3
Control Strategies for Mutagenic Impurities
3.1 Introduction
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.
3.2 Assessment Process
3.2.1 General
The process begins with the expert elicitation of the synthetic route for postulated and/or known impurities [8]. This is followed by structural assessment of agreed “reasonably predicted” impurities along with other route materials and reagents where appropriate. Once the impurities of potential concern are defined, the potential hazard for the identified impurities needs to be established. An alerting material is considered mutagenic until proven otherwise, and therefore where risks are identified, appropriate quantitation may be required or safety testing to confirm/discharge the risk. Once a risk is confirmed, it leads to the establishment of an appropriate control strategy.
The evaluation process is represented schematically in Figure 3.1.
Figure 3.1 Proposed process flow for MI risk assessment for a pharmaceutical product.
The process should be flexible; each API synthesis and drug product formulation has its own distinctive features, and where appropriate, the ordering of the steps described may be changed; however, the overall process should generally remain the same.
There is a clear link between the assessment of risk and the permitted level for a MI. Any such evaluation should therefore take into account the phase of development, the intended dose, and likely clinical trial study duration. Permissible limits are based on the “staged TTC” principle. Limits cited within ICH M7 are reproduced in Table 3.1.
Table 3.1 Acceptable intakes for an individual MI.
| Duration of treatment | ≤1 month | >1–12 months | >1–10 years | >10 years to lifetime |
| Daily intake (μg/day) | 120 | 20 | 10 | 1.5 |
ICH M7 [8] also states that values higher than the TTC may be acceptable under certain conditions including short‐term exposure, for treatment of a life‐threatening condition, when life expectancy is less than five years, or when there is greater exposure from other sources such as food or endogenous metabolism e.g. formaldehyde. This aspect of ICH M7 is examined in greater detail in Chapter 2.
It is recommended that a permitted limit, e.g. staged TTC, is established in advance of instigating the formal evaluation, with the caveat that this limit will change depending on both time (duration of clinical phase) and dose (absolute level of exposure).
3.2.2 Step 1 – Evaluation of Drug Substance and Drug Product Processes for Sources of Potentially Mutagenic Impurities
The responsibility for