When is Excipient Reduced Testing Appropriate?

21 CFR 211.84(d) requirements (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.”

21 CFR 211.84(d) requirements (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 (drug product) manufacturer, and provided that the (drug product) manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.”

USP—NF General Notices (section Tests and Assays under Procedures) “Every compendial article in commerce shall be so constituted that when examined in accordance with these assay and test procedures, it meets all of the requirements in the monograph defining it. However, it is not to be inferred that application of every analytical procedure in the monograph to samples from every production batch is necessarily a prerequisite for assuring compliance with Pharmacopeial standards before the batch is released for distribution. Data derived from manufacturing process validation studies and from in-process controls may provide greater assurance that a batch meets a particular monograph requirement than analytical data derived from an examination of finished units drawn from that batch. On the basis of such assurances, the analytical procedures in the monograph may be omitted by the manufacturer in judging compliance of the batch with the Pharmacopeial standards.”

Survey Results for Reduced Testing

Survey – Reduced Testing Drug Product Manufacturers 91% include COA qualification during their vendor qualification 78% reduce frequency of complete monograph testing based on COA qualification 24% received FDA approval prior to implementing reduced testing

Survey – Reduced Testing Drug Product Manufacturers 49% accept the excipient by ID test and COA when an excipient manufacturer has been audited, qualified, and has performed all tests according to compendia, or as approved in a drug product application 97% perform more than the ID test before accepting an excipient

Survey – Reduced Testing Drug Product Manufacturers Frequency of full testing 3rd lot by 3% 5th lot by 7% 10th lot by 29% Other frequency by 61% The data suggest it is common to fully test every 10th lot.

Survey – Reduced Testing Drug Product Manufacturers

Survey – Reduced Testing Distributor Distributor respondents stated that a reduced testing program is applicable to some, most, or all of the products they distribute

Survey – Reduced Testing for Drug Product and Excipient Manufacturers

Excipient Reduced Testing Issues

Excipient Reduced Testing Issues How should industry resolve problems with ICH Q4B interchangeability?

Excipient Reduced Testing Issues When can Industry start implementing a new signed off general chapter? Once it is published in USP-NF? Wait until the delayed implementation date? When ICH Q4B has been completed?

Excipient Reduced Testing Issues How many tests should be performed to assure an excipients quality for global drug products when there are a number of non-harmonized tests in the global (e.g., USP-NF, Ph.Eur., JP) compendia?

Excipient Reduced Testing Issues What are the regulatory approaches when industry uses Ph.Eur. or JP test results to meet the USP-NF requirements?

Excipient Reduced Testing Issues How is your company filing changes to USP-NF excipient monographs and general chapters, to your previous submission to the FDA? 21 CFR 314.70 regulations apply, but FDA's “Guidance to Industry, Changes to an Approved NDA or ANDA; Specifications–Use of Enforcement Discretion for Compendial Changes” states discretionary enforcement, and industry uncertainty remains. What are your company's policies/practices based on FDA's 21 CFR 314.70 and the FDA’s Guidance on Enforcement Discretion issued on November 19, 2004?

Excipient Reduced Testing Issues How should industry make effective use of PDG harmonization in light of the resulting changed excipient monographs?