By Michael Cooper, Clinical and Regulatory Affairs, Pharmatech Associates
Editor’s note: This article has been revised based on input received from the FDA.
The drug master file (DMF) is one of the most effective ways for companies to protect proprietary information while still collaborating with partners. A DMF is a snapshot of the manufacturing process that is submitted to the FDA to review the suitability of a drug for clinical trials (INDs) or commercialization (NDAs or BLAs). When a DMF is submitted to the FDA, its contents are confidential. The proprietary information may only be cross-referenced, not accessed, by a partner. Under this model, the company that cross-references another company’s DMF is not expected to understand and/or be able to defend the partner’s process and process controls.
The DMF has been around for a long time as a tool to support licensure of products. The oldest DMF that the FDA maintains, for Schering Corporation’s cortate (desoxycoritcosterone acetate), was submitted in 1939.
Recently, while researching DMF requirements for a client who manufactures cell culture media for biologic processes, I reviewed guidance documents and templates on the FDA website. When my client requested a DMF number from the CDER NextGen portal, we were redirected instead to CBER’s Regulatory Information Management Staff (RIMS) to obtain a master file (MF) number. In response to my inquiries as to why and when the process changed, I learned that the process for MFs supporting biologics changed effective March 23, 2020. The impetus for the change was the Biologics Price Competition and Innovation Act (BPCIA) of 2009.
Before proceeding further, it is important for the reader to distinguish between historical requirements for the earliest biologic products (e.g., insulin, human growth hormone, pancreatic enzymes, etc.) vs. requirements for a new product seeking approval today.
The BPCIA was enacted to stimulate the development of biosimilars available at lower prices, as was successfully seen with generic small molecule drugs under the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act). Although the FDA was slower than the European Medicines Agency (EMA) to adopt biosimilars, 28 products have been approved to date.
For a new small molecule product being proposed for testing in the clinic or for marketing authorization under an NDA, it is absolutely appropriate to utilize the DMF for raw materials, starting materials, drug substance, drug substance intermediate, drug product, or packaging materials. For a new biologic product being proposed for testing in the clinic, the FDA may allow the use of DMFs for drug substance, drug substance intermediate, or drug product. For a new biologic product applying for marketing authorization under a BLA, the DMF may be utilized for raw materials, starting materials, and packaging materials, but not for drug substance, drug substance intermediate, or drug product, for reasons that will be discussed further below.
Interestingly, the earliest generation of biologic products was approved under NDAs — not BLAs — and was allowed to use DMFs. Under changes implemented this year by the BPCIA, these products have been reclassified to be approved under BLAs (“deemed to be BLAs”). CDER still maintains oversight of these products and has worked hard to minimize the burden to sponsors of these products, including allowing the continued use of DMFs. A reader with more expertise in this area could certainly write an interesting and informative article on this aspect of the BPCIA alone.
The Process Is The Product For Biologics And Biosimilars
For a new biologic product, the regulations require a sponsor to understand and control the entire manufacturing process. As the saying goes, “the process is the product” for biologics due to the intricacies of three-dimensional molecules, where subtle differences in amino acid sequence, glycosylation, and folding of the molecule can have profound effects on efficacy and safety. The FDA’s use of the term “biosimilar” indicates that large molecules cannot be replicated exactly without access to the innovator company’s equipment, procedures, and intellectual property. In fact, a high degree of variability is often seen within an innovator company’s own process. Therefore, it is not surprising that, to date, the FDA has not approved any interchangeable biosimilars permitting pharmacy-level substitution for patient-administered biosimilars.
For new biologic-related submissions (e.g., an MF for cell culture media), MF numbers for biologics are no longer issued through CDER’s NextGen portal; instead, sponsors must submit an email request through CBER’s Regulatory Information Management Staff at CBERRIMS@fda.hhs.gov with the following information:
- Sponsor name and address
- Primary point of contact information (name, phone #, email, etc.)
- Anticipated submission date
- Biologic product name and indication
- CBER Review Office (e.g., Office of Tissue and Advanced Therapies (OTAT))
Sponsors of biologic products used to referring to the CDER-issued guidance document for DMFs (September 1989) and DMF information on the CDER website should be sure to refer instead to the CDER and CBER-issued draft guidance document (November 2019) and CBER website for MF requirements.
It is important to approach the right center to keep your project on track and to meet your company’s goals. With open communication with the agency and careful regulatory planning, it is possible for every sponsor of biologics-related master files to successfully complete the submission.
Industry And FDA
Ultimately, the change of MF oversight from CDER to CBER affects current and future biologics-related MF and BLA submissions. To be crystal clear, CDER still has oversight responsibility for the BLA process for the earliest biologic products and well-characterized biologic therapeutics.
Through the Regulatory Affairs Professional Society (RAPS), I received feedback from a sponsor of a reclassified biologic product. They indicated that they are working with the same project manager at CDER, with whom they have a good working relationship. The BLA still references several DMFs, including one for drug substance. Based on this case study, the FDA’s efforts to minimize impact to existing sponsors were successful.
It will be interesting to observe any impact from this transition to the MF process. Because the FDA does not review a MF or DMF submission until another company cross-references it, it may take more time to assess any impact.
- Biologics License Applications and Master Files, Federal Register, June 28, 2019
- FDA-Approved Biosimilar Products
- Drugs.com, “How many biosimilars have been approved in the United States?"
- Cancer Treatment Center of America, “What's the difference? Biosimilar and generic drugs,” December 26, 2018
About The Author:
Michael Cooper is a clinical and regulatory affairs program manager at Pharmatech Associates. He has over 20 years of experience in the biopharmaceutical industry, with expertise in regulatory affairs chemistry, manufacturing, and controls (CMC) submissions; GMP inspections for biologics and vaccines; QA lot release of drug substance and drug product; deviation and CAPA resolution; and facilities, utilities, and equipment validation.