PART 1271—HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Authority: 42 U.S.C. 216, 243, 263a, 264, 271. Source: 66 FR 5466, Jan. 19, 2001, unless otherwise noted. Subpart A—General Provisions § 1271.1 What are the purpose and scope of this part? (a) Purpose. (b) Scope. (2) If you are an establishment that manufactures HCT/P's that are regulated as drugs, devices and/or biological products under section 351 of the PHS Act and/or the Federal Food, Drug, and Cosmetic Act, §§ 207.9(a)(5) and 807.20(d) of this chapter require you to register and list your HCT/P's following the procedures in part 207 (if a drug and/or biological product) of this chapter or part 807 (if a device) of this chapter. Sections 210.1(c), 210.2, 211.1(b), and 820.1(a) of this chapter require you to comply with the donor-eligibility procedures in subpart C of this part and the current good tissue practice procedures in subpart D of this part, in addition to all other applicable regulations. [66 FR 5466, Jan. 19, 2001, as amended at 69 FR 29829, May 25, 2004; 81 FR 60223, Aug. 31, 2016] § 1271.3 How does FDA define important terms in this part? The following definitions apply only to this part: (a) Autologous use (b) Establishment (1) Any individual, partnership, corporation, association, or other legal entity engaged in the manufacture of human cells, tissues, and cellular and tissue-based products; and (2) Facilities that engage in contract manufacturing services for a manufacturer of human cells, tissues, and cellular and tissue-based products. (c) Homologous use (d) Human cells, tissues, or cellular or tissue-based products (HCT/Ps) (1) Vascularized human organs for transplantation; (2) Whole blood or blood components or blood derivative products subject to listing under parts 607 and 207 of this chapter, respectively; (3) Secreted or extracted human products, such as milk, collagen, and cell factors; except that semen is considered an HCT/P; (4) Minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow); (5) Ancillary products used in the manufacture of HCT/P; (6) Cells, tissues, and organs derived from animals other than humans; and (7) In vitro diagnostic products as defined in § 809.3(a) of this chapter. (8) Blood vessels recovered with an organ, as defined in 42 CFR 121.2, that are intended for use in organ transplantation and labeled “For use in organ transplantation only.” (e) Manufacture means, (f) Minimal manipulation (1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement; and (2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues. (g) Transfer (h) Biohazard legend (i) Blood component (j) Colloid (1) A protein or polysaccharide solution, such as albumin, dextran, or hetastarch, that can be used to increase or maintain osmotic (oncotic) pressure in the intravascular compartment; or (2) Blood components such as plasma and platelets. (k) Crystalloid (l) Directed reproductive donor (m) Donor (n) Donor medical history interview means (1) With the donor, if the donor is living and able to participate in the interview, or (2) If not, with an individual or individuals able to provide the information sought in the interview (e.g., the donor's next-of-kin, the nearest available relative, a member of the donor's household, an individual with an affinity relationship, and/or the primary treating physician). (o) Physical assessment of a cadaveric donor (p) Plasma dilution (q) Quarantine (r) Relevant communicable disease agent or disease (1)(i) For all human cells and tissues, a communicable disease or disease agent listed as follows: (A) Human immunodeficiency virus, types 1 and 2; (B) Hepatitis B virus; (C) Hepatitis C virus; (D) Human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; and (E) Treponema pallidum. (ii) For viable, leukocyte-rich cells and tissues, a cell-associated disease agent or disease listed as follows: (A) Human T-lymphotropic virus, type I; and (B) Human T-lymphotropic virus, type II. (iii) For reproductive cells or tissues, a disease agent or disease of the genitourinary tract listed as follows: (A) Chlamydia trachomatis (B) Neisseria gonorrhea. (2) A disease agent or disease not listed in paragraph (r)(1) of this section: (i) For which there may be a risk of transmission by an HCT/P, either to the recipient of the HCT/P or to those people who may handle or otherwise come in contact with it, such as medical personnel, because the disease agent or disease: (A) Is potentially transmissible by an HCT/P and (B) Either of the following applies: ( 1 ( 2 (ii) That could be fatal or life-threatening, could result in permanent impairment of a body function or permanent damage to body structure, or could necessitate medical or surgical intervention to preclude permanent impairment of body function or permanent damage to a body structure; and (iii) For which appropriate screening measures have been developed and/or an appropriate screening test for donor specimens has been licensed, approved, or cleared for such use by FDA and is available. (s) Relevant medical records (1) Laboratory test results (other than results of testing for relevant communicable disease agents required under this subpart); (2) Medical records; (3) Coroner and autopsy reports; and (4) Records or other information received from any source pertaining to risk factors for relevant communicable disease (e.g., social behavior, clinical signs and symptoms of relevant communicable disease, and treatments related to medical conditions suggestive of risk for relevant communicable disease). (t) Responsible person (u) Urgent medical need (v) Act (w) PHS Act (x) FDA (y) Adverse reaction (z) Available for distribution (aa) Complaint (1) That an HCT/P has transmitted or may have transmitted a communicable disease to the recipient of the HCT/P; or (2) Any other problem with an HCT/P relating to the potential for transmission of communicable disease, such as the failure to comply with current good tissue practice. (bb) Distribution (cc) Establish and maintain (dd) HCT/P deviation (1) That represents a deviation from applicable regulations in this part or from applicable standards or established specifications that relate to the prevention of communicable disease transmission or HCT/P contamination; or (2) That is an unexpected or unforeseeable event that may relate to the transmission or potential transmission of a communicable disease or may lead to HCT/P contamination. (ee) Importer of record (ff) Processing (gg) Quality audit (hh) Quality program (ii) Recovery (jj) Storage (kk) Validation process validation (ll) Verification (mm) Importer (nn) United States agent [66 FR 5466, Jan. 19, 2001, as amended at 68 FR 3826, Jan. 27, 2004; 69 FR 29829, May 25, 2004; 69 FR 68680, Nov. 24, 2004; 81 FR 60223, Aug. 31, 2016] § 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? (a) An HCT/P is regulated solely under section 361 of the PHS Act and the regulations in this part if it meets all of the following criteria: (1) The HCT/P is minimally manipulated; (2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent; (3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and (4) 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: ( a ( b ( c (b) If you are a domestic or foreign establishment that manufactures an HCT/P described in paragraph (a) of this section: (1) You must register with FDA; (2) You must submit to FDA a list of each HCT/P manufactured; and (3) You must comply with the other requirements contained in this part. [66 FR 5466, Jan. 19, 2001, as amended at 69 FR 68681, Nov. 24, 2004] § 1271.15 Are there any exceptions from the requirements of this part? (a) You are not required to comply with the requirements of this part if you are an establishment that uses HCT/P's solely for nonclinical scientific or educational purposes. (b) You are not required to comply with the requirements of this part if you are an establishment that removes HCT/P's from an individual and implants such HCT/P's into the same individual during the same surgical procedure. (c) You are not required to comply with the requirements of this part if you are a carrier who accepts, receives, carries, or delivers HCT/P's in the usual course of business as a carrier. (d) You are not required to comply with the requirements of this part if you are an establishment that does not recover, screen, test, process, label, package, or distribute, but only receives or stores HCT/P's solely for implantation, transplantation, infusion, or transfer within your facility. (e) You are not required to comply with the requirements of this part if you are an establishment that only recovers reproductive cells or tissue and immediately transfers them into a sexually intimate partner of the cell or tissue donor. (f) You are not required to register or list your HCT/P's independently, but you must comply with all other applicable requirements in this part, if you are an individual under contract, agreement, or other arrangement with a registered establishment and engaged solely in recovering cells or tissues and sending the recovered cells or tissues to the registered establishment. § 1271.20 If my HCT/P's do not meet the criteria in § 1271.10, and I do not qualify for any of the exceptions in § 1271.15, what regulations apply? If you are an establishment that manufactures an HCT/P that does not meet the criteria set out in § 1271.10(a), and you do not qualify for any of the exceptions in § 1271.15, your HCT/P will be regulated as a drug, device, and/or biological product under the act and/or section 351 of the PHS Act, and applicable regulations in title 21, chapter I. Applicable regulations include, but are not limited to, §§ 207.9(a)(5), 210.1(c), 210.2, 211.1(b), 807.20(d), and 820.1(a) of this chapter, which require you to follow the procedures in subparts C and D of this part. [66 FR 5466, Jan. 19, 2001, as amended at 81 FR 60223, Aug. 31, 2016] Subpart B—Procedures for Registration and Listing § 1271.21 When do I register, submit an HCT/P list, and submit updates? (a) You must register and submit a list of every HCT/P that your establishment manufactures within 5 days after beginning operations or within 30 days of the effective date of this regulation, whichever is later. (b) You must update your establishment registration annually in December, except as required by § 1271.26. You may accomplish your annual registration in conjunction with updating your HCT/P list under paragraph (c) of this section. (c)(i) If no change described in § 1271.25(c) has occurred since you previously submitted an HCT/P list, you are not required to update your listing. (ii) If a change described in § 1271.25(c) has occurred, you must update your HCT/P listing with the new information: ( a ( b [69 FR 68681, Nov. 24, 2004] § 1271.22 How do I register and submit an HCT/P list? (a) You must use the electronic registration and listing system at http://www.fda.gov/cber/tissue/tisreg.htm (1) Establishment registration, (2) HCT/P listings, and (3) Updates of registration and HCT/P listing. (b) FDA will periodically issue guidance on recommended procedures for providing registration and listing information in electronic format (for example, method of transmission, media, file formats, preparation, and organization of files). (c) You must provide the information under paragraph (a) of this section in accordance with part 11 of this chapter, except for the requirements in § 11.10(b), (c), and (e) and the corresponding requirements in § 11.30. [81 FR 60223, Aug. 31, 2016] § 1271.23 How is a waiver from the electronic format requirements requested? (a) You may request a waiver from the requirement in § 1271.22 that information must be provided to FDA in electronic format. Submission of a request for waiver does not excuse timely compliance with the registration and listing requirements. FDA will grant a waiver request if FDA determines that the use of electronic means for submission of registration and listing information is not reasonable for the registrant making the waiver request. (b) Waiver requests under this section must be submitted in writing and must include the specific reasons why electronic submission is not reasonable for the registrant and a U.S. telephone number and mailing address where FDA can contact the registrant. Waiver requests may be sent to the Center for Biologics Evaluation and Research (CBER), Document Control Center (see addresses in § 600.2 of this chapter). (c) If FDA grants the waiver request, FDA may limit its duration and will specify terms of the waiver and provide information on how to submit establishment registration, listings, other information, and updates, as applicable. [81 FR 60224, Aug. 31, 2016] § 1271.25 What information is required for establishment registration and HCT/P listing? (a) Your establishment registration must include: (1) The legal name(s) of the establishment; (2) Each physical location, including the street address, telephone number, email address, and the postal service ZIP code of the establishment; (3) The name, address, telephone number, email address, and title of the reporting official; (4) A dated signature by the reporting official affirming that all information contained in the establishment registration and HCT/P listing form is true and accurate, to the best of his or her knowledge. (5) Each foreign establishment must also submit the name, address, telephone number, and email address of each importer that is known to the establishment, and the name of each person who imports or offers for import such HCT/P to the United States for purposes of importation; and (6) Each foreign establishment must also submit the name, address, telephone number, and email address of its United States agent. (i) The United States agent must reside or maintain a place of business in the United States. (ii) Upon request from FDA, the United States agent must assist FDA in communications with the foreign establishment, respond to questions concerning the foreign establishment's products that are imported or offered for import into the United States, and assist FDA in scheduling inspections of the foreign establishment. If the Agency is unable to contact the foreign establishment directly or expeditiously, FDA may provide information or documents to the United States agent, and such an action is equivalent to providing the same information or documents to the foreign establishment. (iii) The foreign establishment or the United States agent must report changes in the United States agent's name, address, telephone number, or email address to FDA within 30 calendar days of the change. (b) Your HCT/P listing must include all HCT/P's (including the established name and the proprietary name) that you recover, process, store, label, package, distribute, or for which you perform donor screening or testing. You must also state whether each HCT/P meets the criteria set out in § 1271.10. (c) Your HCT/P listing update must include: (1) A list of each HCT/P that you have begun recovering, processing, storing, labeling, packaging, distributing, or for which you have begun donor screening or testing, that has not been included in any list previously submitted. You must provide all of the information required by § 1271.25(b) for each new HCT/P. (2) A list of each HCT/P formerly listed in accordance with § 1271.21(a) for which you have discontinued recovery, processing, storage, labeling, packaging, distribution, or donor screening or testing, including for each HCT/P so listed, the identity by established name and proprietary name, and the date of discontinuance. We request but do not require that you include the reason for discontinuance with this information. (3) A list of each HCT/P for which a notice of discontinuance was submitted under paragraph (c)(2) of this section and for which you have resumed recovery, processing, storage, labeling, packaging, distribution, or donor screening or testing, including the identity by established name and proprietary name, the date of resumption, and any other information required by § 1271.25(b) not previously submitted. (4) Any material change in any information previously submitted. Material changes include any change in registration and listing information, submitted, such as whether the HCT/P meets the criteria set out in § 1271.10. (d) If your HCT/P is described under § 1271.20 and is regulated under a BLA, you must submit the information required under part 207 of this chapter using the procedures under subpart E of part 207. [66 FR 5466, Jan. 19, 2001, as amended at 81 FR 60224, Aug. 31, 2016] § 1271.26 When must I amend my establishment registration? If the ownership or location of your establishment changes, or if there is a change in the United States agent's name, address, telephone number, or email address, you must submit an amendment to registration within 30 calendar days of the change. [81 FR 60224, Aug. 31, 2017] § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number. (b) FDA acceptance of an establishment registration and HCT/P listing form does not constitute a determination that an establishment is in compliance with applicable rules and regulations or that the HCT/P is licensed or approved by FDA. § 1271.37 Will establishment registrations and HCT/P listings be available for inspection, and how do I request information on registrations and listings? (a) Any registration on Form FDA 3356 filed in paper or electronic format by each establishment will be available for public inspection through the Center for Biologics Evaluation and Research Human Cell and Tissue Establishment Registration—Public Query Web site by using the CBER electronic Web-based application or by going in person to the Food and Drug Administration, Dockets Management Staff Public Reading Room (see address in § 20.120(a) of this chapter). The following information submitted under the HCT/P requirements is illustrative of the type of information that will be available for public disclosure when it is compiled: (1) A list of all HCT/P's; (2) A list of all HCT/P's manufactured by each establishment; (3) A list of all HCT/P's discontinued; and (4) All data or information that has already become a matter of public record. (b) You should direct your other requests for information regarding HCT/P establishment registrations and HCT/P listings to the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Communication, Outreach and Development, 10903 New Hampshire Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002. [80 FR 18094, Apr. 3, 2015, as amended at 88 FR 45067, July 14, 2023] Subpart C—Donor Eligibility Source: 69 FR 29830, May 25, 2004, unless otherwise noted. § 1271.45 What requirements does this subpart contain? (a) General. (b) Donor-eligibility determination required. (c) Prohibition on use. (d) Applicability of requirements. [69 FR 29830, May 25, 2004, as amended at 69 FR 68681, Nov. 24, 2004] § 1271.47 What procedures must I establish and maintain? (a) General. (b) Review and approval. (c) Availability. (d) Departures from procedures. (e) Standard procedures. § 1271.50 How do I determine whether a donor is eligible? (a) Determination based on screening and testing. (b) Eligible donor. (1) Donor screening in accordance with § 1271.75 indicates that the donor: (i) Is free from risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases; and (ii) Is free from communicable disease risks associated with xenotransplantation; and (2) The results of donor testing for relevant communicable disease agents in accordance with §§ 1271.80 and 1271.85 are negative or nonreactive, except as provided in § 1271.80(d)(1). § 1271.55 What records must accompany an HCT/P after the donor-eligibility determination is complete; and what records must I retain? (a) Accompanying records. (1) A distinct identification code affixed to the HCT/P container, e.g., alphanumeric, that relates the HCT/P to the donor and to all records pertaining to the HCT/P and, except in the case of autologous donations, directed reproductive donations, or donations made by first-degree or second-degree blood relatives, does not include an individual's name, social security number, or medical record number; (2) A statement whether, based on the results of screening and testing, the donor has been determined to be eligible or ineligible; and (3) A summary of the records used to make the donor-eligibility determination. (b) Summary of records. (1) A statement that the communicable disease testing was performed by a laboratory: (i) Certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR part 493; or (ii) That has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services in accordance with those provisions; (2) A listing and interpretation of the results of all communicable disease tests performed; (3) The name and address of the establishment that made the donor-eligibility determination; and (4) In the case of an HCT/P from a donor who is ineligible based on screening and released under paragraph (b) of § 1271.65, a statement noting the reason(s) for the determination of ineligibility. (c) Deletion of personal information. (d) Record retention requirements. (i) Results and interpretation of all testing for relevant communicable disease agents in compliance with §§ 1271.80 and 1271.85, as well as the name and address of the testing laboratory or laboratories; (ii) Results and interpretation of all donor screening for communicable diseases in compliance with § 1271.75; and (iii) The donor-eligibility determination, including the name of the responsible person who made the determination and the date of the determination. (2) All records must be accurate, indelible, and legible. Information on the identity and relevant medical records of the donor, as defined in § 1271.3(s), must be in English or, if in another language, must be retained and translated to English and accompanied by a statement of authenticity by the translator that specifically identifies the translated document. (3) You must retain required records and make them available for authorized inspection by or upon request from FDA. Records that can be readily retrieved from another location by electronic means are considered “retained.” (4) You must retain the records pertaining to a particular HCT/P at least 10 years after the date of its administration, or if the date of administration is not known, then at least 10 years after the date of the HCT/P's distribution, disposition, or expiration, whichever is latest. [69 FR 29830, May 25, 2004, as amended at 70 FR 29952, May 25, 2005] § 1271.60 What quarantine and other requirements apply before the donor-eligibility determination is complete? (a) Quarantine. (b) Identification of HCT/Ps in quarantine. (c) Shipping of HCT/Ps in quarantine. (1) Identifying the donor (e.g., by a distinct identification code affixed to the HCT/P container); (2) Stating that the donor-eligibility determination has not been completed; and (3) Stating that the product must not be implanted, transplanted, infused, or transferred until completion of the donor-eligibility determination, except under the terms of paragraph (d) of this section. (d) Use in cases of urgent medical need. (2) If you make an HCT/P available for use under the provisions of paragraph (d)(1) of this section, you must prominently label it “NOT EVALUATED FOR INFECTIOUS SUBSTANCES,” and “ WARNING: Advise patient of communicable disease risks.” The following information must accompany the HCT/P: (i) The results of any donor screening required under § 1271.75 that has been completed; (ii) The results of any testing required under § 1271.80 or 1271.85 that has been completed; and (iii) A list of any screening or testing required under § 1271.75, 1271.80 or 1271.85 that has not yet been completed. (3) If you are the establishment that manufactured an HCT/P used under the provisions of paragraph (d)(1) of this section, you must document that you notified the physician using the HCT/P that the testing and screening were not complete. (4) In the case of an HCT/P used for an urgent medical need under the provisions of paragraph (d)(1) of this section, you must complete the donor-eligibility determination during or after the use of the HCT/P, and you must inform the physician of the results of the determination. § 1271.65 How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are not prohibited? (a) Storage. (b) Limited uses of HCT/P from ineligible donor. (i) The HCT/P is for allogeneic use in a first-degree or second-degree blood relative; (ii) The HCT/P consists of reproductive cells or tissue from a directed reproductive donor, as defined in § 1271.3(l); or (iii) There is a documented urgent medical need as defined in § 1271.3(u). (2) You must prominently label an HCT/P made available for use under the provisions of paragraph (b)(1) of this section with the Biohazard legend shown in § 1271.3(h) with the statement “WARNING: Advise patient of communicable disease risks,” and, in the case of reactive test results, “WARNING: Reactive test results for (name of disease agent or disease).” The HCT/P must be accompanied by the records required under § 1271.55. (3) If you are the establishment that manufactured an HCT/P used under the provisions of paragraph (b)(1) of this section, you must document that you notified the physician using the HCT/P of the results of testing and screening. (c) Nonclinical use. (1) “For Nonclinical Use Only” and (2) With the Biohazard legend shown in § 1271.3(h). § 1271.75 How do I screen a donor? (a) All donors. (1) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases, including: (i) Human immunodeficiency virus; (ii) Hepatitis B virus; (iii) Hepatitis C virus; (iv) Human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; (v) Treponema pallidum (2) Communicable disease risks associated with xenotransplantation. (b) Donors of viable, leukocyte-rich cells or tissue. (c) Donors of reproductive cells or tissue. (1) Chlamydia trachomatis (2) Neisseria gonorrhea. (d) Ineligible donors. (1) A risk factor for or clinical evidence of any of the relevant communicable disease agents or diseases for which screening is required under paragraphs (a)(1), (b), or (c) of this section; or (2) Any communicable disease risk associated with xenotransplantation. (e) Abbreviated procedure for repeat donors. [66 FR 5466, Jan. 19, 2001, as amended at 71 FR 14798, Mar. 24, 2006] § 1271.80 What are the general requirements for donor testing? (a) Testing for relevant communicable diseases is required. (b) Timing of specimen collection. (1) For donors of peripheral blood stem/progenitor cells, bone marrow (if not excepted under § 1271.3(d)(4)), or oocytes, you may collect the donor specimen for testing up to 30 days before recovery; or (2) In the case of a repeat semen donor from whom a specimen has already been collected and tested, and for whom retesting is required under § 1271.85(d), you are not required to collect a donor specimen at the time of each donation. (c) Tests. Chlamydia trachomatis Neisseria gonorrhea (d) Ineligible donors. (1) A donor whose specimen tests reactive on a screening test for a communicable disease agent in accordance with § 1271.85, except for a donor whose specimen tests reactive on a non-treponemal screening test for syphilis and negative on a specific treponemal confirmatory test; (2)(i) A donor in whom plasma dilution sufficient to affect the results of communicable disease testing is suspected, unless: (A) You test a specimen taken from the donor before transfusion or infusion and up to 7 days before recovery of cells or tissue; or (B) You use an appropriate algorithm designed to evaluate volumes administered in the 48 hours before specimen collection, and the algorithm shows that plasma dilution sufficient to affect the results of communicable disease testing has not occurred. (ii) Clinical situations in which you must suspect plasma dilution sufficient to affect the results of communicable disease testing include but are not limited to the following: (A) Blood loss is known or suspected in a donor over 12 years of age, and the donor has received a transfusion or infusion of any of the following, alone or in combination: ( 1 ( 2 (B) Regardless of the presence or absence of blood loss, the donor is 12 years of age or younger and has received a transfusion or infusion of any amount of any of the following, alone or in combination: ( 1 ( 2 [69 FR 29830, May 25, 2004, as amended at 70 FR 29952, May 25, 2005] § 1271.85 What donor testing is required for different types of cells and tissues? (a) All donors. (1) Human immunodeficiency virus, type 1; (2) Human immunodeficiency virus, type 2; (3) Hepatitis B virus; (4) Hepatitis C virus; and (5) Treponema pallidum. (b) Donors of viable, leukocyte-rich cells or tissue. (1) You must test a specimen from the donor of viable, leukocyte-rich cells or tissue to adequately and appropriately reduce the risk of transmission of relevant cell-associated communicable diseases, including: (i) Human T-lymphotropic virus, type I; and (ii) Human T-lymphotropic virus, type II. (2) You must test a specimen from the donor of viable, leukocyte-rich cells or tissue for evidence of infection due to cytomegalovirus (CMV), to adequately and appropriately reduce the risk of transmission. You must establish and maintain a standard operating procedure governing the release of an HCT/P from a donor whose specimen tests reactive for CMV. (c) Donors of reproductive cells or tissue. (1) Chlamydia trachomatis (2) Neisseria gonorrhea. (d) Retesting anonymous semen donors. (e) Dura mater. § 1271.90 Are there other exceptions and what labeling requirements apply? (a) Donor-eligibility determination not required. (1) Cells and tissues for autologous use; or (2) Reproductive cells or tissue donated by a sexually intimate partner of the recipient for reproductive use; or (3) Cryopreserved cells or tissue for reproductive use, other than embryos, originally excepted under paragraphs (a)(1) or (a)(2) of this section at the time of donation, that are subsequently intended for directed donation, provided that: (i) Additional donations are unavailable, for example, due to the infertility or health of a donor of the cryopreserved reproductive cells or tissue; and (ii) Appropriate measures are taken to screen and test the donor(s) before transfer to the recipient. (4) A cryopreserved embryo, originally excepted under paragraph (a)(2) of this section at the time of recovery or cryopreservation, that is subsequently intended for directed or anonymous donation. When possible, appropriate measures should be taken to screen and test the semen and oocyte donors before transfer of the embryo to the recipient. (b) Exceptions for reproductive use. (c) Required labeling. (1) “FOR AUTOLOGOUS USE ONLY,” if it is stored for autologous use. (2) “NOT EVALUATED FOR INFECTIOUS SUBSTANCES,” unless you have performed all otherwise applicable screening and testing under §§ 1271.75, 1271.80, and 1271.85. This paragraph does not apply to reproductive cells or tissue labeled in accordance with paragraph (c)(6) of this section. (3) Unless the HCT/P is for autologous use only, “WARNING: Advise recipient of communicable disease risks,” (i) When the donor-eligibility determination under § 1271.50(a) is not performed or is not completed; or (ii) If the results of any screening or testing performed indicate: (A) The presence of relevant communicable disease agents and/or (B) Risk factors for or clinical evidence of relevant communicable disease agents or diseases. (4) With the Biohazard legend shown in § 1271.3(h), if the results of any screening or testing performed indicate: (i) The presence of relevant communicable disease agents and/or (ii) Risk factors for or clinical evidence of relevant communicable disease agents or diseases. (5) “WARNING: Reactive test results for (name of disease agent or disease),” in the case of reactive test results. (6) “Advise recipient that screening and testing of the donor(s) were not performed at the time of recovery or cryopreservation of the reproductive cells or tissue, but have been performed subsequently,” for paragraphs (a)(3) or (a)(4) of this section. [69 FR 29830, May 25, 2004, as amended at 70 FR 29952, May 25, 2005; 81 FR 40517, June 22, 2016] Subpart D—Current Good Tissue Practice Source: 69 FR 68681, Nov. 24, 2004, unless otherwise noted. § 1271.145 Prevention of the introduction, transmission, or spread of communicable diseases. You must recover, process, store, label, package, and distribute HCT/Ps, and screen and test cell and tissue donors, in a way that prevents the introduction, transmission, or spread of communicable diseases. § 1271.150 Current good tissue practice requirements. (a) General. (b) Core CGTP requirements. (1) Requirements relating to facilities in § 1271.190(a) and (b); (2) Requirements relating to environmental control in § 1271.195(a); (3) Requirements relating to equipment in § 1271.200(a); (4) Requirements relating to supplies and reagents in § 1271.210(a) and (b); (5) Requirements relating to recovery in § 1271.215; (6) Requirements relating to processing and process controls in § 1271.220; (7) Requirements relating to labeling controls in § 1271.250(a) and (b); (8) Requirements relating to storage in § 1271.260 (a) through (d); (9) Requirements relating to receipt, predistribution shipment, and distribution of an HCT/P in § 1271.265(a) through (d); and (10) Requirements relating to donor eligibility determinations, donor screening, and donor testing in §§ 1271.50, 1271.75, 1271.80, and 1271.85. (c) Compliance with applicable requirements Manufacturing arrangements (ii) If you engage another establishment (e.g., a laboratory to perform communicable disease testing, or an irradiation facility to perform terminal sterilization), under a contract, agreement, or other arrangement, to perform any step in manufacture for you, that establishment is responsible for complying with requirements applicable to that manufacturing step. (iii) Before entering into a contract, agreement, or other arrangement with another establishment to perform any step in manufacture for you, you must ensure that the establishment complies with applicable CGTP requirements. If, during the course of this contract, agreement, or other arrangement, you become aware of information suggesting that the establishment may no longer be in compliance with such requirements, you must take reasonable steps to ensure the establishment complies with those requirements. If you determine that the establishment is not in compliance with those requirements, you must terminate your contract, agreement, or other arrangement with the establishment. (2) If you are the establishment that determines that an HCT/P meets all release criteria and makes the HCT/P available for distribution, whether or not you are the actual distributor, you are responsible for reviewing manufacturing and tracking records to determine that the HCT/P has been manufactured and tracked in compliance with the requirements of this subpart and subpart C of this part and any other applicable requirements. (3) With the exception of §§ 1271.150(c) and 1271.155 of this subpart, the regulations in this subpart are not being implemented for reproductive HCT/Ps described in § 1271.10 and regulated solely under section 361 of the Public Health Service Act and the regulations in this part, or for the establishments that manufacture them. (d) Compliance with parts 210, 211, and 820 of this chapter. (e) Where appropriate. § 1271.155 Exemptions and alternatives. (a) General. (b) Request for exemption or alternative. (1) Information justifying the requested exemption from the requirement, or (2) A description of a proposed alternative method of meeting the requirement. (c) Criteria for granting an exemption or alternative. (1) The information submitted justifies an exemption; or (2) The proposed alternative satisfies the purpose of the requirement. (d) Form of request. (e) Operation under exemption or alternative. (f) Documentation. (1) FDA's grant of the exemption or alternative, and (2) The date on which you began operating under the terms of the exemption or alternative. (g) Issuance of an exemption or alternative by the Director. § 1271.160 Establishment and maintenance of a quality program. (a) General. (b) Functions. (1) Establishing and maintaining appropriate procedures relating to core CGTP requirements, and ensuring compliance with the requirements of § 1271.180 with respect to such procedures, including review, approval, and revision; (2) Ensuring that procedures exist for receiving, investigating, evaluating, and documenting information relating to core CGTP requirements, including complaints, and for sharing any information pertaining to the possible contamination of the HCT/P or the potential for transmission of a communicable disease by the HCT/P with the following: (i) Other establishments that are known to have recovered HCT/Ps from the same donor; (ii) Other establishments that are known to have performed manufacturing steps with respect to the same HCT/P; and (iii) Relating to consignees, in the case of such information received after the HCT/P is made available for distribution, shipped to the consignee, or administered to the recipient, procedures must include provisions for assessing risk and appropriate followup, and evaluating the effect this information has on the HCT/P and for the notification of all entities to whom the affected HCT/P was distributed, the quarantine and recall of the HCT/P, and/or reporting to FDA, as necessary. (3) Ensuring that appropriate corrective actions relating to core CGTP requirements, including reaudits of deficiencies, are taken and documented, as necessary. You must verify corrective actions to ensure that such actions are effective and are in compliance with CGTP. Where appropriate, corrective actions must include both short-term action to address the immediate problem and long-term action to prevent the problem's recurrence. Documentation of corrective actions must include, where appropriate: (i) Identification of the HCT/P affected and a description of its disposition; (ii) The nature of the problem requiring corrective action; (iii) A description of the corrective action taken; and (iv) The date(s) of the corrective action. (4) Ensuring the proper training and education of personnel involved in activities related to core CGTP requirements; (5) Establishing and maintaining appropriate monitoring systems as necessary to comply with the requirements of this subpart (e.g., environmental monitoring); (6) Investigating and documenting HCT/P deviations and trends of HCT/P deviations relating to core CGTP requirements and making reports if required under § 1271.350(b) or other applicable regulations. Each investigation must include a review and evaluation of the HCT/P deviation, the efforts made to determine the cause, and the implementation of corrective action(s) to address the HCT/P deviation and prevent recurrence. (c) Audits. (d) Computers. § 1271.170 Personnel. (a) General. (b) Competent performance of functions. (c) Training. § 1271.180 Procedures. (a) General. (b) Review and approval. (c) Availability. (d) Standard procedures. § 1271.190 Facilities. (a) General. (b) Facility cleaning and sanitation. (2) You must dispose of sewage, trash, and other refuse in a timely, safe, and sanitary manner. (c) Operations. (d) Procedures and records. (2) You must document, and maintain records of, all cleaning and sanitation activities performed to prevent contamination of HCT/Ps. You must retain such records 3 years after their creation. § 1271.195 Environmental control and monitoring. (a) Environmental control. (1) Temperature and humidity controls; (2) Ventilation and air filtration; (3) Cleaning and disinfecting of rooms and equipment to ensure aseptic processing operations; and (4) Maintenance of equipment used to control conditions necessary for aseptic processing operations. (b) Inspections. (c) Environmental monitoring. (d) Records. § 1271.200 Equipment. (a) General. (b) Procedures and schedules. (c) Calibration of equipment. (d) Inspections. (e) Records. § 1271.210 Supplies and reagents. (a) Verification. (b) Reagents. (c) In-house reagents. (d) Records. (1) Records of the receipt of each supply or reagent, including the type, quantity, manufacturer, lot number, date of receipt, and expiration date; (2) Records of the verification of each supply or reagent, including test results or, in the case of vendor verification, a certificate of analysis from the vendor; and (3) Records of the lot of supply or reagent used in the manufacture of each HCT/P. § 1271.215 Recovery. If you are an establishment that recovers HCT/Ps, you must recover each HCT/P in a way that does not cause contamination or cross-contamination during recovery, or otherwise increase the risk of the introduction, transmission, or spread of communicable disease through the use of the HCT/P. § 1271.220 Processing and process controls. (a) General. (b) Pooling. (c) In-process control and testing. (d) Dura mater. (2) When you use a published validated process, you must verify such a process in your establishment. § 1271.225 Process changes. Any change to a process must be verified or validated in accordance with § 1271.230, to ensure that the change does not create an adverse impact elsewhere in the operation, and must be approved before implementation by a responsible person with appropriate knowledge and background. You must communicate approved changes to the appropriate personnel in a timely manner. § 1271.230 Process validation. (a) General. (b) Written representation. (c) Changes. § 1271.250 Labeling controls. (a) General. (b) Verification. (c) Labeling requirements. § 1271.260 Storage. (a) Control of storage areas. (1) Mix-ups, contamination, and cross-contamination of HCT/Ps, supplies, and reagents, and (2) An HCT/P from being improperly made available for distribution. (b) Temperature. (c) Expiration date. (1) HCT/P type; (2) Processing, including the method of preservation; (3) Storage conditions; and (4) Packaging. (d) Corrective action. (e) Acceptable temperature limits. § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. (b) Predistribution shipment. (c) Availability for distribution. (2) You must not make available for distribution an HCT/P that is in quarantine, is contaminated, is recovered from a donor who has been determined to be ineligible or for whom a donor-eligibility determination has not been completed (except as provided under §§ 1271.60, 1271.65, and 1271.90), or that otherwise does not meet release criteria designed to prevent communicable disease transmission. (3) You must not make available for distribution any HCT/P manufactured under a departure from a procedure relevant to preventing risks of communicable disease transmission, unless a responsible person has determined that the departure does not increase the risk of communicable disease through the use of the HCT/P. You must record and justify any departure from a procedure at the time of its occurrence. (d) Packaging and shipping. (e) Procedures. (1) Identification of the HCT/P and the establishment that supplied the HCT/P; (2) Activities performed and the results of each activity; (3) Date(s) of activity; (4) Quantity of HCT/P subject to the activity; and (5) Disposition of the HCT/P (e.g., identity of consignee). (f) Return to inventory. § 1271.270 Records. (a) General. (b) Records management system. (c) Methods of retention. (d) Length of retention. (e) Contracts and agreements. § 1271.290 Tracking. (a) General. (b) System of HCT/P tracking. (i) The donor to the consignee or final disposition; and (ii) The consignee or final disposition to the donor. (2) Alternatively, if you are an establishment that performs some but not all of the steps in the manufacture of an HCT/P in which you handle the HCT/P, you may participate in a system of HCT/P tracking established and maintained by another establishment responsible for other steps in the manufacture of the same HCT/P, provided that the tracking system complies with all the requirements of this section. (c) Distinct identification code. (d) Tracking from consignee to donor. (e) Tracking from donor to consignee or final disposition. (f) Consignees. (g) Requirements specific to dura mater donors. [69 FR 68681, Nov. 24, 2004, as amended at 70 FR 29952, May 25, 2005] § 1271.320 Complaint file. (a) Procedures. (b) Complaint file. (c) Review and evaluation of complaints. Subpart E—Additional Requirements for Establishments Described in § 1271.10 Source: 69 FR 68686, Nov. 24, 2004, unless otherwise noted. § 1271.330 Applicability. The provisions set forth in this subpart are being implemented for nonreproductive HCT/Ps described in § 1271.10 and regulated solely under section 361 of the Public Health Service Act and the regulations in this part, and for the establishments that manufacture those HCT/Ps. HCT/Ps that are drugs or devices regulated under the act, or are biological products regulated under section 351 of the Public Health Service Act, are not subject to the regulations set forth in this subpart. § 1271.350 Reporting. (a) Adverse reaction reports. (i) Is fatal; (ii) Is life-threatening; (iii) Results in permanent impairment of a body function or permanent damage to body structure; or (iv) Necessitates medical or surgical intervention, including hospitalization. (2) You must submit each report on a Form FDA-3500A to the address in paragraph (a)(5) of this section within 15 calendar days of initial receipt of the information. (3) You must, as soon as practical, investigate all adverse reactions that are the subject of these 15-day reports and must submit followup reports within 15 calendar days of the receipt of new information or as requested by FDA. If additional information is not obtainable, a followup report may be required that describes briefly the steps taken to seek additional information and the reasons why it could not be obtained. (4) You may obtain copies of the reporting form (FDA-3500A) from the Center for Biologics Evaluation and Research (see address in paragraph (a)(5) of this section). Electronic Form FDA-3500A may be obtained at http://www.fda.gov/medwatch http://www.hhs.gov/forms. (5) You must submit two copies of each report described in this paragraph to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002. FDA may waive the requirement for the second copy in appropriate circumstances. (b) Reports of HCT/P deviations. (2) You must report any such HCT/P deviation relating to the core CGTP requirements, if the HCT/P deviation occurred in your facility or in a facility that performed a manufacturing step for you under contract, agreement, or other arrangement. Each report must contain a description of the HCT/P deviation, information relevant to the event and the manufacture of the HCT/P involved, and information on all follow-up actions that have been or will be taken in response to the HCT/P deviation (e.g., recalls). (3) You must report each such HCT/P deviation that relates to a core CGTP requirement on Form FDA 3486 within 45 days of the discovery of the event either electronically using the Center for Biologics Evaluation and Research electronic Web-based application or by mail to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002. [69 FR 68686, Nov. 24, 2004, as amended at 80 FR 18095, Apr. 3, 2015] § 1271.370 Labeling. The following requirements apply in addition to §§ 1271.55, 1271.60, 1271.65, and 1271.90: (a) You must label each HCT/P made available for distribution clearly and accurately. (b) The following information must appear on the HCT/P label: (1) Distinct identification code affixed to the HCT/P container, and assigned in accordance with § 1271.290(c); (2) Description of the type of HCT/P; (3) Expiration date, if any; and (4) Warnings required under § 1271.60(d)(2), § 1271.65(b)(2), or § 1271.90(c), if applicable and physically possible. If it is not physically possible to include these warnings on the label, the warnings must, instead, accompany the HCT/P. (c) The following information must either appear on the HCT/P label or accompany the HCT/P: (1) Name and address of the establishment that determines that the HCT/P meets release criteria and makes the HCT/P available for distribution; (2) Storage temperature; (3) Other warnings, where appropriate; and (4) Instructions for use when related to the prevention of the introduction, transmission, or spread of communicable diseases. [69 FR 68686, Nov. 24, 2004, as amended at 70 FR 29952, May 25, 2005; 81 FR 40518, June 22, 2016] Subpart F—Inspection and Enforcement of Establishments Described in § 1271.10 Source: 69 FR 68687, Nov. 24, 2004, unless otherwise noted. § 1271.390 Applicability. The provisions set forth in this subpart are applicable only to HCT/Ps described in § 1271.10 and regulated solely under section 361 of the Public Health Service Act and the regulations in this part, and to the establishments that manufacture those HCT/Ps. HCT/Ps that are drugs or devices regulated under the act, or are biological products regulated under section 351 of the Public Health Service Act, are not subject to the regulations set forth in this subpart. § 1271.400 Inspections. (a) If you are an establishment that manufactures HCT/Ps described in § 1271.10, whether or not under contract, you must permit the Food and Drug Administration (FDA) to inspect any manufacturing location at any reasonable time and in a reasonable manner to determine compliance with applicable provisions of this part. The inspection will be conducted as necessary in the judgment of the FDA and may include your establishment, facilities, equipment, finished and unfinished materials, containers, processes, HCT/Ps, procedures, labeling, records, files, papers, and controls required to be maintained under the part. The inspection may be made with or without prior notification and will ordinarily be made during regular business hours. (b) The frequency of inspection will be at the agency's discretion. (c) FDA will call upon the most responsible person available at the time of the inspection of the establishment and may question the personnel of the establishment as necessary to determine compliance with the provisions of this part. (d) FDA's representatives may take samples, may review and copy any records required to be kept under this part, and may use other appropriate means to record evidence of observations during inspections conducted under this subpart. (e) The public disclosure of records containing the name or other positive identification of donors or recipients of HCT/Ps will be handled in accordance with FDA's procedures on disclosure of information as set forth in parts 20 and 21 of this chapter. § 1271.420 HCT/Ps offered for import. (a) Except as provided in paragraphs (c) and (d) of this section, when an HCT/P is offered for import, the importer of record must notify, either before or at the time of importation, the director of the district of the Food and Drug Administration (FDA) having jurisdiction over the port of entry through which the HCT/P is imported or offered for import, or such officer of the district as the director may designate to act in his or her behalf in administering and enforcing this part, and must provide sufficient information, including information submitted in the Automated Commercial Environment (ACE) system or any other electronic data interchange system authorized by the U.S. Customs and Border Protection Agency as required in part 1, subpart D of this chapter, for FDA to make an admissibility decision. (b) Except as provided in paragraphs (c) and (d) of this section, an HCT/P offered for import must be held intact by the importer or consignee, under conditions necessary to prevent transmission of communicable disease, until an admissibility decision is made by FDA. The HCT/P may be transported under quarantine to the consignee, while the FDA district reviews the documentation accompanying the HCT/P. When FDA makes a decision regarding the admissibility of the HCT/P, FDA will notify the importer of record. (c) This section does not apply to reproductive HCT/Ps regulated solely under section 361 of the Public Health Service Act and the regulations in this part, and donated by a sexually intimate partner of the recipient for reproductive use. (d) This section does not apply to peripheral blood stem/progenitor cells regulated solely under section 361 of the Public Health Service Act and the regulations in this part, except that paragraphs (a) and (b) of this section apply when circumstances occur under which such imported peripheral blood stem/progenitor cells may present an unreasonable risk of communicable disease transmission which indicates the need to review the information referenced in paragraph (a) of this section. [69 FR 68687, Nov. 24, 2004, as amended at 81 FR 85873, Nov. 29, 2016] § 1271.440 Orders of retention, recall, destruction, and cessation of manufacturing. (a) Upon an agency finding that there are reasonable grounds to believe that an HCT/P is a violative HCT/P because it was manufactured in violation of the regulations in this part and, therefore, the conditions of manufacture of the HCT/P do not provide adequate protections against risks of communicable disease transmission; or the HCT/P is infected or contaminated so as to be a source of dangerous infection to humans; or an establishment is in violation of the regulations in this part and, therefore, does not provide adequate protections against the risks of communicable disease transmission, the Food and Drug Administration (FDA) may take one or more of the following actions: (1) Serve upon the person who distributed the HCT/P a written order that the HCT/P be recalled and/or destroyed, as appropriate, and upon persons in possession of the HCT/P that the HCT/P must be retained until it is recalled by the distributor, destroyed, or disposed of as agreed by FDA, or the safety of the HCT/P is confirmed; (2) Take possession of and/or destroy the violative HCT/P; or (3) Serve upon the establishment an order to cease manufacturing until compliance with the regulations of this part has been achieved. When FDA determines there are reasonable grounds to believe there is a danger to health, such order will be effective immediately. In other situations, such order will be effective after one of the following events, whichever is later: (i) Passage of 5 working days from the establishment's receipt of the order; or (ii) If the establishment requests a hearing in accordance with paragraph (e) of this section and part 16 of this chapter, a decision in, and in accordance with, those proceedings. (b) A written order issued under paragraph (a) of this section will state with particularity the facts that justify the order. (c)(1) A written order issued under paragraph (a)(1) of this section will ordinarily provide that the HCT/P be recalled and/or destroyed within 5 working days from the date of receipt of the order. After receipt of an order issued under paragraph (a)(1) of this section, the establishment in possession of the HCT/P must not distribute or dispose of the HCT/P in any manner except to recall and/or destroy the HCT/P consistent with the provisions of the order, under the supervision of FDA. (2) In lieu of paragraph (c)(1) of this section, other arrangements for assuring the proper disposition of the HCT/P may be agreed upon by the person receiving the written order and FDA. Such arrangements may include, among others, providing FDA with records or other written information that adequately ensure that the HCT/P has been recovered, processed, stored, and distributed in conformance with this part, and that, except as provided under §§ 1271.60, 1271.65, and 1271.90, the donor of the cells or tissue for the HCT/P has been determined to be eligible. (d) A written order issued under paragraph (a)(3) of this section will specify the regulations with which you must achieve compliance and will ordinarily specify the particular operations covered by the order. After receipt of an order that is in effect and issued under paragraph (a)(3) of this section, you must not resume operations without prior written authorization of FDA. (e) The recipient of an order issued under this section may request a hearing in accordance with part 16 of this chapter. To request a hearing, the recipient of the written order or prior possessor of such HCT/P must make the request within 5 working days of receipt of a written order for retention, recall, destruction, and/or cessation (or within 5 working days of the agency's possession of an HCT/P under paragraph (a)(2) of this section), in accordance with part 16 of this chapter. An order of destruction will be held in abeyance pending resolution of the hearing request. Upon request under part 16 of this chapter, FDA will provide an opportunity for an expedited hearing for an order of cessation that is not stayed by the Commissioner of Food and Drugs. (f) FDA will not issue an order for the destruction of reproductive tissue under paragraph (a)(1) of this section, nor will it carry out such destruction itself under paragraph (a)(2) of this section.