Drug Master File (DMF) Submission in the Europe

The European Drug Master File (EDMF) system, initially established in 1989-1991 and subsequently revised in 2005, evolved into the Active Substance Master File (ASMF) after the implementation of the Common Technical Document (CTD) in the European Union (EU). This transformation aligns with Directive 2001/83/EC, distinguishing it from the United States' Drug Master File (DMF) system in terms of content and format. The ASMF, colloquially known as the European DMF (EDMF), serves a dual purpose: protecting confidential intellectual property while enabling applicants to assume full responsibility for medicinal product quality and active substance control.

Access and Evaluation

• The European Medicines Agency (EMA) and competent authorities are granted access to essential information within the ASMF, crucial for assessing the suitability of active substances in medicinal products. As of July 1, 2016, the electronic Common Technical Document (eCTD) format became mandatory for the submission of human ASMFs through the centralized procedure.

• EU Directive 2003/63/EC outlines the active substances eligible for ASMF submission and includes details such as the 

1. Full manufacturing process description, 
2. Quality control procedures during manufacture, and 
3. Process validation.

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Market Authorization Application (MAA)

Before submitting an MAA, applicants must notify the European Medicines Agency (EMA) of their intention and provide an estimated submission date. MAAs can be submitted through four different procedures:

1. National Procedure: Suitable for organizations intending to market their product in a single EU country, the national procedure involves informing the relevant authority before filing for national market authorization. This process typically takes 210 days.
2. Centralized Procedure: This procedure grants marketing authorization for the entire EU market, valid across all member states. Regulation (EC) 726/2004 outlines this centralized procedure, featuring a single application, a unified evaluation process, and a single authorization for entry into the EU market.
3. Mutual Recognition Procedure: Companies with market authorization in one EU member state can seek recognition in several countries simultaneously, offering a faster route to multiple markets.
4. Decentralized Procedure: For products beyond the scope of the centralized procedure by the European Medicines Agency (EMA), sponsors can submit under the decentralized procedure. This approach allows simultaneous authorization in multiple EU countries for products not previously authorized in any EU nation.

ASMF Content

The EDMF must encompass all scientific information relevant to market authorizations for medicinal products across EU member states. For human medicinal products, the EDMF must adhere to the CTD format, while veterinary medicinal products require specific details such as the 

• Manufacturer's name and site, 
• Nomenclature, 
• Description, 
• Manufacturing route outline, 
• Detailed manufacturing method description, 
• Quality control during manufacture, 
• Development chemistry, 
• Analytical validation, 
• Impurities, 
• Batch analysis, and 
• Stability studies.

The scientific information in the ASMF consists of two parts:

1. Applicant's Part: Open to inspection, this section contains non-confidential information required for applicants to assume full responsibility for assessing the suitability of the active substance. Although it is considered non-confidential, access to this part requires written consent from the EDMF holder.
2. Restricted Part: Closed and confidential, this section contains sensitive information, including detailed manufacturing methods, reaction conditions, temperatures, and critical step validation data. Access to this part is strictly controlled.

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Both parts must have version numbers, following a unique and logical order.

European ASMF Filing Procedure

• The active substance manufacturer provides the applicant with the DMF's Applicant's Part, which combines both the applicant's and restricted parts. This merged document becomes part of the market authorization application, submitted to the relevant authorities. 
• The ASMF's primary objective is to safeguard active substance information's confidentiality while allowing applicants to assume full responsibility for medicinal product quality, safety, and efficacy. National competent authorities evaluate the complete information to assess the active substance's suitability in medicinal products.

ASMF Applicability

The ASMF procedure can be employed for:

1. New active substances.
2. Existing active substances not included in the European Pharmacopoeia.
3. Pharmacopoeia active substances are included in the European Pharmacopoeia.

EDMF holders must provide the applicant with:

1. A copy of the latest version of the Applicant's Part.
2. A copy of the quality overall summary based on the latest Applicant's Part version.
3. A letter of access (if not previously submitted for the product).
4. For each Market Authorization Application (MAA) or Market Authorization Variation (MAV), the EDMF holder must submit the EDMF to the competent authorities.

Changes and Updates to the ASMF

EDMF holders are responsible for keeping the EDMF content up-to-date with the current synthesis or manufacturing processes. Changes to the EDMF should not occur without the written consent of the applicant and competent authority. Before making any changes, the EMA and the applicant must be informed. The cover letter to the EMA should include:

• A summary of all changes made since the initial EDMF submission.
• A comparison between the old and new EDMF contents.
• Information on whether the changes were accepted, rejected, or withdrawn by other member states.
• An updated quality overall summary.
• The new Applicant's Part/Restricted Part, each with a new version number.

Fees

Stay informed about fee updates and consult official sources for the most current information on DMF submission fees.

Conclusion

Navigating the European ASMF filing system is essential for pharmaceutical companies seeking market authorization for medicinal products in the EU. Understanding the intricacies of ASMF content, filing procedures, and compliance with regulatory changes is crucial to achieving successful market authorization while safeguarding intellectual property and ensuring product quality and safety.

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