concern. It states that no further qualification for mutagenic potential is required provided that an SAR assessment of mutagenic potential has been performed on any impurity present at levels either above or below those defined in ICH Q3A/Q3B. This includes the initial use of (Q)SAR tools to predict bacterial mutagenicity. Only in cases where the amount of the impurity exceeds 1 mg daily dose for chronic administration is further evaluation recommended. There seems little logic in the 1 mg limit; however, in reality this is unlikely to be regularly encountered in the context of reactive mutagenic impurities.
The other notes cover the following topics; Notes 2–6 each are examined as part of other detailed chapters.
Note 2: Ames test – Good Laboratory Practice (GLP)
Note 3: additional safety tests
Note 4: compound‐specific limits – extrapolation of TD50 values
Note 5: compound‐specific limits – class‐based limits – monofunctional alkyl halides
Note 6: thresholded mechanisms
Note 7: derivation of LTL limits
The guideline provides a helpful table that aligns treatment type/disease area to the duration of treatment and hence the applicable durational limit. It should be noted that this is based on median duration not outliers. Many treatments involve multiple and complex patient groups making it impractical to establish the longest potential time small and often specialist subpopulations receive a medicine.
2.3 Conclusions
At the concept stage of the ICH M7 guideline, a series of critical areas were identified, these included:
1 Use of in silico SAR tools for the assessment of mutagenic potential.
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 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 ADI than the TTC, for a genotoxic impurity?
Does ICH M7 adequately address these points? Yes. Certainly most, if not all, of the ambiguity present in earlier guidelines is addressed. Some areas of ambiguity do remain though. Certainly, management of mutagenic metabolites remains an area of uncertainty and some new areas added within the guideline may also prove challenging to interpret; this includes periodic testing and some of the documentation requirements.
2.4 Commentary on ICH M7 Questions and Answers
At the time of writing this commentary, the ICH M7 Q&A (version 29 June 2020) has been signed off as a Step 2 document and released for public consultation. (https://www.ich.org/page/multidisciplinary‐guidelines).
The ICH M7 guideline was adopted by ICH in June 2014, and the first addendum (R1) was adopted in May 2017. The Q&A document was developed to provide additional clarification to details having led to differing interpretation by stakeholders, such as justification of control strategy in marketing authorization applications, organization and detail of information on mutagenic impurities in marketing authorization applications, and clarification with regard to (Q)SAR systems. Ultimately, the intention of the Q&A document was to promote further harmonization in using this guidance in regulation of mutagenic impurities in pharmaceuticals.
During the process of preparation of the Q&A document, stakeholders submitted more than 100 questions to the reference as ICH M7 expert reference group. The EWG consolidated related questions, and finally 25 Q&As were included in the Step 2 document. The Q&A document is structured according to the sections in the original guideline.
This commentary will present the relevant section within the original guideline and then discuss the respective Q&As on that section. Some queries will be put forth showing that not all controversial issues have been clarified, and we can only hope that the further steps of this Q&A document will be modified to clarify these contentious topics.
2.4.1 Section 1 – Introduction
The four Q&As in Section 1 relate to the Note 1 in the M7 guideline and clarify the meaning of mutagenic and genotoxic potential, as well as the recommendations for evaluation of impurities present below and above 1 mg.
Note 1 in the M7 guideline states as follows (emphasis added on the dubious phrases): “The ICH M7 Guideline recommendations provide a state‐of‐the‐art approach for assessing the potential of impurities to induce point mutations and ensure that such impurities are controlled to safe levels so that below or above the ICH Q3A/B qualification threshold no further qualification for mutagenic potential is required. This includes the initial use of (Q)SAR tools to predict bacterial mutagenicity. In cases where the amount of the impurity exceeds 1 mg daily dose for chronic administration, evaluation of genotoxic potential as recommended in ICH Q3A/B could be considered. In cases where the amount of the impurity is less than 1 mg, no further genotoxicity testing is required regardless of other qualification thresholds.”
2.4.1.1 Question 1.1
| Question | Answer |
|---|---|
| Note 1 provides general guidance on the relationship of ICH M7 with ICH Q3A and Q3B. The use of both “mutagenic potential” and “genotoxic potential” in Note 1 is confusing. Are these terms considered interchangeable? | No. The terms “mutagenic potential” and “genotoxic potential” are not interchangeable. Mutagenic potential refers to the ability of a compound to induce point mutations (i.e. bacterial reverse mutation assay), while genotoxic potential refers to both mutagenic and clastogenic potential. ICH M7 focuses specifically on mutagenicity. |
Throughout the ICH M7 guideline it is emphasized that the focus is on DNA reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore potentially cause cancer. These types of mutagenic substances are usually detected in a bacterial reverse mutation assay (i.e. the Ames test). The guideline further states that other types of genotoxicants that are nonmutagenic (i.e. clastogenic) typically have threshold mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities. This will be discussed later in Sections 3 and 6.
2.4.1.2 Question 1.2
| Question | Answer |
|---|---|
| What are the expectations for evaluation of the mutagenic potential for an impurity where the amount of impurity is less than or equal to 1 mg daily dose? |
In the context of ICH M7, (quantitative) structure activity relationships ((Q)SARs) are considered an appropriate initial evaluation of mutagenic potential of an impurity at a daily dose of ≤1 mg. When a structural alert is identified, a follow‐up in vitro evaluation (e.g. bacterial reverse mutation assay) could be conducted,
|