21 CFR 1271Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)

21 CFR Part 1271 is the FDA regulation governing Human Cells, Tissues, and Cellular and Tissue-Based Products — HCT/Ps for short. It was finalised in three rules between 2001 and 2005 to close a gap that pre-2001 existed: tissue allografts (skin, bone, tendon, cornea, heart valves, birth tissue) were neither drugs nor devices nor classical biologics, and were largely unregulated at the federal level. Part 1271 created a single framework that covers everything from a piece of demineralised bone through a corneal graft through a cord-blood unit.

The rule is risk-tiered. Most tissue allografts are regulated solely under Part 1271 (Section 361 of the Public Health Service Act). A smaller set — anything that is more than minimally manipulated, used for a non-homologous purpose, combined with another article, or has a systemic effect — graduates to Section 351 and must be licensed as a biologic, with the full 21 CFR 600s / 211 cGMP burden on top of Part 1271.

An establishment that recovers, processes, screens, tests, packages, labels, distributes, or stores HCT/Ps must register with FDA and list each HCT/P annually. Registration is done electronically through the FDA Unified Registration and Listing System (FURLS / eHCTERS) within 5 days of starting operations.

Before any HCT/P is released for transplantation, a responsible person must make a written eligibility determination based on a donor risk assessment (medical / social history interview, physical assessment for cadaveric donors) and infectious-disease testing using FDA-licensed, approved, or cleared assays. The required test panel at minimum includes HIV-1/2, HBV (HBsAg + anti-HBc), HCV, syphilis, and (for viable leukocyte-rich tissue) HTLV-I/II, CMV, and West Nile virus. WNV is required for living donors of viable tissue in qualifying months. Tests must be performed by a CLIA-certified lab or equivalent.

Time windows matter. Living-donor specimens must be drawn within 7 days before or after recovery. Cadaveric donor specimens must be collected within 24 hours of death (or up to 7 days if antemortem). Plasma dilution must be assessed if the donor received transfusions or infusions before specimen draw.

Subpart D is the operational core. It requires written procedures for every step that could introduce, transmit, or amplify a communicable disease. The headline obligations are:

• Documented personnel competence and ongoing training, including infectious-disease control.
• Validated cleaning and process controls — recovery, processing, packaging, labeling, storage, distribution.
• Environmental controls appropriate to the operation (controlled airflow, surface sanitisation, contamination monitoring).
• Equipment that is calibrated, maintained, inspected, and qualified, with records.
• Supplies and reagents qualified to specifications, including any that contact the HCT/P.
• Quarantine of HCT/Ps until donor eligibility is determined and processing controls are complete.
• Complete records that are reviewable for at least 10 years after the HCT/P is distributed, transplanted, or discarded.

Every HCT/P shipped must be uniquely identified, traceable forward to the consignee and backward to the donor — a chain of identity that survives processing, packaging, and labeling. Most tissue banks implement this with ISBT 128 product codes plus donation identification numbers.

Subpart E creates two reporting streams. An adverse reaction report is required within 15 calendar days of a reportable event — a reaction in a recipient that is fatal, life-threatening, results in permanent impairment, requires medical or surgical intervention to prevent permanent damage, or involves the transmission of a communicable disease. An HCT/P deviation report is required when a deviation related to manufacturing — including processing, labeling, packaging, storage, distribution — could affect safety, purity, or potency, and the HCT/P has been distributed.

Both reports go to FDA Center for Biologics Evaluation and Research (CBER) through MedWatch Form FDA 3500A (adverse reactions) and Form FDA 3486 (HCT/P deviations). Subpart F authorises FDA inspections without prior notice; inspections cover all aspects of registration, listing, cGTP, and records.