The Answers May be in What Is Not Stated – Drug Substance and Drug Product Manufacturers – Partnering to Improve the Process

An interesting session during the GRx+Biosims conference held in Bethesda on November 4, 2019 addressed Drug Substance and Drug Product Manufacturers – Partnering to Improve the Process.  The presentations from the FDA, as well as industry, acknowledged that the adequacy of drug master files (DMFs) for APIs in one cycle has been a lot more challenging compared to that of the first-cycle approval of ANDAs.  The FDA presentation outlined the timeline for the review of DMFs and encouraged sponsors to make sure that the DMFs are submitted three to six months before the ANDAs to ensure that the completeness assessment is done by the time the ANDAs are submitted.

It was also mentioned that the significant delaying factors, which have hindered the DMFs from being adequate, come not from the information provided in the DMFs, but more in the information that was not provided.  One missing item involves hidden facilities, and another is other impurities.  The Agency commented that frequently the ANDA holders do not have a full view of the facilities used by the DMF holder; this is especially true regarding testing facilities, intermediate manufacturing facilities, etc.

Overlooking these hidden facilities often results in the need for additional inspection requests being issued during the later stage of the review cycle.  Also, in many cases, API manufacturers do not identify all the possible and plausible impurities in their DMF.  Identification of these impurities late in the review cycle sometimes leads to the need for qualification reviews through pharm/tox consults.  These issues can cause a delay in the acceptability of the DMF and could delay the ultimate approval of the ANDA referencing the DMF.

The industry representatives provided their perspective about the importance of keeping the lines of communication between the DMF holder, the ANDA holder, and the FDA open.  The importance of R&D and Procurement working together to have effective communication with the API supplier was also mentioned.

ANDA holders were encouraged to read between the lines when they receive the open part of the DMF and understand whether there may be additional testing laboratories involved and the kind of impurity profile the DMF product may have.  It may also be worthwhile to understand whether genotoxic impurities may be formed by the API process and, if so, how the API manufacturer is proposing to mitigate any such risk.  The key is to avoid surprises during the ANDA review cycle.  Several questions arose during the session, including the impact of inspecting late-stage intermediate manufacturing facilities and occasional lack of harmony between the deficiencies cited by the DMF reviewer and the ANDA drug substance reviewer.  The Agency mentioned that the decision to inspect intermediate facilities is made on a case-by-case basis depending on the nature of the API.  Regarding the differences in questions related to the API between the DMF and ANDA reviewers, it was noted that often the differences in deficiencies cited by the ANDA reviewers may be based on the specific finished dosage form and the dose, which may be specific to a particular proposed drug product and something the DMF reviewers may not be aware of since they are looking at the general API information, not the specific finished dosage form.  The FDA also recommended that DMF holders avoid submitting unsolicited amendments towards the end of review cycles to help the FDA complete the reviews in a timely manner.

The session was informative and, based on the discussion, it appeared that, while it may take time to completely harmonize the review of the API and the finished dosage form, the industry and the FDA are making conscious efforts to move in the right direction.