EU ASMF Regulations Guidelines

Inquiry

In this article, we focus on the European Union's Active Substance Master File (ASMF) system, which differs from the U.S. DMF in terms of content, scope of application, and registration procedures.

Introduction of ASMF

Formerly known as the European Medicines Master File (EDMF), the ASMF is a technical document containing confidential information about an API that is submitted by the manufacturer of the API to the EMA or to the Medicines Agency of the Member States of the EU, and which can only be used to support Marketing Authorization Applications (MAA) or Marketing Authorisation Variation (MAV) of manufacturers of medicinal products for human use and veterinary medicinal preparations.

The ASMF is intended to protect the intellectual property or know-how of the manufacturer of an API, while allowing the MA applicant or holder to take full responsibility for the quality of the drug product as well as the API.

The ASMF applies to the following types of API applications:

Brand new APIs
APIs not currently listed in the EP or other Member States' pharmacopoeias
APIs that are listed in the EP or other Member States' pharmacopoeias

It should be noted that biologics are not covered by the ASMF and blood products have a separate plasma master file, the PMF.

ASMF Registration Process

The registration of an ASMF by an API manufacturer requires a Letter of Authorization (LOA) to be reviewed in conjunction with the MA application for preparation. ASMFs related to human medicines are required to be submitted using the electronic Common Technical Document format (eCTD). ASMFs related to veterinary drugs may be submitted in eCTD or NeeS, as appropriate.

Filing routes and processes

1. Prepare the ASMF document

2. Authorize the application for an ASMF registration number two weeks in advance and submit the EMEA/ASMF request form

3. Obtain the ASMF registration number

4. Submit filing via the CESP online portal and provide LOA

5. Registration is completed and awaiting preparation for linkage review

6. After the linkage review, if the preparation is subject to DCP, another linkage review is required in other countries

Electronic submission route.

Guidelines for eCTD submission.

Review process

The review process for ASMF is consistent with the process for filing a marketing authorization for the preparation indexed to ASMF.

1. ASMF provides an authorization to the applicant for the preparation, and the preparation can reference the ASMF by providing an authorization to the CHMP for review of the ASMF

2. Submit an application for preparation

3. Technical review by CHMP or Member State's Medicines Agency

4. Additional information and a response

5. The preparation is approved and the ASMF can be used for that preparation

There is no approval or rejection of the ASMF, but rather a continuous process of sending supplements to obtain a response. If the preparation is used in another NP, MRP, or if the ASMF is used in another preparation application, the ASMF will need to be re-reviewed.

Question and answer process

Question and Answer Process

Worksharing procedure

In order to harmonize ASMF assessments and to reduce the regulatory burden on competent authorities, ASMFs and MA holders, the Worksharing Procedure (WP) has been established with the aim of allowing the regulatory authorities of the various Member States to share the same version of the ASMF-AR.

WP process

1. the primary RMS reviews the ASMF

2. the ASMF-AR is uploaded to the database

3. Master CMS performs a quality review of the AR to confirm and raise issues

4. Sub-RMS/CMS performs quality review of the AR to confirm and raise questions

5. the master RMS revises the AR and uploads it to the database

Advantages of WP

Reduced duplication of assessment efforts
Harmonization of assessment decisions
Reduced frequent updates of ASMF due to different requirements from regulatory authorities
Saves reviewers' time and resources
Increased regulatory efficiency for ASMFs

WP does not have obvious advantages for single-country reviews, but will be of great help for DCPs, MRP processes, or the consideration of NPs from other countries for listing after an NP from one country.

ASMF Filing Information Requirements

The overall content of the ASMF should contain detailed scientific information. The ASMF filing is divided into an Applicant Portion (i.e., Public Portion, AP) and a Restricted Portion (i.e., Confidential Portion, RP).

Submitted by the API manufacturer to the preparation MA applicant or holder. It is mainly considered information that can be disclosed to a preparation company. However, the AP is still a confidential document, and no one can submit it to a third party without the written consent of the ASMF holder.

More detailed information, which may include production processes, quality control and process validation, is submitted by the API manufacturer directly to the reviewing authority.

Module 1

- Cover Letter

- Letter of Access

- Submission Details Form

- Expert's curriculum vitae

Module 2: QOS (AP&RP)

- 2.3 QOS

- 2.3.S APIs

- 2.3.S.1 Basic information

- 2.3.S.2 Production

- 2.3.S.3 Characterization

- 2.3.S.4 Quality Control of APIs

- 2.3.S.5 Comparison products

- 2.3.S.6 Packaging materials and containers

- 2.3.S.7 Stability

- 2.3.A Appendices

- 2.3.A.1 Facilities and equipment (biological or biotechnological products)

- 2.3.A.2 Evaluation of exogenous factors (description based on actual 2.3.A.1)

- 2.3.A.3 Excipients

- 2.3.R Regional information

Module 3

a. If detailed information is available in the RP, only a flow chart and brief description is required. However, complete validation data on the sterilization process is required in the AP (if the final product is not further sterilized)

b. Detailed Information

c. Only information relevant to the applicant or holder needs to be provided

d. Provide parameters specifically related to the process, whether or not the information is relevant to the applicant or holder

e. Provide impurities relevant to the process and, for such impurities, the applicant may provide an affirmation that he/she does not need to control these impurities in the final active substance

f. Information on the detailed description of the manufacturing process, material control and process validation.

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ASMF Common Deficiencies

When preparing an ASMF filing, the regulations and requirements need to be carefully researched and well understood to avoid multiple remedies. Common ASMF deficiencies include:

Inadequate definition of starting materials, requiring redefinition of starting materials
Lack of a control strategy for potential introduction of Class I solvents in the primary solvents used for API production
Lack of or inadequate discussion of the fate or transfer of impurities in the starting material or intermediates
Lack of or inadequate discussion of potential genotoxic impurities in APIs
Insufficient or no discussion of the intentional introduction of elemental impurities during API manufacture
Inadequate or no risk assessment of N-nitrosamine impurities
Failure to include crystallinity and microbiology in API release and stability quality criteria

Proregulations' team of professionals has an in-depth understanding of the European Union's ASMF regime and has extensive experience of producing sound ASMFs that meet regulatory requirements. If you are interested in our services or need more details, please contact us.