What is an HCT/P, and what is the difference between a 361 and a 351 product?

1What counts as an HCT/P.

FDA defines human cells, tissues, and cellular and tissue-based products (HCT/Ps) as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient”.¹ Its examples include bone, ligament, skin, heart valves, corneas, hematopoietic stem/progenitor cells from peripheral and cord blood, and semen.¹

Vascularised organs for transplantation, whole blood and blood components, secreted or extracted products such as milk and collagen, minimally manipulated bone marrow for homologous use, animal tissues and in vitro diagnostic products are not HCT/Ps.¹

The numbers 361 and 351 are sections of the Public Health Service Act. Section 361 (42 U.S.C. 264) authorises regulations “necessary to prevent the introduction, transmission, or spread of communicable diseases”.² Section 351 (42 U.S.C. 262) bars interstate commerce in a biological product unless a biologics licence is in effect for it.³ FDA issued the tissue rules in 21 CFR Part 1271 under section 361 as a “tiered, risk-based approach”: HCT/Ps that meet specific criteria need no premarket review.⁴

2The four criteria for a 361 HCT/P.

An HCT/P is regulated solely under section 361 and Part 1271 only if it meets all four criteria in 21 CFR 1271.10(a).⁵

For structural tissue, minimal manipulation means processing that “does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement”. For cells or nonstructural tissues, it means processing that “does not alter the relevant biological characteristics of cells or tissues”. Homologous use means the HCT/P “performs the same basic function or functions in the recipient as in the donor”.¹

FDA’s July 2020 guidance on these two criteria gives examples. Amniotic membrane preserved in sheets is generally minimally manipulated; ground and lyophilised into particles, it is not. Used to cover the surface of the eye, it is in homologous use; used for wound healing or bone regeneration, it is not. Concentrating hematopoietic stem/progenitor cells from a mobilised apheresis product is generally minimal manipulation; culturing them into terminally differentiated cells is not.⁴

3What a 361 HCT/P establishment must do.

A 361 HCT/P is not licensed, approved or cleared, and must meet only the requirements of Part 1271.⁶⁷

• Registration and listing. Register with FDA and list every HCT/P within 5 days after beginning operations, and update the registration every December (21 CFR 1271.21).
• Donor eligibility. A responsible person documents each donor’s eligibility from screening and testing for relevant communicable diseases, and the HCT/P is not used until the donor is found eligible, with narrow exceptions (21 CFR 1271.45 and 1271.50).
• Current good tissue practice. Methods, facilities and controls that prevent the spread of communicable diseases, including a quality programme, records kept for 10 years, and tracking from donor to consignee and back through a distinct identification code (21 CFR 1271.150, 1271.160, 1271.270 and 1271.290).
• Reporting. Adverse reactions involving a communicable disease that are fatal, life-threatening, permanently damaging or need medical or surgical intervention, within 15 calendar days; and HCT/P deviations relating to core CGTP requirements within 45 days (21 CFR 1271.350).
• Inspection and enforcement. FDA may inspect at any reasonable time, and may order an HCT/P retained, recalled or destroyed, or order manufacturing to stop (21 CFR 1271.400 and 1271.440).

Cord blood shows the line. Stored in a private bank for the baby or a first-degree or second-degree relative, and meeting the other criteria, it needs no approval, though the bank still registers and lists, screens and tests donors (except for use by the original donor), reports, labels and follows current good tissue practice. Stored in a public bank for unrelated patients, it is a biological product under section 351 and must be licensed under a BLA or used under an IND.⁸ Licensed cord blood products such as HEMACORD and ALLOCORD appear on FDA’s list of approved cellular and gene therapy products.⁹

4What changes for a 351 product.

If an HCT/P fails any criterion in 21 CFR 1271.10(a) and no exception applies, it “will be regulated as a drug, device, and/or biological product under the act and/or section 351 of the PHS Act”.¹⁰ Premarket review is then required.⁴ For a biological product, that means clinical studies under an IND and a biologics licence before marketing, granted once FDA finds the product “safe, pure, and potent” and the facility meets standards to keep it so.⁴³

Part 1271 still applies in part. Donor eligibility (subpart C) and current good tissue practice (subpart D) apply alongside drug CGMP in Parts 210 and 211 and the biologics regulations in Parts 600 to 680, or alongside the device rules in Part 820.¹¹¹²⁴ Where they conflict, the regulation more specifically applicable to the product supersedes the more general. A 351 HCT/P registers and lists under Part 207 or Part 807, and subparts E and F of Part 1271 do not apply.⁷

5Who is outside Part 1271 altogether.

Section 1271.15 excepts establishments that use HCT/Ps only for nonclinical scientific or educational purposes; that remove HCT/Ps from a person and implant them into the same person during the same surgical procedure; that only receive or store HCT/Ps for use within their own facility; and carriers.¹³

6How to get FDA’s view on a product.

The Tissue Reference Group, with members from CBER and CDRH, gives an informal recommendation on how the 1271.10(a) criteria apply to an HCT/P for a given indication. A Request for Designation to the Office of Combination Products under 21 CFR Part 3 gives a formal decision on the product’s classification, and a Pre-RFD can get preliminary feedback first.⁴

7How it runs in Seal.

For HCT/Ps and the cell therapies built from them, Seal makes chain of identity part of the record: each relevant material record links to a coded patient or donor identity, a scan that doesn’t match the batch can be set to stop the step, and genealogy gives a route from a released unit back to its starting material. The cell and gene therapy blueprint describes how this supports compliance with 21 CFR 1271 alongside Part 11 and EU GMP for advanced therapies, with the manufacturer remaining responsible for its compliance.

For a donor-based allogeneic process, donor eligibility is held as an explicit pending, eligible or ineligible state, and every object made from material with unresolved eligibility inherits that gate until it is decided. Genealogy connects the donor’s material to every patient who receives product derived from it. For autologous therapies, the treatment order creates one case that carries identity, custody, the batch record, testing and release.