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EMA Releases Updated Final Guideline on Active Substance Master Files

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A new final guideline published on 13 July 2012 by the European medicines Agency (EMA) updated the Active Substance Master File (ASMF) Procedure —its first upgrade since its formation in 2006.

The main objective of the Active Substance Master File (ASMF) procedure, formerly known as the European Drug Master File (EDMF) procedure, is to allow valuable confidential intellectual property or ‘know-how’ of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or Marketing Authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. National Competent Authorities/EMA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.

The overall content of the ASMF should contain detailed scientific information as indicated under the various headings of the relevant Notice to Applicants for Marketing Authorisations for Medicinal Products in the Member States of the European Union (NtA). ASMFs linked to human medicinal products should be presented in the format of the Common Technical Document (CTD). ASMFs linked to veterinary medicinal products should normally be presented in accordance with Parts 1.C and 2 of Directive 2001/82/EC as amended, all parts of such ASMFs (AP, RP, and their summaries) may be presented in the CTD format in the following circumstances.

  1. Where the active substance has been included in a medicinal product for human use authorised in accordance with the requirements of Annex I to Directive 2001/83/EC as amended;
  2. In the case of any application for an animal species or for indications representing smaller market sectors;
  3. Where the competent authority has publicly announced this possibility.

Every five years, Marketing Authorization holders will be required to declare the ASMF is up-to-date and conforms to current guidelines and regulations, and no changes have been made without approval from the National Competent Authorities or EMA.

Under the guideline, sponsors must submit to EMA “detailed, scientific information as indicated under the various headings” of the relevant parties. ASMF content should be presented using the Common Technical Document (CTD) format if they are for human medicines, but applicants of veterinary medicines can use either the CTD format or adhere to an alternate format contained within Annex 1 of the guideline.

The scientific information in the ASMF should be physically divided into two separate parts, namely the Applicant’s Part (AP) and the Restricted Part (RP). The AP contains the information that the ASMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the ASMF holder regards as confidential, see Annex 1. It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the ASMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specification for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product.

The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture of the active substance. The National Competent Authorities/EMA may not accept that particular information has not been disclosed to the Applicant/MA holder. In such cases, the National Competent Authorities/EMA may ask for an amendment to the AP.

In addition to the AP and RP, the ASMF should contain a table of contents, and separate summaries for both the AP and the RP. In cases where the ASMF is provided in the CTD format, both summaries should be presented as a Quality Overall Summary (QOS). In cases where the veterinary NtA format is used, they should be detailed and critical summaries. Each version of the AP and RP should have unique and independent version control numbers.