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it is administered in pure form, e.g., in solution.

(3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the process of absorption (first-class metabolism) so the therapeutic effect and/or toxicity of such drug product is determined by the rate as well as the degree of absorption.

(4) The therapeutic moiety is rapidly metabolized or excreted so that rapid dissolution and absorption are required for effectiveness.

(5) The active drug ingredient or therapeutic moiety is unstable in specific portions of the gastrointestinal tract and requires special coatings or formulations,

buffers, enteric coatings, and film coatings, to assure adequate absorption.

(6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the rate and extent of absorption are important to bioequivalence.

e.g.,

(42 FR 1635, Jan. 7, 1977. Redesignated and amended at 57 FR 18001, Apr. 28, 1992]

320.34 Requirements for batch test.

ing and certification by the Food

and Drug Administration. (a) If the Commissioner determines that individual batch testing by the Food and Drug Administration is necessary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall include in the bioequivalence requirement a requirement for manufacturers to submit samples of each batch to the Food and Drug Administration and to withhold distribution of the batch until notified by the Food and Drug Administration that the batch may be introduced into interstate commerce.

(b) The Commissioner will ordinarily terminate a requirement for a manufacturer to submit samples for batch testing on a finding that the manufacturer has produced four consecutive batches that were tested by the Food and Drug Administration and found to meet the bioequivalence requirement, unless the public health requires that batch testing be extended to additional batches.

8 320.36 Requirements for mainte

nance of records of bioequivalence

testing. (a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure that the product meets a bioequivalence requirement shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitted to the Food and Drug Administration on request.

(b) Any person who contracts with another party to conduct a bioequivalence study from which the data are intended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study sufficient accurate financial information to allow the submission of complete and accurate financial certifications or disclosure statements required under part 54 of this chapter and shall maintain that information and all records relating to the compensation given for that study and all other financial interest information required under part 54 of this chapter for 2 years after the date of approval of the application. The person maintaining these records shall, upon request for any properly authorized officer or employee of the Food and Drug Administration, at reasonable time, permit such officer or employee to have access to and copy and verify these records.

(42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992, as amended at 63 FR 5252, Feb. 2, 1998]

EFFECTIVE DATE NOTE: At 63 FR 5252, Feb. 2, 1998, $320.36 was amended by designating the existing text as paragraph (a) and by adding new paragraph (b), effective Feb. 2, 1999.

(42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992)

$320.38 Retention of bioavailability

samples. (a) The applicant of an application or supplemental application submitted under section 505 or 507 of the Federal Food, Drug, and Cosmetic Act, or, if bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drug product for which the applicant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and reference standard provided by the applicant for the testing.

(b) Reserve samples shall be retained for the following test articles and reference standards and for the studies described:

(1) If the formulation of the test article is the same as the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection.

(2) If the formulation of the test article differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the clinical studies.

(3) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety.

(c) Each reserve sample shall consist of a sufficient quantity to permit FDA

to perform five times all of the release tests required in the application or supplemental application.

(d) Each reserve sample shall be adequately identified so that the reserve sample can be positively identified as having come from the same sample as used in the specific bioavailability study.

(e) Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.

(f) Authorized FDA personnel will ordinarily collect reserve samples directly from the applicant or contract research organization at the storage site during a preapproval inspection. If authorized FDA personnel are unable to collect samples, FDA may require the applicant or contract research organization to submit the reserve samples to the place identified in the agency's request. If FDA has not collected or requested delivery of a reserve sample, or if FDA has not collected or requested delivery of any portion of a reserve sample, the applicant or contract research organization shall retain the sample or remaining sample for the 5year period specified in paragraph (e) of this section.

(8) Upon release of the reserve samples to FDA, the applicant or contract research organization shall provide a written assurance that, to the best knowledge and belief of the individual executing the assurance, the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall be executed by an individual authorized to act for the applicant or contract research organization in releasing the reserve samples to FDA.

Subpart C-Labeling

328.50 Principal display panel of all OTC

drug products intended for oral ingestion that contain alcohol.

AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).

SOURCE: 60 FR 13595, Mar. 13, 1995, unless otherwise noted.

(h) A contract research organization may contract with

with an appropriate, independent third party to provide storage of reserve samples provided that the sponsor of the study has been notified in writing of the name and address of the facility at which the reserve samples will be stored.

(i) If a contract research organization conducting a bioavailability or bioequivalence study that requires reserve sample retention under this section or $320.63 goes out of business, it shall transfer its reserve samples to an appropriate, independent third party, and shall notify in writing the sponsor of the study of the transfer and provide the study sponsor with the name and address of the facility to which the reserve samples have been transferred.

Subpart A-General Provisions

8328.1 Scope.

Reference in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

(58 FR 25927, Apr. 28, 1993)

8 328.3 Definitions.

As used in this part:

(a) Alcohol means the substance known as ethanol, ethyl alcohol, or Alcohol, USP.

(b) Inactive ingredient means any component of a product other than an active ingredient as defined in $210.3(b)(7) of this chapter.

Subpart B-Ingredients

8320.63 Retention of bioequivalence

samples. The applicant of an abbreviated application or a supplemental application submitted under section 505 or 507 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in, $320.38 and shall release the reserve samples to FDA upon request in accordance with $320.38.

(58 FR 25928, Apr. 28, 1993)

$ 328.10 Alcohol. (a) Any over-the-counter (OTC) drug

-) product intended for oral ingestion shall not contain alcohol as an inactive ingredient in concentrations that exceed those established in this part, unless a specific exemption, as provided in paragraph (e) or (f) of this section, has been approved.

(b) For any OTC drug product intended for oral ingestion and labeled for use by adults and children 12 years of age and over, the amount of alcohol in the product shall not exceed 10 percent.

(c) For any OTC drug product intended for oral ingestion and labeled for use by children 6 to under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent.

(d) For any OTC drug product intended for oral ingestion and labeled for use by children under 6 years of age, the amount of alcohol in the product shall not exceed 0.5 percent.

(e) The Food and Drug Administration will grant an exemption from

PART 328-OVER-THE-COUNTER

DRUG PRODUCTS INTENDED FOR ORAL INGESTION THAT CONTAIN ALCOHOL

Subpart A-General Provisions

Sec. 328.1 Scope. 328.3 Definitions.

Subpart B-Ingredients

328.10 Alcohol.

paragraphs (b), (c), and (d) of this section where appropriate, upon petition under the provisions of $ 10.30 of this chapter. Appropriate cause, such as a specific solubility or manufacturing problem, must be adequately documented in the petition. Decisions with respect to requests for exemption shall be maintained in a permanent file for public review by the Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

(f) Ipecac syrup is exempt from the provisions of paragraph (d) of this section.

(g) The following drugs are temporarily exempt from the provisions of paragraphs (b), (c), and (d) of this section:

(1) Aromatic Cascara Fluidextract. (2) Cascara Sagrada Fluidextract.

(3) Orally ingested homeopathic drug products.

anywhere on that label in accord with section 502(e) of the Federal Food, Drug, and Cosmetic Act.

(d) The statement expressing the amount (percentage) of alcohol present in the product shall be in a size reasonably related to the most prominent printed matter on the panel or label on which it appears, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.

(e) For a product to state in its labeling that it is "alcohol free," it must contain no alcohol (0 percent).

(f) For any OTC drug product intended for oral ingestion containing over 5 percent alcohol and labeled for use by adults and children 12 years of age and over, the labeling shall contain the following statement in the directions section: “Consult a physician for use in children under 12 years of age."

(g) For any OTC drug product intended for oral ingestion containing over 0.5 percent alcohol and labeled for use by children ages 6 to under 12 years of age, the labeling shall contain the following statement in the directions section: “Consult a physician for use in children under 6 years of age.”

(h) When the direction regarding age in paragraph (e) or (f) of this section differs from an age-limiting direction contained in any OTC drug monograph in this chapter, the direction containing the more stringent age limitation shall be used.

[60 FR 13595, Mar. 13, 1995, as amended at 61 FR 58630, Nov. 18, 1996)

Subpart C-Labeling

PART 329-HABIT-FORMING DRUGS

Subpart A-Derivatives Designated as

Habit Forming

$ 328.50 Principal display panel of all

OTC drug products intended for

oral ingestion that contain alcohol. (a) The amount (percentage) of alcohol present in a product shall be stated in terms of percent volume of absolute alcohol at 60 ° F (15.56 ° C) in accordance with $201.10(d)(2) of this chapter.

(b) A statement expressing the amount (percentage) of alcohol present in a product shall appear prominently and conspicuously on the "principal display panel," as defined in $201.60 of this chapter. For products whose principal display panel is on the immediate container label and that are not marketed in another retail package (e.g., an outer box), the statement of the percentage of alcohol present in the product shall appear prominently and conspicuously on the principal display panel" of the immediate container label.

(c) For products whose principal display panel is on the retail package and the retail package is not the immediate container, the statement of the percentage of alcohol present in the product shall also appear on the immediate container label; it may appear

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5-Allyl-5-sec-butylbarbituric acid 2

Talbutai

Lotusate. 5-Allyl-5-cyclopentenylbarbituric acid

Cyclopal.

Cyclopen. 5-Allyl-5-isobutylbarbituric acid

Allylbarbituric acid

Sandoptal.

Allylisobutylbarbituric acid.. 5-Allyl-5-isopropylbarbituric acid

Aprobarbital

Alurate.
Allylisopropylbarbituric acid

Numal.

Allylisopropylmalonylurea.. 5-Allyl-5-isopropyl-1-methylbarbituric acid

Narconumal. 5-Allyl-5-(1-methylbutyl)barbituric acid

Secobarbital sodium

Seconal Sodium.
Soluble secobarbital

Evronal Sodium. 5-Allyl-5-(1-methylbutyl)-2-thiobarbituric acid Sodium thiamylal

Surital Sodium. 5-Allyl-1-methyl-5-(1-methyl-2-pentynyi) barbi- Sodium methohexital

Brevital Sodium. turic acid. 5-(2-Bromoallyl)-5-isoprophyl-1-methylbarbituric

Eunarcon. acid. 5-(2-Bromoallyl)-5-1-methylbutyl)-barbituric acid B-Bromoallyl sec-amylbarbituric acid .. Sigmodal. .

Rectidon.

R239. 5-sec-Butyl-5-(2-bromoallyl)-barbituric acid Butallyional

Pernoston.

Pernocton. 5-(1-Cyclohepten-1-yl)-5-ethylbarbituric acid Heptabarbital

Medomin. 5,5-Diallylbarbituric acid

Diallyl barbituric acid

Dial.
Allobarbital.
Allobarbitone.
Curral.

Diadol. 5,5-Diethylbarbituric acid

Barbital

Deba.
Barbitone

Dormonal.
Diethylbarbituric acid

Hypnogene.
Diethylmalonylurea

Malonal.
Medinal.
Sedeval.
Veronal.
Uronal.

Vesperal. 5,5-Diethyl-1-methylbarbituric acid

Metharbital

Gemonil. 1,5-Dimethyl-5-(1-cyclohexenyl)-barbituric acid Hexobarbital sodium

Cyclonal Sodium.
Dorico Soluble.
Evipal Sodium.
Evipan Sodium.
Hexanastab.
Hexobarbitone Sodium.

Methenexyl Sodium. 5,5-Dipropylbarbituric acid

Dipropylbarbituric acid

Proponal. 5-Ethyl-5-butylbarbituric acid

Butethal

Etoval.
Butobarbital

Neonal Butobarbital.

Soneryl. 5-Ethyl-5-sec-butylbarbituric acid

Butabarbital sodium

Butisol Sodium.

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