NITROSAMINE IMPURITIES IN PHARMACEUTICALS: ANALYTICAL METHODS, REGULATORY FRAMEWORK, AND RISK CONTROL– A REVIEW

Nitrosamine impurities have emerged as a major global concern in pharmaceutical quality due to their well-established mutagenic and carcinogenic potential. Since the detection of N-nitrosodimethylamine (NDMA) in angiotensin receptor blockers in 2018, regulatory agencies worldwide have implemented risk-based control frameworks for nitrosamine impurities in drug substances and finished products. Nitrosamines may form through interactions between amines and nitrosating agents during active pharmaceutical ingredient synthesis, solvent reuse, raw material contamination, manufacturing conditions, or storage. Recent attention has also focused on nitrosamine drug substance related impurities (NDSRIs), which are structurally derived from APIs and may arise through degradation or side reactions. Due to extremely low acceptable intake limits, highly sensitive analytical techniques such as LC–MS/MS, GC–MS, and high-resolution mass spectrometry are required. This review summarizes nitrosamine formation mechanisms, analytical detection strategies, regulatory frameworks, case studies, and mitigation approaches, with emphasis on ensuring pharmaceutical safety.