EUROPEAN DRUG MASTER FILE

EU DMF (EDMF or ASMF)• Established in 1989-1991• Revised in 2005 and became ASMF (Active Substance Master File)

after implementation of CTD in EU • Applicable only to active substances • Has been divided into 2 parts • Applicant Part (Open)• ASM Restricted Part (Closed / Confidential)

European Master File

• The DMF contains information which includes valuable know-how which should be kept confidential and submitted to the authorities only. Therefore, it should be divided into 2 parts – an applicant’s part and an ASM Restricted Part. The applicant’s part of a DMF is provided by the ASM (Active Substance Manufacturer) to the applicant directly and becomes part of the application for marketing authorization. Both the applicant’s part and the ASM Restricted Part of the DMF are submitted to the authorities. • Applicant’s part of a DMF – opening part

• The applicant must be supplied by the ASM with sufficient information to be able to take responsibility for an evaluation of the suitability of the active substance specification to control the quality of the substance. This normally includes a brief outline of the manufacturing method, information on potential impurities originating from the manufacturing method, from the isolation procedure (natural products) or from degradation and, where applicable, information on the toxicity of specific impurities.• ASM Restricted Part of DMF – closing part• Detailed information on the individual steps of the manufacturing

method such as reaction conditions, temperature, validation and evaluation data for certain critical steps of the manufacturing method, etc. and on quality control during manufacture may contain valuable know-how. Such information may therefore be supplied to the authorities only.

Use of DMFs• Supporting documents for the registration / approval of drug products• In the Chemistry, Manufacturing and Controls (CMC) sections of the

drug submission, the DMF documents the drugs identity, purity, strength and quality. • Protect Proprietary and Confidential Information

Procedure – Part(1)• ASMF can only be submitted in relation with a MAA• is developed to keep intellectual property of ASM confidential.• Can also be used when no confidentiality issue between MAH and

ASM• MAA: either CEP or ASMFshould be submitted

CEP: Certificate of suitability to the monog of Er Ph• applicable to p'ceutical substances only• through CEP mfgr is able to provide proof that the quality of

substance is suitably controlled by the relevant monograph.• to apply for CEP mfgr will submit a detailed dossier which may contain

confidential data.• CEP files that by applying the relevant monograph of Er Ph it is

possible to check whether or not the quality of substance is suitable for use• this procedure is intended to be used for substances for which a

monograph has been adopted by Er Ph commission.

Steps:• Submission of dossier • Acknowledgement of receipt • Designation of assessors • Assessment • Notification of Decision• Follow up to the certification of suitability

ASMF/EDMF• Applicable to pharmaceutical substances• content: AP, RP• Ap contains the information that the ASMF holder regards as non

confidential to applicant where as RP contains the information that asmf regards as confidential

AP• AP should contain sufficient information to enable the applicant / MA

holder to take full responsibility for an evaluation of suitability of the specifications for the active substance to control the quality of this active substance for use in manufacture of specified medicinal product.

Restricted (confidential) Part• Manufacture• Detailed description• Control of Materials• Control of critical steps and intermediates• Process Validation• Manufacturing Process Development• Impurities: for those impurities which do not need to be controlled in

the final active substance and which are related to detailed description of the manufacturing process.• Justification of specification: for information related to detailed

description of manufacturing process, control of materials and process validation.

Restricted (confidential) Part (2)• Exceptions• Validation data of sterilisation process may be required in Applicant’s

part when no further sterilisation process of the final product (GMP certification to be added)

Procedure – part 2• ASMF holders → Applicant/MA Holder• Copy of latest version of the AP• Copy of QOS (quality overall summary)• Letter of access: where this letter has not been submitted earlier for

the product concerned. letter of access is "Permission of ASMF holder to competent Authorities to access the data in the ASMF in relation to a specific application" (Annex 2).

Procedure – part (3)• ASMF holder should submit EDMF to Competent Authorities• The ASMF (applicant + restricted part) either only once or for each

MA application (depends on national requirements)• Letter of access where this letter has not been submitted earlier by

MAholder / applicant himself or by the EDMF holder for the product concerned.• where the same active substance is used in a no. of applications for

different products in one or more member states, the EDMF holder should submit identical documentation to every competent authority.

EU ASMF Structure: CTD• In EU, ASMF must be submitted in different sections in CTD modules• Module 1: Contains administrative and prescribing information

(administrative information is only required for an ASMF)• Module 2: Contains common overall summaries (QOS) of an

“Applicant’s part” (open part) and “Restricted part” (close part). It is nothing but summary of the information provided in module 3.• Module 3: Contains all Quality information. It contains applicant’s part

and restricted part. Applicant’s Part contains information required for marketing authorization. The Restricted Part contains information that is extremely confidential for the ASMF holder and can share with the health authority only.