is to assign individual limits for each of the impurities in addition to assigning a limit for “Total Mutagenic Impurities.”
2.4.7.5.1 Section 8 – Control
The Q&As in this section relate to the four options described in the Control section of the guideline and provide much needed clarifications to scenarios that have been contentious ever since the guideline's publication. There is not much need for commentary to this section as the questions and respective answers are very apprehensible.
The six Q&As focus on:
Option 4 control strategy.When is it appropriate?Elements recommended when using predictive purge calculations to claim no analytical testing as per Option 4.
Considerations for control of impurities introduced or formed in the last synthetic step.
When is periodic verification testing allowed?
Do level of impurities consistently found <30% TTC in multiple batches justify no testing?
Batch scales recommended to provide experimental data to support control Options 3 and 4.
| # | Question | Answer |
|---|---|---|
| 1 | When is it appropriate to use an Option 4 control strategy? | Use of Option 4 is appropriate when a mutagenic impurity is demonstrated to have a negligible risk of being present in the final DS (e.g. 1% TTC). The risk assessment can be based on scientific principles alone (e.g. impurity reactivity or solubility), calculated purge factors (i.e. predicted), measured purge factors (i.e. spike and purge data), or a combination of these approaches, considering the process‐relevant conditions. The acceptability of Option 4 will be assessed by authorities on a case‐by‐case basis, including additional requests for supporting information. See also Question 8.3 in this document for impurities introduced in the last step. |
| 2 | When predictive purge calculations are used for Option 4 control, what elements should be considered? | When using predictive purge calculations for Option 4 control, the following elements should be considered:Predictive purge calculations should be based on the DS manufacturing process as described in the application and should consider reactivity, solubility, volatility, and other factors of the impurity in each step. The predictive purge calculation should use conservative values and methodology, since predictive purge often does not rely on experimental purge factors. An example predictive purge calculation approach based on scientific principles has been described (Barber et al. 2017). Predictive purge calculations can be paper based or software based.The amount of information (i.e. impurity reactivity or solubility data, spike and purge data under the process relevant conditions) to justify a predictive purge calculation approach should be guided by knowledge of the manufacturing process, risk to the final DS, and the stage of drug development.A predictive purge calculation justification submitted in an application could range from a high‐level summary to detailed information on the calculation (e.g. scientific justification for individual purge factors) and other supporting data. More detailed information on the calculation is expected when the predicted level of the impurity in the DS approaches the TTC. Even if not submitted, information on how each individual purge factor is derived should be available upon request. |
| 3 | What is meant by “for impurities introduced in the last synthetic step, an Option 1 approach would be expected unless otherwise justified” in Section 8.2 Considerations for Control Approaches? | For potential mutagenic impurities introduced or generated in the last synthetic step, given the proximity to the final product, Option 1 is the preferred control strategy. However, Options 2 and 3 control strategies may be possible, for example, when the crude DS is an isolated material that is purified subsequently (e.g. by recrystallization). An Option 4 control strategy for an impurity introduced or generated in the last synthetic step is discouraged and should be reserved for highly reactive species (e.g. thionyl chloride) or materials with low boiling point (e.g. methyl chloride). In case of highly effective purification operations (e.g. chromatography), an Option 4 control approach may also be acceptable for less reactive materials. However, in such cases, the negligible risk of an impurity to be carried to the final product (e.g. 1% TTC) should be justified with experimental data (e.g. spike and purge data under the process‐relevant conditions). A justification solely based on calculations (predictions) is not considered sufficient. |
| 4 | Is periodic verification testing (i.e. skip testing) allowed for Options 2 and 3 control? | No. Periodic verification testing is not appropriate for Options 2 and 3 control. Periodic verification testing is only discussed as a control strategy for Option 1 control in Section 8.1 of ICH M7. The Option 1 periodic verification testing strategy references ICH Q6A. The Option 1 periodic verification testing concept (per ICH Q6A) should generally be implemented post‐approval and applies to testing in the final DS. |
| 5 | If test data (i.e. in‐process, intermediate, or DS impurity test data) for a potential mutagenic impurity is consistently <30% TTC in multiple batches, is that sufficient to justify no testing of that impurity in the control strategy? | No. Batch data alone demonstrating that a potential mutagenic impurity is consistently <30% TTC is not sufficient to justify no testing of that impurity. Options 1, 2, and 3 should test either at release or upstream in the process. However, if there is negligible risk of the impurity to be present in the DS, an Option 4 control strategy may be considered with appropriate justification. See Questions 8.1 and 8.2 for recommendations on supporting an Option 4 control strategy. |
| 6 | What scale considerations are relevant when generating analytical experimental data in support of control Options 3 and 4. | Lab‐scale experiments are typically sufficient when generating measured purge factors or when defining in‐process control points. These studies should employ the final process as described in the application and should consider the potential impact of scale and equipment‐related differences between the laboratory and production environment (e.g. the effects of mixing on impurity levels in heterogeneous systems and the quality of liquid–liquid phase separations). In the case of observed scale dependencies, confirmatory testing on batches manufactured at pilot or commercial scale may be advisable. There is no expectation to perform spiking studies at pilot or commercial scale. |
2.4.8 Section 9 – Documentation
The two Q&As in this section clarify if (Q)SAR predictions made earlier in development are still valid for market authorization and provide recommendations for clarity of ICH M7 risk assessment and control strategy with respect to the location in the CTD and details to be provided in Modules 2, 3, and 4. This section also does not require much commentary as it is straightforward.
| # | Question | Answer |
|---|---|---|
| 1 | If (Q)SAR predictions are made during drug development, should they be repeated for the marketing application? |
(Q)SAR models developed for use under ICH M7 are generally updated regularly with new bacterial reverse mutagenicity assay data and more refined structural alerts. A sponsor is not expected to update their (Q)SAR assessment during drug development unless there is a safety concern such as when newly available bacterial reverse mutagenicity assay data and/or mechanistic knowledge suggest that the prediction is incorrect (see below). It is recommended that the
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