Supplements to the PQRI Workshop Results

Appendix: definitions and regulations, Federal Food, Drug, and Cosmetic Act

Chapter II: Definitions

Section 201(g)(1). The term "drug"means: (A) articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them; (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man; and (D) articles intended for use as a component of any articles specified in clause (A), (B), or (C).

Section 201(j). The term "official compendium" means the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, official National Formulary, or any supplement to any of them.

Chapter V: Adulteration sections

A drug or device shall be deemed to be adulterated —Section 501(a)(2)(B). If it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess or is represented to possess.

A drug or device shall be deemed adulterated —Section 501(b). If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium, except that whenever tests or methods of assay have not been prescribed in such compendium, or such tests or methods of assay as are prescribed are, in the judgment of the Secretary, insufficient for the making of such determination, the Secretary shall bring such fact to the attention of the appropriate body charged with the revision of such compendium, and if such body fails within a reasonable time to prescribe tests or methods of assay which, in the judgment of the Secretary, are sufficient for purposes of this paragraph, then the Secretary shall promulgate regulations prescribing appropriate tests or methods of assay in accordance with which such determination as to strength, quality, or purity shall be made. No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefore set forth in such compendium, if its difference in strength, quality, or purity from such standards is plainly stated on its label. Whenever a drug is recognized in both the United States Pharmacopeia and the Homeopathic Pharmacopeia of the United States it shall be subject to the requirements of the United States Pharmacopeia unless it is labeled and offered for sale as a homeopathic drug, in which case it shall be subject to the provisions of the Homeopathic Pharmacopeia of the United States and not to those of the United States Pharmacopeia.

Appendix: definitions and regulations, Title 21 Code of Federal Regulations

Parts 210 and 211: Current Good Manufacturing Practice for Finished Pharmaceuticals

211.84(d) Samples shall be examined and tested as follows:

(1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.

(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

21 CFR 211. 194 (a) (2) - A statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability of the sample meet proper standards of accuracy and reliability as applied to the product as applied to the product tested. (If the method employed is in the current revision of the United States Pharmacopeia, National Formulary, AOAC INTERNATIONAL, Book of Methods, or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice). The suitability of all testing methods used shall be verified under actual conditions of use.

21 CFR 314.70 Supplements and other changes to an approved application:

(d) Changes to be described in an annual report (minor changes): (1) Changes in the drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product must be documented by the applicant in the next annual report in accordance with 314.81(b)(2).

(2) These changes include, but are not limited to:

(i) Any change made to comply with a change to an official compendium, except a change described in paragraph (c)(2)(iii) of this section, that is consistent with FDA statutory and regulatory requirements.

21 CFR 314.70 (c) Changes requiring supplement submission at least 30 days prior to distribution of the drug product made using the change (moderate changes).

(2) These changes include, but are not limited to:

(iii) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements.

See also, FDA's Guidance to Industry, Changes to an Approved NDA or ANDA; Specifications: Use of Enforcement Discretion for Compendial Changes, dated Nov. 19, 2004 at http://www.fda.gov/cder/guidance/6451fnl.htm

Appendix: definitions and regulations, Compliance Policy Guides

Sub Chapter 420 - Compendial /Test Requirements

Sec. 420.100: Adulteration of Drugs Under Section 501(b) and 501(c) of the Act. *Direct Reference Seizure Authority for Adulterated Drugs Under Section 501(b)* (CPG 7132a.03)

Any official drug which, when tested by compendial methods, fails to conform to compendial standards for quality, strength, or purity, is adulterated unless the differences from such standards are plainly stated on the drug's label.

Sec. 420.200 - Compendium Revisions and Deletions (CPG 7132.02)

All official articles shipped prior to the date that the current USP- NF became official should be in compliance with the official compendia in effect at the time of shipment.

Sec. 420.300 - Changes in Compendial Specifications and NDA Supplements (CPG 7132c.04)

Any change in the compendial specifications for an NDA drug will normally require the submission of an NDA supplement.

Sec. 420.400 - Performance of Tests for Compendial Requirements on Compendial Products (CPG 7132.05) [Section 420.400 presently is under revision by FDA]

Compendial methods need only be applied, as a batch release test, where a firm has made specific commitments to do so (as in a new drug application), or where the official method is the only appropriate test. Neither the USP- NF nor the CGMP regulations necessarily require a firm to utilize, as a batch release test, the methods and procedures stated in the official compendia. What is required is that official drug products conform to the appropriate compendial standards.

The manufacturer's specifications for standards of strength, quality and purity may be less stringent in those cases in which the differences from the official standards are stated on the product label.

Where an official product purports to conform to the standards of the USP- NF the manufacturer must assure that each batch conforms to each monograph requirement. This assurance must be achieved by appropriate means, including process validation and controls and end product testing. Therefore, in some cases it may not be necessary for a manufacturer to test each batch for each monograph requirement.

Sec. 420.500 - Interference with Compendial Tests (CPG 7132a.01)

A compendial drug product containing an added substance which interferes with the compendial assay of the product would be adulterated under 501(b) of the Act.