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data available. If the marketing application is later submitted in other regulatory jurisdictions, reassessment may be considered. As an example, in cases where there is reason to question the outcome of a negative prediction (e.g. an aromatic amine is present, but the model gave a negative prediction). Reassessment may also be considered if the predictions made for the initial global marketing application did not use a recent version of the software. In general, predictions generated with models developed prior to ICH M7's publication in 2014 are considered unacceptable. 2 For marketing applications, what content and CTD placement recommendations could improve the clarity of an ICH M7 risk assessment and control strategy? In Module 2, a brief summary of the ICH M7 risk assessment and control strategy should be included (Sections 2.3 and 2.6). In Module 3, the ICH M7 risk assessment and control strategy should be provided in detail. This type of information is often placed in Section 3.2.S.3.2 Impurities; however, it is sometimes placed in other CTD locations per ICH M4Q guidance. A table summary of the ICH M7 hazard assessment and ICH M7 impurity control strategy is recommended to improve clarity. Information recommended for an ICH M7 hazard assessment table includes impurity chemical structure, (Q)SAR results (pos/neg predictions, out of domain), bacterial reverse mutagenicity assay results (pos/neg, if available), ICH M7 impurity class (1–5) assignment, and supporting information (e.g. information/links for bacterial reverse mutagenicity assays, literature reports, and (Q)SAR expert analysis). The in silico systems used (name, version, and end point) can also be noted.Information recommended for an ICH M7 impurity control strategy table includes impurity origin (e.g. synthetic step introduced and degradant), ICH M7 class, purge factors (e.g. measured or predicted), ICH M7 control option (1–4), control strategy (i.e. including in‐process or compound testing rationale), and supporting information (e.g. information/links for justifications and calculations). The maximum daily dose, TTC, and proposed duration of treatment can also be noted.Additionally, it is recommended that compound code names be cross‐referenced, if Module 3 and Module 4 (including toxicity study reports) use different compound naming conventions. In Module 4, full safety study‐related information on impurities (e.g. bacterial reverse mutagenicity assay reports, (Q)SAR reports, genotoxicity test reports, and additional testing) should be included to support the risk assessment and control strategy. This information is often placed in Section 4.2.3.7.6 Impurities (see ICH M4S for additional information) and can be cross‐referenced to Module 3 by hyperlinks.

For Sections 10 (Illustrative Examples) and 11 (Glossary) there were no Q&As.

To summarize, critical topics were addressed in the Q&A draft document and these are greatly welcome. The main goal of the EWG was to minimize different interpretation of specific aspects of risk assessment and control strategy of mutagenic impurities. Most of the Q&As achieve this goal; however, several still require further clarification, in particular the requirements around testing for impurities found above the 1 mg/day level.

References

1 1 ICH M7 – Assessment and control of dna reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. https://www.ema.europa.eu/en/documents/scientific‐guideline/ich‐guideline‐m7r1‐assessment‐control‐dna‐reactive‐mutagenic‐impurities‐pharmaceuticals‐limit_en.pdf (accessed October 2020).

2 2 Committee for Medicinal Products for Human Use (CHMP). Guidelines on the Limits of Genotoxic Impurities, London 26th June 2006. CPMP/SWP/5199/02.

3 3 Chmp Safety Working Party (SWP). Question & Answers on the CHMP Guideline on the Limits of Genotoxic Impurities. London, 17 December 2009. EMEA/CHMP/QWP/251344/2006Q&A.

4 4 Guidance for Industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches Draft, Center for Drug Evaluation and Research (CDER) December 2008.

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30 30 ICH guideline Q9 on quality risk management, September 2015 EMA/CHMP/ICH/24235/2006.

31 31

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