In Silico Approach for the Identification and Control of Potential Mutagenic Impurities in Drug Substances: A Lansoprazole Case Study

The rigorous assessment of impurities in pharmaceutical drugs is vital to ensuring their safety and efficacy. Recent focus has centered on nitrosamines due to their known mutagenic and carcinogenic potential, initially highlighted by the presence of N-nitrosodimethylamine (NDMA) in a drug in 2018. Subsequently, similar nitrosamines have been found in other pharmaceutical drugs, raising concerns about their potential mutagenic impurities. This underscores the importance of evaluating both actual and potential impurities for bacterial mutagenicity. In alignment with ICH M7 (R2) guidelines, we have undertaken an in-silico study for the identification and control of potential mutagenic impurities in lansoprazole as a case study, which was one of the ranitidine-substituted drugs as recommended by the FDA. Through the synthetic scheme assessments, we identified the actual and potential impurities of lansoprazole. In silico bacterial mutagenicity predictions were carried out using a combination of expert rule-based and statistical rule-based methodologies according to the guidelines outlined in ICH M7 (R2). A total of 35 lansoprazole impurities were evaluated using Derek Nexus, Sarah Nexus, and Case Ultra software, wherein 9 impurities resulted in positive predictions and 26 impurities resulted in negative predictions. The impurities with positive predictions were subsequently subjected to further scrutiny using Mirabilis software to develop a control strategy. Based on the nature of the impurity and its stage of formation/introduction to the process, a hypothetical scenario using an initial concentration of each positively predicted impurity (intermediate/by-product/reagent) at its point of introduction was considered to understand its purge and fate at the final stage. This study provided critical insights into the possible presence of mutagenic impurities and facilitated the development of an appropriate control strategy to ensure the safety of the final drug substance.