A Drug Master File (DMF) is submitted to the Food and Drug Administration (FDA) to provide confidential information about the manufacturing, control or chemistry of an Active Pharmaceutical Ingredient (API). It’s important to note that the submission of a DMF is not required by law, but is submitted by a sponsor completely at its discretion. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA) or another DMF. The key purpose of the DMF is to support the quality, safety and efficacy of the drug product.
But, while it may be used to support an IND, a DMF is not a substitute for one, since it’s not something that gets approved. Rather, its technical contents are typically reviewed only in connection with the review of an IND, NDA or ANDA. A key responsibility of the Contract Development & Manufacturing Organization (CDMO) is to work with a sponsor to help it submit the DMF to the FDA.
During a new drug’s early preclinical development, the sponsor’s primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that can support commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.
Today, the FDA requires that new DMFs provide even more specific information, and be submitted using the electronic Common Technical Document (eCTD) format. eCTD is an electronic common technical document which contains an xml backbone with meta data and eCTD documents organized according to the ICH eCTD specification.
The FDA maintains the list of DMFs, name and DMF number for all the products which have completed administrative review within the FDA DMF database. This is updated quarterly with newly submitted DMFs.
GDUFA Brings New Complexity to DMFs
The Generic Drug User Fee Amendments (GDUFA) was designed to speed access to safe and effective generic drugs to the public. Because of this, GDUFA’s review of DMFs now require many changes to analytical methods for raw materials, process development, impurity levels, validation, optimization and other criteria – stretching back to the starting material – which can set projects back significantly.
As the complexity of filing DMFs grows, it pays for a sponsor to work closely with its API manufacturer to maintain and store critical documentation. Most CDMOs are extremely versed in the requirements and updated information available on DMF filing.
There are several different types of DMFs that can be offered, each requiring different types of information, but with similar levels of complexity and detail. These include:
- Type I: This type is 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: This includes packaging materials, such as bottles and caps to PVC resin used in their manufacture.
- Type IV. Excipients that are chemically inactive, such as starches or cellulose used to bind drug powder for use in a tablet, are included in this DMF.
- Type V. This includes refence information not included in other types of DMFs.
How Long Does it Take to File a DMF?
The FDA requires that DMFs be comprehensive at the time they’re reviewed; and its review of administrative content usually takes two-to-three weeks. Basic checklist items the FDA looks for is evidence that the DMF is active, fees have been paid, the DMF has been reviewed, it pertains to a single API, contains all required information and is written in English.
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 sponsor know of the deficiencies.
How Can Your CDMO Help?
You should be collaborating closely with your CDMO project manager, its regulatory affairs specialists, as well as your consultant to ensure that all information is accurately collected. Completing a DMF submission generally takes several months to develop, involving thousands of pages of documentation.
Before DMFs can be reviewed, a manufacturer must submit a dose form filing that references the DMF. It’s important to note that not all DMFs are reviewed by the FDA, and the possession of a DMF for a product does not ensure that a manufacturer is producing that product or is able to supply it to the United States.
At one time, filing a DMF was a way for less established firms to claim a degree of credibility when trying to sell into the U.S. market. Yet, filing DMFs without any customers in the U.S. has become much less common, so more recent DMFs are a better indicator of intent to manufacture than older DMFs. The FDA ensures that DMFs are current. If a company has not submitted an annual report in for three years, the agency sends an “Overdue Notification Letters” to DMF holders. The holder has 90 days in which to respond and submit its annual report. If they fail to respond, their DMF may be closed.
Given the complexity, API manufacturers with a large number of DMFs are often considered more reliable in terms of quality, regulatory standing, and ability to meet Current Good Manufacturing Process (cGMP) requirements. Chances are they’ve experiences something similar to your project and can offer best practices for filing.
Filing a DMF, while complex, is a critical component to your Investigational New Drug, New Drug Application or Abbreviated New Drug Application. Completing the process can go a long way to properly documenting the quality, safety and efficacy of the API being developed on the road to commercialization. The key, however, is to not go it alone.