On March 14, 2018, FDA issued final guidance on M7(R1) Assessment and Control of Deoxyribonucleic Acid (DNA) Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. The guidance updates and replaces the May 2015 guidance for industry “M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk,” and finalizes draft guidance issued September 28, 2015.

As a result of chemical synthesis, degradation, and metabolism impurities may reside in drug substances and associated drug products. The guidance focuses on DNA reactive impurities that may directly cause DNA damage when present at low levels leading to mutations and, therefore, potentially causing cancer.

The purpose of the guidance is to limit potential carcinogenic risk by providing a practical framework for identification, categorization, qualification, and control of mutagenic impurities. The guidance considers both safety and quality risk management in establishing levels of mutagenic impurities expected to pose negligible carcinogenic risk. In addition, it outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use.

The guidance is applicable to new drug substances and new drug products during clinical development and subsequent applications for marketing. The guidance is not intended to be applied retrospectively, except in cases where post-approval changes warrant a reassessment of safety relative to mutagenic impurities. Additionally, the guidance does not apply to drug substances and drug products intended for advanced cancer indications as defined in the 2010 ICH guidance for industry on S9 Nonclinical Evaluation for Anticancer Pharmaceuticals.

Readers are encouraged to read the final guidance, also available on FDA’s website.