Title 21 Food and Drugs Parts 200 to 299

Revised as of April 1, 2011

Containing a codification of documents of general applicability and future effect

As of April 1, 2011

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

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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 Printing Office Official Edi- tions only. The Superintendent of Documents of the U.S. Govern- ment Printing Office requests that any reprinted edition clearly be labeled as a copy of the authentic work with a new ISBN.

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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 ...... 199

Alphabetical List of Agencies Appearing in the CFR ...... 219

List of CFR Sections Affected ...... 229

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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.

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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, 2011), 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 Mar<15>2010 13:10 May 12, 2011 Jkt 223068 PO 00000 Frm 00005 Fmt 8008 Sfmt 8092 Y:\SGML\223068.XXX 223068 WReier-Aviles on DSKGBLS3C1PROD with CFR 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. OBSOLETE PROVISIONS Provisions that become obsolete before the revision date stated on the cover of each volume are not carried. Code users may find the text of provisions in effect on a given date in the past by using the appropriate numerical list of sections affected. For the period before April 1, 2001, consult either the List of CFR Sections Affected, 1949–1963, 1964–1972, 1973–1985, or 1986–2000, published in eleven separate volumes. For the period beginning April 1, 2001, a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume. ‘‘[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. An index to the text of ‘‘Title 3—The President’’ is carried within that volume.

VerDate Mar<15>2010 13:10 May 12, 2011 Jkt 223068 PO 00000 Frm 00006 Fmt 8008 Sfmt 8092 Y:\SGML\223068.XXX 223068 WReier-Aviles on DSKGBLS3C1PROD with CFR 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 Printing 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 Printing 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.ofr.gov. For more information, contact the GPO Customer Con- tact Center, U.S. Government Printing 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.

RAYMOND A. MOSLEY, Director, Office of the Federal Register. April 1, 2011.

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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, 2011.

For this volume, Susannah C. Hurley was Chief Editor. The Code of Federal Regulations publication program is under the direction of Michael L. White, as- sisted by Ann Worley.

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(This book contains parts 200 to 299)

Part

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

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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 ...... 96 203 Prescription drug marketing ...... 105 205 Guidelines for State licensing of wholesale prescription drug distributors ...... 118 206 Imprinting of solid oral dosage form drug products for human use ...... 123 207 Registration of producers of drugs and listing of drugs in commercial distribution ...... 124 208 Medication Guides for prescription drug products .. 135 209 Requirement for authorized dispensers and pharmacies to distribute a side effects statement ...... 138 210 Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general ...... 140 211 Current good manufacturing practice for finished pharmaceuticals ...... 142 212 Current good manufacturing practice for positron emission tomography drugs (Eff. 12-12-2011) ...... 163 216 Pharmacy compounding...... 172 225 Current good manufacturing practice for medicated feeds ...... 173 226 Current good manufacturing practice for Type A medicated articles ...... 181 250 Special requirements for specific human drugs ...... 185 290 Controlled drugs...... 193 299 Drugs; official names and established names ...... 194

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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

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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

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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

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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.

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

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(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 § 207.3(b) 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

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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 turer, packer, or distributor, and that which of the persons is to be contacted identification does not meet the re- for further information about the prod- quirements of this section. uct. (m) This section does not apply to bi- (4) If a trademark appears on the ological drug products that are subject drug or drug product label or appears to the requirements of section 351 of as a mark directly on the drug product the Public Health Service Act, 42 (e.g., tablet or capsule), the label may U.S.C. 262. identify the holder or licensee of the trademark. The label may also state [45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. 31, 1980, as amended at 48 FR 37620, Aug. 19, whether the person identified holds the 1983] trademark or is licensee of the trademark. § 201.2 Drugs and devices; National (5) If the distributor is named on the Drug Code numbers. label, the name shall be qualified by The National Drug Code (NDC) num- one of the following phrases: ‘‘Manu- ber is requested but not required to ap- factured for ’’, ‘‘Distributed llllll pear on all drug labels and in all drug by ’’, ‘‘Manufactured by llllll labeling, including the label of any pre- for ’’, ‘‘Manu- llllll llllll scription drug container furnished to a factured for by ’’, lllll lllll consumer. If the NDC number is shown ‘‘Distributor: ’’, ‘‘Marketed llllll on a drug label, it shall be displayed as by ’’. The qualifying phrases llllll required in § 207.35(b)(3) of this chapter. may be abbreviated. (6) If the packer is identified on the [40 FR 52002, Nov. 7, 1975] label, the name shall be qualified by the phrase ‘‘Packed by llllll’’ or § 201.5 Drugs; adequate directions for ‘‘Packaged by llllll’’. The quali- use. fying 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:

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(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

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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.

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(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,

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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

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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, April EFFECTIVE DATE NOTE: At 53 FR 49138, Dec. 15, 1987; 53 FR 4135, Feb. 12, 1988] 6, 1988, § 201.20(c) was suspended pending further agency action.

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§ 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

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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.

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

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the request could not reasonably be ad- (i) Identify the specified lots, dressed by measures such as package batches, or other units of the human redesign or use of overwraps; or drug product that would be subject to (ii) an alternative regulatory pro- the exception or alternative; gram or method of product use renders (ii) Identify the labeling provision(s) the bar code unnecessary for patient listed in paragraph (f) of this section safety. that are the subject of the exception or (2) Requests for an exemption should alternative request; be sent to the Office of Compliance, (iii) Explain why compliance with Center for Drug Evaluation and Re- such labeling provision(s) could ad- search, Food and Drug Administration, versely affect the safety, effectiveness, 10903 New Hampshire Ave., Bldg. 51, or availability of the specified lots, Silver Spring, MD 20993–0002 (requests batches, or other units of a human drug involving a drug product) or to the Of- product that are or will be held in the fice of Compliance and Biologics Qual- Strategic National Stockpile; ity (HFM–600), Center for Biologics (iv) Describe any proposed safeguards Evaluation and Research, Food and or conditions that will be implemented Drug Administration, 1401 Rockville so that the labeling of the product in- Pike, Rockville, MD 20852 (requests includes appropriate information nec- volving a biological product). essary for the safe and effective use of [69 FR 9170, Feb. 26, 2004, as amended at 76 the product, given the anticipated cir- FR 12847, Mar. 9, 2011] 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 determines that compliance with such la- (d) A grant of an exception or alter- beling requirement could adversely af- native under this section will include fect the safety, effectiveness, or avail- any safeguards or conditions deemed ability of such product that is or will appropriate by the Center Director so be included in the Strategic National that the labeling of product subject to Stockpile. the exception or alternative includes (b)(1)(i) A Strategic National Stock- the information necessary for the safe pile official or any entity that manu- and effective use of the product, given factures (including labeling, packing, the anticipated circumstances of use. relabeling, or repackaging), distrib- (e) If you are a sponsor receiving a utes, or stores a human drug product grant of a request for an exception or that is or will be included in the Stra- alternative to the labeling require- tegic National Stockpile may submit, ments under this section: with written concurrence from a Stra- (1) You need not submit a supplement tegic National Stockpile official, a under § 314.70(a) through (c) or written request for an exception or al- § 601.12(f)(1) through (f)(2) of this chap- ternative described in paragraph (a) of ter; however, this section to the Center Director. (2) You must report any grant of a re- (ii) The Center Director may grant quest for an exception or alternative an exception or alternative described under this section as part of your an- in paragraph (a) of this section on his nual report under §§ 314.70(d) or or her own initiative. 601.12(f)(3) of this chapter. (2) A written request for an exception (f) The Center Director may grant an or alternative described in paragraph exception or alternative under this sec- (a) of this section must: tion to the following provisions of this

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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 prescription drugs be expressed in terms of the for Prescription Drugs and/or U.S. gallon of 231 cubic inches and Insulin quart, pint, fluid-ounce, and fluid-dram subdivisions thereof, or of the liter and § 201.50 Statement of identity. milliliter, or cubic centimeter, and (a) The label of prescription and insu- shall express the volume at 68 °F. (20 lin-containing drugs in package form °C.). A statement of the liquid measure shall bear as one of its principal fea- of the contents in the case of insulin- tures a statement of the identity of the containing drugs shall be expressed in drug. terms of the liter and milliliter, or (b) Such statement of identity shall cubic centimeter, and shall express the be in terms of the established name of volume at 68 °F. (20 °C.). the drug. In the case of a prescription (c) The declaration shall contain only drug that is a mixture and that has no such fractions as are generally used in established name, the requirement for expressing the quantity of the drug. A statement of identity shall be deemed common fraction shall be reduced to to be satisfied by a listing of the quan- its lowest terms; a decimal fraction titative ingredient information as pre- shall not be carried out to more than scribed by § 201.10. three places, except in the case of a (c) The statement of identity of a statement of the quantity of an active prescription drug shall also comply ingredient in a unit of a drug. with the placement, size and promi- (d) The declaration shall appear as a nence requirements of § 201.10. distinct item on the label and, in the [40 FR 13998, Mar. 27, 1975, as amended at 63 case of large volume parenterals, may FR 26698, May 13, 1998] be embossed on the glass. (e) The declaration shall accurately § 201.51 Declaration of net quantity of reveal the quantity of drug in the contents. package exclusive of wrappers and (a) The label of a prescription or in- other material packed therewith. sulin-containing drug in package form (f) A statement of the quantity of a shall bear a declaration of the net prescription or insulin-containing drug quantity of contents. This shall be ex- in terms of weight or measure applica- pressed in the terms of weight, meas- ble to such drug, under the provisions ure, numerical count, or a combination of paragraph (a) of this section, shall of numerical count and weight or express with prominence and conspicu- measure. The statement of quantity of ousness the number of the largest drugs in tablet, capsule, ampule, or whole unit, as specified in paragraph other unit dosage form shall be ex- (b) of this section, that are contained pressed in terms of numerical count; in the package. Any remainder shall be the statement of quantity for drugs in expressed in terms of common or dec- other dosage forms shall be in terms of imal fractions of such unit or in terms

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

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(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 In- cording to the following schedule: formation (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 on June 30, 2006, or that has been ap- Drug Interactions proved any time from June 30, 2005, up Use in Specific Populations to and including June 30, 2006, a supple- Full Prescribing Information: Contents ment with proposed conforming label- Full Prescribing Information ing must be submitted no later than Boxed Warning June 30, 2009. 1 Indications and Usage (3) For products for which an NDA, 2 Dosage and Administration BLA, or efficacy supplement has been 3 Dosage Forms and Strengths approved anytime from June 30, 2004, 4 Contraindications up to and including June 29, 2005, a sup- 5 Warnings and Precautions plement with proposed conforming la- 6 Adverse Reactions beling must be submitted no later than 7 Drug Interactions June 30, 2010. 8 Use in Specific Populations (4) For products for which an NDA, 8.1 Pregnancy BLA, or efficacy supplement has been 8.2 Labor and delivery approved anytime from June 30, 2003, 8.3 Nursing mothers up to and including June 29, 2004, a sup- 8.4 Pediatric use plement with proposed conforming la- 8.5 Geriatric use beling must be submitted no later than 9 Drug Abuse and Dependence June 30, 2011. 9.1 Controlled substance (5) For products for which an NDA, 9.2 Abuse BLA, or efficacy supplement has been 9.3 Dependence approved anytime from June 30, 2002, 10 Overdosage up to and including June 29, 2003, a sup- 11 Description plement with proposed conforming la- 12 Clinical Pharmacology beling must be submitted no later than 12.1 Mechanism of action June 30, 2012. 12.2 Pharmacodynamics (6) For products for which an NDA, 12.3 Pharmacokinetics BLA, or efficacy supplement has been 13 Nonclinical Toxicology approved anytime from June 30, 2001, 13.1 Carcinogenesis, mutagenesis, up to and including June 29, 2002, a sup- impairment of fertility plement with proposed conforming la- 13.2 Animal toxicology and/or phar- beling must be submitted no later than macology June 30, 2013. 14 Clinical Studies (d) Labeling requirements for new and 15 References more recently approved prescription drug 16 How Supplied/Storage and Han- products. This paragraph applies only dling to prescription drug products described 17 Patient Counseling Information

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

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(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 established name of the drug, if any, as tion. A changed section must be listed defined in section 502(e)(3) of the Fed- under this heading in Highlights for at 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 established name or, for biological products, (7) Dosage and administration. A con- proper name of the product. cise summary of the information re- (4) Boxed warning. A concise sum- quired under paragraph (c)(3) of this mary of any boxed warning required by section, with any appropriate subparagraph (c)(1) of this section, not to headings, including the recommended exceed a length of 20 lines. The sum- dosage regimen, starting dose, dose mary must be preceded by a heading, in range, critical differences among popu- upper-case letters, containing the word lation subsets, monitoring rec- ‘‘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. (c)(2), (c)(3), (c)(5), and (c)(6) of this section, that contain(s) substantive label-

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(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.

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(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,

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(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

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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 evidence of a causal association with a drugs in the same pharmacologically drug; a causal relationship need not active and chemically related class, if have been definitely established. A spe- applicable. The list or lists must be cific 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 specific section or subsection). actions must be listed in decreasing (iii) Monitoring: Laboratory tests. This order of severity. section must identify any laboratory (A) Clinical trials experience. This sec- tests helpful in following the patient’s tion must list the adverse reactions response or in identifying possible ad- identified in clinical trials that oc- verse reactions. If appropriate, infor- curred at or above a specified rate ap- mation must be provided on such fac- propriate to the safety database. The tors 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 information is presented (e.g., ‘‘Drug mined (e.g., adverse reactions were ob- Interactions’’ section). served only in the uncontrolled trial (7) 6 Adverse reactions. This section portion of the overall safety database), must describe the overall adverse reac- adverse reactions must be grouped tion profile of the drug based on the en- within specified frequency ranges as tire safety database. For purposes of appropriate to the safety database for prescription drug labeling, an adverse the drug (e.g., adverse reactions occur- reaction is an undesirable effect, rea- ring at a rate of less than 1/100, adverse sonably associated with use of a drug, reactions occurring at a rate of less that may occur as part of the pharma- than 1/500) or descriptively identified, cological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse

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if frequency ranges cannot be deter- (i) 8.1 Pregnancy. This subsection mined. For adverse reactions with sig- may be omitted only if the drug is not nificant clinical implications, the list- absorbed systemically and the drug is ings must be supplemented with addi- not known to have a potential for indi- tional detail about the nature, fre- rect harm to the fetus. For all other quency, and severity of the adverse re- drugs, this subsection must contain the action and the relationship of the ad- following information: verse reaction to drug dose and demo- (A) Teratogenic effects. Under this sub- graphic characteristics, if data are heading, the labeling must identify one available and important. of the following categories that applies (B) Postmarketing experience. This sec- to the drug, and the labeling must bear tion of the labeling must list the ad- the statement required under the cat- verse reactions, as defined in paragraph egory: (c)(7) of this section, that are identified (1) Pregnancy category A. If adequate from domestic and foreign spontaneous and well-controlled studies in pregnant reports. This listing must be separate women have failed to demonstrate a from the listing of adverse reactions risk to the fetus in the first trimester identified in clinical trials. of pregnancy (and there is no evidence (iii) Comparisons of adverse reactions of a risk in later trimesters), the label- between drugs. For drug products other ing must state: ‘‘Pregnancy Category than biological products, any claim A. Studies in pregnant women have not comparing the drug to which the label- shown that (name of drug) increases the ing applies with other drugs in terms of risk of fetal abnormalities if adminis- frequency, severity, or character of ad- tered during the first (second, third, or verse reactions must be based on ade- all) trimester(s) of pregnancy. If this quate and well-controlled studies as de- drug is used during pregnancy, the pos- fined in § 314.126(b) of this chapter un- sibility of fetal harm appears remote. Because studies cannot rule out the less this requirement is waived under possibility of harm, however, (name of § 201.58 or § 314.126(c) of this chapter. drug) should be used during pregnancy For biological products, any such claim only if clearly needed.’’ The labeling must be based on substantial evidence. must also contain a description of the (8) 7 Drug interactions. (i) This section human studies. If animal reproduction must contain a description of clinically studies are also available and they fail significant interactions, either ob- to demonstrate a risk to the fetus, the served or predicted, with other pre- labeling must also state: ‘‘Reproduc- scription or over-the-counter drugs, tion studies have been performed in classes of drugs, or foods (e.g., dietary (kinds of animal(s)) at doses up to (x) supplements, grapefruit juice), and spe- times the human dose and have re- cific practical instructions for pre- vealed no evidence of impaired fertility venting or managing them. The mecha- or harm to the fetus due to (name of nism(s) of the interaction, if known, drug).’’ The labeling must also contain must be briefly described. Interactions a description of available data on the that are described in the ‘‘Contra- effect of the drug on the later growth, indications’’ or ‘‘Warnings and Pre- development, and functional matura- cautions’’ sections must be discussed in tion of the child. more detail under this section. Details (2) Pregnancy category B. If animal re- of drug interaction pharmacokinetic production studies have failed to dem- studies that are included in the ‘‘Clin- onstrate a risk to the fetus and there ical Pharmacology’’ section that are are no adequate and well-controlled pertinent to clinical use of the drug studies in pregnant women, the label- must not be repeated in this section. ing must state: ‘‘Pregnancy Category (ii) This section must also contain B. Reproduction studies have been per- practical guidance on known inter- formed in (kind(s) of animal(s)) at doses ference of the drug with laboratory up to (x) times the human dose and tests. have revealed no evidence of impaired (9) 8 Use in specific populations. This fertility or harm to the fetus due to section must contain the following sub- (name of drug). There are, however, no sections: adequate and well-controlled studies in

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pregnant women. Because animal reduction studies have not been con- production studies are not always pre- ducted with (name of drug). It is also dictive of human response, this drug not known whether (name of drug) can should be used during pregnancy only cause fetal harm when administered to if clearly needed.’’ If animal reproduc- a pregnant woman or can affect repro- tion studies have shown an adverse ef- duction capacity. (Name of drug) should fect (other than decrease in fertility), be given to a pregnant woman only if but adequate and well-controlled stud- clearly needed.’’ The labeling must ies in pregnant women have failed to contain a description of any available demonstrate a risk to the fetus during data on the effect of the drug on the the first trimester of pregnancy (and later growth, development, and func- there is no evidence of a risk in later tional maturation of the child. trimesters), the labeling must state: ‘‘Pregnancy Category B. Reproduction (4) Pregnancy category D. If there is studies in (kind(s) of animal(s)) have positive evidence of human fetal risk shown (describe findings) at (x) times based on adverse reaction data from in- the human dose. Studies in pregnant vestigational or marketing experience women, however, have not shown that or studies in humans, but the potential (name of drug) increases the risk of ab- benefits from the use of the drug in normalities when administered during pregnant women may be acceptable de- the first (second, third, or all) tri- spite its potential risks (for example, if mester(s) of pregnancy. Despite the the drug is needed in a life-threatening animal findings, it would appear that situation or serious disease for which the possibility of fetal harm is remote, safer drugs cannot be used or are inef- if the drug is used during pregnancy. fective), the labeling must state: Nevertheless, because the studies in ‘‘Pregnancy Category D. See ‘Warnings humans cannot rule out the possibility and Precautions’ section.’’ Under the of harm, (name of drug) should be used ‘‘Warnings and Precautions’’ section, during pregnancy only if clearly need- the labeling must state: ‘‘(Name of ed.’’ The labeling must also contain a drug) can cause fetal harm when ad- description of the human studies and a ministered to a pregnant woman. description of available data on the ef- (Describe the human data and any perti- fect of the drug on the later growth, nent animal data.) If this drug is used development, and functional matura- during pregnancy, or if the patient be- tion of the child. comes pregnant while taking this drug, (3) Pregnancy category C. If animal the patient should be apprised of the reproduction studies have shown an adverse effect on the fetus, if there are no potential hazard to a fetus.’’ adequate and well-controlled studies in (5) Pregnancy category X. If studies in humans, and if the benefits from the animals or humans have demonstrated use of the drug in pregnant women may fetal abnormalities or if there is posi- be acceptable despite its potential tive evidence of fetal risk based on ad- risks, the labeling must state: ‘‘Preg- verse reaction reports from investiga- nancy Category C. (Name of drug) has tional or marketing experience, or been shown to be teratogenic (or to both, and the risk of the use of the have an embryocidal effect or other ad- drug in a pregnant woman clearly out- verse effect) in (name(s) of species) when weighs any possible benefit (for exam- given in doses (x) times the human ple, safer drugs or other forms of ther- dose. There are no adequate and well- apy are available), the labeling must controlled studies in pregnant women. state: ‘‘Pregnancy Category X. See (Name of drug) should be used during ‘Contraindications’ section.’’ Under pregnancy only if the potential benefit ‘‘Contraindications,’’ the labeling must justifies the potential risk to the state: ‘‘(Name of drug) may (can) cause fetus.’’ The labeling must contain a de- fetal harm when administered to a scription of the animal studies. If there pregnant woman. (Describe the human are no animal reproduction studies and data and any pertinent animal data.) no adequate and well-controlled studies (Name of drug) is contraindicated in in humans, the labeling must state: ‘‘Pregnancy Category C. Animal repro-

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women who are or may become preg- tumorigenicity shown for (name of nant. If this drug is used during preg- drug) in (animal or human) studies), a nancy, or if the patient becomes preg- decision should be made whether to nant while taking this drug, the pa- discontinue nursing or to discontinue tient should be apprised of the poten- the drug, taking into account the im- tial hazard to a fetus.’’ portance of the drug to the mother.’’ If (B) Nonteratogenic effects. Under this the drug is not associated with serious subheading the labeling must contain adverse reactions and does not have a other information on the drug’s effects known tumorigenic potential, the la- on reproduction and the drug’s use dur- beling must state: ‘‘Caution should be ing pregnancy that is not required spe- exercised when (name of drug) is admin- cifically by one of the pregnancy cat- istered to a nursing woman.’’ egories, if the information is relevant (C) If a drug is absorbed systemically to the safe and effective use of the and information on excretion in human drug. Information required under this milk is unknown, this subsection must heading must include nonteratogenic contain one of the following state- effects in the fetus or newborn infant ments, as appropriate. If the drug is as- (for example, withdrawal symptoms or sociated with serious adverse reactions hypoglycemia) that may occur because or has a known tumorigenic potential, of a pregnant woman’s chronic use of the labeling must state: ‘‘It is not the drug for a preexisting condition or known whether this drug is excreted in disease. human milk. Because many drugs are (ii) 8.2 Labor and delivery. If the drug excreted in human milk and because of has a recognized use during labor or de- the potential for serious adverse reac- livery (vaginal or abdominal delivery), tions in nursing infants from (name of whether or not the use is stated in the drug) (or, ‘‘Because of the potential for Indications and Usage section, this tumorigenicity shown for (name of subsection must describe the available drug) in (animal or human) studies), a information about the effect of the decision should be made whether to drug on the mother and the fetus, on discontinue nursing or to discontinue the duration of labor or delivery, on the drug, taking into account the im- the possibility that forceps delivery or portance of the drug to the mother.’’ If other intervention or resuscitation of the drug is not associated with serious the newborn will be necessary, and the adverse reactions and does not have a effect of the drug on the later growth, known tumorigenic potential, the la- development, and functional matura- beling must state: ‘‘It is not known tion of the child. If any information re- whether this drug is excreted in human quired under this subsection is un- milk. Because many drugs are excreted known, it must state that the informa- in human milk, caution should be exer- tion is unknown. cised when (name of drug) is adminis- (iii) 8.3 Nursing mothers. (A) If a drug tered to a nursing woman.’’ is absorbed systemically, this sub- (iv) 8.4 Pediatric use. (A) Pediatric section must contain, if known, infor- population(s)/pediatric patient(s): For mation about excretion of the drug in the purposes of paragraphs (c)(9)(iv)(B) human milk and effects on the nursing through (c)(9)(iv)(H) of this section, the infant. Pertinent adverse effects ob- terms pediatric population(s) and pedi- served in animal offspring must be de- atric patient(s) are defined as the pedi- scribed. atric age group, from birth to 16 years, (B) If a drug is absorbed systemically including age groups often called neo- and is known to be excreted in human nates, infants, children, and adoles- milk, this subsection must contain one cents. of the following statements, as appro- (B) If there is a specific pediatric in- priate. If the drug is associated with dication different from those approved serious adverse reactions or if the drug for adults that is supported by ade- has a known tumorigenic potential, the quate and well-controlled studies in labeling must state: ‘‘Because of the the pediatric population, it must be de- potential for serious adverse reactions scribed under the ‘‘Indications and in nursing infants from (name of drug) Usage’’ section, and appropriate pedi- (or, ‘‘Because of the potential for atric dosage information must be given

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under the ‘‘Dosage and Administra- groups is supported by evidence from ade- tion’’ section. The ‘‘Pediatric use’’ sub- quate and well-controlled studies of (drug section must cite any limitations on name) in adults with additional data (insert the pediatric indication, need for spe- wording that accurately describes the data submitted to support a finding of substantial evi- cific monitoring, specific hazards asso- dence of effectiveness in the pediatric popu- ciated with use of the drug in any sub- lation). sets of the pediatric population (e.g., (2) Data summarized in the preceding neonates), differences between pedi- prescribed statement in this subsection atric and adult responses to the drug, must be discussed in more detail, if ap- and other information related to the propriate, under the ‘‘Clinical Pharma- safe and effective pediatric use of the cology’’ or the ‘‘Clinical Studies’’ sec- drug. Data summarized in this sub- tion. For example, pediatric pharmaco- section should be discussed in more de- kinetic or pharmacodynamic studies tail, if appropriate, under the ‘‘Clinical and dose response information should Pharmacology’’ or ‘‘Clinical Studies’’ be described in the ‘‘Clinical Pharma- section. As appropriate, this informa- cology’’ section. Pediatric dosing in- tion must also be contained in the structions must be included in the ‘‘Contraindications’’ and/or ‘‘Warnings ‘‘Dosage and Administration’’ section. and Precautions’’ section(s). Any differences between pediatric and (C) If there are specific statements on adult responses, need for specific moni- pediatric use of the drug for an indica- toring, dosing adjustments, and any tion also approved for adults that are other information related to safe and based on adequate and well-controlled effective use of the drug in pediatric studies in the pediatric population, patients must be cited briefly in the they must be summarized in the ‘‘Pe- ‘‘Pediatric use’’ subsection and, as ap- diatric use’’ subsection and discussed propriate, in the ‘‘Contraindications,’’ in more detail, if appropriate, under ‘‘Warnings and Precautions,’’ and the ‘‘Clinical Pharmacology’’ and ‘‘Dosage and Administration’’ sections. ‘‘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 appro- section, or, if appropriate, the hazard priate, this information must also be must be stated in the ‘‘Contraindica- contained in the ‘‘Contraindications’’ tions’’ or ‘‘Warnings and Precautions’’ and/or ‘‘Warnings and Precautions’’ section and this subsection must refer section(s). to it. (D)(1) When a drug is approved for pe- (F) If the requirements for a finding diatric use based on adequate and well- of substantial evidence to support a pe- controlled studies in adults with other diatric indication or a pediatric use information supporting pediatric use, statement have not been met for any the ‘‘Pediatric use’’ subsection of the pediatric population, this subsection labeling must contain either the fol- must contain the following statement: lowing statement or a reasonable alter- ‘‘Safety and effectiveness in pediatric native: patients have not been established.’’ If The safety and effectiveness of (drug name) use of the drug in premature or neo- have been established in the age groups lll to lll (note any limitations, e.g., no natal infants, or other pediatric sub- data for pediatric patients under 2, or only groups, is associated with a specific applicable to certain indications approved in hazard, the hazard must be described in adults). Use of (drug name) in these age this subsection, or, if appropriate, the

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hazard must be stated in the ‘‘Contra- ‘‘Geriatric use’’ subsection and must indications’’ or ‘‘Warnings and Pre- reflect all information available to the cautions’’ section and this subsection sponsor that is relevant to the appro- must refer to it. priate use of the drug in elderly pa- (G) If the sponsor believes that none tients. This information includes de- of the statements described in para- tailed results from controlled studies graphs (c)(9)(iv)(B) through (c)(9)(iv)(F) that are available to the sponsor and of this section are appropriate or rel- pertinent information from well-docu- evant to the labeling of a particular mented studies obtained from a lit- drug, the sponsor must provide reasons erature search. Controlled studies infor omission of the statements and clude those that are part of the mar- may propose alternative statement(s). keting application and other relevant FDA may permit use of an alternative studies available to the sponsor that statement if FDA determines that no have not been previously submitted in statement described in those para- the investigational new drug applica- graphs is appropriate or relevant to the tion, new drug application, biologics li- drug’s labeling and that the alternative cense application, or a supplement or statement is accurate and appropriate. amendment to one of these applica- (H) If the drug product contains one tions (e.g., postmarketing studies or or more inactive ingredients that adverse drug reaction reports). The present an increased risk of toxic ef- ‘‘Geriatric use’’ subsection must con- fects to neonates or other pediatric tain the following statement(s) or rea- subgroups, a special note of this risk sonable alternative, as applicable, tak- must be made, generally in the ‘‘Con- ing into account available information: traindications’’ or ‘‘Warnings and Pre- (1) If clinical studies did not include cautions’’ section. sufficient numbers of subjects aged 65 (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, ical experience has not identified dif- and other information related to the ferences in responses between the el- safe and effective use of the drug in the derly and younger patients. In general, geriatric population. Unless otherwise dose selection for an elderly patient noted, information contained in the should be cautious, usually starting at ‘‘Geriatric use’’ subsection must per- the low end of the dosing range, retain to use of the drug in persons 65 flecting the greater frequency of de- years of age and older. Data summa- creased hepatic, renal, or cardiac func- rized in this subsection must be dis- tion, and of concomitant disease or cussed in more detail, if appropriate, other drug therapy. under ‘‘Clinical Pharmacology’’ or the (2) If clinical studies (including stud- ‘‘Clinical Studies’’ section. As appro- ies that are part of marketing applica- priate, this information must also be tions and other relevant studies avail- contained in the ‘‘Warnings and Pre- able to the sponsor that have not been cautions’’ and/or ‘‘Contraindications’’ submitted in the sponsor’s applica- section(s). tions) included enough elderly subjects (B) Specific statements on geriatric to make it likely that differences in use of the drug for an indication ap- safety or effectiveness between elderly proved for adults generally, as distin- and younger subjects would have been guished from a specific geriatric indi- detected, but no such differences (in cation, must be contained in the safety or effectiveness) were observed,

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and other reported clinical experience atric use’’ subsection, or, if appro- has not identified such differences, the priate, the hazard must be stated in ‘‘Geriatric use’’ subsection must con- the ‘‘Contraindications’’ or ‘‘Warnings tain the following statement: and Precautions’’ section, and the Of the total number of subjects in clinical ‘‘Geriatric use’’ subsection must refer studies of (name of drug), ll percent were 65 to those sections. and over, while ll percent were 75 and over. (E) Labeling under paragraphs (Alternatively, the labeling may state the (c)(9)(v)(A) through (c)(9)(v)(C) of this total number of subjects included in the section may include statements, if studies who were 65 and over and 75 and they are necessary for safe and effec- over.) No overall differences in safety or effectiveness were observed between these sub- tive use of the drug, and reflect good jects and younger subjects, and other re- clinical practice or past experience in a ported clinical experience has not identified particular situation, e.g., for a sedating differences in responses between the elderly drug, it could be stated that: and younger patients, but greater sensitivity Sedating drugs may cause confusion and of some older individuals cannot be ruled over-sedation in the elderly; elderly patients out. generally should be started on low doses of (3) If evidence from clinical studies (name of drug) and observed closely. and other reported clinical experience (F) If the sponsor believes that none available to the sponsor indicates that of the requirements described in para- use of the drug in elderly patients is graphs (c)(9)(v)(A) through (c)(9)(v)(E) associated with differences in safety or of this section are appropriate or rel- effectiveness, or requires specific moni- evant to the labeling of a particular toring or dosage adjustment, the drug, the sponsor must provide reasons ‘‘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 subsections may be included, as appro- described briefly in the ‘‘Geriatric use’’ priate, if sufficient data are available subsection and in detail under the concerning the use of the drug in other ‘‘Clinical Pharmacology’’ section. The specified subpopulations (e.g., renal or ‘‘Clinical Pharmacology’’ and ‘‘Drug hepatic impairment). Interactions’’ sections ordinarily con- (10) 9 Drug abuse and dependence. This tain information on drug/disease and section must contain the following in- drug/drug interactions that is particu- formation, as appropriate: larly relevant to the elderly, who are (i) 9.1 Controlled substance. If the drug more likely to have concomitant ill- is controlled by the Drug Enforcement ness and to use concomitant drugs. Administration, the schedule in which (2) If a drug is known to be substan- it is controlled must be stated. tially excreted by the kidney, the (ii) 9.2 Abuse. This subsection must ‘‘Geriatric use’’ subsection must in- state the types of abuse that can occur clude the statement: with the drug and the adverse reac- This drug is known to be substantially ex- tions pertinent to them, and must creted by the kidney, and the risk of adverse identify particularly susceptible pa- reactions to this drug may be greater in patients with impaired renal function. Because tient populations. This subsection elderly patients are more likely to have de- must be based primarily on human creased renal function, care should be taken data and human experience, but perti- in dose selection, and it may be useful to nent animal data may also be used. monitor renal function. (iii) 9.3 Dependence. This subsection (D) If use of the drug in the elderly must describe characteristic effects re- appears to cause a specific hazard, the sulting from both psychological and hazard must be described in the ‘‘Geri- physical dependence that occur with

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the drug and must identify the quan- name (as defined in § 600.3 of this chap- tity of the drug over a period of time ter) and any appropriate descriptors; that may lead to tolerance or depend- (B) The type of dosage form(s) and ence, or both. Details must be provided the route(s) of administration to which on the adverse effects of chronic abuse the labeling applies; and the effects of abrupt withdrawal. (C) The same qualitative and/or quan- Procedures necessary to diagnose the titative ingredient information as re- dependent state and the principles of quired under § 201.100(b) for drug labels treating the effects of abrupt with- or §§ 610.60 and 610.61 of this chapter for drawal must be described. biological product labels; (11) 10 Overdosage. This section must (D) If the product is sterile, a state- be based on human data. If human data ment of that fact; are unavailable, appropriate animal (E) The pharmacological or thera- and in vitro data may be used. The fol- peutic class of the drug; lowing specific information must be (F) For drug products other than bio- provided: logical products, the chemical name (i) Signs, symptoms, and laboratory and structural formula of the drug; and findings associated with an overdosage (G) If the product is radioactive, a of the drug; statement of the important nuclear (ii) Complications that can occur physical characteristics, such as the principal radiation emission data, ex- with the drug (for example, organ tox- ternal radiation, and physical decay icity or delayed acidosis); characteristics. (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 (B) 12.2 Pharmacodynamics. This sub- drugs must not be stated. section must include a description of (12) 11 Description. (i) This section any biochemical or physiologic phar- must contain: macologic effects of the drug or active (A) The proprietary name and the es- metabolites related to the drug’s clin- tablished name, if any, as defined in ical effect in preventing, diagnosing, section 502(e)(2) of the act, of the drug mitigating, curing, or treating disease, or, for biological products, the proper or those related to adverse effects or

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toxicity. Exposure-response relation- peated in this subsection, but the loca- ships (e.g., concentration-response, tion of such recommendations must be dose-response) and time course of referenced. pharmacodynamic response (including (ii) Data that demonstrate activity short-term clinical response) must be or effectiveness in in vitro or animal included if known. If this information tests and that have not been shown by is unknown, this subsection must con- adequate and well-controlled clinical tain a statement about the lack of in- studies to be pertinent to clinical use formation. Detailed dosing or moni- may be included under this section toring recommendations based on only under the following cir- pharmacodynamic information that cumstances: appear in other sections (e.g., ‘‘Warn- (A) In vitro data for anti-infective ings and Precautions’’ or ‘‘Dosage and drugs may be included if the data are Administration’’) must not be repeated immediately preceded by the state- in this subsection, but the location of ment ‘‘The following in vitro data are such recommendations must be ref- available but their clinical significance erenced. is unknown.’’ (C) 12.3 Pharmacokinetics. This sub- (B) For other classes of drugs, in section must describe the clinically vitro and animal data that have not significant pharmacokinetics of a drug been shown by adequate and well-con- or active metabolites, (i.e., pertinent trolled studies, as defined in § 314.126(b) absorption, distribution, metabolism, of this chapter, to be necessary for the 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) mutagenesis or impairment of fertility must be presented if clinically signifi- in either males or females, this must cant. Information regarding nonlin- be described. Any precautionary state- earity in pharmacokinetic parameters, ment on these topics must include changes in pharmacokinetics over practical, relevant advice to the pre- time, and binding (plasma protein, scriber on the significance of these ani- erythrocyte) parameters must also be mal findings. Human data suggesting presented if clinically significant. This that the drug may be carcinogenic or section must also include the results of mutagenic, or suggesting that it im- pharmacokinetic studies (e.g., of me- pairs fertility, as described in the tabolism or interaction) that establish ‘‘Warnings and Precautions’’ section, the absence of an effect, including per- must not be included in this subsection tinent human studies and in vitro data. of the labeling. Dosing recommendations based on (ii) 13.2 Animal toxicology and/or phar- clinically significant factors that macology. Significant animal data nec- change the product’s pharmacokinetics essary for safe and effective use of the (e.g., age, gender, race, hepatic or renal drug in humans that is not incor- dysfunction, concomitant therapy) porated in other sections of labeling that appear in other sections (e.g., must be included in this section (e.g., ‘‘Warnings and Precautions,’’ ‘‘Dosage specifics about studies used to support and Administration’’ or ‘‘Use in Spe- approval under § 314.600 or § 601.90 of cific Populations’’) must not be re- this chapter, the absence of chronic

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animal toxicity data for a drug that is mation on the available dosage forms administered over prolonged periods or to which the labeling applies and for is implanted in the body). which the manufacturer or distributor (15) 14 Clinical studies. This section is responsible. The information must must discuss those clinical studies that include, as appropriate: facilitate an understanding of how to (i) The strength or potency of the use the drug safely and effectively. Or- dosage form in metric system (e.g., 10 dinarily, this section will describe the milligram tablets) and, if the apothe- studies that support effectiveness for cary system is used, a statement of the the labeled indication(s), including dis- strength in parentheses after the met- cussion of study design, population, ric designation; endpoints, and results, but must not in- (ii) The units in which the dosage clude an encyclopedic listing of all, or form is ordinarily available for pre- even most, studies performed as part of scribing by practitioners (e.g., bottles the product’s clinical development pro- of 100); gram. If a specific important clinical (iii) Appropriate information to fa- study is mentioned in any section of cilitate identification of the dosage the labeling required under §§ 201.56 and forms, such as shape, color, coating, 201.57 because the study is essential to scoring, imprinting, and National Drug an understandable presentation of the Code number; and 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 (1) All headings and subheadings re- standardized methodology, scale, or quired by paragraphs (a) and (c) of this technique, because the information is section must be highlighted by bold important to prescribing decisions, the type that prominently distinguishes labeling may include a reference to the the headings and subheadings from source of the information. 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 infor- lighting.

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(2) A horizontal line must separate § 201.58 Waiver of labeling require- the information required by paragraphs ments. (a), (b), and (c) of this section. An applicant may ask the Food and (3) The headings listed in paragraphs Drug Administration to waive any re- (a)(5) through (a)(13) of this section quirement under §§ 201.56, 201.57, and must be presented in the center of a 201.80. A waiver request must be sub- horizontal line. mitted in writing to the Director (or (4) If there are multiple subheadings the Director’s designee), Center for listed under paragraphs (a)(4) through Drug Evaluation and Research, Food (a)(13) of this section, each subheading and Drug Administration, Central Doc- must be preceded by a bullet point. ument Room, 5901–B Ammendale Rd., (5) The labeling information required Beltsville, MD 20705–1266, or, if applica- by paragraphs (a)(1) through (a)(4), ble, the Director (or the Director’s des- (a)(11)(ii) through (a)(11)(iv), and (a)(14) ignee), Center for Biologics Evaluation of this section must be in bold print. and Research, Food and Drug Adminis- (6) The letter height or type size for tration, 1401 Rockville Pike, suite 200 all labeling information, headings, and North, Rockville, MD 20852–1448. The subheadings set forth in paragraphs (a), waiver must be granted or denied in (b), and (c) of this section must be a writing by the Director or the Direc- tor’s designee. minimum of 8 points, except for labeling information that is on or within [71 FR 3996, Jan. 24, 2006, as amended at 74 the package from which the drug is to FR 13112, Mar. 26, 2009] be dispensed, which must be a minimum of 6 points. Subpart C—Labeling Require- (7) The identifying numbers required ments for Over-the-Counter by § 201.56(d) and paragraphs (c)(1) Drugs through (c)(18) of this section must be presented in bold print and must pre- SOURCE: 41 FR 6908, Feb. 13, 1976, unless cede the heading or subheading by at otherwise noted. least two square em’s (i.e., two squares of the size of the letter ‘‘m’’ in 8 point § 201.60 Principal display panel. type). The term principal display panel, as it (8) The information required by para- applies to over-the-counter drugs in graph (a) of this section, not including package form and as used in this part, the information required under para- means the part of a label that is most graph (a)(4) of this section, must be likely to be displayed, presented, limited in length to an amount that, if shown, or examined under customary printed in 2 columns on a standard conditions of display for retail sale. sized piece of typing paper (8 1/2 by 11 The principal display panel shall be inches), single spaced, in 8 point type large enough to accommodate all the with 1/2-inch margins on all sides and mandatory label information required between columns, would fit on one-half to be placed thereon by this part with of the page. clarity and conspicuousness and with- (9) Sections or subsections of labeling out obscuring designs, vignettes, or that are identified as containing recent crowding. Where packages bear alter- major changes under paragraph (a)(5) nate principal display panels, informa- of this section must be highlighted in tion required to be placed on the prin- the full prescribing information by the cipal display panel shall be duplicated inclusion of a vertical line on the left on each principal display panel. For edge of the new or modified text. the purpose of obtaining uniform type (10) For the information required by size in declaring the quantity of con- paragraph (b) of this section, each sec- tents for all packages of substantially tion heading must be in bold print. the same size, the term area of the prin- Each subheading within a section must cipal display panel means the area of the side or surface that bears the prin- be indented and not bolded. cipal display panel, which area shall [71 FR 3988, Jan. 24, 2006] be:

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(a) In the case of a rectangular pack- algesic,’’ ‘‘decongestant,’’ ‘‘antihis- age where one entire side properly can taminic,’’ etc. The indications for use be considered to be the principal dis- shall be included in the directions for play panel side, the product of the use of the drug, as required by section height times the width of that side; 502(f)(1) of the act and by the regula- (b) In the case of a cylindrical or tions in this part. nearly cylindrical container, 40 percent (c) The statement of identity shall be of the product of the height of the con- presented in bold face type on the prin- tainer times the circumference; and cipal display panel, shall be in a size (c) In the case of any other shape of reasonably related to the most promi- container, 40 percent of the total sur- nent printed matter on such panel, and face of the container: Provided, how- shall be in lines generally parallel to ever, That where such container pre- the base on which the package rests as sents an obvious ‘‘principal display it is designed to be displayed. panel’’ such as the top of a triangular or circular package, the area shall con- § 201.62 Declaration of net quantity of sist of the entire top surface. contents. In determining the area of the prin- (a) The label of an over-the-counter cipal display panel, exclude tops, bot- drug in package form shall bear a dec- toms, flanges at the tops and bottoms laration of the net quantity of con- of cans, and shoulders and necks of bot- tents. This shall be expressed in the tles or jars. In the case of cylindrical terms of weight, measure, numerical or nearly cylindrical containers, infor- count, or a combination or numerical mation required by this part to appear count and weight, measure, or size. The on the principal display panel shall ap- statement of quantity of drugs in tab- pear within that 40 percent of the cir- let, capsule, ampule, or other unit form cumference which is most likely to be and the quantity of devices shall be ex- displayed, presented, shown, or exam- pressed in terms of numerical count; ined under customary conditions of dis- the statement of quantity for drugs in play for retail sale. other dosage forms shall be in terms of weight if the drug is solid, semisolid, or § 201.61 Statement of identity. viscous, or in terms of fluid measure if (a) The principal display panel of an the drug is liquid. The drug quantity over-the-counter drug in package form statement shall be augmented when shall bear as one of its principal fea- necessary to give accurate information tures a statement of the identity of the as to the strength of such drug in the commodity. package; for example, to differentiate (b) Such statement of identity shall between several strengths of the same be in terms of the established name of drug ‘‘100 tablets, 5 grains each’’ or the drug, if any there be, followed by ‘‘100 capsules, 125 milligrams each’’ or an accurate statement of the general ‘‘100 capsules, 250 milligrams each’’: pharmacological category(ies) of the Provided, That: drug or the principal intended action(s) (1) In the case of a firmly established, of the drug. In the case of an over-the- general consumer usage and trade cus- counter drug that is a mixture and that tom of declaring the quantity of a drug has no established name, this require- 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

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net quantity of contents by weight, principal display panel within the bot- measure, numerical count, or a com- tom 30 percent of the area of the label bination of these does not facilitate panel in lines generally parallel to the value comparisons by consumers, he base on which the package rests as it is shall by regulation designate the ap- designed to be displayed: Provided, propriate term or terms to be used for That: such article. (1) On packages having a principal (b) Statements of weight of the con- display panel of 5 square inches or less tents shall be expressed in terms of av- the requirement for placement within oirdupois pound and ounce. A state- the bottom 30 percent of the area of the ment of liquid measure of the contents label panel shall not apply when the shall be expressed in terms of the U.S. declaration of net quantity of contents gallon of 231 cubic inches and quart, meets the other requirements of this pint, and fluid-ounce subdivisions part; and thereof, and shall express the volume (2) In the case of a drug that is mar- ° ° at 68 F (20 C). See also paragraph (p) keted with both outer and inner retail of this section. containers bearing the mandatory label (c) The declaration may contain com- information required by this part and mon or decimal fractions. A common the inner container is not intended to fraction shall be in terms of halves, be sold separately, the net quantity of quarters, eights, sixteenths, or thirty- contents placement requirement of this seconds; except that if there exists a section applicable to such inner con- firmly established, general consumer tainer is waived. usage and trade custom of employing (3) The principal display panel of a different common fractions in the net drug marketed on a display card to quantity declaration of a particular which the immediate container is af- commodity, they may be employed. A fixed may be considered to be the dis- common fraction shall be reduced to play panel of the card, and the type its lowest terms; a decimal fraction size of the net quantity of contents shall not be carried out to more than 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 label, and with respect to packages in containers designed to deliver the bearing alternate principal panels it drug under pressure, the declaration shall be duplicated on each principal shall state the net quantity of the con- display panel. tents that will be expelled when the in- (e) The declaration shall appear as a structions for use as shown on the con- distinct item on the principal display tainer are followed. The propellant is panel, shall be separated, by at least a included in the net quantity declara- space equal to the height of the let- tion. tering used in the declaration, from (g) The declaration shall appear in other printed label information appear- conspicuous and easily legible boldface ing above or below the declaration and, print or type in distinct contrast (by by at least a space equal to twice the typography, layout, color, embossing, width of the letter ‘‘N’’ of the style of or molding) to other matter on the type used in the quantity of contents package; except that a declaration of statement, from other printed label in- net quantity blown, embossed, or mold- formation appearing to the left or right ed on a glass or plastic surface is per- of the declaration. It shall not include missible when all label information is any term qualifying a unit of weight, so formed on the surface. Requirements measure, or count, such as ‘‘giant pint’’ of conspicuousness and legibility shall and ‘‘full quart’’, that tends to exag- include the specifications that: gerate the amount of the drug in the (1) The ratio of height to width of the container. It shall be placed on the letter shall not exceed a differential of

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3 units to 1 unit, i.e., no more than 3 liquid measure, in the largest whole times as high as it is wide. units (quarts, quarts and pints, or (2) Letter heights pertain to upper pints, as appropriate) with any remain- case or capital letters. When upper and der in terms of fluid ounces or common lower case or all lower case letters are or decimal fractions of the pint or used, it is the lower case letter ‘‘o’’ or quart (see examples set forth in para- its equivalent that shall meet the min- graphs (k) (3) and (4) of this section). If imum standards. the net weight of the package is less (3) When fractions are used, each than 1 ounce avoirdupois or the net component numeral shall meet one- fluid measure is less than 1 fluid ounce, half the minimum height standards. the declaration shall be in terms of (h) The declaration shall be in letters common or decimal fractions of the re- and numerals in a type size established spective ounce and not in terms of in relationship to the area of the prin- drams. cipal display panel of the package and (2) The declaration may appear in shall be uniform for all packages of more than one line. The term net substantially the same size by com- weight shall be used when stating the plying with the following type speci- net quantity of contents in terms of fications: weight. Use of the terms net or net con- (1) Not less than one-sixteenth inch tents in terms of fluid measure or nu- in height on packages the principal dis- merical count is optional. It is suffi- play panel of which has an area of 5 cient to distinguish avoirdupois ounce square inches or less. from fluid ounce through association of (2) Not less than one-eighth inch in terms; for example, ‘‘Net wt. 6 oz’’ or height on packages the principal dis- ‘‘6 oz net wt.,’’ and ‘‘6 fl oz’’ or ‘‘net play panel of which has an area of more contents 6 fl oz’’. than five but not more than 25 square (j) On packages containing 4 pounds inches. or 1 gallon or more and labeled in (3) Not less than three-sixteenths terms of weight or fluid measure, the inch in height on packages the prin- declaration shall be expressed in cipal display panel of which has an pounds for weight units with any re- area of more than 25 but not more than mainder in terms of ounces or common 100 square inches. or decimal fractions of the pound; in (4) Not less than one-fourth inch in the case of fluid measure, it shall be height on packages the principal dis- expressed in the largest whole unit play panel of which has an area of more (gallons, followed by common or dec- than 100 square inches, except not less imal fractions of a gallon or by the than one-half inch in height if the area next smaller whole unit or units is more than 400 square inches. (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

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not in terms of quart and ounce such as terms the net quantity of contents, ‘‘Net 56 fl oz (1 qt 24 oz).’’ provided that such supplemental state- (5) A declaration of 21⁄2 gallons liquid ments of net quantity of contents shall measure shall be expressed as ‘‘Net not include any term qualifying a unit contents 2 gal 2 qt,’’ ‘‘Net contents 2.5 of weight, measure, or count that tends gallons,’’ or ‘‘Net contents 21⁄2 gal’’ but to exaggerate the amount of the drug not as ‘‘2 gal 4 pt’’. contained in the package; for example, (l) For quantities, the following ab- ‘‘giant pint’’ and ‘‘full quart.’’ Dual or breviations and none other may be em- combination declarations of net quan- ployed. Periods and plural forms are tity of contents as provided for in para- optional: graphs (a) and (i) of this section are not regarded as supplemental net quantity Gallon gal milliliter ml quart qt cubic centimeter cc statements and shall be located on the pint pt yard yd principal display panel. ounce oz feet or foot ft (p) A separate statement of net quan- pound lb inch in tity of contents in terms of the metric grain gr meter m system of weight or measure is not re- kilogram kg centimeter cm garded as a supplemental statement gram g millimeter mm milligram mg fluid fl and an accurate statement of the net microgram mcg square sq quantity of contents in terms of the liter l weight wt metric system of weight or measure 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 shall be in terms of inches or common in good manufacturing practice will be or decimal fractions of the foot or recognized. Variations from stated yard; if applicable, as in the case of ad- quantity of contents shall not be un- hesive tape, the initial declaration in reasonably large. linear inches shall be preceded by a (r) A drug shall be exempt from com- statement of the width. Examples of pliance with the net quantity declara- linear measure are ‘‘86 inches (2 yd 1 ft tion required by this section if it is an 2 in),’’ ‘‘90 inches (21⁄2 yd),’’ ‘‘30 inches ointment labeled ‘‘sample,’’ ‘‘physi- (2.5 ft),’’ ‘‘ 3⁄4 inch by 36 in (1 yd),’’ etc. cian’s sample,’’ or a substantially simi- (n) On packages labeled in terms of lar statement and the contents of the area measure, the declaration shall be package do not exceed 8 grams. expressed both in terms of square inches and, if applicable (1 square foot § 201.63 Pregnancy/breast-feeding warning. or more), the largest whole square unit (square yards, square yards and square (a) The labeling for all over-the- feet, square feet). The declaration in counter (OTC) drug products that are terms of the largest whole units shall intended for systemic absorption, un- be in parentheses following the dec- less specifically exempted, shall con- laration in terms of square inches and tain a general warning under the head- any remainder shall be in terms of ing ‘‘Warning’’ (or ‘‘Warnings’’ if it ap- square inches or common or decimal pears with additional warning state- fractions of the square foot or square ments) as follows: ‘‘If pregnant or yard; for example, ‘‘158 sq inches (1 sq breast-feeding, ask a health profes- ft 14 sq in).’’ sional before use.’’ [first four words of (o) Nothing in this section shall pro- this statement in bold type] In addi- hibit supplemental statements at location to the written warning, a symbol tions other than the principal display that conveys the intent of the warning panel(s) describing in nondeceptive may be used in labeling.

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(b) Where a specific warning relating dosage units) is 5 milligrams or more. to use during pregnancy or while nurs- OTC drug products intended for oral in- ing has been established for a par- gestion include gum and lozenge dosage ticular drug product in a new drug ap- forms, but do not include dentifrices, plication (NDA) or for a product cov- mouthwashes, or mouth rinses. ered by an OTC drug final monograph (b) The sodium content shall be ex- in part 330 of this chapter, the specific pressed in milligrams per dosage unit warning shall be used in place of the and shall include the total amount of warning in paragraph (a) of this sec- sodium regardless of the source, i.e., tion, unless otherwise stated in the from both active and inactive ingredi- NDA or in the final OTC drug mono- ents. The sodium content shall be graph. rounded-off to the nearest whole num- (c) The following OTC drugs are ex- ber. The sodium content per dosage empt from the provisions of paragraph unit shall follow the heading ‘‘Other (a) of this section: information’’ as stated in § 201.66(c)(7). (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’’ (se- (e) The term very low sodium may be lect ‘‘aspirin’’ or ‘‘carbaspirin calcium,’’ as 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 single maximum recommended dose of 1 See § 201 .66(b)(4) of this chapter for defini- the product (which may be one or more tion of bullet symbol.

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(h) The terms sodium free, very low so- intended for rectal administration and dium, and low sodium shall be in print that is not labeled as required by this size and style no larger than the prod- paragraph and that is initially intro- uct’s statement of identity and shall duced or initially delivered for intro- not be unduly prominent in print size duction into interstate commerce after or style compared to the statement of November 29, 2005, is misbranded under identity. sections 201(n) and 502(a) and (f) of the (i) Any product subject to this para- act. graph that contains sodium bicarbon- ate, sodium phosphate, or sodium [61 FR 17806, Apr. 22, 1996, as amended at 62 FR 19925, Apr. 24, 1997; 64 FR 13286, Mar. 17, biphosphate as an active ingredient for 1999; 69 FR 13724, Mar. 24, 2004; 69 FR 69280, oral ingestion and that is not labeled Nov. 29, 2004] as required by this paragraph and that is initially introduced or initially de- § 201.66 Format and content require- livered for introduction into interstate ments for over-the-counter (OTC) commerce after April 22, 1997, is mis- drug product labeling. branded under sections 201(n) and 502 (a) Scope. This section sets forth the (a) and (f) of the Federal Food, Drug, content and format requirements for and Cosmetic Act (the act). the labeling of all OTC drug products. (j) Any product subject to paragraphs Where an OTC drug product is the sub- (a) through (h) of this section that is ject of an applicable monograph or reg- not labeled as required and that is ini- ulation that contains content and for- tially introduced or initially delivered mat requirements that conflict with for introduction into interstate com- this section, the content and format re- merce after the following dates is mis- quirements in this section must be fol- branded under sections 201(n) and 502(a) lowed unless otherwise specifically pro- and (f) of the Federal Food, Drug, and vided in the applicable monograph or Cosmetic Act. regulation. (1) As of the date of approval of the application for any single entity and (b) Definitions. The following defini- combination products subject to drug tions apply to this section: marketing applications approved on or (1) Act means the Federal Food, Drug, after April 23, 2004. and Cosmetic Act (secs. 201 et seq. (21 (2) Septemeber 24, 2005, for all OTC U.S.C. 321 et seq.)). drug products subject to any OTC drug (2) Active ingredient means any com- monograph, not yet the subject of any ponent that is intended to furnish OTC drug monograph, or subject to pharmacological activity or other di- drug marketing applications approved rect effect in the diagnosis, cure, miti- before April 23, 2004. gation, 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.

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(5) Established name of a drug or in- subsequent panel containing such ingredient thereof means the applicable formation. official name designated under section (2) ‘‘Active ingredient’’ or ‘‘Active in- 508 of the act (21 U.S.C. 358), or, if there gredients’’ ‘‘(in each [insert the dosage is no designated official name and the unit stated in the directions for use drug or ingredient is recognized in an (e.g., tablet, 5 mL teaspoonful) or in official compendium, the official title each gram as stated in §§ 333.110 and of the drug or ingredient in such com- 333.120 of this chapter])’’, followed by pendium, or, if there is no designated the established name of each active in- official name and the drug or ingre- gredient and the quantity of each ac- dient is not recognized in an official tive ingredient per dosage unit. Unless compendium, the common or usual otherwise provided in an applicable name of the drug or ingredient. OTC drug monograph or approved drug (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 the top of the required OTC drug prod- (4) ‘‘Use’’ or ‘‘Uses’’, followed by the uct labeling, as set forth in paragraph indication(s) for the specific drug prod- (c)(1) of this section. uct. (12) Total surface area available to bear (5) ‘‘Warning’’ or ‘‘Warnings’’, fol- labeling means all surfaces of the out- lowed by one or more of the following, side container of the retail package or, if applicable: 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 warnings set (1) (Title) ‘‘Drug Facts’’. If the drug forth in any applicable OTC drug facts labeling appears on more than monograph or approved drug applica- one panel, the title ‘‘Drug Facts (con- tion for any product that requires a tinued)’’ shall appear at the top of each separate allergy warning. This warning

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shall follow the subheading ‘‘Allergy are those intended only for situations alert:’’ in which consumers should not use the (C) Flammability warning, with ap- product until a doctor is consulted. propriate flammability signal word(s) (v) ‘‘Ask a doctor or pharmacist be- (e.g., §§ 341.74(c)(5)(iii), 344.52(c), fore use if you are’’ [in bold type] or, 358.150(c), and 358.550(c) of this chap- for products labeled only for use in ter). This warning shall follow a sub- children under 12 years of age, ‘‘Ask a heading containing the appropriate doctor or pharmacist before use if the flammability signal word(s) described child is’’ [in bold type], followed by all 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:’’ (H) Sexually transmitted diseases the manufacturer or distributor of the (STDs) warning for vaginal contracep- drug product, the following text shall tive and spermicide drug products con- immediately follow the subheading: taining nonoxynol 9 set forth in ‘‘[Bullet] side effects occur. You may § 201.325(b)(2). This warning shall follow report side effects to FDA at 1–800– the subheading ‘‘Sexually transmitted FDA–1088.’’ The telephone number diseases (STDs) alert:’’ must appear in a minimum 6–point (iii) ‘‘Do not use’’ [in bold type], fol- bold letter height or type size. lowed by all contraindications for use (viii) Any required warnings in an ap- with the product. These contraindica- plicable OTC drug monograph, other tions are absolute and are intended for OTC drug regulations, or approved drug situations in which consumers should application that do not fit within one not use the product unless a prior diag- of the categories listed in paragraphs nosis has been established by a doctor (c)(5)(i) through (c)(5)(vii), (c)(5)(ix), or for situations in which certain con- and (c)(5)(x) of this section. sumers should not use the product (ix) The pregnancy/breast-feeding under any circumstances regardless of warning set forth in § 201.63(a); the whether a doctor or health professional third trimester warning set forth in is consulted. § 201.63(e) for products containing aspi- (iv) ‘‘Ask a doctor before use if you rin or carbaspirin calcium; the third have’’ [in bold type] or, for products la- trimester warning set forth in ap- beled only for use in children under 12 proved drug applications for products years of age, ‘‘Ask a doctor before use containing ketoprofen, naproxen so- if the child has’’ [in bold type], fol- dium, and ibuprofen (not intended ex- lowed by all warnings for persons with clusively for use in children). certain preexisting conditions (exclud- (x) The ‘‘Keep out of reach of chil- ing pregnancy) and all warnings for dren’’ warning and the accidental over- persons experiencing certain symp- dose/ingestion warning set forth in toms. The warnings under this heading § 330.1(g) of this chapter.

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(6) ‘‘Directions’’, followed by the di- the day when a person is available to rections for use described in an appli- respond to questions also be included. cable OTC drug monograph or approved A graphic of a telephone or telephone drug application. receiver may appear before the head- (7) ‘‘Other information’’, followed by ing. The telephone number must ap- additional information that is not in- pear in a minimum 6-point bold type. cluded under paragraphs (c)(2) through (d) Format requirements. The title, (c)(6), (c)(8), and (c)(9) of this section, headings, subheadings, and information but which is required by or is made op- set forth in paragraphs (c)(1) through tional under an applicable OTC drug (c)(9) of this section shall be presented 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 appli- for all other words. The title, headings, cable, shall appear as the next item of and subheadings in paragraphs (c)(1), information. (c)(2), and (c)(4) through (c)(9) of this (iii) Additional information that is section shall be left justified. authorized to appear under this head- (2) The letter height or type size for ing shall appear as the next item(s) of the title ‘‘Drug Facts’’ shall appear in information. There is no required order a type size larger than the largest type for this subsequent information. size used in the Drug Facts labeling. (8) ‘‘Inactive ingredients’’, followed The letter height or type size for the by a listing of the established name of title ‘‘Drug Facts (continued)’’ shall be each inactive ingredient. If the product no smaller than 8-point type. The let- is an OTC drug product that is not also ter height or type size for the headings a cosmetic product, then the inactive in paragraphs (c)(2) through (c)(9) of ingredients shall be listed in alphabet- this section shall be the larger of ei- ical order. If the product is an OTC ther 8-point or greater type, or 2-point drug product that is also a cosmetic sizes greater than the point size of the product, then the inactive ingredients text. The letter height or type size for shall be listed as set forth in § 701.3(a) the subheadings and all other informa- or (f) of this chapter, the names of cos- tion described in paragraphs (c)(2) metic ingredients shall be determined through (c)(9) of this section shall be in accordance with § 701.3(c) of this no smaller than 6-point type. chapter, and the provisions in § 701.3(e), (3) The title, heading, subheadings, (g), (h), (l), (m), (n), and (o) of this and information in paragraphs (c)(1) chapter and § 720.8 of this chapter may through (c)(9) of this section shall be also apply, as appropriate. If there is a legible and clearly presented, shall difference in the labeling provisions in have at least 0.5-point leading (i.e., this § 201.66 and §§ 701.3 and 720.8 of this space between two lines of text), and chapter, the labeling provisions in this shall not have letters that touch. The § 201.66 shall be used. type style for the title, headings, sub- (9) ‘‘Questions?’’ or ‘‘Questions or headings, and all other required infor- comments?’’, followed by the telephone mation described in paragraphs (c)(2) number of a source to answer questions through (c)(9) of this section shall be about the product. It is recommended any single, clear, easy-to-read type that the days of the week and times of style, with no more than 39 characters

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per inch. The title and headings shall graphic (e.g., an arrow) shall be used to be in bold italic, and the subheadings signal the continuation of the Drug shall be in bold type, except that the Facts labeling to the next adjacent word ‘‘(continued)’’ in the title ‘‘Drug panel. Facts (continued)’’ shall be regular (6) The heading and information re- type. The type shall be all black or one quired under paragraph (c)(2) of this color printed on a white or other con- section shall appear immediately adja- trasting background, except that the cent and to the left of the heading and 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 (7) Graphical images (e.g., the UPC ‘‘ems’’ and the complete additional symbol) and information not described bulleted statement(s) shall not con- in paragraphs (c)(1) through (c)(9) of tinue to the next line of text. Addi- this section shall not appear in or in tional bulleted statements appearing any way interrupt the required title, on each subsequent horizontal line of headings, subheadings, and information text under a heading or subheading in paragraphs (c)(1) through (c)(9) of shall be vertically aligned with the this section. Hyphens shall not be used bulleted statements appearing on the except to punctuate compound words. previous line. (8) The information described in (5) The title, headings, subheadings, paragraphs (c)(1) through (c)(9) of this and information set forth in para- section shall be set off in a box or simi- graphs (c)(1) through (c)(9) of this sec- lar enclosure by the use of a barline. A tion may appear on more than one distinctive horizontal barline extend- panel on the outside container of the ing to each end of the ‘‘Drug Facts’’ retail package, or the immediate con- box or similar enclosure shall provide tainer label if there is no outside con- separation between each of the head- tainer or wrapper. The continuation of ings listed in paragraphs (c)(2) through the required content and format onto (c)(9) of this section. When a heading multiple panels must retain the re- listed in paragraphs (c)(2) through quired order and flow of headings, sub- (c)(9) of this section appears on a subse- headings, and information. A visual quent panel immediately after the

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

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

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

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(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:

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(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

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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] 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.

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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.

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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

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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

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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.

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

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development, and functional matura- the patient should be apprised of the tion of the child. potential hazard to the fetus.’’ (c) Pregnancy category C. If animal re- (e) Pregnancy category X. If studies in production studies have shown an ad- animals or humans have demonstrated verse effect on the fetus, if there are no fetal abnormalities or if there is posi- adequate and well-controlled studies in tive evidence of fetal risk based on ad- humans, and if the benefits from the verse reaction reports from investiga- use of the drug in pregnant women may tional or marketing experience, or be acceptable despite its potential both, and the risk of the use of the risks, the labeling shall state: ‘‘Preg- drug in a pregnant woman clearly out- nancy Category C. (Name of drug) has weighs any possible benefit (for exam- been shown to be teratogenic (or to ple, safer drugs or other forms of ther- have an embryocidal effect or other ad- apy are available), the labeling shall verse effect) in (name(s) of species) when state: ‘‘Pregnancy Category X. See given in doses (x) times the human ‘Contraindications’ section.’’ Under dose. There are no adequate and well- ‘‘Contraindications,’’ the labeling shall controlled studies in pregnant women. state: ‘‘(Name of drug) may (can) cause (Name of drug) should be used during fetal harm when administered to a pregnancy only if the potential benefit pregnant woman. (Describe the human justifies the potential risk to the data and any pertinant animal data.) fetus.’’ The labeling shall contain a de- (Name of drug) is contraindicated in scription of the animal studies. If there women who are or may become preg- are no animal reproduction studies and nant. If this drug is used during preg- no adequate and well-controlled studies nancy, or if the patient becomes preg- in humans, the labeling shall state: nant while taking this drug, the pa- ‘‘Pregnancy Category C. Animal repro- tient should be apprised of the poten- duction studies have not been con- tial hazard to the fetus.’’ ducted with (name of drug). It is also (ii) Nonteratogenic effects. Under this not known whether (name of drug) can heading the labeling shall contain cause fetal harm when administered to other information on the drug’s effects a pregnant woman or can affect repro- on reproduction and the drug’s use dur- duction capacity. (Name of drug) should ing pregnancy that is not required spe- be given to a pregnant woman only if cifically by one of the pregnancy cat- clearly needed.’’ The labeling shall egories, if the information is relevant contain a description of any available to the safe and effective use of the data on the effect of the drug on the drug. Information required under this later growth, development, and func- heading shall include nonteratogenic tional maturation of the child. effects in the fetus or newborn infant (d) Pregnancy category D. If there is (for example, withdrawal symptoms or positive evidence of human fetal risk hypoglycemia) that may occur because based on adverse reaction data from in- of a pregnant woman’s chronic use of vestigational or marketing experience the drug for a preexisting condition or or studies in humans, but the potential disease. benefits from the use of the drug in (7) Labor and delivery. If the drug has pregnant women may be acceptable de- a recognized use during labor or deliv- spite its potential risks (for example, if ery (vaginal or abdominal delivery), the drug is needed in a life-threatening whether or not the use is stated in the situation or serious disease for which indications section of the labeling, this safer drugs cannot be used or are inef- subsection of the labeling shall defective), the labeling shall state: scribe the available information about ‘‘Pregnancy Category D. See ‘Warn- the effect of the drug on the mother ings’ section.’’ Under the ‘‘Warnings’’ and the fetus, on the duration of labor section, the labeling states: ‘‘(Name of or delivery, on the possibility that for- drug) can cause fetal harm when ad- ceps delivery or other intervention or ministered to a pregnant woman. resuscitation of the newborn will be (Describe the human data and any perti- necessary, and the effect of the drug on nent animal data.) If this drug is used the later growth, development, and during pregnancy, or if the patient be- functional maturation of the child. If comes pregnant while taking this drug, any information required under this

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subsection is unknown, this subsection beling shall state: ‘‘It is not known of the labeling shall state that the in- whether this drug is excreted in human formation is unknown. milk. Because many drugs are excreted (8) Nursing mothers. (i) If a drug is ab- in human milk, caution should be exer- sorbed systemically, this subsection of cised when (name of drug) is adminis- the labeling shall contain, if known, in- tered to a nursing woman.’’ formation about excretion of the drug (9) Pediatric use. (i) Pediatric popu- in human milk and effects on the nurs- lation(s)/pediatric patient(s): For the ing infant. Pertinent adverse effects purposes of paragraphs (f)(9)(ii) observed in animal offspring shall be through (f)(9)(viii) of this setion, the described. terms pediatric population(s) and pedi- (ii) If a drug is absorbed systemically atric patient(s) are defined as the pedi- and is known to be excreted in human atric age group, from birth to 16 years, milk, this subsection of the labeling including age groups often called neo- shall contain one of the following nates, infants, children, and adoles- statements, as appropriate. If the drug cents. is associated with serious adverse reac- (ii) If there is a specific pediatric in- tions or if the drug has a known dication (i.e., an indication different tumorigenic potential, the labeling from those approved for adults) that is shall state: ‘‘Because of the potential supported by adequate and well-con- for serious adverse reactions in nursing trolled studies in the pediatric popu- infants from (name of drug) (or, ‘‘Be- lation, it shall be described under the cause of the potential for ‘‘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

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the labeling shall also cite any limita- tial evidence of effectiveness in the pe- tions on the pediatric use statement, diatric population).’’ Data summarized need for specific monitoring, specific in the preceding prescribed statement hazards associated with use of the drug in this subsection of the labeling shall 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 information supporting pediatric use. need for specific monitoring, dosing ad- In such cases, the agency will have justments, and any other information concluded that the course of the dis- related to safe and effective use of the ease and the effects of the drug, both drug in pediatric patients shall be cited beneficial and adverse, are sufficiently briefly in the ‘‘Pediatric use’’ sub- similar in the pediatric and adult popu- section and, as appropriate, in the lations to permit extrapolation from ‘‘Contraindications,’’ ‘‘Warnings,’’ the adult efficacy data to pediatric pa- ‘‘Precautions,’’ and ‘‘Dosage and Ad- tients. The additional information sup- ministration’’ sections. porting pediatric use must ordinarily (v) If the requirements for a finding include data on the pharmacokinetics of substantial evidence to support a pe- of the drug in the pediatric population diatric indication or a pediatric use for determination of appropriate dos- statement have not been met for a par- age. Other information, such as data ticular pediatric population, the ‘‘Pe- from pharmacodynamic studies of the diatric use’’ subsection of the labeling drug in the pediatric population, data shall contain an appropriate statement from other studies supporting the safe- such as ‘‘Safety and effectiveness in pe- ty or effectiveness of the drug in pedi- diatric patients below the age of (l) atric patients, pertinent premarketing have not been established.’’ If use of or postmarketing studies or experi- the drug in this pediatric population is ence, may be necessary to show that associated with a specific hazard, the the drug can be used safely and effec- hazard shall be described in this sub- tively in pediatric patients. When a section of the labeling, or, if appro- drug is approved for pediatric use based priate, the hazard shall be stated in the on adequate and well-controlled studies ‘‘Contraindications’’ or ‘‘Warnings’’ in adults with other information sup- section of the labeling and this sub- porting pediatric use, the ‘‘Pediatric section shall refer to it. use’’ subsection of the labeling shall contain either the following statement, (vi) If the requirements for a finding or a reasonable alternative: ‘‘The safe- of substantial evidence to support a pe- ty and effectiveness of (drug name) have diatric indication or a pediatric use been established in the age groups l to statement have not been met for any l (note any limitations, e.g., no data pediatric population, this subsection of for pediatric patients under 2, or only the labeling shall contain the following applicable to certain indications ap- statement: ‘‘Safety and effectiveness in proved in adults). Use of (drug name) in pediatric patients have not been estab- these age groups is supported by evi- lished.’’ If use of the drug in premature dence from adequate and well-con- or neonatal infants, or other pediatric trolled studies of (drug name) in adults subgroups, is associated with a specific with additional data (insert wording hazard, the hazard shall be described in that accurately describes the data sub- this subsection of the labeling, or, if mitted to support a finding of substan- appropriate, the hazard shall be stated

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in the ‘‘Contraindications’’ or ‘‘Warn- ‘‘Geriatric use’’ subsection and shall ings’’ section of the labeling and this reflect all information available to the subsection shall refer to it. sponsor that is relevant to the appro- (vii) If the sponsor believes that none priate use of the drug in elderly pa- of the statements described in para- tients. This information includes de- graphs (f)(9)(ii) through (f)(9)(vi) of this tailed results from controlled studies 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 labeling. The ‘‘Geriatric use’’ subsection ‘‘Clinical studies of (name of drug) did not shall cite any limitations on the geri- include sufficient numbers of subjects aged atric indication, need for specific moni- 65 and over to determine whether they respond differently from younger subjects. toring, specific hazards associated with Other reported clinical experience has not the geriatric indication, and other in- identified differences in responses between formation related to the safe and effec- the elderly and younger patients. In general, tive use of the drug in the geriatric dose selection for an elderly patient should population. Unless otherwise noted, in- be cautious, usually starting at the low end formation contained in the ‘‘Geriatric of the dosing range, reflecting the greater use’’ subsection of the labeling shall frequency of decreased hepatic, renal, or car- pertain to use of the drug in persons 65 diac function, and of concomitant disease or other drug therapy.’’ years of age and older. Data summarized in this subsection of the labeling (B) If clinical studies (including stud- shall be discussed in more detail, if ap- ies that are part of marketing applica- propriate, under ‘‘Clinical Pharma- tions and other relevant studies avail- cology’’ or the ‘‘Clinical Studies’’ sec- able to the sponsor that have not been tion. As appropriate, this information submitted in the sponsor’s applica- shall also be contained in ‘‘Contra- tions) included enough elderly subjects indications,’’ ‘‘Warnings,’’ and else- to make it likely that differences in where in ‘‘Precautions.’’ safety or effectiveness between elderly (ii) Specific statements on geriatric and younger subjects would have been use of the drug for an indication ap- detected, but no such differences (in proved for adults generally, as distin- safety or effectiveness) were observed, guished from a specific geriatric indi- and other reported clinical experience cation, shall be contained in the has not identified such differences, the

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‘‘Geriatric use’’ subsection shall con- (iv) If use of the drug in the elderly tain the following statement: appears to cause a specific hazard, the hazard shall be described in the ‘‘Geri- Of the total number of subjects in clinical atric use’’ subsection of the labeling, studies of (name of drug), l percent were 65 and over, while l percent were 75 and over. or, if appropriate, the hazard shall be (Alternatively, the labeling may state the stated in the ‘‘Contraindications,’’ total number of subjects included in the ‘‘Warnings,’’ or ‘‘Precautions’’ section 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 re- (f)(10)(i) through (f)(10)(iii) of this sec- ported clinical experience has not identified tion may include statements, if they differences in responses between the elderly 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 (name of drug) and observed closely.’’ effectiveness, or requires specific monitoring 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, by severity of the reaction, by fre- ‘‘This drug is known to be substantially ex- quency, or by toxicological mecha- creted by the kidney, and the risk of toxic nism, or by a combination of these, as reactions to this drug may be greater in pa- appropriate. If frequency information tients with impaired renal function. Because 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.

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An adverse reaction that is signifi- types of abuse that can occur with the cantly more severe than the other re- drug and the adverse reactions perti- actions listed in a category, however, nent to them. Particularly susceptible shall be listed before those reactions, patient populations shall be identified. regardless of its frequency. If frequency (3) Dependence. This subsection of the information from adequate clinical labeling shall describe characteristic studies is not available, the categories effects resulting from both psycho- 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 actually exists. (1) Signs, symptoms, and laboratory (3) The ‘‘Warnings’’ section of the la- findings associated with an overdosage beling or, if appropriate, the ‘‘Contra- of the drug. indications’’ section of the labeling (2) Complications that can occur with shall identify any potentially fatal ad- the drug (for example, organ toxicity verse reaction. or delayed acidosis). (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

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forced diuresis. Unqualified rec- the labeling applies and for which the ommendations for which data are lack- manufacturer or distributor is respon- ing with the specific drug or class of sible. The information shall ordinarily drugs, especially treatment using an- include: other drug (for example, central nerv- (1) The strength of the dosage form, ous system stimulants, respiratory e.g., 10-milligram tablets, in metric stimulants) may not be stated unless system and, if the apothecary system 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:

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(1)(i) If the clinical study is cited in (2) It is to be dispensed in accordance the labeling in place of a detailed dis- with section 503(b) cussion of data and information con- (b) The label of the drug bears: cerning an indication for use of the (1) The statement ‘‘Rx only’’ and drug, the clinical study must con- (2) The recommended or usual dosage stitute an adequate and well-controlled and study as described in § 314.126(b) of this (3) The route of administration, if it chapter, except for biological products, is not for oral use; and and must not imply or suggest indications 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, be- designated as such without naming cause the information is important to their components. prescribing decisions, the labeling may (ii) Color additives may be des- include a reference to the source of the ignated as coloring without naming information. specific color components unless the (2) If the clinical study or reference is naming of such components is required cited in the labeling in the place of a by a color additive regulation pre- detailed discussion of data and infor- scribed in subchapter A of this chapter. mation concerning a risk or risks from (iii) Trace amounts of harmless sub- the use of the drug, the risk or risks stances added solely for individual shall also be identified or discussed in product identification need not be the appropriate section of the labeling named. If it is intended for administra- for the drug. tion by parenteral injection, the quan- [44 FR 37462, June 26, 1979, as amended at 55 tity or proportion of all inactive ingre- FR 11576, Mar. 29, 1990; 59 FR 64249, Dec. 13, dients, except that ingredients added 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396, to adjust the pH or to make the drug Dec. 1, 1998. Redesignated and amended at 71 isotonic may be declared by name and FR 3988, 3996, Jan. 24, 2006] 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 history of the package of the drug. A drug subject to the requirements of (7) A statement directed to the phar- section 503(b)(1) of the act shall be exempt 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

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specific container or types of con- drug is to be dispensed, distributed by tainers known to be adequate to main- or on behalf of the manufacturer, pack- tain the identity, strength, quality, er, or distributor of the drug, that fur- and purity of the drug products shall nishes or purports to furnish informa- be described. For example, ‘‘Dispense tion for use or which prescribes, rec- 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,

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the name and address of the manufac- empt from section 502(f)(1) of the act if turer, packer, or distributor or other all the following conditions are met: written, printed, or graphic matter (a) The drug is: containing no representation or sug- (1)(i) In the possession of a person (or gestion relating to the drug product. If his agents or employees) regularly and 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 (2) To be dispensed in accordance provide consumers with information with section 503(f) of the act. concerning the price charged for a pre- (b) The label of the drug bears: scription for a particular drug product (1) The statement ‘‘Caution: Federal shall meet all of the conditions con- law restricts this drug to use by or on tained in § 200.200 of this chapter. Re- the order of a licensed veterinarian’’; minder labeling, other than that sub- and ject to the requirements of § 200.200 of (2) The recommended or usual dos- this chapter, is not permitted for a age; and drug for which an announcement has (3) The route of administration, if it been published pursuant to a review of is not for oral use; and the labeling claims for the drug by the 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 by a color additive regulation pre- [40 FR 13998, Mar. 27, 1975, as amended at 40 scribed in subchapter A of this chapter. FR 58799, Dec. 18, 1975; 42 FR 15674, Mar. 22, (iii) Trace amounts of harmless sub- 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659, stances added solely for individual Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR 25777, Apr. 15, 1980; 63 FR 26698, May 13, 1998; product identification need not be 64 FR 400, Jan. 5, 1999; 67 FR 4906, Feb. 1, 2002; named. 71 FR 3996, Jan. 24, 2006] If it is intended for administration by parenteral injection, the quantity or § 201.105 Veterinary drugs. proportion of all inactive ingredients, A drug subject to the requirements of except that ingredients added to adjust section 503(f)(1) of the act shall be ex- the pH or to make the drug isotonic

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

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comply with paragraphs (e) and (f) of its sequelae. Such products are in- this section and § 201.100. tended for use in the collection, prepa- [40 FR 13998, Mar. 27, 1975, as amended at 42 ration and examination of specimens FR 15674, Mar. 22, 1977; 57 FR 54300, Nov. 18, taken from the human body. These 1992; 72 FR 69119, Dec. 6, 2007] products are drugs or devices as defined in section 201(g) and 201(h), respec- § 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. § 201.120 Prescription chemicals and No exemption shall apply to any other other prescription components. drug which would be a new drug if its labeling bore representations for its in- A drug prepared, packaged, and pri- tended uses. marily sold as a prescription chemical or other component for use by reg- [40 FR 13998, Mar. 27, 1975, as amended at 72 istered pharmacists in compounding FR 69119, Dec. 6, 2007] 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 liquid solution, emulsion, suspension, tab- [41 FR 6910, Feb. 13, 1976] let, capsule, or other dosage unit form; and § 201.117 Inactive ingredients. (b) The label of the drug bears: A harmless drug that is ordinarily (1) The statement ‘‘For prescription used as an inactive ingredient, such as compounding’’; and a coloring, emulsifier, excipient, fla- (2) If in substantially all dosage voring, lubricant, preservative, or sol- forms in which it may be dispensed it vent, in the preparation of other drugs is subject to section 503(b)(1) of the act, shall be exempt from section 502(f)(1) of the statement ‘‘Rx only’’; or the act. This exemption shall not apply (3) If it is not subject to section to any substance intended for a use 503(b)(1) of the act and is by custom which results in the preparation of a among retail pharmacists sold in or new drug, unless an approved new-drug from the interstate package for use by application provides for such use. consumers, ‘‘adequate directions for § 201.119 In vitro diagnostic products. use’’ in the conditions for which it is so sold. (a) ‘‘In vitro diagnostic products’’ are those reagents, instruments and sys- Provided, however, That the informa- tems intended for use in the diagnosis tion referred to in paragraph (b)(3) of of disease or in the determination of this section may be contained in the the state of health in order to cure, labeling on or within the package from mitigate, treat, or prevent disease or which it is to be dispensed.

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(c) This exemption shall not apply to tional use as provided in part 312 or any substance intended for use in § 511.1 or § 516.125 of this chapter; or compounding which results in a new (c) A new drug application or new drug, unless an approved new-drug ap- animal drug application or a request plication covers such use of the drug in for addition to the index covering the compounding prescriptions. use of the drug substance in the production and marketing of a finished [40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002] drug product has been submitted but not yet approved, disapproved, granted, § 201.122 Drugs for processing, repack- or denied, the bulk drug is not ex- ing, or manufacturing. ported, 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 [41 FR 6911, Feb. 13, 1976, as amended at 41 the statement ‘‘Caution: For manufac- 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 state- § 201.125 Drugs for use in teaching, ment ‘‘Rx only’’, or if in substantially law enforcement, research, and all dosage forms in which it may be analysis. dispensed it is subject to section 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

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201.125 shall continue until the drugs § 201.129 Drugs; exemption for radio- are used for the purposes for which active drugs for research use. they are exempted, or until they are A radioactive drug intended for ad- relabeled to comply with section ministration to human research sub- 502(f)(1) of the act. If, however, the jects during the course of a research drug is converted, compounded, or project intended to obtain basic re- manufactured into a dosage form lim- search information regarding metabo- ited to prescription dispensing, no ex- lism (including kinetics, distribution, emption shall thereafter apply to the and localization) of a radioactively la- article unless the dosage form is labeled drug or regarding human physi- beled as required by section 503(b) and ology, pathophysiology, or bio- §§ 201.100 or 201.105. chemistry (but not intended for immediate therapeutic, diagnostic, or simi- [41 FR 6911, Feb. 13, 1976] lar purposes), under the conditions set forth in § 361.1 of this chapter, shall be § 201.128 Meaning of ‘‘intended uses’’. exempt from section 502(f)(1) of the act The words intended uses or words of if the packaging, label, and labeling similar import in §§ 201.5, 201.115, are in compliance with § 361.1(f) of this 201.117, 201.119, 201.120, and 201.122 refer chapter. to the objective intent of the persons [41 FR 6911, Feb. 13, 1976] legally responsible for the labeling of drugs. The intent is determined by Subpart E—Other Exemptions such persons’ expressions or may be shown by the circumstances sur- § 201.150 Drugs; processing, labeling, rounding the distribution of the arti- or repacking. cle. This objective intent may, for ex- (a) Except as provided by paragraphs ample, be shown by labeling claims, ad- (b) and (c) of this section, a shipment vertising matter, or oral or written or other delivery of a drug which is, in statements by such persons or their accordance with the practice of the representatives. It may be shown by trade, to be processed, labeled, or re- the circumstances that the article is, packed in substantial quantity at an with the knowledge of such persons or establishment other than that where their representatives, offered and used originally processed or packed, shall be for a purpose for which it is neither la- exempt, during the time of introduc- beled nor advertised. The intended uses tion into and movement in interstate of an article may change after it has commerce and the time of holding in been introduced into interstate com- such establishment, from compliance merce by its manufacturer. If, for ex- with the labeling and packaging re- ample, a packer, distributor, or seller quirements of sections 501(b) and 502 intends an article for different uses (b), (d), (e), (f), and (g) of the act if: than those intended by the person from (1) The person who introduced such whom he received the drug, such pack- shipment or delivery into interstate commerce is the operator of the estab- er, distributor, or seller is required to lishment where such drug is to be proc- supply adequate labeling in accordance essed, labeled, or repacked; or with the new intended uses. But if a (2) In case such person is not such op- manufacturer knows, or has knowledge erator, such shipment or delivery is of facts that would give him notice, made to such establishment under a that a drug introduced into interstate written agreement, signed by and con- commerce by him is to be used for containing the post-office addresses of ditions, purposes, or uses other than such person and such operator, and the ones for which he offers it, he is re- containing such specifications for the quired to provide adequate labeling for processing, labeling, or repacking, as such a drug which accords with such the case may be, of such drug in such other uses to which the article is to be establishment as will insure, if such put. specifications are followed, that such drug will not be adulterated or mis- [41 FR 6911, Feb. 13, 1976] branded within the meaning of the act

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upon completion of such processing, la- mation required by the Federal Food, beling, or repacking. Such person and Drug, and Cosmetic Act, the following: such operator shall each keep a copy of (1) The warning statement ‘‘Warn- such agreement until 2 years after the ing—Administration of (name of gas) final shipment or delivery of such drug may be hazardous or contraindicated. from such establishment, and shall For use only by or under the super- make such copies available for inspec- vision of a licensed practitioner who is tion at any reasonable hour to any offi- experienced in the use and administra- cer or employee of the Department who tion of (name of gas) and is familiar requests them. with the indications, effects, dosages, (b) An exemption of a shipment or methods, and frequency and duration other delivery of a drug under para- of administration, and with the haz- graph (a)(1) of this section shall, at the ards, contraindications, and side ef- beginning of the act of removing such fects and the precautions to be taken’’; shipment or delivery, or any part and thereof, from such establishment, be- (2) Any needed directions concerning come void ab initio if the drug com- the conditions for storage and warn- prising such shipment, delivery, or part ings against the inherent dangers in is adulterated or misbranded within the handling of the specific compressed the meaning of the act when so re- gas. moved. (b) This labeling exemption does not (c) An exemption of a shipment or apply to mixtures of any one or more other delivery of a drug under para- of these gases with oxygen or with each graph (a)(2) of this section shall be- other. come void ab initio with respect to the (c) Regulatory action may be initi- person who introduced such shipment ated with respect to any article or delivery into interstate commerce shipped within the jurisdiction of the upon refusal by such person to make Act contrary to the provisions of this available for inspection a copy of the section after 60 days following publica- agreement, as required by such para- tion of this section in the FEDERAL graph (a)(2) of this section. REGISTER. (d) An exemption of a shipment or other delivery of a drug under para- Subpart F—Labeling Claims for graph (a)(2) of this section shall expire: Drugs in Drug Efficacy Study (1) At the beginning of the act of removing such shipment or delivery, or § 201.200 Disclosure of drug efficacy study evaluations in labeling and any part thereof, from such establish- advertising. ment if the drug comprising such shipment, delivery, or part is adulterated (a)(1) The National Academy of or misbranded within the meaning of Sciences—National Research Council, the act when so removed; or Drug Efficacy Study Group, has com- (2) Upon refusal by the operator of pleted an exhaustive review of labeling the establishment where such drug is claims made for drugs marketed under to be processed, labeled, or repacked, new-drug and antibiotic drug proce- to make available for inspection a copy dures between 1938 and 1962. The results of the agreement, as required by such are compiled in ‘‘Drug Efficacy Study, clause. A Report to the Commissioner of Food and Drugs from the National Academy [41 FR 6911, Feb. 13, 1976, as amended at 64 of Sciences (1969).’’ As the report notes, FR 400, Jan. 5, 1999] this review has made ‘‘an audit of the state of the art of drug usage that has § 201.161 Carbon dioxide and certain been uniquely extensive in scope and other gases. uniquely intensive in time’’ and is ap- (a) Carbon dioxide, cyclopropane, plicable to more than 80 percent of the ethylene, helium, and nitrous oxide currently marketed drugs. The report gases intended for drug use are exempt- further notes that the quality of the ed from the requirements of § 201.100(b) evidence of efficacy, as well as the (2), (3), and (c)(1) provided the labeling quality of the labeling claims, is poor. bears, in addition to any other infor- Labeling and other promotional claims

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have been evaluated as ‘‘effective,’’ ated as other than ‘‘effective’’ by a ‘‘probably effective,’’ ‘‘possibly effec- panel of the National Academy of tive,’’ ‘‘ineffective,’’ ‘‘ineffective as a Sciences—National Research Council, fixed combination,’’ and ‘‘effective Drug Efficacy Study Group, if such but,’’ and a report for each drug in the claims continue to be included in ei- study has been submitted to the Com- ther the labeling or advertisements. missioner. However, this qualifying information (2) The Food and Drug Administra- will be required in advertisements only tion is processing the reports, seeking if promotional material is included voluntary action on the part of the therein for claims evaluated as less drug manufacturers and distributors in than ‘‘effective’’ or if such claims are the elimination or modification of un- included in the indications section of supported promotional claims, and ini- the portion of the advertisement con- tiating administrative actions as nec- taining the information required in essary to require product and labeling brief summary by § 202.1(e)(1) of this changes. chapter. When, however, the Food and (3) Delays have been encountered in Drug Administration classification of bringing to the attention of the pre- such claim is ‘‘effective’’ (for example, scribers of prescription items the con- on the basis of revision of the language clusions of the expert panels that re- of the claim or submission or existence viewed the promotional claims. of adequate data), such qualification is (b) The Commissioner of Food and not necessary. When the Food and Drug Drugs concludes that: Administration classification of the (1) The failure to disclose in the la- claim, as stated in the implementation beling of a drug and in other pro- notice, differs from that of the Acad- motional material the conclusions of emy but is other than ‘‘effective,’’ the the Academy experts that a claim is qualifying statement shall refer to this ‘‘ineffective,’’ ‘‘possibly effective,’’ classification in lieu of the Academy’s ‘‘probably effective,’’ or ‘‘ineffective as classification. a fixed combination,’’ while labeling (d) For new drugs and antibiotics, and promotional material bearing any supplements to provide for revised la- such claim are being used, is a failure beling in accord with paragraph (c) of to disclose facts that are material in this section shall be submitted under light of the representations made and the provisions of § 314.70 and § 514.8 of causes the drug to be misbranded. this chapter within 90 days after publi- (2) The Academy classification of a cation of the implementation notice in drug as other than ‘‘effective’’ for a the FEDERAL REGISTER or by May 15, claim for which such drug is rec- 1972, for those drugs for which notices ommended establishes that there is a have been published and such labeling material weight of opinion among shall be put into use as soon as possible qualified experts contrary to the rep- but not later than the end of the time resentation made or suggested in the period allowed for submitting supple- labeling, and failure to reveal this fact ments to provide for revised labeling. causes such labeling to be misleading. (e) Qualifying information required (c) Therefore, after publication in the in drug labeling by paragraph (c) of FEDERAL REGISTER of a Drug Efficacy this section in order to advise pre- Study Implementation notice on a prescribers of a drug of the findings made scription drug, unless exempted or oth- by a panel of the Academy in evalu- erwise provided for in the notice, all ating a claim as other than ‘‘effective’’ 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:

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INDICATIONS vertisement which is a single page or Based on a review of this drug by the Na- less shall be keyed to the boxed state- tional Academy of Sciences—National Re- ment by asterisk, by an appropriate search Council and/or other information, statement, or by other suitable means FDA has classified the indication(s) as fol- providing adequate emphasis on the lows: Effective: (list or state in paragraph form). boxed statement. On each page where ‘‘Probably’’ effective: (list or state in para- less-than-effective indication(s) appear graph form). in a mutiple page advertisement, an as- ‘‘Possibly’’ effective: (list or state in para- terisk shall be placed after the most graph form). prominent mention of the indi- Final classification of the less-than-effec- cation(s); if the degree of prominence tive indications requires further investigation. does not vary, an asterisk shall be placed after the first mention of the in- (2) Or the indication(s) for which the dication. The asterisk shall refer to a drug has been found effective may ap- notation at the bottom of the page pear outside the boxed statement and which shall state ‘‘This drug has been be followed immediately by the fol- evaluated as probably effective (or pos- lowing boxed statement: Based on a review of this drug by the sibly effective whichever is appro- National Academy of Sciences—Na- priate) for this indication’’ and ‘‘See tional Research Council and/or other Brief Summary’’ or ‘‘See Prescribing information, FDA has classified the Information,’’ the latter legend to be other indication(s) as follows: used only if the advertisement carries ‘‘Probably’’ effective: (list or state in the required information for profes- paragraph form). sional use as set forth in § 201.100(c)(1). ‘‘Possibly’’ effective: (list or state in (3) For less-than-effective indications paragraph form). which are included in the advertise- Final classification of the less-than- ment only as a part of the information effective indications requires further required in brief summary, the disclo- investigation. sure information shall appear in this (3) In drug labeling (other than that portion of the advertisement in the which is required by § 201.100(c)(1)) same manner as is specified for label- which may contain a promotional mes- ing in paragraph (e) of this section. sage, the promotional message shall be (g) The Commissioner may find cir- keyed to the boxed statement by the cumstances are such that, while the same means as those provided for ad- elimination of claims evaluated as vertisements in paragraph (f)(2) of this section. other than effective will generally (f) Qualifying information required in eliminate the need for disclosure about prescription drug advertising by para- such claims, there will be instances in graph (c) of this section shall contain a which the change in the prescribing or prominent boxed statement of the ad- promotional profile of the drug is so vertised indication(s) and of the limita- substantial as to require a disclosure of tions of effectiveness using the same the reason for the change so that the format, language, and emphasis as that purchaser or prescriber is not misled required in labeling by paragraph (e) of by being left unaware through the this section. sponsor’s silence that a basic change (1) The boxed statement shall appear has taken place. The Food and Drug in (or next to) the information required Administration will identify these situ- in brief summary by § 202.1(e)(1) of this ations in direct correspondence with chapter and shall have prominence at the drug promoters, after which the least equal to that provided for other failure to make the disclosure will be information presented in the brief sum- regarded as misleading and appropriate mary and shall have type size, cap- action will be taken. tions, color, and other physical characteristics comparable to the informa- [40 FR 13998, Mar. 27, 1975, as amended at 55 tion required in the brief summary. FR 11576, Mar. 29, 1990] (2) Less-than-effective indication(s) in the promotional message of an ad-

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Subpart G—Specific Labeling Re- affect. Since any such representations quirements for Specific Drug offering these articles for use as drugs Products would be false or misleading, such articles will be considered to be mis- § 201.300 Notice to manufacturers, branded if they are distributed for use packers, and distributors of glan- as drugs. dular preparations. (d) The amended regulations provide (a) Under date of December 4, 1941, in also that in the case of drugs intended a notice to manufacturers of glandular for parenteral administration there preparations, the Food and Drug Ad- shall be no exemption from the require- ministration expressed the opinion ment that their labelings bear ade- that preparations of inert glandular quate directions for use. Such inert materials intended for medicinal use glandular materials for parenteral use should, in view of the requirement of are therefore subject to the same com- section 201(n) of the Federal Food, ment as applies to those intended for Drug, and Cosmetic Act (52 Stat. 1041; oral administration. 21 U.S.C. 321(n) ), be labeled with a statement of the material fact that § 201.301 Notice to manufacturers, there is no scientific evidence that the packers, and distributors of estro- articles contain any therapeutic or genic hormone preparations. physiologically active constituents. Some drug preparations fabricated Numerous preparations of such inert wholly or in part from estradiol and la- glandular materials were subsequently beled as to potency in terms of inter- marketed with disclaimers of the type national units or in terms of inter- suggested. The term inert glandular ma- national units of estrone activity have terials means preparations incapable of exerting an action or effect of some been marketed. The international unit significant or measurable benefit in of the estrus-producing hormone was one way or another, i.e., in the diag- established by the International Con- nosis, cure, mitigation, treatment, or ference on the Standardization of Sex prevention of disease, or in affecting Hormones at London, England, on Au- the structure or any function of the gust 1, 1932. This unit was defined as body. ‘‘the specific estrus-producing activity (b) Manufacturers have heretofore contained in 0.1 gamma (=0.0001 mg.) of taken advantage of § 201.100 permitting the standard’’ hydroxyketonic hor- omission of directions for use when the mone found in urine (estrone). The label bears the prescription legend. International Conference declared that Section 201.100(c) requires that the la- it did not recommend the determina- beling of the drug, which may include tion of the activity of brochures readily available to licensed nonhydroxyketonic forms of estrogenic practitioners, bear information as to hormones in units of estrone because of the use of the drug by practitioners li- the varying ratios between the activity censed by law to administer it. Obvi- of such nonhydroxyketonic estrogenic ously, information adequate for the use hormones and estrone, when measured of an inert glandular preparation is not by different methods on test animals. available to practitioners licensed by There is no international unit for law. measuring the activity of estradiol and (c) The Department of Health and no accepted relationship between its Human Services is of the opinion that activity and that of estrone, either in inert glandular materials may not be test animals or in humans. The dec- exempted from the requirements of laration of potency of estradiol in section 502(f)(1) of the act that they terms of international units or in bear adequate directions for use; and, terms of international units of estrone accordingly, that their labeling must activity is therefore considered mis- include among other things, represen- leading, within the meaning of 21 tations as to the conditions for which U.S.C. 352(a). The declaration of the es- such articles are intended to be used or tradiol content of an estrogenic hor- as to the structure or function of the mone preparation in terms of weight is human body that they are intended to considered appropriate.

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§ 201.302 Notice to manufacturers, when taken in substantially larger packers, and distributors of drugs amounts. Actually, it is quite toxic for internal use which contain min- when taken in quantities of a teaspoon- eral oil. ful or more. Wintergreen oil and prep- (a) In the past few years research arations containing it have caused a studies have altered medical opinion as number of deaths through accidental to the usefulness and harmfulness of misuse by both adults and children. mineral oil in the human body. These Children are particularly attracted by studies have indicated that when min- the odor and are likely to swallow eral oil is used orally near mealtime it these products when left within reach. interferes with absorption from the di- (b) To safeguard against fatalities gestive tract of provitamin A and the from this cause, the Department of fat-soluble vitamins A, D, and K, and Health and Human Services will regard consequently interferes with the utili- as misbranded under the provisions of zation of calcium and phosphorus, with the Federal Food, Drug, and Cosmetic the result that the user is left liable to Act any drug containing more than 5 deficiency diseases. When so used in percent methyl salicylate (wintergreen pregnancy it predisposes to hemor- oil), the labeling of which fails to warn rhagic disease of the newborn. that use otherwise than as directed (b) There is accumulated evidence therein may be dangerous and that the that the indiscriminate administration article should be kept out of reach of of mineral oil to infants may be fol- children to prevent accidental poi- lowed by aspiration of the mineral oil soning. and subsequent ‘‘lipoid pneumonia.’’ (c) This statement of interpretation (c) In view of these facts, the Depart- in no way exempts methyl salicylate ment of Health and Human Services (wintergreen oil) or its preparations will regard as misbranded under the from complying in all other respects provisions of the Federal Food, Drug, with the requirements of the Federal and Cosmetic Act a drug for oral ad- Food, Drug, and Cosmetic Act. ministration consisting in whole or in part of mineral oil, the labeling of § 201.304 Tannic acid and barium which encourages its use in pregnancy enema preparations. or indicates or implies that such drug (a) It has become a widespread prac- is for administration to infants. tice for tannic acid to be added to bar- (d) It is also this Department’s view ium enemas to improve X-ray pictures. that the act requires the labelings of Tannic acid is capable of causing di- such drugs to bear a warning against minished liver function and severe consumption other than at bedtime liver necrosis when absorbed in suffi- and against administration to infants. cient amounts. The medical literature The following form of warning is sug- reports a number of deaths associated gested: ‘‘Caution: To be taken only at with the addition of tannic acid to bar- bedtime. Do not use at any other time ium enemas. There is a lack of sci- or administer to infants, except upon entific evidence to establish the condi- the advice of a physician.’’ tions, if any, under which tannic acid (e) This statement of interpretation is safe and effective for use in enemas. does not in any way exempt mineral oil Tannic acid for rectal use to enhance or preparations containing mineral oil X-ray visualization is regarded as a from complying in all other respects new drug within the meaning of section with the requirements of the Federal 201(p) of the Federal Food, Drug, and Food, Drug, and Cosmetic Act. Cosmetic Act. (b) In view of the hazards involved § 201.303 Labeling of drug prepara- when tannic acid is used in barium en- tions containing significant propor- emas, any shipments of tannic acid lations of wintergreen oil. beled to come within the exemptions (a) Because methyl salicylate (win- under 502(f) of the Act containing such tergreen oil) manifests no toxicity in phrases as: ‘‘Caution: For manufac- the minute amounts in which it is used turing, processing, or repackaging,’’ as a flavoring, it is mistakenly re- ‘‘For prescription compounding,’’ or garded by the public as harmless even ‘‘Diagnostic reagent—For professional

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use only’’ will be regarded by the Com- isoproterenol inhalation preparations. The missioner of Food and Drugs as mis- cause of this refractory state is unknown. It branded within the meaning of section is advisable that in such instances the use of 502(f) of the Federal Food, Drug, and this preparation be discontinued immediately and alternative therapy instituted, Cosmetic Act unless the label and the since in the reported cases the patients did labeling bear conspicuously a warning not respond to other forms of therapy until to the effect: ‘‘Warning— Not for use in the drug was withdrawn. enemas.’’ Deaths have been reported following exces- (c) Any tannic acid intended for use sive use of isoproterenol inhalation prepara- by man and found within the jurisdic- tions and the exact cause is unknown. Car- tion of the Federal Food, Drug, and diac arrest was noted in several instances. Cosmetic Act labeled contrary to this (c)(1) The Commissioner also con- section after 60 days from the date of cludes that in view of the manner in its publication in the FEDERAL REG- which these preparations are self-ad- ISTER may be made the subject of regu- ministered for relief of attacks of bron- latory proceedings. chial asthma and other chronic bron- § 201.305 Isoproterenol inhalation chopulmonary disorders, it is necessary preparations (pressurized aerosols, for the protection of users that warn- nebulizers, powders) for human ing information to patients be included use; warnings. as a part of the label and as part of any (a) Accumulating reports have been instructions to patients included in the received by the Food and Drug Admin- package dispensed to the patient as fol- istration and have appeared in the lows: medical literature of severe paradox- Warning: Do not exceed the dose prescribed ical bronchoconstriction associated by your physician. If difficulty in breathing with repeated, excessive use of persists, contact your physician imme- isoproterenol inhalation preparations diately. in the treatment of bronchial asthma (2) The warning on the label may be and other chronic bronchopulmonary accomplished (i) by including it on the disorders. The cause of this paradoxical immediate container label with a reaction is unknown; it has been ob- statement directed to pharmacists not served, however, that patients have not to remove the label or (ii) by including responded completely to other forms of therapy until use of the isoproterenol in the package a printed warning with inhalation preparation was discon- instructions to pharmacists to place tinued. In addition, sudden unexpected the warning on the container prior to deaths have been associated with the dispensing. excessive use of isoproterenol inhala- (d) The marketing of isoproterenol tion preparations. The mechanism of inhalation preparations may be contin- these deaths and their relationship, if ued if all the following conditions are any, to the cases of severe paradoxical met: bronchospasm are not clear. Cardiac (1) Within 30 days following the date arrest was noted in several of these of publication of this section in the cases of sudden death. FEDERAL REGISTER: (b) On the basis of the above informa- (i) The label and labeling of such tion and after discussion with and con- preparations shipped within the juris- currence of the Respiratory and Anes- diction of the act are in accordance thetic Drugs Advisory Committee for with paragraphs (b) and (c) of this sec- Food and Drug Administration, the tion. 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. Warning: Occasional patients have been re- (2) Within 90 days following the date ported to develop severe paradoxical airway of publication of this section in the resistance with repeated, excessive use of FEDERAL REGISTER, the manufacturer,

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packer, or distributor of any drug con- oral diuretics. These small-bowel lesions taining isoproterenol intended for in- have caused obstruction, hemorrhage, and halation for which a new-drug approval perforation. Surgery was frequently required is not in effect submits a new-drug ap- and deaths have occurred. Based on a large survey of physicians and hospitals, both plication containing satisfactory infor- United States and foreign, the incidence of mation of the kinds required by § 314.50 these lesions is low, and a causal relation- of this chapter, including appropriate ship in man has not been definitely estab- labeling as described in paragraphs (b) lished. Available information tends to impli- and (c) of this section. cate enteric-coated potassium salts, al- (3) The applicant submits additional though lesions of this type also occur spon- information required for the approval taneously. Therefore, coated potassium-con- of the application as may be specified taining formulations should be administered only when indicated, and should be discon- in a written communication from the tinued immediately if abdominal pain, dis- Food and Drug Administration. tention, nausea, vomiting, or gastro- (e) After 270 days following expira- intestinal bleeding occur. Coated potassium tion of said 90 days, regulatory pro- tablets should be used only when adequate ceedings based on section 505(a) of the dietary supplementation is not practicable. Federal Food, Drug, and Cosmetic Act may be initiated with regard to any (Although the warning statement in- such drug shipped within the jurisdic- cludes references to enteric-coated po- tion of the act for which an approved tassium salt preparations, it applies to new-drug application is not in effect. any capsule or coated tablet of a potassium salt intended for oral ingestion [40 FR 13998, Mar. 27, 1975, as amended at 55 without prior dilution with an ade- FR 11576, Mar. 29, 1990] quate volume of liquid to preclude gastrointestinal injury.) § 201.306 Potassium salt preparations intended for oral ingestion by man. (iii) Any other labeling or additional advertising for the drug conforms to (a) The Food and Drug Administra- the labeling described in paragraph tion will initiate no regulatory action (a)(1)(ii) of this section, in accordance with respect to the continued mar- with §§ 202.1 and 201.100 of this chapter. keting of coated tablets containing po- (2) Within 90 days from the date of tassium chloride or other potassium publication of this statement of policy salts which supply 100 milligrams or in the FEDERAL REGISTER, the manu- more of potassium per tablet provided facturer, packer, or distributor of the all the following conditions are met: drug shall submit a new-drug applica- (1) Within 30 days from the date of tion containing satisfactory informa- publication of this statement of policy tion of the kind required by § 314.50 of in the FEDERAL REGISTER: this chapter, with appropriate labeling (i) The labeling of the drug bears the as described in this paragraph. prescription caution statement quoted (b) The Food and Drug Administra- in section 503(b)(4) of the Federal Food, tion may initiate regulatory pro- Drug, and Cosmetic Act; ceedings after 30 days from the date of (ii) The labeling on or within the publication of this section, with re- package from which the drug is to be spect to the marketing of uncoated dispensed bears adequate information tablets containing potassium chloride for its use by practitioners in accord or other potassium salts which supply with the ‘‘full disclosure’’ labeling re- 100 milligrams or more of potassium quirements of § 201.100 of this chapter, per tablet or with respect to liquid including the following warning state- preparations containing potassium ment: chloride or other potassium salts which Warning—There have been several reports, supply 20 milligrams or more of potas- published and unpublished, concerning non- sium per milliliter, labeled or intended specific small-bowel lesions consisting of ste- for human use, unless all the following nosis, with or without ulceration, associated conditions are met: with the administration of enteric-coated thiazides with potassium salts. These lesions (1) The labeling of the drug bears the may occur with enteric-coated potassium prescription statement quoted in sec- tablets alone or when they are used with tion 503(b)(4) of the Federal Food, nonenteric-coated thiazides, or certain other Drug, and Cosmetic Act; and

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(2) The labeling on or within the (b) Any OTC drug product for lax- package from which the drug is to be ative or bowel cleansing use containing dispensed bears adequate information sodium phosphates as an active ingre- for its use by practitioners in accord dient when marketed as described in with the ‘‘full disclosure’’ labeling re- paragraph (a) of this section is mis- quirements of § 201.100 of this chapter, branded within the meaning of section including a recommendation that pa- 502 of the Federal Food, Drug, and Cos- tients be directed to dissolve any such metic Act unless packaged and labeled tablets in an appropriate amount of as follows: liquid and to dilute any such liquid (1) Package size limitation for so- preparations adequately to assure dium phosphates oral solution: Con- against gastrointestinal injury associ- tainer shall not contain more than 90 ated with the oral ingestion of con- mL (3 oz). centrated potassium salt preparations. (2) Warnings. The following sentences [40 FR 13998, Mar. 27, 1975, as amended at 55 shall appear in boldface type as the FR 11576, Mar. 29, 1990; 67 FR 4906, Feb. 1, first statement under the heading 2002] ‘‘Warnings.’’ (i) Oral dosage forms. ‘‘Taking more § 201.307 Sodium phosphates; package than the recommended dose in 24 hours size limitation, warnings, and direc- can be harmful.’’ tions for over-the-counter sale. (ii) Rectal enema dosage forms. (a) Reports in the medical literature ‘‘Using more than one enema in 24 and data accumulated by the Food and hours can be harmful.’’ Drug Administration indicate that (3) Directions—(i) The labeling of all multiple container sizes of sodium orally or rectally administered OTC phosphates oral solution available in drug products containing sodium the marketplace have caused consumer phosphates shall contain the following confusion and appear to have been in- directions in boldface type imme- volved in several consumer deaths. So- diately preceding the dosage informa- dium phosphates oral solution has been tion: ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) marketed in 45-milliliter (mL), 90-mL, ‘‘more unless directed by a doctor. See and 240-mL container sizes. The 45-mL Warnings.’’ and 90-mL container sizes of sodium (ii) For products containing dibasic phosphates oral solution are often rec- sodium phosphate/monobasic sodium ommended and prescribed by physi- phosphate identified in § 334.16(d) mar- cians for bowel cleansing prior to sur- keted as a solution. Adults and chil- gery and diagnostic procedures of the dren 12 years of age and over: Oral dos- colon. Sodium phosphates oral solution age is dibasic sodium phosphate 3.42 to (adult dose 20 mL to 45 mL) is also used 7.56 grams (g) and monobasic sodium as an over-the-counter (OTC) laxative phosphate 9.1 to 20.2 g (20 to 45 mL di- for the relief of occasional constipa- basic sodium phosphate/monobasic so- tion. Accidental overdosing and deaths dium phosphate oral solution) as a sin- have occurred because the 240-mL con- gle daily dose. ‘‘Do not take more than tainer was mistakenly used instead of 45 mL (9 teaspoonfuls or 3 tablespoon- the 45-mL or 90-mL container. The fuls) in a 24-hour period.’’ Children 10 Food and Drug Administration is lim- and 11 years of age: Oral dosage is diba- iting the amount of sodium phosphates sic sodium phosphate 1.71 to 3.78 g and oral solution to not more than 90 mL (3 monobasic sodium phosphate 4.5 to 10.1 ounces (oz)) per OTC container because g (10 to 20 mL dibasic sodium phos- of the serious health risks associated phate/monobasic sodium phosphate with the ingestion of larger than in- oral solution) as a single daily dose. tended doses of this product. Further, ‘‘Do not take more than 20 mL (4 tea- 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.

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‘‘Do not take more than 10 mL (2 tea- scription so that it will be readily spoonfuls) in a 24-hour period.’’ Chil- available in the household for emer- dren under 5 years of age: ask a doctor. gency treatment of poisonings, under (c) After June 22, 1998, for package medical supervision, and that the drug size limitation and September 18, 1998, be appropriately packaged and labeled for labeling in accord with paragraph for this purpose. (b) of this section, any such OTC drug (c) In view of the above recommenda- product initially introduced or ini- tions, the Commissioner of Food and tially delivered for introduction into Drugs has determined that it is in the interstate commerce, or any such drug interest of the public health for ipecac product that is repackaged or relabeled syrup to be available for sale without after these dates regardless of the date prescription, provided that it is pack- the product was manufactured, ini- aged in a quantity of 1 fluid ounce (30 tially introduced, or initially delivered milliliters), and its label bears, in addi- for introduction into interstate com- tion to other required label informa- merce, that is not in compliance with tion, the following, in a prominent and this section is subject to regulatory ac- conspicuous manner: tion. (1) A statement conspicuously boxed [63 FR 27843, May 21, 1998] and in red letters, to the effect: ‘‘For emergency use to cause vomiting in § 201.308 Ipecac syrup; warnings and poisoning. Before using, call physician, directions for use for over-the- counter sale. the Poison Control Center, or hospital emergency room immediately for ad- (a) It is estimated that each year vice.’’ about 500,000 accidental poisonings (2) A warning to the effect: ‘‘Warn- occur in the United States and result ing—Keep out of reach of children. Do in approximately 1,500 deaths, of which not use in unconscious persons. Ordi- over 400 are children. In the emergency narily, this drug should not be used if treatment of these poisonings, ipecac strychnine, corrosives such as alkalies syrup is considered the emetic of choice. The immediate availability of (lye) and strong acids, or petroleum this drug for use in such situations is distillates such as kerosine, gasoline, critical, since rapid treatment may be coal oil, fuel oil, paint thinner, or the difference between life and death. cleaning fluid have been ingested.’’ The restriction of this drug to prescrip- (3) Usual dosage: 1 tablespoon (15 mil- tion sale limits its availability in liliters) in persons over 1 year of age. emergencies. On the other hand, it is the consensus of informed medical § 201.309 Acetophenetidin (phenacetin)-containing preparations; opinion that ipecac syrup should be necessary warning statement. used only under medical supervision in the emergency treatment of (a) In 1961, the Food and Drug Admin- poisonings. In view of these facts, the istration, pursuant to its statutory re- question of whether ipecac syrup la- sponsibility for the safety and effec- beled as an emergency treatment for tiveness of drugs shipped in interstate use in poisonings should be available commerce, began an active investiga- over the counter has been controver- tion of reports of possible toxic effects sial. and renal damage due to misuse of the (b) In connection with its study of drug acetophenetidin. This study led to this problem, the Food and Drug Ad- the decision that there was probable ministration has obtained the views of cause to conclude that misuse and pro- medical authorities. It is the unani- longed use of the drug were in fact re- mous recommendation of the American sponsible for kidney lesions and dis- Academy of Pediatrics, the American ease. The Commissioner of Food and Association of Poison Control Centers, Drugs, in December 1963, appointed an the American Medical Association, and ad hoc Advisory Committee of Inquiry the Medical Advisory Board of the on Possible Nephrotoxicity Associated Food and Drug Administration that ip- With the Abuse of Acetophenetidin ecac syrup in 1 fluid ounce containers (Phenacetin)-Containing Preparations. be permitted to be sold without pre- This committee, composed of scientists

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in the fields of pharmacology and med- should be discontinued if leukopenia icine, on April 23, 1964, submitted its occurs or if evidence of hyper- findings and conclusions in the matter sensitivity, such as dermatitis or fever, and recommended that all acetophe- appears.’’ netidin (phenacetin)-containing prep- (b) Regulatory action may be initi- arations bear a warning as provided in ated with respect to preparations of section 502(f)(2) of the Federal Food, phenindione intended for use by man Drug, and Cosmetic Act. found within the jurisdiction of the act (b) On the basis of the studies made on or after November 25, 1961, unless by the Food and Drug Administration such preparations are labeled in ac- and the report of the Advisory Com- cordance with paragraph (a) of this sec- mittee, the Commissioner of Food and tion. Drugs has concluded that it is necessary for the protection of users that § 201.311 [Reserved] the label and labeling of all acetophenetidin (phenacetin)-containing prep- § 201.312 Magnesium sulfate heptahydrate; label declaration on arations bear a warning statement to drug products. the following effect: ‘‘Warning—This medication may damage the kidneys Magnesium sulfate heptahydrate when used in large amounts or for a should be listed on the label of a drug long period of time. Do not take more product as epsom salt, which is its than the recommended dosage, nor common or usual name. take regularly for longer than 10 days without consulting your physician.’’ § 201.313 Estradiol labeling. The article presently recognized in § 201.310 Phenindione; labeling of The National Formulary under the drug preparations intended for use heading ‘‘Estradiol’’ and which is said by man. to be ‘‘17-cis-beta estradiol’’ is the (a) Reports in the medical literature same substance formerly recognized in and data accumulated by the Food and the United States Pharmacopeia under Drug Administration indicate that the designation ‘‘Alpha Estradiol.’’ The phenindione, a synthetic anticoagulant substance should no longer be referred drug, has caused a number of cases of to in drug labeling as ‘‘Alpha Estra- agranulocytosis (with two fatalities). diol.’’ The Food and Drug Administra- There are also reports implicating the tion would not object to label ref- drug in cases of hepatitis and hyper- erences to the article as simply ‘‘Es- sensitivity reactions. In view of the po- tradiol’’; nor would it object if the tentially serious effects found to be as- label of a preparation containing this sociated with preparations of this drug substance referred to the presence of intended for use by man, the Commis- ‘‘Estradiol (formerly known as Alpha sioner of Food and Drugs will regard Estradiol).’’ such preparations as misbranded within the meaning of section 502(f) (1) and § 201.314 Labeling of drug prepara- (2) of the Federal Food, Drug, and Cos- tions containing salicylates. metic Act, unless the label and label- (a) The label of any oral drug prepa- ing on or within the package from ration intended for sale without pre- which the drug is to be dispensed, and scription and which contains any salic- any other labeling furnishing or pur- ylate ingredient (including aspirin, sal- porting to furnish information for use icylamide, other salicylates, and com- of the drug, bear a conspicuous warn- binations) must conspicuously bear, on ing statement to the following effect: a clearly contrasting background, the ‘‘Warning: Agranulocytosis and hepa- warning statement: ‘‘Keep out of reach titis have been associated with the use of children [highlighted in bold type]. 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

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warning statements. Such a warning of age consult your physician.’’ How- statement is required for compliance ever, if the directions provide for ad- with section 502(f)(2) of the Federal ministration to children only of an age Food, Drug, and Cosmetic Act and is greater than 3 years (for example, the intended to guard against accidental dosage instructions provide for admin- poisonings. Safety closures that pre- istration of the article to children only vent access to the drug by young chil- down to age 6), the label should bear a dren are also recommended to guard statement such as, ‘‘For younger chil- against accidental poisonings. dren consult your physician.’’ (b) Effervescent preparations and (2) A statement such as, ‘‘For chil- preparations containing para- dren under 3 years of age consult your aminosalicylate as the only salicylate physician’’ or ‘‘For younger children ingredient are exempted from this la- consult your physician’’ is not required beling requirement. on the label of an article clearly of- (c) Aspirin tablets sold as such and fered for administration to adults only. containing no other active ingredients, (f) If the labeling or advertising of a except tablets which cannot be readily salicylate preparation offers it for use subdivided into a child’s dose because in arthritis or rheumatism, the label of their coating or size, should always and labeling should clearly state that bear dosage directions for each age the beneficial effects claimed are lim- group down to 3 years of age, with a ited to: ‘‘For the temporary relief of statement such as ‘‘For children under minor aches and pains of arthritis and 3 years of age, consult your physician.’’ rheumatism.’’ The qualifying phrase It is recommended that: ‘‘for the temporary relief of minor (1) Aspirin tablets especially made aches and pains’’ should appear with for pediatric use be produced only in the same degree of prominence and 11⁄4-grain size to reduce the hazard of conspicuousness as the phrase ‘‘arthri- errors in dosage; tis and rheumatism’’. The label and la- (2) By June 1, 1967, manufacturers beling should bear in juxtaposition and distributors of 11⁄4-grain size aspi- with such directions for use con- rin tablets discontinue the distribution spicuous warning statements to the ef- of such tablets in retail containers containing more than 36 tablets, to reduce fect: ‘‘Caution: If pain persists for more the hazard of accidental poisoning; than 10 days, or redness is present, or (3) The flavoring of 5-grain aspirin in conditions affecting children under tablets or other ‘‘adult aspirin tablets’’ 12 years of age, consult a physician im- be discontinued; and mediately.’’ The salicylate dosage (4) Labeling giving undue emphasis should not exceed 60 grains in a 24-hour to the pleasant flavor of flavored aspi- period or 10 grains in a 4-hour period. If rin tablets be discontinued. the article contains other analgesics, (d) Salicylate preparations other the salicylate dosage should be appro- than aspirin tablets sold as such may, priately reduced. at the option of the distributor, be la- (g)(1) The label of any drug con- beled for use by adults only. If their la- taining more than 5 percent methyl sa- beling and advertising clearly offer licylate (wintergreen oil) should bear a them for administration to adults only. conspicuous warning such as: ‘‘Do not (e)(1) It is the obligation of the dis- use otherwise than as directed.’’ These tributor who labels a salicylate prepa- drug products must also include the ration for administration to children ‘‘Keep out of reach of children’’ warn- to make certain that the article is ing and the accidental ingestion warn- suitable for such use and labeled with ing as required in § 330.1(g) of this chap- adequate directions for use in the age ter. group for which it is offered, but in no (2) If the preparation is a counter- case should such an article bear direc- irritant or rubefacient, it should also tions for use in children under 3 years bear a caution such as, ‘‘Caution: Dis- of age. If the directions provide for ad- continue use if excessive irritation of ministration to children as young as 3 the skin develops. Avoid getting into years of age, the label should bear the the eyes or on mucous membranes.’’ statement, ‘‘For children under 3 years (See also § 201.303.)

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(h)(1) The labeling of orally or rec- subsalicylate as an active ingredient tally administered over-the-counter and have annual sales less than $25,000. drug products containing aspirin or (iv) Compliance dates for all other nonaspirin salicylates as active ingre- OTC drug products containing aspirin dients subject to this paragraph is re- and nonaspirin salicylates as an active quired to prominently bear the fol- ingredient and marketed under an OTC lowing warning: ‘‘Reye’s syndrome drug monograph (for internal analge- [subheading in bold type]: Children and sic, antipyretic, and antirheumatic teenagers who have or are recovering drug products, or for menstrual drug from chicken pox or flu-like symptoms products) will be established when the should not use this product. When final monographs for those products using this product, if changes in behav- are published in a future issue of the ior with nausea and vomiting occur, FEDERAL REGISTER. In the interim, consult a doctor because these symp- these products should continue to be toms could be an early sign of Reye’s labeled with the previous Reye’s syn- syndrome, a rare but serious illness.’’ drome warning that appears in para- (2) This warning statement shall ap- graph (h)(1) of this section. pear on the immediate container label- [40 FR 13998, Mar. 27, 1985, as amended at 51 ing. In cases where the immediate con- FR 8182, Mar. 7, 1986; 53 FR 21637, June 9, tainer is not the retail package, the re- 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, tail package also must bear the warn- Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR ing statement. In addition, the warning 18869, Apr. 17, 2003] statement shall appear on any labeling that contains warnings and, in such § 201.315 Over-the-counter drugs for minor sore throats; suggested warn- cases, the warning statement shall be ing. the first warning statement under the heading ‘‘Warnings.’’ The Food and Drug Administration (3) Over-the-counter drug products has studied the problem of the labeling subject to this paragraph and labeled of lozenges or troches containing a solely for use by children (pediatric local anesthetic, chewing gum containing aspirin, various mouth washes products) shall not recommend the and gargles and other articles sold over product for use in treating flu or chick- the counter for the relief of minor irri- en pox. tations of the mouth or throat. It will (4) Any product subject to paragraphs not object to the labeling of suitable (h)(1), (h)(2), and (h)(3) of this section articles of this type ‘‘For the tem- that is not labeled as required by these porary relief of minor sore throats’’, paragraphs and that is initially intro- provided this is immediately followed duced or initially delivered for intro- in the labeling with a warning state- duction into interstate commerce after ment in prominent type essentially as the following dates is misbranded follows: ‘‘Warning—Severe or per- under sections 201(n) and 502(a) and (f) sistent sore throat or sore throat ac- of the Federal Food, Drug, and Cos- companied by high fever, headache, metic Act. nausea, and vomiting may be serious. (i) Compliance by October 18, 2004, for Consult physician promptly. Do not OTC drug products containing aspirin use more than 2 days or administer to and nonaspirin salicylates as an active children under 3 years of age unless di- ingredient and marketed under a new rected by physician.’’ drug application or abbreviated new drug application. § 201.316 Drugs with thyroid hormone (ii) Compliance by April 19, 2004, for activity for human use; required OTC antidiarrheal and overindulgence warning. drug products that contain bismuth (a) Drugs with thyroid hormone ac- subsalicylate as an active ingredient tivity have been promoted for, and con- 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.

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(b) Drugs for human use with thyroid § 201.319 Water-soluble gums, hydro- hormone activity are misbranded with- philic gums, and hydrophilic in the meaning of section 502 of the mucilloids (including, but not lim- Federal Food, Drug, and Cosmetic Act ited to agar, alginic acid, calcium unless their labeling bears the fol- polycarbophil, carboxymethylcellulose sodium, lowing boxed warning at the beginning carrageenan, chondrus, of the ‘‘Warnings’’ section: glucomannan ((B-1,4 linked) polymannose acetate), guar gum, Drugs with thyroid hormone activity, karaya gum, kelp, methylcellulose, alone or together with other therapeutic plantago seed (psyllium), agents, have been used for the treatment polycarbophil tragacanth, and xan- of obesity. In euthyroid patients, doses than gum) as active ingredients; re- within the range of daily hormonal required warnings and directions. quirements are ineffective for weight re- (a) Reports in the medical literature duction. Larger doses may produce seri- and data accumulated by the Food and ous or even life-threatening manifesta- Drug Administration indicate that tions of toxicity, particularly when esophageal obstruction and asphyxia- given in association with tion have been associated with the in- sympathomimetic amines such as those used for their anorectic effects. gestion of water-soluble gums, hydrophilic gums, and hydrophilic mucilloids including, but not limited [43 FR 22009, May 23, 1978] to, agar, alginic acid, calcium polycarbophil, carboxymethylcellulose § 201.317 Digitalis and related sodium, carrageenan, chondrus, cardiotonic drugs for human use in glucomannan ((B–1,4 linked) oral dosage forms; required warn- polymannose acetate), guar gum, ing. karaya gum, kelp, methylcellulose, (a) Digitalis and related cardiotonic plantago seed (psyllium), drugs for human use in oral dosage polycarbophil, tragacanth, and xan- forms have been promoted for, and con- than gum. Esophageal obstruction and tinue to be dispensed and prescribed asphyxiation due to orally-adminis- for, use in the treatment of obesity, altered drug products containing water- though their safety and effectiveness soluble gums, hydrophilic gums, and for that use have never been estab- hydrophilic mucilloids as active ingre- lished. dients are significant health risks (b) Digitalis and related cardiotonic when these products are taken without drugs for human use in oral dosage adequate fluid or when they are used forms are misbranded within the mean- by individuals with esophageal nar- ing of section 502 of the Federal Food, rowing or dysfunction, or with dif- Drug, and Cosmetic Act unless their la- ficulty in swallowing. Additional label- beling bears the following boxed warning is needed for the safe and effective ing at the beginning of the ‘‘Warnings’’ use of any OTC drug product for human section: use containing a water-soluble gum, hydrophilic gum, or hydrophilic mucilloid as an active ingredient when Digitalis alone or with other drugs has marketed in a dry or incompletely hy- been used in the treatment of obesity. drated form to include, but not limited This use of digoxin or other digitalis to, the following dosage forms: Cap- glycosides is unwarranted. Moreover, since they may cause potentially fatal sules, granules, powders, tablets, and arrhythmias or other adverse effects, wafers. Granular dosage forms con- the use of these drugs in the treatment taining psyllium are not generally rec- of obesity is dangerous. ognized as safe and effective as OTC laxatives (see § 310.545(a)(12)(i)(B) of (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.

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(b) Any drug products for human use graph (b) or (c) of this section, bear the containing a water-soluble gum, hydro- following warning statement: philic gum, or hydrophilic mucilloid as Warning: Contains [or Manufactured with, an active ingredient in an oral dosage if applicable] [insert name of substance], a sub- form when marketed in a dry or incom- stance which harms public health and the pletely hydrated form as described in environment by destroying ozone in the paragraph (a) of this section are mis- upper atmosphere. branded within the meaning of section 502 of the Federal Food, Drug, and Cos- (2) The warning statement shall be metic Act unless their labeling bears clearly legible and conspicuous on the the following warnings (under the sub- product, its immediate container, its heading ‘‘Choking’’) and directions: outer packaging, or other labeling in accordance with the requirements of 40 ‘‘ ‘Choking’ [highlighted in bold CFR part 82 and appear with such type]: Taking this product without prominence and conspicuousness as to adequate fluid may cause it to swell render it likely to be read and under- and block your throat or esophagus and stood by consumers under normal con- may cause choking. Do not take this ditions of purchase. product if you have difficulty in swallowing. If you experience chest pain, (b)(1) For prescription drug products vomiting, or difficulty in swallowing or for human use, the following alter- breathing after taking this product, native warning statement may be used: seek immediate medical attention;’’ NOTE: The indented statement below is re- and quired by the Federal government’s Clean ‘‘ ‘Directions’ [highlighted in bold Air Act for all products containing or manu- type]:’’ (Select one of the following, as factured with chlorofluorocarbons (CFC’s) appropriate: ‘‘Take’’ or ‘‘Mix’’) ‘‘this [or name of other class I substance, if applicable]: product (child or adult dose) with at least 8 ounces (a full glass) of water or This product contains [or is manufactured other fluid. Taking this product with- with, if applicable] [insert name of substance], out enough liquid may cause choking. a substance which harms the environment by See choking warning.’’ destroying ozone in the upper atmosphere. Your physician has determined that this (c) After February 28, 1994, any such product is likely to help your personal OTC drug product initially introduced health. USE THIS PRODUCT AS DIRECTED, or initially delivered for introduction UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any ques- into interstate commerce, or any such tions about alternatives, consult with your drug product that is repackaged or re- physician. labeled after this date regardless of the date the product was manufactured, (2) The warning statement shall be initially introduced, or initially deliv- clearly legible and conspicuous on the ered for introduction into interstate product, its immediate container, its commerce, that is not in compliance outer packaging, or other labeling in with this section is subject to regu- accordance with the requirements of 40 latory action. CFR part 82 and appear with such prominence and conspicuousness as to [58 FR 45201, Aug. 26, 1993, as amended at 64 render it likely to be read and under- FR 13292, Mar. 17, 1999; 72 FR 14674, Mar. 29, stood by consumers under normal con- 2007] ditions of purchase. § 201.320 Warning statements for drug (3) If the warning statement in para- products containing or manufac- graph (b)(1) of this section is used, the tured with chlorofluorocarbons or following warning statement must be other ozone-depleting substances. placed on the package labeling in- (a)(1) All drug products containing or tended to be read by the physician manufactured with (physician package insert) after the chlorofluorocarbons, halons, carbon ‘‘How supplied’’ section, which de- tetrachloride, methyl chloride, or any scribes special handling and storage other class I substance designated by conditions on the physician labeling: the Environmental Protection Agency NOTE: The indented statement below is re- (EPA) shall, except as provided in para- quired by the Federal government’s Clean

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Air Act for all products containing or manu- drug product contains no more than 25 factured with chlorofluorocarbons (CFC’s) μg/L of aluminum. This information [or name of other class I substance, if appli- must be contained in the ‘‘Pre- cable]: cautions’’ section of the labeling of all WARNING: Contains [or Manufactured with, large volume parenterals used in TPN if applicable] [insert name of substance], a sub- therapy. stance which harms public health and the (c) Except as provided in paragraph environment by destroying ozone in the (d) of this section, the maximum level upper atmosphere. A notice similar to the above WARNING of aluminum present at expiry must be has been placed in the information for the stated on the immediate container patient [or patient information leaflet, if ap- label of all small volume parenteral plicable] of this product under the Environ- (SVP) drug products and pharmacy mental Protection Agency’s (EPA’s) regula- bulk packages (PBPs) used in the prep- tions. The patient’s warning states that the aration of TPN solutions. The alu- patient should consult his or her physician if minum content must be stated as fol- there are questions about alternatives. lows: ‘‘Contains no more than ll μg/L (c)(1) For over-the-counter drug prod- of aluminum.’’ The immediate con- ucts for human use, the following al- tainer label of all SVP’s and PBP’s ternative warning statement may be that are lyophilized powders used in used: the preparation of TPN solutions must contain the following statement: NOTE: The indented statement below is required by the Federal government’s Clean ‘‘When reconstituted in accordance Air Act for all products containing or manu- with the package insert instructions, factured with chlorofluorocarbons (CFC’s) the concentration of aluminum will be [or other class I substance, if applicable]: no more than ll μg/L.’’ This max- WARNING: Contains [or Manufactured with, imum level of aluminum must be stat- if applicable] [insert name of substance], a sub- ed as the highest of: stance which harms public health and envi- (1) The highest level for the batches ronment by destroying ozone in the upper at- produced during the last 3 years; mosphere. (2) The highest level for the latest CONSULT WITH YOUR PHYSICIAN OR five batches, or HEALTH PROFESSIONAL IF YOU HAVE ANY QUESTION ABOUT THE USE OF THIS (3) The maximum historical level, PRODUCT. but only until completion of production of the first five batches after July (2) The warning statement shall be 26, 2004. clearly legible and conspicuous on the (d) If the maximum level of alu- product, its immediate container, its minum is 25 μg/L or less, instead of outer packaging, or other labeling in stating the exact amount of aluminum accordance with the requirements of 40 as required in paragraph (c) of this sec- CFR part 82 and appear with such tion, the immediate container label prominence and conspicuousness as to may state: ‘‘Contains no more than 25 render it likely to be read and under- μg/L of aluminum.’’ If the SVP or PBP stood by consumers under normal con- is a lyophilized powder, the immediate ditions of purchase. container label may state: ‘‘When re- (d) This section does not replace or constituted in accordance with the relieve a person from any requirements package insert instructions, the con- imposed under 40 CFR part 82. centration of aluminum will be no [61 FR 20100, May 3, 1996] more than 25 μg/L’’. (e) The package insert for all LVP’s, § 201.323 Aluminum in large and small all SVP’s, and PBP’s used in TPN must volume parenterals used in total contain a warning statement. This parenteral nutrition. warning must be contained in the (a) The aluminum content of large ‘‘Warnings’’ section of the labeling. volume parenteral (LVP) drug products The warning must state: used in total parenteral nutrition WARNING: This product contains alu- (TPN) therapy must not exceed 25 minum that may be toxic. Aluminum may micrograms per liter (μg/L). reach toxic levels with prolonged parenteral (b) The package insert of LVP’s used administration if kidney function is im- in TPN therapy must state that the paired. Premature neonates are particularly

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at risk because their kidneys are immature, other STDs, that use of these products and they require large amounts of calcium can increase vaginal and rectal irrita- and phosphate solutions, which contain alu- tion, which may increase the risk of minum. getting the AIDS virus (HIV) from an Research indicates that patients with impaired kidney function, including premature HIV infected partner, and that the neonates, who receive parenteral levels of products are not for rectal use. Con- aluminum at greater than 4 to 5 μg/kg/day sumers should also be warned that accumulate aluminum at levels associated these products should not be used by with central nervous system and bone tox- persons who have HIV/AIDS or are at icity. Tissue loading may occur at even high risk for HIV/AIDS. lower rates of administration. (b) The labeling of OTC vaginal con- (f) Applicants and manufacturers traceptive and spermicide drug prod- must use validated assay methods to ucts containing nonoxynol 9 as the ac- determine the aluminum content in tive ingredient, whether subject to the parenteral drug products. The assay ongoing OTC drug review or an ap- methods must comply with current proved drug application, must contain good manufacturing practice require- the following warnings under the head- ments. Applicants must submit to the ing ‘‘Warnings,’’ in accordance with 21 Food and Drug Administration valida- CFR 201.66. tion of the method used and release (1) ‘‘[bullet] For vaginal use only data for several batches. Manufactur- [bullet] Not for rectal (anal) use’’ [both ers of parenteral drug products not warnings in bold type]. subject to an approved application (2) ‘‘Sexually transmitted diseases must make assay methodology avail- (STDs) alert [in bold type]: This prod- able to FDA during inspections. Hold- uct does not [word ‘‘not’’ in bold type] ers of pending applications must sub- protect against HIV/AIDS or other mit an amendment under § 314.60 or STDs and may increase the risk of get- § 314.96 of this chapter. ting HIV from an infected partner’’. [65 FR 4110, Jan. 26, 2000, as amended at 67 (3) ‘‘Do not use’’ [in bold type] if you FR 70691, Nov. 26, 2002; 68 FR 32981, June 3, or your sex partner has HIV/AIDS. If 2003] you do not know if you or your sex partner is infected, choose another § 201.325 Over-the-counter drugs for form of birth control’’. vaginal contraceptive and spermicide use containing (4) ‘‘When using this product [in bold nonoxynol 9 as the active ingre- type] [optional, bullet] you may get dient; required warnings and label- vaginal irritation (burning, itching, or ing information. a rash)’’. (a) Studies indicate that use of vag- (5) ‘‘Stop use and ask a doctor if [in inal contraceptive drug products con- bold type] [optional, bullet] you or taining nonoxynol 9 does not protect your partner get burning, itching, a against infection from the human im- rash, or other irritation of the vagina munodeficiency virus (HIV), the virus or penis’’. that causes acquired immunodeficiency (c) The labeling of this product states syndrome (AIDS), or against the trans- under the ‘‘Other information’’ section mission of other sexually transmitted of the Drug Facts labeling in accord- diseases (STDs). Studies also indicate ance with § 201.66(c)(7), ‘‘[bullet] when that use of vaginal contraceptive drug used correctly every time you have sex, products containing nonoxynol 9 can latex condoms greatly reduce, but do increase vaginal irritation, such as the not eliminate, the risk of catching or disruption of the vaginal epithelium, spreading HIV, the virus that causes and also can cause epithelial disruption AIDS. when used in the rectum. These effects (d) The labeling of this product in- may increase the risk of transmission cludes the following statements either of the AIDS virus (HIV) from an in- on the outside container or wrapper of fected partner. Therefore, consumers the retail package, under the ‘‘Other should be warned that these products information’’ section of the Drug Facts do not protect against the trans- labeling in accordance with mission of the AIDS virus (HIV) or § 201.66(c)(7), or in a package insert:

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(1) ‘‘[bullet] studies have raised safe- displayed, and be in one of the fol- ty concerns that products containing lowing sizes, whichever is greater: the spermicide nonoxynol 9 can irritate (A) At least one-quarter as large as the vagina and rectum. Sometimes this the size of the most prominent printed irritation has no symptoms. This irri- matter on the principal display panel tation may increase the risk of getting (PDP), or HIV/AIDS from an infected partner’’. (B) At least as large as the size of the (2) ‘‘[bullet] you can use nonoxynol 9 ‘‘Drug Facts’’ title, as required in for birth control with or without a dia- § 201.66(d)(2). The presence of acetami- phragm or condom if you have sex with nophen must appear as part of the es- only one partner who is not infected tablished name of the drug, as defined with HIV and who has no other sexual in § 299.4 of this chapter. Combination partners or HIV risk factors’’. products containing acetaminophen (3) ‘‘[bullet] use a latex condom with- and a nonanalgesic ingredient(s) (e.g., out nonoxynol 9 if you or your sex cough-cold) must include the name partner has HIV/AIDS, multiple sex ‘‘acetaminophen’’ and the name(s) of partners, or other HIV risk factors’’. the other active ingredient(s) in the (4) ‘‘[bullet] ask a health professional product on the PDP in accord with this if you have questions about your best paragraph. Only the name ‘‘acetami- birth control and STD prevention nophen’’ must appear highlighted or in methods’’. bold type, and in a prominent print (e) Any drug product subject to this size, as described in this paragraph. section that is not labeled as required and that is initially introduced or ini- (ii) Active Ingredient and Purpose tially delivered for introduction into Headings. The information required interstate commerce after June 19, under § 201.66(c)(2) and (c)(3) of this 2008, is misbranded under section 502 of chapter must be included under these the Federal Food, Drug, and Cosmetic headings. The information under these Act (the act) (21 U.S.C. 352), is a new headings, but not the headings, may drug under section 505 of the act (21 appear highlighted. U.S.C. 355), and is subject to regulatory (iii) For products labeled for adults action. only. The labeling of the product states the following warnings under the head- [72 FR 71785, Dec. 19, 2007] ing ‘‘Warnings’’: § 201.326 Over-the-counter drug prod- (A) The liver warning states ‘‘Liver ucts containing internal analgesic/ warning [heading in bold type]: This antipyretic active ingredients; re- product contains acetaminophen. Se- quired warnings and other labeling. vere liver damage may occur if you (a) Labeling. The labeling for all over- take [bullet] more than [insert max- the-counter (OTC) drug products con- imum number of daily dosage units] in taining any internal analgesic/anti- 24 hours, which is the maximum daily pyretic active ingredients (including, amount [optional: ‘for this product’] but not limited to, acetaminophen, as- [bullet] with other drugs containing ac- pirin, carbaspirin calcium, choline sa- etaminophen [bullet] 3 or more alco- licylate, ibuprofen, ketoprofen, magne- holic drinks every day while using this sium salicylate, naproxen sodium, and product’’. This ‘‘Liver’’ warning must sodium salicylate) alone or in combina- be the first warning under the ‘‘Warn- tion must bear the following labeling ings’’ heading. For products that con- in accordance with §§ 201.60, 201.61, and tain both acetaminophen and aspirin, 201.66. this ‘‘Liver’’ warning must appear after (1) Acetaminophen—(i) Statement of the ‘‘Reye’s syndrome’’ and ‘‘Allergy identity. The statement of identity ap- alert’’ warnings in § 201.66(c)(5)(ii)(A) pears in accord with §§ 201.61 and 299.4 and (c)(5)(ii)(B) and before the ‘‘Stom- of this chapter. The ingredient name ach bleeding’’ warning in paragraph ‘‘acetaminophen’’ must appear high- (a)(2)(iii)(A) of this section. If there is lighted (e.g., fluorescent or color con- an outer and immediate container of a trast) or in bold type, be in lines gen- retail package, this warning must ap- erally parallel to the base on which the pear on both the outer and immediate package rests as it is designed to be containers. If the immediate container

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is a blister card, the warning must ap- mation under the heading ‘‘Direc- pear on the blister card and remain in- tions’’: ‘‘this product does not contain tact and readable when drug product is directions or complete warnings for removed from the blister card. The adult use’’ [in bold type]. warning does not need to be included (v) For products labeled for adults and on each blister unit. children under 12 years of age. The label- (B) ‘‘Do not use with any other drug ing of the product states all of the containing acetaminophen (prescrip- warnings in paragraphs (a)(1)(iii)(A), tion or nonprescription). If you are not (a)(1)(iii)(B), and (a)(1)(iii)(C) of this sure whether a drug contains acetami- section with the following modifica- nophen, ask a doctor or pharmacist.’’ tions: (C) ‘‘Ask a doctor before use if you (A) The liver warning states ‘‘Liver have liver disease’’. warning [heading in bold type]: This (D) ‘‘Ask a doctor or pharmacist be- product contains acetaminophen. Se- fore use if you are taking the blood thinning drug warfarin’’ except on the vere liver damage may occur if [bullet] labeling of combination products that adult takes more than [insert max- contain acetaminophen and NSAID(s). imum number of daily dosage units] in (iv) For products labeled only for chil- 24 hours, which is the maximum daily dren under 12 years of age. amount [optional: ‘for this product’] (A) Warnings. The labeling of the [bullet] child takes more than 5 doses product states the following warnings in 24 hours [bullet] taken with other under the heading ‘‘Warnings’’: drugs containing acetaminophen [bul- (1) The liver warning states ‘‘Liver let] adult has 3 or more alcoholic warning [heading in bold type]: This drinks everyday while using this prod- product contains acetaminophen. Se- uct.’’ If there is an outer and imme- vere liver damage may occur if your diate container of a retail package, child takes [bullet] more than 5 doses this warning must appear on both the in 24 hours, which is the maximum outer and immediate containers. If the daily amount [optional: ‘for this prod- immediate container is a blister card, uct’] [bullet] with other drugs con- the warning must appear on the blister taining acetaminophen’’. This ‘‘Liver’’ card and remain intact and readable warning must be the first warning when drug product is removed from the under the ‘‘Warnings’’ heading. If there blister card. The warning is not re- is an outer and immediate container of quired to be included on each blister a retail package, this warning must ap- unit. pear on both the outer and immediate (B) ‘‘Ask a doctor before use if the containers. If the immediate container user has liver disease.’’ is a blister card, the warning must ap- (C) ‘‘Do not use with any other drug pear on the blister card and remain in- containing acetaminophen (prescrip- tact and readable when drug product is tion or nonprescription). If you are not removed from the blister card. The sure whether a drug contains acetami- warning is not required to be included nophen, ask a doctor or pharmacist.’’ on each blister unit. (D) ‘‘Ask a doctor or pharmacist be- (2) ‘‘Do not use with any other drug containing acetaminophen (prescrip- fore use if the user is taking the blood tion or nonprescription). If you are not thinning drug warfarin’’ except on the sure whether a drug contains acetami- labeling of combination products that nophen, ask a doctor or pharmacist.’’ contain acetaminophen and NSAID(s). (3) ‘‘Ask a doctor before use if your (2) Nonsteroidal anti-inflammatory an- child has liver disease’’. algesic/antipyretic active ingredients—in- (4) ‘‘Ask a doctor or pharmacist be- cluding, but not limited to, aspirin, fore use if your child is taking the carbaspirin calcium, choline salicylate, blood thinning drug warfarin’’ except ibuprofen, ketoprofen, magnesium salicy- on the labeling of combination prod- late, naproxen sodium, and sodium salicy- ucts that contain acetaminophen and late. NSAID(s). (i) Statement of identity. The state- (B) Directions. The labeling of the ment of identity appears in accord with product contains the following infor- §§ 201.61 and 299.4 of this chapter. The

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word ‘‘(NSAID)’’ must appear high- thinning (anticoagulant) or steroid lighted (e.g., fluorescent or color con- drug [bullet] take other drugs contrast) or in bold type, be in lines gen- taining prescription or nonprescription erally parallel to the base on which the NSAIDs (aspirin, ibuprofen, naproxen, package rests as it is designed to be or others) [bullet] have 3 or more alco- displayed, and be in one of the fol- holic drinks every day while using this lowing sizes, whichever is greater: product [bullet] take more or for a (A) At least one-quarter as large as longer time than directed’’. This the size of the most prominent printed ‘‘Stomach bleeding’’ warning must ap- matter on the PDP, or pear after the ‘‘Reye’s syndrome’’ and (B) At least as large as the size of the ‘‘Allergy alert’’ warnings in ‘‘Drug Facts’’ title, as required in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For § 201.66(d)(2). The word ‘‘(NSAID)’’ must products that contain both acetamino- appear as part of the established name phen and aspirin, the acetaminophen of the drug, as defined in § 299.4 of this ‘‘Liver’’ warning in paragraph (a)(1)(iii) chapter, or after the general pharma- of this section must appear before the cological (principal intended) action of ‘‘Stomach bleeding’’ warning in this the NSAID ingredient. Combination paragraph. If there is an outer and im- products containing an NSAID and a mediate container of a retail package, nonanalgesic ingredient(s) (e.g., cough- this warning must appear on both the cold) must include the name of the outer and immediate containers. If the NSAID ingredient and the word immediate container is a blister card, ‘‘(NSAID)’’ in accordance with this the warning must appear on the blister paragraph, and the name(s) of the card and remain intact and readable other active ingredient(s) in the prod- when drug product is removed from the uct on the PDP. Only the word blister card. The warning is not re- ‘‘(NSAID)’’ needs to appear highlighted quired to be included on each blister or in bold type, and in a prominent unit. print size, as described in this para- (B) ‘‘Ask a doctor before use if [bul- graph. let] stomach bleeding warning applies (ii) Active Ingredient and Purpose to you [bullet] you have a history of Headings. The information required stomach problems, such as heartburn under § 201.66(c)(2) and (c)(3) of this [bullet] you have high blood pressure, chapter must be included under these heart disease, liver cirrhosis, or kidney headings. The active ingredient(s) sec- disease [bullet] you are taking a diu- tion of the product’s labeling, as de- retic’’. fined in § 201.66(c)(2), contains the term ‘‘(NSAID*)’’ after the NSAID active in- (C) ‘‘Stop use and ask a doctor if gredient with an asterisk statement at [bullet] you experience any of the fol- the end of the active ingredient(s) sec- lowing signs of stomach bleeding:’’ [add tion that defines the term ‘‘NSAID’’ the following as second level of state- and states ‘‘* nonsteroidal anti-inflam- ments: ‘‘[bullet] feel faint [bullet] matory drug.’’ The information under vomit blood [bullet] have bloody or these headings may appear highlighted. black stools [bullet] have stomach pain However, the headings ‘‘Active Ingre- that does not get better’’]. dient’’ and ‘‘Purpose’’ may not appear (iv) For products labeled only for chil- highlighted. dren under 12 years of age. (iii) For products labeled for adults (A) Warnings. The labeling of the only. The labeling of the product states product states the following warnings the following warnings under the head- under the heading ‘‘Warnings’’: ing ‘‘Warnings’’: (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 you [bullet] are age 60 or older stomach ulcers or bleeding problems [bullet] have had stomach ulcers or [bullet] takes a blood thinning (anti- bleeding problems [bullet] take a blood coagulant) or steroid drug [bullet]

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takes other drugs containing prescrip- takes other drugs containing prescription or nonprescription NSAIDs (aspi- tion or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) rin, ibuprofen, naproxen, or others) [bullet] takes more or for a longer time [bullet] takes more or for a longer time than directed’’. The ‘‘Stomach bleed- than directed [bullet] is age 60 or older ing’’ warning must appear after the [bullet] has 3 or more alcoholic drinks ‘‘Reye’s syndrome’’ and ‘‘Allergy everyday while using this product’’. alert’’ warnings in § 201.66(c)(5)(ii)(A) The ‘‘Stomach bleeding’’ warning must and (c)(5)(ii)(B). If there is an outer and appear after the ‘‘Reye’s syndrome‘‘ immediate container of a retail pack- and ‘‘Allergy alert’’ warnings in age, this warning must appear on both § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If the outer and immediate containers. If there is an outer and immediate con- the immediate container is a blister tainer of a retail package, this warning card, the warning must appear on the must appear on both the outer and im- blister card and remain intact and mediate containers. If the immediate readable when drug product is removed container is a blister card, the warning from the blister card. The warning is must appear on the blister card and re- not required to be included on each main intact and readable when drug blister unit. product is removed from the blister (2) ‘‘Ask a doctor before use if [bul- card. The warning is not required to be let] stomach bleeding warning applies included on each blister unit. to your child [bullet] child has a his- (B) The labeling states ‘‘Ask a doctor tory of stomach problems, such as before use if [bullet] stomach bleeding heartburn [bullet] child has not been warning applies to user [bullet] user drinking fluids [bullet] child has lost a has history of stomach problems, such lot of fluid due to vomiting or diarrhea as heartburn [bullet] user has high [bullet] child has high blood pressure, blood pressure, heart disease, liver cir- heart disease, liver cirrhosis, or kidney rhosis, or kidney disease [bullet] user disease [bullet] child is taking a diu- takes a diuretic [bullet] user has not retic’’. been drinking fluids [bullet] user has (3) ‘‘Stop use and ask a doctor if [bul- lost a lot of fluid due to vomiting or di- let] child experiences any of the fol- arrhea’’. lowing signs of stomach bleeding:’’ [add (C) The labeling states ‘‘Stop use and the following as second level of state- ask a doctor if [bullet] user experiences ments: [bullet] feels faint [bullet] vom- any of the following signs of stomach its blood [bullet] has bloody or black bleeding:’’ [add the following as second stools [bullet] has stomach pain that level of statements: [bullet] feels faint does not get better’’]. [bullet] vomits blood [bullet] has (B) Directions. The labeling of the bloody or black stools [bullet] has product contains the following infor- stomach pain that does not get bet- mation under the heading ‘‘Direc- ter’’]. tions’’: ‘‘this product does not contain (b) New warnings information state- directions or complete warnings for ment. The labeling of any drug product adult use’’ [in bold type]. subject to this section that is initially (v) For products labeled for adults and introduced or initially delivered for in- children under 12 years of age. The label- troduction into interstate commerce ing of the product states all of the before or on April 29, 2010, must bear on warnings in paragraphs (a)(2)(iii)(A) its PDP, as defined in § 201.60, the through (a)(2)(iii)(C) of this section statement ‘‘See new warnings informa- with the following modifications: tion’’. This statement must appear (A) The Stomach bleeding warning highlighted (e.g., fluorescent or color states ‘‘Stomach bleeding warning contrast) or in bold type, be in lines [heading in bold type]: This product generally parallel to the base on which contains an NSAID, which may cause the package rests as it is designed to be severe stomach bleeding. The chance is displayed, and be in one of the fol- higher if the user [bullet] has had lowing sizes, whichever is greater: stomach ulcers or bleeding problems (1) At least one-quarter as large as [bullet] takes a blood thinning (anti- the size of the most prominent printed coagulant) or steroid drug [bullet] matter on the PDP, or

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(2) At least as large as the size of the C. Barlines and hairlines ‘‘Drug Facts’’ title, as required in 1. A 2.5-point horizontal barline extends to § 201.66(d)(2). The new warnings infor- each end of the ‘‘Drug Facts’’ box (or similar mation statement must remain on the enclosure), providing separation between PDP of the drug product for at least 1 each of the headings. year from the date the product is ini- 2. A 0.5-point horizontal hairline extends tially introduced into interstate com- within 2 spaces on either side of the ‘‘Drug merce. Facts’’ box (or similar enclosure), imme- (c) Requirements to supplement ap- diately following the title and immediately preceding the subheadings. proved application. Holders of approved 3. A 0.5-point horizontal hairline follows applications for OTC drug products the title, immediately preceding the head- that contain internal analgesic/anti- ing, when a heading appears on a subsequent pyretic active ingredients that are sub- panel immediately after the ‘‘Drug Facts ject to the requirements of paragraph (continued)’’ title. (a) of this section must submit supple- D. Box or Enclosure ments under § 314.70(c) of this chapter to include the required information in 1. All information is enclosed by a 2.5-point the product’s labeling. Such labeling barline. may be put into use without advance II. SECTION 201.66 MODIFIED LABELING approval of FDA provided it includes at FORMAT least the exact information included in paragraph (a) of this section. A. Overall [74 FR 19407, Apr. 29, 2009, as amended at 74 1. The ‘‘Drug Facts’’ labeling is presented FR 31180, June 30, 2009; 74 FR 61514, Nov. 25, in all black type printed on a white color 2009] contrasting background. B. Typeface and size APPENDIX A TO PART 201—EXAMPLES OF GRAPHIC ENHANCEMENTS USED BY FDA 1. ‘‘Drug Facts’’ is set in 9 point Helvetica Bold Italic, left justified. I. SECTION 201.66 STANDARD LABELING FORMAT 2. The headings (e.g., ‘‘Directions’’) are set in 8 point Helvetica Bold Italic, left justified. A. Overall 3. The subheadings (e.g., ‘‘Ask a doctor or 1. The ‘‘Drug Facts’’ labeling is set off in a pharmacist before use if you are’’) are set in box or similar enclosure by the use of a 6 point Helvetica Bold, left justified. barline with all black type printed on a 4. The information is set in 6 point white, color contrasting background. Helvetica Regular with 6.5 point leading, left justified. B. Typeface and size 5. The heading ‘‘Purpose’’ is right justified. 1. ‘‘Drug Facts’’ is set in 14 point Helvetica 6. The bullet is a 5-point solid square. Bold Italic, left justified. 7. Bulleted information may start on same 2. ‘‘Drug Facts (continued)’’ is set in 8 line as headings (except for the ‘‘Warnings’’ point Helvetica Bold Italic for the words heading) and subheadings, with 2 em spacing ‘‘Drug Facts’’ and 8 point Helvetica Regular separating bullets, and need not be vertically for the word ‘‘(continued)’’ and is left justi- aligned. fied. C. Barlines and hairlines 3. The headings (e.g., ‘‘Directions’’) are set in 8 point Helvetica Bold Italic, left justified. 1. A 2.5-point horizontal barline extends to 4. The subheadings (e.g., ‘‘Ask a doctor or each end of the ‘‘Drug Facts’’ box (or similar pharmacist before use if you are’’) are set in enclosure), providing separation between 6 point Helvetica Bold, left justified. each of the headings. 5. The information is set in 6 point 2. A 0.5-point horizontal hairline extends Helvetica Regular with 6.5 point leading, left within 2 spaces on either side of the ‘‘Drug justified. Facts’’ box (or similar enclosure), imme- 6. The heading ‘‘Purpose’’ is right justified. diately following the title and immediately 7. The bullet is a 5-point solid square. preceding the subheadings. 8. Two em spacing separates bullets when more than one bullet is on the same line. D. Box or Enclosure 9. A table format is used for 3 or more dos- 1. All information is set off by color con- age directions. trast. No barline is used. 10. A graphic appears at the bottom of the first panel leading the reader to the next III. EXAMPLES OF § 201.66 STANDARD LABELING panel. AND MODIFIED LABELING FORMATS

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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

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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

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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

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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

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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

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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

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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

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(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

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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

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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.

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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:

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(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.

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(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.

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§ 203.11 Applications for reimportation (a) The purchase or other acquisition to provide emergency medical care. of a drug for its own use by a hospital (a) Applications for reimportation for or other health care entity that is a emergency medical care shall be sub- member of a group purchasing organi- mitted to the director of the FDA Dis- zation from the group purchasing orga- trict Office in the district where re- nization or from other hospitals or importation is sought (addresses found health care entities that are members in part 5, subpart M of this chapter). of the organization. (b) Applications for reimportation to (b) The sale, purchase, or trade of a provide emergency medical care shall drug or an offer to sell, purchase, or be reviewed and approved or dis- trade a drug by a charitable organiza- approved by each district office. tion to a nonprofit affiliate of the organization to the extent otherwise per- [64 FR 67756, Dec. 3, 1999, as amended at 69 FR 17292, Apr. 2, 2004] mitted by law. (c) 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 among hospitals or other An appeal from an adverse decision health care entities that are under by the district office involving insulin- common control. containing drugs or prescription (d) The sale, purchase, or trade of a human drugs, other than biological drug or an offer to sell, purchase, or products, may be made to the Office of trade a drug for emergency medical Compliance, Center for Drug Evalua- reasons. tion and Research, Food and Drug Ad- (e) The sale, purchase, or trade of a ministration, 10903 New Hampshire drug, an offer to sell, purchase, or Ave., Silver Spring, MD 20993–0002. An trade a drug, or the dispensing of a appeal from an adverse decision by the drug under a valid prescription. district office involving prescription (f) The sale, purchase, or trade of a human biological products may be drug or the offer to sell, purchase, or made to the Office of Compliance and trade a drug by hospitals or health care Biologics Quality (HFM–600), Center for entities owned or operated by Federal, Biologics Evaluation and Research, State, or local governmental units to Food and Drug Administration, 1401 other hospitals or health care entities Rockville Pike, Rockville, MD 20852 or owned or operated by Federal, State, or the Office of Compliance, Center for local governmental units. Drug Evaluation and Research, Food (g) The sale, purchase, or trade of, or and Drug Administration, 10903 New the offer to sell, purchase, or trade Hampshire Ave., Silver Spring, MD blood or blood components intended for 20993–0002, depending on the Center re- transfusion. sponsible for regulating the product. (h) The sale, purchase, or trade of, or [64 FR 67756, Dec. 3, 1999, as amended at 69 the offer to sell, purchase, or trade, by FR 48775, Aug. 11, 2004; 70 FR 14980, Mar. 24, a registered blood establishment that 2005; 74 FR 13112, Mar. 26, 2009] qualifies as a health care entity any: (1) Drug indicated for a bleeding or Subpart C—Sales Restrictions clotting disorder, or anemia; (2) Blood collection container ap- § 203.20 Sales restrictions. proved under section 505 of the act; or Except as provided in § 203.22 or (3) Drug that is a blood derivative (or § 203.23, no person may sell, purchase, a recombinant or synthetic form of a or trade, or offer to sell, purchase, or blood derivative); as long as all of the trade any prescription drug that was: health care services that the establish- (a) Purchased by a public or private ment provides are related to its activi- hospital or other health care entity; or ties as a registered blood establishment (b) Donated or supplied at a reduced or the health care services consist of price to a charitable organization. collecting, processing, storing, or administering human hematopoietic § 203.22 Exclusions. stem/progenitor cells or performing di- Section 203.20 does not apply to: agnostic testing of specimens provided

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that these specimens are tested to- conditions were maintained is provided gether with specimens undergoing rou- to the manufacturer or wholesale dis- tine donor testing. Blood establish- tributor to which the drugs are re- ments relying on the exclusion in this turned. paragraph must satisfy all other requirements of the act and this part ap- Subpart D—Samples plicable to a wholesale distributor or retail pharmacy. § 203.30 Sample distribution by mail or (i) The sale, purchase, or trade of, or common carrier. the offer to sell, purchase, or trade, by (a) Requirements for drug sample dis- a comprehensive hemophilia diagnostic tribution by mail or common carrier. A treatment center that is receiving a manufacturer or authorized distributor grant under section 501(a)(2) of the So- of record may distribute a drug sample cial Security Act and that qualifies as to a practitioner licensed to prescribe a health care entity, any drug indi- the drug that is to be sampled or, at cated for a bleeding or clotting dis- the written request of a licensed prac- order, or anemia, or any drug that is a titioner, to the pharmacy of a hospital blood derivative (or a recombinant or or other health care entity, by mail or synthetic form of a blood derivative). common carrier, provided that: 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; [64 FR 67756, Dec. 3, 1999, as amended at 73 (2) The manufacturer or authorized FR 59500, Oct. 9, 2008] distributor of record verifies with the appropriate State authority that the § 203.23 Returns. practitioner requesting the drug sam- The return of a prescription drug ple is licensed or authorized under purchased by a hospital or health care State law to prescribe the drug prod- entity or acquired at a reduced price by uct; or donated to a charitable institution (3) The recipient executes a written is exempt from the prohibitions in receipt, as set forth in paragraph (c) of § 203.20, provided that: this section, when the drug sample is (a) The hospital, health care entity, delivered; and or charitable institution documents (4) The receipt is returned to the the return by filling out a credit memo manufacturer or distributor from specifying: which the drug sample was received. (1) The name and address of the hos- (b) Contents of the written request form pital, health care entity, or charitable for delivery of samples by mail or common institution; carrier. (1) A written request for a drug (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

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

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

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(3) Each drug manufacturer or au- § 203.34 Policies and procedures; ad- thorized distributor of record shall ministrative systems. take appropriate internal control Each manufacturer or authorized dis- measures to guard against error and tributor of record that distributes drug possible fraud in the conduct of the samples shall establish, maintain, and physical inventory and reconciliation, adhere to written policies and proce- and in the preparation of the inventory dures describing its administrative sys- record and reconciliation report. tems for the following: (4) A manufacturer or authorized dis- (a) Distributing drug samples by mail tributor of record shall carefully evalu- or common carrier, including method- ate any apparent discrepancy or sig- ology for reconciliation of requests and nificant loss revealed through the in- receipts; ventory and reconciliation process and (b) Distributing drug samples by shall fully investigate any such dis- means other than mail or common car- crepancy or significant loss that can- rier including the methodology for: not be justified. (1) Reconciling requests and receipts, (e) Lists of manufacturers’ and distribu- identifying patterns of nonresponse, tors’ representatives. Each drug manu- and the manufacturer’s or distributor’s facturer or authorized distributor of response when such patterns are found; record who distributes drug samples by (2) Conducting the annual physical means of representatives shall main- inventory and preparation of the rec- tain a list of the names and addresses onciliation report; of its representatives who distribute (3) Implementing a sample distribu- drug samples and of the sites where tion security and audit system, includ- drug samples are stored. ing conducting random and for-cause audits of sales representatives by per- § 203.32 Drug sample storage and han- sonnel independent of the sales force; dling requirements. and (a) Storage and handling conditions. (4) Storage of drug samples by rep- Manufacturers, authorized distributors resentatives; of record, and their representatives (c) Identifying any significant loss of shall store and handle all drug samples drug samples and notifying FDA of the under conditions that will maintain loss; and their stability, integrity, and effective- (d) Monitoring any loss or theft of ness and ensure that the drug samples drug samples. are free of contamination, deterioration, and adulteration. § 203.35 Standing requests. (b) Compliance with compendial and la- Manufacturers or authorized dis- beling requirements. Manufacturers, au- tributors of record shall not distribute thorized distributors of record, and drug samples on the basis of open- their representatives can generally ended or standing requests, but shall comply with this section by following require separate written requests for the compendial and labeling require- each drug sample or group of samples. ments for storage and handling of a An arrangement by which a licensed particular prescription drug in han- practitioner requests in writing that a dling samples of that drug. specified number of drug samples be delivered over a period of not more than § 203.33 Drug sample forms. 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.

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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. of its representatives for a violation of (b) Responsibility for producing re- section 503(c)(1) of the act or any State quested forms, reports, or records. A man- law involving the sale, purchase, or ufacturer or authorized distributor of 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 sam- (e) Whom to notify at FDA. Notifica- ples, shall: tions and reports concerning prescrip- (1) Notify FDA, by telephone or in tion human drugs and biological prod- writing, within 5 working days; ucts regulated by the Center for Drug (2) Immediately initiate an investiga- Evaluation and Research shall be made tion; and to the Division of Compliance Risk (3) Provide FDA with a complete Management and Surveillance, Office written report, including the reason for of Compliance, Center for Drug Evalua- and the results of the investigation, tion and Research, Food and Drug Ad- not later than 30 days after the date of ministration, 10903 New Hampshire the initial notification in paragraph Ave., Silver Spring, MD 20993–0002. No- (a)(1) of this section. tifications and reports concerning pre- (b) Significant loss or known theft of scription human biological products drug samples. A manufacturer or au- regulated by the Center for Biologics thorized distributor of record that dis- Evaluation and Research shall be made tributes drug samples or a charitable to the Division of Inspections and Sur- institution that receives donated drug veillance (HFM–650), Office of Compli- samples from a licensed practitioner ance and Biologics Quality, Center for shall: (1) Notify FDA, by telephone or in Biologics Evaluation and Research, writing, within 5 working days of be- Food and Drug Administration, 1401 coming aware of a significant loss or Rockville Pike, suite 200N, Rockville, known theft; MD 20852. (2) Immediately initiate an investiga- [64 FR 67756, Dec. 3, 1999, as amended at 69 tion into the significant loss or known FR 48775, Aug. 11, 2004; 70 FR 14981, Mar. 24, theft; and 2005; 74 FR 13112, Mar. 26, 2009]

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§ 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);

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(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

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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.

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(b) Procedure for making application § 205.2 Purpose. for a reward for providing information The purpose of this part is to imple- leading to the institution of a criminal ment the Prescription Drug Marketing proceeding against, and conviction of, a Act of 1987 by providing minimum person for the sale, purchase, or trade of standards, terms, and conditions for a drug sample. A person who provides the licensing by State licensing au- information leading to the institution thorities of persons who engage in of a criminal proceeding against, and wholesale distributions in interstate conviction of, a person for the sale, commerce of prescription drugs. purchase, or trade of a drug sample, or the offer to sell, purchase, or trade a § 205.3 Definitions. drug sample, in violation of section (a) Blood means whole blood collected 503(c)(1) of the act, may apply for a re- from a single donor and processed ei- ward by making written application to: ther for transfusion or further manu- (1) Director, Office of Compliance, facturing. Center for Drug Evaluation and Re- (b) Blood component means that part search, Food and Drug Administration, of blood separated by physical or me- 10903 New Hampshire Ave., Silver chanical means. Spring, MD 20993–0002; or (c) Drug sample means a unit of a pre- (2) Director, Office of Compliance and scription drug that is not intended to Biologics Quality (HFM–600), Center for be sold and is intended to promote the Biologics Evaluation and Research, sale of the drug. Food and Drug Administration, 1401 (d) Manufacturer means anyone who Rockville Pike, Rockville, MD 20852, as is engaged in manufacturing, pre- appropriate. paring, propagating, compounding, [64 FR 67756, Dec. 3, 1999, as amended at 69 processing, packaging, repackaging, or FR 48775, Aug. 11, 2004; 74 FR 13112, Mar. 26, labeling of a prescription drug. 2009] (e) Prescription drug means any human drug required by Federal law or PART 205—GUIDELINES FOR STATE regulation to be dispensed only by a prescription, including finished dosage LICENSING OF WHOLESALE PRE- forms and active ingredients subject to SCRIPTION DRUG DISTRIBUTORS section 503(b) of the Federal Food, Drug, and Cosmetic Act. Sec. (f) Wholesale distribution and wholesale 205.1 Scope. distribution means distribution of pre- 205.2 Purpose. scription drugs to persons other than a 205.3 Definitions. 205.4 Wholesale drug distributor licensing consumer or patient, but does not in- requirement. clude: 205.5 Minimum required information for li- (1) Intracompany sales; censure. (2) The purchase or other acquisition 205.6 Minimum qualifications. by a hospital or other health care enti- 205.7 Personnel. ty that is a member of a group pur- 205.8 Violations and penalties. chasing organization of a drug for its 205.50 Minimum requirements for the stor- own use from the group purchasing or- age and handling of prescription drugs ganization or from other hospitals or and for the establishment and maintenance of prescription drug distribution health care entities that are members records. of such organizations; (3) The sale, purchase, or trade of a AUTHORITY: 21 U.S.C. 351, 352, 353, 371, 374. drug or an offer to sell, purchase, or SOURCE: 55 FR 38023, Sept. 14, 1990, unless trade a drug by a charitable organiza- otherwise noted. tion described in section 501(c)(3) of the Internal Revenue Code of 1954 to a non- § 205.1 Scope. profit affiliate of the organization to This part applies to any person, part- the extent otherwise permitted by law; nership, corporation, or business firm (4) The sale, purchase, or trade of a in a State engaging in the wholesale drug or an offer to sell, purchase, or distribution of human prescription trade a drug among hospitals or other drugs in interstate commerce. health care entities that are under

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

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submitted to the State licensing au- lated to compliance with State licens- thority as required by such authority. ing requirements.

(Approved by the Office of Management and § 205.8 Violations and penalties. Budget under control number 0910–0251) (a) State licensing laws shall provide § 205.6 Minimum qualifications. 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 establishment and maintenance of pre- plicant under Federal, State, or local scription drug distribution records. laws; (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 (1) Be of suitable size and construc- controlled substances; tion to facilitate cleaning, mainte- (6) Compliance with licensing re- nance, and proper operations; quirements under previously granted (2) Have storage areas designed to licenses, if any; provide adequate lighting, ventilation, (7) Compliance with requirements to temperature, sanitation, humidity, maintain and/or make available to the space, equipment, and security condi- State licensing authority or to Fed- tions; eral, State, or local law enforcement (3) Have a quarantine area for stor- officials those records required under age of prescription drugs that are out- this section; and dated, damaged, deteriorated, mis- (8) Any other factors or qualifica- branded, or adulterated, or that are in tions the State licensing authority immediate or sealed, secondary con- considers relevant to and consistent tainers that have been opened; with the public health and safety. (4) Be maintained in a clean and or- (b) The State licensing authority derly condition; and shall have the right to deny a license (5) Be free from infestation by in- to an applicant if it determines that sects, rodents, birds, or vermin of any the granting of such a license would kind. not be in the public interest. (b) Security. (1) All facilities used for wholesale drug distribution shall be se- § 205.7 Personnel. cure from unauthorized entry. The State licensing authority shall (i) Access from outside the premises require that personnel employed in shall be kept to a minimum and be wholesale distribution have appro- well-controlled. priate education and/or experience to (ii) The outside perimeter of the assume responsibility for positions re- premises shall be well-lighted.

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

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(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 following: and regulations. (1) A procedure whereby the oldest (1) Wholesale drug distributors shall approved stock of a prescription drug permit the State licensing authority product is distributed first. The proce- and authorized Federal, State, and dure may permit deviation from this local law enforcement officials to enter requirement, if such deviation is tem- and inspect their premises and delivery porary and appropriate. vehicles, and to audit their records and (2) A procedure to be followed for written operating procedures, at rea- handling recalls and withdrawals of sonable times and in a reasonable man- prescription drugs. Such procedure ner, to the extent authorized by law. shall be adequate to deal with recalls (2) Wholesale drug distributors that and withdrawals due to: deal in controlled substances shall reg- (i) Any action initiated at the re- ister with the appropriate State con- quest of the Food and Drug Adminis- trolled substance authority and with tration or other Federal, State, or the Drug Enforcement Administration local law enforcement or other govern- (DEA), and shall comply with all appli- ment agency, including the State li- cable State, local, and DEA regula- censing agency; tions. (ii) Any voluntary action by the (j) Salvaging and reprocessing. Whole- manufacturer to remove defective or potentially defective drugs from the sale drug distributors shall be subject market; or to the provisions of any applicable Fed- (iii) Any action undertaken to pro- eral, State, or local laws or regulations mote public health and safety by re- placing of existing merchandise with

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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. § 206.7 Exemptions. (Approved by the Office of Management and Budget under control number 0910–0251) (a) The following classes of drug products are exempt from requirements [55 FR 38023, Sept. 14, 1990, as amended at 64 of this part: FR 67763, Dec. 3, 1999] (1) Drug products intended for use in a clinical investigation under section PART 206—IMPRINTING OF SOLID 505(i) of the act, but not including ORAL DOSAGE FORM DRUG drugs distributed under a treatment PRODUCTS FOR HUMAN USE IND under part 312 of this chapter or distributed as part of a nonconcur- Sec. rently controlled study. Placebos in- 206.1 Scope. tended for use in a clinical investiga- 206.3 Definitions. tion are exempt from the requirements 206.7 Exemptions. 206.10 Code imprint required. of this part if they are designed to copy the active drug products used in that AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, investigation. 371; 42 U.S.C. 262. (2) Drugs, other than reference listed SOURCE: 58 FR 47958, Sept. 13, 1993, unless drugs, intended for use in bioequiva- otherwise noted. lence studies. (3) Drugs that are extemporaneously § 206.1 Scope. compounded by a licensed pharmacist, This part applies to all solid oral dos- upon receipt of a valid prescription for age form human drug products, includ- an individual patient from a practi- ing prescription drug products, over- tioner licensed by law to prescribe or the-counter drug products, biological administer drugs, to be used solely by drug products, and homeopathic drug the patient for whom they are pre- products, unless otherwise exempted scribed. under § 206.7. (4) Radiopharmaceutical drug products. § 206.3 Definitions. (b) Exemption of drugs because of The following definitions apply to size or unique physical characteristics: this part: (1) For a drug subject to premarket The act means the Federal Food, approval, FDA may provide an exemp- Drug, and Cosmetic Act (21 U.S.C. 301 tion from the requirements of § 206.10 et seq.). upon a showing that the product’s size, Debossed means imprinted with a shape, texture, or other physical char- mark below the dosage form surface. acteristics make imprinting techno- Drug product means a finished dosage logically infeasible or impossible. form, e.g., a tablet or capsule that con- (i) Exemption requests for products tains a drug substance, generally, but with approved applications shall be not necessarily, in association with one made in writing to the appropriate re- or more other ingredients. view division in the Center for Drug Embossed means imprinted with a Evaluation and Research (CDER), Food mark raised above the dosage form sur- and Drug Administration, 5901–B face. Ammendale Rd., Beltsville, MD 20705– Engraved means imprinted with a 1266 or the Center for Biologics Evalua- code that is cut into the dosage form tion and Research (CBER), Food and surface after it has been completed. Drug Administration, 1401 Rockville Imprinted means marked with an Pike, suite 200N, Rockville, MD 20852– identification code by means of em- 1448. If FDA denies the request, the bossing, debossing, engraving, or print- holder of the approved application will ing with ink. have 1 year after the date of an agency Manufacturer means the manufac- denial to imprint the drug product. turer as described in §§ 201.1 and 600.3(t) (ii) Exemption requests for products of this chapter. that have not yet received approval

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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 requirements of this rule. Controlled [58 FR 47958, Sept. 13, 1993, as amended at 60 settings include physicians’ offices and FR 19846, Apr. 21, 1995; 69 FR 18763, Apr. 8, other health care facilities. Exemption 2004] requests should be submitted in writing to the appropriate review division PART 207—REGISTRATION OF PRO- in CDER or CBER. DUCERS OF DRUGS AND LISTING [58 FR 47958, Sept. 13, 1993, as amended at 70 OF DRUGS IN COMMERCIAL DIS- FR 14981, Mar. 24, 2005; 74 FR 13112, Mar. 26, TRIBUTION 2009] Subpart A—General § 206.10 Code imprint required. (a) Unless exempted under § 206.7, no Sec. drug product in solid oral dosage form 207.3 Definitions. may be introduced or delivered for in- 207.7 Establishment registration and prod- troduction into interstate commerce uct listing for human blood and blood unless it is clearly marked or im- products and for medical devices. printed with a code imprint that, in Subpart B—Exemptions conjunction with the product’s size, shape, and color, permits the unique 207.10 Exemptions for establishments. identification of the drug product and the manufacturer or distributor of the Subpart C—Procedures for Domestic Drug product. Identification of the drug Establishments product requires identification of its active ingredients and its dosage 207.20 Who must register and submit a drug list. strength. Inclusion of a letter or num- 207.21 Times for registration and drug list- ber in the imprint, while not required, ing. is encouraged as a more effective 207.22 How and where to register and list means of identification than a symbol drugs. or logo by itself. Homeopathic drug 207.25 Information required in registration products are required only to bear an and drug listing. imprint that identifies the manufac- 207.26 Amendments to registration. turer and their homeopathic nature. 207.30 Updating drug listing information. (b) A holder of an approved applica- 207.31 Additional drug listing information. tion who has, under § 314.70 (b) of this 207.35 Notification of registrant; drug estab- chapter, supplemented its application lishment registration number and drug to provide for a new imprint is not re- listing number. quired to bring its product into compli- 207.37 Inspection of registrations and drug ance with this section during the pend- listings. ency of the agency’s review. Once the 207.39 Misbranding by reference to registra- review is complete, the drug product is tion or to registration number. subject to the requirements of the rule.

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Subpart D—Procedure for Foreign Drug the same parent, subsidiary, and/or af- Establishments filiate company. For foreign establishments, the term ‘‘commercial distribu- 207.40 Establishment registration and drug listing requirements for foreign estab- tion’’ shall have the same meaning ex- lishments. cept that the term shall not include distribution of any drug that is neither AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 374, 381, 393; 42 U.S.C. 262, 264, imported nor offered for import into 271. the United States. (6) Drug product salvaging means the SOURCE: 45 FR 38043, June 6, 1980, unless otherwise noted. act of segregating drug products that may have been subjected to improper Subpart A—General storage conditions, such as extremes in temperature, humidity, smoke, fumes, § 207.3 Definitions. pressure, age, or radiation, for the pur- (a) The following definitions apply to pose of returning some or all of the this part: products to the marketplace. (1) Act means the Federal Food, Drug, (7) Establishment means a place of and Cosmetic Act approved June 25, business under one management at one 1938 (52 Stat. 1040 et seq., as amended general physical location. The term in- (21 U.S.C. 301–392)), except as otherwise cludes, among others, independent lab- provided. oratories that engage in control activi- (2) Advertising and labeling include the ties for a registered drug establishment promotional material described in (e.g., consulting laboratories), manufac- § 202.1(l) (1) and (2) respectively. turers of medicated feeds and of vita- (3) Any material change includes but is min products that are drugs in accord- not limited to any change in the name ance with section 201(g) of the act, of the drug, any change in the identity human blood donor centers, and animal or quantity of the active ingredient(s), facilities used for the production or any change in the identity or quantity control testing of licensed biologicals, of the inactive ingredient(s) where and establishments engaged in drug quantitative listing of all ingredients product salvaging. is required by § 207.31(a)(2), any signifi- (8) Manufacturing or processing means cant change in the labeling of a pre- the scription drug, and any significant manufacture, preparation, propaga- change in the label or package insert of tion, compounding, or processing of a an over-the-counter drug. Changes that drug or drugs as used in section 510 of are not significant include changes in the act and is the making by chemical, arrangement or printing or changes of physical, biological, or other proce- an editorial nature. dures of any articles that meet the def- (4) Bulk drug substance means any inition of drugs in section 201(g) of the substance that is represented for use in act. The term includes manipulation, a drug and that, when used in the man- sampling, testing, or control proce- ufacturing, processing, or packaging of dures applied to the final product or to a drug, becomes an active ingredient or any part of the process. The term also a finished dosage form of the drug, but includes repackaging or otherwise the term does not include intermedi- changing the container, wrapper, or la- ates used in the synthesis of such sub- beling of any drug package to further stances. the distribution of the drug from the (5) Commercial distribution means any original place of manufacture to the distribution of a human drug except for person who makes final delivery or sale investigational use under part 312 of to the ultimate consumer. this chapter, and any distribution of an (9) Representative sampling of adver- animal drug or animal feed bearing or tisements means typical advertising ma- containing an animal drug for non- terial (excluding labeling as deter- investigational uses, but the term does mined in § 202.1(l) (1) and (2)) that gives not include internal or interplant transfer of a bulk drug substance be- a balanced picture of the promotional tween registered establishments within claims used for the drug, e.g., if more

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than one medical journal advertise- tablishment), and FDA–2892 (Medical ment is used but the promotional con- Device Listing), in accordance with tent is essentially identical, only one part 807. need be submitted. (d) Owners and operators of establish- (10) Representative sampling of any ments engaged in the manufacture or other labeling means typical labeling processing at the same establishment material (excluding labels and package of both drug products and medical de- inserts) that gives a balanced picture vices shall (1) register with the Records of the promotional claims used for the Repository Team (HFD–143), Center for drug, e.g., if more than one brochure is Drug Evaluation and Research, FDA, used but the promotional content is es- and list their drug products in accord- sentially identical, only one need be ance with this part, and (2) register submitted. with the Center for Devices and Radio- (11) United States agent means a per- logical Health and list their medical son residing or maintaining a place of devices in accordance with part 807. business in the United States whom a [45 FR 38043, June 6, 1980, as amended at 50 foreign establishment designates as its FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29, agent. This definition excludes mail- 1990; 66 FR 59156, Nov. 27, 2001; 69 FR 48775, boxes, answering machines or services, Aug. 11, 2004] or other places where an individual acting as the foreign establishment’s Subpart B—Exemptions agent is not physically present. (b) The definitions and interpreta- § 207.10 Exemptions for establish- tions of terms in sections 201, 502(e), ments. and 510 of the act apply to the use of The following classes of persons are terms in this part. exempt from registration and drug list- [45 FR 38043, June 6, 1980, as amended at 55 ing in accordance with this part under FR 11576, Mar. 29, 1990; 66 FR 59156, Nov. 27, section 510(g)(1), (g)(2), and (g)(3) of the 2001] act, or because FDA has found, under section 510(g)(5) of the act, that their § 207.7 Establishment registration and registration is not necessary for the product listing for human blood protection of the public health. The ex- and blood products and for medical emptions in paragraphs (a) and (b) of devices. this section are limited to pharmacies, (a) Owners and operators of human hospitals, clinics, and public health blood and blood product establishments agencies located in any State as de- shall register and list their products fined in section 201(a)(1) of the act. with the Center for Biologics Evalua- (a) Pharmacies that operate under tion and Research (HFM–375), 1401 applicable local laws regulating dis- Rockville Pike, suite 200N, Rockville, pensing of prescription drugs and that MD 20852–1448, on Form FDA–2830 do not manufacture or process drugs (Blood Establishment Registration and for sale other than in the regular Product Listing), in accordance with course of the practice of the profession part 607 of this chapter. Such owners of pharmacy, including dispensing and and operators who also manufacture or selling drugs at retail. The supplying of process other drug products at the prescription drugs by these pharmacies same establishment shall, in addition, to a practitioner licensed to administer register and list all such other drug these drugs for his or her use in the products with the Drug Listing Branch course of professional practice or to in accordance with this part. other pharmacies to meet temporary (b) [Reserved] inventory shortages are not acts that (c) Owners and operators of establish- require pharmacies to register. ments engaged in manufacture or proc- (b) Hospitals, clinics, and public essing of medical devices shall register health agencies that maintain estab- and list their products with the Center lishments in conformance with any ap- for Devices and Radiological Health, plicable local laws regulating the prac- FDA, on Form FDA–2891 (Initial Reg- tices of pharmacy or medicine and that istration of Device Establishments), regularly engage in dispensing pre- FDA–2891a (Registration of Device Es- scription drugs, other than human

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blood or blood products, upon prescrip- Subpart C—Procedures for tion of practitioners licensed by law to Domestic Drug Establishments administer these drugs to patients under their professional care. § 207.20 Who must register and submit (c) Practitioners who are licensed by a drug list. law to prescribe or administer drugs (a) Owners or operators of all drug es- and who manufacture or process drugs tablishments, not exempt under sec- solely for use in their professional tion 510(g) of the act or subpart B of practice. this part 207, that engage in the manu- (d) Persons who manufacture or proc- facture, preparation, propagation, ess drugs not for sale but solely for use compounding, or processing of a drug in research, teaching, or chemical or drugs shall register and submit a analysis. list of every drug in commercial distribution (except that registration and (e) Manufacturers of harmless inac- listing information may be submitted tive ingredients that are excipients, by the parent, subsidiary, and/or affil- colorings, flavorings, emulsifiers, lu- iate company for all establishments bricants, preservatives, or solvents when operations are conducted at more that become components of drugs, and than one establishment and there ex- who otherwise would not be required to ists joint ownership and control among register under this part. all the establishments). Drug listing is (f) Persons who only manufacture the not required for the manufacturing, following: preparation, propagation, (1) Type B or Type C medicated feed compounding, or processing of an ani- using Category I, Type A medicated ar- mal feed bearing or containing an ani- ticles or Category I, Type B or Type C mal drug (i.e., a Type B or Type C medicated feeds, and/or; medicated feed), nor is drug listing re- (2) Type B or Type C medicated feed quired for establishments engaged in drug product salvaging. Drug products using Category II, Type B or Type C manufactured, prepared, propagated, medicated feeds. compounded, or processed in any State (3) Persons who manufacture free- as defined in section 201(a)(1) of the act choice feeds, as defined in § 510.455 of must be listed whether or not the out- this chapter, or medicated liquid feeds, put of such establishments or any par- as defined in § 558.5 of this chapter, ticular drug so listed enters interstate where a medicated feed mill license is commerce. No owner or operator may required are not exempt. register an establishment if any part of (g) Any manufacturer of a virus, the establishment is registered by any serum, toxin, or analogous product in- other owner or operator. tended for treatment of domestic ani- (b) Owners or operators of establish- mals who holds an unsuspended and ments not otherwise required to reg- unrevoked license issued by the Sec- ister under section 510 of the act that retary of Agriculture under the animal distribute under their own label or virus-serum-toxin law of March 4, 1913 trade name a drug manufactured or (37 Stat. 832 (21 U.S.C. 151 et seq.)), pro- processed by a registered establish- vided that this exemption from reg- ment may elect to submit listing infor- istration applies only to the manufac- mation directly to FDA and to obtain a ture or processing of that animal virus, Labeler Code. A distributor who sub- serum, toxin, or analogous product. mits drug listing information shall include the registration number of the (h) Carriers, in their receipt, car- drug establishment that manufactured, riage, holding, or delivery of drugs in prepared, propagated, compounded, or the usual course of business as carriers. processed each drug listed. All distribu- [45 FR 38043, June 6, 1980, as amended at 51 tors who submit drug listing informa- FR 7389, Mar. 3, 1986; 64 FR 63203, Nov. 19, tion to FDA assume full responsibility 1999; 66 FR 59156, Nov. 27, 2001] for compliance with all of the requirements of this part. Each such distributor at the time of submitting or updating drug listing information as

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required under § 207.30 shall certify to procedures for registration and listing the registered establishment that the contained in this part, except that the submission has been made by providing additional listing information require- a signed copy of Form FDA–2656 (Reg- ments in § 207.31 remain applicable. istration of Drug Establishment) to the registered establishment that manu- [45 FR 38043, June 6, 1980, as amended at 45 factures or processes the drug. Each FR 32293, May 16, 1980; 52 FR 2682, Jan. 26, such distributor shall submit the origi- 1987; 55 FR 11576, Mar. 29, 1990; 64 FR 400, Jan. nal of Form FDA–2656 showing this cer- 5, 1999; 64 FR 56448, Oct. 20, 1999; 64 FR 63203, Nov. 19, 1999; 66 FR 5466, Jan. 19, 2001; 66 FR tification to FDA, and shall accompany 59157, Nov. 27, 2001; 66 FR 5447, Jan. 19, 2001; the certification with a list showing 72 FR 69120, Dec. 6, 2007] the National Drug Code number that the distributor has assigned to each § 207.21 Times for registration and drug product. If a distributor does not drug listing. elect to submit drug listing information directly to FDA and to obtain a (a) The owner or operator of an es- Labeler Code, the registered establish- tablishment entering into the manu- ment shall submit the drug listing in- facture or processing of a drug or drugs formation. Distributors or registered shall register the establishment within establishments shall use Form FDA– 5 days after the beginning of the oper- 2658 (Registered Establishments’ Re- ation and shall submit a list of every port of Private Label Distributors) to drug in commercial distribution at submit drug listing information or to that time. If the owner or operator of request a Labeler Code, or both. the establishment has not previously (c) Before beginning manufacture or entered into such an operation, the processing of a drug subject to one of owner or operator shall register within the following applications, an owner or 5 days after submitting a new drug ap- operator of an establishment is re- plication, abbreviated new drug appli- quired to register before the agency ap- cation, new animal drug application, proves or grants it: A new drug applica- abbreviated new animal drug application, an abbreviated new drug application, request for addition to the index, tion, a new animal drug application, an abbreviated new animal drug applica- medicated feed mill license application, a medicated feed mill license ap- tion, or a biologics license application. plication, a biologics license applica- Owners or operators shall renew their tion, or a request for addition to the registration information annually. index. The schedule is as follows: (d) No registration fee is required. Date FDA will (e) Registration and listing do not First letter of company name mail forms constitute an admission, or agreement, or determination that a product is a A or B ...... January drug as defined in section 201(g) of the C, D, or E ...... February act. F, G, or H ...... March I, J, K, L. or M ...... April (f) Owners and operators of establish- N, O, P, Q, or R ...... May ments or persons engaged in the recov- S or T ...... June ery, screening, testing, processing, U, V, W, X, Y, or Z ...... July storage, or distribution of human cells, tissues, and cellular and tissue-based (b) Owners and operators of all reg- products, as defined in § 1271.3(d) of this istered establishments shall update chapter, that are regulated under sec- their drug listing information every tion 351 of the Public Health Service June and December. Act and/or the Federal Food, Drug, and Cosmetic Act must register and list [45 FR 38043, June 6, 1980, as amended at 55 those human cells, tissues, and cellular FR 11576, Mar. 29, 1990; 64 FR 400, Jan. 5, 1999; and tissue-based products with the 64 FR 56448, Oct. 20, 1999; 64 FR 63203, Nov. 19, Center for Biologics Evaluation and 1999; 66 FR 59157, Nov. 27, 2001; 72 FR 69120, Research on Form FDA 3356 following Dec. 6, 2007] the procedures set out in subpart B of part 1271 of this chapter, instead of the

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§ 207.22 How and where to register (1) A list of drugs, including bulk and list drugs. drug substances and Type A articles for (a) An establishment shall register use in the manufacture of animal feeds the first time on Form FDA–2656 (Reg- as well as finished dosage forms, by es- istration of Drug Establishment), ob- tablished name and by proprietary tainable on request from the Records name, that are being manufactured or Repository Team (HFD–143), Center for processed for commercial distribution Drug Evaluation and Research, Food and that have not been included in any and Drug Administration, 5600 Fishers list previously submitted to FDA on Lane, Rockville, MD 20857, or from Form FDA–2657 or in conjunction with FDA district offices. An establishment the FDA voluntary inventory on Form whose drug registration for that year FDA–2422 (Survey Report of Marketed was validated under § 207.35 shall make Drugs), or Form FDA–2250 (National subsequent annual registration on Drug Code Directory Input). Form FDA–2656 as described in (2) For each drug listed that the reg- § 207.21(a) by mailing the completed istrant regards as subject to section 505 form to the above address within 30 or 512 of the act, the new drug applica- days after receipt from FDA. tion number, abbreviated new drug ap- (b) The first list of drugs and later plication number, new animal drug ap- June and December updatings shall be plication number, or abbreviated new on Form FDA–2657 (Drug Product List- animal drug application number and a ing), obtainable upon request as de- copy of all current labeling, except scribed in paragraph (a) of this section. that only one representative container An establishment may submit, in lieu or carton label need be submitted of Form FDA–2657, tapes for computer where differences exist only in the inputs containing the information quantity of contents statement. specified in Form FDA–2657 if formats (3) For each drug listed that the reg- proposed for this use were reviewed and istrant regards as subject to section 351 approved by the Records Repository of the Public Health Service Act, the Team (HFD–143), Center for Drug Eval- license number of the manufacturer. uation and Research, FDA. (4) For each human prescription drug [45 FR 38043, June 6, 1980, as amended at 50 listed that the registrant regards as FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29, not subject to section 505 of the act or 1990; 69 FR 48775, Aug. 11, 2004] 351 of the Public Health Service Act, and that is not manufactured by a reg- § 207.25 Information required in registered blood bank, a copy of all cur- istration and drug listing. rent labeling (except that only one rep- (a) Form FDA–2656 (Registration of resentative container or carton label Drug Establishment) provides for fur- need be submitted where differences nishing or confirming information re- exist only in the quantity of contents quired by the act. This information in- statement) and a representative sam- cludes, for each establishment, the pling of advertisements. name and full address of the drug es- (5) For each human over-the-counter tablishment; all trade names used by drug listed, or each animal drug listed, the establishment; the kind of owner- that the registrant regards as not sub- ship or operation (that is, individually ject to section 505 or 512 of the act or owned, partnership or corporation); 351 of the Public Health Service Act, a and the name of the owner or operator copy of the label (except that only one of the establishment. The term name of representative container or carton the owner or operator includes in the label need be submitted where dif- case of a partnership the name of each ferences exist only in the quantity of partner, and in the case of a corpora- contents statement), the package in- tion the name and title of each cor- sert, and a representative sampling of porate officer and director and the any other labeling. name of the State of incorporation. (6) For each prescription or over-the- (b) Form FDA–2657 (Drug Product counter drug so listed that the reg- Listing) provides that information re- istrant regards as not subject to sec- quired by the act be furnished as fol- tion 505 or 512 of the act or 351 of the lows: Public Health Service Act, and that is

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not manufactured by a registered blood within 6 months of the registration of bank, a quantitative listing of the ac- the establishment is required to be sup- tive ingredient(s). Unless the quan- ported by a signed statement of the es- titative listing is expressed as a per- tablishment’s owner or operator that centage in the offical compendium or the change is not made for the purpose the ingredient is a nonantibiotic ingre- of changing the name of the manufac- dient in a Type A medicated article for turer of a drug product under § 201.1 of use in the manufacture of animal feeds, this chapter. Changes in the names of the quantity of an ingredient shall be officers and directors of the corpora- expressed in terms of the amount, not tions do not require such amendment the percent, of that ingredient in each but must be shown at time of annual dosage unit or, if the drug is not in registration. unit dosage form, the amount of the ingredient in a specific unit of weight or [45 FR 25777, Apr. 15, 1980, as amended at 55 measure of the drug. For a drug formu- FR 11577, Mar. 29, 1990] lation that is a Type A medicated article subject to § 207.35(b)(2)(iii), the reg- § 207.30 Updating drug listing information. istrant may limit the quantitative listing of ingredients to each variation of (a) After submitting the initial drug level of active drug ingredient. listing information, every person who (7) For each drug listed, the registra- is required to list drugs under § 207.20 tion number of every drug establish- shall submit on Form FDA–2657 (Drug ment within the parent company at Product Listing) during each subse- which it is manufactured or processed. quent June and December, or at the (8) For each drug listed, the National discretion of the registrant when the Drug Code (NDC) number. If FDA has change occurs, the following informa- not assigned an NDC Labeler Code, the tion: registrant shall include a Product Code (1) A list of each drug introduced by and Package Code and FDA will assign the registrant for commerical distribu- a Labeler Code as described in tion which has not been included in § 207.35(b)(2)(i). any list previously submitted. The reg- (c) For each drug product listed that istrant shall provide all of the informa- is subject to the imprinting require- tion required by § 207.25(b) for each ments of part 206 of this chapter, in- such drug. cluding products that are exempted (2) A list of each drug formerly listed under § 206.7(b), drug companies must in accordance with § 207.25(b) for which submit a document that provides the commercial distribution has been dis- name of the product, its active ingre- continued, including for each drug so dient(s), dosage strength, National listed the National Drug Code (NDC) Drug Code number, the name of its number, the identity by established manufacturer or distributor, its size, shape, color, and code imprint (if any), name and by proprietary name, and and any other characteristic that iden- date of discontinuance. It is requested tifies the product as unique. but not required that the reason for discontinuance of distribution be in- [45 FR 38043, June 6, 1980, as amended at 52 cluded with this information. FR 2682, Jan. 26, 1987; 55 FR 11577, Mar. 29, (3) A list of each drug for which a no- 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999; 66 FR tice of discontinuance was submitted 59157, Nov. 27, 2001] under paragraph (a)(2) of this section and for which commercial distribution § 207.26 Amendments to registration. has been resumed, including for each Changes in individual ownership, cor- drug so listed the NDC number, the porate or partnership structure loca- identity by established name and by tion or drug-handling activity, shall be proprietary name, the date of resump- submitted by Form FDA–2656 (Reg- tion, and any other information re- istration of Drug Establishment) as quired by § 207.25(b) not previously sub- amendment to registration within 5 mitted. days of such changes. A change in a (4) Any material change in any infor- registered establishment’s firm name mation previously submitted.

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(b) When no changes have occurred istered in accordance with these regu- since the previously submitted list, no lations. report is required. (b) Using the National Drug Code (NDC) numbering system, FDA assigns § 207.31 Additional drug listing infor- a drug listing number to each drug or mation. class of drugs listed as follows: (a) In addition to the information (1) If a drug is already listed in the routinely required by §§ 207.25 and National Drug Code System or in the 207.30, FDA may require submission of National Health Related Items Code the following information by letter or System, the number is the same as by FEDERAL REGISTER notice: that assigned under those codes. FDA (1) For a particular prescription drug adds a lead zero to the first three char- so listed that the registrant regards as acters of the code, which identifies the not subject to section 505 of the act, manufacturer or distributor, to expand upon request by FDA for good cause, a the ‘‘Labeler Code’’ segment to four copy of all advertisements. characters. The National Drug Code, (2) For a particular drug product so Product Code, and Package Code con- listed that the registrant regards as figurations used to describe these not subject to section 505 or 512 of the drugs, or any drugs added to the prod- act, upon a finding by FDA that it is uct line, remain the same, i.e., a four- necessary to carry out the purposes of character Product Code and a two- the act, a quantitative listing of all in- character Package Code. A manufac- gredients. turer or distributor may either retain (3) For a particular drug product, alphanumeric characters that are al- upon request by FDA, a brief state- ready used in the Product Code and ment of the basis for the registrant’s Package Code segments of the National belief that the drug product is not sub- Drug Code or convert these alpha- ject to section 505 or 512 of the act. numeric characters to all numeric digits. The manufacturer or distributor (4) For each registrant, upon a find- shall inform FDA of a decision to con- ing by FDA that it is necessary to vert the alphanumeric characters to all carry out the purposes of the act, a list numeric digits. of each listed drug product containing (2) If a registered establishment or a particular ingredient. distributor has not previously partici- (b) It is requested but not required pated in the National Drug Code Sys- that a qualitative listing of the inac- tem or in the National Health Related tive ingredients be submitted for all Items Code System, FDA uses the Na- listed drugs in the format prescribed in tional Drug Code numbering system in Form FDA–2657 (Drug Product Listing). assigning a number, as follows (only (c) It is requested but not required numerals are used): that a quantitative listing of the active (i) The first 5 numeric characters of ingredients be submitted for all drugs the 10-character code identify the man- listed that are subject to section 505 or ufacturer or distributor and are known 512 of the act or section 351 of the Pub- as the Labeler Code. FDA will expand lic Health Service Act. the Labeler Code from five to six nu- [45 FR 38043, June 6, 1980, as amended at 63 meric characters when the available FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999] five-character code combinations are exhausted. FDA will assign Labeler § 207.35 Notification of registrant; Code numbers and provide them to the drug establishment registration registrant along with the validated number and drug listing number. copy of Form FDA–2656. Any registered (a) FDA will provide to the registrant firm that does not have an assigned La- a validated copy of Form FDA–2656 beler Code will be assigned one when (Registration of Drug Establishment) registration and listing information as evidence of registration. This vali- are submitted. dated copy will be sent to the mailing (ii) The last 5 numeric characters of address shown on the form. FDA will the 10-character code identify the drug assign a permanent registration num- and the trade package size and type. ber to each drug establishment reg- The segment that identifies the drug

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formulation is known as the Product play panel, as used in this paragraph, Code and the segment that identifies means that part of a label most likely the trade package size and type is to be displayed, presented, shown, or known as the Package Code. The man- examined under customary conditions ufacturer or distributor will assign the of display to the consumer (for over- Product Code and the Package Code be- the-counter drug products) or to the fore drug listing and include these dispenser (for prescription drug prod- codes in Form FDA–2657 (Drug Product ucts). Listing). The manufacturer or dis- (ii) The NDC number shall be pre- tributor may use either of two methods ceded by the prefix ‘‘NDC’’ or ‘‘N’’ in assigning the Product and Package when it is used on a label or in label- Codes: a 3–2 Product-Package Code con- ing. The prefix used for a drug product figuration (e.g., 542–12) or a 4–1 Prod- shall be used consistently on the label uct-Package Code configuration (e.g., of the immediate container, outside 5421–2). A manufacturer or distributor container, or wrapper, if any, and on with a given Labeler Code shall use other labeling for that drug product. only one such Product-Package Code (iii) The Product-Package Code con- configuration and shall use this same figuration shall be indicated and the configuration in assigning the Product- segments of the number shall be sepa- Package Codes for all drugs included in rated by a dash, e.g., NDC 15643–542–12 the drug listing. The manufacturer or or N 15643–542–12. distributor shall report to FDA the (iv) All 10 characters shall appear and Product-Package Code configuration the leading zeros in any segment of the used in assigning these codes. NDC number shall be shown, except (iii) If the drug formulation is a Type that leading zeros may be omitted from A medicated article intended for use in any segment of the NDC number when the manufacture of an animal feed, the NDC number is used for product FDA assigns a separate Product Code identification by direct imprinting on only for each variation of level of ac- dosage forms or in the case of con- tive drug ingredient. tainers too small or otherwise unable (3) FDA requests but does not require to accommodate a label with sufficent that the NDC number appear on all space to bear both required and op- drug labels and in other drug labeling, tional labeling information. including the label of any prescription (v) The placing of the assigned NDC drug container furnished to a con- number on a label or in other labeling sumer. If the NDC number is shown on does not require the submission of a a drug label, it shall be placed as fol- supplemental new drug application, lows: supplemental new animal drug applica- (i) The NDC number shall appear tion, or a modification to an index list- prominently in the top third of the ing. principal display panel of the label on (4)(i) If any change occurs in those the immediate container and of any product characteristics that clearly outside container or wrapper. Instead distinguish one drug product version of appearing in the top third of the from another, the registrant shall as- label, the NDC number may appear as sign a new NDC number to the new part of and contiguous to any bar-code product version and submit that infor- symbol for any drug product if two mation to FDA. Such a change in- conditions are met. First, the symbol cludes, but is not limited to, a change appears prominently on the immediate in active ingredient(s); strength or con- container and on any outside container centration of active ingredient(s); dos- or wrapper and in a conspicuous loca- age form; route of administration, if it tion; this condition is not satisfied by also includes a change in product for- the appearance of the symbol only on mulation; product name; and a change the natural bottom of a container or in marketing status from prescription wrapper. Second, the bar-code symbol to over-the-counter or over-the-counter is compatible with the NDC, i.e., the to prescription. If, by notice in the symbol provides a format capable of FEDERAL REGISTER, FDA requires a encoding the numeric characters of an change in drug product characteristics NDC Number. The term principal dis- and determines the change will require

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assignment of a new product code to Team (HFD–325), Office of Compliance, the reformulated product, FDA will an- Center for Drug Evaluation and Re- nounce its determination in the FED- search, Food and Drug Administration, ERAL REGISTER publication that re- 5600 Fishers Lane, Rockville, MD 20857. quires the change, setting forth its rea- Upon request and receipt of a stamped, soning and justification for its deter- self-addressed envelope, the Records mination. If a change only in the trade Repository Team, the Foreign Inspec- package is involved, the registrant tion Team, or the appropriate FDA dis- may revise the trade package code trict office will verify registration without the assignment of a new prod- numbers or provide the location of a uct code segment, but shall inform registered establishment. The mailing FDA of the new code for the trade address for the Foreign Inspection package and the characteristics of the Team is: Division of Manufacturing new trade package. and Product Quality, Office of Compli- (ii) When a registrant has discon- ance, Center for Drug Evaluation and tinued a drug product, its product code Research (HFD–325), Food and Drug may be reassigned to another drug Administration, 5600 Fishers Lane, product 5 years after the expiration Rockville, MD 20857. date of the discontinued product, or, if (1) The following types of informa- there is no expiration date, 5 years tion submitted under the drug listing after the last shipment of the discon- requirements will be available for pub- tinued product into commercial dis- lic disclosure when compiled: tribution. Reuse of product codes may (i) A list of all drug products. occur, under the specified conditions, (ii) A list of all drug products ar- regardless of the NDC, Product Code, ranged by labeled indications or phar- and Package Code configuration used. macological category. (c) Although registration and drug (iii) A list of all drug products ar- listing are required to engage in the ranged by manufacturer. drug activities described in § 207.20, val- (iv) A list of a drug product’s active idation of registration and the assign- ingredients. ment of a drug listing number do not, (v) A list of drug products newly mar- in themselves, establish that the hold- keted or for which marketing is re- er of the registration is legally quali- sumed. fied to deal in such drugs. (vi) A list of drug products discon- [45 FR 38043, June 6, 1980, as amended at 48 tinued. FR 54007, Nov. 30, 1983; 52 FR 2682, Jan. 26, (vii) Labeling. 1987; 55 FR 11577, Mar. 29, 1990; 64 FR 400, Jan. (viii) Advertising. 5, 1999; 72 FR 69120, Dec. 6, 2007] (ix) Information that has become a matter of public knowledge. § 207.37 Inspection of registrations (x) A list of drug products containing and drug listings. a particular active ingredient. (a) A copy of the Form FDA–2656 (xi) A list of all code imprints. (Registration of Drug Establishment) (2) The following types of informa- filed by the registrant will be available tion submitted in accordance with the for inspection in accordance with sec- drug listing requirements will not be tion 510(f) of the act, at the Records available for public disclosure (except Repository Team (HFD–143), Center for that any of the information will be Drug Evaluation and Research, Food available for public disclosure if it has and Drug Administration, 5600 Fishers become a matter of public knowledge Lane, Rockville, MD 20857. In addition, or if FDA finds that confidentiality copies of these forms for establish- would be inconsistent with protection ments located within a particular geo- of the public health): graphic area are available for inspec- (i) Any information submitted as the tion at FDA district offices responsible basis upon which it has been deter- for that geographical area. Copies of mined that a particular drug product is forms submitted by foreign drug estab- not subject to section 505 or 512 of the lishments are available for inspection act. at the Division of Manufacturing and (ii) A list of a drug product’s inactive Product Quality, Foreign Inspection ingredients.

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(iii) A list of drugs containing a par- processed at a registered foreign drug ticular inactive ingredient. establishment; however, this restric- (b) Requests for information about tion does not apply to a drug imported registrations and drug listings of an es- or offered for import under the inves- tablishment should be directed to the tigational use provisions in part 312 of Information Management Team (HFD– this chapter, or the investigational 095), Office of Information Technology, new animal drug use provisions in part Center for Drug Evaluation and Re- 511 of this chapter, or to a component search, Food and Drug Administration, of a drug imported under section 5600 Fishers Lane, Rockville, MD 20857 801(d)(3) of the act. Foreign drug estab- or, with respect to the information de- lishments shall submit all listing infor- scribed in paragraph (a) of this section, to the FDA district office responsible mation, including labels and labeling, for the geographic area in which the es- and registration information in the tablishment is located. English language. (c) Each foreign drug establishment [45 FR 38043, June 6, 1980, as amended at 50 required to register under paragraph FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, (a) of this section shall submit the May 13, 1998; 64 FR 400, Jan. 5, 1999; 66 FR name, address, and phone number of its 59157, Nov. 27, 2001; 69 FR 48775, Aug. 11, 2004] United States agent as part of its initial and updated registration informa- § 207.39 Misbranding by reference to tion in accordance with subpart C of registration or to registration number. this part. Each foreign drug establishment shall designate only one United Registration of a drug establishment States agent. or drug wholesaler, or assignment of a (1) The United States agent shall re- registration number, or assignment of a NDC number does not in any way de- side or maintain a place of business in note approval of the firm or its prod- the United States. ucts. Any representation that creates (2) Upon request from FDA, the an impression of official approval be- United States agent shall assist FDA cause of registration or possession of in communications with the foreign registration number or NDC number is drug establishment, respond to ques- misleading and constitutes mis- tions concerning the foreign drug es- branding. tablishment’s products that are imported or offered for import into the Subpart D—Procedure for Foreign United States, and assist FDA in Drug Establishments scheduling inspections of the foreign drug establishment. If the agency is § 207.40 Establishment registration unable to contact the foreign drug es- and drug listing requirements for tablishment directly or expeditiously, foreign establishments. FDA may provide information or docu- (a) Foreign drug establishments ments to the United States agent, and whose drugs are imported or offered for such an action shall be considered to be import into the United States shall equivalent to providing the same infor- comply with the establishment reg- mation or documents to the foreign istration and drug listing requirements drug establishment. in subpart C of this part, unless exempt (3) The foreign drug establishment or under subpart B of this part or unless the United States agent shall report the drugs enter a foreign trade zone and are re-exported from that foreign changes in the United States agent’s trade zone without having entered U. name, address, or phone number to S. commerce. FDA within 10-business days of the (b) No drug may be imported or of- change. fered for import into the United States [66 FR 59157, Nov. 27, 2001] unless it is listed as required in subpart C of this part and manufactured, prepared, propagated, compounded, or

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PART 208—MEDICATION GUIDES to use, or to continue to use, the prod- FOR PRESCRIPTION DRUG PROD- uct. UCTS (3) The drug product is important to health and patient adherence to direc- Subpart A—General Provisions tions for use is crucial to the drug’s effectiveness. Sec. 208.1 Scope and purpose. § 208.3 Definitions. 208.3 Definitions. For the purposes of this part, the fol- Subpart B—General Requirements for a lowing definitions shall apply: Medication Guide (a) Authorized dispenser means an individual 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 pa- SOURCE: 63 FR 66396, Dec. 1, 1998, unless tient either: otherwise noted. (1) By a licensed practitioner or an agent of a licensed practitioner, either Subpart A—General Provisions directly or indirectly, for self-administration by the patient, or the patient’s § 208.1 Scope and purpose. agent, or outside the licensed practi- (a) This part sets forth requirements tioner’s direct supervision; or for patient labeling for human pre- (2) By an authorized dispenser or an scription drug products, including bio- agent of an authorized dispenser under logical products, that the Food and a lawful prescription of a licensed prac- Drug Administration (FDA) determines titioner. pose a serious and significant public (c) Distribute means the act of deliv- health concern requiring distribution ering, other than by dispensing, a drug of FDA-approved patient information. product to any person. It applies primarily to human prescrip- (d) Distributor means a person who tion drug products used on an out- distributes a drug product. patient basis without direct super- (e) Drug product means a finished dos- vision by a health professional. This age form, e.g., tablet, capsule, or solu- part shall apply to new prescriptions tion, that contains an active drug in- and refill prescriptions. gredient, generally, but not nec- (b) The purpose of patient labeling essarily, in association with inactive for human prescription drug products ingredients. For purposes of this part, required under this part is to provide drug product also means biological information when the FDA determines product within the meaning of section in writing that it is necessary to pa- 351(a) of the Public Health Service Act. tients’ safe and effective use of drug (f) Licensed practitioner means an in- products. dividual licensed, registered, or other- (c) Patient labeling will be required wise permitted by the jurisdiction in if the FDA determines that one or which the individual practices to pre- more of the following circumstances scribe drug products in the course of exists: professional practice. (1) The drug product is one for which (g) Manufacturer means for a drug patient labeling could help prevent se- product that is not also a biological rious adverse effects. product, both the manufacturer as de- (2) The drug product is one that has scribed in § 201.1 and the applicant as serious risk(s) (relative to benefits) of described in § 314.3(b) of this chapter, which patients should be made aware and for a drug product that is also a bi- because information concerning the ological product, the manufacturer as risk(s) could affect patients’ decision described in § 600.3(t) of this chapter.

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

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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 prod- ence on the drug product. uct, such as: (iii) For drug products approved (i) A statement stressing the impor- under section 505 of the act, the fol- tance of adhering to the dosing instruc- lowing verbatim statement: ‘‘Call your tions, if this is particularly important; doctor for medical advice about side ef- (ii) A statement describing any spe- fects. You may report side effects to cial instructions on how to administer FDA at 1–800–FDA–1088.’’ the drug product, if they are important (8) General information about the to the drug’s safety or effectiveness; safe and effective use of prescription (iii) A statement of what patients drug products, including: should do in case of overdose of the (i) The verbatim statement that drug product; and ‘‘Medicines are sometimes prescribed (iv) A statement of what patients for purposes other than those listed in should do if they miss taking a sched- a Medication Guide’’ followed by a uled dose(s) of the drug product, where statement that patients should ask there are data to support the advice, health professionals about any con- and where the wrong behavior could cerns, and a reference to the avail- cause harm or lack of effect. ability of professional labeling; (6) The heading ‘‘What should I avoid (ii) A statement that the drug prod- while taking (name of drug)?’’ followed uct should not be used for a condition by a statement or statements of spe- other than that for which it is pre- cific, important precautions patients scribed, or given to other persons; should take to ensure proper use of the (iii) The name and place of business drug, including: of the manufacturer, packer, or dis- (i) A statement that identifies activi- tributor of a drug product that is not ties (such as driving or sunbathing), also a biological product, or the name and drugs, foods, or other substances and place of business of the manufac- (such as tobacco or alcohol) that pa- turer or distributor of a drug product tients should avoid when using the that is also a biological product, and in medication; any case the name and place of busi- (ii) A statement of the risks to moth- ness of the dispenser of the product ers and fetuses from the use of the drug may also be included; and during pregnancy, if specific, impor- (iv) The date, identified as such, of tant risks are known; the most recent revision of the Medica- (iii) A statement of the risks of the tion Guide placed immediately after drug product to nursing infants, if spe- the last section. cific, important risks are known; (9) Additional headings and sub- (iv) A statement about pediatric headings may be interspersed through- risks, if the drug product has specific out the Medication Guide, if appro- hazards associated with its use in pedi- priate. atric patients; [63 FR 66396, Dec. 1, 1998, as amended at 73 (v) A statement about geriatric risks, FR 404, Jan. 3, 2008] if the drug product has specific hazards associated with its use in geriatric pa- § 208.24 Distributing and dispensing a tients; and Medication Guide. (vi) A statement of special pre- (a) The manufacturer of a drug prod- cautions, if any, that apply to the safe uct for which a Medication Guide is re- and effective use of the drug product in quired under this part shall obtain other identifiable patient populations. FDA approval of the Medication Guide

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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 (a) FDA on its own initiative, or in this part is responsible for ensuring response to a written request from an that Medication Guides are available applicant, may exempt or defer any for distribution to patients by either: Medication Guide content or format re- (1) Providing Medication Guides in quirement, except those requirements sufficient numbers to distributors, in § 208.20 (a)(2) and (a)(6), on the basis packers, or authorized dispensers to that the requirement is inapplicable, permit the authorized dispenser to pro- unnecessary, or contrary to patients’ vide a Medication Guide to each pa- best interests. Requests from appli- tient receiving a prescription for the cants should be submitted to the direc- drug product; or tor 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- (b) If the licensed practitioner who tion Guide to each patient receiving a prescription for the drug product. prescribes a drug product subject to (c) Each distributor or packer that this part determines that it is not in a receives Medication Guides, or the particular patient’s best interest to re- means to produce Medication Guides, ceive a Medication Guide because of from a manufacturer under paragraph significant concerns about the effect of (b) of this section shall provide those a Medication Guide, the licensed prac- Medication Guides, or the means to titioner may direct that the Medica- produce Medication Guides, to each au- tion Guide not be provided to the par- thorized dispenser to whom it ships a ticular patient. However, the author- container of drug product. ized dispenser of a prescription drug (d) The label of each container or product subject to this part shall pro- package, where the container label is vide a Medication Guide to any patient too small, of drug product for which a who requests information when the Medication Guide is required under drug product is dispensed regardless of this part shall instruct the authorized any such direction by the licensed dispenser to provide a Medication practitioner. 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 directly to each patient (or to the pa- Subpart B—Requirements tient’s agent) unless an exemption applies under § 208.26. 209.10 Content and format of the side effects statement. (f) An authorized dispenser or whole- 209.11 Dispensing and distributing the side saler is not subject to section 510 of the effects statement. Federal Food, Drug, and Cosmetic Act, which requires the registration of pro- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, ducers of drugs and the listing of drugs 355, 360, 371; 42 U.S.C. 241. in commercial distribution, solely be- SOURCE: 73 FR 404, Jan. 3, 2008, unless oth- cause of an act performed by the au- erwise noted.

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

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PART 210—CURRENT GOOD MAN- tion to the regulations in this part and UFACTURING PRACTICE IN MAN- in parts 211 through 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 through 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] EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. § 210.1 Status of current good manu- 10, 2009, § 210.1 was amended by removing the facturing practice regulations. phrase ‘‘211 through 226’’ each time it ap- (a) The regulations set forth in this pears and by adding in its place the phrase part and in parts 211 through 226 of this ‘‘211, 225, and 226’’, effective Dec. 12, 2011. chapter contain the minimum current good manufacturing practice for meth- § 210.2 Applicability of current good manufacturing practice regulations. ods to be used in, and the facilities or controls to be used for, the manufac- (a) The regulations in this part and ture, processing, packing, or holding of in parts 211 through 226 of this chapter a drug to assure that such drug meets as they may pertain to a drug; in parts the requirements of the act as to safe- 600 through 680 of this chapter as they ty, and has the identity and strength may pertain to a biological product for and meets the quality and purity char- human use; and in part 1271 of this acteristics that it purports or is rep- chapter as they are applicable to a resented to possess. human cell, tissue, or cellular or tis- (b) The failure to comply with any sue-based product (HCT/P) that is a regulation set forth in this part and in drug (subject to review under an appli- parts 211 through 226 of this chapter in cation submitted under section 505 of the manufacture, processing, packing, the act or under a biological product li- or holding of a drug shall render such cense application under section 351 of drug to be adulterated under section the Public Health Service Act); shall 501(a)(2)(B) of the act and such drug, as be considered to supplement, not super- well as the person who is responsible sede, each other, unless the regulations for the failure to comply, shall be sub- explicitly provide otherwise. In the ject to regulatory action. event of a conflict between applicable (c) Owners and operators of establish- regulations in this part and in other ments engaged in the recovery, donor parts of this chapter, the regulation screening, testing (including donor specifically applicable to the drug testing), processing, storage, labeling, product in question shall supersede the packaging, or distribution of human more general. cells, tissues, and cellular and tissue- (b) If a person engages in only some based products (HCT/Ps), as defined in operations subject to the regulations in § 1271.3(d) of this chapter, that are this part, in parts 211 through 226 of drugs (subject to review under an appli- this chapter, in parts 600 through 680 of cation submitted under section 505 of this chapter, and in part 1271 of this the act or under a biological product li- chapter, and not in others, that person cense application under section 351 of need only comply with those regula- the Public Health Service Act), are tions applicable to the operations in subject to the donor-eligibility and ap- which he or she is engaged. plicable current good tissue practice (c) An investigational drug for use in procedures set forth in part 1271 sub- a phase 1 study, as described in parts C and D of this chapter, in addi- § 312.21(a) of this chapter, is subject to

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the statutory requirements set forth in (5) Fiber means any particulate con- 21 U.S.C. 351(a)(2)(B). The production of taminant with a length at least three such drug is exempt from compliance times greater than its width. with the regulations in part 211 of this (6) Nonfiber releasing filter means any chapter. However, this exemption does filter, which after appropriate not apply to an investigational drug pretreatment such as washing or flush- for use in a phase 1 study once the in- ing, will not release fibers into the vestigational drug has been made component or drug product that is available for use by or for the sponsor being filtered. in a phase 2 or phase 3 study, as de- (7) Active ingredient means any com- scribed in § 312.21(b) and (c) of this ponent that is intended to furnish chapter, or the drug has been lawfully pharmacological activity or other di- marketed. If the investigational drug rect effect in the diagnosis, cure, miti- has been made available in a phase 2 or gation, treatment, or prevention of dis- phase 3 study or the drug has been law- ease, or to affect the structure or any fully marketed, the drug for use in the function of the body of man or other phase 1 study must comply with part animals. The term includes those com- 211. ponents that may undergo chemical [69 FR 29828, May 25, 2004, as amended at 73 change in the manufacture of the drug FR 40462, July 15, 2008] product and be present in the drug EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. product in a modified form intended to 10, 2009, § 210.2(a) and (b) were amended by re- furnish the specified activity or effect. moving the phrase ‘‘211 through 226’’ both (8) Inactive ingredient means any com- times it appears and by adding in its place ponent other than an active ingredient. the phrase ‘‘211, 225, and 226’’, effective Dec. (9) In-process material means any ma- 12, 2011. terial fabricated, compounded, blended, § 210.3 Definitions. or derived by chemical reaction that is produced for, and used in, the prepara- (a) The definitions and interpretation of the drug product. tions contained in section 201 of the act shall be applicable to such terms when (10) Lot means a batch, or a specific used in this part and in parts 211 identified portion of a batch, having through 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 drug product produced by continuous through 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 from which the complete history of the of manufacture. manufacture, processing, packing, (3) Component means any ingredient holding, and distribution of a batch or intended for use in the manufacture of lot of drug product or other material a drug product, including those that can be determined. may not appear in such drug product. (12) Manufacture, processing, packing, (4) Drug product means a finished dos- or holding of a drug product includes age form, for example, tablet, capsule, packaging and labeling operations, solution, etc., that contains an active testing, and quality control of drug drug ingredient generally, but not nec- products. essarily, in association with inactive (13) The term medicated feed means ingredients. The term also includes a any Type B or Type C medicated feed finished dosage form that does not con- as defined in § 558.3 of this chapter. The tain an active ingredient but is in- feed contains one or more drugs as de- tended to be used as a placebo. fined in section 201(g) of the act. The

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manufacture of medicated feeds is sub- units that are drawn based on rational ject to the requirements of part 225 of criteria such as random sampling and this chapter. intended to assure that the sample ac- (14) The term medicated premix means curately portrays the material being a Type A medicated article as defined sampled. in § 558.3 of this chapter. The article (22) Gang-printed labeling means la- contains one or more drugs as defined beling derived from a sheet of material 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] person or organizational element designated by the firm to be responsible EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. for the duties relating to quality con- 10, 2009, § 210.3(a) and (b) introductory text were amended by removing the phrase ‘‘211 trol. through 226’’ and adding in its place the (16) Strength means: phrase ‘‘211, 225, and 226’’, effective Dec. 12, (i) The concentration of the drug sub- 2011. stance (for example, weight/weight, weight/volume, or unit dose/volume PART 211—CURRENT GOOD MAN- basis), and/or UFACTURING PRACTICE FOR FIN- (ii) The potency, that is, the therapeutic activity of the drug product as ISHED PHARMACEUTICALS indicated by appropriate laboratory tests or by adequately developed and Subpart A—General Provisions controlled clinical data (expressed, for Sec. example, in terms of units by reference 211.1 Scope. to a standard). 211.3 Definitions. (17) Theoretical yield means the quantity that would be produced at any ap- Subpart B—Organization and Personnel propriate phase of manufacture, proc- 211.22 Responsibilities of quality control essing, or packing of a particular drug unit. product, based upon the quantity of 211.25 Personnel qualifications. components to be used, in the absence 211.28 Personnel responsibilities. of any loss or error in actual produc- 211.34 Consultants. tion. (18) Actual yield means the quantity Subpart C—Buildings and Facilities that is actually produced at any appro- 211.42 Design and construction features. priate phase of manufacture, proc- 211.44 Lighting. essing, or packing of a particular drug 211.46 Ventilation, air filtration, air heating product. and cooling. (19) Percentage of theoretical yield 211.48 Plumbing. means the ratio of the actual yield (at 211.50 Sewage and refuse. any appropriate phase of manufacture, 211.52 Washing and toilet facilities. processing, or packing of a particular 211.56 Sanitation. drug product) to the theoretical yield 211.58 Maintenance. (at the same phase), stated as a percentage. Subpart D—Equipment (20) Acceptance criteria means the 211.63 Equipment design, size, and location. product specifications and acceptance/ 211.65 Equipment construction. rejection criteria, such as acceptable 211.67 Equipment cleaning and mainte- quality level and unacceptable quality nance. level, with an associated sampling 211.68 Automatic, mechanical, and elec- plan, that are necessary for making a tronic equipment. decision to accept or reject a lot or 211.72 Filters. batch (or any other convenient sub- Subpart E—Control of Components and groups of manufactured units). Drug Product Containers and Closures (21) Representative sample means a sample that consists of a number of 211.80 General requirements.

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211.82 Receipt and storage of untested com- 211.196 Distribution records. ponents, drug product containers, and 211.198 Complaint files. closures. 211.84 Testing and approval or rejection of Subpart K—Returned and Salvaged Drug components, drug product containers, Products and closures. 211.86 Use of approved components, drug 211.204 Returned drug products. product containers, and closures. 211.208 Drug product salvaging. 211.87 Retesting of approved components, drug product containers, and closures. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, 211.89 Rejected components, drug product 371, 374; 42 U.S.C. 216, 262, 263a, 264. containers, and closures. SOURCE: 43 FR 45077, Sept. 29, 1978, unless 211.94 Drug product containers and closures. otherwise noted. Subpart F—Production and Process Controls Subpart A—General Provisions 211.100 Written procedures; deviations. § 211.1 Scope. 211.101 Charge-in of components. (a) The regulations in this part con- 211.103 Calculation of yield. 211.105 Equipment identification. tain the minimum current good manu- 211.110 Sampling and testing of in-process facturing practice for preparation of materials and drug products. drug products for administration to hu- 211.111 Time limitations on production. mans or animals. 211.113 Control of microbiological contami- (b) The current good manufacturing nation. practice regulations in this chapter as 211.115 Reproccessing. 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 biological products for human use; and in part 211.122 Materials examination and usage 1271 of this chapter, as they are appli- criteria. cable to drugs that are also human 211.125 Labeling issuance. cells, tissues, and cellular and tissue- 211.130 Packaging and labeling operations. based products (HCT/Ps) and that are 211.132 Tamper-evident packaging requirements 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 the Public Health Service Act); supple- Subpart H—Holding and Distribution ment 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 other parts of this chapter, or in parts 211.160 General requirements. 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 proposed exemption, published in the FED- Subpart J—Records and Reports 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. are ordinarily marketed and consumed 211.186 Master production and control as human foods, and which products records. 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 part 110 of this

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chapter, and where applicable, parts 113 tions impacting on the identity, to 129 of this chapter, shall be applied strength, quality, and purity of the in determining whether these OTC drug drug product. products that are also foods are manu- (d) The responsibilities and proce- factured, processed, packed, or held dures applicable to the quality control under current good manufacturing unit shall be in writing; such written practice. procedures shall be followed. [43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522, Dec. 19, 1997; 69 FR 29828, May 25, § 211.25 Personnel qualifications. 2004] (a) Each person engaged in the manu- EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. facture, processing, packing, or holding 10, 2009, § 211.1 was amended by revising para- of a drug product shall have education, graph (a), effective Dec. 12, 2011. For the con- training, and experience, or any com- venience of the user, the revised text is set bination thereof, to enable that person forth as follows: to perform the assigned functions. § 211.1 Scope. Training shall be in the particular op- (a) The regulations in this part contain the erations that the employee performs minimum current good manufacturing prac- and in current good manufacturing tice for preparation of drug products (exclud- practice (including the current good ing positron emission tomography drugs) for manufacturing practice regulations in administration to humans or animals. this chapter and written procedures required by these regulations) as they re- * * * * * late to the employee’s functions. Training in current good manufac- § 211.3 Definitions. turing practice shall be conducted by The definitions set forth in § 210.3 of qualified individuals on a continuing this chapter apply in this part. basis and with sufficient frequency to assure that employees remain familiar Subpart B—Organization and with CGMP requirements applicable to Personnel them. (b) Each person responsible for super- § 211.22 Responsibilities of quality vising the manufacture, processing, control unit. packing, or holding of a drug product 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 errors have occurred or, if errors have (c) There shall be an adequate num- occurred, that they have been fully in- ber of qualified personnel to perform vestigated. The quality control unit and supervise the manufacture, proc- shall be responsible for approving or re- essing, packing, or holding of each drug jecting drug products manufactured, product. processed, packed, or held under con- § 211.28 Personnel responsibilities. tract by another company. (b) Adequate laboratory facilities for (a) Personnel engaged in the manu- the testing and approval (or rejection) facture, processing, packing, or holding of components, drug product con- of a drug product shall wear clean tainers, closures, packaging materials, clothing appropriate for the duties in-process materials, and drug products they perform. Protective apparel, such shall be available to the quality con- as head, face, hand, and arm coverings, trol unit. shall be worn as necessary to protect (c) The quality control unit shall drug products from contamination. have the responsibility for approving (b) Personnel shall practice good or rejecting all procedures or specifica- sanitation and health habits.

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(c) Only personnel authorized by su- defined areas or such other control sys- pervisory personnel shall enter those tems for the firm’s operations as are areas of the buildings and facilities necessary to prevent contamination or designated as limited-access areas. mixups during the course of the fol- (d) Any person shown at any time (ei- lowing procedures: ther by medical examination or super- (1) Receipt, identification, storage, visory observation) to have an appar- and withholding from use of compo- ent illness or open lesions that may ad- nents, drug product containers, clo- versely affect the safety or quality of sures, and labeling, pending the appro- drug products shall be excluded from priate sampling, testing, or examina- direct contact with components, drug tion by the quality control unit before product containers, closures, in-process materials, and drug products until the release for manufacturing or pack- condition is corrected or determined by aging; competent medical personnel not to (2) Holding rejected components, jeopardize the safety or quality of drug drug product containers, closures, and products. All personnel shall be in- labeling before disposition; structed to report to supervisory per- (3) Storage of released components, sonnel any health conditions that may drug product containers, closures, and have an adverse effect on drug prod- labeling; ucts. (4) Storage of in-process materials; (5) Manufacturing and processing op- § 211.34 Consultants. erations; Consultants advising on the manu- (6) Packaging and labeling oper- facture, processing, packing, or holding ations; 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 of any consultants and the type of ations; service they provide. (10) Aseptic processing, which includes as appropriate: Subpart C—Buildings and Facilities (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily § 211.42 Design and construction fea- cleanable; tures. (ii) Temperature and humidity con- (a) Any building or buildings used in trols; the manufacture, processing, packing, (iii) An air supply filtered through or holding of a drug product shall be of high-efficiency particulate air filters suitable size, construction and location under positive pressure, regardless of to facilitate cleaning, maintenance, whether flow is laminar or nonlaminar; and proper operations. (iv) A system for monitoring environ- (b) Any such building shall have ade- mental conditions; quate space for the orderly placement (v) A system for cleaning and dis- of equipment and materials to prevent infecting the room and equipment to mixups between different components, produce aseptic conditions; drug product containers, closures, la- (vi) A system for maintaining any beling, in-process materials, or drug equipment used to control the aseptic products, and to prevent contamina- conditions. tion. The flow of components, drug (d) Operations relating to the manu- product containers, closures, labeling, facture, processing, and packing of pen- in-process materials, and drug products icillin shall be performed in facilities through the building or buildings shall separate from those used for other drug be designed to prevent contamination. (c) Operations shall be performed products for human use. within specifically defined areas of ade- [43 FR 45077, Sept. 29, 1978, as amended at 60 quate size. There shall be separate or FR 4091, Jan. 20, 1995]

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§ 211.44 Lighting. § 211.52 Washing and toilet facilities. Adequate lighting shall be provided Adequate washing facilities shall be in all areas. provided, including hot and cold water, soap or detergent, air driers or single- § 211.46 Ventilation, air filtration, air service towels, and clean toilet facili- heating and cooling. ties easily accesible to working areas. (a) Adequate ventilation shall be provided. § 211.56 Sanitation. (b) Equipment for adequate control over air pressure, micro-organisms, (a) Any building used in the manufac- dust, humidity, and temperature shall ture, processing, packing, or holding of be provided when appropriate for the a drug product shall be maintained in a manufacture, processing, packing, or clean and sanitary condition, Any such holding of a drug product. building shall be free of infestation by (c) Air filtration systems, including rodents, birds, insects, and other prefilters and particulate matter air vermin (other than laboratory ani- filters, shall be used when appropriate mals). Trash and organic waste matter on air supplies to production areas. If shall be held and disposed of in a time- air is recirculated to production areas, ly and sanitary manner. measures shall be taken to control re- (b) There shall be written procedures circulation of dust from production. In assigning responsibility for sanitation areas where air contamination occurs and describing in sufficient detail the during production, there shall be ade- cleaning schedules, methods, equip- quate exhaust systems or other sys- ment, and materials to be used in tems adequate to control contami- cleaning the buildings and facilities; nants. such written procedures shall be fol- (d) Air-handling systems for the manufacture, processing, and packing of lowed. penicillin shall be completely separate (c) There shall be written procedures from those for other drug products for for use of suitable rodenticides, insecti- human use. cides, fungicides, fumigating agents, and cleaning and sanitizing agents. § 211.48 Plumbing. Such written procedures shall be de- (a) Potable water shall be supplied signed to prevent the contamination of under continuous positive pressure in a equipment, components, drug product plumbing system free of defects that containers, closures, packaging, label- could contribute contamination to any ing materials, or drug products and drug product. Potable water shall meet shall be followed. Rodenticides, insecti- the standards prescribed in the Envi- cides, and fungicides shall not be used ronmental Protection Agency’s Pri- unless registered and used in accord- mary Drinking Water Regulations set ance with the Federal Insecticide, Fun- forth in 40 CFR part 141. Water not gicide, and Rodenticide Act (7 U.S.C. meeting such standards shall not be 135). permitted in the potable water system. (d) Sanitation procedures shall apply (b) Drains shall be of adequate size to work performed by contractors or and, where connected directly to a temporary employees as well as work sewer, shall be provided with an air performed by full-time employees dur- break or other mechanical device to ing the ordinary course of operations. prevent back-siphonage. [43 FR 45077, Sept. 29, 1978, as amended at 48 § 211.58 Maintenance. FR 11426, Mar. 18, 1983] Any building used in the manufac- § 211.50 Sewage and refuse. ture, processing, packing, or holding of a drug product shall be maintained in a Sewage, trash, and other refuse in good state of repair. and from the building and immediate premises shall be disposed of in a safe and sanitary manner.

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Subpart D—Equipment operations, and the methods of dis- assembling and reassembling equip- § 211.63 Equipment design, size, and ment as necessary to assure proper location. cleaning and maintenance; Equipment used in the manufacture, (4) Removal or obliteration of pre- processing, packing, or holding of a vious batch identification; drug product shall be of appropriate de- (5) Protection of clean equipment sign, adequate size, and suitably lo- from contamination prior to use; cated to facilitate operations for its in- (6) Inspection of equipment for clean- tended use and for its cleaning and liness immediately before use. maintenance. (c) Records shall be kept of maintenance, cleaning, sanitizing, and inspec- § 211.65 Equipment construction. tion as specified in §§ 211.180 and 211.182. (a) Equipment shall be constructed so [43 FR 45077, Sept. 29, 1978, as amended at 73 that surfaces that contact components, FR 51931, Sept. 8, 2008] in-process materials, or drug products shall not be reactive, additive, or ab- § 211.68 Automatic, mechanical, and sorptive so as to alter the safety, iden- electronic equipment. tity, strength, quality, or purity of the (a) Automatic, mechanical, or elec- drug product beyond the official or tronic equipment or other types of other established requirements. equipment, including computers, or re- (b) Any substances required for oper- lated systems that will perform a func- ation, such as lubricants or coolants, tion satisfactorily, may be used in the shall not come into contact with com- manufacture, processing, packing, and ponents, drug product containers, clo- holding of a drug product. If such sures, in-process materials, or drug equipment is so used, it shall be rou- products so as to alter the safety, iden- tinely calibrated, inspected, or checked tity, strength, quality, or purity of the according to a written program de- drug product beyond the official or signed to assure proper performance. other established requirements. Written records of those calibration checks and inspections shall be main- § 211.67 Equipment cleaning and maintained. tenance. (b) Appropriate controls shall be ex- (a) Equipment and utensils shall be ercised over computer or related sys- cleaned, maintained, and, as appro- tems to assure that changes in master priate for the nature of the drug, sani- production and control records or other tized and/or sterilized at appropriate 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,

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inadvertent erasures, or loss shall be ably spaced to permit cleaning and in- maintained. spection. (c) Such automated equipment used (d) Each container or grouping of for performance of operations ad- containers for components or drug dressed by §§ 211.101(c) or (d), 211.103, product containers, or closures shall be 211.182, or 211.188(b)(11) can satisfy the identified with a distinctive code for requirements included in those sec- each lot in each shipment received. tions relating to the performance of an This code shall be used in recording the operation by one person and checking disposition of each lot. Each lot shall by another person if such equipment is be appropriately identified as to its used in conformity with this section, status (i.e., quarantined, approved, or and one person checks that the equip- rejected). ment properly performed the operation. § 211.82 Receipt and storage of untested components, drug product con- [43 FR 45077, Sept. 29, 1978, as amended at 60 tainers, and closures. FR 4091, Jan. 20, 1995; 73 FR 51932, Sept. 8, (a) Upon receipt and before accept- 2008] ance, each container or grouping of § 211.72 Filters. containers of components, drug product containers, and closures shall be Filters for liquid filtration used in examined visually for appropriate la- the manufacture, processing, or pack- beling as to contents, container dam- ing of injectable drug products in- age or broken seals, and contamina- tended for human use shall not release tion. fibers into such products. Fiber-releas- (b) Components, drug product con- ing filters may be used when it is not tainers, and closures shall be stored possible to manufacture such products under quarantine until they have been without the use of these filters. If use tested or examined, whichever is appro- of a fiber-releasing filter is necessary, priate, and released. Storage within an additional nonfiber-releasing filter the area shall conform to the require- having a maximum nominal pore size ments of § 211.80. rating of 0.2 micron (0.45 micron if the manufacturing conditions so dictate) [43 FR 45077, Sept. 29, 1978, as amended at 73 shall subsequently be used to reduce FR 51932, Sept. 8, 2008] the content of particles in the § 211.84 Testing and approval or rejec- injectable drug product. The use of an tion of components, drug product asbestos-containing filter is prohibited. containers, and closures. [73 FR 51932, Sept. 8, 2008] (a) Each lot of components, drug product containers, and closures shall Subpart E—Control of Compo- be withheld from use until the lot has been sampled, tested, or examined, as nents and Drug Product Con- appropriate, and released for use by the tainers and Closures quality control unit. (b) Representative samples of each § 211.80 General requirements. shipment of each lot shall be collected (a) There shall be written procedures for testing or examination. The num- describing in sufficient detail the re- ber of containers to be sampled, and ceipt, identification, storage, handling, the amount of material to be taken sampling, testing, and approval or re- from each container, shall be based jection of components and drug prod- upon appropriate criteria such as sta- uct containers and closures; such writ- tistical criteria for component varia- ten procedures shall be followed. bility, confidence levels, and degree of (b) Components and drug product precision desired, the past quality his- containers and closures shall at all tory of the supplier, and the quantity times be handled and stored in a man- needed for analysis and reserve where ner to prevent contamination. required by § 211.170. (c) Bagged or boxed components of (c) Samples shall be collected in ac- drug product containers, or closures cordance with the following proce- shall be stored off the floor and suit- dures:

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(1) The containers of components se- ducted on such containers/closures by lected shall be cleaned when necessary the manufacturer and provided that in a manner to prevent introduction of the manufacturer establishes the reli- contaminants into the component. ability of the supplier’s test results (2) The containers shall be opened, through appropriate validation of the sampled, and resealed in a manner de- supplier’s test results at appropriate signed to prevent contamination of intervals. their contents and contamination of (4) When appropriate, components other components, drug product con- shall be microscopically examined. tainers, or closures. (5) Each lot of a component, drug (3) Sterile equipment and aseptic product container, or closure that is sampling techniques shall be used when liable to contamination with filth, in- necessary. sect infestation, or other extraneous (4) If it is necessary to sample a com- adulterant shall be examined against ponent from the top, middle, and bottom of its container, such sample sub- established specifications for such con- divisions shall not be composited for tamination. testing. (6) Each lot of a component, drug (5) Sample containers shall be identi- product container, or closure with po- fied so that the following information tential for microbiological contamina- can be determined: name of the mate- tion that is objectionable in view of its rial sampled, the lot number, the con- intended use shall be subjected to tainer from which the sample was microbiological tests before use. taken, the date on which the sample (e) Any lot of components, drug prod- was taken, and the name of the person uct containers, or closures that meets who collected the sample. the appropriate written specifications (6) Containers from which samples of identity, strength, quality, and pu- have been taken shall be marked to rity and related tests under paragraph show that samples have been removed (d) of this section may be approved and from them. released for use. Any lot of such mate- (d) Samples shall be examined and rial that does not meet such specifica- tested as follows: tions shall be rejected. (1) At least one test shall be conducted to verify the identity of each [43 FR 45077, Sept. 29, 1978, as amended at 63 component of a drug product. Specific FR 14356, Mar. 25, 1998; 73 FR 51932, Sept. 8, 2008] identity tests, if they exist, shall be used. § 211.86 Use of approved components, (2) Each component shall be tested drug product containers, and clo- for conformity with all appropriate sures. written specifications for purity, strength, and quality. In lieu of such Components, drug product con- testing by the manufacturer, a report tainers, and closures approved for use of analysis may be accepted from the shall be rotated so that the oldest ap- supplier of a component, provided that proved stock is used first. Deviation at least one specific identity test is from this requirement is permitted if conducted on such component by the such deviation is temporary and appro- manufacturer, and provided that the priate. manufacturer establishes the reliability of the supplier’s analyses § 211.87 Retesting of approved compo- through appropriate validation of the nents, drug product containers, and closures. supplier’s test results at appropriate intervals. Components, drug product con- (3) Containers and closures shall be tainers, and closures shall be retested tested for conformity with all appro- or reexamined, as appropriate, for iden- priate written specifications. In lieu of tity, strength, quality, and purity and such testing by the manufacturer, a approved or rejected by the quality certificate of testing may be accepted control unit in accordance with § 211.84 from the supplier, provided that at as necessary, e.g., after storage for least a visual identification is con- long periods or after exposure to air,

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heat or other conditions that might ad- priate organizational units and re- versely affect the component, drug viewed and approved by the quality product container, or closure. control unit. (b) Written production and process § 211.89 Rejected components, drug control procedures shall be followed in product containers, and closures. the execution of the various production Rejected components, drug product and process control functions and shall containers, and closures shall be iden- be documented at the time of perform- tified and controlled under a quar- ance. Any deviation from the written antine system designed to prevent procedures shall be recorded and justi- their use in manufacturing or proc- fied. essing operations for which they are unsuitable. § 211.101 Charge-in of components. Written production and control pro- § 211.94 Drug product containers and cedures shall include the following, closures. which are designed to assure that the (a) Drug product containers and clo- drug products produced have the iden- sures shall not be reactive, additive, or tity, strength, quality, and purity they absorptive so as to alter the safety, purport or are represented to possess: identity, strength, quality, or purity of (a) The batch shall be formulated the drug beyond the official or estab- with the intent to provide not less than lished requirements. 100 percent of the labeled or established (b) Container closure systems shall amount of active ingredient. provide adequate protection against (b) Components for drug product foreseeable external factors in storage manufacturing shall be weighed, meas- and use that can cause deterioration or ured, or subdivided as appropriate. If a contamination of the drug product. component is removed from the origi- (c) Drug product containers and clo- nal container to another, the new con- sures shall be clean and, where indi- tainer shall be identified with the fol- cated by the nature of the drug, steri- lowing information: lized and processed to remove (1) Component name or item code; pyrogenic properties to assure that (2) Receiving or control number; they are suitable for their intended (3) Weight or measure in new con- use. Such depyrogenation processes tainer; shall be validated. (4) Batch for which component was (d) Standards or specifications, meth- dispensed, including its product name, ods of testing, and, where indicated, strength, and lot number. methods of cleaning, sterilizing, and (c) Weighing, measuring, or subdi- processing to remove pyrogenic prop- viding operations for components shall erties shall be written and followed for be adequately supervised. Each con- drug product containers and closures. tainer of component dispensed to man- [43 FR 45077, Sept. 29, 1978, as amended at 73 ufacturing shall be examined by a sec- FR 51932, Sept. 8, 2008] ond person to assure that: (1) The component was released by Subpart F—Production and the quality control unit; Process Controls (2) The weight or measure is correct as stated in the batch production § 211.100 Written procedures; devi- records; ations. (3) The containers are properly iden- (a) There shall be written procedures tified. If the weighing, measuring, or for production and process control de- subdividing operations are performed signed to assure that the drug products by automated equipment under § 211.68, have the identity, strength, quality, only one person is needed to assure and purity they purport or are rep- paragraphs (c)(1), (c)(2), and (c)(3) of resented to possess. Such procedures this section. shall include all requirements in this (d) Each component shall either be subpart. These written procedures, in- added to the batch by one person and cluding any changes, shall be drafted, verified by a second person or, if the reviewed, and approved by the appro- components are added by automated

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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 FR 51932, Sept. 8, 2008] (1) Tablet or capsule weight variation; § 211.103 Calculation of yield. (2) Disintegration time; Actual yields and percentages of the- (3) Adequacy of mixing to assure uni- oretical yield shall be determined at formity and homogeneity; the conclusion of each appropriate (4) Dissolution time and rate; phase of manufacturing, processing, (5) Clarity, completeness, or pH of so- packaging, or holding of the drug prod- lutions. uct. Such calculations shall either be (6) Bioburden testing. performed by one person and independ- (b) Valid in-process specifications for ently verified by a second person, or, if such characteristics shall be consistent the yield is calculated by automated with drug product final specifications equipment under § 211.68, be independ- and shall be derived from previous ac- ently verified by one person. ceptable process average and process variability estimates where possible [73 FR 51932, Sept. 8, 2008] and determined by the application of § 211.105 Equipment identification. suitable statistical procedures where 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 manufacture of each batch of a drug a quarantine system designed to pre- product. In cases where only one of a vent their use in manufacturing or particular type of equipment exists in processing operations for which they a manufacturing facility, the name of are unsuitable. the equipment may be used in lieu of a distinctive identification number or [43 FR 45077, Sept. 29, 1978, as amended at 73 code. FR 51932, Sept. 8, 2008]

§ 211.110 Sampling and testing of in- § 211.111 Time limitations on produc- process materials and drug prod- tion. ucts. When appropriate, time limits for the (a) To assure batch uniformity and completion of each phase of production integrity of drug products, written pro- shall be established to assure the qual- cedures shall be established and fol- ity of the drug product. Deviation from lowed that describe the in-process con- established time limits may be accept- trols, and tests, or examinations to be able if such deviation does not com- conducted on appropriate samples of promise the quality of the drug prod- in-process materials of each batch. uct. Such deviation shall be justified Such control procedures shall be estab- and documented. lished to monitor the output and to validate the performance of those man- § 211.113 Control of microbiological ufacturing processes that may be re- contamination. sponsible for causing variability in the (a) Appropriate written procedures, characteristics of in-process material designed to prevent objectionable and the drug product. Such control microorganisms in drug products not

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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, packaging lished and followed prescribing a sys- and labeling operations shall include tem for reprocessing batches that do one of the following special control not conform to standards or specifica- procedures: tions and the steps to be taken to in- (1) Dedication of labeling and pack- sure that the reprocessed batches will aging lines to each different strength conform with all established standards, of each different drug product; specifications, and characteristics. (2) Use of appropriate electronic or (b) Reprocessing shall not be per- electromechanical equipment to con- formed without the review and ap- duct a 100-percent examination for cor- proval of the quality control unit. rect labeling during or after completion of finishing operations; or Subpart G—Packaging and (3) Use of visual inspection 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 for hand- usage criteria. applied labeling. Such examination (a) There shall be written procedures shall be performed by one person and describing in sufficient detail the re- independently verified by a second per- ceipt, identification, storage, handling, son. sampling, examination, and/or testing (h) Printing devices on, or associated of labeling and packaging materials; with, manufacturing lines used to im- such written procedures shall be fol- print labeling upon the drug product lowed. Labeling and packaging mate- unit label or case shall be monitored to rials shall be representatively sampled, assure that all imprinting conforms to and examined or tested upon receipt the print specified in the batch produc- and before use in packaging or labeling tion record. of a drug product. [43 FR 45077, Sept. 29, 1978, as amended at 58 (b) Any labeling or packaging mate- FR 41353, Aug. 3, 1993] rials meeting appropriate written specifications may be approved and re- § 211.125 Labeling issuance. leased for use. Any labeling or pack- (a) Strict control shall be exercised aging materials that do not meet such over labeling issued for use in drug specifications shall be rejected to pre- product labeling operations. vent their use in operations for which (b) Labeling materials issued for a they are unsuitable. batch shall be carefully examined for (c) Records shall be maintained for identity and conformity to the labeling each shipment received of each dif- specified in the master or batch pro- ferent labeling and packaging material duction records. indicating receipt, examination or (c) Procedures shall be used to rec- testing, and whether accepted or re- oncile the quantities of labeling issued, jected. used, and returned, and shall require (d) Labels and other labeling mate- evaluation of discrepancies found be- rials for each different drug product, tween the quantity of drug product fin- strength, dosage form, or quantity of ished and the quantity of labeling

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issued when such discrepancies are out- (e) Inspection of the packaging and side narrow preset limits based on his- labeling facilities immediately before torical operating data. Such discrep- use to assure that all drug products ancies shall be investigated in accord- have been removed from previous oper- ance with § 211.192. Labeling reconcili- ations. Inspection shall also be made to ation is waived for cut or roll labeling assure that packaging and labeling ma- if a 100-percent examination for correct terials not suitable for subsequent op- labeling is performed in accordance erations have been removed. Results of with § 211.122(g)(2). inspection shall be documented in the (d) All excess labeling bearing lot or batch production records. control numbers shall be destroyed. [43 FR 45077, Sept. 29, 1978, as amended at 58 (e) Returned labeling shall be main- 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 of labeling; such written procedures the Federal Food, Drug, and Cosmetic shall be followed. Act (the act) to establish a uniform national requirement for tamper-evident [43 FR 45077, Sept. 29, 1978, as amended at 58 packaging of OTC drug products that FR 41354, Aug. 3, 1993] will improve the security of OTC drug packaging and help assure the safety § 211.130 Packaging and labeling operations. and effectiveness of OTC drug products. An OTC drug product (except a der- There shall be written procedures de- matological, dentifrice, insulin, or loz- signed to assure that correct labels, la- enge product) for retail sale that is not beling, and packaging materials are packaged in a tamper-resistant pack- used for drug products; such written age or that is not properly labeled procedures shall be followed. These under this section is adulterated under procedures shall incorporate the fol- section 501 of the act or misbranded lowing features: under section 502 of the act, or both. (a) Prevention of mixups and cross- (b) Requirements for tamper-evident contamination by physical or spatial package. (1) Each manufacturer and separation from operations on other packer who packages an OTC drug drug products. product (except a dermatological, den- (b) Identification and handling of tifrice, insulin, or lozenge product) for filled drug product containers that are retail sale shall package the product in set aside and held in unlabeled condi- a tamper-evident package, if this prod- tion for future labeling operations to uct is accessible to the public while preclude mislabeling of individual con- held for sale. A tamper-evident pack- tainers, lots, or portions of lots. Identi- age is one having one or more indica- fication need not be applied to each in- tors or barriers to entry which, if dividual container but shall be suffi- breached or missing, can reasonably be cient to determine name, strength, expected to provide visible evidence to quantity of contents, and lot or control consumers that tampering has oc- number of each container. curred. To reduce the likelihood of suc- (c) Identification of the drug product cessful tampering and to increase the with a lot or control number that per- likelihood that consumers will discover mits determination of the history of if a product has been tampered with, the manufacture and control of the the package is required to be distinc- batch. tive by design or by the use of one or (d) Examination of packaging and la- more indicators or barriers to entry beling materials for suitability and that employ an identifying char- correctness before packaging oper- acteristic (e.g., a pattern, name, reg- ations, and documentation of such ex- istered trademark, logo, or picture). amination in the batch production For purposes of this section, the term record. ‘‘distinctive by design’’ means the

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packaging cannot be duplicated with envelope as a ‘‘Request for Exemption commonly available materials or from the Tamper-Evident Packaging through commonly available processes. Rule.’’ The petition is required to con- A tamper-evident package may involve tain the following: an immediate-container and closure (1) The name of the drug product or, system or secondary-container or car- if the petition seeks an exemption for a ton system or any combination of sys- drug class, the name of the drug class, tems intended to provide a visual indi- and a list of products within that class. cation of package integrity. The tam- (2) The reasons that the drug prod- per-evident feature shall be designed to uct’s compliance with the tamper-evi- and shall remain intact when handled dent packaging or labeling require- in a reasonable manner during manu- ments of this section is unnecessary or facture, distribution, and retail dis- cannot be achieved. play. (3) A description of alternative steps (2) In addition to the tamper-evident that are available, or that the peti- packaging feature described in para- tioner has already taken, to reduce the graph (b)(1) of this section, any two- likelihood that the product or drug piece, hard gelatin capsule covered by class will be the subject of malicious this section must be sealed using an ac- adulteration. ceptable tamper-evident technology. (4) Other information justifying an (c) Labeling. (1) In order to alert con- exemption. sumers to the specific tamper-evident feature(s) used, each retail package of (e) OTC drug products subject to ap- an OTC drug product covered by this proved new drug applications. Holders of section (except ammonia inhalant in approved new drug applications for crushable glass ampules, containers of OTC drug products are required under compressed medical oxygen, or aerosol § 314.70 of this chapter to provide the products that depend upon the power of agency with notification of changes in a liquefied or compressed gas to expel packaging and labeling to comply with the contents from the container) is re- the requirements of this section. quired to bear a statement that: Changes in packaging and labeling re- (i) Identifies all tamper-evident fea- quired by this regulation may be made ture(s) and any capsule sealing tech- before FDA approval, as provided under nologies used to comply with para- § 314.70(c) of this chapter. Manufac- graph (b) of this section; turing changes by which capsules are (ii) Is prominently placed on the to be sealed require prior FDA approval package; and under § 314.70(b) of this chapter. (iii) Is so placed that it will be unaf- (f) Poison Prevention Packaging Act of fected if the tamper-evident feature of 1970. This section does not affect any the package is breached or missing. requirements for ‘‘special packaging’’ (2) If the tamper-evident feature cho- as defined under § 310.3(l) of this chap- sen to meet the requirements in para- ter and required under the Poison Pre- graph (b) of this section uses an identi- vention Packaging Act of 1970. fying characteristic, that char- (Approved by the Office of Management and acteristic is required to be referred to Budget under OMB control number 0910–0149) in the labeling statement. For example, the labeling statement on a bottle [54 FR 5228, Feb. 2, 1989, as amended at 63 FR with a shrink band could say ‘‘For your 59470, Nov. 4, 1998] protection, this bottle has an im- § 211.134 Drug product inspection. printed seal around the neck.’’ (d) Request for exemptions from pack- (a) Packaged and labeled products aging and labeling requirements. A man- shall be examined during finishing op- ufacturer or packer may request an ex- erations to provide assurance that con- emption from the packaging and label- tainers and packages in the lot have ing requirements of this section. A re- the correct label. quest for an exemption is required to (b) A representative sample of units be submitted in the form of a citizen shall be collected at the completion of petition under § 10.30 of this chapter finishing operations and shall be vis- and should be clearly identified on the ually examined for correct labeling.

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(c) Results of these examinations Subpart H—Holding and shall be recorded in the batch produc- Distribution tion or control records. § 211.142 Warehousing procedures. § 211.137 Expiration dating. Written procedures describing the (a) To assure that a drug product warehousing of drug products shall be meets applicable standards of identity, established and followed. They shall in- strength, quality, and purity at the clude: time of use, it shall bear an expiration (a) Quarantine of drug products be- date determined by appropriate sta- fore release by the quality control bility testing described in § 211.166. unit. (b) Expiration dates shall be related (b) Storage of drug products under to any storage conditions stated on the appropriate conditions of temperature, labeling, as determined by stability humidity, and light so that the iden- studies described in § 211.166. tity, strength, quality, and purity of (c) If the drug product is to be recon- the drug products are not affected. stituted at the time of dispensing, its § 211.150 Distribution procedures. labeling shall bear expiration information for both the reconstituted and Written procedures shall be established, and followed, describing the dis- unreconstituted drug products. tribution of drug products. They shall (d) Expiration dates shall appear on include: labeling in accordance with the re- (a) A procedure whereby the oldest quirements of § 201.17 of this chapter. approved stock of a drug product is dis- (e) Homeopathic drug products shall tributed first. Deviation from this re- be exempt from the requirements of quirement is permitted if such devi- this section. ation is temporary and appropriate. (f) Allergenic extracts that are la- (b) A system by which the distribu- beled ‘‘No U.S. Standard of Potency’’ tion of each lot of drug product can be are exempt from the requirements of readily determined to facilitate its re- this section. call if necessary. (g) New drug products for investigational use are exempt from the require- Subpart I—Laboratory Controls ments of this section, provided that they meet appropriate standards or § 211.160 General requirements. specifications as demonstrated by sta- (a) The establishment of any speci- bility studies during their use in clin- fications, standards, sampling plans, ical investigations. Where new drug test procedures, or other laboratory products for investigational use are to control mechanisms required by this be reconstituted at the time of dis- subpart, including any change in such pensing, their labeling shall bear expi- specifications, standards, sampling ration information for the reconsti- plans, test procedures, or other labora- tuted drug product. tory control mechanisms, shall be (h) Pending consideration of a pro- drafted by the appropriate organizational unit and reviewed and approved posed exemption, published in the FED- by the quality control unit. The re- ERAL REGISTER of September 29, 1978, quirements in this subpart shall be fol- the requirements in this section shall lowed and shall be documented at the not be enforced for human OTC drug time of performance. Any deviation products if their labeling does not bear from the written specifications, stand- dosage limitations and they are stable ards, sampling plans, test procedures, for at least 3 years as supported by ap- or other laboratory control mecha- propriate stability data. nisms shall be recorded and justified. [43 FR 45077, Sept. 29, 1978, as amended at 46 (b) Laboratory controls shall include FR 56412, Nov. 17, 1981; 60 FR 4091, Jan. 20, the establishment of scientifically 1995] sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that

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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 procedures shall also require appro- quality control unit shall be adequate priate retesting of any component, to assure that batches of drug products drug product container, or closure that meet each appropriate specification is subject to deterioration. and appropriate statistical quality con- (2) Determination of conformance to trol criteria as a condition for their ap- written specifications and a descrip- proval and release. The statistical tion of sampling and testing procedures quality control criteria shall include for in-process materials. Such samples appropriate acceptance levels and/or shall be representative and properly appropriate rejection levels. identified. (e) The accuracy, sensitivity, speci- (3) Determination of conformance to ficity, and reproducibility of test written descriptions of sampling proce- methods employed by the firm shall be dures and appropriate specifications established and documented. Such vali- for drug products. Such samples shall dation and documentation may be ac- be representative and properly identi- complished in accordance with fied. § 211.194(a)(2). (4) The calibration of instruments, (f) Drug products failing to meet es- apparatus, gauges, and recording de- tablished standards or specifications vices at suitable intervals in accord- and any other relevant quality control ance with an established written pro- criteria shall be rejected. Reprocessing gram containing specific directions, may be performed. Prior to acceptance schedules, limits for accuracy and pre- and use, reprocessed material must cision, and provisions for remedial ac- meet appropriate standards, specification in the event accuracy and/or preci- tions, and any other relevant critieria. sion limits are not met. Instruments, apparatus, gauges, and recording de- § 211.166 Stability testing. vices not meeting established specifica- (a) There shall be a written testing tions shall not be used. program designed to assess the sta- [43 FR 45077, Sept. 29, 1978, as amended at 73 bility characteristics of drug products. FR 51932, Sept. 8, 2008] The results of such stability testing shall be used in determining appro- § 211.165 Testing and release for dis- priate storage conditions and expira- tribution. tion dates. The written program shall (a) For each batch of drug product, be followed and shall include: there shall be appropriate laboratory (1) Sample size and test intervals determination of satisfactory conform- based on statistical criteria for each ance to final specifications for the drug attribute examined to assure valid esti- product, including the identity and mates of stability; strength of each active ingredient, (2) Storage conditions for samples re- prior to release. Where sterility and/or tained for testing; pyrogen testing are conducted on spe- (3) Reliable, meaningful, and specific cific batches of shortlived radio- test methods;

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(4) Testing of the drug product in the (b) For each batch of ophthalmic same container-closure system as that ointment, there shall be appropriate in which the drug product is marketed; testing to determine conformance to (5) Testing of drug products for re- specifications regarding the presence of constitution at the time of dispensing foreign particles and harsh or abrasive (as directed in the labeling) as well as substances. The test procedures shall after they are reconstituted. be in writing and shall be followed. (b) An adequate number of batches of (c) For each batch of controlled-re- each drug product shall be tested to de- lease dosage form, there shall be appro- termine an appropriate expiration date priate laboratory testing to determine and a record of such data shall be conformance to the specifications for maintained. Accelerated studies, com- the rate of release of each active ingre- bined with basic stability information dient. The test procedures shall be in on the components, drug products, and writing and shall be followed. container-closure system, may be used to support tentative expiration dates § 211.170 Reserve samples. provided full shelf life studies are not (a) An appropriately identified re- available and are being conducted. serve sample that is representative of Where data from accelerated studies each lot in each shipment of each ac- are used to project a tentative expira- tive ingredient shall be retained. The tion date that is beyond a date sup- reserve sample consists of at least ported by actual shelf life studies, twice the quantity necessary for all there must be stability studies con- tests required to determine whether ducted, including drug product testing the active ingredient meets its estab- at appropriate intervals, until the ten- lished specifications, except for ste- tative expiration date is verified or the rility and pyrogen testing. The reten- appropriate expiration date deter- tion time is as follows: mined. (1) For an active ingredient in a drug (c) For homeopathic drug products, product other than those described in the requirements of this section are as paragraphs (a) (2) and (3) of this sec- follows: tion, the reserve sample shall be re- (1) There shall be a written assess- tained for 1 year after the expiration ment of stability based at least on test- date of the last lot of the drug product ing or examination of the drug product containing the active ingredient. for compatibility of the ingredients, (2) For an active ingredient in a ra- and based on marketing experience dioactive drug product, except for non- with the drug product to indicate that radioactive reagent kits, the reserve there is no degradation of the product sample shall be retained for: for the normal or expected period of (i) Three months after the expiration use. date of the last lot of the drug product (2) Evaluation of stability shall be containing the active ingredient if the based on the same container-closure expiration dating period of the drug system in which the drug product is product is 30 days or less; or being marketed. (ii) Six months after the expiration (d) Allergenic extracts that are la- date of the last lot of the drug product beled ‘‘No U.S. Standard of Potency’’ containing the active ingredient if the are exempt from the requirements of expiration dating period of the drug this section. product is more than 30 days. [43 FR 45077, Sept. 29, 1978, as amended at 46 (3) For an active ingredient in an FR 56412, Nov. 17, 1981] OTC drug product that is exempt from bearing an expiration date under § 211.167 Special testing requirements. § 211.137, the reserve sample shall be re- (a) For each batch of drug product tained for 3 years after distribution of purporting to be sterile and/or pyrogen- the last lot of the drug product con- free, there shall be appropriate labora- taining the active ingredient. tory testing to determine conformance (b) An appropriately identified re- to such requirements. The test proce- serve sample that is representative of dures shall be in writing and shall be each lot or batch of drug product shall followed. be retained and stored under conditions

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consistent with product labeling. The suitability for their intended use. They reserve sample shall be stored in the shall be identified, and adequate same immediate container-closure sys- records shall be maintained showing tem in which the drug product is mar- the history of their use. keted or in one that has essentially the same characteristics. The reserve sam- § 211.176 Penicillin contamination. ple consists of at least twice the quan- If a reasonable possibility exists that tity necessary to perform all the re- a non-penicillin drug product has been quired tests, except those for sterility and pyrogens. Except for those for drug exposed to cross-contamination with products described in paragraph (b)(2) penicillin, the non-penicillin drug prod- of this section, reserve samples from uct shall be tested for the presence of representative sample lots or batches penicillin. Such drug product shall not selected by acceptable statistical pro- be marketed if detectable levels are cedures shall be examined visually at found when tested according to proce- least once a year for evidence of dete- dures specified in ‘Procedures for De- rioration unless visual examination tecting and Measuring Penicillin Con- would affect the integrity of the re- tamination in Drugs,’ which is incor- serve sample. Any evidence of reserve porated by reference. Copies are avail- sample deterioration shall be inves- able from the Division of Research and tigated in accordance with § 211.192. Testing (HFD–470), Center for Drug The results of the examination shall be Evaluation and Research, Food and recorded and maintained with other Drug Administration, 5100 Paint stability data on the drug product. Re- Branch Pkwy., College Park, MD 20740, serve samples of compressed medical or available for inspection at the Na- gases need not be retained. The reten- tional Archives and Records Adminis- tion time is as follows: tration (NARA). For information on (1) For a drug product other than those described in paragraphs (b) (2) the availability of this material at and (3) of this section, the reserve sam- NARA, call 202–741–6030, or go to: http:// ple shall be retained for 1 year after www.archives.gov/federallregister/ the expiration date of the drug prod- codeloflfederallregulations/ uct. ibrllocations.html. (2) For a radioactive drug product, [43 FR 45077, Sept. 29, 1978, as amended at 47 except for nonradioactive reagent kits, FR 9396, Mar. 5, 1982; 50 FR 8996, Mar. 6, 1985; the reserve sample shall be retained 55 FR 11577, Mar. 29, 1990; 66 FR 56035, Nov. 6, for: 2001; 69 FR 18803, Apr. 9, 2004] (i) Three months after the expiration date of the drug product if the expira- Subpart J—Records and Reports tion dating period of the drug product is 30 days or less; or § 211.180 General requirements. (ii) Six months after the expiration date of the drug product if the expira- (a) Any production, control, or dis- tion dating period of the drug product tribution record that is required to be is more than 30 days. maintained in compliance with this (3) For an OTC drug product that is part and is specifically associated with exempt for bearing an expiration date a batch of a drug product shall be re- under § 211.137, the reserve sample must tained for at least 1 year after the expi- be retained for 3 years after the lot or ration date of the batch or, in the case batch of drug product is distributed. of certain OTC drug products lacking [48 FR 13025, Mar. 29, 1983, as amended at 60 expiration dating because they meet FR 4091, Jan. 20, 1995] the criteria for exemption under § 211.137, 3 years after distribution of § 211.173 Laboratory animals. the batch. Animals used in testing components, (b) Records shall be maintained for in-process materials, or drug products all components, drug product con- for compliance with established speci- tainers, closures, and labeling for at fications shall be maintained and con- least 1 year after the expiration date trolled in a manner that assures their or, in the case of certain OTC drug

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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 distribution of the last lot of drug product [43 FR 45077, Sept. 29, 1978, as amended at 60 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 readily available for authorized inspec- A written record of major equipment tion during the retention period at the cleaning, maintenance (except routine establishment where the activities de- maintenance such as lubrication and scribed in such records occurred. These adjustments), and use shall be included records or copies thereof shall be sub- in individual equipment logs that show ject to photocopying or other means of the date, time, product, and lot number reproduction as part of such inspec- of each batch processed. If equipment tion. Records that can be immediately is dedicated to manufacture of one retrieved from another location by product, then individual equipment computer or other electronic means logs are not required, provided that shall be considered as meeting the re- lots or batches of such product follow quirements of this paragraph. in numerical order and are manufac- (d) Records required under this part tured in numerical sequence. In cases may be retained either as original where dedicated equipment is em- records or as true copies such as photo- ployed, the records of cleaning, main- copies, microfilm, microfiche, or other tenance, and use shall be part of the accurate reproductions of the original batch record. The persons performing records. Where reduction techniques, and double-checking the cleaning and such as microfilming, are used, suit- maintenance (or, if the cleaning and able reader and photocopying equip- maintenance is performed using auto- ment shall be readily available. mated equipment under § 211.68, just (e) Written records required by this the person verifying the cleaning and part shall be maintained so that data maintenance done by the automated therein can be used for evaluating, at least annually, the quality standards of equipment) shall date and sign or ini- each drug product to determine the tial the log indicating that the work need for changes in drug product speci- was performed. Entries in the log shall fications or manufacturing or control be in chronological order. procedures. Written procedures shall be [73 FR 51933, Sept. 8, 2008] established and followed for such evaluations and shall include provisions § 211.184 Component, drug product for: container, closure, and labeling (1) A review of a representative num- records. ber of batches, whether approved or re- These records shall include the fol- jected, and, where applicable, records lowing: associated with the batch. (a) The identity and quantity of each (2) A review of complaints, recalls, shipment of each lot of components, returned or salvaged drug products, drug product containers, closures, and and investigations conducted under § 211.192 for each drug product. labeling; the name of the supplier; the (f) Procedures shall be established to supplier’s lot number(s) if known; the assure that the responsible officials of receiving code as specified in § 211.80; the firm, if they are not personally in- and the date of receipt. The name and volved in or immediately aware of such location of the prime manufacturer, if actions, are notified in writing of any different from the supplier, shall be investigations conducted under listed if known. §§ 211.198, 211.204, or 211.208 of these reg- (b) The results of any test or exam- ulations, any recalls, reports of ination performed (including those per- inspectional observations issued by the formed as required by § 211.82(a), Food and Drug Administration, or any § 211.84(d), or § 211.122(a)) and the con- regulatory actions relating to good clusions derived therefrom.

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(c) An individual inventory record of (5) A statement concerning any cal- each component, drug product con- culated excess of component; tainer, and closure and, for each com- (6) A statement of theoretical weight ponent, a reconciliation of the use of or measure at appropriate phases of each lot of such component. The inven- processing; tory record shall contain sufficient in- (7) A statement of theoretical yield, formation to allow determination of including the maximum and minimum any batch or lot of drug product associ- percentages of theoretical yield beyond ated with the use of each component, which investigation according to drug product container, and closure. § 211.192 is required; (d) Documentation of the examina- (8) A description of the drug product tion and review of labels and labeling containers, closures, and packaging for conformity with established speci- materials, including a specimen or fications in accord with §§ 211.122(c) and copy of each label and all other label- 211.130(c). ing signed and dated by the person or (e) The disposition of rejected compo- persons responsible for approval of nents, drug product containers, clo- such labeling; sure, and labeling. (9) Complete manufacturing and control instructions, sampling and testing § 211.186 Master production and con- procedures, specifications, special no- trol records. tations, and precautions to be followed. (a) To assure uniformity from batch § 211.188 Batch production and control to batch, master production and con- records. trol records for each drug product, in- Batch production and control records cluding each batch size thereof, shall shall be prepared for each batch of drug be prepared, dated, and signed (full sig- product produced and shall include nature, handwritten) by one person and complete information relating to the independently checked, dated, and production and control of each batch. signed by a second person. The prepara- These records shall include: tion of master production and control (a) An accurate reproduction of the records shall be described in a written appropriate master production or con- procedure and such written procedure trol record, checked for accuracy, shall be followed. dated, and signed; (b) Master production and control (b) Documentation that each signifi- records shall include: cant step in the manufacture, proc- (1) The name and strength of the essing, packing, or holding of the batch product and a description of the dosage was accomplished, including: form; (1) Dates; (2) The name and weight or measure (2) Identity of individual major of each active ingredient per dosage equipment and lines used; unit or per unit of weight or measure (3) Specific identification of each of the drug product, and a statement of batch of component or in-process mate- the total weight or measure of any dos- rial used; age unit; (4) Weights and measures of compo- (3) A complete list of components nents used in the course of processing; designated by names or codes suffi- (5) In-process and laboratory control ciently specific to indicate any special results; quality characteristic; (6) Inspection of the packaging and (4) An accurate statement of the labeling area before and after use; weight or measure of each component, (7) A statement of the actual yield using the same weight system (metric, and a statement of the percentage of avoirdupois, or apothecary) for each theoretical yield at appropriate phases component. Reasonable variations may of processing; be permitted, however, in the amount (8) Complete labeling control records, of components necessary for the prepa- including specimens or copies of all laration in the dosage form, provided beling used; they are justified in the master produc- (9) Description of drug product con- tion and control records; tainers and closures;

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(10) Any sampling performed; ment shall indicate the location of (11) Identification of the persons per- data that establish that the methods forming and directly supervising or used in the testing of the sample meet checking each significant step in the proper standards of accuracy and reli- operation, or if a significant step in the ability as applied to the product tested. operation is performed by automated (If the method employed is in the cur- equipment under § 211.68, the identifica- rent revision of the United States tion of the person checking the signifi- Pharmacopeia, National Formulary, cant step performed by the automated 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. referenced method is not modified, a statement indicating the method and [43 FR 45077, Sept. 29, 1978, as amended at 73 reference will suffice). The suitability FR 51933, Sept. 8, 2008] of all testing methods used shall be § 211.192 Production record review. verified under actual conditions of use. (3) A statement of the weight or All drug product production and con- measure of sample used for each test, trol records, including those for pack- where appropriate. aging and labeling, shall be reviewed and approved by the quality control (4) A complete record of all data se- unit to determine compliance with all cured in the course of each test, includ- established, approved written proce- ing all graphs, charts, and spectra from dures before a batch is released or dis- laboratory instrumentation, properly tributed. Any unexplained discrepancy identified to show the specific compo- (including a percentage of theoretical nent, drug product container, closure, yield exceeding the maximum or min- in-process material, or drug product, imum percentages established in mas- and lot tested. ter production and control records) or (5) A record of all calculations per- the failure of a batch or any of its com- formed in connection with the test, in- ponents to meet any of its specifica- cluding units of measure, conversion tions shall be thoroughly investigated, factors, and equivalency factors. whether or not the batch has already (6) A statement of the results of tests been distributed. The investigation and how the results compare with es- shall extend to other batches of the tablished standards of identity, same drug product and other drug strength, quality, and purity for the products that may have been associ- component, drug product container, ated with the specific failure or disclosure, in-process material, or drug crepancy. A written record of the in- product tested. vestigation shall be made and shall in- (7) The initials or signature of the clude the conclusions and followup. person who performs each test and the § 211.194 Laboratory records. date(s) the tests were performed. (a) Laboratory records shall include (8) The initials or signature of a sec- complete data derived from all tests ond person showing that the original necessary to assure compliance with records have been reviewed for accu- established specifications and stand- racy, completeness, and compliance ards, including examinations and as- with established standards. says, as follows: (b) Complete records shall be main- (1) A description of the sample retained of any modification of an estab- ceived for testing with identification of lished method employed in testing. source (that is, location from where Such records shall include the reason sample was obtained), quantity, lot for the modification and data to verify number or other distinctive code, date that the modification produced results sample was taken, and date sample was received for testing. 1 Copies may be obtained from: AOAC (2) A statement of each method used INTERNATIONAL, 481 North Frederick Ave., in the testing of the sample. The state- suite 500, Gaithersburg, MD 20877.

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that are at least as accurate and reli- complaints shall be maintained at the able for the material being tested as establishment where the drug product the established method. involved was manufactured, processed, (c) Complete records shall be main- or packed, or such file may be maintained of any testing and standardiza- tained at another facility if the written tion of laboratory reference standards, records in such files are readily avail- reagents, and standard solutions. able for inspection at that other facil- (d) Complete records shall be main- ity. Written records involving a drug tained of the periodic calibration of product shall be maintained until at laboratory instruments, apparatus, least 1 year after the expiration date of gauges, and recording devices required the drug product, or 1 year after the by § 211.160(b)(4). date that the complaint was received, (e) Complete records shall be main- whichever is longer. In the case of cer- tained of all stability testing pertain OTC drug products lacking expira- formed in accordance with § 211.166. tion dating because they meet the criteria for exemption under § 211.137, such [43 FR 45077, Sept. 29, 1978, as amended at 55 written records shall be maintained for FR 11577, Mar. 29, 1990; 65 FR 18889, Apr. 10, 3 years after distribution of the drug 2000; 70 FR 40880, July 15, 2005; 70 FR 67651, Nov. 8, 2005] product. (1) The written record shall include § 211.196 Distribution records. the following information, where known: the name and strength of the Distribution records shall contain drug product, lot number, name of the name and strength of the product complainant, nature of complaint, and and description of the dosage form, reply to complainant. name and address of the consignee, (2) Where an investigation under date and quantity shipped, and lot or § 211.192 is conducted, the written control number of the drug product. record shall include the findings of the For compressed medical gas products, investigation and followup. The record distribution records are not required to or copy of the record of the investiga- contain lot or control numbers. tion shall be maintained at the estab- (Approved by the Office of Management and lishment where the investigation oc- Budget under control number 0910–0139) curred in accordance with § 211.180(c). [49 FR 9865, Mar. 16, 1984] (3) Where an investigation under § 211.192 is not conducted, the written § 211.198 Complaint files. record shall include the reason that an (a) Written procedures describing the investigation was found not to be necessary and the name of the responsible handling of all written and oral com- person making such a determination. plaints regarding a drug product shall be established and followed. Such pro- [43 FR 45077, Sept. 29, 1978, as amended at 51 cedures shall include provisions for re- FR 24479, July 3, 1986; 68 FR 15364, Mar. 31, view by the quality control unit, of any 2003] complaint involving the possible failure of a drug product to meet any of its Subpart K—Returned and specifications and, for such drug prod- Salvaged Drug Products ucts, a determination as to the need for an investigation in accordance with § 211.204 Returned drug products. § 211.192. Such procedures shall include Returned drug products shall be iden- provisions for review to determine tified as such and held. If the condi- whether the complaint represents a se- tions under which returned drug prod- rious and unexpected adverse drug ex- ucts have been held, stored, or shipped perience which is required to be re- before or during their return, or if the ported to the Food and Drug Adminis- condition of the drug product, its con- tration in accordance with §§ 310.305 tainer, carton, or labeling, as a result and 514.80 of this chapter. of storage or shipping, casts doubt on (b) A written record of each com- the safety, identity, strength, quality plaint shall be maintained in a file des- or purity of the drug product, the re- ignated for drug product complaints. turned drug product shall be destroyed The file regarding such drug product unless examination, testing, or other

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investigations prove the drug product PART 212—CURRENT GOOD MAN- meets appropriate standards of safety, UFACTURING PRACTICE FOR identity, strength, quality, or purity. A POSITRON EMISSION TOMOG- drug product may be reprocessed provided the subsequent drug product RAPHY DRUGS meets appropriate standards, specifica- Subpart A—General Provisions tions, and characteristics. Records of returned drug products shall be main- Sec. tained and shall include the name and 212.1 What are the meanings of the tech- label potency of the drug product dos- nical terms used in these regulations? age form, lot number (or control num- 212.2 What is current good manufacturing ber or batch number), reason for the re- practice for PET drugs? turn, quantity returned, date of dis- 212.5 To what drugs do the regulations in position, and ultimate disposition of this part apply? the returned drug product. If the rea- Subpart B—Personnel and Resources son for a drug product being returned implicates associated batches, an ap- 212.10 What personnel and resources must I propriate investigation shall be con- have? ducted in accordance with the requirements of § 211.192. Procedures for the Subpart C—Quality Assurance holding, testing, and reprocessing of re- 212.20 What activities must I perform to en- turned drug products shall be in writ- sure drug quality? ing and shall be followed. Subpart D—Facilities and Equipment § 211.208 Drug product salvaging. 212.30 What requirements must my facili- Drug products that have been sub- ties and equipment meet? jected to improper storage conditions including extremes in temperature, hu- Subpart E—Control of Components, midity, smoke, fumes, pressure, age, or Containers, and Closures radiation due to natural disasters, 212.40 How must I control the components I fires, accidents, or equipment failures use to produce PET drugs and the con- shall not be salvaged and returned to tainers and closures I package them in? the marketplace. Whenever there is a question whether drug products have Subpart F—Production and Process been subjected to such conditions, sal- Controls vaging operations may be conducted only if there is (a) evidence from lab- 212.50 What production and process controls must I have? oratory tests and assays (including animal feeding studies where applicable) Subpart G—Laboratory Controls that the drug products meet all applicable standards of identity, strength, 212.60 What requirements apply to the lab- quality, and purity and (b) evidence oratories where I test components, in- from inspection of the premises that process materials, and finished PET drug the drug products and their associated products? 212.61 What must I do to ensure the sta- packaging were not subjected to im- bility of my PET drug products through proper storage conditions as a result of expiry? the disaster or accident. Organoleptic examinations shall be acceptable only Subpart H—Finished Drug Product Controls as supplemental evidence that the drug and Acceptance Criteria products meet appropriate standards of identity, strength, quality, and purity. 212.70 What controls and acceptance criteria must I have for my finished PET Records including name, lot number, drug products? and disposition shall be maintained for 212.71 What actions must I take if a batch drug products subject to this section. of PET drug product does not conform to specifications?

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Subpart I—Packaging and Labeling single production order during the same cycle of production. 212.80 What are the requirements associated Batch production and control record with labeling and packaging PET drug products? means a unique record that references an accepted master production and Subpart J—Distribution control record and documents specific details on production, labeling, and 212.90 What actions must I take to control quality control for a single batch of a the distribution of PET drug products? PET drug. Component means any ingredient in- Subpart K—Complaint Handling tended for use in the production of a 212.100 What do I do if I receive a complaint PET drug, including any ingredients about a PET drug product produced at that may not appear in the final PET my facility? drug product. Conditional final release means a final Subpart L—Records release made prior to completion of a 212.110 How must I maintain records of my required finished-product test because production of PET drugs? of a malfunction involving analytical equipment. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371, 374; Sec. 121, Pub. L. 105–115, 111 Stat. 2296. Final release means the authoritative decision by a responsible person in a SOURCE: 74 FR 65431, Dec. 10, 2009, unless PET production facility to permit the otherwise noted. use of a batch of a PET drug in hu- EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. mans. 10, 2009, Part 212 was added, effective Dec. 12, Inactive ingredient means any in- 2011. tended component of the PET drug other than the active pharmaceutical Subpart A—General Provisions ingredient. In-process material means any mate- § 212.1 What are the meanings of the rial fabricated, compounded, blended, technical terms used in these regu- or derived by chemical reaction that is lations? produced for, and is used in, the prepa- The following definitions apply to ration of a PET drug. words and phrases as they are used in Lot means a batch, or a specifically this part. Other definitions of these identified portion of a batch, having words may apply when they are used in uniform character and quality within other parts of this chapter. specified limits. In the case of a PET Acceptance criteria means numerical drug produced by continuous process, a limits, ranges, or other criteria for lot is a specifically identified amount tests that are used for or in making a produced in a unit of time or quantity decision to accept or reject a unit, lot, in a manner that ensures its having or batch of a PET drug product. uniform character and quality within Act means the Federal Food, Drug, specified limits. and Cosmetic Act, as amended (21 Lot number, control number, or batch U.S.C. 321 et seq.). number means any distinctive combina- Active pharmaceutical ingredient tion of letters, numbers, or symbols means a substance that is intended for from which the complete history of the incorporation into a finished PET drug production, processing, packing, hold- product and is intended to furnish ing, and distribution of a batch or lot pharmacological activity or other di- of a PET drug can be determined. rect effect in the diagnosis or moni- Master production and control record toring of a disease or a manifestation means a compilation of instructions of a disease in humans, but does not in- containing the procedures and speci- clude intermediates used in the syn- fications for the production of a PET thesis of such substance. drug. Batch means a specific quantity of Material release means the authori- PET drug intended to have uniform tative decision by a responsible person character and quality, within specified in a PET production facility to permit limits, that is produced according to a the use of a component, container and

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closure, in-process material, packaging product, component, container-closure material, or labeling in the production system, in-process material, or other of a PET drug. material used in PET drug production, PET means positron emission tomog- when tested according to the described raphy. analytical procedures, meets the listed PET drug means a radioactive drug acceptance criteria. that exhibits spontaneous disintegra- Strength means the concentration of tion of unstable nuclei by the emission the active pharmaceutical ingredient of positrons and is used for providing (radioactivity amount per volume or dual photon positron emission tomo- weight at the time of calibration). graphic diagnostic images. The defini- Sub-batch means a quantity of PET tion includes any nonradioactive rea- drug having uniform character and gent, reagent kit, ingredient, nuclide quality, within specified limits, that is generator, accelerator, target mate- produced during one succession of mul- rial, electronic synthesizer, or other tiple irradiations, using a given syn- apparatus or computer program to be thesis and/or purification operation. used in the preparation of a PET drug. Verification means confirmation that ‘‘PET drug’’ includes a ‘‘PET drug an established method, process, or sys- product’’ as defined in this section. tem meets predetermined acceptance PET drug product means a finished criteria. dosage form of a PET drug, whether or not in association with one or more § 212.2 What is current good manufac- other ingredients. turing practice for PET drugs? PET drug production facility means a Current good manufacturing practice facility that is engaged in the produc- for PET drugs is the minimum require- tion of a PET drug. ments for the methods to be used in, Production means the manufacturing, and the facilities and controls used for, compounding, processing, packaging, the production, quality assurance, labeling, reprocessing, repacking, re- holding, or distribution of PET drugs labeling, and testing of a PET drug. intended for human use. Current good Quality assurance means a system for manufacturing practice is intended to ensuring the quality of active ingredi- ensure that each PET drug meets the ents, PET drugs, intermediates, compo- requirements of the act as to safety nents that yield an active pharma- and has the identity and strength, and ceutical ingredient, analytical sup- meets the quality and purity charac- plies, and other components, including teristics, that it is supposed to have. container-closure systems and in-process materials, through procedures, § 212.5 To what drugs do the regula- tests, analytical methods, and accept- tions in this part apply? ance criteria. (a) Application solely to PET drugs. Receiving facility means any hospital, The regulations in this part apply only institution, nuclear pharmacy, imaging to the production, quality assurance, facility, or other entity or part of an holding, and distribution of PET drugs. entity that accepts a PET drug product Any human drug that does not meet that has been given final release, but the definition of a PET drug must be does not include a common or contract manufactured in accordance with the carrier that transports a PET drug current good manufacturing practice product from a PET production facility requirements in parts 210 and 211 of to a receiving facility. this chapter. Specifications means the tests, analyt- (b) Investigational and research PET ical procedures, and appropriate ac- drugs. For investigational PET drugs ceptance criteria to which a PET drug, for human use produced under an in- PET drug product, component, con- vestigational new drug application in tainer-closure system, in-process mate- accordance with part 312 of this chap- rial, or other material used in PET ter, and PET drugs produced with the drug production must conform to be approval of a Radioactive Drug Re- considered acceptable for its intended search Committee in accordance with use. Conformance to specifications part 361 of this chapter, the require- means that a PET drug, PET drug ment under the act to follow current

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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 brary, 10903 New Hampshire Ave., Sil- have occurred, or a production batch or ver Spring, MD, 20993–0002, 301–796–3504, any component of the batch fails to or at the National Archives and meet any of its specifications, you Records Administration (NARA). For must determine the need for an inves- information on the availability of this tigation, conduct investigations when material at NARA, call 202–741–6030, or necessary, and take appropriate correc- go to http://www.archives.gov/ tive actions. federallregister/ (e) Quality assurance. You must es- codeloflfederallregulations/ tablish and follow written quality as- ibrllocations.html. surance procedures.

Subpart B—Personnel and Subpart D—Facilities and Resources Equipment § 212.10 What personnel and resources § 212.30 What requirements must my must I have? facilities and equipment meet? You must have a sufficient number of (a) Facilities. You must provide ade- personnel with the necessary edu- quate facilities to ensure the orderly cation, background, training, and expe- handling of materials and equipment, rience to perform their assigned func- the prevention of mix-ups, and the pre- tions. You must have adequate re- vention of contamination of equipment sources, including facilities and equip- or product by substances, personnel, or ment, to enable your personnel to per- environmental conditions that could form their functions. reasonably be expected to have an adverse effect on product quality. Subpart C—Quality Assurance (b) Equipment procedures. You must implement procedures to ensure that § 212.20 What activities must I perform all equipment that could reasonably be to ensure drug quality? expected to adversely affect the iden- (a) Production operations. You must tity, strength, quality, or purity of a oversee production operations to en- PET drug, or give erroneous or invalid sure that each PET drug meets the re- test results when improperly used or quirements of the act as to safety and maintained, is clean, suitable for its in- has the identity and strength, and tended purposes, properly installed, meets the quality and purity charac- maintained, and capable of repeatedly teristics, that it is supposed to have. producing valid results. You must doc- (b) Materials. You must examine and ument your activities in accordance approve or reject components, con- with these procedures.

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(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 the containers and closures I and each inactive ingredient. For any package them in? other component, such as a solvent or (a) Written procedures. You must es- reagent, that is not the subject of fin- tablish, maintain, and follow written ished-product testing, you must deter- procedures describing the receipt, mine that each lot complies with writ- login, identification, storage, handling, ten specifications by examining a cer- testing, and acceptance and/or rejec- tificate of analysis provided by the sup- tion of components and drug product plier; if you use such a component to containers and closures. The proce- prepare an inactive ingredient on site, dures must be adequate to ensure that you must perform an identity test on the components, containers, and clo- the components used to make the inac- sures are suitable for their intended tive ingredient before the components use. are released for use. However, if you (b) Written specifications. You must use as an inactive ingredient a product establish appropriate written specifica- that is approved under section 505 of tions for the identity, quality, and pu- the act (21 U.S.C. 355) and is marketed rity of components and for the identity as a finished drug product intended for and quality of drug product containers intravenous administration, you need and closures. not perform a specific identity test on (c) Examination and testing. Upon re- that ingredient. ceipt, each lot of components and con- (2) You must examine a representa- tainers and closures must be uniquely identified and tested or examined to tive sample of each lot of containers determine whether the lot complies and closures for conformity to its writ- with your specifications. You must not ten specifications. You must perform use in PET drug production any lot at least a visual identification of each that does not meet its specifications, lot of containers and closures. including any expiration date if appli- (d) Handling and storage. You must cable, or that has not yet received its handle and store components, con- material release. Any incoming lot tainers, and closures in a manner that must be appropriately designated as prevents contamination, mix-ups, and quarantined, accepted, or rejected. You deterioration and ensures that they are must use a reliable supplier as a source and remain suitable for their intended of each lot of each component, con- use. tainer, and closure. (e) Records. You must keep a record (1)(i) If you conduct finished-product for each shipment of each lot of compo- testing of a PET drug product that in- nents, containers, and closures that cludes testing to ensure that the cor- you receive. The record must include rect components have been used, you the identity and quantity of each ship- must determine that each lot of incom- ment, the supplier’s name and lot num- ing components used in that PET drug ber, the date of receipt, the results of product complies with written speci- any testing performed, the disposition fications by examining a certificate of analysis provided by the supplier. You of rejected material, and the expiration are not required to perform a specific date (where applicable).

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Subpart F—Production and (8) A description of the PET drug Process Controls product containers, closures, and packaging materials, including a specimen § 212.50 What production and process or copy of each label and all other la- controls must I have? beling. You must have adequate production (c) Batch production and control and process controls to ensure the con- records. Each time a batch of a PET sistent production of a PET drug that drug is produced, a unique batch pro- meets the applicable standards of iden- duction and control record must be cre- tity, strength, quality, and purity. ated. The batch production record (a) Written control procedures. You must include the following informa- must have written production and tion: process control procedures to ensure (1) Name and strength of the PET and document that all key process pa- drug; rameters are controlled and that any deviations from the procedures are jus- (2) Identification number or other tified. unique identifier of the specific batch (b) Master production and control that was produced; records. You must have master produc- (3) The name and radioactivity or tion and control records that document other measure of each active pharma- all steps in the PET drug production ceutical ingredient and each inactive process. The master production and ingredient per batch or per unit of ra- control records must include the fol- dioactivity or other measurement of lowing information: the drug product; (1) The name and strength of the PET (4) Each major production step (ob- drug; tained from the approved appropriate (2) If applicable, the name and radio- master production and control record); activity or other measurement of each (5) Weights (or other measure of active pharmaceutical ingredient and quantity) and identification codes of each inactive ingredient per batch or components; per unit of radioactivity or other meas- (6) Dates of production steps and urement of the drug product, and a times of critical production steps; statement of the total radioactivity or other measurement of any dosage unit; (7) Identification of major pieces of (3) A complete list of components equipment used in production of the designated by names and codes suffi- batch; ciently specific to indicate any special (8) Testing results; quality characteristic; (9) Labeling; (4) Identification of all major pieces (10) Initials or signatures of persons of equipment used in production; performing or checking each signifi- (5) An accurate statement of the cant step in the operation; and weight or measurement of each compo- (11) Results of any investigations nent, using the same weight system conducted. (metric, avoirdupois, or apothecary) for (d) Area and equipment checks. The each component. Reasonable variations production area and all equipment in are permitted in the amount of compo- the production area must be checked to nent necessary if they are specified in ensure cleanliness and suitability im- the master production and control mediately before use. A record of these records; (6) A statement of action limits on checks must be kept. radiochemical yield, i.e., the minimum (e) In-process materials controls. Proc- percentage of yield beyond which in- ess controls must include control of investigation and corrective action are process materials to ensure that the required; materials are controlled until required (7) Complete production and control tests or other verification activities instructions, sampling and testing pro- have been completed or necessary ap- cedures, specifications, special nota- provals are received and documented. tions, and precautions to be followed; and

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(f) Process verification. (1) For a PET (e) Equipment. All equipment used to drug for which each entire batch under- perform the testing must be suitable goes full finished-product testing to en- for its intended purposes and capable of sure that the product meets all speci- producing valid results. fications, process verification, as de- (f) Equipment maintenance. Each lab- scribed in paragraph (f)(2) of this sec- oratory must have and follow written tion, is not required. procedures to ensure that equipment is (2) When the results of the produc- routinely calibrated, inspected, tion of an entire batch of a PET drug checked, and maintained, and that are not fully verified through finished- these activities are documented. product testing or when only the ini- (g) Test records. Each laboratory per- tial sub-batch in a series is tested, the forming tests related to the production PET drug producer must demonstrate of a PET drug must keep complete that the process for producing the PET records of all tests performed to ensure drug is reproducible and is capable of compliance with established specifica- producing a drug product that meets tions and standards, including exami- the predetermined acceptance criteria. nations and assays, as follows: Process verification activities and re- (1) A suitable identification of the sults must be documented. Documenta- sample received for testing. tion must include the date and signa- (2) A description of each method used ture of the individual(s) performing the in the testing of the sample, a record of verification, the monitoring and con- all calculations performed in connec- trol methods and data, and the major tion with each test, and a statement of equipment qualified. the weight or measurement of the sample used for each test. (3) A complete record of all data ob- Subpart G—Laboratory Controls tained in the course of each test, including the date and time the test was § 212.60 What requirements apply to the laboratories where I test com- conducted, and all graphs, charts, and ponents, in-process materials, and spectra from laboratory instrumenta- finished PET drug products? tion, properly identified to show the specific component, in-process mate- (a) Testing procedures. Each labora- rial, or drug product for each lot test- tory used to conduct testing of compo- ed. nents, in-process materials, and fin- (4) A statement of the results of tests ished PET drug products must have and how the results compare with es- and follow written procedures for the tablished acceptance criteria. conduct of each test and for the docu- (5) The initials or signature of the mentation of the results. person performing the test and the (b) Specifications and standards. Each date on which the test was performed. laboratory must have sampling and testing procedures designed to ensure § 212.61 What must I do to ensure the that components, in-process materials, stability of my PET drug products and PET drug products conform to ap- through expiry? propriate standards, including estab- (a) Stability testing program. You must lished standards of identity, strength, establish, follow, and maintain a writ- quality, and purity. ten testing program to assess the sta- (c) Analytical methods. Laboratory an- bility characteristics of your PET drug alytical methods must be suitable for products. The test methods must be re- their intended use and must be suffi- liable, meaningful, and specific. The ciently sensitive, specific, accurate, samples tested for stability must be and reproducible. representative of the lot or batch from (d) Materials. The identity, purity, which they were obtained and must be and quality of reagents, solutions, and stored under suitable conditions. supplies used in testing procedures (b) Storage conditions and expiration must be adequately controlled. All so- dates. The results of such stability test- lutions that you prepare must be prop- ing must be documented and used in erly labeled to show their identity and determining appropriate storage condi- expiration date. tions and expiration dates and times

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for each PET drug product you ceeded due to a weekend or holiday. If produce. 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 (c) Conformance to specifications. Be- finished-product tests for a batch of a fore final release, you must conduct an PET drug product because of a mal- appropriate laboratory determination function involving analytical equip- to ensure that each batch of a PET ment, you may approve the conditional drug product conforms to specifica- final release of the product if you meet tions, except for sterility. For a PET the following conditions: drug product produced in sub-batches, (i) You have data documenting that before final release, you must conduct preceding consecutive batches, pro- an appropriate laboratory determina- duced using the same methods used for tion to ensure that each sub-batch con- the conditionally released batch, dem- forms to specifications, except for ste- onstrate that the conditionally re- rility. leased batch will likely meet the estab- (d) Final release procedures. Except as lished specifications; conditional final release is permitted (ii) You determine that all other ac- in accordance with paragraph (f) of this ceptance criteria are met; section, you must establish and follow (iii) You retain a reserve sample of procedures to ensure that each batch of the conditionally released batch of a PET drug product is not given final drug product; release until the following are done: (iv) You promptly correct the mal- (1) An appropriate laboratory deter- function of analytical equipment, com- mination under paragraph (c) of this plete the omitted test using the reserve section is completed; sample after the malfunction is cor- (2) Associated laboratory data and rected, and document that reasonable documentation are reviewed and they efforts have been made to prevent re- demonstrate that the PET drug prod- currence of the malfunction; uct meets specifications, except for (v) If you obtain an out-of-specifica- sterility; and tion result when testing the reserve (3) A designated qualified individual sample, you immediately notify the re- authorizes final release by dated signa- ceiving facility; and ture. (vi) You document all actions regard- (e) Sterility testing. Sterility testing ing the conditional final release of the need not be completed before final re- drug product, including the justifica- lease but must be started within 30 tion for the release, all followup ac- hours after completion of production. tions, results of completed testing, all The 30-hour requirement may be ex- notifications, and corrective actions to

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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. (c) All information stated on each § 212.71 What actions must I take if a label must also be contained in each batch of PET drug product does not conform to specifications? batch production record. (d) Labeling and packaging oper- (a) Rejection of nonconforming product. ations must be controlled to prevent You must reject a batch of a PET drug labeling and product mix-ups. product that does not conform to specifications. You must have and follow procedures to identify and segregate Subpart J—Distribution the product to avoid mix-ups. You § 212.90 What actions must I take to must have and follow procedures to in- control the distribution of PET vestigate the cause(s) of the noncon- drug products? forming product. The investigation (a) Written distribution procedures. You must include, but is not limited to, ex- must establish, maintain, and follow amination of processes, operations, records, complaints, and any other rel- written procedures for the control of evant sources of information con- distribution of PET drug products cerning the nonconforming product. shipped from the PET drug production facility to ensure that the method of (b) Investigation. You must document shipping chosen will not adversely af- the investigation of a PET drug prod- fect the identity, purity, or quality of uct that does not meet specifications, including the results of the investiga- the PET drug product. tion and what happened to the rejected (b) Distribution records. You must PET drug product. maintain distribution records for each (c) Correction of problems. You must PET drug product that include or refer take action to correct any identified to the following: problems to prevent recurrence of a (1) The name, address, and telephone nonconforming product or other qual- number of the receiving facility that ity problem. received each batch of a PET drug (d) Reprocessing. If appropriate, you product; may reprocess a batch of a PET drug (2) The name and quantity of the product that does not conform to speci- PET drug product shipped; fications. If material that does not (3) The lot number, control number, meet acceptance criteria is reproc- or batch number for the PET drug essed, you must follow procedures stat- product shipped; and ed in the product’s approved applica- (4) The date and time you shipped the tion and the finished product must con- PET drug product. form to specifications, except for sterility, before final release.

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Subpart K—Complaint Handling release, including conditional final release, of a PET drug product. § 212.100 What do I do if I receive a complaint about a PET drug prod- PART 216—PHARMACY uct produced at my facility? COMPOUNDING (a) Written complaint procedures. You must develop and follow written proce- Subpart A—General Provisions [Reserved] dures for the receipt and handling of all complaints concerning the quality Subpart B—Compounded Drug Products or purity of, or possible adverse reactions to, a PET drug product. Sec. 216.23 [Reserved] (b) Complaint review. The procedures 216.24 Drug products withdrawn or removed must include review by a designated from the market for reasons of safety or person of any complaint involving the effectiveness. possible failure of a PET drug product AUTHORITY: 21 U.S.C. 351, 352, 353a, 355, and to meet any of its specifications and an 371. investigation to determine the cause of the failure. SOURCE: 64 FR 10944, Mar. 8, 1999, unless (c) Complaint records. A written otherwise noted. record of each complaint must be maintained in a file designated for PET Subpart A—General Provisions drug product complaints. The record [Reserved] must include the name and strength of the PET drug product, the batch num- Subpart B—Compounded Drug ber, the name of the complainant, the Products date the complaint was received, the nature of the complaint, and the re- § 216.23 [Reserved] sponse to the complaint. It must also include the findings of any investiga- § 216.24 Drug products withdrawn or tion and followup. removed from the market for rea- (d) Returned products. A PET drug sons of safety or effectiveness. product that is returned because of a The following drug products were complaint or for any other reason may withdrawn or removed from the mar- not be reprocessed and must be de- ket because such drug products or com- stroyed in accordance with applicable ponents of such drug products were Federal and State law. found to be unsafe or not effective. The following drug products may not be Subpart L—Records compounded under the exemptions provided by section 503A(a) of the Federal § 212.110 How must I maintain records Food, Drug, and Cosmetic Act: of my production of PET drugs? Adenosine phosphate: All drug products con- (a) Record availability. Records must taining adenosine phosphate. be maintained at the PET drug produc- Adrenal cortex: All drug products containing tion facility or another location that is adrenal cortex. reasonably accessible to responsible of- Azaribine: All drug products containing ficials of the production facility and to azaribine. Benoxaprofen: All drug products containing employees of FDA designated to per- benoxaprofen. form inspections. Bithionol: All drug products containing (b) Record quality. All records, includ- bithionol. ing those not stored at the inspected Bromfenac sodium: All drug products con- establishment, must be legible, stored taining bromfenac sodium. to prevent deterioration or loss, and Butamben: All parenteral drug products con- readily available for review and copy- taining butamben. ing by FDA employees. Camphorated oil: All drug products containing camphorated oil. (c) Record retention period. You must Carbetapentane citrate: All oral gel drug prod- maintain all records and documenta- ucts containing carbetapentane citrate. tion referenced in this part for a period Casein, iodinated: All drug products con- of at least 1 year from the date of final taining iodinated casein.

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Chlorhexidine gluconate: All tinctures of Pipamazine: All drug products containing chlorhexidine gluconate formulated for use pipamazine. as a patient preoperative skin preparation. Potassium arsenite: All drug products con- Chlormadinone acetate: All drug products containing potassium arsenite. taining chlormadinone acetate. Potassium chloride: All solid oral dosage form Chloroform: All drug products containing drug products containing potassium chlo- chloroform. ride that supply 100 milligrams or more of Cobalt: All drug products containing cobalt potassium per dosage unit (except for con- salts (except radioactive forms of cobalt trolled-release dosage forms and those and its salts and cobalamin and its deriva- products formulated for preparation of so- tives). lution prior to ingestion). Dexfenfluramine hydrochloride: All drug prod- Povidone: All intravenous drug products con- ucts containing dexfenfluramine hydro- taining povidone. chloride. Reserpine: All oral dosage form drug products Diamthazole dihydrochloride: All drug prod- containing more than 1 milligram of reser- ucts containing diamthazole pine. dihydrochloride. Sparteine sulfate: All drug products con- Dibromsalan: All drug products containing taining sparteine sulfate. dibromsalan. Sulfadimethoxine: All drug products con- Diethylstilbestrol: All oral and parenteral drug taining sulfadimethoxine. products containing 25 milligrams or more of diethylstilbestrol per unit dose. Sulfathiazole: All drug products containing sulfathiazole (except those formulated for Dihydrostreptomycin sulfate: All drug products vaginal use). containing dihydrostreptomycin sulfate. Dipyrone: All drug products containing Suprofen: All drug products containing dipyrone. suprofen (except ophthalmic solutions). Encainide hydrochloride: All drug products Sweet spirits of nitre: All drug products con- containing encainide hydrochloride. taining sweet spirits of nitre. Fenfluramine hydrochloride: All drug products Temafloxacin hydrochloride: All drug products containing fenfluramine hydrochloride. containing temafloxacin. Flosequinan: All drug products containing Terfenadine: All drug products containing flosequinan. terfenadine. Gelatin: All intravenous drug products con- 3,3′,4′,5-tetrachlorosalicylanilide: All drug prod- taining gelatin. ucts containing 3,3′,4′,5-tetrachlorosalicyl- Glycerol, iodinated: All drug products con- anilide. taining iodinated glycerol. Tetracycline: All liquid oral drug products Gonadotropin, chorionic: All drug products formulated for pediatric use containing containing chorionic gonadotropins of ani- tetracycline in a concentration greater mal origin. than 25 milligrams/milliliter. Mepazine: All drug products containing Ticrynafen: All drug products containing mepazine hydrochloride or mepazine ace- ticrynafen. tate. Tribromsalan: All drug products containing Metabromsalan: All drug products containing tribromsalan. metabromsalan. Trichloroethane: All aerosol drug products in- Methamphetamine hydrochloride: All paren- tended for inhalation containing trichloro- teral drug products containing meth- ethane. amphetamine hydrochloride. Urethane: All drug products containing ure- Methapyrilene: All drug products containing thane. methapyrilene. Vinyl chloride: All aerosol drug products con- Methopholine: All drug products containing taining vinyl chloride. methopholine. Zirconium: All aerosol drug products con- Mibefradil dihydrochloride: All drug products taining zirconium. containing mibefradil dihydrochloride. Nitrofurazone: All drug products containing Zomepirac sodium: All drug products con- nitrofurazone (except topical drug products taining zomepirac sodium. formulated for dermatalogic application). Nomifensine maleate: All drug products con- PART 225—CURRENT GOOD MAN- taining nomifensine maleate. UFACTURING PRACTICE FOR Oxyphenisatin: All drug products containing oxyphenisatin. MEDICATED FEEDS Oxyphenisatin acetate: All drug products containing oxyphenisatin acetate. Subpart A—General Provisions Phenacetin: All drug products containing phenacetin. Sec. Phenformin hydrochloride: All drug products 225.1 Current good manufacturing practice. containing phenformin hydrochloride. 225.10 Personnel.

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Subpart B—Construction and Maintenance requirement of the act as to safety and of Facilities and Equipment has the identity and strength, and meets the quality and purity charac- 225.20 Buildings. 225.30 Equipment. teristics, which it purports or is rep- 225.35 Use of work areas, equipment, and resented to possess. storage areas for other manufacturing (b)(1) The provisions of this part set and storage purpose. forth the criteria for determining whether the manufacture of a medi- Subpart C—Product Quality Control cated feed is in compliance with cur- 225.42 Components. rent good manufacturing practice. 225.58 Laboratory controls. These regulations shall apply to all 225.65 Equipment cleanout procedures. types of facilities and equipment used in the production of medicated feeds, Subpart D—Packaging and Labeling and they shall also govern those in- 225.80 Labeling. stances in which failure to adhere to the regulations has caused nonmedi- Subpart E—Records and Reports cated feeds that are manufactured, processed, packed, or held to be adul- 225.102 Master record file and production terated. In such cases, the medicated records. feed shall be deemed to be adulterated 225.110 Distribution records. 225.115 Complaint files. within the meaning of section 501(a)(2)(B) of the act, and the non- Subpart F—Facilities and Equipment medicated feed shall be deemed to be adulterated within the meaning of sec- 225.120 Buildings and grounds. tion 402(a)(2)(D) of the act. 225.130 Equipment. 225.135 Work and storage areas. (2) The regulations in §§ 225.10 through 225.115 apply to facilities man- Subpart G—Product Quality Assurance ufacturing one or more medicated feeds for which an approved medicated feed 225.142 Components. mill license is required. The regula- 225.158 Laboratory assays. tions in §§ 225.120 through 225.202 apply 225.165 Equipment cleanout procedures. to facilities manufacturing solely Subpart H—Labeling medicated feeds for which an approved license is not required. 225.180 Labeling. (c) In addition to the recordkeeping requirements in this part, Type B and Subpart I—Records Type C medicated feeds made from 225.202 Formula, production, and distribu- Type A articles or Type B feeds under tion records. approved NADAs or indexed listings AUTHORITY: 21 U.S.C. 351, 352, 360b, 371, 374. and a medicated feed mill license are subject to the requirements of § 510.301 SOURCE: 41 FR 52618, Nov. 30, 1976, unless of this chapter. otherwise noted. [41 FR 52618, Nov. 30, 1976, as amended at 51 Subpart A—General Provisions FR 7389, Mar. 3, 1986; 64 FR 63203, Nov. 19, 1999; 72 FR 69120, Dec. 6, 2007] § 225.1 Current good manufacturing practice. § 225.10 Personnel. (a) Section 501(a)(2)(B) of the Federal (a) Qualified personnel and adequate Food, Drug, and Cosmetic Act provides personnel training and supervision are that a drug (including a drug contained essential for the proper formulation, in a medicated feed) shall be deemed to manufacture, and control of medicated be adulterated if the methods used in, feeds. Training and experience leads to or the facilities or controls used for, its proper use of equipment, maintenance manufacture, processing, packing, or of accurate records, and detection and holding do not conform to or are not prevention of possible deviations from operated or administered in conformity current good manufacturing practices. with current good manufacturing prac- (b)(1) All employees involved in the tice to assure that such drug meets the manufacture of medicated feeds shall

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have an understanding of the manufac- performance of the following medi- turing or control operation(s) which cated feed manufacturing operations: they perform, including the location (i) The receipt, control, and storage and proper use of equipment. of components. (2) The manufacturer shall provide an (ii) Component processing. on-going program of evaluation and su- (iii) Medicated feed manufacturing. pervision of employees in the manufac- (iv) Packaging and labeling. ture of medicated feeds. (v) Storage of containers, packaging materials, labeling and finished prod- [41 FR 52618, Nov. 30, 1976, as amended at 42 ucts. FR 12426, Mar. 4, 1977] (vi) Routine maintenance of equipment. Subpart B—Construction and Maintenance of Facilities and § 225.30 Equipment. Equipment (a) Equipment which is designed to perform its intended function and is § 225.20 Buildings. properly installed and used is essential (a) The location, design, construc- to the manufacture of medicated feeds. tion, and physical size of the buildings Such equipment permits production of and other production facilities are fac- feeds of uniform quality, facilitates tors important to the manufacture of cleaning, and minimizes spillage of medicated feed. The features of facili- drug components and finished product. ties necessary for the proper manufac- (b)(1) All equipment shall possess the ture of medicated feed include provi- capability to produce a medicated feed sion for ease of access to structures of intended potency, safety, and purity. and equipment in need of routine main- (2) All equipment shall be maintained tenance; ease of cleaning of equipment in a reasonably clean and orderly man- and work areas; facilities to promote ner. personnel hygiene; structural condi- (3) All equipment, including scales tions for control and prevention of and liquid metering devices, shall be of vermin and pest infestation; adequate suitable size, design, construction, pre- space for the orderly receipt and stor- cision, and accuracy for its intended age of drugs and feed ingredients and purpose. the controlled flow of these materials (4) All scales and metering devices through the processing and manufac- shall be tested for accuracy upon in- turing operations; and the equipment stallation and at least once a year for the accurate packaging and deliv- thereafter, or more frequently as may ery of a medicated feed of specified la- be necessary to insure their accuracy. beling and composition. (5) All equipment shall be so constructed and maintained as to prevent (b) The construction and mainte- lubricants and coolants from becoming nance of buildings in which medicated unsafe additives in feed components or feeds are manufactured, processed, medicated feed. packaged, labeled, or held shall con- (6) All equipment shall be designed, form to the following: constructed, installed and maintained (1) The building grounds shall be ade- so as to facilitate inspection and use of quately drained and routinely main- cleanout procedure(s). tained so that they are reasonably free from litter, waste, refuse, uncut weeds § 225.35 Use of work areas, equipment, or grass, standing water, and improp- and storage areas for other manu- erly stored equipment. facturing and storage purpose. (2) The building(s) shall be main- (a) Many manufacturers of medicated tained in a reasonably clean and or- feeds are also involved in the manufac- derly manner. ture, storage, or handling of products (3) The building(s) shall be of suitable which are not intended for animal feed construction to minimize access by ro- use, such as fertilizers, herbicides, in- dents, birds, insects, and other pests. secticides, fungicides, rodenticides, and (4) The buildings shall provide ade- other pesticides. Manufacturing, stor- quate space and lighting for the proper age, or handling of nonfeed and feed

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products in the same facilities may identity, strength, quality, and purity cause adulteration of feed products will be maintained. with toxic or otherwise unapproved (4) Drugs in the mixing areas shall be feed additives. properly identified, stored, handled, (b) Work areas and equipment used and controlled to maintain their integ- for the manufacture or storage of medi- rity and identity. Sufficient space shall cated feeds or components thereof shall be provided for the location of each not be used for, and shall be physically drug. separated from, work areas and equip- (5) A receipt record shall be prepared ment used for the manufacture of fer- and maintained for each lot of drug re- tilizers, herbicides, insecticides, fun- ceived. The receipt record shall accu- gicides, rodenticides, and other pes- rately indicate the identity and quan- ticides unless such articles are ap- tity of the drug, the name of the sup- proved drugs, indexed drugs, or ap- plier, the supplier’s lot number or an proved food additives intended for use identifying number assigned by the in the manufacture of medicated feed. feed manufacturer upon receipt which relates to the particular shipment, the [41 FR 52618, Nov. 30, 1976, as amended at 72 FR 69120, Dec. 6, 2007] date of receipt, the condition of the drug when received, and the return of any damaged drugs. Subpart C—Product Quality (6) A daily inventory record for each Control drug used shall be maintained and shall list by manufacturer’s lot number or § 225.42 Components. the feed manufacturer’s shipment iden- (a) A medicated feed, in addition to tification number at least the fol- providing nutrients, is a vehicle for the lowing information: administration of a drug, or drugs, to (i) The quantity of drug on hand at animals. To ensure proper safety and the beginning and end of the work day effectiveness, such medicated feeds (the beginning amount being the same must contain the labeled amounts of as the previous day’s closing inventory drugs. It is necessary that adequate if this amount has been established to procedures be established for the re- be correct); the quantity shall be deter- ceipt, storage, and inventory control mined by weighing, counting, or meas- for all such drugs to aid in assuring uring, as appropriate. their identity, strength, quality, and (ii) The amount of each drug used, purity when incorporated into prod- sold, or otherwise disposed of. ucts. (iii) The batches or production runs (b) The receipt, storage, and inven- of medicated feed in which each drug tory of drugs, including undiluted drug was used. components, medicated premixes, and (iv) When the drug is used in the semiprocessed (i.e., intermediate pre- preparation of a semiprocessed inter- mixes, inplant premixes and con- mediate mix intended for use in the centrates) intermediate mixes con- manufacture of medicated feed, any ad- taining drugs, which are used in the ditional information which may be re- manufacture and processing of medi- quired for the purpose of paragraph cated feeds shall conform to the fol- (b)(7) of this section. lowing: (v) Action taken to reconcile any dis- (1) Incoming shipments of drugs shall crepancies in the daily inventory be visually examined for identity and record. damage. Drugs which have been sub- (7) Drug inventory shall be main- jected to conditions which may have tained of each lot or shipment of drug adversely affected their identity, by means of a daily comparison of the strength, quality, or purity shall not actual amount of drug used with the be accepted for use. theoretical drug usage in terms of the (2) Packaged drugs in the storage semiprocessed, intermediate and fin- areas shall be stored in their original ished medicated feeds manufactured. closed containers. Any significant discrepancy shall be in- (3) Bulk drugs shall be identified and vestigated and corrective action taken. stored in a manner such that their The medicated feed(s) remaining on the

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premises which are affected by this dis- tion where the medicated feed fails to crepancy shall be detained until the meet the labeled drug potency. Dis- discrepancy is reconciled. tribution of subsequent production of (8) All records required by this sec- the particular feed shall not begin tion shall be maintained on the prem- until it has been determined that prop- ises for at least one year after com- er control procedures have been estab- plete use of a drug component of a spe- lished. cific lot number or feed manufacturer’s shipment identification number. [41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 55 FR 11577, Mar. 29, § 225.58 Laboratory controls. 1990; 64 FR 63203, Nov. 19, 1999] (a) The periodic assay of medicated § 225.65 Equipment cleanout proce- feeds for drug components provides a dures. measure of performance of the manufacturing process in manufacturing a (a) Adequate cleanout procedures for uniform product of intended potency. all equipment used in the manufacture (b) The following assay requirements and distribution of medicated feeds are shall apply to medicated feeds: essential to maintain proper drug po- (1) For feeds requiring a medicated tency and avoid unsafe contamination feed mill license (Form FDA 3448) for of feeds with drugs. Such procedures their manufacture and marketing, at may consist of cleaning by physical least three representative samples of means, e.g., vacuuming, sweeping, medicated feed containing each drug or washing, etc. Alternatively, flushing or drug combination used in the establish- sequencing or other equally effective ment shall be collected and assayed by techniques may be used whereby the approved official methods, at periodic equipment is cleaned either through intervals during the calendar year, un- use of a feed containing the same less otherwise specified in this chapter. drug(s) or through use of drug free At least one of these assays shall be feedstuffs. performed on the first batch using the (b) All equipment, including that drug. If a medicated feed contains a combination of drugs, only one of the used for storage, processing, mixing, drugs need be subject to analysis each conveying, and distribution that comes time, provided the one tested is dif- in contact with the active drug compo- ferent from the one(s) previously test- nent, feeds in process, or finished medi- ed. cated feed shall be subject to all rea- (2) [Reserved] sonable and effective procedures to pre- (c) The originals or copies of all re- vent unsafe contamination of manufac- sults of assays, including those from tured feed. The steps used to prevent State feed control officials and any unsafe contamination of feeds shall in- other governmental agency, shall be clude one or more of the following, or maintained on the premises for a pe- other equally effective procedures: riod of not less than 1 year after dis- (1) Such procedures shall, where ap- tribution of the medicated feed. The re- propriate, consist of physical means sults of assays performed by State feed (vacuuming, sweeping, or washing), control officials may be considered to- flushing, and/or sequential production ward fulfillment of the periodic assay of feeds. requirements of this section. (2) If flushing is utilized, the flush (d) Where the results of assays indi- material shall be properly identified, cate that the medicated feed is not in stored, and used in a manner to pre- accord with label specifications or is not within permissible assay limits as vent unsafe contamination of other specified in this chapter, investigation feeds. and corrective action shall be imple- (3) If sequential production of medi- mented and an original or copy of the cated feeds is utilized, it shall be on a record of such action maintained on predetermined basis designed to pre- the premises. vent unsafe contamination of feeds (e) Corrective action shall include with residual drugs. provisions for discontinuing distribu-

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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 adhered to, will assure that the article year after production of the last batch is safe and effective for its intended or production run of medicated feed to purposes. which it pertains. The Master Record (b)(1) Labels and labeling, including File or card shall include at least the placards, shall be received, handled, following: and stored in a manner that prevents (i) The name of the medicated feed. labeling mixups and assures that cor- (ii) The name and weight percentage rect labeling is employed for the medi- or measure of each drug or drug com- cated feed. bination and each nondrug ingredient (2) Labels and labeling, including to be used in manufacturing a stated placards, upon receipt from the printer weight of the medicated feed. shall be proofread against the Master (iii) A copy or description of the label Record File to verify their suitability or labeling that will accompany the and accuracy. The proofread label shall medicated feed. be dated, initialed by a responsible in- (iv) Manufacturing instructions or dividual, and kept for 1 year after all reference thereto that have been deter- the labels from that batch have been mined to yield a properly mixed medi- used. cated feed of the specified formula for (3) In those instances where medi- each medicated feed produced on a cated feeds are distributed in bulk, batch or continuous operation basis, complete labeling shall accompany the including mixing steps, mixing times shipment and be supplied to the con- and, in the case of medicated feeds pro- signee at the time of delivery. Such la- duced by continuous production run, beling may consist of a placard or any additional manufacturing direc- other labels attached to the invoice or tions including, when indicated, the delivery ticket, or manufacturer’s in- settings of equipment. voice that identifies the medicated feed (v) Appropriate control directions or and includes adequate information for reference thereto, including the man- the safe and effective use of the medi- ner and frequency of collecting the re- cated feed. quired number of samples for specified (4) Label stock shall be reviewed pe- laboratory assay. riodically and discontinued labels shall (2) The original production record or be discarded. copy thereof shall be prepared by qualified personnel for each batch or run of Subpart E—Records and Reports medicated feed produced and shall be retained on the premises for not less § 225.102 Master record file and pro- than 1 year. The production record duction records. shall include at least the following: (a) The Master Record File provides (i) Product identification, date of the complete procedure for manufac- production, and a written endorsement turing a specific product, setting forth in the form of a signature or initials by the formulation, theoretical yield, a responsible individual. manufacturing procedures, assay re- (ii) The quantity and name of drug quirements, and labeling of batches or components used. production runs. The production (iii) The theoretical quantity of record(s) includes the complete history medicated feed to be produced. of a batch or production run. This (iv) The actual quantity of medicated record includes the amounts of drugs feed produced. In those instances where used, the amount of medicated feed the finished feed is stored in bulk and manufactured, and provides a check for actual yield cannot be accurately de- the daily inventory record of drug com- termined, the firm shall estimate the ponents. quantity produced and provide the

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basis for such estimate in the Master § 225.115 Complaint files. Record File. (a) Complaints and reports of experi- (3) In the case of a custom formula ences of product defects relative to the feed made to the specifications of a drug’s efficacy or safety may provide customer, the Master Record File and an indicator as to whether or not medi- production records required by this cated feeds have been manufactured in section shall consist either of such conformity with current good manufac- records or of copies of the customer’s turing practices. These complaints and purchase orders and the manufactur- experiences may reveal the existence of er’s invoices bearing the information manufacturing problems not otherwise required by this section. When a cus- detected through the normal quality tom order is received by telephone, the control procedures. Timely and appro- manufacturer shall prepare the re- priate follow-up action can serve to quired production records. correct a problem and minimize future (4) Batch production records shall be problems. checked by a responsible individual at (b) The medicated feed manufacturer the end of the working day in which shall maintain on the premises a file the product was manufactured to de- which contains the following informa- termine whether all required production: tion steps have been performed. If sig- (1) The original or copy of a record of nificant discrepancies are noted, an in- each oral and written complaint re- vestigation shall be instituted imme- ceived relating to the safety and effec- diately, and the production record tiveness of the product produced. The shall describe the corrective action record shall include the date of the taken. complaint, the complainant’s name and (5) Each batch or production run of address, name and lot or control num- medicated feed shall be identified with ber or date of manufacture of the medi- its own individual batch or production cated feed involved, and the specific de- run number, code, date, or other suit- tails of the complaint. This record able identification applied to the label, shall also include all correspondence package, invoice or shipping document. from the complainant and/or memo- This identification shall permit the randa of conversations with the com- tracing of the complete and accurate plainant, and a description of all inves- manufacturing history of the product tigations made by the manufacturer by the manufacturer. and of the method of disposition of the § 225.110 Distribution records. complaint. (2) For medicated feeds whose manu- (a) Distribution records permit the facture require a medicated feed mill manufacturer to relate complaints to license (Form FDA 3448), records and specific batches and/or production runs reports of clinical and other experience of medicated feed. This information with the drug shall be maintained and may be helpful in instituting a recall. reported, under § 510.301 of this chapter. (b) Distribution records for each shipment of a medicated feed shall comply [41 FR 52618, Nov. 30, 1976, as amended at 51 with the following provisions: FR 7390, Mar. 3, 1986; 57 FR 6475, Feb. 25, 1992; (1) Each distribution record shall in- 64 FR 63203, Nov. 19, 1999] clude the date of shipment, the name and address of purchaser, the quantity Subpart F—Facilities and shipped, and the name of the medicated Equipment feed. A lot or control number, or date of manufacture or other suitable iden- SOURCE: 51 FR 7390, Mar. 3, 1986, unless oth- tification shall appear on the distribu- erwise noted. tion record or the label issued with each shipment. § 225.120 Buildings and grounds. (2) The originals or copies of the dis- Buildings used for production of tribution records shall be retained on medicated feed shall provide adequate the premises for not less than one year space for equipment, processing, and after the date of shipment of the medi- orderly receipt and storage of medicated feed. cated feed. Areas shall include access

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for routine maintenance and cleaning All Type A medicated articles and of equipment. Buildings and grounds Type B medicated feeds shall be used in shall be constructed and maintained in accordance with their labeled mixing a manner to minimize vermin and pest directions. infestation. § 225.158 Laboratory assays. § 225.130 Equipment. Where the results of laboratory as- Equipment shall be capable of pro- says of drug components, including as- ducing a medicated feed of intended po- says by State feed control officials, in- tency and purity, and shall be main- dicate that the medicated feed is not in tained in a reasonably clean and or- accord with the permissible limits derly manner. Scales and liquid meter- specified in this chapter, investigation ing devices shall be accurate and of and corrective action shall be imple- suitable size, design, construction, precision, and accuracy for their intended mented immediately by the firm and purposes. All equipment shall be de- such records shall be maintained on signed, constructed, installed, and the premises for a period of 1 year. maintained so as to facilitate inspection and use of cleanout procedure(s). § 225.165 Equipment cleanout procedures. § 225.135 Work and storage areas. Adequate procedures shall be estab- Work areas and equipment used for lished and used for all equipment used the production or storage of medicated in the production and distribution of feeds or components thereof shall not medicated feeds to avoid unsafe con- be used for, and shall be physically sep- tamination of medicated and nonmedi- arated from, work areas and equipment cated feeds. used for the manufacture and storage of fertilizers, herbicides, insecticides, Subpart H—Labeling fungicides, rodenticides, and other pesticides unless such articles are ap- § 225.180 Labeling. proved or index listed for use in the manufacture of animal feed. Labels shall be received, handled, and stored in a manner that prevents label [72 FR 69120, Dec. 6, 2007] mixups and assures that the correct labels are used for the medicated feed. Subpart G—Product Quality All deliveries of medicated feeds, Assurance whether bagged or in bulk, shall be adequately labeled to assure that the SOURCE: 51 FR 7390, Mar. 3, 1986, unless oth- feed can be properly used. erwise noted. [51 FR 7390, Mar. 3, 1986] § 225.142 Components. Adequate procedures shall be estab- Subpart I—Records lished and maintained for the identification, storage, and inventory control § 225.202 Formula, production, and (receipt and use) of all Type A medi- distribution records. cated articles and Type B medicated Records shall be maintained identi- feeds intended for use in the manufac- fying the formulation, date of mixing, ture of medicated feeds to aid in assur- and if not for own use, date of ship- ing the identity, strength, quality, and ment. The records shall be adequate to purity of these drug sources. Packaged facilitate the recall of specific batches Type A medicated articles and Type B of medicated feed that have been dis- medicated feeds shall be stored in des- tributed. Such records shall be retained ignated areas in their original closed on the premises for 1 year following the containers. Bulk Type A medicated ar- date of last distribution. ticles and bulk Type B medicated feeds shall be identified and stored in a man- (Approved by the Office of Management and ner such that their identity, strength, Budget under control number 0910–0152) quality, and purity will be maintained. [51 FR 7390, Mar. 3, 1986]

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PART 226—CURRENT GOOD MAN- ity control procedures are used to as- UFACTURING PRACTICE FOR sure proper performance. TYPE A MEDICATED ARTICLES (b) In addition to maintaining records and reports required in this Subpart A—General Provisions part, Type A medicated articles requiring approved NADAs are subject to the Sec. requirements of § 514.80 of this chapter. 226.1 Current good manufacturing practice. Similarly, Type A medicated articles 226.10 Personnel. listed in the index are subject to the Subpart B—Construction and Maintenance requirements of § 516.165 of this chap- of Facilities and Equipment ter. 226.20 Buildings. [40 FR 14031, Mar. 27, 1975, as amended at 68 226.30 Equipment. FR 15364, Mar. 31, 2003; 72 FR 69120, Dec. 6, 2007] Subpart C—Product Quality Control § 226.10 Personnel. 226.40 Production and control procedures. 226.42 Components. The key personnel and any consult- 226.58 Laboratory controls. ants involved in the manufacture and control of the Type A medicated arti- Subpart D—Packaging and Labeling cle(s) shall have a background of appropriate education or appropriate ex- 226.80 Packaging and labeling. perience or combination thereof for as- Subpart E—Records and Reports suming responsibility to assure that the Type A medicated article(s) has the 226.102 Master-formula and batch-produc- proper labeling and the safety, iden- tion records. tity, strength, quality, and purity that 226.110 Distribution records. it purports to possess. 226.115 Complaint files. AUTHORITY: 21 U.S.C. 351, 352, 360b, 371, 374. Subpart B—Construction and SOURCE: 40 FR 14031, Mar. 27, 1975, unless Maintenance of Facilities and otherwise noted. Equipment

Subpart A—General Provisions § 226.20 Buildings. § 226.1 Current good manufacturing Buildings in which Type A medicated practice. article(s) are manufactured, processed, (a) The criteria in §§ 226.10 through packaged, labeled, or held shall be 226.115, inclusive, shall apply in deter- maintained in a clear and orderly man- mining whether the methods used in, ner and shall be of suitable size, con- or the facilities and controls used for struction and location in relation to the manufacture, processing, packing, surroundings to facilitate maintenance or holding of a Type A medicated arti- and operation for their intended pur- cle(s) conform to or are operated or ad- pose. The building shall: ministered in conformity with current (a) Provide adequate space for the or- good manufacturing practice to assure derly placement of equipment and ma- that a Type A medicated article(s) terials used in any of the following op- meets the requirements of the act as to erations for which they are employed safety, and has the identity and to minimize risk of mixups between strength, and meets the quality and different Type A medicated article(s), purity characteristics which it pur- their components, packaging, or label- ports or is represented to possess, as ing: required by section 501(a)(2)(B) of the (1) The receipt, sampling, control, act. The regulations in this part 226 and storage of components. permit the use of precision, automatic, (2) Manufacturing and processing op- mechanical, or electronic equipment in erations performed on the Type A the production of a Type A medicated medicated article(s). article(s) when adequate inspection (3) Packaging and labeling oper- and checking procedures or other qual- ations.

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(4) Storage of containers, packaging and to assure the exclusion from Type materials, labeling, and finished prod- A medicated article(s) of contamina- ucts. tion, including cross-contamination (5) Control laboratory operations. from manufacturing operations. (b) Provide adequate lighting and (d) Be suitably grounded electrically ventilation, and when necessary for the to prevent lack of uniform mixing due intended production or control pur- to electrically charged particles. poses, adequate screening, dust and (e) Be of suitable size and accuracy temperature controls, to avoid con- for use in any intended measuring, tamination of Type A medicated arti- mixing, or weighing operations. cle(s), and to avoid other conditions unfavorable to the safety, identity, Subpart C—Product Quality strength, quality, and purity of the raw Control materials and Type A medicated article(s) before, during, and after produc- § 226.40 Production and control proce- tion. dures. (c) Provide for adequate washing, Production and control procedures cleaning, toilet, and locker facilities. shall include all reasonable pre- Work areas and equipment used for the cautions, including the following, to production of Type A medicated arti- assure that the Type A medicated article(s) or for the storage of the compo- cle(s) produced have the identity, nents of Type A medicated article(s) strength, quality, and purity they pur- shall not be used for the production, port to possess: mixing or storage of finished or unfin- (a) Each critical step in the process, ished insecticides, fungicides, such as the selection, weighing, and rodenticides, or other pesticides or measuring of components; the addition their components unless such mate- of drug components during the process; rials are recognized as approved drugs weighing and measuring during various intended for use in animal feeds. stages of the processing; and the determination of the finished yield, shall be § 226.30 Equipment. performed by one or more competent, Equipment used for the manufacture, responsible individuals. If such steps in processing, packaging, bulk shipment, the processing are controlled by preci- labeling, holding, or control of Type A sion, automatic, mechanical, or elec- medicated article(s) or their compo- tronic equipment, their proper per- nents shall be maintained in a clean formance shall be adequately checked and orderly manner and shall be of by one or more competent, responsible suitable design, size, construction, and individuals. location to facilitate maintenance and (b) All containers to be used for undi- operation for its intended purpose. The luted drugs, drug components, inter- equipment shall: mediate mixtures thereof, and Type A (a) Be so constructed that any sur- medicated article(s) shall be received, faces that come into contact with Type adequately identified, and properly A medicated article(s) are suitable, in stored and handled in a manner ade- that they are not reactive, additive, or quate to avoid mixups and contamina- absorptive to an extent that signifi- tion. cantly affects the identity, strength, (c) Equipment, including dust-con- quality, or purity of the Type A medi- trol and other equipment, such as that cated article(s) or its components. used for holding and returning recov- (b) Be so constructed that any sub- ered or flush-out materials back into stance required for the operation of the production, shall be maintained and equipment, such as lubricants, cool- operated in a manner to avoid contami- ants, etc., may be employed without nation of the Type A medicated arti- hazard of becoming an unsafe additive cle(s) and to insure the integrity of the to the Type A medicated article(s). finished product. (c) Be constructed to facilitate ad- (d) Competent and responsible per- justment, cleaning, and maintenance, sonnel shall check actual against theo- and to assure uniformity of production retical yield of a batch of Type A medi- and reliability of control procedures cated article(s), and, in the event of

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any significant discrepancies, key per- § 226.58 Laboratory controls. sonnel shall prevent distribution of the Laboratory controls shall include the batch in question and other associated establishment of adequate specifica- batches of Type A medicated article(s) tions and test procedures to assure that may have been involved in a that the drug components and the Type mixup with it. A medicated article(s) conform to ap- (e) Adequate procedures for cleaning propriate standards of identity, of those parts of storage, mixing con- strength, quality, and purity. Labora- veying and other equipment coming in tory controls shall include: contact with the drug component of (a) The establishment of master the Type A medicated article(s) shall records containing appropriate speci- be used to avoid contamination of Type fications and a description of the test A medicated article(s). procedures used to check them for each (f) If there is sequential production of kind of drug component used in the batches of a Type A medicated arti- manufacture of Type A medicated article(s) containing the same drug compo- cle(s). This may consist of the manu- nent (or components) at the same or facturer’s or supplier’s statement of lower levels, there shall be sufficient specifications and methods of analyses. safeguards to avoid any buildup above (b) The establishment of specifica- the specified levels of the drug compo- tions for Type A medicated article(s) nents in any of the batches of the Type and a description of necessary labora- A medicated article(s). tory test procedures to check such (g) Production and control proce- specifications. dures shall include provision for dis- (c) Assays which shall be made of continuing distribution of any Type A representative samples of finished medicated article(s) found by the assay Type A medicated article(s) in accord- procedures, or other controls per- ance with the following schedule: formed to fail to conform to appro- (1) Each batch of a Type A medicated priate specifications. Distribution of article(s) manufactured from an undi- subsequent production of such Type A luted drug shall be assayed for its drug medicated article(s) shall not begin component(s). until it has been determined that prop- (2) In the case of Type A medicated er control procedures have been estab- article(s) which are manufactured by lished. dilution of Type A medicated article(s) assayed in accordance with paragraph § 226.42 Components. (c)(1) of this section, each batch shall be assayed for its drug component(s) (a) Drug components, including undi- with the first five consecutive batches luted drugs and any intermediate assaying within the limitations, fol- mixes containing drugs used in the lowed thereafter by assay of represent- manufacture and processing of Type A ative samples of not less than 5 percent medicated article(s), shall be received, of all batches produced. When any examined or tested, stored, handled, batch does not assay within limita- and otherwise controlled in a manner tions, each batch should again be as- to maintain the integrity and identi- sayed until five consecutive batches fication of such articles. Appropriate are within limitations. receipt and inventory records shall be (d) A determination establishing that maintained for 2 years, and such the drug components remain uniformly records shall show the origin of any dispersed and stable in the Type A drug components, the manufacturer’s medicated article(s) under ordinary control number (if any), the dates and conditions of shipment, storage, and batches in which they were used, and use. This may consist of a determina- the results of any testing of them. tion on a Type A medicated article(s) (b) Nondrug components shall be of substantially the same formula and stored and otherwise handled in a man- characteristics. Suitable expiration ner to avoid contamination, including dates shall appear on the labels of the cross-contamination from manufac- Type A medicated article(s) to assure turing operations. that the articles meet the appropriate

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standards of identity, strength, qual- (2) For careful checking of labeling ity, and purity at the time of use. for identity and conformity to the la- (e) Adequate provision to check the beling specified in the batch-produc- reliability, accuracy, and precision of tion records. any laboratory test procedure used. (3) For adequate control of the quan- The official methods in ‘‘Methods of tities of labeling issued for use with Analysis of the Association of Official the Type A medicated article(s). Analytical Chemists,’’ 1 methods de- (c) Type A medicated article(s) shall scribed in an official compendium, and be distributed in suitable containers to any method submitted as a part of a insure the safety, identity, strength, food additive petition or new-drug ap- and quality of the finished product. plication that has been accepted by the Food and Drug Administration shall be Subpart E—Records and Reports regarded as meeting this provision. (f) Provisions for the maintenance of § 226.102 Master-formula and batch- the results of any assays, including production records. dates and endorsement of analysts. (a) For each Type A medicated arti- Such records shall be retained in the cle(s) master-formula records shall be possession of the manufacturer and prepared, endorsed, and dated by a shall be maintained for a period of at competent and responsible individual least 2 years after distribution by the and shall be independently checked, manufacturer of the Type A medicated reconciled, endorsed, and dated by a article(s) has been completed. second competent and responsible individual. The record shall include: [40 FR 14031, Mar. 27, 1975, as amended at 55 FR 11577, Mar. 29, 1990; 55 FR 23703, June 12, (1) The name of the Type A medi- 1990; 70 FR 40880, July 15, 2005; 70 FR 67651, cated article(s) and a specimen copy of Nov. 8, 2005] its label. (2) The weight or measure of each in- Subpart D—Packaging and gredient, adequately identified, to be used in manufacturing a stated weight Labeling of the Type A medicated article(s). § 226.80 Packaging and labeling. (3) A complete formula for each batch size, or of appropriate size in the (a) Packaging and labeling oper- case of continuous systems to be pro- ations shall be adequately controlled: duced from the master-formula record, (1) To assure that only those Type A including a complete list of ingredients medicated article(s) that have met the designated by names or codes suffi- specifications established in the mas- ciently specific to indicate any special ter-formula records shall be distrib- quality characteristics; an accurate uted. statement of the weight or measure of (2) To prevent mixups during the each ingredient, except that reasonable packaging and labeling operations. variations may be permitted in the (3) To assure that correct labeling is amount of ingredients necessary in the employed for each Type A medicated preparation of the Type A medicated article(s). article(s), provided that the variations (4) To identify Type A medicated ar- are stated in the master formula; an ticle(s) with lot or control numbers appropriate statement concerning any that permit determination of the his- calculated excess of an ingredient; and tory of the manufacture and control of a statement of the theoretical yield. the batch of Type A medicated arti- (4) Manufacturing instructions for cle(s). each type of Type A medicated arti- (b) Packaging and labeling oper- cle(s) produced on a batch or contin- ations shall provide: uous operation basis, including mixing (1) For storage of labeling in a man- steps and mixing times that have been ner to avoid mixups. determined to yield an adequately mixed Type A medicated article(s); and 1 Copies may be obtained from: AOAC in the case of Type A medicated arti- INTERNATIONAL, 481 North Frederick Ave., cle(s) produced by continuous produc- suite 500, Gaithersburg, MD 20877. tion run, any additional manufacturing

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directions including, when indicated, by competent and responsible per- the settings of equipment that have sonnel and, where indicated, appro- been determined to yield an adequately priate action shall be taken. The mixed Type A medicated article(s) of record shall indicate the evaluation the specified formula. and the action. (5) Control instructions, procedures, specifications, special notations, and PART 250—SPECIAL REQUIREMENTS precautions to be followed. FOR SPECIFIC HUMAN DRUGS (b) A separate batch-production and control record shall be prepared for Subpart A—Drugs Regarded as each batch or run of Type A medicated Misbranded article(s) produced and shall be retained for at least 2 years after dis- Sec. tribution by the manufacturer has been 250.11 Thyroid-containing drug preparations completed. The batch-production and intended for treatment of obesity in hu- control record shall include: mans. 250.12 Stramonium preparations labeled (1) Product identification, date of with directions for use in self-medication production, and endorsement by a com- regarded as misbranded. petent and responsible individual. (2) Records of each step in the manu- Subpart B—New Drug or Prescription Status facturing, packaging, labeling, and of Specific Drugs controlling of the batch, including dates, specific identification of drug 250.100 Amyl nitrite inhalant as a prescription drug for human use. components used, weights or measures 250.101 Amphetamine and methamphet- of all components, laboratory-control amine inhalers regarded as prescription results, mixing times, and the endorse- drugs. ments of the individual actively per- 250.102 Drug preparations intended for forming or the individual actively su- human use containing certain ‘‘coronary pervising or checking each step in the vasodilators’’. operation. 250.103–250.104 [Reserved] (3) A batch number that permits de- 250.105 Gelsemium-containing preparations regarded as prescription drugs. termination of all laboratory-control 250.106–250.107 [Reserved] procedures and results on the batch 250.108 Potassium permanganate prepara- and all lot or control numbers appear- tions as prescription drugs. ing on the labels of the Type A medicated article(s). Subpart C—Requirements for Drugs and Foods § 226.110 Distribution records. 250.201 Preparations for the treatment of Complete records shall be maintained pernicious anemia. for each shipment of Type A medicated article(s) in a manner that will facili- Subpart D—Requirements for Drugs and tate the recall, diversion, or destruc- Cosmetics tion of the Type A medicated article(s), if necessary. Such records shall be re- 250.250 Hexachlorophene, as a component of drug and cosmetic products. tained for at least 2 years after the date of the shipment by the manufac- AUTHORITY: 21 U.S.C. 321, 336, 342, 352, 353, turer and shall include the name and 355, 361(a), 362(a) and (c), 371, 375(b). address of the consignee, the date and SOURCE: 40 FR 14033, Mar. 27, 1975, unless quantity shipped, and the manufac- otherwise noted. turing dates, control numbers, or marks identifying the Type A medi- Subpart A—Drugs Regarded as cated article(s) shipped. Misbranded § 226.115 Complaint files. § 250.11 Thyroid-containing drug prep- Records shall be maintained for a pe- arations intended for treatment of riod of 2 years of all written or verbal obesity in humans. complaints concerning the safety or ef- (a) Investigation by the Food and ficacy of each Type A medicated arti- Drug Administration has revealed that cle(s). Complaints shall be evaluated a large number of drug preparations

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containing thyroid or thyrogenic sub- ingestion for the purpose of producing stances in combination with central hallucinations. Reports of such use nervous system stimulants, with or have been received from physicians and without one or more additional drug police and other law enforcement au- substances such as barbiturates or lax- thorities. Reports have also appeared atives, are being marketed for or as ad- in the public press and in medical jour- juncts to the treatment, control, or nals. management of obesity in humans. The (b) Labeling these products with a Commissioner of Food and Drugs finds warning that they are not for oral in- that the administration of such com- gestion has not been effective in pro- binations for said purposes is without tecting the public. Misuse of stramo- medical rationale except possibly in nium preparations can cause serious those relatively uncommon instances toxic effects including toxic delirium, where the condition is directly related visual disturbances, fever, and coma. A to hypothyroidism and there exists a number of serious reactions have al- concurrent need for appetite control ready occurred from the oral ingestion (in such instances the safety and effec- of such products. tiveness of such combinations are not (c) On the basis of this information, generally recognized). In particular, the Commissioner of Food and Drugs the Commissioner of Food and Drugs has concluded that such articles have a finds that neither the consensus of in- potentiality for harmful effect through formed medical opinion nor clinical ex- misuse and are not safe for use except perience justifies any representation under the supervision of a physician. In that such combinations are safe and ef- the interest of public health protec- fective in connection with the treat- tion, therefore, the Food and Drug Ad- ment, control, or management of obe- ministration adopts the following pol- sity in patients having normal thyroid icy: function. (1) Preparations containing stramo- (b) Combinations of thyroid or other nium supplied from the leaves, seeds, thyrogenic drugs with central nervous or any other part of the plant in the system stimulants with or without form of a powder, pipe mixture, ciga- other drug substances when offered for rette, or any other form, with or with- or as adjuncts to the treatment, con- out admixture of other ingredients, trol, or management of obesity not re- will be regarded as misbranded if they lated to hypothyroidism are regarded are labeled with directions for use in as misbranded. Such combinations self-medication. when offered for obesity in humans di- (2) The Food and Drug Administra- rectly attributable to established tion will, on request, furnish comment hypothyroidism are regarded as new on proposed labeling limiting any such drugs within the meaning of section preparation to prescription sale. 201(p) of the Federal Food, Drug, and (d) The labeling or dispensing of stra- Cosmetic Act. monium preparations contrary to this statement after 60 days following the § 250.12 Stramonium preparations la- date of its publication in the FEDERAL beled with directions for use in self- REGISTER may be made the subject of medication regarded as mis- regulatory proceedings. branded. (a) Stramonium products for inhala- Subpart B—New Drug or Prescrip- tion have been offered for use in the tion Status of Specific Drugs therapy of the acute attacks of bronchial asthma for many years although § 250.100 Amyl nitrite inhalant as a their reliability and effectiveness are prescription drug for human use. questionable. Recently, a significantly (a) Amyl nitrite inhalant has been increased number of reports have come available over-the-counter for emer- to the attention of the Food and Drug gency use by the patient in the man- Administration showing that such agement of angina pectoris for a num- products have been subject to abuse ber of years. As a result of a proposed and misuse on a fairly large scale, policy statement published August 25, mostly by young people, through oral 1967 (32 FR 12404), the Commissioner of

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Food and Drugs received reports of the sale because of their potentiality for abuse of this drug by those who do not harm to the user. require it for medical purposes. Addi- (b) It is the considered opinion of the tionally, comment included a great Food and Drug Administration that, in deal of concern expressed by individual order to adequately protect the public physicians, medical associations, phar- health, inhalers containing meth- maceutical associations, manufactur- amphetamine or methamphetamine ers, and State and local health authori- salts (d-desoxyephedrine, or dl-desoxy- ties. Based on the information avail- ephedrine, or their salts), as well as able, it is the opinion of the Commis- amphetamine inhalers should be re- sioner of Food and Drugs, concurred in stricted to prescription sale and should by the Food and Drug Administration be labeled with the statement ‘‘Rx Medical Advisory Board, that amyl ni- only.’’ trite inhalant is a drug with a potentiality for harmful effect and that it [40 FR 14033, Mar. 27, 1975, as amended at 67 should be removed from over-the- FR 4906, Feb. 1, 2002] counter status and restricted to sale on § 250.102 Drug preparations intended the prescription of a practitioner li- for human use containing certain censed by law to administer such drug. ‘‘coronary vasodilators’’. (b) Therefore, amyl nitrite inhalant will be regarded as misbranded unless (a)(1) The Food and Drug Administra- the labeling on or within the package tion finds that the following ‘‘coronary from which the drug is to be dispensed vasodilators’’ are extensively regarded bears adequate information for its safe by physicians as safe and useful as em- and effective use by physicians, in ac- ployed under medical supervision for cordance with § 201.100(c) of this chap- the management of angina pectoris in ter, and its label bears the statement some patients: ‘‘Rx only.’’ Amyl nitrite. (c) Regulatory proceedings may be Erythrityl tetranitrate. initiated with regard to the interstate Mannitol hexanitrate. shipment of amyl nitrite inhalant that Nitroglycerin. is labeled, advertised, or dispensed con- Potassium nitrite. trary to this statement of policy if Sodium nitrite. such act occurs after July 1, 1969. (2) Additionally, new-drug applica- [40 FR 14033, Mar. 27, 1975, as amended at 67 tions have been approved for products FR 4906, Feb. 1, 2002] containing:

§ 250.101 Amphetamine and meth- Inositol hexanitrate. amphetamine inhalers regarded as Isosorbide dinitrate. prescription drugs. Octyl nitrite. Pentaerythritol tetranitrate. (a) Recurring reports of abuse and Triethanolamine trinitrate biphosphate misuse of methamphetamine (also (trolnitrate phosphate). known as desoxyephedrine) inhalers show that they have a potentiality for (b) The Food and Drug Administra- harmful effect and that they should tion also finds that there is neither not be freely available to the public substantial evidence of effectiveness through over-the-counter sale. From nor a general recognition by qualified complaints by law-enforcement offi- experts that such drugs are effective cials, health officials, individual physi- for any of the other purposes for which cians, parents, and others as well as some such drugs are promoted to the from Food and Drug Administration in- medical profession in labeling and ad- vestigations, it is evident that the vertising. In particular, neither clin- wicks from these inhalers are being re- ical investigations nor clinical experi- moved and the methamphetamine they ence justify any representations that contain is being used as a substitute such drugs are effective in the manage- for amphetamine tablets. Amphet- ment of hypertension; in the manage- amine tablets and amphetamine inhal- ment of coronary insufficiency or coro- ers have been restricted to prescription nary artery disease, except for their

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anginal manifestations; or in the man- §§ 250.106–250.107 [Reserved] agement of the post coronary state, except angina pectoris present after coro- § 250.108 Potassium permanganate nary occlusion and myocardial infarc- preparations as prescription drugs. tion. (a) There have been a number of re- (c) Any preparation containing such ports in the medical literature of seri- drugs that is labeled or advertised for ous injuries to women resulting from any use other than management of an- the misuse of potassium permanganate gina pectoris, or that is represented to in an effort to induce abortion. Reports be efficacious for any other purpose by from physicians who have treated such reason of its containing such drug, will cases show that the injuries are com- be regarded by the Food and Drug Ad- monly caused by introducing tablets or ministration as misbranded and subject crystals of potassium permanganate to regulatory proceedings, unless such into the vagina. Experience with these cases shows that such use of potassium recommendations are covered by the permanganate is not effective in pro- approval of a new-drug application ducing abortion, but that instead the based on a showing of safety and effec- drug produces serious and painful in- tiveness. jury to the walls of the vagina, causing (d) Any such drug in long-acting dos- ulcers, massive hemorrhage, and infec- age form is regarded as a new drug that tion. Such dangerous and useless em- requires an approved new-drug applica- ployment of potassium permanganate tion before marketing. is apparently encouraged among the (e) Any of the drugs listed in para- misinformed by the mistaken idea that graph (a)(2) of this section is regarded the vaginal bleeding caused by the cor- as a new drug that requires an ap- rosive action of the drug indicates a proved new-drug application. Articles termination of pregnancy, which it for which new-drug approvals are now does not. in effect should be covered by supple- (b) Potassium permanganate is a mental new-drug applications as nec- strong oxidizing agent, a highly caus- essary to provide for labeling revisions tic, tissue-destroying chemical, and a consistent with this policy statement. poison. There are no circumstances under which crystals and tablets of po- §§ 250.103–250.104 [Reserved] tassium permanganate constitute safe dosage forms for use in self-medica- § 250.105 Gelsemium-containing prep- tion. It is the consensus of informed arations regarded as prescription medical opinion that the only dosage drugs. forms of potassium permanganate It is the consensus of informed med- known to be safe for use in self-medica- ical opinion that the margin of safety tion are aqueous solutions containing between the therapeutic and toxic con- not more than 0.04 percent potassium centration of gelsemium is narrow and permanganate. Such solutions are safe it is difficult to predict the point at for use in self-medication only by ex- which the dose will be toxic. Very ternal application to the skin. small doses may cause toxic symptoms. (c) In view of the very real poten- It is therefore the view of the Food and tiality for harmful effect, and the ac- Drug Administration that gelsemium tual injuries caused by the misuse of is not a proper ingredient in any prod- potassium permanganate, the Food and uct that is to be sold without prescrip- Drug Administration believes that in tion. Accordingly, any drug containing order adequately to protect the public gelsemium will be regarded as mis- health: (1) Potassium permanganate and po- branded under section 503(b)(4) of the tassium permanganate tablets intended Federal Food, Drug, and Cosmetic Act for human use are drugs subject to sec- if its label fails to bear in a prominent tion 503(b)(1) of the Federal Food, and conspicuous fashion the statement Drug, and Cosmetic Act and should be ‘‘Rx only.’’ restricted to prescription sale. Such [40 FR 14033, Mar. 27, 1975, as amended at 67 drugs will be regarded as misbranded if FR 4906, Feb. 1, 2002] at any time prior to dispensing the

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label fails to bear the statement ‘‘Rx publication in the FEDERAL REGISTER only.’’ may be made the subject of regulatory (2) Potassium permanganate labeled proceedings. for use as a prescription component in [40 FR 14033, Mar. 27, 1975, as amended at 67 human drugs under the exemption pro- FR 4906, Feb. 1, 2002] vided in § 201.120 of this chapter or labeled for manufacturing use under the Subpart C—Requirements for exemption provided in § 201.122 of this chapter will be regarded as misbranded Drugs and Foods unless the label bears the statement, § 250.201 Preparations for the treat- ‘‘Rx only.’’ ment of pernicious anemia. (3) These drugs will be regarded as (a) The ninth announcement of the misbranded when intended for veteri- Anti-anemia Preparations Advisory nary use unless the label bears the leg- Board of the United States Pharma- end, ‘‘Caution: Federal law restricts copeia is concerned with the status of this drug to sale by or on the order of the treatment of pernicious anemia. It a licensed veterinarian’’; Provided, how- clearly presents the following facts: ever, That this shall not apply to a drug (1) The Sixteenth Revision of the labeled and marketed for veterinary Pharmacopeia of the United States, use if such drug contains not more which became official on October 1, than 50 percent of potassium per- 1960, does not include preparations in- manganate and includes other ingredi- tended for the treatment of pernicious ents which make it unsuitable for anemia by oral administration. human use and unlikely that the arti- (2) The U.S.P. unit for anti-anemia cle would be used in an attempt to in- preparations no longer has any signifi- duce abortion. cance. (4) Any preparation of potassium per- (3) The U.S.P. Anti-anemia Prepara- manganate intended for over-the- tions Advisory Board was disbanded. counter sale for human use internally (b) On the basis of the scientific evi- or by application to any mucous mem- dence and conclusions summarized in branes or for use in the vagina will be the statement of the U.S.P. Anti-ane- regarded as misbranded under the pro- mia Preparations Advisory Board as visions of section 502(f) (1) and (2) and well as pertinent information from section 502(j) of the act. other sources, the Commissioner of (5) Any other preparation of potas- Food and Drugs finds it is the con- sium permanganate intended for over- sensus of well informed medical opin- the-counter sale for human use will be ion that: regarded as misbranded under section (1) The parenteral administration of 502(f) (1) and (2) and section 502(j) of the cyanocobalamin or vitamin B12 is gen- act unless, among other things, all of erally recognized as a fully effective the following conditions are met: treatment of pernicious anemia. Paren- (i) It is an aqueous solution con- teral cyanocobalamin preparations taining not more than 0.04 percent po- have not been and are not authorized tassium permanganate. for use except by or on the prescription (ii) The label and labeling bear, in of a duly licensed medical practitioner. juxtaposition with adequate directions (2) Some patients afflicted with per- for use, clear warning statements des- nicious anemia do not respond to oral- ignated as ‘‘Warning,’’ and to the ef- ly ingested products. There is no fect: ‘‘Warning—For external use on known way to predict which patients the skin only. Severe injury may result will fail to respond or will cease to re- from use internally or as a douche. spond to the treatment of pernicious Avoid contact with mucous mem- anemia with orally ingested prepara- branes.’’ tions. (d) The labeling or dispensing of any (3) The substitution of a possibly in- potassium permanganate preparations adequate treatment, such as the inges- intended for drug use within the juris- tion of oral preparations of vitamin B12 diction of the Federal Food, Drug, and with intrinsic factor concentrate, in Cosmetic Act contrary to this state- place of parenteral vitamin B12 prod- ment after 60 days from the date of its ucts for a disease condition as serious

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as pernicious anemia cannot be re- ing of section 503(b) of the Federal garded as safe in all cases. Food, Drug, and Cosmetic Act unless it (4) The development of the classical is labeled with the statement ‘‘Rx symptoms of pernicious anemia that only.’’ would cause a person to seek medical (e) Any drug for oral ingestion in- attention may in some cases be delayed tended, represented, or advertised for by oral ingestion of intrinsic factor. the prevention or treatment of per- Pernicious anemia is a disease that is nicious anemia or which purports to associated, among other things, with a contain any substance or mixture of higher than normal incidence of cancer substances described in paragraph (d) of the stomach and that for the safety of this section (other than diagnostic of the patient, requires continuous ex- drugs containing radioactive cyano- pert medical supervision. cobalamin) will be regarded as mis- (5) With inadequate treatment there branded under sections 502 (f)(2) and (j) may be markedly deleterious effects on of the act unless its labeling bears a the nervous system. It is well estab- statement to the effect that some pa- lished that whereas the development of tients afflicted with pernicious anemia anemia is completely reversible with may not respond to the orally ingested adequate treatment, the involvement product and that there is no known of the nervous system may not be com- way to predict which patients will re- pletely reversible and thus may result spond or which patients may cease to in permanent damage. respond to the orally ingested prod- (6) Some hematologists prescribe oral ucts. The labeling shall also bear a preparations of vitamin B12 in the statement that periodic examinations treatment of pernicious-anemia pa- and laboratory studies of pernicious tients. anemia patients are essential and rec- (7) Intrinsic factor and intrinsic fac- ommended. tor concentrate serve no known useful (f) Under section 409 of the Federal therapeutic or nutritive purpose except Food, Drug, and Cosmetic Act, intrin- to the extent that they do increase the sic factor and intrinsic factor con- gastrointestinal absorption of vitamin centrate are regarded as food additives. B12 in patients with a deficiency or ab- No food additive regulation nor exist- sence of intrinsic factor, which may ing extension of the effective date of eventually lead to pernicious anemia. section 409 of the act authorizes these This conclusion does not apply to diag- additives in foods, including foods for nostic procedures using radioactive special dietary uses. Any food con- cyanocobalamin. taining added intrinsic factor or intrin- (8) Medical expertise is required for sic factor concentrate will be regarded the diagnosis as well as the manage- as adulterated within the meaning of ment of pernicious anemia. section 402(a)(2)(C) of the act. (c) The Eleventh Edition of The Na- (g) Regulatory action may be initi- tional Formulary and its first Interim ated with respect to any article Revision include monographs for oral shipped within the jurisdiction of the preparations of vitamin B12 with in- act contrary to the provisions of this trinsic factor concentrate, establish a policy statement after the 180th day unit of vitamin B12 with intrinsic fac- following publication of this statement tor concentrate, and provide for a Na- in the FEDERAL REGISTER. tional Formulary Anti-anemia Prep- arations Advisory Board to assign the [40 FR 14033, Mar. 27, 1975, as amended at 67 potency of such preparations. This pro- FR 4906, Feb. 1, 2002] vides for the availability of such oral preparations, standardized within the Subpart D—Requirements for meaning of the broad limits char- Drugs and Cosmetics acteristic of the evaluation of such preparations. § 250.250 Hexachlorophene, as a com- (d) Any drug that is offered for or ponent of drug and cosmetic prod- purports to contain intrinsic factor or ucts. intrinsic factor concentrate will be re- (a) Antibacterial component. The use of garded as misbranded within the mean- hexachlorophene as an antibacterial

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component in drug and cosmetic prod- and the labeling on or within the pack- ucts has expanded widely in recent age from which the drug is to be dis- years. It is used in such products be- pensed bears adequate information for cause of its bacteriostatic action its safe and effective use by practi- against gram-positive organisms, espe- tioners, in accord with § 201.100(c) of cially against strains of staphy- this chapter. lococcus; however, hexachlorophene of- (2) The Food and Drug Administra- fers no protection against gram-nega- tion recognizes that hexachlorophene tive infections. In addition the anti- is useful as a bacteriostatic skin bacterial activity depends largely on cleanser. It further concludes that the repeated use. A notice published in the margin of safety is such that products FEDERAL REGISTER of April 4, 1972 (37 containing hexachlorophene may ap- FR 6775), invited data on OTC anti- propriately be used within clearly de- microbial ingredients, including lineated conditions of use. hexachlorophene, for review by an OTC (3) In order for such drugs to bear Drug Advisory Review Panel to be con- adequate information for safe and ef- vened under the procedures set forth in fective use the following statements the FEDERAL REGISTER of May 11, 1972 are representative of the type of label- (37 FR 9464). This statement of policy ing for products shown to be effective will remain in effect unless and until bacteriostatic skin cleansers. Labeling replaced by a monograph resulting for products other than bacteriostatic from the OTC Drug Advisory Review skin cleansers will be determined Panel. through the new drug procedures based (b) Adverse effects. Though considered on the available data. safe for many years, recent informa- (i) In the labeling other than on the tion has become available associating immediate container label. hexachlorophene with toxic effects, including deaths. Studies have shown INDICATIONS that toxic amounts of hexachlorophene can be absorbed through the skin of hu- 1. Bacteriostatic skin cleanser for surgical mans, especially the skin of premature scrubbing or handwashing as part of patient care. babies or damaged skin. Human tox- 2. For topical application to control an icity reports include data on symp- outbreak of gram-positive infection where tomatology, blood and tissue levels of other infection control procedures have been hexachlorophene, and descriptions of unsuccessful. Use only as long as necessary neuropathologic lesions. Recent infant for infection control. deaths due to use of baby powder accidentally contaminated with 6 percent CONTRAINDICATIONS hexachlorophene have occurred. The 1. Not for use on burned or denuded skin or accumulated evidence of toxicity is on mucous membranes. sufficient to require that continued 2. Not for routine prophylactic total body marketing of hexachlorophene con- bathing. taining products be carefully defined in WARNINGS order to protect consumers. (c) Prescription drugs. (1) Because of Rinse thoroughly after use. Patients their potential for harmful effect, should be closely monitored and use should be immediately discontinued at the first sign drugs containing hexachlorophene, of any of the symptoms described below. other than as a preservative as de- Hexachlorophene is rapidly absorbed and scribed below, are not considered to may produce toxic blood levels when applied have been shown to be safe and effec- to skin lesions such as ichthyosis congenita tive, are regarded as new drugs requir- or the dermatitis of Letterer-Siwe’s syn- ing approved new drug applications, drome or other generalized dermatologic and would be misbranded for over-the- conditions. Application to burns has also counter distribution. In the interest of produced neurotoxicity and death. public health protection, Infants have developed dermatitis, irrita- bility, generalized clonic muscular contrac- hexachlorophene containing drugs will tions and decerebrate rigidity following ap- be regarded as misbranded and subject plication of a 6 percent hexachlorophene to regulatory proceedings unless the powder. Examination of brainstems of those label bears the statement ‘‘Rx only,’’ infants revealed vacuolization like that

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which can be produced in newborn experi- cation in accord with § 314.50 of the new mental animals following repeated topical drug regulations (21 CFR 314.50), in- application of 3 percent hexachlorophene. cluding blood level data obtained from Moreover, a study of histologic sections of use of the drug as recommended. premature infants who died of unrelated causes has shown a positive correlation be- (5) Prescription drug products may tween hexachlorophene baths and lesions in contain hexachlorophene as part of an white matter of brains. effective preservative system only under the conditions and limitations (ii) On the immediate container label provided for under paragraph (d) of this prominently displayed and in bold section. print: (d) Over-the-counter (OTC) drugs. ‘‘Special Warning: This compound may be Over-the-counter drug products, other toxic if used other than as directed. Rinse than those which in normal use may be thoroughly after use. Monitor patients close- applied to mucous membranes or which ly for toxicity symptoms.’’ are intended to be used on mucous (4) Marketing of products for the in- membranes, may contain dications listed in paragraph (c)(3) of hexachlorophene only as part of an ef- this section may be continued without fective preservative system, at a level an approved new drug application (or that is no higher than necessary to required supplement thereto) either achieve the intended preservative func- until a notice of opportunity for hear- tion, and in no event higher than 0.1 ing is issued on a proposal by the Di- percent. Such use of hexachlorophene rector of the Center for Drug Evalua- shall be limited to situations where an tion and Research to refuse to approve alternative preservative has not yet such new drug application (or required been shown to be as effective or where supplement) or until January 31, 1978, adequate integrity and stability data whichever comes first, if all the fol- for the reformulated product are not lowing conditions were met after Sep- yet available. This use of tember 27, 1972: hexachlorophene will not, by itself, re- (i) The product is labeled with the quire an approved new drug applica- statement ‘‘Rx only’’ and adequate in- tion. Use of hexachlorophene as a pre- formation for safe and effective use as servative at a level higher than 0.1 per- set forth in paragraph (c)(3) of this sec- cent is regarded as a new drug use re- tion. quiring an approved new drug applica- (ii) Within 30 days, or by (10–27–72) tion, which must be submitted within the holder of an approved new drug ap- the time set out in paragraph (c)(4) of plication submits a supplement to pro- this section. vide for the revised label and full dis- (e) Cosmetics. Hexachlorophene may closure labeling. As the label and label- be used as a preservative in cosmetic ing will have been put into use, the products other than those which in supplement should be submitted under normal use may be applied to mucous the provision of § 314.70(c)(6)(iii) of this membranes or which are intended to be chapter. used on mucous membranes, at a level (iii) Within 30 days, or by (10–27–72) that is no higher than necessary to the holder of an approved new drug ap- achieve the intended preservative func- plication submits a supplement to pro- tion, and in no event higher than 0.1 vide for a revised formulation where percent. Such use of hexachlorophene appropriate to comply with this order. shall be limited to situations where an (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.

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(1) Adequate safety data do not pres- 290.5 Drugs; statement of required warning. ently exist to justify wider use of 290.6 Spanish-language version of required hexachlorophene in cosmetics. warning. (2) Antibacterial ingredients used as 290.10 Definition of emergency situation. substitutes for hexachlorophene in cos- Subpart B [Reserved] metic products, and finished cosmetic products containing such ingredients, Subpart C—Requirements for Specific shall be adequately tested for safety Controlled Drugs [Reserved] prior to marketing. Any such ingredient or product whose safety is not AUTHORITY: 21 U.S.C. 352, 353, 355, 371. adequately substantiated prior to marketing may be adulterated and will in SOURCE: 40 FR 14040, Mar. 27, 1975, unless any event be deemed misbranded unless otherwise noted. it contains a conspicuous front panel statement that the product has not Subpart A—General Provisions been adequately tested for safety and may be hazardous. § 290.1 Controlled substances. (f) Content statement. All reference to Any drug that is a controlled sub- hexachlorophene limit in this order is stance listed in schedule II, III, IV, or on a weight-in-weight (w/w) basis. V of the Federal Controlled Substances Quantitative declaration of Act or implementing regulations must hexachlorophene content on the label- be dispensed by prescription only as re- ing of the products, where required, quired by section 503(b)(1) of the Fed- shall be on a w/w basis. eral Food, Drug, and Cosmetic Act un- (g) Shipments of products. Shipments less specifically exempted in § 290.2. of products falling within the scope of paragraphs (c), (d), or (e) of this section [67 FR 4906, Feb. 1, 2002] which are not in compliance with the § 290.2 Exemption from prescription guidelines stated herein shall be the requirements. subject of regulatory proceedings after the effective date of the final order. The prescription-dispensing require- (h) Prior notices. This order preempts ments of section 503(b)(1) of the Fed- any conditions for marketing products eral Food, Drug, and Cosmetic Act are set forth in the following prior notices. not necessary for the protection of the public health with respect to a com- 1. DESI No. 4749 (34 FR 15389, October 2, 1969), pound, mixture, or preparation con- ‘‘Certain OTC Drugs for Topical Use.’’ taining not more than 200 milligrams 2. DESI No. 2855 (35 FR 12423, August 4, 1970), ‘‘Certain Mouthwash and Gargle Prepara- of codeine per 100 milliliters or per 100 tions.’’ grams that also includes one or more 3. DESI No. 8940 (36 FR 14510, August 6, 1971), nonnarcotic active medicinal ingredi- ‘‘Topical Cream Containing Pyrilamine ents in sufficient proportion to confer Maleate, Benzocaine, Hexachlorophene, upon the compound, mixture, or prepa- and Cetrimonium Bromide.’’ ration valuable medicinal qualities 4. DESI No. 6615 (36 FR 18022, September 8, other than those possessed by codeine 1971), ‘‘Deodorant/Antiperspirant.’’ alone. 5. DESI No. 6270 (36 FR 23330, December 8, 1971), ‘‘Certain Preparations Containing [67 FR 4907, Feb. 1, 2002] Hexachlorophene’’. [40 FR 14033, Mar. 27, 1975, as amended at 42 § 290.5 Drugs; statement of required FR 63773, Dec. 20, 1977; 55 FR 11577, Mar. 29, warning. 1990; 67 FR 4906, Feb. 1, 2002; 69 FR 18763, Apr. The label of any drug listed as a 8, 2004] ‘‘controlled substance’’ in schedule II, III, or IV of the Federal Controlled PART 290—CONTROLLED DRUGS Substances Act shall, when dispensed to or for a patient, contain the fol- Subpart A—General Provisions lowing warning: ‘‘Caution: Federal law Sec. prohibits the transfer of this drug to 290.1 Controlled substances. any person other than the patient for 290.2 Exemption from prescription require- whom it was prescribed.’’ This statements. ment is not required to appear on the

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label of a controlled substance dis- 299.4 Established names for drugs. pensed for use in clinical investiga- 299.5 Drugs; compendial name. tions which are ‘‘blind.’’ AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 358, 360b, 371. § 290.6 Spanish-language version of required warning. SOURCE: 40 FR 14041, Mar. 27, 1975, unless otherwise noted. By direction of section 305(c) of the Federal Controlled Substances Act, § 290.5, promulgated under section Subpart A—General Provisions 503(b) of the Federal Food, Drug, and Cosmetic Act, requires the following § 299.3 Definitions and interpretations. warning on the label of certain drugs (a) As used in this part 299, act means when dispensed to or for a patient: the Federal Food, Drug, and Cosmetic ‘‘Caution: Federal law prohibits the Act, sections 201–902, 52 Stat. 1040 (21 transfer of this drug to any person U.S.C. 321–392), with all amendments other than the patient for whom it was thereto. prescribed.’’ The Spanish version of (b) The definitions and interpreta- this is: ‘‘Precaucion: La ley Federal tions contained in section 201 of the act prohibe el transferir de esta droga a shall be applicable to such terms when otra persona que no sea el paciente used in this part 299. para quien fue recetada.’’ (c) The term official name means, with respect to a drug or ingredient § 290.10 Definition of emergency situa- thereof, the name designated in this tion. part 299 under section 508 of the act as For the purposes of authorizing an the official name. oral prescription of a controlled substance listed in schedule II of the Fed- § 299.4 Established names for drugs. eral Controlled Substances Act, the (a) Section 508 of the Federal Food, term emergency situation means those Drug, and Cosmetic Act (added by the situations in which the prescribing Kefauver-Harris Drug Amendments of practitioner determines: 1962; Pub. L. 87–781) authorizes the (a) That immediate administration of Commissioner of Food and Drugs to the controlled substance is necessary, designate an official name for any drug for proper treatment of the intended if he determines that such action is ultimate user; and necessary or desirable in the interest of (b) That no appropriate alternative usefulness and simplicity. Section treatment is available, including ad- 502(e) of the act (as amended by said ministration of a drug which is not a Drug Amendments) prescribes that the controlled substance under schedule II labeling of a drug must bear its estab- of the Act, and lished name, if there is one, to the ex- (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 cific Controlled Drugs [Re- (1) an official name designated pursu- served] ant to section 508 of the act; (2) if no 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 ap- Sec. plies, then the common or usual name 299.3 Definitions and interpretations. of the drug.

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(c) The Food and Drug Administra- name, the common and usual name of tion recognizes the skill and experience the drug. Interested persons, in the ab- of the U.S. Adopted Names Council sence of the designation by the food (USAN) in deriving names for drugs. and Drug Administration of an official The U.S. Adopted Names Council is a name, may rely on as the established private organization sponsored by the name for any drug the current American Medical Association, the compendial name or the USAN adopted United States Pharmacopeia, and the name listed in USAN and the USP Dic- American Pharmaceutical Association, tionary of Drug Names. The Food and and has been engaged in the assign- Drug Administration, however, will ment of names to drugs since January continue to publish official names 1964. The Council negotiates with man- under the provisions of section 508 of ufacturing firms in the selection of the act when the agency determines nonproprietary names for drugs. that: (d) The Food and Drug Administra- (1) The USAN or other official or tion cooperates with and is represented common or usual name is unduly com- on the USAN Council. In addition, the plex or is not useful for any other rea- Food and Drug Administration agrees son; with ‘‘Guiding Principles for Coining (2) Two or more official names have U.S. Adopted Names for Drugs,’’ pub- been applied to a single drug, or to two lished in USAN and the USP Dictionary or more drugs that are identical in of Drug Names (USAN 1985 ed., 1961–1984 chemical structure and pharma- cumulative list), which is incorporated cological action and that are substan- by reference. Copies are available from: tially identical in strength, quality, U.S. Pharmacopeial Convention, Inc., and purity; or 12601 Twinbrook Parkway, Rockville, (3) No USAN or other official or com- MD 20852, or are available for inspec- mon or usual name has been applied to tion at the National Archives and a medically useful drug. Any official Records Administration (NARA). For name published under section 508 of the information on the availability of this act will be the established name of the material at NARA, call 202–741–6030, or drug. go to: http://www.archives.gov/ (f) A cumulative list of U.S. adopted federallregister/ names selected and released since June codeloflfederallregulations/ 15, 1961, is published yearly by the U.S. ibrllocations.html. All applicants for Pharmacopeial Convention, Inc., in new-drug applications and sponsors for USAN and the USP Dictionary of Drug ‘‘Investigational New Drug Applica- Names. Copies may be purchased from tions’’ (IND’s) are encouraged to con- the U.S. Pharmacopeial Convention, tact the USAN Council for assistance Inc., 12601 Twinbrook Parkway, Rock- in selection of a simple and useful ville, MD 20852. name for a new chemical entity. Ap- proval of a new-drug application pro- [40 FR 14041, Mar. 27, 1975, as amended at 49 viding for the use of a new drug sub- FR 37575, Sept. 25, 1984; 53 FR 5369, Feb. 24, stance may be delayed if a simple and 1988; 55 FR 11577, Mar. 29, 1990; 64 FR 401, Jan. useful nonproprietary name does not 5, 1999; 69 FR 18803, Apr. 9, 2004] exist for the substance and if one is not § 299.5 Drugs; compendial name. proposed in the application that meets the above-cited guidelines. Prior use of (a) The name by which a drug is des- a name in the medical literature or ignated shall be clearly distinguishing otherwise will not commit the Food and differentiating from any name rec- and Drug Administration to adopting ognized in an official compendium un- such terminology as official. less such drug complies in identity (e) The Food and Drug Administra- with the identity prescribed in an offi- tion will not routinely designate official compendium under such recog- cial names under section 508 of the act. nized name. As a result, the established name under (b) The term drug defined in an official section 502(e) of the act will ordinarily compendium means a drug having the be either the compendial name of the identity prescribed for a drug in an of- drug or, if there is no compendial ficial compendium.

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(c) A statement that a drug defined set forth for such drug in an official in an official compendium differs in compendium shall show all the respects strength, quality, or purity from the in which such drug so differs, and the standard of strength, quality, or purity extent of each such difference.

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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

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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—500)

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 100—199) II Office of Management and Budget Circulars and Guidance (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) VIII Department of Veterans Affairs (Parts 800—899) IX Department of Energy (Parts 900—999) 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 1880— 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 Housing and Urban Development (Parts 2400—2499) XXV National Science Foundation (Parts 2500—2599) XXVI National Archives and Records Administration (Parts 2600—2699) XXVII Small Business Administration (Parts 2700—2799) XXVIII Department of Justice (Parts 2800—2899) XXX Department of Homeland Security (Parts 3000—3099)

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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) XXXV Export-Import Bank of the United States (Parts 3500—3599) XXXVII Peace Corps (Parts 3700—3799) LVIII Election Assistance Commission (Parts 5800—5899)

Title 3—The President

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

Title 4—Accounts

I Government Accountability Office (Parts 1—99) II Recovery Accountability and Transparency Board (Parts 200— 299)

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) 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) XV Office of Administration, Executive Office of the President (Parts 2500—2599) 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) 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)

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XXXV Office of Personnel Management (Parts 4500—4599) 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) LXXI Consumer Product Safety Commission (Parts 8100—8199) LXXII Special Inspector General for Iraq Reconstruction (Parts 8200— 8299) LXXIII Department of Agriculture (Parts 8300—8399) 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 8700—8799) LXXXII Special Inspector General for Iraq Reconstruction (Parts 9200— 9299) XCVII Department of Homeland Security Human Resources Manage- ment System (Department of Homeland Security—Office of Personnel Management) (Parts 9700—9799)

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XCIX Department of Defense Human Resources Management and Labor Relations Systems (Department of Defense—Office of Personnel Management) (Parts 9900—9999)

Title 6—Domestic Security

I Department of Homeland Security, Office of the Secretary (Parts 0—99)

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) 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)

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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) L Rural Business-Cooperative Service, Rurual Housing Service, and Rural Utilities Service, Department of Agriculture (Parts 5000—5099)

Title 8—Aliens and Nationality

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)

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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 1303—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 Office of Thrift Supervision, Department of the Treasury (Parts 500—599) 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) XI Federal Financial Institutions Examination Council (Parts 1100—1199) XII Federal Housing Finance Agency (Parts 1200—1299) XIV Farm Credit System Insurance Corporation (Parts 1400—1499) XV Department of the Treasury (Parts 1500—1599) 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)

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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—499) 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 Technology Administration, Department of Commerce (Parts 1100—1199) 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)

Title 16—Commercial Practices

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

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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)

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) 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)

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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 Millenium 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) 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 HousingCommissioner, Department of Housing and Urban De- velopment (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)

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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) X Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Interstate Land Sales Registration Program) (Parts 1700—1799) 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) 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) XXV Neighborhood Reinvestment Corporation (Parts 4100—4199)

Title 25—Indians

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—799) V Bureau of Indian Affairs, Department of the Interior, and Indian Health Service, Department of Health and Human Services (Part 900) 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)

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I Internal Revenue Service, Department of the Treasury (Parts 1— 899)

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) 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)

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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 Ocean Energy Management, Regulation, and Enforce- ment, Department of the Interior (Parts 200—299) IV Geological Survey, Department of the Interior (Parts 400—499) 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) VIII Office of International Investment, 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, Departmnent 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)

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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 (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) IV Office of Vocational and Adult Education, Department of Edu- cation (Parts 400—499) V Office of Bilingual Education and Minority Languages Affairs, Department of Education (Parts 500—599) VI Office of Postsecondary Education, Department of Education (Parts 600—699) VII Office of Educational Research and Improvmeent, Department of Education [Reserved] XI National Institute for Literacy (Parts 1100—1199) SUBTITLE C—REGULATIONS RELATING TO EDUCATION 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)

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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 Copyright Office, Library of Congress (Parts 200—299) III Copyright Royalty Board, Library of Congress (Parts 301—399) IV Assistant Secretary for Technology Policy, Department of Com- merce (Parts 400—499) V Under Secretary for Technology, Department of Commerce (Parts 500—599)

Title 38—Pensions, Bonuses, and Veterans’ Relief

I Department of Veterans Affairs (Parts 0—99) II Armed Forces Retirement Home

Title 39—Postal Service

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)

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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) 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) IV Centers for Medicare & Medicaid Services, Department of Health and Human Services (Parts 400—499) V Office of Inspector General-Health Care, Department of Health and Human Services (Parts 1000—1999)

Title 43—Public Lands: Interior

SUBTITLE A—OFFICE OF THE SECRETARY OF THE INTERIOR (PARTS 1—199) SUBTITLE B—REGULATIONS RELATING TO PUBLIC LANDS

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I Bureau of Reclamation, Department of the Interior (Parts 200— 499) 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) 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) [Reserved] 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 Office of Human Development Services, 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 on Fine Arts (Parts 2100—2199) XXIII Arctic Research Commission (Part 2301) XXIV James Madison Memorial Fellowship Foundation (Parts 2400— 2499)

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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)

Title 48—Federal Acquisition Regulations System

1 Federal Acquisition Regulation (Parts 1—99) 2 Defense Acquisition Regulations System, Department of Defense (Parts 200—299) 3 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)

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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 [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) 63 Department of Transportation Board of Contract Appeals (Parts 6300—6399) 99 Cost Accounting Standards Board, Office of Federal Procure- ment Policy, Office of Management and Budget (Parts 9900— 9999)

Title 49—Transportation

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)

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X Surface Transportation Board, Department of Transportation (Parts 1000—1399) XI Research and Innovative Technology Administration, Depart- ment of Transportation [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)

CFR Index and Finding Aids

Subject/Agency Index List of Agency Prepared Indexes Parallel Tables of Statutory Authorities and Rules List of CFR Titles, Chapters, Subchapters, and Parts Alphabetical List of Agencies Appearing in the CFR

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CFR Title, Subtitle or Agency Chapter Administrative Committee of the Federal Register 1, I Administrative Conference of the United States 1, III Advanced Research Projects Agency 32, I Advisory Council on Historic Preservation 36, VIII African Development Foundation 22, XV Federal Acquisition Regulation 48, 57 Agency for International Development 22, II Federal Acquisition Regulation 48, 7 Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Agriculture Department 2, IV; 5, LXXIII 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, L Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV, L Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII, L Secretary of Agriculture, Office of 7, Subtitle A Transportation, Office of 7, XXXIII World Agricultural Outlook Board 7, XXXVIII Air Force Department 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 Appalachian Regional Commission 5, IX

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2001 21 CFR—Continued 66 FR Page 21 CFR 66 FR Chapter I—Continued Page 211.194 (a)(2) amended ...... 18889 Chapter I 291 Removed ...... 4090 200.51 Added; eff. 5–27–02...... 34089 Regulation at 66 FR 4090 eff. date 201 Compliance date extention...... 38191 delayed to 5–18–01 ...... 15347 201.66 (c)(5)(ii)(C) revised; eff. 5– 16–02 ...... 46867 (c)(5)(ii)(C) revised; eff. 5–17–02 2002 ...... 48904 21 CFR 67 FR 201.323 Regulation at 65 FR 4110 Page eff. date delayed to 1–26–03 ...... 7864 Chapter I 203 Hearing...... 56480 201 Compliance date extension...... 16304 203.3 Regulation at 64 FR 67757 ef- 201.10 (a) amended; eff. 4–2–02 ...... 4906 fective date delayed in part to 201.16 Revised; eff. 4–2–02 ...... 4906 4–1–02...... 12851 201.100 (b)(1) amended; eff. 4–2– Regulation at 64 FR 67757 effec- 02 ...... 4906 tive delayed in part to 10–01–01 ...... 25639 201.120 (b)(2) amended; eff. 4–2– 203.50 Regulation at 64 FR 67757 02 ...... 4906 effective delayed to 4–1–02 ...... 12851 201.122 Introductory text amend- Regulation at 64 FR 67761 effec- ed; eff. 4–2–02...... 4906 tive date delayed to 10–01–01 ...... 25639 201.306 (b)(1) amended; eff. 4–2– 205 Hearing...... 56480 02 ...... 4906 207 Authority citation revised...... 5466, 201.323 Regulation at 65 FR 4110 59156 eff. date delayed to 1–26–04...... 70691 207.3 (a)(5) revised; (a)(11) (c)(3) amended...... 70692 added...... 59156 203.3 Regulation at 64 FR 67761 eff. 207.7 (a) revised...... 59156 date delayed in part to 4–1– 207.10 Heading and introductory 03 ...... 6645 text revised ...... 59156 203.50 Regulation at 64 FR 67761 207.20 Heading revised, eff. 4–4–01; eff. date delayed to 4–1–03...... 6645 (f) added, eff. 1–21–03 ...... 5466 211.198 (a) amended; interim; eff. 207.21 (a) revised ...... 59157 8–11–02...... 5056 207.25 (b)(2) amended...... 59157 Regulation at 67 FR 5056 eff. date 207.37 (a) introductory text and delayed; interim ...... 49568 (b) revised...... 59157 226.1 Existing text redesignated 207.40 Revised ...... 59157 as (a); (b) added; interim; eff. 8– 211 Nomenclature change ...... 56034 11–02...... 5056

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21 CFR—Continued 67 FR 21 CFR—Continued 69 FR Page Page Chapter I—Continued Chapter I—Continued Regulation at 67 FR 5056 eff. date Regulation at 69 FR 266 with- delayed; interim ...... 49568 drawn ...... 78280 250.100 (b) amended; eff. 4–2–02 ...... 4906 201.64 Regulation at 61 FR 17806 250.101 (b) amended; eff. 4–2–02 ...... 4906 eff. date confirmed...... 13717 250.105 Amended; eff. 4–2–02...... 4906 (a), (c) and (d) revised; (j) added 250.108 (c)(1) and (2) amended; eff...... 13724 4–2–02 ...... 4906 (k) added ...... 69280 250.201 (d) amended; eff. 4–2–02 ...... 4906 201.66 (c)(7)(i) revised ...... 13733 250.250 (c)(1) and (4)(i) amended; Regulation at 64 FR 13286 and 64 eff. 4–2–02...... 4906 FR 18571 implementation date 290.1 Added; eff. 4–2–02 ...... 4906 delayed ...... 53801 290.2 Added; eff. 4–2–02 ...... 4907 201.70 Added ...... 13733 201.71 Added ...... 13734 2003 201.72 Added ...... 13734 203 Technical correction...... 12792 21 CFR 68 FR 203.3 (u) Regulation at 64 FR 67757 Page eff. date delayed to Dec. 1, Chapter I 2006 ...... 8105 201 Technical correction...... 12584 203.11 (a) revised ...... 17292 Nomenclature change ...... 24879 203.12 Amended...... 48775 201.24 Added ...... 6081 203.37 (e) amended...... 48775 201.122 Corrected; CFR correc- 203.50 Regulation at 64 FR 67761 tion ...... 55822 eff. date delayed to Dec. 1, 201.314 (h)(1) and (4) revised ...... 18869 2006 ...... 8105 201.323 Regulation at 65 FR 4110 203.70 (b)(1) amended...... 48775 eff. date delayed; (c) introduc- 206.10 (b) amended...... 18763 tory text revised; (c)(3) amend- 207.7 (d) amended ...... 48775 ed; (d) and (e) redesignated as 207.22 (a) and (b) amended...... 48775 (e) and (f); new (d) added; eff. 7– 207.37 (a) introductory text re- 26–04 ...... 32981 vised...... 48775 203.3 Regulation at 64 FR 67761 eff. 210 Authority citation revised ...... 29828 date delayed in part...... 4912 210.1 (c) added ...... 29828 203.50 Regulation at 64 FR 67761 210.2 Revised ...... 29828 eff. date delayed ...... 4912 211 Authority citation revised ...... 29828 207.20 Regulation at 66 FR 5466 eff. 211.1 (b) revised...... 29828 date delayed to 1–21–04...... 2690 250.250 (c)(4)(ii) amended...... 18763 211.198 Regulation at 67 FR 5056 withdrawn...... 15355 (a) amended; eff. 6–30–03...... 15364 2005 226.1 Regulation at 67 FR 5056 21 CFR 70 FR withdrawn...... 15355 Page Existing text designated as (a); Chapter I (b) added; eff. 6–30–03...... 15364 201.58 Amended...... 14980 203.12 Amended...... 14980 2004 203.37 (e) revised ...... 14981 206.7 (b)(1)(i) revised ...... 14981 21 CFR 69 FR 211 Nomenclature change ....40880, 67651 Page 211.194 (a)(2) amended ...... 40880 Chapter I 226 Nomenclature change ....40880, 67651 201 Technical correction...... 1320, 7114, 18255 Nomenclature change ...... 13717 2006 201.25 Added; eff. 4–26–04 ...... 9170 21 CFR 71 FR 201.59 (a)(3) table amended ...... 266 Page Regulation at 69 FR 266 eff. date Chapter I corrected to 1–4–05 ...... 1320 201.56 Revised; eff. 6-30-06...... 3986

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21 CFR—Continued 71 FR 21 CFR—Continued 72 FR Page Page Chapter I—Continued Chapter I—Continued 201.57 Redesignated as 201.80; new 211.188 (b)(11) revised; eff. 4–17– 201.57 added; eff. 6-30-06 ...... 3988 08...... 68070 201.58 Revised; eff. 6-30-06 ...... 3996 225.1 (c) revised...... 69120 201.59 Removed; eff. 6-30-06 ...... 3996 225.35 (b) revised ...... 69120 201.80 Redesignated from 201.57; 225.135 Revised ...... 69120 eff. 6-30-06...... 3988 226.1 (b) amended ...... 69120 Heading, (c)(2), (f)(2) and (m)(1) revised; (b)(2)(ii), (c)(3)(i), (v), 2008 (g)(4), (i)(6) and (j) amended; eff. 6-30-06 ...... 3996 21 CFR 73 FR Page 201.100 (d)(3) revised; eff. 6-30- 06 ...... 3996 Chapter I 201 Policy statement ...... 58739 201.66 (c)(5)(vii) amended; in- 203 Regulation at 64 FR 67756 con- terim...... 403 firmed ...... 34249 201.66 Regulation at 73 FR 403 con- Policy statement ...... 66448 firmed ...... 63897 205 Policy statement ...... 66448 203.3 (q) revised...... 59500 210.2 (c) added; eff. 6–1–06 ...... 2462 203.22 (h) and (i) added ...... 59500 Regulation at 71 FR 2462 with- 205.3 (h) revised...... 59501 drawn ...... 25747 208.20 (b)(7)(iii) added; interim ...... 404 208.20 Regulation at 73 FR 404 confirmed ...... 63897 2007 209 Added; interim...... 404 21 CFR 72 FR 209 Regulation at 73 FR 404 con- Page firmed ...... 63897 Chapter I 210 Technical correction...... 63361 201.26 Added; interim...... 73599 210.2 (c) added ...... 40462 201.66 (c)(5)(ii)(H) added; eff. 6–19– 210.3 Regulation at 72 FR 68068 08...... 71785 withdrawn...... 18440 201.105 (c)(2) and (d)(1) revised ...... 69119 (b)(6) revised ...... 51931 201.115 (a) and (b) revised...... 69119 211 Technical correction...... 63361 201.122 (a), (b) and (c) revised ...... 69119 211.48 Regulation at 72 FR 68068 201.319 (a) revised; eff. 10–1–07 ...... 14674 withdrawn...... 18440 201.325 Added; eff. 6–19–08 ...... 71785 211.67 Regulation at 72 FR 68068 202.1 (e)(4)(i)(a) revised ...... 69119 withdrawn...... 18440 207.20 (c) revised ...... 69120 (a) revised ...... 51931 207.21 (a) amended...... 69120 211.68 Regulation at 72 FR 68068 207.35 (b)(3)(v) revised ...... 69120 withdrawn...... 18440 210.3 (b)(6) revised; eff. 4–17–08 ...... 68068 (c) added ...... 51932 211.48 (a) revised; eff. 4–17–08...... 68068 211.72 Regulation at 72 FR 68068 211.67 (a) revised; eff. 4–17–08...... 68068 withdrawn...... 18440 211.68 (c) added; eff. 4–17–08 ...... 68068 Revised...... 51932 211.72 Revised; eff. 4–17–08 ...... 68068 211.82 Regulation at 72 FR 68069 211.82 (b) revised; eff. 4–17–08...... 68069 withdrawn...... 18440 211.84 (c)(1), (d)(3) and (6) revised; (b) revised ...... 51932 eff. 4–17–08...... 68069 211.84 Regulation at 72 FR 68069 211.94 (c) revised; eff. 4–17–08...... 68069 withdrawn...... 18440 211.101 (c) and (d) revised; eff. 4– (c)(1), (d)(3) and (6) revised ...... 51932 17–08 ...... 68069 211.94 Regulation at 72 FR 68069 211.103 Revised; eff. 4–17–08...... 68069 withdrawn...... 18440 211.110 (a) introductory text re- (c) revised ...... 51932 vised; (a)(6) added; eff. 4–17– 211.101 Regulation at 72 FR 68069 08...... 68069 withdrawn...... 18440 211.113 (b) revised; eff. 4–17–08 ...... 68069 (c) and (d) revised ...... 51932 211.160 (b)(1) revised; eff. 4–17– 211.103 Regulation at 72 FR 68069 08...... 68069 withdrawn...... 18440 211.182 Revised; eff. 4–17–08...... 68069 Revised...... 51932

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21 CFR—Continued 73 FR 21 CFR—Continued 74 FR Page Page Chapter I—Continued Chapter I—Continued 211.110 Regulation at 72 FR 68069 (a)(1)(iii)(A), (iv)(A)(1), (v)(A), withdrawn...... 18440 (2)(iii)(A), (iv)(A)(1), (v)(A) and (a) introductory text revised; (b) revised; eff. 4–29–10...... 61514 (a)(6) added ...... 51932 203.12 Amended...... 13112 211.113 Regulation at 72 FR 68069 203.37 (e) amended...... 13112 withdrawn...... 18440 203.70 (b)(1) amended...... 13112 (b) revised ...... 51932 206.7 (b)(1)(i) amended...... 13112 211.160 Regulation at 72 FR 68069 210.1 Amended; eff. 12–12–11 ...... 65431 withdrawn...... 18440 210.2 (a) and (b) amended; eff. 12– (b)(1) revised ...... 51932 12–11 ...... 65431 211.182 Regulation at 72 FR 68069 210.3 (a) and (b) introductory text withdrawn...... 18440 amended; eff. 12–12–11...... 65431 Revised...... 51933 211.1 (a) revised; eff. 12–12–11...... 65431 211.188 Regulation at 72 FR 68070 212 Added; eff. 12–12–11 ...... 65431 withdrawn...... 18440 (b)(11) revised...... 51933 2010 2009 (No regulations published during this year.) 21 CFR 74 FR Page Chapter I 2011 201.58 Amended...... 13112 (Regulations published from January 1, 201.66 (c)(5)(ii)(E) revised; eff. 4– 2011 through April 1, 2011) 29–10 ...... 19407 201.322 Removed; eff. 4–29–10...... 19407 21 CFR 76 FR 201.326 Added; eff. 4–29–10 ...... 19407 Page (a)(2)(iii)(A), (iv)(A)(1) and (v)(A) Chapter I corrected; eff. 4–29–10...... 31180 201.25 (d)(2) revised ...... 12847 Æ

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