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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, mutagenic impurities in products used 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.