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A New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities

Burns, Michael, Ott, Martin, Teasdale, Andrew, Stalford, Susanne, Antonucci, Vincent, Baumann, Jens-Christoph, Brown, Roland, Covey-Crump, Elisabeth, Elder, David, Elliott, Eric, Fennell, Jarred, Gallou, Fabrice, Ide, Nathan, Itoh, Tetsuji, Jordine, Guido, Kallemeyn, Jeffrey, Lauwers, Dick, Looker, Adam, Lovelle, Lucie, Molzahn, Robert, Schills, Didier, Schulte Oestrich, Rolf, Sluggett, Gregory, Stevenson, Neil, Talavera, Pere, Urquhart, Michael, Varie, David and Welch, Dennie (2019) A New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities. Organic process research & development.


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 tech-nique 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 which aims to build on the semi-quantitative purge approach, and harmonise industry best practices by enabling the calculations to be conducted in a standardised, consistent and repro-ducible 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 oxa-late and Camicinal.

Item Type: Article
Date Deposited: 18 Oct 2019 00:45
Last Modified: 18 Oct 2019 00:45