The Nitrite-Amines Nexus in Nitrosamine Formation: Mechanisms, Mutagenic Implications, Regulations, and Root Causes in Medicines.

Abstract

Introduction: Nitrosamines are genotoxic impurities formed from reactions between amines and nitrosating agents, which are commonly found in many consumer products and pharmaceuticals. Their presence poses serious risks due to their established carcinogenic potential, particularly with long-term exposure.

Methods: A comprehensive literature review was conducted using PubMed, Scopus, and Web of Science to investigate the mechanisms, sources, analytical detection methods, and regulatory frameworks of nitrosamine formation. Relevant studies and guidelines were analyzed to identify risk patterns and control strategies.

Results: Nitrosamines may form during the synthesis of Active Pharmaceutical Ingredients (APIs), due to excipient contamination, or through degradation during storage. Sensitive techniques, such as LC-MS and GC-MS, enable trace-level detection. Regulatory bodies, including the FDA and EMA, have established Acceptable Intake (AI) limits and mandated risk assessments and control measures.

Discussion: Nitrosamine formation is influenced by factors, such as pH, heat, moisture, and the interaction of amines with nitrosating agents. The variability in excipient composition and manufacturing processes adds complexity to prevention efforts, underscoring the need for productspecific risk evaluation.

Conclusion: Minimizing nitrosamine contamination requires robust risk assessment, sensitive analytical techniques, and strict adherence to evolving regulatory requirements. This review highlights the importance of proactive control throughout the formulation, manufacturing, and storage stages to ensure patient safety and pharmaceutical quality.