FDA regulation of human tissue (HCT/Ps)

The United States Food and Drug Administration (FDA) regulates most human cells, tissues, and cellular and tissue-based products (HCT/Ps) under 21 CFR Part 1271, a tiered, risk-based framework that distinguishes lower-risk products regulated solely under Section 361 of the Public Health Service Act from higher-risk products that are also regulated as drugs, devices, or biological products requiring premarket approval.[1][2] The framework is administered primarily by FDA's Center for Biologics Evaluation and Research (CBER) and is designed chiefly to prevent the introduction, transmission, and spread of communicable disease.[1][3]

Whole vascularized organs intended for transplantation are excluded from this framework and are instead overseen through the Health Resources and Services Administration (HRSA) and the Organ Procurement and Transplantation Network (OPTN).[4][2] See Organ transplantation.

What is an HCT/P?

An HCT/P is defined at 21 CFR 1271.3 as an article "containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient."[4] Examples expressly named in the regulation and FDA materials include bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.[4][1] Related product categories are described in Tissue bank, Bone and musculoskeletal allografts, and Amniotic membrane.

The same definition excludes a list of articles that are not HCT/Ps, including: vascularized human organs for transplantation; whole blood, blood components, or blood derivatives regulated under other parts; secreted or extracted human products such as milk, collagen, and cell factors (except that semen is included); minimally manipulated bone marrow for homologous use that is not combined with another article; ancillary products used in manufacturing; cells, tissues, and organs derived from animals other than humans; and in vitro diagnostic products.[4]

Statutory basis and the two regulatory approaches

Part 1271 implements two distinct statutory pathways, set out at 21 CFR 1271.1.[3]

• Section 361 pathway. HCT/Ps that meet all of the criteria in 21 CFR 1271.10(a) are regulated solely under Section 361 of the Public Health Service Act (the communicable-disease authority) and the regulations in Part 1271. They do not require premarket review or approval. The manufacturer must register with CBER, list its products, and comply with Part 1271 (donor eligibility and current good tissue practice).[3][5]
• Section 351 / FD&C Act pathway. HCT/Ps that do not meet all of the 1271.10(a) criteria are regulated as drugs, devices, and/or biological products under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and/or Section 351 of the PHS Act. These products generally require premarket authorization, such as an investigational new drug application (IND) and a biologics license application (BLA), or the device equivalents, and must also comply with the donor-eligibility and good-tissue-practice provisions of Part 1271.[3][6]

Section 361 vs. Section 351 HCT/Ps

| Feature | Section 361 HCT/P | Section 351 HCT/P | |---|---|---| | Governing authority | PHS Act §361; 21 CFR Part 1271 only[3] | FD&C Act and/or PHS Act §351, plus applicable Part 1271 provisions[3] | | Premarket review | None required[5] | Required (e.g., IND then BLA, or device pathway)[6] | | Manufacturing standard | Current Good Tissue Practice (CGTP), Part 1271 Subpart D[7] | CGTP plus current good manufacturing practice (CGMP)[6] | | Registration | Register and list with CBER on Form FDA 3356, Subpart B[5][8] | Register under Part 207 (drugs/biologics) or Part 807 (devices)[3] | | Regulatory status | FDA-registered, not FDA-approved[6] | FDA-approved/licensed product[6] |

The distinction is consequential: an HCT/P that fails any one of the four 1271.10(a) criteria is, by default, regulated under the more demanding Section 351 pathway.[6][2]

The four criteria of 21 CFR 1271.10(a)

An HCT/P is regulated solely under Section 361 only if it meets all four of the following criteria.[5]

• Minimal manipulation. The HCT/P is minimally manipulated.[5]
• Homologous use. The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent.[5]
• No prohibited combination. The manufacture of the HCT/P does not involve combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition does not raise new clinical safety concerns with respect to the HCT/P.[5]
• No systemic effect / not metabolism-dependent (with exceptions). Either: (i) the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or (ii) the HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function and is for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use.[5]

A manufacturer of a product meeting all four criteria must register and list and comply with the other requirements of Part 1271, but does not submit a premarket application.[5]

"Minimal manipulation"

The regulation defines minimal manipulation differently depending on the type of tissue, at 21 CFR 1271.3(f):[4]

• For structural tissue (tissue that physically supports or serves as a barrier or conduit, such as bone, skin, or tendon): processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement.[4]
• For cells or nonstructural tissues (tissue that serves predominantly metabolic or other biochemical roles, such as cells or hematopoietic cells): processing that does not alter the relevant biological characteristics of cells or tissues.[4]

"Homologous use"

Homologous use is defined at 21 CFR 1271.3(c) as the "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."[4]

The 2017 minimal manipulation / homologous use guidance

In November 2017 (corrected December 2017), CBER and the Center for Devices and Radiological Health issued the final guidance Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use. The guidance addresses how FDA interprets the 1271.10(a)(1) minimal-manipulation criterion and the 1271.10(a)(2) homologous-use criterion, including worked examples by tissue type.[9][10]

Because applying the clarified interpretation could move certain products from the Section 361 pathway into the Section 351 pathway, FDA paired the guidance with a period of enforcement discretion for certain HCT/Ps offered for use other than as Section 361 products, intended to give manufacturers time to determine whether an IND or marketing application was needed and to prepare it. The original 36-month period ran through November 2020; it was extended in July 2020 through May 31, 2021, after which FDA's stated compliance-and-enforcement policy ended.[10][11] FDA has emphasized that the enforcement-discretion policy did not change its underlying interpretation of the criteria.[10]

Exceptions and exemptions (21 CFR 1271.15)

Section 1271.15 carves out activities and establishments that need not comply with some or all of Part 1271, including:[12]

• An establishment that removes and implants an HCT/P into the same individual during the same surgical procedure ("same surgical procedure" exception).[12]
• A carrier that only receives, stores, or transports HCT/Ps.[12]
• An establishment that does not recover, screen, test, process, label, package, or distribute, but only receives or stores HCT/Ps solely for implantation within its own facility.[12]
• Recovery of reproductive cells or tissue that are immediately transferred into a sexually intimate partner of the donor.[12]
• Use of HCT/Ps solely for nonclinical scientific or educational purposes.[12]

Establishments that manufacture only HCT/Ps described in 1271.15 are addressed in 21 CFR 1271.20, which generally relieves them of the registration and listing obligations of Subpart B for those activities.[2][12]

A separate threshold exclusion is built into the definition itself: certain minimally manipulated bone marrow for homologous use, not combined with another article, is excluded from the HCT/P definition and is regulated by HRSA rather than under Part 1271.[4]

Establishment registration and listing (Subpart B)

Subpart B requires domestic and foreign establishments that recover, process, store, label, package, or distribute HCT/Ps, or that screen or test donors, to register with FDA and to list each HCT/P they manufacture, using Form FDA 3356.[8][5] Registration and the initial product list are due within 5 days after beginning operations, and registrations must be updated annually in December; certain changes trigger interim updates.[8] Registration information is publicly searchable through CBER's Human Cell and Tissue Establishment Registration public query.[8] Registration does not constitute FDA approval or endorsement of the establishment or its products.[6]

Donor eligibility: screening and testing (Subpart C)

Subpart C requires a donor-eligibility determination before an HCT/P is implanted, transplanted, infused, or transferred, based on donor screening (relevant medical records and risk-factor history) and donor testing for relevant communicable disease agents and diseases.[1][13] The determination must be made by a responsible person and documented; an HCT/P generally may not be released for distribution until the donor has been determined eligible, subject to narrow exceptions such as urgent medical need with appropriate labeling.[1]

FDA designates relevant communicable disease agents and diseases (RCDADs) that donors must be screened and, where required, tested for. These include, among others, HIV types 1 and 2; hepatitis B virus (HBV); hepatitis C virus (HCV); human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; Treponema pallidum (syphilis); and, for donors of viable, leukocyte-rich cells or tissue, human T-lymphotropic virus (HTLV) types I and II and cytomegalovirus (CMV). Donors of reproductive cells or tissue are additionally screened and tested for agents such as Chlamydia trachomatis and Neisseria gonorrhoeae.[13][1] Testing must use FDA-licensed, approved, or cleared donor-screening assays where available, run by a laboratory meeting applicable standards.[13]

Current Good Tissue Practice (Subpart D)

Subpart D establishes Current Good Tissue Practice (CGTP) requirements governing the methods, facilities, and controls used in the manufacture of HCT/Ps, where "manufacture" includes recovery, processing, storage, labeling, packaging, and distribution.[7] The core CGTP requirement at 21 CFR 1271.150 directs establishments to recover, process, store, label, package, and distribute HCT/Ps, and to screen and test donors, in a way that prevents the introduction, transmission, or spread of communicable diseases.[7] CGTP provisions cover, among other things, facilities and environmental controls, equipment, supplies and reagents, process controls and process validation, labeling controls, storage, receipt and distribution, and tracking from donor to recipient (and back).[7] Section 351 HCT/Ps must satisfy CGTP in addition to the CGMP requirements applicable to drugs and biologics.[6][7]

Enforcement

Inspection and enforcement provisions appear in Part 1271 Subparts E and F. FDA may inspect HCT/P establishments and, where it finds violations, may pursue actions such as orders to cease manufacturing, recall, retention, or destruction of HCT/Ps, as well as the agency's other enforcement tools (warning letters, injunctions, and seizure) under the FD&C Act and PHS Act.[2][1] Marketing a Section 351 HCT/P without the required IND or approved/licensed marketing application is a principal enforcement trigger; this was the focus of the post-2017 framework and the time-limited enforcement discretion that ended May 31, 2021.[10][11]

Relationship to organ transplantation

The Part 1271 framework is distinct from the regulation of whole vascularized organs (such as kidney, liver, heart, lung, and pancreas) for transplantation. Such organs are excluded from the HCT/P definition and are overseen under the National Organ Transplant Act through HRSA and the OPTN rather than by FDA.[4][2] Tissues such as corneas, heart valves, skin, and bone, by contrast, fall within FDA's HCT/P framework.[4][1] See Organ transplantation.

History

• March 4, 1997. FDA published A Proposed Approach to the Regulation of Cellular and Tissue-Based Products (62 FR 9721), announcing its intent to establish a comprehensive, tiered, risk-based program for HCT/Ps in a new Part 1271.[1][14]
• January 19, 2001. The first of three implementing final rules, the Establishment Registration and Listing rule, was published (66 FR 5447), creating Subpart B and the registration/listing system.[14]
• May 25, 2004. The Eligibility Determination for Donors (donor eligibility) final rule was published (69 FR 29786), creating Subpart C.[15]
• November 24, 2004. The Current Good Tissue Practice final rule was published (69 FR 68612), creating Subpart D and related provisions.[14]
• May 25, 2005. The donor-eligibility and CGTP requirements became effective, applicable to HCT/Ps recovered on or after that date, completing the tiered framework.[16][14]
• November 16, 2017. FDA announced its comprehensive regenerative medicine policy framework, built around four guidance documents, including the Minimal Manipulation and Homologous Use guidance and a Same Surgical Procedure guidance, together with guidances implementing the 21st Century Cures Act provisions on Regenerative Medicine Advanced Therapy (RMAT) designation and on devices used with such therapies.[17][9] The framework included a 36-month period of enforcement discretion for certain HCT/Ps, later extended through May 31, 2021.[10][11]

See also

• Tissue bank
• Bone and musculoskeletal allografts
• Amniotic membrane
• Organ transplantation

References

• FDA / CBER, Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps): Small Entity Compliance Guide. https://www.fda.gov/media/70689/download
• eCFR, 21 CFR Part 1271: Human Cells, Tissues, and Cellular and Tissue-Based Products. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271
• eCFR, 21 CFR 1271.1: What are the purpose and scope of this part? https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.1
• eCFR, 21 CFR 1271.3: How does FDA define important terms in this part? https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.3
• eCFR, 21 CFR 1271.10: Are my HCT/P's regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.10
• FDA / CBER, Vaccines, Blood & Biologics: Tissue & Tissue Products / regulatory overview of 361 vs. 351 HCT/Ps (FDA program pages on HCT/P regulation). https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products
• eCFR, 21 CFR Part 1271 Subpart D: Current Good Tissue Practice (including 21 CFR 1271.150). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-D
• eCFR, 21 CFR Part 1271 Subpart B: Procedures for Registration and Listing. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-B
• FDA, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (guidance, November 2017). https://www.fda.gov/media/109176/download
• Federal Register, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance; Availability (85 FR, July 21, 2020). https://www.federalregister.gov/documents/2020/07/21/2020-15718/regulatory-considerations-for-human-cells-tissues-and-cellular-and-tissue-based-products-minimal
• FDA, Questions and Answers Regarding the End of the Compliance and Enforcement Policy for Certain Human Cells, Tissues, or Cellular or Tissue-based Products (HCT/Ps). https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/questions-and-answers-regarding-end-compliance-and-enforcement-policy-certain-human-cells-tissues-or
• eCFR, 21 CFR 1271.15: Are there any exceptions from the requirements of this part? https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.15
• eCFR, 21 CFR Part 1271 Subpart C: Donor Eligibility (including §§ 1271.75, 1271.80, 1271.85). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-C
• FDA, Tissue & Tissue Products: final rules history (Establishment Registration and Listing; CGTP); see also Federal Register dockets for 66 FR 5447 and 69 FR 68612. https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products
• Federal Register, Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (final rule, 69 FR 29786, May 25, 2004). https://www.federalregister.gov/documents/2004/05/25/04-11245/eligibility-determination-for-donors-of-human-cells-tissues-and-cellular-and-tissue-based-products
• Federal Register, Human Cells, Tissues, and Cellular and Tissue-Based Products; Donor Screening and Testing, and Related Labeling (May 25, 2005). https://www.federalregister.gov/documents/2005/05/25/05-10583/human-cells-tissues-and-cellular-and-tissue-based-products-donor-screening-and-testing-and-related
• FDA, Framework for the Regulation of Regenerative Medicine Products (announced November 16, 2017). https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/framework-regulation-regenerative-medicine-products