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Changes to the DS manufacturing route or process should be evaluated to determine whether they result in any new mutagenic impurities or higher acceptance criteria for existing mutagenic impurities. An important point is that the reevaluation of impurities should focus on those stages impacted by the change, and that other stages and their associated impurities unaffected by the change do not require reevaluation.

Another important point is that changes should be assessed from the registered starting material (RSM) onward. However, this should be put into the context of where in the synthesis the RSM is introduced (see ICH Q11 [20]). If the RSM is introduced four or five stages before the active pharmaceutical ingredient (API), then there is likely to be effective purging of any mutagenic impurities in the downstream chemistry, whereas for an RSM introduced in the penultimate stage, such an assessment is very important. This is reflected in Section 5.1. (Relationship between the risk assessment and testing of starting materials):

For starting materials that are introduced late in the synthesis of the drug substance (and where the synthetic route of the starting material is known) the final steps of the starting material synthesis should be evaluated for potential mutagenic impurities.

This may suggest that in the context of an existing product, where a starting material is introduced late in the synthesis and changes are subsequently made to the route/process of the material (i.e. preregistered stages), that in such instances a reevaluation would be necessary.