Regulatory Insights: Navigating ASMF and CEP Procedures

Continuing our series of articles concerning sensitive topics on the Chemistry, Manufacturing, and Controls (CMC) section of a drug product dossier, second topic we would like to discuss is the Active Substance Master File (ASMF) and the Certification of Suitability to the monographs of the European Pharmacopoeia (CEP). This topic arises from the common confusion regarding definitions “Restricted part” and “Applicant’s part”, or uncertainty which data should be presented in the drug product dossier when referencing an ASMF or CEP.

The management of active substances in pharmaceutical manufacturing is crucial for ensuring product quality and regulatory compliance. In Europe, two key mechanisms, the Active Substance Master File (ASMF) and the Certification of Suitability to the monographs of the European Pharmacopoeia (CEP), play pivotal roles in this process.

The ASMF procedure allows active substance manufacturers to share essential information while protecting their intellectual property. Through structured documentation, ASMF holders provide detailed insights into manufacturing processes and quality controls, empowering regulatory authorities and medicinal product manufacturers alike.

Similarly, the CEP scheme validates active substances’ adherence to European Pharmacopoeia standards, bolstering confidence in their safety and efficacy.

ASMF – why and how it works?

Active substance manufacturers frequently provide their active substances to numerous marketing authorization (MA) holders for use in various medicinal products. Since active substance becomes part of medicinal products, its manufacturing details should also become part of medicinal product dossier. This means that all active substance chemistry, manufacturing, and quality control details should be disclosed to these numerous marketing authorization holders of medicinal products. Hereby we can assume that active substance manufacturers are seeking to supply their products to various medicinal product manufacturers. However, they are not seeking in parallel to share their intellectual property.

To protect active substance manufacturers, the Drug Master File (DMF) mechanism was created by the United States Food and Drug Administration (FDA) in 1982. Later, in 1989, the Active Substance Master File (ASMF) procedure, formerly known as the European Drug Master File (EDMF) procedure was adopted in the European Union.

As stated in Guideline on Active Substance Master File Procedure, the main objective of the Active Substance Master File (ASMF) procedure, is to allow valuable confidential intellectual property or ‘know-how’ of the manufacturer of the active substance to be protected, while at the same time allowing the Applicant or Marketing Authorisation 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.

How it works?

1. Active Substance manufacturer creates a set of files (in eCTD format) consisting of Applicants Part (AP) and Restricted Part (RP). In this scope, the manufacturer is called ASMF holder.

• Applicant’s part (AP) has the information on chemistry manufacturing and control (CMC) information of API. It is more general information, which is disclosed to medicinal product manufacturers. AP is still a confidential document that cannot be submitted by anyone without the written consent of the ASMF holder.
• Restricted Part (RP) has 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.

2. ASMF holders provide full dossier (AP+RP) to competent authorities for evaluation.

3. ASMF holder provides Applicants Part (AP) to medicinal product manufacturer. Together with AP, ASMF holder provides Letter of Access (LoA), allowing DP manufacturer to reference ASMF restricted part. AP is further included in the Marketing Authorization Application (MAA) Dossier and submitted to various European agencies through National, MRP, Repeat Use and DCP procedures.

These 3 steps assure that:

• Active substance manufacturer intellectual property is protected and remains confidential.
• Medicinal product manufacturers can be sure that the process of used active substance manufacturing is well developed, controlled, and described (since it is evaluated and accepted by competent authority).
• Competent authorities can save some resources, since the same single ASMF can be submitted for multiple different MAAs.

Evaluation of ASMF

ASMF is not an independent dossier and can only be submitted as a support of a Marketing Authorization Application (MAA). And same as MAA, ASMF submission can follow several EU registration pathways, like MAA: Nationalized Procedure; Mutual Recognition Procedure; Decentralized Procedure; Centralized Procedure.

Consequently, the same ASMF could be included in applications for new MA across various Member States using any of the above listed authorization pathways available in Europe. And since the same ASMF can be assessed by different Member States, it can result in duplication of work, inconsistent decisions on the same data, numerous updates of the ASMF (requested by NCAs). This leads to workload increase for all parties.

To tackle this concern, the European ASMF Worksharing Procedure was introduced. This marked a significant and positive advancement in dealing with the above-mentioned issues. Nonetheless, it’s crucial to note that this procedure is voluntary, applicable solely to new ASMFs and specific authorization pathways.

CEP: The certification scheme of the Ph. Eur.

30 years ago (in 1994), EDQM established the procedure for the “Certification of Suitability to the monographs of the European Pharmacopoeia”, also known as CEP. This certification procedure empowers active substance manufacturers to demonstrate that the quality of the active substance is suitably controlled by the relevant monographs of the European Pharmacopoeia (Ph. Eur.) and is in compliance with current regulatory requirements.

Certification background, process and benefits are briefly and visually presented at EDQM “CEP at a glance” section. 

To obtain a CEP, an active substance manufacturer submits an application to the EDQM describing active substance manufacturing process and applied quality control methods. A network of experienced quality assessors evaluates provided data and when assessors’ conclusion is positive, EDQM grants a CEP. A copy of this certificate is then provided to the MA holder for inclusion in their MAA. Additionally, CEP holder provides MAH information, critical to perform quality evaluation of the active substance.

Who accepts CEPs?

As stated by EDQM, CEPs are recognised by all European Pharmacopoeia member states and by a number of other countries, such as Australia, Canada, New Zealand, Saudi Arabia, Singapore and South Africa, and regulatory organisations, including the Taiwan FDA and the World Health Organization. An increasing number of licensing authorities worldwide accept CEPs to support.

The CEP 2.0: What is new?

After 30 years of operation and consultation with stakeholders, the EDQM has redesigned the CEP to increase the user-friendliness and transparency of provided information. This resulted in a “new-look” CEP called “CEP 2.0”. CEP 2.0 (from 1^st June 2023) impacts CEP applicants, holders, and users.

The changes linked to its implementation in total cover 9 areas, such as reported information, assessment of CEP applications, changes in databases of public certification and authorities, etc. The changes covering all these areas are further explained at EDQM website and can be downloaded as a document. The listed changes should be implemented for new CEPs and during upcoming CEP renewal procedures. Gradually, all existing CEPs are expected to switch to CEP 2.0.

To conclude, the ASMF and CEP procedures serve as vital pillars in pharmaceutical regulation, facilitating the integration of active substances into medicinal products while upholding stringent quality standards. As we delve deeper, it becomes evident that these mechanisms play complementary roles in ensuring regulatory compliance and safeguarding patient welfare. Since this article summarizes theory from ASMF and CEP guidelines, in further article clear comparison of these mechanisms followed by our insights will be shared.