Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses

Abstract

The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript.

Characterizing the free volume of ultrahigh molecular weight polyethylene to predict diffusion coefficients in orthopedic liners

“…For a 5‐mm‐thick slab geometry where leaching occurs on only one side, this corresponds to 57 g in total mass. Notably, the ICH M7 recommended threshold of toxicological concern (TTC) value is 10 µg/person/day for individual transformation products . I.C.…”

“…Notably, the ICH M7 recommended threshold of toxicological concern (TTC) value is 10 mg/person/day for individual transformation products. 51 I.C. Munro et al define the TTC value as "a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data."…”

In silico toxicology: From structure–activity relationships towards deep learning and adverse outcome pathways

“…If both systems are predicting the compound as negative, no in vitro Ames test has to be conducted. For an ambiguous outcome—for example, contradicting predictions, an out of domain or inconclusive prediction—the expert review plays a crucial role for further decisions . The expert review can, by adding additional evidence, clarify the prediction and make a final decision.…”

“…The expert review can, by adding additional evidence, clarify the prediction and make a final decision. In addition, it can also be used to refute a positive prediction, but substantial evidence is needed . This application of in silico prediction also highlights the need for certain negative predictions and the applicability domain.…”

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

“…The rather conservative recommendation in ICH M7 for two complementary systems, one expert rule‐based and one statistical‐based, accommodates the variability worldwide in expertise among regulatory agencies and among companies, and the reluctance therefore to rely on “expert knowledge,” although this is acknowledged in ICH M7 as an important component, necessary in evaluating the outcome of the computer‐based assessments, especially when the types of molecules encountered are not well represented in the data used to design the computer models. More recently, expanded advice on interpretation of in silico analyses and examples of application of “expert knowledge” has been published [Amberg et al, ], in addition to further exploration of the confidence in negative predictions from in silico expert systems, which is very high [Williams et al, ].…”