The quality of the active substances being used must be documented in the marketing authorisation dossier for medicinal products. The applicant may submit the information required for this either in Module 3.2.S of the CTD (Common Technical Document) or in a European Drug Master File (EDMF) or Active Substance Master File (ASMF). It would also be possible to submit a CEP for the active substance (Certificate of Suitability to the Monographs of the European Pharmacopoeia). An applicant (usually the active substance manufacturer or wholesale dealer) can apply for this certificate from the EDQM.
EDMF stands for European Drug Master File and ASMF for Active Substance Master File. They describe similar procedures, but the older term EDMF is currently being phased out in favour of the newer term ASMF.
Wikipedia defines EDMF/ASMF as “… a document prepared by a pharmaceutical manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market, … containing complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. It is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF)”.
The EDMF/ASMF procedure is described in Guideline CHMP/QWP/227/02 Rev 3, which went into effect on 01 October 2012. The general requirements for active substances in the quality section of the dossier are presented in Guideline CHMP/QWP/297/97 Rev 1.
The manufacturer of the active substance may create an EDMF/ASMF if a chemical or herbal active substance is used:
The EDMF/ASMF is subdivided into an
The Applicant‘s Part is available to the pharmaceutical entity that submits the application. It contains general information on the active substance. The Restricted Part is only accessible to authorities and includes comparatively more specific and confidential information. The Applicant‘s Part and the Restricted Part of the EDMF/ASMF together then correspond to the CTD Module 3.2.S.
When requesting marketing authorisation, the applicant submits “only” the Applicant‘s Part and a Letter of Access, in which the holder of the EDMF/ASMF (in other words the manufacturer of the active substance) confirms that he works with the applicant. There is some risk involved for the applicant using an EDMF/ASMF. If the active substance manufacturer does not cooperate with the competent authorities in responding to a deficiency letter, the application procedure could fail as a result.
CEP stands for Certificate of Suitability to the Monographs of the European Pharmacopoeia of the European Directorate for the Quality of Medicines and Healthcare (EDQM). An applicant (usually the active substance manufacturer or wholesale dealer) can request this certificate from the EDQM. It serves as proof that a(n) (active) substance manufactured in accordance with the production process submitted by the manufacturer can be properly tested and inspected for quality in monographic tests to determine the content and impurities contained in the substance.
Unlike the EDMF/ASMF, a CEP can be requested not only for any type of active substance such as:
but also for excipients.
When the EDQM reviews documentation it simultaneously performs the same legal and substantive investigations as those made during the marketing authorisation procedure for an active substance or excipient. For this reason, when the applicant refers to a granted, valid CEP during the marketing authorisation procedure for a medicinal product, the EU/EEA marketing authorisation authorities and other competent authorities will generally accept this as proper proof of the active substance quality in marketing authorisation proceedings or notifications of changes (variations). Therefore, the CEP offers certain advantages to those involved (active substance manufacturers, pharmaceutical companies, marketing authorisation authorities) with regard to the flexibility and workflow of marketing authorisation procedures. The CEP certification procedure is described in greater detail in the Council of Europe Resolution AP-CSP (07) 1 and the Directives 2001/83/EC, 2001/82/EC and 2003/63/EC.
As described above, both EDMF/ASMF and/or CEP are standardised, structured marketing authorisation documents that are usually prepared and submitted by the manufacturer of the active substances (or excipients, if applicable, in the case of CEPs). The degree of acceptance of the documents is based solely on a review of these documents and does not include any additional onsite inspection of the manufacturing companies.
Thus, an EDMF/ASMF or a granted CEP does not necessarily represent a “quality certificate” nor does it allow any conclusions on the status of GMP-compliant manufacturing.
Revocation and suspension are very important actions in a CEP. They are among the possible actions that can be taken against GMP-noncompliant manufacturers following official inspections. These actions pave the way for a variety of steps that may become necessary for the supervisory authorities and the marketing authorisation holder within the regulatory framework of the European Union. The quality and safety of the medicinal product must be assured and maintained through these actions.
This article is an excerpt of Chapter 21 Active Pharmaceutical Ingredients of our GMP MANUAL.
Dr. Stefan Kettelhoit
blue inspection body GmbH, Münster, Germany