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To understand “actual” purge for the alkyl chloride 8, the Stage 4b product crude GW641597X was checked by ¹H NMR (Figure 3.6), which confirmed that the level of 8 was present at approximately 0.2% m/m (0.12% w/w¹¹) and is in good alignment with the predicted purge factor of 100 for Stages 4a and b.¹² While the observed level in this typical batch of crude GW641597X is already significantly below the required TTC for a monofunctional alkyl chloride of 0.5% w/w, checking the ¹H NMR for GW641597X derived from the Stage 5 product confirmed that alkyl chloride 8 is no longer observed, giving confidence that it is present at levels <0.10% w/w. These observations fully justify an ICH M7 [8] Option 4 control for alkyl chloride 8.

Figure 3.6 ¹H NMR of Stage 4b product crude GW641597X.

The use of ¹H NMR to confirm purging for both ethyl bromoisobutyrate 2 and alkyl chloride 8 helps to verify the purge predictions from the process. They are also useful examples of the expected additional “non‐trace” experimental data (solubility, reactivity, and volatility) recommended for both noncommercial and commercial API routes to support an ICH M7 control Option 4 scientific rationale as advocated by the pharmaceutical consortium within the Barber publication [19].