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Since the advent of guidelines relating to mutagenic impurities (MIs), the chronology of which is defined in Chapter 1, it has been necessary for pharmaceutical companies to consider the potential risk posed by MIs within their products. This has therefore driven the need to develop an effective strategy that both identifies and assesses the risk posed by any MI, both those directly related to the synthesis and those resulting from degradation within the formulated product.

In order to synthesize any small synthetic active pharmaceutical ingredient (API) efficiently, it is necessary to build up the molecular structure through the combination of simple structural motifs. This typically involves the formation of carbon‐carbon, carbon‐nitrogen, and carbon‐oxygen bonds. The current status of synthetic methodology [1] is such that this is impractical to achieve without the use of electrophilic species that fall into the broad class of alkylating agents, and hence are a potentially mutagenic impurity (PMI).

Thus, many intrinsically reactive starting materials, intermediates, and reagents used in the synthesis of APIs are potentially mutagenic, and furthermore may present as residual impurities within the API. Although avoidance is generally considered to be the preferable option from a regulator's perspective, there is tacit acceptance of the fact that this is impractical, and hence rather than avoidance, the issue becomes one of control. Indeed, Elder et al. [1] concluded that the average number of registered steps required to synthesize each API was 6 (5.9) and that the average number of reactive intermediates per synthetic route was 4 (4.1), roughly equating to just under one PMI per stage.

Several organizations have published details of their approach to MI risk assessment [2–4] and these are discussed below; all are based on the same general principal.

 First, identify potential impurities that are associated with the synthesis of the active and also potential degradation products. Potential synthetic impurities require expert elicitation, reviewing the synthetic route for what is known and “reasonably” predicted.

 Second, the identified potential impurities are screened for potential mutagenicity, typically through the application of an appropriate (quantitative) structure activity relationship [(Q)SAR] process.

 For those impurities still considered a concern i.e. structurally alerting, an evaluation of the likelihood of the material in question carrying through to the API is undertaken. This should take into consideration the properties of the compound in question and the downstream process conditions. For those still considered a risk in terms of potential carryover, actual levels may be measured by the development of a suitable analytical method to confirm the impurity is not present at levels that would constitute a concern to the patient (<30% Threshold of Toxicological Concern [TTC]).

 Either prior to, or after, the evaluation of the fate of the impurity (impurities) in question, the actual mutagenicity of the impurity can be confirmed through conduct of an Ames test [5]. This may be followed by further relevant in vivo testing (Chapter 6) to further understand the risk.

 Finally, once the evaluation is complete a suitable control strategy may be established; this may range from control based on existing process controls through to control through specification or even modification of the route/process for manufacture of the API. These control options are described in detail below.

The following chapter describes this evaluation process in detail. A structured approach is defined based on the principals of quality by design (International Council for Harmonisation [ICH] Q8 [6]) and risk assessment (ICH Q9 [7]), providing an effective, robust process that identifies and addresses the risk posed by MIs, including recent amendments made to specifically manage the risk posed by N‐nitrosamines. It examines the scope of such activities and the critical factors to consider when assessing risk. The relationship between analytical and safety testing, as well as the relative timing of such activities is also considered.

The practical application of this process is then demonstrated in several case studies.