Addendum to ICH M7 on Risk Assessment and Control of N-Nitrosamine Impurities

Guidance, Documents, Resources
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Final Concept Paper of ICH M7 on Risk Assessment and Control of N-Nitrosamine Impurities is available.

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Thanks for sharing @Yosukemino … I would love to hear our community’s feedback and comments!

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This is a great activity. We want to thank all the WG members for their efforts. Oh, there are so many challenges to be harmonized. It is anticipated that it will take 3 years to reach Step 1 of each topic. We still have a long, long way to go. It will be some time before we experts have to worry about unemployment. Let’s go slowly and not rush. :grinning: :grinning: :grinning:

3. Issues to be resolved and expected deliverable(s)
The ICH M7 Addendum on N-nitrosamines will include recommendations for safety and quality topics to support consistency across the ICH regions. The following topics will be addressed:

  • Recommendations for the design and interpretation of the EAT to assess mutagenic hazard.
  • Potential to develop a weight of evidence approach based on the outcome of other in vitro mutagenicity assays (e.g., in vitro assays described in ICH S2(R1)), metabolism/activation data, and in vivo studies (e.g., transgenic rodent assay), as warranted for establishing an AI.
  • Recommendations for defining acceptable intake limits based on physicochemical and structural features of a nitrosamine. This will include enhancing the CPCA with additional features, as well as a framework for deriving acceptable intake limits based on read-across to a surrogate with compound-specific data.
  • Application of less-than-lifetime (LTL) adjustments to acceptable intake limits based on exposure duration and relevant nitrosamine control in clinical development and for marketing authorizations.
  • Control of multiple nitrosamines within a drug substance and/or drug product.
  • Principles for the design and interpretation of in vivo mutation studies, and whether and how the generated data may be used for derivation of acceptable intake limits (including quantitative assessment of in vivo data when the results show evidence of mutagenicity).
  • Framework for using quality principles recommended in the ICH M7(R2) guideline and its Q&A. The following topic areas will be covered:
    o Recommended principles for conducting robust quality risk assessments for drug products, drug substances, and other drug product components, including high level guidance concerning risk factors for nitrosamines.
    o Recommendations for control strategies for drug substances and extension of control strategies to drug products. This can include options 1-4. High level guidance on documentation in CTDs.
  • Monographs and compound-specific acceptable intake limits will be established for some nitrosamines based on the need to support the CPCA framework, and potential establishment of acceptable intake limits based on in vivo mutagenicity data. The Methods section of the ICH M7(R2) Addendum on Application of the Principles of the ICH M7 Guideline to Calculations of Compound-Specific Acceptable Intake Limits will be updated if needed.
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Its a mixed bag and should be handled with caution!

The good part:

  1. Application of LTL
  2. Consideration for the application of ICH M7 Control strategies Option 1-4.
  3. Development of monographs and compound-specific acceptable intake limits

The missing part:

  1. Implementation of molecular weight corrected AIs. A lot of work has already been done in this area, for example:

  • Joerg Schlingemann Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage, Regulatory Toxicology and Pharmacology 145 (2023) 105505. Redirecting

  • Bassan, A., et al., 2011. Applicability of physicochemical data, QSARs and read-across in Threshold of Toxicological Concern assessment sp.efsa.2011.EN-159.pdf

  • David J. Snodin, Mutagenic impurities in pharmaceuticals: A critical assessment of the cohort of concern with a focus on N-nitrosamines, Regulatory Toxicology and Pharmacology 141 (2023) 105403, Redirecting

  1. Timeframe for the implementation of these guidelines is too long! Shouldn’t this be taken on a triage given that the current regulatory limits have threatened the access to several life-saving drugs?
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Buon pomeriggio e’ possibile per le aziende mandare un feedback al sub-group in merito agli argomenti elencati nel concept paper? Si può esprimere un opinione. Oppure si deve attendere l’apertura della consultazione sul draft?

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@Valentina_Renzi There is no official mechanism for providing feedback on the concept paper. The paper is the proposed revision path presented to the management committee for approval. As highlighted by the final version of the paper, some compromises had to be made. But I am sure the revision sub-group will be open to any feedback.
I suggest to include here your feedback or comments as first step to start the conversation.

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Dear colleagues
Let’s hope that we will finally achieve harmonization between FDA and EMA guidelines.

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Hopefully, the guidelines will be established soon.

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