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  • FDA guidance on M7(R2) Assessment and control of DNA-Reactive (Mutagenic) Impurities in Pharmaceuticals

    The FDA’s recent announcement, on July 25th, 2023, of the “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance for Industry” is a significant development in pharmaceutical regulation.

    Understanding FDA Guidance

    The FDA’s guidance serves a crucial purpose: to provide a practical framework applicable to the categorization, identification, qualification, and control of mutagenic impurities. The primary objective is to limit potential carcinogenic risks. This framework emphasizes the importance of quality risk management and safety considerations in establishing acceptable levels of mutagenic impurities.

    Impurities in Drug Substances

    The synthesis of a drug substance involves the use of reagents, reactive chemicals, solvents, catalysts, and other processing aids. Consequently, as an outcome of chemical synthesis or subsequent degradation, impurities are inevitable in all the drug substances and associated drug products.

    Application of the M7(R2) Guidance

    The guidance is for new drug products and new drug substances during their clinical development and subsequent applications for marketing. Also, it applies to post-approval submissions of marketed products, and new marketing applications for products with a drug substance that is present in a previously approved product in both cases only where:

    • Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities,
    • Changes in the composition, formulation, or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products,
    • Changes in indication or dosing regimen are made, which significantly affect the acceptable cancer risk level.


    Notably, the guidance excludes certain drug products and substances from its mutagenic potential assessment. These exclusions apply to biotechnological/biological products, oligonucleotides, peptides, fermentation products, radiopharmaceuticals, herbal products, and crude products of plant or animal origin.

    Assessing Impurities

    During the synthesis and storage of new drug substances, it’s imperative to assess both actual and potential impurities due to the high likeliness of them arising. The guidance outlines the assessment of identified impurities for mutagenic potential and recommends evaluating potential pollutants that may be present in the final drug substance.

    Focus on DNA-Reactive Substances

    This guidance focuses on DNA-reactive substance that has the potential to directly cause DNA damage when present at low levels directing to mutations and as a result potentially causing cancer. This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay.

    Threshold of Toxicological Concern (TTC)

    Furthermore, other types of genotoxicants that are non-mutagenic typically operate within threshold mechanisms and generally do not present a carcinogenic risk to humans at the levels usually found in impurities. Consequently, to mitigate potential human cancer risks associated with exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is employed to evaluate their mutagenic potential and the necessity for control measures.

    Structure-based assessments are useful for predicting bacterial mutagenicity outcomes based on established knowledge.

    A threshold of toxicological concern (TTC) concept was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects.

    In conclusion, the FDA’s guidance provides valuable insights into the control of process-related impurities, lifecycle management, degradation products, control approaches, clinical testing, and periodic testing.

    Refer to the guidance in detail on M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance for Industry.

    Contact Veeprho for Assessment and control of DNA-Reactive (Mutagenic) Impurities

    Get in touch with our team to understand how we can help you with the assessment and control of DNA-reactive impurities.


    What is the FDA ICH M7 R2?

    ICH M7 (R2) focuses specifically on mutagenicity and in the context of ICH M7 (R2) (quantitative) structure-activity relationship QSARs are considered an appropriate initial evaluation of mutagenic potential of an impurity at a dose of less than or equal to 1 mg.

    What is the ICH M7 guideline?

    It recommends and outlines the assessment and control of mutagenic impurities that reside or are reasonably expected to reside in the final drug product or drug substance taking into consideration the intended conditions of human use.