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Once impurities with a potential mutagenic safety concern have been identified by the SAR evaluation process, the next step is to consider the likelihood of them being present in the isolated API, often referred to as impurity fate mapping.

The impurities under consideration are often highly reactive, and hence their removal during downstream processing is facilitated by this intrinsic reactivity. This removal can also occur as a result of a variety of factors including solubility, through extractive processes, or within the isolation solvent, i.e. mother liquors during isolation of the desired product, volatility, etc. For example, acidic and/or basic workup conditions frequently encountered in manufacturing processes may lead to decomposition and/or removal of the material of concern. Similarly, other reagents used in downstream processing may react with the material rendering it nonmutagenic, and thus the resulting impurity can be controlled to levels aligned with ICH Q3A or the appropriate clinical phase. It is important as part of such an assessment to consider the fate and effects with respect to what the downstream product could be “reasonably predicted” to be. While rare, it is possible that a PMI could be converted to another PMI through processing, e.g. oxiranes ring opening with HCl to the chloro‐alcohol.

It is important that some consideration should be given to what the impurity might be converted to. Factors that contribute to removal of such impurities are reviewed below in the following section. A more detailed examination is provided in Chapter 9.

Initially, such impurity fate assessments were largely based on the theoretical knowledge and experience of the evaluating chemist. Unfortunately, however compelling the arguments developed, they were viewed as nonquantitative and subjective from a regulatory perspective. Thus, in many cases there is a need to provide further analytical data to substantiate the impurity fate assessment. Hence, a quality by testing (QbT) approach was adopted rather than a quality by design (QbD) approach.

It was against this context that Teasdale et al. [14, 15] looked to define a potentially standardized approach to such assessments. The aim was to assess fate semiquantitatively based on factors linked to the impurity's physicochemical properties (and taking into account those of the API and intermediates) and the process conditions employed in the route of manufacture to the API. Pierson et al. [4] had earlier suggested that an assumption could be made of a 10‐fold reduction per synthetic stage. In many cases this would suffice and indeed may even be a cautious estimate of the risk. However, in certain circumstances, for example an unreactive mutagenic reagent or intermediate used in a “telescoped” process (no isolations between stages), this may be too simplistic and may even overestimate the potential purge. For this reason, a more quantitative approach, based on actual process conditions and the physicochemical properties of the MI in question, was sought and is outlined below.

A number of contributory factors have been defined that should be taken into account for such an assessment; these are described in detail in Chapter 9.