N-nitrosamine Impurities in Medicines: Toxicity, Formation Pathways, Methods of Determination, and Limits (Review)

Abstract

Introduction. N-nitrosamine compounds are potent genotoxic agents in animal species and some are classified as probable human carcinogens. This group of genotoxic impurities was found in drugs such as angiotensin II receptor blockers, histamine H1 receptor antagonists, and synthetic antidiabetic drugs. This discovery caused a flurry of alarm in the global pharmaceutical industry and resulted in a series of international investigations trying to determine root causes of nitrosamine formation in medicinal products and to find ways to minimize risks associated with nitrosamine contamination.Text. This paper provides an overview of the current state of the problem. It summarises the main pathways of N-nitrosamine formation in medicinal products at the stages from synthesis of active pharmaceutical ingredients to storage of finished pharmaceutical products. The paper describes the main mechanism responsible for the toxic effect of this group of impurities in human body. It also describes methods of extraction and analysis of N-nitrosamines found in medicinal products. It was demonstrated that high-performance liquid chromatography and gas chromatography-mass spectrometry are a golden standard for the detection of these contaminants. The paper also touches upon the main principles of setting limits for nitrosamine impurities in medicinal products.Conclusion. The data presented give a picture of the root causes of N-nitrosamine formation in medicinal products, as well as current detection and control methods used worldwide. Meanwhile, the paper raises a key issue about the need to develop Russian standards that would control the purity of medicinal products in terms of N-nitrosamine impurities. For that end, it will be necessary to draw on the experience of the leading USA and EU regulatory authorities.