Excipient Regulatory for drug formulations

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Excipients are a vital part of all formulations. There is a need for the excipient manufacturer to provide certain information to the excipient user for inclusion in regulatory applications; IND or equivalent, or NDA or equivalent. However, there is no uniform approach to the filing of such regulatory information for excipients since the regulations and options differ in the different global regions, and according to the compendial status of the excipient.

In the US it is possible to file a Type 4 DMF with the FDA for CMC data and a type 5 DMF for excipient safety data, and then give permission for the FDA to review the relevant file(s) in conjunction with a particular application. The US DMF system can be used for any type of excipient; single entity, simple mixtures (mixed or pre-mixed excipients) or co-processed excipients. However, if the excipient is covered by a USP or NF monograph, the FDA typically does not review the excipient DMF even if permission has been given.

Japan also has an excipient master file system which was only introduced comparatively recently and does not appear to handle mixed or pre-mixed excipients so well.

In Europe no excipient master file system exists. For those excipients that have a monograph in the European Pharmacopoeia (Ph.Eur) it is possible to submit a dossier to the European Department for the Quality of Medicines (EDQM) and obtain a Certificate of Suitability (CEP) which simply confirms that the Ph.Eur monograph is adequate to control the excipient. With the exception of those materials subject to Bovine Spongiform Encephalopathy or Transmissible Spongiform Encephalopathy controls (BSE/TSE) for which a CEP can be obtained for any excipient, the CEP system is only applicable to excipients that have a monograph in the Ph.Eur. The CEP is not available for new excipients, mixed excipients or co-processed excipients that do not have Ph.Eur monographs.

In a regulatory sense, one of the most important aspects of excipients is their safety. Simple physical mixtures are regarded by the regulatory agencies as simple combinations and their safety is the sum of the safety of the two individual components.

Co-processed excipients, in contrast, are new and their safety is not necessarily the sum of its component parts. It is important to be able to demonstrate that with co-processing no new chemistry is created during the co-processing so that bridging to the safety data for the individual components can be scientifically justified.

FinnBrit Consulting can advise clients on the appropriate investigations for new, mixed and co-processed excipients and on the compilation of data for regulatory submissions, both for an excipient master file and for individual product applications.

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