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Another topic addressed within the EMEA Q&A document was the question as to how to relate the ICH identification threshold to unknown impurities and how this related to MI assessments. The answer provided by SWP was to confirm that the identification threshold outlined in ICH Q3a remained appropriate, because the overall quality of drug substance is supported by a well‐defined and reasoned risk assessment of the manufacturing process, which serves to identify significant potential major concerns. This focused risk assessment is employed to assure the quality of the drug substance and should mean that the level of risk associated with any unknown impurity present below the identification threshold has a low probability of being potentially mutagenic. As demonstrated by the discovery of N‐nitrosamines in sartans, this relies very heavily on a detailed knowledge of the chemistry employed; this is explored in detail in Chapter 12.

The EMEA guideline and subsequent Q&A document [10] of course are technically related only to Europe. Up to the end of 2008, the FDA's position remained somewhat unclear although it was clear from podium presentations that the FDA supported the underlying principles, e.g. the TTC of the EMEA guideline. In December 2008 the FDA finally published their draft guideline addressing the topic of genotoxic impurities [17].