Welcome to Alston & Bird’s introduction to biological products regulation. In this five-part intro-level series, we provide answers to a number of questions drug developers may have about the regulation and regulatory pathway for their products.
The series includes:
- What Is the Regulatory Pathway for Biological Products?
- Unlocking Reference Product Exclusivity: What Biologics Sponsors Need to Know
- Biosimilars 101
- Preparing for the FDA’s Pre-License Inspection
Sponsors developing innovative therapeutics often face a critical question early in development: Is the product regulated as a biological product under the Public Health Service Act (PHSA) or as a drug under the Federal Food, Drug, and Cosmetic Act (FDCA)? This determination drives the development pathway, dictates whether the sponsor will pursue a biologics license application (BLA) or a new drug application (NDA), and shapes expectations for chemistry, manufacturing, and controls (CMC), clinical studies, and post-market requirements. Because this classification can significantly impact development timelines, data requirements, and long-term regulatory strategy, it is essential for sponsors to understand how the Food and Drug Administration (FDA) interprets the statutory framework.
In Section 351(i)(1) of the PHSA, Congress defines a biological product to include:
A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.
The analysis is generally straightforward for most products. Much of the complexity for innovative therapeutics stems from how the FDA interprets the term “protein,” which now governs the classification of a wide range of peptide and recombinant products.
The FDA defines a protein in 21 C.F.R. 600.3(h)(6) as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” This threshold serves as a bright line for sponsors: products with longer amino acid chains are generally treated as proteins and regulated as biologics, while shorter peptides typically fall under the drug pathway, unless they qualify as an “analogous” product or fit within another enumerated category.
The FDA’s approach differs from Europe. The European Medicines Agency does not apply a fixed amino acid cutoff; instead, it evaluates products based on how they are manufactured. Products produced through recombinant expression or cell-based systems are generally treated as biological medicinal products—even if they fall below the size threshold that would trigger biologics regulation in the United States. Sponsors planning submissions should therefore assess early whether region-specific strategies will be needed to satisfy each regulatory framework.
A related issue for sponsors is determining whether the product will be reviewed by the FDA’s Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER). Although both centers regulate biologic products, the FDA assigns responsibility based on product category, mechanism of action, and the center’s expertise. Vaccines, cell and gene therapies, and blood- or plasma-derived products fall under CBER, while therapeutic proteins, monoclonal antibodies, and enzymes are regulated by CDER.
Products that raise classification questions—particularly combination products—may require input from the Office of Combination Products. Sponsors can request a formal designation to confirm which center will regulate the product and which regulatory framework applies.
Product classification becomes even more nuanced for antibody-drug conjugates (ADCs), targeted therapies that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. The FDA considers an ADC to be a combination product composed of a biological constituent part and a drug constituent part. The agency generally recommends submission of a BLA under Section 351 of the PHSA as the most appropriate application for ADCs.
Taken together, these considerations demonstrate why conversations about early classification are essential for development programs. Sponsors should evaluate the statutory definitions, analyze the molecular characteristics of the proposed product, and consider early engagement with the FDA for novel therapeutic products as part of their regulatory strategy.
If you have any questions, or would like additional information, please contact one of the attorneys on our FDA: Drug & Device team.
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