Drug Master File Workshop

Erik Swain

A three-day workshop convening drug companies, packagers, FDA officials, and academics has produced a document to help suppliers better prepare their drug master files (DMFs). This will allow FDA to review applications more quickly.

DMFs are held on file at the agency and contain information crucial to a new drug application (NDA) or other submission to FDA. The supplier does not want to show the information to its customer or make it public, usually for proprietary reasons. Much of an application's packaging-related information is usually contained in Type III DMFs. Although these are not required by law, the alternative for a supplier is to give the information directly to the applicant for use in the submission.

Submissions often have referrals to specific DMFs, which are then read by FDA's application reviewer. If information is missing from the DMF, or if the reviewer cannot find it because the file is poorly organized, the vendor receives a deficiency letter, and the application process is delayed until it is resolved, much to the chagrin of the applicant.

To prevent this from happening so often, the workshop organizers convened a subcommittee to draft a white paper, or proposed industry guideline for the format and content of Type III DMFs. That document was presented at the workshop held March 25–27, 2002, in Arlington, VA. The workshop, sponsored by the Michigan State University School of Packaging, also covered DMFs for other areas, such as active ingredients (Type II), excipients (Type IV), and contract laboratory and packaging facilities (Type V).

The white paper on packaging covers what sort of information should be included in a Type III DMF. It also addresses characterization of the package and the way it is produced as well as formatting of the Letters of Authorization (LOAs) from suppliers that allow a drug company to reference a specific DMF in an NDA or other submission. The control of changes to a DMF is also discussed. The paper includes examples of what a DMF and an LOA should look like and encourages suppliers to familiarize themselves with the 1999 guidance on container closure systems, which outlines what sort of packaging information FDA expects to see in an NDA.

The document is on the workshop's Web site at http://dmfworkshop.msu.edu, where it will remain for at least six months to allow others to submit written comments. FDA officials present at the workshop said that while the document would not have the weight of an official FDA guidance, it could be a useful resource for the agency, which is authorized to heed guidelines from other sources if it does not have one of its own. There is no FDA guidance specific to Type III DMFs, and the last one covering all types of DMFs was published in 1989.

Some of the most important issues to emerge from the workshop were:

  • How far back in the packaging supply chain should DMFs, and by extension GMPs, be required? Most attendees said they presumed that the supplier of the finished package will have a DMF, and that the finished-package supplier's material vendors will, too, but beyond that, the issue is not clear.
  • Whether it is best for a supplier to generate an individual LOA for each specific submission where the DMF will be referenced, or if a generic one for each DMF would suffice.
  • Whether DMFs should be considered the best vehicle for change control. Many attendees said they should not, but that they should be incorporated as seamlessly as possible into change control procedures.
  • How to resolve the disconnect between FDA's Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) over the use of Type V DMFs, which generally cover facilities-related issues. Vendors, including contract packagers, must obtain prior approval from the agency to file these. CDER discourages their use on the grounds that that information is better left to evaluation during field inspections. However, because of the sensitive nature of some of the products it reviews, and because the facilities producing them may be small research labs with no prior FDA regulation experience, CBER encourages their use and is about to finalize a guidance covering them. As a result, firms with products that need to be reviewed by both CDER and CBER may not be sure how to proceed.

Organizers also said they would like to see an FDA-sponsored forum in which the agency educates industry on how its reviewers use and maintain DMFs. They would also like a global DMF system established, perhaps through the International Conference on Harmonization.

The workshop's main theme was the need for applicants and vendors to communicate closely and frequently on DMF issues, and for every firm involved to designate specific contact people for DMF-related topics.

"Each party has to define its requirements and expectations," said Maxine M. Gallagher, vice president of regulatory affairs for West Pharmaceutical Services Inc. (Lionville, PA) and a member of the subcommittee that drafted the white paper. "Don't make assumptions."

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