Abstract
Nitrosamine impurities have emerged as a critical safety concern in pharmaceutical products due to their potent genotoxic and carcinogenic nature. Since the detection of N-nitrosodimethylamine (NDMA) in angiotensin receptor blockers, global regulatory agencies have intensified scrutiny on nitrosamine contamination across drug substances and products. This review comprehensively examines smart analytical techniques employed for the detection and quantification of nitrosamine impurities, integrating a risk-based approach aligned with regulatory expectations. Advanced methodologies including liquid chromatography–mass spectrometry (LC-MS/MS), gas chromatography–mass spectrometry (GC-MS), high-resolution mass spectrometry (HRMS), and emerging microanalytical platforms are critically discussed. The article further explores mechanisms of nitrosamine formation, sources of contamination, and the role of predictive risk assessment tools in pharmaceutical manufacturing. Emphasis is placed on analytical challenges such as trace-level detection, matrix interference, and sample preparation complexities. Comparative evaluation of conventional and modern techniques highlights advancements in sensitivity, selectivity, and regulatory compliance. Additionally, the integration of artificial intelligence and digital analytical frameworks in impurity profiling is addressed as a future direction. This review provides a holistic understanding of nitrosamine impurity detection, offering practical insights for pharmaceutical scientists, regulatory professionals, and analytical chemists to ensure drug safety and quality.