Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances

The assessment and control of genotoxic impurities (GTI) in pharmaceutical products has received considerable attention in recent years. Molecular functional groups that render starting materials and synthetic intermediates useful as reactive building blocks for small molecules may also be responsible for their genotoxicity. As a potential safety concern, it is important to understand the various issues related to GTIs and how they can be addressed for clinical and commercial phases of development. Justification that these impurities are controlled to safe levels must be obtained during development. This article will briefly discuss the multiple sources of anticipated impurities in a drug substance (also known as active pharmaceutical ingredient or API) synthetic route and how they are identified as GTIs in early chemical process development. A risk-based approach consistent with regulatory expectations is described for establishing control of GTIs. The approach includes process design considerations, impurity rejection information, and appropriate application of specifications. Analytical considerations for determination of GTIs at low levels are also discussed.