Matter of choice

Certificate of Suitability or European Drug Master File? That is the question facing the active pharmaceutical ingredient manufacturer. Paul G O'Neill examines the options

The Active Pharmaceutical Ingredient (API) manufacturer can present information for the European regulatory agencies in one of two styles.API manufacturers can obtain a Certificate of Suitability of the Monograph of the European Pharmacopoeia, or the pharmacopoeia of an EU Member State, (CEP), also known as a Certificate of Suitability (CoS). Alternatively, they can prepare a European Drug Master File (EDMF), also referred to as the Active Substance Master File (ASMF). The latter is submitted by each of their customers in their Marketing Authorisation Applications (MAA). An EDMF can be prepared for a material not described in the European Pharmacopoeia (Ph. Eur.).

wide recognition

CEPs are recognised by 31 signatory states of the European Pharmacopoeia Convention and European Union; other countries also accept them. CEPs for chemical purity and microbiological quality are the same for APIs and excipients. Where several grades of a material are prepared to different standards or by distinct methods an API may be the subject of more than one CEP.

The CEP is obtained and maintained by the API manufacturer, and this can considerably reduce and simplify the work for an active substance that is widely used. The EDQM issues a CEP after a satisfactory assessment by two experts; this includes the resolution of any issues raised about the API dossier submitted. Generally, the subsequent MAA assessments will not lead to further questions about aspects of the API presented in the CEP dossier.

The API manufacturer supplies MA applicants with a copy of the latest CEP - a single sheet of paper - and an assurance that no significant changes have been made subsequently; certificates of analysis are required for each batch supplied. The MAA is considerably shorter as it refers to the CEP; however, there may be further requirements for a particular use of the API. These would be included in the drug substance parts of the CTD Modules 2 and 3 by the MA applicant.

The CEP provides an assurance that the API would meet the Ph. Eur. monograph specifications and requirements if tested by the pharmacopoeial

methods, and any other tests included in the CEP. The dossier describes in detail the manufacture and control of the API, and particular attention to the control of impurities is required. The Ph. Eur. monograph may not address these if an alternative synthetic route is used.

A CEP must be maintained with regards to any changes in the pharmacopoeial monograph.

maintenance requirement

The EDMF approach can be adopted for new APIs, and APIs either described or not described in the Ph. Eur. or the pharmacopoeia of an EU Member State.

An EDMF is linked to an individual MAA made by the finished drug product manufacturer. A new EDMF submission is required for each MAA. This can lead to new issues being raised by the regulatory agencies and could cause divergence in the information about the API for different drug products.

The API manufacturer is required to maintain the EDMF and keep the MA holder(s) informed of any changes in the chemistry, manufacture or control of the API, thus ensuring identical documentation in each MAA. This involves updating the EDMF and supplying amended pages or sections of the open part (see below) of the EDMF to each MA holder, with a covering letter. Changes to the closed part are notified to the MAA holder in a covering letter, with any amendments to the open part; and, the new information in the closed part is submitted directly to the authorities.

The MA holder is responsible for presenting any variations to the MA to the regulatory agencies. A new MAA should be prepared using the latest version of the EDMF.

confidential document

The EDMF is divided into two parts: the open/MA applicant's part and the closed/restricted part. The open part contains the 'non-confidential' information passed to the MA applicant, including summaries and flow charts pertaining to the closed part, where this is pertinent to the MA applicant. The open part is a confidential document containing sufficient information for the MA applicant to evaluate the suitability of the API for the specified drug product.

The closed part contains information that the EDMF holder regards to be confidential; this includes details of the manufacturing process and controls; control of critical steps and intermediates; the control of materials; process development and validation; impurities and the justification of the specification. Both parts are presented with their own Quality Overall Summaries (QOS).

APIs described in the Ph. Eur., or pharmacopoeia of an EU Member State may be the subject of a CEP or EDMF. The CEP route of licensing is the method preferred by the EMEA, when it is available; however, this is not considered pejorative to an MAA. An API manufacturer can hold an EDMF and CEP for a single substance; however, one MAA should only refer to either the EDMF or CEP.

stability data

CEPs and EDMFs do not include details of the storage and packing of the API, or the stability data used to support the re-test period. This information is required in the MAA. In some cases the pharmacopoeial monograph includes suitable limits for the degradation products, obviating the need for stability studies.

Alternatively, either the API manufacturer or each MA applicant will be responsible for the stability studies and their conclusions. In the latter case, the stability information and re-test period may differ between MAAs.

The Ph. Eur. monographs are being reviewed in the light of current scientific knowledge and the current Notes for Guidance. Where a monograph has yet to be reviewed, the applicant for a CEP, or EDMF subject to a monograph, should make a proposal for a revised specification that satisfies the Ph. Eur. general monograph 2034 'Substances for pharmaceutical use' and the general chapter 'Control of impurities in substances for pharmaceutical use', chapter 5.10 in Ph. Eur. 5. Once the proposal has been accepted it will progress into the revision of the monograph.

review opportunity

The same knowledge base by the API manufacturer is required for both a CEP and an EDMF. The applications by either route contain the same details; however, the EDMF system gives the regulatory authorities the opportunity to review the information with each MAA. Any particular properties of an API required for a specific drug product will be reviewed with the MAA in each case.

Both CEPs and EDMFs require updating every five years. However, since changes made during the period of the licence have been notified to the authorities or MA holders respectively, this should be a declaration that no changes have been made that have not been notified, previously.

The initial question - Certificate of Suitability or European Drug Master File - for a drug substance with an official monograph in the Ph. Eur. or an EU Member State's pharmacopoeia, is essentially one of experience for the API manufacturer.

A manufacturer producing a range of APIs meeting the Ph. Eur. specifications will probably have regulatory affairs staff and experience resulting in preference for the CEP route.

The resultant MAA dossier will be smaller and the drug substance part less complicated. Furthermore, the MA applicant knows that the API has been previously evaluated satisfactorily and that new issues are unlikely.

An API manufacturer may prefer the EDMF route; the specification of the drug substance will need to meet that in the official monograph.

The API manufacturer may be producing a wide range of substances with EDMFs and prefer to use the same system for all its APIs. Where there is no official monograph the EDMF system is employed.

Finally, there is an alternative for use in circumstances where the API manufacturer considers that the MA applicant can see the closed part of the EDMF. Then the entire EDMF information can be submitted to the MA applicant for inclusion in their dossier. In this case it is the responsibility of the MA applicant to assemble the information in the correct format.