DRUG MASTER FILE

Drug Master File or DMF is a document prepared by a pharmaceutical manufacturer and submitted to the appropriate regulatory authority in the intended drug market. DMF is a document containing complete information on an Active Pharmaceutical Ingredient (API) / drug substance, intermediate of drug substance, packaging material, excipient or drug product.

The DMF contains complete information on quality aspect such as chemistry, manufacture, purity, impurity profile, packaging, stability etc.

In Europe, it is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) whereas in US, it is United State Drug Master File (US-DMF).

There is no regulatory requirement to file a DMF. DMF is never Approved or Disapproved. A DMF is NOT a substitute for an IND (Investigational new drug), NDA (New Drug Application), ANDA(Abbreviated New Drug Application), or Export Application. Technical contents of a DMF/ASMF are reviewed only in connection with drug product registration application where it is used as raw material, packaging or other relevance.

TYPES OF DMF: AS PER US FDA

In US A Drug Master File (DMF) is submitted to the Food and Drug Administration (FDA).

There are five types of US DMF’s:

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel. As per a Rule 65 FR 1776 published on January 12, 2000, Type I DMF are no longer accepted and it is now one can file under Type V.

Type II: Drug substance, its intermediate and material used in their preparation or drug product.

Type III: Packaging material

Type IV: Excipients or material used in their preparation

Type V: FDA accepted reference information

Each DMF should contain only one type of information and all supporting data. Supporting information and data in a DMF can be cross referenced to any other DMF.

Status of DMF: AS PER US FDA

“A” = Active. This means that the DMF is acceptable for filing, and has not been closed.

“C” = Complete.

“I” = Inactive. Holder or FDA has closed the DMF.

“P” = Pending. DMF is pending for Administrative Filing review

“N” = Not an assigned number.

Format of DMF

Different countries have different requirement for format and submission of DMF. For instance, the United States Food and Drug Administration require two copies of each Type DMF in the CTD format, but not in CTD module form. FDA requires one continuous document in the CTD format. There are no different sections as an “Applicant’s Part” or “Restricted Part” such as Europe.

Review of DMFs

After receiving DMF; is reviewed for administrative content. This may take 2-3 weeks. If DMF is ok with administrative content then acknowledgement letter will be issued, and notice has been sent to holder of the DMF number. If DMF is not ok with administrative point of view, the holder will be notified with letter of deficiency.

All DMFs are subject to a complete review for technical information only when all of the following events occur:

1. The DMF holder submits a Letter of Authorization (LOA) for the DMF to respective regulatory authority. This LOA should contain DMF number / acknowledgement number.

2. The holder will send a copy of the LOA to the authorized party (customer).

3. The customer submits an application to the FDA that contains a copy of the LOA.

In EU, ASMF must be submitted in different sections in CTD modules as

Module 1: It contains administrative and prescribing information (administrative information is only required for an ASMF)

Module 2: It contains common overall summaries (QOS) of an “Applicant’s part” (open part) and “Restricted part” (close part). It is nothing but summary of the information provided in module 3.

Module 3: It contains all Quality information. It contains applicant’s part and restricted part. Applicant’s Part contains information required for marketing authorization. The Restricted Part contains information that is extremely confidential for the ASMF holder and can share with the health authority only.

Different countries of EU have different requirements. The United Kingdom and The Netherlands accepts DMF in electronic copies in their own separate electronic format, where as France requires both a paper and an electronic copy. France also requires an application forms notifying that the electronic version of DMF is identical to the paper copy. Several other countries are in the way of converting DMF to the non-ICH (XML), and non-eCTD electronic submissions (NeeS) format. These countries include Belgium, Denmark, Germany, France, Hungary, Portugal, Spain, and Sweden. Canada and Australia accepts different DMF Type.

Formats of DMF submission

It’s better to submit DMF in Electronic format since submission of it in mixed format (paper and electronic) may delay its review.

All electronic submissions must have a pre-assigned number. Pre assigned number is not required in case of conversion from paper to electronic format. Previously assigned number is in 6-digit format should be used e.g. 2345 becomes 002345. Sequence number for first submission in electronic format should be given as “0000”. Paper DMF can be converted in to electronic format only when the entire DMF is submitted in electronic format. Electronic format cannot be converted to paper format. Every subsequent submission should be in electronic format once the DMF holder has made an electronic submission.

Advantages of DMF

DMF maintain confidentiality of proprietary information (e.g. manufacturing procedure) for the holder.

Number of applicants can refer the information.

Finished product manufacturing companies consider API manufacturer having DMF number / CEP (certificate of suitability) more reliable in terms of quality and regulatory stand.

Reference

http://pharma.about.com/od/D/g/Drug-Master-File-Dmf.htm

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm

http://www.gpo.gov/fdsys/pkg/CFR-2013-title21-vol5/xml/CFR-2013-title21-vol5-sec314-420.xml

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002814.pdf

ICH– Organization of the Common Technical Document for Registration of Pharmaceuticals for Human Use M4, Rev. 4 (Brussels, Belgium, Nov. 2005) http://www.ich.org/.


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