Risk Assessment and Analytical Control of Nitrosamine and NDSRI Impurities in Pharmaceutical Dosage Forms

Abstract

Nitrosamine impurities and nitrosamine drug substance-related impurities (NDSRIs) have emerged as major pharmaceutical safety concerns because of their potent genotoxic and carcinogenic properties. The global detection of nitrosamines in several pharmaceutical products, including valsartan, losartan, ranitidine, metformin, rifampicin, and varenicline, resulted in widespread recalls and intensified regulatory scrutiny worldwide. Nitrosamines are generally formed through nitrosation reactions involving secondary or tertiary amines and nitrosating agents under favourable conditions such as acidic pH, elevated temperature, moisture, and prolonged storage. In addition to classical nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), recently identified NDSRIs represent structurally complex impurities directly associated with active pharmaceutical ingredients and degradation pathways. This review comprehensively discusses the chemistry, formation mechanisms, sources, toxicological risks, analytical challenges, regulatory perspectives, and mitigation strategies associated with nitrosamine impurities in pharmaceutical dosage forms. Particular emphasis is given to risk assessment approaches, including Threshold of Toxicological Concern (TTC), acceptable intake limits, QSAR-based predictive toxicology, and lifecycle impurity management. Advanced analytical techniques, including LC–MS/MS, GC–MS/MS, LC-HRMS, Orbitrap HRMS, and QTOF-MS, are critically reviewed for ultra-trace detection and characterisation of nitrosamines and NDSRIs. The review further summarises method development strategies, validation requirements, and analytical challenges such as matrix interference, artefact formation, co-elution, and lack of certified reference standards. Additionally, recent regulatory guidelines issued by ICH, FDA, EMA, WHO, and USP are discussed along with major pharmaceutical recall events and future perspectives involving artificial intelligence, predictive toxicology, green analytical chemistry, and continuous manufacturing technologies. Overall, effective nitrosamine control requires integrated analytical, toxicological, regulatory, and manufacturing approaches to ensure pharmaceutical quality, patient safety, and global regulatory compliance.