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The LTL concept, previously known as “staged TTC,” is based on the assumption that cancer risk of known carcinogens increases as a function of cumulative dose. The guideline explains that the LTL approach is applied to mutagenic impurities in which the acceptable cumulative lifetime dose is uniformly distributed over the total number of exposure days during LTL exposure. This would allow higher daily intake of mutagenic impurities than would be the case for lifetime exposure and still maintain comparable risk levels for daily and non‐daily treatment regimens.

Question	Answer
Can an LTL approach be applied to AIs or PDEs using the same ratio as in Table 2.2?	The LTL approach can be applied to compounds with exposure limits based on the TTC or a compound/class specific AI. However, this approach is not applicable to PDEs. Higher levels of exposure for short‐term exposure (30 days or less) may be acceptable on a case‐by‐case basis.

The Q&A here makes the distinction between limits that derive from TTC or compound/class specific AI and PDEs. The limits that derive from mutagenicity/carcinogenicity data fall under the assumption that cancer risk of known carcinogens increases as a function of cumulative dose; however, the toxicity of other end points that are used in order to calculate PDEs does not necessarily increase as a function of cumulative dose; therefore, LTL is not applicable to PDEs. Conversely, the answer to this question also refers to an option of assigning higher limits than a calculated PDE for short‐term dosing (30 days or less), as mentioned in the ICH Q3C and Q3D guidelines. This concept is further elaborated in Harvey et al. (https://doi.org/10.1016/j.yrtph.2016.12.011) where it is proposed to modify the AI of nonmutagenic impurities for clinical studies of less than six months duration, based on the Haber's Law (the same rule upon which the LTL concept is based on).

An interesting example for the use of LTL is the case of monofunctional alkyl chlorides that have a class‐specific AI of 10 times the default TTC (Note 5 in the ICH M7 guideline). For a monofunctional alkyl chloride in a DP that is administered for ≤1 month, the theoretical LTL AI can be calculated to be: 15 μg/day × 80 (the ratio between 120 and 1.5 μg/day) = 1200 μg/day. However, this limit now exceeds the 1 mg/day, and thus it may be necessary to perform a screen of genotoxicity studies to qualify such a level (see Question 1.3 above).