Assessment and Acceptance of Thresholds of Genotoxic Impurities in New Drug Substances

Abstract

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'. From a toxicological point of view, different approaches for assessing acceptable limits are suggested depending on the availability of data. For known genotoxic carcinogens, where a full genotoxicity and carcinogenicity set of data is available, risk assessment can be carried out either by applying quantitative risk assessment based on mathematical modelling or using no effect levels of the carcinogenic response modified by uncertainty factors. For in vivo genotoxins of unknown carcinogenicity, use of a 'no-effect-level-uncertainty-factor approach' is justified in those (probably rare) cases where adequate data for demonstrating a threshold for genotoxic effects are available. Whether such an approach is also applicable to in vivo genotoxins with no evidence of a threshold is currently a controversial issue. For most impurities, where there may only be limited in vitro data available, a pragmatic approach is needed, which recognises that the presence of very low levels of genotoxic impurities might be without appreciable risk. The application of a target level for an acceptable daily intake of 1.5 μg/day for most genotoxic impurities, based on the concept of threshold of toxicological concern (TTC), is currently under discussion for this purpose. From this threshold value, a permitted level in the drug substance can be calculated based on the expected dose to the patient. A higher threshold may be justified taking into consideration duration of treatment, as well as therapeutic indication and exposed populations. On the other hand, unusually potent genotoxic and/or carcinogenic impurities may have to be excluded from the TTC approach and may need individual risk assessment.