community Development Financial Institutions Fund, Depart- ment of the Treasury (Parts 1800—1899)

Title 13—Business Credit and Assistance

I Small Business Administration (Parts 1—199) III Economic Development Administration, Department of Com- merce (Parts 300—399) IV Emergency Steel Guarantee Loan Board (Parts 400—499) V Emergency Oil and Gas Guaranteed Loan Board (Parts 500—599)

Title 14—Aeronautics and Space

I Federal Aviation Administration, Department of Transportation (Parts 1—199) II Office of the Secretary, Department of Transportation (Aviation Proceedings) (Parts 200—399) III Commercial Space Transportation, Federal Aviation Adminis- tration, Department of Transportation (Parts 400—1199) V National Aeronautics and Space Administration (Parts 1200— 1299) VI Air Transportation System Stabilization (Parts 1300—1399)

Title 15—Commerce and Foreign Trade

SUBTITLE A—OFFICE OF THE SECRETARY OF COMMERCE (PARTS 0— 29) SUBTITLE B—REGULATIONS RELATING TO COMMERCE AND FOREIGN TRADE I Bureau of the Census, Department of Commerce (Parts 30—199) II National Institute of Standards and Technology, Department of Commerce (Parts 200—299) III International Trade Administration, Department of Commerce (Parts 300—399) IV Foreign-Trade Zones Board, Department of Commerce (Parts 400—499) VII Bureau of Industry and Security, Department of Commerce (Parts 700—799) VIII Bureau of Economic Analysis, Department of Commerce (Parts 800—899) IX National Oceanic and Atmospheric Administration, Department of Commerce (Parts 900—999) XI National Technical Information Service, Department of Com- merce (Parts 1100—1199)

223

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00233 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 15—Commerce and Foreign Trade—Continued Chap.

XIII East-West Foreign Trade Board (Parts 1300—1399) XIV Minority Business Development Agency (Parts 1400—1499) SUBTITLE C—REGULATIONS RELATING TO FOREIGN TRADE AGREE- MENTS XX Office of the United States Trade Representative (Parts 2000— 2099) SUBTITLE D—REGULATIONS RELATING TO TELECOMMUNICATIONS AND INFORMATION XXIII National Telecommunications and Information Administration, Department of Commerce (Parts 2300—2399) [Reserved]

Title 16—Commercial Practices

I Federal Trade Commission (Parts 0—999) II Consumer Product Safety Commission (Parts 1000—1799)

Title 17—Commodity and Securities Exchanges

I Commodity Futures Trading Commission (Parts 1—199) II Securities and Exchange Commission (Parts 200—399) IV Department of the Treasury (Parts 400—499)

Title 18—Conservation of Power and Water Resources

I Federal Energy Regulatory Commission, Department of Energy (Parts 1—399) III Delaware River Basin Commission (Parts 400—499) VI Water Resources Council (Parts 700—799) VIII Susquehanna River Basin Commission (Parts 800—899) XIII Tennessee Valley Authority (Parts 1300—1399)

Title 19—Customs Duties

I U.S. Customs and Border Protection, Department of Homeland Security; Department of the Treasury (Parts 0—199) II United States International Trade Commission (Parts 200—299) III International Trade Administration, Department of Commerce (Parts 300—399) IV U.S. Immigration and Customs Enforcement, Department of Homeland Security (Parts 400—599) [Reserved]

Title 20—Employees’ Benefits

I Office of Workers’ Compensation Programs, Department of Labor (Parts 1—199) II Railroad Retirement Board (Parts 200—399) III Social Security Administration (Parts 400—499)

224

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00234 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 20—Employees’ Benefits—Continued Chap.

IV Employees’ Compensation Appeals Board, Department of Labor (Parts 500—599) V Employment and Training Administration, Department of Labor (Parts 600—699) VI Office of Workers’ Compensation Programs, Department of Labor (Parts 700—799) VII Benefits Review Board, Department of Labor (Parts 800—899) VIII Joint Board for the Enrollment of Actuaries (Parts 900—999) IX Office of the Assistant Secretary for Veterans’ Employment and Training Service, Department of Labor (Parts 1000—1099)

Title 21—Food and Drugs

I Food and Drug Administration, Department of Health and Human Services (Parts 1—1299) II Drug Enforcement Administration, Department of Justice (Parts 1300—1399) III Office of National Drug Control Policy (Parts 1400—1499)

Title 22—Foreign Relations

I Department of State (Parts 1—199) II Agency for International Development (Parts 200—299) III Peace Corps (Parts 300—399) IV International Joint Commission, United States and Canada (Parts 400—499) V Broadcasting Board of Governors (Parts 500—599) VII Overseas Private Investment Corporation (Parts 700—799) IX Foreign Service Grievance Board (Parts 900—999) X Inter-American Foundation (Parts 1000—1099) XI International Boundary and Water Commission, United States and Mexico, United States Section (Parts 1100—1199) XII United States International Development Cooperation Agency (Parts 1200—1299) XIII Millennium Challenge Corporation (Parts 1300—1399) XIV Foreign Service Labor Relations Board; Federal Labor Relations Authority; General Counsel of the Federal Labor Relations Authority; and the Foreign Service Impasse Disputes Panel (Parts 1400—1499) XV African Development Foundation (Parts 1500—1599) XVI Japan-United States Friendship Commission (Parts 1600—1699) XVII United States Institute of Peace (Parts 1700—1799)

Title 23—Highways

I Federal Highway Administration, Department of Transportation (Parts 1—999)

225

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00235 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 23—Highways—Continued Chap.

II National Highway Traffic Safety Administration and Federal Highway Administration, Department of Transportation (Parts 1200—1299) III National Highway Traffic Safety Administration, Department of Transportation (Parts 1300—1399)

Title 24—Housing and Urban Development

SUBTITLE A—OFFICE OF THE SECRETARY, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT (PARTS 0—99) SUBTITLE B—REGULATIONS RELATING TO HOUSING AND URBAN DE- VELOPMENT I Office of Assistant Secretary for Equal Opportunity, Department of Housing and Urban Development (Parts 100—199) II Office of Assistant Secretary for Housing-Federal Housing Com- missioner, Department of Housing and Urban Development (Parts 200—299) III Government National Mortgage Association, Department of Housing and Urban Development (Parts 300—399) IV Office of Housing and Office of Multifamily Housing Assistance Restructuring, Department of Housing and Urban Develop- ment (Parts 400—499) V Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 500—599) VI Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 600—699) [Reserved] VII Office of the Secretary, Department of Housing and Urban Devel- opment (Housing Assistance Programs and Public and Indian Housing Programs) (Parts 700—799) VIII Office of the Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Section 8 Housing Assistance Programs, Section 202 Di- rect Loan Program, Section 202 Supportive Housing for the El- derly Program and Section 811 Supportive Housing for Persons With Disabilities Program) (Parts 800—899) IX Office of Assistant Secretary for Public and Indian Housing, De- partment of Housing and Urban Development (Parts 900—1699) XII Office of Inspector General, Department of Housing and Urban Development (Parts 2000—2099) XV Emergency Mortgage Insurance and Loan Programs, Depart- ment of Housing and Urban Development (Parts 2700—2799) [Reserved] XX Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Parts 3200—3899) XXIV Board of Directors of the HOPE for Homeowners Program (Parts 4000—4099) [Reserved] XXV Neighborhood Reinvestment Corporation (Parts 4100—4199)

226

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00236 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 25—Indians Chap.

I Bureau of Indian Affairs, Department of the Interior (Parts 1— 299) II Indian Arts and Crafts Board, Department of the Interior (Parts 300—399) III National Indian Gaming Commission, Department of the Inte- rior (Parts 500—599) IV Office of Navajo and Hopi Indian Relocation (Parts 700—899) V Bureau of Indian Affairs, Department of the Interior, and Indian Health Service, Department of Health and Human Services (Part 900—999) VI Office of the Assistant Secretary, Indian Affairs, Department of the Interior (Parts 1000—1199) VII Office of the Special Trustee for American Indians, Department of the Interior (Parts 1200—1299)

Title 26—Internal Revenue

I Internal Revenue Service, Department of the Treasury (Parts 1— End)

Title 27—Alcohol, Tobacco Products and Firearms

I Alcohol and Tobacco Tax and Trade Bureau, Department of the Treasury (Parts 1—399) II Bureau of Alcohol, Tobacco, Firearms, and Explosives, Depart- ment of Justice (Parts 400—699)

Title 28—Judicial Administration

I Department of Justice (Parts 0—299) III Federal Prison Industries, Inc., Department of Justice (Parts 300—399) V Bureau of Prisons, Department of Justice (Parts 500—599) VI Offices of Independent Counsel, Department of Justice (Parts 600—699) VII Office of Independent Counsel (Parts 700—799) VIII Court Services and Offender Supervision Agency for the District of Columbia (Parts 800—899) IX National Crime Prevention and Privacy Compact Council (Parts 900—999) XI Department of Justice and Department of State (Parts 1100— 1199)

Title 29—Labor

SUBTITLE A—OFFICE OF THE SECRETARY OF LABOR (PARTS 0—99) SUBTITLE B—REGULATIONS RELATING TO LABOR I National Labor Relations Board (Parts 100—199)

227

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00237 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 29—Labor—Continued Chap.

II Office of Labor-Management Standards, Department of Labor (Parts 200—299) III National Railroad Adjustment Board (Parts 300—399) IV Office of Labor-Management Standards, Department of Labor (Parts 400—499) V Wage and Hour Division, Department of Labor (Parts 500—899) IX Construction Industry Collective Bargaining Commission (Parts 900—999) X National Mediation Board (Parts 1200—1299) XII Federal Mediation and Conciliation Service (Parts 1400—1499) XIV Equal Employment Opportunity Commission (Parts 1600—1699) XVII Occupational Safety and Health Administration, Department of Labor (Parts 1900—1999) XX Occupational Safety and Health Review Commission (Parts 2200—2499) XXV Employee Benefits Security Administration, Department of Labor (Parts 2500—2599) XXVII Federal Mine Safety and Health Review Commission (Parts 2700—2799) XL Pension Benefit Guaranty Corporation (Parts 4000—4999)

Title 30—Mineral Resources

I Mine Safety and Health Administration, Department of Labor (Parts 1—199) II Bureau of Safety and Environmental Enforcement, Department of the Interior (Parts 200—299) IV Geological Survey, Department of the Interior (Parts 400—499) V Bureau of Ocean Energy Management, Department of the Inte- rior (Parts 500—599) VII Office of Surface Mining Reclamation and Enforcement, Depart- ment of the Interior (Parts 700—999) XII Office of Natural Resources Revenue, Department of the Interior (Parts 1200—1299)

Title 31—Money and Finance: Treasury

SUBTITLE A—OFFICE OF THE SECRETARY OF THE TREASURY (PARTS 0—50) SUBTITLE B—REGULATIONS RELATING TO MONEY AND FINANCE I Monetary Offices, Department of the Treasury (Parts 51—199) II Fiscal Service, Department of the Treasury (Parts 200—399) IV Secret Service, Department of the Treasury (Parts 400—499) V Office of Foreign Assets Control, Department of the Treasury (Parts 500—599) VI Bureau of Engraving and Printing, Department of the Treasury (Parts 600—699) VII Federal Law Enforcement Training Center, Department of the Treasury (Parts 700—799)

228

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00238 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 31—Money and Finance: Treasury—Continued Chap.

VIII Office of Investment Security, Department of the Treasury (Parts 800—899) IX Federal Claims Collection Standards (Department of the Treas- ury—Department of Justice) (Parts 900—999) X Financial Crimes Enforcement Network, Department of the Treasury (Parts 1000—1099)

Title 32—National Defense

SUBTITLE A—DEPARTMENT OF DEFENSE I Office of the Secretary of Defense (Parts 1—399) V Department of the Army (Parts 400—699) VI Department of the Navy (Parts 700—799) VII Department of the Air Force (Parts 800—1099) SUBTITLE B—OTHER REGULATIONS RELATING TO NATIONAL DE- FENSE XII Defense Logistics Agency (Parts 1200—1299) XVI Selective Service System (Parts 1600—1699) XVII Office of the Director of National Intelligence (Parts 1700—1799) XVIII National Counterintelligence Center (Parts 1800—1899) XIX Central Intelligence Agency (Parts 1900—1999) XX Information Security Oversight Office, National Archives and Records Administration (Parts 2000—2099) XXI National Security Council (Parts 2100—2199) XXIV Office of Science and Technology Policy (Parts 2400—2499) XXVII Office for Micronesian Status Negotiations (Parts 2700—2799) XXVIII Office of the Vice President of the United States (Parts 2800— 2899)

Title 33—Navigation and Navigable Waters

I Coast Guard, Department of Homeland Security (Parts 1—199) II Corps of Engineers, Department of the Army, Department of De- fense (Parts 200—399) IV Saint Lawrence Seaway Development Corporation, Department of Transportation (Parts 400—499)

Title 34—Education

SUBTITLE A—OFFICE OF THE SECRETARY, DEPARTMENT OF EDU- CATION (PARTS 1—99) SUBTITLE B—REGULATIONS OF THE OFFICES OF THE DEPARTMENT OF EDUCATION I Office for Civil Rights, Department of Education (Parts 100—199) II Office of Elementary and Secondary Education, Department of Education (Parts 200—299) III Office of Special Education and Rehabilitative Services, Depart- ment of Education (Parts 300—399)

229

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00239 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 34—Education—Continued Chap.

IV Office of Career, Technical and Adult Education, Department of Education (Parts 400—499) V Office of Bilingual Education and Minority Languages Affairs, Department of Education (Parts 500—599) [Reserved] VI Office of Postsecondary Education, Department of Education (Parts 600—699) VII Office of Educational Research and Improvement, Department of Education (Parts 700—799) [Reserved] SUBTITLE C—REGULATIONS RELATING TO EDUCATION XI (Parts 1100—1199) [Reserved] XII National Council on Disability (Parts 1200—1299)

Title 35 [Reserved]

Title 36—Parks, Forests, and Public Property

I National Park Service, Department of the Interior (Parts 1—199) II Forest Service, Department of Agriculture (Parts 200—299) III Corps of Engineers, Department of the Army (Parts 300—399) IV American Battle Monuments Commission (Parts 400—499) V Smithsonian Institution (Parts 500—599) VI [Reserved] VII Library of Congress (Parts 700—799) VIII Advisory Council on Historic Preservation (Parts 800—899) IX Pennsylvania Avenue Development Corporation (Parts 900—999) X Presidio Trust (Parts 1000—1099) XI Architectural and Transportation Barriers Compliance Board (Parts 1100—1199) XII National Archives and Records Administration (Parts 1200—1299) XV Oklahoma City National Memorial Trust (Parts 1500—1599) XVI Morris K. Udall Scholarship and Excellence in National Environ- mental Policy Foundation (Parts 1600—1699)

Title 37—Patents, Trademarks, and Copyrights

I United States Patent and Trademark Office, Department of Commerce (Parts 1—199) II U.S. Copyright Office, Library of Congress (Parts 200—299) III Copyright Royalty Board, Library of Congress (Parts 300—399) IV National Institute of Standards and Technology, Department of Commerce (Parts 400—599)

Title 38—Pensions, Bonuses, and Veterans’ Relief

I Department of Veterans Affairs (Parts 0—199) II Armed Forces Retirement Home (Parts 200—299)

230

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00240 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 39—Postal Service Chap.

I United States Postal Service (Parts 1—999) III Postal Regulatory Commission (Parts 3000—3099)

Title 40—Protection of Environment

I Environmental Protection Agency (Parts 1—1099) IV Environmental Protection Agency and Department of Justice (Parts 1400—1499) V Council on Environmental Quality (Parts 1500—1599) VI Chemical Safety and Hazard Investigation Board (Parts 1600— 1699) VII Environmental Protection Agency and Department of Defense; Uniform National Discharge Standards for Vessels of the Armed Forces (Parts 1700—1799) VIII Gulf Coast Ecosystem Restoration Council (Parts 1800—1899)

Title 41—Public Contracts and Property Management

SUBTITLE A—FEDERAL PROCUREMENT REGULATIONS SYSTEM [NOTE] SUBTITLE B—OTHER PROVISIONS RELATING TO PUBLIC CONTRACTS 50 Public Contracts, Department of Labor (Parts 50–1—50–999) 51 Committee for Purchase From People Who Are Blind or Severely Disabled (Parts 51–1—51–99) 60 Office of Federal Contract Compliance Programs, Equal Employ- ment Opportunity, Department of Labor (Parts 60–1—60–999) 61 Office of the Assistant Secretary for Veterans’ Employment and Training Service, Department of Labor (Parts 61–1—61–999) 62—100 [Reserved] SUBTITLE C—FEDERAL PROPERTY MANAGEMENT REGULATIONS SYSTEM 101 Federal Property Management Regulations (Parts 101–1—101–99) 102 Federal Management Regulation (Parts 102–1—102–299) 103—104 [Reserved] 105 General Services Administration (Parts 105–1—105–999) 109 Department of Energy Property Management Regulations (Parts 109–1—109–99) 114 Department of the Interior (Parts 114–1—114–99) 115 Environmental Protection Agency (Parts 115–1—115–99) 128 Department of Justice (Parts 128–1—128–99) 129—200 [Reserved] SUBTITLE D—OTHER PROVISIONS RELATING TO PROPERTY MANAGE- MENT [RESERVED] SUBTITLE E—FEDERAL INFORMATION RESOURCES MANAGEMENT REGULATIONS SYSTEM [RESERVED] SUBTITLE F—FEDERAL TRAVEL REGULATION SYSTEM 300 General (Parts 300–1—300–99) 301 Temporary Duty (TDY) Travel Allowances (Parts 301–1—301–99)

231

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00241 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 41—Public Contracts and Property Management—Continued Chap.

302 Relocation Allowances (Parts 302–1—302–99) 303 Payment of Expenses Connected with the Death of Certain Em- ployees (Part 303–1—303–99) 304 Payment of Travel Expenses from a Non-Federal Source (Parts 304–1—304–99)

Title 42—Public Health

I Public Health Service, Department of Health and Human Serv- ices (Parts 1—199) II—III [Reserved] IV Centers for Medicare & Medicaid Services, Department of Health and Human Services (Parts 400—699) V Office of Inspector General-Health Care, Department of Health and Human Services (Parts 1000—1099)

Title 43—Public Lands: Interior

SUBTITLE A—OFFICE OF THE SECRETARY OF THE INTERIOR (PARTS 1—199) SUBTITLE B—REGULATIONS RELATING TO PUBLIC LANDS I Bureau of Reclamation, Department of the Interior (Parts 400— 999) II Bureau of Land Management, Department of the Interior (Parts 1000—9999) III Utah Reclamation Mitigation and Conservation Commission (Parts 10000—10099)

Title 44—Emergency Management and Assistance

I Federal Emergency Management Agency, Department of Home- land Security (Parts 0—399) IV Department of Commerce and Department of Transportation (Parts 400—499)

Title 45—Public Welfare

SUBTITLE A—DEPARTMENT OF HEALTH AND HUMAN SERVICES (PARTS 1—199) SUBTITLE B—REGULATIONS RELATING TO PUBLIC WELFARE II Office of Family Assistance (Assistance Programs), Administra- tion for Children and Families, Department of Health and Human Services (Parts 200—299) III Office of Child Support Enforcement (Child Support Enforce- ment Program), Administration for Children and Families, Department of Health and Human Services (Parts 300—399) IV Office of Refugee Resettlement, Administration for Children and Families, Department of Health and Human Services (Parts 400—499)

232

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00242 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 45—Public Welfare—Continued Chap.

V Foreign Claims Settlement Commission of the United States, Department of Justice (Parts 500—599) VI National Science Foundation (Parts 600—699) VII Commission on Civil Rights (Parts 700—799) VIII Office of Personnel Management (Parts 800—899) IX Denali Commission (Parts 900—999) X Office of Community Services, Administration for Children and Families, Department of Health and Human Services (Parts 1000—1099) XI National Foundation on the Arts and the Humanities (Parts 1100—1199) XII Corporation for National and Community Service (Parts 1200— 1299) XIII Administration for Children and Families, Department of Health and Human Services (Parts 1300—1399) XVI Legal Services Corporation (Parts 1600—1699) XVII National Commission on Libraries and Information Science (Parts 1700—1799) XVIII Harry S. Truman Scholarship Foundation (Parts 1800—1899) XXI Commission of Fine Arts (Parts 2100—2199) XXIII Arctic Research Commission (Parts 2300—2399) XXIV James Madison Memorial Fellowship Foundation (Parts 2400— 2499) XXV Corporation for National and Community Service (Parts 2500— 2599)

Title 46—Shipping

I Coast Guard, Department of Homeland Security (Parts 1—199) II Maritime Administration, Department of Transportation (Parts 200—399) III Coast Guard (Great Lakes Pilotage), Department of Homeland Security (Parts 400—499) IV Federal Maritime Commission (Parts 500—599)

Title 47—Telecommunication

I Federal Communications Commission (Parts 0—199) II Office of Science and Technology Policy and National Security Council (Parts 200—299) III National Telecommunications and Information Administration, Department of Commerce (Parts 300—399) IV National Telecommunications and Information Administration, Department of Commerce, and National Highway Traffic Safe- ty Administration, Department of Transportation (Parts 400— 499) V The First Responder Network Authority (Parts 500—599)

233

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00243 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 48—Federal Acquisition Regulations System Chap.

1 Federal Acquisition Regulation (Parts 1—99) 2 Defense Acquisition Regulations System, Department of Defense (Parts 200—299) 3 Department of Health and Human Services (Parts 300—399) 4 Department of Agriculture (Parts 400—499) 5 General Services Administration (Parts 500—599) 6 Department of State (Parts 600—699) 7 Agency for International Development (Parts 700—799) 8 Department of Veterans Affairs (Parts 800—899) 9 Department of Energy (Parts 900—999) 10 Department of the Treasury (Parts 1000—1099) 12 Department of Transportation (Parts 1200—1299) 13 Department of Commerce (Parts 1300—1399) 14 Department of the Interior (Parts 1400—1499) 15 Environmental Protection Agency (Parts 1500—1599) 16 Office of Personnel Management, Federal Employees Health Benefits Acquisition Regulation (Parts 1600—1699) 17 Office of Personnel Management (Parts 1700—1799) 18 National Aeronautics and Space Administration (Parts 1800— 1899) 19 Broadcasting Board of Governors (Parts 1900—1999) 20 Nuclear Regulatory Commission (Parts 2000—2099) 21 Office of Personnel Management, Federal Employees Group Life Insurance Federal Acquisition Regulation (Parts 2100—2199) 23 Social Security Administration (Parts 2300—2399) 24 Department of Housing and Urban Development (Parts 2400— 2499) 25 National Science Foundation (Parts 2500—2599) 28 Department of Justice (Parts 2800—2899) 29 Department of Labor (Parts 2900—2999) 30 Department of Homeland Security, Homeland Security Acquisi- tion Regulation (HSAR) (Parts 3000—3099) 34 Department of Education Acquisition Regulation (Parts 3400— 3499) 51 Department of the Army Acquisition Regulations (Parts 5100— 5199) 52 Department of the Navy Acquisition Regulations (Parts 5200— 5299) 53 Department of the Air Force Federal Acquisition Regulation Supplement (Parts 5300—5399) [Reserved] 54 Defense Logistics Agency, Department of Defense (Parts 5400— 5499) 57 African Development Foundation (Parts 5700—5799) 61 Civilian Board of Contract Appeals, General Services Adminis- tration (Parts 6100—6199) 99 Cost Accounting Standards Board, Office of Federal Procure- ment Policy, Office of Management and Budget (Parts 9900— 9999)

234

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00244 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Title 49—Transportation Chap.

SUBTITLE A—OFFICE OF THE SECRETARY OF TRANSPORTATION (PARTS 1—99) SUBTITLE B—OTHER REGULATIONS RELATING TO TRANSPORTATION I Pipeline and Hazardous Materials Safety Administration, De- partment of Transportation (Parts 100—199) II Federal Railroad Administration, Department of Transportation (Parts 200—299) III Federal Motor Carrier Safety Administration, Department of Transportation (Parts 300—399) IV Coast Guard, Department of Homeland Security (Parts 400—499) V National Highway Traffic Safety Administration, Department of Transportation (Parts 500—599) VI Federal Transit Administration, Department of Transportation (Parts 600—699) VII National Railroad Passenger Corporation (AMTRAK) (Parts 700—799) VIII National Transportation Safety Board (Parts 800—999) X Surface Transportation Board (Parts 1000—1399) XI Research and Innovative Technology Administration, Depart- ment of Transportation (Parts 1400—1499) [Reserved] XII Transportation Security Administration, Department of Home- land Security (Parts 1500—1699)

Title 50—Wildlife and Fisheries

I United States Fish and Wildlife Service, Department of the Inte- rior (Parts 1—199) II National Marine Fisheries Service, National Oceanic and Atmos- pheric Administration, Department of Commerce (Parts 200— 299) III International Fishing and Related Activities (Parts 300—399) IV Joint Regulations (United States Fish and Wildlife Service, De- partment of the Interior and National Marine Fisheries Serv- ice, National Oceanic and Atmospheric Administration, De- partment of Commerce); Endangered Species Committee Reg- ulations (Parts 400—499) V Marine Mammal Commission (Parts 500—599) VI Fishery Conservation and Management, National Oceanic and Atmospheric Administration, Department of Commerce (Parts 600—699)

235

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00245 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00246 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 Alphabetical List of Agencies Appearing in the CFR (Revised as of April 1, 2019)

CFR Title, Subtitle or Agency Chapter Administrative Conference of the United States 1, III Advisory Council on Historic Preservation 36, VIII Advocacy and Outreach, Office of 7, XXV Afghanistan Reconstruction, Special Inspector General for 5, LXXXIII African Development Foundation 22, XV Federal Acquisition Regulation 48, 57 Agency for International Development 2, VII; 22, II Federal Acquisition Regulation 48, 7 Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Agriculture, Department of 2, IV; 5, LXXIII Advocacy and Outreach, Office of 7, XXV Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Animal and Plant Health Inspection Service 7, III; 9, I Chief Financial Officer, Office of 7, XXX Commodity Credit Corporation 7, XIV Economic Research Service 7, XXXVII Energy Policy and New Uses, Office of 2, IX; 7, XXIX Environmental Quality, Office of 7, XXXI Farm Service Agency 7, VII, XVIII Federal Acquisition Regulation 48, 4 Federal Crop Insurance Corporation 7, IV Food and Nutrition Service 7, II Food Safety and Inspection Service 9, III Foreign Agricultural Service 7, XV Forest Service 36, II Grain Inspection, Packers and Stockyards Administration 7, VIII; 9, II Information Resources Management, Office of 7, XXVII Inspector General, Office of 7, XXVI National Agricultural Library 7, XLI National Agricultural Statistics Service 7, XXXVI National Institute of Food and Agriculture 7, XXXIV Natural Resources Conservation Service 7, VI Operations, Office of 7, XXVIII Procurement and Property Management, Office of 7, XXXII Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Secretary of Agriculture, Office of 7, Subtitle A Transportation, Office of 7, XXXIII World Agricultural Outlook Board 7, XXXVIII Air Force, Department of 32, VII Federal Acquisition Regulation Supplement 48, 53 Air Transportation Stabilization Board 14, VI Alcohol and Tobacco Tax and Trade Bureau 27, I Alcohol, Tobacco, Firearms, and Explosives, Bureau of 27, II AMTRAK 49, VII American Battle Monuments Commission 36, IV American Indians, Office of the Special Trustee 25, VII Animal and Plant Health Inspection Service 7, III; 9, I

237

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00247 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Appalachian Regional Commission 5, IX Architectural and Transportation Barriers Compliance Board 36, XI Arctic Research Commission 45, XXIII Armed Forces Retirement Home 5, XI Army, Department of 32, V Engineers, Corps of 33, II; 36, III Federal Acquisition Regulation 48, 51 Bilingual Education and Minority Languages Affairs, Office of 34, V Blind or Severely Disabled, Committee for Purchase from 41, 51 People Who Are Broadcasting Board of Governors 22, V Federal Acquisition Regulation 48, 19 Career, Technical, and Adult Education, Office of 34, IV Census Bureau 15, I Centers for Medicare & Medicaid Services 42, IV Central Intelligence Agency 32, XIX Chemical Safety and Hazardous Investigation Board 40, VI Chief Financial Officer, Office of 7, XXX Child Support Enforcement, Office of 45, III Children and Families, Administration for 45, II, III, IV, X, XIII Civil Rights, Commission on 5, LXVIII; 45, VII Civil Rights, Office for 34, I Council of the Inspectors General on Integrity and Efficiency 5, XCVIII Court Services and Offender Supervision Agency for the 5, LXX District of Columbia Coast Guard 33, I; 46, I; 49, IV Coast Guard (Great Lakes Pilotage) 46, III Commerce, Department of 2, XIII; 44, IV; 50, VI Census Bureau 15, I Economic Analysis, Bureau of 15, VIII Economic Development Administration 13, III Emergency Management and Assistance 44, IV Federal Acquisition Regulation 48, 13 Foreign-Trade Zones Board 15, IV Industry and Security, Bureau of 15, VII International Trade Administration 15, III; 19, III National Institute of Standards and Technology 15, II; 37, IV National Marine Fisheries Service 50, II, IV National Oceanic and Atmospheric Administration 15, IX; 50, II, III, IV, VI National Technical Information Service 15, XI National Telecommunications and Information 15, XXIII; 47, III, IV Administration National Weather Service 15, IX Patent and Trademark Office, United States 37, I Secretary of Commerce, Office of 15, Subtitle A Commercial Space Transportation 14, III Commodity Credit Corporation 7, XIV Commodity Futures Trading Commission 5, XLI; 17, I Community Planning and Development, Office of Assistant 24, V, VI Secretary for Community Services, Office of 45, X Comptroller of the Currency 12, I Construction Industry Collective Bargaining Commission 29, IX Consumer Financial Protection Bureau 5, LXXXIV; 12, X Consumer Product Safety Commission 5, LXXI; 16, II Copyright Royalty Board 37, III Corporation for National and Community Service 2, XXII; 45, XII, XXV Cost Accounting Standards Board 48, 99 Council on Environmental Quality 40, V Court Services and Offender Supervision Agency for the 5, LXX; 28, VIII District of Columbia Customs and Border Protection 19, I Defense Contract Audit Agency 32, I Defense, Department of 2, XI; 5, XXVI; 32, Subtitle A; 40, VII Advanced Research Projects Agency 32, I Air Force Department 32, VII

238

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00248 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Army Department 32, V; 33, II; 36, III; 48, 51 Defense Acquisition Regulations System 48, 2 Defense Intelligence Agency 32, I Defense Logistics Agency 32, I, XII; 48, 54 Engineers, Corps of 33, II; 36, III National Imagery and Mapping Agency 32, I Navy Department 32, VI; 48, 52 Secretary of Defense, Office of 2, XI; 32, I Defense Contract Audit Agency 32, I Defense Intelligence Agency 32, I Defense Logistics Agency 32, XII; 48, 54 Defense Nuclear Facilities Safety Board 10, XVII Delaware River Basin Commission 18, III Denali Commission 45, IX Disability, National Council on 5, C; 34, XII District of Columbia, Court Services and Offender Supervision 5, LXX; 28, VIII Agency for the Drug Enforcement Administration 21, II East-West Foreign Trade Board 15, XIII Economic Analysis, Bureau of 15, VIII Economic Development Administration 13, III Economic Research Service 7, XXXVII Education, Department of 2, XXXIV; 5, LIII Bilingual Education and Minority Languages Affairs, Office 34, V of Career, Technical, and Adult Education, Office of 34, IV Civil Rights, Office for 34, I Educational Research and Improvement, Office of 34, VII Elementary and Secondary Education, Office of 34, II Federal Acquisition Regulation 48, 34 Postsecondary Education, Office of 34, VI Secretary of Education, Office of 34, Subtitle A Special Education and Rehabilitative Services, Office of 34, III Educational Research and Improvement, Office of 34, VII Election Assistance Commission 2, LVIII; 11, II Elementary and Secondary Education, Office of 34, II Emergency Oil and Gas Guaranteed Loan Board 13, V Emergency Steel Guarantee Loan Board 13, IV Employee Benefits Security Administration 29, XXV Employees’ Compensation Appeals Board 20, IV Employees Loyalty Board 5, V Employment and Training Administration 20, V Employment Policy, National Commission for 1, IV Employment Standards Administration 20, VI Endangered Species Committee 50, IV Energy, Department of 2, IX; 5, XXIII; 10, II, III, X Federal Acquisition Regulation 48, 9 Federal Energy Regulatory Commission 5, XXIV; 18, I Property Management Regulations 41, 109 Energy, Office of 7, XXIX Engineers, Corps of 33, II; 36, III Engraving and Printing, Bureau of 31, VI Environmental Protection Agency 2, XV; 5, LIV; 40, I, IV, VII Federal Acquisition Regulation 48, 15 Property Management Regulations 41, 115 Environmental Quality, Office of 7, XXXI Equal Employment Opportunity Commission 5, LXII; 29, XIV Equal Opportunity, Office of Assistant Secretary for 24, I Executive Office of the President 3, I Environmental Quality, Council on 40, V Management and Budget, Office of 2, Subtitle A; 5, III, LXXVII; 14, VI; 48, 99 National Drug Control Policy, Office of 2, XXXVI; 21, III National Security Council 32, XXI; 47, 2

239

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00249 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Presidential Documents 3 Science and Technology Policy, Office of 32, XXIV; 47, II Trade Representative, Office of the United States 15, XX Export-Import Bank of the United States 2, XXXV; 5, LII; 12, IV Family Assistance, Office of 45, II Farm Credit Administration 5, XXXI; 12, VI Farm Credit System Insurance Corporation 5, XXX; 12, XIV Farm Service Agency 7, VII, XVIII Federal Acquisition Regulation 48, 1 Federal Aviation Administration 14, I Commercial Space Transportation 14, III Federal Claims Collection Standards 31, IX Federal Communications Commission 5, XXIX; 47, I Federal Contract Compliance Programs, Office of 41, 60 Federal Crop Insurance Corporation 7, IV Federal Deposit Insurance Corporation 5, XXII; 12, III Federal Election Commission 5, XXXVII; 11, I Federal Emergency Management Agency 44, I Federal Employees Group Life Insurance Federal Acquisition 48, 21 Regulation Federal Employees Health Benefits Acquisition Regulation 48, 16 Federal Energy Regulatory Commission 5, XXIV; 18, I Federal Financial Institutions Examination Council 12, XI Federal Financing Bank 12, VIII Federal Highway Administration 23, I, II Federal Home Loan Mortgage Corporation 1, IV Federal Housing Enterprise Oversight Office 12, XVII Federal Housing Finance Agency 5, LXXX; 12, XII Federal Housing Finance Board 12, IX Federal Labor Relations Authority 5, XIV, XLIX; 22, XIV Federal Law Enforcement Training Center 31, VII Federal Management Regulation 41, 102 Federal Maritime Commission 46, IV Federal Mediation and Conciliation Service 29, XII Federal Mine Safety and Health Review Commission 5, LXXIV; 29, XXVII Federal Motor Carrier Safety Administration 49, III Federal Prison Industries, Inc. 28, III Federal Procurement Policy Office 48, 99 Federal Property Management Regulations 41, 101 Federal Railroad Administration 49, II Federal Register, Administrative Committee of 1, I Federal Register, Office of 1, II Federal Reserve System 12, II Board of Governors 5, LVIII Federal Retirement Thrift Investment Board 5, VI, LXXVI Federal Service Impasses Panel 5, XIV Federal Trade Commission 5, XLVII; 16, I Federal Transit Administration 49, VI Federal Travel Regulation System 41, Subtitle F Financial Crimes Enforcement Network 31, X Financial Research Office 12, XVI Financial Stability Oversight Council 12, XIII Fine Arts, Commission of 45, XXI Fiscal Service 31, II Fish and Wildlife Service, United States 50, I, IV Food and Drug Administration 21, I Food and Nutrition Service 7, II Food Safety and Inspection Service 9, III Foreign Agricultural Service 7, XV Foreign Assets Control, Office of 31, V Foreign Claims Settlement Commission of the United States 45, V Foreign Service Grievance Board 22, IX Foreign Service Impasse Disputes Panel 22, XIV Foreign Service Labor Relations Board 22, XIV Foreign-Trade Zones Board 15, IV Forest Service 36, II General Services Administration 5, LVII; 41, 105

240

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00250 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Contract Appeals, Board of 48, 61 Federal Acquisition Regulation 48, 5 Federal Management Regulation 41, 102 Federal Property Management Regulations 41, 101 Federal Travel Regulation System 41, Subtitle F General 41, 300 Payment From a Non-Federal Source for Travel Expenses 41, 304 Payment of Expenses Connected With the Death of Certain 41, 303 Employees Relocation Allowances 41, 302 Temporary Duty (TDY) Travel Allowances 41, 301 Geological Survey 30, IV Government Accountability Office 4, I Government Ethics, Office of 5, XVI Government National Mortgage Association 24, III Grain Inspection, Packers and Stockyards Administration 7, VIII; 9, II Gulf Coast Ecosystem Restoration Council 2, LIX; 40, VIII Harry S. Truman Scholarship Foundation 45, XVIII Health and Human Services, Department of 2, III; 5, XLV; 45, Subtitle A Centers for Medicare & Medicaid Services 42, IV Child Support Enforcement, Office of 45, III Children and Families, Administration for 45, II, III, IV, X, XIII Community Services, Office of 45, X Family Assistance, Office of 45, II Federal Acquisition Regulation 48, 3 Food and Drug Administration 21, I Indian Health Service 25, V Inspector General (Health Care), Office of 42, V Public Health Service 42, I Refugee Resettlement, Office of 45, IV Homeland Security, Department of 2, XXX; 5, XXXVI; 6, I; 8, I Coast Guard 33, I; 46, I; 49, IV Coast Guard (Great Lakes Pilotage) 46, III Customs and Border Protection 19, I Federal Emergency Management Agency 44, I Human Resources Management and Labor Relations 5, XCVII Systems Immigration and Customs Enforcement Bureau 19, IV Transportation Security Administration 49, XII HOPE for Homeowners Program, Board of Directors of 24, XXIV Housing and Urban Development, Department of 2, XXIV; 5, LXV; 24, Subtitle B Community Planning and Development, Office of Assistant 24, V, VI Secretary for Equal Opportunity, Office of Assistant Secretary for 24, I Federal Acquisition Regulation 48, 24 Federal Housing Enterprise Oversight, Office of 12, XVII Government National Mortgage Association 24, III Housing—Federal Housing Commissioner, Office of 24, II, VIII, X, XX Assistant Secretary for Housing, Office of, and Multifamily Housing Assistance 24, IV Restructuring, Office of Inspector General, Office of 24, XII Public and Indian Housing, Office of Assistant Secretary for 24, IX Secretary, Office of 24, Subtitle A, VII Housing—Federal Housing Commissioner, Office of Assistant 24, II, VIII, X, XX Secretary for Housing, Office of, and Multifamily Housing Assistance 24, IV Restructuring, Office of Immigration and Customs Enforcement Bureau 19, IV Immigration Review, Executive Office for 8, V Independent Counsel, Office of 28, VII Independent Counsel, Offices of 28, VI Indian Affairs, Bureau of 25, I, V Indian Affairs, Office of the Assistant Secretary 25, VI

241

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00251 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Indian Arts and Crafts Board 25, II Indian Health Service 25, V Industry and Security, Bureau of 15, VII Information Resources Management, Office of 7, XXVII Information Security Oversight Office, National Archives and 32, XX Records Administration Inspector General Agriculture Department 7, XXVI Health and Human Services Department 42, V Housing and Urban Development Department 24, XII, XV Institute of Peace, United States 22, XVII Inter-American Foundation 5, LXIII; 22, X Interior, Department of 2, XIV American Indians, Office of the Special Trustee 25, VII Endangered Species Committee 50, IV Federal Acquisition Regulation 48, 14 Federal Property Management Regulations System 41, 114 Fish and Wildlife Service, United States 50, I, IV Geological Survey 30, IV Indian Affairs, Bureau of 25, I, V Indian Affairs, Office of the Assistant Secretary 25, VI Indian Arts and Crafts Board 25, II Land Management, Bureau of 43, II National Indian Gaming Commission 25, III National Park Service 36, I Natural Resource Revenue, Office of 30, XII Ocean Energy Management, Bureau of 30, V Reclamation, Bureau of 43, I Safety and Enforcement Bureau, Bureau of 30, II Secretary of the Interior, Office of 2, XIV; 43, Subtitle A Surface Mining Reclamation and Enforcement, Office of 30, VII Internal Revenue Service 26, I International Boundary and Water Commission, United States 22, XI and Mexico, United States Section International Development, United States Agency for 22, II Federal Acquisition Regulation 48, 7 International Development Cooperation Agency, United 22, XII States International Joint Commission, United States and Canada 22, IV International Organizations Employees Loyalty Board 5, V International Trade Administration 15, III; 19, III International Trade Commission, United States 19, II Interstate Commerce Commission 5, XL Investment Security, Office of 31, VIII James Madison Memorial Fellowship Foundation 45, XXIV Japan–United States Friendship Commission 22, XVI Joint Board for the Enrollment of Actuaries 20, VIII Justice, Department of 2, XXVIII; 5, XXVIII; 28, I, XI; 40, IV Alcohol, Tobacco, Firearms, and Explosives, Bureau of 27, II Drug Enforcement Administration 21, II Federal Acquisition Regulation 48, 28 Federal Claims Collection Standards 31, IX Federal Prison Industries, Inc. 28, III Foreign Claims Settlement Commission of the United 45, V States Immigration Review, Executive Office for 8, V Independent Counsel, Offices of 28, VI Prisons, Bureau of 28, V Property Management Regulations 41, 128 Labor, Department of 2, XXIX; 5, XLII Employee Benefits Security Administration 29, XXV Employees’ Compensation Appeals Board 20, IV Employment and Training Administration 20, V Employment Standards Administration 20, VI Federal Acquisition Regulation 48, 29 Federal Contract Compliance Programs, Office of 41, 60

242

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00252 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Federal Procurement Regulations System 41, 50 Labor-Management Standards, Office of 29, II, IV Mine Safety and Health Administration 30, I Occupational Safety and Health Administration 29, XVII Public Contracts 41, 50 Secretary of Labor, Office of 29, Subtitle A Veterans’ Employment and Training Service, Office of the 41, 61; 20, IX Assistant Secretary for Wage and Hour Division 29, V Workers’ Compensation Programs, Office of 20, I, VII Labor-Management Standards, Office of 29, II, IV Land Management, Bureau of 43, II Legal Services Corporation 45, XVI Libraries and Information Science, National Commission on 45, XVII Library of Congress 36, VII Copyright Royalty Board 37, III U.S. Copyright Office 37, II Local Television Loan Guarantee Board 7, XX Management and Budget, Office of 5, III, LXXVII; 14, VI; 48, 99 Marine Mammal Commission 50, V Maritime Administration 46, II Merit Systems Protection Board 5, II, LXIV Micronesian Status Negotiations, Office for 32, XXVII Military Compensation and Retirement Modernization 5, XCIX Commission Millennium Challenge Corporation 22, XIII Mine Safety and Health Administration 30, I Minority Business Development Agency 15, XIV Miscellaneous Agencies 1, IV Monetary Offices 31, I Morris K. Udall Scholarship and Excellence in National 36, XVI Environmental Policy Foundation Museum and Library Services, Institute of 2, XXXI National Aeronautics and Space Administration 2, XVIII; 5, LIX; 14, V Federal Acquisition Regulation 48, 18 National Agricultural Library 7, XLI National Agricultural Statistics Service 7, XXXVI National and Community Service, Corporation for 2, XXII; 45, XII, XXV National Archives and Records Administration 2, XXVI; 5, LXVI; 36, XII Information Security Oversight Office 32, XX National Capital Planning Commission 1, IV, VI National Counterintelligence Center 32, XVIII National Credit Union Administration 5, LXXXVI; 12, VII National Crime Prevention and Privacy Compact Council 28, IX National Drug Control Policy, Office of 2, XXXVI; 21, III National Endowment for the Arts 2, XXXII National Endowment for the Humanities 2, XXXIII National Foundation on the Arts and the Humanities 45, XI National Geospatial-Intelligence Agency 32, I National Highway Traffic Safety Administration 23, II, III; 47, VI; 49, V National Imagery and Mapping Agency 32, I National Indian Gaming Commission 25, III National Institute of Food and Agriculture 7, XXXIV National Institute of Standards and Technology 15, II; 37, IV National Intelligence, Office of Director of 5, IV; 32, XVII National Labor Relations Board 5, LXI; 29, I National Marine Fisheries Service 50, II, IV National Mediation Board 5, CI; 29, X National Oceanic and Atmospheric Administration 15, IX; 50, II, III, IV, VI National Park Service 36, I National Railroad Adjustment Board 29, III National Railroad Passenger Corporation (AMTRAK) 49, VII National Science Foundation 2, XXV; 5, XLIII; 45, VI Federal Acquisition Regulation 48, 25 National Security Council 32, XXI

243

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00253 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter National Security Council and Office of Science and 47, II Technology Policy National Technical Information Service 15, XI National Telecommunications and Information 15, XXIII; 47, III, IV, V Administration National Transportation Safety Board 49, VIII Natural Resources Conservation Service 7, VI Natural Resource Revenue, Office of 30, XII Navajo and Hopi Indian Relocation, Office of 25, IV Navy, Department of 32, VI Federal Acquisition Regulation 48, 52 Neighborhood Reinvestment Corporation 24, XXV Northeast Interstate Low-Level Radioactive Waste 10, XVIII Commission Nuclear Regulatory Commission 2, XX; 5, XLVIII; 10, I Federal Acquisition Regulation 48, 20 Occupational Safety and Health Administration 29, XVII Occupational Safety and Health Review Commission 29, XX Ocean Energy Management, Bureau of 30, V Oklahoma City National Memorial Trust 36, XV Operations Office 7, XXVIII Overseas Private Investment Corporation 5, XXXIII; 22, VII Patent and Trademark Office, United States 37, I Payment From a Non-Federal Source for Travel Expenses 41, 304 Payment of Expenses Connected With the Death of Certain 41, 303 Employees Peace Corps 2, XXXVII; 22, III Pennsylvania Avenue Development Corporation 36, IX Pension Benefit Guaranty Corporation 29, XL Personnel Management, Office of 5, I, XXXV; 5, IV; 45, VIII Human Resources Management and Labor Relations 5, XCVII Systems, Department of Homeland Security Federal Acquisition Regulation 48, 17 Federal Employees Group Life Insurance Federal 48, 21 Acquisition Regulation Federal Employees Health Benefits Acquisition Regulation 48, 16 Pipeline and Hazardous Materials Safety Administration 49, I Postal Regulatory Commission 5, XLVI; 39, III Postal Service, United States 5, LX; 39, I Postsecondary Education, Office of 34, VI President’s Commission on White House Fellowships 1, IV Presidential Documents 3 Presidio Trust 36, X Prisons, Bureau of 28, V Privacy and Civil Liberties Oversight Board 6, X Procurement and Property Management, Office of 7, XXXII Public Contracts, Department of Labor 41, 50 Public and Indian Housing, Office of Assistant Secretary for 24, IX Public Health Service 42, I Railroad Retirement Board 20, II Reclamation, Bureau of 43, I Refugee Resettlement, Office of 45, IV Relocation Allowances 41, 302 Research and Innovative Technology Administration 49, XI Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Safety and Environmental Enforcement, Bureau of 30, II Saint Lawrence Seaway Development Corporation 33, IV Science and Technology Policy, Office of 32, XXIV Science and Technology Policy, Office of, and National 47, II Security Council Secret Service 31, IV Securities and Exchange Commission 5, XXXIV; 17, II

244

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00254 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 CFR Title, Subtitle or Agency Chapter Selective Service System 32, XVI Small Business Administration 2, XXVII; 13, I Smithsonian Institution 36, V Social Security Administration 2, XXIII; 20, III; 48, 23 Soldiers’ and Airmen’s Home, United States 5, XI Special Counsel, Office of 5, VIII Special Education and Rehabilitative Services, Office of 34, III State, Department of 2, VI; 22, I; 28, XI Federal Acquisition Regulation 48, 6 Surface Mining Reclamation and Enforcement, Office of 30, VII Surface Transportation Board 49, X Susquehanna River Basin Commission 18, VIII Tennessee Valley Authority 5, LXIX; 18, XIII Trade Representative, United States, Office of 15, XX Transportation, Department of 2, XII; 5, L Commercial Space Transportation 14, III Emergency Management and Assistance 44, IV Federal Acquisition Regulation 48, 12 Federal Aviation Administration 14, I Federal Highway Administration 23, I, II Federal Motor Carrier Safety Administration 49, III Federal Railroad Administration 49, II Federal Transit Administration 49, VI Maritime Administration 46, II National Highway Traffic Safety Administration 23, II, III; 47, IV; 49, V Pipeline and Hazardous Materials Safety Administration 49, I Saint Lawrence Seaway Development Corporation 33, IV Secretary of Transportation, Office of 14, II; 49, Subtitle A Transportation Statistics Bureau 49, XI Transportation, Office of 7, XXXIII Transportation Security Administration 49, XII Transportation Statistics Bureau 49, XI Travel Allowances, Temporary Duty (TDY) 41, 301 Treasury, Department of the 2, X;5, XXI; 12, XV; 17, IV; 31, IX Alcohol and Tobacco Tax and Trade Bureau 27, I Community Development Financial Institutions Fund 12, XVIII Comptroller of the Currency 12, I Customs and Border Protection 19, I Engraving and Printing, Bureau of 31, VI Federal Acquisition Regulation 48, 10 Federal Claims Collection Standards 31, IX Federal Law Enforcement Training Center 31, VII Financial Crimes Enforcement Network 31, X Fiscal Service 31, II Foreign Assets Control, Office of 31, V Internal Revenue Service 26, I Investment Security, Office of 31, VIII Monetary Offices 31, I Secret Service 31, IV Secretary of the Treasury, Office of 31, Subtitle A Truman, Harry S. Scholarship Foundation 45, XVIII United States and Canada, International Joint Commission 22, IV United States and Mexico, International Boundary and Water 22, XI Commission, United States Section U.S. Copyright Office 37, II Utah Reclamation Mitigation and Conservation Commission 43, III Veterans Affairs, Department of 2, VIII; 38, I Federal Acquisition Regulation 48, 8 Veterans’ Employment and Training Service, Office of the 41, 61; 20, IX Assistant Secretary for Vice President of the United States, Office of 32, XXVIII Wage and Hour Division 29, V Water Resources Council 18, VI Workers’ Compensation Programs, Office of 20, I, VII World Agricultural Outlook Board 7, XXXVIII

245

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00255 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00256 Fmt 8092 Sfmt 8092 Y:\SGML\247073.XXX 247073 List of CFR Sections Affected All changes in this volume of the Code of Federal Regulations (CFR) that were made by documents published in the FEDERAL REGISTER since January 1, 2014 are enumerated in the following list. Entries indicate the nature of the changes effected. Page numbers refer to FEDERAL REGISTER pages. The user should consult the entries for chapters, parts and sub- parts as well as sections for revisions. For changes to this volume of the CFR prior to this listing, consult the annual edition of the monthly List of CFR Sections Affected (LSA). The LSA is available at www.govinfo.gov. For changes to this volume of the CFR prior to 2001, see the ‘‘List of CFR Sections Affected, 1949–1963, 1964–1972, 1973–1985, and 1986–2000’’ published in 11 separate volumes. The ‘‘List of CFR Sections Affected 1986–2000’’ is available at www.govinfo.gov.

2014 21 CFR—Continued 81 FR Page 21 CFR 79 FR Page Chapter I—Continued 201.25 (c)(1) introductory text Chapter I amended...... 60212 201.56 (d)(1) amended; eff. 6-30- 201.161 Revised ...... 81696 15...... 72101 201.57 (c)(9)(i), (ii) and (iii) re- 201.328 Added ...... 81696 vised; eff. 6-30-15...... 72101 207 Revised ...... 60212 201.80 (f)(6)(i)(a) through (e) Technical correction ...... 89848 amended; eff. 6-30-15...... 72103 211 Nomenclature change ...... 49897 225.1 (b)(1) correctly amended...... 3739 Policy statement ...... 57784 211.94 (e) added...... 81697 2015 211.125 (c) amended ...... 81697 216 Heading and authority cita- 21 CFR 80 FR Page tion revised ...... 69676 Chapter I 216.24 Revised ...... 69676 201.25 (d)(2) amended...... 18090 201.58 Amended...... 18090 2017 203.12 Revised ...... 18090 21 CFR 82 FR 203.37 (e) revised ...... 18090 Page 203.70 (b)(2) revised ...... 18091 206.7 (b)(1)(i) amended...... 18091 Chapter I 207.7 (a) amended ...... 18091 201.128 Revised ...... 2217 211.1 (c) amended ...... 56168 Regulation at 82 FR 2217 eff. date Compliance date clarification...... 71934 delayed to 3-21-17 ...... 9501 Regulation at 82 FR 2217 eff. date 2016 further delayed to 3-19-18...... 14319 Regulation at 82 FR 2217 com- 21 CFR 81 FR Page ment period extended to 7-18-17 Chapter I ...... 22741 201 Technical correction...... 89848 201.1 (f) amended...... 60212 201.2 Amended ...... 60212

247

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00257 Fmt 8060 Sfmt 8060 Y:\SGML\247073.XXX 247073 21 CFR (4–1–19 Edition) 2018 2019 21 CFR 83 FR (Regulations published from January 1, Page 2019, through April 1, 2019) Chapter I 201.128 Regulation at 82 FR 2217 21 CFR 84 FR eff. date delayed indefi- Page nitely ...... 11639 Chapter I 211 Policy statement ...... 598 216.23 Added ...... 4710 Notification...... 22193 216.24 Amended...... 63573 Æ

248

VerDate Sep<11>2014 14:18 Jul 16, 2019 Jkt 247073 PO 00000 Frm 00258 Fmt 8060 Sfmt 8006 Y:\SGML\247073.XXX 247073