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.
1.1.5.2 Application of the Guideline to Existing Products
The EMA guideline [9] limited the application to existing products to “known causes for concern” and to “change management.” However, the lack of a definition of what constituted a “cause for concern” was a real shortfall in the guidance. This shortfall had led to difficulty in interpretation and to inconsistent application of the guidance both by regulatory agencies and industry. This led to the SWP looking to provide a clarification, again via the official Q/A publication, that a “cause of concern” is a material with either preexisting or new known genetic toxicology findings (and in their answer the SWP gives one example class of impurity that would be considered as constituting a cause for concern – mesylates and alkyl mesylates).
If a manufacturing procedure for API remains essentially unchanged a re‐evaluation with respect to the presence of potentially genotoxic impurities is generally not needed. However, new knowledge may indicate a previously unknown cause for concern. One example is the mesylate salt drug substances for which a few years ago, a concern regarding the potential for formation of genotoxic alkyl mesylates was raised. This concern resulted in the “Production Statement” requesting a specific evaluation of the potential for formation of these highly toxic products now included as part of the PhEur monographs for all the mesylates salts.
The European Directorate for the quality of Medicines (EDQM) have further extended the clarity on this point by noting, in a PharmEuropa publication [16], that structurally alerting functionality alone does not constitute a cause for concern, without actual toxicology data.
Structural alert does not automatically imply genotoxicity.
Action is needed only where there is study data demonstrating genotoxicity of the impurity. The existence of structural alerts alone is considered insufficient to trigger follow‐up measures.
In reality for many this interpretation of cause for concern was not entirely accepted and hence uncertainty remained, again establishing a key area for clarification within ICH M7 [1].
EDQM also addressed this issue through its PharmEuropa publication, discussing the applicability of the guideline to pharmaceutical monographs. The statement made provides a very useful, risk‐based approach to managing the application of the guideline to monographed materials. The EDQM article stated that “Substances included in medicinal products authorised in recent years have been thoroughly evaluated for safety and in view of the experience with their use the need for retrospective application of a policy on genotoxic impurities is not considered necessary unless there is specific cause for concern,” again emphasizing the role of prior clinical exposure and pharmacovigilance in their management of the existing products. The detailed Appendix table from this EDQM publication provides a variety of tiers of potential change and the action considered necessary to support each “change.” This vastly helpful table is reproduced in Table 1.3.
Table 1.3 EDQM decision table for use during elaboration or revision of monographs.
| Status | Action |
|---|---|
| Substance included in a medicinal product authorized after | Monograph should be based on marketing |
| issuance of the CHMP guideline | authorization(s) |
| Substance included in a medicinal product authorized before issuance of the CHMP guideline: no PGI expected from synthetic route | No action needed, monograph based on marketing authorization |
| Substance included in a medicinal product authorized before issuance of the CHMP guideline: PGI expected from synthetic route of first authorized product – subsequently authorized products (if any) have no expected PGI or same PGI as the first authorized product at same or lower level and no data showing genotoxicity | No action needed during elaboration of monograph (based on marketing authorization), no revision of existing monographs |
| Substance included in a medicinal product authorized before issuance of the CHMP guideline: PGI expected from synthetic route of an authorized product and data showing genotoxicity of an expected PGI | Monograph should be elaborated or revised based on evaluation by the Competent Authority |
| Substance included in a medicinal product authorized before issuance of the CHMP guideline: PGI expected from synthetic route of first authorized product and subsequently authorized products have a new expected PGI or same PGI as innovator product at a higher level and data showing genotoxicity of an expected PGI | Monograph should be elaborated or revised based on evaluation of new PGI or higher level of previously known PGI by the Competent Authority |
|
Substance included in a medicinal product authorized before issuance of the CHMP guideline: PGI not expected from synthetic route of first authorized product and subsequently authorized product(s) have a new
|