Assessment of Regulatory Requirements for Nitrosamine Impurities on the Drug Development and Post Approval

Abstract

Nitrosamines describes a class of compounds having the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O).  They are a group of carcinogens that are formed by the reaction of secondary and tertiary amines, amides, carbamates, and derivatives of urea with nitrite or other nitrogenous agents during the manufacturing of API and Finished products. Although they are also present in some foods and drinking water supplies, Nitrosamine-contaminated medicinal products have raised safety concerns towards the use of various drugs as they are probable human carcinogens when exposed above acceptable levels and over a long period of time. These can form at any stage from drug substance synthesis till product life cycle of the finished product and hence health authorities have issued public health alerts and tight guidance on nitrosamine contamination for all drug products in the market. This review emphasises, assessment of regulatory requirements on Nitrosamine impurity sources, the EMA and USFDA approach and recommendation to the applicant/Marketing authorisation holder on Risk evaluation, route cause, control strategy and mitigation plan for under progress and approved drug products.