The 361 Status Eligibility Playbook
The strongest case for eligibility is built long before the actual submission.
FDA’s Tissue Reference Group (TRG) reviews the four criteria for 361 HCT/P regulatory status eligibility. TRG’s workload has steadily increased, but not size or resources, which significantly limits their ability to respond quickly to questions, and there are no public database of decisions that give you easy access to their thinking. Furthermore, FDA is prevented from telling you what to do due to good guidance practices, and this is reflected in the feedback that doesn’t give you a clear path to 361 eligibility.
The TRG struggle is real and can have a major impact on your program. About 40% of TRG submissions come back incomplete, and with hundreds of backlogged submissions, responding to questions can extend your TRG review time by at least 6 months. Even worse, roughly one in four ultimately fail to achieve the requested 361 classification even after revision. Good documentation is helpful, but these struggles are ultimately a strategy failure, not formatting.
This playbook helps with the behind-the-scenes layer: how to read your own product honestly, navigate the criterion most likely to present a challenge, and build an argument that holds up under FDA scrutiny.
LIMITATION TO TRG FEEDBACK
When TRG identifies deficiencies, its feedback is deliberately non-prescriptive. FDA identifies the problematic areas but cannot tell you how to fix it. A well-crafted strategy put together before you file your TRG submission, is the single highest-impact thing you can do.
Step 1. Are you in scope
Before the four criteria matter, answer two threshold questions. First: does your product actually meet the definition of an HCT/P? Second: does the Same Surgical Procedure Exception under §1271.15(b) apply? If the exception applies, no need for a TRG submission. Otherwise, move on!
Step 2. Carefully scrutinize 361’s eligibility criteria
FDA’s review will walk through each criterion, and your strategy should focus on a clear assessment of each one. Pay careful attention to homologous use and minimal manipulation, these are where industry and FDA differ the most on interpretation.
CRITERION
WHERE COMPANIES GO WRONG
Homologous use
Your labeling, website, sales decks, and indications are the evidence. Claims of regenerative or anti-aging benefit are more likely to be non-homologous.
Minimal manipulation
A vague, high-level process description doesn’t read as reassuring, it reads as something to hide. Provide the right level of detail, supported by rationale for noteworthy steps, to support why processing is minimal manipulation. For structural tissues, focus on the original relevant characteristics and/or relevant biological characteristics for nonstructural tissues.
No combination
A scaffold, carrier, growth factor, or any added drug generally disqualifies you. Only water, crystalloids, and certain sterilizing/preserving/storage agents are safe.
No systemic effect or not reliant on metabolism (with carve-outs)
An allogeneic living-cell product with systemic effect, intended for unrelated recipients, cannot meet this criterion.
Step 3. Identify your best arguments
You don’t need a perfect product, but you do need a defensible position on all four criteria. Identify the criterion most likely to draw a question, then deliberately choose how you’ll handle it:
- Tighten the indication and labeling. If the concern is homologous use, narrow the claim to the donor tissue’s basic function and conform customer-facing material to match. This is where most submissions get into trouble, and a narrower claim set is an easy fix.
- Strengthen the processing story. If the concern is minimal manipulation, provide a precise, step-by-step description plus characterization data showing the relevant characteristics are unchanged. Provide clear rationale for key steps to proactively address questions about the purpose of borderline processing steps.
- Re-scope the product. If the concern is combination or systemic effect, consider removing the added article or confining use to the carve-out population.
Step 4. Tell one consistent story
Your processing narrative, labeling, IFU, intended-use statement, website, and the §1271.10(a) analysis must all describe the same product in the same terms. Internal inconsistency is the most common reason a submission stalls because it forces the TRG to write back for clarification before it can recommend anything.
Step 5. Decide whether and when to engage the TRG
A TRG recommendation is informal and non-binding, but carries real weight. Engage when your argument is ready. Understand that “test the waters” risks your company’s credibility and you can’t easily rebuild. Once you have a strategy, then you’re ready for the submission.
WHAT GOOD STRATEGY LOOKS LIKE
A solid position for all four criteria. Know your weakest criterion and have a deliberate posture for it. Your labeling has been narrowed to a defensible homologous-use claim, and there is consistency across your indication for use, labeling, website, sales materials. You engage the TRG with a complete, consistent record, and you know your binding fallback before you need it.
Worked scenarios: the four criteria in practice
The five steps are easier to apply against real product types. Three HCT/Ps appear again and again in front of the TRG, and each has a characteristic place where it slips from 361 into 351 territory. None of the readings below is a verdict on any particular product — the analysis always turns on your exact processing and your exact claims — but they show how to run the criterion-by-criterion method in practice.
Scenario 1 — Demineralized bone matrix (DBM)
DBM is allograft bone that has been cleaned, milled, and demineralized to fill bony voids or as an adjunct in spinal fusion. It is one of the most common 361 HCT/Ps on the market, but can easily be pushed out of 361 status with the wrong carrier, claim, or processing step.
CRITERION
HOW IT TYPICALLY READS
Homologous use
Bone’s basic functions include providing structural support and serving as a scaffold for the body’s own bone repair and remodeling. Filling or supplementing a bony defect tracks those functions and reads as homologous. It tips when labeling claims the DBM actively induces new bone via cellular activity or when the product is placed at non-bony sites. The specific language matters: osteoconductive and osteoinductive are acceptable claims, but TRG makes a clear distinction between these and osteogenesis. Keep the indication on bone repair, void filling, and bony supplementation.
Minimal manipulation
Bone is structural tissue, so the test is whether processing alters the original characteristics relevant to its reparative and reconstructive utility. Milling and demineralization are generally accepted as minimal manipulation. Describe each step precisely with rationale for each one. Be careful that the rationale is aligned with minimal manipulation; chemical or thermal steps that change the matrix’s relevant properties are where the analysis gets harder; cutting, milling, and disinfection or sterilization are easier.
No combination
DBM can be shipped dry, but is frequently provided in glycerol, sodium hyaluronate, carboxymethylcellulose, lecithin, a reverse-phase poloxamer, or calcium sulfate to form a putty, gel, or strip. §1271.10(a) tolerates only water, crystalloids, or a sterilizing, preserving, or storage agent that raises no new clinical safety concern. Adding carrier purely for improved handling properties pushes the product to be identified as a medical device regulated in CDRH via 510(k).
Systemic effect / carve-out
DBM acts locally and does not depend on the metabolic activity of living cells for its primary function, so this criterion is rarely the obstacle.
Scenario 2 — Amniotic membrane wound coverings
Dehydrated or cryopreserved human amniotic membrane, sometimes with chorion, is widely used as a covering or barrier over chronic and surgical wounds and on the ocular surface. As a sheet that covers and protects, it sits comfortably in 361 territory. Companies run into trouble with marketing shifts from covering and protecting to stimulating regeneration and angiogenesis. Even without problematic use claims, the product form factor matters too: powdered amniotic membrane or an injectable version is also unlikely to be homologous use even if you are only seeking to cover and protect due to failing minimal manipulation.
CRITERION
HOW IT TYPICALLY READS
Homologous use
In the donor, amniotic membrane serves as a protective covering and barrier. Using it to cover and protect a wound is homologous. It tips quickly when the labeling leans on bioactivity-type claims such as growth-factor delivery, anti-inflammatory action, angiogenesis, reduced scarring, “regeneration”, or when the product is injected into a joint or soft tissue, where the membrane performs no corresponding donor function. Keep the claim on covering, protection, and barrier function.
Minimal manipulation
As structural tissue, the test is whether processing alters the membrane’s barrier and covering characteristics. Cleaning, cutting, dehydration, and decellularization are generally minimal. Micronizing or particulating the membrane into a flowable, or processing aimed at concentrating or extracting growth factors, frequently reads as more than minimal manipulation. This usually arrives paired with non-homologous claims.
No combination
A sheet preserved with allowed storage agents is fine. Added antimicrobials, antibiotics, or other active agents raise combination questions.
Systemic effect / carve-out
A sheet acts locally and, for dehydrated products, does not depend on living-cell metabolic activity. Cryopreserved “viable” products that claim a living-cell mechanism can implicate the dependence-on-metabolic-activity prong — watch this if your marketing leans on viable cells.
Scenario 3 — When two criteria fail at once
Not every weak position can be narrowed into compliance. The clearest example is the micronized or flowable amniotic, amniotic-fluid, or umbilical-cord product marketed as an injectable for orthopedic, joint, or systemic “regenerative” use.
A COMMON TRAP
These products tend to fail two criteria at the same time: particulating or fluid-processing the tissue reads as more than minimal manipulation, and injecting it for joint, orthopedic, or systemic benefit is non-homologous — the tissue performs no such function in the donor. FDA has treated many of these injectables as unapproved 351 products. When both the processing and the claim move away from the tissue’s donor function at once, no labeling fix rescues the 361 position; the honest answer is the 351 pathway, and the real question becomes how to get there efficiently.
FDA sources & references
- SOPP 8004 — Tissue Reference Group: procedures, timing, and responsibilities. fda.gov ↗
- Guidance — Regulatory Considerations for HCT/Ps: Minimal Manipulation and Homologous Use (Guidance for Industry and FDA Staff, July 2020). fda.gov ↗
- Guidance — Same Surgical Procedure Exception under 21 CFR 1271.15(b): Q&A (Guidance for Industry, November 2017). fda.gov ↗
- Regulation — 21 CFR Part 1271 — §1271.10(a), §1271.15; 21 CFR Part 3 (Requests for Designation); Sections 351 & 361 of the PHS Act.
The hardest part is the part FDA won’t do for you.
Deffai conducts a criterion-by-criterion evaluation of your classification — and where we find vulnerabilities, we give you the specific, prescriptive direction the Agency will not.
Johnny Lam, PhD — Head of Regulatory Strategy · Laura Rose, PhD — Cofounder & Chief Regulatory Officer
This document is general regulatory-strategy guidance, not legal advice, and does not create an attorney–client or consulting relationship. HCT/P jurisdiction is highly product- and indication-specific, and FDA’s views evolve. TRG recommendations are informal, non-binding, and based on the information presented; only a Request for Designation under 21 CFR Part 3 yields a binding determination. Confirm current FDA procedures and consult qualified regulatory counsel before acting.