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Within the guideline, this subsection of the overall control strategy section provides further clarification as to what is required to support the specific control options in terms of data. Of particular note is the need to take into consideration the effect of scale, i.e. it is important to address the expected scale dependence or independence of any data especially where supporting data are derived from lab or pilot scale manufacture.

If options 3 and 4 cannot be justified, then a test for the impurity on the specification for a raw material, starting material or intermediate, or as an in‐process control (Option 2) or DS (Option 1) at the acceptable limit should be included.

Another important point made within this specific section relates to impurities introduced in the last synthetic step; it states that an Option 1 control approach would be expected unless otherwise justified. The caveat that other options may be justified is an important caveat and potentially allows other control options to be justified based on a scientific risk assessment as opposed to simplistic dogma.

Earlier regional guidelines had been predicated on the application of “As Low As Reasonably Practicable” (ALARP) even where levels were below the TTC. They also talked about avoidance of the use of mutagenic reagents. ICH M7 addresses both points directly. It is not necessary, if the level of the mutagenic impurity is below acceptable limits, to implement limits based on the ALARP principle. Similarly, it is not necessary to demonstrate that alternate routes of synthesis have been explored.

Where the ALARP principle is applicable is in cases where efforts to reduce the level of a mutagenic impurity to below the acceptable limit have proven unsuccessful. In this instance, that provided levels are ALARP – a higher limit may be justified based on a risk/benefit analysis.