Food and Drugs

21 Parts 200 to 299 Revised as of April 1, 2004

Food and Drugs

Containing a codification of documents of general applicability and future effect

As of April 1, 2004

With Ancillaries

Published by Office of the Federal Register National Archives and Records Administration

A Special Edition of the Federal Register

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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:

Material Approved for Incorporation by Reference ...... 167

Table of CFR Titles and Chapters ...... 169

Alphabetical List of Agencies Appearing in the CFR ...... 187

List of CFR Sections Affected ...... 197

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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, 2004), 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<24>2004 15:04 Jul 07, 2004 Jkt 203067 PO 00000 Frm 00005 Fmt 8008 Sfmt 8092 Y:\SGML\203067F.XXX 203067F 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 January 1, 2001, consult either the List of CFR Sections Affected, 1949–1963, 1964–1972, 1973–1985, or 1986–2000, published in 11 separate volumes. For the period beginning January 1, 2001, a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume. 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. Properly approved incorporations by reference in this volume are listed in the Finding Aids at the end of this volume. What if the material incorporated by reference cannot be found? If you have any problem locating or obtaining a copy of material listed in the Finding Aids of this volume 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, Washington DC 20408, 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 Statutory Authorities and Agency Rules (Table I). A list of CFR titles, chapters, 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. 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.

VerDate mar<24>2004 15:04 Jul 07, 2004 Jkt 203067 PO 00000 Frm 00006 Fmt 8008 Sfmt 8092 Y:\SGML\203067F.XXX 203067F 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, Washington, DC 20408 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 202–512–2250, 24 hours a day. For payment by check, write to the Superintendent of Documents, Attn: New Orders, P.O. Box 371954, Pittsburgh, PA 15250–7954. For GPO Customer Serv- ice call 202–512–1803. ELECTRONIC SERVICES The full text of the Code of Federal Regulations, The United States Govern- ment Manual, the Federal Register, Public Laws, Public Papers, Weekly Compila- tion of Presidential Documents and the Privacy Act Compilation are available in electronic format at www.gpoaccess.gov/nara. For more information, contact Electronic Information Dissemination Services, U.S. Government Printing Office. Phone 202–512–1530, or 888–293–6498 (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/federallregister. The NARA site also contains links to GPO Access.

RAYMOND A. MOSLEY, Director, Office of the Federal Register. April 1, 2004.

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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–end. The first eight volumes, containing parts 1–1299, comprise Chapter I—Food and Drug Administration, Department of Health and Human Services. The ninth volume, containing part 1300 to end, includes Chapter II—Drug Enforcement Administration, Department of Justice, 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, 2004.

For this volume, Bonnie Fritts was Chief Editor. The Code of Federal Regula- tions publication program is under the direction of Frances D. McDonald, assisted by Alomha S. Morris.

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VerDate mar<24>2004 15:04 Jul 07, 2004 Jkt 203067 PO 00000 Frm 00010 Fmt 8092 Sfmt 8092 Y:\SGML\203067F.XXX 203067F CFRORDR.FRM Title 21—Food and Drugs

(This book contains parts 200 to 299)

Part

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

CROSS REFERENCES: Food Safety and Inspection Service, Department of Agriculture: See Meat and Poultry Inspection, 9 CFR chapter III. Federal Trade Commission: See Commercial Practices, 16 CFR chapter I. U.S. Customs Service, Department of the Treasury: See Customs Duties, 19 CFR chapter I. Internal Revenue Service, Department of the Treasury: See Internal Revenue, 26 CFR chapter I. Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury: See Alcohol, To- bacco Products and Firearms, 27 CFR chapter I.

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(Parts 200 to 299)

EDITORIAL NOTE: For nomenclature changes to chapter I see 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 ...... 78 203 Prescription drug marketing ...... 86 205 Guidelines for State licensing of wholesale prescription drug distributors ...... 98 206 Imprinting of solid oral dosage form drug products for human use ...... 103 207 Registration of producers of drugs and listing of drugs in commercial distribution ...... 105 208 Medication Guides for prescription drug products .. 115 210 Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general ...... 119 211 Current good manufacturing practice for finished pharmaceuticals ...... 121 216 Pharmacy compounding...... 141 225 Current good manufacturing practice for medicated feeds ...... 142 226 Current good manufacturing practice for Type A medicated articles ...... 149 250 Special requirements for specific human drugs ...... 154 290 Controlled drugs...... 162 299 Drugs; official names and established names ...... 163

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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 Subpart B—Labeling Requirements for that charged for a prescription shall in- Prescription Drugs and/or Insulin clude all charges to the consumer including, but not limited to, the cost of 201.50 Statement of identity. the drug product, professional fees, and 201.51 Declaration of net quantity of con- handling fees, if any. Mailing fees and tents. delivery fees, if any, may be stated sep- 201.55 Statement of dosage. arately and without repetition. 201.56 General requirements on content and format of labeling for human prescrip- (b) This exemption from §§ 201.100 and tion drugs. 202.1 of this chapter is applicable to all 201.57 Specific requirements on content and prescription drug reminder labeling format of labeling for human prescrip- and reminder advertisements solely in- tion drugs. tended to provide consumers with in- 201.58 Requests for waiver of requirement formation regarding the price charged for adequate and well-controlled studies for prescriptions including price lists, to substantiate certain labeling state- catalogs, and other promotional mate- ments. 201.59 Effective date of §§ 201.56, 201.57, rial, whether mailed, posted in a phar- 201.100(d)(3), and 201.100(e). macy, placed in a newspaper, or aired on radio or television. Subpart C—Labeling Requirements for (c) Any reminder advertisement or Over-the-Counter Drugs reminder labeling intended to provide consumers with prescription price in- 201.60 Principal display panel. formation which is not in compliance 201.61 Statement of identity. 201.62 Declaration of net quantity of con- with this section shall be the subject of tents. appropriate regulatory action. Such ac- 201.63 Pregnancy/breast-feeding warning. tion may be taken against the product 201.64 Sodium labeling. and/or the responsible person. 201.66 Format and content requirements for over-the-counter (OTC) drug product la- [40 FR 58799, Dec. 18, 1975] beling. 201.70 Calcium labeling. PART 201—LABELING 201.71 Magnesium labeling. 201.72 Potassium labeling. Subpart A—General Labeling Provisions Subpart D—Exemptions From Adequate Sec. Directions for Use 201.1 Drugs; name and place of business of manufacturer, packer, or distributor. 201.100 Prescription drugs for human use. 201.2 Drugs and devices; National Drug Code 201.105 Veterinary drugs. numbers. 201.115 New drugs or new animal drugs. 201.5 Drugs; adequate directions for use. 201.116 Drugs having commonly known di- 201.6 Drugs; misleading statements. rections. 201.10 Drugs; statement of ingredients. 201.117 Inactive ingredients.

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201.119 In vitro diagnostic products. 201.317 Digitalis and related cardiotonic 201.120 Prescription chemicals and other drugs for human use in oral dosage prescription components. forms; required warning. 201.122 Drugs for processing, repacking, or 201.319 Water-soluble gums, hydrophilic manufacturing. gums, and hydrophilic mucilloids (in- 201.125 Drugs for use in teaching, law en- cluding, but not limited to agar, alginic forcement, research, and analysis. acid, calcium polycarbophil, 201.127 Drugs; expiration of exemptions. carboxymethylcellulose sodium, carra- 201.128 Meaning of ‘‘intended uses’’. geenan, chondrus, glucomannan ((B-1,4 201.129 Drugs; exemption for radioactive linked) polymannose acetate), guar gum, drugs for research use. karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil Subpart E—Other Exemptions tragacanth, and xanthan gum) as active ingredients; required warnings and direc- 201.150 Drugs; processing, labeling, or re- tions. packing. 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 201.322 Over-the-counter drug products containing internal analgesic/antipyretic ac- 201.200 Disclosure of drug efficacy study tive ingredients; required alcohol warn- evaluations in labeling and advertising. ing. 201.323 Aluminum in large and small vol- Subpart G—Specific Labeling ume parenterals used in total parenteral Requirements for Specific Drug Products nutrition. APPENDIX A TO PART 201—EXAMPLES OF 201.300 Notice to manufacturers, packers, GRAPHIC ENHANCEMENTS USED BY FDA and distributors of glandular preparations. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 201.301 Notice to manufacturers, packers, 355, 358, 360, 360b, 360gg–360ss, 371, 374, 379e; 42 and distributors of estrogenic hormone U.S.C. 216, 241, 262, 264. preparations. 201.302 Notice to manufacturers, packers, SOURCE: 40 FR 13998, Mar. 27, 1975, unless and distributors of drugs for internal use otherwise noted. which contain mineral oil. EDITORIAL NOTE: Nomenclature changes to 201.303 Labeling of drug preparations con- part 201 appear at 69 FR 13717, Mar. 24, 2004. taining significant proportions of wintergreen oil. 201.304 Tannic acid and barium enema prep- Subpart A—General Labeling arations. Provisions 201.305 Isoproterenol inhalation preparations (pressurized aerosols, nebulizers, § 201.1 Drugs; name and place of busi- powders) for human use; warnings. ness of manufacturer, packer, or 201.306 Potassium salt preparations in- distributor. tended for oral ingestion by man. 201.307 Sodium phosphates; package size (a) A drug or drug product (as defined limitation, warnings, and directions for in § 320.1 of this chapter) in finished over-the-counter sale. package form is misbranded under sec- 201.308 Ipecac syrup; warnings and direction 502 (a) and (b)(1) of the act if its tions for use for over-the-counter sale. label does not bear conspicuously the 201.309 Acetophenetidin (phenacetin)-con- name and place of business of the man- taining preparations; necessary warning ufacturer, packer, or distributor. This statement. 201.310 Phenindione; labeling of drug prep- paragraph does not apply to any drug arations intended for use by man. or drug product dispensed in accord- 201.311 [Reserved] ance with section 503(b)(1) of the act. 201.312 Magnesium sulfate heptahydrate; (b) As used in this section, and for label declaration on drug products. purposes of section 502 (a) and (b)(1) of 201.313 Estradiol labeling. the act, the manufacturer of a drug 201.314 Labeling of drug preparations con- product is the person who performs all taining salicylates. 201.315 Over-the-counter drugs for minor of the following operations that are re- sore throats; suggested warning. quired to produce the product: (1) Mix- 201.316 Drugs with thyroid hormone activity ing, (2) granulating, (3) milling, (4) for human use; required warning. molding, (5) lyophilizing, (6) tableting,

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(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 stating on the product label that ‘‘Cer- owned or leased by the person and sub- tain manufacturing operations have ject to the person’s direction and con- been performed by other firms.’’; or trol; and (2) If the person performs at least one (3) On equipment that is continu- applicable operation listed in para- ously owned or leased by the person. As graph (b) of this section and identifies used in this paragraph, person, when it by appropriate designation all other identifies a corporation, includes a par- persons who have performed the re- ent, subsidiary, or affiliate company maining applicable operations, e.g., where the related companies are under ‘‘Made by (Person A), Filled by (Person common ownership and control. B), Sterilized by (Person C)’’; or (f) The name of the person rep- (3) If the person performs at least one resented as manufacturer under para- applicable operation listed in paragraph (b) or (c) of this section must be graph (b) of this section and the person the same as either (1) the name of the is listed along with all other persons establishment (as defined in § 207.3(b) of who have performed the remaining ap- this chapter) under which that person plicable operations as ‘‘joint manufac- is registered at the time the labeled turers.’’ A list of joint manufacturers product is produced or (2) the reg- shall be qualified by the phrase istered establishment name of a par- ‘‘Jointly Manufactured By ent, subsidiary, or affiliate company llllll,’’ and the names of all of where the related companies are under the manufacturers shall be printed to- common ownership and control. In ad- gether in the same type size and style; dition, the name shall meet the re- or quirements of paragraph (g) of this sec- (4) If the person performs all application. ble operations listed in paragraph (b) of this section except for those operations (g) The requirement for declaration listed in paragraph (d) of this section. of the name of the manufacturer, pack- For purposes of this paragraph, person, er, or distributor shall be deemed to be when it identifies a corporation, in- satisfied, in the case of a corporate per- cludes a parent, subsidiary, or affiliate son, only by the actual corporate company where the related companies name, except that the corporate name are under common ownership and con- may be the name of a parent, sub- trol. sidiary, or affiliate company where the (d) The Food and Drug Administra- related companies are under common tion finds that it is the common prac- ownership and control. The corporate tice in the drug industry to contract name may be preceded or followed by out the performance of certain manu- the name of the particular division of facturing operations listed in para- the corporation. ‘‘Company,’’ ‘‘Incor- graph (b) of this section. These oper- porated,’’ etc., may be abbreviated or ations include: (1) Soft-gelatin encap- omitted and ‘‘The’’ may be omitted. In sulating, (2) aerosol filling, (3) steri- the case of an individual, partnership, lizing by irradiation, (4) lyophilizing, or association, the name under which and (5) ethylene oxide sterilization. the business is conducted shall be used.

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(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 [45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. trademark. The label may also state 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 Drug Code numbers. (5) If the distributor is named on the 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 llllll’’, ‘‘Distributed pear on all drug labels and in all drug by llllll’’, ‘‘Manufactured by labeling, including the label of any pre- llllll for llllll’’, ‘‘Manu- scription drug container furnished to a factured for lllllby lllll’’, consumer. If the NDC number is shown ‘‘Distributor: llllll’’, ‘‘Marketed on a drug label, it shall be displayed as by llllll’’. The qualifying phrases required in § 207.35(b)(3) of this chapter. may be abbreviated. [40 FR 52002, Nov. 7, 1975] (6) If the packer is identified on the label, the name shall be qualified by § 201.5 Drugs; adequate directions for the phrase ‘‘Packed by llllll’’ or use. ‘‘Packaged by llllll’’. The quali- Adequate directions for use means di- fying phrases may be abbreviated. rections under which the layman can (i) The statement of the place of busi- use a drug safely and for the purposes ness shall include the street address, for which it is intended. (Section city, State, and ZIP Code. For a foreign 201.128 defines ‘‘intended use.’’) Direc- manufacturer, the statement of the tions for use may be inadequate be- place of business shall include the cause, among other reasons, of omis- street address, city, country, and any sion, in whole or in part, or incorrect applicable mailing code. The street ad- specification of: dress may be omitted if it is shown in (a) Statements of all conditions, pur- a current city directory or telephone poses, or uses for which such drug is in- directory. The requirement for inclu- tended, including conditions, purposes, sion of the ZIP Code shall apply to con- or uses for which it is prescribed, rec- sumer commodity labels developed or ommended, or suggested in its oral, revised after July 1, 1969. In the case of written, printed, or graphic adver- nonconsumer packages, the ZIP Code tising, and conditions, purposes, or

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

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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 chem- such column of running text in larger ical action. size type, the established name shall be (f) If an ingredient is a derivative or used at least once in association with, preparation of a substance specifically and in type at least half as large as the named in section 502(e) of the act and type used for, the most prominent pres- the established name of such ingre- entation of the proprietary name or dient does not indicate that it is a de- designation in such column of running rivative or preparation of the parent text. Where the established name is re- substance named in section 502(e) of quired to accompany or to be used in the act, the labeling shall, in conjunc- association with the proprietary name tion with the listing of the established or designation, the established name name of such ingredient, declare that shall be placed in direct conjunction such article is a derivative or prepara- with the proprietary name or designation of such parent substance. tion, and the relationship between the (g)(1) If the label or labeling of a pre- proprietary name or designation and scription drug bears a proprietary the established name shall be made name or designation for the drug or clear by use of a phrase such as ‘‘brand any ingredient thereof, the established of’’ preceding the established name, by name, if such there be, corresponding brackets surrounding the established to such proprietary name or designa- name, or by other suitable means. tion shall accompany such proprietary (2) The established name shall be name or designation each time it is printed in letters that are at least half featured on the label or in the labeling as large as the letters comprising the for the drug; but, except as provided in proprietary name or designation with this subparagraph, the established which it is joined, and the established name need not be used with the propri- name shall have a prominence com- etary name or designation in the run- mensurate with the prominence with ning text of the label or labeling. On which such proprietary name or des- any label or page of labeling in which ignation appears, taking into account the proprietary name or designation is all pertinent factors, including typog- not featured but is used in the running raphy, layout, contrast, and other text, the established name shall be printing features. used at least once in the running text (h)(1) In the case of a prescription in association with such proprietary drug containing two or more active in- name or designation and in the same gredients, if the label bears a propri- type size used in such running text: etary name or designation for such Provided, however, That if the propri- mixture and there is no established

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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 (iv) The name of the manufacturer, vignettes, or crowding with other writ- packer, or distributor of the drug; and ten, printed, or graphic matter. (2) All the information required to (b) No exemption depending on insuf- appear on the label by the act and the ficiency of label space, as prescribed in regulations in this chapter appears on regulations promulgated under section the carton or other outer container or 502 (b) or (e) of the act, shall apply if wrapper if such carton, outer con- such insufficiency is caused by: tainer, or wrapper has sufficient space (1) The use of label space for any to bear such information, or such com- word, statement, design, or device plete label information appears on a which is not required by or under au- leaflet with the package. thority of the act to appear on the [40 FR 13998, Mar. 27, 1975, as amended at 67 label; FR 4906, Feb. 1, 2002] (2) The use of label space to give greater conspicuousness to any word, § 201.15 Drugs; prominence of required statement, or other information than label statements. is required by section 502(c) of the act; (a) A word, statement, or other infor- or mation required by or under authority (3) The use of label space for any rep- of the act to appear on the label may resentation in a foreign language.

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(c)(1) All words, statements, and diate container and also the outer other information required by or under package, if any, unless it is easily leg- authority of the act to appear on the ible through such outer package. How- label or labeling shall appear thereon ever, when single-dose containers are in the English language: Provided, how- packed in individual cartons, the expi- ever, That in the case of articles dis- ration date may properly appear on the tributed solely in the Commonwealth individual carton instead of the imme- of Puerto Rico or in a Territory where diate product container. the predominant language is one other [43 FR 45076, Sept. 29, 1978] than English, the predominant language may be substituted for English. § 201.18 Drugs; significance of control (2) If the label contains any represen- numbers. tation in a foreign language, all words, The lot number on the label of a drug statements, and other information re- should be capable of yielding the com- quired by or under authority of the act plete manufacturing history of the to appear on the label shall appear package. An incorrect lot number may thereon in the foreign language. be regarded as causing the article to be (3) If the labeling contains any rep- misbranded. resentation in a foreign language, all words, statements, and other informa- § 201.19 Drugs; use of term ‘‘infant’’. tion required by or under authority of The regulations affecting special die- the act to appear on the label or label- tary foods (§ 105.3(e) of this chapter) de- ing shall appear on the labeling in the fine an infant as a child not more than foreign language. 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 FD&C Yellow No. 5 and/or FD&C of the warning. Section 503(b)(4) of the Yellow No. 6 in certain drugs for Federal Food, Drug, and Cosmetic Act human use. requires, at a minimum, that the label (a) The label for over-the-counter and bear the statement ‘‘Rx only.’’ The 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 FD&C Yellow No. 5 as a color additive § 201.17 Drugs; location of expiration using the names FD&C Yellow No. 5 date. and tartrazine. The labeling for over- When an expiration date of a drug is the-counter and prescription drug prod- required, e.g., expiration dating of drug ucts shall bear a statement such as products required by § 211.137 of this ‘‘Contains FD&C Yellow No. 5 chapter, it shall appear on the imme- (tartrazine) as a color additive’’ or

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‘‘Contains color additives including phenylalanine and aspartic acid. When 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 over- (b) The label and labeling of all overall incidence of FD&C Yellow No. 5 the-counter human drug products con- (tartrazine) sensitivity in the general taining aspartame as an inactive ingre- population is low, it is frequently seen dient shall bear a statement to the fol- in patients who also have aspirin lowing effect: Phenylketonurics: Con- hypersensitivity.’’ This warning state- tains Phenylalanine (l)mg Per (Dos- ment shall appear in the ‘‘Precautions’’ age Unit). section of the labeling. (c) The package labeling and other (c) The label for over-the-counter labeling providing professional use in- drug products intended for human use formation concerning prescription administered orally, nasally, rectally, drugs for human use containing aspar- or vaginally containing FD&C Yellow tame as an inactive ingredient shall No. 6 shall specifically declare the bear a statement to the following ef- presence of FD&C Yellow No. 6 by list- fect under the ‘‘Precautions’’ section of ing the color additive using the name the labeling, as required in § 201.57(f)(2): FD&C Yellow No. 6. The labeling for Phenylketonurics: Contains over-the-counter and prescription drug Phenylalanine (l)mg Per (Dosage products containing FD&C Yellow No. Unit). 6 shall declare the presence of FD&C (d) Holders of approved new drug ap- Yellow No. 6. The labels of certain drug plications who reformulate their drug products subject to this labeling re- products under the provisions of this quirement that are also cosmetics, section shall submit supplements under such as antibacterial mouthwashes and § 314.70 of this chapter to provide for fluoride toothpastes, need not comply the new composition and the labeling with this requirement provided they changes. comply with the requirements of § 701.3 of this chapter. (Approved by the Office of Management and Budget under control number 0910–0242) [45 FR 60422, Sept. 12, 1980, as amended at 51 FR 41783, Nov. 19, 1986; 52 FR 21509, June 8, [52 FR 2111, Jan. 20, 1987; 52 FR 12152, April 1987; 59 FR 60898, Nov. 29, 1994] 15, 1987; 53 FR 4135, Feb. 12, 1988] EFFECTIVE DATE NOTE: At 53 FR 49138, Dec. § 201.22 Prescription drugs containing 6, 1988, § 201.20(c) was suspended pending fur- sulfites; required warning state- ther agency action. ments. § 201.21 Declaration of presence of (a) Sulfites are chemical substances phenylalanine as a component of that are added to certain drug products aspartame in over-the-counter and to inhibit the oxidation of the active prescription drugs for human use. drug ingredient. Oxidation of the ac- (a) Aspartame is the methylester of a tive drug ingredient may result in in- dipeptide composed of two amino acids, stability and a loss of potency of the

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drug product. Examples of specific sul- § 201.23 Required pediatric studies. fites used to inhibit this oxidation (a) A manufacturer of a marketed process include sodium bisulfite, so- drug product, including a biological dium metabisulfite, sodium sulfite, po- drug product, that is used in a substan- tassium bisulfite, and potassium tial number of pediatric patients, or metabisulfite. Recent studies have that provides a meaningful therapeutic demonstrated that sulfites may cause benefit over existing treatments for pe- allergic-type reactions in certain sus- diatric patients, as defined in ceptible persons, especially asthmatics. §§ 314.55(c)(5) and 601.27(c)(5) of this The labeling for any prescription drug chapter, but whose label does not pro- product to which sulfites have been vide adequate information to support added as an inactive ingredient, regard- its safe and effective use in pediatric less of the amount added, must bear populations for the approved indica- the warning specified in paragraph (b) tions may be required to submit an ap- or (c) of this section. plication containing data adequate to (b) The labeling required by §§ 201.57 assess whether the drug product is safe and 201.100(d) for prescription drugs for and effective in pediatric populations. human use containing a sulfite, except The application may be required to epinephrine for injection when in- contain adequate evidence to support tended for use in allergic or other dosage and administration in some or emergency situations, shall bear the all pediatric subpopulations, including warning statement ‘‘Contains (insert neonates, infants, children, and adoles- the name of the sulfite, e.g., sodium cents, depending upon the known or ap- metabisulfite), a sulfite that may cause propriate use of the drug product in allergic-type reactions including such subpopulations. The applicant anaphylactic symptoms and life- may also be required to develop a pedi- threatening or less severe asthmatic atric formulation for a drug product episodes in certain susceptible people. that represents a meaningful thera- The overall prevalence of sulfite sensi- peutic benefit over existing therapies tivity in the general population is un- for pediatric populations for whom a known and probably low. Sulfite sensi- pediatric formulation is necessary, un- tivity is seen more frequently in asth- less the manufacturer demonstrates matic than in nonasthmatic people.’’ that reasonable attempts to produce a This statement shall appear in the pediatric formulation have failed. ‘‘Warnings’’ section of the labeling. (b) The Food and Drug Administra- (c) The labeling required by §§ 201.57 tion (FDA) may by order, in the form and 201.100(d) for sulfite-containing epi- of a letter, after notifying the manu- nephrine for injection for use in aller- facturer of its intent to require an as- gic emergency situations shall bear the sessment of pediatric safety and effec- warning statement ‘‘Epinephrine is the tiveness of a pediatric formulation, and preferred treatment for serious allergic after offering an opportunity for a or other emergency situations even written response and a meeting, which though this product contains (insert the may include an advisory committee name of the sulfite, e.g., sodium meeting, require a manufacturer to metabisulfite), a sulfite that may in submit an application containing the other products cause allergic-type re- information or request for approval of actions including anaphylactic symp- a pediatric formulation described in toms or life-threatening or less severe paragraph (a) of this section within a asthmatic episodes in certain suscep- time specified in the order, if FDA tible persons. The alternatives to using finds that: epinephrine in a life-threatening situa- (1) The drug product is used in a sub- tion may not be satisfactory. The pres- stantial number of pediatric patients ence of a sulfite(s) in this product for the labeled indications and the ab- should not deter administration of the sence of adequate labeling could pose drug for treatment of serious allergic significant risks to pediatric patients; or other emergency situations.’’ This or statement shall appear in the ‘‘Warn- (2) There is reason to believe that the ings’’ section of the labeling. drug product would represent a mean- [51 FR 43904, Dec. 5, 1986] ingful therapeutic benefit over existing

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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 (C) The absence of adequate labeling only to treat or prevent infections that are 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- that age group have failed. ceptibility information are available, they (3) FDA shall grant a full or partial should be considered in selecting or modi- waiver, as appropriate, if the agency fying antibacterial therapy. In the absence finds that there is a reasonable basis of such data, local epidemiology and suscep- tibility patterns may contribute to the em- on which to conclude that one or more piric selection of therapy. of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this sec- (c) In the ‘‘Precautions’’ section, tion have been met. If a waiver is under the ‘‘General’’ subsection, the la- granted on the ground that it is not beling must state: possible to develop a pediatric formulation, the waiver will cover only those Prescribing (insert name of antibacterial drug product) in the absence of a proven or pediatric age groups requiring that for- strongly suspected bacterial infection or a mulation. If a waiver is granted be- prophylactic indication is unlikely to pro- cause there is evidence that the prod- vide benefit to the patient and increases the uct would be ineffective or unsafe in risk of the development of drug-resistant pediatric populations, this information bacteria.

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(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). product is ‘‘commonly used in hos- When (insert name of antibacterial drug prod- pitals’’ if it is packaged for hospital uct) is prescribed to treat a bacterial infec- use, labeled for hospital use (or uses tion, patients should be told that although it 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) Where does the bar code go? decrease the effectiveness of the immediate (1) Each drug product described in treatment and (2) increase the likelihood paragraph (b) of this section must have that bacteria will develop resistance and will a bar code that contains, at a min- not be treatable by (insert name of antibacterial drug product) or other antibacterial imum, the appropriate National Drug drugs in the future. Code (NDC) number in a linear bar code that meets European Article Number/ [68 FR 6081, Feb. 6, 2003] Uniform Code Council (EAN.UCC) or § 201.25 Bar code label requirements. Health Industry Business Communica- tions Council (HIBCC) standards. Addi- (a) Who is subject to these bar code re- tionally, the bar code must: ? Manufacturers, repackers, quirements (i) Be surrounded by sufficient blank relabelers, and private label distribu- space so that the bar code can be tors of a human prescription drug prod- scanned correctly; and uct or an over-the-counter (OTC) drug (ii) Remain intact under normal con- product that is regulated under the ditions of use. Federal Food, Drug, and Cosmetic Act 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) Can a drug be exempted from the bar Drug, and Cosmetic Act. code requirement? (b) What drugs are subject to these bar (1) On our own initiative, or in re- code requirements? The following drug sponse to a written request from a products are subject to the bar code manufacturer, repacker, relabeler or label requirements: private label distributor, we may ex- (1) Prescription drug products, how- empt a drug product from the bar code ever: label requirements set forth in this sec- (i) The bar code requirement does not tion. The exemption request must doc- apply to the following entities: ument 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 (E) Radiopharmaceuticals; and the request could not reasonably be ad- (F) Low-density polyethylene form dressed by measures such as package fill and seal containers that are not redesign or use of overwraps; or packaged with an overwrap. (ii) an alternative regulatory pro- (ii) The bar code requirement does gram or method of product use renders not apply to prescription drugs sold by the bar code unnecessary for patient a manufacturer, repacker, relabeler, or safety. private label distributor directly to pa- (2) Requests for an exemption should tients, but versions of the same drug be sent to the Office of New Drugs product that are sold to or used in hos- (HFD-020), Center for Drug Evaluation

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and Research, Food and Drug Adminis- if the drug is liquid. When the drug tration, 5600 Fishers Lane, Rockville, quantity statement is in terms of the MD 20857 (requests involving a drug numerical count of the drug units, it product) or to the Office of Compliance shall be augmented to give the weight and Biologics Quality (HFM-600), Cen- or measure of the drug units or the ter for Biologics Evaluation and Re- quantity of each active ingredient in search, Food and Drug Administration, each drug unit or, when quantity does 1401 Rockville Pike, Rockville, MD not accurately reflect drug potency, a 20852 (requests involving a biological statement of the drug potency. product). (b) Statements of weight of the con- [69 FR 9170, Feb. 26, 2004] tents shall in the case of prescription drugs be expressed in terms of avoirdu- EFFECTIVE DATE NOTE: At 69 FR 9170, Feb. pois pound, ounce, and grain or of kilo- 26, 2004, § 201.25 was added, effective Apr. 26, 2004. gram, gram, and subdivisions thereof. A statement of liquid measure of the contents shall in the case of prescrip- Subpart B—Labeling Requirements tion 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 weight if the drug is solid, semi-solid, of the next smaller whole unit and or viscous, or in terms of fluid measure common or decimal fractions thereof.

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(g) The declaration of net quantity of § 201.56 General requirements on con- contents shall express an accurate tent and format of labeling for statement of the quantity of contents human prescription drugs. of the package. Reasonable variations Prescription drug labeling described caused by loss or gain of moisture dur- in § 201.100(d) shall contain the informa- ing the course of good distribution tion in the format required by § 201.57 practice or by unavoidable deviations and shall meet the following general in good manufacturing practice will be requirements: recognized. Variations from stated (a) The labeling shall contain a sum- quantity of contents shall not be un- mary of the essential scientific infor- reasonably large. In the case of a liquid mation needed for the safe and effec- drug in ampules or vials, intended for tive use of the drug. (b) The labeling shall 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. measure shall comply with the excess (c) The labeling shall be based when- volume prescribed by the National For- ever possible on data derived from mulary or the U.S. Pharmacopeia for human experience. No implied claims filling of ampules. In the case of a solid or suggestions of drug use may be made drug in ampules or vials, the declara- if there is inadequate evidence of safe- tion shall be considered to express the ty or a lack of substantial evidence of accurate net weight. Variations shall effectiveness. Conclusions based on comply with the limitations provided animal data but necessary for safe and in the U.S. Pharmacopeia or the Na- effective use of the drug in humans tional Formulary. shall be identified as such and included (h) A drug shall be exempt from com- with human data in the appropriate pliance with the net quantity declara- section of the labeling, headings for tion required by this section if it is an which are listed in paragraph (d) of this ointment labeled ‘‘sample’’, ‘‘physi- section. cian’s sample’’, or a substantially simi- (d)(1) The labeling shall contain spe- lar statement and the contents of the cific information required under § 201.57 package do not exceed 8 grams. under the following section headings and in the following order: § 201.55 Statement of dosage. Description. Section 201.100(b)(2) requires that la- Clinical Pharmacology. Indications and Usage. bels for prescription drugs bear a state- Contraindications. ment of the recommended or usual dos- Warnings. age. Since the dosage for some pre- Precautions. scription drugs varies within extremely Adverse Reactions. wide limits, depending upon the condi- Drug Abuse and Dependence. Overdosage. tions being treated, it may not be pos- Dosage and Administration. sible in all cases to present an inform- How Supplied. ative or useful statement of the rec- (2) The labeling may contain the fol- ommended or usual dosage in the space lowing additional section headings if available on the label or carton of the appropriate and if in compliance with package. It is the view of the Food and § 201.57 (l) and (m): Drug Administration that when such a situation prevails, compliance with Animal Pharmacology and/or Animal Toxi- cology. this requirement would be met by a Clinical Studies. statement such as ‘‘See package insert References. for dosage information’’, where the detailed information is contained in such (3) The labeling may omit any section or subsection of the labeling for- insert. However, if an informative, re- mat if clearly inapplicable. alistic, recommended or usual dosage (4) The labeling may contain a can readily be set forth on the label, it ‘‘Product Title’’ section preceding the should appear thereon. ‘‘Description’’ section and containing

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only the information required by wise pertinent to human therapeutics. § 201.57(a)(1)(i), (ii), (iii), and (iv) and Pharmacokinetic information that is § 201.100(e). The information required important to safe and effective use of by § 201.57(a)(1)(i), (ii), (iii), and (iv) the drug is required, if known, e.g., de- shall appear in the ‘‘Description’’ sec- gree and rate of absorption, pathways tion of the labeling, whether or not it of biotransformation, percentage of also appears in a ‘‘Product Title.’’ dose as unchanged drug and metabo- (e) The labeling shall contain the lites, rate or half-time of elimination, date of the most recent revision of the concentration in body fluids associated labeling, identified as such, placed with therapeutic and/or toxic effects, prominently immediately after the last degree of binding to plasma proteins, section of the labeling. degree of uptake by a particular organ [44 FR 37462, June 26, 1979] or in the fetus, and passage across the blood brain barrier. Inclusion of phar- § 201.57 Specific requirements on con- macokinetic information is restricted tent and format of labeling for to that which relates to clinical use of human prescription drugs. 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(b) 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

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in patients with congestive heart fail- (iii) If there are specific conditions ure; and/or that should be met before the drug is (iii) The drug is indicated for the re- used on a long-term basis, e.g., dem- lief of symptoms associated with a dis- onstration of responsiveness to the ease or syndrome, e.g., drug in a short-term trial, the labeling chlorpheniramine is indicated for the shall identify the conditions; or, if the symptomatic relief of nasal congestion indications for long-term use are dif- in patients with vasomotor rhinitis; ferent from those for short-term use, and/or the labeling shall identify the specific (iv) The drug, if used for a particular indications for each use. indication only in conjuction with a (iv) If there is a common belief that primary mode of therapy, e.g., diet, the drug may be effective for a certain surgery, or some other drug, is an ad- use or if there is a common use of the junct to the mode of therapy. drug for a condition, but the prepon- (2) All indications shall be supported derance of evidence related to the use by substantial evidence of effectiveness or condition shows that the drug is in- based on adequate and well-controlled effective, the Food and Drug Adminis- studies as defined in § 314.126(b) of this tration may require that the labeling chapter unless the requirement is state that there is a lack of evidence waived under § 201.58 or § 314.126(b) of that the drug is effective for that use or condition. this chapter. (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(b) 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(b) 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 (ii) If safety considerations are such adverse reactions and potential safety that the drug should be reserved for hazards, limitations in use imposed by certain situations, e.g., cases refrac- them, and steps that should be taken if tory to other drugs, this information they occur. The labeling shall be re- shall be stated in this section. vised to include a warning as soon as

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there is reasonable evidence of an asso- reprinted at the end of the labeling. ciation of a serious hazard with a drug; The print size requirements for the a causal relationship need not have Medication Guide set forth in § 208.20 of been proved. A specific warning relat- this chapter, however, do not apply to ing to a use not provided for under the the Medication Guide that is reprinted ‘‘Indications and Usage’’ section of the in the professional labeling. labeling may be required by the Food (3) Laboratory tests. This subsection of and Drug Administration if the drug is the labeling shall identify any labora- commonly prescribed for a disease or tory tests that may be helpful in fol- condition, and there is lack of substan- lowing the patient’s response or in tial evidence of effectivenes for that identifying possible adverse reactions. disease or condition, and such usage is If appropriate, information shall be associated with serious risk or hazard. provided on such factors as the range Special problems, particularly those of normal and abnormal values ex- that may lead to death or serious in- pected in the particular situation and jury, may be required by the Food and the recommended frequency with Drug Administration to be placed in a which tests should be done before, dur- prominently displayed box. The boxed ing, and after therapy. warning ordinarily shall be based on (4)(i) Drug interactions. This sub- clinical data, but serious animal tox- section of the labeling shall contain icity may also be the basis of a boxed specific practical guidance for the phy- warning in the absence of clinical data. sician on preventing clinically signifi- If a boxed warning is required, its loca- cant drug/drug and drug/food inter- tion will be specified by the Food and actions that may occur in vivo in pa- Drug Administration. The frequency of tients taking the drug. Specific drugs these serious adverse reactions and, if or classes of drugs with which the drug known, the approximate mortality and to which the labeling applies may morbidity rates for patients sustaining interact in vivo shall be identified, and the reaction, which are important to the mechanism(s) of the interaction safe and effective use of the drug, shall shall be briefly described. Information be expressed as provided under the in this subsection of the labeling shall ‘‘Adverse Reactions’’ section of the la- be limited to that pertaining to clin- beling. ical use of the drug in patients. Drug (f) Precautions. Under this section interactions supported only by animal heading, the labeling shall contain the or in vitro experiments may not ordi- following subsections as appropriate narily be included, but animal or in for the drug: vitro data may be used if shown to be (1) General. This subsection of the la- clinically relevant. Drug incompati- beling shall contain information re- bilities, i.e., drug interactions that garding any special care to be exer- may occur when drugs are mixed in cised by the practitioner for safe and vitro, as in a solution for intravenous effective use of the drug, e.g., pre- administration, shall be discussed cautions not required under any other under the ‘‘Dosage and Administra- specific section or subsection of the lation’’ section of the labeling rather beling. than under this subsection of the label- (2) Information for patients. This sub- ing. section of the labeling shall contain in- (ii) Drug/laboratory test interactions. formation to be given to patients for This subsection of the labeling shall safe and effective use of the drug, e.g., contain practical guidance on known precautions concerning driving or the interference of the drug with labora- concomitant use of other substances tory tests. that may have harmful additive ef- (5) Carcinogenesis, mutagenesis, impair- fects. Any printed patient information ment of fertility. This subsection of the or Medication Guide required under labeling shall state whether long-term this chapter to be distributed to the studies in animals have been performed patient shall be referred to under the to evaluate carcinogenic potential and, ‘‘Precautions’’ section of the labeling if so, the species and results. If repro- and the full text of such patient infor- duction studies or other data in ani- mation or Medication Guide shall be mals reveal a problem or potential

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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, studies are available and they fail to development, and functional matura- demonstrate a risk to the fetus, the lation of the child. beling shall also state: ‘‘Reproduction (c) Pregnancy category C. If animal re- studies have been performed in (kinds production studies have shown an ad- of animal(s)) at doses up to (x) times the verse effect on the fetus, if there are no human dose and have revealed no evi- adequate and well-controlled studies in dence of impaired fertility or harm to humans, and if the benefits from the the fetus due to (name of drug).’’ The use of the drug in pregnant women may

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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 based on adverse reaction data from in- hypoglycemia) that may occur because vestigational or marketing experience of a pregnant woman’s chronic use of or studies in humans, but the potential the drug for a preexisting condition or benefits from the use of the drug in disease. pregnant women may be acceptable de- (7) Labor and delivery. If the drug has spite its potential risks (for example, if a recognized use during labor or deliv- the drug is needed in a life-threatening ery (vaginal or abdominal delivery), situation or serious disease for which whether or not the use is stated in the safer drugs cannot be used or are inef- indications section of the labeling, this fective), the labeling shall state: subsection of the labeling shall de- ‘‘Pregnancy Category D. See ‘Warn- scribe the available information about ings’ section.’’ Under the ‘‘Warnings’’ the effect of the drug on the mother section, the labeling states: ‘‘(Name of and the fetus, on the duration of labor drug) can cause fetal harm when ad- or delivery, on the possibility that for- ministered to a pregnant woman. ceps delivery or other intervention or (Describe the human data and any perti- resuscitation of the newborn will be nent animal data.) If this drug is used necessary, and the effect of the drug on during pregnancy, or if the patient be- the later growth, development, and comes pregnant while taking this drug, functional maturation of the child. If the patient should be apprised of the any information required under this potential hazard to the fetus.’’ subsection is unknown, this subsection (e) Pregnancy category X. If studies in of the labeling shall state that the in- animals or humans have demonstrated formation is unknown. fetal abnormalities or if there is posi- (8) Nursing mothers. (i) If a drug is ab- tive evidence of fetal risk based on ad- sorbed systemically, this subsection of verse reaction reports from investiga- the labeling shall contain, if known, in- tional or marketing experience, or formation about excretion of the drug

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

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

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

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

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and adverse reactions within each cat- logical and physical dependence that egory shall be listed in decreasing occur with the drug and shall identify order of severity. The approximate fre- the quantity of the drug over a period quency of each adverse reaction shall of time that may lead to tolerance or be expressed in rough estimates or or- dependence, or both. Details shall be ders of magnitude essentially as fol- provided on the adverse effects of lows: ‘‘The most frequent adverse reac- chronic abuse and the effects of abrupt tion(s) to (name of drug) is (are) (list re- withdrawal. Procedures necessary to actions). This (these) occur(s) in about diagnose the dependent state shall be (e.g., one-third of patients; one in 30 provided, and the principles of treating patients; less than one-tenth of pa- the effects of abrupt withdrawal shall tients). Less frequent adverse reactions be described. are (list reactions), which occur in ap- (i) Overdosage. Under this section proximately (e.g., one in 100 patients). heading, the labeling shall describe the Other adverse reactions, which occur signs, symptoms, and laboratory find- rarely, in approximately (e.g., one in ings of acute overdosage and the gen- 1,000 patients), are (list reactions).’’ Per- eral principles of treatment. This sec- cent figures may not ordinarily be used tion shall be based on human data, unless they are documented by ade- when available. If human data are un- quate and well-controlled studies as de- available, appropriate animal and in fined in § 314.126(b) of this chapter, they vitro data may be used. Specific infor- are shown to reflect general experi- mation shall be provided about the fol- ence, and they do not falsely imply a lowing: greater degree of accuracy than actu- (1) Signs, symptoms, and laboratory ally exists. findings associated with an overdosage (3) The ‘‘Warnings’’ section of the la- of the drug. beling or, if appropriate, the ‘‘Contra- (2) Complications that can occur with indications’’ section of the labeling the drug (for example, organ toxicity shall identify any potentially fatal ad- or delayed acidosis). verse reaction. (4) Any claim comparing the drug to (3) Oral LD50 of the drug in animals; which the labeling applies with other concentrations of the drug in biologic drugs in terms of frequency, severity, fluids associated with toxicity and/or or character of adverse reactions shall death; physiologic variables influ- be based on adequate and well-con- encing excretion of the drug, such as trolled studies as defined in § 314.126(b) urine pH; and factors that influence of this chapter unless this requirement the dose response relationship of the is waived under § 201.58 or § 314.126(b) 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, induced emesis, gas- types of abuse that can occur with the tric lavage, and forced diuresis. Un- drug and the adverse reactions perti- qualified recommendations for which nent to them. Particularly susceptible data are lacking with the specific drug patient populations shall be identified. or class of drugs, especially treatment (3) Dependence. This subsection of the using another drug (for example, cen- labeling shall describe characteristic tral nervous system stimulants, res- effects resulting from both psycho- piratory stimulants) may not be stated

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

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constitute, an adequate and well-con- tially deliver for introduction into trolled clinical investigation under interstate commerce any drug to which § 314.126(b) of this chapter. §§ 201.56, 201.57, 201.100(d)(3) apply unless (2) If the clinical study or reference is the drug’s labeling complies with the cited in the labeling in the place of a requirements set forth in the regula- detailed discussion of data and infor- tions, with the following exceptions: mation concerning a risk or risks from (1) If the drug is a prescription drug the use of the drug, the risk or risks that is not a biologic and not subject shall also be identified or discussed in to section 505 of the act (21 U.S.C. 355), the appropriate section of the labeling for the drug. and was not subject to former section 507 of the act (21 U.S.C. 357, repealed [44 FR 37462, June 26, 1979, as amended at 55 1997), §§ 201.56, 201.57, and 201.100(d)(3) FR 11576, Mar. 29, 1990; 59 FR 64249, Dec. 13, are effective on April 10, 1981. 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396, Dec. 1, 1998] (2) If the drug is a prescription drug that on December 26, 1979 is (i) a li- § 201.58 Requests for waiver of re- censed biologic, (ii) a new drug subject quirement for adequate and well- to an approved new drug application or controlled studies to substantiate abbreviated new drug application under certain labeling statements. section 505 of the act or (iii) an anti- A request under § 201.57(b)(2)(ii), biotic drug subject to an approved anti- (c)(2), (c)(3)(i), (c)(3)(v), (f)(9), and (g)(4) biotic form, §§ 201.56, 201.57, and for a waiver of the requirements of 201.100(d)(3) are effective on the date § 314.126(b) of this chapter shall be sub- listed below for the class of drugs to mitted in writing as provided in which the drug belongs. Dates are also § 314.126(b) to the Director, Center for Drug Evaluation and Research, Food listed below for the submission of sup- and Drug Administration, 5600 Fishers plemental applications, amendments, Lane, Rockville, MD 20587, or, if appli- and license changes. cable, the Director, Center for Bio- (3) If the drug is approved after De- logics Evaluation and Research, 8800 cember 26, 1979 but is a duplicate of a Rockville Pike, Bethesda, MD 20892. drug approved on or before that date The waiver shall be granted or denied (for example, a drug approved under an in writing by such Director or the Di- abbreviated new drug application or an rector’s designee. antibiotic form), §§ 201.56, 201.57, and [55 FR 11576, Mar. 29, 1990] 201.100(d)(3) are effective on the date listed below for the class of drugs to § 201.59 Effective date of §§ 201.56, which the drug belongs. Dates are also 201.57, 201.100(d)(3), and 201.100(e). listed below for the submission of sup- (a) On and after December 26, 1979, no plemental applications, amendments, person may initially introduce or ini- and license changes.

Revised label- Effective ing due Drug class Mail routing code

BIOLOGICS

Nov. 1, 1982 Nov. 1, 1980 Bacterial vaccines and antigens with no U.S. standard of po- HFB–240 tency. Do ...... do ...... Skin test antigens ...... HFB–240 Nov. 1, 1982 1 Nov. 1,1980 2 Bacteral vaccines and toxoids with standards of potency...... HFB–240 Do ...... do ...... Viral and rickettsial vaccines ...... HFB–240 Do ...... do ...... Allergenic extracts ...... HFB–240 Do ...... do ...... Blood and blood derivatives ...... HFB–240

NEW DRUGS AND ANTIBIOTIC DRUGS

Nov. 1, 1982 Nov. 1, 1980 Antiarrhythmics ...... HFD–110 Do ...... do ...... Replenishers and regulators of electrolytes and water balance ... HFD–110, HFD–510, and HFD–160 Do ...... do ...... Anticonvulsants ...... HFD–120 Do ...... do ...... Adrenal corticosteroids ...... HFD–510 and HFD–150 Do ...... do ...... Aminoglycosides ...... HFD–520 Do ...... do ...... Scabicides ...... Do. Do ...... do ...... Pediculicides ...... Do.

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Revised label- Effective ing due Drug class Mail routing code

Do ...... do ...... General anesthetics ...... HFD–160 Dec. 1, 1982 Dec. 1, 1980 Antivirals ...... HFD–520 Do ...... do ...... Dermatologics ...... Do. Jan. 1, 1983 .. Jan. 1, 1981 Glaucoma ophthalmics ...... HFD–520 Do ...... do ...... Topical otics ...... Do. Feb. 1, 1983 Feb. 1, 1981 Antispasmodics ...... HFD–110 Do ...... do ...... Anticholinergics ...... Do. Do ...... do ...... Diuretics ...... Do. Do ...... do ...... Narcotic antagonists ...... HFD–120 Do ...... do ...... Alcohol antagonists ...... Do. Do ...... do ...... Antipsychotics/antimanics ...... Do. Do ...... do ...... Androgens ...... HFD–510 Do ...... do ...... Anabolic steroids ...... Do. Do ...... do ...... Hyperlipidemia ...... Do. Do ...... do ...... Anthelmintics ...... HFD–520 Do ...... do ...... Antigout ...... HFD–150 Mar. 1, 1983 Mar. 1, 1981 Vaginal antibiotics ...... HFD–520 Apr. 1, 1983 .. Apr. 1, 1981 Cephalosporins ...... HFD–520 May 1, 1983 .. May 1, 1981 General analgesics ...... HFD–120 Do ...... do ...... Anterior pituitary hormones ...... HFD–510 Do ...... do ...... Hypothalamic hormones ...... Do. Do ...... do ...... Progestins ...... Do. Do ...... do ...... Mydriatic ophthalmics ...... HFD–520 Do ...... do ...... Cycloplegic ophthalmics ...... Do. Do ...... do ...... Radiopharmaceuticals, diagnostic ...... HFD–150 Do ...... do ...... Radiopharmaceuticals, therapeutic ...... Do. Do ...... do ...... Contrast agents diagnostic radiopaque ...... Do. Do ...... do ...... Local anesthetics ...... HFD–160 Do ...... do ...... Antihistamines ...... Do. June 1, 1983 June 1, 1981 Antifungals ...... HFD–520 July 1, 1983 .. July 1, 1981 .. Antidiarrheals ...... HFD–110 Do ...... do ...... Cardiac glycosides ...... Do. Do ...... do ...... Sedatives ...... HFD–120 Do ...... do ...... Hypnotics ...... Do. Do ...... do ...... Tetracyclines ...... HFD–520 Aug. 1, 1983 Aug. 1, 1981 Calcium metabolism ...... HFD–510 Do ...... do ...... Vitamins and minerals ...... Do. Do ...... do ...... Antiinfective ophthalmics ...... HFD–520 Do ...... do ...... Antiinflammatory ophthalmics ...... Do. Sept. 1, 1983 Sept. 1, 1981 Antihypertensives ...... HFD–110 Do ...... do ...... Drugs indicated for extrapyramidal movement disorders ...... HFD–120 Do ...... do ...... Antiprotozoals ...... HFD–520 Oct. 1, 1983 .. Oct. 1, 1981 Penicillins ...... HFD–520 Nov. 1, 1983 Nov. 1, 1981 Blood glucose regulators (except sulfonylureas) ...... HFD–510 Oct. 9, 1984 .. July 10, 1984 Sulfonylurea blood glucose regulators ...... HFN–130 Nov. 1, 1983 Nov. 1, 1981 Drugs indicated for parenteral nutrition ...... HFD–510 and HFD–160 Do ...... do ...... Drugs indicated for enteral nutrition ...... Do. Do ...... do ...... Miscellaneous ophthalmics ...... HFD–520 Do ...... do ...... Immunomodulators ...... HFD–150 Dec. 1, 1983 Dec. 1, 1981 Anticoagulants ...... HFD–110 Do ...... do ...... Thrombolytics ...... Do. Do ...... do ...... Drugs indicated for acid peptic disorders ...... Do. Do ...... do ...... Antidepressants ...... HFD–120 Do ...... do ...... Drugs indicated for skeletal muscle hyperactivity ...... Do. Do ...... do ...... Sulfonamides and related sulfa compounds ...... HFD–520 Do ...... do ...... Dental preparations ...... HFD–160 Jan. 1, 1984 .. Jan. 1, 1982 Miscellaneous antibacterials ...... HFD–520 Feb. 1, 1984 Feb. 1, 1982 Drugs indicated for infertility ...... HFD–510 Do ...... do ...... Thyroids ...... Do. Do ...... do ...... Antithyroids ...... Do. Do ...... do ...... Polymyxins ...... HFD–520 Do ...... do ...... Antineoplastics ...... HFD–150 Mar. 1, 1984 Mar. 1, 1982 Urinary tract stimulants ...... HFD–110 Do ...... do ...... Urinary tract relaxants ...... Do. Do ...... do ...... Antimigraine ...... HFD–120 Antimycobacterials (including antileprosy) ...... HFD–520 Do ...... do ...... Adjuncts to anethesia ...... HFD–160 Apr. 1, 1984 .. Apr. 1, 1982 Antianginals ...... HFD–110 Do ...... do ...... Laxatives ...... Do. Do ...... do ...... CNS stimulants ...... HFD–120 Do ...... do ...... Anorexiants ...... Do. Do ...... do ...... Chloramphenicol and derivatives ...... HFD–520 May 1, 1984 .. May 1, 1982 Drugs indicated for vertigo/motion sickness/vomiting ...... HFD–120

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Revised label- Effective ing due Drug class Mail routing code

Do ...... do ...... Antidiuretics ...... HFD–510 Do ...... do ...... Contraceptives ...... Do. Do ...... do ...... Macrolides ...... HFD–520 Do ...... do ...... Lincosamides ...... Do. Do ...... do ...... Antiarthritics ...... HFD–150 Do ...... do ...... Antitussives ...... HFD–160 Do ...... do ...... Expectorants ...... Do. Do ...... do ...... Inhalants ...... Do. June 1, 1984 June 1, 1982 Urinary tract antiseptics ...... HFD–520 July 1, 1984 .. July 1, 1982 .. Chelating agents/heavy metal antagonists ...... HFD–110 Do ...... do ...... All other gastrointestinal drugs ...... HFD–110 Do ...... do ...... Antianxiety ...... HFD–120 Do ...... do ...... Drugs indicated for myasthenia gravis ...... HFD–120 Do ...... do ...... All other antiinfective drugs ...... HFD–520 Do ...... do ...... Bronchodilators/antiasthmatics ...... HFD–160 Aug. 1, 1984 Aug. 1, 1982 Estrogens ...... HFD–510 Do ...... do ...... Uterine stimulants ...... HFD–510 Do ...... do ...... Uterine relaxants ...... Do. Sept. 1, 1984 Sept. 1, 1982 Drugs indicated for hypotension and shock ...... HFD–110 Oct. 1, 1984 .. Oct. 1, 1982 All other cardiac drugs ...... HFD–110 Do ...... do ...... Nasal decongestants ...... HFD–160 Nov. 1, 1984 Nov. 1, 1982 All other prescription drugs. 1 Except the effective date for all biological products reviewed generically by the advisory panel is 30 months after a final order is published under 21 CFR 601.25(g). 2 Except the due date for all biological products reviewed generically by the advisory panel is 6 months after a final order is published under 21 CFR 601.25(g).

(b) Section 201.100(e) is effective April ettsial vaccines’’ and in the NEW DRUG 10, 1981. AND ANTIBIOTIC DRUGS section of the table for the drug class ‘‘Sulfonylurea blood [45 FR 32552, May 16, 1980, as amended at 46 glucose regulators’’, under ‘‘Mail routing FR 7272, Jan. 23, 1981; 49 FR 14331, Apr. 11, code,’’ by removing ‘‘HFN–130’’ and adding in 1984; 50 FR 8995, Mar. 6, 1985; 55 FR 11576, its place ‘‘HFM–99’’, effective Jan. 4, 2003. In Mar. 29, 1990; 64 FR 400, Jan. 5, 1999] a document filed in the Office of the Federal EFFECTIVE DATE NOTE: At 69 FR 266, Jan. 5, Register on Jan. 6, 2004, the effective date 2004, § 201.59 was amended in the BIOLOGICS was corrected to read Jan. 4, 2005. At 69 FR section of the table, under ‘‘Mail Routing 1320, Jan. 8, 2004, the effective date was cor- Code’’ by removing ‘‘HFB–240’’ everywhere it rected to read Jan. 4, 2005. For the conven- appears and adding in its place ‘‘HFM–99’’; in ience of the user, the revised text follows: the BIOLOGICS section of the table, under the headings ‘‘Effective’’ and ‘‘Revised label- § 201.59 Effective date of §§ 201.56, 201.57, ing due’’ by revising the entries for the drug 201.100(d)(3), and 201.100(e). classes ‘‘Bacterial vaccines and toxoids with (a) * * * standards of potency’’ and ‘‘Viral and rick- (3) * * *

Revised labeling Effective due Drug class Mail routing code

Biologics

July 5, 2006 See footnote3 Bacterial vaccines and toxoids with HFM–99 standards of potency ******* Nov. 1, 19821 Nov. 1, 19802 Viral and rickettsial vaccines HFM–99 *******

New Drugs and Antibiotic Drugs

******* Oct. 9, 1984 July 10, 1984 Sulfonylurea blood glucose regulators HFM–99 *******

1 Except the effective date for all biological products reviewed generically by the advisory panel is 30 months after a final order is published under § 601.25(g) of this chapter. 2 Except the due date for all biological products reviewed generically by the advisory panel is 6 months after a final order is published under § 601.25(g) of this chapter. 3 FDA has determined that a review of product labeling under this section is unnecessary.

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Subpart C—Labeling Require- on the principal display panel shall ap- ments for Over-the-Counter pear within that 40 percent of the cir- Drugs cumference which is most likely to be displayed, presented, shown, or examined under customary conditions of dis- SOURCE: 41 FR 6908, Feb. 13, 1976, unless play for retail sale. otherwise noted. § 201.61 Statement of identity. § 201.60 Principal display panel. (a) The principal display panel of an The term principal display panel, as it over-the-counter drug in package form applies to over-the-counter drugs in shall bear as one of its principal fea- package form and as used in this part, tures a statement of the identity of the means the part of a label that is most commodity. likely to be displayed, presented, (b) Such statement of identity shall shown, or examined under customary be in terms of the established name of conditions of display for retail sale. the drug, if any there be, followed by The principal display panel shall be an accurate statement of the general large enough to accommodate all the pharmacological category(ies) of the mandatory label information required drug or the principal intended action(s) to be placed thereon by this part with of the drug. In the case of an over-the- clarity and conspicuousness and with- counter drug that is a mixture and that out obscuring designs, vignettes, or has no established name, this require- crowding. Where packages bear alter- ment shall be deemed to be satisfied by nate principal display panels, informa- a prominent and conspicuous state- tion required to be placed on the prin- ment of the general pharmacological cipal display panel shall be duplicated action(s) of the mixture or of its prin- on each principal display panel. For cipal intended action(s) in terms that the purpose of obtaining uniform type are meaningful to the layman. Such size in declaring the quantity of con- statements shall be placed in direct tents for all packages of substantially conjunction with the most prominent the same size, the term area of the prin- display of the proprietary name or des- cipal display panel means the area of ignation and shall employ terms de- the side or surface that bears the prin- scriptive of general pharmacological cipal display panel, which area shall category(ies) or principal intended ac- be: tion(s); for example, ‘‘antacid,’’ ‘‘an- (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

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statement of quantity of drugs in tab- different common fractions in the net let, capsule, ampule, or other unit form quantity declaration of a particular and the quantity of devices shall be ex- commodity, they may be employed. A pressed in terms of numerical count; common fraction shall be reduced to the statement of quantity for drugs in its lowest terms; a decimal fraction other dosage forms shall be in terms of shall not be carried out to more than weight if the drug is solid, semisolid, or two places. A statement that includes viscous, or in terms of fluid measure if small fractions of an ounce shall be the drug is liquid. The drug quantity deemed to permit smaller variations statement shall be augmented when than one which does not include such necessary to give accurate information fractions. as to the strength of such drug in the (d) The declaration shall be located package; for example, to differentiate on the principal display panel of the between several strengths of the same label, and with respect to packages drug ‘‘100 tablets, 5 grains each’’ or bearing alternate principal panels it ‘‘100 capsules, 125 milligrams each’’ or shall be duplicated on each principal ‘‘100 capsules, 250 milligrams each’’: display panel. Provided, That: (e) The declaration shall appear as a (1) In the case of a firmly established, distinct item on the principal display general consumer usage and trade cus- panel, shall be separated, by at least a tom of declaring the quantity of a drug space equal to the height of the let- in terms of linear measure or measure tering used in the declaration, from of area, such respective term may be other printed label information appear- used. Such term shall be augmented ing above or below the declaration and, when necessary for accuracy of infor- by at least a space equal to twice the mation by a statement of the weight, width of the letter ‘‘N’’ of the style of measure, or size of the individual units type used in the quantity of contents or of the entire drug; for example, the statement, from other printed label in- net quantity of adhesive tape in pack- formation appearing to the left or right age form shall be expressed in terms of of the declaration. It shall not include linear measure augmented by a state- any term qualifying a unit of weight, ment of its width. (2) Whenever the Commissioner de- measure, or count, such as ‘‘giant pint’’ termines for a specific packaged drug and ‘‘full quart’’, that tends to exag- that an existing practice of declaring gerate the amount of the drug in the net quantity of contents by weight, container. It shall be placed on the measure, numerical count, or a com- principal display panel within the bot- bination of these does not facilitate tom 30 percent of the area of the label value comparisons by consumers, he panel in lines generally parallel to the shall by regulation designate the ap- base on which the package rests as it is propriate term or terms to be used for designed to be displayed: Provided, such article. That: (b) Statements of weight of the con- (1) On packages having a principal tents shall be expressed in terms of av- display panel of 5 square inches or less oirdupois pound and ounce. A state- the requirement for placement within ment of liquid measure of the contents the bottom 30 percent of the area of the shall be expressed in terms of the U.S. label panel shall not apply when the gallon of 231 cubic inches and quart, declaration of net quantity of contents pint, and fluid-ounce subdivisions meets the other requirements of this thereof, and shall express the volume part; and at 68 °F (20 °C). See also paragraph (p) (2) In the case of a drug that is mar- of this section. keted with both outer and inner retail (c) The declaration may contain com- containers bearing the mandatory label mon or decimal fractions. A common information required by this part and fraction shall be in terms of halves, the inner container is not intended to quarters, eights, sixteenths, or thirty- be sold separately, the net quantity of seconds; except that if there exists a contents placement requirement of this firmly established, general consumer section applicable to such inner con- usage and trade custom of employing tainer is waived.

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(3) The principal display panel of a (2) Not less than one-eighth inch in drug marketed on a display card to height on packages the principal dis- which the immediate container is af- play panel of which has an area of more fixed may be considered to be the dis- than five but not more than 25 square play panel of the card, and the type inches. size of the net quantity of contents (3) Not less than three-sixteenths statement is governed by the dimen- inch in height on packages the prin- sions of the display card. cipal display panel of which has an (f) The declaration shall accurately area of more than 25 but not more than reveal the quantity of drug or device in 100 square inches. the package exclusive of wrappers and (4) Not less than one-fourth inch in other material packed therewith: Pro- height on packages the principal dis- vided, That in the case of drugs packed play panel of which has an area of more in containers designed to deliver the than 100 square inches, except not less drug under pressure, the declaration than one-half inch in height if the area shall state the net quantity of the con- is more than 400 square inches. tents that will be expelled when the in- Where the declaration is blown, em- structions for use as shown on the con- bossed, or molded on a glass or plastic tainer are followed. The propellant is surface rather than by printing, typ- included in the net quantity declara- ing, or coloring, the lettering sizes tion. specified in paragraphs (h) (1) through (g) The declaration shall appear in (4) of this section shall be increased by conspicuous and easily legible boldface one-sixteenth of an inch. print or type in distinct contrast (by (i) On packages containing less than typography, layout, color, embossing, 4 pounds or 1 gallon and labeled in or molding) to other matter on the terms of weight or fluid measure: package; except that a declaration of (1) The declaration shall be expressed net quantity blown, embossed, or mold- both in ounces, with identification by ed on a glass or plastic surface is per- weight or by liquid measure and, if applicable (1 pound or 1 pint or more) fol- missible when all label information is lowed in parentheses by a declaration so formed on the surface. Requirements in pounds for weight units, with any re- of conspicuousness and legibility shall mainder in terms of ounces or common include the specifications that: or decimal fractions of the pound (see (1) The ratio of height to width of the examples set forth in paragraphs (k) (1) letter shall not exceed a differential of and (2) of this section), or in the case of 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

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terms; for example, ‘‘Net wt. 6 oz’’ or (m) On packages labeled in terms of ‘‘6 oz net wt.,’’ and ‘‘6 fl oz’’ or ‘‘net linear measure, the declaration shall contents 6 fl oz’’. be expressed both in terms of inches (j) On packages containing 4 pounds and, if applicable (1 foot or more), the or 1 gallon or more and labeled in largest whole units (yards, yards and terms of weight or fluid measure, the feet, feet). The declaration in terms of declaration shall be expressed in the largest whole units shall be in pa- pounds for weight units with any re- rentheses following the declaration in mainder in terms of ounces or common terms of inches and any remainder or decimal fractions of the pound; in shall be in terms of inches or common the case of fluid measure, it shall be or decimal fractions of the foot or expressed in the largest whole unit yard; if applicable, as in the case of ad- (gallons, followed by common or dec- hesive tape, the initial declaration in imal fractions of a gallon or by the linear inches shall be preceded by a next smaller whole unit or units statement of the width. Examples of (quarts or quarts and pints)) with any linear measure are ‘‘86 inches (2 yd 1 ft remainder in terms of fluid ounces or 2 in),’’ ‘‘90 inches (21⁄2 yd),’’ ‘‘30 inches common or decimal fractions of the (2.5 ft),’’ ‘‘ 3⁄4 inch by 36 in (1 yd),’’ etc. pint or quart; see paragraph (k)(5) of (n) On packages labeled in terms of this section. area measure, the declaration shall be (k) Examples: expressed both in terms of square (1) A declaration of 11⁄2 pounds weight inches and, if applicable (1 square foot shall be expressed as ‘‘Net wt. 24 oz (1 or more), the largest whole square unit lb 8 oz),’’ or ‘‘Net wt. 24 oz (11⁄2 lb)’’ or (square yards, square yards and square ‘‘Net wt. 24 oz (1.5 lb)’’. feet, square feet). The declaration in (2) A declaration of three-fourths terms of the largest whole units shall pound avoirdupois weight shall be ex- be in parentheses following the dec- pressed as ‘‘Net wt. 12 oz’’. laration in terms of square inches and any remainder shall be in terms of (3) A declaration of 1 quart liquid square inches or common or decimal measure shall be expressed as ‘‘Net fractions of the square foot or square contents 32 fl oz (1 qt)’’ or ‘‘32 fl oz (1 yard; for example, ‘‘158 sq inches (1 sq qt)’’. ft 14 sq in).’’ (4) A declaration of 13⁄4 quarts liquid (o) Nothing in this section shall pro- measure shall be expressed as ‘‘Net hibit supplemental statements at loca- contents 56 fl oz (1 qt 1 pt 8 oz)’’ or tions other than the principal display ‘‘Net contents 56 fl oz (1 qt 1.5 pt),’’ but panel(s) describing in nondeceptive 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- 1 (5) A declaration of 2 ⁄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 1 gallons,’’ or ‘‘Net contents 2 ⁄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 Gallon gal milliliter ml regarded as supplemental net quantity 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 gram g millimeter mm garded as a supplemental statement 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

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may also appear on the principal dis- paragraph (a) of this section where ap- play panel or on other panels. propriate upon petition under the pro- (q) The declaration of net quantity of visions of § 10.30 of this chapter. Deci- contents shall express an accurate sions with respect to requests for ex- statement of the quantity of contents emptions shall be maintained in a per- of the package. Reasonable variations manent file for public review by the Di- caused by loss or gain of moisture dur- vision of Dockets Management (HFA– ing the course of good distribution 305), Food and Drug Administration, practice or by unavoidable deviations 5630 Fishers Lane, rm. 1061, Rockville, in good manufacturing practice will be MD 20852. recognized. Variations from stated (e) The labeling of orally or rectally quantity of contents shall not be un- administered OTC aspirin and aspirin- reasonably large. containing drug products must bear a (r) A drug shall be exempt from com- warning that immediately follows the pliance with the net quantity declara- general warning identified in para- tion required by this section if it is an graph (a) of this section. The warning ointment labeled ‘‘sample,’’ ‘‘physi- shall be as follows: cian’s sample,’’ or a substantially simi- ‘‘It is especially important not to use’’ (se- lar statement and the contents of the lect ‘‘aspirin’’ or ‘‘carbaspirin calcium,’’ as package do not exceed 8 grams. appropriate) ‘‘during the last 3 months of pregnancy unless definitely directed to do so § 201.63 Pregnancy/breast-feeding by a doctor because it may cause problems in warning. the unborn child or complications during de- (a) The labeling for all over-the- livery.’’ counter (OTC) drug products that are [47 FR 54757, Dec. 3, 1982, as amended at 55 intended for systemic absorption, un- FR 27784, July 5, 1990; 59 FR 14364, Mar. 28, less specifically exempted, shall con- 1994; 64 FR 13286, Mar. 17, 1999; 68 FR 24879, tain a general warning under the head- May 9, 2003] ing ‘‘Warning’’ (or ‘‘Warnings’’ if it appears with additional warning state- § 201.64 Sodium labeling. ments) as follows: ‘‘If pregnant or (a) The labeling of over-the-counter breast-feeding, ask a health profes- (OTC) drug products intended for oral sional before use.’’ [first four words of ingestion shall contain the sodium con- this statement in bold type] In addi- tent per dosage unit (e.g., tablet, tea- tion to the written warning, a symbol spoonful) if the sodium content of a that conveys the intent of the warning single recommended dose of the prod- may be used in labeling. uct (which may be one or more dosage (b) Where a specific warning relating units) is 5 milligrams or more. OTC to use during pregnancy or while nurs- drug products intended for oral inges- ing has been established for a par- tion 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 warning 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

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dose of the product is more than 140 (a) and (f) of the Federal Food, Drug, milligrams: ‘‘Do not use this product if and Cosmetic Act (the act). you are on a sodium-restricted diet un- [61 FR 17806, Apr. 22, 1996, as amended at 62 less directed by a doctor.’’ FR 19925, Apr. 24, 1997; 64 FR 13286, Mar. 17, (d) The term sodium free may be used 1999] in the labeling of OTC drug products EFFECTIVE DATE NOTE: At 62 FR 19925, Apr. intended for oral ingestion if the 24, 1997, the effective date for § 201.64 (a) amount of sodium in the labeled max- through (h) was delayed until further notice. imum daily dose is 0 milligram. For ex- At 69 FR 13717, Mar. 24, 2004, the effective- ample, a product containing 0.4 (round- ness of paragraphs (a) through (h) was further delayed until Apr. 23, 2004. ed-off to zero (0)) milligram sodium per tablet with directions to take one tab- EFFECTIVE DATE NOTE: At 69 FR 13724, Mar. 24, 2004, § 201.64 was amended by revising let daily may use the term ‘‘sodium paragraphs (a), (c), and (d) and by adding free’’ in its labeling. However, when paragraph (j), effective Apr. 23, 2004. For the the recommended dose provides for convenience of the user, the revised and taking more than one dosage unit per added text is set forth as follows: day, e.g., take one or two tablets, or § 201.64 Sodium labeling. take two tablets, the same product (a) The labeling of over-the-counter (OTC) containing 0.4 milligram sodium per drug products intended for oral ingestion tablet shall not use the term ‘‘sodium shall contain the sodium content per dosage free’’ because the labeled maximum unit (e.g., tablet, teaspoonful) if the sodium daily dose contains 0.8 milligram so- content of a single maximum recommended dium. dose of the product (which may be one or more dosage units) is 5 milligrams or more. (e) The term very low sodium may be OTC drug products intended for oral inges- used in the labeling of OTC drug prod- tion include gum and lozenge dosage forms, ucts intended for oral ingestion if the but do not include dentifrices, mouthwashes, amount of sodium in the labeled max- or mouth rinses. imum daily dose is 35 milligrams or less. * * * * * (f) The term low sodium may be used (c) The labeling of OTC drug products in- in the labeling of OTC drug products tended for oral ingestion shall contain the intended for oral ingestion if the following statement under the heading amount of sodium in the labeled max- ‘‘Warning’’ (or ‘‘Warnings’’ if it appears with additional warning statements) if the imum daily dose is 140 milligrams or amount of sodium present in the labeled less. maximum daily dose of the product is more (g) The term salt is not synonymous than 140 milligrams: ‘‘Ask a doctor before with the term sodium and shall not be use if you have [in bold type] [bullet]1 a so- used interchangeably or substituted for dium-restricted diet’’. The warnings in §§ 201.64(c), 201.70(c), 201.71(c), and 201.72(c) the term sodium. may be combined, if applicable, provided the (h) The terms sodium free, very low so- ingredients are listed in alphabetical order, e dium, and low sodium shall be in print g., a calcium or sodium restricted diet. size and style no larger than the prod- (d) The term sodium free may be used in the uct’s statement of identity and shall labeling of OTC drug products intended for oral ingestion if the amount of sodium in the not be unduly prominent in print size labeled maximum daily dose is 5 milligrams or style compared to the statement of or less and the amount of sodium per dosage identity. unit is 0 milligram (when rounded-off in ac- (i) Any product subject to this para- cord with paragraph (b) of this section). graph that contains sodium bicarbon- ate, sodium phosphate, or sodium * * * * * biphosphate as an active ingredient for (j) Any product subject to paragraphs (a) oral ingestion and that is not labeled through (h) of this section that is not labeled as required by this paragraph and that as required and that is initially introduced is initially introduced or initially de- or initially delivered for introduction into interstate commerce after the following livered for introduction into interstate commerce after April 22, 1997, is mis- 1 See § 201 .66(b)(4) of this chapter for defi- branded under sections 201(n) and 502 nition of bullet symbol.

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dates is misbranded under sections 201(n) and 508 of the act (21 U.S.C. 358), or, if there 502(a) and (f) of the Federal Food, Drug, and is no designated official name and the Cosmetic Act. drug or ingredient is recognized in an (1) As of the date of approval of the application for any single entity and combination official compendium, the official title products subject to drug marketing applica- of the drug or ingredient in such com- tions approved on or after April 23, 2004. pendium, or, if there is no designated (2) Septemeber 24, 2005, for all OTC drug official name and the drug or ingre- products subject to any OTC drug mono- dient is not recognized in an official graph, not yet the subject of any OTC drug compendium, the common or usual monograph, or subject to drug marketing ap- name of the drug or ingredient. plications approved before April 23, 2004. (6) FDA means the Food and Drug § 201.66 Format and content require- Administration. ments for over-the-counter (OTC) (7) Heading means the required state- drug product labeling. ments in quotation marks listed in (a) Scope. This section sets forth the paragraphs (c)(2) through (c)(9) of this content and format requirements for section, excluding subheadings (as de- the labeling of all OTC drug products. fined in paragraph (a)(9) of this sec- Where an OTC drug product is the sub- tion). ject of an applicable monograph or reg- (8) Inactive ingredient means any com- ulation that contains content and for- ponent other than an active ingredient. mat requirements that conflict with (9) Subheading means the required this section, the content and format re- statements in quotation marks listed quirements in this section must be fol- in paragraphs (c)(5)(ii) through lowed unless otherwise specifically pro- (c)(5)(vii) of this section. vided in the applicable monograph or (10) Drug facts labeling means the regulation. title, headings, subheadings, and infor- (b) . The following defini- Definitions mation required under or otherwise de- tions apply to this section: scribed in paragraph (c) of this section. (1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201 et seq. (21 (11) Title means the heading listed at U.S.C. 321 et seq.)). the top of the required OTC drug prod- (2) Active ingredient means any com- uct labeling, as set forth in paragraph ponent that is intended to furnish (c)(1) of this section. pharmacological activity or other di- (12) Total surface area available to bear rect effect in the diagnosis, cure, miti- labeling means all surfaces of the out- gation, treatment, or prevention of dis- side container of the retail package or, ease, or to affect the structure or any if there is no such outside container, function of the body of humans. The all surfaces of the immediate container term includes those components that or container wrapper except for the may undergo chemical change in the flanges at the tops and bottoms of cans manufacture of the drug product and and the shoulders and necks of bottles be present in the drug product in a and jars. modified form intended to furnish the (c) Content requirements. The outside specified activity or effect. container or wrapper of the retail (3) Approved drug application means a package, or the immediate container new drug (NDA) or abbreviated new label if there is no outside container or drug (ANDA) application approved wrapper, shall contain the title, head- under section 505 of the act (21 U.S.C. ings, subheadings, and information set 355). forth in paragraphs (c)(1) through (c)(8) (4) Bullet means a geometric symbol of this section, and may contain the in- that precedes each statement in a list formation under the heading in para- of statements. For purposes of this sec- graph (c)(9) of this section, in the order tion, the bullet style is limited to solid listed. squares or solid circles, in the format (1) (Title) ‘‘Drug Facts’’. If the drug set forth in paragraph (d)(4) of this sec- facts labeling appears on more than tion. one panel, the title ‘‘Drug Facts (con- (5) Established name of a drug or in- tinued)’’ shall appear at the top of each gredient thereof means the applicable subsequent panel containing such in- official name designated under section formation.

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(2) ‘‘Active ingredient’’ or ‘‘Active in- (C) Flammability warning, with ap- gredients’’ ‘‘(in each [insert the dosage propriate flammability signal word(s) unit stated in the directions for use (e.g., §§ 341.74(c)(5)(iii), 344.52(c), (e.g., tablet, 5 mL teaspoonful) or in 358.150(c), and 358.550(c) of this chap- each gram as stated in §§ 333.110 and ter). This warning shall follow a sub- 333.120 of this chapter])’’, followed by heading containing the appropriate the established name of each active in- flammability signal word(s) described gredient and the quantity of each ac- in an applicable OTC drug monograph tive ingredient per dosage unit. Unless or approved drug application. otherwise provided in an applicable (D) Water soluble gums warning set OTC drug monograph or approved drug forth in § 201.319. This warning shall application, products marketed with- follow the subheading ‘‘Choking:’’ out discrete dosage units (e.g., (E) Alcohol warning set forth in topicals) shall state the proportion § 201.322. This warning shall follow the (rather than the quantity) of each ac- subheading ‘‘Alcohol warning:’’ tive ingredient. (F) Sore throat warning set forth in (3) ‘‘Purpose’’ or ‘‘Purposes’’, fol- § 201.315. This warning shall follow the lowed by the general pharmacological subheading ‘‘Sore throat warning:’’ category(ies) or the principal intended (G) Warning for drug products con- action(s) of the drug or, where the drug taining sodium phosphates set forth in consists of more than one ingredient, § 201.307(b)(2)(i) or (b)(2)(ii). This warn- the general pharmacological categories ing shall follow the subheading ‘‘Dos- or the principal intended actions of age warning:’’ each active ingredient. When an OTC (iii) ‘‘Do not use’’ [in bold type], fol- drug monograph contains a statement lowed by all contraindications for use of identity, the pharmacological action with the product. These contraindica- described in the statement of identity tions are absolute and are intended for shall also be stated as the purpose of situations in which consumers should the active ingredient. not use the product unless a prior diagnosis has been established by a doctor (4) ‘‘Use’’ or ‘‘Uses’’, followed by the or for situations in which certain con- indication(s) for the specific drug prod- sumers should not use the product uct. under any circumstances regardless of (5) ‘‘Warning’’ or ‘‘Warnings’’, fol- whether a doctor or health professional lowed by one or more of the following, is consulted. if applicable: (iv) ‘‘Ask a doctor before use if you (i) ‘‘For external use only’’ [in bold have’’ [in bold type] or, for products la- type] for topical drug products not in- beled only for use in children under 12 tended for ingestion, or ‘‘For’’ (select years of age, ‘‘Ask a doctor before use one of the following, as appropriate: if the child has’’ [in bold type], fol- ‘‘rectal’’ or ‘‘vaginal’’) ‘‘use only’’ [in lowed by all warnings for persons with bold type]. certain preexisting conditions (exclud- (ii) All applicable warnings listed in ing pregnancy) and all warnings for paragraphs (c)(5)(ii)(A) through persons experiencing certain symp- (c)(5)(ii)(G) of this section with the ap- toms. The warnings under this heading propriate subheadings highlighted in are those intended only for situations bold type: in which consumers should not use the (A) Reye’s syndrome warning for product until a doctor is consulted. drug products containing salicylates (v) ‘‘Ask a doctor or pharmacist be- set forth in § 201.314(h)(1). This warning fore use if you are’’ [in bold type] or, shall follow the subheading ‘‘Reye’s for products labeled only for use in syndrome:’’ children under 12 years of age, ‘‘Ask a (B) Allergic reaction warnings set doctor or pharmacist before use if the forth in any applicable OTC drug child is’’ [in bold type], followed by all monograph or approved drug applica- drug-drug and drug-food interaction tion for any product that requires a warnings. separate allergy warning. This warning (vi) ‘‘When using this product’’ [in shall follow the subheading ‘‘Allergy bold type], followed by the side effects alert:’’ that the consumer may experience, and

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the substances (e.g., alcohol) or activi- (iii) Additional information that is ties (e.g., operating machinery, driving authorized to appear under this head- a car, warnings set forth in § 369.21 of ing shall appear as the next item(s) of this chapter for drugs in dispensers information. There is no required order pressurized by gaseous propellants) to for this subsequent information. avoid while using the product. (8) ‘‘Inactive ingredients’’, followed (vii) ‘‘Stop use and ask a doctor if’’ by a listing of the established name of [in bold type], followed by any signs of each inactive ingredient. If the product toxicity or other reactions that would is an OTC drug product that is not also necessitate immediately discontinuing a cosmetic product, then the inactive use of the product. ingredients shall be listed in alphabet- (viii) Any required warnings in an ap- ical order. If the product is an OTC plicable OTC drug monograph, other drug product that is also a cosmetic OTC drug regulations, or approved drug product, then the inactive ingredients application that do not fit within one shall be listed as set forth in § 701.3(a) of the categories listed in paragraphs or (f) of this chapter, the names of cos- (c)(5)(i) through (c)(5)(vii), (c)(5)(ix), metic ingredients shall be determined and (c)(5)(x) of this section. in accordance with § 701.3(c) of this (ix) The pregnancy/breast-feeding chapter, and the provisions in § 701.3(e), warning set forth in § 201.63(a); the (g), (h), (l), (m), (n), and (o) of this third trimester warning set forth in chapter and § 720.8 of this chapter may § 201.63(e) for products containing aspi- also apply, as appropriate. If there is a rin or carbaspirin calcium; the third difference in the labeling provisions in trimester warning set forth in ap- this § 201.66 and §§ 701.3 and 720.8 of this proved drug applications for products chapter, the labeling provisions in this containing ketoprofen, naproxen so- § 201.66 shall be used. dium, and ibuprofen (not intended ex- (9) ‘‘Questions?’’ or ‘‘Questions or clusively for use in children). comments?’’, followed by the telephone (x) The ‘‘Keep out of reach of chil- number of a source to answer questions dren’’ warning and the accidental over- about the product. It is recommended dose/ingestion warning set forth in that the days of the week and times of § 330.1(g) of this chapter. the day when a person is available to (6) ‘‘Directions’’, followed by the di- respond to questions also be included. rections for use described in an appli- A graphic of a telephone or telephone cable OTC drug monograph or approved receiver may appear before the head- drug application. ing. The telephone number must ap- (7) ‘‘Other information’’, followed by pear in a minimum 6-point bold type. additional information that is not in- (d) Format requirements. The title, cluded under paragraphs (c)(2) through headings, subheadings, and information (c)(6), (c)(8), and (c)(9) of this section, set forth in paragraphs (c)(1) through but which is required by or is made op- (c)(9) of this section shall be presented tional under an applicable OTC drug on OTC drug products in accordance monograph, other OTC drug regulation, with the following specifications. In or is included in the labeling of an ap- the interest of uniformity of presen- proved drug application. tation, FDA strongly reccommends (i) Required information about cer- that the Drug Facts labeling be pre- tain ingredients in OTC drug products sented using the graphic specifications (e.g., sodium in § 201.64(c)) shall appear set forth in appendix A to part 201. as follows: ‘‘each (insert appropriate (1) The title ‘‘Drug Facts’’ or ‘‘Drug dosage unit) contains:’’ [in bold type] Facts (continued)’’ shall use uppercase (insert name(s) of ingredient(s) and the letters for the first letter of the words quantity of each ingredient). This in- ‘‘Drug’’ and ‘‘Facts.’’ All headings and formation shall be the first statement subheadings in paragraphs (c)(2) under this heading. through (c)(9) of this section shall use (ii) The phenylalanine/aspartame an uppercase letter for the first letter content required by § 201.21(b), if appli- in the first word and lowercase letters cable, shall appear as the next item of for all other words. The title, headings, information. and subheadings in paragraphs (c)(1),

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(c)(2), and (c)(4) through (c)(9) of this bulleted statement on each horizontal section shall be left justified. line of text shall be either left justified (2) The letter height or type size for or separated from an appropriate head- the title ‘‘Drug Facts’’ shall appear in ing or subheading by at least two a type size larger than the largest type square ‘‘ems’’ (i.e., two squares of the size used in the Drug Facts labeling. size of the letter ‘‘M’’). If more than The letter height or type size for the one bulleted statement is placed on the title ‘‘Drug Facts (continued)’’ shall be same horizontal line, the end of one no smaller than 8-point type. The let- bulleted statement shall be separated ter height or type size for the headings from the beginning of the next bulleted in paragraphs (c)(2) through (c)(9) of statement by at least two square this section shall be the larger of ei- ‘‘ems’’ and the complete additional ther 8-point or greater type, or 2-point bulleted statement(s) shall not con- sizes greater than the point size of the tinue to the next line of text. Addi- text. The letter height or type size for tional bulleted statements appearing the subheadings and all other informa- on each subsequent horizontal line of tion described in paragraphs (c)(2) text under a heading or subheading through (c)(9) of this section shall be shall be vertically aligned with the no smaller than 6-point type. bulleted statements appearing on the (3) The title, heading, subheadings, previous line. and information in paragraphs (c)(1) (5) The title, headings, subheadings, through (c)(9) of this section shall be and information set forth in para- legible and clearly presented, shall graphs (c)(1) through (c)(9) of this sec- have at least 0.5-point leading (i.e., tion may appear on more than one space between two lines of text), and panel on the outside container of the shall not have letters that touch. The retail package, or the immediate con- type style for the title, headings, sub- tainer label if there is no outside con- headings, and all other required infor- tainer or wrapper. The continuation of mation described in paragraphs (c)(2) the required content and format onto through (c)(9) of this section shall be multiple panels must retain the re- any single, clear, easy-to-read type quired order and flow of headings, sub- style, with no more than 39 characters headings, and information. A visual 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

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(i.e., through the use of brackets, dot other FDA required information for leaders, or other graphical features). drug products, and, as appropriate, cos- The information described in para- metic products, other than information graphs (c)(4) and (c)(6) through (c)(9) of required to appear on a principle dis- this section may start on the same line play panel, requires more than 60 per- as the required headings. None of the cent of the total surface area available information described in paragraph to bear labeling, then the Drug Facts (c)(5) of this section shall appear on the labeling shall be printed in accordance same line as the ‘‘Warning’’ or ‘‘Warn- with the specifications set forth in ings’’ heading. paragraphs (d)(10)(i) through (d)(10)(v) (7) Graphical images (e.g., the UPC of this section. In determining whether symbol) and information not described more than 60 percent of the total sur- in paragraphs (c)(1) through (c)(9) of face area available to bear labeling is this section shall not appear in or in any way interrupt the required title, required, the indications for use listed headings, subheadings, and information under the ‘‘Use(s)’’ heading, as set in paragraphs (c)(1) through (c)(9) of forth in paragraph (c)(4) of this section, this section. Hyphens shall not be used shall be limited to the minimum re- except to punctuate compound words. quired uses reflected in the applicable (8) The information described in monograph, as provided in § 330.1(c)(2) paragraphs (c)(1) through (c)(9) of this of this chapter. section shall be set off in a box or simi- (i) Paragraphs (d)(1), (d)(5), (d)(6), and lar enclosure by the use of a barline. A (d)(7) of this section shall apply. distinctive horizontal barline extend- (ii) Paragraph (d)(2) of this section ing to each end of the ‘‘Drug Facts’’ shall apply except that the letter box or similar enclosure shall provide height or type size for the title ‘‘Drug separation between each of the head- Facts (continued)’’ shall be no smaller ings listed in paragraphs (c)(2) through than 7-point type and the headings in (c)(9) of this section. When a heading paragraphs (c)(2) through (c)(9) of this listed in paragraphs (c)(2) through section shall be the larger of either 7- (c)(9) of this section appears on a subse- point or greater type, or 1-point size quent panel immediately after the greater than the point size of the text. ‘‘Drug Facts (continued)’’ title, a hori- (iii) Paragraph (d)(3) of this section zontal hairline shall follow the title shall apply except that less than 0.5- and immediately precede the heading. A horizontal hairline extending within point leading may be used, provided two spaces on either side of the ‘‘Drug the ascenders and descenders do not Facts’’ box or similar enclosure shall touch. immediately follow the title and shall (iv) Paragraph (d)(4) of this section immediately precede each of the sub- shall apply except that if more than headings set forth in paragraph (c)(5) of one bulleted statement is placed on the this section, except the subheadings in same horizontal line, the additional paragraphs (c)(5)(ii)(A) through bulleted statements may continue to (c)(5)(ii)(G) of this section. the next line of text, and except that (9) The information set forth in para- the bullets under each heading or sub- graph (c)(6) of this section under the heading need not be vertically aligned. heading ‘‘Directions’’ shall appear in a (v) Paragraph (d)(8) of this section table format when dosage directions shall apply except that the box or simi- are provided for three or more age lar enclosure required in paragraph groups or populations. The last line of (d)(8) of this section may be omitted if the table may be the horizontal barline the Drug Facts labeling is set off from immediately preceding the heading of the rest of the labeling by use of color the next section of the labeling. contrast. (10) If the title, headings, sub- (11)(i) The following labeling outlines headings, and information in paragraphs (c)(1) through (c)(9) of this sec- the various provisions in paragraphs (c) tion, printed in accordance with the and (d) of this section: specifications in paragraphs (d)(1) through (d)(9) of this section, and any

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

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drug marketing applications approved troduction into interstate commerce before April 23, 2004. after the following dates is misbranded under sections 201(n) and 502(a) and (f) [69 FR 13733, Mar. 24, 2004] of the Federal Food, Drug, and Cos- EFFECTIVE DATE NOTE: At 69 FR 13733, Mar. metic Act. 24, 2004, § 201.70 was added, effective Apr. 23, (1) As of the date of approval of the 2004. application for any single entity and § 201.71 Magnesium labeling. combination products subject to drug marketing applications approved on or (a) The labeling of over-the-counter after April 23, 2004. (OTC) drug products intended for oral ingestion shall contain the magnesium (2) September 24. 2005, for all OTC content per dosage unit (e.g., tablet, drug products subject to any OTC drug teaspoonful) if the magnesium content monograph, not yet the subject of any of a single maximum recommended OTC drug monograph, or subject to dose of the product (which may be one drug marketing applications approved or more dosage units) is 8 milligrams before April 23, 2004. or more. OTC drug products intended [69 FR 13734, Mar. 24, 2004] for oral ingestion include gum and lozenge dosage forms, but do not include EFFECTIVE DATE NOTE: At 69 FR 13734, Mar. 24, 2004, § 201.71 was added, effective Apr. 23, dentifrices, mouthwashes, or mouth 2004. rinses. (b) The magnesium content shall be § 201.72 Potassium labeling. expressed in milligrams or grams per dosage unit and shall include the total (a) The labeling of over-the-counter amount of magnesium regardless of the (OTC) drug products intended for oral source, i.e., from both active and inac- ingestion shall contain the potassium tive ingredients. If the dosage unit con- content per dosage unit (e.g., tablet, tains less than 1 gram of magnesium, teaspoonful) if the potassium content milligrams should be used. The magne- of a single maximum recommended sium content shall be rounded-off to dose of the product (which may be one the nearest 5 milligrams (or nearest or more dosage units) is 5 milligrams tenth of a gram if over 1 gram). The or more. OTC drug products intended magnesium content per dosage unit for oral ingestion include gum and loz- shall follow the heading ‘‘Other infor- enge dosage forms, but do not include mation’’ as stated in § 201.66(c)(7). dentifrices, mouthwashes, or mouth (c) The labeling of OTC drug products rinses. intended for oral ingestion shall con- (b) The potassium content shall be tain the following statement under the expressed in milligrams or grams per heading ‘‘Warning’’ (or ‘‘Warnings’’ if dosage unit and shall include the total it appears with additional warning amount of potassium regardless of the statements) if the amount of magne- source, i.e., from both active and inac- sium present in the labeled maximum tive ingredients. If the dosage unit con- daily dose of the product is more than tains less than 1 gram of potassium, 600 milligrams: ‘‘Ask a doctor before milligrams should be used. The potas- use if you have [in bold type] [bullet]1 sium content shall be rounded-off to kidney disease [bullet] a magnesium- the nearest 5 milligrams (or nearest restricted diet’’. The warnings in tenth of a gram if over 1 gram). The po- §§ 201.64(c), 201.70(c), 201.71(c), and tassium content per dosage unit shall 201.72(c) may be combined, if applica- follow the heading ‘‘Other informa- ble, provided the ingredients are listed tion’’ as stated in § 201.66(c)(7). in alphabetical order, e.g., a magne- (c) The labeling of OTC drug products sium or potassium-restricted diet. intended for oral ingestion shall con- (d) Any product subject to this para- tain the following statement under the graph that is not labeled as required by heading ‘‘Warning’’ (or ‘‘Warnings’’ if this paragraph and that is initially in- it appears with additional warning troduced or initially delivered for in- statements) if the amount of potassium present in the labeled maximum daily 1 See § 201.66(b)(4) of this chapter for defini- dose of the product is more than 975 tion of bullet symbol. milligrams: ‘‘Ask a doctor before use if

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you have [in bold type] [bullet]1 kidney (iii) In the possession of a practi- disease [bullet] a potassium-restricted tioner licensed by law to administer or diet’’. The warnings in §§ 201.64(c), prescribe such drugs; and 201.70(c), 201.71(c), and 201.72(c) may be (2) It is to be dispensed in accordance combined, if applicable, provided the with section 503(b) ingredients are listed in alphabetical (b) The label of the drug bears: order, e.g., a magnesium or potassium- (1) The statement ‘‘Rx only’’ and restricted diet. (2) The recommended or usual dosage (d) Any product subject to this para- and graph that is not labeled as required by (3) The route of administration, if it this paragraph and that is initially in- is not for oral use; and troduced or initially delivered for in- (4) The quantity or proportion of troduction into interstate commerce each active ingredient, as well as the after the following dates is misbranded information required by section 502 (d) under sections 201(n) and 502(a) and (f) and (e); and of the Federal Food, Drug, and Cos- (5) If it is for other than oral use, the metic Act. names of all inactive ingredients, ex- (1) As of the date of approval of the cept that: application for any single entity and (i) Flavorings and perfumes may be combination products subject to drug designated as such without naming marketing applications approved on or their components. after April 23, 2004. (ii) Color additives may be des- (2) September 24, 2005, for all OTC ignated as coloring without naming drug products subject to any OTC drug specific color components unless the monograph, not yet the subject of any naming of such components is required OTC drug monograph, or subject to by a color additive regulation pre- drug marketing applications approved scribed in subchapter A of this chapter. before April 23, 2004. (iii) Trace amounts of harmless substances added solely for individual [69 FR 13734, Mar. 24, 2004] product identification need not be EFFECTIVE DATE NOTE: At 69 FR 13734, Mar. named. If it is intended for administra- 24, 2004, § 201.72 was added, effective Apr. 23, tion by parenteral injection, the quan- 2004. tity or proportion of all inactive ingredients, except that ingredients added Subpart D—Exemptions From to adjust the pH or to make the drug Adequate Directions for Use isotonic may be declared by name and a statement of their effect; and if the § 201.100 Prescription drugs for vehicle is water for injection it need human use. not be named. A drug subject to the requirements of (6) An identifying lot or control num- section 503(b)(1) of the act shall be ex- ber from which it is possible to deter- empt from section 502(f)(1) if all the mine the complete manufacturing his- following conditions are met: tory of the package of the drug. (a) The drug is: (7) A statement directed to the pharmacist specifying the type of container (1)(i) In the possession of a person (or to be used in dispensing the drug prod- his agents or employees) regularly and uct to maintain its identity, strength, lawfully engaged in the manufacture, quality, and purity. Where there are transportation, storage, or wholesale standards and test procedures for de- distribution of prescription drugs; or termining that the container meets the (ii) In the possession of a retail, hos- requirements for specified types of con- pital, or clinic pharmacy, or a public tainers as defined in an official com- health agency, regularly and lawfully pendium, such terms may be used. For engaged in dispensing prescription example, ‘‘Dispense in tight, light-re- drugs; or sistant container as defined in the Na- tional Formulary’’. Where standards 1 See § 201.66(b)(4) of this chapter for defini- and test procedures for determining tion of bullet symbol. the types of containers to be used in

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dispensing the drug product are not in- (d) Any labeling, as defined in section cluded in an official compendium, the 201(m) of the act, whether or not it is specific container or types of con- on or within a package from which the tainers known to be adequate to main- drug is to be dispensed, distributed by tain the identity, strength, quality, or on behalf of the manufacturer, pack- and purity of the drug products shall er, or distributor of the drug, that fur- be described. For example, ‘‘Dispense nishes or purports to furnish informa- in containers which (statement of spection for use or which prescribes, rec- ifications which clearly enable the dis- ommends, or suggests a dosage for the pensing pharmacist to select an ade- use of the drug (other than dose infor- quate container)’’: Provided, however, mation required by paragraph (b)(2) of That in the case of containers too this section and § 201.105(b)(2) contains: small or otherwise unable to accommo- (1) Adequate information for such date a label with sufficient space to use, including indications, effects, dos- bear all such information, but which ages, routes, methods, and frequency are packaged within an outer container and duration of administration and any from which they are removed for dis- relevant warnings, hazards, contra- pensing or use, the information re- indications, side effects, and pre- quired by paragraph (b) (2), (3), (5), and cautions, under which practitioners li- (7) of this section may be contained in censed by law to administer the drug other labeling on or within the package can use the drug safely and for the pur- from which it is to be dispensed; the in- poses for which it is intended, including 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 and dosages, routes, methods, and fre- 201.57. 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,

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

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except that ingredients added to adjust sioner will offer an opinion on a pro- the pH or to make the drug isotonic posal to omit such information from may be declared by name and a state- the dispensing package under this pro- ment of their effect; and if the vehicle viso. is water for injection, it need not be (d) Any labeling, as defined in section named. 201(m) of the act, whether or not it is (6) An identifying lot or control num- on or within a package from which the ber from which it is possible to deter- drug is to be dispensed, distributed by mine the complete manufacturing his- or on behalf of the manufacturer, pack- tory of the package of the drug; er, or distributor of the drug, that fur- Provided, however, That in the case of nishes or purports to furnish informa- containers too small or otherwise un- tion for use or which prescribes, rec- able to accommodate a label with suffi- ommends, or suggests a dosage for the cient space to bear all such informa- use of the drug (other than dose infor- tion, but which are packaged within an mation required by paragraph (b)(2) of outer container from which they are this section and § 201.100(b)(2)) contains: removed for dispensing or use, the in- (1) Adequate information for such formation required by paragraphs (b) use, including indications, effects, dos- (2), (3), and (5) of this section may be ages, routes, methods, and frequency contained in other labeling on or with- and duration of administration, and in the package from which it is to be so any relevant warnings, hazards, con- dispensed, and the information referred traindications, side effects, and pre- to in paragraph (b)(1) of this section cautions, and including information may be placed on such outer container relevant to compliance with the new only, and the information required by animal drug provisions of the act, paragraph (b)(6) of this section may be under which veterinarians licensed by on the crimp of the dispensing tube. law to administer the drug can use the (c)(1) Labeling on or within the pack- drug safely and for the purposes for age from which the drug is to be dis- which it is intended, including all con- pensed bears adequate information for ditions for which it is advertised or its use, including indications, effects, represented; and if the article is sub- dosages, routes, methods, and fre- ject to section 512 of the act, the parts quency and duration of administration, of the labeling providing such informa- and any relevant hazards, contra- tion are the same in language and em- indications, side effects, and pre- phasis as labeling approved or per- cautions under which veterinarians li- mitted under the provisions of section censed by law to administer the drug 512, and any other parts of the labeling can use the drug safely and for the pur- are consistent with and not contrary to poses for which it is intended, includ- such approved or permitted labeling; ing all purposes for which it is adver- and tised or represented; and (2) The same information concerning (2) If the article is subject to section the ingredients of the drug as appears 512 of the act, the labeling bearing such on the label and labeling on or within information is the labeling authorized the package from which the drug is to by the approved new animal drug appli- be dispensed; cation or required as a condition for the certification or the exemption from Provided, however, That the informa- certification requirements applicable tion required by paragraphs (d) (1) and to preparations of antibiotic drugs: (2) of this section is not required on the Provided, however, That the informa- so-called reminder-piece labeling which tion required by paragraph (c)(1) of this calls attention to the name of the drug section may be omitted from the dis- but does not include indications or dos- pensing package if, but only if, the ar- age recommendations for use of the ticle is a drug for which directions, drug. hazards, warnings, and use information (e) All labeling, except labels and are commonly known to veterinarians cartons, bearing information for use of licensed by law to administer the drug. the drug also bears the date of the Upon written request, stating reason- issuance or the date of the latest revi- able grounds therefore, the Commis- sion of such labeling.

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(f) A prescription drug intended for products are drugs or devices as defined both human and veterinary use shall in section 201(g) and 201(h), respec- comply with paragraphs (e) and (f) of tively, of the Federal Food, Drug, and this section and § 201.100. Cosmetic Act (the act) or are a com- [40 FR 13998, Mar. 27, 1975, as amended at 42 bination of drugs and devices, and may FR 15674, Mar. 22, 1977; 57 FR 54300, Nov. 18, also be a biological product subject to 1992] section 351 of the Public Health Service Act. § 201.115 New drugs or new animal (b) A product intended for use in the drugs. diagnosis of disease and which is an in A new drug shall be exempt from sec- vitro diagnostic product as defined in tion 502(f)(1) of the act: paragraph (a) of this section shall be (a) To the extent to which such ex- deemed to be in compliance with the emption is claimed in an approved ap- requirements of this section and sec- plication with respect to such drug tion 502(f)(1) of the act if it meets the under section 505 or 512 of the act; or requirements of § 809.10 of this chapter. (b) If no application under section 505 of the act is approved with respect to [41 FR 6910, Feb. 13, 1976] such drug but it complies with section 505(i) or 512 of the act and regulations § 201.120 Prescription chemicals and thereunder. other prescription components. No exemption shall apply to any other A drug prepared, packaged, and pri- drug which would be a new drug if its marily sold as a prescription chemical labeling bore representations for its in- or other component for use by reg- tended uses. istered pharmacists in compounding prescriptions or for dispensing in dos- § 201.116 Drugs having commonly age unit form upon prescriptions shall known directions. be exempt from section 502(f)(1) of the A drug shall be exempt from section act if all the following conditions are 502(f)(1) of the act insofar as adequate met: directions for common uses thereof are (a) The drug is an official liquid acid known to the ordinary individual. or official liquid alkali, or is not a liq- [41 FR 6910, Feb. 13, 1976] uid solution, emulsion, suspension, tablet, capsule, or other dosage unit form; § 201.117 Inactive ingredients. and A harmless drug that is ordinarily (b) The label of the drug bears: used as an inactive ingredient, such as (1) The statement ‘‘For prescription a coloring, emulsifier, excipient, fla- compounding’’; and voring, lubricant, preservative, or sol- (2) If in substantially all dosage vent, in the preparation of other drugs forms in which it may be dispensed it shall be exempt from section 502(f)(1) of is subject to section 503(b)(1) of the act, the act. This exemption shall not apply the statement ‘‘Rx only’’; or to any substance intended for a use (3) If it is not subject to section which results in the preparation of a 503(b)(1) of the act and is by custom new drug, unless an approved new-drug among retail pharmacists sold in or application provides for such use. from the interstate package for use by consumers, ‘‘adequate directions for § 201.119 In vitro diagnostic products. use’’ in the conditions for which it is so (a) ‘‘In vitro diagnostic products’’ are sold. those reagents, instruments and systems intended for use in the diagnosis Provided, however, That the informa- of disease or in the determination of tion referred to in paragraph (b)(3) of the state of health in order to cure, this section may be contained in the mitigate, treat, or prevent disease or labeling on or within the package from its sequelae. Such products are in- which it is to be dispensed. tended for use in the collection, prepa- (c) This exemption shall not apply to ration and examination of specimens any substance intended for use in taken from the human body. These compounding which results in a new

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

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article unless the dosage form is la- chemistry (but not intended for imme- beled as required by section 503(b) and diate therapeutic, diagnostic, or simi- §§ 201.100 or 201.105. lar purposes), under the conditions set [41 FR 6911, Feb. 13, 1976] forth in § 361.1 of this chapter, shall be exempt from section 502(f)(1) of the act § 201.128 Meaning of ‘‘intended uses’’. if the packaging, label, and labeling The words intended uses or words of are in compliance with § 361.1(f) of this similar import in §§ 201.5, 201.115, chapter. 201.117, 201.119, 201.120, and 201.122 refer [41 FR 6911, Feb. 13, 1976] to the objective intent of the persons legally responsible for the labeling of Subpart E—Other Exemptions drugs. The intent is determined by such persons’ expressions or may be § 201.150 Drugs; processing, labeling, shown by the circumstances sur- or repacking. rounding the distribution of the article. 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 er, distributor, or seller is required to commerce is the operator of the estab- supply adequate labeling in accordance lishment where such drug is to be proc- with the new intended uses. But if a essed, labeled, or repacked; or manufacturer knows, or has knowledge (2) In case such person is not such op- of facts that would give him notice, erator, such shipment or delivery is that a drug introduced into interstate made to such establishment under a commerce by him is to be used for con- written agreement, signed by and conditions, purposes, or uses other than taining the post-office addresses of the ones for which he offers it, he is re- such person and such operator, and quired to provide adequate labeling for containing such specifications for the such a drug which accords with such processing, labeling, or repacking, as other uses to which the article is to be the case may be, of such drug in such put. establishment as will insure, if such [41 FR 6911, Feb. 13, 1976] specifications are followed, that such drug will not be adulterated or mis- § 201.129 Drugs; exemption for radio- branded within the meaning of the act active drugs for research use. upon completion of such processing, la- A radioactive drug intended for ad- beling, or repacking. Such person and ministration to human research sub- such operator shall each keep a copy of jects during the course of a research such agreement until 2 years after the project intended to obtain basic re- final shipment or delivery of such drug search information regarding metabo- from such establishment, and shall lism (including kinetics, distribution, make such copies available for inspec- and localization) of a radioactively lation at any reasonable hour to any offi- beled drug or regarding human physi- cer or employee of the Department who ology, pathophysiology, or bio- requests them.

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(b) An exemption of a shipment or of administration, and with the haz- other delivery of a drug under para- ards, contraindications, and side ef- graph (a)(1) of this section shall, at the fects and the precautions to be taken’’; beginning of the act of removing such and shipment or delivery, or any part (2) Any needed directions concerning thereof, from such establishment, be- the conditions for storage and warn- come void ab initio if the drug com- ings against the inherent dangers in prising such shipment, delivery, or part the handling of the specific compressed is adulterated or misbranded within gas. the meaning of the act when so re- (b) This labeling exemption does not moved. apply to mixtures of any one or more (c) An exemption of a shipment or of these gases with oxygen or with each other delivery of a drug under para- other. graph (a)(2) of this section shall be- (c) Regulatory action may be initi- come void ab initio with respect to the ated with respect to any article person who introduced such shipment shipped within the jurisdiction of the or delivery into interstate commerce Act contrary to the provisions of this upon refusal by such person to make section after 60 days following publica- available for inspection a copy of the tion of this section in the FEDERAL agreement, as required by such para- REGISTER. graph (a)(2) of this section. (d) An exemption of a shipment or Subpart F—Labeling Claims for other delivery of a drug under para- Drugs in Drug Efficacy Study graph (a)(2) of this section shall expire: (1) At the beginning of the act of re- § 201.200 Disclosure of drug efficacy moving such shipment or delivery, or study evaluations in labeling and any part thereof, from such establish- advertising. ment if the drug comprising such ship- (a)(1) The National Academy of ment, delivery, or part is adulterated Sciences—National Research Council, or misbranded within the meaning of Drug Efficacy Study Group, has com- the act when so removed; or pleted an exhaustive review of labeling (2) Upon refusal by the operator of claims made for drugs marketed under the establishment where such drug is new-drug and antibiotic drug proce- to be processed, labeled, or repacked, dures between 1938 and 1962. The results to make available for inspection a copy are compiled in ‘‘Drug Efficacy Study, of the agreement, as required by such A Report to the Commissioner of Food clause. 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 mation required by the Federal Food, have been evaluated as ‘‘effective,’’ Drug, and Cosmetic Act, the following: ‘‘probably effective,’’ ‘‘possibly effec- (1) The warning statement ‘‘Warn- tive,’’ ‘‘ineffective,’’ ‘‘ineffective as a ing—Administration of (name of gas) fixed combination,’’ and ‘‘effective may be hazardous or contraindicated. but,’’ and a report for each drug in the For use only by or under the super- study has been submitted to the Com- vision of a licensed practitioner who is missioner. experienced in the use and administra- (2) The Food and Drug Administra- tion of (name of gas) and is familiar tion is processing the reports, seeking with the indications, effects, dosages, voluntary action on the part of the methods, and frequency and duration drug manufacturers and distributors in

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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: ated as other than ‘‘effective’’ by a INDICATIONS panel of the National Academy of Sciences—National Research Council, Based on a review of this drug by the Drug Efficacy Study Group, if such National Academy of Sciences—Na- claims continue to be included in ei- tional Research Council and/or other ther the labeling or advertisements. information, FDA has classified the in- However, this qualifying information dication(s) as follows: will be required in advertisements only Effective: (list or state in paragraph if promotional material is included form). therein for claims evaluated as less ‘‘Probably’’ effective: (list or state in than ‘‘effective’’ or if such claims are paragraph form).

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‘‘Possibly’’ effective: (list or state in terisk shall be placed after the most paragraph form). prominent mention of the indi- Final classification of the less-than- cation(s); if the degree of prominence effective indications requires further does not vary, an asterisk shall be investigation. 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: sibly effective whichever is appro- Based on a review of this drug by the priate) for this indication’’ and ‘‘See National Academy of Sciences—Na- Brief Summary’’ or ‘‘See Prescribing tional Research Council and/or other Information,’’ the latter legend to be information, FDA has classified the used only if the advertisement carries other indication(s) as follows: the required information for profes- ‘‘Probably’’ effective: (list or state in sional use as set forth in § 201.100(c)(1). paragraph form). (3) For less-than-effective indications ‘‘Possibly’’ effective: (list or state in which are included in the advertise- paragraph form). ment only as a part of the information Final classification of the less-than- required in brief summary, the disclo- effective indications requires further sure information shall appear in this investigation. portion of the advertisement in the (3) In drug labeling (other than that same manner as is specified for label- which is required by § 201.100(c)(1)) ing in paragraph (e) of this section. which may contain a promotional mes- (g) The Commissioner may find cir- sage, the promotional message shall be cumstances are such that, while the keyed to the boxed statement by the elimination of claims evaluated as same means as those provided for ad- other than effective will generally vertisements in paragraph (f)(2) of this eliminate the need for disclosure about section. such claims, there will be instances in (f) Qualifying information required in which the change in the prescribing or prescription drug advertising by para- promotional profile of the drug is so graph (c) of this section shall contain a substantial as to require a disclosure of prominent boxed statement of the ad- the reason for the change so that the vertised indication(s) and of the limita- purchaser or prescriber is not misled tions of effectiveness using the same by being left unaware through the format, language, and emphasis as that sponsor’s silence that a basic change required in labeling by paragraph (e) of has taken place. The Food and Drug Administration will identify these situ- this section. ations in direct correspondence with (1) The boxed statement shall appear the drug promoters, after which the in (or next to) the information required failure to make the disclosure will be in brief summary by § 202.1(e)(1) of this regarded as misleading and appropriate chapter and shall have prominence at action will be taken. least equal to that provided for other information presented in the brief sum- [40 FR 13998, Mar. 27, 1975, as amended at 55 mary and shall have type size, cap- FR 11576, Mar. 29, 1990] tions, color, and other physical characteristics comparable to the informa- Subpart G—Specific Labeling Re- tion required in the brief summary. quirements for Specific Drug (2) Less-than-effective indication(s) Products in the promotional message of an advertisement which is a single page or § 201.300 Notice to manufacturers, less shall be keyed to the boxed state- packers, and distributors of glan- ment by asterisk, by an appropriate dular preparations. statement, or by other suitable means (a) Under date of December 4, 1941, in providing adequate emphasis on the a notice to manufacturers of glandular boxed statement. On each page where preparations, the Food and Drug Ad- less-than-effective indication(s) appear ministration expressed the opinion in a mutiple page advertisement, an as- that preparations of inert glandular

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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 estrogenic hormone preparations. articles contain any therapeutic or 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 been marketed. The international unit exerting an action or effect of some of the estrus-producing hormone was significant or measurable benefit in established by the International Con- one way or another, i.e., in the diag- ference on the Standardization of Sex nosis, cure, mitigation, treatment, or Hormones at London, England, on Au- prevention of disease, or in affecting gust 1, 1932. This unit was defined as the structure or any function of the ‘‘the specific estrus-producing activity body. contained in 0.1 gamma (=0.0001 mg.) of (b) Manufacturers have heretofore the standard’’ hydroxyketonic hor- taken advantage of § 201.100 permitting mone found in urine (estrone). The omission of directions for use when the International Conference declared that label bears the prescription legend. it did not recommend the determina- Section 201.100(c) requires that the lation of the activity of nonhydroxyke- beling of the drug, which may include tonic forms of estrogenic hormones in brochures readily available to licensed units of estrone because of the varying practitioners, bear information as to ratios between the activity of such nonhydroxyketonic estrogenic hor- the use of the drug by practitioners li- mones and estrone, when measured by censed by law to administer it. Obvi- different methods on test animals. ously, information adequate for the use There is no international unit for of an inert glandular preparation is not measuring the activity of estradiol and available to practitioners licensed by no accepted relationship between its law. activity and that of estrone, either in (c) The Department of Health and test animals or in humans. The dec- Human Services is of the opinion that laration of potency of estradiol in inert glandular materials may not be terms of international units or in exempted from the requirements of terms of international units of estrone section 502(f)(1) of the act that they activity is therefore considered mis- bear adequate directions for use; and, leading, within the meaning of 21 accordingly, that their labeling must U.S.C. 352(a). The declaration of the es- include among other things, represen- tradiol content of an estrogenic hor- tations as to the conditions for which mone preparation in terms of weight is such articles are intended to be used or considered appropriate. as to the structure or function of the human body that they are intended to § 201.302 Notice to manufacturers, affect. Since any such representations packers, and distributors of drugs offering these articles for use as drugs for internal use which contain min- would be false or misleading, such arti- eral oil. cles will be considered to be mis- (a) In the past few years research branded if they are distributed for use studies have altered medical opinion as as drugs. to the usefulness and harmfulness of (d) The amended regulations provide mineral oil in the human body. These also that in the case of drugs intended studies have indicated that when min- for parenteral administration there eral oil is used orally near mealtime it shall be no exemption from the require- interferes with absorption from the di- ment that their labelings bear ade- gestive tract of provitamin A and the quate directions for use. Such inert fat-soluble vitamins A, D, and K, and

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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 when taken in substantially larger use only’’ will be regarded by the Com- amounts. Actually, it is quite toxic missioner of Food and Drugs as mis- when taken in quantities of a teaspoon- branded within the meaning of section ful or more. Wintergreen oil and prep- 502(f) of the Federal Food, Drug, and arations containing it have caused a Cosmetic Act unless the label and the number of deaths through accidental labeling bear conspicuously a warning misuse by both adults and children. to the effect: ‘‘Warning— Not for use in Children are particularly attracted by enemas.’’ the odor and are likely to swallow (c) Any tannic acid intended for use these products when left within reach. by man and found within the jurisdic- (b) To safeguard against fatalities tion of the Federal Food, Drug, and from this cause, the Department of Cosmetic Act labeled contrary to this Health and Human Services will regard section after 60 days from the date of

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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 bronchopulmonary disorders, it is necessary § 201.305 Isoproterenol inhalation for the protection of users that warn- preparations (pressurized aerosols, ing information to patients be included nebulizers, powders) for human as a part of the label and as part of any use; warnings. instructions to patients included in the (a) Accumulating reports have been package dispensed to the patient as fol- received by the Food and Drug Admin- lows: istration and have appeared in the 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 immediately. isoproterenol inhalation preparations 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 in the package a printed warning with therapy until use of the isoproterenol instructions to pharmacists to place inhalation preparation was discon- the warning on the container prior to tinued. In addition, sudden unexpected dispensing. deaths have been associated with the (d) The marketing of isoproterenol excessive use of isoproterenol inhala- inhalation preparations may be contin- tion preparations. The mechanism of ued if all the following conditions are these deaths and their relationship, if met: any, to the cases of severe paradoxical (1) Within 30 days following the date bronchospasm are not clear. Cardiac of publication of this section in the arrest was noted in several of these FEDERAL REGISTER: cases of sudden death. (i) The label and labeling of such (b) On the basis of the above informa- preparations shipped within the juris- tion and after discussion with and con- diction of the act are in accordance currence of the Respiratory and Anes- with paragraphs (b) and (c) of this sec- thetic Drugs Advisory Committee for tion. Food and Drug Administration, the (ii) The holder of an approved new- Commissioner of Food and Drugs con- drug application for such preparation cludes that in order for the labeling of submits a supplement to his new-drug such drugs to bear adequate informa- application to provide for appropriate tion for their safe use, as required by labeling changes as described in para- § 201.100, such labeling must include the graphs (b) and (c) of this section. following: (2) Within 90 days following the date Warning: Occasional patients have been re- of publication of this section in the ported to develop severe paradoxical airway FEDERAL REGISTER, the manufacturer, resistance with repeated, excessive use of packer, or distributor of any drug con- isoproterenol inhalation preparations. The taining isoproterenol intended for in- cause of this refractory state is unknown. It halation for which a new-drug approval is advisable that in such instances the use of is not in effect submits a new-drug ap- this preparation be discontinued imme- plication containing satisfactory infor- diately and alternative therapy instituted, since in the reported cases the patients did mation of the kinds required by § 314.50 not respond to other forms of therapy until of this chapter, including appropriate the drug was withdrawn. labeling as described in paragraphs (b) Deaths have been reported following exces- and (c) of this section. sive use of isoproterenol inhalation prepara- (3) The applicant submits additional tions and the exact cause is unknown. Car- information required for the approval diac arrest was noted in several instances. of the application as may be specified (c)(1) The Commissioner also con- in a written communication from the cludes that in view of the manner in Food and Drug Administration.

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(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 (Although the warning statement in- may be initiated with regard to any cludes references to enteric-coated po- such drug shipped within the jurisdiction 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 gas- § 201.306 Potassium salt preparations trointestinal injury.) intended for oral ingestion by man. (iii) Any other labeling or additional (a) The Food and Drug Administra- advertising for the drug conforms to tion will initiate no regulatory action the labeling described in paragraph with respect to the continued mar- (a)(1)(ii) of this section, in accordance keting of coated tablets containing po- with §§ 202.1 and 201.100 of this chapter. tassium chloride or other potassium (2) Within 90 days from the date of salts which supply 100 milligrams or publication of this statement of policy more of potassium per tablet provided in the FEDERAL REGISTER, the manu- all the following conditions are met: facturer, packer, or distributor of the (1) Within 30 days from the date of drug shall submit a new-drug applica- publication of this statement of policy tion containing satisfactory informa- in the FEDERAL REGISTER: tion of the kind required by § 314.50 of (i) The labeling of the drug bears the this chapter, with appropriate labeling prescription caution statement quoted as described in this paragraph. in section 503(b)(4) of the Federal Food, (b) The Food and Drug Administra- Drug, and Cosmetic Act; tion may initiate regulatory pro- (ii) The labeling on or within the ceedings after 30 days from the date of package from which the drug is to be publication of this section, with re- dispensed bears adequate information for its use by practitioners in accord spect to the marketing of uncoated with the ‘‘full disclosure’’ labeling re- tablets containing potassium chloride quirements of § 201.100 of this chapter, or other potassium salts which supply including the following warning state- 100 milligrams or more of potassium ment: per tablet or with respect to liquid preparations containing potassium Warning—There have been several reports, chloride or other potassium salts which published and unpublished, concerning non- specific small-bowel lesions consisting of ste- supply 20 milligrams or more of potas- nosis, with or without ulceration, associated sium per milliliter, labeled or intended with the administration of enteric-coated for human use, unless all the following thiazides with potassium salts. These lesions conditions are met: may occur with enteric-coated potassium (1) The labeling of the drug bears the tablets alone or when they are used with nonenteric-coated thiazides, or certain other prescription statement quoted in sec- oral diuretics. These small-bowel lesions tion 503(b)(4) of the Federal Food, have caused obstruction, hemorrhage, and Drug, and Cosmetic Act; and perforation. Surgery was frequently required (2) The labeling on or within the and deaths have occurred. Based on a large package from which the drug is to be survey of physicians and hospitals, both dispensed bears adequate information United States and foreign, the incidence of these lesions is low, and a causal relation- for its use by practitioners in accord ship in man has not been definitely estab- with the ‘‘full disclosure’’ labeling re- lished. Available information tends to impli- quirements of § 201.100 of this chapter, cate enteric-coated potassium salts, al- including a recommendation that pa- though lesions of this type also occur spon- tients be directed to dissolve any such taneously. Therefore, coated potassium-con- tablets in an appropriate amount of taining formulations should be administered only when indicated, and should be discon- liquid and to dilute any such liquid tinued immediately if abdominal pain, dis- preparations adequately to assure tention, nausea, vomiting, or gastro-

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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 shall appear in boldface type as the [40 FR 13998, Mar. 27, 1975, as amended at 55 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. (b) Any OTC drug product for lax- ‘‘Do not take more than 10 mL (2 tea- ative or bowel cleansing use containing spoonfuls) in a 24-hour period.’’ Chil- sodium phosphates as an active ingre- dren under 5 years of age: ask a doctor. dient when marketed as described in (c) After June 22, 1998, for package paragraph (a) of this section is mis- size limitation and September 18, 1998, branded within the meaning of section for labeling in accord with paragraph 502 of the Federal Food, Drug, and Cos- (b) of this section, any such OTC drug metic Act unless packaged and labeled product initially introduced or ini- as follows: tially delivered for introduction into (1) Package size limitation for so- interstate commerce, or any such drug dium phosphates oral solution: Con- product that is repackaged or relabeled

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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- the Poison Control Center, or hospital counter sale. 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 (lye) and strong acids, or petroleum choice. The immediate availability of distillates such as kerosine, gasoline, this drug for use in such situations is coal oil, fuel oil, paint thinner, or critical, since rapid treatment may be cleaning fluid have been ingested.’’ the difference between life and death. (3) Usual dosage: 1 tablespoon (15 mil- The restriction of this drug to prescrip- liliters) in persons over 1 year of age. tion sale limits its availability in emergencies. On the other hand, it is § 201.309 Acetophenetidin (phen- the consensus of informed medical acetin)-containing preparations; opinion that ipecac syrup should be necessary warning statement. used only under medical supervision in (a) In 1961, the Food and Drug Admin- the emergency treatment of istration, pursuant to its statutory re- poisonings. In view of these facts, the sponsibility for the safety and effec- question of whether ipecac syrup la- tiveness of drugs shipped in interstate beled as an emergency treatment for commerce, began an active investiga- use in poisonings should be available tion of reports of possible toxic effects over the counter has been controver- and renal damage due to misuse of the sial. drug acetophenetidin. This study led to (b) In connection with its study of the decision that there was probable this problem, the Food and Drug Ad- cause to conclude that misuse and pro- ministration has obtained the views of longed use of the drug were in fact re- medical authorities. It is the unani- sponsible for kidney lesions and dis- mous recommendation of the American ease. The Commissioner of Food and Academy of Pediatrics, the American Drugs, in December 1963, appointed an Association of Poison Control Centers, ad hoc Advisory Committee of Inquiry the American Medical Association, and on Possible Nephrotoxicity Associated the Medical Advisory Board of the With the Abuse of Acetophenetidin Food and Drug Administration that ip- (Phenacetin)-Containing Preparations. ecac syrup in 1 fluid ounce containers This committee, composed of scientists be permitted to be sold without pre- in the fields of pharmacology and med- scription so that it will be readily icine, on April 23, 1964, submitted its available in the household for emer- findings and conclusions in the matter gency treatment of poisonings, under and recommended that all acetophe- medical supervision, and that the drug netidin (phenacetin)-containing prep- be appropriately packaged and labeled arations bear a warning as provided in for this purpose. section 502(f)(2) of the Federal Food, (c) In view of the above recommenda- Drug, and Cosmetic Act. tions, the Commissioner of Food and (b) On the basis of the studies made Drugs has determined that it is in the by the Food and Drug Administration interest of the public health for ipecac and the report of the Advisory Com- syrup to be available for sale without mittee, the Commissioner of Food and

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Drugs has concluded that it is nec- § 201.311 [Reserved] essary for the protection of users that the label and labeling of all acetophe- § 201.312 Magnesium sulfate heptahy- netidin (phenacetin)-containing prep- drate; label declaration on drug arations bear a warning statement to products. the following effect: ‘‘Warning—This Magnesium sulfate heptahydrate medication may damage the kidneys should be listed on the label of a drug when used in large amounts or for a product as epsom salt, which is its long period of time. Do not take more common or usual name. than the recommended dosage, nor take regularly for longer than 10 days § 201.313 Estradiol labeling. without consulting your physician.’’ 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 preparations containing salicylates. (2) of the Federal Food, Drug, and Cos- 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 should be discontinued if leukopenia warning statements. Such a warning occurs or if evidence of hyper- statement is required for compliance sensitivity, such as dermatitis or fever, with section 502(f)(2) of the Federal appears.’’ Food, Drug, and Cosmetic Act and is (b) Regulatory action may be initi- intended to guard against accidental ated with respect to preparations of poisonings. Safety closures that pre- phenindione intended for use by man vent access to the drug by young chil- found within the jurisdiction of the act dren are also recommended to guard on or after November 25, 1961, unless against accidental poisonings. such preparations are labeled in ac- (b) Effervescent preparations and cordance with paragraph (a) of this sec- preparations containing para- tion. aminosalicylate as the only salicylate

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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 1 and distributors of 1 ⁄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 con- fect: ‘‘Caution: If pain persists for more taining more than 36 tablets, to reduce than 10 days, or redness is present, or the hazard of accidental poisoning; in conditions affecting children under (3) The flavoring of 5-grain aspirin 12 years of age, consult a physician im- tablets or other ‘‘adult aspirin tablets’’ mediately.’’ The salicylate dosage be discontinued; and should not exceed 60 grains in a 24-hour (4) Labeling giving undue emphasis period or 10 grains in a 4-hour period. If to the pleasant flavor of flavored aspi- the article contains other analgesics, rin tablets be discontinued. the salicylate dosage should be appro- (d) Salicylate preparations other priately reduced. than aspirin tablets sold as such may, (g)(1) The label of any drug con- at the option of the distributor, be la- taining more than 5 percent methyl sa- beled for use by adults only. If their labeling 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.) of age consult your physician.’’ How- (h)(1) The labeling of orally or rec- ever, if the directions provide for ad- tally administered over-the-counter as- ministration to children only of an age pirin and aspirin-containing drug prod- greater than 3 years (for example, the ucts subject to this paragraph is re- dosage instructions provide for admin- quired to prominently bear a warning. istration of the article to children only The warning shall be as follows: ‘‘Chil- down to age 6), the label should bear a dren and teenagers should not use this statement such as, ‘‘For younger chil- medicine for chicken pox or flu symp- dren consult your physician.’’ toms before a doctor is consulted about (2) A statement such as, ‘‘For chil- Reye’s syndrome, a rare but serious ill- dren under 3 years of age consult your ness reported to be associated with as- physician’’ or ‘‘For younger children pirin.’’

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(2) This warning statement shall ap- delivered for introduction into interstate pear on the immediate container label- commerce after the following dates is mis- ing. In cases where the immediate con- branded under sections 201(n) and 502(a) and tainer is not the retail package, the re- (f) of the Federal Food, Drug, and Cosmetic tail package also must bear the warn- Act. ing statement. In addition, the warning (i) Compliance by October 18, 2004, for OTC statement shall appear on any labeling drug products containing aspirin and non- that contains warnings and, in such aspirin salicylates as an active ingredient cases, the warning statement shall be and marketed under a new drug application the first warning statement under the or abbreviated new drug application. heading ‘‘Warnings.’’ (ii) Compliance by April 19, 2004, for OTC (3) Over-the-counter drug products antidiarrheal and overindulgence drug prod- subject to this paragraph and labeled ucts that contain bismuth subsalicylate as an active ingredient and have annual sales solely for use by children (pediatric greater than $25,000. products) shall not recommend the product for use in treating flu or chick- (iii) Compliance by April 18, 2005, for OTC en pox. antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as (4) Any product subject to this para- an active ingredient and have annual sales graph that is not labeled as required by less than $25,000. this paragraph and that is initially in- (iv) Compliance dates for all other OTC troduced or initially delivered for in- drug products containing aspirin and non- troduction into interstate commerce aspirin salicylates as an active ingredient after June 5, 1986, is misbranded under and marketed under an OTC drug monograph sections 201(n) and 502 (a) and (f) of the (for internal analgesic, antipyretic, and Federal Food, Drug, and Cosmetic Act. antirheumatic drug products, or for men- strual drug products) will be established [40 FR 13998, Mar. 27, 1985, as amended at 51 when the final monographs for those prod- FR 8182, Mar. 7, 1986; 53 FR 21637, June 9, ucts are published in a future issue of the 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, FEDERAL REGISTER. In the interim, these Mar. 17, 1999; 65 FR 8, Jan. 3, 2000] products should continue to be labeled with EFFECTIVE DATE NOTE: At 68 FR 18869, the previous Reye’s syndrome warning that April 17, 2003, § 201.314 was amended by revis- appears in paragraph (h)(1) of this section. ing paragraphs (h)(1) and (h)(4), effective April 19, 2004. For the convenience of the § 201.315 Over-the-counter drugs for user, the revised text is set forth below. minor sore throats; suggested warning. § 201.314 Labeling of drug preparations containing salicylates. The Food and Drug Administration has studied the problem of the labeling * * * * * of lozenges or troches containing a local anesthetic, chewing gum con- (h)(1) The labeling of orally or rectally administered over-the-counter drug products taining aspirin, various mouth washes containing aspirin or nonaspirin salicylates and gargles and other articles sold over as active ingredients subject to this para- the counter for the relief of minor irri- graph is required to prominently bear the tations of the mouth or throat. It will following warning: ‘‘Reye’s syndrome [sub- not object to the labeling of suitable heading in bold type]: Children and teenagers articles of this type ‘‘For the tem- who have or are recovering from chicken pox or flu-like symptoms should not use this porary relief of minor sore throats’’, product. When using this product, if changes provided this is immediately followed in behavior with nausea and vomiting occur, in the labeling with a warning state- consult a doctor because these symptoms ment in prominent type essentially as could be an early sign of Reye’s syndrome, a follows: ‘‘Warning—Severe or per- rare but serious illness.’’ sistent sore throat or sore throat ac- companied by high fever, headache, * * * * * nausea, and vomiting may be serious. Consult physician promptly. Do not (4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of this section that is use more than 2 days or administer to not labeled as required by these paragraphs children under 3 years of age unless di- and that is initially introduced or initially rected by physician.’’

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§ 201.316 Drugs with thyroid hormone (c) This section does not apply to dig- activity for human use; required oxin products for oral use, which shall warning. be labeled according to the require- (a) Drugs with thyroid hormone ac- ments of § 310.500 of this chapter. tivity have been promoted for, and con- [43 FR 22009, May 23, 1978] tinue to be dispensed and prescribed for, use in the treatment of obesity, al- § 201.319 Water-soluble gums, hydro- though their safety and effectiveness philic gums, and hydrophilic for that use have never been estab- mucilloids (including, but not lim- lished. ited to agar, alginic acid, calcium (b) Drugs for human use with thyroid polycarbophil, carboxymethylcellu- hormone activity are misbranded with- lose sodium, carrageenan, chondrus, glucomannan ((B-1,4 in the meaning of section 502 of the linked) polymannose acetate), guar Federal Food, Drug, and Cosmetic Act gum, karaya gum, kelp, unless their labeling bears the fol- methylcellulose, plantago seed lowing boxed warning at the beginning (psyllium), polycarbophil of the ‘‘Warnings’’ section: tragacanth, and xanthan gum) as Drugs with thyroid hormone activ- active ingredients; required warn- ity, alone or together with other thera- ings and directions. peutic agents, have been used for the (a) Reports in the medical literature treatment of obesity. In euthyroid pa- and data accumulated by the Food and tients, doses within the range of daily Drug Administration indicate that hormonal requirements are ineffective esophageal obstruction and asphyxia- for weight reduction. Larger doses may tion have been associated with the in- produce serious or even life-threat- gestion of water-soluble gums, hydro- ening manifestations of toxicity, par- philic gums, and hydrophilic ticularly when given in association mucilloids including, but not limited with sympathomimetic amines such as to, agar, alginic acid, calcium those used for their anorectic effects. polycarbophil, carboxymethylcellulose [43 FR 22009, May 23, 1978] sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose § 201.317 Digitalis and related acetate), guar gum, karaya gum, kelp, cardiotonic drugs for human use in methylcellulose, plantago seed (psyl- oral dosage forms; required warn- lium), polycarbophil, tragacanth, and ing. xanthan gum. Esophageal obstruction (a) Digitalis and related cardiotonic and asphyxiation due to orally-admin- drugs for human use in oral dosage istered drug products containing forms have been promoted for, and con- water-soluble gums, hydrophilic gums, tinue to be dispensed and prescribed and hydrophylic mucilloids as active for, use in the treatment of obesity, al- ingredients are significant health risks though their safety and effectiveness when these products are taken without for that use have never been estab- adequate fluid or when they are used lished. by individuals with esophageal nar- (b) Digitalis and related cardiotonic rowing or dysfunction, or with dif- drugs for human use in oral dosage ficulty in swallowing. Additional label- forms are misbranded within the meaning is needed for the safe and effective ing of section 502 of the Federal Food, use of any OTC drug product for human Drug, and Cosmetic Act unless their la- use containing a water-soluble gum, beling bears the following boxed warn- hydrophilic gum, or hydrophilic ing at the beginning of the ‘‘Warnings’’ mucilloid as an active ingredient when section: marketed in a dry or incompletely hy- Digitalis alone or with other drugs drated form to include, but not limited has been used in the treatment of obe- to, the following dosage forms: cap- sity. This use of digoxin or other digi- sules, granules, powders, tablets, and talis glycosides is unwarranted. More- wafers. over, since they may cause potentially (b) Any drug products for human use fatal arrhythmias or other adverse ef- containing a water-soluble gum, hydro- fects, the use of these drugs in the philic gum, or hydrophilic mucilloid as treatment of obesity is dangerous. an active ingredient in an oral dosage

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

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environment by destroying ozone in the a physician. Accordingly, any OTC upper atmosphere. drug product, labeled for adult use, A notice similar to the above WARNING containing any internal analgesic/anti- has been placed in the information for the pyretic active ingredients (including, patient [or patient information leaflet, if applicable] of this product under the Environ- but not limited to, acetaminophen, as- mental Protection Agency’s (EPA’s) regula- pirin, carbaspirin calcium, choline sa- tions. The patient’s warning states that the licylate, ibuprofen, ketoprofen, magne- patient should consult his or her physician if sium salicylate, naproxen sodium, and there are questions about alternatives. sodium salicylate) alone or in combina- (c)(1) For over-the-counter drug prod- tion shall bear an alcohol warning ucts for human use, the following al- statement in its labeling as follows: ternative warning statement may be (1) Acetaminophen. ‘‘Alcohol Warn- used: ing’’ [heading in boldface type]: ‘‘If you consume 3 or more alcoholic drinks NOTE: The indented statement below is re- every day, ask your doctor whether quired by the Federal government’s Clean you should take acetaminophen or Air Act for all products containing or manufactured with chlorofluorocarbons (CFC’s) other pain relievers/fever reducers. Ac- [or other class I substance, if applicable]: etaminophen may cause liver damage.’’ (2) Nonsteroidal anti-inflammatory an- WARNING: Contains [or Manufactured with, if applicable] [insert name of substance], a sub- algesic/antipyretic active ingredients—in- stance which harms public health and envi- cluding but not limited to aspirin, ronment by destroying ozone in the upper at- carbaspirin calcium, choline salicylate, mosphere. ibuprofen, ketoprofen, magnesium salicy- CONSULT WITH YOUR PHYSICIAN OR late, naproxen sodium, and sodium salicy- HEALTH PROFESSIONAL IF YOU HAVE late. ‘‘Alcohol Warning’’ [heading in ANY QUESTION ABOUT THE USE OF THIS boldface type]: ‘‘If you consume 3 or PRODUCT. more alcoholic drinks every day, ask (2) The warning statement shall be your doctor whether you should take clearly legible and conspicuous on the [insert one nonsteroidal anti-inflam- product, its immediate container, its matory analgesic/antipyretic active in- outer packaging, or other labeling in gredient] or other pain relievers/fever accordance with the requirements of 40 reducers. [Insert one nonsteroidal anti- CFR part 82 and appear with such inflammatory analgesic/antipyretic ac- prominence and conspicuousness as to tive ingredient] may cause stomach render it likely to be read and under- bleeding.’’ stood by consumers under normal con- (3) Combinations of acetaminophen with ditions of purchase. nonsteroidal anti-inflammatory analgesic/ (d) This section does not replace or antipyretic active ingredients—including relieve a person from any requirements but not limited to aspirin, carbaspirin cal- imposed under 40 CFR part 82. cium, choline salicylate, ibuprofen, [61 FR 20100, May 3, 1996] ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate. § 201.322 Over-the-counter drug prod- ‘‘Alcohol Warning’’ [heading in bold- ucts containing internal analgesic/ face type]: ‘‘If you consume 3 or more antipyretic active ingredients; re- alcoholic drinks every day, ask your quired alcohol warning. doctor whether you should take [insert (a) People who regularly consume acetaminophen and one nonsteroidal large quantities of alcohol (three or anti-inflammatory analgesic/anti- more drinks every day) have an in- pyretic active ingredient—including, creased risk of adverse effects (possible but not limited to aspirin, carbaspirin liver damage or gastrointestinal bleed- calcium, choline salicylate, magnesium ing). OTC drug products containing in- salicylate, or sodium salicylate] or ternal analgesic/antipyretic active in- other pain relievers/fever reducers. [Ac- gredients may cause similar adverse ef- etaminophen and (insert one nonste- fects. FDA concludes that the labeling roidal anti-inflammatory analgesic/ of OTC drug products containing inter- antipyretic ingredient—including, but nal analgesic/antipyretic active ingre- not limited to aspirin, carbaspirin cal- dients should advise consumers with a cium, choline salicylate, magnesium history of heavy alcohol use to consult salicylate, or sodium salicylate] may

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cause liver damage and stomach bleed- will be no more than ll µg/L.’’ This ing.’’ maximum level of aluminum must be (b) Requirements to supplement ap- stated as the highest of: proved application. Holders of approved (1) The highest level for the batches applications for OTC drug products produced during the last 3 years; that contain internal analgesic/anti- (2) The highest level for the latest pyretic active ingredients that are sub- five batches, or ject to the requirements of paragraph (3) The maximum historical level, (a) of this section must submit supple- but only until completion of produc- ments under § 314.70(c) of this chapter tion of the first five batches after Jan- to include the required warning in the uary 26, 2001. product’s labeling. Such labeling may (d) The package insert for all LVP’s, be put into use without advance ap- all SVP’s, and PBP’s used in TPN must proval of FDA provided it includes the contain a warning statement. This exact information included in para- warning must be contained in the graph (a) of this section. ‘‘Warnings’’ section of the labeling. (c) Any drug product subject to this section that is not labeled as required The warning must state: and that is initially introduced or ini- WARNING: This product contains alu- tially delivered for introduction into minum that may be toxic. Aluminum may interstate commerce after April 23, reach toxic levels with prolonged parenteral 1999, is misbranded under section 502 of administration if kidney function is im- the Federal Food, Drug, and Cosmetic paired. Premature neonates are particularly Act (21 U.S.C. 352) and is subject to reg- at risk because their kidneys are immature, and they require large amounts of calcium ulatory action. and phosphate solutions, which contain alu- [63 FR 56801, Oct. 23, 1998] minum. Research indicates that patients with im- § 201.323 Aluminum in large and small paired kidney function, including premature volume parenterals used in total neonates, who receive parenteral levels of parenteral nutrition. aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated (a) The aluminum content of large with central nervous system and bone tox- volume parenteral (LVP) drug products icity. Tissue loading may occur at even used in total parenteral nutrition lower rates of administration. (TPN) therapy must not exceed 25 micrograms per liter (µg/L). (e) Applicants and manufacturers (b) The package insert of LVP’s used must use validated assay methods to in TPN therapy must state that the determine the aluminum content in drug product contains no more than 25 parenteral drug products. The assay µg/L of aluminum. This information methods must comply with current must be contained in the ‘‘Pre- good manufacturing practice require- cautions’’ section of the labeling of all ments. Applicants must submit to the large volume parenterals used in TPN Food and Drug Administration valida- therapy. tion of the method used and release (c) The maximum level of aluminum data for several batches. Manufactur- present at expiry must be stated on the ers of parenteral drug products not immediate container label of all small subject to an approved application volume parenteral (SVP) drug products must make assay methodology avail- and pharmacy bulk packages (PBP’s) able to FDA during inspections. Hold- used in the preparation of TPN solu- ers of pending applications must sub- tions. The aluminum content must be mit an amendment under § 314.60 or stated as follows: ‘‘Contains no more § 314.96 of this chapter. µ than ll g/L of aluminum.’’ The im- EFFECTIVE DATE NOTE 1: At 65 FR 4110, Jan. mediate container label of all SVP’s 26, 2000, § 201.323 was added, effective Jan. 26, and PBP’s that are lyophilized powders 2001. At 66 FR 7864, Jan. 26, 2001, the effective used in the preparation of TPN solu- date was delayed until Jan. 26, 2003. tions must contain the following state- EFFECTIVE DATE NOTE 2: At 67 FR 70691, ment: ‘‘When reconstituted in accord- Nov. 26, 2002, § 201.323 was amended in para- ance with the package insert instruc- graph (c)(3) by removing the date ‘‘2001’’ and tions, the concentration of aluminum adding in its place the date ‘‘2004’’, and the

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effective date of the section was delayed 5. The information is set in 6 point until Jan. 26, 2004. Helvetica Regular with 6.5 point leading, left justified. EFFECTIVE DATE NOTE 3: At 68 FR 32981, June 3, 2003, the effective date of § 201.323 was 6. The heading ‘‘Purpose’’ is right justified. further delayed until July 26, 2004, and the 7. The bullet is a 5-point solid square. section was amended by revising the first 8. Two em spacing separates bullets when sentence of the introductory text of para- more than one bullet is on the same line. graph (c); by removing from paragraph (c)(3) 9. A table format is used for 3 or more dos- the word ‘‘January’’ and adding in its place age directions. the word ‘‘July’’; by redesignating para- 10. A graphic appears at the bottom of the graphs (d) and (e) as paragraphs (e) and (f), first panel leading the reader to the next respectively; and by adding new paragraph panel. (d). For the convenience of the user, the re- C. Barlines and hairlines vised and added text is set forth as follows: 1. A 2.5-point horizontal barline extends to § 201.323 Aluminum in large and small vol- each end of the ‘‘Drug Facts’’ box (or similar ume parenterals used in total parenteral enclosure), providing separation between nutrition. each of the headings. 2. A 0.5-point horizontal hairline extends * * * * * within 2 spaces on either side of the ‘‘Drug (c) Except as provided in paragraph (d) of Facts’’ box (or similar enclosure), imme- this section, the maximum level of alu- diately following the title and immediately minum present at expiry must be stated on preceding the subheadings. the immediate container label of all small 3. A 0.5-point horizontal hairline follows volume parenteral (SVP) drug products and the title, immediately preceding the head- pharmacy bulk packages (PBPs) used in the ing, when a heading appears on a subsequent preparation of TPN solutions.* * * panel immediately after the ‘‘Drug Facts (d) If the maximum level of aluminum is 25 (continued)’’ title. µg/L or less, instead of stating the exact D. Box or Enclosure amount of aluminum as required in paragraph (c) of this section, the immediate con- 1. All information is enclosed by a 2.5-point tainer label may state: ‘‘Contains no more barline. than 25 µg/L of aluminum.’’ If the SVP or PBP is a lyophilized powder, the immediate II. SECTION 201.66 MODIFIED LABELING container label may state: ‘‘When reconsti- FORMAT tuted in accordance with the package insert A. Overall instructions, the concentration of aluminum will be no more than 25 µg/L’’. 1. The ‘‘Drug Facts’’ labeling is presented in all black type printed on a white color * * * * * 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.

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2. A 0.5-point horizontal hairline extends D. Box or Enclosure within 2 spaces on either side of the ‘‘Drug 1. All information is set off by color con- Facts’’ box (or similar enclosure), imme- trast. No barline is used. diately following the title and immediately preceding the subheadings. III. EXAMPLES OF § 201.66 STANDARD LABELING AND MODIFIED LABELING FORMATS

A. SECTION 201.66 STANDARD LABELING FORMAT

B. SECTION 201.66 MODIFIED LABELING FORMAT

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PART 202—PRESCRIPTION DRUG etary name or designation in the run- ADVERTISING ning text of the advertisement. On any page of an advertisement in which the proprietary name or designation is not AUTHORITY: 21 U.S.C. 321, 331, 352, 355, 360b, featured but is used in the running 371. text, the established name shall be § 202.1 Prescription-drug advertise- used at least once in the running text ments. in association with such proprietary (a)(1) The ingredient information re- name or designation and in the same quired by section 502(n) of the Federal type size used in the running text: Pro- Food, Drug, and Cosmetic Act shall ap- vided, however, That if the proprietary pear together, without any intervening name or designation is used in the run- 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 designate a drug or ingredient by a propri- text. Where the established name is re- etary name that, because of similarity quired to accompany or to be used in in spelling or pronunciation, may be association with the proprietary name 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

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name shall have a prominence com- most prominent listing of the names of mensurate with the prominence with such dosage forms. which such proprietary name or des- (e) True statement of information in ignation appears, taking into account brief summary relating to side effects, all pertinent factors, including typog- contraindications, and effectiveness: raphy, layout, contrast, and other (1) When required. All advertisements printing features. for any prescription drug (‘‘prescrip- (c) In the case of a prescription drug tion drug’’ as used in this section containing two or more active ingredi- means drugs defined in section 503(b)(1) ents, if the advertisement bears a proof the act and § 201.105, applicable to prietary name or designation for such drugs for use by man and veterinary mixture and there is no established drugs, respectively), except advertise- 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,

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

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

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

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evidence or substantial clinical experi- apy as provided by the fixed combina- ence, by selective presentation of infor- tion drug is indicated, unless such con- mation from published articles or other dition is included in the uses permitted references that report no side effects or under paragraph (e)(4) of this section. 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 advertisement promotes the drug for use by (xvi) Uses statements or representa- man). tions that a drug differs from or does (vii) Contains favorable data or con- not contain a named drug or category clusions from nonclinical studies of a of drugs, or that it has a greater po- drug, such as in laboratory animals or tency per unit of weight, in a way that in vitro, in a way that suggests they suggests falsely or misleadingly or have clinical significance when in fact without substantial evidence or sub- no such clinical significance has been stantial clinical experience that the demonstrated. advertised drug is safer or more effec- (viii) Uses a statement by a recog- tive than such other drug or drugs. nized authority that is apparently fa- (xvii) Uses data favorable to a drug vorable about a drug but fails to refer derived from patients treated with dos- to concurrent or more recent unfavor- ages different from those recommended able data or statements from the same in approved or permitted labeling if the authority on the same subject or sub- drug advertised is subject to section 505 jects. of the act, or, in the case of other (ix) Uses a quote or paraphrase out of drugs, if the dosages employed were context to convey a false or misleading different from those recommended in idea. the labeling and generally recognized (x) Uses literature, quotations, or ref- as safe and effective. This provision is erences that purport to support an ad- not intended to prevent citation of re- vertising claim but in fact do not sup- ports of studies that include some pa- port the claim or have relevance to the tients treated with dosages different claim. from those authorized, if the results in (xi) Uses literature, quotations, or such patients are not used. references for the purpose of recom- (xviii) Uses headline, subheadline, or mending or suggesting conditions of pictorial or other graphic matter in a drug use that are not approved or per- way that is misleading. mitted in the drug package labeling. (xix) Represents or suggests that (xii) Offers a combination of drugs for drug dosages properly recommended for the treatment of patients suffering use in the treatment of certain classes from a condition amenable to treat- of patients or disease conditions are ment by any of the components rather safe and effective for the treatment of than limiting the indications for use to other classes of patients or disease con- patients for whom concomitant ther- ditions when such is not the case.

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(xx) Presents required information (iv) Uses tables or graphs to distort relating to side effects or contraindica- or misrepresent the relationships, tions by means of a general term for a trends, differences, or changes among group in place of disclosing each spe- the variables or products studied; for cific side effect and contraindication example, by failing to label abscissa (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, lating to side effects and contraindica- lacking in fair balance, or otherwise tions with a prominence and read- misleading or otherwise violative of ability reasonably comparable with the section 502(n) of the act if it: presentation of information relating to (i) Contains favorable information or effectiveness of the drug, taking into conclusions from a study that is inad- account all implementing factors such equate in design, scope, or conduct to as typography, layout, contrast, head- furnish significant support for such in- lines, paragraphing, white space, and formation or conclusions. any other techniques apt to achieve (ii) Uses the concept of ‘‘statistical emphasis. significance’’ to support a claim that (ix) Fails to provide adequate empha- has not been demonstrated to have sis (for example, by the use of color clinical significance or validity, or scheme, borders, headlines, or copy fails to reveal the range of variations that extends across the gutter) for the around the quoted average results. fact that two facing pages are part of (iii) Uses statistical analyses and the same advertisement when one page techniques on a retrospective basis to contains information relating to side discover and cite findings not soundly effects and contraindications. supported by the study, or to suggest (x) In an advertisement promoting scientific validity and rigor for data use of the drug in a selected class of pa- from studies the design or protocol of tients (for example, geriatric patients which are not amenable to formal sta- or depressed patients), fails to present tistical evaluations. with adequate emphasis the significant

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side effects and contraindications or Secretary’s rights, as authorized by the significant dosage considerations, law, to issue publicity, to suspend any when dosage recommendations are in- new-drug application, to decertify any cluded in an advertisement, especially antibiotic, or to recommend any regu- applicable to that selected class of pa- latory action. tients. (2) Within a reasonable time after in- (xi) Fails to present on a page facing formation concerning the possibility another page (or on another full page) that a drug may cause fatalities or se- of an advertisement on more than one rious damage has been widely pub- page, information relating to side ef- licized in medical literature, the Food fects and contraindications when such and Drug Administration shall notify information is in a distinct part of the the sponsor of the drug by mail that advertisement. prior approval of advertisements for (xii) Fails to include on each page or 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 (i) The sponsor or the Food and Drug any regulatory action is taken under Administration has received informa- this section. Notification to the adver- tion that has not been widely pub- tiser that a proposed advertisement is licized in medical literature that the or is not considered to be in violation use of the drug may cause fatalities or shall be in written form. serious damage; (5) The sponsor shall have an oppor- (ii) The Commissioner (or in his absence the officer acting as Commis- tunity for a regulatory hearing before sioner), after evaluating the reliability the Food and Drug Administration pur- of such information, has notified the suant to part 16 of this chapter with re- sponsor that the information must be a spect to any determination that prior part of the advertisements for the approval is required for advertisements drug; and concerning a particular prescription (iii) The sponsor has failed within a drug, or that a particular advertise- reasonable time as specified in such no- ment is not approvable. tification to present to the Food and (k) An advertisement issued or Drug Administration a program, ade- caused to be issued by the manufac- quate in light of the nature of the in- turer, packer, or distributor of the formation, for assuring that such infor- drug promoted by the advertisement mation will be publicized promptly and and which is not in compliance with adequately to the medical profession in section 502(n) of the act and the appli- subsequent advertisements. cable regulations thereunder shall If the Commissioner finds that the pro- cause stocks of such drug in possession gram presented is not being followed, of the person responsible for issuing or he will notify the sponsor that prior causing the issuance of the advertise- approval of all advertisements for the ment, and stocks of the drug distrib- particular drug will be required. Noth- uted by such person and still in the ing in this paragraph is to be construed channels of commerce, to be mis- as limiting the Commissioner’s or the branded under section 502(n) of the act.

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(l)(1) Advertisements subject to sec- safety or effectiveness is supported by sub- tion 502(n) of the act include advertise- stantial evidence derived from adequate and ments in published journals, maga- well–controlled studies as defined in zines, other periodicals, and news- § 314.111(a)(5)(ii) of this chapter, or unless the requirement for adequate and well–con- papers, and advertisements broadcast trolled studies is waived as provided in through media such as radio, tele- § 314.111(a)(5)(ii) of this chapter. vision, and telephone communication 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 of a prescription drug, such as studies in lab- house organs, letters, motion picture oratory animals or in vitro, that the studies films, film strips, lantern slides, sound have clinical significance, if clinical signifi- recordings, exhibits, literature, and re- cance has not been demonstrated. Data that prints and similar pieces of printed, demonstrate activity or effectiveness for a audio, or visual matter descriptive of 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 except that (a), in the case of anti–infective tioners, pharmacists, or nurses, con- drugs, in vitro data may be included in the taining drug information supplied by advertisement, if data are immediately pre- the manufacturer, packer, or dis- ceded by the statement ‘‘The following in tributor of the drug and which are dis- vitro data are available but their clinical seminated by or on behalf of its manu- 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; 64 FR 400, Jan. 5, 1999] § 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 PART 203—PRESCRIPTION DRUG FR 400, Jan. 5, 1999, these paragraphs were 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.

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203.31 Sample distribution by means other § 203.2 Purpose. than mail or common carrier (direct delivery by a representative or detailer). The purpose of this part is to imple- 203.32 Drug sample storage and handling re- ment the Prescription Drug Marketing quirements. Act of 1987 and the Prescription Drug 203.33 Drug sample forms. Amendments of 1992, except for those 203.34 Policies and procedures; administra- sections relating to State licensing of tive systems. wholesale distributors (see part 205 of 203.35 Standing requests. this chapter), to protect the public 203.36 Fulfillment houses, shipping and health, and to protect the public mailing services, comarketing agree- against drug diversion by establishing ments, and third-party recordkeeping. procedures, requirements, and min- 203.37 Investigation and notification re- imum standards for the distribution of quirements. prescription drugs and prescription 203.38 Sample lot or control numbers; label- drug samples. ing of sample units. 203.39 Donation of drug samples to chari- § 203.3 Definitions. table institutions. (a) The act means the Federal Food, Subpart E—Wholesale Distribution Drug, and Cosmetic Act, as amended (21 U.S.C. 301 et seq.). 203.50 Requirements for wholesale distribu- (b) Authorized distributor of record tion 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. 203.60 Request and receipt forms, reports, (c) Blood means whole blood collected and records. from a single donor and processed either 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- ates used in the synthesis of such sub- This part sets forth procedures and stances. requirements pertaining to the re- (f) Charitable institution or charitable importation and wholesale distribution organization means a nonprofit hos- of prescription drugs, including both pital, health care entity, organization, bulk drug substances and finished dos- institution, foundation, association, or age forms; the sale, purchase, or trade corporation that has been granted an of (or the offer to sell, purchase, or exemption under section 501(c)(3) of the trade) prescription drugs, including Internal Revenue Code of 1954, as bulk drug substances, that were pur- amended. chased by hospitals or health care enti- (g) Common control means the power ties, or donated to charitable organiza- to direct or cause the direction of the tions; and the distribution of prescrip- management and policies of a person or tion drug samples. Blood and blood an organization, whether by ownership components intended for transfusion of stock, voting rights, by contract, or are excluded from the restrictions in otherwise. and the requirements of the Prescrip- (h) Distribute means to sell, offer to tion Drug Marketing Act of 1987 and sell, deliver, or offer to deliver a drug the Prescription Drug Amendments of to a recipient, except that the term 1992. ‘‘distribute’’ does not include:

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(1) Delivering or offering to deliver a drugs by a retail pharmacy to another drug by a common carrier in the usual retail pharmacy to alleviate a tem- course of business as a common carrier; porary shortage; but do not include or regular and systematic sales to li- (2) Providing of a drug sample to a censed practitioners of prescription patient by: drugs that will be used for routine of- (i) A practitioner licensed to pre- fice procedures. scribe such drug; (n) FDA means the U.S. Food and (ii) A health care professional acting Drug Administration. at the direction and under the super- (o) Group purchasing organization vision of such a practitioner; or means any entity established, main- (iii) The pharmacy of a hospital or of tained, and operated for the purchase another health care entity that is act- of prescription drugs for distribution ing at the direction of such a practi- exclusively to its members with such tioner and that received such sample in 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. A person cannot adopted, or authorized by an individual simultaneously be a ‘‘health care enti- to be the legally binding equivalent of ty’’ and a retail pharmacy or wholesale the individual’s handwritten signature. distributor. (m) Emergency medical reasons in- (r) Licensed practitioner means any clude, but are not limited to, transfers person licensed or authorized by State of a prescription drug between health law to prescribe drugs. care entities or from a health care en- (s) Manufacturer means any person tity to a retail pharmacy to alleviate a 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

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the distributor is not authorized to dis- nization to the extent otherwise per- tribute a manufacturer’s entire prod- mitted by law; uct line, the agreement must identify (4) The sale, purchase, or trade of a the specific drug products that the dis- drug or an offer to sell, purchase, or tributor is authorized to distribute. trade a drug among hospitals or other (v) PDA means the Prescription health care entities that are under Drug 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. (y) Prescription drug means any drug (6) The sale, purchase, or trade of a (including any biological product, ex- drug, an offer to sell, purchase, or cept for blood and blood components trade a drug, or the dispensing of a intended for transfusion or biological drug under a prescription executed in products that are also medical devices) accordance with section 503(b) of the required by Federal law (including Fed- act; 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, card, blister pack, bottle, container, or practitioners for office use. other single package comprised of one (dd) Wholesale distributor means any or more dosage units of a prescription person engaged in wholesale distribu- drug sample, intended by the manufac- tion of prescription drugs, including, turer or distributor to be provided by a but not limited to, manufacturers; re- licensed practitioner to a patient in an packers; own-label distributors; pri- unbroken or unopened condition. vate-label distributors; jobbers; bro- (bb) Unauthorized distributor means a kers; warehouses, including manufac- distributor who does not have an ongo- turers’ and distributors’ warehouses, ing relationship with a manufacturer chain drug warehouses, and wholesale to sell or distribute its products. drug warehouses; independent whole- (cc) Wholesale distribution means dis- sale drug traders; and retail phar- tribution of prescription drugs to per- macies that conduct wholesale dis- sons other than a consumer or patient, tributions. but does not include: (1) Intracompany sales; EFFECTIVE DATE NOTE: At 64 FR 67756, Dec. (2) The purchase or other acquisition 3, 1999, § 203.3 was added, effective Dec. 4, by a hospital or other health care enti- 2000. At 65 FR 25639, May 3, 2000, the effective ty that is a member of a group pur- date for § 203.3(u) was delayed until Oct. 1, 2001. At 66 FR 12851, Mar. 1, 2001, § 203.3(u) chasing organization of a drug for its was further delayed until Apr. 1, 2002. At 67 own use from the group purchasing or- FR 6646, Feb. 13, 2002, the effective date was ganization or from other hospitals or further delayed until Apr. 1, 2003. At 68 FR health care entities that are members 4912, Jan. 31, 2003, the effective date was fur- of such organizations; ther delayed until Apr. 1, 2004. At 69 FR 8105, (3) The sale, purchase, or trade of a Feb. 23, 2004, the effective date of § 203.3(u) drug or an offer to sell, purchase, or was further delayed until Dec. 1, 2006. trade a drug by a charitable organization to a nonprofit affiliate of the orga-

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Subpart B—Reimportation (b) Donated or supplied at a reduced price to a charitable organization. § 203.10 Restrictions on reimportation. § 203.22 Exclusions. No prescription drug or drug composed wholly or partly of insulin that Section 203.20 does not apply to: was manufactured in a State and ex- (a) The purchase or other acquisition ported from the United States may be of a drug for its own use by a hospital reimported by anyone other than its or other health care entity that is a manufacturer, except that FDA may member of a group purchasing organi- grant permission to a person other zation from the group purchasing orga- than the manufacturer to reimport a nization or from other hospitals or prescription drug or insulin-containing health care entities that are members drug if it determines that such re- of the organization. importation is required for emergency (b) The sale, purchase, or trade of a medical care. drug or an offer to sell, purchase, or trade a drug by a charitable organiza- § 203.11 Applications for reimportation tion to a nonprofit affiliate of the orga- to provide emergency medical care. nization to the extent otherwise per- (a) Applications for reimportation for mitted by law. (c) The sale, purchase, or trade of a emergency medical care shall be sub- drug or an offer to sell, purchase, or mitted to the director of the FDA Dis- trade a drug among hospitals or other trict Office in the district where re- health care entities that are under importation is sought (addresses found common control. in § 5.115 of this chapter). (d) The sale, purchase, or trade of a (b) Applications for reimportation to drug or an offer to sell, purchase, or provide emergency medical care shall trade a drug for emergency medical be reviewed and approved or dis- reasons. approved by each district office. (e) The sale, purchase, or trade of a § 203.12 An appeal from an adverse de- drug, an offer to sell, purchase, or cision by the district office. trade a drug, or the dispensing of a drug under a valid prescription. An appeal from an adverse decision (f) The sale, purchase, or trade of a by the district office involving insulin- drug or the offer to sell, purchase, or containing drugs or prescription trade a drug by hospitals or health care human drugs, other than biological entities owned or operated by Federal, products, may be made to the Office of State, or local governmental units to Compliance (HFD–300), Center for Drug other hospitals or health care entities Evaluation and Research, Food and owned or operated by Federal, State, or Drug Administration, 7520 Standish local governmental units. Pl., Rockville, MD 20855. An appeal (g) The sale, purchase, or trade of, or from an adverse decision by the dis- the offer to sell, purchase, or trade trict office involving prescription blood or blood components intended for human biological products may be transfusion. made to the Office of Compliance and Biologics Quality (HFM–600), Center for § 203.23 Returns. Biologics Evaluation and Research, The return of a prescription drug Food and Drug Administration, 1401 purchased by a hospital or health care Rockville Pike, Rockville, MD 20852. entity or acquired at a reduced price by or donated to a charitable institution Subpart C—Sales Restrictions is exempt from the prohibitions in § 203.20, provided that: § 203.20 Sales restrictions. (a) The hospital, health care entity, Except as provided in § 203.22 or or charitable institution documents § 203.23, no person may sell, purchase, the return by filling out a credit memo or trade, or offer to sell, purchase, or specifying: trade any prescription drug that was: (1) The name and address of the hos- (a) Purchased by a public or private pital, health care entity, or charitable hospital or other health care entity; or institution;

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(2) The name and address of the man- sample to be delivered by mail or com- ufacturer or wholesale distributor from mon carrier to a licensed practitioner which it was acquired; is required to contain the following: (3) The product name and lot or con- (i) The name, address, professional trol number; title, and signature of the practitioner (4) The quantity returned; and making the request; (5) The date of the return. (ii) The practitioner’s State license (b) The hospital, health care entity, or authorization number or, where a or charitable institution forwards a scheduled drug product is requested, copy of each credit memo to the manu- the practitioner’s Drug Enforcement facturer and retains a copy of each Administration number. credit memo for its records; (iii) The proprietary or established (c) Any drugs returned to a manufac- name and the strength of the drug sam- turer or wholesale distributor are kept ple requested; under proper conditions for storage, (iv) The quantity requested; handling, and shipping, and written (v) The name of the manufacturer documentation showing that proper and the authorized distributor of conditions were maintained is provided record, if the drug sample is requested to the manufacturer or wholesale dis- from an authorized distributor of tributor to which the drugs are re- record; and turned. (vi) The date of the request. (2) A written request for a drug sam- Subpart D—Samples ple to be delivered by mail or common carrier to the pharmacy of a hospital § 203.30 Sample distribution by mail or or other health care entity is required common carrier. to contain, in addition to all of the in- (a) Requirements for drug sample dis- formation in paragraph (b)(l) of this tribution by mail or common carrier. A section, the name and address of the manufacturer or authorized distributor pharmacy of the hospital or other of record may distribute a drug sample health care entity to which the drug to a practitioner licensed to prescribe sample is to be delivered. the drug that is to be sampled or, at (c) Contents of the receipt to be com- the written request of a licensed prac- pleted upon delivery of a drug sample. titioner, to the pharmacy of a hospital The receipt is to be on a form des- or other health care entity, by mail or ignated by the manufacturer or dis- common carrier, provided that: tributor, and is required to contain the (1) The licensed practitioner executes following: and submits a written request to the (1) If the drug sample is delivered to manufacturer or authorized distributor the licensed practitioner who requested of record, as set forth in paragraph (b) it, the receipt is required to contain of this section, before the delivery of the name, address, professional title, the drug sample; and signature of the practitioner or the (2) The manufacturer or authorized practitioner’s designee who acknowl- distributor of record verifies with the edges delivery of the drug sample; the appropriate State authority that the proprietary or established name and practitioner requesting the drug sam- strength of the drug sample and the ple is licensed or authorized under quantity of the drug sample delivered; State law to prescribe the drug prod- and the date of the delivery. uct; (2) If the drug sample is delivered to (3) The recipient executes a written the pharmacy of a hospital or other receipt, as set forth in paragraph (c) of health care entity at the request of a this section, when the drug sample is licensed practitioner, the receipt is re- delivered; and quired to contain the name and address (4) The receipt is returned to the of the requesting licensed practitioner; manufacturer or distributor from the name and address of the hospital or which the drug sample was received. health care entity pharmacy des- (b) Contents of the written request form ignated to receive the drug sample; the for delivery of samples by mail or common name, address, professional title, and carrier. (1) A written request for a drug signature of the person acknowledging

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delivery of the drug sample; the propri- (v) The name of the manufacturer etary or established name and strength and the authorized distributor of of the drug sample; the quantity of the record, if the drug sample is requested drug sample delivered; and the date of from an authorized distributor of the delivery. record; and (vi) The date of the request. § 203.31 Sample distribution by means 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. tioner licensed to prescribe the drug to (c) Contents of the receipt to be com- be sampled or, at the written request of pleted upon delivery of a drug sample. such a licensed practitioner, to the The receipt is to be on a form des- pharmacy of a hospital or other health ignated by the manufacturer or dis- care entity, provided that: tributor, and is required to contain the (1) The manufacturer or authorized following: distributor of record receives from the (1) If the drug sample is received at licensed practitioner a written request the address of the licensed practitioner signed by the licensed practitioner be- who requested it, the receipt is re- fore the delivery of the drug sample; quired to contain the name, address, (2) The manufacturer or authorized professional title, and signature of the distributor of record verifies with the practitioner or the practitioner’s des- appropriate State authority that the ignee who acknowledges delivery of the practitioner requesting the drug sam- drug sample; the proprietary or estab- ple is licensed or authorized under lished name and strength of the drug State law to prescribe the drug prod- sample; the quantity of the drug sam- uct; ple delivered; and the date of the deliv- (3) A receipt is signed by the recipi- ery. ent, as set forth in paragraph (c) of this (2) If the drug sample is received by section, when the drug sample is deliv- the pharmacy of a hospital or other ered; health care entity at the request of a (4) The receipt is returned to the licensed practitioner, the receipt is re- manufacturer or distributor; and quired to contain the name and address (5) The requirements of paragraphs (d) through (e) of this section are met. of the requesting licensed practitioner; (b) Contents of the written request the name and address of the hospital or forms for delivery of samples by a rep- health care entity pharmacy des- resentative. (1) A written request for de- ignated to receive the drug sample; the livery of a drug sample by a represent- name, address, professional title, and ative to a licensed practitioner is re- signature of the person acknowledging quired to contain the following: delivery of the drug sample; the propri- (i) The name, address, professional etary or established name and strength title, and signature of the practitioner of the drug sample; the quantity of the making the request; drug sample delivered; and the date of (ii) The practitioner’s State license the delivery. or authorization number, or, where a (d) Inventory and reconciliation of scheduled drug product is requested, drug samples of manufacturers’ and dis- the practitioner’s Drug Enforcement tributors’ representatives. Each drug Administration number; manufacturer or authorized distributor (iii) The proprietary or established of record that distributes drug samples name and the strength of the drug sam- by means of representatives shall con- ple requested; duct, at least annually, a complete and (iv) The quantity requested; accurate physical inventory of all drug

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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.’’ resentative’s stock by the proprietary (3) Each drug manufacturer or au- or established name, dosage strength, thorized distributor of record shall and number of units. take appropriate internal control (2) The reconciliation report is re- measures to guard against error and quired to include: possible fraud in the conduct of the physical inventory and reconciliation, (i) The inventory record for the most and in the preparation of the inventory recently completed prior inventory; record and reconciliation report. (ii) A record of each drug sample (4) A manufacturer or authorized dis- shipment received since the most re- tributor of record shall carefully evalu- cently completed prior inventory, in- ate any apparent discrepancy or sig- cluding the sender and date of the ship- nificant loss revealed through the in- ment, and the proprietary or estab- ventory and reconciliation process and lished name, dosage strength, and num- shall fully investigate any such dis- ber of sample units received; crepancy or significant loss that can- (iii) A record of drug sample distribu- not be justified. tions since the most recently com- (e) Lists of manufacturers’ and distribu- pleted inventory showing the name and tors’ representatives. Each drug manu- address of each recipient of each sam- facturer or authorized distributor of ple unit shipped, the date of the ship- record who distributes drug samples by ment, and the proprietary or estab- means of representatives shall main- lished name, dosage strength, and num- tain a list of the names and addresses ber of sample units shipped. For the of its representatives who distribute purposes of this paragraph and para- drug samples and of the sites where graph (d)(2)(v) of this section, ‘‘dis- drug samples are stored. tributions’’ includes distributions to health care practitioners or designated § 203.32 Drug sample storage and han- hospital or health care entity phar- dling requirements. macies, transfers or exchanges with (a) Storage and handling conditions. other firm representatives, returns to Manufacturers, authorized distributors the manufacturer or authorized dis- of record, and their representatives tributor, destruction of drug samples shall store and handle all drug samples by a sales representative, and other under conditions that will maintain types of drug sample dispositions. The their stability, integrity, and effective- specific type of distribution must be ness and ensure that the drug samples specified in the record; are free of contamination, deteriora- (iv) A record of drug sample thefts or tion, and adulteration. significant losses reported by the rep- (b) Compliance with compendial and resentative since the most recently labeling requirements. Manufacturers, completed prior inventory, including authorized distributors of record, and the approximate date of the occurrence their representatives can generally and the proprietary or established comply with this section by following

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the compendial and labeling require- require separate written requests for ments for storage and handling of a each drug sample or group of samples. particular prescription drug in han- An arrangement by which a licensed dling samples of that drug. practitioner requests in writing that a specified number of drug samples be de- § 203.33 Drug sample forms. livered over a period of not more than A sample request or receipt form 6 months, with the actual delivery may be delivered by mail, common car- dates for parts of the order to be set by rier, or private courier or may be subsequent oral communication or transmitted photographically or elec- electronic transmission, is not consid- tronically (i.e., by telephoto, wire- ered to be a standing request. photo, radiophoto, facsimile transmission (FAX), xerography, or elec- § 203.36 Fulfillment houses, shipping tronic data transfer) or by any other and mailing services, comarketing system, provided that the method for agreements, and third-party recordkeeping. transmission meets the security requirements set forth in § 203.60(c). (a) Responsibility for creating and maintaining forms, reports, and records. § 203.34 Policies and procedures; ad- Any manufacturer or authorized dis- ministrative systems. tributor of record that uses a fulfill- Each manufacturer or authorized dis- ment house, shipping or mailing serv- tributor of record that distributes drug ice, or other third party, or engages in samples shall establish, maintain, and a comarketing agreement with another adhere to written policies and proce- manufacturer or distributor to dis- dures describing its administrative sys- tribute drug samples or to meet any of tems for the following: the requirements of PDMA, PDA, or (a) Distributing drug samples by mail this part, remains responsible for cre- or common carrier, including method- ating and maintaining all requests, re- ology for reconciliation of requests and ceipts, forms, reports, and records re- receipts; quired under PDMA, PDA, and this (b) Distributing drug samples by part. means other than mail or common car- (b) Responsibility for producing re- rier including the methodology for: quested forms, reports, or records. A man- (1) Reconciling requests and receipts, ufacturer or authorized distributor of identifying patterns of nonresponse, record that contracts with a third and the manufacturer’s or distributor’s party to maintain some or all of its response when such patterns are found; records shall produce requested forms, (2) Conducting the annual physical reports, records, or other required doc- inventory and preparation of the rec- uments within 2 business days of a re- onciliation report; quest by an authorized representative (3) Implementing a sample distribu- of FDA or another Federal, State, or tion security and audit system, includ- local regulatory or law enforcement of- ing conducting random and for-cause ficial. audits of sales representatives by personnel independent of the sales force; § 203.37 Investigation and notification and requirements. (4) Storage of drug samples by rep- (a) Investigation of falsification of resentatives; drug sample records. A manufacturer or (c) Identifying any significant loss of authorized distributor of record that drug samples and notifying FDA of the has reason to believe that any person loss; and has falsified drug sample requests, re- (d) Monitoring any loss or theft of ceipts, or records, or is diverting drug drug samples. samples, shall: (1) Notify FDA, by telephone or in § 203.35 Standing requests. writing, within 5 working days; Manufacturers or authorized dis- (2) Immediately initiate an investiga- tributors of record shall not distribute tion; and drug samples on the basis of open- (3) Provide FDA with a complete ended or standing requests, but shall written report, including the reason for

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and the results of the investigation, ports concerning prescription human not later than 30 days after the date of biological products shall be made to the initial notification in paragraph the Division of Inspections and Surveil- (a)(1) of this section. lance (HFM–650), Office of Compliance, (b) Significant loss or known theft of Center for Biologics Evaluation and drug samples. A manufacturer or au- Research, Food and Drug Administra- thorized distributor of record that dis- tion, 1401 Rockville Pike, Rockville, tributes drug samples or a charitable MD 20852. institution that receives donated drug samples from a licensed practitioner § 203.38 Sample lot or control num- shall: bers; labeling of sample units. (1) Notify FDA, by telephone or in (a) Lot or control number required on writing, within 5 working days of be- drug sample labeling and sample unit coming aware of a significant loss or label. The manufacturer or authorized known theft; distributor of record of a drug sample (2) Immediately initiate an investiga- shall include on the label of the sample tion into the significant loss or known unit and on the outside container or theft; and packaging of the sample unit, if any, (3) Provide FDA with a complete an identifying lot or control number written report, including the reason for that will permit the tracking of the and the results of the investigation, distribution of each drug sample unit. not later than 30 days after the date of (b) Records containing lot or control the initial notification in paragraph numbers required for all drug samples dis- (b)(1) of this section. tributed. A manufacturer or authorized (c) Conviction of a representative. (1) A distributor of record shall maintain for manufacturer or authorized distributor all samples distributed records of drug of record that distributes drug samples sample distribution containing lot or shall notify FDA, by telephone or in control numbers that are sufficient to writing, within 30 days of becoming permit the tracking of sample units to aware of the conviction of one or more the point of the licensed practitioner. of its representatives for a violation of (c) Labels of sample units. Each sam- section 503(c)(1) of the act or any State ple unit shall bear a label that clearly law involving the sale, purchase, or denotes its status as a drug sample, trade of a drug sample or the offer to e.g., ‘‘sample,’’ ‘‘not for sale,’’ ‘‘profes- sell, purchase, or trade a drug sample. sional courtesy package.’’ (2) A manufacturer or authorized dis- (1) A drug that is labeled as a drug tributor of record shall provide FDA sample is deemed to be a drug sample with a complete written report not within the meaning of the act. later than 30 days after the date of the (2) A drug product dosage unit that initial notification. bears an imprint identifying the dosage (d) Selection of individual responsible form as a drug sample is deemed to be for drug sample information. A manufac- a drug sample within the meaning of turer or authorized distributor of the act. record that distributes drug samples (3) Notwithstanding paragraphs (c)(1) shall inform FDA in writing within 30 and (c)(2) of this section, any article days of selecting the individual respon- that is a drug sample as defined in sec- sible for responding to a request for in- tion 503(c)(1) of the act and § 203.3(i) formation about drug samples of that that fails to bear the label required in individual’s name, business address, this paragraph (c) is a drug sample. and telephone number. (e) Whom to notify at FDA. Notifica- § 203.39 Donation of drug samples to tions and reports concerning prescrip- charitable institutions. tion human drugs shall be made to the A charitable institution may receive Division of Prescription Drug Compli- a drug sample donated by a licensed ance and Surveillance (HFD–330), Office practitioner or another charitable in- of Compliance, Center for Drug Evalua- stitution for dispensing to a patient of tion and Research, Food and Drug Ad- the charitable institution, or donate a ministration, 7520 Standish Pl., Rock- drug sample to another charitable in- ville, MD 20855. Notifications and re- stitution for dispensing to its patients,

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provided that the following require- record, a copy of which shall be re- ments are met: tained by the recipient charitable in- (a) A drug sample donated by a li- stitution for at least 3 years, con- censed practitioner or donating chari- taining the following information: table institution shall be received by a (1) The name, address, and telephone charitable institution in its original, number of the licensed practitioner (or unopened packaging with its labeling donating charitable institution); intact. (2) The manufacturer, brand name, (b) Delivery of a donated drug sample quantity, and lot or control number of to a recipient charitable institution the drug sample donated; and shall be completed by mail or common (3) The date of the donation. carrier, collection by an authorized (f) Each recipient charitable institu- agent or employee of the recipient tion shall maintain complete and accu- charitable institution, or personal de- rate records of donation, receipt, in- livery by a licensed practitioner or an spection, inventory, dispensing, redis- agent or employee of the donating tribution, destruction, and returns suf- charitable institution. Donated drug ficient for complete accountability and samples shall be placed by the donor in auditing of drug sample stocks. a sealed carton for delivery to or col- (g) Each recipient charitable institu- lection by the recipient charitable in- tion shall conduct, at least annually, stitution. an inventory of prescription drug sam- (c) A donated drug sample shall not ple stocks and shall prepare a report be dispensed to a patient or be distrib- reconciling the results of each inven- uted to another charitable institution tory with the most recent prior inven- until it has been examined by a li- tory. Drug sample inventory discrep- censed practitioner or registered phar- ancies and reconciliation problems macist at the recipient charitable in- shall be investigated by the charitable stitution to confirm that the donation institution and reported to FDA. record accurately describes the drug (h) A recipient charitable institution sample delivered and that no drug sam- shall store drug samples under condi- ple is adulterated or misbranded for tions that will maintain the sample’s any reason, including, but not limited stability, integrity, and effectiveness, to, the following: and will ensure that the drug samples (1) The drug sample is out of date; will be free of contamination, deterio- (2) The labeling has become muti- ration, and adulteration. lated, obscured, or detached from the (i) A charitable institution shall no- drug sample packaging; tify FDA within 5 working days of be- (3) The drug sample shows evidence coming aware of a significant loss or of having been stored or shipped under known theft of prescription drug sam- conditions that might adversely affect ples. its stability, integrity, or effectiveness; (4) The drug sample is for a prescrip- Subpart E—Wholesale Distribution tion drug product that has been re- called or is no longer marketed; or § 203.50 Requirements for wholesale (5) The drug sample is otherwise pos- distribution of prescription drugs. sibly contaminated, deteriorated, or (a) Identifying statement for sales by adulterated. unauthorized distributors. Before the (d) The recipient charitable institu- completion of any wholesale distribution shall dispose of any drug sample tion by a wholesale distributor of a found to be unsuitable by destroying it prescription drug for which the seller is or by returning it to the manufacturer. not an authorized distributor of record The charitable institution shall main- to another wholesale distributor or retain complete records of the disposi- tail pharmacy, the seller shall provide tion of all destroyed or returned drug to the purchaser a statement identi- samples. fying each prior sale, purchase, or (e) The recipient charitable institu- trade of such drug. This identifying tion shall prepare at the time of collec- statement shall include: tion or delivery of a drug sample a (1) The proprietary and established complete and accurate donation name of the drug;

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(2) Dosage; Subpart F—Request and Receipt (3) Container size; Forms, Reports, and Records (4) Number of containers; (5) The drug’s lot or control num- § 203.60 Request and receipt forms, re- ber(s); ports, and records. (6) The business name and address of all parties to each prior transaction in- (a) Use of electronic records, electronic volving the drug, starting with the signatures, and handwritten signatures manufacturer; and executed to electronic records. (1) Pro- (7) The date of each previous trans- vided the requirements of part 11 of action. this chapter are met, electronic (b) The drug origin statement is sub- records, electronic signatures, and ject to the record retention require- handwritten signatures executed to ments of § 203.60 and must be retained electronic records may be used as an by all wholesale distributors involved alternative to paper records and hand- in the distribution of the drug product, written signatures executed on paper whether authorized or unauthorized, to meet any of the record and signa- for 3 years. ture requirements of PDMA, PDA, or (c) Identifying statement not required this part. when additional manufacturing processes (2) Combinations of paper records and are completed. A manufacturer that sub- electronic records, electronic records jects a drug to any additional manufac- and handwritten signatures executed turing processes to produce a different on paper, or paper records and elec- drug is not required to provide to a tronic signatures or handwritten signa- purchaser a statement identifying the tures executed to electronic records, previous sales of the component drug may be used to meet any of the record or drugs. and signature requirements of PDMA, (d) List of authorized distributors of PDA, or this part, provided that: record. Each manufacturer shall main- (i) The requirements of part 11 of this tain at the corporate offices a current chapter are met for the electronic written list of all authorized distribu- records, electronic signatures, or hand- tors of record. written signatures executed to elec- (1) Each manufacturer’s list of au- tronic records; and thorized distributors of record shall (ii) A reasonably secure link between specify whether each distributor listed thereon is authorized to distribute the the paper-based and electronic compo- manufacturer’s full product line or nents exists such that the combined only particular, specified products. records and signatures are trustworthy (2) Each manufacturer shall update and reliable, and to ensure that the its list of authorized distributors of signer cannot readily repudiate the record on a continuing basis. signed records as not genuine. (3) Each manufacturer shall make its (3) For the purposes of this paragraph list of authorized distributors of record (a), the phrase ‘‘record and signature available on request to the public for requirements of PDMA, PDA, or this inspection or copying. A manufacturer part’’ includes drug sample request and may impose reasonable copying receipt forms, reports, records, and charges for such requests from mem- other documents, and their associated bers of the public. signatures required by PDMA, PDA, and this part. EFFECTIVE DATE NOTE: At 64 FR 67756, Dec. 3, 1999, § 203.50 was added, effective Dec. 4, (b) Maintenance of request and receipt 2000. At 65 FR 25639, May 3, 2000, the effective forms, reports, records, and other docu- date for § 203.50 was delayed until Oct. 1, 2001. ments created on paper. Request and re- At 66 FR 12851, Mar. 1, 2001, § 203.50 was fur- ceipt forms, reports, records, and other ther delayed until Apr. 1, 2002. At 67 FR 6646, documents created on paper may be Feb. 13, 2002, the effective date was further maintained on paper or by photo- delayed until April 1, 2003. At 68 FR 4912, Jan. 31, 2003, the effective date was further graphic imaging (i.e., photocopies or delayed until Apr. 1, 2004. At 69 FR 8105, Feb. microfiche), provided that the security 23, 2004, the effective date of § 203.50 was fur- and authentication requirements de- ther delayed until Dec. 1, 2006. scribed in paragraph (c) of this section

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are followed. Where a required docu- Subpart G—Rewards ment is created on paper and electronically scanned into a computer, the re- § 203.70 Application for a reward. sulting record is an electronic record (a) Reward for providing information that must meet the requirements of leading to the institution of a criminal part 11 of this chapter. proceeding against, and conviction of, a (c) Security and authentication require- person for the sale, purchase, or trade of ments for request and receipt forms, re- a drug sample. A person who provides ports, records, and other documents cre- information leading to the institution ated on paper. A request or receipt of a criminal proceeding against, and form, report, record, or other docu- conviction of, a person for the sale, ment, and any signature appearing purchase, or trade of a drug sample, or thereon, that is created on paper and the offer to sell, purchase, or trade a that is maintained by photographic im- drug sample, in violation of section aging, or transmitted electronically 503(c)(1) of the act, is entitled to one- (i.e., by facsimile) shall be maintained half the criminal fine imposed and col- or transmitted in a form that provides lected for such violation, but not more reasonable assurance of being: than $125,000. (b) Procedure for making application (1) Resistant to tampering, revision, for a reward for providing information modification, fraud, unauthorized use, leading to the institution of a criminal or alteration; proceeding against, and conviction of, a (2) Preserved in accessible and re- person for the sale, purchase, or trade of trievable fashion; and a drug sample. A person who provides (3) Available to permit copying for information leading to the institution purposes of review, analysis, of a criminal proceeding against, and verification, authentication, and repro- conviction of, a person for the sale, duction by the person who executed the purchase, or trade of a drug sample, or form or created the record, by the man- the offer to sell, purchase, or trade a ufacturer or distributor, and by au- drug sample, in violation of section thorized personnel of FDA and other 503(c)(1) of the act, may apply for a re- regulatory and law enforcement agen- ward by making written application to: cies. (1) Director, Office of Compliance (d) Retention of request and receipt (HFD–300), Center for Drug Evaluation forms, reports, lists, records, and other and Research, Food and Drug Adminis- documents. Any person required to cre- tration, 7500 Standish Pl., Rockville, ate or maintain reports, lists, or other MD 20855; or records under PDMA, PDA, or this (2) Director, Office of Compliance and part, including records relating to the Biologics Quality (HFM–600), Center for Biologics Evaluation and Research, distribution of drug samples, shall re- Food and Drug Administration, 1401 tain them for at least 3 years after the Rockville Pike, Rockville, MD 20852, as date of their creation. appropriate. (e) Availability of request and receipt forms, reports, lists, and records. Any person required to create or maintain PART 205—GUIDELINES FOR STATE request and receipt forms, reports, LICENSING OF WHOLESALE PRE- lists, or other records under PDMA, SCRIPTION DRUG DISTRIBUTORS PDA, or this part shall make them available, upon request, in a form that Sec. 205.1 Scope. permits copying or other means of du- 205.2 Purpose. plication, to FDA or other Federal, 205.3 Definitions. State, or local regulatory and law en- 205.4 Wholesale drug distributor licensing forcement officials for review and re- requirement. production. The records shall be made 205.5 Minimum required information for li- available within 2 business days of a re- censure. 205.6 Minimum qualifications. quest. 205.7 Personnel. 205.8 Violations and penalties.

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205.50 Minimum requirements for the stor- chasing organization of a drug for its age and handling of prescription drugs own use from the group purchasing or- and for the establishment and mainte- ganization or from other hospitals or nance of prescription drug distribution health care entities that are members records. of such organizations; AUTHORITY: 21 U.S.C. 351, 352, 353, 371, 374. (3) The sale, purchase, or trade of a SOURCE: 55 FR 38023, Sept. 14, 1990, unless drug or an offer to sell, purchase, or otherwise noted. trade a drug by a charitable organization described in section 501(c)(3) of the § 205.1 Scope. Internal Revenue Code of 1954 to a non- This part applies to any person, part- profit affiliate of the organization to nership, corporation, or business firm the extent otherwise permitted by law; in a State engaging in the wholesale (4) The sale, purchase, or trade of a distribution of human prescription drug or an offer to sell, purchase, or drugs in interstate commerce. trade a drug among hospitals or other health care entities that are under § 205.2 Purpose. common control; for purposes of this The purpose of this part is to imple- section, common control means the ment the Prescription Drug Marketing power to direct or cause the direction Act of 1987 by providing minimum of the management and policies of a standards, terms, and conditions for person or an organization, whether by the licensing by State licensing au- ownership of stock, voting rights, by thorities of persons who engage in contract, or otherwise; wholesale distributions in interstate (5) The sale, purchase, or trade of a commerce of prescription drugs. drug or an offer to sell, purchase, or § 205.3 Definitions. trade a drug for emergency medical reasons; for purposes of this section, (a) Blood means whole blood collected emergency medical reasons includes from a single donor and processed ei- transfers of prescription drugs by a re- ther for transfusion or further manu- tail pharmacy to another retail phar- facturing. macy to alleviate a temporary short- (b) Blood component means that part age; of blood separated by physical or me- (6) The sale, purchase, or trade of a chanical means. drug, an offer to sell, purchase, or (c) means a unit of a pre- Drug sample trade a drug, or the dispensing of a scription drug that is not intended to drug pursuant to a prescription; be sold and is intended to promote the (7) The distribution of drug samples sale of the drug. by manufacturers’ representatives or (d) Manufacturer means anyone who is engaged in manufacturing, pre- distributors’ representatives; or paring, propagating, compounding, (8) The sale, purchase, or trade of processing, packaging, repackaging, or blood and blood components intended labeling of a prescription drug. for transfusion. (e) Prescription drug means any (9) Drug returns, when conducted by human drug required by Federal law or a hospital, health care entity, or chari- regulation to be dispensed only by a table institution in accordance with prescription, including finished dosage § 203.23 of this chapter; or forms and active ingredients subject to (10) The sale of minimal quantities of section 503(b) of the Federal Food, drugs by retail pharmacies to licensed Drug, and Cosmetic Act. practitioners for office use. (f) Wholesale distribution and wholesale (g) Wholesale distributor means any distribution means distribution of pre- one engaged in wholesale distribution scription drugs to persons other than a of prescription drugs, including, but consumer or patient, but does not in- not limited to, manufacturers; re- clude: packers; own-label distributors; pri- (1) Intracompany sales; vate-label distributors; jobbers; bro- (2) The purchase or other acquisition kers; warehouses, including manufac- by a hospital or other health care enti- turers’ and distributors’ warehouses, ty that is a member of a group pur- chain drug warehouses, and wholesale

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drug warehouses; independent whole- (iv) If a sole proprietorship, the full sale drug traders; and retail phar- name of the sole proprietor and the macies that conduct wholesale dis- name of the business entity. tributions. (b) The State licensing authority (h) Health care entity means any per- may provide for a single license for a son that provides diagnostic, medical, business entity operating more than surgical, or dental treatment, or chron- one facility within that State, or for a ic or rehabilitative care, but does not parent entity with divisions, subsidi- include any retail pharmacy or any aries, and/or affiliate companies within wholesale distributor. A person cannot that State when operations are con- simultaneously be a ‘‘health care enti- ducted at more than one location and ty’’ and a retail pharmacy or wholesale there exists joint ownership and con- distributor. trol among all the entities. [55 FR 38023, Sept. 14, 1990, as amended at 64 (c) Changes in any information in FR 67762, Dec. 3, 1999] paragraph (a) of this section shall be submitted to the State licensing au- § 205.4 Wholesale drug distributor li- thority as required by such authority. censing requirement. (Approved by the Office of Management and Every wholesale distributor in a Budget under control number 0910–0251) State who engages in wholesale distributions of prescription drugs in § 205.6 Minimum qualifications. interstate commerce must be licensed (a) The State licensing authority by the State licensing authority in ac- shall consider, at a minimum, the fol- cordance with this part before engag- lowing factors in reviewing the quali- ing in wholesale distributions of pre- fications of persons who engage in scription drugs in interstate com- wholesale distribution of prescription merce. drugs within the State: § 205.5 Minimum required information (1) Any convictions of the applicant for licensure. under any Federal, State, or local laws relating to drug samples, wholesale or (a) The State licensing authority retail drug distribution, or distribution shall require the following minimum of controlled substances; information from each wholesale drug distributor as part of the license de- (2) Any felony convictions of the ap- scribed in § 205.4 and as part of any re- plicant under Federal, State, or local newal of such license: laws; (1) The name, full business address, (3) The applicant’s past experience in and telephone number of the licensee; the manufacture or distribution of pre- (2) All trade or business names used scription drugs, including controlled by the licensee; substances; (3) Addresses, telephone numbers, (4) The furnishing by the applicant of and the names of contact persons for false or fraudulent material in any ap- all facilities used by the licensee for plication made in connection with drug the storage, handling, and distribution manufacturing or distribution; of prescription drugs; (5) Suspension or revocation by Fed- (4) The type of ownership or oper- eral, State, or local government of any ation (i.e., partnership, corporation, or license currently or previously held by sole proprietorship); and the applicant for the manufacture or (5) The name(s) of the owner and/or distribution of any drugs, including operator of the licensee, including: controlled substances; (i) If a person, the name of the per- (6) Compliance with licensing re- son; quirements under previously granted (ii) If a partnership, the name of each licenses, if any; partner, and the name of the partner- (7) Compliance with requirements to ship; maintain and/or make available to the (iii) If a corporation, the name and State licensing authority or to Fed- title of each corporate officer and di- eral, State, or local law enforcement rector, the corporate names, and the officials those records required under name of the State of incorporation; and this section; and

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(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. lated to compliance with State licens- (iii) Entry into areas where prescrip- ing requirements. tion drugs are held shall be limited to authorized personnel. § 205.8 Violations and penalties. (2) All facilities shall be equipped (a) State licensing laws shall provide with an alarm system to detect entry for the suspension or revocation of li- after hours. censes upon conviction of violations of (3) All facilities shall be equipped Federal, State, or local drug laws or with a security system that will pro- regulations, and may provide for fines, vide suitable protection against theft imprisonment, or civil penalties. and diversion. When appropriate, the (b) State licensing laws shall provide security system shall provide protec- for suspension or revocation of li- tion against theft or diversion that is censes, where appropriate, for viola- facilitated or hidden by tampering with tions of its provisions. computers or electronic records. (c) Storage. All prescription drugs § 205.50 Minimum requirements for shall be stored at appropriate tempera- the storage and handling of pre- tures and under appropriate conditions scription drugs and for the estab- in accordance with requirements, if lishment and maintenance of pre- any, in the labeling of such drugs, or scription drug distribution records. with requirements in the current edi- The State licensing law shall include tion of an official compendium, such as the following minimum requirements the United States Pharmacopeia/Na- for the storage and handling of pre- tional Formulary (USP/NF). scription drugs, and for the establish- (1) If no storage requirements are es- ment and maintenance of prescription tablished for a prescription drug, the drug distribution records by wholesale drug may be held at ‘‘controlled’’ room drug distributors and their officers, temperature, as defined in an official agents, representatives, and employees: compendium, to help ensure that its (a) Facilities. All facilities at which identity, strength, quality, and purity prescription drugs are stored, are not adversely affected. warehoused, handled, held, offered, (2) Appropriate manual, marketed, or displayed shall: electromechanical, or electronic tem- (1) Be of suitable size and construc- perature and humidity recording equip- tion to facilitate cleaning, mainte- ment, devices, and/or logs shall be uti- nance, and proper operations; lized to document proper storage of (2) Have storage areas designed to prescription drugs. provide adequate lighting, ventilation, (3) The recordkeeping requirements temperature, sanitation, humidity, in paragraph (f) of this section shall be space, equipment, and security condi- followed for all stored drugs. tions; (d) Examination of materials. (1) Upon (3) Have a quarantine area for stor- receipt, each outside shipping con- age of prescription drugs that are out- tainer shall be visually examined for dated, damaged, deteriorated, mis- identity and to prevent the acceptance

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of contaminated prescription drugs or teriorated, misbranded, or adulterated prescription drugs that are otherwise prescription drugs. unfit for distribution. This examina- (f) Recordkeeping. (1) Wholesale drug tion shall be adequate to reveal con- distributors shall establish and main- tainer damage that would suggest pos- tain inventories and records of all sible contamination or other damage transactions regarding the receipt and to the contents. distribution or other disposition of pre- (2) Each outgoing shipment shall be scription drugs. These records shall in- carefully inspected for identity of the clude the following information: prescription drug products and to en- (i) The source of the drugs, including sure that there is no delivery of pre- the name and principal address of the scription drugs that have been dam- seller or transferor, and the address of aged in storage or held under improper the location from which the drugs were conditions. shipped; (3) The recordkeeping requirements (ii) The identity and quantity of the in paragraph (f) of this section shall be drugs received and distributed or dis- followed for all incoming and outgoing posed of; and prescription drugs. (iii) The dates of receipt and distribu- (e) Returned, damaged, and outdated tion or other disposition of the drugs. prescription drugs. (1) Prescription (2) Inventories and records shall be drugs that are outdated, damaged, de- made available for inspection and teriorated, misbranded, or adulterated photocopying by authorized Federal, shall be quarantined and physically State, or local law enforcement agency separated from other prescription officials for a period of 3 years after the drugs until they are destroyed or re- date of their creation. turned to their supplier. (3) Records described in this section (2) Any prescription drugs whose im- that are kept at the inspection site or mediate or sealed outer or sealed sec- that can be immediately retrieved by ondary containers have been opened or computer or other electronic means used shall be identified as such, and shall be readily available for author- shall be quarantined and physically ized inspection during the retention pe- separated from other prescription riod. Records kept at a central location drugs until they are either destroyed apart from the inspection site and not or returned to the supplier. electronically retrievable shall be (3) If the conditions under which a made available for inspection within 2 prescription drug has been returned working days of a request by an au- cast doubt on the drug’s safety, iden- thorized official of a Federal, State, or tity, strength, quality, or purity, then local law enforcement agency. the drug shall be destroyed, or re- (g) Written policies and procedures. turned to the supplier, unless examina- Wholesale drug distributors shall es- tion, testing, or other investigation tablish, maintain, and adhere to writ- proves that the drug meets appropriate ten policies and procedures, which standards of safety, identity, strength, shall be followed for the receipt, secu- quality, and purity. In determining rity, storage, inventory, and distribu- whether the conditions under which a tion of prescription drugs, including drug has been returned cast doubt on policies and procedures for identifying, the drug’s safety, identity, strength, recording, and reporting losses or quality, or purity, the wholesale drug thefts, and for correcting all errors and distributor shall consider, among other inaccuracies in inventories. Wholesale things, the conditions under which the drug distributors shall include in their drug has been held, stored, or shipped written policies and procedures the fol- before or during its return and the con- lowing: dition of the drug and its container, (1) A procedure whereby the oldest carton, or labeling, as a result of stor- approved stock of a prescription drug age or shipping. product is distributed first. The proce- (4) The recordkeeping requirements dure may permit deviation from this in paragraph (f) of this section shall be requirement, if such deviation is tem- followed for all outdated, damaged, de- porary and appropriate.

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(2) A procedure to be followed for sonable times and in a reasonable man- handling recalls and withdrawals of ner, to the extent authorized by law. prescription drugs. Such procedure (2) Wholesale drug distributors that shall be adequate to deal with recalls deal in controlled substances shall reg- and withdrawals due to: ister with the appropriate State con- (i) Any action initiated at the re- trolled substance authority and with quest of the Food and Drug Adminis- the Drug Enforcement Administration tration or other Federal, State, or (DEA), and shall comply with all appli- local law enforcement or other govern- cable State, local, and DEA regula- ment agency, including the State li- tions. censing agency; (j) Salvaging and reprocessing. Whole- (ii) Any voluntary action by the sale drug distributors shall be subject manufacturer to remove defective or to the provisions of any applicable Fed- potentially defective drugs from the eral, State, or local laws or regulations market; or that relate to prescription drug prod- (iii) Any action undertaken to pro- uct salvaging or reprocessing, includ- mote public health and safety by re- ing parts 207, 210, and 211 of this chap- placing of existing merchandise with ter. an improved product or new package (Approved by the Office of Management and design. Budget under control number 0910–0251) (3) A procedure to ensure that whole- [55 FR 38023, Sept. 14, 1990, as amended at 64 sale drug distributors prepare for, pro- FR 67763, Dec. 3, 1999] tect against, and handle any crisis that affects security or operation of any fa- PART 206—IMPRINTING OF SOLID cility in the event of strike, fire, flood, or other natural disaster, or other situ- ORAL DOSAGE FORM DRUG ations of local, State, or national PRODUCTS FOR HUMAN USE emergency. (4) A procedure to ensure that any Sec. 206.1 Scope. outdated prescription drugs shall be 206.3 Definitions. segregated from other drugs and either 206.7 Exemptions. returned to the manufacturer or de- 206.10 Code imprint required. stroyed. This procedure shall provide for written documentation of the dis- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, position of outdated prescription drugs. 371; 42 U.S.C. 262. This documentation shall be main- SOURCE: 58 FR 47958, Sept. 13, 1993, unless tained for 2 years after disposition of otherwise noted. the outdated drugs. (h) Responsible persons. Wholesale § 206.1 Scope. drug distributors shall establish and This part applies to all solid oral dos- maintain lists of officers, directors, age form human drug products, includ- managers, and other persons in charge ing prescription drug products, over- of wholesale drug distribution, storage, the-counter drug products, biological and handling, including a description drug products, and homeopathic drug of their duties and a summary of their products, unless otherwise exempted qualifications. under § 206.7. (i) Compliance with Federal, State, and local law. Wholesale drug distributors § 206.3 Definitions. shall operate in compliance with appli- The following definitions apply to cable Federal, State, and local laws this part: and regulations. The act means the Federal Food, (1) Wholesale drug distributors shall Drug, and Cosmetic Act (21 U.S.C. 301 permit the State licensing authority et seq.). and authorized Federal, State, and Debossed means imprinted with a local law enforcement officials to enter mark below the dosage form surface. and inspect their premises and delivery Drug product means a finished dosage vehicles, and to audit their records and form, e.g., a tablet or capsule that con- written operating procedures, at rea- tains a drug substance, generally, but

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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) or mark raised above the dosage form sur- the Center for Biologics Evaluation face. and Research (CBER), Food and Drug Engraved means imprinted with a Administration, 5600 Fishers Lane, code that is cut into the dosage form Rockville, MD 20857. If FDA denies the surface after it has been completed. request, the holder of the approved ap- Imprinted means marked with an plication will have 1 year after the date identification code by means of em- of an agency denial to imprint the drug bossing, debossing, engraving, or print- product. ing with ink. (ii) Exemption requests for products Manufacturer means the manufac- that have not yet received approval turer as described in §§ 201.1 and 600.3(t) shall be made in writing to the appro- of this chapter. priate review division in CDER or Solid oral dosage form means capsules, CBER. tablets, or similar drug products in- (2) Any product not subject to pre- tended for oral use. market approval is exempt from the requirement of § 206.10 if, based on the § 206.7 Exemptions. product’s size, shape, texture, or other (a) The following classes of drug physical characteristics, the manufac- products are exempt from requirements turer or distributor of the product is of this part: prepared to demonstrate that imprint- (1) Drug products intended for use in ing the dosage form is technologically a clinical investigation under section infeasible or impossible. 505(i) of the act, but not including (c) For drugs that are administered drugs distributed under a treatment solely in controlled health care set- IND under part 312 of this chapter or tings and not provided to patients for distributed as part of a nonconcur- self-administration, sponsors may sub- rently controlled study. Placebos in- mit requests for exemptions from the tended for use in a clinical investiga- requirements of this rule. Controlled tion are exempt from the requirements settings include physicians’ offices and of this part if they are designed to copy other health care facilities. Exemption the active drug products used in that requests should be submitted in writ- investigation. ing to the appropriate review division (2) Drugs, other than reference listed in CDER or CBER. drugs, intended for use in bioequiva- lence studies. § 206.10 Code imprint required. (3) Drugs that are extemporaneously (a) Unless exempted under § 206.7, no compounded by a licensed pharmacist, drug product in solid oral dosage form upon receipt of a valid prescription for may be introduced or delivered for in- an individual patient from a practi- troduction into interstate commerce tioner licensed by law to prescribe or unless it is clearly marked or im- administer drugs, to be used solely by printed with a code imprint that, in the patient for whom they are pre- conjunction with the product’s size, scribed. shape, and color, permits the unique (4) Radiopharmaceutical drug prod- identification of the drug product and ucts. the manufacturer or distributor of the (b) Exemption of drugs because of product. Identification of the drug size or unique physical characteristics: product requires identification of its (1) For a drug subject to premarket active ingredients and its dosage approval, FDA may provide an exemp- strength. Inclusion of a letter or num- tion from the requirements of § 206.10 ber in the imprint, while not required, upon a showing that the product’s size, is encouraged as a more effective shape, texture, or other physical char- means of identification than a symbol acteristics make imprinting techno- or logo by itself. Homeopathic drug logically infeasible or impossible. products are required only to bear an (i) Exemption requests for products imprint that identifies the manufac- with approved applications shall be turer and their homeopathic nature.

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(b) A holder of an approved applica- 207.35 Notification of registrant; drug estab- tion who has, under § 314.70 (b)(2)(xi) or lishment registration number and drug (b)(2)(xii) of this chapter, supplemented listing number. its application to provide for a new im- 207.37 Inspection of registrations and drug listings. print is not required to bring its prod- 207.39 Misbranding by reference to registra- uct into compliance with this section tion or to registration number. during the pendency of the agency’s review. Once the review is complete, the Subpart D—Procedure for Foreign Drug drug product is subject to the require- Establishments ments of the rule. 207.40 Establishment registration and drug (c) A solid oral dosage form drug listing requirements for foreign estab- product that does not meet the require- lishments. ment for imprinting in paragraph (a) of this section and is not exempt from the AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 374, 381, 393; 42 U.S.C. 262, 264, requirement may be considered adul- 271. terated and misbranded and may be an unapproved new drug. SOURCE: 45 FR 38043, June 6, 1980, unless otherwise noted. (d) For purposes of this section, code imprint means any single letter or number or any combination of letters and Subpart A—General numbers, including, e.g., words, com- § 207.3 Definitions. pany name, and National Drug Code, or a mark, symbol, logo, or monogram, or (a) The following definitions apply to a combination of letters, numbers, and this part: marks or symbols, assigned by a drug (1) Act means the Federal Food, Drug, firm to a specific drug product. and Cosmetic Act approved June 25, 1938 (52 Stat. 1040 et seq., as amended [58 FR 47958, Sept. 13, 1993, as amended at 60 (21 U.S.C. 301–392)), except as otherwise FR 19846, Apr. 21, 1995] provided. (2) Advertising and labeling include the PART 207—REGISTRATION OF PRO- promotional material described in DUCERS OF DRUGS AND LISTING § 202.1(l) (1) and (2) respectively. OF DRUGS IN COMMERCIAL DIS- (3) Any material change includes but is TRIBUTION not limited to any change in the name of the drug, any change in the identity Subpart A—General or quantity of the active ingredient(s), any change in the identity or quantity Sec. of the inactive ingredient(s) where 207.3 Definitions. quantitative listing of all ingredients 207.7 Establishment registration and prod- is required by § 207.31(a)(2), any signifi- uct listing for human blood and blood cant change in the labeling of a pre- products and for medical devices. scription drug, and any significant change in the label or package insert of Subpart B—Exemptions an over-the-counter drug. Changes that 207.10 Exemptions for establishments. are not significant include changes in arrangement or printing or changes of Subpart C—Procedures for Domestic Drug an editorial nature. Establishments (4) Bulk drug substance means any substance that is represented for use in 207.20 Who must register and submit a drug a drug and that, when used in the man- list. ufacturing, processing, or packaging of 207.21 Times for registration and drug listing. a drug, becomes an active ingredient or 207.22 How and where to register and list a finished dosage form of the drug, but drugs. the term does not include intermedi- 207.25 Information required in registration ates used in the synthesis of such sub- and drug listing. stances. 207.26 Amendments to registration. (5) Commercial distribution means any 207.30 Updating drug listing information. distribution of a human drug except for 207.31 Additional drug listing information. investigational use under part 312 of

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this chapter, and any distribution of an terial (excluding labeling as deter- animal drug or animal feed bearing or mined in § 202.1(l) (1) and (2)) that gives containing an animal drug for non- a balanced picture of the promotional investigational uses, but the term does claims used for the drug, e.g., if more not include internal or interplant than one medical journal advertise- transfer of a bulk drug substance be- ment is used but the promotional con- tween registered establishments within tent is essentially identical, only one the same parent, subsidiary, and/or af- need be submitted. filiate company. For foreign establish- (10) Representative sampling of any ments, the term ‘‘commercial distribu- other labeling means typical labeling tion’’ shall have the same meaning ex- material (excluding labels and package cept that the term shall not include inserts) that gives a balanced picture distribution of any drug that is neither of the promotional claims used for the imported nor offered for import into drug, e.g., if more than one brochure is the United States. used but the promotional content is es- (6) Drug product salvaging means the sentially identical, only one need be act of segregating drug products that submitted. may have been subjected to improper (11) United States agent means a per- storage conditions, such as extremes in son residing or maintaining a place of temperature, humidity, smoke, fumes, business in the United States whom a pressure, age, or radiation, for the pur- foreign establishment designates as its pose of returning some or all of the agent. This definition excludes mail- products to the marketplace. boxes, answering machines or services, (7) Establishment means a place of or other places where an individual business under one management at one acting as the foreign establishment’s general physical location. The term in- agent is not physically present. cludes, among others, independent lab- (b) The definitions and interpreta- oratories that engage in control activi- tions of terms in sections 201, 502(e), ties for a registered drug establishment and 510 of the act apply to the use of (e.g., consulting laboratories), manufac- terms in this part. turers of medicated feeds and of vita- [45 FR 38043, June 6, 1980, as amended at 55 min products that are drugs in accord- FR 11576, Mar. 29, 1990; 66 FR 59156, Nov. 27, ance with section 201(g) of the act, 2001] human blood donor centers, and animal facilities used for the production or § 207.7 Establishment registration and control testing of licensed biologicals, product listing for human blood and establishments engaged in drug and blood products and for medical product salvaging. devices. (8) Manufacturing or processing means (a) Owners and operators of human the manufacture, preparation, propaga- blood and blood product establishments tion, compounding, or processing of a shall register and list their products drug or drugs as used in section 510 of with the Center for Biologics Evalua- the act and is the making by chemical, tion and Research (HFM–375), 1401 physical, biological, or other proce- Rockville Pike, suite 200N, Rockville, dures of any articles that meet the def- MD 20852–1448, on Form FDA–2830 inition of drugs in section 201(g) of the (Blood Establishment Registration and act. The term includes manipulation, Product Listing), in accordance with sampling, testing, or control proce- part 607 of this chapter. Such owners dures applied to the final product or to and operators who also manufacture or any part of the process. The term also process other drug products at the includes repackaging or otherwise same establishment shall, in addition, changing the container, wrapper, or la- register and list all such other drug beling of any drug package to further products with the Drug Listing Branch the distribution of the drug from the in accordance with this part. original place of manufacture to the (b) [Reserved] person who makes final delivery or sale (c) Owners and operators of establish- to the ultimate consumer. ments engaged in manufacture or proc- (9) Representative sampling of adver- essing of medical devices shall register tisements means typical advertising ma- and list their products with the Center

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for Devices and Radiological Health, tices of pharmacy or medicine and that FDA, on Form FDA–2891 (Initial Reg- regularly engage in dispensing pre- istration of Device Establishments), scription drugs, other than human FDA–2891a (Registration of Device Es- blood or blood products, upon prescrip- tablishment), and FDA–2892 (Medical tion of practitioners licensed by law to Device Listing), in accordance with administer these drugs to patients part 807. under their professional care. (d) Owners and operators of establish- (c) Practitioners who are licensed by ments engaged in the manufacture or law to prescribe or administer drugs processing at the same establishment of both drug products and medical de- and who manufacture or process drugs vices shall (1) register with the Drug solely for use in their professional Listing Branch (HFD–334), Center for practice. Drug Evaluation and Research, FDA, (d) Persons who manufacture or proc- and list their drug products in accord- ess drugs not for sale but solely for use ance with this part, and (2) register in research, teaching, or chemical with the Center for Devices and Radio- analysis. logical Health and list their medical (e) Manufacturers of harmless inac- devices in accordance with part 807. tive ingredients that are excipients, [45 FR 38043, June 6, 1980, as amended at 50 colorings, flavorings, emulsifiers, lu- FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29, bricants, preservatives, or solvents 1990; 66 FR 59156, Nov. 27, 2001] that become components of drugs, and who otherwise would not be required to Subpart B—Exemptions register under this part. (f) Persons who only manufacture the § 207.10 Exemptions for establish- following: ments. (1) Type B or Type C medicated feed The following classes of persons are using Category I, Type A medicated ar- exempt from registration and drug list- ticles or Category I, Type B or Type C ing in accordance with this part under medicated feeds, and/or; section 510(g)(1), (g)(2), and (g)(3) of the (2) Type B or Type C medicated feed act, or because FDA has found, under using Category II, Type B or Type C section 510(g)(5) of the act, that their registration is not necessary for the medicated feeds. protection of the public health. The ex- (3) Persons who manufacture free- emptions in paragraphs (a) and (b) of choice feeds, as defined in § 510.455 of this section are limited to pharmacies, this chapter, or medicated liquid feeds, hospitals, clinics, and public health as defined in § 558.5 of this chapter, agencies located in any State as de- where a medicated feed mill license is fined in section 201(a)(1) of the act. required are not exempt. (a) Pharmacies that operate under (g) Any manufacturer of a virus, applicable local laws regulating dis- serum, toxin, or analogous product in- pensing of prescription drugs and that tended for treatment of domestic ani- do not manufacture or process drugs mals who holds an unsuspended and for sale other than in the regular unrevoked license issued by the Sec- course of the practice of the profession retary of Agriculture under the animal of pharmacy, including dispensing and virus-serum-toxin law of March 4, 1913 selling drugs at retail. The supplying of (37 Stat. 832 (21 U.S.C. 151 et seq.)), pro- prescription drugs by these pharmacies vided that this exemption from reg- to a practitioner licensed to administer istration applies only to the manufac- these drugs for his or her use in the ture or processing of that animal virus, course of professional practice or to serum, toxin, or analogous product. other pharmacies to meet temporary (h) Carriers, in their receipt, car- inventory shortages are not acts that require pharmacies to register. riage, holding, or delivery of drugs in (b) Hospitals, clinics, and public the usual course of business as carriers. health agencies that maintain estab- [45 FR 38043, June 6, 1980, as amended at 51 lishments in conformance with any ap- FR 7389, Mar. 3, 1986; 64 FR 63203, Nov. 19, plicable local laws regulating the prac- 1999; 66 FR 59156, Nov. 27, 2001]

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Subpart C—Procedures for required under § 207.30 shall certify to Domestic Drug Establishments the registered establishment that the submission has been made by providing § 207.20 Who must register and submit a signed copy of Form FDA–2656 (Reg- a drug list. istration of Drug Establishment) to the (a) Owners or operators of all drug es- registered establishment that manu- tablishments, not exempt under sec- factures or processes the drug. Each tion 510(g) of the act or subpart B of such distributor shall submit the origi- this part 207, that engage in the manu- nal of Form FDA–2656 showing this cer- facture, preparation, propagation, tification to FDA, and shall accompany compounding, or processing of a drug the certification with a list showing or drugs shall register and submit a the National Drug Code number that list of every drug in commercial dis- the distributor has assigned to each tribution (except that registration and drug product. If a distributor does not listing information may be submitted elect to submit drug listing informa- by the parent, subsidiary, and/or affil- tion directly to FDA and to obtain a iate company for all establishments Labeler Code, the registered establish- when operations are conducted at more ment shall submit the drug listing in- than one establishment and there ex- formation. Distributors or registered ists joint ownership and control among establishments shall use Form FDA– all the establishments). Drug listing is 2658 (Registered Establishments’ Re- not required for the manufacturing, port of Private Label Distributors) to preparation, propagation, submit drug listing information or to compounding, or processing of an ani- request a Labeler Code, or both. mal feed bearing or containing an ani- (c) Before beginning manufacture or mal drug (i.e., a Type B or Type C processing of a drug subject to one of medicated feed), nor is drug listing re- the following applications, an owner or quired for establishments engaged in operator of an establishment is re- drug product salvaging. Drug products quired to register before the agency ap- manufactured, prepared, propagated, proves it: A new drug application, an compounded, or processed in any State abbreviated new drug application, a as defined in section 201(a)(1) of the act new animal drug application, an abbre- must be listed whether or not the out- viated new animal drug application, a put of such establishments or any par- medicated feed mill license applica- ticular drug so listed enters interstate tion, or a biologics license application. commerce. No owner or operator may (d) No registration fee is required. register an establishment if any part of (e) Registration and listing do not the establishment is registered by any constitute an admission, or agreement, other owner or operator. or determination that a product is a (b) Owners or operators of establish- drug as defined in section 201(g) of the ments not otherwise required to reg- act. ister under section 510 of the act that (f) Owners and operators of establish- distribute under their own label or ments or persons engaged in the recov- trade name a drug manufactured or ery, screening, testing, processing, processed by a registered establish- storage, or distribution of human cells, ment may elect to submit listing infor- tissues, and cellular and tissue-based mation directly to FDA and to obtain a products, as defined in § 1271.3(d) of this Labeler Code. A distributor who subchapter, that are regulated under sec- mits drug listing information shall in- tion 351 of the Public Health Service clude the registration number of the Act and/or the Federal Food, Drug, and drug establishment that manufactured, Cosmetic Act must register and list prepared, propagated, compounded, or those human cells, tissues, and cellular processed each drug listed. All distribu- and tissue-based products with the tors who submit drug listing informa- Center for Biologics Evaluation and tion to FDA assume full responsibility Research on Form FDA 3356 following for compliance with all of the require- the procedures set out in subpart B of ments of this part. Each such dis- part 1271 of this chapter, instead of the tributor at the time of submitting or procedures for registration and listing updating drug listing information as contained in this part, except that the

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additional listing information require- Lane, Rockville, MD 20857, or from ments in § 207.31 remain applicable. FDA district offices. An establishment whose drug registration for that year [45 FR 38043, June 6, 1980, as amended at 45 FR 32293, May 16, 1980; 52 FR 2682, Jan. 26, was validated under § 207.35 shall make 1987; 55 FR 11576, Mar. 29, 1990; 64 FR 400, Jan. subsequent annual registration on 5, 1999; 64 FR 56448, Oct. 20, 1999; 64 FR 63203, Form FDA–2656 as described in Nov. 19, 1999; 66 FR 5466, Jan. 19, 2001; 66 FR § 207.21(a) by mailing the completed 59157, Nov. 27, 2001; 66 FR 5447, Jan. 19, 2001] form to the above address within 30 days after receipt from FDA. § 207.21 Times for registration and (b) The first list of drugs and later drug listing. June and December updatings shall be (a) The owner or operator of an es- on Form FDA–2657 (Drug Product List- tablishment entering into the manu- ing), obtainable upon request as de- facture or processing of a drug or drugs scribed in paragraph (a) of this section. shall register the establishment within An establishment may submit, in lieu 5 days after the beginning of the oper- of Form FDA–2657, tapes for computer ation and shall submit a list of every inputs containing the information drug in commercial distribution at specified in Form FDA–2657 if formats that time. If the owner or operator of proposed for this use were reviewed and the establishment has not previously approved by the Drug Listing Branch entered into such an operation, the (HFD–334), Center for Drug Evaluation owner or operator shall register within and Research, FDA. 5 days after submitting a new drug ap- [45 FR 38043, June 6, 1980, as amended at 50 plication, abbreviated new drug appli- FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29, cation, new animal drug application, 1990] abbreviated new animal drug application, medicated feed mill license appli- § 207.25 Information required in reg- cation, or a biologics license applica- istration and drug listing. tion. Owners or operators shall renew (a) Form FDA–2656 (Registration of their registration information annu- Drug Establishment) provides for fur- ally. nishing or confirming information re- The schedule is as follows: quired by the act. This information in- Date FDA will cludes, for each establishment, the First letter of company name mail forms name and full address of the drug establishment; all trade names used by A or B ...... January C, D, or E ...... February the establishment; the kind of owner- F, G, or H ...... March ship or operation (that is, individually I, J, K, L. or M ...... April owned, partnership or corporation); N, O, P, Q, or R ...... May S or T ...... June and the name of the owner or operator U, V, W, X, Y, or Z ...... July of the establishment. The term name of the owner or operator includes in the (b) Owners and operators of all reg- case of a partnership the name of each istered establishments shall update partner, and in the case of a corpora- their drug listing information every tion the name and title of each cor- June and December. porate officer and director and the [45 FR 38043, June 6, 1980, as amended at 55 name of the State of incorporation. FR 11576, Mar. 29, 1990; 64 FR 400, Jan. 5, 1999; (b) Form FDA–2657 (Drug Product 64 FR 56448, Oct. 20, 1999; 64 FR 63203, Nov. 19, Listing) provides that information re- 1999; 66 FR 59157, Nov. 27, 2001] quired by the act be furnished as follows: § 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 Drug List- name, that are being manufactured or ing Branch (HFD–334), Center for Drug processed for commercial distribution Evaluation and Research, Food and and that have not been included in any Drug Administration, 5600 Fishers list previously submitted to FDA on

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Form FDA–2657 or in conjunction with expressed in terms of the amount, not the FDA voluntary inventory on Form the percent, of that ingredient in each FDA–2422 (Survey Report of Marketed dosage unit or, if the drug is not in Drugs), or Form FDA–2250 (National unit dosage form, the amount of the in- Drug Code Directory Input). gredient in a specific unit of weight or (2) For each drug listed that the reg- measure of the drug. For a drug formu- istrant regards as subject to section 505 lation that is a Type A medicated arti- or 512 of the act, the new drug applica- cle subject to § 207.35(b)(2)(iii), the reg- tion number, abbreviated new drug ap- istrant may limit the quantitative list- plication number, new animal drug ap- ing of ingredients to each variation of plication number, or abbreviated new level of active drug ingredient. animal drug application number and a (7) For each drug listed, the registra- copy of all current labeling, except tion number of every drug establish- that only one representative container ment within the parent company at or carton label need be submitted which it is manufactured or processed. where differences exist only in the (8) For each drug listed, the National quantity of contents statement. Drug Code (NDC) number. If FDA has (3) For each drug listed that the reg- not assigned an NDC Labeler Code, the istrant regards as subject to section 351 registrant shall include a Product Code of the Public Health Service Act, the and Package Code and FDA will assign license number of the manufacturer. a Labeler Code as described in (4) For each human prescription drug § 207.35(b)(2)(i). listed that the registrant regards as (c) For each drug product listed that not subject to section 505 of the act or is subject to the imprinting require- 351 of the Public Health Service Act, ments of part 206 of this chapter, in- and that is not manufactured by a reg- cluding products that are exempted istered blood bank, a copy of all cur- under § 206.7(b), drug companies must rent labeling (except that only one rep- submit a document that provides the resentative container or carton label name of the product, its active ingre- need be submitted where differences exist only in the quantity of contents dient(s), dosage strength, National statement) and a representative sam- Drug Code number, the name of its pling of advertisements. manufacturer or distributor, its size, (5) For each human over-the-counter shape, color, and code imprint (if any), drug listed, or each animal drug listed, and any other characteristic that iden- that the registrant regards as not sub- tifies the product as unique. ject to section 505 or 512 of the act or [45 FR 38043, June 6, 1980, as amended at 52 351 of the Public Health Service Act, a FR 2682, Jan. 26, 1987; 55 FR 11577, Mar. 29, copy of the label (except that only one 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, representative container or carton May 13, 1998; 64 FR 400, Jan. 5, 1999; 66 FR label need be submitted where dif- 59157, Nov. 27, 2001] ferences exist only in the quantity of contents statement), the package in- § 207.26 Amendments to registration. sert, and a representative sampling of Changes in individual ownership, cor- any other labeling. porate or partnership structure loca- (6) For each prescription or over-the- tion or drug-handling activity, shall be counter drug so listed that the reg- submitted by Form FDA–2656 (Reg- istrant regards as not subject to sec- istration of Drug Establishment) as tion 505 or 512 of the act or 351 of the amendment to registration within 5 Public Health Service Act, and that is days of such changes. A change in a not manufactured by a registered blood registered establishment’s firm name bank, a quantitative listing of the ac- within 6 months of the registration of tive ingredient(s). Unless the quan- the establishment is required to be sup- titative listing is expressed as a per- ported by a signed statement of the es- centage in the offical compendium or tablishment’s owner or operator that the ingredient is a nonantibiotic ingre- the change is not made for the purpose dient in a Type A medicated article for of changing the name of the manufac- use in the manufacture of animal feeds, turer of a drug product under § 201.1 of the quantity of an ingredient shall be this chapter. Changes in the names of

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officers and directors of the corpora- the following information by letter or tions do not require such amendment by FEDERAL REGISTER notice: but must be shown at time of annual (1) For a particular prescription drug registration. so listed that the registrant regards as not subject to section 505 of the act, [45 FR 25777, Apr. 15, 1980, as amended at 55 upon request by FDA for good cause, a FR 11577, Mar. 29, 1990] copy of all advertisements. § 207.30 Updating drug listing informa- (2) For a particular drug product so tion. listed that the registrant regards as not subject to section 505 or 512 of the (a) After submitting the initial drug act, upon a finding by FDA that it is listing information, every person who necessary to carry out the purposes of is required to list drugs under § 207.20 the act, a quantitative listing of all in- shall submit on Form FDA–2657 (Drug gredients. Product Listing) during each subse- (3) For a particular drug product, quent June and December, or at the upon request by FDA, a brief state- discretion of the registrant when the ment of the basis for the registrant’s change occurs, the following informa- belief that the drug product is not sub- tion: ject to section 505 or 512 of the act. (1) A list of each drug introduced by (4) For each registrant, upon a find- the registrant for commerical distribu- ing by FDA that it is necessary to tion which has not been included in carry out the purposes of the act, a list any list previously submitted. The reg- of each listed drug product containing istrant shall provide all of the informa- a particular ingredient. tion required by § 207.25(b) for each (b) It is requested but not required such drug. that a qualitative listing of the inac- (2) A list of each drug formerly listed tive ingredients be submitted for all in accordance with § 207.25(b) for which listed drugs in the format prescribed in commercial distribution has been dis- Form FDA–2657 (Drug Product Listing). continued, including for each drug so (c) It is requested but not required listed the National Drug Code (NDC) that a quantitative listing of the active number, the identity by established ingredients be submitted for all drugs name and by proprietary name, and listed that are subject to section 505 or date of discontinuance. It is requested 512 of the act or section 351 of the Pub- but not required that the reason for lic Health Service Act. discontinuance of distribution be included with this information. [45 FR 38043, June 6, 1980, as amended at 63 FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999] (3) A list of each drug for which a notice of discontinuance was submitted § 207.35 Notification of registrant; under paragraph (a)(2) of this section drug establishment registration and for which commercial distribution number and drug listing number. has been resumed, including for each (a) FDA will provide to the registrant drug so listed the NDC number, the a validated copy of Form FDA–2656 identity by established name and by (Registration of Drug Establishment) proprietary name, the date of resump- as evidence of registration. This vali- tion, and any other information re- dated copy will be sent to the mailing quired by § 207.25(b) not previously sub- address shown on the form. FDA will mitted. assign a permanent registration num- (4) Any material change in any infor- ber to each drug establishment reg- mation previously submitted. istered in accordance with these regu- (b) When no changes have occurred lations. since the previously submitted list, no (b) Using the National Drug Code report is required. (NDC) numbering system, FDA assigns a drug listing number to each drug or § 207.31 Additional drug listing infor- class of drugs listed as follows: mation. (1) If a drug is already listed in the (a) In addition to the information National Drug Code System or in the routinely required by §§ 207.25 and National Health Related Items Code 207.30, FDA may require submission of System, the number is the same as

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that assigned under those codes. FDA in assigning the Product and Package adds a lead zero to the first three char- Codes: a 3–2 Product-Package Code con- acters of the code, which identifies the figuration (e.g., 542–12) or a 4–1 Prod- manufacturer or distributor, to expand uct-Package Code configuration (e.g., the ‘‘Labeler Code’’ segment to four 5421–2). A manufacturer or distributor characters. The National Drug Code, with a given Labeler Code shall use Product Code, and Package Code con- only one such Product-Package Code figurations used to describe these configuration and shall use this same drugs, or any drugs added to the prod- configuration in assigning the Product- uct line, remain the same, i.e., a four- Package Codes for all drugs included in character Product Code and a two- the drug listing. The manufacturer or character Package Code. A manufac- distributor shall report to FDA the turer or distributor may either retain Product-Package Code configuration alphanumeric characters that are al- used in assigning these codes. ready used in the Product Code and (iii) If the drug formulation is a Type Package Code segments of the National A medicated article intended for use in Drug Code or convert these alpha- the manufacture of an animal feed, numeric characters to all numeric dig- FDA assigns a separate Product Code its. The manufacturer or distributor only for each variation of level of ac- shall inform FDA of a decision to con- tive drug ingredient. vert the alphanumeric characters to all (3) FDA requests but does not require numeric digits. that the NDC number appear on all (2) If a registered establishment or drug labels and in other drug labeling, distributor has not previously partici- including the label of any prescription pated in the National Drug Code Sys- drug container furnished to a con- tem or in the National Health Related sumer. If the NDC number is shown on Items Code System, FDA uses the Na- a drug label, it shall be placed as fol- tional Drug Code numbering system in lows: assigning a number, as follows (only (i) The NDC number shall appear numerals are used): prominently in the top third of the (i) The first 5 numeric characters of principal display panel of the label on the 10-character code identify the man- the immediate container and of any ufacturer or distributor and are known outside container or wrapper. Instead as the Labeler Code. FDA will expand of appearing in the top third of the the Labeler Code from five to six nu- label, the NDC number may appear as meric characters when the available part of and contiguous to any bar-code five-character code combinations are symbol for any drug product if two exhausted. FDA will assign Labeler conditions are met. First, the symbol Code numbers and provide them to the appears prominently on the immediate registrant along with the validated container and on any outside container copy of Form FDA–2656. Any registered or wrapper and in a conspicuous loca- firm that does not have an assigned La- tion; this condition is not satisfied by beler Code will be assigned one when the appearance of the symbol only on registration and listing information the natural bottom of a container or are submitted. wrapper. Second, the bar-code symbol (ii) The last 5 numeric characters of is compatible with the NDC, i.e., the the 10-character code identify the drug symbol provides a format capable of and the trade package size and type. encoding the numeric characters of an The segment that identifies the drug NDC Number. The term principal dis- 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’’

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when it is used on a label or in label- FDA of the new code for the trade ing. The prefix used for a drug product package and the characteristics of the shall be used consistently on the label new trade package. of the immediate container, outside (ii) When a registrant has discon- container, or wrapper, if any, and on tinued a drug product, its product code other labeling for that drug product. may be reassigned to another drug (iii) The Product-Package Code con- product 5 years after the expiration figuration shall be indicated and the date of the discontinued product, or, if segments of the number shall be sepa- there is no expiration date, 5 years rated by a dash, e.g., NDC 15643–542–12 after the last shipment of the discon- or N 15643–542–12. tinued product into commercial dis- (iv) All 10 characters shall appear and tribution. Reuse of product codes may the leading zeros in any segment of the occur, under the specified conditions, NDC number shall be shown, except regardless of the NDC, Product Code, that leading zeros may be omitted from and Package Code configuration used. any segment of the NDC number when (c) Although registration and drug the NDC number is used for product listing are required to engage in the identification by direct imprinting on drug activities described in § 207.20, dosage forms or in the case of con- validation of registration and the as- tainers too small or otherwise unable signment of a drug listing number do to accommodate a label with sufficent not, in themselves, establish that the space to bear both required and op- holder of the registration is legally tional labeling information. qualified to deal in such drugs. (v) The placing of the assigned NDC [45 FR 38043, June 6, 1980, as amended at 48 number on a label or in other labeling FR 54007, Nov. 30, 1983; 52 FR 2682, Jan. 26, does not require the submission of a 1987; 55 FR 11577, Mar. 29, 1990; 64 FR 400, Jan. supplemental new drug application, 5, 1999] supplemental new animal drug application. § 207.37 Inspection of registrations (4)(i) If any change occurs in those and drug listings. product characteristics that clearly (a) A copy of the Form FDA–2656 distinguish one drug product version (Registration of Drug Establishment) from another, the registrant shall as- filed by the registrant will be available sign a new NDC number to the new for inspection in accordance with sec- product version and submit that infor- tion 510(f) of the act, at the Division of mation to FDA. Such a change in- Labeling and Non-Prescription Drug cludes, but is not limited to, a change Compliance (HFD–310), Office of Com- in active ingredient(s); strength or con- pliance, Center for Drug Evaluation centration of active ingredient(s); dos- and Research, Food and Drug Adminis- age form; route of administration, if it tration, 7520 Standish Pl., Rockville, also includes a change in product for- MD 20855. In addition, copies of these mulation; product name; and a change forms for establishments located within marketing status from prescription in a particular geographic area are to over-the-counter or over-the-counter available for inspection at FDA district to prescription. If, by notice in the offices responsible for that geo- FEDERAL REGISTER, FDA requires a graphical area. Copies of forms sub- change in drug product characteristics mitted by foreign drug establishments and determines the change will require are available for inspection at the For- assignment of a new product code to eign Inspection Team (HFD–322), Office the reformulated product, FDA will an- of Compliance, Center for Drug Evalua- nounce its determination in the FED- tion and Research, 7520 Standish Pl., ERAL REGISTER publication that re- Rockville, MD 20855. Upon request and quires the change, setting forth its rea- receipt of a stamped, self-addressed en- soning and justification for its deter- velope, the Division of Labeling and mination. If a change only in the trade Non-Prescription Drug Compliance, the package is involved, the registrant Foreign Inspection Team, or the appro- may revise the trade package code priate FDA district office will verify without the assignment of a new prod- registration numbers or provide the lo- uct code segment, but shall inform cation of a registered establishment.

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(1) The following types of informa- for the geographic area in which the es- tion submitted under the drug listing tablishment is located. requirements will be available for pub- [45 FR 38043, June 6, 1980, as amended at 50 lic disclosure when compiled: FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, (i) A list of all drug products. 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, (ii) A list of all drug products ar- May 13, 1998; 64 FR 400, Jan. 5, 1999; 66 FR 59157, Nov. 27, 2001] ranged by labeled indications or pharmacological category. § 207.39 Misbranding by reference to (iii) A list of all drug products ar- registration or to registration num- ranged by manufacturer. ber. (iv) A list of a drug product’s active Registration of a drug establishment ingredients. or drug wholesaler, or assignment of a registration number, or assignment of (v) A list of drug products newly mar- a NDC number does not in any way de- keted or for which marketing is re- note approval of the firm or its prod- sumed. ucts. Any representation that creates (vi) A list of drug products discon- an impression of official approval be- tinued. cause of registration or possession of (vii) Labeling. registration number or NDC number is (viii) Advertising. misleading and constitutes mis- (ix) Information that has become a branding. matter of public knowledge. (x) A list of drug products containing Subpart D—Procedure for Foreign a particular active ingredient. Drug Establishments (xi) A list of all code imprints. § 207.40 Establishment registration (2) The following types of informa- and drug listing requirements for tion submitted in accordance with the foreign establishments. drug listing requirements will not be (a) Foreign drug establishments available for public disclosure (except whose drugs are imported or offered for that any of the information will be import into the United States shall available for public disclosure if it has comply with the establishment reg- become a matter of public knowledge istration and drug listing requirements or if FDA finds that confidentiality in subpart C of this part, unless exempt would be inconsistent with protection under subpart B of this part or unless of the public health): the drugs enter a foreign trade zone and are re-exported from that foreign (i) Any information submitted as the trade zone without having entered U. basis upon which it has been deter- S. commerce. mined that a particular drug product is (b) No drug may be imported or of- not subject to section 505 or 512 of the fered for import into the United States act. unless it is listed as required in subpart (ii) A list of a drug product’s inactive C of this part and manufactured, pre- ingredients. pared, propagated, compounded, or (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 investigational use provisions in part 312 of tablishment should be directed to the this chapter, or the investigational Information Management Team (HFD– new animal drug use provisions in part 095), Office of Information Technology, 511 of this chapter, or to a component Center for Drug Evaluation and Re- of a drug imported under section search, Food and Drug Administration, 801(d)(3) of the act. Foreign drug estab- 5600 Fishers Lane, Rockville, MD 20857 lishments shall submit all listing infor- or, with respect to the information de- mation, including labels and labeling, scribed in paragraph (a) of this section, and registration information in the to the FDA district office responsible English language.

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(c) Each foreign drug establishment SOURCE: 63 FR 66396, Dec. 1, 1998, unless required to register under paragraph otherwise noted. (a) of this section shall submit the name, address, and phone number of its Subpart A—General Provisions United States agent as part of its initial and updated registration informa- § 208.1 Scope and purpose. tion in accordance with subpart C of (a) This part sets forth requirements this part. Each foreign drug establish- for patient labeling for human pre- ment shall designate only one United scription drug products, including bio- States agent. logical products, that the Food and (1) The United States agent shall re- Drug Administration (FDA) determines side or maintain a place of business in pose a serious and significant public the United States. health concern requiring distribution (2) Upon request from FDA, the of FDA-approved patient information. United States agent shall assist FDA It applies primarily to human prescrip- in communications with the foreign tion drug products used on an out- drug establishment, respond to ques- patient basis without direct super- tions concerning the foreign drug es- vision by a health professional. This tablishment’s products that are im- part shall apply to new prescriptions ported or offered for import into the and refill prescriptions. United States, and assist FDA in (b) The purpose of patient labeling scheduling inspections of the foreign for human prescription drug products drug establishment. If the agency is required under this part is to provide unable to contact the foreign drug es- information when the FDA determines tablishment directly or expeditiously, in writing that it is necessary to pa- FDA may provide information or docu- tients’ safe and effective use of drug ments to the United States agent, and products. such an action shall be considered to be (c) Patient labeling will be required equivalent to providing the same infor- if the FDA determines that one or mation or documents to the foreign more of the following circumstances drug establishment. exists: (3) The foreign drug establishment or (1) The drug product is one for which the United States agent shall report patient labeling could help prevent se- changes in the United States agent’s rious adverse effects. name, address, or phone number to (2) The drug product is one that has FDA within 10-business days of the serious risk(s) (relative to benefits) of change. which patients should be made aware because information concerning the [66 FR 59157, Nov. 27, 2001] risk(s) could affect patients’ decision to use, or to continue to use, the prod- PART 208—MEDICATION GUIDES uct. FOR PRESCRIPTION DRUG PROD- (3) The drug product is important to UCTS health and patient adherence to directions for use is crucial to the drug’s ef- Subpart A—General Provisions fectiveness. Sec. § 208.3 Definitions. 208.1 Scope and purpose. For the purposes of this part, the fol- 208.3 Definitions. lowing definitions shall apply: (a) Authorized dispenser means an in- Subpart B—General Requirements for a dividual licensed, registered, or other- Medication Guide wise permitted by the jurisdiction in 208.20 Content and format of a Medication which the individual practices to pro- Guide. vide drug products on prescription in 208.24 Distributing and dispensing a Medica- the course of professional practice. tion Guide. (b) Dispense to patients means the act 208.26 Exemptions and deferrals. of delivering a prescription drug prod- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, uct to a patient or an agent of the pa- 355, 356, 357, 360, 371, 374; 42 U.S.C. 262. tient either:

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(1) By a licensed practitioner or an Subpart B—General Requirements agent of a licensed practitioner, either for a Medication Guide directly or indirectly, for self-administration by the patient, or the patient’s § 208.20 Content and format of a Medi- agent, or outside the licensed practi- cation Guide. tioner’s direct supervision; or (a) A Medication Guide shall meet all of the following conditions: (2) By an authorized dispenser or an (1) The Medication Guide shall be agent of an authorized dispenser under written in English, in nontechnical, a lawful prescription of a licensed prac- understandable language, and shall not titioner. be promotional in tone or content. (c) Distribute means the act of deliv- (2) The Medication Guide shall be sci- ering, other than by dispensing, a drug entifically accurate and shall be based product to any person. on, and shall not conflict with, the approved professional labeling for the (d) Distributor means a person who drug product under § 201.57 of this chap- distributes a drug product. ter, but the language of the Medication Guide need not be identical to the sec- (e) Drug product means a finished dos- tions of approved labeling to which it age form, e.g., tablet, capsule, or solu- corresponds. tion, that contains an active drug in- (3) The Medication Guide shall be gredient, generally, but not nec- specific and comprehensive. essarily, in association with inactive (4) The letter height or type size ingredients. For purposes of this part, shall be no smaller than 10 points (1 drug product also means biological point = 0.0138 inches) for all sections of product within the meaning of section the Medication Guide, except the man- 351(a) of the Public Health Service Act. ufacturer’s name and address and the (f) Licensed practitioner means an in- revision date. (5) The Medication Guide shall be dividual licensed, registered, or other- legible and clearly presented. Where wise permitted by the jurisdiction in appropriate, the Medication Guide which the individual practices to pre- shall also use boxes, bold or underlined scribe drug products in the course of print, or other highlighting techniques professional practice. to emphasize specific portions of the (g) Manufacturer means for a drug text. product that is not also a biological (6) The words ‘‘Medication Guide’’ product, both the manufacturer as de- shall appear prominently at the top of scribed in § 201.1 and the applicant as the first page of a Medication Guide. described in § 314.3(b) of this chapter, The verbatim statement ‘‘This Medica- and for a drug product that is also a bi- tion Guide has been approved by the ological product, the manufacturer as U.S. Food and Drug Administration’’ described in § 600.3(t) of this chapter. shall appear at the bottom of a Medica- tion Guide. (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 or proper name shall be no less than (i) Packer means a person who pack- one-half the height of the brand name. ages a drug product. (b) A Medication Guide shall contain (j) Patient means any individual with those of the following headings rel- respect to whom a drug product is in- evant to the drug product and to the tended to be, or has been, used. need for the Medication Guide in the specified order. Each heading shall con- (k) Serious risk or serious adverse effect tain the specific information as fol- means an adverse drug experience, or lows: the risk of such an experience, as that (1) The brand name (e.g., the trade- term is defined in §§ 310.305, 312.32, mark or proprietary name), if any, and 314.80, and 600.80 of this chapter. established or proper name. Those

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products not having an established or the drug product, if they are important proper name shall be designated by to the drug’s safety or effectiveness; their active ingredients. The Medica- (iii) A statement of what patients tion Guide shall include the phonetic should do in case of overdose of the spelling of either the brand name or drug product; and the established name, whichever is (iv) A statement of what patients used throughout the Medication Guide. should do if they miss taking a sched- (2) The heading, ‘‘What is the most uled dose(s) of the drug product, where important information I should know there are data to support the advice, about (name of drug)?’’ followed by a and where the wrong behavior could statement describing the particular se- cause harm or lack of effect. rious and significant public health con- (6) The heading ‘‘What should I avoid cern that has created the need for the while taking (name of drug)?’’ followed Medication Guide. The statement by a statement or statements of spe- should describe specifically what the cific, important precautions patients patient should do or consider because should take to ensure proper use of the of that concern, such as, weighing par- drug, including: ticular risks against the benefits of the (i) A statement that identifies activi- drug, avoiding particular behaviors ties (such as driving or sunbathing), (e.g., activities, drugs), observing cer- and drugs, foods, or other substances tain events (e.g., symptoms, signs) that (such as tobacco or alcohol) that pa- could prevent or mitigate a serious ad- tients should avoid when using the verse effect, or engaging in particular medication; behaviors (e.g., adhering to the dosing (ii) A statement of the risks to moth- regimen). ers and fetuses from the use of the drug (3) The heading, ‘‘What is (name of during pregnancy, if specific, impor- drug)?’’ followed by a section that iden- tant risks are known; tifies a drug product’s indications for (iii) A statement of the risks of the use. The Medication Guide may not drug product to nursing infants, if spe- identify an indication unless the indi- cific, important risks are known; cation is identified in the indications (iv) A statement about pediatric and usage section of the professional risks, if the drug product has specific labeling for the product required under hazards associated with its use in pedi- § 201.57 of this chapter. In appropriate atric patients; circumstances, this section may also (v) A statement about geriatric risks, explain the nature of the disease or if the drug product has specific hazards condition the drug product is intended associated with its use in geriatric pa- to treat, as well as the benefit(s) of tients; and treating the condition. (vi) A statement of special pre- (4) The heading, ‘‘Who should not cautions, if any, that apply to the safe take (name of drug)?’’ followed by in- and effective use of the drug product in formation on circumstances under other identifiable patient populations. which the drug product should not be (7) The heading, ‘‘What are the pos- used for its labeled indication (its con- sible or reasonably likely side effects traindications). The Medication Guide of (name of drug)?’’ followed by: shall contain directions regarding what (i) A statement of the adverse reac- to do if any of the contraindications tions reasonably likely to be caused by apply to a patient, such as contacting the drug product that are serious or the licensed practitioner or dis- occur frequently. continuing use of the drug product. (ii) A statement of the risk, if there (5) The heading, ‘‘How should I take is one, of patients’ developing depend- (name of drug)?’’ followed by informa- ence on the drug product. tion on the proper use of the drug prod- (8) General information about the uct, such as: safe and effective use of prescription (i) A statement stressing the impor- drug products, including: tance of adhering to the dosing instruc- (i) The verbatim statement that tions, if this is particularly important; ‘‘Medicines are sometimes prescribed (ii) A statement describing any spe- for purposes other than those listed in cial instructions on how to administer a Medication Guide’’ followed by a

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statement that patients should ask (b) of this section shall provide those health professionals about any con- Medication Guides, or the means to cerns, and a reference to the avail- produce Medication Guides, to each au- ability of professional labeling; thorized dispenser to whom it ships a (ii) A statement that the drug prod- container of drug product. uct should not be used for a condition (d) The label of each container or other than that for which it is pre- package, where the container label is scribed, or given to other persons; too small, of drug product for which a (iii) The name and place of business Medication Guide is required under of the manufacturer, packer, or dis- this part shall instruct the authorized tributor of a drug product that is not dispenser to provide a Medication also a biological product, or the name Guide to each patient to whom the and place of business of the manufac- drug product is dispensed, and shall turer or distributor of a drug product state how the Medication Guide is pro- that is also a biological product, and in vided. These statements shall appear any case the name and place of busi- on the label in a prominent and con- ness of the dispenser of the product spicuous manner. may also be included; and (e) Each authorized dispenser of a (iv) The date, identified as such, of prescription drug product for which a the most recent revision of the Medica- Medication Guide is required under tion Guide placed immediately after this part shall, when the product is dis- the last section. pensed to a patient (or to a patient’s (9) Additional headings and sub- agent), provide a Medication Guide di- headings may be interspersed through- rectly to each patient (or to the pa- out the Medication Guide, if appro- tient’s agent) unless an exemption ap- priate. plies under § 208.26. § 208.24 Distributing and dispensing a (f) An authorized dispenser or whole- Medication Guide. saler is not subject to section 510 of the Federal Food, Drug, and Cosmetic Act, (a) The manufacturer of a drug product for which a Medication Guide is re- which requires the registration of pro- quired under this part shall obtain ducers of drugs and the listing of drugs FDA approval of the Medication Guide in commercial distribution, solely be- before the Medication Guide may be cause of an act performed by the au- distributed. thorized dispenser or wholesaler under (b) Each manufacturer who ships a this part. container of drug product for which a § 208.26 Exemptions and deferrals. Medication Guide is required under this part is responsible for ensuring (a) FDA on its own initiative, or in that Medication Guides are available response to a written request from an for distribution to patients by either: applicant, may exempt or defer any (1) Providing Medication Guides in Medication Guide content or format re- sufficient numbers to distributors, quirement, except those requirements packers, or authorized dispensers to in § 208.20 (a)(2) and (a)(6), on the basis permit the authorized dispenser to pro- that the requirement is inapplicable, vide a Medication Guide to each pa- unnecessary, or contrary to patients’ tient receiving a prescription for the best interests. Requests from appli- drug product; or cants should be submitted to the direc- (2) Providing the means to produce tor of the FDA division responsible for Medication Guides in sufficient num- reviewing the marketing application bers to distributors, packers, or au- for the drug product, or for a biological thorized dispensers to permit the au- product, to the application division in thorized dispenser to provide a Medica- the office with product responsibility. tion Guide to each patient receiving a (b) If the licensed practitioner who 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

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a Medication Guide, the licensed prac- as they may pertain to a drug and in titioner may direct that the Medica- parts 600 through 680 of this chapter as tion Guide not be provided to the par- they may pertain to a biological prod- ticular patient. However, the author- uct for human use, shall be considered ized dispenser of a prescription drug to supplement, not supersede, each product subject to this part shall pro- other, unless the regulations explicitly vide a Medication Guide to any patient provide otherwise. In the event that it who requests information when the is impossible to comply with all appli- drug product is dispensed regardless of cable regulations in these parts, the any such direction by the licensed regulations specifically applicable to practitioner. the drug in question shall supersede the more general. PART 210—CURRENT GOOD MAN- (b) If a person engages in only some UFACTURING PRACTICE IN MAN- operations subject to the regulations in UFACTURING, PROCESSING, this part and in parts 211 through 226 PACKING, OR HOLDING OF and parts 600 through 680 of this chap- DRUGS; GENERAL ter, and not in others, that person need only comply with those regulations ap- Sec. plicable to the operations in which he 210.1 Status of current good manufacturing or she is engaged. practice regulations. 210.2 Applicability of current good manu- § 210.3 Definitions. facturing practice regulations. (a) The definitions and interpreta- 210.3 Definitions. tions contained in section 201 of the act AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, shall be applicable to such terms when 371, 374. used in this part and in parts 211 SOURCE: 43 FR 45076, Sept, 29, 1978, unless through 226 of this chapter. otherwise noted. (b) The following definitions of terms apply to this part and to parts 211 § 210.1 Status of current good manufacturing practice regulations. through 226 of this chapter. (1) Act means the Federal Food, Drug, (a) The regulations set forth in this and Cosmetic Act, as amended (21 part and in parts 211 through 226 of this U.S.C. 301 et seq.). chapter contain the minimum current (2) Batch means a specific quantity of good manufacturing practice for meth- a drug or other material that is in- ods to be used in, and the facilities or tended to have uniform character and controls to be used for, the manufacture, processing, packing, or holding of quality, within specified limits, and is a drug to assure that such drug meets produced according to a single manu- the requirements of the act as to safe- facturing order during the same cycle ty, and has the identity and strength of manufacture. and meets the quality and purity char- (3) Component means any ingredient acteristics that it purports or is rep- intended for use in the manufacture of resented to possess. a drug product, including those that (b) The failure to comply with any may not appear in such drug product. regulation set forth in this part and in (4) Drug product means a finished dos- parts 211 through 226 of this chapter in age form, for example, tablet, capsule, the manufacture, processing, packing, solution, etc., that contains an active or holding of a drug shall render such drug ingredient generally, but not nec- drug to be adulterated under section essarily, in association with inactive 501(a)(2)(B) of the act and such drug, as ingredients. The term also includes a well as the person who is responsible finished dosage form that does not con- for the failure to comply, shall be sub- tain an active ingredient but is in- ject to regulatory action. tended to be used as a placebo. (5) Fiber means any particulate con- § 210.2 Applicability of current good taminant with a length at least three manufacturing practice regulations. times greater than its width. (a) The regulations in this part and (6) Non-fiber-releasing filter means any in parts 211 through 226 of this chapter filter, which after any appropriate

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pretreatment such as washing or flush- (14) The term medicated premix means ing, will not release fibers into the a Type A medicated article as defined component or drug product that is in § 558.3 of this chapter. The article being filtered. All filters composed of contains one or more drugs as defined asbestos are deemed to be fiber-releas- in section 201(g) of the act. The manu- ing filters. facture of medicated premixes is sub- (7) Active ingredient means any com- ject to the requirements of part 226 of ponent that is intended to furnish this chapter. pharmacological activity or other di- (15) Quality control unit means any rect effect in the diagnosis, cure, miti- person or organizational element des- gation, treatment, or prevention of dis- ignated by the firm to be responsible ease, or to affect the structure or any for the duties relating to quality con- function of the body of man or other trol. animals. The term includes those com- (16) Strength means: ponents that may undergo chemical (i) The concentration of the drug sub- change in the manufacture of the drug stance (for example, weight/weight, product and be present in the drug weight/volume, or unit dose/volume product in a modified form intended to basis), and/or furnish the specified activity or effect. (ii) The potency, that is, the thera- (8) Inactive ingredient means any com- peutic activity of the drug product as ponent other than an active ingredient. indicated by appropriate laboratory (9) In-process material means any ma- tests or by adequately developed and terial fabricated, compounded, blended, controlled clinical data (expressed, for or derived by chemical reaction that is example, in terms of units by reference produced for, and used in, the prepara- to a standard). tion of the drug product. (17) Theoretical yield means the quan- (10) Lot means a batch, or a specific tity that would be produced at any ap- identified portion of a batch, having propriate phase of manufacture, proc- uniform character and quality within essing, or packing of a particular drug specified limits; or, in the case of a product, based upon the quantity of drug product produced by continuous components to be used, in the absence process, it is a specific identified of any loss or error in actual produc- amount produced in a unit of time or tion. quantity in a manner that assures its (18) Actual yield means the quantity having uniform character and quality that is actually produced at any appro- within specified limits. priate phase of manufacture, proc- (11) Lot number, control number, or essing, or packing of a particular drug batch number means any distinctive product. combination of letters, numbers, or (19) Percentage of theoretical yield symbols, or any combination of them, means the ratio of the actual yield (at from which the complete history of the any appropriate phase of manufacture, manufacture, processing, packing, processing, or packing of a particular holding, and distribution of a batch or drug product) to the theoretical yield lot of drug product or other material (at the same phase), stated as a per- can be determined. centage. (12) Manufacture, processing, packing, (20) Acceptance criteria means the or holding of a drug product includes product specifications and acceptance/ packaging and labeling operations, rejection criteria, such as acceptable testing, and quality control of drug quality level and unacceptable quality products. level, with an associated sampling (13) The term medicated feed means plan, that are necessary for making a any Type B or Type C medicated feed decision to accept or reject a lot or as defined in § 558.3 of this chapter. The batch (or any other convenient sub- feed contains one or more drugs as de- groups of manufactured units). fined in section 201(g) of the act. The (21) Representative sample means a manufacture of medicated feeds is sub- sample that consists of a number of ject to the requirements of part 225 of units that are drawn based on rational this chapter. criteria such as random sampling and

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intended to assure that the sample ac- 211.89 Rejected components, drug product curately portrays the material being containers, and closures. sampled. 211.94 Drug product containers and closures. (22) Gang-printed labeling means la- Subpart F—Production and Process beling derived from a sheet of material Controls on which more than one item of labeling is printed. 211.100 Written procedures; deviations. 211.101 Charge-in of components. [43 FR 45076, Sept. 29, 1978, as amended at 51 211.103 Calculation of yield. FR 7389, Mar. 3, 1986; 58 FR 41353, Aug. 3, 1993] 211.105 Equipment identification. 211.110 Sampling and testing of in-process PART 211—CURRENT GOOD MAN- materials and drug products. 211.111 Time limitations on production. UFACTURING PRACTICE FOR FIN- 211.113 Control of microbiological contami- ISHED PHARMACEUTICALS nation. 211.115 Reproccessing. Subpart A—General Provisions Subpart G—Packaging and Labeling Sec. Control 211.1 Scope. 211.3 Definitions. 211.122 Materials examination and usage criteria. Subpart B—Organization and Personnel 211.125 Labeling issuance. 211.130 Packaging and labeling operations. 211.22 Responsibilities of quality control 211.132 Tamper-evident packaging require- unit. ments for over-the-counter (OTC) human 211.25 Personnel qualifications. drug products. 211.28 Personnel responsibilities. 211.134 Drug product inspection. 211.34 Consultants. 211.137 Expiration dating.

Subpart C—Buildings and Facilities Subpart H—Holding and Distribution 211.42 Design and construction features. 211.142 Warehousing procedures. 211.44 Lighting. 211.150 Distribution procedures. 211.46 Ventilation, air filtration, air heating and cooling. Subpart I—Laboratory Controls 211.48 Plumbing. 211.160 General requirements. 211.50 Sewage and refuse. 211.165 Testing and release for distribution. 211.52 Washing and toilet facilities. 211.166 Stability testing. 211.56 Sanitation. 211.167 Special testing requirements. 211.58 Maintenance. 211.170 Reserve samples. 211.173 Laboratory animals. Subpart D—Equipment 211.176 Penicillin contamination. 211.63 Equipment design, size, and location. Subpart J—Records and Reports 211.65 Equipment construction. 211.67 Equipment cleaning and mainte- 211.180 General requirements. nance. 211.182 Equipment cleaning and use log. 211.68 Automatic, mechanical, and elec- 211.184 Component, drug product container, tronic equipment. closure, and labeling records. 211.72 Filters. 211.186 Master production and control records. Subpart E—Control of Components and 211.188 Batch production and control Drug Product Containers and Closures records. 211.192 Production record review. 211.80 General requirements. 211.194 Laboratory records. 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. 211.204 Returned drug products. 211.86 Use of approved components, drug 211.208 Drug product salvaging. product containers, and closures. 211.87 Retesting of approved components, AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, drug product containers, and closures. 371, 374.

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SOURCE: 43 FR 45077, Sept. 29, 1978, unless Subpart B—Organization and otherwise noted. Personnel

§ 211.22 Responsibilities of quality Subpart A—General Provisions control unit. § 211.1 Scope. (a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all (a) The regulations in this part con- components, drug product containers, tain the minimum current good manu- closures, in-process materials, pack- facturing practice for preparation of aging material, labeling, and drug drug products for administration to hu- products, and the authority to review mans or animals. production records to assure that no errors have occurred or, if errors have (b) The current good manufacturing occurred, that they have been fully in- practice regulations in this chapter, as vestigated. The quality control unit they pertain to drug products, and in shall be responsible for approving or re- parts 600 through 680 of this chapter, as jecting drug products manufactured, they pertain to biological products for processed, packed, or held under con- human use, shall be considered to sup- tract by another company. plement, not supersede, the regulations (b) Adequate laboratory facilities for in this part unless the regulations ex- the testing and approval (or rejection) plicitly provide otherwise. In the event of components, drug product con- it is impossible to comply with applica- tainers, closures, packaging materials, ble regulations both in this part and in in-process materials, and drug products other parts of this chapter or in parts shall be available to the quality con- 600 through 680 of this chapter, the reg- trol unit. ulation specifically applicable to the (c) The quality control unit shall drug product in question shall super- have the responsibility for approving sede the regulation in this part. or rejecting all procedures or specifications impacting on the identity, (c) Pending consideration of a pro- strength, quality, and purity of the posed exemption, published in the FED- drug product. ERAL REGISTER of September 29, 1978, (d) The responsibilities and proce- the requirements in this part shall not dures applicable to the quality control be enforced for OTC drug products if unit shall be in writing; such written the products and all their ingredients procedures shall be followed. are ordinarily marketed and consumed as human foods, and which products § 211.25 Personnel qualifications. may also fall within the legal definition of drugs by virtue of their in- (a) Each person engaged in the manu- tended use. Therefore, until further no- facture, processing, packing, or holding of a drug product shall have education, tice, regulations under part 110 of this training, and experience, or any com- chapter, and where applicable, parts 113 bination thereof, to enable that person to 129 of this chapter, shall be applied to perform the assigned functions. in determining whether these OTC drug Training shall be in the particular op- products that are also foods are manu- erations that the employee performs factured, processed, packed, or held and in current good manufacturing under current good manufacturing practice (including the current good practice. manufacturing practice regulations in this chapter and written procedures re- [43 FR 45077, Sept. 29, 1978, as amended at 62 quired by these regulations) as they re- FR 66522, Dec. 19, 1997] late to the employee’s functions. Training in current good manufac- § 211.3 Definitions. turing practice shall be conducted by qualified individuals on a continuing The definitions set forth in § 210.3 of basis and with sufficient frequency to this chapter apply in this part. assure that employees remain familiar

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with CGMP requirements applicable to Records shall be maintained stating them. the name, address, and qualifications (b) Each person responsible for super- of any consultants and the type of vising the manufacture, processing, service they provide. packing, or holding of a drug product shall have the education, training, and Subpart C—Buildings and Facilities experience, or any combination thereof, to perform assigned functions in § 211.42 Design and construction fea- such a manner as to provide assurance tures. that the drug product has the safety, (a) Any building or buildings used in identity, strength, quality, and purity the manufacture, processing, packing, that it purports or is represented to or holding of a drug product shall be of possess. suitable size, construction and location (c) There shall be an adequate num- to facilitate cleaning, maintenance, ber of qualified personnel to perform and proper operations. and supervise the manufacture, processing, packing, or holding of each drug (b) Any such building shall have ade- product. quate space for the orderly placement of equipment and materials to prevent § 211.28 Personnel responsibilities. mixups between different components, drug product containers, closures, la- (a) Personnel engaged in the manu- beling, in-process materials, or drug facture, processing, packing, or holding products, and to prevent contamina- of a drug product shall wear clean tion. The flow of components, drug clothing appropriate for the duties product containers, closures, labeling, they perform. Protective apparel, such in-process materials, and drug products as head, face, hand, and arm coverings, through the building or buildings shall shall be worn as necessary to protect be designed to prevent contamination. drug products from contamination. (b) Personnel shall practice good (c) Operations shall be performed sanitation and health habits. within specifically defined areas of ade- (c) Only personnel authorized by su- quate size. There shall be separate or pervisory personnel shall enter those defined areas or such other control sys- areas of the buildings and facilities tems for the firm’s operations as are designated as limited-access areas. necessary to prevent contamination or (d) Any person shown at any time (ei- mixups during the course of the fol- ther by medical examination or super- lowing procedures: visory observation) to have an appar- (1) Receipt, identification, storage, ent illness or open lesions that may ad- and withholding from use of compo- versely affect the safety or quality of nents, drug product containers, clo- drug products shall be excluded from sures, and labeling, pending the appro- direct contact with components, drug priate sampling, testing, or examina- product containers, closures, in-process tion by the quality control unit before 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;

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(9) Control and laboratory oper- from those for other drug products for ations; human use. (10) Aseptic processing, which includes as appropriate: § 211.48 Plumbing. (i) Floors, walls, and ceilings of (a) Potable water shall be supplied smooth, hard surfaces that are easily under continuous positive pressure in a cleanable; plumbing system free of defects that (ii) Temperature and humidity con- could contribute contamination to any trols; drug product. Potable water shall meet (iii) An air supply filtered through the standards prescribed in the Envi- high-efficiency particulate air filters ronmental Protection Agency’s Pri- under positive pressure, regardless of mary Drinking Water Regulations set whether flow is laminar or nonlaminar; forth in 40 CFR part 141. Water not (iv) A system for monitoring environ- meeting such standards shall not be mental conditions; permitted in the potable water system. (v) A system for cleaning and dis- (b) Drains shall be of adequate size infecting the room and equipment to and, where connected directly to a produce aseptic conditions; sewer, shall be provided with an air (vi) A system for maintaining any break or other mechanical device to equipment used to control the aseptic prevent back-siphonage. conditions. [43 FR 45077, Sept. 29, 1978, as amended at 48 (d) Operations relating to the manu- FR 11426, Mar. 18, 1983] facture, processing, and packing of penicillin shall be performed in facilities § 211.50 Sewage and refuse. separate from those used for other drug Sewage, trash, and other refuse in products for human use. and from the building and immediate [43 FR 45077, Sept. 29, 1978, as amended at 60 premises shall be disposed of in a safe FR 4091, Jan. 20, 1995] and sanitary manner.

§ 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 (a) Any building used in the manufac- over air pressure, micro-organisms, ture, processing, packing, or holding of dust, humidity, and temperature shall a drug product shall be maintained in a be provided when appropriate for the clean and sanitary condition, Any such manufacture, processing, packing, or building shall be free of infestation by holding of a drug product. rodents, birds, insects, and other (c) Air filtration systems, including vermin (other than laboratory ani- prefilters and particulate matter air mals). Trash and organic waste matter filters, shall be used when appropriate shall be held and disposed of in a time- on air supplies to production areas. If ly and sanitary manner. air is recirculated to production areas, (b) There shall be written procedures measures shall be taken to control re- assigning responsibility for sanitation circulation of dust from production. In and describing in sufficient detail the areas where air contamination occurs cleaning schedules, methods, equip- during production, there shall be ade- ment, and materials to be used in quate exhaust systems or other sys- cleaning the buildings and facilities; tems adequate to control contami- such written procedures shall be fol- nants. lowed. (d) Air-handling systems for the man- (c) There shall be written procedures ufacture, processing, and packing of for use of suitable rodenticides, insecti- penicillin shall be completely separate cides, fungicides, fumigating agents,

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and cleaning and sanitizing agents. appropriate intervals to prevent mal- Such written procedures shall be de- functions or contamination that would signed to prevent the contamination of alter the safety, identity, strength, equipment, components, drug product quality, or purity of the drug product containers, closures, packaging, label- beyond the official or other established ing materials, or drug products and requirements. shall be followed. Rodenticides, insecti- (b) Written procedures shall be estab- cides, and fungicides shall not be used lished and followed for cleaning and unless registered and used in accord- maintenance of equipment, including ance with the Federal Insecticide, Fun- utensils, used in the manufacture, gicide, and Rodenticide Act (7 U.S.C. processing, packing, or holding of a 135). drug product. These procedures shall (d) Sanitation procedures shall apply include, but are not necessarily limited to work performed by contractors or to, the following: temporary employees as well as work (1) Assignment of responsibility for performed by full-time employees dur- cleaning and maintaining equipment; ing the ordinary course of operations. (2) Maintenance and cleaning schedules, including, where appropriate, § 211.58 Maintenance. sanitizing schedules; Any building used in the manufac- (3) A description in sufficient detail ture, processing, packing, or holding of of the methods, equipment, and mate- a drug product shall be maintained in a rials used in cleaning and maintenance good state of repair. operations, and the methods of dis- assembling and reassembling equip- Subpart D—Equipment ment as necessary to assure proper cleaning and maintenance; § 211.63 Equipment design, size, and (4) Removal or obliteration of pre- location. vious batch identification; Equipment used in the manufacture, (5) Protection of clean equipment processing, packing, or holding of a from contamination prior to use; drug product shall be of appropriate de- (6) Inspection of equipment for clean- sign, adequate size, and suitably lo- liness immediately before use. cated to facilitate operations for its in- (c) Records shall be kept of mainte- tended use and for its cleaning and nance, cleaning, sanitizing, and inspec- maintenance. tion as specified in §§ 211.180 and 211.182.

§ 211.65 Equipment construction. § 211.68 Automatic, mechanical, and (a) Equipment shall be constructed so electronic equipment. that surfaces that contact components, (a) Automatic, mechanical, or elec- in-process materials, or drug products tronic equipment or other types of shall not be reactive, additive, or ab- equipment, including computers, or re- sorptive so as to alter the safety, iden- lated systems that will perform a func- tity, strength, quality, or purity of the tion satisfactorily, may be used in the drug product beyond the official or manufacture, processing, packing, and other established requirements. holding of a drug product. If such (b) Any substances required for oper- equipment is so used, it shall be rou- ation, such as lubricants or coolants, tinely calibrated, inspected, or checked shall not come into contact with com- according to a written program de- ponents, drug product containers, clo- signed to assure proper performance. sures, in-process materials, or drug Written records of those calibration products so as to alter the safety, iden- checks and inspections shall be main- tity, strength, quality, or purity of the tained. drug product beyond the official or (b) Appropriate controls shall be ex- other established requirements. ercised over computer or related systems to assure that changes in master § 211.67 Equipment cleaning and main- production and control records or other tenance. records are instituted only by author- (a) Equipment and utensils shall be ized personnel. Input to and output cleaned, maintained, and sanitized at from the computer or related system of

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formulas or other records or data shall Subpart E—Control of Compo- be checked for accuracy. The degree nents and Drug Product Con- and frequency of input/output tainers and Closures verification shall be based on the com- plexity and reliability of the computer § 211.80 General requirements. or related system. A backup file of data (a) There shall be written procedures entered into the computer or related describing in sufficient detail the re- system shall be maintained except ceipt, identification, storage, handling, where certain data, such as calcula- sampling, testing, and approval or re- tions performed in connection with lab- jection of components and drug prod- oratory analysis, are eliminated by uct containers and closures; such writ- computerization or other automated ten procedures shall be followed. processes. In such instances a written (b) Components and drug product record of the program shall be main- containers and closures shall at all tained along with appropriate valida- times be handled and stored in a man- tion data. Hard copy or alternative sys- ner to prevent contamination. tems, such as duplicates, tapes, or (c) Bagged or boxed components of microfilm, designed to assure that drug product containers, or closures backup data are exact and complete shall be stored off the floor and suitably spaced to permit cleaning and in- and that it is secure from alteration, spection. inadvertent erasures, or loss shall be (d) Each container or grouping of maintained. containers for components or drug product containers, or closures shall be [43 FR 45077, Sept. 29, 1978, as amended at 60 identified with a distinctive code for FR 4091, Jan. 20, 1995] each lot in each shipment received. This code shall be used in recording the disposition of each lot. Each lot shall § 211.72 Filters. be appropriately identified as to its status (i.e., quarantined, approved, or Filters for liquid filtration used in rejected). the manufacture, processing, or pack- § 211.82 Receipt and storage of untest- ing of injectable drug products ined components, drug product con- tended for human use shall not release tainers, and closures. fibers into such products. Fiber-releas- (a) Upon receipt and before accept- ing filters may not be used in the man- ance, each container or grouping of ufacture, processing, or packing of containers of components, drug prod- these injectable drug products unless it uct containers, and closures shall be is not possible to manufacture such examined visually for appropriate la- drug products without the use of such beling as to contents, container dam- filters. If use of a fiber-releasing filter age or broken seals, and contamina- is necessary, an additional non-fiber- tion. releasing filter of 0.22 micron max- (b) Components, drug product con- imum mean porosity (0.45 micron if the tainers, and closures shall be stored manufacturing conditions so dictate) under quarantine until they have been shall subsequently be used to reduce tested or examined, as appropriate, and the content of particles in the released. Storage within the area shall injectable drug product. Use of an as- conform to the requirements of § 211.80. bestos-containing filter, with or with- § 211.84 Testing and approval or rejec- out subsequent use of a specific non- tion of components, drug product fiber-releasing filter, is permissible containers, and closures. only upon submission of proof to the (a) Each lot of components, drug appropriate bureau of the Food and product containers, and closures shall Drug Administration that use of a non- be withheld from use until the lot has fiber-releasing filter will, or is likely been sampled, tested, or examined, as to, compromise the safety or effective- appropriate, and released for use by the ness of the injectable drug product. quality control unit.

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(b) Representative samples of each at least one specific identity test is shipment of each lot shall be collected conducted on such component by the for testing or examination. The num- manufacturer, and provided that the ber of containers to be sampled, and manufacturer establishes the reli- the amount of material to be taken ability of the supplier’s analyses from each container, shall be based through appropriate validation of the upon appropriate criteria such as sta- supplier’s test results at appropriate tistical criteria for component varia- intervals. bility, confidence levels, and degree of (3) Containers and closures shall be precision desired, the past quality his- tested for conformance with all appro- tory of the supplier, and the quantity priate written procedures. In lieu of needed for analysis and reserve where such testing by the manufacturer, a required by § 211.170. certificate of testing may be accepted (c) Samples shall be collected in ac- from the supplier, provided that at cordance with the following proce- least a visual identification is con- dures: ducted on such containers/closures by (1) The containers of components se- the manufacturer and provided that lected shall be cleaned where nec- the manufacturer establishes the reli- essary, by appropriate means. 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 bot- established specifications for such con- tom of its container, such sample sub- tamination. divisions shall not be composited for (6) Each lot of a component, drug testing. product container, or closure that is (5) Sample containers shall be identi- liable to microbiological contamina- fied so that the following information tion that is objectionable in view of its can be determined: name of the mate- intended use shall be subjected to rial sampled, the lot number, the con- microbiological tests before use. tainer from which the sample was (e) Any lot of components, drug prod- taken, the date on which the sample uct containers, or closures that meets was taken, and the name of the person the appropriate written specifications who collected the sample. of identity, strength, quality, and pu- (6) Containers from which samples rity and related tests under paragraph have been taken shall be marked to (d) of this section may be approved and show that samples have been removed released for use. Any lot of such mate- from them. rial that does not meet such specifica- (d) Samples shall be examined and tions shall be rejected. tested as follows: [43 FR 45077, Sept. 29, 1978, as amended at 63 (1) At least one test shall be con- FR 14356, Mar. 25, 1998] ducted to verify the identity of each component of a drug product. Specific § 211.86 Use of approved components, identity tests, if they exist, shall be drug product containers, and clo- used. sures. (2) Each component shall be tested Components, drug product con- for conformity with all appropriate tainers, and closures approved for use written specifications for purity, shall be rotated so that the oldest ap- strength, and quality. In lieu of such proved stock is used first. Deviation testing by the manufacturer, a report from this requirement is permitted if of analysis may be accepted from the such deviation is temporary and appro- supplier of a component, provided that priate.

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§ 211.87 Retesting of approved compo- signed to assure that the drug products nents, drug product containers, and have the identity, strength, quality, closures. and purity they purport or are rep- Components, drug product con- resented to possess. Such procedures tainers, and closures shall be retested shall include all requirements in this or reexamined, as appropriate, for iden- subpart. These written procedures, in- tity, strength, quality, and purity and cluding any changes, shall be drafted, approved or rejected by the quality reviewed, and approved by the appro- control unit in accordance with § 211.84 priate organizational units and re- as necessary, e.g., after storage for viewed and approved by the quality long periods or after exposure to air, control unit. heat or other conditions that might ad- (b) Written production and process versely affect the component, drug control procedures shall be followed in product container, or closure. the execution of the various production and process control functions and shall § 211.89 Rejected components, drug be documented at the time of perform- product containers, and closures. ance. Any deviation from the written Rejected components, drug product procedures shall be recorded and justi- containers, and closures shall be iden- fied. tified and controlled under a quarantine system designed to prevent § 211.101 Charge-in of components. their use in manufacturing or proc- Written production and control pro- essing operations for which they are cedures shall include the following, unsuitable. which are designed to assure that the § 211.94 Drug product containers and drug products produced have the iden- closures. tity, strength, quality, and purity they purport or are represented to possess: (a) Drug product containers and clo- (a) The batch shall be formulated sures shall not be reactive, additive, or with the intent to provide not less than absorptive so as to alter the safety, 100 percent of the labeled or established identity, strength, quality, or purity of amount of active ingredient. the drug beyond the official or established requirements. (b) Components for drug product (b) Container closure systems shall manufacturing shall be weighed, meas- provide adequate protection against ured, or subdivided as appropriate. If a foreseeable external factors in storage component is removed from the origi- and use that can cause deterioration or nal container to another, the new con- contamination of the drug product. tainer shall be identified with the fol- (c) Drug product containers and clo- lowing information: sures shall be clean and, where indi- (1) Component name or item code; cated by the nature of the drug, steri- (2) Receiving or control number; lized and processed to remove (3) Weight or measure in new con- pyrogenic properties to assure that tainer; they are suitable for their intended (4) Batch for which component was use. dispensed, including its product name, (d) Standards or specifications, meth- strength, and lot number. ods of testing, and, where indicated, (c) Weighing, measuring, or subdi- methods of cleaning, sterilizing, and viding operations for components shall processing to remove pyrogenic prop- be adequately supervised. Each con- erties shall be written and followed for tainer of component dispensed to man- drug product containers and closures. ufacturing shall be examined by a second person to assure that: Subpart F—Production and (1) The component was released by Process Controls the quality control unit; (2) The weight or measure is correct § 211.100 Written procedures; devi- as stated in the batch production ations. records; (a) There shall be written procedures (3) The containers are properly iden- for production and process control de- tified.

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(d) Each component shall be added to (3) Adequacy of mixing to assure uni- the batch by one person and verified by formity and homogeneity; a second person. (4) Dissolution time and rate; (5) Clarity, completeness, or pH of so- § 211.103 Calculation of yield. lutions. Actual yields and percentages of the- (b) Valid in-process specifications for oretical yield shall be determined at such characteristics shall be consistent the conclusion of each appropriate with drug product final specifications phase of manufacturing, processing, and shall be derived from previous ac- packaging, or holding of the drug prod- ceptable process average and process uct. Such calculations shall be per- variability estimates where possible formed by one person and independ- and determined by the application of ently verified by a second person. suitable statistical procedures where appropriate. Examination and testing § 211.105 Equipment identification. of samples shall assure that the drug (a) All compounding and storage con- product and in-process material containers, processing lines, and major form to specifications. equipment used during the production (c) In-process materials shall be test- of a batch of a drug product shall be ed for identity, strength, quality, and properly identified at all times to indi- purity as appropriate, and approved or cate their contents and, when nec- rejected by the quality control unit, essary, the phase of processing of the during the production process, e.g., at batch. commencement or completion of sig- (b) Major equipment shall be identi- nificant phases or after storage for fied by a distinctive identification long periods. number or code that shall be recorded (d) Rejected in-process materials in the batch production record to show shall be identified and controlled under the specific equipment used in the a quarantine system designed to pre- manufacture of each batch of a drug vent their use in manufacturing or product. In cases where only one of a processing operations for which they particular type of equipment exists in are unsuitable. a manufacturing facility, the name of the equipment may be used in lieu of a § 211.111 Time limitations on produc- distinctive identification number or tion. code. When appropriate, time limits for the § 211.110 Sampling and testing of in- completion of each phase of production process materials and drug prod- shall be established to assure the qual- ucts. ity of the drug product. Deviation from (a) To assure batch uniformity and established time limits may be accept- integrity of drug products, written pro- able if such deviation does not com- cedures shall be established and fol- promise the quality of the drug prod- lowed that describe the in-process con- uct. Such deviation shall be justified trols, and tests, or examinations to be and documented. conducted on appropriate samples of in-process materials of each batch. § 211.113 Control of microbiological contamination. Such control procedures shall be established to monitor the output and to (a) Appropriate written procedures, validate the performance of those man- designed to prevent objectionable ufacturing processes that may be re- microorganisms in drug products not sponsible for causing variability in the required to be sterile, shall be estab- characteristics of in-process material lished and followed. and the drug product. Such control (b) Appropriate written procedures, procedures shall include, but are not designed to prevent microbiological limited to, the following, where appro- contamination of drug products pur- priate: porting to be sterile, shall be estab- (1) Tablet or capsule weight vari- lished and followed. Such procedures ation; shall include validation of any steri- (2) Disintegration time; lization process.

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§ 211.115 Reprocessing. adequately differentiated by size, shape, or color. (a) Written procedures shall be established and followed prescribing a sys- (g) If cut labeling is used, packaging tem for reprocessing batches that do and labeling operations shall include not conform to standards or specifica- one of the following special control tions and the steps to be taken to in- procedures: sure that the reprocessed batches will (1) Dedication of labeling and pack- conform with all established standards, aging lines to each different strength specifications, and characteristics. of each different drug product; (b) Reprocessing shall not be per- (2) Use of appropriate electronic or formed without the review and ap- electromechanical equipment to con- proval of the quality control unit. duct a 100-percent examination for correct 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 usage criteria. tion of finishing operations for hand- 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. (b) Any labeling or packaging mate- [43 FR 45077, Sept. 29, 1978, as amended at 58 rials meeting appropriate written spec- FR 41353, Aug. 3, 1993] ifications may be approved and released for use. Any labeling or pack- § 211.125 Labeling issuance. aging materials that do not meet such (a) Strict control shall be exercised specifications shall be rejected to pre- over labeling issued for use in drug vent their use in operations for which product labeling operations. they are unsuitable. (b) Labeling materials issued for a (c) Records shall be maintained for batch shall be carefully examined for each shipment received of each dif- identity and conformity to the labeling ferent labeling and packaging material specified in the master or batch pro- indicating receipt, examination or duction records. testing, and whether accepted or re- (c) Procedures shall be used to rec- jected. oncile the quantities of labeling issued, (d) Labels and other labeling mate- used, and returned, and shall require rials for each different drug product, evaluation of discrepancies found be- strength, dosage form, or quantity of tween the quantity of drug product fin- contents shall be stored separately ished and the quantity of labeling with suitable identification. Access to issued when such discrepancies are out- the storage area shall be limited to au- side narrow preset limits based on his- thorized personnel. torical operating data. Such discrep- (e) Obsolete and outdated labels, la- ancies shall be investigated in accord- beling, and other packaging materials ance with § 211.192. Labeling reconcili- shall be destroyed. ation is waived for cut or roll labeling (f) Use of gang-printed labeling for if a 100-percent examination for correct different drug products, or different labeling is performed in accordance strengths or net contents of the same with § 211.122(g)(2). drug product, is prohibited unless the (d) All excess labeling bearing lot or labeling from gang-printed sheets is control numbers shall be destroyed.

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(e) Returned labeling shall be main- § 211.132 Tamper-evident packaging tained and stored in a manner to pre- requirements for over-the-counter vent mixups and provide proper identi- (OTC) human drug products. fication. (a) General. The Food and Drug Ad- (f) Procedures shall be written de- ministration has the authority under scribing in sufficient detail the control the Federal Food, Drug, and Cosmetic procedures employed for the issuance of labeling; such written procedures Act (the act) to establish a uniform na- shall be followed. tional requirement for tamper-evident packaging of OTC drug products that [43 FR 45077, Sept. 29, 1978, as amended at 58 will improve the security of OTC drug FR 41354, Aug. 3, 1993] packaging and help assure the safety § 211.130 Packaging and labeling oper- and effectiveness of OTC drug products. ations. 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. (c) Identification of the drug product curred. To reduce the likelihood of suc- with a lot or control number that per- cessful tampering and to increase the mits determination of the history of likelihood that consumers will discover the manufacture and control of the if a product has been tampered with, batch. the package is required to be distinc- (d) Examination of packaging and la- tive by design or by the use of one or beling materials for suitability and more indicators or barriers to entry correctness before packaging oper- that employ an identifying char- ations, and documentation of such ex- acteristic (e.g., a pattern, name, reg- amination in the batch production istered trademark, logo, or picture). record. For purposes of this section, the term (e) Inspection of the packaging and ‘‘distinctive by design’’ means the labeling facilities immediately before packaging cannot be duplicated with use to assure that all drug products commonly available materials or have been removed from previous oper- through commonly available processes. ations. Inspection shall also be made to A tamper-evident package may involve assure that packaging and labeling ma- an immediate-container and closure terials not suitable for subsequent op- system or secondary-container or car- erations have been removed. Results of ton system or any combination of sys- inspection shall be documented in the tems intended to provide a visual indi- batch production records. cation of package integrity. The tam- [43 FR 45077, Sept. 29, 1978, as amended at 58 per-evident feature shall be designed to FR 41354, Aug. 3, 1993] and shall remain intact when handled

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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 (e) OTC drug products subject to ap- feature(s) used, each retail package of proved new drug applications. Holders of an OTC drug product covered by this approved new drug applications for section (except ammonia inhalant in OTC drug products are required under crushable glass ampules, containers of § 314.70 of this chapter to provide the compressed medical oxygen, or aerosol agency with notification of changes in products that depend upon the power of packaging and labeling to comply with a liquefied or compressed gas to expel the requirements of this section. the contents from the container) is re- Changes in packaging and labeling required to bear a statement that: quired by this regulation may be made (i) Identifies all tamper-evident fea- before FDA approval, as provided under ture(s) and any capsule sealing tech- § 314.70(c) of this chapter. Manufac- nologies used to comply with para- turing changes by which capsules are graph (b) of this section; to be sealed require prior FDA approval (ii) Is prominently placed on the under § 314.70(b) of this chapter. package; and (f) Poison Prevention Packaging Act of (iii) Is so placed that it will be unaf- 1970. This section does not affect any fected if the tamper-evident feature of requirements for ‘‘special packaging’’ the package is breached or missing. as defined under § 310.3(l) of this chap- (2) If the tamper-evident feature cho- ter and required under the Poison Pre- sen to meet the requirements in para- vention Packaging Act of 1970. graph (b) of this section uses an identifying 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 exam- [54 FR 5228, Feb. 2, 1989, as amended at 63 FR ple, the labeling statement on a bottle 59470, Nov. 4, 1998] with a shrink band could say ‘‘For your protection, this bottle has an im- § 211.134 Drug product inspection. printed seal around the neck.’’ (a) Packaged and labeled products (d) Request for exemptions from pack- shall be examined during finishing op- aging and labeling requirements. A man- erations to provide assurance that con- ufacturer or packer may request an ex- tainers and packages in the lot have emption from the packaging and label- the correct label. ing requirements of this section. A request 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. envelope as a ‘‘Request for Exemption (c) Results of these examinations from the Tamper-Evident Packaging shall be recorded in the batch produc- Rule.’’ The petition is required to con- tion or control records. tain the following: (1) The name of the drug product or, § 211.137 Expiration dating. if the petition seeks an exemption for a (a) To assure that a drug product drug class, the name of the drug class, meets applicable standards of identity, and a list of products within that class. strength, quality, and purity at the (2) The reasons that the drug prod- time of use, it shall bear an expiration uct’s compliance with the tamper-evi- date determined by appropriate sta- dent packaging or labeling require- bility testing described in § 211.166.

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(b) Expiration dates shall be related tity, strength, quality, and purity of to any storage conditions stated on the the drug products are not affected. labeling, as determined by stability studies described in § 211.166. § 211.150 Distribution procedures. (c) If the drug product is to be recon- Written procedures shall be estab- stituted at the time of dispensing, its lished, and followed, describing the dis- labeling shall bear expiration informa- tribution of drug products. They shall tion for both the reconstituted and include: unreconstituted drug products. (a) A procedure whereby the oldest (d) Expiration dates shall appear on approved stock of a drug product is dis- labeling in accordance with the re- tributed first. Deviation from this requirements of § 201.17 of this chapter. quirement is permitted if such devi- (e) Homeopathic drug products shall ation is temporary and appropriate. be exempt from the requirements of (b) A system by which the distribu- this section. tion of each lot of drug product can be (f) Allergenic extracts that are la- readily determined to facilitate its re- beled ‘‘No U.S. Standard of Potency’’ are exempt from the requirements of call if necessary. this section. (g) New drug products for investiga- Subpart I—Laboratory Controls tional use are exempt from the requirements of this section, provided that § 211.160 General requirements. they meet appropriate standards or (a) The establishment of any speci- specifications as demonstrated by sta- fications, standards, sampling plans, bility studies during their use in clin- test procedures, or other laboratory ical investigations. Where new drug control mechanisms required by this products for investigational use are to subpart, including any change in such be reconstituted at the time of dis- specifications, standards, sampling pensing, their labeling shall bear expi- plans, test procedures, or other labora- ration information for the reconsti- tory control mechanisms, shall be tuted drug product. drafted by the appropriate organiza- (h) Pending consideration of a pro- tional 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 Subpart H—Holding and procedures designed to assure that Distribution components, drug product containers, closures, in-process materials, labeling, § 211.142 Warehousing procedures. and drug products conform to appro- Written procedures describing the priate standards of identity, strength, warehousing of drug products shall be quality, and purity. Laboratory con- established and followed. They shall in- trols shall include: clude: (1) Determination of conformance to (a) Quarantine of drug products be- appropriate written specifications for fore release by the quality control the acceptance of each lot within each unit. shipment of components, drug product (b) Storage of drug products under containers, closures, and labeling used appropriate conditions of temperature, in the manufacture, processing, pack- humidity, and light so that the iden- ing, or holding of drug products. The

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specifications shall include a descrip- (d) Acceptance criteria for the sam- tion of the sampling and testing proce- pling and testing conducted by the dures used. Samples shall be represent- quality control unit shall be adequate ative and adequately identified. Such to assure that batches of drug products procedures shall also require appro- meet each appropriate specification priate retesting of any component, and appropriate statistical quality con- drug product container, or closure that trol criteria as a condition for their ap- is subject to deterioration. proval and release. The statistical (2) Determination of conformance to quality control criteria shall include written specifications and a descrip- appropriate acceptance levels and/or tion of sampling and testing procedures appropriate rejection levels. for in-process materials. Such samples (e) The accuracy, sensitivity, speci- shall be representative and properly ficity, and reproducibility of test identified. methods employed by the firm shall be (3) Determination of conformance to established and documented. Such vali- written descriptions of sampling proce- dation and documentation may be ac- dures and appropriate specifications complished in accordance with for drug products. Such samples shall § 211.194(a)(2). be representative and properly identi- (f) Drug products failing to meet es- fied. tablished standards or specifications (4) The calibration of instruments, and any other relevant quality control apparatus, gauges, and recording de- criteria shall be rejected. Reprocessing vices at suitable intervals in accord- may be performed. Prior to acceptance ance with an established written pro- and use, reprocessed material must gram containing specific directions, meet appropriate standards, specifica- schedules, limits for accuracy and pre- tions, and any other relevant critieria. cision, and provisions for remedial action in the event accuracy and/or preci- § 211.166 Stability testing. sion limits are not met. Instruments, (a) There shall be a written testing apparatus, gauges, and recording de- program designed to assess the sta- vices not meeting established specifica- bility characteristics of drug products. tions shall not be used. 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; pharmaceuticals, such batches may be (4) Testing of the drug product in the released prior to completion of ste- same container-closure system as that rility and/or pyrogen testing, provided in which the drug product is marketed; such testing is completed as soon as (5) Testing of drug products for re- possible. constitution at the time of dispensing (b) There shall be appropriate labora- (as directed in the labeling) as well as tory testing, as necessary, of each after they are reconstituted. batch of drug product required to be (b) An adequate number of batches of free of objectionable microorganisms. each drug product shall be tested to de- (c) Any sampling and testing plans termine an appropriate expiration date shall be described in written proce- and a record of such data shall be dures that shall include the method of maintained. Accelerated studies, com- sampling and the number of units per bined with basic stability information batch to be tested; such written proce- on the components, drug products, and dure shall be followed. container-closure system, may be used

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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. (3) For an active ingredient in an [43 FR 45077, Sept. 29, 1978, as amended at 46 OTC drug product that is exempt from FR 56412, Nov. 17, 1981] bearing an expiration date under § 211.137, the reserve sample shall be re- § 211.167 Special testing requirements. tained for 3 years after distribution of (a) For each batch of drug product the last lot of the drug product con- purporting to be sterile and/or pyrogen- taining the active ingredient. free, there shall be appropriate labora- (b) An appropriately identified re- tory testing to determine conformance serve sample that is representative of to such requirements. The test proce- each lot or batch of drug product shall dures shall be in writing and shall be be retained and stored under conditions followed. consistent with product labeling. The (b) For each batch of ophthalmic reserve sample shall be stored in the ointment, there shall be appropriate same immediate container–closure sys- testing to determine conformance to tem in which the drug product is mar- specifications regarding the presence of keted or in one that has essentially the foreign particles and harsh or abrasive same characteristics. The reserve sam- substances. The test procedures shall ple consists of at least twice the quan- be in writing and shall be followed. tity necessary to perform all the re- (c) For each batch of controlled-required tests, except those for sterility lease dosage form, there shall be appro- and pyrogens. Except for those for drug priate laboratory testing to determine products described in paragraph (b)(2) conformance to the specifications for of this section, reserve samples from the rate of release of each active ingre- representative sample lots or batches dient. The test procedures shall be in selected by acceptable statistical pro- writing and shall be followed. cedures shall be examined visually at

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least once a year for evidence of dete- tecting and Measuring Penicillin Con- rioration unless visual examination tamination in Drugs,’ which is incor- would affect the integrity of the re- porated by reference. Copies are avail- serve sample. Any evidence of reserve able from the Division of Research and sample deterioration shall be inves- Testing (HFD–470), Center for Drug tigated in accordance with § 211.192. Evaluation and Research, Food and The results of the examination shall be Drug Administration, 5100 Paint recorded and maintained with other Branch Pkwy., College Park, MD 20740, stability data on the drug product. Re- or available for inspection at the Office serve samples of compressed medical of the Federal Register, 800 North Cap- gases need not be retained. The reten- itol Street, NW., suite 700, Washington, tion time is as follows: DC 20408. (1) For a drug product other than [43 FR 45077, Sept. 29, 1978, as amended at 47 those described in paragraphs (b) (2) FR 9396, Mar. 5, 1982; 50 FR 8996, Mar. 6, 1985; and (3) of this section, the reserve sam- 55 FR 11577, Mar. 29, 1990; 66 FR 56035, Nov. 6, ple shall be retained for 1 year after 2001] the expiration date of the drug product. Subpart J—Records and Reports (2) For a radioactive drug product, except for nonradioactive reagent kits, § 211.180 General requirements. the reserve sample shall be retained (a) Any production, control, or dis- for: tribution record that is required to be (i) Three months after the expiration maintained in compliance with this date of the drug product if the expira- part and is specifically associated with tion dating period of the drug product a batch of a drug product shall be re- is 30 days or less; or tained for at least 1 year after the expi- (ii) Six months after the expiration ration date of the batch or, in the case date of the drug product if the expira- of certain OTC drug products lacking tion dating period of the drug product expiration dating because they meet is more than 30 days. the criteria for exemption under (3) For an OTC drug product that is § 211.137, 3 years after distribution of exempt for bearing an expiration date the batch. under § 211.137, the reserve sample must (b) Records shall be maintained for be retained for 3 years after the lot or all components, drug product con- batch of drug product is distributed. tainers, closures, and labeling for at [48 FR 13025, Mar. 29, 1983, as amended at 60 least 1 year after the expiration date FR 4091, Jan. 20, 1995] or, in the case of certain OTC drug products lacking expiration dating be- § 211.173 Laboratory animals. cause they meet the criteria for exemp- Animals used in testing components, tion under § 211.137, 3 years after dis- in-process materials, or drug products tribution of the last lot of drug product for compliance with established speci- incorporating the component or using fications shall be maintained and con- the container, closure, or labeling. trolled in a manner that assures their (c) All records required under this suitability for their intended use. They part, or copies of such records, shall be shall be identified, and adequate readily available for authorized inspec- records shall be maintained showing tion during the retention period at the the history of their use. establishment where the activities described in such records occurred. These § 211.176 Penicillin contamination. records or copies thereof shall be sub- If a reasonable possibility exists that ject to photocopying or other means of a non-penicillin drug product has been reproduction as part of such inspec- exposed to cross-contamination with tion. Records that can be immediately penicillin, the non-penicillin drug prod- retrieved from another location by uct shall be tested for the presence of computer or other electronic means penicillin. Such drug product shall not shall be considered as meeting the re- be marketed if detectable levels are quirements of this paragraph. found when tested according to proce- (d) Records required under this part dures specified in ‘Procedures for De- may be retained either as original

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records or as true copies such as photo- tenance, and use shall be part of the copies, microfilm, microfiche, or other batch record. The persons performing accurate reproductions of the original and double-checking the cleaning and records. Where reduction techniques, maintenance shall date and sign or ini- such as microfilming, are used, suit- tial the log indicating that the work able reader and photocopying equip- was performed. Entries in the log shall ment shall be readily available. be in chronological order. (e) Written records required by this part shall be maintained so that data § 211.184 Component, drug product therein can be used for evaluating, at container, closure, and labeling least annually, the quality standards of records. each drug product to determine the These records shall include the fol- need for changes in drug product speci- lowing: fications or manufacturing or control (a) The identity and quantity of each procedures. Written procedures shall be shipment of each lot of components, established and followed for such eval- drug product containers, closures, and uations and shall include provisions labeling; the name of the supplier; the for: supplier’s lot number(s) if known; the (1) A review of a representative num- receiving code as specified in § 211.80; ber of batches, whether approved or re- and the date of receipt. The name and jected, and, where applicable, records location of the prime manufacturer, if associated with the batch. different from the supplier, shall be (2) A review of complaints, recalls, listed if known. returned or salvaged drug products, (b) The results of any test or exam- and investigations conducted under ination performed (including those per- § 211.192 for each drug product. formed as required by § 211.82(a), (f) Procedures shall be established to § 211.84(d), or § 211.122(a)) and the con- assure that the responsible officials of clusions derived therefrom. the firm, if they are not personally in- (c) An individual inventory record of volved in or immediately aware of such each component, drug product con- actions, are notified in writing of any tainer, and closure and, for each com- investigations conducted under ponent, a reconciliation of the use of §§ 211.198, 211.204, or 211.208 of these reg- each lot of such component. The inven- ulations, any recalls, reports of tory record shall contain sufficient in- inspectional observations issued by the formation to allow determination of Food and Drug Administration, or any any batch or lot of drug product associ- regulatory actions relating to good ated with the use of each component, manufacturing practices brought by drug product container, and closure. the Food and Drug Administration. (d) Documentation of the examina- [43 FR 45077, Sept. 29, 1978, as amended at 60 tion and review of labels and labeling FR 4091, Jan. 20, 1995] for conformity with established specifications in accord with §§ 211.122(c) and § 211.182 Equipment cleaning and use 211.130(c). log. (e) The disposition of rejected compo- A written record of major equipment nents, drug product containers, clo- cleaning, maintenance (except routine sure, and labeling. maintenance such as lubrication and adjustments), and use shall be included § 211.186 Master production and con- in individual equipment logs that show trol records. the date, time, product, and lot number (a) To assure uniformity from batch of each batch processed. If equipment to batch, master production and con- is dedicated to manufacture of one trol records for each drug product, in- product, then individual equipment cluding each batch size thereof, shall logs are not required, provided that be prepared, dated, and signed (full sig- lots or batches of such product follow nature, handwritten) by one person and in numerical order and are manufac- independently checked, dated, and tured in numerical sequence. In cases signed by a second person. The prepara- where dedicated equipment is em- tion of master production and control ployed, the records of cleaning, main- records shall be described in a written

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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; (3) A complete list of components (4) Weights and measures of compo- designated by names or codes suffi- nents used in the course of processing; ciently specific to indicate any special (5) In-process and laboratory control quality characteristic; results; (4) An accurate statement of the (6) Inspection of the packaging and weight or measure of each component, labeling area before and after use; using the same weight system (metric, (7) A statement of the actual yield avoirdupois, or apothecary) for each and a statement of the percentage of component. Reasonable variations may theoretical yield at appropriate phases be permitted, however, in the amount of processing; of components necessary for the prepa- (8) Complete labeling control records, ration in the dosage form, provided including specimens or copies of all la- they are justified in the master produc- beling used; tion and control records; (9) Description of drug product con- (5) A statement concerning any cal- tainers and closures; culated excess of component; (10) Any sampling performed; (6) A statement of theoretical weight (11) Identification of the persons per- or measure at appropriate phases of forming and directly supervising or processing; checking each significant step in the (7) A statement of theoretical yield, operation; including the maximum and minimum (12) Any investigation made accord- percentages of theoretical yield beyond ing to § 211.192. which investigation according to (13) Results of examinations made in § 211.192 is required; accordance with § 211.134. (8) A description of the drug product containers, closures, and packaging § 211.192 Production record review. materials, including a specimen or copy of each label and all other label- All drug product production and con- ing signed and dated by the person or trol records, including those for pack- persons responsible for approval of aging and labeling, shall be reviewed such labeling; and approved by the quality control (9) Complete manufacturing and con- unit to determine compliance with all trol instructions, sampling and testing established, approved written proce- procedures, specifications, special no- dures before a batch is released or dis- tations, and precautions to be followed. tributed. Any unexplained discrepancy (including a percentage of theoretical § 211.188 Batch production and control yield exceeding the maximum or min- records. imum percentages established in mas- Batch production and control records ter production and control records) or shall be prepared for each batch of drug the failure of a batch or any of its com- product produced and shall include ponents to meet any of its specifica- complete information relating to the tions shall be thoroughly investigated, production and control of each batch. whether or not the batch has already These records shall include: been distributed. The investigation (a) An accurate reproduction of the shall extend to other batches of the appropriate master production or con- same drug product and other drug

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products that may have been associ- (6) A statement of the results of tests ated with the specific failure or dis- and how the results compare with es- crepancy. A written record of the in- tablished standards of identity, vestigation shall be made and shall in- strength, quality, and purity for the clude the conclusions and followup. component, drug product container, closure, in-process material, or drug § 211.194 Laboratory records. product tested. (a) Laboratory records shall include (7) The initials or signature of the complete data derived from all tests person who performs each test and the necessary to assure compliance with date(s) the tests were performed. established specifications and stand- (8) The initials or signature of a sec- ards, including examinations and as- ond person showing that the original says, as follows: records have been reviewed for accu- (1) A description of the sample re- racy, completeness, and compliance ceived for testing with identification of with established standards. source (that is, location from where (b) Complete records shall be main- sample was obtained), quantity, lot tained of any modification of an estab- number or other distinctive code, date lished method employed in testing. sample was taken, and date sample was Such records shall include the reason received for testing. for the modification and data to verify (2) A statement of each method used that the modification produced results in the testing of the sample. The state- that are at least as accurate and reli- ment shall indicate the location of able for the material being tested as data that establish that the methods the established method. used in the testing of the sample meet (c) Complete records shall be main- proper standards of accuracy and reli- tained of any testing and standardiza- ability as applied to the product tested. tion of laboratory reference standards, (If the method employed is in the cur- reagents, and standard solutions. rent revision of the United States (d) Complete records shall be main- Pharmacopeia, National Formulary, tained of the periodic calibration of Association of Official Analytical laboratory instruments, apparatus, Chemists, Book of Methods,1 or in gauges, and recording devices required other recognized standard references, by § 211.160(b)(4). or is detailed in an approved new drug (e) Complete records shall be main- application and the referenced method tained of all stability testing per- is not modified, a statement indicating formed in accordance with § 211.166. the method and reference will suffice). [43 FR 45077, Sept. 29, 1978, as amended at 55 The suitability of all testing methods FR 11577, Mar. 29, 1990; 65 FR 18889, Apr. 10, used shall be verified under actual con- 2000] ditions of use. (3) A statement of the weight or § 211.196 Distribution records. measure of sample used for each test, Distribution records shall contain where appropriate. the name and strength of the product (4) A complete record of all data se- and description of the dosage form, cured in the course of each test, includ- name and address of the consignee, ing all graphs, charts, and spectra from date and quantity shipped, and lot or laboratory instrumentation, properly control number of the drug product. identified to show the specific compo- For compressed medical gas products, nent, drug product container, closure, distribution records are not required to in-process material, or drug product, contain lot or control numbers. and lot tested. (5) A record of all calculations per- (Approved by the Office of Management and Budget under control number 0910–0139) formed in connection with the test, including units of measure, conversion [49 FR 9865, Mar. 16, 1984] factors, and equivalency factors. § 211.198 Complaint files. 1 Copies may be obtained from: Association (a) Written procedures describing the of Official Analytical Chemists, 2200 Wilson handling of all written and oral com- Blvd., Suite 400, Arlington, VA 22201–3301. plaints regarding a drug product shall

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be established and followed. Such pro- essary and the name of the responsible cedures shall include provisions for re- person making such a determination. view by the quality control unit, of any [43 FR 45077, Sept. 29, 1978, as amended at 51 complaint involving the possible fail- FR 24479, July 3, 1986; 68 FR 15364, Mar. 31, ure of a drug product to meet any of its 2003] specifications and, for such drug products, a determination as to the need for Subpart K—Returned and an investigation in accordance with Salvaged Drug Products § 211.192. Such procedures shall include provisions for review to determine § 211.204 Returned drug products. whether the complaint represents a se- Returned drug products shall be iden- rious and unexpected adverse drug ex- tified as such and held. If the condi- perience which is required to be re- tions under which returned drug prod- ported to the Food and Drug Adminis- ucts have been held, stored, or shipped tration in accordance with §§ 310.305 before or during their return, or if the and 514.80 of this chapter. condition of the drug product, its con- (b) A written record of each com- tainer, carton, or labeling, as a result plaint shall be maintained in a file des- of storage or shipping, casts doubt on ignated for drug product complaints. the safety, identity, strength, quality The file regarding such drug product or purity of the drug product, the re- complaints shall be maintained at the turned drug product shall be destroyed establishment where the drug product unless examination, testing, or other involved was manufactured, processed, investigations prove the drug product or packed, or such file may be main- meets appropriate standards of safety, tained at another facility if the written identity, strength, quality, or purity. A records in such files are readily avail- drug product may be reprocessed pro- able for inspection at that other facil- vided the subsequent drug product ity. Written records involving a drug meets appropriate standards, specifica- product shall be maintained until at tions, and characteristics. Records of least 1 year after the expiration date of returned drug products shall be main- the drug product, or 1 year after the tained and shall include the name and date that the complaint was received, label potency of the drug product dos- whichever is longer. In the case of cer- age form, lot number (or control num- tain OTC drug products lacking expira- ber or batch number), reason for the re- tion dating because they meet the cri- turn, quantity returned, date of dis- teria for exemption under § 211.137, such position, and ultimate disposition of written records shall be maintained for the returned drug product. If the reason for a drug product being returned 3 years after distribution of the drug implicates associated batches, an ap- product. propriate investigation shall be con- (1) The written record shall include ducted in accordance with the require- the following information, where ments of § 211.192. Procedures for the known: the name and strength of the holding, testing, and reprocessing of re- drug product, lot number, name of turned drug products shall be in writ- complainant, nature of complaint, and ing and shall be followed. reply to complainant. (2) Where an investigation under § 211.208 Drug product salvaging. § 211.192 is conducted, the written Drug products that have been sub- record shall include the findings of the jected to improper storage conditions investigation and followup. The record including extremes in temperature, hu- or copy of the record of the investiga- midity, smoke, fumes, pressure, age, or tion shall be maintained at the estab- radiation due to natural disasters, lishment where the investigation oc- fires, accidents, or equipment failures curred in accordance with § 211.180(c). shall not be salvaged and returned to (3) Where an investigation under the marketplace. Whenever there is a § 211.192 is not conducted, the written question whether drug products have record shall include the reason that an been subjected to such conditions, sal- investigation was found not to be nec- vaging operations may be conducted

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only if there is (a) evidence from lab- Adrenal cortex: All drug products containing oratory tests and assays (including ani- adrenal cortex. mal feeding studies where applicable) Azaribine: All drug products containing azaribine. that the drug products meet all appli- Benoxaprofen: All drug products containing cable standards of identity, strength, benoxaprofen. quality, and purity and (b) evidence Bithionol: All drug products containing from inspection of the premises that bithionol. the drug products and their associated Bromfenac sodium: All drug products con- packaging were not subjected to im- taining bromfenac sodium. proper storage conditions as a result of Butamben: All parenteral drug products con- the disaster or accident. Organoleptic taining butamben. Camphorated oil: All drug products con- examinations shall be acceptable only taining camphorated oil. as supplemental evidence that the drug Carbetapentane citrate: All oral gel drug prod- products meet appropriate standards of ucts containing carbetapentane citrate. identity, strength, quality, and purity. Casein, iodinated: All drug products con- Records including name, lot number, taining iodinated casein. and disposition shall be maintained for Chlorhexidine gluconate: All tinctures of drug products subject to this section. chlorhexidine gluconate formulated for use as a patient preoperative skin preparation. Chlormadinone acetate: All drug products con- PART 216—PHARMACY taining chlormadinone acetate. COMPOUNDING Chloroform: All drug products containing chloroform. Cobalt: All drug products containing cobalt Subpart A—General Provisions [Reserved] salts (except radioactive forms of cobalt and its salts and cobalamin and its deriva- Subpart B—Compounded Drug Products tives). Dexfenfluramine hydrochloride: All drug prod- Sec. ucts containing dexfenfluramine hydro- 216.23 [Reserved] chloride. 216.24 Drug products withdrawn or removed Diamthazole dihydrochloride: All drug prod- from the market for reasons of safety or ucts containing diamthazole effectiveness. dihydrochloride. AUTHORITY: 21 U.S.C. 351, 352, 353a, 355, and Dibromsalan: All drug products containing 371. dibromsalan. Diethylstilbestrol: All oral and parenteral drug SOURCE: 64 FR 10944, Mar. 8, 1999, unless products containing 25 milligrams or more otherwise noted. of diethylstilbestrol per unit dose. Dihydrostreptomycin sulfate: All drug products Subpart A—General Provisions containing dihydrostreptomycin sulfate. Dipyrone: All drug products containing [Reserved] dipyrone. Encainide hydrochloride: All drug products Subpart B—Compounded Drug containing encainide hydrochloride. Fenfluramine hydrochloride: All drug products Products containing fenfluramine hydrochloride. Flosequinan: All drug products containing § 216.23 [Reserved] flosequinan. Gelatin: All intravenous drug products con- § 216.24 Drug products withdrawn or taining gelatin. removed from the market for rea- Glycerol, iodinated: All drug products con- sons of safety or effectiveness. taining iodinated glycerol. The following drug products were Gonadotropin, chorionic: All drug products withdrawn or removed from the mar- containing chorionic gonadotropins of ani- ket because such drug products or com- mal origin. Mepazine: All drug products containing ponents of such drug products were mepazine hydrochloride or mepazine ace- found to be unsafe or not effective. The tate. following drug products may not be Metabromsalan: All drug products containing compounded under the exemptions pro- metabromsalan. vided by section 503A(a) of the Federal Methamphetamine hydrochloride: All paren- Food, Drug, and Cosmetic Act: teral drug products containing methamphetamine hydrochloride. Adenosine phosphate: All drug products con- Methapyrilene: All drug products containing taining adenosine phosphate. methapyrilene.

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Methopholine: All drug products containing Zirconium: All aerosol drug products con- methopholine. taining zirconium. Mibefradil dihydrochloride: All drug products Zomepirac sodium: All drug products con- containing mibefradil dihydrochloride. taining zomepirac sodium. Nitrofurazone: All drug products containing nitrofurazone (except topical drug products formulated for dermatalogic application). PART 225—CURRENT GOOD MAN- Nomifensine maleate: All drug products con- UFACTURING PRACTICE FOR taining nomifensine maleate. MEDICATED FEEDS Oxyphenisatin: All drug products containing oxyphenisatin. Subpart A—General Provisions Oxyphenisatin acetate: All drug products containing oxyphenisatin acetate. Sec. Phenacetin: All drug products containing 225.1 Current good manufacturing practice. phenacetin. 225.10 Personnel. Phenformin hydrochloride: All drug products containing phenformin hydrochloride. Subpart B—Construction and Maintenance Pipamazine: All drug products containing of Facilities and Equipment pipamazine. Potassium arsenite: All drug products con- 225.20 Buildings. taining potassium arsenite. 225.30 Equipment. Potassium chloride: All solid oral dosage form 225.35 Use of work areas, equipment, and drug products containing potassium chlo- storage areas for other manufacturing ride that supply 100 milligrams or more of and storage purpose. potassium per dosage unit (except for controlled-release dosage forms and those products formulated for preparation of so- Subpart C—Product Quality Control lution prior to ingestion). 225.42 Components. Povidone: All intravenous drug products con- 225.58 Laboratory controls. taining povidone. 225.65 Equipment cleanout procedures. Reserpine: All oral dosage form drug products containing more than 1 milligram of reser- Subpart D—Packaging and Labeling pine. Sparteine sulfate: All drug products con- 225.80 Labeling. taining sparteine sulfate. Sulfadimethoxine: All drug products con- Subpart E—Records and Reports taining sulfadimethoxine. Sulfathiazole: All drug products containing 225.102 Master record file and production sulfathiazole (except those formulated for records. vaginal use). 225.110 Distribution records. Suprofen: All drug products containing 225.115 Complaint files. suprofen (except ophthalmic solutions). Sweet spirits of nitre: All drug products con- Subpart F—Facilities and Equipment taining sweet spirits of nitre. Temafloxacin hydrochloride: All drug products 225.120 Buildings and grounds. containing temafloxacin. 225.130 Equipment. Terfenadine: All drug products containing 225.135 Work and storage areas. terfenadine. 3,3′,4′,5-tetrachlorosalicylanilide: All drug Subpart G—Product Quality Assurance products containing 3,3′,4′,5-tetrachlorosalicylanilide. 225.142 Components. Tetracycline: All liquid oral drug products 225.158 Laboratory assays. formulated for pediatric use containing 225.165 Equipment cleanout procedures. tetracycline in a concentration greater than 25 milligrams/milliliter. Subpart H—Labeling Ticrynafen: All drug products containing ticrynafen. 225.180 Labeling. Tribromsalan: All drug products containing tribromsalan. Subpart I—Records Trichloroethane: All aerosol drug products intended for inhalation containing trichloro- 225.202 Formula, production, and distribu- ethane. tion records. Urethane: All drug products containing ure- AUTHORITY: 21 U.S.C. 351, 352, 360b, 371, 374. thane. Vinyl chloride: All aerosol drug products con- SOURCE: 41 FR 52618, Nov. 30, 1976, unless taining vinyl chloride. otherwise noted.

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Subpart A—General Provisions § 225.10 Personnel. (a) Qualified personnel and adequate § 225.1 Current good manufacturing personnel training and supervision are practice. essential for the proper formulation, (a) Section 501(a)(2)(B) of the Federal manufacture, and control of medicated Food, Drug, and Cosmetic Act provides feeds. Training and experience leads to that a drug (including a drug contained proper use of equipment, maintenance in a medicated feed) shall be deemed to of accurate records, and detection and be adulterated if the methods used in, prevention of possible deviations from or the facilities or controls used for, its current good manufacturing practices. manufacture, processing, packing, or (b)(1) All employees involved in the holding do not conform to or are not manufacture of medicated feeds shall operated or administered in conformity have an understanding of the manufac- with current good manufacturing prac- turing or control operation(s) which tice to assure that such drug meets the they perform, including the location requirement of the act as to safety and and proper use of equipment. has the identity and strength, and (2) The manufacturer shall provide an meets the quality and purity charac- on-going program of evaluation and su- teristics, which it purports or is rep- pervision of employees in the manufac- resented to possess. ture of medicated feeds. (b)(1) The provisions of this part set forth the criteria for determining [41 FR 52618, Nov. 30, 1976, as amended at 42 whether the manufacture of a medi- FR 12426, Mar. 4, 1977] cated feed is in compliance with current good manufacturing practice. Subpart B—Construction and These regulations shall apply to all Maintenance of Facilities and types of facilities and equipment used Equipment in the production of medicated feeds, and they shall also govern those in- § 225.20 Buildings. stances in which failure to adhere to (a) The location, design, construc- the regulations has caused nonmedi- tion, and physical size of the buildings cated feeds that are manufactured, and other production facilities are fac- processed, packed, or held to be adul- tors important to the manufacture of terated. In such cases, the medicated medicated feed. The features of facili- feed shall be deemed to be adulterated ties necessary for the proper manufac- within the meaning of section ture of medicated feed include provi- 501(a)(2)(B) of the act, and the non- sion for ease of access to structures medicated feed shall be deemed to be and equipment in need of routine main- adulterated within the meaning of sec- tenance; ease of cleaning of equipment tion 402(a)(2)(D) of the act. and work areas; facilities to promote (2) The regulations in §§ 225.10 personnel hygiene; structural condi- through 225.115 apply to facilities man- tions for control and prevention of ufacturing one or more medicated feeds vermin and pest infestation; adequate for which an approved medicated feed space for the orderly receipt and stor- mill license is required. The regula- age of drugs and feed ingredients and tions in §§ 225.120 through 225.202 apply the controlled flow of these materials to facilities manufacturing solely through the processing and manufac- medicated feeds for which an approved turing operations; and the equipment license is not required. for the accurate packaging and deliv- (c) In addition to the recordkeeping ery of a medicated feed of specified la- requirements in this part, Type B and beling and composition. Type C medicated feeds made from (b) The construction and mainte- Type A articles or Type B feeds under nance of buildings in which medicated approved NADA’s and a medicated feed feeds are manufactured, processed, mill license are subject to the require- packaged, labeled, or held shall con- ments of § 510.301 of this chapter. form to the following: [41 FR 52618, Nov. 30, 1976, as amended at 51 (1) The building grounds shall be ade- FR 7389, Mar. 3, 1986; 64 FR 63203, Nov. 19, quately drained and routinely main- 1999] tained so that they are reasonably free

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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 performance of the following medi- products in the same facilities may cated feed manufacturing operations: cause adulteration of feed products (i) The receipt, control, and storage with toxic or otherwise unapproved of components. feed additives. (ii) Component processing. (b) Work areas and equipment used (iii) Medicated feed manufacturing. for the manufacture or storage of medi- (iv) Packaging and labeling. cated feeds or components thereof shall not be used for, and shall be physically (v) Storage of containers, packaging separated from, work areas and equip- materials, labeling and finished prod- ment used for the manufacture of fer- ucts. tilizers, herbicides, insecticides, fun- (vi) Routine maintenance of equip- gicides, rodenticides, and other pes- ment. ticides unless such articles are approved drugs or approved food additives § 225.30 Equipment. intended for use in the manufacture of (a) Equipment which is designed to medicated feed. perform its intended function and is properly installed and used is essential Subpart C—Product Quality to the manufacture of medicated feeds. Such equipment permits production of Control feeds of uniform quality, facilitates § 225.42 Components. cleaning, and minimizes spillage of (a) A medicated feed, in addition to drug components and finished product. providing nutrients, is a vehicle for the (b)(1) All equipment shall possess the administration of a drug, or drugs, to capability to produce a medicated feed animals. To ensure proper safety and of intended potency, safety, and purity. effectiveness, such medicated feeds (2) All equipment shall be maintained must contain the labeled amounts of in a reasonably clean and orderly man- drugs. It is necessary that adequate ner. procedures be established for the re- (3) All equipment, including scales ceipt, storage, and inventory control and liquid metering devices, shall be of for all such drugs to aid in assuring suitable size, design, construction, pre- their identity, strength, quality, and cision, and accuracy for its intended purity when incorporated into prod- purpose. ucts. (4) All scales and metering devices (b) The receipt, storage, and inven- shall be tested for accuracy upon in- tory of drugs, including undiluted drug stallation and at least once a year components, medicated premixes, and thereafter, or more frequently as may semiprocessed (i.e., intermediate pre- be necessary to insure their accuracy. mixes, inplant premixes and con- (5) All equipment shall be so con- centrates) intermediate mixes constructed and maintained as to prevent taining drugs, which are used in the lubricants and coolants from becoming manufacture and processing of medi- unsafe additives in feed components or cated feeds shall conform to the fol- medicated feed. lowing: (6) All equipment shall be designed, (1) Incoming shipments of drugs shall constructed, installed and maintained be visually examined for identity and so as to facilitate inspection and use of damage. Drugs which have been sub- cleanout procedure(s). jected to conditions which may have

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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 identity, strength, quality, and purity premises which are affected by this dis- will be maintained. crepancy shall be detained until the (4) Drugs in the mixing areas shall be discrepancy is reconciled. properly identified, stored, handled, (8) All records required by this sec- and controlled to maintain their integ- tion shall be maintained on the prem- rity and identity. Sufficient space shall ises for at least one year after com- be provided for the location of each plete use of a drug component of a spe- drug. cific lot number or feed manufacturer’s (5) A receipt record shall be prepared shipment identification number. and maintained for each lot of drug received. The receipt record shall accu- § 225.58 Laboratory controls. rately indicate the identity and quan- (a) The periodic assay of medicated tity of the drug, the name of the sup- feeds for drug components provides a plier, the supplier’s lot number or an measure of performance of the manu- identifying number assigned by the facturing process in manufacturing a feed manufacturer upon receipt which uniform product of intended potency. relates to the particular shipment, the (b) The following assay requirements date of receipt, the condition of the shall apply to medicated feeds: drug when received, and the return of (1) For feeds requiring a medicated any damaged drugs. feed mill license (Form FDA 3448) for (6) A daily inventory record for each their manufacture and marketing, at drug used shall be maintained and shall least three representative samples of list by manufacturer’s lot number or medicated feed containing each drug or the feed manufacturer’s shipment iden- drug combination used in the establish- tification number at least the fol- ment shall be collected and assayed by lowing information: approved official methods, at periodic (i) The quantity of drug on hand at intervals during the calendar year, un- the beginning and end of the work day less otherwise specified in this chapter. (the beginning amount being the same At least one of these assays shall be as the previous day’s closing inventory performed on the first batch using the if this amount has been established to drug. If a medicated feed contains a be correct); the quantity shall be deter- combination of drugs, only one of the mined by weighing, counting, or meas- drugs need be subject to analysis each uring, as appropriate. time, provided the one tested is dif- (ii) The amount of each drug used, ferent from the one(s) previously test- sold, or otherwise disposed of. ed. (iii) The batches or production runs (2) [Reserved] of medicated feed in which each drug (c) The originals or copies of all re- was used. sults of assays, including those from (iv) When the drug is used in the State feed control officials and any preparation of a semiprocessed inter- other governmental agency, shall be mediate mix intended for use in the maintained on the premises for a pe- manufacture of medicated feed, any ad- riod of not less than 1 year after dis- ditional information which may be re- tribution of the medicated feed. The required for the purpose of paragraph sults of assays performed by State feed (b)(7) of this section. control officials may be considered to- (v) Action taken to reconcile any dis- ward fulfillment of the periodic assay crepancies in the daily inventory requirements of this section. record. (d) Where the results of assays indi- (7) Drug inventory shall be main- cate that the medicated feed is not in tained of each lot or shipment of drug accord with label specifications or is

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

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

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of manufacture or other suitable iden- Subpart F—Facilities and tification shall appear on the distribu- Equipment tion record or the label issued with each shipment. SOURCE: 51 FR 7390, Mar. 3, 1986, unless oth- (2) The originals or copies of the dis- erwise noted. tribution records shall be retained on the premises for not less than one year § 225.120 Buildings and grounds. after the date of shipment of the medi- Buildings used for production of cated feed. medicated feed shall provide adequate space for equipment, processing, and § 225.115 Complaint files. orderly receipt and storage of medi- (a) Complaints and reports of experi- cated feed. Areas shall include access ences of product defects relative to the for routine maintenance and cleaning drug’s efficacy or safety may provide of equipment. Buildings and grounds an indicator as to whether or not medi- shall be constructed and maintained in cated feeds have been manufactured in a manner to minimize vermin and pest conformity with current good manufac- infestation. turing practices. These complaints and experiences may reveal the existence of § 225.130 Equipment. manufacturing problems not otherwise Equipment shall be capable of pro- detected through the normal quality ducing a medicated feed of intended po- control procedures. Timely and appro- tency and purity, and shall be main- priate follow-up action can serve to tained in a reasonably clean and or- correct a problem and minimize future derly manner. Scales and liquid meter- problems. ing devices shall be accurate and of (b) The medicated feed manufacturer suitable size, design, construction, pre- shall maintain on the premises a file cision, and accuracy for their intended which contains the following informa- purposes. All equipment shall be designed, constructed, installed, and tion: maintained so as to facilitate inspec- (1) The original or copy of a record of tion and use of cleanout procedure(s). each oral and written complaint received relating to the safety and effec- § 225.135 Work and storage areas. tiveness of the product produced. The Work areas and equipment used for record shall include the date of the the production or storage of medicated complaint, the complainant’s name and feeds or components thereof shall not address, name and lot or control num- be used for, and shall be physically sep- ber or date of manufacture of the medi- arated from, work areas and equipment cated feed involved, and the specific de- used for the manufacture and storage tails of the complaint. This record of fertilizers, herbicides, insecticides, shall also include all correspondence fungicides, rodenticides, and other pes- from the complainant and/or memo- ticides unless such articles are ap- randa of conversations with the com- proved for use in the manufacture of plainant, and a description of all inves- animal feed. tigations made by the manufacturer and of the method of disposition of the Subpart G—Product Quality complaint. Assurance (2) For medicated feeds whose manufacture require a medicated feed mill SOURCE: 51 FR 7390, Mar. 3, 1986, unless oth- license (Form FDA 3448), records and erwise noted. reports of clinical and other experience with the drug shall be maintained and § 225.142 Components. reported, under § 510.301 of this chapter. Adequate procedures shall be estab- [41 FR 52618, Nov. 30, 1976, as amended at 51 lished and maintained for the identi- FR 7390, Mar. 3, 1986; 57 FR 6475, Feb. 25, 1992; fication, storage, and inventory control 64 FR 63203, Nov. 19, 1999] (receipt and use) of all Type A medicated articles and Type B medicated

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feeds intended for use in the manufac- ment. The records shall be adequate to ture of medicated feeds to aid in assur- facilitate the recall of specific batches ing the identity, strength, quality, and of medicated feed that have been dis- purity of these drug sources. Packaged tributed. Such records shall be retained Type A medicated articles and Type B on the premises for 1 year following the medicated feeds shall be stored in des- date of last distribution. ignated areas in their original closed (Approved by the Office of Management and containers. Bulk Type A medicated ar- Budget under control number 0910–0152) ticles and bulk Type B medicated feeds shall be identified and stored in a man- [51 FR 7390, Mar. 3, 1986] ner such that their identity, strength, quality, and purity will be maintained. PART 226—CURRENT GOOD MAN- All Type A medicated articles and UFACTURING PRACTICE FOR Type B medicated feeds shall be used in TYPE A MEDICATED ARTICLES accordance with their labeled mixing directions. Subpart A—General Provisions § 225.158 Laboratory assays. Sec. Where the results of laboratory as- 226.1 Current good manufacturing practice. 226.10 Personnel. says of drug components, including assays by State feed control officials, in- Subpart B—Construction and Maintenance dicate that the medicated feed is not in of Facilities and Equipment accord with the permissible limits specified in this chapter, investigation 226.20 Buildings. and corrective action shall be imple- 226.30 Equipment. mented immediately by the firm and Subpart C—Product Quality Control such records shall be maintained on the premises for a period of 1 year. 226.40 Production and control procedures. 226.42 Components. § 225.165 Equipment cleanout proce- 226.58 Laboratory controls. dures. Adequate procedures shall be estab- Subpart D—Packaging and Labeling lished and used for all equipment used 226.80 Packaging and labeling. in the production and distribution of medicated feeds to avoid unsafe con- Subpart E—Records and Reports tamination of medicated and nonmedi- 226.102 Master-formula and batch-produc- cated feeds. tion records. 226.110 Distribution records. Subpart H—Labeling 226.115 Complaint files. AUTHORITY: 21 U.S.C. 351, 352, 360b, 371, 374. § 225.180 Labeling. Labels shall be received, handled, and SOURCE: 40 FR 14031, Mar. 27, 1975, unless otherwise noted. stored in a manner that prevents label mixups and assures that the correct labels are used for the medicated feed. Subpart A—General Provisions All deliveries of medicated feeds, § 226.1 Current good manufacturing whether bagged or in bulk, shall be practice. adequately labeled to assure that the feed can be properly used. (a) The criteria in §§ 226.10 through 226.115, inclusive, shall apply in deter- [51 FR 7390, Mar. 3, 1986] mining whether the methods used in, or the facilities and controls used for Subpart I—Records the manufacture, processing, packing, or holding of a Type A medicated arti- § 225.202 Formula, production, and cle(s) conform to or are operated or ad- distribution records. ministered in conformity with current Records shall be maintained identi- good manufacturing practice to assure fying the formulation, date of mixing, that a Type A medicated article(s) and if not for own use, date of ship- meets the requirements of the act as to

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safety, and has the identity and (2) Manufacturing and processing op- strength, and meets the quality and erations performed on the Type A purity characteristics which it pur- medicated article(s). ports or is represented to possess, as (3) Packaging and labeling oper- required by section 501(a)(2)(B) of the ations. act. The regulations in this part 226 (4) Storage of containers, packaging permit the use of precision, automatic, materials, labeling, and finished prod- mechanical, or electronic equipment in ucts. the production of a Type A medicated (5) Control laboratory operations. article(s) when adequate inspection (b) Provide adequate lighting and and checking procedures or other qual- ventilation, and when necessary for the ity control procedures are used to as- intended production or control pur- sure proper performance. poses, adequate screening, dust and (b) In addition to maintaining temperature controls, to avoid con- records and reports required in this tamination of Type A medicated arti- part, Type A medicated articles requir- cle(s), and to avoid other conditions ing approved NADAs are subject to the unfavorable to the safety, identity, requirements of § 514.80 of this chapter. strength, quality, and purity of the raw [40 FR 14031, Mar. 27, 1975, as amended at 68 materials and Type A medicated arti- FR 15364, Mar. 31, 2003] cle(s) before, during, and after production. § 226.10 Personnel. (c) Provide for adequate washing, The key personnel and any consult- cleaning, toilet, and locker facilities. ants involved in the manufacture and Work areas and equipment used for the control of the Type A medicated arti- production of Type A medicated article(s) shall have a background of ap- cle(s) or for the storage of the compo- propriate education or appropriate ex- nents of Type A medicated article(s) perience or combination thereof for as- shall not be used for the production, suming responsibility to assure that mixing or storage of finished or unfin- the Type A medicated article(s) has the ished insecticides, fungicides, proper labeling and the safety, iden- rodenticides, or other pesticides or tity, strength, quality, and purity that their components unless such mate- it purports to possess. rials are recognized as approved drugs intended for use in animal feeds. Subpart B—Construction and Maintenance of Facilities and § 226.30 Equipment. Equipment Equipment used for the manufacture, processing, packaging, bulk shipment, § 226.20 Buildings. labeling, holding, or control of Type A Buildings in which Type A medicated medicated article(s) or their compo- article(s) are manufactured, processed, nents shall be maintained in a clean packaged, labeled, or held shall be and orderly manner and shall be of maintained in a clear and orderly man- suitable design, size, construction, and ner and shall be of suitable size, con- location to facilitate maintenance and struction and location in relation to operation for its intended purpose. The surroundings to facilitate maintenance equipment shall: and operation for their intended pur- (a) Be so constructed that any sur- pose. The building shall: faces that come into contact with Type (a) Provide adequate space for the or- A medicated article(s) are suitable, in derly placement of equipment and ma- that they are not reactive, additive, or terials used in any of the following op- absorptive to an extent that signifi- erations for which they are employed cantly affects the identity, strength, to minimize risk of mixups between quality, or purity of the Type A medi- different Type A medicated article(s), cated article(s) or its components. their components, packaging, or label- (b) Be so constructed that any sub- ing: stance required for the operation of the (1) The receipt, sampling, control, equipment, such as lubricants, cool- and storage of components. ants, etc., may be employed without

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

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(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 standards of identity, strength, qual- § 226.58 Laboratory controls. ity, and purity at the time of use. Laboratory controls shall include the (e) Adequate provision to check the establishment of adequate specifica- reliability, accuracy, and precision of tions and test procedures to assure any laboratory test procedure used. that the drug components and the Type The official methods in ‘‘Methods of A medicated article(s) conform to ap- Analysis of the Association of Official propriate standards of identity, Analytical Chemists,’’ 1 methods de- strength, quality, and purity. Labora- scribed in an official compendium, and tory controls shall include: any method submitted as a part of a (a) The establishment of master food additive petition or new-drug ap- records containing appropriate speci- plication that has been accepted by the fications and a description of the test Food and Drug Administration shall be procedures used to check them for each regarded as meeting this provision. kind of drug component used in the (f) Provisions for the maintenance of manufacture of Type A medicated arti- the results of any assays, including cle(s). This may consist of the manu- dates and endorsement of analysts. facturer’s or supplier’s statement of Such records shall be retained in the specifications and methods of analyses. possession of the manufacturer and (b) The establishment of specifica- shall be maintained for a period of at tions for Type A medicated article(s) least 2 years after distribution by the and a description of necessary labora- manufacturer of the Type A medicated tory test procedures to check such article(s) has been completed. specifications. [40 FR 14031, Mar. 27, 1975, as amended at 55 (c) Assays which shall be made of FR 11577, Mar. 29, 1990; 55 FR 23703, June 12, representative samples of finished 1990] Type A medicated article(s) in accordance with the following schedule: (1) Each batch of a Type A medicated Subpart D—Packaging and article(s) manufactured from an undi- Labeling luted drug shall be assayed for its drug § 226.80 Packaging and labeling. component(s). (2) In the case of Type A medicated (a) Packaging and labeling oper- article(s) which are manufactured by ations shall be adequately controlled: dilution of Type A medicated article(s) (1) To assure that only those Type A assayed in accordance with paragraph medicated article(s) that have met the (c)(1) of this section, each batch shall specifications established in the mas- be assayed for its drug component(s) ter-formula records shall be distrib- with the first five consecutive batches uted. assaying within the limitations, fol- (2) To prevent mixups during the lowed thereafter by assay of represent- packaging and labeling operations. ative samples of not less than 5 percent (3) To assure that correct labeling is of all batches produced. When any employed for each Type A medicated batch does not assay within limita- article(s). tions, each batch should again be as- (4) To identify Type A medicated ar- sayed until five consecutive batches ticle(s) with lot or control numbers are within limitations. that permit determination of the his- (d) A determination establishing that tory of the manufacture and control of the drug components remain uniformly the batch of Type A medicated arti- dispersed and stable in the Type A cle(s). medicated article(s) under ordinary conditions of shipment, storage, and 1 Copies may be obtained from: Association use. This may consist of a determina- of Official Analytical Chemists, 2200 Wilson tion on a Type A medicated article(s) Blvd., Suite 400, Arlington, VA 22201–3301.

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

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§ 226.115 Complaint files. Subpart A—Drugs Regarded as Records shall be maintained for a pe- Misbranded riod of 2 years of all written or verbal complaints concerning the safety or ef- § 250.11 Thyroid-containing drug preparations intended for treatment of ficacy of each Type A medicated arti- obesity in humans. cle(s). Complaints shall be evaluated by competent and responsible per- (a) Investigation by the Food and sonnel and, where indicated, appro- Drug Administration has revealed that priate action shall be taken. The a large number of drug preparations record shall indicate the evaluation containing thyroid or thyrogenic substances in combination with central and the action. nervous system stimulants, with or without one or more additional drug PART 250—SPECIAL REQUIREMENTS substances such as barbiturates or lax- FOR SPECIFIC HUMAN DRUGS atives, are being marketed for or as adjuncts to the treatment, control, or Subpart A—Drugs Regarded as management of obesity in humans. The Misbranded Commissioner of Food and Drugs finds that the administration of such com- Sec. binations for said purposes is without 250.11 Thyroid-containing drug preparations medical rationale except possibly in intended for treatment of obesity in humans. those relatively uncommon instances 250.12 Stramonium preparations labeled where the condition is directly related with directions for use in self-medication to hypothyroidism and there exists a regarded as misbranded. concurrent need for appetite control (in such instances the safety and effec- Subpart B—New Drug or Prescription Status tiveness of such combinations are not of Specific Drugs generally recognized). In particular, the Commissioner of Food and Drugs 250.100 Amyl nitrite inhalant as a prescrip- finds that neither the consensus of in- tion drug for human use. formed medical opinion nor clinical ex- 250.101 Amphetamine and methamphet- perience justifies any representation amine inhalers regarded as prescription drugs. that such combinations are safe and ef- 250.102 Drug preparations intended for fective in connection with the treat- human use containing certain ‘‘coronary ment, control, or management of obe- vasodilators’’. sity in patients having normal thyroid 250.103–250.104 [Reserved] function. 250.105 Gelsemium-containing preparations (b) Combinations of thyroid or other regarded as prescription drugs. thyrogenic drugs with central nervous 250.106–250.107 [Reserved] system stimulants with or without 250.108 Potassium permanganate prepara- other drug substances when offered for tions as prescription drugs. or as adjuncts to the treatment, control, or management of obesity not re- Subpart C—Requirements for Drugs and lated to hypothyroidism are regarded Foods as misbranded. Such combinations 250.201 Preparations for the treatment of when offered for obesity in humans di- pernicious anemia. rectly attributable to established hypothyroidism are regarded as new Subpart D—Requirements for Drugs and drugs within the meaning of section Cosmetics 201(p) of the Federal Food, Drug, and Cosmetic Act. 250.250 Hexachlorophene, as a component of drug and cosmetic products. § 250.12 Stramonium preparations la- AUTHORITY: 21 U.S.C. 321, 336, 342, 352, 353, beled with directions for use in self- 355, 361(a), 362(a) and (c), 371, 375(b). medication regarded as misbranded. SOURCE: 40 FR 14033, Mar. 27, 1975, unless otherwise noted. (a) Stramonium products for inhalation have been offered for use in the

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

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

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Federal Food, Drug, and Cosmetic Act (1) Potassium permanganate and po- if its label fails to bear in a prominent tassium permanganate tablets intended and conspicuous fashion the statement for human use are drugs subject to sec- ‘‘Rx only.’’ tion 503(b)(1) of the Federal Food, Drug, and Cosmetic Act and should be [40 FR 14033, Mar. 27, 1975, as amended at 67 restricted to prescription sale. Such FR 4906, Feb. 1, 2002] drugs will be regarded as misbranded if §§ 250.106–250.107 [Reserved] at any time prior to dispensing the label fails to bear the statement ‘‘Rx § 250.108 Potassium permanganate only.’’ preparations as prescription drugs. (2) Potassium permanganate labeled for use as a prescription component in (a) There have been a number of re- human drugs under the exemption pro- ports in the medical literature of seri- vided in § 201.120 of this chapter or la- ous injuries to women resulting from beled for manufacturing use under the the misuse of potassium permanganate exemption provided in § 201.122 of this in an effort to induce abortion. Reports chapter will be regarded as misbranded from physicians who have treated such unless the label bears the statement, cases show that the injuries are com- ‘‘Rx only.’’ monly caused by introducing tablets or (3) These drugs will be regarded as crystals of potassium permanganate misbranded when intended for veteri- into the vagina. Experience with these nary use unless the label bears the leg- cases shows that such use of potassium end, ‘‘Caution: Federal law restricts permanganate is not effective in pro- this drug to sale by or on the order of ducing abortion, but that instead the a licensed veterinarian’’; Provided, how- drug produces serious and painful in- ever, That this shall not apply to a drug jury to the walls of the vagina, causing labeled and marketed for veterinary ulcers, massive hemorrhage, and infec- use if such drug contains not more tion. Such dangerous and useless em- than 50 percent of potassium per- ployment of potassium permanganate manganate and includes other ingredi- is apparently encouraged among the ents which make it unsuitable for misinformed by the mistaken idea that human use and unlikely that the arti- the vaginal bleeding caused by the cor- cle would be used in an attempt to in- rosive action of the drug indicates a duce abortion. termination of pregnancy, which it (4) Any preparation of potassium per- does not. manganate intended for over-the- (b) Potassium permanganate is a counter sale for human use internally strong oxidizing agent, a highly caus- or by application to any mucous mem- tic, tissue-destroying chemical, and a branes or for use in the vagina will be poison. There are no circumstances regarded as misbranded under the pro- under which crystals and tablets of po- visions of section 502(f) (1) and (2) and tassium permanganate constitute safe section 502(j) of the act. dosage forms for use in self-medica- (5) Any other preparation of potas- tion. It is the consensus of informed sium permanganate intended for over- medical opinion that the only dosage the-counter sale for human use will be forms of potassium permanganate regarded as misbranded under section known to be safe for use in self-medica- 502(f) (1) and (2) and section 502(j) of the tion are aqueous solutions containing act unless, among other things, all of not more than 0.04 percent potassium the following conditions are met: permanganate. Such solutions are safe (i) It is an aqueous solution con- for use in self-medication only by ex- taining not more than 0.04 percent po- ternal application to the skin. tassium permanganate. (c) In view of the very real poten- (ii) The label and labeling bear, in tiality for harmful effect, and the ac- juxtaposition with adequate directions tual injuries caused by the misuse of for use, clear warning statements des- potassium permanganate, the Food and ignated as ‘‘Warning,’’ and to the ef- Drug Administration believes that in fect: ‘‘Warning—For external use on order adequately to protect the public the skin only. Severe injury may result health: from use internally or as a douche.

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

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

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

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

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

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Subpart B [Reserved] tablished name of each active ingredient. (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 PART 299—DRUGS; OFFICIAL for the drug and the drug is an article NAMES AND ESTABLISHED NAMES recognized in an official compendium, then the official title thereof in such Subpart A—General Provisions compendium; and (3) if neither paragraphs (b) (1) or (2) of this section ap- Sec. plies, then the common or usual name 299.3 Definitions and interpretations. of the drug. 299.4 Established names for drugs. (c) The Food and Drug Administra- 299.5 Drugs; compendial name. tion recognizes the skill and experience AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 358, of the U.S. Adopted Names Council 360b, 371. (USAN) in deriving names for drugs. SOURCE: 40 FR 14041, Mar. 27, 1975, unless The U.S. Adopted Names Council is a otherwise noted. private organization sponsored by the American Medical Association, the Subpart A—General Provisions United States Pharmacopeia, and the American Pharmaceutical Association, § 299.3 Definitions and interpretations. and has been engaged in the assignment of names to drugs since January (a) As used in this part 299, act means 1964. The Council negotiates with man- the Federal Food, Drug, and Cosmetic ufacturing firms in the selection of Act, sections 201–902, 52 Stat. 1040 (21 nonproprietary names for drugs. U.S.C. 321–392), with all amendments (d) The Food and Drug Administra- thereto. tion cooperates with and is represented (b) The definitions and interpreta- on the USAN Council. In addition, the tions contained in section 201 of the act Food and Drug Administration agrees shall be applicable to such terms when with ‘‘Guiding Principles for Coining used in this part 299. U.S. Adopted Names for Drugs,’’ pub- (c) The term official name means, lished in USAN and the USP Dictionary with respect to a drug or ingredient of Drug Names (USAN 1985 ed., 1961–1984 thereof, the name designated in this cumulative list), which is incorporated part 299 under section 508 of the act as by reference. Copies are available from: the official name. U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, § 299.4 Established names for drugs. MD 20852, or are available for inspec- (a) Section 508 of the Federal Food, tion at the Office of the Federal Reg- Drug, and Cosmetic Act (added by the ister, 800 North Capitol Street, NW., Kefauver-Harris Drug Amendments of suite 700, Washington, DC 20408. All ap- 1962; Pub. L. 87–781) authorizes the plicants for new-drug applications and Commissioner of Food and Drugs to sponsors for ‘‘Investigational New Drug designate an official name for any drug Applications’’ (IND’s) are encouraged if he determines that such action is to contact the USAN Council for as- necessary or desirable in the interest of sistance in selection of a simple and usefulness and simplicity. Section useful name for a new chemical entity. 502(e) of the act (as amended by said Approval of a new-drug application Drug Amendments) prescribes that the providing for the use of a new drug sub- labeling of a drug must bear its estab- stance may be delayed if a simple and lished name, if there is one, to the ex- useful nonproprietary name does not clusion of any other nonproprietary exist for the substance and if one is not name (except the applicable systematic proposed in the application that meets chemical name or the chemical for- the above-cited guidelines. Prior use of mula) and, if the drug is fabricated a name in the medical literature or from two or more ingredients, the es- otherwise will not commit the Food

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

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The Director of the Federal Register has approved under 5 U.S.C. 552(a) and 1 CFR Part 51 the incorporation by reference of the following publications. This list contains only those incorporations by reference effective as of the revision date of this volume. Incorporations by reference found within a regulation are effective upon the effective date of that regulation. For more information on incorporation by reference, see the preliminary pages of this volume.

21 CFR (PARTS 200 TO 299) FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES 21 CFR American Plywood Association P.O. Box 11700, Tacoma, WA 98411–0770 APA PRP–108, ‘‘Performance Standards and Policies for Structural- 200.944 Use Panels,’’ June 1988. Form No. E30K, ‘‘APA Design/Construction Guide-Residential and 200.944 Commercial,’’ January 1989. American Society for Testing and Materials 100 Barr Harbor Drive, West Conshohocken, PA 19428-2959, Tele- phone (610) 832-9585, FAX (610) 832-9555 ASTM D–3043–87, ‘‘Standard Methods of Testing Structural Panels 200.944 in Flexure,’’ August 28, 1987. U.S. Department of Commerce National Institute of Standards and Technology, Office of Product Standards, Gaithersburg, MD 20899 Voluntary Product Standard, PS 1–83, ‘‘Construction and Industrial 200.944 Plywood,’’ May 1984. U.S. Pharmacopeial Convention, Inc. 12601 Twinbrook Parkway, Rockville, MD 20852 USAN and the USP Dictionary of Drug Names: ‘‘Guiding Principles 299.4 for Coining U.S. Adopted Names for Drugs’’ (USAN 1985). Note: The following materials are available through the Food and Drug Administration at the addresses indicated. Center for Food Safety and Applied Nutrition (HFS–215), Food and Drug Administration 5100 Paint Branch Parkway, College Park, Maryland 20740 ‘‘Procedures for Detecting and Measuring Penicillin Contamination 211.176 in Drugs’’.

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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) IV Miscellaneous Agencies (Parts 400—500)

Title 2 [Reserved]

Title 3—The President

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

Title 4—Accounts

I General Accounting Office (Parts 1—99)

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 (Part 2100) 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 (Part 3201) XXIII Department of Energy (Part 3301) XXIV Federal Energy Regulatory Commission (Part 3401) XXV Department of the Interior (Part 3501) XXVI Department of Defense (Part 3601)

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XXVIII Department of Justice (Part 3801) 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 (Part 4301) XXXV Office of Personnel Management (Part 4501) XL Interstate Commerce Commission (Part 5001) XLI Commodity Futures Trading Commission (Part 5101) XLII Department of Labor (Part 5201) XLIII National Science Foundation (Part 5301) XLV Department of Health and Human Services (Part 5501) XLVI Postal Rate Commission (Part 5601) XLVII Federal Trade Commission (Part 5701) XLVIII Nuclear Regulatory Commission (Part 5801) L Department of Transportation (Part 6001) LII Export-Import Bank of the United States (Part 6201) LIII Department of Education (Parts 6300—6399) LIV Environmental Protection Agency (Part 6401) LV National Endowment for the Arts (Part 6501) LVI National Endowment for the Humanities (Part 6601) LVII General Services Administration (Part 6701) LVIII Board of Governors of the Federal Reserve System (Part 6801) LIX National Aeronautics and Space Administration (Part 6901) LX United States Postal Service (Part 7001) LXI National Labor Relations Board (Part 7101) LXII Equal Employment Opportunity Commission (Part 7201) LXIII Inter-American Foundation (Part 7301) LXV Department of Housing and Urban Development (Part 7501) LXVI National Archives and Records Administration (Part 7601) LXVII Institute of Museum and Library Services (Part 7701) LXIX Tennessee Valley Authority (Part 7901) LXXI Consumer Product Safety Commission (Part 8101) LXXIII Department of Agriculture (Part 8301) LXXIV Federal Mine Safety and Health Review Commission (Part 8401) LXXVI Federal Retirement Thrift Investment Board (Part 8601) LXXVII Office of Management and Budget (Part 8701)

Title 6—Homeland Security

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

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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) 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, Department of Agriculture (Parts 2900—2999) XXX Office of the Chief Financial Officer, Department of Agriculture (Parts 3000—3099)

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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 Cooperative State Research, Education, and Extension Service, Department of 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)

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)

Title 10—Energy

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

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I Federal Election Commission (Parts 1—9099)

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) 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, Department of Com- merce (Parts 400—499) V Emergency Oil and Gas Guaranteed Loan Board, Department of Commerce (Parts 500—599)

Title 14—Aeronautics and Space

I Federal Aviation Administration, Department of Transportation (Parts 1—199) II Office of the Secretary, Department of Transportation (Aviation Proceedings) (Parts 200—399) III Commercial Space Transportation, Federal Aviation Adminis- tration, Department of Transportation (Parts 400—499) V National Aeronautics and Space Administration (Parts 1200— 1299) VI Air Transportation System Stabilization (Parts 1300—1399)

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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)

Title 17—Commodity and Securities Exchanges

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

Title 18—Conservation of Power and Water Resources

I Federal Energy Regulatory Commission, Department of Energy (Parts 1—399) III Delaware River Basin Commission (Parts 400—499) VI Water Resources Council (Parts 700—799)

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VIII Susquehanna River Basin Commission (Parts 800—899) XIII Tennessee Valley Authority (Parts 1300—1399)

Title 19—Customs Duties

I Bureau of Customs and Border Protection, Department of Home- land 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 Bureau of 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 Employment Standards Administration, 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, Department of Labor (Parts 1000—1099)

Title 21—Food and Drugs

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

Title 22—Foreign Relations

I Department of State (Parts 1—199) II Agency for International Development (Parts 200—299) III Peace Corps (Parts 300—399) IV International Joint Commission, United States and Canada (Parts 400—499) V Broadcasting Board of Governors (Parts 500—599) VII Overseas Private Investment Corporation (Parts 700—799) IX Foreign Service Grievance Board Regulations (Parts 900—999)

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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) 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 Housing Com- missioner, Department of Housing and Urban Development (Parts 200—299) III Government National Mortgage Association, Department of Housing and Urban Development (Parts 300—399) IV Office of Housing and Office of Multifamily Housing Assistance Restructuring, Department of Housing and Urban Develop- ment (Parts 400—499) V Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 500—599) VI Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 600—699) [Reserved] VII Office of the Secretary, Department of Housing and Urban Devel- opment (Housing Assistance Programs and Public and Indian Housing Programs) (Parts 700—799)

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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) XX Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Parts 3200—3899) 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 (Part 1200)

Title 26—Internal Revenue

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)

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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) 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 Minerals Management Service, Department of the Interior (Parts 200—299) III Board of Surface Mining and Reclamation Appeals, Department of the Interior (Parts 300—399) IV Geological Survey, Department of the Interior (Parts 400—499)

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VII Office of Surface Mining Reclamation and Enforcement, Depart- ment of the Interior (Parts 700—999)

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)

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) 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)

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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) XI National Institute for Literacy (Parts 1100—1199) SUBTITLE C—REGULATIONS RELATING TO EDUCATION XII National Council on Disability (Parts 1200—1299)

Title 35—Panama Canal

I Panama Canal Regulations (Parts 1—299)

Title 36—Parks, Forests, and Public Property

I National Park Service, Department of the Interior (Parts 1—199) II Forest Service, Department of Agriculture (Parts 200—299) III Corps of Engineers, Department of the Army (Parts 300—399) IV American Battle Monuments Commission (Parts 400—499) V Smithsonian Institution (Parts 500—599) 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 (Part 1501) XVI Morris K. Udall Scholarship and Excellence in National Environ- mental Policy Foundation (Parts 1600—1699)

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I United States Patent and Trademark Office, Department of Commerce (Parts 1—199) II Copyright Office, Library of Congress (Parts 200—299) 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)

Title 39—Postal Service

I United States Postal Service (Parts 1—999) III Postal Rate 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)

Title 41—Public Contracts and Property Management

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) 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) 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)

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128 Department of Justice (Parts 128–1—128–99) SUBTITLE D—OTHER PROVISIONS RELATING TO PROPERTY MANAGE- MENT [RESERVED] SUBTITLE E—FEDERAL INFORMATION RESOURCES MANAGEMENT REGULATIONS SYSTEM 201 Federal Information Resources Management Regulation (Parts 201–1—201–99) [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 303–70) 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 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—10010)

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

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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) 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) 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)

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III National Telecommunications and Information Administration, Department of Commerce (Parts 300—399)

Title 48—Federal Acquisition Regulations System

1 Federal Acquisition Regulation (Parts 1—99) 2 Department of Defense (Parts 200—299) 3 Department of Health and Human Services (Parts 300—399) 4 Department of Agriculture (Parts 400—499) 5 General Services Administration (Parts 500—599) 6 Department of State (Parts 600—699) 7 United States Agency for International Development (Parts 700—799) 8 Department of Veterans Affairs (Parts 800—899) 9 Department of Energy (Parts 900—999) 10 Department of the Treasury (Parts 1000—1099) 12 Department of Transportation (Parts 1200—1299) 13 Department of Commerce (Parts 1300—1399) 14 Department of the Interior (Parts 1400—1499) 15 Environmental Protection Agency (Parts 1500—1599) 16 Office of Personnel Management, Federal Employees Health Benefits Acquisition Regulation (Parts 1600—1699) 17 Office of Personnel Management (Parts 1700—1799) 18 National Aeronautics and Space Administration (Parts 1800— 1899) 19 Broadcasting Board of Governors (Parts 1900—1999) 20 Nuclear Regulatory Commission (Parts 2000—2099) 21 Office of Personnel Management, Federal Employees Group Life Insurance Federal Acquisition Regulation (Parts 2100—2199) 23 Social Security Administration (Parts 2300—2399) 24 Department of Housing and Urban Development (Parts 2400— 2499) 25 National Science Foundation (Parts 2500—2599) 28 Department of Justice (Parts 2800—2899) 29 Department of Labor (Parts 2900—2999) 30 Department of Homeland Security, Homeland Security Acquisi- tion Regulation (HSAR) (Parts 3000—3099) 34 Department of Education Acquisition Regulation (Parts 3400— 3499) 35 Panama Canal Commission (Parts 3500—3599) 44 Federal Emergency Management Agency (Parts 4400—4499) 51 Department of the Army Acquisition Regulations (Parts 5100— 5199) 52 Department of the Navy Acquisition Regulations (Parts 5200— 5299) 53 Department of the Air Force Federal Acquisition Regulation Supplement (Parts 5300—5399)

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54 Defense Logistics Agency, Department of Defense (Parts 5400— 5499) 57 African Development Foundation (Parts 5700—5799) 61 General Services Administration Board of Contract Appeals (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 Research and Special Programs Administration, Department of Transportation (Parts 100—199) II Federal Railroad Administration, Department of Transportation (Parts 200—299) III Federal Motor Carrier Safety Administration, Department of Transportation (Parts 300—399) IV Coast Guard, Department of Homeland Security (Parts 400—499) V National Highway Traffic Safety Administration, Department of Transportation (Parts 500—599) VI Federal Transit Administration, Department of Transportation (Parts 600—699) VII National Railroad Passenger Corporation (AMTRAK) (Parts 700—799) VIII National Transportation Safety Board (Parts 800—999) X Surface Transportation Board, Department of Transportation (Parts 1000—1399) XI Bureau of Transportation Statistics, Department of Transpor- tation (Parts 1400—1499) XII Transportation Security Administration, Department of Home- land Security (Parts 1500—1599)

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)

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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 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, United States 22, II Federal Acquisition Regulation 48, 7 Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Agriculture Department 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 Cooperative State Research, Education, and Extension 7, XXXIV Service Economic Research Service 7, XXXVII Energy, Office of 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 Natural Resources Conservation Service 7, VI Operations, Office of 7, XXVIII Procurement and Property Management, Office of 7, XXXII Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Secretary of Agriculture, Office of 7, Subtitle A Transportation, Office of 7, XXXIII World Agricultural Outlook Board 7, XXXVIII Air Force Department 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 68 FR Page Page Chapter I—Continued Chapter I—Continued Regulation at 67 FR 5056 eff. date 211.198 Regulation at 67 FR 5056 delayed; interim ...... 49568 withdrawn...... 15355 250.100 (b) amended; eff. 4–2–02 ...... 4906 (a) amended; eff. 6–30–03...... 15364 250.101 (b) amended; eff. 4–2–02 ...... 4906 226.1 Regulation at 67 FR 5056 250.105 Amended; eff. 4–2–02...... 4906 withdrawn...... 15355 250.108 (c)(1) and (2) amended; eff. Existing text designated as (a); 4–2–02 ...... 4906 (b) added; eff. 6–30–03...... 15364 250.201 (d) amended; eff. 4–2–02 ...... 4906 250.250 (c)(1) and (4)(i) amended; 2004 eff. 4–2–02...... 4906 (Regulations published from January 1, 290.1 Added; eff. 4–2–02 ...... 4906 2004, through April 1, 2004) 290.2 Added; eff. 4–2–02 ...... 4907 21 CFR 69 FR 2003 Page Chapter I 21 CFR 68 FR 201 Technical correction...... 1320, 7114 Page Nomenclature change ...... 13717 Chapter I 201.25 Added; eff. 4–26–04 ...... 9170 201 Technical correction...... 12584 201.59 (a)(3) table amended ...... 266 Nomenclature change ...... 24879 Regulation at 69 FR 266 eff. date 201.24 Added ...... 6081 corrected to 1–4–05 ...... 1320 201.122 Corrected; CFR correc- 201.64 Regulation at 61 FR 17806 tion ...... 55822 eff. date confirmed...... 13717 201.314 (h)(1) and (4) revised ...... 18869 (a), (c) and (d) revised; (j) added 201.323 Regulation at 65 FR 4110 ...... 13724 eff. date delayed; (c) introduc- 201.66 (c)(7)(i) revised ...... 13733 tory text revised; (c)(3) amend- 201.70 Added ...... 13733 ed; (d) and (e) redesignated as 201.71 Added ...... 13734 (e) and (f); new (d) added; eff. 7– 201.72 Added ...... 13734 26–04 ...... 32981 203 Technical correction...... 12792 203.3 Regulation at 64 FR 67761 eff. 203.3 (u) Regulation at 64 FR 67757 date delayed in part...... 4912 eff. date delayed to Dec. 1, 203.50 Regulation at 64 FR 67761 2006 ...... 8105 eff. date delayed ...... 4912 203.50 Regulation at 64 FR 67761 207.20 Regulation at 66 FR 5466 eff. eff. date delayed to Dec. 1, date delayed to 1–21–04...... 2690 2006 ...... 8105 Æ

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