Subchapter C—Drugs: General

SUBCHAPTER C—DRUGS: GENERAL

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

Subpart A—General Provisions IMPORTANT

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

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

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

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

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201.116 Drugs having commonly known di- 201.315 Over-the-counter drugs for minor rections. sore throats; suggested warning. 201.117 Inactive ingredients. 201.316 Drugs with thyroid hormone activity 201.119 In vitro diagnostic products. for human use; required warning. 201.120 Prescription chemicals and other 201.317 Digitalis and related cardiotonic prescription components. drugs for human use in oral dosage 201.122 Drugs for processing, repacking, or forms; required warning. manufacturing. 201.319 Water-soluble gums, hydrophilic 201.125 Drugs for use in teaching, law en- gums, and hydrophilic mucilloids (in- forcement, research, and analysis. cluding, but not limited to agar, alginic 201.127 Drugs; expiration of exemptions. acid, calcium polycarbophil, 201.128 Meaning of ‘‘intended uses’’. carboxymethylcellulose sodium, carrageenan, 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 201.150 Drugs; processing, labeling, or re- ingredients; required warnings and direc- packing. tions. 201.161 Carbon dioxide and certain other 201.320 Warning statements for drug prod- gases. ucts containing or manufactured with chlorofluorocarbons or other ozone-de- Subpart F—Labeling Claims for Drugs in pleting substances. 201.322 Over-the-counter drug products con- Drug Efficacy Study taining 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 nutrition. Requirements for Specific Drug Products 201.325 Over-the-counter drugs for vaginal 201.300 Notice to manufacturers, packers, contraceptive and spermicide use con- and distributors of glandular prepara- taining nonoxynol 9 as the active ingre- tions. dient; required warnings and labeling in- 201.301 Notice to manufacturers, packers, formation. and distributors of estrogenic hormone 201.326 Over-the-counter drug products con- preparations. taining internal analgesic/antipyretic ac- 201.302 Notice to manufacturers, packers, tive ingredients; required warnings and and distributors of drugs for internal use other labeling. which contain mineral oil. APPENDIX A TO PART 201—EXAMPLES OF 201.303 Labeling of drug preparations con- GRAPHIC ENHANCEMENTS USED BY FDA taining significant proportions of winter- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, green oil. 355, 358, 360, 360b, 360gg–360ss, 371, 374, 379e; 42 201.304 Tannic acid and barium enema prep- U.S.C. 216, 241, 262, 264. arations. 201.305 Isoproterenol inhalation prepara- SOURCE: 40 FR 13998, Mar. 27, 1975, unless tions (pressurized aerosols, nebulizers, otherwise noted. powders) for human use; warnings. EDITORIAL NOTE: Nomenclature changes to 201.306 Potassium salt preparations in- part 201 appear at 69 FR 13717, Mar. 24, 2004. tended for oral ingestion by man. 201.307 Sodium phosphates; package size limitation, warnings, and directions for Subpart A—General Labeling over-the-counter sale. Provisions 201.308 Ipecac syrup; warnings and directions for use for over-the-counter sale. § 201.1 Drugs; name and place of busi- 201.309 Acetophenetidin (phenacetin)-con- ness of manufacturer, packer, or taining preparations; necessary warning distributor. statement. (a) A drug or drug product (as defined 201.310 Phenindione; labeling of drug prep- in § 320.1 of this chapter) in finished arations intended for use by man. package form is misbranded under sec- 201.311 [Reserved] 201.312 Magnesium sulfate heptahydrate; tion 502 (a) and (b)(1) of the act if its label declaration on drug products. label does not bear conspicuously the 201.313 Estradiol labeling. name and place of business of the man- 201.314 Labeling of drug preparations con- ufacturer, packer, or distributor. This taining salicylates. paragraph does not apply to any drug

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or drug product dispensed in accord- (d) The Food and Drug Administra- ance with section 503(b)(1) of the act. tion finds that it is the common prac- (b) As used in this section, and for tice in the drug industry to contract purposes of section 502 (a) and (b)(1) of out the performance of certain manu- the act, the manufacturer of a drug facturing operations listed in para- product is the person who performs all graph (b) of this section. These oper- of the following operations that are re- ations include: (1) Soft-gelatin encap- quired to produce the product: (1) Mix- sulating, (2) aerosol filling, (3) steri- ing, (2) granulating, (3) milling, (4) lizing by irradiation, (4) lyophilizing, molding, (5) lyophilizing, (6) tableting, and (5) ethylene oxide sterilization. (7) encapsulating, (8) coating, (9) steri- (e) A person performs an operation lizing, and (10) filling sterile, aerosol, listed in paragraph (b) of this section or gaseous drugs into dispensing con- only if the operation is performed, in- tainers. cluding the performance of the appro- (c) If no person performs all of the priate in-process quality control oper- applicable operations listed in para- ations, except laboratory testing of graph (b) of this section, no person may samples taken during processing, as be represented as manufacturer except follows: as follows: (1) By individuals, a majority of (1) If the person performs more than whom are employees of the person and, one half of the applicable operations throughout the performance of the op- listed in paragraph (b) of this section eration, are subject to the person’s di- and acknowledges the contribution of rection and control; other persons who have performed the (2) On premises that are continuously remaining applicable operations by owned or leased by the person and sub- stating on the product label that ‘‘Cer- ject to the person’s direction and contain manufacturing operations have trol; and been performed by other firms.’’; or (3) On equipment that is continu- (2) If the person performs at least one ously owned or leased by the person. As applicable operation listed in para- used in this paragraph, person, when it graph (b) of this section and identifies identifies a corporation, includes a par- by appropriate designation all other ent, subsidiary, or affiliate company persons who have performed the re- where the related companies are under maining applicable operations, e.g., common ownership and control. ‘‘Made by (Person A), Filled by (Person (f) The name of the person rep- B), Sterilized by (Person C)’’; or resented as manufacturer under para- (3) If the person performs at least one graph (b) or (c) of this section must be applicable operation listed in para- the same as either (1) the name of the graph (b) of this section and the person establishment (as defined in § 207.3(b) of is listed along with all other persons this chapter) under which that person who have performed the remaining ap- is registered at the time the labeled plicable operations as ‘‘joint manufac- product is produced or (2) the reg- turers.’’ A list of joint manufacturers istered establishment name of a par- shall be qualified by the phrase ent, subsidiary, or affiliate company ‘‘Jointly Manufactured By where the related companies are under llllll,’’ and the names of all of common ownership and control. In ad- the manufacturers shall be printed to- dition, the name shall meet the re- gether in the same type size and style; quirements of paragraph (g) of this sec- or tion. (4) If the person performs all applica- (g) The requirement for declaration ble operations listed in paragraph (b) of of the name of the manufacturer, pack- this section except for those operations er, or distributor shall be deemed to be listed in paragraph (d) of this section. satisfied, in the case of a corporate per- For purposes of this paragraph, person, son, only by the actual corporate when it identifies a corporation, in- name, except that the corporate name cludes a parent, subsidiary, or affiliate may be the name of a parent, sub- company where the related companies sidiary, or affiliate company where the are under common ownership and con- related companies are under common trol. ownership and control. The corporate

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name may be preceded or followed by applicable mailing code. The street ad- the name of the particular division of dress may be omitted if it is shown in the corporation. ‘‘Company,’’ ‘‘Incor- a current city directory or telephone porated,’’ etc., may be abbreviated or directory. The requirement for inclu- omitted and ‘‘The’’ may be omitted. In sion of the ZIP Code shall apply to con- the case of an individual, partnership, sumer commodity labels developed or or association, the name under which revised after July 1, 1969. In the case of the business is conducted shall be used. nonconsumer packages, the ZIP Code (h)(1) Except as provided in this sec- shall appear either on the label or the tion, no person other than the manu- labeling (including the invoice). facturer, packer, or distributor may be (j) If a person manufactures, packs, identified on the label of a drug or drug or distributes a drug or drug product at product. (2) The appearance on a drug product a place other than the person’s prin- label of a person’s name without quali- cipal place of business, the label may fication is a representation that the state the principal place of business in named person is the sole manufacturer lieu of the actual place where such of the product. That representation is drug or drug product was manufactured false and misleading, and the drug or packed or is to be distributed, unless product is misbranded under section such statement would be misleading. 502(a) of the act, if the person is not (k) Paragraphs (b), (c), (d), (e), and (f) the manufacturer of the product in ac- of this section, do not apply to the la- cordance with this section. beling of drug components. (3) If the names of two or more per- (l) A drug product is misbranded sons appear on the label of a drug or under section 502(a) of the act if its la- drug product, the label may identify beling identifies a person as manufac- which of the persons is to be contacted turer, packer, or distributor, and that for further information about the prod- identification does not meet the re- uct. quirements of this section. (4) If a trademark appears on the (m) This section does not apply to bi- drug or drug product label or appears ological drug products that are subject as a mark directly on the drug product to the requirements of section 351 of (e.g., tablet or capsule), the label may the Public Health Service Act, 42 identify the holder or licensee of the trademark. The label may also state U.S.C. 262. whether the person identified holds the [45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. trademark or is licensee of the trade- 31, 1980, as amended at 48 FR 37620, Aug. 19, mark. 1983] (5) If the distributor is named on the label, the name shall be qualified by § 201.2 Drugs and devices; National one of the following phrases: ‘‘Manu- Drug Code numbers. factured for llllll’’, ‘‘Distributed The National Drug Code (NDC) num- by llllll’’, ‘‘Manufactured by ber is requested but not required to ap- llllll for llllll’’, ‘‘Manu- pear on all drug labels and in all drug factured for lllllby lllll’’, labeling, including the label of any pre- ‘‘Distributor: llllll’’, ‘‘Marketed scription drug container furnished to a by llllll’’. The qualifying phrases consumer. If the NDC number is shown may be abbreviated. on a drug label, it shall be displayed as (6) If the packer is identified on the required in § 207.35(b)(3) of this chapter. label, the name shall be qualified by the phrase ‘‘Packed by llllll’’ or [40 FR 52002, Nov. 7, 1975] ‘‘Packaged by llllll’’. The qualifying phrases may be abbreviated. § 201.5 Drugs; adequate directions for (i) The statement of the place of busi- use. ness shall include the street address, Adequate directions for use means di- city, State, and ZIP Code. For a foreign rections under which the layman can manufacturer, the statement of the use a drug safely and for the purposes place of business shall include the for which it is intended. (Section street address, city, country, and any

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

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

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

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which is not required by or under au- Spanish-language version of this must thority of the act to appear on the be ‘‘Solamente Rx’’. label; (2) The use of label space to give [67 FR 4906, Feb. 1, 2002] greater conspicuousness to any word, § 201.17 Drugs; location of expiration statement, or other information than date. is required by section 502(c) of the act; or When an expiration date of a drug is (3) The use of label space for any rep- required, e.g., expiration dating of drug resentation in a foreign language. products required by § 211.137 of this (c)(1) All words, statements, and chapter, it shall appear on the imme- other information required by or under diate container and also the outer authority of the act to appear on the package, if any, unless it is easily leg- label or labeling shall appear thereon ible through such outer package. How- in the English language: Provided, however, when single-dose containers are ever, That in the case of articles dis- packed in individual cartons, the expi- tributed solely in the Commonwealth ration date may properly appear on the of Puerto Rico or in a Territory where individual carton instead of the imme- the predominant language is one other diate product container. than English, the predominant language may be substituted for English. [43 FR 45076, Sept. 29, 1978] (2) If the label contains any representation in a foreign language, all words, § 201.18 Drugs; significance of control statements, and other information re- numbers. quired by or under authority of the act The lot number on the label of a drug to appear on the label shall appear should be capable of yielding the com- thereon in the foreign language. plete manufacturing history of the (3) If the labeling contains any rep- package. An incorrect lot number may resentation in a foreign language, all be regarded as causing the article to be words, statements, and other informa- misbranded. tion required by or under authority of the act to appear on the label or label- § 201.19 Drugs; use of term ‘‘infant’’. ing shall appear on the labeling in the foreign language. The regulations affecting special dietary foods (§ 105.3(e) of this chapter) de- [41 FR 6908, Feb. 13, 1976] fine an infant as a child not more than 12 months old. Apart from this, the § 201.16 Drugs; Spanish-language version of certain required state- Food and Drug Administration has not ments. established any definition of the term infant. Some question has arisen An increasing number of medications whether, for the purposes of drug label- restricted to prescription use only are being labeled solely in Spanish for dis- ing, an infant means a child up to 1 tribution in the Commonwealth of year of age or a child up to 2 years of Puerto Rico where Spanish is the pre- age. Until the term is more precisely dominant language. Such labeling is defined by legislation or formal regula- authorized under § 201.15(c). One re- tion, where the exact meaning of the quired warning, the wording of which is term is significant, manufacturers fixed by law in the English language, should qualify any reference to ‘‘in- could be translated in various ways, fant’’ to indicate whether it refers to a from literal translation to loose inter- child who is not more than 1 year of pretation. The statutory nature of this age, or a child not more than 2 years of warning requires that the translation age. convey the meaning properly to avoid confusion and dilution of the purpose [40 FR 13998, Mar. 27, 1975, as amended at 42 FR 14091, Mar. 15, 1977; 44 FR 16006, Mar. 16, of the warning. Section 503(b)(4) of the 1979] Federal Food, Drug, and Cosmetic Act requires, at a minimum, that the label bear the statement ‘‘Rx only.’’ The

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

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the new composition and the labeling name of the sulfite, e.g., sodium changes. metabisulfite), a sulfite that may in other products cause allergic-type re- (Approved by the Office of Management and Budget under control number 0910–0242) actions including anaphylactic symptoms or life-threatening or less severe [52 FR 2111, Jan. 20, 1987; 52 FR 12152, April asthmatic episodes in certain suscep- 15, 1987; 53 FR 4135, Feb. 12, 1988] tible persons. The alternatives to using § 201.22 Prescription drugs containing epinephrine in a life-threatening situa- sulfites; required warning state- tion may not be satisfactory. The pres- ments. ence of a sulfite(s) in this product (a) Sulfites are chemical substances should not deter administration of the that are added to certain drug products drug for treatment of serious allergic to inhibit the oxidation of the active or other emergency situations.’’ This drug ingredient. Oxidation of the ac- statement shall appear in the ‘‘Warn- tive drug ingredient may result in in- ings’’ section of the labeling. stability and a loss of potency of the [51 FR 43904, Dec. 5, 1986] drug product. Examples of specific sulfites used to inhibit this oxidation § 201.23 Required pediatric studies. process include sodium bisulfite, so- (a) A manufacturer of a marketed dium metabisulfite, sodium sulfite, po- drug product, including a biological tassium bisulfite, and potassium drug product, that is used in a substan- metabisulfite. Recent studies have tial number of pediatric patients, or demonstrated that sulfites may cause that provides a meaningful therapeutic allergic-type reactions in certain sus- benefit over existing treatments for pe- ceptible persons, especially asthmatics. diatric patients, as defined in The labeling for any prescription drug §§ 314.55(c)(5) and 601.27(c)(5) of this product to which sulfites have been chapter, but whose label does not pro- added as an inactive ingredient, regard- vide adequate information to support less of the amount added, must bear its safe and effective use in pediatric the warning specified in paragraph (b) populations for the approved indica- or (c) of this section. tions may be required to submit an ap- (b) The labeling required by §§ 201.57 plication containing data adequate to and 201.100(d) for prescription drugs for assess whether the drug product is safe human use containing a sulfite, except and effective in pediatric populations. epinephrine for injection when in- The application may be required to tended for use in allergic or other contain adequate evidence to support emergency situations, shall bear the dosage and administration in some or warning statement ‘‘Contains (insert all pediatric subpopulations, including the name of the sulfite, e.g., sodium neonates, infants, children, and adoles- metabisulfite), a sulfite that may cause cents, depending upon the known or ap- allergic-type reactions including propriate use of the drug product in anaphylactic symptoms and life- such subpopulations. The applicant threatening or less severe asthmatic may also be required to develop a pedi- episodes in certain susceptible people. atric formulation for a drug product The overall prevalence of sulfite sensi- that represents a meaningful thera- tivity in the general population is un- peutic benefit over existing therapies known and probably low. Sulfite sensi- for pediatric populations for whom a tivity is seen more frequently in asth- pediatric formulation is necessary, un- matic than in nonasthmatic people.’’ less the manufacturer demonstrates This statement shall appear in the that reasonable attempts to produce a ‘‘Warnings’’ section of the labeling. pediatric formulation have failed. (c) The labeling required by §§ 201.57 (b) The Food and Drug Administra- and 201.100(d) for sulfite-containing epi- tion (FDA) may by order, in the form nephrine for injection for use in aller- of a letter, after notifying the manu- gic emergency situations shall bear the facturer of its intent to require an as- warning statement ‘‘Epinephrine is the sessment of pediatric safety and effec- preferred treatment for serious allergic tiveness of a pediatric formulation, and or other emergency situations even after offering an opportunity for a though this product contains (insert the written response and a meeting, which

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

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should be considered in selecting or modi- (A) Prescription drug samples; fying antibacterial therapy. In the absence (B) Allergenic extracts; of such data, local epidemiology and suscep- (C) Intrauterine contraceptive de- tibility patterns may contribute to the em- vices regulated as drugs; piric selection of therapy. (D) Medical gases; (c) In the ‘‘Precautions’’ section, (E) Radiopharmaceuticals; and under the ‘‘General’’ subsection, the la- (F) Low-density polyethylene form beling must state: fill and seal containers that are not Prescribing (insert name of antibacterial packaged with an overwrap. drug product) in the absence of a proven or (ii) The bar code requirement does strongly suspected bacterial infection or a not apply to prescription drugs sold by prophylactic indication is unlikely to pro- a manufacturer, repacker, relabeler, or vide benefit to the patient and increases the private label distributor directly to pa- risk of the development of drug-resistant tients, but versions of the same drug bacteria. product that are sold to or used in hos- (d) In the ‘‘Precautions’’ section, pitals are subject to the bar code re- under the ‘‘Information for Patients’’ quirements. subsection, the labeling must state: (2) Biological products; and (3) OTC drug products that are dis- Patients should be counseled that antibacterial 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 similar terms), or marketed, promoted, is common to feel better early in the course or sold to hospitals. of therapy, the medication should be taken 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? (1) Each decrease the effectiveness of the immediate drug product described in paragraph (b) treatment and (2) increase the likelihood of this section must have a bar code that bacteria will develop resistance and will that contains, at a minimum, the ap- not be treatable by (insert name of anti- propriate National Drug Code (NDC) bacterial drug product) or other antibacterial number in a linear bar code that meets drugs in the future. European Article Number/Uniform [68 FR 6081, Feb. 6, 2003] Code Council (EAN.UCC) or Health In- dustry Business Communications § 201.25 Bar code label requirements. Council (HIBCC) standards. Addition- (a) Who is subject to these bar code re- ally, the bar code must: quirements? Manufacturers, repackers, (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 (2) The bar code must appear on the or the Public Health Service Act are drug’s label as defined by section 201(k) subject to these bar code requirements of the Federal Food, Drug, and Cos- unless they are exempt from the reg- metic Act. istration and drug listing requirements (d) Can a drug be exempted from the bar in section 510 of the Federal Food, code requirement? (1) On our own initia- Drug, and Cosmetic Act. tive, or in response to a written re- (b) What drugs are subject to these bar quest from a manufacturer, repacker, code requirements? The following drug relabeler or private label distributor, products are subject to the bar code we may exempt a drug product from label requirements: the bar code label requirements set (1) Prescription drug products, how- forth in this section. The exemption re- ever: quest must document why: (i) The bar code requirement does not (i) compliance with the bar code re- apply to the following entities: quirement would adversely affect the

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safety, effectiveness, purity or potency (2) A written request for an exception of the drug or not be technologically or alternative described in paragraph feasible, and the concerns underlying (a) of this section must: the request could not reasonably be ad- (i) Identify the specified lots, dressed by measures such as package batches, or other units of the human redesign or use of overwraps; or drug product that would be subject to (ii) an alternative regulatory pro- the exception or alternative; gram or method of product use renders (ii) Identify the labeling provision(s) the bar code unnecessary for patient listed in paragraph (f) of this section safety. that are the subject of the exception or (2) Requests for an exemption should alternative request; be sent to the Office of New Drugs (iii) Explain why compliance with (HFD-020), Center for Drug Evaluation such labeling provision(s) could ad- and Research, Food and Drug Adminis- versely affect the safety, effectiveness, tration, 5600 Fishers Lane, Rockville, or availability of the specified lots, MD 20857 (requests involving a drug batches, or other units of a human drug product) or to the Office of Compliance product that are or will be held in the and Biologics Quality (HFM-600), Cen- Strategic National Stockpile; ter for Biologics Evaluation and Re- (iv) Describe any proposed safeguards search, Food and Drug Administration, or conditions that will be implemented 1401 Rockville Pike, Rockville, MD so that the labeling of the product in- 20852 (requests involving a biological cludes appropriate information nec- product). essary for the safe and effective use of the product, given the anticipated cir- [69 FR 9170, Feb. 26, 2004] cumstances of use of the product; § 201.26 Exceptions or alternatives to (v) Provide a draft of the proposed la- labeling requirements for human beling of the specified lots, batches, or drug products held by the Strategic other units of the human drug product National Stockpile. subject to the exception or alternative; (a) The appropriate FDA Center Di- and rector may grant an exception or alter- (vi) Provide any other information native to any provision listed in para- requested by the Center Director in graph (f) of this section and not explic- support of the request. itly required by statute, for specified (c) The Center Director must respond lots, batches, or other units of a human in writing to all requests under this drug product, if the Center Director de- section. termines that compliance with such la- (d) A grant of an exception or alter- beling requirement could adversely af- native under this section will include fect the safety, effectiveness, or avail- any safeguards or conditions deemed ability of such product that is or will appropriate by the Center Director so be included in the Strategic National that the labeling of product subject to Stockpile. the exception or alternative includes (b)(1)(i) A Strategic National Stock- the information necessary for the safe pile official or any entity that manu- and effective use of the product, given factures (including labeling, packing, the anticipated circumstances of use. relabeling, or repackaging), distrib- (e) If you are a sponsor receiving a utes, or stores a human drug product grant of a request for an exception or that is or will be included in the Stra- alternative to the labeling require- tegic National Stockpile may submit, ments under this section: with written concurrence from a Stra- (1) You need not submit a supplement tegic National Stockpile official, a under § 314.70(a) through (c) or written request for an exception or al- § 601.12(f)(1) through (f)(2) of this chap- ternative described in paragraph (a) of ter; however, this section to the Center Director. (2) You must report any grant of a re- (ii) The Center Director may grant quest for an exception or alternative an exception or alternative described under this section as part of your an- in paragraph (a) of this section on his nual report under §§ 314.70(d) or or her own initiative. 601.12(f)(3) of this chapter.

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

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

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

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

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(a) Highlights of prescribing informa- ing changes that have been approved tion. The following information must by FDA or authorized under appear in all prescription drug label- § 314.70(c)(6) or (d)(2), or § 601.12(f)(1) ing: through (f)(3) of this chapter. The head- (1) Highlights limitation statement. The ing(s) and, if appropriate, the sub- verbatim statement ‘‘These highlights heading(s) of the labeling section(s) af- do not include all the information fected by the change must be listed to- needed to use (insert name of drug prod- gether with each section’s identifying uct) safely and effectively. See full pre- number and the date (month/year) on scribing information for (insert name which the change was incorporated in of drug product).’’ labeling. These labeling sections must (2) Drug names, dosage form, route of be listed in the order in which they ap- administration, and controlled substance pear in the full prescribing informa- symbol. The proprietary name and the established name of the drug, if any, as tion. A changed section must be listed defined in section 502(e)(3) of the Fed- under this heading in Highlights for at eral Food, Drug, and Cosmetic Act (the least 1 year after the date of the label- act) or, for biological products, the ing change and must be removed at the proper name (as defined in § 600.3 of this first printing subsequent to the 1 year chapter) including any appropriate period. descriptors. This information must be (6) Indications and usage. A concise followed by the drug’s dosage form and statement of each of the product’s indi- route of administration. For controlled cations, as required under paragraph substances, the controlled substance (c)(2) of this section, with any appro- symbol designating the schedule in priate subheadings. Major limitations which the controlled substance is listed of use (e.g., lack of effect in particular must be included as required by subsets of the population, or second § 1302.04 of this chapter. line therapy status) must be briefly (3) Initial U.S. approval. The verbatim noted. If the product is a member of an statement ‘‘Initial U.S. Approval’’ fol- established pharmacologic class, the lowed by the four-digit year in which concise statement under this heading FDA initially approved a new molec- in Highlights must identify the class in ular entity, new biological product, or the following manner: ‘‘(Drug) is a new combination of active ingredients. (name of class) indicated for (indica- The statement must be placed on the tion(s)).’’ line immediately beneath the established name or, for biological products, (7) Dosage and administration. A con- proper name of the product. cise summary of the information re- (4) Boxed warning. A concise sum- quired under paragraph (c)(3) of this mary of any boxed warning required by section, with any appropriate subparagraph (c)(1) of this section, not to headings, including the recommended exceed a length of 20 lines. The sum- dosage regimen, starting dose, dose mary must be preceded by a heading, in range, critical differences among popu- upper-case letters, containing the word lation subsets, monitoring rec- ‘‘WARNING’’ and other words that are ommendations, and other clinically appropriate to identify the subject of significant clinical pharmacologic in- the warning. The heading and the sum- formation. mary must be contained within a box (8) Dosage forms and strengths. A con- and bolded. The following verbatim cise summary of the information re- statement must be placed immediately quired under paragraph (c)(4) of this following the heading of the boxed section, with any appropriate sub- warning: ‘‘See full prescribing informa- headings (e.g., tablets, capsules, tion for complete boxed warning.’’ injectable, suspension), including the (5) Recent major changes. A list of the strength or potency of the dosage form section(s) of the full prescribing infor- in metric system (e.g., 10-milligram mation, limited to the labeling sec- tablets) and whether the product is tions described in paragraphs (c)(1), scored. (c)(2), (c)(3), (c)(5), and (c)(6) of this section, that contain(s) substantive label-

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

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

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

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

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

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

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

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

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hazard must be stated in the ‘‘Contra- ‘‘Geriatric use’’ subsection and must indications’’ or ‘‘Warnings and Pre- reflect all information available to the cautions’’ section and this subsection sponsor that is relevant to the appro- must refer to it. priate use of the drug in elderly pa- (G) If the sponsor believes that none tients. This information includes de- of the statements described in para- tailed results from controlled studies graphs (c)(9)(iv)(B) through (c)(9)(iv)(F) that are available to the sponsor and of this section are appropriate or rel- pertinent information from well-docu- evant to the labeling of a particular mented studies obtained from a lit- drug, the sponsor must provide reasons erature search. Controlled studies infor omission of the statements and clude those that are part of the mar- may propose alternative statement(s). keting application and other relevant FDA may permit use of an alternative studies available to the sponsor that statement if FDA determines that no have not been previously submitted in statement described in those para- the investigational new drug applica- graphs is appropriate or relevant to the tion, new drug application, biologics li- drug’s labeling and that the alternative cense application, or a supplement or statement is accurate and appropriate. amendment to one of these applica- (H) If the drug product contains one tions (e.g., postmarketing studies or or more inactive ingredients that adverse drug reaction reports). The present an increased risk of toxic ef- ‘‘Geriatric use’’ subsection must con- fects to neonates or other pediatric tain the following statement(s) or rea- subgroups, a special note of this risk sonable alternative, as applicable, tak- must be made, generally in the ‘‘Con- ing into account available information: traindications’’ or ‘‘Warnings and Pre- (1) If clinical studies did not include cautions’’ section. sufficient numbers of subjects aged 65 (v) 8.5 Geriatric use. (A) A specific and over to determine whether elderly geriatric indication, if any, that is sup- subjects respond differently from ported by adequate and well-controlled younger subjects, and other reported studies in the geriatric population clinical experience has not identified must be described under the ‘‘Indica- such differences, the ‘‘Geriatric use’’ tions and Usage’’ section, and appro- subsection must include the following priate geriatric dosage must be stated statement: under the ‘‘Dosage and Administra- Clinical studies of (name of drug) did tion’’ section. The ‘‘Geriatric use’’ sub- not include sufficient numbers of subsection must cite any limitations on jects aged 65 and over to determine the geriatric indication, need for spe- whether they respond differently from cific monitoring, specific hazards asso- younger subjects. Other reported clin- ciated with the geriatric indication, ical experience has not identified dif- and other information related to the ferences in responses between the el- safe and effective use of the drug in the derly and younger patients. In general, geriatric population. Unless otherwise dose selection for an elderly patient noted, information contained in the should be cautious, usually starting at ‘‘Geriatric use’’ subsection must per- the low end of the dosing range, retain to use of the drug in persons 65 flecting the greater frequency of de- years of age and older. Data summa- creased hepatic, renal, or cardiac func- rized in this subsection must be dis- tion, and of concomitant disease or cussed in more detail, if appropriate, other drug therapy. under ‘‘Clinical Pharmacology’’ or the (2) If clinical studies (including stud- ‘‘Clinical Studies’’ section. As appro- ies that are part of marketing applica- priate, this information must also be tions and other relevant studies avail- contained in the ‘‘Warnings and Pre- able to the sponsor that have not been cautions’’ and/or ‘‘Contraindications’’ submitted in the sponsor’s applica- section(s). tions) included enough elderly subjects (B) Specific statements on geriatric to make it likely that differences in use of the drug for an indication ap- safety or effectiveness between elderly proved for adults generally, as distin- and younger subjects would have been guished from a specific geriatric indi- detected, but no such differences (in cation, must be contained in the safety or effectiveness) were observed,

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and other reported clinical experience atric use’’ subsection, or, if appro- has not identified such differences, the priate, the hazard must be stated in ‘‘Geriatric use’’ subsection must con- the ‘‘Contraindications’’ or ‘‘Warnings tain the following statement: and Precautions’’ section, and the Of the total number of subjects in clinical ‘‘Geriatric use’’ subsection must refer studies of (name of drug), ll percent were 65 to those sections. and over, while ll percent were 75 and over. (E) Labeling under paragraphs (Alternatively, the labeling may state the (c)(9)(v)(A) through (c)(9)(v)(C) of this total number of subjects included in the section may include statements, if studies who were 65 and over and 75 and they are necessary for safe and effec- over.) No overall differences in safety or effectiveness were observed between these sub- tive use of the drug, and reflect good jects and younger subjects, and other re- clinical practice or past experience in a ported clinical experience has not identified particular situation, e.g., for a sedating differences in responses between the elderly drug, it could be stated that: and younger patients, but greater sensitivity Sedating drugs may cause confusion and of some older individuals cannot be ruled over-sedation in the elderly; elderly patients out. generally should be started on low doses of (3) If evidence from clinical studies (name of drug) and observed closely. and other reported clinical experience (F) If the sponsor believes that none available to the sponsor indicates that of the requirements described in para- use of the drug in elderly patients is graphs (c)(9)(v)(A) through (c)(9)(v)(E) associated with differences in safety or of this section are appropriate or rel- effectiveness, or requires specific moni- evant to the labeling of a particular toring or dosage adjustment, the drug, the sponsor must provide reasons ‘‘Geriatric use’’ subsection must con- for omission of the statements and tain a brief description of observed dif- may propose an alternative statement. ferences or specific monitoring or dos- FDA may permit omission of the state- age requirements and, as appropriate, ments if FDA determines that no state- must refer to more detailed discussions ment described in those paragraphs is in the ‘‘Contraindications,’’ ‘‘Warnings appropriate or relevant to the drug’s and Precautions,’’ ‘‘Dosage and Admin- labeling. FDA may permit use of an al- istration,’’ or other sections. ternative statement if the agency de- (C)(1) If specific pharmacokinetic or termines that such statement is accu- pharmacodynamic studies have been rate and appropriate. carried out in the elderly, they must be (vi) Additional subsections. Additional subsections may be included, as appro- described briefly in the ‘‘Geriatric use’’ priate, if sufficient data are available subsection and in detail under the concerning the use of the drug in other ‘‘Clinical Pharmacology’’ section. The specified subpopulations (e.g., renal or ‘‘Clinical Pharmacology’’ and ‘‘Drug hepatic impairment). Interactions’’ sections ordinarily con- (10) 9 Drug abuse and dependence. This tain information on drug/disease and section must contain the following in- drug/drug interactions that is particu- formation, as appropriate: larly relevant to the elderly, who are (i) 9.1 Controlled substance. If the drug more likely to have concomitant ill- is controlled by the Drug Enforcement ness and to use concomitant drugs. Administration, the schedule in which (2) If a drug is known to be substan- it is controlled must be stated. tially excreted by the kidney, the (ii) 9.2 Abuse. This subsection must ‘‘Geriatric use’’ subsection must in- state the types of abuse that can occur clude the statement: with the drug and the adverse reac- This drug is known to be substantially ex- tions pertinent to them, and must creted by the kidney, and the risk of adverse identify particularly susceptible pa- reactions to this drug may be greater in patients with impaired renal function. Because tient populations. This subsection elderly patients are more likely to have de- must be based primarily on human creased renal function, care should be taken data and human experience, but perti- in dose selection, and it may be useful to nent animal data may also be used. monitor renal function. (iii) 9.3 Dependence. This subsection (D) If use of the drug in the elderly must describe characteristic effects re- appears to cause a specific hazard, the sulting from both psychological and hazard must be described in the ‘‘Geri- physical dependence that occur with

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the drug and must identify the quan- name (as defined in § 600.3 of this chap- tity of the drug over a period of time ter) and any appropriate descriptors; that may lead to tolerance or depend- (B) The type of dosage form(s) and ence, or both. Details must be provided the route(s) of administration to which on the adverse effects of chronic abuse the labeling applies; and the effects of abrupt withdrawal. (C) The same qualitative and/or quan- Procedures necessary to diagnose the titative ingredient information as re- dependent state and the principles of quired under § 201.100(b) for drug labels treating the effects of abrupt with- or §§ 610.60 and 610.61 of this chapter for drawal must be described. biological product labels; (11) 10 Overdosage. This section must (D) If the product is sterile, a state- be based on human data. If human data ment of that fact; are unavailable, appropriate animal (E) The pharmacological or thera- and in vitro data may be used. The fol- peutic class of the drug; lowing specific information must be (F) For drug products other than bio- provided: logical products, the chemical name (i) Signs, symptoms, and laboratory and structural formula of the drug; and findings associated with an overdosage (G) If the product is radioactive, a of the drug; statement of the important nuclear (ii) Complications that can occur physical characteristics, such as the principal radiation emission data, ex- with the drug (for example, organ tox- ternal radiation, and physical decay icity or delayed acidosis); characteristics. (iii) Concentrations of the drug in (ii) If appropriate, other important biologic fluids associated with toxicity chemical or physical information, such or death; physiologic variables influ- as physical constants or pH, must be encing excretion of the drug, such as stated. urine pH; and factors that influence (13) 12 Clinical pharmacology. (i) This the dose response relationship of the section must contain information re- drug, such as tolerance. The pharmaco- lating to the human clinical pharma- kinetic data given in the ‘‘Clinical cology and actions of the drug in hu- Pharmacology’’ section also may be mans. Pharmacologic information referenced here, if applicable to based on in vitro data using human overdoses; biomaterials or pharmacologic animal (iv) The amount of the drug in a sin- models, or relevant details about in gle dose that is ordinarily associated vivo study designs or results (e.g., drug with symptoms of overdosage and the interaction studies), may be included amount of the drug in a single dose in this section if essential to under- that is likely to be life threatening; stand dosing or drug interaction infor- (v) Whether the drug is dialyzable; mation presented in other sections of and the labeling. This section must include (vi) Recommended general treatment the following subsections: procedures and specific measures for (A) 12.1 Mechanism of action. This sub- support of vital functions (e.g., proven section must summarize what is known antidotes, gastric lavage, forced diure- about the established mechanism(s) of sis, or as per Poison Control Center). the drug’s action in humans at various Such recommendations must be based levels (e.g., receptor, membrane, tis- on data available for the specific drug sue, organ, whole body). If the mecha- or experience with pharmacologically nism of action is not known, this sub- related drugs. Unqualified rec- section must contain a statement ommendations for which data are lack- about the lack of information. ing for the specific drug or class of (B) 12.2 Pharmacodynamics. This sub- drugs must not be stated. section must include a description of (12) 11 Description. (i) This section any biochemical or physiologic phar- must contain: macologic effects of the drug or active (A) The proprietary name and the es- metabolites related to the drug’s clin- tablished name, if any, as defined in ical effect in preventing, diagnosing, section 502(e)(2) of the act, of the drug mitigating, curing, or treating disease, or, for biological products, the proper or those related to adverse effects or

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toxicity. Exposure-response relation- peated in this subsection, but the loca- ships (e.g., concentration-response, tion of such recommendations must be dose-response) and time course of referenced. pharmacodynamic response (including (ii) Data that demonstrate activity short-term clinical response) must be or effectiveness in in vitro or animal included if known. If this information tests and that have not been shown by is unknown, this subsection must con- adequate and well-controlled clinical tain a statement about the lack of in- studies to be pertinent to clinical use formation. Detailed dosing or moni- may be included under this section toring recommendations based on only under the following cir- pharmacodynamic information that cumstances: appear in other sections (e.g., ‘‘Warn- (A) In vitro data for anti-infective ings and Precautions’’ or ‘‘Dosage and drugs may be included if the data are Administration’’) must not be repeated immediately preceded by the state- in this subsection, but the location of ment ‘‘The following in vitro data are such recommendations must be ref- available but their clinical significance erenced. is unknown.’’ (C) 12.3 Pharmacokinetics. This sub- (B) For other classes of drugs, in section must describe the clinically vitro and animal data that have not significant pharmacokinetics of a drug been shown by adequate and well-con- or active metabolites, (i.e., pertinent trolled studies, as defined in § 314.126(b) absorption, distribution, metabolism, of this chapter, to be necessary for the and excretion parameters). Informa- safe and effective use may be included tion regarding bioavailability, the ef- in this section only if a waiver is fect of food, minimum concentration granted under § 201.58 or § 314.126(c) of (Cmin), maximum concentration (Cmax), this chapter. time to maximum concentration (Tmax), (14) 13 Nonclinical toxicology. This sec- area under the curve (AUC), pertinent tion must contain the following sub- half-lives (t1/2), time to reach steady sections as appropriate: state, extent of accumulation, route(s) (i) 13.1 Carcinogenesis, mutagenesis, im- of elimination, clearance (renal, he- pairment of fertility. This subsection patic, total), mechanisms of clearance must state whether long term studies (e.g., specific enzyme systems), drug/ in animals have been performed to drug and drug/food (e.g., dietary sup- evaluate carcinogenic potential and, if plements, grapefruit juice) pharmaco- so, the species and results. If results kinetic interactions (including inhibi- from reproduction studies or other tion, induction, and genetic character- data in animals raise concern about istics), and volume of distribution (Vd) mutagenesis or impairment of fertility must be presented if clinically signifi- in either males or females, this must cant. Information regarding nonlin- be described. Any precautionary state- earity in pharmacokinetic parameters, ment on these topics must include changes in pharmacokinetics over practical, relevant advice to the pre- time, and binding (plasma protein, scriber on the significance of these ani- erythrocyte) parameters must also be mal findings. Human data suggesting presented if clinically significant. This that the drug may be carcinogenic or section must also include the results of mutagenic, or suggesting that it im- pharmacokinetic studies (e.g., of me- pairs fertility, as described in the tabolism or interaction) that establish ‘‘Warnings and Precautions’’ section, the absence of an effect, including per- must not be included in this subsection tinent human studies and in vitro data. of the labeling. Dosing recommendations based on (ii) 13.2 Animal toxicology and/or phar- clinically significant factors that macology. Significant animal data nec- change the product’s pharmacokinetics essary for safe and effective use of the (e.g., age, gender, race, hepatic or renal drug in humans that is not incor- dysfunction, concomitant therapy) porated in other sections of labeling that appear in other sections (e.g., must be included in this section (e.g., ‘‘Warnings and Precautions,’’ ‘‘Dosage specifics about studies used to support and Administration’’ or ‘‘Use in Spe- approval under § 314.600 or § 601.90 of cific Populations’’) must not be re- this chapter, the absence of chronic

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animal toxicity data for a drug that is mation on the available dosage forms administered over prolonged periods or to which the labeling applies and for is implanted in the body). which the manufacturer or distributor (15) 14 Clinical studies. This section is responsible. The information must must discuss those clinical studies that include, as appropriate: facilitate an understanding of how to (i) The strength or potency of the use the drug safely and effectively. Or- dosage form in metric system (e.g., 10 dinarily, this section will describe the milligram tablets) and, if the apothe- studies that support effectiveness for cary system is used, a statement of the the labeled indication(s), including dis- strength in parentheses after the met- cussion of study design, population, ric designation; endpoints, and results, but must not in- (ii) The units in which the dosage clude an encyclopedic listing of all, or form is ordinarily available for pre- even most, studies performed as part of scribing by practitioners (e.g., bottles the product’s clinical development pro- of 100); gram. If a specific important clinical (iii) Appropriate information to fa- study is mentioned in any section of cilitate identification of the dosage the labeling required under §§ 201.56 and forms, such as shape, color, coating, 201.57 because the study is essential to scoring, imprinting, and National Drug an understandable presentation of the Code number; and information in that section of the la- (iv) Special handling and storage beling, any detailed discussion of the conditions. study must appear in this section. (18) 17 Patient counseling information. (i) For drug products other than bio- This section must contain information logical products, any clinical study necessary for patients to use the drug that is discussed in prescription drug safely and effectively (e.g., precautions labeling that relates to an indication concerning driving or the concomitant for or use of the drug must be adequate use of other substances that may have and well-controlled as described in harmful additive effects). Any FDA-ap- § 314.126(b) of this chapter and must not proved patient labeling must be ref- imply or suggest indications or uses or erenced in this section and the full text dosing regimens not stated in the ‘‘In- of such patient labeling must be re- dications and Usage’’ or ‘‘Dosage and printed immediately following this sec- Administration’’ section. For biologi- tion or, alternatively, accompany the cal products, any clinical study that is prescription drug labeling. Any FDA- discussed that relates to an indication approved patient labeling printed im- for or use of the biological product mediately following this section or ac- must constitute or contribute to sub- companying the labeling is subject to stantial evidence and must not imply the type size requirements in para- or suggest indications or uses or dosing graph (d)(6) of this section, except for a regimens not stated in the ‘‘Indications Medication Guide to be detached and and Usage’’ or ‘‘Dosage and Adminis- distributed to patients in compliance tration’’ section. with § 208.24 of this chapter. Medication (ii) Any discussion of a clinical study Guides for distribution to patients are that relates to a risk from the use of subject to the type size requirements the drug must also refer to the other set forth in § 208.20 of this chapter. sections of the labeling where the risk (d) Format requirements. All labeling is identified or discussed. information required under paragraphs (16) 15 References. When prescription (a), (b), and (c) of this section must be drug labeling must summarize or oth- printed in accordance with the fol- erwise rely on a recommendation by an lowing specifications: authoritative scientific body, or on a (1) All headings and subheadings re- standardized methodology, scale, or quired by paragraphs (a) and (c) of this technique, because the information is section must be highlighted by bold important to prescribing decisions, the type that prominently distinguishes labeling may include a reference to the the headings and subheadings from source of the information. other labeling information. Reverse (17) 16 How supplied/storage and han- type is not permitted as a form of high- dling. This section must contain infor- lighting.

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

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(a) In the case of a rectangular pack- algesic,’’ ‘‘decongestant,’’ ‘‘antihis- age where one entire side properly can taminic,’’ etc. The indications for use be considered to be the principal dis- shall be included in the directions for play panel side, the product of the use of the drug, as required by section height times the width of that side; 502(f)(1) of the act and by the regula- (b) In the case of a cylindrical or tions in this part. nearly cylindrical container, 40 percent (c) The statement of identity shall be of the product of the height of the con- presented in bold face type on the prin- tainer times the circumference; and cipal display panel, shall be in a size (c) In the case of any other shape of reasonably related to the most promi- container, 40 percent of the total sur- nent printed matter on such panel, and face of the container: Provided, how- shall be in lines generally parallel to ever, That where such container pre- the base on which the package rests as sents an obvious ‘‘principal display it is designed to be displayed. panel’’ such as the top of a triangular or circular package, the area shall con- § 201.62 Declaration of net quantity of sist of the entire top surface. contents. In determining the area of the prin- (a) The label of an over-the-counter cipal display panel, exclude tops, bot- drug in package form shall bear a dec- toms, flanges at the tops and bottoms laration of the net quantity of con- of cans, and shoulders and necks of bot- tents. This shall be expressed in the tles or jars. In the case of cylindrical terms of weight, measure, numerical or nearly cylindrical containers, infor- count, or a combination or numerical mation required by this part to appear count and weight, measure, or size. The on the principal display panel shall ap- statement of quantity of drugs in tab- pear within that 40 percent of the cir- let, capsule, ampule, or other unit form cumference which is most likely to be and the quantity of devices shall be ex- displayed, presented, shown, or exam- pressed in terms of numerical count; ined under customary conditions of dis- the statement of quantity for drugs in play for retail sale. other dosage forms shall be in terms of weight if the drug is solid, semisolid, or § 201.61 Statement of identity. viscous, or in terms of fluid measure if (a) The principal display panel of an the drug is liquid. The drug quantity over-the-counter drug in package form statement shall be augmented when shall bear as one of its principal fea- necessary to give accurate information tures a statement of the identity of the as to the strength of such drug in the commodity. package; for example, to differentiate (b) Such statement of identity shall between several strengths of the same be in terms of the established name of drug ‘‘100 tablets, 5 grains each’’ or the drug, if any there be, followed by ‘‘100 capsules, 125 milligrams each’’ or an accurate statement of the general ‘‘100 capsules, 250 milligrams each’’: pharmacological category(ies) of the Provided, That: drug or the principal intended action(s) (1) In the case of a firmly established, of the drug. In the case of an over-the- general consumer usage and trade cus- counter drug that is a mixture and that tom of declaring the quantity of a drug has no established name, this require- in terms of linear measure or measure ment shall be deemed to be satisfied by of area, such respective term may be a prominent and conspicuous state- used. Such term shall be augmented ment of the general pharmacological when necessary for accuracy of infor- action(s) of the mixture or of its prin- mation by a statement of the weight, cipal intended action(s) in terms that measure, or size of the individual units are meaningful to the layman. Such or of the entire drug; for example, the statements shall be placed in direct net quantity of adhesive tape in pack- conjunction with the most prominent age form shall be expressed in terms of display of the proprietary name or des- linear measure augmented by a state- ignation and shall employ terms de- ment of its width. scriptive of general pharmacological (2) Whenever the Commissioner de- category(ies) or principal intended ac- termines for a specific packaged drug tion(s); for example, ‘‘antacid,’’ ‘‘an- that an existing practice of declaring

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

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3 units to 1 unit, i.e., no more than 3 liquid measure, in the largest whole times as high as it is wide. units (quarts, quarts and pints, or (2) Letter heights pertain to upper pints, as appropriate) with any remain- case or capital letters. When upper and der in terms of fluid ounces or common lower case or all lower case letters are or decimal fractions of the pint or used, it is the lower case letter ‘‘o’’ or quart (see examples set forth in para- its equivalent that shall meet the min- graphs (k) (3) and (4) of this section). If imum standards. the net weight of the package is less (3) When fractions are used, each than 1 ounce avoirdupois or the net component numeral shall meet one- fluid measure is less than 1 fluid ounce, half the minimum height standards. the declaration shall be in terms of (h) The declaration shall be in letters common or decimal fractions of the re- and numerals in a type size established spective ounce and not in terms of in relationship to the area of the prin- drams. cipal display panel of the package and (2) The declaration may appear in shall be uniform for all packages of more than one line. The term net substantially the same size by com- weight shall be used when stating the plying with the following type speci- net quantity of contents in terms of fications: weight. Use of the terms net or net con- (1) Not less than one-sixteenth inch tents in terms of fluid measure or nu- in height on packages the principal dis- merical count is optional. It is suffi- play panel of which has an area of 5 cient to distinguish avoirdupois ounce square inches or less. from fluid ounce through association of (2) Not less than one-eighth inch in terms; for example, ‘‘Net wt. 6 oz’’ or height on packages the principal dis- ‘‘6 oz net wt.,’’ and ‘‘6 fl oz’’ or ‘‘net play panel of which has an area of more contents 6 fl oz’’. than five but not more than 25 square (j) On packages containing 4 pounds inches. or 1 gallon or more and labeled in (3) Not less than three-sixteenths terms of weight or fluid measure, the inch in height on packages the prin- declaration shall be expressed in cipal display panel of which has an pounds for weight units with any re- area of more than 25 but not more than mainder in terms of ounces or common 100 square inches. or decimal fractions of the pound; in (4) Not less than one-fourth inch in the case of fluid measure, it shall be height on packages the principal dis- expressed in the largest whole unit play panel of which has an area of more (gallons, followed by common or dec- than 100 square inches, except not less imal fractions of a gallon or by the than one-half inch in height if the area next smaller whole unit or units is more than 400 square inches. (quarts or quarts and pints)) with any Where the declaration is blown, em- remainder in terms of fluid ounces or bossed, or molded on a glass or plastic common or decimal fractions of the surface rather than by printing, typ- pint or quart; see paragraph (k)(5) of ing, or coloring, the lettering sizes this section. specified in paragraphs (h) (1) through (k) Examples: (4) of this section shall be increased by (1) A declaration of 11⁄2 pounds weight one-sixteenth of an inch. shall be expressed as ‘‘Net wt. 24 oz (1 (i) On packages containing less than lb 8 oz),’’ or ‘‘Net wt. 24 oz (11⁄2 lb)’’ or 4 pounds or 1 gallon and labeled in ‘‘Net wt. 24 oz (1.5 lb)’’. terms of weight or fluid measure: (2) A declaration of three-fourths (1) The declaration shall be expressed pound avoirdupois weight shall be ex- both in ounces, with identification by pressed as ‘‘Net wt. 12 oz’’. weight or by liquid measure and, if ap- (3) A declaration of 1 quart liquid plicable (1 pound or 1 pint or more) fol- measure shall be expressed as ‘‘Net lowed in parentheses by a declaration contents 32 fl oz (1 qt)’’ or ‘‘32 fl oz (1 in pounds for weight units, with any re- qt)’’. mainder in terms of ounces or common (4) A declaration of 13⁄4 quarts liquid or decimal fractions of the pound (see measure shall be expressed as ‘‘Net examples set forth in paragraphs (k) (1) contents 56 fl oz (1 qt 1 pt 8 oz)’’ or and (2) of this section), or in the case of ‘‘Net contents 56 fl oz (1 qt 1.5 pt),’’ but

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

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(b) Where a specific warning relating dosage units) is 5 milligrams or more. to use during pregnancy or while nurs- OTC drug products intended for oral in- ing has been established for a par- gestion include gum and lozenge dosage ticular drug product in a new drug ap- forms, but do not include dentifrices, plication (NDA) or for a product cov- mouthwashes, or mouth rinses. ered by an OTC drug final monograph (b) The sodium content shall be ex- in part 330 of this chapter, the specific pressed in milligrams per dosage unit warning shall be used in place of the and shall include the total amount of warning in paragraph (a) of this sec- sodium regardless of the source, i.e., tion, unless otherwise stated in the from both active and inactive ingredi- NDA or in the final OTC drug mono- ents. The sodium content shall be graph. rounded-off to the nearest whole num- (c) The following OTC drugs are ex- ber. The sodium content per dosage empt from the provisions of paragraph unit shall follow the heading ‘‘Other (a) of this section: information’’ as stated in § 201.66(c)(7). (1) Drugs that are intended to benefit (c) The labeling of OTC drug products the fetus or nursing infant during the intended for oral ingestion shall con- period of pregnancy or nursing. tain the following statement under the (2) Drugs that are labeled exclusively heading ‘‘Warning’’ (or ‘‘Warnings’’ if for pediatric use. it appears with additional warning (d) The Food and Drug Administra- statements) if the amount of sodium tion will grant an exemption from present in the labeled maximum daily paragraph (a) of this section where ap- dose of the product is more than 140 propriate upon petition under the pro- milligrams: ‘‘Ask a doctor before use if visions of § 10.30 of this chapter. Deci- you have [in bold type] [bullet] 1 a so- sions with respect to requests for ex- dium-restricted diet’’. The warnings in emptions shall be maintained in a per- §§ 201.64(c), 201.70(c), 201.71(c), and manent file for public review by the Di- 201.72(c) may be combined, if applica- vision of Dockets Management (HFA– ble, provided the ingredients are listed 305), Food and Drug Administration, in alphabetical order, e g., a calcium or 5630 Fishers Lane, rm. 1061, Rockville, sodium restricted diet. MD 20852. (d) The term sodium free may be used (e) The labeling of orally or rectally in the labeling of OTC drug products administered OTC aspirin and aspirin- intended for oral ingestion if the containing drug products must bear a amount of sodium in the labeled max- warning that immediately follows the imum daily dose is 5 milligrams or less general warning identified in para- and the amount of sodium per dosage graph (a) of this section. The warning unit is 0 milligram (when rounded-off shall be as follows: in accord with paragraph (b) of this section). ‘‘It is especially important not to use’’ (se- (e) The term very low sodium may be lect ‘‘aspirin’’ or ‘‘carbaspirin calcium,’’ as appropriate) ‘‘during the last 3 months of used in the labeling of OTC drug prod- pregnancy unless definitely directed to do so ucts intended for oral ingestion if the by a doctor because it may cause problems in amount of sodium in the labeled max- the unborn child or complications during de- imum daily dose is 35 milligrams or livery.’’ less. [47 FR 54757, Dec. 3, 1982, as amended at 55 (f) The term low sodium may be used FR 27784, July 5, 1990; 59 FR 14364, Mar. 28, in the labeling of OTC drug products 1994; 64 FR 13286, Mar. 17, 1999; 68 FR 24879, intended for oral ingestion if the May 9, 2003] amount of sodium in the labeled maximum daily dose is 140 milligrams or § 201.64 Sodium labeling. less. (a) The labeling of over-the-counter (g) The term salt is not synonymous (OTC) drug products intended for oral with the term sodium and shall not be ingestion shall contain the sodium con- used interchangeably or substituted for tent per dosage unit (e.g., tablet, tea- the term sodium. spoonful) if the sodium content of a single maximum recommended dose of 1 See § 201 .66(b)(4) of this chapter for defini- the product (which may be one or more tion of bullet symbol.

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

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(5) Established name of a drug or in- subsequent panel containing such ingredient thereof means the applicable formation. official name designated under section (2) ‘‘Active ingredient’’ or ‘‘Active in- 508 of the act (21 U.S.C. 358), or, if there gredients’’ ‘‘(in each [insert the dosage is no designated official name and the unit stated in the directions for use drug or ingredient is recognized in an (e.g., tablet, 5 mL teaspoonful) or in official compendium, the official title each gram as stated in §§ 333.110 and of the drug or ingredient in such com- 333.120 of this chapter])’’, followed by pendium, or, if there is no designated the established name of each active in- official name and the drug or ingre- gredient and the quantity of each ac- dient is not recognized in an official tive ingredient per dosage unit. Unless compendium, the common or usual otherwise provided in an applicable name of the drug or ingredient. OTC drug monograph or approved drug (6) FDA means the Food and Drug application, products marketed with- Administration. out discrete dosage units (e.g., (7) Heading means the required state- topicals) shall state the proportion ments in quotation marks listed in (rather than the quantity) of each ac- paragraphs (c)(2) through (c)(9) of this tive ingredient. section, excluding subheadings (as de- (3) ‘‘Purpose’’ or ‘‘Purposes’’, fol- fined in paragraph (a)(9) of this sec- lowed by the general pharmacological tion). category(ies) or the principal intended (8) Inactive ingredient means any com- action(s) of the drug or, where the drug ponent other than an active ingredient. consists of more than one ingredient, (9) Subheading means the required the general pharmacological categories statements in quotation marks listed or the principal intended actions of in paragraphs (c)(5)(ii) through each active ingredient. When an OTC (c)(5)(vii) of this section. drug monograph contains a statement (10) Drug facts labeling means the of identity, the pharmacological action title, headings, subheadings, and infor- described in the statement of identity mation required under or otherwise de- shall also be stated as the purpose of scribed in paragraph (c) of this section. the active ingredient. (11) Title means the heading listed at the top of the required OTC drug prod- (4) ‘‘Use’’ or ‘‘Uses’’, followed by the uct labeling, as set forth in paragraph indication(s) for the specific drug prod- (c)(1) of this section. uct. (12) Total surface area available to bear (5) ‘‘Warning’’ or ‘‘Warnings’’, fol- labeling means all surfaces of the out- lowed by one or more of the following, side container of the retail package or, if applicable: if there is no such outside container, (i) ‘‘For external use only’’ [in bold all surfaces of the immediate container type] for topical drug products not in- or container wrapper except for the tended for ingestion, or ‘‘For’’ (select flanges at the tops and bottoms of cans one of the following, as appropriate: and the shoulders and necks of bottles ‘‘rectal’’ or ‘‘vaginal’’) ‘‘use only’’ [in and jars. bold type]. (c) Content requirements. The outside (ii) All applicable warnings listed in container or wrapper of the retail paragraphs (c)(5)(ii)(A) through package, or the immediate container (c)(5)(ii)(G) of this section with the ap- label if there is no outside container or propriate subheadings highlighted in wrapper, shall contain the title, head- bold type: ings, subheadings, and information set (A) Reye’s syndrome warning for forth in paragraphs (c)(1) through (c)(8) drug products containing salicylates of this section, and may contain the in- set forth in § 201.314(h)(1). This warning formation under the heading in para- shall follow the subheading ‘‘Reye’s graph (c)(9) of this section, in the order syndrome:’’ listed. (B) Allergic reaction warnings set (1) (Title) ‘‘Drug Facts’’. If the drug forth in any applicable OTC drug facts labeling appears on more than monograph or approved drug applica- one panel, the title ‘‘Drug Facts (con- tion for any product that requires a tinued)’’ shall appear at the top of each separate allergy warning. This warning

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shall follow the subheading ‘‘Allergy for products labeled only for use in alert:’’ children under 12 years of age, ‘‘Ask a (C) Flammability warning, with ap- doctor or pharmacist before use if the propriate flammability signal word(s) child is’’ [in bold type], followed by all (e.g., §§ 341.74(c)(5)(iii), 344.52(c), drug-drug and drug-food interaction 358.150(c), and 358.550(c) of this chap- warnings. ter). This warning shall follow a sub- (vi) ‘‘When using this product’’ [in heading containing the appropriate bold type], followed by the side effects flammability signal word(s) described that the consumer may experience, and in an applicable OTC drug monograph the substances (e.g., alcohol) or activi- or approved drug application. ties (e.g., operating machinery, driving (D) Water soluble gums warning set a car, warnings set forth in § 369.21 of forth in § 201.319. This warning shall this chapter for drugs in dispensers follow the subheading ‘‘Choking:’’ pressurized by gaseous propellants) to (E) Alcohol warning set forth in avoid while using the product. § 201.322. This warning shall follow the subheading ‘‘Alcohol warning:’’ (vii) ‘‘Stop use and ask a doctor if’’ (F) Sore throat warning set forth in [in bold type], followed by any signs of § 201.315. This warning shall follow the toxicity or other reactions that would subheading ‘‘Sore throat warning:’’ necessitate immediately discontinuing (G) Warning for drug products con- use of the product. For all OTC drug taining sodium phosphates set forth in products under an approved drug appli- § 201.307(b)(2)(i) or (b)(2)(ii). This warn- cation whose packaging does not in- ing shall follow the subheading ‘‘Dos- clude a toll-free number through which age warning:’’ consumers can report complaints to (H) Sexually transmitted diseases the manufacturer or distributor of the (STDs) warning for vaginal contracep- drug product, the following text shall tive and spermicide drug products con- immediately follow the subheading: taining nonoxynol 9 set forth in ‘‘[Bullet] side effects occur. You may § 201.325(b)(2). This warning shall follow report side effects to FDA at 1–800– the subheading ‘‘Sexually transmitted FDA–1088.’’ The telephone number diseases (STDs) alert:’’ must appear in a minimum 6–point (iii) ‘‘Do not use’’ [in bold type], fol- bold letter height or type size. lowed by all contraindications for use (viii) Any required warnings in an ap- with the product. These contraindica- plicable OTC drug monograph, other tions are absolute and are intended for OTC drug regulations, or approved drug situations in which consumers should application that do not fit within one not use the product unless a prior diag- of the categories listed in paragraphs nosis has been established by a doctor (c)(5)(i) through (c)(5)(vii), (c)(5)(ix), or for situations in which certain con- and (c)(5)(x) of this section. sumers should not use the product (ix) The pregnancy/breast-feeding under any circumstances regardless of warning set forth in § 201.63(a); the whether a doctor or health professional third trimester warning set forth in is consulted. (iv) ‘‘Ask a doctor before use if you § 201.63(e) for products containing aspi- have’’ [in bold type] or, for products la- rin or carbaspirin calcium; the third beled only for use in children under 12 trimester warning set forth in ap- years of age, ‘‘Ask a doctor before use proved drug applications for products if the child has’’ [in bold type], fol- containing ketoprofen, naproxen so- lowed by all warnings for persons with dium, and ibuprofen (not intended ex- certain preexisting conditions (exclud- clusively for use in children). ing pregnancy) and all warnings for (x) The ‘‘Keep out of reach of chil- persons experiencing certain symp- dren’’ warning and the accidental over- toms. The warnings under this heading dose/ingestion warning set forth in are those intended only for situations § 330.1(g) of this chapter. in which consumers should not use the (6) ‘‘Directions’’, followed by the di- product until a doctor is consulted. rections for use described in an appli- (v) ‘‘Ask a doctor or pharmacist be- cable OTC drug monograph or approved fore use if you are’’ [in bold type] or, drug application.

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

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

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

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

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

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

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

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interchangeably in the labeling of OTC 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 69 FR 13733, Mar. 24, 2004; 72 FR 71785, Dec. 19, dose of the product is more than 3.2 2007; 73 FR 403, Jan. 3, 2008] grams: ‘‘Ask a doctor before use if you EFFECTIVE DATE NOTE: At 74 FR 19407, Apr. have [in bold type] [bullet] 1 kidney 29, 2009, § 201.66 was amended by revising stones [bullet] a calcium-restricted paragraph (c)(5)(ii)(E), effective Apr. 29, 2010. diet’’. The warnings in §§ 201.64(c), For the convenience of the user, the revised 201.70(c), 201.71(c), and 201.72(c) may be text is set forth as follows: combined, if applicable, provided the § 201.66 Format and content requirements ingredients are listed in alphabetical for over-the-counter (OTC) drug product order, e.g., a calcium or sodium relabeling. stricted diet. (d) Any product subject to this para- * * * * * graph that is not labeled as required by (c) * * * this paragraph and that is initially in- (5) * * * troduced or initially delivered for in- (ii) * * * troduction into interstate commerce (E) Liver warning set forth in after the following dates is misbranded § 201.326(a)(1)(iii) and/or stomach bleeding under sections 201(n) and 502(a) and (f) warning set forth in § 201.326(a)(2)(iii). The liver warning shall follow the subheading of the Federal Food, Drug, and Cos- ‘‘Liver warning:’’ and the stomach bleeding metic Act. warning shall follow the subheading ‘‘Stom- (1) As of the date of approval of the ach bleeding warning:’’ 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 of the Federal Food, Drug, and Cos- before April 23, 2004. metic Act. (1) As of the date of approval of the [69 FR 13733, Mar. 24, 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 (2) September 24. 2005, for all OTC ingestion shall contain the magnesium drug products subject to any OTC drug content per dosage unit (e.g., tablet, monograph, not yet the subject of any teaspoonful) if the magnesium content OTC drug monograph, or subject to of a single maximum recommended drug marketing applications approved dose of the product (which may be one before April 23, 2004. or more dosage units) is 8 milligrams 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 § 201.72 Potassium labeling. dentifrices, mouthwashes, or mouth (a) The labeling of over-the-counter rinses. (OTC) drug products intended for oral (b) The magnesium content shall be ingestion shall contain the potassium expressed in milligrams or grams per content per dosage unit (e.g., tablet, dosage unit and shall include the total teaspoonful) if the potassium content amount of magnesium regardless of the of a single maximum recommended source, i.e., from both active and inac- dose of the product (which may be one tive ingredients. If the dosage unit con- or more dosage units) is 5 milligrams tains less than 1 gram of magnesium, or more. OTC drug products intended milligrams should be used. The magne- for oral ingestion include gum and loz- sium content shall be rounded-off to enge dosage forms, but do not include the nearest 5 milligrams (or nearest dentifrices, mouthwashes, or mouth tenth of a gram if over 1 gram). The rinses. magnesium content per dosage unit (b) The potassium content shall be shall follow the heading ‘‘Other infor- expressed in milligrams or grams per mation’’ as stated in § 201.66(c)(7). dosage unit and shall include the total (c) The labeling of OTC drug products amount of potassium regardless of the intended for oral ingestion shall con- source, i.e., from both active and inac- tain the following statement under the tive ingredients. If the dosage unit con- heading ‘‘Warning’’ (or ‘‘Warnings’’ if tains less than 1 gram of potassium, it appears with additional warning milligrams should be used. The potas- statements) if the amount of magnesium content shall be rounded-off to sium present in the labeled maximum the nearest 5 milligrams (or nearest daily dose of the product is more than tenth of a gram if over 1 gram). The po- 600 milligrams: ‘‘Ask a doctor before tassium content per dosage unit shall use if you have [in bold type] [bullet] 1 follow the heading ‘‘Other informa- kidney disease [bullet] a magnesium- tion’’ as stated in § 201.66(c)(7). restricted diet’’. The warnings in (c) The labeling of OTC drug products §§ 201.64(c), 201.70(c), 201.71(c), and intended for oral ingestion shall con- 201.72(c) may be combined, if applica- tain the following statement under the ble, provided the ingredients are listed heading ‘‘Warning’’ (or ‘‘Warnings’’ if in alphabetical order, e.g., a magne- it appears with additional warning sium or potassium-restricted diet. statements) if the amount of potassium (d) Any product subject to this para- present in the labeled maximum daily graph that is not labeled as required by dose of the product is more than 975 this paragraph and that is initially in- milligrams: ‘‘Ask a doctor before use if troduced or initially delivered for in- you have [in bold type] [bullet] 1 kidney troduction into interstate commerce disease [bullet] a potassium-restricted after the following dates is misbranded diet’’. The warnings in §§ 201.64(c), under sections 201(n) and 502(a) and (f) 201.70(c), 201.71(c), and 201.72(c) may be

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

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combined, if applicable, provided the (2) If appropriate, other important ingredients are listed in alphabetical chemical or physical information, such order, e.g., a magnesium or potassium- as physical constants, or pH, shall be restricted diet. stated. (d) Any product subject to this para- (b) Clinical Pharmacology. (1) Under graph that is not labeled as required by this section heading, the labeling shall this paragraph and that is initially in- contain a concise factual summary of troduced or initially delivered for in- the clinical pharmacology and actions troduction into interstate commerce of the drug in humans. The summary after the following dates is misbranded may include information based on in under sections 201(n) and 502(a) and (f) vitro and/or animal data if the infor- of the Federal Food, Drug, and Cos- mation is essential to a description of metic Act. the biochemical and/or physiological (1) As of the date of approval of the mode of action of the drug or is other- application for any single entity and wise pertinent to human therapeutics. combination products subject to drug Pharmacokinetic information that is marketing applications approved on or important to safe and effective use of after April 23, 2004. the drug is required, if known, e.g., de- (2) September 24, 2005, for all OTC gree and rate of absorption, pathways drug products subject to any OTC drug of biotransformation, percentage of monograph, not yet the subject of any dose as unchanged drug and metabo- OTC drug monograph, or subject to lites, rate or half-time of elimination, drug marketing applications approved concentration in body fluids associated before April 23, 2004. with therapeutic and/or toxic effects, [69 FR 13734, Mar. 24, 2004] degree of binding to plasma proteins, degree of uptake by a particular organ § 201.80 Specific requirements on con- or in the fetus, and passage across the tent and format of labeling for blood brain barrier. Inclusion of phar- human prescription drug and biological products; older drugs not macokinetic information is restricted described in § 201.56(b)(1). to that which relates to clinical use of 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 heading, the labeling shall contain: (2) Data that demonstrate activity or (i) The proprietary name and the es- effectiveness in in vitro or animal tests tablished name, if any, as defined in and that have not been shown by ade- section 502(e)(2) of the act, of the drug; quate and well-controlled clinical stud- (ii) The type of dosage form and the ies to be pertinent to clinical use may route of administration to which the be included under this section of the la- labeling applies; beling only under the following cir- (iii) The same qualitative and/or cumstances: quantitative ingredient information as (i) In vitro data for anti-infective required under § 201.100(b) for labels; drugs may be included if the data are (iv) If the product is sterile, a state- immediately preceded by the statement of that fact; ment ‘‘The following in vitro data are (v) The pharmacological or thera- available but their clinical significance peutic class of the drug; is unknown.’’ (vi) The chemical name and struc- (ii) For other classes of drugs, in tural formula of the drug; vitro and animal data that have not (vii) If the product is radioactive, a been shown by adequate and well-con- statement of the important nuclear trolled clinical studies, as defined in physical characteristics, such as the § 314.126(b) of this chapter, to be perti- principal radiation emission data, ex- nent to clinical use may be used only if ternal radiation, and physical decay a waiver is granted under § 201.58 or characteristics. § 314.126(c) of this chapter.

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(c) Indications and Usage. (1) Under of the drug. The labeling shall also this section heading, the labeling shall identify specific tests needed for selec- state that: tion or monitoring of the patients who (i) The drug is indicated in the treat- need the drug, e.g., microbe suscepti- ment, prevention, or diagnosis of a rec- bility tests. Information on the approx- ognized disease or condition, e.g., peni- imate kind, degree, and duration of im- cillin is indicated for the treatment of provement to be anticipated shall be pneumonia due to susceptible stated if available and shall be based pneumococci; and/or on substantial evidence derived from (ii) The drug is indicated for the adequate and well-controlled studies as treatment, prevention, or diagnosis of defined in § 314.126(b) of this chapter an important manifestation of a dis- unless the requirement is waived under ease or condition, e.g., chlorothiazide § 201.58 or § 314.126(c) of this chapter. If is indicated for the treatment of edema the information is relevant to the rec- in patients with congestive heart fail- ommended intervals between doses, the ure; and/or usual duration of treatment, or any (iii) The drug is indicated for the re- modification of dosage, it shall be stat- lief of symptoms associated with a dis- ed in the ‘‘Dosage and Administration’’ ease or syndrome, e.g., section of the labeling and referenced chlorpheniramine is indicated for the in this section. symptomatic relief of nasal congestion (ii) If safety considerations are such in patients with vasomotor rhinitis; that the drug should be reserved for and/or certain situations, e.g., cases refrac- (iv) The drug, if used for a particular tory to other drugs, this information indication only in conjuction with a shall be stated in this section. primary mode of therapy, e.g., diet, (iii) If there are specific conditions surgery, or some other drug, is an ad- that should be met before the drug is junct to the mode of therapy. used on a long-term basis, e.g., dem- (2)(i) For drug products other than onstration of responsiveness to the biological products, all indications list- drug in a short-term trial, the labeling ed in this section must be supported by shall identify the conditions; or, if the substantial evidence of effectiveness indications for long-term use are dif- based on adequate and well-controlled ferent from those for short-term use, studies as defined in § 314.126(b) of this the labeling shall identify the specific chapter unless the requirement is indications for each use. waived under § 201.58 or § 314.126(c) of (iv) If there is a common belief that this chapter. Indications or uses must the drug may be effective for a certain not be implied or suggested in other use or if there is a common use of the sections of labeling if not included in drug for a condition, but the prepon- this section. derance of evidence related to the use (ii) For biological products, all indi- or condition shows that the drug is in- cations listed in this section must be effective, the Food and Drug Adminis- supported by substantial evidence of ef- tration may require that the labeling fectiveness. Indications or uses must state that there is a lack of evidence not be implied or suggested in other that the drug is effective for that use sections of labeling if not included in or condition. this section. (v) Any statements comparing the (3) This section of the labeling shall safety or effectiveness, either greater also contain the following additional or less, of the drug with other agents information: for the same indication shall be sup- (i) If evidence is available to support ported by adequate and well-controlled the safety and effectiveness of the drug studies as defined in § 314.126(b) of this only in selected subgroups of the larger chapter unless this requirement is population with a disease, syndrome, waived under § 201.58 or § 314.126(c) of or symptom under consideration, e.g., this chapter. patients with mild disease or patients (d) Contraindications. Under this sec- in a special age group, the labeling tion heading, the labeling shall de- shall describe the available evidence scribe those situations in which the and state the limitations of usefulness drug should not be used because the

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risk of use clearly outweighs any pos- (f) Precautions. Under this section sible benefit. These situations include heading, the labeling shall contain the administration of the drug to patients following subsections as appropriate known to have a hypersensitivity to it; for the drug: use of the drug in patients who, be- (1) General. This subsection of the la- cause of their particular age, sex, con- beling shall contain information re- comitant therapy, disease state, or garding any special care to be exer- other condition, have a substantial cised by the practitioner for safe and risk of being harmed by it; or contin- effective use of the drug, e.g., pre- ued use of the drug in the face of an un- cautions not required under any other acceptably hazardous adverse reaction. specific section or subsection of the la- Known hazards and not theoretical pos- beling. sibilities shall be listed, e.g., if hyper- (2) Information for patients. This sub- sensitivity to the drug has not been section must contain information nec- demonstrated, it should not be listed as essary for patients to use the drug safe- a contraindication. If no contraindica- ly and effectively (e.g., precautions tions are known, this section of the la- concerning driving or the concomitant beling shall state ‘‘None known.’’ use of other substances that may have harmful additive effects). Any FDA-ap- (e) Warnings. Under this section head- proved patient labeling must be ref- ing, the labeling shall describe serious erenced in this section and the full text adverse reactions and potential safety of such patient labeling must be re- hazards, limitations in use imposed by printed immediately following the last them, and steps that should be taken if section of labeling or, alternatively, they occur. The labeling shall be re- accompany the prescription drug label- vised to include a warning as soon as ing. The type size requirement for the there is reasonable evidence of an asso- Medication Guide set forth in § 208.20 of ciation of a serious hazard with a drug; this chapter does not apply to the a causal relationship need not have Medication Guide that is reprinted in been proved. A specific warning relat- or accompanying the prescription drug ing to a use not provided for under the labeling unless such Medication Guide ‘‘Indications and Usage’’ section of the is to be detached and distributed to pa- labeling may be required by the Food tients in compliance with § 208.24 of and Drug Administration if the drug is this chapter. commonly prescribed for a disease or (3) Laboratory tests. This subsection of condition, and there is lack of substan- the labeling shall identify any labora- tial evidence of effectivenes for that tory tests that may be helpful in fol- disease or condition, and such usage is lowing the patient’s response or in associated with serious risk or hazard. identifying possible adverse reactions. Special problems, particularly those If appropriate, information shall be that may lead to death or serious in- provided on such factors as the range jury, may be required by the Food and of normal and abnormal values ex- Drug Administration to be placed in a pected in the particular situation and prominently displayed box. The boxed the recommended frequency with warning ordinarily shall be based on which tests should be done before, dur- clinical data, but serious animal tox- ing, and after therapy. icity may also be the basis of a boxed (4)(i) Drug interactions. This sub- warning in the absence of clinical data. section of the labeling shall contain If a boxed warning is required, its loca- specific practical guidance for the phy- tion will be specified by the Food and sician on preventing clinically signifi- Drug Administration. The frequency of cant drug/drug and drug/food inter- these serious adverse reactions and, if actions that may occur in vivo in pa- known, the approximate mortality and tients taking the drug. Specific drugs morbidity rates for patients sustaining or classes of drugs with which the drug the reaction, which are important to to which the labeling applies may safe and effective use of the drug, shall interact in vivo shall be identified, and be expressed as provided under the the mechanism(s) of the interaction ‘‘Adverse Reactions’’ section of the la- shall be briefly described. Information beling. in this subsection of the labeling shall

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

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‘‘Pregnancy Category B. Reproduction (d) Pregnancy category D. If there is studies in (kind(s) of animal(s)) have positive evidence of human fetal risk shown (describe findings) at (x) times based on adverse reaction data from in- the human dose. Studies in pregnant vestigational or marketing experience women, however, have not shown that or studies in humans, but the potential (name of drug) increases the risk of ab- benefits from the use of the drug in normalities when administered during pregnant women may be acceptable de- the first (second, third, or all) tri- spite its potential risks (for example, if mester(s) of pregnancy. Despite the the drug is needed in a life-threatening animal findings, it would appear that situation or serious disease for which the possibility of fetal harm is remote, safer drugs cannot be used or are inef- if the drug is used during pregnancy. fective), the labeling shall state: Nevertheless, because the studies in ‘‘Pregnancy Category D. See ‘Warn- humans cannot rule out the possibility ings’ section.’’ Under the ‘‘Warnings’’ of harm, (name of drug) should be used section, the labeling states: ‘‘(Name of during pregnancy only if clearly need- drug) can cause fetal harm when ad- ed.’’ The labeling shall also contain a ministered to a pregnant woman. description of the human studies and a (Describe the human data and any perti- description of available data on the ef- nent animal data.) If this drug is used fect of the drug on the later growth, during pregnancy, or if the patient be- development, and functional matura- comes pregnant while taking this drug, the patient should be apprised of the tion of the child. potential hazard to the fetus.’’ (c) Pregnancy category C. If animal re- (e) Pregnancy category X. If studies in production studies have shown an ad- animals or humans have demonstrated verse effect on the fetus, if there are no fetal abnormalities or if there is posi- adequate and well-controlled studies in tive evidence of fetal risk based on ad- humans, and if the benefits from the verse reaction reports from investiga- use of the drug in pregnant women may tional or marketing experience, or be acceptable despite its potential both, and the risk of the use of the risks, the labeling shall state: ‘‘Preg- drug in a pregnant woman clearly out- nancy Category C. (Name of drug) has weighs any possible benefit (for exam- been shown to be teratogenic (or to ple, safer drugs or other forms of ther- have an embryocidal effect or other ad- apy are available), the labeling shall verse effect) in (name(s) of species) when state: ‘‘Pregnancy Category X. See given in doses (x) times the human ‘Contraindications’ section.’’ Under dose. There are no adequate and well- ‘‘Contraindications,’’ the labeling shall controlled studies in pregnant women. state: ‘‘(Name of drug) may (can) cause (Name of drug) should be used during fetal harm when administered to a pregnancy only if the potential benefit pregnant woman. (Describe the human justifies the potential risk to the data and any pertinant animal data.) fetus.’’ The labeling shall contain a de- (Name of drug) is contraindicated in scription of the animal studies. If there women who are or may become preg- are no animal reproduction studies and nant. If this drug is used during preg- no adequate and well-controlled studies nancy, or if the patient becomes preg- in humans, the labeling shall state: nant while taking this drug, the pa- ‘‘Pregnancy Category C. Animal repro- tient should be apprised of the poten- duction studies have not been con- tial hazard to the fetus.’’ ducted with (name of drug). It is also (ii) Nonteratogenic effects. Under this not known whether (name of drug) can heading the labeling shall contain cause fetal harm when administered to other information on the drug’s effects a pregnant woman or can affect repro- on reproduction and the drug’s use dur- duction capacity. (Name of drug) should ing pregnancy that is not required spe- be given to a pregnant woman only if cifically by one of the pregnancy cat- clearly needed.’’ The labeling shall egories, if the information is relevant contain a description of any available to the safe and effective use of the data on the effect of the drug on the drug. Information required under this later growth, development, and func- heading shall include nonteratogenic tional maturation of the child. effects in the fetus or newborn infant

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(for example, withdrawal symptoms or section of the labeling shall contain hypoglycemia) that may occur because one of the following statements, as ap- of a pregnant woman’s chronic use of propriate. If the drug is associated with the drug for a preexisting condition or serious adverse reactions or has a disease. known tumorigenic potential, the la- (7) Labor and delivery. If the drug has beling shall state: ‘‘It is not known a recognized use during labor or deliv- whether this drug is excreted in human ery (vaginal or abdominal delivery), milk. Because many drugs are excreted whether or not the use is stated in the in human milk and because of the po- indications section of the labeling, this tential for serious adverse reactions in subsection of the labeling shall de- nursing infants from (name of drug) (or, scribe the available information about ‘‘Because of the potential for the effect of the drug on the mother tumorigenicity shown for (name of and the fetus, on the duration of labor drug) in (animal or human) studies), a or delivery, on the possibility that for- decision should be made whether to ceps delivery or other intervention or discontinue nursing or to discontinue resuscitation of the newborn will be necessary, and the effect of the drug on the drug, taking into account the im- the later growth, development, and portance of the drug to the mother.’’ If functional maturation of the child. If the drug is not associated with serious any information required under this adverse reactions and does not have a subsection is unknown, this subsection known tumorigenic potential, the la- of the labeling shall state that the in- beling shall state: ‘‘It is not known formation is unknown. whether this drug is excreted in human (8) Nursing mothers. (i) If a drug is ab- milk. Because many drugs are excreted sorbed systemically, this subsection of in human milk, caution should be exer- the labeling shall contain, if known, in- cised when (name of drug) is adminis- formation about excretion of the drug tered to a nursing woman.’’ in human milk and effects on the nurs- (9) Pediatric use. (i) Pediatric popu- ing infant. Pertinent adverse effects lation(s)/pediatric patient(s): For the observed in animal offspring shall be purposes of paragraphs (f)(9)(ii) described. through (f)(9)(viii) of this 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 drug) in (animal or human) studies), a ‘‘Indications and Usage’’ section of the decision should be made whether to labeling, and appropriate pediatric dos- discontinue nursing or to discontinue age information shall be given under the drug, taking into account the im- the ‘‘Dosage and Administration’’ sec- portance of the drug to the mother.’’ If tion of the labeling. The ‘‘Pediatric the drug is not associated with serious use’’ subsection shall cite any limita- adverse reactions and does not have a tions on the pediatric indication, need known tumorigenic potential, the la- for specific monitoring, specific haz- beling shall state: ‘‘Caution should be ards associated with use of the drug in exercised when (name of drug) is admin- any subsets of the pediatric population istered to a nursing woman.’’ (e.g., neonates), differences between pe- (iii) If a drug is absorbed system- diatric and adult responses to the drug, ically and information on excretion in and other information related to the human milk is unknown, this sub- safe and effective pediatric use of the

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drug. Data summarized in this sub- or postmarketing studies or experi- section of the labeling should be dis- ence, may be necessary to show that cussed in more detail, if appropriate, the drug can be used safely and effec- under the ‘‘Clinical Pharmacology’’ or tively in pediatric patients. When a ‘‘Clinical Studies’’ section. As appro- drug is approved for pediatric use based priate, this information shall also be on adequate and well-controlled studies contained in the ‘‘Contraindications,’’ in adults with other information sup- ‘‘Warnings,’’ and elsewhere in the porting pediatric use, the ‘‘Pediatric ‘‘Precautions’’ sections. use’’ subsection of the labeling shall (iii) If there are specific statements contain either the following statement, on pediatric use of the drug for an indi- or a reasonable alternative: ‘‘The safe- cation also approved for adults that are ty and effectiveness of (drug name) have based on adequate and well-controlled been established in the age groups l to studies in the pediatric population, l (note any limitations, e.g., no data they shall be summarized in the ‘‘Pe- for pediatric patients under 2, or only diatric use’’ subsection of the labeling applicable to certain indications ap- and discussed in more detail, if appro- proved in adults). Use of (drug name) in priate, under the ‘‘Clinical Pharma- these age groups is supported by evi- cology’’ and ‘‘Clinical Studies’’ sec- dence from adequate and well-con- tions. Appropriate pediatric dosage trolled studies of (drug name) in adults shall be given under the ‘‘Dosage and with additional data (insert wording Administration’’ section of the label- that accurately describes the data sub- ing. The ‘‘Pediatric use’’ subsection of mitted to support a finding of substan- the labeling shall also cite any limita- tial evidence of effectiveness in the pe- tions on the pediatric use statement, diatric population).’’ Data summarized need for specific monitoring, specific in the preceding prescribed statement hazards associated with use of the drug in this subsection of the labeling shall in any subsets of the pediatric popu- be discussed in more detail, if appro- lation (e.g., neonates), differences be- priate, under the ‘‘Clinical Pharma- tween pediatric and adult responses to cology’’ or the ‘‘Clinical Studies’’ sec- the drug, and other information related tion. For example, pediatric pharmaco- to the safe and effective pediatric use kinetic or pharmacodynamic studies of the drug. As appropriate, this infor- and dose-response information should mation shall also be contained in the be described in the ‘‘Clinical Pharma- ‘‘Contraindications,’’ ‘‘Warnings,’’ and cology’’ section. Pediatric dosing in- elsewhere in the ‘‘Precautions’’ sec- structions shall be included in the tions. ‘‘Dosage and Administration’’ section (iv) FDA may approve a drug for pe- of the labeling. Any differences be- diatric use based on adequate and well- tween pediatric and adult responses, controlled studies in adults, with other 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

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associated with a specific hazard, the the geriatric indication, and other in- hazard shall be described in this sub- formation related to the safe and effec- section of the labeling, or, if appro- tive use of the drug in the geriatric priate, the hazard shall be stated in the population. Unless otherwise noted, in- ‘‘Contraindications’’ or ‘‘Warnings’’ formation contained in the ‘‘Geriatric section of the labeling and this sub- use’’ subsection of the labeling shall section shall refer to it. pertain to use of the drug in persons 65 (vi) If the requirements for a finding years of age and older. Data summa- of substantial evidence to support a pe- rized in this subsection of the labeling diatric indication or a pediatric use shall be discussed in more detail, if ap- statement have not been met for any propriate, under ‘‘Clinical Pharma- pediatric population, this subsection of cology’’ or the ‘‘Clinical Studies’’ sec- the labeling shall contain the following tion. As appropriate, this information statement: ‘‘Safety and effectiveness in shall also be contained in ‘‘Contra- pediatric patients have not been estab- indications,’’ ‘‘Warnings,’’ and else- lished.’’ If use of the drug in premature where in ‘‘Precautions.’’ or neonatal infants, or other pediatric (ii) Specific statements on geriatric subgroups, is associated with a specific use of the drug for an indication ap- hazard, the hazard shall be described in proved for adults generally, as distin- this subsection of the labeling, or, if guished from a specific geriatric indi- appropriate, the hazard shall be stated cation, shall be contained in the in the ‘‘Contraindications’’ or ‘‘Warn- ‘‘Geriatric use’’ subsection and shall ings’’ section of the labeling and this reflect all information available to the subsection shall refer to it. sponsor that is relevant to the appro- (vii) If the sponsor believes that none priate use of the drug in elderly pa- of the statements described in para- tients. This information includes de- graphs (f)(9)(ii) through (f)(9)(vi) of this tailed results from controlled studies section is appropriate or relevant to that are available to the sponsor and the labeling of a particular drug, the pertinent information from well-docu- sponsor shall provide reasons for omis- mented studies obtained from a lit- sion of the statements and may pro- erature search. Controlled studies in- pose alternative statement(s). FDA clude those that are part of the mar- may permit use of an alternative state- keting application and other relevant ment if FDA determines that no state- studies available to the sponsor that ment described in those paragraphs is have not been previously submitted in appropriate or relevant to the drug’s the investigational new drug applica- labeling and that the alternative state- tion, new drug application, biological ment is accurate and appropriate. license application, or a supplement or (viii) If the drug product contains one amendment to one of these applica- or more inactive ingredients that tions (e.g., postmarketing studies or present an increased risk of toxic ef- adverse drug reaction reports). The fects to neonates or other pediatric ‘‘Geriatric use’’ subsection shall con- subgroups, a special note of this risk tain the following statement(s) or rea- shall be made, generally in the ‘‘Con- sonable alternative, as applicable, tak- traindications,’’ ‘‘Warnings,’’ or ‘‘Pre- ing into account available information: cautions’’ section. (A) If clinical studies did not include (10) Geriatric use. (i) A specific geri- sufficient numbers of subjects aged 65 atric indication, if any, that is sup- and over to determine whether elderly ported by adequate and well-controlled subjects respond differently from studies in the geriatric population younger subjects, and other reported shall be described under the ‘‘Indica- clinical experience has not identified tions and Usage’’ section of the label- such differences, the ‘‘Geriatric use’’ ing, and appropriate geriatric dosage subsection shall include the following shall be stated under the ‘‘Dosage and statement: Administration’’ section of the 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

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identified differences in responses between section and ‘‘Drug interactions’’ sub- the elderly and younger patients. In general, section of the ‘‘Precautions’’ section dose selection for an elderly patient should ordinarily contain information on be cautious, usually starting at the low end of the dosing range, reflecting the greater drug-disease and drug-drug inter- frequency of decreased hepatic, renal, or car- actions that is particularly relevant to diac function, and of concomitant disease or the elderly, who are more likely to other drug therapy.’’ have concomitant illness and to utilize (B) If clinical studies (including stud- concomitant drugs. ies that are part of marketing applica- (B) If a drug is known to be substan- tions and other relevant studies avail- tially excreted by the kidney, the able to the sponsor that have not been ‘‘Geriatric use’’ subsection shall in- submitted in the sponsor’s applica- clude the statement: tions) included enough elderly subjects ‘‘This drug is known to be substantially ex- to make it likely that differences in creted by the kidney, and the risk of toxic safety or effectiveness between elderly reactions to this drug may be greater in pa- and younger subjects would have been tients with impaired renal function. Because detected, but no such differences (in elderly patients are more likely to have de- safety or effectiveness) were observed, creased renal function, care should be taken and other reported clinical experience in dose selection, and it may be useful to has not identified such differences, the monitor renal function.’’ ‘‘Geriatric use’’ subsection shall con- (iv) If use of the drug in the elderly tain the following statement: appears to cause a specific hazard, the Of the total number of subjects in clinical hazard shall be described in the ‘‘Geri- studies of (name of drug), l percent were 65 atric use’’ subsection of the labeling, and over, while l percent were 75 and over. or, if appropriate, the hazard shall be (Alternatively, the labeling may state the stated in the ‘‘Contraindications,’’ total number of subjects included in the ‘‘Warnings,’’ or ‘‘Precautions’’ section studies who were 65 and over and 75 and of the labeling, and the ‘‘Geriatric use’’ over.) No overall differences in safety or effectiveness were observed between these sub- subsection shall refer to those sections. jects and younger subjects, and other re- (v) Labeling under paragraphs ported 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 par- (C) If evidence from clinical studies ticular situation, e.g., for a sedating and other reported clinical experience drug, it could be stated that: available to the sponsor indicates that use of the drug in elderly patients is ‘‘Sedating drugs may cause confusion and 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 ‘‘Geriatric use’’ subsection of the label- (vi) If the sponsor believes that none ing shall contain a brief description of of the requirements described in para- observed differences or specific moni- graphs (f)(10)(i) through (f)(10)(v) of toring or dosage requirements and, as this section is appropriate or relevant appropriate, shall refer to more de- to the labeling of a particular drug, the tailed discussions in the ‘‘Contra- sponsor shall provide reasons for omis- indications,’’ ‘‘Warnings,’’ ‘‘Dosage and sion of the statements and may pro- Administration,’’ or other sections of pose an alternative statement. FDA the labeling. may permit omission of the statements (iii)(A) If specific pharmacokinetic or if FDA determines that no statement pharmacodynamic studies have been described in those paragraphs is appro- carried out in the elderly, they shall be priate or relevant to the drug’s label- described briefly in the ‘‘Geriatric use’’ ing. FDA may permit use of an alter- subsection of the labeling and in detail native statement if the agency deter- under the ‘‘Clinical Pharmacology’’ mines that such statement is accurate section. The ‘‘Clinical Pharmacology’’ and appropriate.

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(g) Adverse Reactions. An adverse re- (4) Any claim comparing the drug to action is an undesirable effect, reason- which the labeling applies with other ably associated with the use of the drugs in terms of frequency, severity, drug, that may occur as part of the or character of adverse reactions shall pharmacological action of the drug or be based on adequate and well-con- may be unpredictable in its occurrence. trolled studies as defined in § 314.126(b) (1) This section of the labeling shall of this chapter unless this requirement list the adverse reactions that occur is waived under § 201.58 or § 314.126(c) of with the drug and with drugs in the this chapter. same pharmacologically active and (h) Drug Abuse and Dependence. Under chemically related class, if applicable. this section heading, the labeling shall (2) In this listing, adverse reactions contain the following subsections, as may be categorized by organ system, appropriate for the drug: by severity of the reaction, by fre- (1) Controlled Substance. If the drug is quency, or by toxicological mecha- controlled by the Drug Enforcement nism, or by a combination of these, as Administration, the schedule in which appropriate. If frequency information it is controlled shall be stated. from adequate clinical studies is avail- (2) Abuse. This subsection of the la- able, the categories and the adverse re- beling shall be based primarily on actions within each category shall be human data and human experience, but listed in decreasing order of frequency. pertinent animal data may also be An adverse reaction that is signifi- used. This subsection shall state the cantly more severe than the other re- types of abuse that can occur with the actions listed in a category, however, drug and the adverse reactions perti- shall be listed before those reactions, nent to them. Particularly susceptible regardless of its frequency. If frequency patient populations shall be identified. information from adequate clinical (3) Dependence. This subsection of the studies is not available, the categories labeling shall describe characteristic and adverse reactions within each cat- effects resulting from both psycho- egory shall be listed in decreasing logical and physical dependence that order of severity. The approximate fre- occur with the drug and shall identify quency of each adverse reaction shall the quantity of the drug over a period be expressed in rough estimates or or- of time that may lead to tolerance or ders of magnitude essentially as fol- dependence, or both. Details shall be lows: ‘‘The most frequent adverse reac- provided on the adverse effects of tion(s) to (name of drug) is (are) (list re- chronic abuse and the effects of abrupt actions). This (these) occur(s) in about withdrawal. Procedures necessary to (e.g., one-third of patients; one in 30 diagnose the dependent state shall be patients; less than one-tenth of pa- provided, and the principles of treating tients). Less frequent adverse reactions the effects of abrupt withdrawal shall are (list reactions), which occur in ap- be described. proximately (e.g., one in 100 patients). (i) Overdosage. Under this section Other adverse reactions, which occur heading, the labeling shall describe the rarely, in approximately (e.g., one in signs, symptoms, and laboratory find- 1,000 patients), are (list reactions).’’ Per- ings of acute overdosage and the gen- cent figures may not ordinarily be used eral principles of treatment. This sec- unless they are documented by ade- tion shall be based on human data, quate and well-controlled studies as de- when available. If human data are un- fined in § 314.126(b) of this chapter, they available, appropriate animal and in are shown to reflect general experi- vitro data may be used. Specific infor- ence, and they do not falsely imply a mation shall be provided about the fol- greater degree of accuracy than actu- lowing: ally exists. (1) Signs, symptoms, and laboratory (3) The ‘‘Warnings’’ section of the la- findings associated with an overdosage beling or, if appropriate, the ‘‘Contra- of the drug. indications’’ section of the labeling (2) Complications that can occur with shall identify any potentially fatal ad- the drug (for example, organ toxicity verse reaction. or delayed acidosis).

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(3) Oral LD50 of the drug in animals; pared according to instructions, in concentrations of the drug in biologic terms of milligrams active ingredient fluids associated with toxicity and/or per milliliter of reconstituted solution, death; physiologic variables influ- unless another measure of the strength encing excretion of the drug, such as is more appropriate), and administra- urine pH; and factors that influence tion of the dosage form, if needed, e.g., the dose response relationship of the the rate of administration of paren- drug, such as tolerance. The pharmaco- teral drug in milligrams per minute; kinetic data given in the ‘‘Clinical storage conditions for stability of the Pharmacology’’ section also may be drug or reconstituted drug, when im- referenced here, if applicable to portant; essential information on drug overdoses. incompatibilities if the drug is mixed (4) The amount of the drug in a single in vitro with other drugs; and the fol- dose that is ordinarily associated with lowing statement for parenterals: symptoms of overdosage and the ‘‘Parenteral drug products should be amount of the drug in a single dose inspected visually for particulate mat- that is likely to be life-threatening. ter and discoloration prior to adminis- (5) Whether the drug is dialyzable. tration, whenever solution and con- (6) Recommended general treatment tainer permit.’’ procedures and specific measures for (k) How Supplied. This section of the support of vital functions, such as labeling shall contain information on proven antidotes, gastric lavage, and the available dosage forms to which forced diuresis. Unqualified rec- the labeling applies and for which the ommendations for which data are lack- manufacturer or distributor is respon- ing with the specific drug or class of sible. The information shall ordinarily drugs, especially treatment using an- include: other drug (for example, central nerv- (1) The strength of the dosage form, ous system stimulants, respiratory e.g., 10-milligram tablets, in metric stimulants) may not be stated unless system and, if the apothecary system specific data or scientific rationale ex- is used, a statement of the strength is ists to support safe and effective use. placed in parentheses after the metric (j) Dosage and Administration. This designation; section of the labeling shall state the (2) The units in which the dosage recommended usual dose, the usual form is ordinarily available for pre- dosage range, and, if appropriate, an scribing by practitioners, e.g., bottles upper limit beyond which safety and ef- of 100; fectiveness have not been established; (3) Appropriate information to facili- dosages shall be stated for each indica- tate identification of the dosage forms, tion when appropriate. Dosing regi- such as shape, color, coating, scoring, mens must not be implied or suggested and National Drug Code; and in other sections of labeling if not in- (4) Special handling and storage concluded in this section. This section ditions. shall also state the intervals rec- (l) Animal Pharmacology and/or Animal ommended between doses, the optimal Toxicology. In most cases, the labeling method of titrating dosage, the usual need not include this section. Signifi- duration of treatment, and any modi- cant animal data necessary for safe and fication of dosage needed in special pa- effective use of the drug in humans tient populations, e.g., in children, in shall ordinarily be included in one or geriatric age groups, or in patients more of the other sections of the label- with renal or hepatic disease. Specific ing, as appropriate. Commonly for a tables or monographs may be included drug that has been marketed for a long to clarify dosage schedules. Radiation time, and in rare cases for a new drug, dosimetry information shall be stated chronic animal toxicity studies have for both the patient receiving a radio- not been performed or completed for a active drug and the person admin- drug that is administered over pro- istering it. This section shall also con- longed periods or is implanted in the tain specific direction on dilution, body. The unavailability of such data preparation (including the strength of shall be stated in the appropriate sec- the final dosage solution, when pre- tion of the labeling for the drug. If the

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pertinent animal data cannot be appro- Subpart D—Exemptions From priately incorporated into other sec- Adequate Directions for Use tions of the labeling, this section may be used. § 201.100 Prescription drugs for (m) ‘‘Clinical Studies’’ and ‘‘Ref- human use. erences’’. These sections may appear in A drug subject to the requirements of labeling in the place of a detailed dis- section 503(b)(1) of the act shall be ex- cussion of a subject that is of limited empt from section 502(f)(1) if all the interest but nonetheless important. A following conditions are met: reference to a specific important clin- (a) The drug is: ical study may be made in any section (1)(i) In the possession of a person (or of the format required under §§ 201.56 his agents or employees) regularly and and 201.57 if the study is essential to an lawfully engaged in the manufacture, understandable presentation of the transportation, storage, or wholesale available information. References may distribution of prescription drugs; or appear in sections of the labeling for- (ii) In the possession of a retail, hos- mat, other than the ‘‘Clinical Studies’’ pital, or clinic pharmacy, or a public or ‘‘References’’ section, in rare cir- health agency, regularly and lawfully cumstances only. A clinical study or engaged in dispensing prescription drugs; or reference may be cited in prescription (iii) In the possession of a practi- drug labeling only under the following tioner licensed by law to administer or conditions: prescribe such drugs; and (1)(i) If the clinical study is cited in (2) It is to be dispensed in accordance the labeling in place of a detailed dis- with section 503(b) cussion of data and information con- (b) The label of the drug bears: cerning an indication for use of the (1) The statement ‘‘Rx only’’ and drug, the clinical study must con- (2) The recommended or usual dosage stitute an adequate and well-controlled and study as described in § 314.126(b) of this (3) The route of administration, if it chapter, except for biological products, is not for oral use; and and must not imply or suggest indica- (4) The quantity or proportion of tions or uses or dosing regimens not each active ingredient, as well as the stated in the ‘‘Indications and Usage’’ information required by section 502 (d) or ‘‘Dosage and Administration’’ sec- and (e); and tion. (5) If it is for other than oral use, the (ii) When prescription drug labeling names of all inactive ingredients, ex- must summarize or otherwise rely on a cept that: recommendation by an authoritative (i) Flavorings and perfumes may be scientific body, or on a standardized designated as such without naming their components. methodology, scale, or technique, be- (ii) Color additives may be des- cause the information is important to ignated as coloring without naming prescribing decisions, the labeling may specific color components unless the include a reference to the source of the naming of such components is required information. by a color additive regulation pre- (2) If the clinical study or reference is scribed in subchapter A of this chapter. cited in the labeling in the place of a (iii) Trace amounts of harmless sub- detailed discussion of data and infor- stances added solely for individual mation concerning a risk or risks from product identification need not be the use of the drug, the risk or risks named. If it is intended for administra- shall also be identified or discussed in tion by parenteral injection, the quan- the appropriate section of the labeling tity or proportion of all inactive ingre- for the drug. dients, except that ingredients added [44 FR 37462, June 26, 1979, as amended at 55 to adjust the pH or to make the drug FR 11576, Mar. 29, 1990; 59 FR 64249, Dec. 13, isotonic may be declared by name and 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396, a statement of their effect; and if the Dec. 1, 1998. Redesignated and amended at 71 vehicle is water for injection it need FR 3988, 3996, Jan. 24, 2006] not be named.

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(6) An identifying lot or control num- quency and duration of administration, ber from which it is possible to deter- and any relevant hazards, contra- mine the complete manufacturing his- indications, side effects, and pre- tory of the package of the drug. cautions under which practitioners li- (7) A statement directed to the phar- censed by law to administer the drug macist specifying the type of container can use the drug safely and for the pur- to be used in dispensing the drug prod- poses for which it is intended, includ- uct to maintain its identity, strength, ing all purposes for which it is adver- quality, and purity. Where there are tised or represented; and standards and test procedures for de- (2) If the article is subject to section termining that the container meets the 505 of the act, the labeling bearing such requirements for specified types of con- information is the labeling authorized tainers as defined in an official com- by the approved new drug application pendium, such terms may be used. For or required as a condition for the cer- example, ‘‘Dispense in tight, light-re- tification or the exemption from cer- sistant container as defined in the Na- tification requirements applicable to tional Formulary’’. Where standards preparations of insulin or antibiotic and test procedures for determining drugs. the types of containers to be used in (d) Any labeling, as defined in section dispensing the drug product are not in- 201(m) of the act, whether or not it is cluded in an official compendium, the on or within a package from which the specific container or types of con- drug is to be dispensed, distributed by tainers known to be adequate to main- or on behalf of the manufacturer, pack- tain the identity, strength, quality, er, or distributor of the drug, that fur- and purity of the drug products shall nishes or purports to furnish informa- be described. For example, ‘‘Dispense tion for use or which prescribes, rec- in containers which (statement of spec- ommends, or suggests a dosage for the ifications which clearly enable the dis- use of the drug (other than dose infor- pensing pharmacist to select an ade- mation required by paragraph (b)(2) of quate container)’’: Provided, however, this section and § 201.105(b)(2) contains: That in the case of containers too (1) Adequate information for such small or otherwise unable to accommo- use, including indications, effects, dos- date a label with sufficient space to ages, routes, methods, and frequency bear all such information, but which and duration of administration and any are packaged within an outer container relevant warnings, hazards, contra- from which they are removed for dis- indications, side effects, and pre- pensing or use, the information re- cautions, under which practitioners li- quired by paragraph (b) (2), (3), (5), and censed by law to administer the drug (7) of this section may be contained in can use the drug safely and for the pur- other labeling on or within the package poses for which it is intended, includ- from which it is to be dispensed; the in- ing all conditions for which it is adver- formation referred to in paragraph tised or represented; and if the article (b)(1) of this section may be placed on is subject to section 505 of the act, the such outer container only; and the in- parts of the labeling providing such information required by paragraph (b)(6) formation are the same in language of this section may be on the crimp of and emphasis as labeling approved or the dispensing tube. The information permitted, under the provisions of sec- required by this paragraph (b)(7) is not tion 505, and any other parts of the la- required for prescription drug products beling are consistent with and not con- packaged in unit-dose, unit-of-use, on trary to such approved or permitted la- other packaging format in which the beling; and manufacturer’s original package is de- (2) The same information concerning signed and intended to be dispensed to the ingredients of the drug as appears patients without repackaging. on the label and labeling on or within (c)(1) Labeling on or within the pack- the package from which the drug is to age from which the drug is to be dis- be dispensed. pensed bears adequate information for (3) The information required, and in its use, including indications, effects, the format specified, by §§ 201.56, 201.57, dosages, routes, methods, and fre- and 201.80.

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(e) All labeling described in para- than ‘‘possibly effective.’’ If the Com- graph (d) of this section bears con- missioner finds the circumstances are spicuously the name and place of busi- such that reminder labeling may be ness of the manufacturer, packer, or misleading to prescribers of drugs sub- distributor, as required for the label of ject to NAS/NRC evaluation, such re- the drug under § 201.1. minder labeling will not be allowed and (f) Reminder labeling which calls at- the manufacturer, packer, or dis- tention to the name of the drug prod- tributor will be notified either in the uct but does not include indications or publication of the conclusions on the dosage recommendations for use of the effectiveness of the drug or by letter. drug product is exempted from the provisions of paragraph (d) of this section. [40 FR 13998, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975; 42 FR 15674, Mar. 22, This reminder labeling shall contain 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659, only the proprietary name of the drug Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR product, if any; the established name of 25777, Apr. 15, 1980; 63 FR 26698, May 13, 1998; the drug product, if any; the estab- 64 FR 400, Jan. 5, 1999; 67 FR 4906, Feb. 1, 2002; lished name of each active ingredient 71 FR 3996, Jan. 24, 2006] in the drug product; and, optionally, 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 per- other than price lists and catalogs sole- son authorized under State law to dis- ly intended to convey price informa- pense veterinary prescription drugs, tion including, but not limited to, who is regularly and lawfully engaged those subject to the requirements of in dispensing drugs that are to be used § 200.200 of this chapter, is not per- only by or on the prescription or other mitted for a prescription drug product order of a licensed veterinarian; or whose labeling contains a boxed warn- (iii) In the possession of a licensed ing relating to a serious hazard associ- veterinarian for use in the course of his ated with the use of the drug product. professional practice; and Reminder labeling which is intended to provide consumers with information (2) To be dispensed in accordance concerning the price charged for a pre- with section 503(f) of the act. scription for a particular drug product (b) The label of the drug bears: shall meet all of the conditions con- (1) The statement ‘‘Caution: Federal tained in § 200.200 of this chapter. Re- law restricts this drug to use by or on minder labeling, other than that sub- the order of a licensed veterinarian’’; ject to the requirements of § 200.200 of and this chapter, is not permitted for a (2) The recommended or usual dos- drug for which an announcement has age; and been published pursuant to a review of (3) The route of administration, if it the labeling claims for the drug by the is not for oral use; and National Academy of Sciences/National (4) The quantity or proportion of Research Council (NAS/NRC), Drug Ef- each active ingredient as well as the ficacy Study Group, and for which no information required by section 502(e) claim has been evaluated as higher of the act; and

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(5) If it is for other than oral use, the ing all purposes for which it is adver- names of all inactive ingredients, ex- tised or represented; and cept that: (2) If the article is subject to section (i) Flavorings and perfumes may be 512 or 572 of the act, the labeling bear- designated as such without naming ing such information is the labeling au- their components. thorized by the approved new animal (ii) Color additives may be des- drug application or contained in the ignated as coloring without naming index listing: Provided, however, That specific color components unless the the information required by paragraph naming of such components is required (c)(1) of this section may be omitted by a color additive regulation pre- from the dispensing package if, but scribed in subchapter A of this chapter. only if, the article is a drug for which (iii) Trace amounts of harmless sub- directions, hazards, warnings, and use stances added solely for individual information are commonly known to product identification need not be veterinarians licensed by law to admin- named. ister the drug. Upon written request, If it is intended for administration by stating reasonable grounds therefore, parenteral injection, the quantity or the Commissioner will offer an opinion proportion of all inactive ingredients, on a proposal to omit such information except that ingredients added to adjust from the dispensing package under this the pH or to make the drug isotonic proviso. may be declared by name and a state- (d) Any labeling, as defined in section ment of their effect; and if the vehicle 201(m) of the act, whether or not it is is water for injection, it need not be on or within a package from which the named. drug is to be dispensed, distributed by (6) An identifying lot or control num- or on behalf of the manufacturer, pack- ber from which it is possible to deter- er, or distributor of the drug, that fur- mine the complete manufacturing his- nishes or purports to furnish informa- tory of the package of the drug; tion for use or which prescribes, rec- Provided, however, That in the case of ommends, or suggests a dosage for the containers too small or otherwise un- use of the drug (other than dose infor- able to accommodate a label with suffi- mation required by paragraph (b)(2) of cient space to bear all such informa- this section and § 201.100(b)(2)) contains: tion, but which are packaged within an (1) Adequate information for such outer container from which they are use, including indications, effects, dos- removed for dispensing or use, the in- ages, routes, methods, and frequency formation required by paragraphs (b) and duration of administration, and (2), (3), and (5) of this section may be any relevant warnings, hazards, con- contained in other labeling on or with- traindications, side effects, and pre- in the package from which it is to be so cautions, and including information dispensed, and the information referred relevant to compliance with the new to in paragraph (b)(1) of this section animal drug provisions of the act, may be placed on such outer container under which veterinarians licensed by only, and the information required by law to administer the drug can use the paragraph (b)(6) of this section may be drug safely and for the purposes for on the crimp of the dispensing tube. which it is intended, including all con- (c)(1) Labeling on or within the pack- ditions for which it is advertised or age from which the drug is to be dis- represented; and if the article is sub- pensed bears adequate information for ject to section 512 or 572 of the act, the its use, including indications, effects, parts of the labeling providing such in- dosages, routes, methods, and fre- formation are the same in language quency and duration of administration, and emphasis as labeling approved, per- and any relevant hazards, contra- mitted, or indexed under the provisions indications, side effects, and pre- of section 512 or 572, and any other cautions under which veterinarians li- parts of the labeling are consistent censed by law to administer the drug with and not contrary to such ap- can use the drug safely and for the pur- proved, permitted, or indexed labeling; poses for which it is intended, includ- and

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(2) The same information concerning § 201.117 Inactive ingredients. the ingredients of the drug as appears A harmless drug that is ordinarily on the label and labeling on or within used as an inactive ingredient, such as the package from which the drug is to a coloring, emulsifier, excipient, fla- be dispensed; voring, lubricant, preservative, or sol- Provided, however, That the informa- vent, in the preparation of other drugs tion required by paragraphs (d) (1) and shall be exempt from section 502(f)(1) of (2) of this section is not required on the the act. This exemption shall not apply so-called reminder-piece labeling which to any substance intended for a use calls attention to the name of the drug which results in the preparation of a but does not include indications or dos- new drug, unless an approved new-drug age recommendations for use of the application provides for such use. drug. (e) All labeling, except labels and § 201.119 In vitro diagnostic products. cartons, bearing information for use of (a) ‘‘In vitro diagnostic products’’ are the drug also bears the date of the those reagents, instruments and sys- issuance or the date of the latest revi- tems intended for use in the diagnosis sion of such labeling. of disease or in the determination of (f) A prescription drug intended for the state of health in order to cure, both human and veterinary use shall mitigate, treat, or prevent disease or comply with paragraphs (e) and (f) of its sequelae. Such products are in- this section and § 201.100. tended for use in the collection, preparation and examination of specimens [40 FR 13998, Mar. 27, 1975, as amended at 42 FR 15674, Mar. 22, 1977; 57 FR 54300, Nov. 18, taken from the human body. These 1992; 72 FR 69119, Dec. 6, 2007] products are drugs or devices as defined in section 201(g) and 201(h), respec- § 201.115 New drugs or new animal tively, of the Federal Food, Drug, and drugs. Cosmetic Act (the act) or are a com- A new drug shall be exempt from sec- bination of drugs and devices, and may tion 502(f)(1) of the act: also be a biological product subject to (a) To the extent to which such ex- section 351 of the Public Health Service emption is claimed in an approved ap- Act. plication with respect to such drug (b) A product intended for use in the under section 505 or 512 of the act or an diagnosis of disease and which is an in index listing with respect to such drug vitro diagnostic product as defined in under section 572 of the act; or paragraph (a) of this section shall be (b) If no application under section 505 deemed to be in compliance with the or 512 of the act is approved and no re- requirements of this section and sec- quest for addition to the index is grant- tion 502(f)(1) of the act if it meets the ed under section 572 with respect to requirements of § 809.10 of this chapter. such drug but it complies with section [41 FR 6910, Feb. 13, 1976] 505(i), 512(j), or 572(g) of the act and regulations thereunder. § 201.120 Prescription chemicals and other prescription components. No exemption shall apply to any other drug which would be a new drug if its A drug prepared, packaged, and pri- labeling bore representations for its in- marily sold as a prescription chemical tended uses. or other component for use by registered pharmacists in compounding [40 FR 13998, Mar. 27, 1975, as amended at 72 prescriptions or for dispensing in dos- FR 69119, Dec. 6, 2007] age unit form upon prescriptions shall § 201.116 Drugs having commonly be exempt from section 502(f)(1) of the known directions. act if all the following conditions are met: A drug shall be exempt from section (a) The drug is an official liquid acid 502(f)(1) of the act insofar as adequate or official liquid alkali, or is not a liq- directions for common uses thereof are uid solution, emulsion, suspension, tab- known to the ordinary individual. let, capsule, or other dosage unit form; [41 FR 6910, Feb. 13, 1976] and

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(b) The label of the drug bears: the production and delivery of the drug (1) The statement ‘‘For prescription substance to the application or index compounding’’; and listing holder by persons named in the (2) If in substantially all dosage application or in the request for deter- forms in which it may be dispensed it mination of eligibility for indexing, is subject to section 503(b)(1) of the act, and, for a new drug substance, the ex- the statement ‘‘Rx only’’; or port of it by such persons under (3) If it is not subject to section § 314.410 of this chapter; or 503(b)(1) of the act and is by custom (b) If no application is approved with among retail pharmacists sold in or respect to such new drug or new animal from the interstate package for use by drug, and it is not listed in the index, consumers, ‘‘adequate directions for the label statement ‘‘Caution: For use’’ in the conditions for which it is so manufacturing, processing, or repack- sold. ing’’ is immediately supplemented by the words ‘‘in the preparation of a new Provided, however, That the informa- drug or new animal drug limited by tion referred to in paragraph (b)(3) of Federal law to investigational use’’, this section may be contained in the and the delivery is made for use only in labeling on or within the package from the manufacture of such new drug or which it is to be dispensed. new animal drug limited to investiga- (c) This exemption shall not apply to tional use as provided in part 312 or any substance intended for use in § 511.1 or § 516.125 of this chapter; or compounding which results in a new (c) A new drug application or new drug, unless an approved new-drug ap- animal drug application or a request plication covers such use of the drug in for addition to the index covering the compounding prescriptions. use of the drug substance in the pro- [40 FR 13998, Mar. 27, 1975, as amended at 67 duction and marketing of a finished FR 4906, Feb. 1, 2002] drug product has been submitted but not yet approved, disapproved, granted, § 201.122 Drugs for processing, repack- or denied, the bulk drug is not ex- ing, or manufacturing. ported, and the finished drug product is A drug in a bulk package, except tab- not further distributed after it is man- lets, capsules, or other dosage unit ufactured until after the new drug ap- forms, intended for processing, repack- plication or new animal drug applica- ing, or use in the manufacture of an- tion is approved or the request for ad- other drug shall be exempt from sec- dition to the index is granted. tion 502(f)(1) of the act if its label bears [41 FR 6911, Feb. 13, 1976, as amended at 41 the statement ‘‘Caution: For manufac- FR 15844, Apr. 15, 1976; 50 FR 7492, Feb. 22, turing, processing, or repacking’’; and 1985; 55 FR 11576, Mar. 29, 1990; 57 FR 54301, if in substantially all dosage forms in Nov. 18, 1992; 67 FR 4906, Feb. 1, 2002; 72 FR which it may be dispensed it is subject 69119, Dec. 6, 2007] to section 503(b)(1) of the act, the statement ‘‘Rx only’’, or if in substantially § 201.125 Drugs for use in teaching, law enforcement, research, and all dosage forms in which it may be analysis. dispensed it is subject to section 503(f)(1) of the act, the statement A drug subject to § 201.100 or § 201.105, ‘‘Caution: Federal law restricts this shall be exempt from section 502(f)(1) of drug to use by or on the order of a li- the act if shipped or sold to, or in the censed veterinarian’’. This exemption possession of, persons regularly and and the exemption under § 201.120 may lawfully engaged in instruction in be claimed for the same article. How- pharmacy, chemistry, or medicine not ever, the exemption shall not apply to involving clinical use, or engaged in a substance intended for a use in manu- law enforcement, or in research not in- facture, processing, or repacking which volving clinical use, or in chemical causes the finished article to be a new analysis, or physical testing, and is to drug or new animal drug, unless: be used only for such instruction, law (a) An approved new drug application enforcement, research, analysis, or or new animal drug application or a testing. new animal drug index listing covers [41 FR 6911, Feb. 13, 1976]

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§ 201.127 Drugs; expiration of exemp- than those intended by the person from tions. whom he received the drug, such pack- (a) If a shipment or delivery, or any er, distributor, or seller is required to part thereof, of a drug which is exempt supply adequate labeling in accordance under the regulations in this section is with the new intended uses. But if a made to a person in whose possession manufacturer knows, or has knowledge the article is not exempt, or is made of facts that would give him notice, for any purpose other than those speci- that a drug introduced into interstate fied, such exemption shall expire, with commerce by him is to be used for con- respect to such shipment or delivery or ditions, purposes, or uses other than part thereof, at the beginning of that the ones for which he offers it, he is re- shipment or delivery. The causing of an quired to provide adequate labeling for exemption to expire shall be considered such a drug which accords with such an act which results in such drug being other uses to which the article is to be misbranded unless it is disposed of put. under circumstances in which it ceases [41 FR 6911, Feb. 13, 1976] to be a drug or device. (b) The exemptions conferred by § 201.129 Drugs; exemption for radio- §§ 201.117, 201.119, 201.120, 201.122, and active drugs for research use. 201.125 shall continue until the drugs A radioactive drug intended for ad- are used for the purposes for which ministration to human research sub- they are exempted, or until they are jects during the course of a research relabeled to comply with section project intended to obtain basic re- 502(f)(1) of the act. If, however, the search information regarding metabo- drug is converted, compounded, or manufactured into a dosage form lim- lism (including kinetics, distribution, ited to prescription dispensing, no ex- and localization) of a radioactively la- emption shall thereafter apply to the beled drug or regarding human physi- article unless the dosage form is la- ology, pathophysiology, or bio- beled as required by section 503(b) and chemistry (but not intended for imme- §§ 201.100 or 201.105. diate therapeutic, diagnostic, or similar 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 drugs. The intent is determined by Subpart E—Other Exemptions such persons’ expressions or may be shown by the circumstances sur- § 201.150 Drugs; processing, labeling, rounding the distribution of the arti- or repacking. cle. This objective intent may, for ex- (a) Except as provided by paragraphs ample, be shown by labeling claims, ad- (b) and (c) of this section, a shipment vertising matter, or oral or written or other delivery of a drug which is, in statements by such persons or their accordance with the practice of the representatives. It may be shown by trade, to be processed, labeled, or re- the circumstances that the article is, packed in substantial quantity at an with the knowledge of such persons or establishment other than that where their representatives, offered and used originally processed or packed, shall be for a purpose for which it is neither la- exempt, during the time of introduc- beled nor advertised. The intended uses tion into and movement in interstate of an article may change after it has commerce and the time of holding in been introduced into interstate com- such establishment, from compliance merce by its manufacturer. If, for ex- with the labeling and packaging re- ample, a packer, distributor, or seller quirements of sections 501(b) and 502 intends an article for different uses (b), (d), (e), (f), and (g) of the act if:

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(1) The person who introduced such (2) Upon refusal by the operator of shipment or delivery into interstate the establishment where such drug is commerce is the operator of the estab- to be processed, labeled, or repacked, lishment where such drug is to be proc- to make available for inspection a copy essed, labeled, or repacked; or of the agreement, as required by such (2) In case such person is not such op- clause. erator, such shipment or delivery is [41 FR 6911, Feb. 13, 1976, as amended at 64 made to such establishment under a FR 400, Jan. 5, 1999] written agreement, signed by and containing the post-office addresses of § 201.161 Carbon dioxide and certain such person and such operator, and other gases. containing such specifications for the (a) Carbon dioxide, cyclopropane, processing, labeling, or repacking, as ethylene, helium, and nitrous oxide the case may be, of such drug in such gases intended for drug use are exempt- establishment as will insure, if such ed from the requirements of § 201.100(b) specifications are followed, that such (2), (3), and (c)(1) provided the labeling drug will not be adulterated or mis- bears, in addition to any other infor- branded within the meaning of the act mation required by the Federal Food, upon completion of such processing, la- Drug, and Cosmetic Act, the following: beling, or repacking. Such person and (1) The warning statement ‘‘Warn- such operator shall each keep a copy of ing—Administration of (name of gas) such agreement until 2 years after the may be hazardous or contraindicated. final shipment or delivery of such drug For use only by or under the super- from such establishment, and shall vision of a licensed practitioner who is make such copies available for inspec- experienced in the use and administration at any reasonable hour to any offi- tion of (name of gas) and is familiar cer or employee of the Department who with the indications, effects, dosages, requests them. methods, and frequency and duration (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

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claims made for drugs marketed under labeling, and failure to reveal this fact new-drug and antibiotic drug proce- causes such labeling to be misleading. dures between 1938 and 1962. The results (c) Therefore, after publication in the are compiled in ‘‘Drug Efficacy Study, FEDERAL REGISTER of a Drug Efficacy A Report to the Commissioner of Food Study Implementation notice on a pre- and Drugs from the National Academy scription drug, unless exempted or oth- of Sciences (1969).’’ As the report notes, erwise provided for in the notice, all this review has made ‘‘an audit of the package labeling (other than the im- state of the art of drug usage that has mediate container or carton label, un- been uniquely extensive in scope and less such labeling contains information uniquely intensive in time’’ and is ap- required by § 201.100(c)(1) in lieu of a plicable to more than 80 percent of the package insert), promotional labeling, currently marketed drugs. The report and advertisements shall include, as further notes that the quality of the part of the information for practi- evidence of efficacy, as well as the tioners under which the drug can be quality of the labeling claims, is poor. safely and effectively used, an appro- Labeling and other promotional claims priate qualification of all claims evalu- have been evaluated as ‘‘effective,’’ ated as other than ‘‘effective’’ by a ‘‘probably effective,’’ ‘‘possibly effec- panel of the National Academy of tive,’’ ‘‘ineffective,’’ ‘‘ineffective as a Sciences—National Research Council, fixed combination,’’ and ‘‘effective Drug Efficacy Study Group, if such but,’’ and a report for each drug in the claims continue to be included in ei- study has been submitted to the Com- ther the labeling or advertisements. missioner. However, this qualifying information (2) The Food and Drug Administra- will be required in advertisements only tion is processing the reports, seeking voluntary action on the part of the if promotional material is included drug manufacturers and distributors in therein for claims evaluated as less the elimination or modification of un- than ‘‘effective’’ or if such claims are supported promotional claims, and ini- included in the indications section of tiating administrative actions as nec- the portion of the advertisement con- essary to require product and labeling taining the information required in changes. brief summary by § 202.1(e)(1) of this (3) Delays have been encountered in chapter. When, however, the Food and bringing to the attention of the pre- Drug Administration classification of scribers of prescription items the con- such claim is ‘‘effective’’ (for example, clusions of the expert panels that re- on the basis of revision of the language viewed the promotional claims. of the claim or submission or existence (b) The Commissioner of Food and of adequate data), such qualification is Drugs concludes that: not necessary. When the Food and Drug (1) The failure to disclose in the la- Administration classification of the beling of a drug and in other pro- claim, as stated in the implementation motional material the conclusions of notice, differs from that of the Acad- the Academy experts that a claim is emy but is other than ‘‘effective,’’ the ‘‘ineffective,’’ ‘‘possibly effective,’’ qualifying statement shall refer to this ‘‘probably effective,’’ or ‘‘ineffective as classification in lieu of the Academy’s a fixed combination,’’ while labeling classification. and promotional material bearing any (d) For new drugs and antibiotics, such claim are being used, is a failure supplements to provide for revised la- to disclose facts that are material in beling in accord with paragraph (c) of light of the representations made and this section shall be submitted under causes the drug to be misbranded. the provisions of § 314.70 and § 514.8 of (2) The Academy classification of a this chapter within 90 days after publi- drug as other than ‘‘effective’’ for a cation of the implementation notice in claim for which such drug is rec- the FEDERAL REGISTER or by May 15, ommended establishes that there is a 1972, for those drugs for which notices material weight of opinion among have been published and such labeling qualified experts contrary to the rep- shall be put into use as soon as possible resentation made or suggested in the but not later than the end of the time

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period allowed for submitting supple- graph (c) of this section shall contain a ments to provide for revised labeling. prominent boxed statement of the ad- (e) Qualifying information required vertised indication(s) and of the limita- in drug labeling by paragraph (c) of tions of effectiveness using the same this section in order to advise pre- format, language, and emphasis as that scribers of a drug of the findings made required in labeling by paragraph (e) of by a panel of the Academy in evalu- this section. ating a claim as other than ‘‘effective’’ (1) The boxed statement shall appear shall be at least of the same size and in (or next to) the information required color and degree of prominence as in brief summary by § 202.1(e)(1) of this other printing in the labeling and shall chapter and shall have prominence at be presented in a prominent box using least equal to that provided for other one of the following formats and proce- information presented in the brief sum- dures: mary and shall have type size, cap- (1) In drug labeling the box state- tions, color, and other physical charac- ment may entirely replace the indica- teristics comparable to the informa- tions section and be in the following tion required in the brief summary. format: (2) Less-than-effective indication(s) in the promotional message of an ad- INDICATIONS vertisement which is a single page or Based on a review of this drug by the Na- less shall be keyed to the boxed state- tional Academy of Sciences—National Re- ment by asterisk, by an appropriate search Council and/or other information, statement, or by other suitable means FDA has classified the indication(s) as fol- providing adequate emphasis on the lows: Effective: (list or state in paragraph form). boxed statement. On each page where ‘‘Probably’’ effective: (list or state in para- less-than-effective indication(s) appear graph form). in a mutiple page advertisement, an as- ‘‘Possibly’’ effective: (list or state in para- terisk shall be placed after the most graph form). prominent mention of the indi- Final classification of the less-than-effec- cation(s); if the degree of prominence tive indications requires further investiga- does not vary, an asterisk shall be tion. 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

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substantial as to require a disclosure of of an inert glandular preparation is not the reason for the change so that the available to practitioners licensed by purchaser or prescriber is not misled law. by being left unaware through the (c) The Department of Health and sponsor’s silence that a basic change Human Services is of the opinion that has taken place. The Food and Drug inert glandular materials may not be Administration will identify these situ- exempted from the requirements of ations in direct correspondence with section 502(f)(1) of the act that they the drug promoters, after which the bear adequate directions for use; and, failure to make the disclosure will be accordingly, that their labeling must regarded as misleading and appropriate include among other things, represen- action will be taken. tations as to the conditions for which [40 FR 13998, Mar. 27, 1975, as amended at 55 such articles are intended to be used or FR 11576, Mar. 29, 1990] as to the structure or function of the human body that they are intended to Subpart G—Specific Labeling Re- affect. Since any such representations quirements for Specific Drug offering these articles for use as drugs would be false or misleading, such arti- Products cles will be considered to be mis- § 201.300 Notice to manufacturers, branded if they are distributed for use packers, and distributors of glan- as drugs. dular preparations. (d) The amended regulations provide (a) Under date of December 4, 1941, in also that in the case of drugs intended a notice to manufacturers of glandular for parenteral administration there preparations, the Food and Drug Ad- shall be no exemption from the require- ministration expressed the opinion ment that their labelings bear ade- that preparations of inert glandular quate directions for use. Such inert materials intended for medicinal use glandular materials for parenteral use should, in view of the requirement of are therefore subject to the same com- section 201(n) of the Federal Food, ment as applies to those intended for Drug, and Cosmetic Act (52 Stat. 1041; oral administration. 21 U.S.C. 321(n) ), be labeled with a statement of the material fact that § 201.301 Notice to manufacturers, packers, and distributors of estro- there is no scientific evidence that the genic 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 beling of the drug, which may include nonhydroxyketonic forms of estrogenic brochures readily available to licensed hormones in units of estrone because of practitioners, bear information as to the varying ratios between the activity the use of the drug by practitioners li- of such nonhydroxyketonic estrogenic censed by law to administer it. Obvi- hormones and estrone, when measured ously, information adequate for the use by different methods on test animals.

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There is no international unit for (e) This statement of interpretation measuring the activity of estradiol and does not in any way exempt mineral oil no accepted relationship between its or preparations containing mineral oil activity and that of estrone, either in from complying in all other respects test animals or in humans. The dec- with the requirements of the Federal laration of potency of estradiol in Food, Drug, and Cosmetic Act. terms of international units or in terms of international units of estrone § 201.303 Labeling of drug prepara- activity is therefore considered mis- tions containing significant propor- leading, within the meaning of 21 tions of wintergreen oil. U.S.C. 352(a). The declaration of the es- (a) Because methyl salicylate (win- tradiol content of an estrogenic hor- tergreen oil) manifests no toxicity in mone preparation in terms of weight is the minute amounts in which it is used considered appropriate. as a flavoring, it is mistakenly regarded by the public as harmless even § 201.302 Notice to manufacturers, when taken in substantially larger packers, and distributors of drugs amounts. Actually, it is quite toxic for internal use which contain min- when taken in quantities of a teaspoon- eral oil. ful or more. Wintergreen oil and prep- (a) In the past few years research arations containing it have caused a studies have altered medical opinion as number of deaths through accidental to the usefulness and harmfulness of misuse by both adults and children. mineral oil in the human body. These Children are particularly attracted by studies have indicated that when min- the odor and are likely to swallow eral oil is used orally near mealtime it these products when left within reach. interferes with absorption from the di- (b) To safeguard against fatalities gestive tract of provitamin A and the from this cause, the Department of fat-soluble vitamins A, D, and K, and Health and Human Services will regard consequently interferes with the utili- as misbranded under the provisions of zation of calcium and phosphorus, with the Federal Food, Drug, and Cosmetic the result that the user is left liable to Act any drug containing more than 5 deficiency diseases. When so used in percent methyl salicylate (wintergreen pregnancy it predisposes to hemor- oil), the labeling of which fails to warn rhagic disease of the newborn. that use otherwise than as directed (b) There is accumulated evidence therein may be dangerous and that the that the indiscriminate administration article should be kept out of reach of of mineral oil to infants may be fol- children to prevent accidental poi- lowed by aspiration of the mineral oil soning. and subsequent ‘‘lipoid pneumonia.’’ (c) This statement of interpretation (c) In view of these facts, the Depart- in no way exempts methyl salicylate ment of Health and Human Services (wintergreen oil) or its preparations will regard as misbranded under the from complying in all other respects provisions of the Federal Food, Drug, with the requirements of the Federal and Cosmetic Act a drug for oral ad- Food, Drug, and Cosmetic Act. ministration consisting in whole or in part of mineral oil, the labeling of § 201.304 Tannic acid and barium which encourages its use in pregnancy enema preparations. or indicates or implies that such drug (a) It has become a widespread prac- is for administration to infants. tice for tannic acid to be added to bar- (d) It is also this Department’s view ium enemas to improve X-ray pictures. that the act requires the labelings of Tannic acid is capable of causing di- such drugs to bear a warning against minished liver function and severe consumption other than at bedtime liver necrosis when absorbed in suffi- and against administration to infants. cient amounts. The medical literature The following form of warning is sug- reports a number of deaths associated gested: ‘‘Caution: To be taken only at with the addition of tannic acid to bar- bedtime. Do not use at any other time ium enemas. There is a lack of sci- or administer to infants, except upon entific evidence to establish the condi- the advice of a physician.’’ tions, if any, under which tannic acid

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is safe and effective for use in enemas. arrest was noted in several of these Tannic acid for rectal use to enhance cases of sudden death. X-ray visualization is regarded as a (b) On the basis of the above informa- new drug within the meaning of section tion and after discussion with and con- 201(p) of the Federal Food, Drug, and currence of the Respiratory and Anes- Cosmetic Act. thetic Drugs Advisory Committee for (b) In view of the hazards involved Food and Drug Administration, the when tannic acid is used in barium en- Commissioner of Food and Drugs con- emas, any shipments of tannic acid la- cludes that in order for the labeling of beled to come within the exemptions such drugs to bear adequate informa- under 502(f) of the Act containing such tion for their safe use, as required by phrases as: ‘‘Caution: For manufac- § 201.100, such labeling must include the turing, processing, or repackaging,’’ following: ‘‘For prescription compounding,’’ or ‘‘Diagnostic reagent—For professional Warning: Occasional patients have been reported to develop severe paradoxical airway use only’’ will be regarded by the Com- resistance with repeated, excessive use of missioner of Food and Drugs as mis- isoproterenol inhalation preparations. The branded within the meaning of section cause of this refractory state is unknown. It 502(f) of the Federal Food, Drug, and is advisable that in such instances the use of Cosmetic Act unless the label and the this preparation be discontinued imme- labeling bear conspicuously a warning diately and alternative therapy instituted, to the effect: ‘‘Warning— Not for use in since in the reported cases the patients did enemas.’’ not respond to other forms of therapy until (c) Any tannic acid intended for use the drug was withdrawn. by man and found within the jurisdic- Deaths have been reported following excessive use of isoproterenol inhalation preparation of the Federal Food, Drug, and tions and the exact cause is unknown. Car- Cosmetic Act labeled contrary to this diac arrest was noted in several instances. section after 60 days from the date of its publication in the FEDERAL REG- (c)(1) The Commissioner also con- ISTER may be made the subject of regu- cludes that in view of the manner in latory proceedings. which these preparations are self-administered for relief of attacks of bron- § 201.305 Isoproterenol inhalation chial asthma and other chronic bron- preparations (pressurized aerosols, chopulmonary disorders, it is necessary nebulizers, powders) for human for the protection of users that warn- use; warnings. ing information to patients be included (a) Accumulating reports have been as a part of the label and as part of any received by the Food and Drug Admin- instructions to patients included in the istration and have appeared in the package dispensed to the patient as fol- medical literature of severe paradox- lows: ical bronchoconstriction associated with repeated, excessive use of Warning: Do not exceed the dose prescribed by your physician. If difficulty in breathing isoproterenol inhalation preparations persists, contact your physician imme- in the treatment of bronchial asthma diately. and other chronic bronchopulmonary disorders. The cause of this paradoxical (2) The warning on the label may be reaction is unknown; it has been ob- accomplished (i) by including it on the served, however, that patients have not immediate container label with a responded completely to other forms of statement directed to pharmacists not therapy until use of the isoproterenol to remove the label or (ii) by including inhalation preparation was discon- in the package a printed warning with tinued. In addition, sudden unexpected instructions to pharmacists to place deaths have been associated with the the warning on the container prior to excessive use of isoproterenol inhala- dispensing. tion preparations. The mechanism of (d) The marketing of isoproterenol these deaths and their relationship, if inhalation preparations may be contin- any, to the cases of severe paradoxical ued if all the following conditions are bronchospasm are not clear. Cardiac met:

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

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publication of this section, with re- tainer was mistakenly used instead of spect to the marketing of uncoated the 45-mL or 90-mL container. The tablets containing potassium chloride Food and Drug Administration is lim- or other potassium salts which supply iting the amount of sodium phosphates 100 milligrams or more of potassium oral solution to not more than 90 mL (3 per tablet or with respect to liquid ounces (oz)) per OTC container because preparations containing potassium of the serious health risks associated chloride or other potassium salts which with the ingestion of larger than in- supply 20 milligrams or more of potas- tended doses of this product. Further, sium per milliliter, labeled or intended because an overdose of either oral or for human use, unless all the following rectal enema sodium phosphates can conditions are met: cause an electrolyte imbalance, addi- (1) The labeling of the drug bears the tional warning and direction state- prescription statement quoted in sec- ments are required for the safe use of tion 503(b)(4) of the Federal Food, any OTC laxative drug product con- Drug, and Cosmetic Act; and taining sodium phosphates. (2) The labeling on or within the (b) Any OTC drug product for lax- package from which the drug is to be ative or bowel cleansing use containing dispensed bears adequate information sodium phosphates as an active ingre- for its use by practitioners in accord dient when marketed as described in with the ‘‘full disclosure’’ labeling re- paragraph (a) of this section is mis- quirements of § 201.100 of this chapter, branded within the meaning of section including a recommendation that pa- 502 of the Federal Food, Drug, and Cos- tients be directed to dissolve any such metic Act unless packaged and labeled tablets in an appropriate amount of as follows: liquid and to dilute any such liquid (1) Package size limitation for so- preparations adequately to assure dium phosphates oral solution: Con- against gastrointestinal injury associ- tainer shall not contain more than 90 ated with the oral ingestion of con- mL (3 oz). centrated potassium salt preparations. (2) Warnings. The following sentences [40 FR 13998, Mar. 27, 1975, as amended at 55 shall appear in boldface type as the FR 11576, Mar. 29, 1990; 67 FR 4906, Feb. 1, first statement under the heading 2002] ‘‘Warnings.’’ (i) Oral dosage forms. ‘‘Taking more § 201.307 Sodium phosphates; package than the recommended dose in 24 hours size limitation, warnings, and direc- can be harmful.’’ tions for over-the-counter sale. (ii) Rectal enema dosage forms. (a) Reports in the medical literature ‘‘Using more than one enema in 24 and data accumulated by the Food and hours can be harmful.’’ Drug Administration indicate that (3) Directions—(i) The labeling of all multiple container sizes of sodium orally or rectally administered OTC phosphates oral solution available in drug products containing sodium the marketplace have caused consumer phosphates shall contain the following confusion and appear to have been in- directions in boldface type imme- volved in several consumer deaths. So- diately preceding the dosage informa- dium phosphates oral solution has been tion: ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) marketed in 45-milliliter (mL), 90-mL, ‘‘more unless directed by a doctor. See and 240-mL container sizes. The 45-mL Warnings.’’ and 90-mL container sizes of sodium (ii) For products containing dibasic phosphates oral solution are often rec- sodium phosphate/monobasic sodium ommended and prescribed by physi- phosphate identified in § 334.16(d) mar- cians for bowel cleansing prior to sur- keted as a solution. Adults and chil- gery and diagnostic procedures of the dren 12 years of age and over: Oral dos- colon. Sodium phosphates oral solution age is dibasic sodium phosphate 3.42 to (adult dose 20 mL to 45 mL) is also used 7.56 grams (g) and monobasic sodium as an over-the-counter (OTC) laxative phosphate 9.1 to 20.2 g (20 to 45 mL di- for the relief of occasional constipa- basic sodium phosphate/monobasic so- tion. Accidental overdosing and deaths dium phosphate oral solution) as a sin- have occurred because the 240-mL con- gle daily dose. ‘‘Do not take more than

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45 mL (9 teaspoonfuls or 3 tablespoon- beled as an emergency treatment for fuls) in a 24-hour period.’’ Children 10 use in poisonings should be available and 11 years of age: Oral dosage is diba- over the counter has been controver- sic sodium phosphate 1.71 to 3.78 g and sial. monobasic sodium phosphate 4.5 to 10.1 (b) In connection with its study of g (10 to 20 mL dibasic sodium phos- this problem, the Food and Drug Ad- phate/monobasic sodium phosphate ministration has obtained the views of oral solution) as a single daily dose. medical authorities. It is the unani- ‘‘Do not take more than 20 mL (4 tea- mous recommendation of the American spoonfuls) in a 24-hour period.’’ Chil- Academy of Pediatrics, the American dren 5 to 9 years of age: Oral dosage is Association of Poison Control Centers, dibasic sodium phosphate 0.86 to 1.89 g the American Medical Association, and and monobasic sodium phosphate 2.2 to the Medical Advisory Board of the 5.05 g (5 to 10 mL dibasic sodium phos- Food and Drug Administration that ip- phate/monobasic sodium phosphate ecac syrup in 1 fluid ounce containers oral solution) as a single daily dose. be permitted to be sold without pre- ‘‘Do not take more than 10 mL (2 tea- scription so that it will be readily spoonfuls) in a 24-hour period.’’ Chil- available in the household for emer- dren under 5 years of age: ask a doctor. gency treatment of poisonings, under (c) After June 22, 1998, for package medical supervision, and that the drug size limitation and September 18, 1998, be appropriately packaged and labeled for labeling in accord with paragraph for this purpose. (b) of this section, any such OTC drug (c) In view of the above recommenda- product initially introduced or ini- tions, the Commissioner of Food and tially delivered for introduction into Drugs has determined that it is in the interstate commerce, or any such drug interest of the public health for ipecac product that is repackaged or relabeled syrup to be available for sale without after these dates regardless of the date prescription, provided that it is pack- the product was manufactured, ini- aged in a quantity of 1 fluid ounce (30 tially introduced, or initially delivered milliliters), and its label bears, in addi- for introduction into interstate com- tion to other required label informa- merce, that is not in compliance with tion, the following, in a prominent and this section is subject to regulatory ac- conspicuous manner: tion. (1) A statement conspicuously boxed [63 FR 27843, May 21, 1998] and in red letters, to the effect: ‘‘For emergency use to cause vomiting in § 201.308 Ipecac syrup; warnings and poisoning. Before using, call physician, directions for use for over-the- 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

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commerce, began an active investiga- metic Act, unless the label and label- tion of reports of possible toxic effects ing on or within the package from and renal damage due to misuse of the which the drug is to be dispensed, and drug acetophenetidin. This study led to any other labeling furnishing or pur- the decision that there was probable porting to furnish information for use cause to conclude that misuse and pro- of the drug, bear a conspicuous warn- longed use of the drug were in fact re- ing statement to the following effect: sponsible for kidney lesions and dis- ‘‘Warning: Agranulocytosis and hepa- ease. The Commissioner of Food and titis have been associated with the use Drugs, in December 1963, appointed an of phenindione. Patients should be inad hoc Advisory Committee of Inquiry structed to report promptly prodromal on Possible Nephrotoxicity Associated symptoms such as marked fatigue, With the Abuse of Acetophenetidin chill, fever, and sore throat. Periodic (Phenacetin)-Containing Preparations. This committee, composed of scientists blood studies and liver function tests in the fields of pharmacology and med- should be performed. Use of the drug icine, on April 23, 1964, submitted its should be discontinued if leukopenia findings and conclusions in the matter occurs or if evidence of hyper- and recommended that all acetophe- sensitivity, such as dermatitis or fever, netidin (phenacetin)-containing prep- appears.’’ arations bear a warning as provided in (b) Regulatory action may be initi- section 502(f)(2) of the Federal Food, ated with respect to preparations of Drug, and Cosmetic Act. phenindione intended for use by man (b) On the basis of the studies made found within the jurisdiction of the act by the Food and Drug Administration on or after November 25, 1961, unless and the report of the Advisory Com- such preparations are labeled in ac- mittee, the Commissioner of Food and cordance with paragraph (a) of this sec- Drugs has concluded that it is nec- tion. essary for the protection of users that the label and labeling of all acetophe- § 201.311 [Reserved] netidin (phenacetin)-containing preparations bear a warning statement to § 201.312 Magnesium sulfate the following effect: ‘‘Warning—This heptahydrate; label declaration on medication may damage the kidneys drug products. when used in large amounts or for a Magnesium sulfate heptahydrate long period of time. Do not take more should be listed on the label of a drug than the recommended dosage, nor product as epsom salt, which is its take regularly for longer than 10 days common or usual name. without consulting your physician.’’ § 201.313 Estradiol labeling. § 201.310 Phenindione; labeling of drug preparations intended for use The article presently recognized in by man. The National Formulary under the (a) Reports in the medical literature heading ‘‘Estradiol’’ and which is said and data accumulated by the Food and to be ‘‘17-cis-beta estradiol’’ is the Drug Administration indicate that same substance formerly recognized in phenindione, a synthetic anticoagulant the United States Pharmacopeia under drug, has caused a number of cases of the designation ‘‘Alpha Estradiol.’’ The agranulocytosis (with two fatalities). substance should no longer be referred There are also reports implicating the to in drug labeling as ‘‘Alpha Estra- drug in cases of hepatitis and hyper- diol.’’ The Food and Drug Administra- sensitivity reactions. In view of the po- tion would not object to label ref- tentially serious effects found to be as- erences to the article as simply ‘‘Es- sociated with preparations of this drug tradiol’’; nor would it object if the intended for use by man, the Commis- label of a preparation containing this sioner of Food and Drugs will regard substance referred to the presence of such preparations as misbranded with- ‘‘Estradiol (formerly known as Alpha in the meaning of section 502(f) (1) and Estradiol).’’ (2) of the Federal Food, Drug, and Cos-

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§ 201.314 Labeling of drug prepara- at the option of the distributor, be lations containing salicylates. beled for use by adults only. If their la- (a) The label of any oral drug prepa- beling and advertising clearly offer ration intended for sale without pre- them for administration to adults only. scription and which contains any salic- (e)(1) It is the obligation of the dis- ylate ingredient (including aspirin, sal- tributor who labels a salicylate prepa- icylamide, other salicylates, and com- ration for administration to children binations) must conspicuously bear, on to make certain that the article is a clearly contrasting background, the suitable for such use and labeled with warning statement: ‘‘Keep out of reach adequate directions for use in the age of children [highlighted in bold type]. group for which it is offered, but in no In case of overdose, get medical help or case should such an article bear direc- contact a Poison Control Center right tions for use in children under 3 years away,’’ or ‘‘Keep out of reach of chil- of age. If the directions provide for ad- dren [highlighted in bold type],’’ except ministration to children as young as 3 that if the article is an aspirin prepara- years of age, the label should bear the tion, it shall bear the first of these statement, ‘‘For children under 3 years warning statements. Such a warning of age consult your physician.’’ How- statement is required for compliance ever, if the directions provide for ad- with section 502(f)(2) of the Federal ministration to children only of an age Food, Drug, and Cosmetic Act and is greater than 3 years (for example, the intended to guard against accidental dosage instructions provide for admin- poisonings. Safety closures that pre- istration of the article to children only vent access to the drug by young chil- down to age 6), the label should bear a dren are also recommended to guard statement such as, ‘‘For younger chil- against accidental poisonings. dren consult your physician.’’ (b) Effervescent preparations and (2) A statement such as, ‘‘For chil- preparations containing para- dren under 3 years of age consult your aminosalicylate as the only salicylate physician’’ or ‘‘For younger children ingredient are exempted from this la- consult your physician’’ is not required beling requirement. on the label of an article clearly of- (c) Aspirin tablets sold as such and fered for administration to adults only. containing no other active ingredients, except tablets which cannot be readily (f) If the labeling or advertising of a subdivided into a child’s dose because salicylate preparation offers it for use of their coating or size, should always in arthritis or rheumatism, the label bear dosage directions for each age and labeling should clearly state that group down to 3 years of age, with a the beneficial effects claimed are lim- statement such as ‘‘For children under ited to: ‘‘For the temporary relief of 3 years of age, consult your physician.’’ minor aches and pains of arthritis and It is recommended that: rheumatism.’’ The qualifying phrase (1) Aspirin tablets especially made ‘‘for the temporary relief of minor for pediatric use be produced only in aches and pains’’ should appear with 11⁄4-grain size to reduce the hazard of the same degree of prominence and errors in dosage; conspicuousness as the phrase ‘‘arthri- (2) By June 1, 1967, manufacturers tis and rheumatism’’. The label and la- and distributors of 11⁄4-grain size aspi- beling should bear in juxtaposition rin tablets discontinue the distribution with such directions for use con- of such tablets in retail containers conspicuous warning statements to the ef- taining more than 36 tablets, to reduce fect: ‘‘Caution: If pain persists for more the hazard of accidental poisoning; than 10 days, or redness is present, or (3) The flavoring of 5-grain aspirin in conditions affecting children under tablets or other ‘‘adult aspirin tablets’’ 12 years of age, consult a physician im- be discontinued; and mediately.’’ The salicylate dosage (4) Labeling giving undue emphasis should not exceed 60 grains in a 24-hour to the pleasant flavor of flavored aspi- period or 10 grains in a 4-hour period. If rin tablets be discontinued. the article contains other analgesics, (d) Salicylate preparations other the salicylate dosage should be appro- than aspirin tablets sold as such may, priately reduced.

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(g)(1) The label of any drug con- of the Federal Food, Drug, and Cos- taining more than 5 percent methyl sa- metic Act. licylate (wintergreen oil) should bear a (i) Compliance by October 18, 2004, for conspicuous warning such as: ‘‘Do not OTC drug products containing aspirin use otherwise than as directed.’’ These and nonaspirin salicylates as an active drug products must also include the ingredient and marketed under a new ‘‘Keep out of reach of children’’ warn- drug application or abbreviated new ing and the accidental ingestion warn- drug application. ing as required in § 330.1(g) of this chap- (ii) Compliance by April 19, 2004, for ter. OTC antidiarrheal and overindulgence (2) If the preparation is a counter- drug products that contain bismuth irritant or rubefacient, it should also subsalicylate as an active ingredient bear a caution such as, ‘‘Caution: Dis- and have annual sales greater than continue use if excessive irritation of $25,000. the skin develops. Avoid getting into (iii) Compliance by April 18, 2005, for the eyes or on mucous membranes.’’ OTC antidiarrheal and overindulgence (See also § 201.303.) drug products that contain bismuth (h)(1) The labeling of orally or rec- subsalicylate as an active ingredient tally administered over-the-counter and have annual sales less than $25,000. drug products containing aspirin or (iv) Compliance dates for all other nonaspirin salicylates as active ingre- OTC drug products containing aspirin dients subject to this paragraph is re- and nonaspirin salicylates as an active quired to prominently bear the fol- ingredient and marketed under an OTC lowing warning: ‘‘Reye’s syndrome [subheading in bold type]: Children and drug monograph (for internal analge- teenagers who have or are recovering sic, antipyretic, and antirheumatic from chicken pox or flu-like symptoms drug products, or for menstrual drug should not use this product. When products) will be established when the using this product, if changes in behav- final monographs for those products ior with nausea and vomiting occur, are published in a future issue of the consult a doctor because these symp- FEDERAL REGISTER. In the interim, toms could be an early sign of Reye’s these products should continue to be syndrome, a rare but serious illness.’’ labeled with the previous Reye’s syn- (2) This warning statement shall ap- drome warning that appears in para- pear on the immediate container label- graph (h)(1) of this section. ing. In cases where the immediate con- [40 FR 13998, Mar. 27, 1985, as amended at 51 tainer is not the retail package, the re- FR 8182, Mar. 7, 1986; 53 FR 21637, June 9, tail package also must bear the warn- 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, ing statement. In addition, the warning Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR statement shall appear on any labeling 18869, Apr. 17, 2003] that contains warnings and, in such cases, the warning statement shall be § 201.315 Over-the-counter drugs for the first warning statement under the minor sore throats; suggested warn- heading ‘‘Warnings.’’ ing. (3) Over-the-counter drug products The Food and Drug Administration subject to this paragraph and labeled has studied the problem of the labeling solely for use by children (pediatric of lozenges or troches containing a products) shall not recommend the local anesthetic, chewing gum con- product for use in treating flu or chick- taining aspirin, various mouth washes en pox. and gargles and other articles sold over (4) Any product subject to paragraphs the counter for the relief of minor irri- (h)(1), (h)(2), and (h)(3) of this section tations of the mouth or throat. It will that is not labeled as required by these not object to the labeling of suitable paragraphs and that is initially intro- articles of this type ‘‘For the tem- duced or initially delivered for intro- porary relief of minor sore throats’’, duction into interstate commerce after provided this is immediately followed the following dates is misbranded in the labeling with a warning state- under sections 201(n) and 502(a) and (f) ment in prominent type essentially as

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follows: ‘‘Warning—Severe or per- beling bears the following boxed warn- sistent sore throat or sore throat ac- ing at the beginning of the ‘‘Warnings’’ companied by high fever, headache, section: nausea, and vomiting may be serious. Consult physician promptly. Do not use more than 2 days or administer to Digitalis alone or with other drugs has been used in the treatment of obesity. children under 3 years of age unless di- This use of digoxin or other digitalis rected by physician.’’ glycosides is unwarranted. Moreover, since they may cause potentially fatal § 201.316 Drugs with thyroid hormone arrhythmias or other adverse effects, activity for human use; required the use of these drugs in the treatment warning. of obesity is dangerous. (a) Drugs with thyroid hormone activity have been promoted for, and con- (c) This section does not apply to dig- tinue to be dispensed and prescribed oxin products for oral use, which shall for, use in the treatment of obesity, al- be labeled according to the require- though their safety and effectiveness ments of § 310.500 of this chapter. for that use have never been established. [43 FR 22009, May 23, 1978] (b) Drugs for human use with thyroid hormone activity are misbranded with- § 201.319 Water-soluble gums, hydro- in the meaning of section 502 of the philic gums, and hydrophilic Federal Food, Drug, and Cosmetic Act mucilloids (including, but not limited to agar, alginic acid, calcium unless their labeling bears the fol- polycarbophil, lowing boxed warning at the beginning carboxymethylcellulose sodium, of the ‘‘Warnings’’ section: carrageenan, chondrus, glucomannan ((B-1,4 linked) Drugs with thyroid hormone activity, polymannose acetate), guar gum, alone or together with other therapeutic karaya gum, kelp, methylcellulose, agents, have been used for the treatment plantago seed (psyllium), of obesity. In euthyroid patients, doses polycarbophil tragacanth, and xan- within the range of daily hormonal re- than gum) as active ingredients; requirements are ineffective for weight required warnings and directions. duction. Larger doses may produce seri- (a) Reports in the medical literature ous or even life-threatening manifestations of toxicity, particularly when and data accumulated by the Food and given in association with Drug Administration indicate that sympathomimetic amines such as those esophageal obstruction and asphyxia- used for their anorectic effects. tion have been associated with the ingestion of water-soluble gums, hydrophilic gums, and hydrophilic [43 FR 22009, May 23, 1978] mucilloids including, but not limited § 201.317 Digitalis and related to, agar, alginic acid, calcium cardiotonic drugs for human use in polycarbophil, carboxymethylcellulose oral dosage forms; required warn- sodium, carrageenan, chondrus, ing. glucomannan ((B–1,4 linked) (a) Digitalis and related cardiotonic polymannose acetate), guar gum, drugs for human use in oral dosage karaya gum, kelp, methylcellulose, forms have been promoted for, and con- plantago seed (psyllium), tinue to be dispensed and prescribed polycarbophil, tragacanth, and xan- for, use in the treatment of obesity, al- than gum. Esophageal obstruction and though their safety and effectiveness asphyxiation due to orally-adminis- for that use have never been estab- tered drug products containing water- lished. soluble gums, hydrophilic gums, and (b) Digitalis and related cardiotonic hydrophilic mucilloids as active ingre- drugs for human use in oral dosage dients are significant health risks forms are misbranded within the mean- when these products are taken without ing of section 502 of the Federal Food, adequate fluid or when they are used Drug, and Cosmetic Act unless their la-

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by individuals with esophageal nar- date the product was manufactured, rowing or dysfunction, or with dif- initially introduced, or initially deliv- ficulty in swallowing. Additional label- ered for introduction into interstate ing is needed for the safe and effective commerce, that is not in compliance use of any OTC drug product for human with this section is subject to regu- use containing a water-soluble gum, latory action. hydrophilic gum, or hydrophilic mucilloid as an active ingredient when [58 FR 45201, Aug. 26, 1993, as amended at 64 marketed in a dry or incompletely hy- FR 13292, Mar. 17, 1999; 72 FR 14674, Mar. 29, drated form to include, but not limited 2007] to, the following dosage forms: Cap- § 201.320 Warning statements for drug sules, granules, powders, tablets, and products containing or manufac- wafers. Granular dosage forms con- tured with chlorofluorocarbons or taining psyllium are not generally rec- other ozone-depleting substances. ognized as safe and effective as OTC laxatives (see § 310.545(a)(12)(i)(B) of (a)(1) All drug products containing or this chapter) and may not be marketed manufactured with without an approved new drug applica- chlorofluorocarbons, halons, carbon tion because the warnings and direc- tetrachloride, methyl chloride, or any tions in paragraph (b) of this section other class I substance designated by have been found inadequate for these the Environmental Protection Agency products. (EPA) shall, except as provided in para- (b) Any drug products for human use graph (b) or (c) of this section, bear the containing a water-soluble gum, hydro- following warning statement: philic gum, or hydrophilic mucilloid as Warning: Contains [or Manufactured with, an active ingredient in an oral dosage if applicable] [insert name of substance], a sub- form when marketed in a dry or incom- stance which harms public health and the pletely hydrated form as described in environment by destroying ozone in the paragraph (a) of this section are mis- upper atmosphere. branded within the meaning of section 502 of the Federal Food, Drug, and Cos- (2) The warning statement shall be metic Act unless their labeling bears clearly legible and conspicuous on the the following warnings (under the sub- product, its immediate container, its heading ‘‘Choking’’) and directions: outer packaging, or other labeling in ‘‘ ‘Choking’ [highlighted in bold accordance with the requirements of 40 type]: Taking this product without CFR part 82 and appear with such adequate fluid may cause it to swell prominence and conspicuousness as to and block your throat or esophagus and render it likely to be read and under- may cause choking. Do not take this stood by consumers under normal con- product if you have difficulty in swal- ditions of purchase. lowing. If you experience chest pain, (b)(1) For prescription drug products vomiting, or difficulty in swallowing or for human use, the following alter- breathing after taking this product, native warning statement may be used: seek immediate medical attention;’’ NOTE: The indented statement below is re- and quired by the Federal government’s Clean ‘‘ ‘Directions’ [highlighted in bold Air Act for all products containing or manu- type]:’’ (Select one of the following, as factured with chlorofluorocarbons (CFC’s) appropriate: ‘‘Take’’ or ‘‘Mix’’) ‘‘this [or name of other class I substance, if appli- product (child or adult dose) with at cable]: least 8 ounces (a full glass) of water or This product contains [or is manufactured other fluid. Taking this product with- with, if applicable] [insert name of substance], out enough liquid may cause choking. a substance which harms the environment by See choking warning.’’ destroying ozone in the upper atmosphere. (c) After February 28, 1994, any such Your physician has determined that this product is likely to help your personal OTC drug product initially introduced health. USE THIS PRODUCT AS DIRECTED, or initially delivered for introduction UNLESS INSTRUCTED TO DO OTHERWISE into interstate commerce, or any such BY YOUR PHYSICIAN. If you have any ques- drug product that is repackaged or re- tions about alternatives, consult with your labeled after this date regardless of the physician.

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(2) The warning statement shall be accordance with the requirements of 40 clearly legible and conspicuous on the CFR part 82 and appear with such product, its immediate container, its prominence and conspicuousness as to outer packaging, or other labeling in render it likely to be read and under- accordance with the requirements of 40 stood by consumers under normal con- CFR part 82 and appear with such ditions of purchase. prominence and conspicuousness as to (d) This section does not replace or render it likely to be read and under- relieve a person from any requirements stood by consumers under normal con- imposed under 40 CFR part 82. ditions of purchase. [61 FR 20100, May 3, 1996] (3) If the warning statement in paragraph (b)(1) of this section is used, the § 201.322 Over-the-counter drug prod- following warning statement must be ucts containing internal analgesic/ placed on the package labeling in- antipyretic active ingredients; re- tended to be read by the physician quired alcohol warning. (physician package insert) after the (a) People who regularly consume ‘‘How supplied’’ section, which de- large quantities of alcohol (three or scribes special handling and storage more drinks every day) have an in- conditions on the physician labeling: creased risk of adverse effects (possible liver damage or gastrointestinal bleed- NOTE: The indented statement below is required by the Federal government’s Clean ing). OTC drug products containing in- Air Act for all products containing or manu- ternal analgesic/antipyretic active in- factured with chlorofluorocarbons (CFC’s) gredients may cause similar adverse ef- [or name of other class I substance, if appli- fects. FDA concludes that the labeling cable]: of OTC drug products containing inter- WARNING: Contains [or Manufactured with, nal analgesic/antipyretic active ingre- if applicable] [insert name of substance], a sub- dients should advise consumers with a stance which harms public health and the history of heavy alcohol use to consult 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 patient [or patient information leaflet, if ap- pyretic active ingredients (including, plicable] 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 manu- other pain relievers/fever reducers. Ac- factured with chlorofluorocarbons (CFC’s) [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

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reducers. [Insert one nonsteroidal anti- § 201.323 Aluminum in large and small inflammatory analgesic/antipyretic ac- volume parenterals used in total tive ingredient] may cause stomach parenteral nutrition. bleeding.’’ (a) The aluminum content of large (3) Combinations of acetaminophen with volume parenteral (LVP) drug products nonsteroidal anti-inflammatory analgesic/ used in total parenteral nutrition antipyretic active ingredients—including (TPN) therapy must not exceed 25 but not limited to aspirin, carbaspirin cal- micrograms per liter (μg/L). cium, choline salicylate, ibuprofen, (b) The package insert of LVP’s used ketoprofen, magnesium salicylate, in TPN therapy must state that the naproxen sodium, and sodium salicylate. drug product contains no more than 25 ‘‘Alcohol Warning’’ [heading in bold- μg/L of aluminum. This information face type]: ‘‘If you consume 3 or more must be contained in the ‘‘Pre- alcoholic drinks every day, ask your cautions’’ section of the labeling of all doctor whether you should take [insert large volume parenterals used in TPN acetaminophen and one nonsteroidal therapy. anti-inflammatory analgesic/anti- (c) Except as provided in paragraph pyretic active ingredient—including, (d) of this section, the maximum level but not limited to aspirin, carbaspirin of aluminum present at expiry must be calcium, choline salicylate, magnesium stated on the immediate container salicylate, or sodium salicylate] or label of all small volume parenteral other pain relievers/fever reducers. [Ac- (SVP) drug products and pharmacy etaminophen and (insert one nonste- bulk packages (PBPs) used in the prep- roidal anti-inflammatory analgesic/ aration of TPN solutions. The alu- antipyretic ingredient—including, but minum content must be stated as fol- not limited to aspirin, carbaspirin cal- lows: ‘‘Contains no more than ll μg/L cium, choline salicylate, magnesium of aluminum.’’ The immediate con- salicylate, or sodium salicylate] may tainer label of all SVP’s and PBP’s cause liver damage and stomach bleed- that are lyophilized powders used in ing.’’ the preparation of TPN solutions must (b) Requirements to supplement ap- contain the following statement: proved application. Holders of approved ‘‘When reconstituted in accordance applications for OTC drug products with the package insert instructions, that contain internal analgesic/anti- the concentration of aluminum will be pyretic active ingredients that are sub- no more than ll μg/L.’’ This max- ject to the requirements of paragraph imum level of aluminum must be stat- (a) of this section must submit supple- ed as the highest of: ments under § 314.70(c) of this chapter (1) The highest level for the batches to include the required warning in the produced during the last 3 years; product’s labeling. Such labeling may (2) The highest level for the latest be put into use without advance ap- five batches, or proval of FDA provided it includes the (3) The maximum historical level, exact information included in para- but only until completion of produc- graph (a) of this section. tion of the first five batches after July (c) Any drug product subject to this 26, 2004. section that is not labeled as required (d) If the maximum level of alu- and that is initially introduced or ini- minum is 25 μg/L or less, instead of tially delivered for introduction into stating the exact amount of aluminum interstate commerce after April 23, as required in paragraph (c) of this sec- 1999, is misbranded under section 502 of tion, the immediate container label the Federal Food, Drug, and Cosmetic may state: ‘‘Contains no more than 25 Act (21 U.S.C. 352) and is subject to reg- μg/L of aluminum.’’ If the SVP or PBP ulatory action. is a lyophilized powder, the immediate container label may state: ‘‘When re- [63 FR 56801, Oct. 23, 1998] constituted in accordance with the EFFECTIVE DATE NOTE: At 74 FR 19407, Apr. package insert instructions, the con- 29, 2009, § 201.322 was removed, effective Apr. centration of aluminum will be no 29, 2010. more than 25 μg/L’’.

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

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not eliminate, the risk of catching or in accordance with §§ 201.60, 201.61, and spreading HIV, the virus that causes 201.66. AIDS. (1) Acetaminophen—(i) Statement of (d) The labeling of this product in- identity. The statement of identity ap- cludes the following statements either pears in accord with §§ 201.61 and 299.4 on the outside container or wrapper of of this chapter. The ingredient name the retail package, under the ‘‘Other ‘‘acetaminophen’’ must appear high- information’’ section of the Drug Facts lighted (e.g., fluorescent or color con- labeling in accordance with trast) or in bold type, be in lines gen- § 201.66(c)(7), or in a package insert: erally parallel to the base on which the (1) ‘‘[bullet] studies have raised safe- package rests as it is designed to be ty concerns that products containing displayed, and be in one of the fol- the spermicide nonoxynol 9 can irritate lowing sizes, whichever is greater: the vagina and rectum. Sometimes this (A) At least one-quarter as large as irritation has no symptoms. This irri- the size of the most prominent printed tation may increase the risk of getting matter on the principal display panel HIV/AIDS from an infected partner’’. (PDP), or (2) ‘‘[bullet] you can use nonoxynol 9 (B) At least as large as the size of the for birth control with or without a dia- ‘‘Drug Facts’’ title, as required in phragm or condom if you have sex with § 201.66(d)(2). The presence of acetami- only one partner who is not infected nophen must appear as part of the es- with HIV and who has no other sexual tablished name of the drug, as defined partners or HIV risk factors’’. in § 299.4 of this chapter. Combination (3) ‘‘[bullet] use a latex condom with- products containing acetaminophen out nonoxynol 9 if you or your sex and a nonanalgesic ingredient(s) (e.g., partner has HIV/AIDS, multiple sex cough-cold) must include the name partners, or other HIV risk factors’’. ‘‘acetaminophen’’ and the name(s) of the other active ingredient(s) in the (4) ‘‘[bullet] ask a health professional product on the PDP in accord with this if you have questions about your best paragraph. Only the name ‘‘acetami- birth control and STD prevention nophen’’ must appear highlighted or in methods’’. bold type, and in a prominent print (e) Any drug product subject to this size, as described in this paragraph. section that is not labeled as required (ii) Active Ingredient and Purpose and that is initially introduced or ini- Headings. The information required tially delivered for introduction into under § 201.66(c)(2) and (c)(3) of this interstate commerce after June 19, chapter must be included under these 2008, is misbranded under section 502 of headings. The information under these the Federal Food, Drug, and Cosmetic headings, but not the headings, may Act (the act) (21 U.S.C. 352), is a new appear highlighted. drug under section 505 of the act (21 (iii) For products labeled for adults U.S.C. 355), and is subject to regulatory only. The labeling of the product states action. the following warnings under the head- [72 FR 71785, Dec. 19, 2007] ing ‘‘Warnings’’: (A) The liver warning states ‘‘Liver § 201.326 Over-the-counter drug prod- warning [heading in bold type]: This ucts containing internal analgesic/ product contains acetaminophen. Se- antipyretic active ingredients; re- vere liver damage may occur if you quired warnings and other labeling. take [bullet] more than [insert max- (a) Labeling. The labeling for all over- imum number of daily dosage units] in the-counter (OTC) drug products con- 24 hours, which is the maximum daily taining any internal analgesic/anti- amount [optional: ‘for this product’] pyretic active ingredients (including, [bullet] with other drugs containing ac- but not limited to, acetaminophen, as- etaminophen [bullet] 3 or more alco- pirin, carbaspirin calcium, choline sa- holic drinks every day while using this licylate, ibuprofen, ketoprofen, magne- product’’. This ‘‘Liver’’ warning must sium salicylate, naproxen sodium, and be the first warning under the ‘‘Warn- sodium salicylate) alone or in combina- ings’’ heading. For products that con- tion must bear the following labeling tain both acetaminophen and aspirin,

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this ‘‘Liver’’ warning must appear after (3) ‘‘Ask a doctor before use if your the ‘‘Reye’s syndrome’’ and ‘‘Allergy child has liver disease’’. alert’’ warnings in § 201.66(c)(5)(ii)(A) (4) ‘‘Ask a doctor or pharmacist be- and (c)(5)(ii)(B) and before the ‘‘Stom- fore use if your child is taking the ach bleeding’’ warning in paragraph blood thinning drug warfarin’’ except (a)(2)(iii)(A) of this section. If there is on the labeling of combination prod- an outer and immediate container of a ucts that contain acetaminophen and retail package, this warning must ap- NSAID(s). pear on both the outer and immediate (B) Directions. The labeling of the containers. If the immediate container product contains the following infor- is a blister card, the warning must ap- mation under the heading ‘‘Direc- pear on the blister card and remain in- tions’’: ‘‘this product does not contain tact and readable when drug product is directions or complete warnings for removed from the blister card. The adult use’’ [in bold type]. warning does not need to be included on each blister unit. (v) For products labeled for adults and (B) ‘‘Do not use with any other drug children under 12 years of age. The label- containing acetaminophen (prescrip- ing of the product states all of the tion or nonprescription). If you are not warnings in paragraphs (a)(1)(iii)(A), sure whether a drug contains acetami- (a)(1)(iii)(B), and (a)(1)(iii)(C) of this nophen, ask a doctor or pharmacist.’’ section with the following modifica- (C) ‘‘Ask a doctor before use if you tions: have liver disease’’. (A) The liver warning states ‘‘Liver (D) ‘‘Ask a doctor or pharmacist be- warning [heading in bold type]: This fore use if you are taking the blood product contains acetaminophen. Se- thinning drug warfarin’’ except on the vere liver damage may occur if [bullet] labeling of combination products that adult takes more than [insert max- contain acetaminophen and NSAID(s). imum number of daily dosage units] in (iv) For products labeled only for chil- 24 hours, which is the maximum daily dren under 12 years of age. amount [optional: ‘for this product’] (A) Warnings. The labeling of the [bullet] child takes more than 5 doses product states the following warnings in 24 hours [bullet] taken with other under the heading ‘‘Warnings’’: drugs containing acetaminophen [bul- (1) The liver warning states ‘‘Liver let] adult has 3 or more alcoholic warning [heading in bold type]: This drinks everyday while using this prod- product contains acetaminophen. Se- uct.’’ If there is an outer and imme- vere liver damage may occur if your diate container of a retail package, child takes [bullet] more than 5 doses this warning must appear on both the in 24 hours, which is the maximum outer and immediate containers. If the daily amount [optional: ‘for this prod- immediate container is a blister card, uct’] [bullet] with other drugs con- the warning must appear on the blister taining acetaminophen’’. This ‘‘Liver’’ card and remain intact and readable warning must be the first warning when drug product is removed from the under the ‘‘Warnings’’ heading. If there blister card. The warning is not re- is an outer and immediate container of quired to be included on each blister a retail package, this warning must ap- unit. pear on both the outer and immediate containers. If the immediate container (B) ‘‘Ask a doctor before use if the is a blister card, the warning must ap- user has liver disease.’’ pear on the blister card and remain in- (C) ‘‘Do not use with any other drug tact and readable when drug product is containing acetaminophen (prescrip- removed from the blister card. The tion or nonprescription). If you are not warning is not required to be included sure whether a drug contains acetami- on each blister unit. nophen, ask a doctor or pharmacist.’’ (2) ‘‘Do not use with any other drug (D) ‘‘Ask a doctor or pharmacist be- containing acetaminophen (prescrip- fore use if the user is taking the blood tion or nonprescription). If you are not thinning drug warfarin’’ except on the sure whether a drug contains acetami- labeling of combination products that nophen, ask a doctor or pharmacist.’’ contain acetaminophen and NSAID(s).

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(2) Nonsteroidal anti-inflammatory an- the following warnings under the head- algesic/antipyretic active ingredients—in- ing ‘‘Warnings’’: cluding, but not limited to, aspirin, (A) The stomach bleeding warning carbaspirin calcium, choline salicylate, states ‘‘Stomach bleeding warning ibuprofen, ketoprofen, magnesium salicy- [heading in bold type]: This product late, naproxen sodium, and sodium salicy- contains an NSAID, which may cause late. severe stomach bleeding. The chance is (i) Statement of identity. The state- higher if you [bullet] are age 60 or older ment of identity appears in accord with [bullet] have had stomach ulcers or §§ 201.61 and 299.4 of this chapter. The bleeding problems [bullet] take a blood word ‘‘(NSAID)’’ must appear high- thinning (anticoagulant) or steroid lighted (e.g., fluorescent or color con- drug [bullet] take other drugs contrast) or in bold type, be in lines gen- taining prescription or nonprescription erally parallel to the base on which the NSAIDs (aspirin, ibuprofen, naproxen, package rests as it is designed to be or others) [bullet] have 3 or more alco- displayed, and be in one of the fol- holic drinks every day while using this lowing sizes, whichever is greater: product [bullet] take more or for a (A) At least one-quarter as large as longer time than directed’’. This the size of the most prominent printed ‘‘Stomach bleeding’’ warning must ap- matter on the PDP, or pear after the ‘‘Reye’s syndrome’’ and (B) At least as large as the size of the ‘‘Allergy alert’’ warnings in ‘‘Drug Facts’’ title, as required in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For § 201.66(d)(2). The word ‘‘(NSAID)’’ must products that contain both acetamino- appear as part of the established name phen and aspirin, the acetaminophen of the drug, as defined in § 299.4 of this ‘‘Liver’’ warning in paragraph (a)(1)(iii) chapter, or after the general pharma- of this section must appear before the cological (principal intended) action of ‘‘Stomach bleeding’’ warning in this the NSAID ingredient. Combination paragraph. If there is an outer and im- products containing an NSAID and a mediate container of a retail package, nonanalgesic ingredient(s) (e.g., cough- this warning must appear on both the cold) must include the name of the outer and immediate containers. If the NSAID ingredient and the word immediate container is a blister card, ‘‘(NSAID)’’ in accordance with this the warning must appear on the blister paragraph, and the name(s) of the card and remain intact and readable other active ingredient(s) in the prod- when drug product is removed from the uct on the PDP. Only the word blister card. The warning is not re- ‘‘(NSAID)’’ needs to appear highlighted quired to be included on each blister or in bold type, and in a prominent unit. print size, as described in this para- (B) ‘‘Ask a doctor before use if [bul- graph. let] stomach bleeding warning applies (ii) Active Ingredient and Purpose to you [bullet] you have a history of Headings. The information required stomach problems, such as heartburn under § 201.66(c)(2) and (c)(3) of this [bullet] you have high blood pressure, chapter must be included under these heart disease, liver cirrhosis, or kidney headings. The active ingredient(s) sec- disease [bullet] you are taking a diu- tion of the product’s labeling, as de- retic’’. fined in § 201.66(c)(2), contains the term (C) ‘‘Stop use and ask a doctor if ‘‘(NSAID*)’’ after the NSAID active in- [bullet] you experience any of the fol- gredient with an asterisk statement at lowing signs of stomach bleeding:’’ [add the end of the active ingredient(s) sec- the following as second level of state- tion that defines the term ‘‘NSAID’’ ments: ‘‘[bullet] feel faint [bullet] and states ‘‘* nonsteroidal anti-inflam- vomit blood [bullet] have bloody or matory drug.’’ The information under black stools [bullet] have stomach pain these headings may appear highlighted. that does not get better’’]. However, the headings ‘‘Active Ingre- (iv) For products labeled only for chil- dient’’ and ‘‘Purpose’’ may not appear dren under 12 years of age. highlighted. (A) Warnings. The labeling of the (iii) For products labeled for adults product states the following warnings only. The labeling of the product states under the heading ‘‘Warnings’’:

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

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highlighted (e.g., fluorescent or color 4. The subheadings (e.g., ‘‘Ask a doctor or contrast) or in bold type, be in lines pharmacist before use if you are’’) are set in generally parallel to the base on which 6 point Helvetica Bold, left justified. the package rests as it is designed to be 5. The information is set in 6 point Helvetica Regular with 6.5 point leading, left displayed, and be in one of the fol- justified. lowing sizes, whichever is greater: 6. The heading ‘‘Purpose’’ is right justified. (1) At least one-quarter as large as 7. The bullet is a 5-point solid square. the size of the most prominent printed 8. Two em spacing separates bullets when matter on the PDP, or more than one bullet is on the same line. (2) At least as large as the size of the 9. A table format is used for 3 or more dos- ‘‘Drug Facts’’ title, as required in age directions. 10. A graphic appears at the bottom of the § 201.66(d)(2). The new warnings infor- first panel leading the reader to the next mation statement must remain on the panel. PDP of the drug product for at least 1 year from the date the product is ini- C. Barlines and hairlines tially introduced into interstate com- 1. A 2.5-point horizontal barline extends to merce. each end of the ‘‘Drug Facts’’ box (or similar (c) Requirements to supplement ap- enclosure), providing separation between proved application. Holders of approved each of the headings. applications for OTC drug products 2. A 0.5-point horizontal hairline extends within 2 spaces on either side of the ‘‘Drug that contain internal analgesic/anti- Facts’’ box (or similar enclosure), imme- pyretic active ingredients that are sub- diately following the title and immediately ject to the requirements of paragraph preceding the subheadings. (a) of this section must submit supple- 3. A 0.5-point horizontal hairline follows ments under § 314.70(c) of this chapter the title, immediately preceding the head- to include the required information in ing, when a heading appears on a subsequent the product’s labeling. Such labeling panel immediately after the ‘‘Drug Facts may be put into use without advance (continued)’’ title. approval of FDA provided it includes at D. Box or Enclosure least the exact information included in 1. All information is enclosed by a 2.5-point paragraph (a) of this section. barline. [74 FR 19407, Apr. 29, 2009; 74 FR 31180, June II. SECTION 201.66 MODIFIED LABELING 30, 2009, as amended at 74 FR 61514, Nov. 25, FORMAT 2009]

EFFECTIVE DATE NOTE: At 74 FR 19407, Apr. A. Overall 29, 2009, as corrected at 74 FR 31180, June 30, 1. The ‘‘Drug Facts’’ labeling is presented 2009, and amended at 74 FR 61514, Nov. 25, in all black type printed on a white color 2009, § 201.326 was added, effective Apr. 29, contrasting background. 2010. B. Typeface and size APPENDIX A TO PART 201—EXAMPLES OF 1. ‘‘Drug Facts’’ is set in 9 point Helvetica GRAPHIC ENHANCEMENTS USED BY FDA Bold Italic, left justified. 2. The headings (e.g., ‘‘Directions’’) are set I. SECTION 201.66 STANDARD LABELING FORMAT in 8 point Helvetica Bold Italic, left justified. A. Overall 3. The subheadings (e.g., ‘‘Ask a doctor or pharmacist before use if you are’’) are set in 1. The ‘‘Drug Facts’’ labeling is set off in a 6 point Helvetica Bold, left justified. box or similar enclosure by the use of a 4. The information is set in 6 point barline with all black type printed on a Helvetica Regular with 6.5 point leading, left white, color contrasting background. justified. 5. The heading ‘‘Purpose’’ is right justified. B. Typeface and size 6. The bullet is a 5-point solid square. 1. ‘‘Drug Facts’’ is set in 14 point Helvetica 7. Bulleted information may start on same Bold Italic, left justified. line as headings (except for the ‘‘Warnings’’ 2. ‘‘Drug Facts (continued)’’ is set in 8 heading) and subheadings, with 2 em spacing point Helvetica Bold Italic for the words separating bullets, and need not be vertically ‘‘Drug Facts’’ and 8 point Helvetica Regular aligned. for the word ‘‘(continued)’’ and is left justi- C. Barlines and hairlines fied. 3. The headings (e.g., ‘‘Directions’’) are set 1. A 2.5-point horizontal barline extends to in 8 point Helvetica Bold Italic, left justified. each end of the ‘‘Drug Facts’’ box (or similar

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

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 pro- of 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 indication in such labeling that relates effects and contraindications shall dis- to the uses of the advertised drug dos- close each specific side effect and con- age form(s) or shall otherwise conform traindication (which include side ef- to the provisions of paragraph (e)(3)(iii) fects, warnings, precautions, and con- of this section. traindications and include any such in- (b) If a prescription drug was covered formation under such headings as cau- by a new-drug application or a supple- tions, special considerations, impor- ment thereto that became effective tant notes, etc.; see paragraph (e)(1) of prior to October 10, 1962, an advertise- this section) contained in required, ap- ment may recommend or suggest: proved, or permitted labeling for the (1) Uses contained in the labeling ac- advertised drug dosage form(s): Pro- cepted in such new-drug application vided, however, and any effective, approved, or per- (a) The side effects and contraindica- mitted supplement thereto. tions disclosed may be limited to those (2) Additional uses contained in la- pertinent to the indications for which beling in commercial use on October 9, the drug is recommended or suggested 1962, to the extent that such uses did in the advertisement to the extent that such limited disclosure has previously not cause the drug to be an unapproved been approved or permitted in drug la- ‘‘new drug’’ as ‘‘new drug’’ was defined beling conforming to the provisions of in section 201(p) of the act as then in §§ 201.100 or 201.105; and force, and to the extent that such uses (b) The use of a single term for a would be permitted were the drug sub- group of side effects and contraindica- ject to paragraph (e)(4)(iii) of this sections (for example, ‘‘blood dyscrasias’’ tion. for disclosure of ‘‘leukopenia,’’ (3) Additional uses contained in la- ‘‘agranulocytosis,’’ and ‘‘neutropenia’’) beling in current commercial use to is permitted only to the extent that the extent that such uses do not cause the use of such a single term in place of the drug to be an unapproved ‘‘new disclosure of each specific side effect drug’’ as defined in section 201(p) of the and contraindication has been pre- act as amended or a ‘‘new animal drug’’ viously approved or permitted in drug as defined in section 201(v) of the act as labeling conforming to the provisions amended. of §§ 201.100 or 201.105. The advertisement shall present infor- (4) Substance of information to be in- mation from labeling required, ap- cluded in brief summary. (i)(a) An adver- proved, or permitted in a new-drug ap- tisement for a prescription drug cov- plication relating to each specific side ered by a new-drug application ap- effect and contraindication in such la- proved pursuant to section 505 of the beling that relates to the uses of the act after October 10, 1962, or a prescrip- advertised drug dosage form(s) or shall tion drug covered by a new animal drug otherwise conform to the provisions of application approved pursuant to sec- paragraph (e)(3)(iii) of this section. tion 512 of the act after August 1, 1969, (ii) In the case of an advertisement or any approved supplement thereto, or for a prescription drug other than a for a prescription drug listed in the index pursuant to section 572 of the drug the labeling of which causes it to act, or any granted modification there- be an unapproved ‘‘new drug’’ and to, shall not recommend or suggest any other than drugs covered by paragraph use that is not in the labeling accepted (e)(4)(i) of this section, an advertise- in such approved new-drug application ment may recommend and suggest the or supplement, new animal drug appli- drug only for those uses contained in cation or supplement, or new animal the labeling thereof: drug index listing or modification. The (a) For which the drug is generally advertisement shall present informa- recognized as safe and effective among tion from labeling required, approved, experts qualified by scientific training permitted, or granted in a new-drug or and experience to evaluate the safety new animal drug application or new and effectiveness of such drugs; or animal drug index listing relating to (b) For which there exists substantial each specific side effect and contra- evidence of safety and effectiveness,

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

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

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(xviii) Uses headline, subheadline, or fails to reveal the range of variations pictorial or other graphic matter in a around the quoted average results. way that is misleading. (iii) Uses statistical analyses and (xix) Represents or suggests that techniques on a retrospective basis to drug dosages properly recommended for discover and cite findings not soundly use in the treatment of certain classes supported by the study, or to suggest of patients or disease conditions are scientific validity and rigor for data safe and effective for the treatment of from studies the design or protocol of other classes of patients or disease con- which are not amenable to formal sta- ditions when such is not the case. tistical evaluations. (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

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that extends across the gutter) for the mation will be publicized promptly and fact that two facing pages are part of adequately to the medical profession in the same advertisement when one page subsequent advertisements. contains information relating to side If the Commissioner finds that the pro- effects and contraindications. gram presented is not being followed, (x) In an advertisement promoting he will notify the sponsor that prior use of the drug in a selected class of pa- approval of all advertisements for the tients (for example, geriatric patients particular drug will be required. Noth- or depressed patients), fails to present ing in this paragraph is to be construed with adequate emphasis the significant as limiting the Commissioner’s or the 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 another page (or on another full page) formation concerning the possibility of an advertisement on more than one that a drug may cause fatalities or se- page, information relating to side ef- rious damage has been widely pub- fects and contraindications when such licized in medical literature, the Food information is in a distinct part of the and Drug Administration shall notify advertisement. the sponsor of the drug by mail that (xii) Fails to include on each page or prior approval of advertisements for spread of an advertisement the infor- the drug is no longer necessary. mation relating to side effects and con- (3) Dissemination of an advertise- traindications or a prominent ref- ment not in compliance with this para- erence to its presence and location graph shall be deemed to be an act that when it is presented as a distinct part causes the drug to be misbranded under of an advertisement. section 502(n) of the act. (xiii) Contains information from pub- (4) Any advertisement may be sub- lished or unpublished reports or opin- mitted to the Food and Drug Adminis- ions falsely or misleadingly rep- tration prior to publication for com- resented or suggested to be authentic ment. If the advertiser is notified that or authoritative. the submitted advertisement is not in (f)–(i) [Reserved] violation and, at some subsequent (j)(1) No advertisement concerning a time, the Food and Drug Administra- particular prescription drug may be tion changes its opinion, the advertiser disseminated without prior approval by will be so notified and will be given a the Food and Drug Administration if: reasonable time for correction before (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 ab- tunity for a regulatory hearing before sence the officer acting as Commis- the Food and Drug Administration pur- sioner), after evaluating the reliability suant to part 16 of this chapter with re- of such information, has notified the spect to any determination that prior sponsor that the information must be a approval is required for advertisements part of the advertisements for the concerning a particular prescription drug; and drug, or that a particular advertise- (iii) The sponsor has failed within a ment is not approvable. reasonable time as specified in such no- (k) An advertisement issued or tification to present to the Food and caused to be issued by the manufac- Drug Administration a program, ade- turer, packer, or distributor of the quate in light of the nature of the in- drug promoted by the advertisement formation, for assuring that such infor- and which is not in compliance with

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section 502(n) of the act and the appli- by implication, e.g., by use of comparative cable regulations thereunder shall test data or reference to published reports, cause stocks of such drug in possession represent that the drug is safer or more ef- of the person responsible for issuing or fective than another drug, nor may an advertisement contain a quantitative statement causing the issuance of the advertise- of safety or effectiveness (a) unless the rep- ment, and stocks of the drug distrib- resentation has been approved as part of the uted by such person and still in the labeling in a new drug application or bio- channels of commerce, to be mis- logic license, or (b) if the drug is not a new branded under section 502(n) of the act. drug or biologic, unless the representation of (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 § 314.111(a)(5)(ii) of this chapter, or unless the zines, other periodicals, and news- 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; 72 FR 69119, Dec. 6, 2007] § 314.111(a)(5)(ii) of this chapter.

EFFECTIVE DATE NOTE: At 44 FR 37467, June 26, 1979, § 202.1(e)(6) (ii) and (vii) were revised. * * * * * At 44 FR 74817, Dec. 18, 1979, paragraphs (e)(6) (ii) and (vii) were stayed indefinitely. At 64 FR 400, Jan. 5, 1999, these paragraphs were PART 203—PRESCRIPTION DRUG amended. For the convenience of the user, MARKETING paragraphs (e)(6) (ii) and (vii), published at 44 FR 37467, are set forth below: Subpart A—General Provisions § 202.1 Prescription-drug advertisements. Sec. 203.1 Scope. * * * * * 203.2 Purpose. 203.3 Definitions. (e) * * * (6) * * * Subpart B—Reimportation (ii) Represents or suggests that a prescription drug is safer or more effective than an- 203.10 Restrictions on reimportation. other drug in some particular when the dif- 203.11 Applications for reimportation to ference has not been demonstrated by sub- provide emergency medical care. stantial evidence. An advertisement for a 203.12 An appeal from an adverse decision prescription drug may not, either directly or by the district office.

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Subpart C—Sales Restrictions components intended for transfusion are excluded from the restrictions in 203.20 Sales restrictions. and the requirements of the Prescrip- 203.22 Exclusions. 203.23 Returns. tion Drug Marketing Act of 1987 and the Prescription Drug Amendments of Subpart D—Samples 1992. 203.30 Sample distribution by mail or com- § 203.2 Purpose. mon carrier. 203.31 Sample distribution by means other The purpose of this part is to imple- than mail or common carrier (direct de- ment the Prescription Drug Marketing livery by a representative or detailer). Act of 1987 and the Prescription Drug 203.32 Drug sample storage and handling re- Amendments of 1992, except for those quirements. sections relating to State licensing of 203.33 Drug sample forms. wholesale distributors (see part 205 of 203.34 Policies and procedures; administra- this chapter), to protect the public tive systems. 203.35 Standing requests. health, and to protect the public 203.36 Fulfillment houses, shipping and against drug diversion by establishing mailing services, comarketing agree- procedures, requirements, and min- ments, and third-party recordkeeping. imum standards for the distribution of 203.37 Investigation and notification re- prescription drugs and prescription quirements. drug samples. 203.38 Sample lot or control numbers; labeling of sample units. § 203.3 Definitions. 203.39 Donation of drug samples to charitable institutions. (a) The act means the Federal Food, Drug, and Cosmetic Act, as amended Subpart E—Wholesale Distribution (21 U.S.C. 301 et seq.). (b) Authorized distributor of record 203.50 Requirements for wholesale distribu- means a distributor with whom a man- tion of prescription drugs. ufacturer has established an ongoing Subpart F—Request and Receipt Forms, relationship to distribute such manu- Reports, and Records facturer’s products. (c) Blood means whole blood collected 203.60 Request and receipt forms, reports, from a single donor and processed ei- and records. ther for transfusion or further manufacturing. Subpart G—Rewards (d) Blood component means that part 203.70 Application for a reward. of a single-donor unit of blood separated by physical or mechanical means. AUTHORITY: 21 U.S.C. 331, 333, 351, 352, 353, 360, 371, 374, 381. (e) Bulk drug substance means any substance that is represented for use in SOURCE: 64 FR 67756, Dec. 3, 1999, unless a drug and that, when used in the man- otherwise noted. ufacturing, processing, or packaging of a drug, becomes an active ingredient or Subpart A—General Provisions a finished dosage form of the drug, but the term does not include intermedi- § 203.1 Scope. 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

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

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

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was manufactured in a State and ex- Subpart C—Sales Restrictions ported from the United States may be reimported by anyone other than its § 203.20 Sales restrictions. manufacturer, except that FDA may Except as provided in § 203.22 or grant permission to a person other § 203.23, no person may sell, purchase, than the manufacturer to reimport a or trade, or offer to sell, purchase, or prescription drug or insulin-containing trade any prescription drug that was: drug if it determines that such re- (a) Purchased by a public or private importation is required for emergency hospital or other health care entity; or medical care. (b) Donated or supplied at a reduced price to a charitable organization. § 203.11 Applications for reimportation to provide emergency medical care. § 203.22 Exclusions. (a) Applications for reimportation for Section 203.20 does not apply to: emergency medical care shall be sub- (a) The purchase or other acquisition of a drug for its own use by a hospital mitted to the director of the FDA Dis- or other health care entity that is a trict Office in the district where re- member of a group purchasing organi- importation is sought (addresses found zation from the group purchasing orga- in part 5, subpart M of this chapter). nization or from other hospitals or (b) Applications for reimportation to health care entities that are members provide emergency medical care shall of the organization. be reviewed and approved or dis- (b) The sale, purchase, or trade of a approved by each district office. drug or an offer to sell, purchase, or trade a drug by a charitable organiza- [64 FR 67756, Dec. 3, 1999, as amended at 69 FR 17292, Apr. 2, 2004] tion to a nonprofit affiliate of the organization to the extent otherwise per- § 203.12 An appeal from an adverse de- mitted by law. cision by the district office. (c) The sale, purchase, or trade of a drug or an offer to sell, purchase, or An appeal from an adverse decision trade a drug among hospitals or other by the district office involving insulin- health care entities that are under containing drugs or prescription common control. human drugs, other than biological (d) The sale, purchase, or trade of a products, may be made to the Office of drug or an offer to sell, purchase, or Compliance, Center for Drug Evalua- trade a drug for emergency medical tion and Research, Food and Drug Ad- reasons. ministration, 10903 New Hampshire (e) The sale, purchase, or trade of a Ave., Silver Spring, MD 20993–0002. An drug, an offer to sell, purchase, or appeal from an adverse decision by the trade a drug, or the dispensing of a district office involving prescription drug under a valid prescription. human biological products may be (f) The sale, purchase, or trade of a made to the Office of Compliance and drug or the offer to sell, purchase, or Biologics Quality (HFM–600), Center for trade a drug by hospitals or health care Biologics Evaluation and Research, entities owned or operated by Federal, Food and Drug Administration, 1401 State, or local governmental units to Rockville Pike, Rockville, MD 20852 or other hospitals or health care entities the Office of Compliance, Center for owned or operated by Federal, State, or local governmental units. Drug Evaluation and Research, Food (g) The sale, purchase, or trade of, or and Drug Administration, 10903 New the offer to sell, purchase, or trade Hampshire Ave., Silver Spring, MD blood or blood components intended for 20993–0002, depending on the Center re- transfusion. sponsible for regulating the product. (h) The sale, purchase, or trade of, or [64 FR 67756, Dec. 3, 1999, as amended at 69 the offer to sell, purchase, or trade, by FR 48775, Aug. 11, 2004; 70 FR 14980, Mar. 24, a registered blood establishment that 2005; 74 FR 13112, Mar. 26, 2009] qualifies as a health care entity any: (1) Drug indicated for a bleeding or clotting disorder, or anemia;

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(2) Blood collection container ap- (3) The product name and lot or con- proved under section 505 of the act; or trol number; (3) Drug that is a blood derivative (or (4) The quantity returned; and a recombinant or synthetic form of a (5) The date of the return. blood derivative); as long as all of the (b) The hospital, health care entity, health care services that the establish- or charitable institution forwards a ment provides are related to its activi- copy of each credit memo to the manu- ties as a registered blood establishment facturer and retains a copy of each or the health care services consist of credit memo for its records; collecting, processing, storing, or ad- (c) Any drugs returned to a manufac- ministering human hematopoietic turer or wholesale distributor are kept stem/progenitor cells or performing di- under proper conditions for storage, agnostic testing of specimens provided handling, and shipping, and written that these specimens are tested to- documentation showing that proper gether with specimens undergoing rou- conditions were maintained is provided tine donor testing. Blood establish- to the manufacturer or wholesale dis- ments relying on the exclusion in this tributor to which the drugs are re- paragraph must satisfy all other returned. quirements of the act and this part applicable to a wholesale distributor or Subpart D—Samples retail pharmacy. (i) The sale, purchase, or trade of, or § 203.30 Sample distribution by mail or the offer to sell, purchase, or trade, by common carrier. a comprehensive hemophilia diagnostic (a) Requirements for drug sample dis- treatment center that is receiving a tribution by mail or common carrier. A grant under section 501(a)(2) of the So- manufacturer or authorized distributor cial Security Act and that qualifies as of record may distribute a drug sample a health care entity, any drug indi- to a practitioner licensed to prescribe cated for a bleeding or clotting dis- the drug that is to be sampled or, at order, or anemia, or any drug that is a the written request of a licensed prac- blood derivative (or a recombinant or titioner, to the pharmacy of a hospital synthetic form of a blood derivative). or other health care entity, by mail or Comprehensive hemophilia diagnostic common carrier, provided that: treatment centers relying on the exclu- (1) The licensed practitioner executes sion in this paragraph must satisfy all and submits a written request to the other requirements of the act and this manufacturer or authorized distributor part applicable to a wholesale dis- of record, as set forth in paragraph (b) tributor or retail pharmacy. of this section, before the delivery of the drug sample; [64 FR 67756, Dec. 3, 1999, as amended at 73 (2) The manufacturer or authorized FR 59500, Oct. 9, 2008] distributor of record verifies with the § 203.23 Returns. appropriate State authority that the practitioner requesting the drug sam- The return of a prescription drug ple is licensed or authorized under purchased by a hospital or health care State law to prescribe the drug prod- entity or acquired at a reduced price by uct; or donated to a charitable institution (3) The recipient executes a written is exempt from the prohibitions in receipt, as set forth in paragraph (c) of § 203.20, provided that: this section, when the drug sample is (a) The hospital, health care entity, delivered; and or charitable institution documents (4) The receipt is returned to the the return by filling out a credit memo manufacturer or distributor from specifying: which the drug sample was received. (1) The name and address of the hos- (b) Contents of the written request form pital, health care entity, or charitable for delivery of samples by mail or common institution; carrier. (1) A written request for a drug (2) The name and address of the man- sample to be delivered by mail or com- ufacturer or wholesale distributor from mon carrier to a licensed practitioner which it was acquired; is required to contain the following:

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

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

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record must show, for each type of § 203.33 Drug sample forms. sample unit (i.e., sample units having A sample request or receipt form the same established or proprietary may be delivered by mail, common car- name and dosage strength), the total rier, or private courier or may be number of sample units received, dis- transmitted photographically or elec- tributed, lost, or stolen since the most tronically (i.e., by telephoto, wire- recently completed prior inventory. photo, radiophoto, facsimile trans- For example, a typical entry in this mission (FAX), xerography, or elec- record may read ‘‘50 units risperidone tronic data transfer) or by any other (1 mg) returned to manufacturer’’ or system, provided that the method for simply ‘‘Risperidone (1 mg)/50/returned transmission meets the security re- to manufacturer.’’ quirements set forth in § 203.60(c). (3) Each drug manufacturer or authorized distributor of record shall § 203.34 Policies and procedures; ad- take appropriate internal control ministrative systems. measures to guard against error and Each manufacturer or authorized dis- possible fraud in the conduct of the tributor of record that distributes drug physical inventory and reconciliation, samples shall establish, maintain, and and in the preparation of the inventory adhere to written policies and proce- record and reconciliation report. dures describing its administrative sys- (4) A manufacturer or authorized dis- tems for the following: tributor of record shall carefully evalu- (a) Distributing drug samples by mail ate any apparent discrepancy or sig- or common carrier, including method- nificant loss revealed through the in- ology for reconciliation of requests and ventory and reconciliation process and receipts; shall fully investigate any such dis- (b) Distributing drug samples by crepancy or significant loss that can- means other than mail or common car- not be justified. rier including the methodology for: (e) Lists of manufacturers’ and distribu- (1) Reconciling requests and receipts, tors’ representatives. Each drug manu- identifying patterns of nonresponse, facturer or authorized distributor of and the manufacturer’s or distributor’s record who distributes drug samples by response when such patterns are found; means of representatives shall main- (2) Conducting the annual physical tain a list of the names and addresses inventory and preparation of the rec- of its representatives who distribute onciliation report; drug samples and of the sites where (3) Implementing a sample distribu- drug samples are stored. tion security and audit system, including conducting random and for-cause § 203.32 Drug sample storage and han- audits of sales representatives by per- dling requirements. sonnel independent of the sales force; (a) Storage and handling conditions. and Manufacturers, authorized distributors (4) Storage of drug samples by rep- of record, and their representatives resentatives; shall store and handle all drug samples (c) Identifying any significant loss of under conditions that will maintain drug samples and notifying FDA of the their stability, integrity, and effective- loss; and ness and ensure that the drug samples (d) Monitoring any loss or theft of are free of contamination, deteriora- drug samples. tion, and adulteration. (b) Compliance with compendial and la- § 203.35 Standing requests. beling requirements. Manufacturers, au- Manufacturers or authorized dis- thorized distributors of record, and tributors of record shall not distribute their representatives can generally drug samples on the basis of open- comply with this section by following ended or standing requests, but shall the compendial and labeling require- require separate written requests for ments for storage and handling of a each drug sample or group of samples. particular prescription drug in han- An arrangement by which a licensed dling samples of that drug. practitioner requests in writing that a

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specified number of drug samples be de- (b) Significant loss or known theft of livered over a period of not more than drug samples. A manufacturer or au- 6 months, with the actual delivery thorized distributor of record that dis- dates for parts of the order to be set by tributes drug samples or a charitable subsequent oral communication or institution that receives donated drug electronic transmission, is not consid- samples from a licensed practitioner ered to be a standing request. shall: (1) Notify FDA, by telephone or in § 203.36 Fulfillment houses, shipping writing, within 5 working days of be- and mailing services, comarketing coming aware of a significant loss or agreements, and third-party record- known theft; keeping. (2) Immediately initiate an investiga- (a) Responsibility for creating and tion into the significant loss or known maintaining forms, reports, and records. theft; and Any manufacturer or authorized dis- (3) Provide FDA with a complete tributor of record that uses a fulfill- written report, including the reason for ment house, shipping or mailing serv- and the results of the investigation, ice, or other third party, or engages in not later than 30 days after the date of a comarketing agreement with another the initial notification in paragraph manufacturer or distributor to dis- (b)(1) of this section. tribute drug samples or to meet any of (c) Conviction of a representative. (1) A the requirements of PDMA, PDA, or manufacturer or authorized distributor this part, remains responsible for cre- of record that distributes drug samples ating and maintaining all requests, re- shall notify FDA, by telephone or in ceipts, forms, reports, and records re- writing, within 30 days of becoming quired under PDMA, PDA, and this aware of the conviction of one or more part. of its representatives for a violation of (b) Responsibility for producing re- section 503(c)(1) of the act or any State quested forms, reports, or records. A man- law involving the sale, purchase, or ufacturer or authorized distributor of trade of a drug sample or the offer to record that contracts with a third sell, purchase, or trade a drug sample. party to maintain some or all of its (2) A manufacturer or authorized dis- records shall produce requested forms, tributor of record shall provide FDA reports, records, or other required doc- with a complete written report not uments within 2 business days of a re- later than 30 days after the date of the quest by an authorized representative initial notification. of FDA or another Federal, State, or (d) Selection of individual responsible local regulatory or law enforcement of- for drug sample information. A manufac- ficial. turer or authorized distributor of record that distributes drug samples § 203.37 Investigation and notification shall inform FDA in writing within 30 requirements. days of selecting the individual respon- (a) Investigation of falsification of drug sible for responding to a request for in- sample records. A manufacturer or au- formation about drug samples of that thorized distributor of record that has individual’s name, business address, reason to believe that any person has and telephone number. falsified drug sample requests, receipts, (e) Whom to notify at FDA. Notifica- or records, or is diverting drug sam- tions and reports concerning prescrip- ples, shall: tion human drugs and biological prod- (1) Notify FDA, by telephone or in ucts regulated by the Center for Drug writing, within 5 working days; Evaluation and Research shall be made (2) Immediately initiate an investiga- to the Division of Compliance Risk tion; and Management and Surveillance, Office (3) Provide FDA with a complete of Compliance, Center for Drug Evalua- written report, including the reason for tion and Research, Food and Drug Ad- and the results of the investigation, ministration, 10903 New Hampshire not later than 30 days after the date of Ave., Silver Spring, MD 20993–0002. No- the initial notification in paragraph tifications and reports concerning pre- (a)(1) of this section. scription human biological products

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regulated by the Center for Biologics stitution for dispensing to a patient of Evaluation and Research shall be made the charitable institution, or donate a to the Division of Inspections and Sur- drug sample to another charitable in- veillance (HFM–650), Office of Compli- stitution for dispensing to its patients, ance and Biologics Quality, Center for provided that the following require- Biologics Evaluation and Research, ments are met: Food and Drug Administration, 1401 (a) A drug sample donated by a li- Rockville Pike, suite 200N, Rockville, censed practitioner or donating chari- MD 20852. table institution shall be received by a charitable institution in its original, [64 FR 67756, Dec. 3, 1999, as amended at 69 FR 48775, Aug. 11, 2004; 70 FR 14981, Mar. 24, unopened packaging with its labeling 2005; 74 FR 13112, Mar. 26, 2009] intact. (b) Delivery of a donated drug sample § 203.38 Sample lot or control num- to a recipient charitable institution bers; labeling of sample units. shall be completed by mail or common (a) Lot or control number required on carrier, collection by an authorized drug sample labeling and sample unit agent or employee of the recipient label. The manufacturer or authorized charitable institution, or personal de- distributor of record of a drug sample livery by a licensed practitioner or an shall include on the label of the sample agent or employee of the donating unit and on the outside container or charitable institution. Donated drug packaging of the sample unit, if any, samples shall be placed by the donor in an identifying lot or control number a sealed carton for delivery to or col- that will permit the tracking of the lection by the recipient charitable in- distribution of each drug sample unit. stitution. (b) Records containing lot or control (c) A donated drug sample shall not numbers required for all drug samples dis- be dispensed to a patient or be distrib- tributed. A manufacturer or authorized uted to another charitable institution distributor of record shall maintain for until it has been examined by a li- all samples distributed records of drug censed practitioner or registered phar- sample distribution containing lot or macist at the recipient charitable in- control numbers that are sufficient to stitution to confirm that the donation permit the tracking of sample units to record accurately describes the drug the point of the licensed practitioner. sample delivered and that no drug sam- (c) Labels of sample units. Each sample ple is adulterated or misbranded for unit shall bear a label that clearly de- any reason, including, but not limited notes its status as a drug sample, e.g., to, the following: ‘‘sample,’’ ‘‘not for sale,’’ ‘‘professional (1) The drug sample is out of date; courtesy package.’’ (2) The labeling has become muti- (1) A drug that is labeled as a drug lated, obscured, or detached from the sample is deemed to be a drug sample drug sample packaging; within the meaning of the act. (3) The drug sample shows evidence (2) A drug product dosage unit that of having been stored or shipped under bears an imprint identifying the dosage conditions that might adversely affect form as a drug sample is deemed to be its stability, integrity, or effectiveness; a drug sample within the meaning of (4) The drug sample is for a prescrip- the act. tion drug product that has been re- (3) Notwithstanding paragraphs (c)(1) called or is no longer marketed; or and (c)(2) of this section, any article (5) The drug sample is otherwise pos- that is a drug sample as defined in sec- sibly contaminated, deteriorated, or tion 503(c)(1) of the act and § 203.3(i) adulterated. that fails to bear the label required in (d) The recipient charitable institu- this paragraph (c) is a drug sample. tion shall dispose of any drug sample found to be unsuitable by destroying it § 203.39 Donation of drug samples to or by returning it to the manufacturer. charitable institutions. The charitable institution shall main- A charitable institution may receive tain complete records of the disposi- a drug sample donated by a licensed tion of all destroyed or returned drug practitioner or another charitable in- samples.

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

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Subpart F—Request and Receipt cally scanned into a computer, the re- Forms, Reports, and Records sulting record is an electronic record that must meet the requirements of § 203.60 Request and receipt forms, re- part 11 of this chapter. ports, and records. (c) Security and authentication require- (a) Use of electronic records, electronic ments for request and receipt forms, re- signatures, and handwritten signatures ports, records, and other documents cre- executed to electronic records. (1) Pro- ated on paper. A request or receipt vided the requirements of part 11 of form, report, record, or other docu- this chapter are met, electronic ment, and any signature appearing records, electronic signatures, and thereon, that is created on paper and handwritten signatures executed to that is maintained by photographic im- electronic records may be used as an aging, or transmitted electronically alternative to paper records and hand- (i.e., by facsimile) shall be maintained written signatures executed on paper or transmitted in a form that provides to meet any of the record and signa- reasonable assurance of being: ture requirements of PDMA, PDA, or (1) Resistant to tampering, revision, this part. modification, fraud, unauthorized use, (2) Combinations of paper records and or alteration; electronic records, electronic records (2) Preserved in accessible and re- and handwritten signatures executed trievable fashion; and on paper, or paper records and elec- (3) Available to permit copying for tronic signatures or handwritten signa- purposes of review, analysis, tures executed to electronic records, verification, authentication, and repro- may be used to meet any of the record duction by the person who executed the and signature requirements of PDMA, form or created the record, by the man- PDA, or this part, provided that: ufacturer or distributor, and by au- (i) The requirements of part 11 of this thorized personnel of FDA and other chapter are met for the electronic regulatory and law enforcement agen- records, electronic signatures, or hand- cies. written signatures executed to elec- (d) Retention of request and receipt tronic records; and forms, reports, lists, records, and other (ii) A reasonably secure link between documents. Any person required to cre- the paper-based and electronic compo- ate or maintain reports, lists, or other nents exists such that the combined records under PDMA, PDA, or this records and signatures are trustworthy part, including records relating to the and reliable, and to ensure that the distribution of drug samples, shall re- signer cannot readily repudiate the tain them for at least 3 years after the signed records as not genuine. date of their creation. (3) For the purposes of this paragraph (e) Availability of request and receipt (a), the phrase ‘‘record and signature forms, reports, lists, and records. Any requirements of PDMA, PDA, or this person required to create or maintain part’’ includes drug sample request and request and receipt forms, reports, receipt forms, reports, records, and lists, or other records under PDMA, other documents, and their associated PDA, or this part shall make them signatures required by PDMA, PDA, available, upon request, in a form that and this part. permits copying or other means of du- (b) Maintenance of request and receipt plication, to FDA or other Federal, forms, reports, records, and other docu- State, or local regulatory and law en- ments created on paper. Request and re- forcement officials for review and receipt forms, reports, records, and other production. The records shall be made documents created on paper may be available within 2 business days of a re- maintained on paper or by photo- quest. graphic imaging (i.e., photocopies or microfiche), provided that the security Subpart G—Rewards and authentication requirements described in paragraph (c) of this section § 203.70 Application for a reward. are followed. Where a required docu- (a) Reward for providing information ment is created on paper and electroni- leading to the institution of a criminal

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proceeding against, and conviction of, a nance of prescription drug distribution person for the sale, purchase, or trade of records. a drug sample. A person who provides AUTHORITY: 21 U.S.C. 351, 352, 353, 371, 374. information leading to the institution SOURCE: 55 FR 38023, Sept. 14, 1990, unless of a criminal proceeding against, and otherwise noted. conviction of, a person for the sale, purchase, or trade of a drug sample, or § 205.1 Scope. the offer to sell, purchase, or trade a This part applies to any person, part- drug sample, in violation of section nership, corporation, or business firm 503(c)(1) of the act, is entitled to one- in a State engaging in the wholesale half the criminal fine imposed and col- distribution of human prescription lected for such violation, but not more drugs in interstate commerce. than $125,000. (b) Procedure for making application § 205.2 Purpose. for a reward for providing information The purpose of this part is to imple- leading to the institution of a criminal ment the Prescription Drug Marketing proceeding against, and conviction of, a Act of 1987 by providing minimum person for the sale, purchase, or trade of standards, terms, and conditions for a drug sample. A person who provides the licensing by State licensing au- information leading to the institution thorities of persons who engage in of a criminal proceeding against, and wholesale distributions in interstate conviction of, a person for the sale, commerce of prescription drugs. purchase, or trade of a drug sample, or the offer to sell, purchase, or trade a § 205.3 Definitions. drug sample, in violation of section (a) Blood means whole blood collected 503(c)(1) of the act, may apply for a re- from a single donor and processed ei- ward by making written application to: ther for transfusion or further manu- (1) Director, Office of Compliance, facturing. Center for Drug Evaluation and Re- (b) Blood component means that part search, Food and Drug Administration, of blood separated by physical or me- 10903 New Hampshire Ave., Silver chanical means. Spring, MD 20993–0002; or (c) Drug sample means a unit of a pre- (2) Director, Office of Compliance and scription drug that is not intended to Biologics Quality (HFM–600), Center for be sold and is intended to promote the Biologics Evaluation and Research, sale of the drug. Food and Drug Administration, 1401 (d) Manufacturer means anyone who Rockville Pike, Rockville, MD 20852, as is engaged in manufacturing, pre- appropriate. paring, propagating, compounding, [64 FR 67756, Dec. 3, 1999, as amended at 69 processing, packaging, repackaging, or FR 48775, Aug. 11, 2004; 74 FR 13112, Mar. 26, labeling of a prescription drug. 2009] (e) Prescription drug means any human drug required by Federal law or PART 205—GUIDELINES FOR STATE regulation to be dispensed only by a LICENSING OF WHOLESALE PRE- prescription, including finished dosage forms and active ingredients subject to SCRIPTION DRUG DISTRIBUTORS section 503(b) of the Federal Food, Drug, and Cosmetic Act. Sec. 205.1 Scope. (f) Wholesale distribution and wholesale 205.2 Purpose. distribution means distribution of pre- 205.3 Definitions. scription drugs to persons other than a 205.4 Wholesale drug distributor licensing consumer or patient, but does not in- requirement. clude: 205.5 Minimum required information for li- (1) Intracompany sales; censure. (2) The purchase or other acquisition 205.6 Minimum qualifications. by a hospital or other health care enti- 205.7 Personnel. 205.8 Violations and penalties. ty that is a member of a group pur- 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

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health care entities that are members (h) Health care entity means any per- of such organizations; son that provides diagnostic, medical, (3) The sale, purchase, or trade of a surgical, or dental treatment, or chron- drug or an offer to sell, purchase, or ic or rehabilitative care, but does not trade a drug by a charitable organiza- include any retail pharmacy or any tion described in section 501(c)(3) of the wholesale distributor. Except as pro- Internal Revenue Code of 1954 to a non- vided in § 203.22(h) and (i) of this chap- profit affiliate of the organization to ter, a person cannot simultaneously be the extent otherwise permitted by law; a ‘‘health care entity’’ and a retail (4) The sale, purchase, or trade of a pharmacy or wholesale distributor. drug or an offer to sell, purchase, or trade a drug among hospitals or other [55 FR 38023, Sept. 14, 1990, as amended at 64 health care entities that are under FR 67762, Dec. 3, 1999, 73 FR 59501, Oct. 9, common control; for purposes of this 2008] section, common control means the § 205.4 Wholesale drug distributor li- power to direct or cause the direction censing requirement. of the management and policies of a person or an organization, whether by Every wholesale distributor in a ownership of stock, voting rights, by State who engages in wholesale dis- contract, or otherwise; tributions of prescription drugs in (5) The sale, purchase, or trade of a interstate commerce must be licensed drug or an offer to sell, purchase, or by the State licensing authority in ac- trade a drug for emergency medical cordance with this part before engag- reasons; for purposes of this section, ing in wholesale distributions of pre- emergency medical reasons includes scription drugs in interstate com- transfers of prescription drugs by a re- merce. tail pharmacy to another retail pharmacy to alleviate a temporary short- § 205.5 Minimum required information age; for licensure. (6) The sale, purchase, or trade of a (a) The State licensing authority drug, an offer to sell, purchase, or shall require the following minimum trade a drug, or the dispensing of a information from each wholesale drug drug pursuant to a prescription; distributor as part of the license de- (7) The distribution of drug samples scribed in § 205.4 and as part of any re- by manufacturers’ representatives or newal of such license: distributors’ representatives; or (1) The name, full business address, (8) The sale, purchase, or trade of and telephone number of the licensee; blood and blood components intended (2) All trade or business names used for transfusion. by the licensee; (9) Drug returns, when conducted by (3) Addresses, telephone numbers, a hospital, health care entity, or chari- and the names of contact persons for table institution in accordance with all facilities used by the licensee for § 203.23 of this chapter; or the storage, handling, and distribution (10) The sale of minimal quantities of of prescription drugs; drugs by retail pharmacies to licensed (4) The type of ownership or oper- practitioners for office use. ation (i.e., partnership, corporation, or (g) Wholesale distributor means any one engaged in wholesale distribution sole proprietorship); and of prescription drugs, including, but (5) The name(s) of the owner and/or not limited to, manufacturers; re- operator of the licensee, including: packers; own-label distributors; pri- (i) If a person, the name of the per- vate-label distributors; jobbers; bro- son; kers; warehouses, including manufac- (ii) If a partnership, the name of each turers’ and distributors’ warehouses, partner, and the name of the partner- chain drug warehouses, and wholesale ship; drug warehouses; independent whole- (iii) If a corporation, the name and sale drug traders; and retail phar- title of each corporate officer and di- macies that conduct wholesale dis- rector, the corporate names, and the tributions. name of the State of incorporation; and

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

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(3) Have a quarantine area for stor- (d) Examination of materials. (1) Upon age of prescription drugs that are out- receipt, each outside shipping con- dated, damaged, deteriorated, mis- tainer shall be visually examined for branded, or adulterated, or that are in identity and to prevent the acceptance immediate or sealed, secondary con- of contaminated prescription drugs or tainers that have been opened; prescription drugs that are otherwise (4) Be maintained in a clean and or- unfit for distribution. This examina- derly condition; and tion shall be adequate to reveal con- (5) Be free from infestation by in- tainer damage that would suggest pos- sects, rodents, birds, or vermin of any sible contamination or other damage kind. to the contents. (b) Security. (1) All facilities used for (2) Each outgoing shipment shall be wholesale drug distribution shall be se- carefully inspected for identity of the cure from unauthorized entry. prescription drug products and to en- (i) Access from outside the premises sure that there is no delivery of pre- shall be kept to a minimum and be scription drugs that have been dam- well-controlled. aged in storage or held under improper conditions. (ii) The outside perimeter of the (3) The recordkeeping requirements premises shall be well-lighted. in paragraph (f) of this section shall be (iii) Entry into areas where prescrip- followed for all incoming and outgoing tion drugs are held shall be limited to prescription drugs. authorized personnel. (e) Returned, damaged, and outdated (2) All facilities shall be equipped prescription drugs. (1) Prescription with an alarm system to detect entry drugs that are outdated, damaged, de- after hours. teriorated, misbranded, or adulterated (3) All facilities shall be equipped shall be quarantined and physically with a security system that will pro- separated from other prescription vide suitable protection against theft drugs until they are destroyed or re- and diversion. When appropriate, the turned to their supplier. security system shall provide protec- (2) Any prescription drugs whose im- tion against theft or diversion that is mediate or sealed outer or sealed sec- facilitated or hidden by tampering with ondary containers have been opened or computers or electronic records. used shall be identified as such, and (c) Storage. All prescription drugs shall be quarantined and physically shall be stored at appropriate tempera- separated from other prescription tures and under appropriate conditions drugs until they are either destroyed in accordance with requirements, if or returned to the supplier. any, in the labeling of such drugs, or (3) If the conditions under which a with requirements in the current edi- prescription drug has been returned tion of an official compendium, such as cast doubt on the drug’s safety, iden- the United States Pharmacopeia/Na- tity, strength, quality, or purity, then tional Formulary (USP/NF). the drug shall be destroyed, or re- (1) If no storage requirements are es- turned to the supplier, unless examina- tablished for a prescription drug, the tion, testing, or other investigation drug may be held at ‘‘controlled’’ room proves that the drug meets appropriate temperature, as defined in an official standards of safety, identity, strength, compendium, to help ensure that its quality, and purity. In determining identity, strength, quality, and purity whether the conditions under which a are not adversely affected. drug has been returned cast doubt on (2) Appropriate manual, the drug’s safety, identity, strength, electromechanical, or electronic tem- quality, or purity, the wholesale drug perature and humidity recording equip- distributor shall consider, among other ment, devices, and/or logs shall be uti- things, the conditions under which the lized to document proper storage of drug has been held, stored, or shipped prescription drugs. before or during its return and the con- (3) The recordkeeping requirements dition of the drug and its container, in paragraph (f) of this section shall be carton, or labeling, as a result of stor- followed for all stored drugs. age or shipping.

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

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

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made in writing to the appropriate re- means of identification than a symbol view division in the Center for Drug or logo by itself. Homeopathic drug Evaluation and Research (CDER), Food products are required only to bear an and Drug Administration, 5901–B imprint that identifies the manufac- Ammendale Rd., Beltsville, MD 20705– turer and their homeopathic nature. 1266 or the Center for Biologics Evalua- (b) A holder of an approved application and Research (CBER), Food and tion who has, under § 314.70 (b) of this Drug Administration, 1401 Rockville chapter, supplemented its application Pike, suite 200N, Rockville, MD 20852– to provide for a new imprint is not re- 1448. If FDA denies the request, the quired to bring its product into compli- holder of the approved application will ance with this section during the pend- have 1 year after the date of an agency ency of the agency’s review. Once the denial to imprint the drug product. review is complete, the drug product is (ii) Exemption requests for products subject to the requirements of the rule. that have not yet received approval (c) A solid oral dosage form drug shall be made in writing to the appro- product that does not meet the require- priate review division in CDER or ment for imprinting in paragraph (a) of CBER. this section and is not exempt from the (2) Any product not subject to pre- requirement may be considered adul- market approval is exempt from the re- terated and misbranded and may be an quirement of § 206.10 if, based on the unapproved new drug. product’s size, shape, texture, or other (d) For purposes of this section, code physical characteristics, the manufac- imprint means any single letter or num- turer or distributor of the product is ber or any combination of letters and prepared to demonstrate that imprint- numbers, including, e.g., words, coming the dosage form is technologically pany name, and National Drug Code, or infeasible or impossible. a mark, symbol, logo, or monogram, or (c) For drugs that are administered a combination of letters, numbers, and solely in controlled health care set- marks or symbols, assigned by a drug tings and not provided to patients for firm to a specific drug product. self-administration, sponsors may submit requests for exemptions from the [58 FR 47958, Sept. 13, 1993, as amended at 60 requirements of this rule. Controlled FR 19846, Apr. 21, 1995; 69 FR 18763, Apr. 8, settings include physicians’ offices and 2004] other health care facilities. Exemption requests should be submitted in writ- PART 207—REGISTRATION OF PRO- ing to the appropriate review division DUCERS OF DRUGS AND LISTING in CDER or CBER. OF DRUGS IN COMMERCIAL DIS- [58 FR 47958, Sept. 13, 1993, as amended at 70 TRIBUTION FR 14981, Mar. 24, 2005; 74 FR 13112, Mar. 26, 2009] Subpart A—General

§ 206.10 Code imprint required. Sec. (a) Unless exempted under § 206.7, no 207.3 Definitions. drug product in solid oral dosage form 207.7 Establishment registration and prod- may be introduced or delivered for in- uct listing for human blood and blood products and for medical devices. troduction into interstate commerce unless it is clearly marked or im- Subpart B—Exemptions printed with a code imprint that, in conjunction with the product’s size, 207.10 Exemptions for establishments. shape, and color, permits the unique identification of the drug product and Subpart C—Procedures for Domestic Drug the manufacturer or distributor of the Establishments product. Identification of the drug 207.20 Who must register and submit a drug product requires identification of its list. active ingredients and its dosage 207.21 Times for registration and drug list- strength. Inclusion of a letter or num- ing. ber in the imprint, while not required, 207.22 How and where to register and list is encouraged as a more effective drugs.

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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 207.35 Notification of registrant; drug establishment registration number and drug this chapter, and any distribution of an listing number. animal drug or animal feed bearing or 207.37 Inspection of registrations and drug containing an animal drug for non- listings. investigational uses, but the term does 207.39 Misbranding by reference to registra- not include internal or interplant tion or to registration number. transfer of a bulk drug substance between registered establishments within Subpart D—Procedure for Foreign Drug the same parent, subsidiary, and/or af- Establishments filiate company. For foreign establish- 207.40 Establishment registration and drug ments, the term ‘‘commercial distribu- listing requirements for foreign estab- tion’’ shall have the same meaning ex- lishments. cept that the term shall not include distribution of any drug that is neither AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 374, 381, 393; 42 U.S.C. 262, 264, imported nor offered for import into 271. the United States. (6) Drug product salvaging means the SOURCE: 45 FR 38043, June 6, 1980, unless act of segregating drug products that otherwise noted. may have been subjected to improper storage conditions, such as extremes in Subpart A—General temperature, humidity, smoke, fumes, pressure, age, or radiation, for the pur- § 207.3 Definitions. pose of returning some or all of the (a) The following definitions apply to products to the marketplace. this part: (7) Establishment means a place of (1) Act means the Federal Food, Drug, business under one management at one and Cosmetic Act approved June 25, general physical location. The term in- 1938 (52 Stat. 1040 et seq., as amended cludes, among others, independent lab- (21 U.S.C. 301–392)), except as otherwise oratories that engage in control activi- provided. ties for a registered drug establishment (2) Advertising and labeling include the (e.g., consulting laboratories), manufac- promotional material described in turers of medicated feeds and of vita- § 202.1(l) (1) and (2) respectively. min products that are drugs in accord- (3) Any material change includes but is ance with section 201(g) of the act, not limited to any change in the name human blood donor centers, and animal of the drug, any change in the identity facilities used for the production or or quantity of the active ingredient(s), control testing of licensed biologicals, any change in the identity or quantity and establishments engaged in drug of the inactive ingredient(s) where product salvaging. quantitative listing of all ingredients (8) Manufacturing or processing means is required by § 207.31(a)(2), any signifi- the manufacture, preparation, propaga- cant change in the labeling of a pre- tion, compounding, or processing of a scription drug, and any significant drug or drugs as used in section 510 of change in the label or package insert of the act and is the making by chemical, an over-the-counter drug. Changes that physical, biological, or other proce- are not significant include changes in dures of any articles that meet the def- arrangement or printing or changes of inition of drugs in section 201(g) of the an editorial nature. act. The term includes manipulation, (4) Bulk drug substance means any sampling, testing, or control proce- substance that is represented for use in dures applied to the final product or to a drug and that, when used in the man- any part of the process. The term also ufacturing, processing, or packaging of includes repackaging or otherwise a drug, becomes an active ingredient or changing the container, wrapper, or la- a finished dosage form of the drug, but beling of any drug package to further the term does not include intermedi- the distribution of the drug from the

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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 terial (excluding labeling as deter- for Devices and Radiological Health, mined in § 202.1(l) (1) and (2)) that gives FDA, on Form FDA–2891 (Initial Reg- a balanced picture of the promotional istration of Device Establishments), claims used for the drug, e.g., if more FDA–2891a (Registration of Device Es- than one medical journal advertise- tablishment), and FDA–2892 (Medical ment is used but the promotional con- Device Listing), in accordance with tent is essentially identical, only one part 807. need be submitted. (d) Owners and operators of establish- (10) Representative sampling of any ments engaged in the manufacture or other labeling means typical labeling processing at the same establishment material (excluding labels and package of both drug products and medical de- inserts) that gives a balanced picture vices shall (1) register with the Records of the promotional claims used for the Repository Team (HFD–143), Center for drug, e.g., if more than one brochure is Drug Evaluation and Research, FDA, used but the promotional content is es- and list their drug products in accord- sentially identical, only one need be ance with this part, and (2) register submitted. with the Center for Devices and Radio- (11) United States agent means a per- logical Health and list their medical son residing or maintaining a place of devices in accordance with part 807. business in the United States whom a [45 FR 38043, June 6, 1980, as amended at 50 foreign establishment designates as its FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29, agent. This definition excludes mail- 1990; 66 FR 59156, Nov. 27, 2001; 69 FR 48775, boxes, answering machines or services, Aug. 11, 2004] or other places where an individual acting as the foreign establishment’s Subpart B—Exemptions agent is not physically present. (b) The definitions and interpreta- § 207.10 Exemptions for establish- tions of terms in sections 201, 502(e), ments. and 510 of the act apply to the use of The following classes of persons are terms in this part. exempt from registration and drug listing in accordance with this part under [45 FR 38043, June 6, 1980, as amended at 55 FR 11576, Mar. 29, 1990; 66 FR 59156, Nov. 27, section 510(g)(1), (g)(2), and (g)(3) of the 2001] act, or because FDA has found, under section 510(g)(5) of the act, that their § 207.7 Establishment registration and registration is not necessary for the product listing for human blood protection of the public health. The ex- and blood products and for medical emptions in paragraphs (a) and (b) of devices. this section are limited to pharmacies, (a) Owners and operators of human hospitals, clinics, and public health blood and blood product establishments agencies located in any State as de- shall register and list their products fined in section 201(a)(1) of the act. with the Center for Biologics Evalua- (a) Pharmacies that operate under tion and Research (HFM–375), 1401 applicable local laws regulating dis- Rockville Pike, suite 200N, Rockville, pensing of prescription drugs and that MD 20852–1448, on Form FDA–2830 do not manufacture or process drugs (Blood Establishment Registration and for sale other than in the regular Product Listing), in accordance with course of the practice of the profession part 607 of this chapter. Such owners of pharmacy, including dispensing and and operators who also manufacture or selling drugs at retail. The supplying of process other drug products at the prescription drugs by these pharmacies same establishment shall, in addition, to a practitioner licensed to administer register and list all such other drug these drugs for his or her use in the products with the Drug Listing Branch course of professional practice or to in accordance with this part. other pharmacies to meet temporary

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

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

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their drug listing information every partner, and in the case of a corpora- June and December. tion the name and title of each corporate officer and director and the [45 FR 38043, June 6, 1980, as amended at 55 FR 11576, Mar. 29, 1990; 64 FR 400, Jan. 5, 1999; name of the State of incorporation. 64 FR 56448, Oct. 20, 1999; 64 FR 63203, Nov. 19, (b) Form FDA–2657 (Drug Product 1999; 66 FR 59157, Nov. 27, 2001; 72 FR 69120, Listing) provides that information re- Dec. 6, 2007] 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 Records name, that are being manufactured or Repository Team (HFD–143), Center for processed for commercial distribution Drug Evaluation and Research, Food and that have not been included in any and Drug Administration, 5600 Fishers list previously submitted to FDA on Lane, Rockville, MD 20857, or from Form FDA–2657 or in conjunction with FDA district offices. An establishment the FDA voluntary inventory on Form whose drug registration for that year FDA–2422 (Survey Report of Marketed was validated under § 207.35 shall make Drugs), or Form FDA–2250 (National subsequent annual registration on Drug Code Directory Input). Form FDA–2656 as described in (2) For each drug listed that the reg- § 207.21(a) by mailing the completed istrant regards as subject to section 505 form to the above address within 30 or 512 of the act, the new drug applica- days after receipt from FDA. tion number, abbreviated new drug ap- (b) The first list of drugs and later plication number, new animal drug ap- June and December updatings shall be plication number, or abbreviated new on Form FDA–2657 (Drug Product List- animal drug application number and a ing), obtainable upon request as de- copy of all current labeling, except scribed in paragraph (a) of this section. that only one representative container An establishment may submit, in lieu or carton label need be submitted of Form FDA–2657, tapes for computer where differences exist only in the inputs containing the information quantity of contents statement. specified in Form FDA–2657 if formats (3) For each drug listed that the reg- proposed for this use were reviewed and istrant regards as subject to section 351 approved by the Records Repository of the Public Health Service Act, the Team (HFD–143), Center for Drug Eval- license number of the manufacturer. uation and Research, FDA. (4) For each human prescription drug [45 FR 38043, June 6, 1980, as amended at 50 listed that the registrant regards as FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29, not subject to section 505 of the act or 1990; 69 FR 48775, Aug. 11, 2004] 351 of the Public Health Service Act, and that is not manufactured by a reg- § 207.25 Information required in registered blood bank, a copy of all cur- istration and drug listing. rent labeling (except that only one rep- (a) Form FDA–2656 (Registration of resentative container or carton label Drug Establishment) provides for fur- need be submitted where differences nishing or confirming information re- exist only in the quantity of contents quired by the act. This information in- statement) and a representative sam- cludes, for each establishment, the pling of advertisements. name and full address of the drug es- (5) For each human over-the-counter tablishment; all trade names used by drug listed, or each animal drug listed, the establishment; the kind of owner- that the registrant regards as not sub- ship or operation (that is, individually ject to section 505 or 512 of the act or owned, partnership or corporation); 351 of the Public Health Service Act, a and the name of the owner or operator copy of the label (except that only one of the establishment. The term name of representative container or carton the owner or operator includes in the label need be submitted where dif- case of a partnership the name of each ferences exist only in the quantity of

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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 expressed in terms of the amount, not officers and directors of the corpora- the percent, of that ingredient in each tions do not require such amendment dosage unit or, if the drug is not in but must be shown at time of annual unit dosage form, the amount of the in- registration. gredient in a specific unit of weight or [45 FR 25777, Apr. 15, 1980, as amended at 55 measure of the drug. For a drug formu- FR 11577, Mar. 29, 1990] lation that is a Type A medicated article subject to § 207.35(b)(2)(iii), the reg- § 207.30 Updating drug listing informa- istrant may limit the quantitative list- tion. ing of ingredients to each variation of (a) After submitting the initial drug level of active drug ingredient. listing information, every person who (7) For each drug listed, the registra- is required to list drugs under § 207.20 tion number of every drug establish- shall submit on Form FDA–2657 (Drug ment within the parent company at Product Listing) during each subse- which it is manufactured or processed. quent June and December, or at the (8) For each drug listed, the National discretion of the registrant when the Drug Code (NDC) number. If FDA has change occurs, the following informa- not assigned an NDC Labeler Code, the tion: registrant shall include a Product Code (1) A list of each drug introduced by and Package Code and FDA will assign the registrant for commerical distribution which has not been included in a Labeler Code as described in any list previously submitted. The reg- § 207.35(b)(2)(i). istrant shall provide all of the informa- (c) For each drug product listed that tion required by § 207.25(b) for each is subject to the imprinting require- such drug. ments of part 206 of this chapter, in- (2) A list of each drug formerly listed cluding products that are exempted in accordance with § 207.25(b) for which under § 206.7(b), drug companies must commercial distribution has been dis- submit a document that provides the continued, including for each drug so name of the product, its active ingre- listed the National Drug Code (NDC) dient(s), dosage strength, National number, the identity by established Drug Code number, the name of its name and by proprietary name, and manufacturer or distributor, its size, date of discontinuance. It is requested shape, color, and code imprint (if any), but not required that the reason for and any other characteristic that iden- discontinuance of distribution be in- tifies the product as unique. cluded with this information. [45 FR 38043, June 6, 1980, as amended at 52 (3) A list of each drug for which a no- FR 2682, Jan. 26, 1987; 55 FR 11577, Mar. 29, tice of discontinuance was submitted 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, under paragraph (a)(2) of this section May 13, 1998; 64 FR 400, Jan. 5, 1999; 66 FR and for which commercial distribution 59157, Nov. 27, 2001] has been resumed, including for each

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

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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’’ in assigning the Product and Package when it is used on a label or in label- Codes: a 3–2 Product-Package Code con- ing. The prefix used for a drug product figuration (e.g., 542–12) or a 4–1 Prod- shall be used consistently on the label uct-Package Code configuration (e.g., of the immediate container, outside 5421–2). A manufacturer or distributor container, or wrapper, if any, and on with a given Labeler Code shall use other labeling for that drug product. only one such Product-Package Code (iii) The Product-Package Code con- configuration and shall use this same figuration shall be indicated and the configuration in assigning the Product- segments of the number shall be sepa- Package Codes for all drugs included in rated by a dash, e.g., NDC 15643–542–12 the drug listing. The manufacturer or or N 15643–542–12. distributor shall report to FDA the (iv) All 10 characters shall appear and Product-Package Code configuration the leading zeros in any segment of the used in assigning these codes. NDC number shall be shown, except (iii) If the drug formulation is a Type that leading zeros may be omitted from A medicated article intended for use in any segment of the NDC number when the manufacture of an animal feed, the NDC number is used for product FDA assigns a separate Product Code identification by direct imprinting on only for each variation of level of ac- dosage forms or in the case of con- tive drug ingredient. tainers too small or otherwise unable (3) FDA requests but does not require to accommodate a label with sufficent that the NDC number appear on all space to bear both required and op- drug labels and in other drug labeling, tional labeling information. including the label of any prescription (v) The placing of the assigned NDC drug container furnished to a con- number on a label or in other labeling sumer. If the NDC number is shown on does not require the submission of a a drug label, it shall be placed as fol- supplemental new drug application, lows: supplemental new animal drug applica- (i) The NDC number shall appear tion, or a modification to an index list- prominently in the top third of the ing. principal display panel of the label on (4)(i) If any change occurs in those the immediate container and of any product characteristics that clearly outside container or wrapper. Instead distinguish one drug product version of appearing in the top third of the from another, the registrant shall as- label, the NDC number may appear as sign a new NDC number to the new part of and contiguous to any bar-code product version and submit that infor- symbol for any drug product if two mation to FDA. Such a change in- conditions are met. First, the symbol cludes, but is not limited to, a change

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

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become a matter of public knowledge under subpart B of this part or unless or if FDA finds that confidentiality the drugs enter a foreign trade zone would be inconsistent with protection and are re-exported from that foreign of the public health): trade zone without having entered U. (i) Any information submitted as the S. commerce. basis upon which it has been deter- (b) No drug may be imported or of- mined that a particular drug product is fered for import into the United States not subject to section 505 or 512 of the unless it is listed as required in subpart act. C of this part and manufactured, pre- (ii) A list of a drug product’s inactive pared, propagated, compounded, or ingredients. processed at a registered foreign drug (iii) A list of drugs containing a par- establishment; however, this restric- ticular inactive ingredient. tion does not apply to a drug imported (b) Requests for information about or offered for import under the inves- registrations and drug listings of an es- tigational 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. for the geographic area in which the es- (c) Each foreign drug establishment tablishment is located. required to register under paragraph [45 FR 38043, June 6, 1980, as amended at 50 (a) of this section shall submit the FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, name, address, and phone number of its 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, United States agent as part of its ini- May 13, 1998; 64 FR 400, Jan. 5, 1999; 66 FR tial and updated registration informa- 59157, Nov. 27, 2001; 69 FR 48775, Aug. 11, 2004] tion in accordance with subpart C of this part. Each foreign drug establish- § 207.39 Misbranding by reference to ment shall designate only one United registration or to registration num- States agent. ber. (1) The United States agent shall re- Registration of a drug establishment side or maintain a place of business in or drug wholesaler, or assignment of a the United States. registration number, or assignment of (2) Upon request from FDA, the a NDC number does not in any way de- United States agent shall assist FDA note approval of the firm or its prod- in communications with the foreign ucts. Any representation that creates drug establishment, respond to ques- an impression of official approval be- tions concerning the foreign drug es- cause of registration or possession of tablishment’s products that are im- registration number or NDC number is ported or offered for import into the misleading and constitutes mis- United States, and assist FDA in branding. scheduling inspections of the foreign drug establishment. If the agency is Subpart D—Procedure for Foreign unable to contact the foreign drug es- Drug Establishments tablishment directly or expeditiously, FDA may provide information or docu- § 207.40 Establishment registration ments to the United States agent, and and drug listing requirements for such an action shall be considered to be foreign establishments. equivalent to providing the same infor- (a) Foreign drug establishments mation or documents to the foreign whose drugs are imported or offered for drug establishment. import into the United States shall (3) The foreign drug establishment or comply with the establishment reg- the United States agent shall report istration and drug listing requirements changes in the United States agent’s in subpart C of this part, unless exempt name, address, or phone number to

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FDA within 10-business days of the (2) The drug product is one that has change. serious risk(s) (relative to benefits) of which patients should be made aware [66 FR 59157, Nov. 27, 2001] because information concerning the risk(s) could affect patients’ decision PART 208—MEDICATION GUIDES to use, or to continue to use, the prod- FOR PRESCRIPTION DRUG PROD- uct. UCTS (3) The drug product is important to health and patient adherence to direc- Subpart A—General Provisions tions for use is crucial to the drug’s effectiveness. Sec. 208.1 Scope and purpose. § 208.3 Definitions. 208.3 Definitions. For the purposes of this part, the fol- Subpart B—General Requirements for a lowing definitions shall apply: Medication Guide (a) Authorized dispenser means an individual licensed, registered, or other- 208.20 Content and format of a Medication wise permitted by the jurisdiction in Guide. which the individual practices to pro- 208.24 Distributing and dispensing a Medica- vide drug products on prescription in tion Guide. the course of professional practice. 208.26 Exemptions and deferrals. (b) Dispense to patients means the act AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, of delivering a prescription drug prod- 355, 356, 357, 360, 371, 374; 42 U.S.C. 262. uct to a patient or an agent of the patient either: SOURCE: 63 FR 66396, Dec. 1, 1998, unless otherwise noted. (1) By a licensed practitioner or an agent of a licensed practitioner, either directly or indirectly, for self-adminis- Subpart A—General Provisions tration by the patient, or the patient’s agent, or outside the licensed practi- § 208.1 Scope and purpose. tioner’s direct supervision; or (a) This part sets forth requirements (2) By an authorized dispenser or an for patient labeling for human pre- agent of an authorized dispenser under scription drug products, including bio- a lawful prescription of a licensed prac- logical products, that the Food and titioner. Drug Administration (FDA) determines (c) Distribute means the act of deliv- pose a serious and significant public ering, other than by dispensing, a drug health concern requiring distribution product to any person. of FDA-approved patient information. (d) Distributor means a person who It applies primarily to human prescrip- distributes a drug product. tion drug products used on an out- (e) Drug product means a finished dos- patient basis without direct super- age form, e.g., tablet, capsule, or solu- vision by a health professional. This tion, that contains an active drug in- part shall apply to new prescriptions gredient, generally, but not nec- and refill prescriptions. essarily, in association with inactive (b) The purpose of patient labeling ingredients. For purposes of this part, for human prescription drug products drug product also means biological required under this part is to provide product within the meaning of section information when the FDA determines 351(a) of the Public Health Service Act. in writing that it is necessary to pa- (f) Licensed practitioner means an in- tients’ safe and effective use of drug dividual licensed, registered, or other- products. wise permitted by the jurisdiction in (c) Patient labeling will be required which the individual practices to pre- if the FDA determines that one or scribe drug products in the course of more of the following circumstances professional practice. exists: (g) Manufacturer means for a drug (1) The drug product is one for which product that is not also a biological patient labeling could help prevent se- product, both the manufacturer as de- rious adverse effects. scribed in § 201.1 and the applicant as

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

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

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

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209.11 Dispensing and distributing the side Side effects statement means the fol- effects statement. lowing verbatim statement: ‘‘Call your AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, doctor for medical advice about side ef- 355, 360, 371; 42 U.S.C. 241. fects. You may report side effects to

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

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PART 210—CURRENT GOOD MAN- tion to the regulations in this part and UFACTURING PRACTICE IN MAN- in parts 211 through 226 of this chapter. UFACTURING, PROCESSING, Failure to comply with any applicable regulation set forth in this part, in PACKING, OR HOLDING OF parts 211 through 226 of this chapter, in DRUGS; GENERAL part 1271 subpart C of this chapter, or in part 1271 subpart D of this chapter Sec. with respect to the manufacture, proc- 210.1 Status of current good manufacturing essing, packing or holding of a drug, practice regulations. 210.2 Applicability of current good manu- renders an HCT/P adulterated under facturing practice regulations. section 501(a)(2)(B) of the act. Such 210.3 Definitions. HCT/P, as well as the person who is responsible for the failure to comply, is AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264. subject to regulatory action. SOURCE: 43 FR 45076, Sept, 29, 1978, unless [43 FR 45076, Sept, 29, 1978, as amended at 69 otherwise noted. FR 29828, May 25, 2004] EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. § 210.1 Status of current good manu- 10, 2009, § 210.1 was amended by removing the facturing practice regulations. phrase ‘‘211 through 226’’ each time it ap- (a) The regulations set forth in this pears and by adding in its place the phrase part and in parts 211 through 226 of this ‘‘211, 225, and 226’’, effective Dec. 12, 2011. chapter contain the minimum current good manufacturing practice for meth- § 210.2 Applicability of current good manufacturing practice regulations. ods to be used in, and the facilities or controls to be used for, the manufac- (a) The regulations in this part and ture, processing, packing, or holding of in parts 211 through 226 of this chapter a drug to assure that such drug meets as they may pertain to a drug; in parts the requirements of the act as to safe- 600 through 680 of this chapter as they ty, and has the identity and strength may pertain to a biological product for and meets the quality and purity char- human use; and in part 1271 of this acteristics that it purports or is rep- chapter as they are applicable to a resented to possess. human cell, tissue, or cellular or tis- (b) The failure to comply with any sue-based product (HCT/P) that is a regulation set forth in this part and in drug (subject to review under an appli- parts 211 through 226 of this chapter in cation submitted under section 505 of the manufacture, processing, packing, the act or under a biological product li- or holding of a drug shall render such cense application under section 351 of drug to be adulterated under section the Public Health Service Act); shall 501(a)(2)(B) of the act and such drug, as be considered to supplement, not super- well as the person who is responsible sede, each other, unless the regulations for the failure to comply, shall be sub- explicitly provide otherwise. In the ject to regulatory action. event of a conflict between applicable (c) Owners and operators of establish- regulations in this part and in other ments engaged in the recovery, donor parts of this chapter, the regulation screening, testing (including donor specifically applicable to the drug testing), processing, storage, labeling, product in question shall supersede the packaging, or distribution of human more general. cells, tissues, and cellular and tissue- (b) If a person engages in only some based products (HCT/Ps), as defined in operations subject to the regulations in § 1271.3(d) of this chapter, that are this part, in parts 211 through 226 of drugs (subject to review under an appli- this chapter, in parts 600 through 680 of cation submitted under section 505 of this chapter, and in part 1271 of this the act or under a biological product li- chapter, and not in others, that person cense application under section 351 of need only comply with those regula- the Public Health Service Act), are tions applicable to the operations in subject to the donor-eligibility and ap- which he or she is engaged. plicable current good tissue practice (c) An investigational drug for use in procedures set forth in part 1271 sub- a phase 1 study, as described in parts C and D of this chapter, in addi- § 312.21(a) of this chapter, is subject to

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the statutory requirements set forth in (5) Fiber means any particulate con- 21 U.S.C. 351(a)(2)(B). The production of taminant with a length at least three such drug is exempt from compliance times greater than its width. with the regulations in part 211 of this (6) Nonfiber releasing filter means any chapter. However, this exemption does filter, which after appropriate not apply to an investigational drug pretreatment such as washing or flush- for use in a phase 1 study once the in- ing, will not release fibers into the vestigational drug has been made component or drug product that is available for use by or for the sponsor being filtered. in a phase 2 or phase 3 study, as de- (7) Active ingredient means any com- scribed in § 312.21(b) and (c) of this ponent that is intended to furnish chapter, or the drug has been lawfully pharmacological activity or other di- marketed. If the investigational drug rect effect in the diagnosis, cure, miti- has been made available in a phase 2 or gation, treatment, or prevention of dis- phase 3 study or the drug has been law- ease, or to affect the structure or any fully marketed, the drug for use in the function of the body of man or other phase 1 study must comply with part animals. The term includes those com- 211. ponents that may undergo chemical [69 FR 29828, May 25, 2004, as amended at 73 change in the manufacture of the drug FR 40462, July 15, 2008] product and be present in the drug EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. product in a modified form intended to 10, 2009, § 210.2(a) and (b) were amended by re- furnish the specified activity or effect. moving the phrase ‘‘211 through 226’’ both (8) Inactive ingredient means any com- times it appears and by adding in its place ponent other than an active ingredient. the phrase ‘‘211, 225, and 226’’, effective Dec. (9) In-process material means any ma- 12, 2011. terial fabricated, compounded, blended, § 210.3 Definitions. or derived by chemical reaction that is produced for, and used in, the prepara- (a) The definitions and interpretation of the drug product. tions contained in section 201 of the act shall be applicable to such terms when (10) Lot means a batch, or a specific used in this part and in parts 211 identified portion of a batch, having through 226 of this chapter. uniform character and quality within (b) The following definitions of terms specified limits; or, in the case of a apply to this part and to parts 211 drug product produced by continuous through 226 of this chapter. process, it is a specific identified (1) Act means the Federal Food, Drug, amount produced in a unit of time or and Cosmetic Act, as amended (21 quantity in a manner that assures its U.S.C. 301 et seq.). having uniform character and quality (2) Batch means a specific quantity of within specified limits. a drug or other material that is in- (11) Lot number, control number, or tended to have uniform character and batch number means any distinctive quality, within specified limits, and is combination of letters, numbers, or produced according to a single manu- symbols, or any combination of them, facturing order during the same cycle from which the complete history of the of manufacture. manufacture, processing, packing, (3) Component means any ingredient holding, and distribution of a batch or intended for use in the manufacture of lot of drug product or other material a drug product, including those that can be determined. may not appear in such drug product. (12) Manufacture, processing, packing, (4) Drug product means a finished dos- or holding of a drug product includes age form, for example, tablet, capsule, packaging and labeling operations, solution, etc., that contains an active testing, and quality control of drug drug ingredient generally, but not nec- products. essarily, in association with inactive (13) The term medicated feed means ingredients. The term also includes a any Type B or Type C medicated feed finished dosage form that does not con- as defined in § 558.3 of this chapter. The tain an active ingredient but is in- feed contains one or more drugs as de- tended to be used as a placebo. fined in section 201(g) of the act. The

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manufacture of medicated feeds is sub- units that are drawn based on rational ject to the requirements of part 225 of criteria such as random sampling and this chapter. intended to assure that the sample ac- (14) The term medicated premix means curately portrays the material being a Type A medicated article as defined sampled. in § 558.3 of this chapter. The article (22) Gang-printed labeling means la- contains one or more drugs as defined beling derived from a sheet of material in section 201(g) of the act. The manu- on which more than one item of label- facture of medicated premixes is sub- ing is printed. ject to the requirements of part 226 of [43 FR 45076, Sept. 29, 1978, as amended at 51 this chapter. FR 7389, Mar. 3, 1986; 58 FR 41353, Aug. 3, 1993; (15) Quality control unit means any 73 FR 51931, Sept. 8, 2008] person or organizational element designated by the firm to be responsible EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. for the duties relating to quality con- 10, 2009, § 210.3(a) and (b) introductory text were amended by removing the phrase ‘‘211 trol. through 226’’ and adding in its place the (16) Strength means: phrase ‘‘211, 225, and 226’’, effective Dec. 12, (i) The concentration of the drug sub- 2011. stance (for example, weight/weight, weight/volume, or unit dose/volume PART 211—CURRENT GOOD MAN- basis), and/or UFACTURING PRACTICE FOR FIN- (ii) The potency, that is, the therapeutic activity of the drug product as ISHED PHARMACEUTICALS indicated by appropriate laboratory tests or by adequately developed and Subpart A—General Provisions controlled clinical data (expressed, for Sec. example, in terms of units by reference 211.1 Scope. to a standard). 211.3 Definitions. (17) Theoretical yield means the quantity that would be produced at any ap- Subpart B—Organization and Personnel propriate phase of manufacture, proc- 211.22 Responsibilities of quality control essing, or packing of a particular drug unit. product, based upon the quantity of 211.25 Personnel qualifications. components to be used, in the absence 211.28 Personnel responsibilities. of any loss or error in actual produc- 211.34 Consultants. tion. (18) Actual yield means the quantity Subpart C—Buildings and Facilities that is actually produced at any appro- 211.42 Design and construction features. priate phase of manufacture, proc- 211.44 Lighting. essing, or packing of a particular drug 211.46 Ventilation, air filtration, air heating product. and cooling. (19) Percentage of theoretical yield 211.48 Plumbing. means the ratio of the actual yield (at 211.50 Sewage and refuse. any appropriate phase of manufacture, 211.52 Washing and toilet facilities. processing, or packing of a particular 211.56 Sanitation. drug product) to the theoretical yield 211.58 Maintenance. (at the same phase), stated as a percentage. Subpart D—Equipment (20) Acceptance criteria means the 211.63 Equipment design, size, and location. product specifications and acceptance/ 211.65 Equipment construction. rejection criteria, such as acceptable 211.67 Equipment cleaning and mainte- quality level and unacceptable quality nance. level, with an associated sampling 211.68 Automatic, mechanical, and elec- plan, that are necessary for making a tronic equipment. decision to accept or reject a lot or 211.72 Filters. batch (or any other convenient sub- Subpart E—Control of Components and groups of manufactured units). Drug Product Containers and Closures (21) Representative sample means a sample that consists of a number of 211.80 General requirements.

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211.82 Receipt and storage of untested com- 211.196 Distribution records. ponents, drug product containers, and 211.198 Complaint files. closures. 211.84 Testing and approval or rejection of Subpart K—Returned and Salvaged Drug components, drug product containers, Products and closures. 211.86 Use of approved components, drug 211.204 Returned drug products. product containers, and closures. 211.208 Drug product salvaging. 211.87 Retesting of approved components, drug product containers, and closures. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 360b, 211.89 Rejected components, drug product 371, 374; 42 U.S.C. 216, 262, 263a, 264. containers, and closures. SOURCE: 43 FR 45077, Sept. 29, 1978, unless 211.94 Drug product containers and closures. otherwise noted. Subpart F—Production and Process Controls Subpart A—General Provisions 211.100 Written procedures; deviations. § 211.1 Scope. 211.101 Charge-in of components. (a) The regulations in this part con- 211.103 Calculation of yield. 211.105 Equipment identification. tain the minimum current good manu- 211.110 Sampling and testing of in-process facturing practice for preparation of materials and drug products. drug products for administration to hu- 211.111 Time limitations on production. mans or animals. 211.113 Control of microbiological contami- (b) The current good manufacturing nation. practice regulations in this chapter as 211.115 Reproccessing. they pertain to drug products; in parts Subpart G—Packaging and Labeling 600 through 680 of this chapter, as they Control pertain to drugs that are also biological products for human use; and in part 211.122 Materials examination and usage 1271 of this chapter, as they are appli- criteria. cable to drugs that are also human 211.125 Labeling issuance. cells, tissues, and cellular and tissue- 211.130 Packaging and labeling operations. based products (HCT/Ps) and that are 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drugs (subject to review under an appli- drug products. cation submitted under section 505 of 211.134 Drug product inspection. the act or under a biological product li- 211.137 Expiration dating. cense application under section 351 of the Public Health Service Act); supple- Subpart H—Holding and Distribution ment and do not supersede the regula- 211.142 Warehousing procedures. tions in this part unless the regula- 211.150 Distribution procedures. tions explicitly provide otherwise. In the event of a conflict between applica- Subpart I—Laboratory Controls ble regulations in this part and in other parts of this chapter, or in parts 211.160 General requirements. 211.165 Testing and release for distribution. 600 through 680 of this chapter, or in 211.166 Stability testing. part 1271 of this chapter, the regulation 211.167 Special testing requirements. specifically applicable to the drug 211.170 Reserve samples. product in question shall supersede the 211.173 Laboratory animals. more general. 211.176 Penicillin contamination. (c) Pending consideration of a proposed exemption, published in the FED- Subpart J—Records and Reports ERAL REGISTER of September 29, 1978, 211.180 General requirements. the requirements in this part shall not 211.182 Equipment cleaning and use log. be enforced for OTC drug products if 211.184 Component, drug product container, the products and all their ingredients closure, and labeling records. are ordinarily marketed and consumed 211.186 Master production and control as human foods, and which products records. 211.188 Batch production and control may also fall within the legal defini- records. tion of drugs by virtue of their in- 211.192 Production record review. tended use. Therefore, until further no- 211.194 Laboratory records. tice, regulations under part 110 of this

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chapter, and where applicable, parts 113 tions impacting on the identity, to 129 of this chapter, shall be applied strength, quality, and purity of the in determining whether these OTC drug drug product. products that are also foods are manu- (d) The responsibilities and proce- factured, processed, packed, or held dures applicable to the quality control under current good manufacturing unit shall be in writing; such written practice. procedures shall be followed. [43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522, Dec. 19, 1997; 69 FR 29828, May 25, § 211.25 Personnel qualifications. 2004] (a) Each person engaged in the manu- EFFECTIVE DATE NOTE: At 74 FR 65431, Dec. facture, processing, packing, or holding 10, 2009, § 211.1 was amended by revising para- of a drug product shall have education, graph (a), effective Dec. 12, 2011. For the con- training, and experience, or any com- venience of the user, the revised text is set bination thereof, to enable that person forth as follows: to perform the assigned functions. § 211.1 Scope. Training shall be in the particular op- (a) The regulations in this part contain the erations that the employee performs minimum current good manufacturing prac- and in current good manufacturing tice for preparation of drug products (exclud- practice (including the current good ing positron emission tomography drugs) for manufacturing practice regulations in administration to humans or animals. this chapter and written procedures required by these regulations) as they re- * * * * * late to the employee’s functions. Training in current good manufac- § 211.3 Definitions. turing practice shall be conducted by The definitions set forth in § 210.3 of qualified individuals on a continuing this chapter apply in this part. basis and with sufficient frequency to assure that employees remain familiar Subpart B—Organization and with CGMP requirements applicable to Personnel them. (b) Each person responsible for super- § 211.22 Responsibilities of quality vising the manufacture, processing, control unit. packing, or holding of a drug product shall have the education, training, and (a) There shall be a quality control experience, or any combination there- unit that shall have the responsibility of, to perform assigned functions in and authority to approve or reject all such a manner as to provide assurance components, drug product containers, that the drug product has the safety, closures, in-process materials, pack- identity, strength, quality, and purity aging material, labeling, and drug that it purports or is represented to products, and the authority to review possess. production records to assure that no errors have occurred or, if errors have (c) There shall be an adequate num- occurred, that they have been fully in- ber of qualified personnel to perform vestigated. The quality control unit and supervise the manufacture, proc- shall be responsible for approving or re- essing, packing, or holding of each drug jecting drug products manufactured, product. processed, packed, or held under con- § 211.28 Personnel responsibilities. tract by another company. (b) Adequate laboratory facilities for (a) Personnel engaged in the manu- the testing and approval (or rejection) facture, processing, packing, or holding of components, drug product con- of a drug product shall wear clean tainers, closures, packaging materials, clothing appropriate for the duties in-process materials, and drug products they perform. Protective apparel, such shall be available to the quality con- as head, face, hand, and arm coverings, trol unit. shall be worn as necessary to protect (c) The quality control unit shall drug products from contamination. have the responsibility for approving (b) Personnel shall practice good or rejecting all procedures or specifica- sanitation and health habits.

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(c) Only personnel authorized by su- defined areas or such other control sys- pervisory personnel shall enter those tems for the firm’s operations as are areas of the buildings and facilities necessary to prevent contamination or designated as limited-access areas. mixups during the course of the fol- (d) Any person shown at any time (ei- lowing procedures: ther by medical examination or super- (1) Receipt, identification, storage, visory observation) to have an appar- and withholding from use of compo- ent illness or open lesions that may ad- nents, drug product containers, clo- versely affect the safety or quality of sures, and labeling, pending the appro- drug products shall be excluded from priate sampling, testing, or examina- direct contact with components, drug tion by the quality control unit before product containers, closures, in-process materials, and drug products until the release for manufacturing or pack- condition is corrected or determined by aging; competent medical personnel not to (2) Holding rejected components, jeopardize the safety or quality of drug drug product containers, closures, and products. All personnel shall be in- labeling before disposition; structed to report to supervisory per- (3) Storage of released components, sonnel any health conditions that may drug product containers, closures, and have an adverse effect on drug prod- labeling; ucts. (4) Storage of in-process materials; (5) Manufacturing and processing op- § 211.34 Consultants. erations; Consultants advising on the manu- (6) Packaging and labeling oper- facture, processing, packing, or holding ations; of drug products shall have sufficient (7) Quarantine storage before release education, training, and experience, or of drug products; any combination thereof, to advise on (8) Storage of drug products after re- the subject for which they are retained. lease; Records shall be maintained stating (9) Control and laboratory oper- the name, address, and qualifications of any consultants and the type of ations; service they provide. (10) Aseptic processing, which includes as appropriate: Subpart C—Buildings and Facilities (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily § 211.42 Design and construction fea- cleanable; tures. (ii) Temperature and humidity con- (a) Any building or buildings used in trols; the manufacture, processing, packing, (iii) An air supply filtered through or holding of a drug product shall be of high-efficiency particulate air filters suitable size, construction and location under positive pressure, regardless of to facilitate cleaning, maintenance, whether flow is laminar or nonlaminar; and proper operations. (iv) A system for monitoring environ- (b) Any such building shall have ade- mental conditions; quate space for the orderly placement (v) A system for cleaning and dis- of equipment and materials to prevent infecting the room and equipment to mixups between different components, produce aseptic conditions; drug product containers, closures, la- (vi) A system for maintaining any beling, in-process materials, or drug equipment used to control the aseptic products, and to prevent contamina- conditions. tion. The flow of components, drug (d) Operations relating to the manu- product containers, closures, labeling, facture, processing, and packing of pen- in-process materials, and drug products icillin shall be performed in facilities through the building or buildings shall separate from those used for other drug be designed to prevent contamination. (c) Operations shall be performed products for human use. within specifically defined areas of ade- [43 FR 45077, Sept. 29, 1978, as amended at 60 quate size. There shall be separate or FR 4091, Jan. 20, 1995]

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

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Subpart D—Equipment operations, and the methods of dis- assembling and reassembling equip- § 211.63 Equipment design, size, and ment as necessary to assure proper location. cleaning and maintenance; Equipment used in the manufacture, (4) Removal or obliteration of pre- processing, packing, or holding of a vious batch identification; drug product shall be of appropriate de- (5) Protection of clean equipment sign, adequate size, and suitably lo- from contamination prior to use; cated to facilitate operations for its in- (6) Inspection of equipment for clean- tended use and for its cleaning and liness immediately before use. maintenance. (c) Records shall be kept of maintenance, cleaning, sanitizing, and inspec- § 211.65 Equipment construction. tion as specified in §§ 211.180 and 211.182. (a) Equipment shall be constructed so [43 FR 45077, Sept. 29, 1978, as amended at 73 that surfaces that contact components, FR 51931, Sept. 8, 2008] in-process materials, or drug products shall not be reactive, additive, or ab- § 211.68 Automatic, mechanical, and sorptive so as to alter the safety, iden- electronic equipment. tity, strength, quality, or purity of the (a) Automatic, mechanical, or elec- drug product beyond the official or tronic equipment or other types of other established requirements. equipment, including computers, or re- (b) Any substances required for oper- lated systems that will perform a func- ation, such as lubricants or coolants, tion satisfactorily, may be used in the shall not come into contact with com- manufacture, processing, packing, and ponents, drug product containers, clo- holding of a drug product. If such sures, in-process materials, or drug equipment is so used, it shall be rou- products so as to alter the safety, iden- tinely calibrated, inspected, or checked tity, strength, quality, or purity of the according to a written program de- drug product beyond the official or signed to assure proper performance. other established requirements. Written records of those calibration checks and inspections shall be main- § 211.67 Equipment cleaning and maintained. tenance. (b) Appropriate controls shall be ex- (a) Equipment and utensils shall be ercised over computer or related sys- cleaned, maintained, and, as appro- tems to assure that changes in master priate for the nature of the drug, sani- production and control records or other tized and/or sterilized at appropriate records are instituted only by author- intervals to prevent malfunctions or ized personnel. Input to and output contamination that would alter the from the computer or related system of safety, identity, strength, quality, or formulas or other records or data shall purity of the drug product beyond the be checked for accuracy. The degree official or other established require- and frequency of input/output ments. verification shall be based on the com- (b) Written procedures shall be estab- plexity and reliability of the computer lished and followed for cleaning and or related system. A backup file of data maintenance of equipment, including entered into the computer or related utensils, used in the manufacture, system shall be maintained except processing, packing, or holding of a where certain data, such as calcula- drug product. These procedures shall tions performed in connection with lab- include, but are not necessarily limited oratory analysis, are eliminated by to, the following: computerization or other automated (1) Assignment of responsibility for processes. In such instances a written cleaning and maintaining equipment; record of the program shall be main- (2) Maintenance and cleaning sched- tained along with appropriate valida- ules, including, where appropriate, tion data. Hard copy or alternative sys- sanitizing schedules; tems, such as duplicates, tapes, or (3) A description in sufficient detail microfilm, designed to assure that of the methods, equipment, and mate- backup data are exact and complete rials used in cleaning and maintenance and that it is secure from alteration,

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

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

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

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equipment under § 211.68, only verified procedures shall include, but are not by one person. limited to, the following, where appropriate: [43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008] (1) Tablet or capsule weight variation; § 211.103 Calculation of yield. (2) Disintegration time; Actual yields and percentages of the- (3) Adequacy of mixing to assure uni- oretical yield shall be determined at formity and homogeneity; the conclusion of each appropriate (4) Dissolution time and rate; phase of manufacturing, processing, (5) Clarity, completeness, or pH of so- packaging, or holding of the drug prod- lutions. uct. Such calculations shall either be (6) Bioburden testing. performed by one person and independ- (b) Valid in-process specifications for ently verified by a second person, or, if such characteristics shall be consistent the yield is calculated by automated with drug product final specifications equipment under § 211.68, be independ- and shall be derived from previous ac- ently verified by one person. ceptable process average and process variability estimates where possible [73 FR 51932, Sept. 8, 2008] and determined by the application of § 211.105 Equipment identification. suitable statistical procedures where appropriate. Examination and testing (a) All compounding and storage con- of samples shall assure that the drug tainers, processing lines, and major product and in-process material con- equipment used during the production form to specifications. of a batch of a drug product shall be (c) In-process materials shall be test- properly identified at all times to indi- ed for identity, strength, quality, and cate their contents and, when nec- purity as appropriate, and approved or essary, the phase of processing of the rejected by the quality control unit, batch. during the production process, e.g., at (b) Major equipment shall be identi- commencement or completion of sig- fied by a distinctive identification nificant phases or after storage for number or code that shall be recorded long periods. in the batch production record to show (d) Rejected in-process materials the specific equipment used in the shall be identified and controlled under manufacture of each batch of a drug a quarantine system designed to pre- product. In cases where only one of a vent their use in manufacturing or particular type of equipment exists in processing operations for which they a manufacturing facility, the name of are unsuitable. the equipment may be used in lieu of a distinctive identification number or [43 FR 45077, Sept. 29, 1978, as amended at 73 code. FR 51932, Sept. 8, 2008]

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

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required to be sterile, shall be estab- contents shall be stored separately lished and followed. with suitable identification. Access to (b) Appropriate written procedures, the storage area shall be limited to au- designed to prevent microbiological thorized personnel. contamination of drug products pur- (e) Obsolete and outdated labels, la- porting to be sterile, shall be estab- beling, and other packaging materials lished and followed. Such procedures shall be destroyed. shall include validation of all aseptic (f) Use of gang-printed labeling for and sterilization processes. different drug products, or different strengths or net contents of the same [43 FR 45077, Sept. 29, 1978, as amended at 73 drug product, is prohibited unless the FR 51932, Sept. 8, 2008] labeling from gang-printed sheets is § 211.115 Reprocessing. adequately differentiated by size, shape, or color. (a) Written procedures shall be estab- (g) If cut labeling is used, packaging lished and followed prescribing a sys- and labeling operations shall include tem for reprocessing batches that do one of the following special control not conform to standards or specifica- procedures: tions and the steps to be taken to in- (1) Dedication of labeling and pack- sure that the reprocessed batches will aging lines to each different strength conform with all established standards, of each different drug product; specifications, and characteristics. (2) Use of appropriate electronic or (b) Reprocessing shall not be per- electromechanical equipment to con- formed without the review and ap- duct a 100-percent examination for cor- proval of the quality control unit. rect labeling during or after completion of finishing operations; or Subpart G—Packaging and (3) Use of visual inspection to con- Labeling Control duct a 100-percent examination for correct labeling during or after comple- § 211.122 Materials examination and tion of finishing operations for hand- usage criteria. applied labeling. Such examination (a) There shall be written procedures shall be performed by one person and describing in sufficient detail the re- independently verified by a second per- ceipt, identification, storage, handling, son. sampling, examination, and/or testing (h) Printing devices on, or associated of labeling and packaging materials; with, manufacturing lines used to im- such written procedures shall be fol- print labeling upon the drug product lowed. Labeling and packaging mate- unit label or case shall be monitored to rials shall be representatively sampled, assure that all imprinting conforms to and examined or tested upon receipt the print specified in the batch produc- and before use in packaging or labeling tion record. of a drug product. [43 FR 45077, Sept. 29, 1978, as amended at 58 (b) Any labeling or packaging mate- FR 41353, Aug. 3, 1993] rials meeting appropriate written specifications may be approved and re- § 211.125 Labeling issuance. leased for use. Any labeling or pack- (a) Strict control shall be exercised aging materials that do not meet such over labeling issued for use in drug specifications shall be rejected to pre- product labeling operations. vent their use in operations for which (b) Labeling materials issued for a they are unsuitable. batch shall be carefully examined for (c) Records shall be maintained for identity and conformity to the labeling each shipment received of each dif- specified in the master or batch pro- ferent labeling and packaging material duction records. indicating receipt, examination or (c) Procedures shall be used to rec- testing, and whether accepted or re- oncile the quantities of labeling issued, jected. used, and returned, and shall require (d) Labels and other labeling mate- evaluation of discrepancies found be- rials for each different drug product, tween the quantity of drug product fin- strength, dosage form, or quantity of ished and the quantity of labeling

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issued when such discrepancies are out- (e) Inspection of the packaging and side narrow preset limits based on his- labeling facilities immediately before torical operating data. Such discrep- use to assure that all drug products ancies shall be investigated in accord- have been removed from previous oper- ance with § 211.192. Labeling reconcili- ations. Inspection shall also be made to ation is waived for cut or roll labeling assure that packaging and labeling ma- if a 100-percent examination for correct terials not suitable for subsequent op- labeling is performed in accordance erations have been removed. Results of with § 211.122(g)(2). inspection shall be documented in the (d) All excess labeling bearing lot or batch production records. control numbers shall be destroyed. [43 FR 45077, Sept. 29, 1978, as amended at 58 (e) Returned labeling shall be main- FR 41354, Aug. 3, 1993] tained and stored in a manner to prevent mixups and provide proper identi- § 211.132 Tamper-evident packaging fication. requirements for over-the-counter (f) Procedures shall be written de- (OTC) human drug products. scribing in sufficient detail the control (a) General. The Food and Drug Ad- procedures employed for the issuance ministration has the authority under of labeling; such written procedures the Federal Food, Drug, and Cosmetic shall be followed. Act (the act) to establish a uniform national requirement for tamper-evident [43 FR 45077, Sept. 29, 1978, as amended at 58 packaging of OTC drug products that FR 41354, Aug. 3, 1993] will improve the security of OTC drug packaging and help assure the safety § 211.130 Packaging and labeling operations. and effectiveness of OTC drug products. An OTC drug product (except a der- There shall be written procedures de- matological, dentifrice, insulin, or loz- signed to assure that correct labels, la- enge product) for retail sale that is not beling, and packaging materials are packaged in a tamper-resistant pack- used for drug products; such written age or that is not properly labeled procedures shall be followed. These under this section is adulterated under procedures shall incorporate the fol- section 501 of the act or misbranded lowing features: under section 502 of the act, or both. (a) Prevention of mixups and cross- (b) Requirements for tamper-evident contamination by physical or spatial package. (1) Each manufacturer and separation from operations on other packer who packages an OTC drug drug products. product (except a dermatological, den- (b) Identification and handling of tifrice, insulin, or lozenge product) for filled drug product containers that are retail sale shall package the product in set aside and held in unlabeled condi- a tamper-evident package, if this prod- tion for future labeling operations to uct is accessible to the public while preclude mislabeling of individual con- held for sale. A tamper-evident pack- tainers, lots, or portions of lots. Identi- age is one having one or more indica- fication need not be applied to each in- tors or barriers to entry which, if dividual container but shall be suffi- breached or missing, can reasonably be cient to determine name, strength, expected to provide visible evidence to quantity of contents, and lot or control consumers that tampering has oc- number of each container. curred. To reduce the likelihood of suc- (c) Identification of the drug product cessful tampering and to increase the with a lot or control number that per- likelihood that consumers will discover mits determination of the history of if a product has been tampered with, the manufacture and control of the the package is required to be distinc- batch. tive by design or by the use of one or (d) Examination of packaging and la- more indicators or barriers to entry beling materials for suitability and that employ an identifying char- correctness before packaging oper- acteristic (e.g., a pattern, name, reg- ations, and documentation of such ex- istered trademark, logo, or picture). amination in the batch production For purposes of this section, the term record. ‘‘distinctive by design’’ means the

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

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

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

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

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

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products lacking expiration dating be- manufacturing practices brought by cause they meet the criteria for exemp- the Food and Drug Administration. tion under § 211.137, 3 years after distribution of the last lot of drug product [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995] incorporating the component or using the container, closure, or labeling. § 211.182 Equipment cleaning and use (c) All records required under this log. part, or copies of such records, shall be readily available for authorized inspec- A written record of major equipment tion during the retention period at the cleaning, maintenance (except routine establishment where the activities de- maintenance such as lubrication and scribed in such records occurred. These adjustments), and use shall be included records or copies thereof shall be sub- in individual equipment logs that show ject to photocopying or other means of the date, time, product, and lot number reproduction as part of such inspec- of each batch processed. If equipment tion. Records that can be immediately is dedicated to manufacture of one retrieved from another location by product, then individual equipment computer or other electronic means logs are not required, provided that shall be considered as meeting the re- lots or batches of such product follow quirements of this paragraph. in numerical order and are manufac- (d) Records required under this part tured in numerical sequence. In cases may be retained either as original where dedicated equipment is em- records or as true copies such as photo- ployed, the records of cleaning, main- copies, microfilm, microfiche, or other tenance, and use shall be part of the accurate reproductions of the original batch record. The persons performing records. Where reduction techniques, and double-checking the cleaning and such as microfilming, are used, suit- maintenance (or, if the cleaning and able reader and photocopying equip- maintenance is performed using auto- ment shall be readily available. mated equipment under § 211.68, just (e) Written records required by this the person verifying the cleaning and part shall be maintained so that data maintenance done by the automated therein can be used for evaluating, at least annually, the quality standards of equipment) shall date and sign or ini- each drug product to determine the tial the log indicating that the work need for changes in drug product speci- was performed. Entries in the log shall fications or manufacturing or control be in chronological order. procedures. Written procedures shall be [73 FR 51933, Sept. 8, 2008] established and followed for such evaluations and shall include provisions § 211.184 Component, drug product for: container, closure, and labeling (1) A review of a representative num- records. ber of batches, whether approved or re- These records shall include the fol- jected, and, where applicable, records lowing: associated with the batch. (a) The identity and quantity of each (2) A review of complaints, recalls, shipment of each lot of components, returned or salvaged drug products, drug product containers, closures, and and investigations conducted under § 211.192 for each drug product. labeling; the name of the supplier; the (f) Procedures shall be established to supplier’s lot number(s) if known; the assure that the responsible officials of receiving code as specified in § 211.80; the firm, if they are not personally in- and the date of receipt. The name and volved in or immediately aware of such location of the prime manufacturer, if actions, are notified in writing of any different from the supplier, shall be investigations conducted under listed if known. §§ 211.198, 211.204, or 211.208 of these reg- (b) The results of any test or exam- ulations, any recalls, reports of ination performed (including those per- inspectional observations issued by the formed as required by § 211.82(a), Food and Drug Administration, or any § 211.84(d), or § 211.122(a)) and the con- regulatory actions relating to good clusions derived therefrom.

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

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(10) Any sampling performed; ment shall indicate the location of (11) Identification of the persons per- data that establish that the methods forming and directly supervising or used in the testing of the sample meet checking each significant step in the proper standards of accuracy and reli- operation, or if a significant step in the ability as applied to the product tested. operation is performed by automated (If the method employed is in the cur- equipment under § 211.68, the identifica- rent revision of the United States tion of the person checking the signifi- Pharmacopeia, National Formulary, cant step performed by the automated AOAC INTERNATIONAL, Book of equipment. Methods, 1 or in other recognized stand- (12) Any investigation made accord- ard references, or is detailed in an ap- ing to § 211.192. proved new drug application and the (13) Results of examinations made in accordance with § 211.134. referenced method is not modified, a statement indicating the method and [43 FR 45077, Sept. 29, 1978, as amended at 73 reference will suffice). The suitability FR 51933, Sept. 8, 2008] of all testing methods used shall be § 211.192 Production record review. verified under actual conditions of use. (3) A statement of the weight or All drug product production and con- measure of sample used for each test, trol records, including those for pack- where appropriate. aging and labeling, shall be reviewed and approved by the quality control (4) A complete record of all data se- unit to determine compliance with all cured in the course of each test, includ- established, approved written proce- ing all graphs, charts, and spectra from dures before a batch is released or dis- laboratory instrumentation, properly tributed. Any unexplained discrepancy identified to show the specific compo- (including a percentage of theoretical nent, drug product container, closure, yield exceeding the maximum or min- in-process material, or drug product, imum percentages established in mas- and lot tested. ter production and control records) or (5) A record of all calculations per- the failure of a batch or any of its com- formed in connection with the test, in- ponents to meet any of its specifica- cluding units of measure, conversion tions shall be thoroughly investigated, factors, and equivalency factors. whether or not the batch has already (6) A statement of the results of tests been distributed. The investigation and how the results compare with es- shall extend to other batches of the tablished standards of identity, same drug product and other drug strength, quality, and purity for the products that may have been associ- component, drug product container, ated with the specific failure or disclosure, in-process material, or drug crepancy. A written record of the in- product tested. vestigation shall be made and shall in- (7) The initials or signature of the clude the conclusions and followup. person who performs each test and the § 211.194 Laboratory records. date(s) the tests were performed. (a) Laboratory records shall include (8) The initials or signature of a sec- complete data derived from all tests ond person showing that the original necessary to assure compliance with records have been reviewed for accu- established specifications and stand- racy, completeness, and compliance ards, including examinations and as- with established standards. says, as follows: (b) Complete records shall be main- (1) A description of the sample retained of any modification of an estab- ceived for testing with identification of lished method employed in testing. source (that is, location from where Such records shall include the reason sample was obtained), quantity, lot for the modification and data to verify number or other distinctive code, date that the modification produced results sample was taken, and date sample was received for testing. 1 Copies may be obtained from: AOAC (2) A statement of each method used INTERNATIONAL, 481 North Frederick Ave., in the testing of the sample. The state- suite 500, Gaithersburg, MD 20877.

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

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investigations prove the drug product PART 212—CURRENT GOOD MAN- meets appropriate standards of safety, UFACTURING PRACTICE FOR identity, strength, quality, or purity. A POSITRON EMISSION TOMOG- drug product may be reprocessed provided the subsequent drug product RAPHY DRUGS (Eff. 12-12-2011) meets appropriate standards, specifica- Subpart A—General Provisions tions, and characteristics. Records of returned drug products shall be main- Sec. tained and shall include the name and 212.1 What are the meanings of the tech- label potency of the drug product dos- nical terms used in these regulations? age form, lot number (or control num- 212.2 What is current good manufacturing ber or batch number), reason for the re- practice for PET drugs? turn, quantity returned, date of dis- 212.5 To what drugs do the regulations in position, and ultimate disposition of this part apply? the returned drug product. If the rea- Subpart B—Personnel and Resources son for a drug product being returned implicates associated batches, an ap- 212.10 What personnel and resources must I propriate investigation shall be con- have? ducted in accordance with the requirements of § 211.192. Procedures for the Subpart C—Quality Assurance holding, testing, and reprocessing of re- 212.20 What activities must I perform to en- turned drug products shall be in writ- sure drug quality? ing and shall be followed. Subpart D—Facilities and Equipment § 211.208 Drug product salvaging. 212.30 What requirements must my facili- Drug products that have been sub- ties and equipment meet? jected to improper storage conditions including extremes in temperature, hu- Subpart E—Control of Components, midity, smoke, fumes, pressure, age, or Containers, and Closures radiation due to natural disasters, 212.40 How must I control the components I fires, accidents, or equipment failures use to produce PET drugs and the con- shall not be salvaged and returned to tainers and closures I package them in? the marketplace. Whenever there is a question whether drug products have Subpart F—Production and Process been subjected to such conditions, sal- Controls vaging operations may be conducted only if there is (a) evidence from lab- 212.50 What production and process controls must I have? oratory tests and assays (including animal feeding studies where applicable) Subpart G—Laboratory Controls that the drug products meet all applicable standards of identity, strength, 212.60 What requirements apply to the lab- quality, and purity and (b) evidence oratories where I test components, in- from inspection of the premises that process materials, and finished PET drug the drug products and their associated products? 212.61 What must I do to ensure the sta- packaging were not subjected to im- bility of my PET drug products through proper storage conditions as a result of expiry? the disaster or accident. Organoleptic examinations shall be acceptable only Subpart H—Finished Drug Product Controls as supplemental evidence that the drug and Acceptance Criteria products meet appropriate standards of identity, strength, quality, and purity. 212.70 What controls and acceptance criteria must I have for my finished PET Records including name, lot number, drug products? and disposition shall be maintained for 212.71 What actions must I take if a batch drug products subject to this section. of PET drug product does not conform to specifications?

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

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

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good manufacturing practice is met by tainers, closures, in-process materials, complying with the regulations in this packaging materials, labeling, and fin- part or by producing PET drugs in ac- ished dosage forms to ensure compli- cordance with Chapter 823, ‘‘Radio- ance with procedures and specifica- pharmaceuticals for Positron Emission tions affecting the identity, strength, Tomography—Compounding,’’ May 1, quality, or purity of a PET drug. 2009, pp. 365–369, 32d ed. of the United (c) Specifications and processes. You States Pharmacopeia (USP) National must approve or reject, before imple- Formulary (NF) (USP 32/NF 27) (2009). mentation, any initial specifications, The Director of the Federal Register methods, processes, or procedures, and approves this incorporation by ref- any proposed changes to existing speci- erence in accordance with 5 U.S.C. fications, methods, processes, or proce- 552(a) and 1 CFR part 51. You may ob- dures, to ensure that they maintain tain a copy from the United States the identity, strength, quality, and pu- Pharmacopeial Convention, Inc., 12601 rity of a PET drug. You must dem- Twinbrook Pkwy., Rockville, MD 20852, onstrate that any change does not ad- Geeta M. Tirumalai, 301–816–8352, e- versely affect the identity, strength, mail: [email protected], Internet address: quality, or purity of any PET drug. http://www.usp.org/USPNF/notices. You (d) Production records. You must re- may inspect a copy at the Food and view production records to determine Drug Administration Biosciences Li- whether errors have occurred. If errors brary, 10903 New Hampshire Ave., Sil- have occurred, or a production batch or ver Spring, MD, 20993–0002, 301–796–3504, any component of the batch fails to or at the National Archives and meet any of its specifications, you Records Administration (NARA). For must determine the need for an inves- information on the availability of this tigation, conduct investigations when material at NARA, call 202–741–6030, or necessary, and take appropriate correc- go to http://www.archives.gov/ tive actions. federallregister/ (e) Quality assurance. You must es- codeloflfederallregulations/ tablish and follow written quality as- ibrllocations.html. surance procedures.

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

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(c) Equipment construction and mainte- identity test on any of those compo- nance. Equipment must be constructed nents. and maintained so that surfaces that (ii) If you do not conduct finished- contact components, in-process mate- product testing of a PET drug product rials, or PET drugs are not reactive, that ensures that the correct compo- additive, or absorptive so as to alter nents have been used, you must con- the quality of PET drugs. duct identity testing on each lot of a component that yields an active ingre- Subpart E—Control of Compo- dient and each lot of an inactive ingre- nents, Containers, and Clo- dient used in that PET drug product. sures This testing must be conducted using tests that are specific to each compo- § 212.40 How must I control the com- nent that yields an active ingredient ponents I use to produce PET drugs and the containers and closures I and each inactive ingredient. For any package them in? other component, such as a solvent or (a) Written procedures. You must es- reagent, that is not the subject of fin- tablish, maintain, and follow written ished-product testing, you must deter- procedures describing the receipt, mine that each lot complies with writ- login, identification, storage, handling, ten specifications by examining a cer- testing, and acceptance and/or rejec- tificate of analysis provided by the sup- tion of components and drug product plier; if you use such a component to containers and closures. The proce- prepare an inactive ingredient on site, dures must be adequate to ensure that you must perform an identity test on the components, containers, and clo- the components used to make the inac- sures are suitable for their intended tive ingredient before the components use. are released for use. However, if you (b) Written specifications. You must use as an inactive ingredient a product establish appropriate written specifica- that is approved under section 505 of tions for the identity, quality, and pu- the act (21 U.S.C. 355) and is marketed rity of components and for the identity as a finished drug product intended for and quality of drug product containers intravenous administration, you need and closures. not perform a specific identity test on (c) Examination and testing. Upon re- that ingredient. ceipt, each lot of components and con- (2) You must examine a representa- tainers and closures must be uniquely identified and tested or examined to tive sample of each lot of containers determine whether the lot complies and closures for conformity to its writ- with your specifications. You must not ten specifications. You must perform use in PET drug production any lot at least a visual identification of each that does not meet its specifications, lot of containers and closures. including any expiration date if appli- (d) Handling and storage. You must cable, or that has not yet received its handle and store components, con- material release. Any incoming lot tainers, and closures in a manner that must be appropriately designated as prevents contamination, mix-ups, and quarantined, accepted, or rejected. You deterioration and ensures that they are must use a reliable supplier as a source and remain suitable for their intended of each lot of each component, con- use. tainer, and closure. (e) Records. You must keep a record (1)(i) If you conduct finished-product for each shipment of each lot of compo- testing of a PET drug product that in- nents, containers, and closures that cludes testing to ensure that the cor- you receive. The record must include rect components have been used, you the identity and quantity of each ship- must determine that each lot of incom- ment, the supplier’s name and lot num- ing components used in that PET drug ber, the date of receipt, the results of product complies with written speci- any testing performed, the disposition fications by examining a certificate of analysis provided by the supplier. You of rejected material, and the expiration are not required to perform a specific date (where applicable).

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

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

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for each PET drug product you ceeded due to a weekend or holiday. If produce. the sample for sterility testing is held longer than 30 hours, you must dem- Subpart H—Finished Drug Product onstrate that the longer period does Controls and Acceptance not adversely affect the sample and the test results obtained will be equivalent § 212.70 What controls and acceptance to test results that would have been criteria must I have for my finished obtained if the test had been started PET drug products? within the 30-hour time period. Tested (a) Specifications. You must establish samples must be from individual specifications for each PET drug prod- batches and not pooled. If the product uct, including criteria for determining fails to meet a criterion for sterility, identity, strength, quality, purity, and, you must immediately notify all facili- if appropriate, sterility and pyrogens. ties that received the product of the (b) Test procedures. Before you imple- test results and provide any appro- ment a new test procedure in a speci- priate recommendations. The notifica- fication, you must establish and docu- tion must be documented. Upon comment the accuracy, sensitivity, speci- pletion of an investigation into the ficity, and reproducibility of the proce- failure to meet a criterion for sterility, dure. If you use an established you must notify all facilities that re- compendial test procedure in a speci- ceived the product of the findings from fication, you must first verify and doc- the investigation. ument that the test works under the (f) Conditional final release. (1) If you conditions of actual use. cannot complete one of the required (c) Conformance to specifications. Be- finished-product tests for a batch of a fore final release, you must conduct an PET drug product because of a mal- appropriate laboratory determination function involving analytical equip- to ensure that each batch of a PET ment, you may approve the conditional drug product conforms to specifica- final release of the product if you meet tions, except for sterility. For a PET the following conditions: drug product produced in sub-batches, (i) You have data documenting that before final release, you must conduct preceding consecutive batches, pro- an appropriate laboratory determina- duced using the same methods used for tion to ensure that each sub-batch con- the conditionally released batch, dem- forms to specifications, except for ste- onstrate that the conditionally re- rility. leased batch will likely meet the estab- (d) Final release procedures. Except as lished specifications; conditional final release is permitted (ii) You determine that all other ac- in accordance with paragraph (f) of this ceptance criteria are met; section, you must establish and follow (iii) You retain a reserve sample of procedures to ensure that each batch of the conditionally released batch of a PET drug product is not given final drug product; release until the following are done: (iv) You promptly correct the mal- (1) An appropriate laboratory deter- function of analytical equipment, com- mination under paragraph (c) of this plete the omitted test using the reserve section is completed; sample after the malfunction is cor- (2) Associated laboratory data and rected, and document that reasonable documentation are reviewed and they efforts have been made to prevent re- demonstrate that the PET drug prod- currence of the malfunction; uct meets specifications, except for (v) If you obtain an out-of-specifica- sterility; and tion result when testing the reserve (3) A designated qualified individual sample, you immediately notify the re- authorizes final release by dated signa- ceiving facility; and ture. (vi) You document all actions regard- (e) Sterility testing. Sterility testing ing the conditional final release of the need not be completed before final re- drug product, including the justifica- lease but must be started within 30 tion for the release, all followup ac- hours after completion of production. tions, results of completed testing, all The 30-hour requirement may be ex- notifications, and corrective actions to

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prevent recurrence of the malfunction Subpart I—Packaging and involving analytical equipment. Labeling (2) Even if the criteria in paragraph (f)(1) of this section are met, you may § 212.80 What are the requirements as- not approve the conditional final re- sociated with labeling and pack- lease of the product if the malfunction aging PET drug products? involving analytical equipment pre- (a) A PET drug product must be suit- vents the performance of a ably labeled and packaged to protect radiochemical identity/purity test or the product from alteration, contami- prevents the determination of the prod- nation, and damage during the estab- uct’s specific activity. lished conditions of shipping, distribu- (3) You may not release another tion, handling, and use. batch of the PET drug product until (b) Labels must be legible and applied you have corrected the problem con- so as to remain legible and affixed dur- cerning the malfunction of analytical ing the established conditions of proc- equipment and completed the omitted essing, storage, handling, distribution, finished-product test. and use. (c) All information stated on each § 212.71 What actions must I take if a label must also be contained in each batch of PET drug product does not conform to specifications? batch production record. (d) Labeling and packaging oper- (a) Rejection of nonconforming product. ations must be controlled to prevent You must reject a batch of a PET drug labeling and product mix-ups. product that does not conform to specifications. You must have and follow procedures to identify and segregate Subpart J—Distribution the product to avoid mix-ups. You § 212.90 What actions must I take to must have and follow procedures to in- control the distribution of PET vestigate the cause(s) of the noncon- drug products? forming product. The investigation (a) Written distribution procedures. You must include, but is not limited to, ex- must establish, maintain, and follow amination of processes, operations, records, complaints, and any other rel- written procedures for the control of evant sources of information con- distribution of PET drug products cerning the nonconforming product. shipped from the PET drug production facility to ensure that the method of (b) Investigation. You must document shipping chosen will not adversely af- the investigation of a PET drug prod- fect the identity, purity, or quality of uct that does not meet specifications, including the results of the investiga- the PET drug product. tion and what happened to the rejected (b) Distribution records. You must PET drug product. maintain distribution records for each (c) Correction of problems. You must PET drug product that include or refer take action to correct any identified to the following: problems to prevent recurrence of a (1) The name, address, and telephone nonconforming product or other qual- number of the receiving facility that ity problem. received each batch of a PET drug (d) Reprocessing. If appropriate, you product; may reprocess a batch of a PET drug (2) The name and quantity of the product that does not conform to speci- PET drug product shipped; fications. If material that does not (3) The lot number, control number, meet acceptance criteria is reproc- or batch number for the PET drug essed, you must follow procedures stat- product shipped; and ed in the product’s approved applica- (4) The date and time you shipped the tion and the finished product must con- PET drug product. form to specifications, except for sterility, before final release.

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

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

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

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

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

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

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Subpart D—Packaging and (b) The Master Record File and pro- Labeling duction records shall comply with the following provisions: § 225.80 Labeling. (1) A Master Record File shall be pre- (a) Appropriate labeling identifies pared, checked, dated, and signed or the medicated feed, and provides the initialed by a qualified person and user with directions for use which, if shall be retained for not less than 1 adhered to, will assure that the article year after production of the last batch is safe and effective for its intended or production run of medicated feed to purposes. which it pertains. The Master Record (b)(1) Labels and labeling, including File or card shall include at least the placards, shall be received, handled, following: and stored in a manner that prevents (i) The name of the medicated feed. labeling mixups and assures that cor- (ii) The name and weight percentage rect labeling is employed for the medi- or measure of each drug or drug com- cated feed. bination and each nondrug ingredient (2) Labels and labeling, including to be used in manufacturing a stated placards, upon receipt from the printer weight of the medicated feed. shall be proofread against the Master (iii) A copy or description of the label Record File to verify their suitability or labeling that will accompany the and accuracy. The proofread label shall medicated feed. be dated, initialed by a responsible in- (iv) Manufacturing instructions or dividual, and kept for 1 year after all reference thereto that have been deter- the labels from that batch have been mined to yield a properly mixed medi- used. cated feed of the specified formula for (3) In those instances where medi- each medicated feed produced on a cated feeds are distributed in bulk, batch or continuous operation basis, complete labeling shall accompany the including mixing steps, mixing times shipment and be supplied to the con- and, in the case of medicated feeds pro- signee at the time of delivery. Such la- duced by continuous production run, beling may consist of a placard or any additional manufacturing direc- other labels attached to the invoice or tions including, when indicated, the delivery ticket, or manufacturer’s in- settings of equipment. voice that identifies the medicated feed (v) Appropriate control directions or and includes adequate information for reference thereto, including the man- the safe and effective use of the medi- ner and frequency of collecting the re- cated feed. quired number of samples for specified (4) Label stock shall be reviewed pe- laboratory assay. riodically and discontinued labels shall (2) The original production record or be discarded. copy thereof shall be prepared by qualified personnel for each batch or run of Subpart E—Records and Reports medicated feed produced and shall be retained on the premises for not less § 225.102 Master record file and pro- than 1 year. The production record duction records. shall include at least the following: (a) The Master Record File provides (i) Product identification, date of the complete procedure for manufac- production, and a written endorsement turing a specific product, setting forth in the form of a signature or initials by the formulation, theoretical yield, a responsible individual. manufacturing procedures, assay re- (ii) The quantity and name of drug quirements, and labeling of batches or components used. production runs. The production (iii) The theoretical quantity of record(s) includes the complete history medicated feed to be produced. of a batch or production run. This (iv) The actual quantity of medicated record includes the amounts of drugs feed produced. In those instances where used, the amount of medicated feed the finished feed is stored in bulk and manufactured, and provides a check for actual yield cannot be accurately de- the daily inventory record of drug com- termined, the firm shall estimate the ponents. quantity produced and provide the

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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which can be produced in newborn experi- cation in accord with § 314.50 of the new mental animals following repeated topical drug regulations (21 CFR 314.50), in- application of 3 percent hexachlorophene. cluding blood level data obtained from Moreover, a study of histologic sections of use of the drug as recommended. premature infants who died of unrelated causes has shown a positive correlation be- (5) Prescription drug products may tween hexachlorophene baths and lesions in contain hexachlorophene as part of an white matter of brains. effective preservative system only under the conditions and limitations (ii) On the immediate container label provided for under paragraph (d) of this prominently displayed and in bold section. print: (d) Over-the-counter (OTC) drugs. ‘‘Special Warning: This compound may be Over-the-counter drug products, other toxic if used other than as directed. Rinse than those which in normal use may be thoroughly after use. Monitor patients close- applied to mucous membranes or which ly for toxicity symptoms.’’ are intended to be used on mucous (4) Marketing of products for the in- membranes, may contain dications listed in paragraph (c)(3) of hexachlorophene only as part of an ef- this section may be continued without fective preservative system, at a level an approved new drug application (or that is no higher than necessary to required supplement thereto) either achieve the intended preservative func- until a notice of opportunity for hear- tion, and in no event higher than 0.1 ing is issued on a proposal by the Di- percent. Such use of hexachlorophene rector of the Center for Drug Evalua- shall be limited to situations where an tion and Research to refuse to approve alternative preservative has not yet such new drug application (or required been shown to be as effective or where supplement) or until January 31, 1978, adequate integrity and stability data whichever comes first, if all the fol- for the reformulated product are not lowing conditions were met after Sep- yet available. This use of tember 27, 1972: hexachlorophene will not, by itself, re- (i) The product is labeled with the quire an approved new drug applica- statement ‘‘Rx only’’ and adequate in- tion. Use of hexachlorophene as a pre- formation for safe and effective use as servative at a level higher than 0.1 per- set forth in paragraph (c)(3) of this sec- cent is regarded as a new drug use re- tion. quiring an approved new drug applica- (ii) Within 30 days, or by (10–27–72) tion, which must be submitted within the holder of an approved new drug ap- the time set out in paragraph (c)(4) of plication submits a supplement to pro- this section. vide for the revised label and full dis- (e) Cosmetics. Hexachlorophene may closure labeling. As the label and label- be used as a preservative in cosmetic ing will have been put into use, the products other than those which in supplement should be submitted under normal use may be applied to mucous the provision of § 314.70(c)(6)(iii) of this membranes or which are intended to be chapter. used on mucous membranes, at a level (iii) Within 30 days, or by (10–27–72) that is no higher than necessary to the holder of an approved new drug ap- achieve the intended preservative func- plication submits a supplement to pro- tion, and in no event higher than 0.1 vide for a revised formulation where percent. Such use of hexachlorophene appropriate to comply with this order. shall be limited to situations where an (iv) Within 90 days, or by (12–26–72) alternative preservative has not yet the holder of an approved new drug ap- been shown to be as effective or where plication submits a supplement con- adequate integrity and stability data taining blood level data obtained from for the reformulated product are not use of the drug as recommended, unless yet available. The component of a pre- such information is a part of the new servative system whether drug application file. hexachlorophene or other anti- (v) Within 90 days, or by (12–26–72), microbial agent, should be selected on the manufacturer or distributor of such the basis of the effect on the total mi- a drug for which a new drug approval is crobial ecology of the product, not not in effect submits a new drug appli- merely on gram-positive bacteria.

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

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label of a controlled substance dis- 299.4 Established names for drugs. pensed for use in clinical investiga- 299.5 Drugs; compendial name. tions which are ‘‘blind.’’ AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 358, 360b, 371. § 290.6 Spanish-language version of required warning. SOURCE: 40 FR 14041, Mar. 27, 1975, unless otherwise noted. By direction of section 305(c) of the Federal Controlled Substances Act, § 290.5, promulgated under section Subpart A—General Provisions 503(b) of the Federal Food, Drug, and Cosmetic Act, requires the following § 299.3 Definitions and interpretations. warning on the label of certain drugs (a) As used in this part 299, act means when dispensed to or for a patient: the Federal Food, Drug, and Cosmetic ‘‘Caution: Federal law prohibits the Act, sections 201–902, 52 Stat. 1040 (21 transfer of this drug to any person U.S.C. 321–392), with all amendments other than the patient for whom it was thereto. prescribed.’’ The Spanish version of (b) The definitions and interpreta- this is: ‘‘Precaucion: La ley Federal tions contained in section 201 of the act prohibe el transferir de esta droga a shall be applicable to such terms when otra persona que no sea el paciente used in this part 299. para quien fue recetada.’’ (c) The term official name means, with respect to a drug or ingredient § 290.10 Definition of emergency situa- thereof, the name designated in this tion. part 299 under section 508 of the act as For the purposes of authorizing an the official name. oral prescription of a controlled substance listed in schedule II of the Fed- § 299.4 Established names for drugs. eral Controlled Substances Act, the (a) Section 508 of the Federal Food, term emergency situation means those Drug, and Cosmetic Act (added by the situations in which the prescribing Kefauver-Harris Drug Amendments of practitioner determines: 1962; Pub. L. 87–781) authorizes the (a) That immediate administration of Commissioner of Food and Drugs to the controlled substance is necessary, designate an official name for any drug for proper treatment of the intended if he determines that such action is ultimate user; and necessary or desirable in the interest of (b) That no appropriate alternative usefulness and simplicity. Section treatment is available, including ad- 502(e) of the act (as amended by said ministration of a drug which is not a Drug Amendments) prescribes that the controlled substance under schedule II labeling of a drug must bear its estab- of the Act, and lished name, if there is one, to the ex- (c) That it is not reasonably possible clusion of any other nonproprietary for the prescribing practitioner to pro- name (except the applicable systematic vide a written prescription to be pre- chemical name or the chemical for- sented to the person dispensing the mula) and, if the drug is fabricated substance, prior to the dispensing. from two or more ingredients, the established name of each active ingre- Subpart B [Reserved] dient. (b) The term established name is de- Subpart C—Requirements for Spe- fined in section 502(e)(3) of the act as cific Controlled Drugs [Re- (1) an official name designated pursu- served] ant to section 508 of the act; (2) if no such official name has been designated for the drug and the drug is an article PART 299—DRUGS; OFFICIAL recognized in an official compendium, NAMES AND ESTABLISHED NAMES then the official title thereof in such compendium; and (3) if neither para- Subpart A—General Provisions graphs (b) (1) or (2) of this section ap- Sec. plies, then the common or usual name 299.3 Definitions and interpretations. of the drug.

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

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

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