Comparative Evaluation of Nitrosamine Impurity Control Strategies in USFDA, EMA, and WHO Pharmaceutical Submissions

Abstract

Nitrosamine impurities are of significant concern to the pharmaceutical industry because of their genotoxic and carcinogenic effects. They are formed during the manufacturing, storage, and/or packaging of APIs and/or drug products owing to the nitrosation reactions of amines with nitrosating reagents. The detection of nitrosamine impurities, such as N-nitrosodimethylamine and N-nitrosodiethylamine in medicinal products, including angiotensin II receptor blockers, ranitidine, and metformin, has raised significant concerns in the industry. Regulatory agencies have developed guidelines for controlling nitrosamine impurities. This review aims to evaluate the guidelines developed by the United States Food and Drug Administration, European Medicines Agency, and World Health Organization for controlling nitrosamine impurities and to identify the similarities and differences in the guidelines developed by the above agencies and the literature for risk evaluation, testing, and limits of intake, detection, and control of nitrosamine impurities. The review highlights the importance of strengthening international cooperation and developing standardised control strategies for the control of nitrosamine impurities in medicinal products, which is of significant importance for the quality and safety of medicinal products worldwide. Conclusion: Effective control of nitrosamine impurities requires harmonized global guidelines, robust risk assessment, and advanced detection strategies to ensure the safety and quality of pharmaceutical products. Strengthening international collaboration is essential for developing consistent and reliable control measures worldwide.