The ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes Option 4, which leverages existing process knowledge and/or data to justify control of PMIs without the need for routine analytical release testing during manufacturing.
One such technique highlighted uses systematic, semi-quantitative calculations to define the degree of “purge” of PMIs within a synthetic route to an API based on physicochemical properties of the impurities in question, and the manufacturing process being undertaken.
This paper introduces a consortium-led initiative, Mirabilis, which aims to build on the semi-quantitative purge approach, and harmonize industry best practices by enabling the calculations to be conducted in a standardized, consistent and reproducible manner. The development of an expert-derived knowledge base for the prediction of reactivity by enhancing expert opinion using evidence derived from published literature and experimental data is also discussed. Furthermore, this paper describes the application of the Mirabilis software for the processes involved in the synthesis of Verbecestat, Naloxegol oxalate and Camicinal.
This paper is Open Access.