FDA Issues Draft Guidance of Genotoxic Impurities

Rockville, MD (Dec. 16)-The US Food and Drug Administration issued a draft guidance, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches. The draft guidance is intended to inform pharmaceutical manufacturers of the agency’s thinking regarding genotoxic and carcinogenic impurities in drug substances and drug products, including biologic products that are regulated by the Center for Drug Evaluation and Research, and to provide recommendations on how to evaluate the safety of these impurities during clinical development and for marketing applications.

The draft guidance, when finalized, will clarify FDA's additional testing and exposure threshold recommendations for situations in which genotoxic or carcinogenic impurities are present. The draft guidance addresses synthetic impurities and degradants in drug substances, but does not address the genotoxicity or carcinogenicity of actual drug substances or intended drug product ingredients. This draft guidance also applies to known starting materials or anticipated reaction products.

The draft guidance describes acceptable approaches for initially evaluating the genotoxic potential of impurities as well as approaches for handling impurities with known genotoxic or carcinogenic potential. These approaches include prevention of the impurity formation, reduction of the impurity level to an acceptable threshold, or additional characterization of the genotoxic and carcinogenic risk. The draft guidance also discusses various factors that should be considered in the overall risk assessment based on the drug indication, duration of use, and the clinical development stage.