Guide
21 CFR 1271 HCT/P: Donor Eligibility, CGTP and the 361/351 Boundary
21 CFR Part 1271 governs Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) in the United States. The rule sets out establishment registration and product listing (Subpart B), donor eligibility (Subpart C), Current Good Tissue Practice (CGTP — Subpart D), adverse reaction reporting (§1271.350), and the regulatory boundary between Section 361 HCT/Ps (regulated solely under the Public Health Service Act) and 351 HCT/Ps (regulated as drugs, devices or biologics requiring an IND/IDE/BLA). The 2017 framework guidance on regenerative medicine and the ongoing enforcement against unapproved stem-cell clinics have moved the 361/351 boundary from a technical question into a sharp commercial one. This guide walks the structure, the recurring inspection findings, and a practical path to a defensible HCT/P programme.
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The 361 vs 351 boundary and the four-prong test
§1271.10 sets out the four criteria for solely-361 regulation: minimal manipulation, intended for homologous use, not combined with a drug/device (with narrow exceptions), and either no systemic effect or autologous/first/second-degree relative use. Failing any one criterion moves the HCT/P into 351 territory — IND/BLA, full GMP, the device or drug review pathway. The 2017 framework and the 2020 enforcement deferral expiry have led to FDA enforcement actions against many clinics offering "minimal manipulation" stromal vascular fraction products that fail the test. The boundary is the single highest-stakes regulatory question for any new HCT/P.
Donor eligibility, screening and testing (Subpart C)
§1271.45 through §1271.90 set out the donor eligibility determination — medical history, physical assessment, infectious disease testing for HIV-1/2, HBV, HCV, syphilis, HTLV-I/II, CMV, WNV, T. cruzi and others per the FDA-approved test list, and the urgent medical need exception. Reproductive tissue carries additional requirements (Zika risk, anonymous donor handling). The recurring finding is a donor file that satisfies the test result records but does not document the eligibility determination as an integrated review.
Current Good Tissue Practice (CGTP) and the cross-contamination prevention focus
Subpart D sets out CGTP — personnel competency, facilities and environmental control, equipment, supplies and reagents, recovery, processing, storage, labelling, shipment, and adverse reaction reporting. The cross-contamination prevention requirements at §1271.195 are inspected as the practical test of CGTP — environmental monitoring, cleaning validation, segregation of donors, and the prevention of donor-to-donor transmission. Inspections have intensified post-2024 enforcement on contaminated allograft cases.
Adverse reaction reporting and the §1271.350 clock
§1271.350 requires investigation of any adverse reaction involving a communicable disease related to an HCT/P, and reporting to FDA on Form 3500A within 15 calendar days of receipt. The clock starts when the establishment receives the information, not when it decides the report is necessary. Late reporting is a routine inspection finding and a routine Warning Letter trigger. The investigation must be substantive — the report itself is the deliverable to FDA, but the investigation file is what the inspector reads.
A 60-day readiness path
Days 1–10: 361/351 four-prong analysis refresh across every product line; flag any product where the boundary has drifted. Days 11–25: donor eligibility integrated-review reconciliation; close determination-document gaps. Days 26–40: CGTP cross-contamination prevention review with environmental monitoring trend analysis. Days 41–50: §1271.350 adverse reaction process audit with clock-discipline review; rehearse a real case. Days 51–60: internal CGTP audit, management review and inspection readiness rehearsal.
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Frequently asked
Is autologous always Section 361?
No — autologous use is one of two pathways to satisfy the fourth criterion (no systemic effect, or autologous/first/second-degree relative use), but the other three criteria (minimal manipulation, homologous use, no combination) still apply. Many autologous stem-cell products fail the homologous use or minimal manipulation criteria and are therefore 351.
How long must donor records be retained?
§1271.270 requires retention for 10 years after the date of administration or, where the date is unknown, 10 years after distribution, disposition or expiration. Reproductive tissue retention may be longer under state rules.
Does CGTP apply to reproductive tissue establishments?
Yes — reproductive HCT/Ps are within scope of 1271, with the additional considerations in the donor eligibility subpart. Some states (notably New York) impose additional state-level requirements.
What is the relationship between 1271 CGTP and 21 CFR 211 GMP?
A Section 361 HCT/P is subject to CGTP under 1271, not 211 GMP. A Section 351 HCT/P (regulated as a biologic) is subject to 211 GMP and the relevant biologics requirements; many cellular therapy products operate under both regimes during transition.
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