Section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 requires that on March 23, 2020, all New Drug Applications (NDAs) for biological products will be “deemed to be a license” under Section 351 of the Public Health Service Act (PHSA).  In December of last year, the FDA published a final guidance as well as a Questions and Answers guidance regarding the complex logistics of this regulatory transition.  One thing missing from those guidances was the impact that the transition from NDA to BLA would have on these applications with regards to the use of Drug Master Files (DMFs).

Historically, holders of NDAs and Abbreviated New Drug Applications (ANDA) have been allowed to support their applications by referencing manufacturing and testing information that has been submitted to the FDA in Drug Master Files.  There are no significant limits on this practice for NDAs and ANDAs.  DMFs are often used for information regarding components, excipients, active pharmaceutical ingredients (APIs), API intermediates, and even finished drug products.

This is not the case for Biologic License Applications (BLAs).  The FDA requires that BLA holders have direct control over the manufacturing process for the Drug Substance (DS), Drug Substance Intermediates (DSI), and the Drug Product (DP) in order to effectively ensure product quality.  The referencing of DMFs for other components (e.g., excipients and container-closures) of a biological product by BLA holders is allowed.

So, what happens to the NDAs that refer to DMFs for their Drug Substance, Drug Substance Intermediates, or Drug Product when they are “deemed to be a License” in March of 2020?  This was a major conundrum.  Without the ability to continue to reference these DMFs, most, if not all, of this subset of NDAs would have to cease distribution until they were able to demonstrate to the Agency that they have direct control over the DS, DSI, and DP manufacturing processes.  Of course, this would very likely lead to drug shortages or outright unavailability of these products to patients.  Not a good situation.  But fear not.  The FDA is creative and has come up with a solution that will allow manufacturers to continue to produce and market these products without making major changes to their applications.

Enter 21 CFR 601.2(h).

This is a newly proposed addition to the Biologic Product Licensing regulations that the FDA published in today’s Federal Register (June 28, 2019) and Docket No. FDA-2019-N-1363.  It is a fix; a patch; a work-around.  This proposed regulation (on which the FDA is accepting comments until the end of August) specifically states that those NDAs which are “deemed to be a License” on March 23, 2020 and which reference DS, DSI, or DP information contained in a DMF may continue to do so after the transition to a BLA.

According to the preamble of the proposed regulation, the FDA’s justification for allowing this discrepancy between the BLAs approved under Section 351 of the PHSA and those that are adopted into the BLA family on March 23rd is that the application holders of the “deemed to be a License” applications have “longstanding relationships” with the DMF holders.  Due to this longstanding relationship, the FDA believes that “the license holder of a deemed BLA may have accumulated knowledge about the quality of the biological product supplied by the DMF holder over an extended period of time” and that “(t)his accumulated knowledge allows the deemed BLA holder to implement a more robust control strategy to mitigate the risk to product quality posed by the applicant’s limited knowledge of the manufacturing process described in the DMF.”

Note well:

The FDA’s justification, as transcribed above, addresses the referencing of DMFs that are already referenced in the NDA when the transition occurs on March 23, 2020.  However, there is another proposed regulation, 21 CFR 601.2(g), that was also published in conjunction with 601.2(h).  The 601.2(g) regulation says that BLAs originally approved under Section 351 and NDAs “deemed to be a License” “may not incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file…”  Therefore, if you hold an NDA that is deemed to be a License, you will not be allowed to reference a new DMF (i.e., one that you are not referencing on March 23, 2020) if it is for DS, DSI, or DP information.  If you lose the ability to reference such a DMF after your NDA becomes a BLA, you will need to have direct control over the manufacturing processes for the Drug Substance, Drug Substance Intermediates, and/or Drug Product that were included in the lost DMF.

So the almost fatal twist, has been untwisted by the FDA’s proposed rule, which can be found here.  Leave it to the creativity of the Agency to try to make things right, especially when they see the problem in advance!