API mixtures and CEP Procedure: What should be considered?

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5/6 December 2023

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In some cases, it is necessary to produce APIs not in pure form, but as a mixture. Among others, easier manageability or API stability can be a reason for that. Chlorhexidine digluconate in aqueous solution, a clavulanate potassium auxiliary mixture or simvastatin blended with an antioxidant are typical examples. In April 2016, the QWP of the EMA published a Q and A document entitled "Quality Working Party questions and answers on API mix" (EMA/CHMP/CVMP/QWP/152772/2016) on this issue. It clarifies how these API mixes are to be handled in an ASMF or CEP procedure during an authorisation. We had reported about this in our news "Quality Documentation of API mix in the Marketing Authorisation Procedure".

In December 2016, the EDQM published a "Public Document" called "API-Mix (or mixtures) and CEPs" (PA/PH/CEP (16) 70). This document describes the procedure of applying for a CEP for API mixtures.

An application for a CEP for an API mix must contain at least the following information:

• Information on the mixing process, on qualitative/quantitative composition and on the control strategy
• Supporting data on the choice and amount of the excipient, unless already covered by the pharmacopoeial monograph itself
• Supporting data on the choice and amount of the excipient, if these are allowed according to the monograph but not defined in any more detail ("...a suitable antioxidant may be added ..."). Additional data (stability data e.g.) are required for changes in the content of the antioxidant and in the impurity profile of the mix. The EMA guideline provisions "Excipients in the dossier for application for marketing authorisation of a medicinal product" (EMEA/CHMP/QWP/396951/2006) must be observed.

A CEP for an API mix contains the following information (unless already contained in the pharmacopoeial monograph):

• designation of the excipient(s) used and their amount
• in case of antioxidant, a validated test method for its control (as an annex to the CEP)
• information on the labelling of the mixture, if the monograph contains a paragraph on labelling

As of 1 December 2016, a CEP is generally granted for an API mix if the excipient used is listed in the "Definition" paragraph of the pharmacopoeia. If the mixture does not comply with the monograph regarding qualitative and/or quantitative composition, the application for a CEP will be refused.