Points to Consider When Referencing a Master File in FDA Regulatory Submissions (IND, BLA, NDA)

January 16, 2019 Becky Hurt

Authored by: Mo Heidaran, Mark Levi and Robert Iser, PAREXEL Consulting

Drug Master Files (DMF or MF) are elective submissions of largely confidential information by the MF holder for use by their clients, who are often competitors. The MF allows the client (IND, BLA or NDA applicants) to cross reference certain information without having access to the confidential information. A MF could include a variety of information related to drug substance, drug product, drug substance intermediate, ancillary materials, packaging, container closure, facility and other information. Although this information is reviewed by FDA, MFs are neither approved nor disapproved. Typically, sponsors (IND) or applicants (NDA, BLA) cross reference the content of one or more MFs in support of their submission to FDA. There are 4 types of MFs currently in use, types II-V. Type II includes the information for Drug substance, Drug substance intermediate and Drug Product. Type III includes information about packaging materials, while type IV contains detailed information about excipients. Finally, Type V MF includes reference materials and sometimes is used to describe detailed information about the manufacturing facility.

Starting May 5, 2018, any new submissions of MF should be submitted in eCTD format. The previous master files already submitted to the agency in paper format do not need to be converted to eCTD format, although any new amendments to these previously submitted, MFs should be in eCTD format.

For cross-referencing the content of an MF, the IND, BLA, or NDA holders should provide a Letter of Authorization (LOA) in module 1 of eCTD submission obtained from MF holder and clearly state what type of information is being cross referenced. As noted in the recently published FDA guidance covering the Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), if the LOA is absent or the information in the cross reference file is not adequate for the purpose cited, FDA will notify the IND holder or applicants that such information is not sufficient to be relied upon.

Although there are no well-defined restrictions on the content of a MF, it is important to note that the type of information which can be relied upon depends upon a variety of factors, including:

  • specific type of product (small molecule versus biologics)

  • the stage of product development (IND versus BLA/NDA), and

  • the quality of material cited

PAREXEL can assist MF holders with eCTD submission of the regulatory information to the agency and can familiarize IND/BLA/NDA holders with the best practices used to properly cross reference certain materials and to better identify what type of information found in MFs can be relied upon for regulatory submissions to FDA.

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