Overview of DMF/CEP for Regulatory Submission

Drug Master File (DMF) is one of the important parts of the documents submitted to the regulatory authorities including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and Japan’s Ministry of Health, Labor and Welfare (MHLW).

What is Drug Master File (DMF)

Drug Master File is a type of voluntary submission of confidential information in length to the FDA that includes data on the facilities, processes, or articles used in the developing, processing, packaging, and storing of drug items.

This document is usually prepared by a pharmaceutical company that is further submitted to the concerned regulatory agency in the intended drug market. DMF usually contains detailed information about any Active Pharmaceutical Ingredient (API), drug substance, medium of drug substance, packaging material etc.

These files are also used to allow the DMF holder to handover the authority to sponsors or applicants who support a submission to FDA without the DMF holders having to disclose the information to them.

Overview of DMF in regulatory submissions

DMF contains complete information on an Active Pharmaceutical Ingredient (API) or Finished Drug substance. It is referred in the following ways in different countries. For instance in US it is known as US-Drug Master file (US-DMF) and in Europe it is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) in United States and Europe respectively.

DMFs usually cover the Chemistry, Manufacturing and Controls (CMC) of a component of a drug product e.g. drug substance, excipient, packaging material. Drug product information or non-CMC information (e.g., facilities, toxicological) may be filed in a DMF.

DMFs have significant importance because they support the NDAs, ANDAs, and INDs which represent multi-billion dollar potential profits for drug applicants, and several hundred thousand to several million dollars each in corresponding investment time and research.

1.1 Parts of DMF

Unlike US-Drug Master file, the scientific information of EDMF or ASMF is physically divided into 2 parts as per European filing procedures.

A. Restricted part (Closed part) –

Information regarded as to be confidential and to be submitted only to the Authority.

  • Manufacture
  • Manufacturer(s)/site of manufacture
  • Detailed description of the manufacturing process and process controls
  • Control of materials (Starting material of the API, reagents, solvents, other materials used)
  • Control of critical steps and intermediates
  • Process validation and/or evaluation
  • Manufacturing process development

B. Applicant’s part (Open part) – Information regarded as to be non-confidential and to be given to the applicant. This information is also given to the authority as part of DMF services.

These parts include:

  • General information
  • Characterization
  • Control of API
  • Reference standards or materials
  • Container closure system
  • Stability

1.2 DMFs format

DMFs may be submitted following the format recommended in the “Guidance for Industry M4Q: the CTD – Quality”. The Common Technical Document (CTD) is a set of specification for application dossier for the registration of Medicines and designed to be used across Europe, Japan and the United States. It was developed by the European Medicines Agency (EMA, Europe), the Food and Drug Administration (FDA, U.S.) and the Ministry of Health, Labour and Welfare (Japan).

TYPES OF DMFs (FDA)

Type I

- Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)

Type II

-Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product

Type III

-Packaging Material

Type IV

-Excipient, Colorant, Flavor, Essence, or Material used in Their Preparation

Type V

-FDA Accepted Reference Information

Status of DMF database as per US FDA

  • “A” = Active. This means that the DMF is not closed and it’s still accepting
  • “C” = Complete
  • “I” = Inactive. This suggests the Holder or FDA has closed the DMF submission
  • “P” = Pending
  • “N” = Not an assigned number

DMF Formats

Different countries follow different DMF formats and submissions. For instance, the United States Food and Drug Administration asks for two copies of each Type DMF in the CTD format, but not in CTD module form. One continuous document in the CTD format is mandatory. In US there are no different sections as an “Applicant’s Part” or “Restricted Part” followed unlike European DMF format.

It’s suggested to submit drug master file in Electronic format as submission of the data in a mixed format of paper and electronic may delay its review.

All electronic submissions must have a pre-assigned number. However, this pre-assigned number is not required when data is converted to paper to electronic format from paper. A 6-digit assigned number is used e.g. 2345 must be submitted as 002345. “0000” is used as sequence number for first submission in electronic format.

While paper format can be converted into electronic format, the electronic format however cannot be converted back to paper format. Therefore, every consecutive submission should be processed in electronic format once the DMF application form has made an electronic submission.

Benefits of DMF services

  • Ensures confidentiality of proprietary information
  • Gives you an edge over your competitors
  • Several applicants can refer the information
  • Adds value to the product and company on the whole
  • Considered more reliable in terms of quality and regulatory stand by manufacturing companies
  • Builds confidence within the customers
  • Improves sales anywhere in the world
  • Penetrates high entry barrier US market

What is CEP?

CEP is Certificate of Suitability to the monographs of the European Pharmacopoeia or Certification of suitability of European Pharmacopoeia monographs. It is also informally referred to as Certificate of Suitability (COS)

This certificate, which is issued by Certification of Substances Division of European Directorate for the Quality of Medicines (EDQM), was established in 1994. It is issued only when the manufacturer of any drug product provides proof regarding the quality of the product which is then suitably guarded by the significant monographs of the European Pharmacopoeia.

Benefits of the CEP

  • Ensures confidentiality of the submitted data
  • Facilitates consolidated evaluation by the EDQM
  • Offers recognition by all Member States of the European Pharmacopoeia Convention across 36 countries nations
  • Smooth dealing of applications for marketing authorization (MAA) for medicinal products across those nations
  • Simplifies the approval process of a medicinal product as compared to the active substance master file (ASMF) or European drug master file (EDMF)

Who needs CEP?

Manufacturers or suppliers who are willing to avail for a marketing authorization for

  • Active products or excipients (natural/synthetic substance formulated side by side the active ingredient of a medication) to regulate the purity of the chemicals used and microbiological quality of their products
  • Substances whose TSE risk has been reduced down as per the general monograph
  • Herbal items used in the manufacturing of pharmaceutical products are to be evaluated according to the suitability of the monograph

(The data is shared as described in Resolution AP CSP 1 and Directives 2001/83/EC, 2001/82/EC)

Submission of drug master file by the manufacturers to the authority creates the quality impact on the consumers and hence it can increase the trust of the manufacturer in the market pertaining to organisation & quality of product.