What is the difference between an NDA, an ANDA and a BLA?

1What each application is for.

The new drug application (NDA) has been the basis of US drug regulation for decades: since 1938, every new drug has been the subject of an approved NDA before it was sold in the US. It gives FDA reviewers enough to decide whether the drug is safe and effective in its proposed use, whether its proposed labelling is appropriate, and whether its manufacturing methods and controls are adequate “to preserve the drug’s identity, strength, quality, and purity”.¹

The abbreviated new drug application (ANDA) is for a generic drug: one comparable to an innovator product in dosage form, strength, route of administration, quality, performance characteristics and intended use. It is abbreviated because it generally need not include preclinical and clinical data to establish safety and effectiveness; instead the applicant shows that its product performs in the same manner as the innovator drug, usually through bioequivalence. The Drug Price Competition and Patent Term Restoration Act of 1984, the Hatch-Waxman Amendments, established bioequivalence as the basis for approving generic copies of brand-name drugs.²

The biologics license application (BLA) is the formal request for permission to introduce a biological product into interstate commerce. FDA gives vaccines, blood and blood components, allergenics, somatic cells, gene therapy products, tissues and recombinant therapeutic proteins as examples of products that need one.³ Section 351 of the Public Health Service Act bars interstate commerce in a biological product unless a biologics licence is in effect for it.⁴

The approval standards come from 21 CFR 314.105(c) for NDAs and ANDAs and from section 351(a)(2)(C) of the PHS Act for BLAs.⁵⁴ A BLA is submitted to the Director of either CBER or CDER.⁶

2What goes in each.

An NDA for a new chemical entity generally contains an application form, an index, a summary, the technical sections, case report tabulations and forms, drug samples and labelling. The technical sections under 21 CFR 314.50(d) are chemistry, manufacturing and controls; nonclinical pharmacology and toxicology; human pharmacokinetics and bioavailability; microbiology, for an anti-infective; clinical data; statistics; and paediatric use. Patent information and a financial certification or disclosure for clinical investigators are also required.⁵

An ANDA under 21 CFR 314.94 must refer to a listed drug, normally the one FDA has selected as the reference standard for bioequivalence testing. It shows that the conditions of use in its labelling were already approved for that reference listed drug; that the active ingredient, route of administration, dosage form and strength are the same; and that the product is bioequivalent. It carries the same chemistry, manufacturing and controls information an NDA does, characterises the inactive ingredients, and makes a certification or statement for each listed patent, such as the Paragraph I to IV certifications.⁵

A BLA under 21 CFR 601.2 carries nonclinical and clinical data showing that the product “meets prescribed requirements of safety, purity, and potency”, with statements on good laboratory practice and on institutional review and informed consent. It also includes a full description of the manufacturing methods, stability data through the dating period, representative samples with test results, the proposed labels, and the address of each manufacturing location. A BLA is not filed until all pertinent information and data have been received.⁶

All three, with their amendments, supplements and reports, must be submitted to CDER and CBER in the electronic Common Technical Document format; for blood and blood components it is optional.⁷

3Where the 505(b)(2) application fits.

Between a full NDA and an ANDA sits the 505(b)(2) application. It is an NDA for which at least some of the investigations the applicant relies on for approval “were not conducted by or for the applicant”, and for which the applicant has no right of reference to them.⁵

The FD&C Act does not permit an ANDA for a new indication, nor for another change to a listed drug when investigations other than bioavailability or bioequivalence studies are essential to approving it. A product that modifies a listed drug, such as a new indication or a new dosage form, can instead be submitted as a 505(b)(2) application, containing only the information needed to support the modification.⁵

4How biosimilars and transitioned proteins fit.

The BLA has its own abbreviated route. Section 351(k) licenses a biosimilar: a product “highly similar to the reference product notwithstanding minor differences in clinically inactive components”, with no clinically meaningful differences in safety, purity and potency. An interchangeable product may be substituted for the reference product without the intervention of the prescriber.⁴

Some proteins were historically approved in NDAs, including insulin and insulin analogues, human growth hormone, pancreatic enzymes and reproductive hormones. Under the Biologics Price Competition and Innovation Act of 2009, an approved NDA for a biological product was deemed to be a BLA on 23 March 2020. Since then, a sponsor of such a product must submit a 351(a) BLA or a 351(k) BLA for a proposed biosimilar or interchangeable product.⁸

5How approval works.

FDA approves an NDA when the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labelling, and an ANDA when it meets the standards for manufacturing and controls, labelling and, where applicable, bioequivalence. A tentative approval means an application meets the requirements but cannot yet be approved, for example because of an exclusivity period or patent conditions; a tentatively approved product is not an approved drug.⁵

A BLA is approved only after FDA examines the product and determines that it complies with the standards in the application and with the regulations, including the good manufacturing practice requirements in 21 CFR Parts 210, 211, 600, 606 and 820. The product must be available for inspection during all phases of manufacture, and the licence is issued only after FDA inspects the establishments listed in the application.⁶ Under the Prescription Drug User Fee Act goals, FDA aims to act on a standard BLA within 10 months of the date it is accepted for filing, and on a priority one within 6 months.³

After approval, the holder must notify FDA of each change to a condition established in an approved NDA or ANDA, by supplement or in the annual report depending on the type of change; a major change needs an approved supplement before product made with it is distributed.⁵

6How it runs in Seal.

Whichever application it is, the dossier rests on studies, batches and results that keep changing. In Seal’s regulatory submissions workflow, each section keeps the studies, batches and results it rests on, with missing evidence recorded, and new source data creates review work instead of silently changing approved text. Neil, Seal’s AI agent, drafts source-linked sections and flags claims the evidence does not support; it does not approve content, choose a filing category or send anything to an authority, and dossier assembly and transmission stay with your publishing tools.

CMC content such as Module 3 stability tables keeps the data cut that produced each submitted version, so it can be reproduced as submitted. After approval, regulatory information management keeps each market’s approved state distinct from the next submission, so a change can be assessed against what was actually approved.