Author: Pinky Mazumder
On January 19, 2018 Health Canada announced the adoption of the ICH guidance on M7: The Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (the “Guidance”). The Guidance was prepared by the ICH and reviewed by the regulatory bodies during consultations. By adopting the Guidance, Health Canada has endorsed the principles within
The Guidance provides a framework for the identification, categorization, and control of mutagenic impurities (DNA reactive) in order to limit the potential of carcinogenic risks. It applies to drug substances and drug products throughout the product lifecycle. The Guidance can also apply to post-approval changes to an approved drug product where the manufacturing process or synthesis of the drug substance is changed and poses the possibility of mutagenic impurities. The Guidance may also apply to drug products facing formulation leading to the possibility of new degradation products. However, the Guidance would not apply to biological drugs, peptides, radiopharmaceuticals, and herbal products among others. It also does not apply to drug products indicated for advanced cancers and drug products that have already been approved for market authorization
The Guidance focuses on DNA reactive substances which are usually identified in bacterial reverse mutation assays of mutagenicity. Other assessments include structure assessments to predict the possibility of bacterial mutagenicity. Impurity assessment usually consists of two steps where the actual impurities with mutagenic potential are first identified and if they are also present in the final drug substance
The impurities are also evaluated per the Hazard Assessment based on literature searches. The potential impurity is then classified from Class 1 to 5 where Class 1 consists of known mutagenic carcinogens and Class 5 is to be treated as a non-mutagenic impurity. Table 1 of the Guidance lists the classification of impurities and the proposed controls.
In addition to adopting the Guidance, Health Canada is informing the industry that regulatory requirements per the assessment of such potentially mutagenic impurities (e.g. literature references, bacterial mutagenicity assay reports, etc.) provided in Module 4.2.3.7.6 Impurities with Study Tagging Files (STFs) for each impurity. The documents are also to be provided in PDF format. For more information on Health Canada’s adoption of ICH M7, please see the reference below.
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Reference:
Health Canada Notice: Adoption of International Council for Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) Guidance Document: M7. File number: 18-100716-962