Assessment and Acceptance of Thresholds of Genotoxic Impurities in New Drug SubstancesA Regulatory Perspective

Impurities in drug substances can arise from a variety of sources during the manufacturing process, and include residues from starting materials, by-products, intermediates, reagents, ligands and catalysts, as well as degradation products arising during storage. The Safety Working Party of the European Committee for Medicinal Products for Human Use (CHMP) is currently in a process of preparing a position paper intended to provide guidance on how to define acceptable limits of those impurities in new drug substances and novel excipients which have been found to be genotoxic. According to the existing International Conference on Harmonisation (ICH) Q3A(R) Guideline on Impurities in New Drug Substances, impurity acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability. How can these demands be applied to impurities with genotoxic properties? In current regulatory practice, genotoxic compounds are usually considered to operate by a non-threshold mode of action and, thus, any level of exposure carries — at least theoretically — a risk. This precautious view implies that pharmaceutical measurements should be guided by the so-called ‘ALARA’ principle, i.e. where avoidance is not possible, genotoxic impurities must be kept to a level ‘As Low As Reasonably Achievable’.