Innovations in the Detection of N-Nitrosamine Impurities in Pharmaceuticals: Analytical and Regulatory Challenges.

Abstract

The emergence of N-nitrosamine impurities (NAIs) in pharmaceutical products has raised significant global concern due to their confirmed carcinogenic and genotoxic potential. Their presence in widely prescribed medications like metformin, ranitidine, and valsartan has triggered widespread recalls and prompted stringent guidelines by agencies like the USFDA and EMA. Despite technological advancements, the detection and quantification of NAIs at the trace level remain analytically challenging, primarily due to their structural diversity and exceptionally low permissible thresholds for detection. Given the recent surge in regulatory scrutiny and product recalls, this review offers an up-to-date critical evaluation of the origin, mechanism of formation, toxicological implications, and evolving regulatory framework for NAIs. Particular emphasis is placed on the state-of-the-art analytical techniques, including LC-MS, GC-MS, and emerging high-resolution mass spectrometry (HRMS) platforms, along with current practices in sample preparation and method validations. Methodological gaps, including challenges in sample preparation and instrument-specific limitations, are thoroughly analyzed to propose future strategies for robust, high-throughput, and regulatory-compliant analysis of NAIs in complex pharmaceutical matrices. A comprehensive literature search spanning 2018-2025 was performed using PubMed, Web of Science, ScienceDirect, and Scopus. Keywords, such as "nitrosamine impurities", "N-nitrosodimethylamine (NDMA)", and "regulatory guidelines" were used to select articles relevant to ongoing method optimization and harmonization to ensure consistent monitoring and mitigation of NAIs. This work also aims to serve as a valuable resource for pharmaceutical scientists, chemists, toxicologists, and regulatory professionals in their commitment to enhance drug safety and protect public health.