Читать книгу Mutagenic Impurities - Группа авторов - Страница 109

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).