505(b)(2) Eligibility for Biologics: The Drug-Biologic Boundary and the Deemed-BLA Transition
Choosing between an NDA and a BLA is one of the earliest and least reversible decisions in a development program. It determines which application a sponsor files, which exclusivity and patent provisions apply, how later competitors can reference the product, and whether a literature- or listed-drug-supported 505(b)(2) strategy is available at all. For protein products in particular, the statutory category shifted under sponsors mid-lifecycle, so teams working on legacy molecules or their follow-ons need to know which regime governs today.
The analysis below sets out how the FD&C Act and the Public Health Service Act divide products between drugs and biological products, where FDA has drawn that line for proteins, peptides, and other borderline molecules, and what the deemed-BLA transition did to previously approved NDAs. It also covers the routes that remain open once a product falls on the biologics side of the boundary, with citations to the governing statute, FDA guidance, and the transition documentation.
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505(b)(2) and biologics: the drug-versus-biologic boundary and the deemed-BLA transition
The short answer
The 505(b)(2) pathway is a New Drug Application (NDA) route under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 5. It cannot be used for a product that must be licensed as a biological product under section 351 of the Public Health Service (PHS) Act. Whether a given molecule is a "drug" (eligible for an NDA, including 505(b)(2)) or a "biological product" (which must be licensed via a Biologics License Application, or BLA) turns on the statutory definition of "biological product," which Congress amended to include "protein" 24. Since March 23, 2020, proteins that were historically approved as NDAs, most prominently insulin and human growth-hormone-related products, are regulated as biologics; on that date their approved NDAs were "deemed to be" BLAs by operation of the Biologics Price Competition and Innovation (BPCI) Act 13. The practical consequence for regulatory strategy is that 505(b)(2) is no longer an available route for a protein product; sponsors instead use a stand-alone BLA under section 351(a) or a biosimilar/interchangeable application under section 351(k) 311.
How FDA draws the drug-versus-biologic line
The category boundary is statutory. The definition of "biological product" in section 351(i) of the PHS Act was modified by Congress to include a "protein," and FDA interprets the term "protein" to mean "an alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids" 2. That 40-amino-acid line is the operative cut point RA teams should keep in mind:
- A molecule that is an alpha amino acid polymer greater than 40 amino acids is a protein and therefore a biological product. It must be licensed under section 351 of the PHS Act (a BLA), not approved under section 505 of the FD&C Act (an NDA) 24.
- A peptide at or below 40 amino acids, and a chemically synthesized polypeptide, generally remains regulable as a drug and can proceed through an NDA, including the 505(b)(2) route where the applicant relies in part on data it does not own 25.
FDA codified this interpretation and the broader consequences of the amended definition through its "Definition of the Term 'Biological Product'" rulemaking 4. The immediate significance is jurisdictional: the definition, not the sponsor's preference, determines whether a marketing application is an NDA or a BLA, and therefore which exclusivity regime, competition pathway, and review center apply.
Can a 505(b)(2) application be used for a biologic?
For a product that is a biological product regulated under section 351 of the PHS Act, the answer is no. Section 505 of the FD&C Act (which houses 505(b)(1), 505(b)(2), and 505(j)) is the NDA/ANDA framework for "drugs" 5. A biological product is licensed under the PHS Act, so its marketing application is a BLA, not an NDA. FDA's own guidance on choosing between an ANDA and a 505(b)(2) application frames both as section 505 drug routes, which by construction excludes products that must be licensed as biologics 6.
The nuance that trips people up is historical. Before the transition, several protein products, including insulins, were in fact approved as NDAs under section 505, and some relied on the 505(b)(2) route. That was a product of the pre-2020 statutory text and FDA's transitional regulation of certain proteins as drugs. Once those proteins became "biological products" under the amended definition and their applications were converted to BLAs, the 505(b)(2) route ceased to be available for them going forward 23. In short: 505(b)(2) was never a biologics pathway; it was a drug pathway that some proteins temporarily used while they were still regulated as drugs.
The deemed-BLA transition: what happened on March 23, 2020
The BPCI Act created a hard cut-over date. On March 23, 2020, the BPCI Act required that an approved application for a "biological product" under section 505 of the FD&C Act be deemed to be a license for that biological product, that is, an approved BLA under section 351 of the PHS Act 3. FDA issued dedicated procedural guidance, "The 'Deemed to be a License' Provision of the BPCI Act: Questions and Answers," from CDER and CBER to explain the mechanics of the conversion 1, and published submission (eCTD) instructions for the former NDAs that became BLAs so that sponsors could keep filing lifecycle submissions against the new BLA numbers 3.
Concretely, the approved NDA did not disappear; it was re-characterized as a licensed biologic. Drugs@FDA records for the affected applications now carry the notation that the former NDA "Was Deemed To Be a BLA on March 23, 2020." Examples visible in Drugs@FDA include:
- SOMAVERT (pegvisomant), now BLA 021106 (a growth-hormone receptor antagonist) 7;
- MENOPUR (menotropins), now BLA 021663 8; and
- HYLENEX RECOMBINANT (hyaluronidase, recombinant human), now BLA 021859 9.
The insulin franchise is the clearest illustration of the scale of the change. In the Purple Book, marketed insulins now appear as 351(a) licensed biological products reviewed by CDER, and they retain their original application numbers as BLA numbers, for example Humulin R (BLA 18780, first approved in 1982), Novolin R (BLA 19938), Humalog/insulin lispro (BLA 20563), NovoLog/insulin aspart (BLA 20986), Lantus/insulin glargine (BLA 21081), and Levemir/insulin detemir (BLA 21536) 10. The low, "NDA-style" numbers are the tell that these were former NDAs converted in place.
Two important features of the transition for regulatory planning:
- Center and review framework. Many transitioned protein products, including the insulins, continue to be reviewed within CDER, but they are now governed by the PHS Act and the BLA framework rather than the NDA framework 10. The transition changed the legal instrument, not necessarily the review office.
- Downstream competition. Because the originator products are now section 351(a) reference products, competitors no longer file 505(b)(2) NDAs or ANDAs against them; they file biosimilar or interchangeable applications under section 351(k). This is exactly what occurred for insulin glargine, where sponsors filed 351(k) BLAs proposing biosimilars (and interchangeables) to U.S.-licensed Lantus 11. FDA's evolving Q&As on biosimilar development under the BPCI Act sit alongside the deemed-license guidance as the governing policy set 12.
What this means for regulatory strategy
- Classify the molecule first. Apply the >40-amino-acid protein test early 2. If the candidate is a protein, plan for a BLA (351(a) originator or 351(k) biosimilar/interchangeable), not an NDA, and do not build a 505(b)(2) strategy around it 23.
- 505(b)(2) remains open only for genuine "drugs." Small peptides at or below the 40-amino-acid threshold, chemically synthesized polypeptides, and conventional small molecules can still use 505(b)(2), including reliance on published literature or a listed drug's findings of safety and effectiveness 56.
- Legacy protein NDAs are gone as NDAs. For products transitioned on March 23, 2020, there is no residual NDA to reference; a follow-on entrant must proceed under 351(k) against the deemed BLA as the reference product 311.
- Watch the exclusivity and reference-product consequences. Moving a product from the NDA/Orange Book world into the BLA/Purple Book world changes the applicable exclusivity and the competitive pathway available to follow-on sponsors, which is often the most consequential strategic effect of the boundary 41012.
For a specific molecule, the decisive questions are its amino-acid length and defined sequence (protein vs. peptide) and whether any legacy section 505 approval was swept into the March 23, 2020 deemed-license conversion. Both are answerable from FDA's definition materials and the Drugs@FDA / Purple Book records for the product in question.