Nitrosamine Impurities in Active Pharmaceutical Ingredients: Formation Mechanisms, Analytical Profiling, Toxicological Risk Assessment, and Regulatory Control Strategies
Year: 2026
Type: article
Abstract: Nitrosamine impurities in active pharmaceutical ingredients (APIs) and finished medicines require careful control because some members of this chemical group are genotoxic and carcinogenic. They may be introduced through contaminated starting materials, reagents, solvents or shared equipment, or form when susceptible amines encounter nitrosating agents during synthesis, formulation or storage. Nitrosamine drug substance-related impurities (NDSRIs) are especially challenging because their structures and toxicological profiles may be specific to the parent drug. This narrative review discusses nitrosamine classes and formation pathways, analytical methods, toxicological assessment, regulatory expectations and risk-reduction measures. LC–MS/MS and GC–MS/MS support targeted measurement, whereas LC–HRMS can help investigate unexpected impurities. Performance must be established for each analyte and sample matrix. Assessment is also complicated by limited reference standards and toxicological data for some NDSRIs. A suitable control programme therefore combines product-specific risk assessment, validated testing, justified acceptable-intake limits and preventive controls throughout the product lifecycle. Better characterisation of NDSRIs, comparable reporting of analytical performance and further validation of predictive toxicology tools remain research priorities.
Language: English
Subfield: Analytical Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7222950588