A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products

N-nitrosamines are carcinogenic impurities most commonly found in groundwater, treated water, foods, bev-erages and consumer products. The recent discovery of N-nitrosamines in pharmaceutical products and subse-quent recalls pose a significant health risk to patients. Initial investigation by the regulatory agency identified Active Pharmaceutical Ingredients (API) as a source of contamination. However, N-nitrosamine formation during API synthesis is a consequence of numerous factors like chemistry selection for synthesis, contaminated solvents and water. Furthermore, apart from API, N-nitrosamines have also been found to embed in the final product due to degradation during formulation processing or storage through contaminated excipients and printing inks. The landscape of N-nitrosamine contamination of pharmaceutical products is very complex and needs a compre-hensive compilation of sources responsible for N-nitrosamine contamination of pharmaceutical products. Therefore, this review aims to extensively compile all the reported and plausible sources of nitrosamine impu-rities in pharmaceutical products. The topics like risk assessment and quantitative strategies to estimate nitro-samines in pharmaceutical products are out of the scope of this review.

Automated summary

N-nitrosamines are carcinogenic impurities commonly found in various sources such as groundwater, treated water, foods, beverages, consumer products, and even pharmaceutical products. The contamination of pharmaceutical products with N-nitrosamines can result from multiple factors including API synthesis, contaminated solvents and water, degradation during formulation processing or storage, as well as contaminated excipients and printing inks. This review aims to comprehensively compile and analyze the reported and plausible sources of nitrosamine impurities in pharmaceutical products, providing valuable insights into the complex landscape of N-nitrosamine contamination.