for treatment of indications under the scope of ICH S9 should be considered for management consistent with the concepts outlined in ICH Q3A/B (see Question 4.12).
This reinforces the statement within M7 [1] making the specific point that where ICH M7 is not applicable the concepts outlined in ICH Q3A [5]/Q3B [6] should be applied.
The scope section also addresses the scenario whereby the therapeutic agent in question is itself genotoxic. Importantly and, it is assumed deliberately, the wider term genotoxic is chosen, as opposed to the specific term mutagenic. Hence this encapsulates pharmacologically active agents whose mechanism of action can be described as genotoxic, for example, inhibition of cell proliferation e.g. topoisomerase inhibition. The guideline specifically states that:
Exposure to a mutagenic impurity in these cases would not significantly add to the cancer risk of the drug substance. Therefore, impurities could be controlled at acceptable levels for non‐mutagenic impurities.
However, there exists an equally important question. “Does ICH M7 apply to other non‐cancer, therapeutic disorders (e.g. rare diseases), where there is a significantly reduced life expectancy, i.e. <2 years (i.e. life threatening disorders, with a poor prognosis and with a similar risk benefit as is seen with cancer indications)?” The logical answer would be yes, but in the absence of an “ICH S9‐like” guidance for rare diseases, this will require discussion with authorities on a case‐by‐case basis.
2.2.2.3 Nature of Therapeutic Agent/Excipients
The guideline makes clear that an assessment of the mutagenic potential is not required for the following types of DSs and DPs:
Biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin.
Close scrutiny of this highlights some anomalies; certainly many peptides and oligonucleotides are synthetic/semisynthetic in nature, and it is perhaps difficult to rationalize their exclusion (indeed, there was some commentary about these classes in the penultimate draft version of the guideline).
Established excipients are confirmed as also being out of scope. However, the guidance does indicate that it may be applicable for new synthetic excipients. “The safety risk assessment principles of this guideline can be used, if warranted, for impurities in excipients that are used for the first time in a drug product and are chemically synthesized.”
The position in relation to extractables and leachables is somewhat ambiguous, while stating that the guidance is not applicable to leachables, it states that “Application of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used, if warranted.” In practice the use of the TTC in the assessment of mutagenic impurities has become common.
2.2.3 General Principles
Key within this section, (Section 3 of the guideline), is the reaffirmation of the specific focus of the guideline on mutagenic impurities. Indeed, the guideline goes further in making the specific statement that:
Other types of genotoxicants that are non‐mutagenic typically have thresholded mechanisms and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities.
It also makes clear that in assessing mutagenic potential that this can be achieved through a combination of in silico SAR evaluation, and where required, with a bacterial reverse mutation assay (Ames test [10]). This is certainly useful in clarifying that in silico SAR assessments should focus specifically on mutagenicity. Other SAR models for other toxicological end points such as chromosomal activity and carcinogenicity exist within many of the in silico systems utilized; however, these do not need to be specifically applied in the evaluation of impurities; the primary focus is mutagenicity. It can be further concluded that in terms of in vitro/in vivo assays that no other test other than a reverse mutation assay is required, precluding in particular a mammalian cell assay defined as part of impurity qualification within ICH Q3A [6].
What is less clear is if there is evidence that an impurity is clastogenic/aneugenic, whether or not this can be ignored, or if limits should be based on an evaluation of the available data – i.e. a limit calculated based on an observed no observable effect level (NOEL) using the permitted daily exposure (PDE) calculation shown in ICH Q3C [11]. In practice it seems logical to use such safety data to set acceptable limits even though such impurities are effectively outside of the scope and would be defined as Class 5 (see Table 2.2).
Also reaffirmed within this section is the fact that the guideline remains, as per earlier regional EMA and FDA guidelines, based on the TTC principle [12–16], and a limit of 1.5 μg/day based on a 1 in 100 000 risk following lifetime exposure (70 years). While clear flaws within the TTC have been identified by Snodin [17] and Delaney [18], what is singularly lacking is any scientifically justified alternative. The TTC is without doubt an overtly conservative interpretation of the risk; one that employs multiple worst‐case scenarios, but to date an alternative to it remains elusive. This innate conservatism is even recognized within the guideline itself:
The use of a numerical cancer risk value (1 in 100,000) and its translation into risk‐based doses (TTC) is a highly hypothetical concept that should not be regarded as a realistic indication of the actual risk. Nevertheless, the TTC concept provides an estimate of safe exposures for any mutagenic compound. However, exceeding the TTC is not necessarily associated with an increased cancer risk given the conservative assumptions employed in the derivation of the TTC value. The most likely increase in cancer incidence is actually much less than 1 in 100,000.
Finally, within this section a passing reference is made to metabolites. The guideline simply states that where an impurity is also a metabolite its mutagenic potential should be addressed through evaluation of the metabolite. Again this was a specific area highlighted within the concept paper; however, it is difficult to see how this has been meaningfully addressed and sits as perhaps the one remaining area of uncertainty following publication of ICH M7. The issue is thoroughly examined in detail by Dobo et al. [19].
2.2.4 Considerations for Marketed Products
Section 4 of the guideline is intended to be applied to products that were either marketed prior to, or after, the adoption of this guideline. The two types of products are treated differently. For those marketed after implementation, a further set of requirements (Section 8.5 Lifecycle Management) apply.
The need for further evaluation is defined in terms of changes. For those products marketed before the advent of ICH M7, application of the guideline is limited to the criteria defined within Section 4 of the guideline. This itself is divided into four subsections:
Changes to Drug Substance
Changes to Drug Product
Changes to Clinical Use
Other Considerations
2.2.4.1 Post‐approval Changes to Drug Substance, Chemistry, and Manufacturing Controls
Changes to the DS manufacturing route or process should be evaluated to determine whether they result in any new mutagenic impurities or higher acceptance criteria for existing mutagenic impurities. An important point is that the reevaluation of impurities should focus on those stages impacted by the change, and that other stages and their associated impurities unaffected by the change do not require reevaluation.
Another important