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Once analytical and/or safety test data are available, these are used to finalize the risk assessment.

Possible outcomes include:

 A PMI returns a negative Ames test result and thus no longer requires control as an MI but defaults to ICH Q3 levels of control [13, 14].

 A PMI returns a positive Ames test result, but analytical testing demonstrates adequate process control over levels, i.e. level well below appropriate TTC limit.

 Analytical data demonstrates that a PMI/MI is below a current staged TTC but above future permitted dose duration levels (i.e. where studies are of longer duration or higher doses are needed). In such circumstances this may necessitate a modification of the process to reduce or eliminate the impurity in question. If the material is potentially mutagenic rather than a known genotoxin, expediting safety testing, with the possibility of a negative Ames test result, would either remove the need for further process development and analytical control at trace levels, or confirm that additional control is required.

 Analytical and safety data reveal an Ames positive material above a staged TTC level for a planned clinical study.⁴ In such a scenario, it is likely that the material in question would need to be reprocessed, unless a compelling case could be made for the benefit of the treatment over the risk posed (see ICH S9 [20] for example). In most cases, the process would need to be redeveloped to bring levels of the mutagen in question within the TTC for the envisaged marketed product dose and duration. For this reason it is important that an appropriate procedure to link the assessment to the formal release of material for clinical trial use sits alongside the risk assessment. Similarly, it is also important to understand whether an impurity is above the TTC prior to manufacture of drug product given that once formulated, any reprocessing becomes very difficult and secondary processing equipment could become compromised. For this reason, most companies will have an analytical release process for the drug substance that includes having a completed MI risk assessment and that any described controls for any PMIs have been met. Additionally, conducting the MI risk assessment prior to the drug substance manufacturing campaign will help identify PMIs that may be introduced late within the process, and therefore may not efficiently purge. This will allow additional processing to be engineered into the drug substance manufacturing campaign to reduce the likelihood of failed drug substance batches and reprocessing.

This is not meant to be an exhaustive list but serves to illustrate some of the potential outcomes and likely courses of action in each case.

It should be recognized that the evaluation of mutagenic risk is an iterative process and needs to be updated in line with any process‐related changes and/or emerging information relating to impurities, and/or degradants, in drug substance or drug product. Other factors such as a change in the trial duration, trial population, specifically in terms of oncology where the treatment is extended from an initial S9 population to a non‐S9 population and/or dose may also require a review of the risk assessment.