Chapter 12 - Mutagenic impurities

Abstract

Regulatory expectations for assessment and control of mutagenic impurities (MI) have been given in ICH M7(R1) guidelines. Control strategies need to be developed for impurities identified as MIs throughout the product life cycle. Degradation product MIs identified during stress testing need to be confirmed as actual impurities in materials held under normal storage conditions. Options for control include specifications at staged threshold of toxicological concern limits in the drug substance or drug product, higher limits at upstream process points coupled with purification data, and using a chemical or purification rationale that no specification is needed. Analytical methods for MIs need to be selective with adequate sensitivity. These requirements are often met with separation techniques coupled with mass spectrometric detection. Three case studies are presented describing degradation product MIs, synthetic process MIs, and analytical approaches used for N-nitrosamine determination in valsartan and related compounds.