2 What are acceptable levels of genotoxic impurities during drug development?
3 What are acceptable levels of genotoxic impurities for marketing?
4 Should those impurities be regulated differently that are likely to have threshold effects?
5 Should levels of genotoxic impurities be regulated using a Threshold of Toxicological Concern (TTC) approach?
6 Structurally related genotoxic impurities are likely to have similar mechanisms of action. Should these be summed in calculating a TTC?
7 What process of qualification testing should be followed for impurities that are metabolites?
8 What additional data are needed to support having no special restrictions, or a higher acceptable daily intake (ADI) than the TTC, for a genotoxic impurity?
The following chapter will look in detail at the ICH M7 guideline, examining each aspect of the guideline, seeking in doing so to give a comprehensive overview of its practical implementation. It will also examine whether or not the guideline has succeeded in addressing the critical areas outlined in the concept paper.
2.2 ICH M7
The format and structure of ICH M7 [1] is understandably very similar to that of the preceding regional guidelines, with specific sections focused on quality and safety aspects, although terminology does differ. Crucially, the fundamental concept upon which the guideline is predicated has not changed; the principle of a TTC, i.e. a virtually safe dose (VSD), remains the underpinning principle upon which the guideline is based. In addition to the overall framework, there are additional sections intended to provide definitive guidance in specific areas, these include:
1 Established Products
2 Documentation
3 Case Studies
These and other sections are now described in detail below.
2.2.1 Introduction
The introduction, Section 1 of the guideline, provides an overview of the relationship between the guideline and the closely related quality guidelines, ICH Q3A [5] and Q3B [6]. It also makes clear that the focus of the guideline is on DNA reactive, mutagenic impurities, emphasizing for the first time the specific focus on such impurities as opposed to the more general group of genotoxic impurities. This is a point returned to in more detail in the general principles section.
2.2.2 Scope
The scope (Section 2) seeks to outline when and where the guideline is applicable, in terms of previously established products (predating the introduction of the guideline), anticancer treatments, and therapy class.
2.2.2.1 Established Products
Previous guidelines, especially the EMA [2] guideline, have struggled to address the thorny question of the potential retrospective application of the guideline to existing products. This had led to variable interpretation, often resulting in requests for application to existing products triggered by apparent trivial changes (in the context of effect on levels of mutagenic impurities within the DS/DP) such as change in dose size or formulation volume. A lot of the uncertainty is related to the inclusion within the original EMA guideline of a catchall phrase of “cause for concern.” Attempts to resolve these uncertainties made via the EMA Q&A process [3] proved only partially successful.
In contrast ICH M7 is clear and concise. Existing products are only in scope where:
1 changes to the DS synthesis result in new impurities or increased acceptance criteria for existing impurities;
2 changes in the formulation, composition, or manufacturing process result in new degradants or increased acceptance criteria for existing degradants;
3 changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.
It is hoped that this addresses much, if not all, of the uncertainty that has existed previously. One remaining area is how this applies to products marketed after the introduction of regional guidelines, particularly the EMA guideline, as this was formally issued and became effective in January 2007. Although not stated directly, many have assumed such products, marketed after the introduction of earlier regional guidelines, to be in scope.
2.2.2.2 Anticancer Treatments
A challenging question has long been, what is the relationship between guidelines pertaining to mutagenic impurities and the ICH S9 [8] Guideline – Non‐Clinical Evaluation for Anti‐Cancer Pharmaceuticals? ICH S9 lays out clear principles relating to the nonclinical (i.e. toxicological) evaluation of impurities present within an anticancer agent. Specific within this is mutagenic impurities, S9 making clear that control to levels defined by EMA, FDA, and now ICH M7 guidelines are not appropriate. ICH M7, within Section 2 (scope), makes it clear that ICH S9 holds primacy.
The only remaining uncertainty relates to what is an acceptable level for a mutagenic impurity? This is not expressly defined. ICH S9 states “Such limits are not appropriate for pharmaceuticals intended to treat patients with advanced cancer, and justifications described above should be considered to set higher limits.” Many have interpreted this to mean that you can default to ICH Q3A [5]/Q3B [6]; however, in reality it is likely that limits will be established on a case‐by‐case basis, with levels typically lower than ICH Q3A/3B but higher than defined in ICH M7 being agreed.
In 2018 ICH S9 was augmented by a Q&A document [9]. Within this specifically in relation to ICH M7 the following is tabulated (Table 2.1):
Table 2.1 Relationship between ICH S9 and ICH M7 [1] [9].
Source: Reproduced from ICH S9 Q&A document.
| 4.12 | Should impurities exceeding the established qualification limits in ICH Q3A/B be assessed in genotoxicity studies? When the API is genotoxic? When the API is nongenotoxic? | API genotoxic? | Impurity exceeds 3A/B qualification threshold? | Proposed action |
| Yes | No | None | ||
| Yes | Yes | None | ||
| No | No | None | ||
| No | Yes | Genotoxicity assessment of impurities should be conducted. | ||
| 4.13 | Is ICH M7, giving guidance for the management of mutagenic impurities, applicable to the patient population covered in the scope of ICH S9? |
The scope of ICH M7 specifically states that the guidance does not apply to “drug substances and drug products intended for advanced cancer indications as defined in the scope of ICH S9.” Therefore,
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