Industrial Case Studies Demonstrating Applicability of ICH M7 Control Options 3 and 4 for Nitrosamine Control

The assessment and control of potential mutagenic impurities (PMIs) within pharmaceutical products are managed in accordance with the ICH M7 guideline “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”. This guidance highlights four control options that can be used to give assurance of control of PMIs to below a level of toxicological concern for the intended use. These control options range from testing to confirm that impurity levels within the active pharmaceutical ingredient or product are below an acceptable limit (ICH M7 Option 1 Control) to a control strategy that relies on process controls and scientific principles (e.g., purging) to demonstrate impurity presence to below a level of concern in lieu of analytical testing (option 4). While ICH M7 control option 4 is an established approach to justify that levels of a potential mutagenic impurity are below an acceptable limit, there have been health authority challenges that the use of ICH M7 control option 4 rationales is not appropriate for N-nitrosamines without included confirmatory analytical testing data to confirm absence. The reasons behind this lack of acceptance for ICH M7 control option 4 alone may include (i) a higher perceived potency for nitrosamines over other mutagenic impurities as they alert as part of the cohort of concern and (ii) inappropriate application of purge rationales such that, in some instances, confirmatory testing data highlighted higher levels for the impurity than had been predicted to be present. Through the inclusion of industry relevant case studies, this publication outlines that, while some nitrosamines may require control to lower levels than the ICH M7 threshold of toxicological concern, the concept of the ICH M7 option 4 control is scientifically justified when the properties for the nitrosamine are considered and an appropriate conservative purge rationale is applied.