Why Drug Master Files Are An Important Part of API Manufacturing


While not required by law, a Drug Master File (DMF) is submitted to the Food and Drug Administration (FDA) to provide detailed information about facilities, processes and materials used in the manufacturing, processing and packaging of human drugs.  It’s a prerequisite to securing approval and commercialization and ensures confidentiality of proprietary information related to the Active Pharmaceutical Ingredient (API). The information contained in a DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or related documents.

Beginning this past May 2018, The FDA began requiring that new DMFs, as well as all documents submitted to existing DMFs, must be submitted using the Electronic Common Technical Document (eCTD). In addition to this new electronic filing requirement, the nature of DMFs has changed dramatically, requiring a more disciplined approach and specific information.

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Years ago, DMFs were filed even before a CDMO had a customer – simply based on the compound developed and with very scarce information.  This DMF would remain until a customer came along to purchase the required API.

GDUFA Changing the Rules

Today, the DMF requirements are quite complex and specific, encompassing every detail involved with the manufacture of the API – from raw materials to analytical methods, process development and optimization. The increased scrutiny goes all the way back to registered starting materials used.

This new complexity is partly attributed to the Generic Drug User Fee Amendments (GDUFA), an act implemented in 2012.  While it was designed to speed access to safe and effective generic drugs to the public, GDUFA’s review of DMFs can often now require many changes to analytical methods for raw materials, identified impurities, validation, and other activities which can set projects back by months or a year.  In some instances, APIs that have not yet been commercialized but filed before GDUFA, are reviewed and are sent back with 12-13 pages of required actions.

The Ins and Outs of DMFs

There are several types of DMFs that can be granted, each requiring different types of information, but with similar levels of complexity and detail. These include:

  • Type I: Manufacturing site, facilities, operating procedures and staff not specific to a drug substance. Type I DMFs are no longer accepted by the FDA, but old ones remain on file.
  • Type II:The most common form of a DMF, Type II covers drug substances, substance intermediates, and materials used in their preparation, or a drug product.
  • Type III:Packaging materials, from bottles and caps to PVC resin used in their manufacture must be covered in a DMF.
  • Type IV. Excipients, which are chemically inactive substances such as starches or cellulose used to bind drug powder together so that it can be pressed into a tablet.
  • Type V: FDA accepted reference information not included in the other types.

The FDA requires that DMFs be current at the time they’re reviewed; and when it receives a DMF, it reviews it for administrative content, which usually takes two-to-three weeks. If the DMF is acceptable, the FDA issues an acknowledgement letter, which notifies the holder of the DMF number. If the FDA finds the DMF not acceptable, it lets the CDMO know of the deficiencies.

So What’s the Role of the CDMO?

Completing a DMF submission generally takes several months to develop, involving thousands of pages of documentation. Typically, the head of regulatory affairs with the CDMO is responsible for its development.

The CDMO is responsible for collaborating closely with the various projects managers and specialists across the firm to ensure that all information is accurately collected. Once filed, the FDA will check to see if the following requirements have been met, including whether:

  • The DMF is active
  • The fees have been paid
  • The DMF has been reviewed previously
  • The DMF pertains to a single API
  • The submission contains required administrative information, as well as all the necessary scientific information
  • The DMF is written in English
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The scientific information required really depends on the type of DMF being submitted. For a Type II DMF, the CDMO will need to demonstrate the significant steps in manufacturing and controls of the drug substance, and the manufacturing procedures and controls for the finished dosage. Additional information that may be required for different types of DMFs could include the manufacturing site’s equipment capabilities, operational layout; or the names of suppliers and fabricators used.

The process of filing a DMF can be complex and time-consuming for CDMOs. But securing DMFs ensures the quality of the API being developed,  It’s especially important when working with polymers, as PCI Synthesis does, because some drugs may react badly when encased in certain plastic packaging, and a DMF can identify steps to take during the formulation process to avoid potential side affects from the packaging. DMFs can be useful from a liability perspective and to protect a company’s intellectual property when with working with a partner.