Simulation of nitrosamine drug substance-related impurities from secondary amine-related impurities in approved human drug products.

Nitrosamines, recognized as potential carcinogens, have emerged as impurities of concern in pharmaceutical products. This study evaluates the formation risk of active pharmaceutical ingredient (API) fragment nitrosamine drug substance-related impurities (NDSRIs) derived from secondary amine related impurities that may be present in human drug products throughout their shelf life. Leveraging publicly available data from the Food and Drug Administration (FDA) Global Substance Registration System (GSRS), the carcinogenic potency categorization approach (CPCA), and available maximum daily dose (MDD) information, we identified 446 secondary amine related impurities linked to 218 individual APIs in human drug products. A simulation was conducted to assess the risk of API fragment NDSRI formation from these secondary amine related impurities, incorporating factors such as impurity levels, nitrosamine conversion ratio, MDD, and acceptable intake (AI) limits. The findings reveal that, under varying conditions of secondary amine related impurity levels and nitrosamine conversion ratios, a proportion of the API fragment NDSRI impurities may exceed recommended AI limits. Based on these simulation outcomes, we propose and discuss control strategies to mitigate nitrosamine-related risks.