Biologic license application (BLA) filing and approval guide

A biologic license application (BLA) is the formal submission a company files with the US FDA to request permission to introduce a biological product into interstate commerce. FDA calls it a "biologics license application". Requirements are in 21 CFR Parts 600-680, and the licensing rules are in Part 601.

The legal basis is section 351 of the Public Health Service (PHS) Act. FDA approves a license only if the product is "safe, pure, and potent" and the manufacturing facility meets required standards (42 USC 262(a)).

What counts as a biological product

The statute covers a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein or analogous product (42 USC 262(i)). The definition applies when the product is for prevention, treatment or cure of a disease or condition (42 USC 262(i)). Depending on the product, either FDA's Center for Biologics Evaluation and Research (CBER) or FDA's Center for Drug Evaluation and Research (CDER) reviews the BLA (FDA).

Insulin shows why older approval records still confuse people. On March 23, 2020, approved NDAs for biological products were "deemed to be a license". Insulin, insulin analogs, human growth hormone, pancreatic enzymes and reproductive hormones were among the affected products (FDA).

What goes into a BLA submission

FDA expects chemistry, manufacturing and controls (CMC) data on the facility, production process, quality and analytical methods. A BLA also includes nonclinical reports, clinical pharmacology, human clinical trial results and proposed labeling (CBER).

21 CFR 601.2(a) also addresses stability data, samples and lot-test summaries, manufacturing locations, investigator financial disclosure and environmental documentation.

• Use Form FDA 356h. It covers NDA and BLA submissions, and it asks you to mark a 351(a) or 351(k) application.
• File in eCTD. BLAs must use eCTD format unless FDA grants a waiver or exemption, and a non-conforming submission will not be filed (FDA eCTD guidance).
• Check whether a user fee applies. PDUFA covers 351(a) applications, but a product licensed only for further manufacturing use is excluded (FDA).

Under 601.2(a), an application is not considered filed until FDA has all pertinent information and data, and FDA can refuse to file an incomplete submission. CBER's procedure is in SOPP 8404. Filing acceptance does not mean approval.

BLA approval and review timelines

Approval covers both the product and its manufacturing establishment. FDA examines the product and inspects the establishment for compliance, including good manufacturing practice (21 CFR 601.20). If FDA will not approve the application in its present form, it issues a complete response letter. A license remains valid until suspended or revoked.

Under PDUFA VII, FDA aims to act on 90% of original BLAs in its review program. Standard review has a 10-month goal. Priority review has a 6-month goal. Each goal runs from the 60-day filing date (PDUFA VII goals). Standard review is then about 12 months from submission. A major amendment can extend the goal date by three months. These are action goals, not promises of approval.

BLA vs NDA

An NDA is a new drug application under the Federal Food, Drug, and Cosmetic Act. A BLA covers biological products subject to licensure under the PHS Act. Both use Form 356h (FDA FAQ).

NDA regulations are in 21 CFR Part 314. BLA licensing follows Part 601. For follow-on products, the NDA route uses abbreviated new drug applications for generics. Follow-on biologics use the abbreviated 351(k) pathway for biosimilars and interchangeable products (FDA).

Reference products are approved through standalone 351(a) applications. A biosimilar must be highly similar to its reference product, with no clinically meaningful differences in safety, purity and potency (42 USC 262(i)(2)). An interchangeable product may be substituted for the reference product without the health care provider intervening (262(i)(3)). A 351(k) application cannot be submitted until four years after the reference product's first licensure. Approval cannot take effect until 12 years after that first licensure (262(k)(7)). Pediatric exclusivity can add 6 months (Purple Book FAQ).

BLA supplements (sBLA) under 21 CFR 601.12

After approval, changes to the product, manufacturing process, facilities or labeling fall under 21 CFR 601.12. The reporting route depends on the potential adverse effect on product quality. FDA's CMC guidance describes the same three tiers for CMC changes to certain 351(a) products.

When people say sBLA, they usually mean an efficacy supplement, which adds a new indication or makes another clinical change. Under PDUFA VII, FDA aims to act on original efficacy supplements within 10 months for standard review and 6 months for priority review, counted from receipt. Prior-approval manufacturing supplements have a 4-month goal (PDUFA VII goals).

• Substantial potential: submit a prior approval supplement (PAS). FDA must approve it before distribution of product made with the change.
• Moderate potential: generally submit a changes-being-effected supplement at least 30 days before distribution (CBE-30). FDA can permit distribution on receipt for some changes.
• Minimal potential: report the change in the annual report, due within 60 days of the approval anniversary.

Labeling has separate provisions in section 601.12(f). Most changes need prior approval. Certain safety-strengthening changes based on newly acquired information can be distributed when the supplement is submitted, before FDA approves it. Editorial changes belong in the annual report. Don't use the NDA change rule in 21 CFR 314.70. 21 CFR 314.1 says Part 314 does not apply to products licensed under the PHS Act.

CBER or CDER review of a BLA

CDER reviews monoclonal antibodies for in vivo use, plus cytokines, enzymes, immunomodulators and growth factors. CBER reviews vaccines, allergenic products, blood and plasma derivatives, antitoxins, and cell and gene therapies. The split dates to FDA's June 30, 2003 transfer of therapeutic biologics.

To check which center licensed a product, start with the Purple Book. It lists FDA-licensed biological products, including reference products, biosimilars and interchangeables, with licensure dates and exclusivity information. Drugs@FDA does not include CBER-regulated products, so one database search will not cover every BLA.

RegAffairs AI's answer on BLAs cites the FDA pages behind these rules.