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When finalized the EMA guideline stated that it did not apply to excipients used in pharmaceutical manufacture, this being addressed by a separate EMA publication [13] (discussed further below). Clearly, some excipients are also manufactured by chemical synthesis and may therefore also be exposed to routes of manufacture that contain reactive and “at risk” reagents and intermediates. Global pharmacopoeias such as the EP and United States Pharmacopeia (USP) contain many synthetic excipients; some like polyethylene glycol (PEG) are polymers of epoxides or use epoxides to derivatize other materials (e.g. cyclodextrins). Epoxides are alkylating materials and hence are potentially mutagenic potential impurities in the excipients. Clearly with excipients often being a more significant percentage in weight terms of a medicine than the active substance, the potential risk associated with excipient impurities might also be of concern. Despite these potential risks, it is clear that many of the excipients have a significant history of safe use, many indeed are listed within the Food and Drug Administration (FDA) generally regarded as safe (GRAS) list [14] and hence the guidance ultimately concluded that there are no significant issues associated with well‐precedented excipients given their long‐established and demonstrated safety profile.

But what of the potential risk associated with manufacturing process changes related to excipient manufacture? What of the increasing case of a novel excipient being developed? In the case of a novel excipient, it is very likely that the expectations for the assessment of MIs should mirror that of any new chemical entity (NCE).