One of the specialized capabilities in Premier Consulting’s toolbox is coordinating the Active Substance Master File (ASMF) submission process on behalf of sponsors. The ASMF procedure (formerly known as the European Drug Master File [EDMF] procedure) has in recent years become an increasingly utilized instrument for securing a marketing authorization (MA) for a medicinal product in the European Union (EU), particularly when the active substance manufacturer (ASM) and MA holder are two different entities.

Essentially, the procedure enables the protection of the ASM’s intellectual property and “know-how” while also allowing the MA holder to take full responsibility for the medicinal product as well as the quality and quality control of the active substance. The ASMF process thus provides various countries’ national competent authorities (NCAs) unfettered access to the complete dossier of information needed to evaluate whether the use of the active substance in the medicinal product is suitable.¹

What is included in an ASMF submission?

The core elements of the ASMF are:

• Applicant’s Part (AP), which contains the scientific information that the ASMF holder (usually the ASM) regards as non-confidential to the MA holder
• Restricted Part (RP), which comprises confidential information

The AP should contain sufficient information to enable the 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, including details on the individual steps in the manufacturing method (e.g., reaction conditions, temperature, validation, and evaluation data of critical steps) and quality control during the manufacture of the active substance.¹

The ASMF should be submitted in the format of the electronic Common Technical Document (eCTD).¹

When can an ASMF be submitted?

An ASMF can be submitted only in support of a Marketing Authorization Application (MAA). An MA holder can pursue any of the following EU registration pathways for an ASMF submission:

• Centralized Procedure – the EU-wide pathway for the authorization of medicines, where there is a single application, a single evaluation, and a single authorization throughout the EU.² Under the centralized procedure, the European Medicines Agency (EMA) evaluates the application.
• Decentralized Procedure – the pathway for authorizing medicines in more than one EU Member State in parallel, particularly for medicines that do not need to be authorized via the centralized procedure and have not already been authorized in any Member State.³ In this case, the Member States’ NCAs evaluate the application.
• Mutual Recognition Procedure – the pathway allowing applicants to obtain an MA in Member States other than those where the drug was previously approved.⁴ As with the decentralized procedure, the Member States’ NCAs evaluate the application.
• Nationalized Procedure – the pathway allowing applicants to obtain an MA in one Member State only.⁴ In this case, the NCA in that Member State evaluates the application.

The ASMF procedure can be used for the following active substances (including herbal active substances/preparations) but not for biological active substances:¹

• New active substances
• Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State
• Pharmacopeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member State

What are the timelines for an ASMF submission?

Coordinating an ASMF submission requires strict adherence to MAA timelines, The relevant documentation by the ASM must be synchronized to arrive at the NCAs/EMA not more than one month before, but not after, the intended MAA submission date.¹

An important pre-submission step is the request for an EMA ASMF reference number (for a centralized submission) or an EU ASMF reference number (for a decentralized or mutual recognition submission), which must be made up to two weeks before submitting a complete ASMF. An EU ASMF reference number is not mandatory for a decentralized or mutual recognition procedure, though it is highly recommended in cases of multiple procedures.¹

Timelines for the assessment of an ASMF are the same as the those for the associated MAA. Thus, for example, once an ASMF in support of a decentralized MAA has been submitted and validated, the assessment process begins in earnest. The process is broadly comprised of Assessment Step I and Assessment Step II. Each step contains its own unique requirements, timelines, and intermediate steps. Overall, the procedure takes up to 210 days, but it can be closed at any point before Day 210 if the Reference Member State (RMS) reaches a consensus that the product is approvable. During the assessment, the NCA/EMA will communicate with both the ASM (for the RP) and the MA holder (for the AP), particularly if further clarification is requested. The following table outlines the Assessment Steps for a Decentralized Procedure:

ASMF in Support of a Decentralized Procedure: Assessment Steps

Step	Description
Assessment Step I	A 120-day period for preparing the Draft Assessment Report (DAR), comments on the draft Summary of Product Characteristics (SmPC), draft package leaflet (PL), and draft labeling. Key milestones include: Day 70: The Preliminary Assessment Report (PrAR) is sent to the ASM and the applicant (i.e., the MA holder). Day 105: The product is approved, or the RMS issues a Request for Supplementary Information. Days 106-120: The PrAR is updated to prepare the DAR. Clock-stop period: The MA holder supplements the dossier by responding to any RMS questions within three months (this period can be extended for an additional three months if the MA holder needs more time). The clock typically restarts within six weeks of receipt of the draft response.
Assessment Step II	Final assessment period, culminating either in product approval or a determination that the product is not approvable. Key milestones include: Day 150: The product is approved, or the RMS informs the applicant of issues pertaining to the application. Day 160 or earlier: The applicant submits additional clarification as needed. Day 210: The process is closed with either a positive outcome or a conclusion that the product is not approvable.
National Step	The NCA of each involved Member State adopts a national decision within 30 days of the procedure’s closure by the RMS.

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The requisite steps and timelines of the ASMF submission process can be challenging to navigate, and there is relatively little written regulatory guidance for sponsors. Nevertheless, Premier Consulting – with our experienced, multidisciplinary team of experts in chemistry, manufacturing, and controls (CMC); regulatory operations; regulatory affairs; and other functions – is well-equipped to manage the communications and logistical challenges of an ASMF submission. To learn more about our ASMF capabilities, contact us.

Authors:

Federica Martini
Associate Director, Regulatory Affairs

Omar Raswan
Senior Associate, Regulatory Affairs CMC

References:

1. Guideline on Active Substance Master File Procedure – Final. European Medicines Agency (EMA); 2021.
2. Centralized procedure. Glossary of Regulatory Terms, European Medicines Agency (EMA); 2022. https://www.ema.europa.eu/en/about-us/about-website/glossary/name_az/C.
3. Decentralised procedure. Glossary of Regulatory Terms, European Medicines Agency (EMA); 2022. https://www.ema.europa.eu/en/glossary/decentralised-procedure.
4. Authorisation of medicines. European Medicines Agency (EMA); 2022. https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines#:~:text=mutual%2Drecognition%20procedure%2C%20whereby%20a,in%20several%20EU%20Member%20States.