A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities

Trace level genotoxic impurities (GTIs) in pharmaceutical products require precise, accurate, and robust analytical methodologies for their analysis and control. The need to control most genotoxic impurities to the low ppm level in combination with the very often reactive and labile nature of genotoxic impurities presents significant analytical challenges. This article reports a systematic GTI method development strategy (MDS) based on our successful experiences in GTI analysis in recent years and quality by design (QbD) principles emphasizing the expected method performance being built into the method. It starts with a predefined method goal, followed by method understanding and a risk control strategy. Due to the nature of the GTI analysis, sophisticated analytical methodologies such as chemical derivatization and mass spectrometry detection are often developed, especially in the research and development (R&D) phase of drug development. Such methods usually consist of more variables than conventional methods in pharmaceutical analysis. Therefore, sound scientific understanding and risk control strategies are of great importance to ensure the method performance for trace GTI analysis. For methods to be implemented in manufacturing quality control laboratories that are lacking sophisticated instrumentation and skilled analysts, method simplicity, robustness, and ruggedness become more prominent in addition to method accuracy. This article describes QbD approaches for developing such methods using real world case studies including dimethyl sulfate analysis of a recently approved drug, pazopanib HCl (Votrient).