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For PMIs that have been assessed as having a reasonable likelihood of being present in API at levels of concern, it may be appropriate to attempt to determine the level in parallel with, or in lieu of, the safety testing described above. The level of concern will be set by the appropriate limit (ADI, PDE, or TTC), which itself is impacted by factors such as maximum clinical dose and the maximum duration of the proposed trial(s). This in turn will have an effect on the choice of analytical technique.

 Choice of technique?The nature of the impurity (analyte), the characteristics of the API or intermediate (matrix), and the level to be determined will influence the detection technique employed. Many organizations have developed specific strategies for refining such selections; this is examined in detail in Chapters 12 and 13.

 Where in the process to test?Testing may be performed on upstream intermediates, API, or drug product as appropriate. It is often desirable to test as close as possible to the point of introduction of a PMI into the process. This approach may permit standard techniques, such as high‐performance liquid chromatography (HPLC) with ultraviolet (UV) detection, to be used, if this is allied to spiking experiments demonstrating the removal in the downstream process. Indeed, such an approach aligns with one of the control concepts defined within ICH M7, Section 8.1 of ICH M7 (specifically control Option 3). While development laboratories may be equipped with more sensitive techniques suitable for analysis at the low ppm level, manufacturing quality control laboratories are unlikely to have such facilities.

  Quantitative assay or limit test.Both types of methods are used in the analysis of MIs. Quantitative tests are useful to furnish data for process development and to support further process modifications to reduce or more consistently control levels of a PMI. Having established a validated process, limit tests are likely to be favored for routine quality control (QC) testing.Limit tests are also more likely to be applied to upstream testing at an intermediate stage where they are used in conjunction with demonstrated evidence of further reduction through processing (control Option 3 – ICH M7) [8].Quantitative assays are usually applied at the final isolated API, as they provide a measure of true levels of the PMI/MI that would be present in the drug product, and the material would not be administered to patients if measured levels are found to be too high. Since the staged TTC concept for acceptable levels of PMIs/MIs is routinely applied during clinical stages of development, a quantitative test is generally desirable since acceptable levels vary as the clinical program develops. However, limit tests may be appropriate at the API or DP stage if this figure is well below the staged TTC control level.