Controlling a Cohort: Use of Mirabilis-Based Purge Calculations to Understand Nitrosamine-Related Risk and Control Strategy Options

The recent discovery of nitrosamines within marketed drugs, such as Valsartan, has led to changes within the regulatory landscape. Most notably, the requirement for a risk evaluation of the presence of nitrosamines within the drug product has been extended from sartan-type tetrazole containing drugs to all marketed products. The largest inherent risks associated with a drug substance will generally arise from impurity formation and carryover in the synthetic manufacturing process. Despite the classification of nitrosamines within the cohort of concern, the understanding of their behavior based on physicochemical properties is unaffected by this status, and as such all control options laid out in ICH M7 should be considered acceptable. This communication aims to show how the use of purge calculations, utilizing the Mirabilis software, fully de-risked nitrosamine concerns related to the development of Candesartan cilexetil. Aligned to the principles of impurity control in the ICH M7 guideline, this provided a suitable strategy to determine, and subsequently demonstrate control of, the nitrosamine risk.