N-NITROSAMINE IMPURITIES IN PHARMACEUTICALS: FORMATION PATHWAYS, TOXICOLOGICAL CONCERNS, REGULATORY APPROACHES AND RISK MITIGATION STRATEGIES

Abstract

Background: N-nitrosamine impurities represent an important pharmaceutical quality and patient safety concern because several members of this chemical class exhibit mutagenic and carcinogenic potential. Objective: To synthesize scientific and regulatory evidence concerning their formation, toxicological assessment, and risk control in medicines. Methods: A narrative literature review and bibliographic synthesis was undertaken using selected scientific publications and international guidance, particularly from EMA, FDA and ICH. Results and discussion: The literature identifies nitrosatable amines, nitrosating species and favourable manufacturing or storage conditions as key determinants of formation. Risks arise from active substances, excipients, solvents, processing operations, and packaging-related factors. Evaluation of nitrosamine drug substance-related impurities requires structure-informed approaches, including carcinogenic potency categorization and justified read-across when compound-specific data are limited. Risk management combines systematic assessment, targeted confirmatory testing, preventive controls and lifecycle monitoring. Conclusion: An integrated, science-based approach encompassing formulation, manufacturing, and regulatory requirements is essential to reduce patient exposure to N-nitrosamine impurities.