7/8 February 2023
As part of the authorisation procedure for a medicinal product, applicants have to provide detailed information about the quality of the API. Generally, the applicant doesn't manufacture the API himself but receives it from an API manufacturer and has to submit the quality-related information regarding the API directly to the authority (see Directive 2001/83/EC, Annex I) in a separate document: the "Active Substance Master File" (ASMF, former name: "European Drug Master file"). An ASMF is always composed of two parts: the "open" part (applicant's part) which doesn't contain any confidential information and is known by the applicant - and the "closed" part which is much more detailed and represents the manufacturer's know-how with regard to the manufacture of the API and its analytics. For the competent authority, this closed part of the ASMF represents the basis for the assessment of the API's quality and safety in the context of the proceeding of the marketing authorisation application.
Although this procedure has been established for several years now, there are time and again uncertainties regarding certain points. In the Question and Answer document entitled "Pre-authorisation Procedural Advice for Users of the Centralised Procedure" (EMA/339324/2007) which has been recently revised and published in December 2013, the EMA covers the topic extensively under Question No 24 "How shall I submit an Active Substance Master File". The answer to this question is treated in 7 pages which were also revised in December 2013 and are thus up-to-date. There are in total 9 sub-chapters dealing with the following issues:
The issues dealt with within the sub-chapters indicate how urgent the update of the Question and Answer document was. Indeed, there are now two numbering systems for ASMFs: EU's ASMF reference number and EMEA's ASMF reference number. Whereas EU's ASMF number is used for centralised, decentrialised as well as national authorisation procedures, an EMEA's reference number has to be applied for in case of new applications or variation applications which are submitted after the 1st September 2013 (possibly in addition to an already existing EU ASMF number). This is a requirement from the "Guideline on Active Substance Master File Procedure" dated 1st October 2012. The Question and Answer document should now help avoiding confusion with regard to applications, the two numbering systems and life-cycle management.
Further clarifications concern the framework of the ASMF procedure. The API has to be "well defined" in an ASMF. Biological APIs used in vaccines or cell therapeutic medicines or APIs obtained from blood are not "well defined" chemical entities in this sense and thus the ASMF procedure is not applicable to them.