Application of Quality by Design Principles to Support Development of a Control Strategy for the Control of Genotoxic Impurities in the Manufacturing Process of a Drug Substance

As part of the search for drugs with activity on the central nervous system (CNS) a fluoroaryl-amine was identified and developed by GlaxoSmithKline. The manufacturing process was developed and optimised by following a quality by design approach whereby a control strategy was developed, underpinned by process understanding and risk analysis, for enhanced level of quality assurance. A summary of the overall control strategy for this process includes different elements of control (Quality Process Parameters, control of the Quality Attributes of starting materials, intermediates, solvents, in-process controls). The drug substance Critical Quality Attributes (drug substance-CQAs) related to the genotoxin content, methyl methanesulfonate (methyl mesylate, MMS), ethyl methanesulfonate (ethyl mesylate, EMS) and isopropyl methanesulfonate (isopropyl mesylate, IMS) are identified and discussed in detail to show the process development studies carried out to ensure quality control for the final drug substance. The process understanding developed could allow for the elimination of testing of the genotoxic impurities in the final drug substance.