Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products

Abstract

This paper outlines strategies in alignment with ICH M7 for systematically assessing the potential risk posed by mutagenic degradants in active pharmaceutical ingredients (API) and formulated products. A mutagen risk assessment (MRA) process that involves degradation should include results from focused drug substance and drug product stress testing experiments (e.g., at elevated temperature, a wide pH range in solution, oxidative, and photolytic stress) as well as accelerated and long-term stability studies in the solid-state. While the MRA may include hypothetical (theoretically predicted) degradation products from computer based and/or knowledge-based approaches, investigations for numerous hypothetical degradation products whose significance have not been verified experimentally should not be initiated based on these results alone. Drug substance and drug product stress (forced degradation) studies should be designed to generate a comprehensive range of potential degradants that encompass all degradati...