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The alkyl chloride 8 is a monofunctional alkyl chloride⁸ and as such can be controlled to a class‐specific limit of <15 μg/day; refer Note 5 of ICH M7 [8]. This control limit approximates to 2.5% w/w, but as per ICH M7 section 7.2, the allowable intake of an MI should be capped at 0.5%; therefore, the impurity purge calculations for this material were set against this lower limit. This reagent is charged into the Stage 4 process at 1.15 equivalents, meaning that up to 0.15 equivalents could remain at the end of the reaction assuming a high yielding process, which would need to be reduced to <5000 μg/g of GW641597X, which gives a required purge factor of 30 (150 000/5000 = 30).

The alkyl chloride 8 reacts with the phenolate derived from 4 to provide the ethyl ester 9. An excess of reagent is used (1.15 eq.) to ensure reaction completion and maximize yield of product. It is assumed that 1 equivalent is required to form the high yield of ethyl ester 9, and therefore the residual 0.15 molar excess should be assessed.⁹ Reactivity for alkyl chloride 8 could be anticipated within Stage 4a through side reactions with the ethanol solvent and base to form the corresponding ethyl ether 10, but this was not scored. A moderate reactivity was predicted during Stage 4b where hydrolysis to alcohol 11 or ethanolysis to 10 could be reasonably predicted. Solubility was anticipated during product isolations in Stages 4b and 5. The resulting purge ratio (Table 3.9) was insufficient to justify an ICH M7 Option 4 control strategy as the purge ratio is less than 1000 and, without further data to support an Option 4 control strategy, an alternative ICH M7 control option would be recommended [19].

Table 3.9 Purge predictions for alkyl chloride 8.

Stage	Reactivity	Solubility	Volatility	Total	Rationale
4a	1	1	1	1	1 Equivalent of 8 reacts with the phenolate from 4, and a high yield of the ethyl ester product 9 is formed. This has been reflected in starting equivalents. Anticipated reactivity to form ethyl ether 10 and hydrolysis product 11 have not been included in the prediction.
4b	10	10	1	100	Excess alkyl chloride 8 anticipated to react to form ether 10, hydrolysis product 11, and potential homo coupled products. Anticipated to be soluble within the aqueous ethanol isolation solvents.
5	1	10	1	10	Solubility expected within the crystallization/isolation solvent (denatured ethanol).
Predicted purge factor (Required purge)	1000 (30)Purge ratio = 33 (would inform ICH M7 Option 1, 2, or 3 control without additional data, e.g. experimentally measure PMI purging)