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In the absence of specific carcinogenicity data, the ICH M7 guideline outlines AIs based on the TTC. Critically, for both products in clinical development and marketed products, limits are based on duration of exposure, i.e. a staged approach [26]. The recognition that limits should be based on duration of exposure irrespective of phase of development or marketing status is a major step forward as prior to finalization of the guideline the lifetime limit of 1.5 μg/day was routinely applied to marketed products, irrespective of their intended use and likely duration.

The calculation of less‐than‐lifetime (LTL) AIs is ultimately based on the principle of Haber's law, where concentration (C) × time (T) = a constant (k). The limits are described in Table 2.3.

Table 2.4 Acceptable intakes for an individual impurity.

Source: Reproduced from ICH M7.

Duration of treatment	≤1 month	>1–12 months	>1–10 years	>10 years to lifetime
Daily intake (μg/day)	120	20	10	1.5

Within this section of the guideline is a specific section dedicated to clinical development. This proposes that for studies of <14 days in duration that limits only apply to those impurities for which there is actual in vitro safety data (Class 2), and that no specific controls are required over levels of impurities where there is only a structural alert (Class 3). While this is an interesting concept that would appear to provide flexibility, it remains to be seen whether or not this is utilized to a significant extent by applicants. In many cases it is unlikely that material will be restricted to use in clinical studies of <14 days duration, in which case in order to utilize material for longer duration studies, compliance with the limits outlined in Table 2.4 will be required for both Class 2 and Class 3 impurities.

In the context of marketed products, a particular challenge is defining duration. Again this is addressed through a specific note in the guideline, (Note 7), taking the form of a table where, based on specific therapeutic areas, the likely treatment durations are discussed. Useful advice is provided within the guideline itself where it is made clear that the duration of use should be defined based on typical use. This recognizes that, in some cases, a subset of the population of patients may extend treatment beyond the marketed products' anticipated duration of use. It states that in such instances the increase in risk is negligible.

It is important to note also the existence of a “quality cap.” Because limits for MIs are based on dose, this can create scenarios within low dose products where limits for an MI are very high in concentration terms, well beyond a level acceptable from a quality perspective. The guideline addresses this with the following statement:

The acceptable intakes derived from compound‐specific risk assessments (Section 7.2) can be adjusted for shorter duration of use in the same proportions as defined in the following sections (Section 7.3.1 and 7.3.2) or should be limited to not more than 0.5%, whichever is lower.