GENOTOXIC IMPURITIES IN PHARMACEUTICALS: ADVANCES IN RISK ASSESSMENT, ANALYTICAL STRATEGIES, REGULATORY PERSPECTIVES, AND CONTROL APPROACHES

Abstract

Genotoxic impurities (GTIs) are trace-level contaminants capable of damaging DNA and increasing the potential for mutation and carcinogenesis. They may arise from starting materials, reagents, catalysts, intermediates, by-products, degradation pathways, manufacturing operations, or packaging interactions. Their control is therefore a critical component of pharmaceutical quality assurance. This review summarizes the major sources and classes of GTIs, mechanisms of DNA damage, toxicological risk-assessment approaches, regulatory expectations, in silico prediction, analytical strategies, method validation, genotoxicity testing, and practical control measures. Particular attention is given to ICH M7(R2), the Threshold of Toxicological Concern (TTC), Acceptable Intake (AI), (Q)SAR, read-across and weight-of-evidence approaches. Modern analytical platforms such as LC-MS/MS, GC-MS/MS, high-resolution mass spectrometry, ICP-MS and ICP-OES provide sensitive detection, while optimized sample preparation and analytical quality by design improve method performance. Quality by Design (QbD), Process Analytical Technology (PAT), impurity purge studies, green chemistry and continuous manufacturing support prevention rather than relying only on end-product testing. Nitrosamines, including drug substance-related nitrosamines, remain an important area because of their very low acceptable exposure levels and their occurrence through synthesis, degradation and storage. Emerging approaches involving artificial intelligence, digital laboratories, chemometrics, metabolomics, portable devices and real-time release testing are expected to strengthen lifecycle impurity control.