Risk management of nitrosamines

Abstract

Nitrosamine impurities are mutagenic and carcinogenic chemical compounds that can be present during the active pharmaceutical ingredient (API) manufacturing process either by formation or contamination. Awareness of the nitrosamine contamination was triggered in 2018 where drugs classified as ‘sartans’ were reported to contain N-nitrosodimethylamine (NDMA) and N-nitrosdiethylamine (NDEA) compounds. The two main regulatory bodies; the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) established guidance documents for the pharmaceutical industry on nitrosamine impurities. The aim of this study was to develop and validate a risk assessment to determine the risk of having N-nitrosamine impurities in the API. A risk assessment tool was developed and validated by five people working in the Quality Assurance sector. The developed tool consisted of two sections: Section I; a questionnaire with seventeen statements followed by Section II; Failure Mode and Effects Analysis (FMEA) which included twenty-five potential failure modes on N-nitrosamine contamination in the API. The developed risk assessment tool used a 5-point Likert scale for severity, occurrence and detection. The product of severity, occurrence and detection gave the risk priority number (RPN), which was used to categorise risks as high, medium or low. The purpose of the developed FMEA risk assessment tool was to indicate whether a drug substance is possibly contaminated with N-nitrosamine impurities or not prior being manufactured into the finished product. A focus group consisting of five participants was set up to assess the risk of N-nitrosamine impurities on two drug substances: perindopril and valsartan. Perindopril served as the control. The developed risk assessment tool was compared to risk assessment reports provided by one local pharmaceutical company. A high average RPN of 12.8 and 20.6 were obtained for perindopril and valsartan respectively. The widest RPN range (1-48) obtained for valsartan indicated that valsartan was more inclined to N-nitrosamine contamination risk than perindopril with the widest RPN range being 1-36. The risk assessments performed indicated that drug substances like valsartan have a higher risk of contamination with N- nitrosamine than perindopril. Risk control strategies that can be considered are revalidation of the cleaning strategies, replacement of key starting materials that may trigger nitrosamine formation, and implementation of Process Analytical Technology to obtain real time data and information of synthesis processes. The developed risk assessment tool was compared with a risk assessment report of one local pharmaceutical company where similarities and differences were observed. The findings from the comparative analysis indicated the need for further harmonisation between regulatory bodies and market authorization holders to cooperate and achieve a standardised nitrosamine risk assessment. The potential possibility of inclusion of N-nitrosamine impurities is a global concern where resources and knowledge are still limited. The process of identifying possible root causes of nitrosamine formation and the development of the risk assessment tool may assist market authorisation holders to mitigate the N-nitrosamine risk in drug substances and prevent drug recalls.