Biologics License Application Explained

The difference is the legal basis and what the approval covers. An NDA is approved under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to market a new drug. A BLA is a licence under section 351 of the Public Health Service (PHS) Act for a biological product. 21 CFR Part 314, the NDA regulation, says outright that it "does not apply to drug products subject to licensing by FDA under the Public Health Service Act" ^[4].

	NDA (drugs)	BLA (biologics)
Statute	FD&C Act section 505; procedures in 21 CFR Part 314 [4]	PHS Act section 351; 21 CFR Parts 600-680 (covered last turn)
Reviewing centre	CDER	CDER or CBER, depending on the product. The Purple Book lists products under both centres
Approval standard	FDA approves when the drug "meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling" [5]	A finding that the product and establishment(s) meet requirements "to ensure the continued safety, purity, and potency" (21 CFR 601.2(d))
Application variants	A stand-alone 505(b)(1) NDA, or a 505(b)(2) NDA, which relies on some investigations "not conducted by or for the applicant" and with no right of reference [6]	351(a) full BLA, or 351(k) biosimilar or interchangeable
Follow-on copies	ANDA under 505(j) (generics)	351(k) biosimilar or interchangeable licence
Published register	Orange Book. Example: Uceris (budesonide), N203634, with listed patents and a TE code of AB [7]	Purple Book

What the NDA side has that a BLA doesn't (in Part 314)

• Patent listing. An NDA applicant must submit patent information for drug substance, drug product and method-of-use patents on Form FDA 3542/3542a. FDA publishes it in the Orange Book ^[8].
• Patent certifications. A 505(b)(2) applicant has to certify against the listed patents, including a "Paragraph IV" certification where it claims a patent is invalid or not infringed ^[9].
• Exclusivity under 21 CFR 314.108 ^[10]:
  • New chemical entity: no 505(b)(2) application or ANDA can be submitted for 5 years after the first NDA approval, or 4 years with an invalidity or non-infringement certification.
  • New clinical investigations essential to approval: 3 years of exclusivity.
• Tentative approval. FDA can tentatively approve an NDA that is blocked only by patents or exclusivity. A tentatively approved product "is not an approved drug" ^[5].

How the content requirements compare. An NDA for a new chemical entity generally contains "an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labeling" ^[9]. That is broadly the same set of CMC, nonclinical, clinical and labeling data as a BLA. The legal difference is that a BLA licenses the manufacturing establishment as well as the product.

In practice. CDER's 2025 novel approvals register records 34 NDAs, such as Grafapex, NDA 214759 ^[11], and 12 BLAs, such as Yartemlea, BLA 761152 ^[12].

Approach: I used the current eCFR text of 21 CFR Part 314, the FDA Orange Book, CDER's Novel Drug Approvals register, and last turn's Purple Book and 21 CFR 601.2 findings. The datasets I searched don't hold the PHS Act's biologics exclusivity and biosimilar provisions, so I haven't covered them here.

Once a product is approved, you file a supplement for changes to that same approved application. FDA does not treat it as a separate submission: Part 314 defines an "NDA" as including "all amendments and supplements to the application" ^[6]. You need a new application only when the change makes it a different product. Within the supplement route, how much risk the change carries decides whether FDA has to approve it before you distribute.

The general rule (NDA, 21 CFR 314.70(a)) The holder must notify FDA of "each change in each condition established in an approved NDA beyond the variations already provided for in the NDA." Depending on the type of change, it goes in a supplement under 314.70(b) or (c), or in the annual report under (d) ^[13]. Only the applicant can submit a supplement. It goes through the same procedures as an application, but it only needs the information that supports the change (21 CFR 314.71) ^[14].

Reporting categories for NDAs ^[13]

Category	Trigger	When you can distribute	Examples in the rule
Prior Approval Supplement (major, 314.70(b))	"substantial potential to have an adverse effect" on identity, strength, quality, purity or potency	Only after FDA approves it	Formulation or specification changes; changes needing part 320 bioequivalence studies; sterility-assurance changes; drug-substance synthesis changes that may affect impurities; most labeling changes; for recombinant proteins and similar products, a new cell line, a new master cell bank or a different viral clearance method
CBE-30 (moderate, 314.70(c))	"moderate potential" for an adverse effect	30 days after FDA receives it, unless FDA says within those 30 days that prior approval is needed	Container closure changes that don't affect quality; scale changes with different equipment for protein products; relaxing a criterion to match the compendium
CBE-0 ("Changes Being Effected", 314.70(c)(6))	Categories FDA has designated	As soon as FDA receives it	Tightened specifications; safety labeling based on newly acquired information (adding or strengthening a contraindication, warning or adverse reaction, or dosing instructions that increase safe use)
Annual report (minor, 314.70(d))	"minimal potential" for an adverse effect	Immediately; documented in the next annual report	Compendial updates; like-for-like equipment replacement; shelf-life extension under an approved protocol; editorial labeling changes

Other points in 314.70:

• If a regulation or guidance allows a lower reporting category for a change, you must use it (314.70(a)(3)).
• You can file a comparability protocol as a prior approval supplement. Once approved, it can justify a lower category for later changes of that type (314.70(e)).
• If FDA disapproves a CBE supplement, it can order you to stop distributing product made with the change (314.70(c)(7)).

Efficacy supplements (clinical changes). Part 314 defines an efficacy supplement as one that changes labeling to ^[6]:

• add or modify an indication or claim
• revise the dose or regimen
• add a new route of administration
• make a comparative efficacy claim naming another drug
• significantly alter the patient population
• switch from prescription to OTC
• convert an accelerated (subpart H) approval to traditional approval
• add information based on at least one adequate and well-controlled study

If a supplemental NDA includes new clinical investigations the applicant ran that were essential to its approval, it earns 3 years of exclusivity for that change (314.108) ^[10]. Any claimed exclusivity has to be supported with the 314.50(j) information in the supplement (314.70(g)).

When a supplement is not enough and you need a new application

• 505(b)(2) NDA: you can't supplement to get approval of a "different drug," meaning a different active ingredient, route or dosage form, or an excipient change that needs a separate clinical study (or, for topicals, a separate in vivo bioequivalence demonstration). A new strength can still be added by supplement (314.70(h)) ^[13].
• ANDA: supplements follow 314.70 and 314.71. But if the change would make the product pharmaceutically equivalent to a different reference listed drug, it needs a new ANDA. A new strength can still be added by supplement (314.97) ^[15].
• ANDA to new indication: the FD&C Act doesn't allow an ANDA for a new indication, or for changes that need studies other than BA/BE. Those go in a 505(b)(2) application (314.54(a)) ^[16].

BLAs (21 CFR 601.12) use the same tiered structure (21 CFR 601.12, GovInfo 2024 edition):

• Scope: you must report changes to the product, production process, quality controls, equipment, facilities, labeling, and also "responsible personnel."
• Prior approval for changes with "substantial potential to have an adverse effect." Examples include formulation changes, changes needing new human studies, viral clearance changes, a new source material or cell line, a new master cell bank, and sterilization changes.
• CBE-30 for "moderate potential." Under 601.12(c)(5), FDA may allow distribution as soon as it receives the supplement, for example where the change has been validated under an approved protocol.
• Annual report for "minimal potential," filed within 60 days of the approval anniversary date.
• Labeling (601.12(f)):
  • Most changes to the package insert, label or Medication Guide need prior approval.
  • Safety strengthening and removing false claims can go ahead before approval.
  • Editorial and how-supplied changes go in the annual report.

Approach: I used the current eCFR text of 21 CFR Part 314 (sections 314.3, 314.54, 314.70, 314.71, 314.97 and 314.108) from the datasets. The datasets don't hold 21 CFR Part 601, so the BLA section comes from the official 21 CFR 601.12 text on GovInfo (2024 edition). It is summarised there rather than quoted in full.

A supplement is reviewed by the same FDA centre that holds the approved application, so the answer depends on the product, not the submission type. Most NDAs and their supplements go to CDER. BLAs are split: the Purple Book records each licensed biologic under either CDER or CBER, and supplements stay with that centre.

NDAs and ANDAs (21 CFR 314.440) ^[17]

• Default is CDER. NDA supplements go to the Central Document Room in Beltsville, "to the attention of the appropriate division". After filing, FDA tells the applicant which division is responsible. ANDA supplements go to the Central Document Room, Center for Drug Evaluation and Research.
• NDAs that go to CBER. Under 314.440(b), applications and correspondence for these drug products go to CBER's Document Control Center:
  1. ingredients packaged with containers for collecting, processing or storing blood and blood components
  2. plasma volume expanders and hydroxyethyl starch for leukapheresis
  3. blood component processing solutions and shelf-life extenders
  4. oxygen carriers

BLAs. 21 CFR 601.2(a) (covered earlier) sends a BLA to the Director of CBER or of CDER. The Purple Book shows how products divide in practice, including at supplement level:

Centre	Product type	Examples
CDER	Monoclonal antibodies	Keytruda (pembrolizumab), BLA 125514, supplement 1 [18]; Danyelza (naxitamab-gqgk), BLA 761171 [19]
CDER	Biosimilars	Herzuma (trastuzumab-pkrb), 351(k), supplement 1 [20]; Kanjinti (trastuzumab-anns) [21]
CDER	Insulins	Ryzodeg 70/30, BLA 203313 [22]
CBER	Vaccines	Vaxelis, BLA 125563, supplement 34 [23]; Flucelvax, BLA 125408, supplement 575 [24]
CBER	Gene therapies	Zolgensma, BLA 125694 [25]; ITVISMA, BLA 125856 [26]
CBER	Plasma-derived products	Human Albumin Grifols, BLA 103352, supplement 5024 [27]

CBER's own approval listings show it handling efficacy-type supplements for its vaccines. Examples:

• Adding intramuscular administration to M-M-R II (STN 101069/5846, 27 February 2023) ^[28]
• The same change for VARIVAX ^[29] and ProQuad ^[30]
• Co-administration data for BOOSTRIX with SHINGRIX (STN 125106/1530) ^[31]

For a particular product, the Purple Book "Center" field (BLAs) or the 314.440(b) list (NDAs) tells you where its supplements go. If you give me a BLA or NDA number, I can look it up.

Approach: I used the current eCFR text of 21 CFR Part 314, the FDA Purple Book and CBER's biologics approval listings. FDA's intercentre jurisdiction agreements, which set the CDER/CBER split by product class, are not in the datasets I searched, so this answer doesn't cover them.