Well, here we are. We’ve crossed the transition date (i.e., March 23, 2020) and now the New Drug Applications (NDAs) for the biologic products that were approved by FDA under the Federal Food, Drug, and Cosmetic Act (FFDCA) should now be deemed to be Biologic License Applications (BLAs). According to the FDA’s website, a total of 95 NDAs became BLAs on Monday – including 27 insulins, 13 somatotropins, 8 follitropins, 6 gonadotropins, and 6 pancrealipases. A complete list of products is available here. As the FDA promised, the file numbers for the transitioned products have not changed. They have simply substituted “BLA” for “NDA” as the file designation. There are, however, a number of regulatory changes that holders of these transitioned applications will need to be aware of.
Product distribution reports (refer to 21 CFR 600.81) for these transitioned products will need to be submitted every six (6) months (as opposed to annually for NDAs) and must include more information than was required when the products were regulated under the FFDCA alone. In addition to the National Drug Code (NDC number) and the quantities of each strength distributed (to both domestic and foreign markets), product distribution reports for BLAs must include lot numbers of the products distributed, as well as the lot numbers of their bulk drug substance lots and their expiration dates, the lot release dates of finished product lots, and information on any returned products.
In the event that a BLA-holder thinks that their product in distribution may be misbranded or adulterated, they must submit a Biological Product Deviation Report (21 CFR 600.14) to the Division of Compliance Management and Surveillance at FDA’s Center for Drug Evaluation and Research (CDER). This report is to be submitted using Form FDA 3486 soon as possible but no later than 45 days after becoming aware that the potentially violative lots have been distributed.
The regulations for NDA products generally don’t specify testing methods. However, this is not so for biological drug products and sponsors of transitioned products should become familiar with the product safety testing requirements in the biological product regulations at 21 CFR 610.12, 610.13, and 610.30. The first regulation specifies how sterility testing should be performed, the second regulation describes requisite testing for pyrogenic substances (e.g., endotoxin), and the third describes how testing for mycoplasma contamination should be done. Although the FDA may not require that transitioned products retrospectively comply with these regulations, it should be anticipated that compliance may be required for post-approval manufacturing supplements related to changes in manufacturing or testing that could impact sterility, pyrogenic impurities, or mycoplasma contamination. In this regard, it is important to note that 21 CFR 610.9 allows manufacturers to get approval for, and utilize, alternative methods if they demonstrate that the alternative method provides an assurance of safety equivalent to that of the specified method.
And almost last, but not least, there are product labeling differences that sponsors of transitioned biologics will need to address. Under the biological product regulations, the labeling of a product must include: the address of the manufacturer; the license number; the year of initial approval of a new biological product; the recommended individual dose for multi-dose containers; and the identity of micro-organisms used in the manufacture of the product. Fear not, however. The FDA is allowing a five-year grace period (until March 23, 2025) for manufacturers to implement these labeling requirements. However, they recommend that BLA-holders submit the requisite labeling changes in a single Prior Approval Supplement before March 23, 2022 in order to ensure adequate time for the changes to be reviewed approved.
And now for “last” – today, March 24, 2020, FDA posted what it calls its “BPCIA Transition Edition” of the Orange Book (OB). The Agency discusses the changes in the first few paragraphs of the preface to the OB “BPCIA Transition Edition” which can be found here.
All in all, though change can be disconcerting and risky, the consolidation of all biologic products to be regulated under the PHS Act is likely to be an improvement and will help to ensure regulatory consistency, unfettered by statutory differences.