361 HCT/Ps vs. Section 351 Biologics: FDA's Regulatory Line and Enforcement Against Unapproved Regenerative Medicine Products

361 HCT/Ps vs. section 351 biologics: where FDA draws the line and how it enforces against unapproved regenerative medicine products

The short answer

An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 only if it meets all four criteria in 21 CFR 1271.10(a): minimal manipulation, homologous use only, no combination with another article (with narrow exceptions), and either no systemic effect and no dependence on living-cell metabolic activity, or one of the permitted autologous uses, allogeneic use in a first- or second-degree blood relative, or reproductive uses ^75767778. If it fails any one criterion and no 21 CFR 1271.15 exception applies, it is regulated as a drug, device and/or biological product under the FD&C Act and/or section 351 of the PHS Act ¹²⁸. If FDA regulates it as a section 351 biologic, that means a BLA for marketing and an IND for clinical investigation; a product regulated instead as a device or a non-biologic drug follows the device or NDA pathway.

FDA's enforcement record follows a consistent pattern. The agency starts with untitled letters and mass "it has come to our attention" correspondence. It escalates to warning letters that apply the 1271.10(a) analysis criterion by criterion. In the most serious cases it has used seizures and permanent injunctions, and appellate courts in both the Eleventh and Ninth Circuits have sided with FDA on stromal vascular fraction (SVF) ^487570505602.

The regulatory test under 21 CFR Part 1271

Key definitions (21 CFR 1271.3)

• HCT/P: articles containing or consisting of human cells or tissues intended for implantation, transplantation, infusion or transfer into a human recipient ¹¹⁵.
• Minimal manipulation, structural tissue: processing that does not alter the tissue's original relevant characteristics relating to its utility for reconstruction, repair or replacement ¹¹⁶.
• Minimal manipulation, cells or nonstructural tissue: processing that does not alter the relevant biological characteristics of the cells or tissues ¹¹⁷.
• Homologous use: repair, reconstruction, replacement or supplementation of a recipient's cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor ¹¹⁸.

Several articles are expressly excluded from the HCT/P definition. The exclusion that matters most for regenerative medicine enforcement covers secreted or extracted human products such as milk, collagen and cell factors (semen remains an HCT/P) ¹²¹. Minimally manipulated bone marrow for homologous use that is not combined with another article is also excluded ¹²², as are vascularized organs, blood and blood components, and nonhuman animal cells and tissues ^119120124.

The four 1271.10(a) criteria

All four must be met ⁷⁵. An HCT/P that fails, with no 1271.15 exception, is regulated under the FD&C Act and/or section 351 ¹²⁸.

Exceptions from Part 1271 (21 CFR 1271.15)

The exception most often argued by clinics is the same surgical procedure exception. It covers "an establishment that removes HCT/P's from an individual and implants such HCT/P's into the same individual during the same surgical procedure" ¹³¹. Other exceptions cover nonclinical scientific or educational use, carriers, facilities that only receive or store HCT/Ps for use within the facility, and immediate transfer of reproductive cells to a sexually intimate partner ^130132133134.

How FDA interprets minimal manipulation

FDA's final guidance Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (July 20, 2020) is the main interpretive document ¹⁹. Three principles drive the analysis:

• "Original" and "relevant" have specific meanings. "Original" means present in the donor tissue. "Relevant" means capable of meaningfully bearing on the structural tissue's utility, for example strength, flexibility, cushioning or covering properties ²⁴²⁵.
• The donor tissue anchors the analysis. FDA assesses the effect of processing on the tissue as it existed in the donor, not on the product's intended use in the recipient ²⁴²⁵. Isolating cells from structural adipose tissue does not move the analysis to the nonstructural definition ²⁶.
• The effect of processing controls, not the name of the step ²⁷²⁸.

How FDA interprets homologous use

Homologous use means the HCT/P performs the same basic function or functions in the recipient as in the donor. It need not perform every donor function or be placed in the same anatomical location, but every function it is expected to perform in the recipient must be a basic donor function ³⁵³⁶³⁷. Intended use is judged from labeling, advertising and other indications of objective intent, and those indications must refer only to homologous uses ³⁸. This is why website and social media claims feature so heavily in warning letters.

The guidance separates basic tissue function from hoped-for clinical effect:

• Adipose tissue: filling facial or hand voids or supporting breast reconstruction is homologous. Using adipose-derived HCT/Ps to regenerate cartilage or tendon, or to promote remyelination, generally is not ³⁹.
• Amniotic membrane: covering and protecting the eye is homologous. Use to regenerate bone, or to heal wounds by reducing scarring and inflammation rather than by covering and protecting, is not ⁴⁰.
• Bone: supplementing bone in defects across anatomical sites is homologous ⁴¹.
• Cord blood HSPCs: infusion to treat cerebral palsy through purported brain-tissue repair is not homologous ⁴²⁴³.

The same surgical procedure exception

FDA's guidance on the 1271.15(b) exception requires removal and implantation in the same individual, during the same surgical procedure, of "such HCT/Ps," meaning the HCT/P in its original form ¹⁰². FDA generally means one operation at one establishment, such as an autologous skin graft or a coronary bypass using the patient's own vessel. Limited exceptions apply for later reimplantation of cranial bone flaps or parathyroid tissue ¹⁰³¹⁰⁴.

Permitted processing is generally limited to rinsing, cleansing, sizing and shaping. Centrifugation or filtration solely to remove debris can count as cleansing ¹⁰⁵¹⁰⁶. Processing that qualifies as minimal manipulation does not necessarily preserve "such HCT/P" ¹⁰⁷. Cell isolation, expansion, activation and enzymatic digestion generally take the tissue outside the exception. FDA contrasts lipoaspirate centrifuged only to remove debris, which may qualify, with adipose tissue digested or disrupted to isolate SVF, which generally does not ¹⁰⁸¹⁰⁹.

Products that are not HCT/Ps at all: amniotic fluid and exosomes

Two product categories fall outside the 361 framework because they are not HCT/Ps in the first place:

• Amniotic fluid. In the Kimera Labs warning letter, FDA said secreted body fluids such as amniotic fluid are excluded from the HCT/P definition and cannot be regulated under section 361 ³⁵⁷. The Invitrx, Amnio Technology and Chara letters make the same point ^422456381. A CBER untitled letter to Pacific Stem Cells said clinical-use amniotic fluid is generally subject to biological product and unapproved drug premarket requirements ⁵⁴⁵.
• Exosomes. FDA's Public Safety Notification on Exosome Products (December 6, 2019) states that exosomes used to treat diseases or conditions in humans are generally regulated as drugs and biological products requiring premarket review. It reported serious adverse events in Nebraska patients treated with unapproved products marketed as containing exosomes, and noted that no exosome products were FDA-approved ^494495496. Recent warning letters cite this notification directly ^483468366.

What section 351 status means in practice

An HCT/P that fails 1271.10(a) needs a BLA to be marketed and an IND for clinical use during development ¹²⁸⁵³⁸. On the positive side, these products can qualify for expedited development. FDA's Expedited Programs for Regenerative Medicine Therapies for Serious Conditions guidance defines regenerative medicine therapies to include cell therapies, therapeutic tissue-engineering products, human cell and tissue products, and combination products using them. The definition excludes products regulated solely under section 361 ⁷⁰. RMAT designation also requires a serious condition and preliminary clinical evidence of potential to address an unmet medical need ⁷¹⁷²⁷³.

The enforcement discretion period and its end

When FDA announced its regenerative medicine policy framework in November 2017, it issued final guidances on the same surgical procedure exception and on minimal manipulation and homologous use ⁵⁸⁸. FDA said it intended to exercise enforcement discretion for 36 months for certain products subject to premarket review. That discretion would not extend to products posing potential significant safety concerns, and enforcement would weigh how a product is administered and the condition it is used for ⁵⁸⁹. In July 2020, citing COVID-19, FDA extended the period from November 2020 to May 2021 ^5909192. The extension again excluded products with reported or potential significant safety concerns ⁵⁹¹⁵⁹². The guidance states that FDA would focus on higher-risk products, including risk associated with route and site of administration ⁹³.

Since that period ended, warning letters have been issued against products with lower-risk profiles, including topical and wound-care placental matrices (see below).

Enforcement record

CBER untitled letters

CBER's "Untitled Letters (CBER)" page describes an untitled letter as initial correspondence citing violations that do not meet the threshold for a warning letter ⁵³²⁵³³. Note that CBER's untitled letters for HCT/Ps are separate from OPDP's promotional untitled letters to drug sponsors. Representative CBER letters to regenerative medicine marketers:

FDA's index also lists untitled letters to Regener-Eyes, LLC (October 5, 2022) and Amnion Florida, LLC (March 12, 2024), among others ⁵³⁰. FDA also announced untitled letters to RichSource Stem Cells and Chara Biologics alongside the December 2019 Liveyon warning letter ⁵²⁰. It announced an untitled letter to R3 Stem Cell in May 2019 ⁵⁶⁴.

Mass "it has come to our attention" correspondence

In April 2019, FDA reported sending regulatory correspondence, including warning letters, to 45 manufacturers and health care providers over the prior year. It sent 20 more letters that day to firms that might be offering unapproved stem cell products ⁵⁶³. FDA repeated the 20-letter batches with the Cord for Life (April 2019), Stemell (September 2019) and Liveyon (December 2019) actions ^517518519520.

Warning letters

A search of FDA's warning letter database for HCT/P, stem cell, cord blood, amniotic, SVF and exosome terms returned 57 matching letters dated from 2012 to October 2026. The letters fall into distinct waves.

Wave 1: adipose-derived SVF and cultured MSCs (2012 to 2018).

• Celltex Therapeutics (Sept. 24, 2012): cultured, expanded autologous adipose-derived MSCs failed minimal manipulation and homologous use. FDA cited no BLA or IND and significant CGMP/CGTP deviations ^398399400.
• Irvine Stem Cell Treatment Center (Dec. 30, 2015): SVF given by injection or nebulization for autism, Parkinson's disease, COPD, MS and ALS. Failed (a)(1) and (a)(2) ⁴¹⁴⁴¹⁵.
• US Stem Cell Clinic (Aug. 24, 2017): SVF given intravenously and intrathecally. Failed minimal manipulation and homologous use; BLA required; CGMP/CGTP deviations ^335336337338.
• American CryoStem (Jan. 3, 2018): ATCELL, culture-expanded SVF. Failed (a)(1) and (a)(2); no 1271.15 exception; no BLA or IND ^388389390.
• StemGenex Biologic Laboratories (Oct. 31, 2018): SVF marketed for Alzheimer's disease, diabetes, COPD and MS. FDA said treating these diseases does not perform adipose tissue's cushioning and support functions ^393394395.

Wave 2: umbilical cord blood and cord tissue (2018 to 2020). These letters introduced (a)(4) as a central ground. Allogeneic, living-cell-dependent products for unrelated recipients cannot meet it.

• Genetech (Nov. 29, 2018): cord blood products; no BLA or IND; CGMP/CGTP deviations ³¹⁸³¹⁹. FDA separately reported that 12 patients who received Genetech-processed products distributed by Liveyon became ill with blood or other bacterial infections, including E. coli ⁵²²⁵²³.
• Cord for Life (Mar. 29, 2019): PremierMaxCB, an allogeneic cord blood product marketed for orthopedic conditions. Failed (a)(2) and (a)(4) ^292293294.
• Stemell (Aug. 28, 2019): cord blood product (failed homologous use and (a)(4)) and cord tissue product (failed homologous use and minimal manipulation) ³²⁷³²⁸.
• Liveyon Labs (Dec. 5, 2019): PURE and PURE PRO cord blood products failed (a)(4) ^443444445446.
• Invitrx Therapeutics (Mar. 16, 2020): cord blood, Wharton's jelly, amniotic fluid and amniotic membrane products. FDA cited donor eligibility and aseptic processing deficiencies ^418421422423.

Wave 3: COVID-19 claims (2020). CBER issued warning letters for unapproved products related to COVID-19 to firms including EUCYT Laboratories, Create Wellness Clinics, PA Green Wellness, Predictive Biotech, Lattice Biologics and Vibrant Health Care ^{158154171181183168}. The Lattice letter addressed AmnioBoost, an amniotic fluid product promoted for COVID-19-related ARDS ^331332333.

Wave 4: placental, amniotic, cord and exosome products after the discretion period (2023 to 2026). These letters typically say FDA "did not evaluate" the remaining criteria once one failure was established ^472407454.

• Kimera Labs (Sept. 1, 2023): XoGlo exosome products and Amnio2X. An IND for XoGlo Pro did not legalize commercial distribution. The letter references an April 2020 untitled letter and a December 2022 FDA letter ^354357358359.
• MiMedx Group (Dec. 20, 2023): AXIOFILL placental collagen matrix for wound care failed minimal manipulation alone ^470471473.
• Amnio Technology (Oct. 1, 2024): PalinGen Flow failed (a)(1) because processing destroyed the membrane's barrier properties, and (a)(2) because of wound-healing claims ^451453455.
• Skye Biologics (Dec. 16, 2024): BioECM flowable cord matrix. Processing changed the cord from a conduit into a flowable product ^403406408.
• Chara Biologics (Jan. 17, 2025): escalation from the 2019 untitled letter. Covered CharaCore, CharaOmni and the CharaExo amniotic fluid/extracellular vesicle product, and included a misbranding count for unsupported expiry dating ^378380384386.
• BioStem Life Sciences (Jan. 17, 2025): cord and amniotic products processed into injectable forms for joint and tissue repair ^428430432.
• Celularity (Dec. 1, 2025): Interfyl decellularized placental matrix. Nonhomologous use only. The letter references a 2004 Request for Designation letter covering narrower uses ^297299305.
• BioXtek (Dec. 1, 2025): amniotic membrane products for wound healing failed homologous use ⁴³⁷⁴³⁹.
• Microvascular Tissue (Dec. 3, 2025): mVASC hypodermis-derived ECM for diabetic foot ulcers ^308311314.
• 2026 clinic and seller letters: Dynamic Stem Cell Therapy ^478479481, Blue Horizon International ^361362364, R3 Medical Companies (which follows the 2019 notice to R3 Stem Cell) ^368371375, NexCell Scientific ^341344346, Beaute Bounty ³²¹³²³ and Calibrate IV Hydration (an IV hydration business offering "Stem Cell IV" and "Exosome IV") ⁴⁶¹⁴⁶³.

Seizures, injunctions and court decisions

• Seizure (Aug. 25, 2017): U.S. Marshals seized five vials of Vaccinia Virus Vaccine (Live) belonging to StemImmune. The vaccine was being combined with fat-derived stem cells and injected into cancer patients at California Stem Cell Treatment Centers ⁴⁸⁷⁴⁸⁸.
• Injunction complaints (May 9, 2018): DOJ filed complaints for permanent injunction against US Stem Cell Clinic (S.D. Fla.) and against California Stem Cell Treatment Center and Cell Surgical Network (C.D. Cal.) ^570571575577.
• Florida outcome: on June 3, 2019, the district court granted summary judgment that the defendants adulterated and misbranded SVF products. On June 25, 2019, it enjoined manufacture and distribution of all SVF products until the defendants came into compliance ⁵⁷³. A separate consent decree bound former manager Theodore Gradel ⁵⁷⁴. On June 2, 2021, the Eleventh Circuit affirmed. It held that the same surgical procedure exception was unambiguously inapplicable because the reinjected SVF was no longer the HCT/P that had been removed, and that the marketed uses were not solely homologous ^505506507.
• California outcome: the district court ruled for the defendants, holding that SVF was not a drug and alternatively that the same surgical procedure exception applied ⁶⁰¹⁵⁹⁵. On September 27, 2024, the Ninth Circuit reversed and remanded. It held that SVF is a drug and that the procedure removes fat but implants SVF, so it does not qualify for the exception ^602603604.

Practical takeaways for regulatory teams

1. Any single 1271.10(a) failure is enough. Recent letters stop after one or two failed criteria and expressly decline to evaluate the rest ^472407300.
2. Promotional claims decide homologous use. Anti-inflammatory, regenerative, joint repair and systemic disease claims for amniotic, placental and cord products repeatedly triggered (a)(2) findings ^40439463.
3. Allogeneic products for unrelated recipients fail (a)(4) when they have a systemic effect or depend on living-cell metabolic activity for their primary function. Cord blood products have failed this way since 2019 ^293445344.
4. Converting sheets or conduits into flowable or injectable forms is a red flag for minimal manipulation ^30406430.
5. Amniotic fluid and exosomes are outside the 361 pathway entirely ³⁵⁷⁴⁹⁴.
6. An IND does not authorize commercial sale ³⁵⁸.
7. Wound care is not a safe harbor. Since 2023, FDA has issued warning letters for topical placental and ECM products marketed for wounds and diabetic foot ulcers ^470308437.

Open questions a team would typically pursue next include product-specific Request for Designation strategy, CBER untitled letters not summarized here (such as Regener-Eyes and Amnion Florida), and whether firms named in 2019 to 2021 untitled letters later received warning letters.