Understanding the 361 vs 351 HCT/P Classification: What Every Regenerative Medicine Company Must Know

Every regenerative medicine product in the United States falls under one of two sections of the Public Health Service Act. Which section applies decides whether a product can be distributed after a registration filing, or whether it needs years of clinical trials and a Biologics License Application first. For physicians evaluating exosome products, this single distinction explains most of what they will hear from suppliers, from regulators, and from their own compliance counsel.

Two sections, two very different paths

The Public Health Service Act gives FDA two distinct authorities over human cells, tissues, and cellular and tissue-based products, known as HCT/Ps.

Section 361 is the communicable-disease authority. Products regulated solely under Section 361 are subject to registration and listing, donor eligibility screening and testing, and current Good Tissue Practice under 21 CFR Part 1271. They do not require premarket review. Classic examples are minimally processed bone, skin, and cord tissue used for the same function they performed in the donor.

Section 351 is the biological-product authority. A 351 product is a drug or biologic. It requires an Investigational New Drug application before it can be studied in humans and a Biologics License Application, supported by clinical evidence of safety and effectiveness, before it can be marketed. It must also meet current Good Manufacturing Practice.

A 351 product still has to follow Part 1271 rules on registration and donor screening. The difference is what comes on top: a 361 product stops at those rules; a 351 product adds the full drug-approval pathway.

The four criteria that decide the question

21 CFR 1271.10(a) sets out four criteria. An HCT/P is regulated solely under Section 361 only if it meets all four. Miss any one and the product is a 351 biological product.

1. Minimal manipulation. Processing must not alter the tissue's original relevant characteristics for structural tissue, or the relevant biological characteristics for cells and nonstructural tissue. Cutting, grinding, shaping, freezing, and sterilizing are generally minimal. Culturing cells to expand them, or isolating a subset of what the cells produce, generally is not.
2. Homologous use. The product must perform the same basic function in the recipient that it performed in the donor. Cord tissue used to cushion a joint is not doing what it did in the umbilical cord.
3. No combination with another article, except water, crystalloids, or a sterilizing, preserving, or storage agent that does not raise new clinical safety concerns.
4. Either the product has no systemic effect and does not depend on the metabolic activity of living cells for its primary function, or, if it does, it is for autologous use, for allogeneic use in a first- or second-degree blood relative, or for reproductive use.

FDA's 2020 guidance, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use, is the reference document for how the agency applies the first two criteria. It is worth reading in full before taking any supplier's characterization at face value.

Why exosomes are not 361 products

Exosomes are extracellular vesicles secreted by cells. To produce an exosome product, cells are cultured, the material they release into the culture medium is collected, and the vesicles are isolated and concentrated from that medium. Each of those steps moves the product away from the four criteria.

• Culturing cells to harvest what they secrete is not minimal manipulation of the source tissue.
• An isolated fraction of secreted vesicles is not the tissue itself performing its original function, so the homologous-use criterion fails as well.
• Exosomes are used for their signaling activity, which is a biological effect rather than a structural one, and they are allogeneic in almost every commercial setting.

FDA has said this plainly. In December 2019 the agency issued a public safety notification after patients in Nebraska were hospitalized following treatment with unapproved exosome products, stating that there are no FDA-approved exosome products and that clinics marketing them were offering unapproved products. Since then FDA has issued warning letters to companies marketing exosome products for the treatment of disease, in each case treating the products as unapproved drugs and biologics under Section 351.

What "research use only" means in this context

Because no exosome product holds a BLA, legitimate suppliers distribute exosome material for research use only. That designation carries obligations for the supplier and for the physician.

For the supplier, it means no therapeutic claims in marketing, on labeling, or in sales conversations; traceable manufacturing under documented quality systems; donor screening and testing that meets Part 1271; and a Certificate of Analysis for every lot so the buyer can verify what they received. A supplier who characterizes exosomes as a 361 product, or who tells you a product is "FDA registered" as though that were an approval, is describing the regulation incorrectly. Registration of a facility is not approval of a product.

For the physician, it means understanding that research use is exactly that. Clinical use in patients requires an IND, an IRB-approved protocol, and informed consent that explains the investigational status. Physicians should also expect their state medical board to take an interest; several boards have issued their own guidance on unapproved regenerative products.

Questions to ask a supplier

1. Under which section do you classify this product, and can you show me the basis for that classification in writing?
2. Is your facility registered with FDA under Part 1271, and can you provide the registration number and the most recent inspection outcome?
3. Do you provide a lot-specific, third-party Certificate of Analysis showing particle count, size distribution, sterility, endotoxin, and mycoplasma results?
4. What are your donor eligibility procedures, and what infectious-disease testing is performed on every donor?
5. Do your marketing materials make any therapeutic claims? If so, why?

A supplier who answers all five directly, with documents rather than assurances, is one you can build a research relationship with. Our guide to red flags when buying exosomes covers the warning signs in more detail, and how to read a Certificate of Analysis explains what each line of the COA should tell you.

Where the regulation is heading

FDA has signaled through its guidance program and its enforcement record that it does not expect the classification of exosome products to change without clinical evidence. Several sponsors are pursuing INDs for specific exosome-based candidates, and if any reach a BLA, that product, and only that product, would be approved for the indication studied. Until then, the honest position for suppliers and physicians alike is the one FDA has already stated: exosomes are Section 351 products, there are no approved exosome therapies, and research use is the only lawful route to working with them. For a broader look at the current environment, see our 2026 physician guide to FDA regulation of exosome products.