Comprehensive Review of Genotoxic Impurities: Current Trend, Challenges and Control Strategies for Pharmaceutical Drug Products
Dipen Purohit *
Analytical Development & Quality Control, Navinta LLC, Ewing, NJ 08618, USA.
Ravi Patel
Research & Development, Thermo Fisher Scientific, Greenville, NC 27834, USA.
Krupal Morker
Drug Product Development, Frontage Laboratories Inc., Exton, PA 19341, USA.
*Author to whom correspondence should be addressed.
Abstract
Genotoxic impurities (GIs) in pharmaceuticals pose a significant risk due to their potential to induce DNA damage, mutations, and carcinogenesis even at trace levels. Regulatory frameworks, including ICH M7 (R1), FDA, and EMA guidelines, have established stringent impurity assessment and control strategies based on the Threshold of Toxicological Concern (TTC) approach. This review explores the sources of GIs, including synthetic process-related byproducts, degradation products, excipient interactions, and environmental contaminants. The mechanisms of genotoxicity, encompassing DNA alkylation, chromosomal aberrations, and oxidative stress, are discussed alongside structural alerts for impurity risk prediction. Advanced analytical techniques such as LC-MS/MS, GC-MS, NMR, and in silico modeling (DEREK, TOPKAT, MCASE) facilitate impurity detection and risk assessment. Control strategies, including process optimization, solvent selection, purification techniques, and green chemistry approaches, are key to mitigating impurity formation. Future directions emphasize harmonization of global regulatory limits, AI-driven predictive toxicology, and next-generation analytical methodologies for improved impurity management. This review provides a comprehensive scientific framework for genotoxic impurity risk assessment, control, and regulatory compliance, ensuring drug safety and quality.
Keywords: Genotoxic impurities, pharmaceutical drug product, nitrosamine, artificial intelligence, impurity profiling, analytical techniques, green chemistry, ICH