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GW641597X was developed as a PPAR‐alpha agonist for the treatment of dyslipidemia. Described below is an overview of the MI risk assessment, and while this product predated ICH M7 [8], a useful retrospective assessment in alignment with ICH M7 was performed using current best practice to inform the reader of the specific steps required. The development of the process to GW641597X and a discussion of the MI control strategy has been published [21].

Applying mutagenic, or potentially mutagenic, impurity (PMI) controls in accordance with ICH M7 [8] for chronic dosing allows up to 1.5 μg/day for an individual MI specified in the drug substance or up to 5 μg/day for the total quantity of three or more PMIs that may be specified. A maximum dose of 600 μg/day was predicted for GW641597X, and therefore the “commercial” TTC‐based acceptable limit for GW641597X was determined as 2500 μg/g for individual MIs, and for three or more specified MIs, 8333 μg/g would be the maximum total amount.

The first stage for the assessment was to identify potential impurities, this was performed by assessing identified and reasonably predicted drug substance impurities (Figure 3.3), together with assessment of the synthetic process (Figure 3.4) for starting materials, intermediates, and reasonably predicted reaction by‐products from the synthetic process.

Figure 3.3 Identified (I) and reasonably predicted (RP) impurities within GW641597X drug substance.

Figure 3.4 Synthetic process to GW641597X.

The identified drug substance impurities and reasonably predicted impurities (derived from route reagents, intermediates, and potential by‐products/degradants) were all assessed for potential mutagenicity by (Q)SAR screening, which amounted to > 20 separate structures. In accordance with ICH M7, two methodologies were employed, one expert rule‐based software (Derek Nexus v6.0) [22] and one statistics‐based software (Leadscope v2.2.1) [23], and all output results were subject to expert assessment [2].

Out of all the materials assessed, only three structures of potential mutagenic or carcinogenic concern were identified, which were the reagents ethyl bromoisobutyrate 2, hydroxylamine hydrochloride, and the alkyl chloride 8 (Table 3.6).⁵

Table 3.6 Summary of mutagenicity assessment for synthetic process to GW641597X.

Compound	Derek	Leadscope	Ames assay	ICH M7 impurity classification
Ethyl bromoisobutyrate 2	Positive	Positive	Positive	2
Hydroxylamine hydrochloride	Negative	Negative	Negative	5a
Chloromethyloxadiazole 8	Positive	Positive	Not tested	3b

a Hydroxylamine is not mutagenic but is carcinogenic in rats and has a permitted daily exposure (PDE) of 23 μg/day. Hydroxylamine is non‐SAR alerting using the SAR tools for this case study. A published review of available data considers carcinogenesis to be via a non‐thresholded mechanism and as such hydroxylamine can therefore be considered ICH M7 Class 5, i.e. Ref. [19].

^b Alkyl chloride 8 is a monofunctional alkyl chloride and should be controlled to a class‐specific limit <15 μg/day.

The remaining compounds were Ames negative, non‐SAR alerting, or the equivocal predictions could be refuted following expert review.

The next stage was to assess the probability for these impurities to be present within the drug substance at a level of concern. This was achieved using a paper‐based purge calculation using the principles established by Teasdale et al. [14, 15], and detailed knowledge of the processing as well as of the material attributes greatly facilitates this process. In each case, once the predicted purge was calculated, this purge was compared to the required purge (based on dose/duration factors) and a purge ratio calculated the magnitude that helps inform likely control strategy for that material [19]. For clarity, each of the potential mutagenic materials is discussed below together with a rationale for its proposed control.