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Unlike earlier regional guidelines, ICH M7 clearly defines a start point in terms of the risk assessment, indicating that such an assessment may begin at the starting materials. As described above there is a caveat that relates to the proximity of the starting material to the final API. The guideline states that for starting materials that are introduced late in the synthesis of the DS (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. One may consider – what is meant by final steps? Two steps or perhaps three? This is not defined. Despite this uncertainty, the guideline provided by ICH M7 is much clearer in terms of its starting point than previously and should make the process simpler as a consequence.

Another important aspect of this section of the guideline is the clear recognition that proximity to the final API is a key factor in determining risk (i.e. purging capacity of the downstream process), that early stages will, in general, represent a lower risk of carryover than later stages. This point is returned to later in the guideline within the control options section and is again a key, new, aspect in the guideline.

In the context of synthetic impurities, mutagenic impurities can arise via three sources:

1 Mutagenic reagents used deliberately in the synthesis. Many of the common reagents used in the synthesis of the DS are mutagenic. The use of such reagents, i.e. methyl iodide, epichlorohydrin, etc., is effectively unavoidable; it is simply impractical to construct C⏤C and C⏤N bonds without the use of such reagents [21].

2 Mutagenic intermediates – often the use of a deliberately formed, highly reactive, intermediate is required – examples include tosylates, hydrazides, and epoxides; such an intermediate being deliberately utilized to effect an efficient synthesis.

3 Side reactions. Perhaps the most difficult to assess, those impurities formed as a result of predictable side reactions. Wherever possible this should be based on existing scientific knowledge. This has been drawn into sharp focus by events surrounding N‐nitrosamines. The risk of MIs arising from side reactions is the focus of Chapter 11.