FDA Q&A on DMFs and drug substances

Risk Assessment Strategy / Tools & Technology
1

On April 14th, FDA made public recordings on their YouTube channel their Drug Master File (DMF) and Drug Substance Question and Answer Webinar Following March 3-4, 2021 Workshop

Few interesting questions were raised:

Part I:

  1. API with approval previous to ICH M7 mutagenic impurities guidance and risk assessment not performed. Manufacture is transfering manufacturing to a new supplier but no changes have been made to the manufacturing process, reagents, or specifications. Do they need to conduct risk assessment now? [36:00]

Part II:

  1. Is the API manufacturer required to include the route of synthesis and impurity discussion/controls for the regulatory starting material in a Drug Master File?

  2. Visual inspection of a compound for structural alerts for classification purposes was not ICH M7 compliance. What does visual inspection here refer to?

  3. If the impurity listed in USP monograph is a probable genotoxic based on (Q)SAR, can we go ahead with USP limit or do we need to control based on TTC limit?

  4. If a manufacturer shows that the levels of a potential mutagenic impurity are consistently 30% below the TTC limit in three commercial scale batches of the API, is this sufficient evidence to omit routine control of the mutagenic impurity from the release specifications?