Addressing the Complex Problem of Degradation‐Derived Mutagenic Impurities in Drug Substances and Products

The safety of potential or actual impurities in drug substances (DSs) and drug products (DPs) has been a significant concern within the pharmaceutical industry for many years, long before the landmark ICH Q3A and Q3B guidance on organic impurities, first adopted in 1995 and 1996, respectively. Strategies for assessing and controlling mutagenic impurities arising from drug synthesis have received considerable attention in regulatory guidance and scientific literature. DSs that are small organic molecules typically possess a variety of functional groups, resulting in a wide array of potential inter- and intramolecular reactions, rearrangements, and other degradation pathways. ICH M7(R1) indicates that the mutagenic impurity risk assessment (MRA) should include potential and actual degradation products "likely to be present in the DS and DP and where the structure is known." MRA process will be illustrated in four case studies: Molecule A; Galunisertib; Naloxegol; and Selumetinib side chain.