Regulations for Blood Bankers III: The World of 361 Tissues

In Part Two, we followed the fork in the road: cellular and tissue-based products that meet all four criteria in 21 CFR 1271.10(a) can stay in the lighter 361 pathway, while those that don’t become 351 biologics. Now let’s zoom in fully on the 361 side — the “tissue world.”

What Counts as a 361 Tissue?

Classic 361 HCT/Ps include:

• Tendons → structural grafts used in orthopedic repair.

• Corneas → restore vision by replacing a damaged cornea.

• Skin grafts → cover burns or wounds.

• Bone grafts → structural repair of skeletal defects.

• Amniotic membranes → used as wound coverings.

  
  

These are all minimally manipulated and used for their original, homologous function in the body. They’re not combined with active drugs or devices, and most are structural rather than systemic. That’s why they can remain in the 361 category.

Reproductive Tissues: A Special Subset

Reproductive tissues also fall under the 361 framework, but they’re worth highlighting separately because they are an explicit exception to the “systemic effect” rule.

• Examples: semen, oocytes, embryos, ovarian and testicular tissue.

• Why 361? They are minimally manipulated (collected, frozen, thawed) and used for their homologous function — to enable reproduction.

• The carve-out: Most HCT/Ps must not depend on systemic or metabolic activity to qualify as 361, but reproductive cells and tissues are the exception. Without this carve-out, assisted reproduction would require INDs and BLAs — an impossible barrier for routine fertility practice.

  
  

Like other 361 tissues, reproductive HCT/Ps are regulated under 21 CFR 1271 Subparts A–D: donor screening/testing, registration, and good tissue practice. FDA also issues special guidance for communicable disease testing in this context.

Why Minimal Manipulation + Homologous Use Matters

These two criteria are the backbone of the 361 definition.

• Minimal manipulation means the processing doesn’t alter the tissue’s relevant structural or biological characteristics. Freezing, shaping, or disinfecting = fine. Digesting into cells or culturing extensively = not minimal.

• Homologous use means the product is used for the same basic function in the recipient that it served in the donor.

  • Cornea → restores sight (same function).

  • Bone → provides structural support (same function).

  • Amnion → covers wounds (same barrier function).

  • Sperm → fertilizes eggs (same function).

    
    

Stay within those guardrails, and you remain a 361 product. Step outside, and you move into 351.

When Tissues “Flip” Into 351 Territory

Many products marketed as “stem cell” or “regenerative” therapies are actually tissues that don’t meet the 361 criteria.

• Amniotic membrane: If marketed simply as a wound covering = 361. If marketed as a source of stem cells with regenerative potential = 351.

• Bone grafts: Structural bone chips or paste = 361. Demineralized bone matrix marketed for its “inductive” properties to stimulate new bone growth = 351.

• Adipose tissue: Fat grafting for cushioning = 361. Isolating stromal vascular fraction for systemic regenerative claims = 351.

  
  

The rule of thumb: once you claim systemic or metabolic effects—or manipulate the tissue beyond its natural form—you’ve crossed into biologics.

Regulations That Apply

361 HCT/Ps are regulated under:

• PHS Act §361 → authority to prevent communicable disease transmission.

• 21 CFR 1271, Subparts A–D → the tissue rules:

  • Registration and listing of establishments

  • Donor eligibility determination

  • Screening/testing for communicable disease

  • Current good tissue practice (cGTP): clean facilities, recordkeeping, labeling

    
    

Notably, 361 products are not required to demonstrate clinical efficacy before use. The regulatory framework is about safety from infection, not effectiveness.

Contrast With Blood and 351 Cell Therapies

This narrower focus sets 361 tissues apart from other regulated biologics:

• Blood: Regulated as both a drug and a biologic (FD&C Act + PHS Act), with requirements for manufacturing controls, labeling, and adverse event reporting in addition to donor testing.

• 351 Cell Therapies: Must prove safety, purity, and potency through INDs, clinical trials, and BLAs. Every lot is produced under GMP and often requires product-specific release testing.

• 361 Tissues (including reproductive tissues): Avoid the heavy biologics framework entirely, so long as they stay minimally manipulated and used homologously.

  
  

Why It Matters

The 361 pathway explains why corneas, tendons, semen, and skin grafts can be transplanted or used clinically every day without going through years of clinical trials. At the same time, it highlights why the FDA is cracking down on “stem cell clinics” that try to stretch 361 definitions beyond recognition.

Understanding this distinction helps clarify not only what the law says, but also why some cellular therapies cost thousands and others cost hundreds of thousands. The difference often comes down to which side of the 351/361 fork a product falls on.

📌 Wrapping Up the Series:

• Part One: Laws vs. regulations, FDA structure, and why blood is both a drug and a biologic.

• Part Two: The fork in the road — 351 vs. 361, and how FDA decides.

• Part Three: The 361 tissue world, including reproductive tissues, its boundaries, and its contrasts with blood and biologics.

  
  

By untangling the alphabet soup, we can see the underlying logic: each pathway—blood, 351 cell therapies, 361 tissues—grew from the same legal roots but branched into different regulatory frameworks. And knowing those roots helps us understand where cellular therapy is headed next.