Drug master files (DMFs) usually benefit both suppliers and users of packaging materials. Suppliers can submit to FDA proprietary information about their materials regarding formulation, testing results, and other data for use with new drug applications (NDAs) and other petitions without making the information public. Drug manufacturers that select these materials for their packaging can simply reference the files in their submissions without having to provide reams of their own testing data. Overall, DMFs help suppliers save secrets and manufacturers save time.
Problems can arise, however, when DMF holders do not update their files when they make material changes or fail to notify users when they do. FDA requires DMF holders to notify in writing each person authorized to reference the file if the holder adds, changes, or deletes any information in the file. Despite this requirement, there is a lot of confusion and frustration among holders and users alike regarding such notifications, explains Amy E. Fortenberry, an attorney with Paul, Hastings, Janofsky & Walker (Atlanta).
Such confusion has led to information gaps. "If the DMF is not clear, complete, and concise, there can be time delays while FDA asks questions about the meaning of the DMF," explains professor Hugh Lockhart, PhD, of Michigan State University's (MSU) School of Packaging. "DMF use helps the packaging professional because, when done correctly, it makes the proprietary information readily accessible to FDA when they need it to review an NDA. When the DMF is not done correctly, it can slow the process."
And if applicants believe an incomplete file to be complete and say so in their submissions, they could receive deficiency letters. "If the applicant thinks that information is in the drug master file, when in fact it is not, they might get a deficiency letter that can hold up the approval of their product," says Maxine Gallagher of West Pharmaceutical Services Inc. (Lionville, PA). "FDA will not approve a product until the DMF holder resolves the deficiencies cited."
Frustration could escalate even further with the release of the long-awaited PACPAC guidelines. "There is real controversy regarding DMFs and interchangeability," Fortenberry says. "PACPAC will ease confusion by clarifying what materials are viewed as appropriately interchangeable, or at least which activities can slide under the limbo bar. But putting examples into writing for the ease of industry as a whole does not change the fact that these types of changes are part of a [supplier's] process that goes on every week, virtually unregulated, and, in most cases, without notice to the applicant or final packaging manufacturer." However, she adds, for many packaging companies with properly constructed DMFs, the issue of interchangeability will be a nonissue.
The solution to good DMF maintenance is therefore a good manufacturer-supplier relationship, says consultant Ron McManus. "A good DMF is at the heart of a good vendor relationship. There is no excuse for a deficient DMF, because there is plenty of help available," he says.
Material suppliers like Perlen Converting (Hockessin, DE), for instance, do regularly update their DMFs, says Dieter Feldberg. "We want our materials to be candidates for interchangeability," he explains.
Lending a hand is MSU's School of Packaging with a workshop designed to help suppliers create DMFs that help manufacturers speed NDA approvals. Held in Washington, DC, on March 25–27, 2002, the DMF workshop will aim "to establish a common understanding among DMF holders, users, and FDA about what a good DMF is and how it works," says Lockhart. The workshop was designed by more than 20 DMF experts including holders, users, FDA, and attorneys. There will be break-out sessions to answer specific questions and for the audience to provide input to the group about manufacturer needs. To learn more and to register for the workshop, go to http://www.DMFWorkshop.msu.edu.
As users of DMFs, you should consider attending a workshop like this, especially since it brings together suppliers and users. But you should also work closely with your own suppliers to encourage a constant exchange about DMF updates. You don't need to know what DMFs say, but you do need to know that they have the information FDA wants to see. As West's Gallagher recommends, "If the DMF is lacking, then you need to negotiate with the DMF holder to correct it. Otherwise, you will need to submit the additional information yourselves."
Daphne Allen, Editor