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Through the Q&A document [10], it was clarified that durational adjustments to the TTC limit are acceptable for investigational studies. This approach of extrapolating the lifetime‐based TTC limit to shorter duration exposures had originally been proposed by a PhRMA [8] cross‐industry workgroup led by Lutz Mueller (Roche) who as described earlier proposed a set of “staged” TTC limits dependent upon study duration. The SWP accepted the principle of such duration‐dependent modifications to the TTC but published a set of durational limits that are slightly different from the original PhRMA proposal. These are (see also Table 1.2):

Table 1.2 Acceptable limits for MIs based on duration of exposure.

	Duration of exposure
	Single dose	≤1 months	≤3 months	≤6 months	≤12 months
Allowable daily intake (μg)	120	60	20	10	5

The acceptable limits for daily intake of genotoxic impurities are 5, 10, 20, and 60 μg/day for a duration of exposure of 6‐12 months, 3‐6 months, 1‐3 months, and less than 1 month, respectively. For a single dose an intake up to 120 μg is acceptable.

Compared to the proposal of a staged TTC in the Mueller et al (Reg Tox & Pharm, 2006, 44, 198–211) paper these values incorporate a dose rate correction factor of 2 to account for deviations from the linear extrapolation model.

The scientific basis/driver behind the proposal by the SWP to apply a correction factor to the linear model was unclear given the conservative nature of the linear extrapolation model itself; as is the rationale that requires restricting the 120 μg/day to a single dose. This was a topic revisited in the development of ICH M7 [1].

In the published Q/As, the SWP also stated that these modified limits while applicable in the investigational phase only could not be automatically presumed to apply to commercial products that are used for short durations. The applicant for such an acute‐use therapy could, however, propose amended control limits in their MAA and the approval of product‐specific limits for the commercial product will be established during the review process, considering the full product‐specific risk benefit of the product. Like the proposed adjusted durational limits, this became a key topic during development of ICH M7.