Control of Mutagenic Impurities: Survey of Pharmaceutical Company Practices and a Proposed Framework for Industry Alignment

ICH M7 provides several risk-based control options to manage mutagenic and potentially mutagenic impurities (MI and PMIs) in the manufacture of pharmaceuticals. A Working Group in the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org) performed a survey of pharmaceutical manufacturers to gain insight into the use and regulatory acceptance of mutagenic impurity control strategies and control options across the industry. Information on the regulatory acceptance of ICH M7 control strategies was collected on late-stage clinical and commercial programs with regulatory feedback from the FDA, EMA, and PMDA. The data show a preference for ICH M7 Option 4 as it allows the utilization of process knowledge to reduce analytical testing without any compromise on patient safety. This approach appeared globally acceptable when appropriately applied. The survey data collected show that the ability of a manufacturing process to purge impurities is a strong indicator of purity control, and the data provide additional evidence that the purge factor calculation as proposed by Teasdale et al. produces a conservative prediction of the purging ability of a process. As such, the use of predicted purge factors and purge ratio assessments relative to the required process purge provides a sound framework for mutagenic impurity controls. Experimental purge data may be generated to support Option 4 strategies when predicted purge factors offer insufficient assurance for process control.