Nitrosamine impurities: Critical insights into chemistry, analytical tools, and worldwide regulatory requirements.

N-nitrosamines are organic impurities identified as a critical cohort of concern in the pharmaceutical industry due to their strong carcinogenic, mutagenic, and genotoxic potential. These impurities have been detected in various drug products, including angiotensin receptor blockers, antidiabetic agents, histamine H2-receptor antagonists, and antimicrobial agents. Global regulatory authorities, along with pharmaceutical manufacturers, are actively addressing issues related to product recalls arising from nitrosamine drug substance-related impurities. The United States Food and Drug Administration has specified acceptable daily intake limits for different nitrosamine compounds to guide manufacturers and analysts in ensuring product safety and compliance. Comprehensive quality risk management frameworks have been established under the guidelines of the International Council for Harmonisation and the International Organization for Standardization to control and prevent nitrosamine contamination. The quality management system plays a vital role in implementing risk-based approaches, establishing preventive control measures, and ensuring the integrity of pharmaceutical manufacturing processes. The evaluation and identification of nitrosamine impurities present analytical challenges related to their detection, quantification, and characterization. Various advanced analytical methods, including liquid chromatography coupled with mass spectrometry, gas chromatography coupled with mass spectrometry, and high-resolution mass spectrometry, are adopted for reliable detection and monitoring of nitrosamine impurities in pharmaceutical products.