Regulatory Open Forum

 View Only
  • 1.  In-Vitro Genotoxicity Study in NDA package- API with enriched Impurity Vs. Isolated Impurity

    This message was posted by a user wishing to remain anonymous
    Posted 15-Apr-2024 09:12
    This message was posted by a user wishing to remain anonymous

    Dear Forum',

    Need your support in the interpretation of ICH M7 guidance, If an API impurity has a structural alert in prediction software as Class 3, and In-vitro bacterial reverse mutation test study is to be conducted to evaluate mutagenic potential.

    In such cases, can bacterial reverse mutation test be conducted with 'API (enriched with probable genotox impurity)' instead of 'isolated probable genotox impurity'.

    Kindly advise. It would be a great help. Many thanks in advance.



  • 2.  RE: In-Vitro Genotoxicity Study in NDA package- API with enriched Impurity Vs. Isolated Impurity

    Posted 16-Apr-2024 08:22

    Is there a reason that the impurity is not being isolated? Class 3 implies that it is structurally unrelated to the drug substance. If so, it should be feasible to isolate by chromatography, extraction, etc.

    Regardless, Note 2 in the guidance (excerpt below) provides a path. It depends on how enriched it is. I would make sure that the drug substance itself would not be at a high enough concentration to interfere.

    For impurities that are not feasible to isolate or synthesize or when compound quantity is limited, it may not be possible to achieve the highest test concentrations recommended for an ICH-compliant bacterial mutagenicity assay according to the current testing guidelines. In this case, bacterial mutagenicity testing could be carried out using a miniaturized assay format with proven high concordance to the ICH-compliant assay to enable testing at higher concentrations with justification.



    ------------------------------
    Scott Buckley
    Regulatory Affairs Specialist
    W. R. Grace & Co.-Conn.
    South Haven MI
    United States
    ------------------------------



  • 3.  RE: In-Vitro Genotoxicity Study in NDA package- API with enriched Impurity Vs. Isolated Impurity

    This message was posted by a user wishing to remain anonymous
    Posted 18-Apr-2024 09:29
    This message was posted by a user wishing to remain anonymous

    Dear Mr Scott

    I appreciate you taking the time to provide inputs on below , further would the USFDA require a reason to perform studies using enriched API , if you could let us know more on miniaturized assay format.




  • 4.  RE: In-Vitro Genotoxicity Study in NDA package- API with enriched Impurity Vs. Isolated Impurity

    Posted 18-Apr-2024 10:57

    As per the excerpt previously provided, the phrase "with justification" implies that explanation would be required as to why this path was taken.

    And in regards to the miniaturized assay format, I cannot speak to that. I have no experience with it. I was merely citing the guidance. I'd recommend reading into ICH M7 (and its addendum), ICH S2 , and researching miniaturized assays to get a better idea of what the practice.



    ------------------------------
    Scott Buckley
    Regulatory Affairs Specialist
    W. R. Grace & Co.-Conn.
    South Haven MI
    United States
    ------------------------------