Regulations for Blood Bankers II: 351 vs. 361 and The Fork in the Road
- caitlinraymondmdphd
- Sep 1
- 4 min read
In Part One, we mapped out how laws and regulations interact, how the FDA is structured, and why blood is both a drug and a biologic. Now we turn to one of the most important dividing lines in cellular therapy regulation: the split between Section 351 and Section 361 of the Public Health Service (PHS) Act.
This fork in the road determines how HCT/Ps (human cells, tissues, and cellular and tissue-based products) are regulated. Some are treated as 361 HCT/Ps (tissues, regulated mainly for communicable disease control), while others are classified as 351 HCT/Ps (biologics, requiring full FDA approval).
It’s one of the first—and most consequential—questions to ask when thinking about any cellular product.
The Four Criteria: 21 CFR 1271.10(a)
FDA uses four criteria to decide if an HCT/P can remain a 361 product. To qualify, all four must be true:
Minimal manipulation — the tissue isn’t processed in a way that alters its original characteristics.
Example: Cleaning, shaping, or cryopreserving a tendon = minimal. Digesting it into cells and reseeding a scaffold = more than minimal.
Homologous use — the product is used for the same function in the recipient as in the donor.
Example: Cornea used to restore sight = homologous. Amniotic membrane marketed for “stem cell regenerative properties” = not homologous.
Not combined with another active drug or device — except for simple carriers or preservatives.
No systemic effect / dependence on metabolic activity — unless the use is autologous, in a first- or second-degree relative, or for reproductive use.
This is the critical rule that separates many “tissues” from “biologics.”
If a product fails even one of these, it is regulated as a 351 biologic.
361 HCT/P: The “Tissue” Path
If all four criteria are met, the product stays under PHS Act 361 and 21 CFR 1271 (Subparts A–D).
Focus: communicable disease control, not clinical efficacy.
Requirements: donor eligibility testing, good tissue practice (cGTP), registration and listing with FDA.
Examples: tendons, corneas, skin grafts, bone fragments, semen.
The Fourth Rule and Bone Marrow Transplants
The “no systemic effect” rule is where confusion often arises. Most tissues—like tendons or corneas—are structural or local, so they qualify as 361. But what about hematopoietic stem cell (HSC) transplants?
Bone marrow, peripheral blood stem cells, and cord blood all have systemic effects and depend on metabolic activity to engraft and restore hematopoiesis. By the strict letter of the rule, they should be 351 biologics.
FDA carves out an exception: if HSCs are for homologous use (to reconstitute bone marrow), in an autologous setting, or between close relatives, they may remain under the 361 pathway. This is why routine bone marrow transplant programs operate under tissue-style regulation, not full BLAs.
But once HSCs are expanded, manipulated, or gene-modified, they cross the line into 351. That’s why CAR-T cells and ex vivo expanded HSCs require more regulation.
351 HCT/P: The “Biologic” Path
If you don’t meet all four criteria, you’re in PHS Act 351 territory.
Regulation: under PHS 351, the FD&C Act, and Title 21 CFR (1271 + 210/211 + 600+).
Burden: must demonstrate safety, purity, and potency to FDA’s satisfaction.
Examples: CAR-T cells, most gene therapies, expanded stem cells.
The Lifecycle of a 351 Product
The development path is long, resource-intensive, and tightly monitored:
Preclinical — laboratory and animal studies show feasibility and basic safety. These are the foundation for first-in-human use.
IND (Investigational New Drug application) — filed with FDA before any patient receives the product. It includes preclinical data, detailed manufacturing protocols, and a proposed clinical trial plan. FDA reviews the IND mainly for patient safety.
Clinical Trials
Phase 1 → small numbers, focus on safety and dose-finding.
Phase 2 → expands to measure efficacy signals while continuing safety monitoring.
Phase 3 → large, often multicenter studies that provide definitive safety and efficacy data.
BLA (Biologics License Application) — the final submission. It must prove the product is safe, pure, and potent, and that the facility itself is GMP-compliant. FDA inspects the facility and reviews manufacturing controls as closely as it reviews clinical data.
Post-market — the responsibilities don’t stop at approval. Manufacturers must monitor for adverse events, report annually, and in some cases, conduct post-marketing studies. For CAR-T cells, each lot is tested and reviewed before release.
This lifecycle explains why the cost and complexity of 351 products is so much higher than 361. A tendon graft can move directly from a tissue bank to a surgeon. A CAR-T product must travel through a decade of trials and regulatory scrutiny before reaching a patient.
Safety, Purity, and Potency: The Statutory Triad
The PHS Act requires every biologic to be safe, pure, and potent. For cellular products, those abstract words translate into specific assays:
Safety
Sterility testing (bacterial/fungal cultures)
Mycoplasma PCR or culture
Endotoxin (LAL assay)
Replication-competent retrovirus (for gene-modified cells)
Purity
Flow cytometry (e.g., % CD3+ T cells in CAR-T products)
Residual bead/cytokine/reagent testing
Ensuring absence of contaminating cell types
Potency
Cytotoxicity assays (CAR-T killing tumor cells in vitro)
Cytokine release assays (e.g., IFN-γ production)
Colony-forming unit (CFU) assays for stem cells
Differentiation assays for mesenchymal stromal cells
These aren’t just lab tests—they’re the evidence that a product meets the PHS Act’s standard. They bridge the gap between statutory language and scientific reality.
Why This Fork Matters
The 351 vs. 361 split determines whether a product needs simple donor testing and tissue practice standards—or the full might of INDs, BLAs, and GMP inspections. It shapes the cost of therapies, the infrastructure required to deliver them, and the pace at which innovation reaches patients.
Bone marrow, tendons, CAR-T cells—all fall somewhere on this spectrum. And the dividing line comes straight from the PHS Act, carried into practice through FDA’s regulations.
📌 Coming up in Part Three: We’ll focus fully on the 361 world: tissues. What qualifies, what doesn’t, and how these products are regulated when they stay inside the 1271 box.
