N‐Nitrosamines

This chapter summarizes the chemistry of both formation and potential removal of N -Nitrosamines. In the case of the reported presence of N -Nitroso-methyl-4-aminobutyric acid in Losartan, it was generated due to the formation of N -methyl-4-aminobutyric acid during solvent recycling due to hydrolysis of the N -methyl-2-pyrrolidinone solvent and subsequent reaction of the freed secondary amine with nitrite. The result of the combination of these concerns triggered regulatory action from authorities, this took the form of direct, specific product-related requests to marketing authorization holders and in Europe centralized action via the Article 31 process. The pharmaceutical industry is engaged in active research trying to better understand N -Nitrosamine contamination and formation risk in drug products during manufacture and over shelf life. To have any chance of addressing the concerns surrounding N -Nitrosamines needs industry and regulators to work in partnership to ensure the real risks are identified, targeted, and removed.