FDA guidance covers frequently asked CMC questions for generic drugs

Regulatory NewsRegulatory News | 21 September 2021 |  By 

The US Food and Drug Administration’s Center for Drug Evaluation and Research (FDA’s CDER) on Monday issued a draft guidance that provides generic drug applicants with answers to commonly asked questions in the drug quality area. The new guidance is designed to provide an immediate response to such questions to reduce the number of controlled correspondence on identical topics.
The guidance, which is in a question-and-answer format, covers FDA’s policies on quality-related scientific and regulatory topics that “appear frequently” in controlled correspondence submissions CDER’s Office of Pharmaceutical Quality. The intent of the guidance is to help industry “to move forward with certain generic drug development activities without the need to submit controlled correspondence to FDA,” according to a 20 September agency email.
Under the Generic Drug User Fee Amendments (GDUFA II), manufacturers that submit a question through the controlled correspondence mechanism may wait up to 60 or 120 calendar days for a response, depending on the type of controlled correspondence, as the agency reiterated in its final guidance issued last December (RELATED: Generics: FDA finalizes guidance on controlled correspondence, Regulatory Focus 17 December 2020).
The nine questions and answers contained in the guidance to date are “derived from numerous controlled correspondence submissions” and cover expectations for bracketing and matrixing, container closure changes, dissolution, endotoxin testing, the number of exhibit batches needed, and scoring and split tablet testing.
Some of these commonly asked questions, and FDA’s responses, follow:
Bracketing and matrixing
FDA clarified that a bracketing approach is acceptable for a drug product with multiple strengths, as long as the active and inactive ingredients are dose proportional.
The agency was responding to a question on whether it is acceptable to use a bracketing approach for manufacturing exhibit batches of a generic drug product with multiple strengths produced from common bulk granulations or blends, and whether all of these batches need to be placed on a stability program.
The guidance specifies that sponsors should produce three separate intermediate bulk batches, with one batch representing all the proposed strengths, one batch should reflect the lowest strength and one batch should reflect the highest strength. For more information, sponsors should consult FDA’s May 2014 guidance entitled “ANDAs: Stability Testing of Drug Substances and Products Questions and Answers.”
Container closure systems
A proposed generic drug product need not have the same container closure system (CCS) as the reference-listed product, the agency said in responding to a question on whether a generic drug product can be packaged in a vial if the RLD is packaged in an ampule.
Yet, the application “must contain information to show that the proposed generic drug product has the same conditions of use and the same labeling, with certain permissible differences, as the RLD.”
Bacterial endotoxins
The guidance provides answers to two questions related to bacterial endotoxins. The first answer addresses how a criterion for endotoxins test acceptance should be determined for a finished drug product. Here, FDA points generic developers to General Chapter 85 in the US Pharmacopeia, which lays out maximum endotoxin exposure for drugs in general and for topical and intrathecal drugs.
Topical ophthalmic drugs products do not have to be tested for bacterial endotoxins, said FDA, in responding to a second question as to whether it is acceptable to omit bacterial testing limits for such products. However, endotoxin testing may be required if the product is to be used on an abraded eye or used during surgery.
FDA advised industry to review these questions before submitting a controlled correspondence on these topics. The agency intends to add additional questions and answers as needed to address more commonly asked questions that may arise.
FDA guidance on controlled correspondence


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