Читать книгу Mutagenic Impurities - Группа авторов - Страница 18

A Pharmaceutical Research and Manufacturers of America (PhRMA) expert group, led by Lutz Mueller, sought to establish acceptable limits for MIs linked to duration of exposure. This was referred to as a “staged TTC” approach and was based on the established principle that certain types of exposure risk can be defined in terms of cumulative dose [8]. Inherent to this principle is that the risk associated with an overall cumulative dose of a mutagen will be equivalent in terms of risk, irrespective of dose rate and duration. Thus, short‐term exposure limits could be based on linear extrapolation from accepted long‐term exposure limits.

The group published the outcome of their deliberations in January 2006. The key aspect of this paper, the proposed “staged TTC” limits, is displayed in tabular form in Table 1.1.

Table 1.1 Proposed allowable daily intakes (μg/day) for potential genotoxic impurity (PGIs) during clinical development, a staged TTC approach depending on duration of exposure.

	Duration of Exposure
	≤1 month	>1–3 month	>3–6 month	>6–12 month	>12 month
Allowable daily intake (μg/day) for different duration of exposure (as normally used in clinical development)	120a or 0.5%b whichever is lower	40a or 0.5%b whichever is lower	20a or 0.5%b whichever is lower	10a or 0.5%b whichever is lower	1.5c b

^a Probability of not exceeding a 10⁻⁶ risk is 93%.

^b Other limits (higher or lower) may be appropriate, and the approaches used to identify, qualify, and control ordinary impurities during development should be applied.

^c Probability of not exceeding a 10⁻⁵ risk is 93%, which considers a 70‐year exposure.

It is important to note that included within this proposal is the application of a 1 in 1 000 000 risk factor when calculating limits for durations <12 months, as opposed to the 1 in 100 000 applied in relation to the standard TTC based on lifetime exposure. This precautionary approach was taken in recognition of the fact that during the clinical phase studies are often performed on healthy human volunteers and also that, even for patients at this stage, the therapeutic benefit has often yet to be established.

As well as the staged TTC principle, the paper also proposed a classification system for impurities, defining five classes:

 Class 1: genotoxic carcinogens

 Class 2: genotoxic – carcinogenicity unknown

 Class 3: alerting structure – unrelated to parent

 Class 4: alert related to parent, with associated known toxicological potential

 Class 5: no alerts

This classification and effectively the limits defined within this paper have become the basis of the impurity management system used in ICH M7.

Based on this classification system, the paper defined a strategy for impurity assessment based on the use of structure activity relationships (SARs). SAR evaluation is used as the first stage to give a preliminary evaluation of risk. Thereafter, this can be augmented by the use of safety testing, specifically the Ames test, to determine whether or not the impurity is actually genotoxic. This is particularly true where the impurity is classified as Class 3. Alternatively, one can simply assume the compound in question to be genotoxic on the basis of the prediction and control in line with the appropriate TTC level.

Such a strategy, often augmented by a science‐based impurity purge assessment (incorporating factors such as reactivity of the impurity and downstream process conditions), has become the foundation of most, if not all, control strategies used within the industry (see Chapter 9 for a detailed evaluation of such strategies).