FDA Standards for Human Blood and Blood Products

The U.S. Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) regulates human blood and blood products as "biological products" under the Public Health Service Act — subjecting every unit of blood, every bag of plasma, and every vial of albumin or immune globulin to federal product standards, manufacturing controls, and lot-release requirements before it can reach a patient or a pharmaceutical fractionator. These regulations cover the entire chain: from donor eligibility at the blood center, through collection, processing, labeling, storage, and distribution, to the product standards each component must meet. The system underpins both the U.S. hospital blood supply (approximately 13 million units of whole blood and red blood cells donated per year) and the global commercial plasma supply chain (the U.S. is the world's dominant source of source plasma, supplying more than 40% of global plasma for pharmaceutical fractionation).

Legal Authority

• 42 U.S.C. § 262 — Public Health Service Act § 351: authorizes FDA/CBER to require biological product licenses; biologics (including blood products) must be licensed before interstate distribution; unlicensed biologics are adulterated or misbranded
• 21 U.S.C. § 321 et seq. — Federal Food, Drug, and Cosmetic Act (FDCA): defines drugs and devices; blood products are subject to both PHS Act biologics requirements and FDCA adulteration and misbranding standards
• 21 CFR Part 640 — FDA product standards for blood and blood components; specifies the quality, purity, and potency requirements for each licensed blood product category
• 21 CFR Parts 600–610 — General biologics standards; covers establishment registration, inspection, lot release, labeling, and minimum quality standards applicable to all licensed biologics including blood
• 21 CFR Part 606 — Current good manufacturing practice for blood and blood components; the cGMP requirements for blood banks and transfusion services
• 21 CFR Part 630 — Requirements for blood and blood components intended for transfusion or for further manufacturing use; donor eligibility standards

Key Mechanics

The FDA blood regulation framework is a layered licensing system: establishments must hold a biologics license (issued by CBER after pre-approval inspection) and must comply with ongoing GMP requirements enforced through routine facility inspections. Each product (Whole Blood, Red Blood Cells, Platelets, Plasma, etc.) must meet the product-specific standards in Part 640 — which specify acceptable hemoglobin levels, volume ranges, residual leukocyte counts, and other parameters for each product type. Deviations from product standards must be reported to CBER and may trigger lot rejection or mandatory hold. The donor eligibility framework (Part 630) requires evaluation of donors for risk factors for transfusion-transmitted infections (HIV, hepatitis B, hepatitis C, West Nile virus, etc.) — ineligible donors' blood may not enter the licensed supply.

Current Rule (2026)

What This Rule Does

21 CFR Part 640 establishes the product-specific standards for each category of human blood product licensed under the biologics framework — the precise physical and biochemical specifications that each product must meet to be labeled and distributed. It functions as the product monograph layer on top of the manufacturing quality framework in Parts 606 (current good manufacturing practice for blood and blood components), 610 (general biologics standards including sterility, potency, and labeling), and 630 (donor eligibility and source qualification). An establishment that makes a deviation from Part 640 standards must either obtain an exception from CBER or refrain from releasing the affected lot.

The regulation divides human blood products into several categories, each with its own subpart and its own set of definitions, donor eligibility rules, collection procedures, processing specifications, quality controls, and storage requirements:

Transfusion components — products given directly to patients to treat hemorrhage, anemia, clotting disorders, or immune deficiency:

• Whole Blood (Subpart A): blood collected from volunteer donors and transfused without separation; must be collected under licensed establishment supervision with an anticoagulant prescribed by CBER; stored at 1–6°C; rarely used today because component therapy (separate red cells, plasma, platelets) is more efficient
• Red Blood Cells (Subpart B): the dominant transfusion product; prepared by removing most plasma from whole blood; must be stored at 1–6°C; frozen RBCs (stored at −65°C or colder with a cryophylactic agent) may be used for rare blood types or long-term stockpiling; segments of integral tubing must accompany each unit for compatibility testing; hematocrit requirements apply
• Platelets (Subpart C): collected from whole blood or by apheresis; must be resuspended in plasma at approximately 5.5 × 10¹⁰ platelets per unit; must be stored at 20–24°C under continuous gentle agitation (rocking) to prevent clumping and maintain viability; apheresis donors may donate platelets no more than twice in any 7-day period and no more than 24 times per year; whole-blood-derived platelet donors must meet whole blood donation intervals
• Plasma (Subpart D): the liquid component separated from whole blood; Fresh Frozen Plasma (FFP) must be frozen within the timeframe specified for the collection system; plasma frozen within 24 hours of phlebotomy (PF24) and plasma frozen within 24 hours after phlebotomy held at 1–6°C (PF24RT24) are distinct licensed products with specific coagulation factor retention requirements
• Cryoprecipitate (Subpart F): the cold-insoluble fraction of FFP — the protein precipitate that forms when FFP is thawed at 1–6°C; contains concentrated Factor VIII, von Willebrand factor, fibrinogen, Factor XIII, and fibronectin; used to treat hemophilia A, von Willebrand disease, afibrinogenemia, and hypofibrinogenemia; must contain at least 80 IU of Factor VIII per unit; storage at −18°C or colder; must be transfused within 6 hours of thawing

Commercial plasma-derived products — plasma collected at scale for pharmaceutical fractionation into biological medicines:

• Source Plasma (Subpart G): plasma collected by plasmapheresis (automated machine separation of plasma with red cell return) from paid donors at commercial plasma collection centers; unlike volunteer whole-blood donation (maximum every 8 weeks), source plasma donors may donate as frequently as twice in any 7-day period; each donor may donate a maximum of 110 liters per 12-month period; the U.S. source plasma industry operates approximately 1,000 licensed collection centers; collected plasma is frozen and shipped to pharmaceutical fractionators who manufacture albumin, clotting factors, immune globulins, and alpha-1 antitrypsin from pooled plasma
• Albumin (Human) (Subpart H): the most abundant protein in human plasma, fractionated from pooled source plasma; must be a 4–5% or 20–25% solution; viral inactivation by heat treatment (60°C for 10 hours) is required — the pasteurization step that eliminated the risk of transmitting bloodborne viruses through albumin; used for volume replacement in trauma, burns, surgery, and hypovolemia; and for therapeutic plasma exchange
• Plasma Protein Fraction (Human) (Subpart I): similar to albumin but containing a higher proportion of other plasma proteins; 5% solution; also pasteurized; used as a volume expander; less commonly used than albumin
• Immune Globulin (Human) (Subpart J): a 16.5% ± 1.5% sterile solution of antibodies (IgG) concentrated from pooled plasma by the Cohn fractionation process; must contain minimum levels of antibodies against diphtheria, measles, and at least one type of poliomyelitis; used for post-exposure prophylaxis (hepatitis A, measles, varicella, rabies when combined with vaccine) and for agammaglobulinemia treatment; each lot must be tested for potency before release; must not cause adverse reactions when tested in animals

Key Provisions

• § 640.2 — Manufacturing responsibility: all steps of whole blood manufacturing — donor examination, collection, testing, labeling, storage, and issuance — must occur under the supervision and control of the same licensed establishment; CBER may authorize specific steps (e.g., component preparation) to be performed under contract arrangements, but licensure accountability cannot be fragmented
• § 640.4 — Collection of Whole Blood: blood must be collected by aseptic technique; phlebotomy site must be cleaned using an approved antiseptic; the quantity drawn must be calibrated to the anticoagulant volume; collection time must not exceed 15 minutes (longer collection degrades platelet and coagulation factor quality)
• § 640.5 — Testing: blood must be tested for ABO and Rh(D) blood group to enable compatibility matching; tested for transmissible diseases per § 610.40 (which requires screening for HIV-1 and HIV-2, HTLV-I and II, hepatitis B surface antigen, hepatitis C antibody, West Nile virus, Zika virus, T. cruzi, and other agents as directed by CBER)
• § 640.7 — Labeling: every unit of blood must be labeled with the proper name, volume, name of anticoagulant, ABO and Rh(D) type, donor identification number, expiration date, name and address of collecting establishment, required statements (e.g., "For homologous use only" or "Volunteer Donor" designation)
• § 640.16 — Processing (Red Blood Cells): RBCs may be prepared by centrifugation (performed in a manner that does not increase blood temperature) or normal undisturbed sedimentation; leukocyte-reduced and washed RBC modifications are permitted subject to additional CBER-approved procedures
• § 640.24 — Platelets processing: platelet yield and concentration must meet minimum specifications; resuspension volume must maintain appropriate pH; the continuous agitation requirement prevents platelet clumping and maintains 5–7 day viability
• §§ 640.60–640.76 — Source Plasma: automated plasmapheresis equipment must be licensed; donor medical history must be reviewed by a physician or trained health professional before each donation; protein and protein electrophoresis testing required periodically; serum protein must be ≥6.0 g/dL; source plasma must be frozen within specified time frames and stored at −18°C or colder; the § 640.76 labeling requirements distinguish source plasma (for further manufacture only) from transfusable plasma products
• § 640.80–640.84 — Albumin: pasteurization at 60°C for 10 hours required; protein concentration must meet USP specifications; sodium content must not exceed 160 mEq/liter; each lot must be tested for sterility, pyrogens, and pH before release; shelf life of 5 years from date of manufacture
• § 640.120 — Alternative Procedures: CBER's Center Director may grant exceptions or alternatives to any Part 640 requirement for investigational purposes, emergency situations, or when a manufacturer demonstrates that an alternative procedure provides equivalent or superior safety and efficacy — the primary flexibility mechanism when standard methods are impractical

How It Affects You

If you're a blood center or hospital transfusion service: Part 640 compliance is non-negotiable for any establishment that collects, processes, or distributes blood across state lines — a federal biologics license from CBER is required. The product standards in Part 640 establish your minimum release criteria: every unit of red cells must meet hematocrit requirements, every bag of FFP must be frozen within the required window, every platelet unit must be continuously agitated and meet potency specifications. CBER conducts establishment inspections and can issue untitled letters, warning letters, or injunctions for violations. The 2015 donor eligibility final rule updated the HIV risk assessment approach — moving from a categorical men-who-have-sex-with-men (MSM) deferral to a behavior-based deferral policy; the 2023 updated guidance further reduced the deferral period to 3 months for any person with a recent new or multiple sexual partner — changes that expanded the donor pool while maintaining safety standards. Contact CBER's Office of Blood Research and Review at fda.gov/vaccines-blood-biologics for compliance guidance and inspection preparation resources.

If you're a patient receiving a transfusion or plasma-derived therapy: The Part 640 system is the foundation of blood safety in the U.S. Every unit of blood given to you has been tested for HIV, hepatitis B, hepatitis C, West Nile virus, Zika, and other pathogens before release. The viral inactivation steps required for albumin and immune globulin (pasteurization, solvent/detergent treatment, nanofiltration) have essentially eliminated the risk of viral transmission through plasma-derived products — a risk that was tragically real in the 1980s when thousands of hemophilia patients were infected with HIV through contaminated Factor VIII concentrates. Immune globulin preparations are used for passive immunity and immunodeficiency treatment; albumin is used in surgery and critical care. If your physician prescribes a plasma-derived product, it has passed multiple safety barriers required by this regulation.

If you're a pharmaceutical company or plasma fractionator: Source plasma (Subpart G) is the raw material for your products. U.S. source plasma collection is the largest in the world — the U.S. supplies more than 40% of global plasma for fractionation, with no other country even close. The twice-weekly donation frequency (vs. whole blood's 8-week interval) is the operational basis for the U.S.'s supply dominance: a motivated paid donor can donate 104 times per year within the 110-liter annual maximum. Part 640 Subpart G compliance — including donor health screening, protein testing, and rigorous cold-chain management — is prerequisite for source plasma to be accepted by European and Japanese regulators whose markets require plasma sourced under FDA-equivalent standards.

Diagnostic Reagents — Blood Grouping and Immunology (21 CFR Part 660)

The FDA regulations in 21 CFR Part 660 — Additional Standards for Diagnostic Substances for Laboratory Tests — establish specific product standards for the diagnostic reagents used in blood banking and transfusion medicine. These are the products that determine whether a unit of donated blood is compatible with a patient who needs a transfusion; getting them wrong can kill. Part 660 is separate from Part 640 (blood components) and applies to manufacturers of diagnostic biologics sold to hospitals, blood banks, and clinical laboratories.

• § 660.1 — Hepatitis B surface antigen (HBsAg) test reagents: standards for the antigen and antibody reference preparations used to calibrate diagnostic tests for Hepatitis B surface antigen; the regulation specifies that CBER will provide reference standards and that each lot of HBsAg diagnostic product must be tested against the CBER reference before release
• § 660.20 — Blood Grouping Reagents: the anti-sera used in ABO and Rh blood typing — the fundamental compatibility test performed on every unit of blood before transfusion; every patient who receives a transfusion has their blood type determined using reagents manufactured under this section; blood grouping reagents must react with specific blood group antigens in a defined pattern (anti-A agglutinates A and AB cells; anti-B agglutinates B and AB cells; anti-A,B reacts with both; anti-D detects the Rh-positive antigen)
• § 660.22 — Potency requirements: each lot of blood grouping reagent must be tested against CBER reference red cell preparations before release; the reagent must agglutinate (clump together) the appropriate red blood cell samples at a specific titer to confirm it has sufficient potency to reliably detect the relevant antigen; under-potent reagents can fail to detect an ABO incompatibility, leading to a potentially fatal hemolytic transfusion reaction
• § 660.25 — Potency tests: the specific test protocols — including the anti-human globulin test, the albumin method, and the saline method — that manufacturers must use to establish and confirm reagent potency; results must meet CBER-specified thresholds
• § 660.26 — Specificity and avidity tests: reagents must demonstrate specificity (reacting only with the intended antigen, not with antigens on unrelated red cell types) and avidity (the speed and strength of agglutination within defined timeframes); an avid reagent produces rapid, strong clumping that is clearly distinguishable from non-reactive — a critical safety property because weak or slow reactions can be misread as negative in a busy transfusion service

Blood grouping reagents under Part 660 are among the highest-volume biologics manufactured in the United States — essentially every unit of donated blood and every patient requiring a transfusion is typed using these reagents. CBER licenses manufacturers and conducts lot release testing for certain high-risk products. The regulation's requirement that manufacturers test against CBER reference preparations ensures that all marketed lots meet a nationally uniform potency standard — a critical consistency requirement for reagents that are foundational to the safety of the entire blood transfusion system.

General Biologics Standards (21 CFR Part 610)

21 CFR Part 610 establishes the across-the-board release standards that apply to all licensed biological products — vaccines, blood products, insulin, human growth hormone, and other biologics — before any lot can be distributed. Where Part 640 sets blood-product-specific standards and Part 610 sets cross-cutting baseline requirements. No lot of any licensed biological product may be released without completing every applicable Part 610 test. Key provisions:

• § 610.1 — Pre-release testing requirement: no lot of any licensed product may be released by the manufacturer until testing for conformity with applicable standards is complete; each required test must be performed on a sample taken from a final container; for CBER-regulated products (blood, vaccines, gene therapy), CBER may require submission of samples and protocols to the agency before release
• § 610.2 — Official release (CBER-regulated products): CBER may require manufacturers to submit samples and test protocols before a lot is released to commerce; CBER retains the right to test lots independently and to prohibit release of any lot that fails to meet standards; official lot release by CBER is required for certain high-risk products (live vaccines, seasonal influenza vaccines, some blood products) — meaning the manufacturer cannot distribute until CBER confirms compliance with a formal release letter
• § 610.10 — Potency: every licensed biologic must demonstrate potency — the specific ability or capacity to produce the intended effect as defined for each product; potency tests may be in vitro (cell culture, biochemical assay) or in vivo (animal models) as validated for each product; potency is the most product-specific standard in Part 610 — the FDA-approved license specifies the validated potency assay and acceptable potency range for each product; a lot below minimum potency cannot be released even if all other standards are met
• § 610.12 — Sterility: every lot of every biological product must be tested for sterility using validated methods (typically USP sterility test with media fill confirmation for terminally sterilized products, or bioburden testing for products not terminally sterilized); the test must be performed on final container material; bacterial or fungal contamination detected at any stage triggers hold and investigation; exemptions for certain dried products are product-specific
• § 610.13 — Purity: products must be free of extraneous material except what is unavoidable in the approved manufacturing process; purity testing includes pyrogen/endotoxin testing (to confirm the absence of bacterial endotoxin that can cause fever, even if the bacteria were killed), protein content, and residual manufacturing materials (formaldehyde, antibiotics, host-cell protein limits for recombinant products)
• § 610.14 — Identity: the contents of each final container must be tested for identity after all labeling is complete, using tests specific enough to confirm the product is what the label claims (not merely that it meets general standards); identity failures — wrong product in a container — have historically been among the most serious biologic product errors
• § 610.15 — Constituent materials: all ingredients (preservatives, diluents, adjuvants, stabilizers) must meet generally accepted standards of purity and quality; adjuvants (aluminum salts in vaccines) and preservatives (thimerosal in multi-dose influenza vaccine vials) must be within approved concentration ranges; the approved BLA or PLA specifies every acceptable constituent with its allowable range
• § 610.17 — Combinations prohibited without license: a licensed product may not be combined with another licensed product (therapeutic, prophylactic, or diagnostic) without obtaining a separate license for the combination; this prevents manufacturers from combining products with different safety/efficacy profiles into a single product without going through FDA's combination review — the requirement that drove separate licensure of combination childhood vaccines (DTaP-IPV, MMR-V, etc.)
• §§ 610.60–610.68 — Labeling standards: the label of every biological product must include: (a) the proper name; (b) name, address, and license number of the manufacturer; (c) lot number; (d) expiration date; (e) preservative contents; (f) recommended storage temperature; (g) contents in terms of volume or number of doses; labels must be machine-readable for traceability; the license number links each distributed product to the specific licensed establishment

Part 610's lot-testing framework operates as the last quality gate before a biologic reaches patients. Unlike small-molecule drugs where analytical chemistry can characterize a product's composition precisely, biologics are complex molecules whose potency and safety characteristics must be demonstrated through functional testing — you cannot fully characterize a vaccine's immunogenicity from its chemical formula. This biological complexity is why Part 610's testing requirements are mandatory rather than default and why CBER's official lot release authority for highest-risk products (which can delay distribution by days or weeks) is a real operational constraint on vaccine supply chains, particularly during outbreak response.

Blood Establishment Registration (21 CFR Part 607)

21 CFR Part 607 establishes the registration and product listing framework for all manufacturers of human blood and blood products — the gatekeeping mechanism that gives FDA a current, accurate picture of who is making blood products in the United States and what they are making. Registration under Part 607 is a legal prerequisite to operating a blood bank or plasma collection center; an unregistered establishment may not manufacture or distribute blood products in interstate commerce. Key provisions:

• § 607.20 — Who must register: owners or operators of all establishments engaged in the manufacturing of blood or blood products must register; "manufacturing" includes collecting, preparing, processing, packing, storing, or distributing any blood product subject to 21 CFR Part 640; exceptions cover establishments that perform only those operations exempted by § 607.65 (e.g., hospital blood banks that do not ship blood in interstate commerce)
• § 607.21 — Timing: initial registration must be submitted before the establishment begins commercial distribution; annual updates (re-registration) must be submitted between October 1 and December 31 of each year; an establishment that discontinues operations must notify FDA within 30 days
• § 607.22 — Electronic registration: registration must be submitted electronically through FDA's Blood Establishment Registration (BER) system (the FDA website at fda.gov/BiologicsBloodVaccines); paper registration is no longer accepted except under approved waiver; the electronic system ties establishment registration to the CBER biologics license application (BLA) system, creating a unified identifier for each licensed facility
• § 607.25 — Required information: the registration must include the establishment's name, address, and all locations involved in manufacturing; a list of all blood products manufactured by the establishment; the FDA registration number for each product (assigned after BLA approval); names of all partners, members, officers, and directors if the establishment is a partnership, LLC, or corporation; name and title of the person submitting the registration; and the type of operations performed at the establishment (collection, testing, processing, storage, distribution — or combinations)
• § 607.30 — Product listing updates: after initial registration, product listing information must be updated by June 15 and December 15 of each year; updates must reflect any new products added to manufacturing, any products discontinued, and any changes in product formulation or labeling; the biannual product listing cycle creates a twice-yearly checkpoint on what each establishment is making
• § 607.37 — Public disclosure: registration and product listing information is publicly disclosed by FDA, except that information declared trade secret or confidential commercial information is protected; the public database of registered blood establishments and their licensed products is maintained by CBER and is searchable by FDA
• § 607.40 — Foreign establishment registration: every foreign establishment that manufactures blood products for import into the United States must register and list products in the same manner as domestic establishments; the foreign registration requirement — strengthened after multiple imported blood product safety incidents — gives FDA advance identification of all overseas establishments before their products reach U.S. commerce; foreign establishments that fail to register or that are delinquent on product listing updates may have their products detained at the border
• § 607.65 — Exemptions: hospital blood banks and transfusion services that (a) do not manufacture blood products for interstate distribution and (b) transfuse only at the immediate facility where the blood is collected are exempt; small in-house transfusion services serving only their own patients are the primary exempted category; the exemption is narrow — a hospital blood bank that ships even one unit of blood to another hospital triggers the registration requirement

Part 607's registration database serves as FDA's real-time national inventory of blood product manufacturing locations. CBER uses it for inspection scheduling (every registered establishment receives periodic CBER or state surrogate inspections), outbreak investigation (tracing contaminated blood products back to their source establishment), and enforcement (unregistered establishments are subject to seizure and injunction). The blood product supply chain runs through approximately 2,300 registered blood collection establishments, hundreds of licensed plasma collection centers, and thousands of hospital blood banks — Part 607 registration is the mechanism through which CBER maintains visibility across this entire distributed system.

Blood GMP — Manufacturing Standards (21 CFR Part 606)

21 CFR Part 606 — Current Good Manufacturing Practice for Blood and Blood Components — sets the facility, personnel, equipment, and procedural requirements that blood collection establishments and transfusion services must follow to collect, process, test, store, and distribute blood and blood components safely. Part 606 is the GMP regulation that applies to each individual operation within a blood establishment; Part 610's lot-testing requirements and Part 640's product-specific standards layer on top of the Part 606 GMP framework. Together, the three Parts define what a compliant blood program looks like end-to-end. Authority: 42 U.S.C. § 216 (PHSA), 21 U.S.C. § 321 (FDCA).

• § 606.20 — Personnel: staff responsible for collection, processing, compatibility testing, storage, or distribution must be adequate in number and have the education, training, and experience to perform their assigned functions; a qualified person must be designated responsible for each operation; training records must be maintained — establishing the accountability structure that ties GMP compliance to individual staff qualifications rather than facility-level certification alone
• § 606.40 — Facilities: facilities must be maintained in a clean, orderly manner; must be of suitable size, construction, and location to facilitate adequate cleaning, maintenance, and proper operations; must prevent contamination of blood products and protect them from environmental hazards; adequate space must be provided for each operation to prevent mixups between products, donors, and samples — the spatial separation requirement is especially critical for blood banks that handle multiple product types simultaneously
• § 606.60 — Equipment: equipment used in collection, processing, compatibility testing, storage, and distribution must be maintained in a clean, orderly manner; equipment must be qualified for its intended function, calibrated at defined intervals, and have performance records maintained; refrigerators, freezers, and centrifuges must be routinely checked and must have temperature alarms — equipment failure in blood storage is among the most common causes of blood product loss and transfusion reactions
• § 606.100 — Standard operating procedures (SOPs): all operations must be governed by current, written SOPs; SOPs must be followed in all instances except clinical investigations; SOPs must be reviewed and approved by a designated official; deviations from SOPs must be documented; the SOP requirement operationalizes GMP at the bench level — ensuring that each unit of blood is collected and processed identically regardless of which staff member performs the operation
• § 606.120–606.122 — Labeling: labeling operations must be physically or spatially separated from other operations to prevent mixups; each unit's container label must include the product name, donor ABO group and Rh type, expiration date, volume, required storage temperature, and facility license number; the label must be attached before the unit leaves direct control of the labeling station; a circular of information must be available for any product intended for transfusion, providing directions for use, contraindications, and adverse reaction information
• § 606.140 — Laboratory controls: scientifically sound and appropriate specifications, standards, and test procedures must be established and followed for all products; test procedures must be validated; reagents must be of documented quality; laboratory results must be reviewed by a qualified person before product release — the "laboratory controls" standard ensures that each unit meets specification before it goes into inventory
• § 606.145 — Control of bacterial contamination of platelets: blood collection establishments and transfusion services must have measures adequate to control the risk of bacterial contamination in platelets — the most contamination-prone blood component due to room-temperature storage; acceptable control methods include pathogen reduction technology (PRT), bacterial detection testing at a defined time point after collection, or point-of-issue rapid testing; this 2021-era requirement reflects FDA's updated guidance on platelet contamination after decades of transfusion-associated sepsis deaths that were the leading cause of transfusion-related fatalities in the U.S.
• § 606.151 — Compatibility testing: SOPs for compatibility testing must include: a method for collecting and identifying recipient blood samples to ensure positive identification; ABO and Rh typing of the recipient; a crossmatch procedure to detect incompatibility between donor red cells and recipient plasma; the standard addresses the most fatal transfusion complication — ABO-incompatible transfusion from a patient identification or crossmatch error
• § 606.160 — Records: records must be maintained concurrently with the performance of each significant step; records must be attributable (who did it), legible, contemporaneous, original, and accurate (ALCOA); records must be retained for a period sufficient to facilitate investigation of adverse reactions and must be available for inspection by FDA; the records requirement creates the traceability chain that connects each transfused unit to its donor, testing results, and distribution chain — essential for the trace-back investigations that follow transfusion-transmitted infection reports
• § 606.171 — Reporting of product deviations: blood establishments must report to FDA any event, and information relevant to that event, for which there is a reasonable probability that a distributed product caused or contributed to a serious injury or death, or where there was a deviation from cGMP, applicable regulations, or applicable standards; deviations must be reported within 45 calendar days of discovery; the product deviation reporting requirement creates FDA's real-time surveillance of blood safety incidents across the approximately 2,300 registered blood collection establishments

Part 606 is enforced through CBER inspections of registered blood establishments — every registered establishment is subject to periodic comprehensive inspections on a risk-based schedule (typically every 1–2 years for hospital blood banks, annually or more frequently for plasma collection centers and large blood suppliers). Inspection findings are classified as: OAI (Official Action Indicated) — significant GMP failures requiring corrective action before continued operation; VAI (Voluntary Action Indicated) — deficiencies the establishment should correct but that don't require CBER-imposed corrective action; and NAI (No Action Indicated) — clean inspection. Establishments with OAI findings risk consent decrees, product recalls, and license suspension or revocation. CBER publishes inspection classification data on its website, and major consent decrees (American Red Cross's decade-long GMP consent decree from 1993 to 2003 being the most prominent) have reshaped blood safety regulatory practice.

Blood Donor Eligibility (21 CFR Part 630)

21 CFR Part 630 establishes the minimum donor eligibility requirements that blood collection establishments must apply before collecting blood or blood components intended for transfusion or further manufacturing use. Part 630 implemented the 2015 Donor Eligibility Rule (80 FR 29905), which consolidated and updated donor screening requirements previously scattered across multiple regulations and guidance documents. Authority: 42 U.S.C. § 216 (PHSA), 21 U.S.C. §§ 321, 360j (FDCA).

• § 630.3 — Definitions: "blood" is a fluid containing dissolved and suspended elements collected from a human donor; "communicable disease agent" includes any infectious agent transmissible by blood transfusion; "donor history questionnaire (DHQ)" is the standardized questionnaire used to screen donors for communicable disease risk factors; CBER develops and approves DHQs — individual establishments cannot substitute their own questions
• § 630.10 — General donor eligibility requirements: an establishment may not collect blood from a donor unless the establishment has made a determination, based on the donor's medical history and physical examination, that the donor meets all applicable eligibility criteria; the general requirements include: (1) the donor must not be currently deferred from donation; (2) the donor must not have a communicable disease or be at risk for one; (3) the collection must not adversely affect the donor's health; (4) the donation must be suitable for its intended use
• § 630.15 — Requirements specific to Whole Blood, RBCs, and apheresis plasma: additional eligibility criteria apply to donors of whole blood and apheresis components: donors must have adequate hemoglobin (generally ≥12.5 g/dL for women, ≥13.0 g/dL for men); blood pressure and pulse must be within defined limits; donors must weigh at least 110 pounds; at each donation, the establishment must review communicable disease test results from prior donations and check current deferral registries
• § 630.20 — Exceptions for certain ineligible donors: an establishment may collect blood from a donor who would otherwise be ineligible if: the collection is for autologous use only (the donor receives their own blood); the collection is from a paid donor for source plasma and appropriate risk mitigation is applied; or FDA has granted an exception in response to a specific establishment petition
• § 630.25 — Exceptions for infrequent plasma donors: for donors who do not donate plasma more than once a month, certain eligibility requirements (specifically those designed for frequent commercial plasma donors) may be relaxed; this acknowledges that the physiological risks of frequent plasma donation (protein depletion, iron loss) do not apply equally to occasional plasma donors
• § 630.30 — Donation suitability requirements: a donation is suitable when (1) the donor is not currently deferred, (2) the donor's medical history and physical exam show no disqualifying conditions, and (3) the donation's communicable disease test results are negative or non-reactive; any donation where test results indicate potential infection must be quarantined and cannot be released until appropriate investigation and disposition
• § 630.35 — Requalification of previously deferred donors: an establishment may requalify a previously deferred donor if: the reason for deferral no longer applies (e.g., a temporary behavioral deferral has expired; a medication-based deferral is resolved); there is laboratory evidence that the risk factor is no longer present; or FDA guidance permits requalification under specific circumstances. The HIV deferral policy evolution — from indefinite MSM deferral (pre-2015) to behavior-based 3-month deferral (2023 updated guidance) — is the most prominent recent example of requalification policy change

Part 630 operates as the front-end screening layer in a multi-layer blood safety system. Even with negative screening results, blood components undergo mandatory infectious disease testing under Part 610 before release; Part 630's donor eligibility screening reduces the risk that test windows miss recent infections and ensures medically compromised donors are not harmed by donation. The 2015 rule's shift from categorical-demographic deferrals (MSM) to behavioral risk assessment (recent new sexual partner, regardless of sex) updated blood safety policy to align with current epidemiology and reduce discriminatory exclusions that blocked many low-risk donors.

Human Cells, Tissues, and Cellular and Tissue-Based Products (21 CFR Part 1271)

21 CFR Part 1271 establishes FDA's regulatory framework for human cells, tissues, and cellular and tissue-based products (HCT/Ps) — a category that includes bone allografts, skin grafts, corneas, tendons, ligaments, heart valves, amniotic membrane products, and a wide range of cellular therapies and regenerative medicine products. Authority: 42 U.S.C. § 264 (PHS Act § 361, communicable disease control) and 42 U.S.C. § 262 (PHS Act § 351, biologics licensing).

The central regulatory question under Part 1271 is whether an HCT/P is regulated solely under Section 361 (lower burden — registration, donor eligibility, CGTP) or also requires a Section 351 biologics license (BLA — equivalent to a drug application with clinical trials). The decision tree:

• § 1271.10 — Section 361-only criteria: an HCT/P is regulated only under Part 1271 (not as a drug or biologic) if it meets all four criteria: (1) minimal manipulation — the processing does not alter the biological characteristics of the tissue; (2) homologous use — the HCT/P performs the same basic function in the recipient as in the donor; (3) not combined with a drug or device (with limited exceptions); (4) no systemic effect — the HCT/P does not have a systemic effect and the patient/donor is not dependent on the metabolic activity of the HCT/P. A bone allograft (minimally processed, used to fill the same anatomical role it served in the donor) meets all four — it needs only Part 1271 compliance. A stem cell product processed to derive a specific cell type and intended to treat a systemic disease fails criteria 1 and 2 — it needs a BLA.
• § 1271.15 — Exceptions from Part 1271: certain HCT/Ps are completely exempt: (a) autologous use in the same surgical procedure (the patient's own tissue removed and reimplanted in the same procedure — no third-party involvement); (b) use for a first-degree or second-degree relative; (c) reproductive tissues (regulated separately under CLIA and state law); (d) whole organs (regulated by NOTA, not FDA)
• § 1271.20 — Section 351 application requirement: if an HCT/P does not meet the §1271.10 criteria and does not qualify for a §1271.15 exception, the manufacturer must obtain a biologics license (BLA) or investigational new drug exemption (IND) before distributing the product — the same regulatory pathway as novel biologic drugs; this is how FDA regulates CAR-T cell therapies, allogeneic hematopoietic stem cell products, and other advanced cellular therapies that are "more than minimally manipulated"

Registration and Listing (Subpart B, §§ 1271.21–1271.37):

• § 1271.21 — All HCT/P establishments must register with FDA and submit a product list before beginning operations; annual updates required; registration is not FDA approval — it is a listing mechanism that puts establishments in FDA's surveillance system
• § 1271.22 — Registration is submitted electronically through FDA's establishment registration system; FDA assigns a permanent registration number to each location; registration acceptance does not constitute FDA approval of the HCT/P or the establishment's practices

Donor Eligibility (Subpart C, §§ 1271.50–1271.90):

• § 1271.50 — Establishments must determine donor eligibility for all donors of HCT/Ps intended for allogeneic use; eligibility determination requires a donor medical history screen, physical assessment (for living donors), and communicable disease testing; a donor who tests reactive for HIV, HBV, HCV, syphilis, CMV (for certain products), or other specified agents is ineligible unless specific exceptions apply
• § 1271.75 — Communicable disease screening tests: FDA specifies required tests (which must use FDA-licensed or -approved test kits); establishments cannot substitute their own screening protocols; testing standards are updated through CBER guidance as new disease risks emerge (the emergence of West Nile Virus and Zika testing requirements followed this path)

Current Good Tissue Practice (Subpart D, §§ 1271.145–1271.290):

• § 1271.150 — CGTP requirements: establishments must establish and maintain CGTP procedures covering all manufacturing steps; the CGTP framework parallels GMP for pharmaceuticals but is scaled to the tissue banking context — smaller establishments with simpler manufacturing can comply without the full cGMP infrastructure required for drug manufacturing
• § 1271.160 — Quality program: each establishment must maintain a quality program that provides for monitoring, detection, and correction of deviations, complaints, and problems; the quality program must include review of adverse reaction reports
• § 1271.290 — Tracking: establishments must track each HCT/P from donor to consignee (and vice versa) using a system that allows tracing from the donor to the ultimate recipient or disposition; the tracking requirement supports rapid identification of all recipients who received HCT/Ps from a donor who is later found to have been ineligible or to have transmitted disease

Part 1271's practical significance: approximately 1,750 registered HCT/P establishments operate in the United States, processing roughly 2 million tissue products transplanted annually (including 1.5 million bone allografts, 40,000 corneas, 30,000+ skin grafts, and large volumes of soft-tissue products). The §1271.10 "more than minimal manipulation" boundary has been FDA's primary enforcement tool against unproven stem cell clinics: dozens of clinics offering "stem cell therapy" using autologous fat tissue (stromal vascular fraction) or bone marrow were found to be processing products in ways that exceed minimal manipulation, subjecting them to the full BLA pathway and — when they lacked an IND or BLA — to FDA injunctive actions under 21 U.S.C. § 332. The Supreme Court confirmed FDA's enforcement authority in this context in United States v. US Stem Cell Clinic (11th Cir. 2019, cert. denied 2020). Recent rulemakings: 66 FR 5447 (January 2001) — original Part 1271 establishment (the three-tiered HCT/P framework); 69 FR 29786 (May 2004) — CGTP requirements finalized; FDA Guidance (November 2017 and November 2020) — clarified the "same surgical procedure" exception and "homologous use" definitions, significantly affecting the unproven stem cell clinic enforcement wave of 2018–2021.

Statutory Authority

This rule implements:

• 42 U.S.C. § 216 — Section 351 of the Public Health Service Act, authorizing the Secretary of HHS to establish standards for the safety, purity, and potency of biological products (including blood and blood components), and to require licensure of establishments engaged in their manufacture and distribution; the foundational authority for FDA biologics licensing
• 21 U.S.C. § 321 — Section 201 of the Federal Food, Drug, and Cosmetic Act, defining "drug" and "biological product" in a way that brings blood products under FDA's adulteration and misbranding prohibitions, enabling FDCA enforcement authority alongside the PHSA licensing framework

Recent Rulemakings

• 80 FR 29905 (May 2015) — Donor Eligibility Rule: major revision to donor qualification standards across Parts 630 and 640; established the current approach to communicable disease-based deferrals including updated HIV risk assessment criteria; requires establishments to use approved donor history questionnaires developed with CBER input
• 64 FR 45372 (August 1999) — Platelets and Plasma updates: updated quality control specifications for platelet products and revised plasma processing timeframes to reflect improved processing technologies
• 55 FR 11013 (March 1990) — Source Plasma pheresis frequency: established the twice-weekly donation maximum and the annual 110-liter limit for source plasma donors; the framework that continues to define commercial plasma collection capacity

No major amendments since 2015 — CBER has primarily updated blood safety requirements through guidance documents (rather than rulemaking) addressing emerging pathogen risks (Zika, babesiosis), new testing technologies (pathogen reduction), and donor eligibility policy modernization.

Pending Action