PART 610—GENERAL BIOLOGICAL PRODUCTS STANDARDS Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264. Source: 38 FR 32056, Nov. 20, 1973, unless otherwise noted. Cross References: For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111. Subpart A—Release Requirements § 610.1 Tests prior to release required for each lot. No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. Each applicable test shall be made on each lot after completion of all processes of manufacture which may affect compliance with the standard to which the test applies. The results of all tests performed shall be considered in determining whether or not the test results meet the test objective, except that a test result may be disregarded when it is established that the test is invalid due to causes unrelated to the product. § 610.2 Requests for samples and protocols; official release. (a) Licensed biological products regulated by CBER. Provided, (b) Licensed biological products regulated by CDER. Provided [40 FR 31313, July 25, 1975, as amended at 49 FR 23834, June 8, 1984; 50 FR 10941, Mar. 19, 1985; 55 FR 11013, 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] Subpart B—General Provisions § 610.9 Equivalent methods and processes. Modification of any particular test method or manufacturing process or the conditions under which it is conducted as required in this part or in the additional standards for specific biological products in parts 620 through 680 of this chapter shall be permitted only under the following conditions: (a) The applicant presents evidence, in the form of a license application, or a supplement to the application submitted in accordance with § 601.12(b) or (c), demonstrating that the modification will provide assurances of the safety, purity, potency, and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified in the general standards or additional standards for the biological product; and (b) Approval of the modification is received in writing from the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research. [62 FR 39903, July 24, 1997, as amended at 70 FR 14984, Mar. 24, 2005] § 610.10 Potency. Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter. § 610.11-610.11a [Reserved] § 610.12 Sterility. (a) The test. (b) Test requirements. (2) The sterility test must be validated to demonstrate that the test is capable of reliably and consistently detecting the presence of viable contaminating microorganisms. (3) The sterility test and test components must be verified to demonstrate that the test method can consistently detect the presence of viable contaminating microorganisms. (c) Written procedures. (1) The sterility test method to be used; (i) If culture-based test methods are used, include, at a minimum: (A) Composition of the culture media; (B) Growth-promotion test requirements; and (C) Incubation conditions (time and temperature). (ii) If non-culture-based test methods are used, include, at a minimum: (A) Composition of test components; (B) Test parameters, including acceptance criteria; and (C) Controls used to verify the method's ability to detect the presence of viable contaminating microorganisms. (2) The method of sampling, including the number, volume, and size of articles to be tested; (3) Written specifications for the acceptance or rejection of each lot; and (4) A statement of any other function critical to the particular sterility test method to ensure consistent and accurate results. (d) The sample. (1) The size and volume of the final product lot; (2) The duration of manufacturing of the drug product; (3) The final container configuration and size; (4) The quantity or concentration of inhibitors, neutralizers, and preservatives, if present, in the tested material; (5) For a culture-based test method, the volume of test material that results in a dilution of the product that is not bacteriostatic or fungistatic; and (6) For a non-culture-based test method, the volume of test material that results in a dilution of the product that does not inhibit or otherwise hinder the detection of viable contaminating microorganisms. (e) Verification. (2) For non-culture-based test methods, within the test itself, appropriate controls must be used to demonstrate the ability of the test method to continue to consistently detect the presence of viable contaminating microorganisms. (f) Repeat test procedures. (2) If the investigation described in paragraph (f)(1) of this section finds that the initial test indicated the presence of microorganisms due to laboratory error or the use of faulty materials, a sterility test may be repeated one time. If no evidence of microorganisms is found in the repeat test, the product examined complies with the sterility test requirements. If evidence of microorganisms is found in the repeat test, the product examined does not comply with the sterility test requirements. (3) If a repeat test is conducted, the same test method must be used for both the initial and repeat tests, and the repeat test must be conducted with comparable product that is reflective of the initial sample in terms of sample location and the stage in the manufacturing process from which it was obtained. (g) Records. (h) Exceptions. (1) This section does not require sterility testing for Whole Blood, Cryoprecipitated Antihemophilic Factor, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, and Blood Grouping Reagents. (2) A manufacturer is not required to comply with the sterility test requirements if the Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research, as appropriate, determines that data submitted in the biologics license application or supplement adequately establish that the route of administration, the method of preparation, or any other aspect of the product precludes or does not necessitate a sterility test to assure the safety, purity, and potency of the product. [77 FR 26174, May 3, 2012] § 610.13 Purity. Products shall be free of extraneous material except that which is unavoidable in the manufacturing process described in the approved biologics license application. In addition, products shall be tested as provided in paragraphs (a) and (b) of this section. (a)(1) Test for residual moisture. (2) Records. (b) Test for pyrogenic substances. Provided, (1) Test dose. (2) Test procedure, results, and interpretation; standards to be met. (3) Retest. [38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975; 41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289, July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984; 50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990; 64 FR 56453, Oct. 20, 1999; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005] § 610.14 Identity. The contents of a final container of each filling of each lot shall be tested for identity after all labeling operations shall have been completed. The identity test shall be specific for each product in a manner that will adequately identify it as the product designated on final container and package labels and circulars, and distinguish it from any other product being processed in the same laboratory. Identity may be established either through the physical or chemical characteristics of the product, inspection by macroscopic or microscopic methods, specific cultural tests, or in vitro or in vivo immunological tests. § 610.15 Constituent materials. (a) Ingredients, preservatives, diluents, adjuvants. (1) 0.85 milligrams if determined by assay; (2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or (3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter). (b) Extraneous protein; cell culture produced vaccines. (c) Antibiotics. (d) The Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research may approve an exception or alternative to any requirement in this section. Requests for such exceptions or alternatives must be in writing. [38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981; 48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834, June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 76 FR 20518, Apr. 13, 2011; 80 FR 18093, Apr. 3, 2015] § 610.16 Total solids in serums. Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids. § 610.17 Permissible combinations. Licensed products may not be combined with other licensed products either therapeutic, prophylactic or diagnostic, except as a license is obtained for the combined product. Licensed products may not be combined with nonlicensable therapeutic, prophylactic, or diagnostic substances except as a license is obtained for such combination. § 610.18 Cultures. (a) Storage and maintenance. (b) Identity and verification. (c) Cell lines used for manufacturing biological products General requirements. (i) Identified by history; (ii) Described with respect to cytogenetic characteristics and tumorigenicity; (iii) Characterized with respect to in vitro growth characteristics and life potential; and (iv) Tested for the presence of detectable microbial agents. (2) Tests. (3) Applicability. (d) Records. [38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986; 55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005] Subparts C—D [Reserved] Subpart E—Testing Requirements for Relevant Transfusion-Transmitted Infections § 610.39 Definitions. The definitions set out in § 630.3 of this chapter apply to this subpart. [80 FR 29896, May 22, 2015] § 610.40 Test requirements. (a) Human blood and blood components. (1) Test each donation for evidence of infection due to the relevant transfusion-transmitted infections described in § 630.3(h)(1)(i) through (iii) of this chapter (HIV, HBV, and HCV). (2) Test each donation for evidence of infection due to the relevant transfusion-transmitted infections described in § 630.3(h)(1)(iv) through (vii) of this chapter (HTLV, syphilis, West Nile virus, and Chagas disease). The following exceptions apply: (i) To identify evidence of infection with syphilis in donors of Source Plasma, you must test donors for evidence of such infection in accordance with § 640.65(b) of this chapter, and not under this section. (ii) You are not required to test donations of Source Plasma for evidence of infection due to the relevant transfusion-transmitted infections described in § 630.3(h)(1)(iv), (vi), and (vii) of this chapter (HTLV, West Nile virus, and Chagas disease). (iii) For each of the relevant transfusion-transmitted infections described in § 630.3(h)(1)(iv) through (vii) of this chapter (HTLV, syphilis, West Nile virus, and Chagas disease): (A) If, based on evidence related to the risk of transmission of that relevant transfusion-transmitted infection, testing each donation is not necessary to reduce adequately and appropriately the risk of transmission of such infection by blood or a blood component, you may adopt an adequate and appropriate alternative testing procedure that has been found acceptable for this purpose by FDA. (B) If, based on evidence related to the risk of transmission of that relevant transfusion-transmitted infection, testing previously required for that infection is no longer necessary to reduce adequately and appropriately the risk of transmission of such infection by blood or a blood component, you may stop such testing in accordance with procedures found acceptable for this purpose by FDA. (3) For each of the relevant transfusion-transmitted infections described in § 630.3(h)(1)(viii) through (x) of this chapter (CJD, vCJD, malaria) and § 630.3(h)(2) of this chapter (other transfusion-transmitted infections): (i) You must test for evidence of infection when the following conditions are met: (A) A test(s) for the relevant transfusion-transmitted infection is licensed, approved or cleared by FDA for use as a donor screening test and is available for such use; and (B) Testing for the relevant transfusion-transmitted infection is necessary to reduce adequately and appropriately the risk of transmission of the relevant transfusion-transmitted infection by blood, or blood component, or blood derivative product manufactured from the collected blood or blood component. (ii) You must perform this testing on each donation, unless one of the following exceptions applies: (A) Testing of each donation is not necessary to reduce adequately and appropriately the risk of transmission of such infection by blood, blood component, or blood derivative product manufactured from the collected blood or blood component. When evidence related to the risk of transmission of such infection supports this determination, you may adopt an adequate and appropriate alternative testing procedure that has been found acceptable for this purpose by FDA. (B) Testing of each donation is not necessary to reduce adequately and appropriately the risk of transmission of such infection by blood, blood component, or blood derivative product manufactured from the collected blood or blood component. When evidence related to the risk of transmission of such infection supports this determination, you may stop such testing in accordance with procedures found acceptable for this purpose by FDA. (4) Evidence related to the risk of transmission of a relevant transfusion-transmitted infection that would support a determination that testing is not necessary, or that testing of each donation is not necessary, to reduce adequately and appropriately the risk of transmission of such infection by blood or blood component, as described in paragraphs (a)(2)(iii)(A) and (B) of this section, or by blood, blood component, or blood derivative, as described in paragraphs (a)(3)(ii)(A) and (B) of this section, includes epidemiological or other scientific evidence. It may include evidence related to the seasonality or geographic limitation of risk of transmission of such infection by blood or blood component, or other information related to when and how a donation is at risk of transmitting a relevant transfusion-transmitted infection. It may also include evidence related to the effectiveness of manufacturing steps (for example, the use of pathogen reduction technology) that reduce the risk of transmission of the relevant transfusion-transmitted infection by blood, blood components, or blood derivatives, as applicable. (b) Testing using one or more licensed, approved, or cleared screening tests. (c) Exceptions to testing for dedicated donations, medical devices, and samples. Dedicated donations. (ii) Each donation must be labeled as required under § 606.121 of this chapter and with a label entitled “INTENDED RECIPIENT INFORMATION LABEL” containing the name and identifying information of the recipient. Each donation must also have the following label, as appropriate: Donor Testing Status Label Tests negative Label as required under § 606.121 Tested negative within the last 30 days “DONOR TESTED WITHIN THE LAST 30 DAYS” (2) Medical device. (ii) Donations of human blood and blood components intended solely as a component of, or used to prepare, a medical device must be labeled “Caution: For Further Manufacturing Use as a Component of, or to Prepare, a Medical Device.” (3) Samples. (d) Autologous donations. (1) If you allow any autologous donation to be used for allogeneic transfusion, you must assure that all autologous donations are tested under this section. (2) If you ship autologous donations to another establishment that allows autologous donations to be used for allogeneic transfusion, you must assure that all autologous donations shipped to that establishment are tested under this section. (3) If you ship autologous donations to another establishment that does not allow autologous donations to be used for allogeneic transfusion, you must assure that, at a minimum, the first donation in each 30-day period is tested under this section. (4) Each autologous donation must be labeled as required under § 606.121 of this chapter and with the following label, as appropriate: Donor Testing Status Label Untested “DONOR UNTESTED” Tests negative Label as required under § 606.121 Reactive on current collection/reactive in the last 30 days “BIOHAZARD” legend in § 610.40(h)(2)(ii)(B) Tested negative within the last 30 days “DONOR TESTED WITHIN THE LAST 30 DAYS” (e) Further testing. (1) For autologous donations: (i) You must further test under this section, at a minimum, the first reactive donation in each 30 calendar day period; or (ii) If you have a record for that donor of a positive result on further testing performed under this section, you do not have to further test an autologous donation. (2) You are not required to perform further testing of a donation found to be reactive by a treponemal donor screening test for syphilis. (f) Testing responsibility. (g) Release or shipment prior to testing. (1) Only in appropriately documented medical emergency situations; or (2) For further manufacturing use as approved in writing by FDA. (h) Restrictions on shipment or use Reactive screening test. (2) Exceptions. (ii) You must not ship or use human blood or blood components that have a reactive screening test for evidence of infection due to a relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section or that are collected from a donor deferred under § 610.41(a) unless you meet the following conditions: (A) Except for autologous donations, you must obtain from FDA written approval for the shipment or use; (B) You must appropriately label such blood or blood components as required under § 606.121 of this chapter, and with the “BIOHAZARD” legend; (C) Except for autologous donations, you must label such human blood and blood components as reactive for the appropriate screening test for evidence of infection due to the identified relevant transfusion-transmitted infection(s); (D) If the blood or blood components are intended for further manufacturing use into injectable products, you must include a statement on the container label indicating the exempted use specifically approved by FDA. (E) Each blood or blood component with a reactive screening test and intended solely as a component of, or used to prepare a medical device, must be labeled with the following label, as appropriate: Type of Medical Device Label A medical device other than an in vitro diagnostic reagent “Caution: For Further Manufacturing Use as a Component of a Medical Device For Which There Are No Alternative Sources” An in vitro diagnostic reagent “Caution: For Further Manufacturing Into In Vitro Diagnostic Reagents For Which There Are No Alternative Sources” (iii) The restrictions on shipment or use do not apply to samples of blood, blood components, plasma, or sera if used or distributed for clinical laboratory testing or research purposes, and not intended for administration in humans or in the manufacture of a product. (iv) You may use human blood or blood components from a donor with a previous record of a reactive screening test(s) for evidence of infection due to a relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section, if: (A) At the time of donation, the donor is shown or was previously shown to be eligible by a requalification method or process found acceptable for such purposes by FDA under § 610.41(b); and (B) tests performed under paragraphs (a) and (b) of this section are nonreactive. (v) Anti-HBc reactive donations, otherwise nonreactive when tested as required under this section, may be used for further manufacturing into plasma derivatives without prior FDA approval or a “BIOHAZARD” legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of this section. (vi) You may use human blood or blood components, excluding Source Plasma, that test reactive by a screening test for syphilis as required under paragraph (a) of this section if, the donation is further tested by an adequate and appropriate test which demonstrates that the reactive screening test is a biological false positive. You must label the blood or blood components with both test results. (vii) You may use Source Plasma from a donor who tests reactive by a screening test for syphilis as required under § 640.65(b)(1)(i) of this chapter, if the donor meets the requirements of § 640.65(b)(2)(ii) through (iv) of this chapter. [66 FR 31162, June 11, 2001, as amended at 77 FR 18, Jan. 3, 2012; 80 FR 29896, May 22, 2015; 86 FR 49922, July 9, 2021] § 610.41 Donor deferral. (a) You, an establishment that collects human blood or blood components, must defer donors testing reactive by a screening test for evidence of infection due to a relevant transfusion-transmitted infection(s) under § 610.40(a), from future donations of human blood and blood components, except: (1) You are not required to defer a donor who tests reactive for anti-HBc or anti-HTLV, types I and II, on only one occasion. However, you must defer the donor if further testing for HBV or HTLV has been performed under § 610.40(e) and the donor is found to be positive, or if a second, licensed, cleared, or approved screening test for HBV or HTLV has been performed on the same donation under § 610.40(a) and is reactive, or if the donor tests reactive for anti-HBc or anti-HTLV, types I and II, on more than one occasion; (2) A deferred donor who tests reactive for evidence of infection due to a relevant transfusion-transmitted infection(s) under § 610.40(a) may serve as a donor for blood or blood components shipped or used under § 610.40(h)(2)(ii); (3) A deferred donor who showed evidence of infection due to hepatitis B surface antigen (HBsAg) when previously tested under § 610.40(a), (b), and (e) subsequently may donate Source Plasma for use in the preparation of Hepatitis B Immune Globulin (Human) provided the current donation tests nonreactive for HBsAg and the donor is otherwise determined to be eligible; (4) A deferred donor, who otherwise is determined to be eligible for donation and tests reactive for anti-HBc or for evidence of infection due to HTLV, types I and II, may serve as a donor of Source Plasma; (5) A deferred donor who tests reactive for a relevant transfusion-transmitted infections(s) under § 610.40(a), may serve as an autologous donor under § 610.40(d). (b) A deferred donor subsequently may be found to be eligible as a donor of blood or blood components by a requalification method or process found acceptable for such purposes by FDA. Such a donor is considered no longer deferred. (c) You must comply with the requirements under §§ 610.46 and 610.47 when a donor tests reactive by a screening test for HIV or HCV required under § 610.40(a) and (b), or when you are aware of other reliable test results or information indicating evidence of HIV or HCV infection. [66 FR 31164, June 11, 2001, as amended at 72 FR 48798, Aug. 24, 2007; 80 FR 29897, May 22, 2015] § 610.42 Restrictions on use for further manufacture of medical devices. (a) In addition to labeling requirements in subchapter H of this chapter, when a medical device contains human blood or a blood component as a component of the final device, and the human blood or blood component was found to be reactive by a screening test performed under § 610.40(a) and (b), then you must include in the device labeling a statement of warning indicating that the product was manufactured from a donation found to be reactive by a screening test for evidence of infection due to the identified relevant transfusion-transmitted infection(s). (b) FDA may approve an exception or alternative to the statement of warning required in paragraph (a) of this section based on evidence that the reactivity of the human blood or blood component in the medical device presents no significant health risk through use of the medical device. [66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015] § 610.44 Use of reference panels by manufacturers of test kits. (a) When available and appropriate to verify acceptable sensitivity and specificity, you, a manufacturer of test kits, must use a reference panel you obtain from FDA or from an FDA designated source to test lots of the following products. You must test each lot of the following products, unless FDA informs you that less frequent testing is appropriate, based on your consistent prior production of products of acceptable sensitivity and specificity: (1) A test kit approved for use in testing donations of human blood and blood components for evidence of infection due to relevant transfusion-transmitted infections under § 610.40(a); and (2) Human immunodeficiency virus (HIV) test kit approved for use in the diagnosis, prognosis, or monitoring of this relevant transfusion-transmitted infection. (b) You must not distribute a lot that is found to be not acceptable for sensitivity and specificity under § 610.44(a). FDA may approve an exception or alternative to this requirement. Applicants must submit such requests in writing. However, in limited circumstances, such requests may be made orally and permission may be given orally by FDA. Oral requests and approvals must be promptly followed by written requests and written approvals. [66 FR 31164, June 11, 2001, as amended at 80 FR 29897, May 22, 2015] § 610.46 Human immunodeficiency virus (HIV) “lookback” requirements. (a) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions: (1) Within 3 calendar days after a donor tests reactive for evidence of human immunodeficiency virus (HIV) infection when tested under § 610.40(a) and (b) or when you are made aware of other reliable test results or information indicating evidence of HIV infection, you must review all records required under § 606.160(d) of this chapter, to identify blood and blood components previously donated by such a donor. For those identified blood and blood components collected: (i) Twelve months and less before the donor's most recent nonreactive screening tests, or (ii) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test or HIV p24 antigen test, and nonreactive antibody screening test, whichever is the lesser period, you must: (A) Quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and (B) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; (2) You must perform further testing for HIV as required under § 610.40(e) of this chapter on the reactive donation. (3) You must notify consignees of the results of further testing for HIV, or the results of the reactive screening test if further testing under paragraph (a)(2) of this section is not available, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA, within 45 calendar days after the donor tests reactive for evidence of HIV infection under § 610.40(a) and (b) of this chapter. Notification of consignees must include the test results for blood and blood components identified under paragraph (a)(1) of this section that were previously collected from donors who later test reactive for evidence of HIV infection. (4) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the further testing performed under paragraph (a)(2) of this section or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, exempted for such use by FDA. (b) If you are a consignee of Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions: (1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment. (2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the further testing performed under paragraph (a)(2) of this section, or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, is exempted for such use by FDA. (3) When further testing for HIV is positive or when the screening test is reactive and further testing is not available, or if under an IND or IDE is exempted for such use by FDA, you must notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HIV infection, or the recipient's physician of record, of the need for recipient HIV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, deceased, adjudged incompetent by a State court, or, if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient. You must make reasonable attempts to perform the notification within 12 weeks after receiving the results of further testing for evidence of HIV infection from the collecting establishment, or after receiving the donor's reactive screening test result for HIV if further testing is not available, or if under an IND or IDE is exempted for such use by FDA. (c) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter. [72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015] § 610.47 Hepatitis C virus (HCV) “lookback” requirements. (a) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions: (1) Within 3 calendar days after a donor tests reactive for evidence of hepatitis C virus (HCV) infection when tested under § 610.40(a) and (b) of this chapter or when you are made aware of other reliable test results or information indicating evidence of HCV infection, you must review all records required under § 606.160(d) of this chapter, to identify blood and blood components previously donated by such a donor. For those identified blood and blood components collected: (i) Twelve months and less before the donor's most recent nonreactive screening tests, or (ii) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test and nonreactive antibody screening test, whichever is the lesser period, you must: (A) Quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and (B) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; (2) You must perform further testing for HCV as required under § 610.40(e) on the reactive donation. (3) You must notify consignees of the results of further testing for HCV, or the results of the reactive screening test if further testing is not available, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA, within 45 calendar days after the donor tests reactive for evidence of HCV infection under § 610.40(a) and (b). Notification of consignees must include the test results for blood and blood components identified under paragraph (a)(1) of this section that were previously collected from donors who later test reactive for evidence of HCV infection. (4) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the further testing performed under paragraph (a)(2) of this section, or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, exempted for such use by FDA. (b) If you are a consignee of Whole Blood or blood components, including Source Plasma or Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions: (1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment. (2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the further testing performed under paragraph (a)(2) of this section, or the results of the reactive screening test if further testing is not available, or if under an IND or IDE, is exempted for such use by FDA. (3) When the further testing for HCV is positive or when the screening test is reactive and further testing is not available, or if under an IND or IDE, is exempted for such use by FDA, you must notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HCV infection, or the recipient's physician of record, of the need for recipient HCV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, adjudged incompetent by a State court, or if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient. You must make reasonable attempts to perform the notification within 12 weeks after receiving the results of further testing for evidence of HCV infection from the collecting establishment, or after receiving the donor's reactive screening test result for HCV if further testing is not available, or if under an IND or IDE, is exempted for such use by FDA. (c) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter. [72 FR 48799, Aug. 24, 2007, as amended at 80 FR 29897, May 22, 2015] § 610.48 [Reserved] Subpart F—Dating Period Limitations § 610.50 Date of manufacture for biological products. (a) When the dating period begins. (b) Determining the date of manufacture for biological products other than Whole Blood and blood components. (1) Potency test or other specific test as described in a biologics license application or supplement to the application; (2) Removal from animals or humans; (3) Extraction; (4) Solution; (5) Cessation of growth; (6) Final sterile filtration of a bulk solution; (7) Manufacture as described in part 660 of this chapter; or (8) Other specific manufacturing activity described in a biologics license application or supplement to the biologics license application. (c) Determining the date of manufacture for Whole Blood and blood components. (i) Collection date and/or time; (ii) Irradiation date; (iii) The time the red blood cell product was removed from frozen storage for deglycerolization; (iv) The time the additive or rejuvenation solution was added; (v) The time the product was entered for washing or removing plasma (if prepared in an open system); (vi) As specified in the instructions for use by the blood collection, processing, and storage system approved or cleared for such use by FDA; or (vii) As approved by the Director, Center for Biologics Evaluation and Research, in a biologics license application or supplement to the application. (2) For licensed Whole Blood and blood components, the date of manufacture must be identified in the approved biologics license application or supplement to the application. [81 FR 26691, May 4, 2016] § 610.53 Dating periods for Whole Blood and blood components. (a) General. (b) Table of dating periods. Whole Blood and Blood Components Storage Temperatures and Dating Periods A B C Product Storage temperature Dating period Whole Blood ACD, CPD, CP2D Between 1 and 6 °C 21 days from date of collection. CPDA-1 do 1 35 days from date of collection. Red Blood Cells ACD, CPD, CP2D Between 1 and 6 °C 21 days from date of collection. CPDA-1 do 35 days from date of collection. Additive solutions do 42 days from date of collection. Open system do 24 hours after entering bag. Deglycerolized in closed system with additive solution added do 14 days after entering bag. Irradiated do 28 days from date of irradiation or original dating, whichever is shorter. Frozen −65 °C or colder 10 years from date of collection. Platelets Platelets Between 20 and 24 °C 5 days from date of collection. Platelets Other temperatures according to storage bag instructions As specified in the instructions for use by the blood collection, processing and storage system approved or cleared for such use by FDA. Plasma Fresh Frozen Plasma −18 °C or colder 1 year from date of collection. Plasma Frozen Within 24 Hours After Phlebotomy do 1 year from date of collection. Plasma Frozen Within 24 Hours After Phlebotomy Held at Room Temperature Up To 24 Hours After Phlebotomy do 1 year from date of collection. Plasma Cryoprecipitate Reduced do 1 year from date of collection. Plasma do 5 years from date of collection. Liquid Plasma Between 1 and 6 °C 5 days from end of Whole Blood dating period. Source Plasma (frozen injectable) −20 °C or colder 10 years from date of collection. Source Plasma Liquid (injectable) 10 °C or colder According to approved biologics license application. Source Plasma (noninjectable) Temperature appropriate for final product 10 years from date of collection. Therapeutic Exchange Plasma −20 °C or colder 10 years from date of collection. Cryoprecipitated AHF Cryoprecipitated AHF −18 °C or colder 1 year from date of collection of source blood or from date of collection of oldest source blood in pre-storage pool. Source Leukocytes Source Leukocytes Temperature appropriate for final product In lieu of expiration date, the collection date must appear on the label. 1 [81 FR 26691, May 4, 2016] Subpart G—Labeling Standards § 610.60 Container label. (a) Full label. (1) The proper name of the product; (2) The name, address, and license number of manufacturer; (3) The lot number or other lot identification; (4) The expiration date; (5) The recommended individual dose, for multiple dose containers. (6) The statement: “ ‘Rx only’ ” for prescription biologicals. (7) If a Medication Guide is required under part 208 of this chapter, the statement required under § 208.24(d) of this chapter instructing the authorized dispenser to provide a Medication Guide to each patient to whom the drug is dispensed and stating how the Medication Guide is provided, except where the container label is too small, the required statement may be placed on the package label. (b) Package label information. (c) Partial label. (d) No container label. (e) Visual inspection. [38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 63 FR 66400, Dec. 1, 1998; 67 FR 4907, Feb. 1, 2002] § 610.61 Package label. The following items shall appear on the label affixed to each package containing a product: (a) The proper name of the product; (b) The name, address, and license number of manufacturer; (c) The lot number or other lot identification; (d) The expiration date; (e) The preservative used and its concentration, or if no preservative is used and the absence of a preservative is a safety factor, the words “no preservative”; (f) The number of containers, if more than one; (g) The amount of product in the container expressed as (1) the number of doses, (2) volume, (3) units of potency, (4) weight, (5) equivalent volume (for dried product to be reconstituted), or (6) such combination of the foregoing as needed for an accurate description of the contents, whichever is applicable; (h) The recommended storage temperature; (i) The words “Shake Well”, “Do not Freeze” or the equivalent, as well as other instructions, when indicated by the character of the product; (j) The recommended individual dose if the enclosed container(s) is a multiple-dose container; (k) The route of administration recommended, or reference to such directions in an enclosed circular; (l) Known sensitizing substances, or reference to an enclosed circular containing appropriate information; (m) The type and calculated amount of antibiotics added during manufacture; (n) The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information; (o) The adjuvant, if present; (p) The source of the product when a factor in safe administration; (q) The identity of each microorganism used in manufacture, and, where applicable, the production medium and the method of inactivation, or reference to an enclosed circular containing appropriate information; (r) Minimum potency of product expressed in terms of official standard of potency or, if potency is a factor and no U.S. standard of potency has been prescribed, the words “No U.S. standard of potency.” (s) The statement: “ ‘Rx only’ ” for prescription biologicals. [38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 55 FR 10423, Mar. 21, 1990; 67 FR 4907, Feb. 1, 2002] § 610.62 Proper name; package label; legible type. (a) Position. (b) Prominence. (c) Legible type. § 610.63 Divided manufacturing responsibility to be shown. If two or more licensed manufacturers participate in the manufacture of a biological product, the name, address, and license number of each must appear on the package label, and on the label of the container if capable of bearing a full label. [64 FR 56453, Oct. 20, 1999] § 610.64 Name and address of distributor. The name and address of the distributor of a product may appear on the label provided that the name, address, and license number of the manufacturer also appears on the label and the name of the distributor is qualified by one of the following phrases: “Manufactured for _____”, “Distributed by ______”, “Manufactured by _____ for _____”, “Manufactured for _____ by ____”, “Distributor: _____”, or “Marketed by _____”. The qualifying phrases may be abbreviated. [61 FR 57330, Nov. 6, 1996] § 610.65 Products for export. Labels on packages or containers of products for export may be adapted to meet specific requirements of the regulations of the country to which the product is to be exported provided that in all such cases the minimum label requirements prescribed in § 610.60 are observed. § 610.67 Bar code label requirements. Biological products must comply with the bar code requirements at § 201.25 of this chapter. However, the bar code requirements do not apply to devices regulated by the Center for Biologics Evaluation and Research or to blood and blood components intended for transfusion. For blood and blood components intended for transfusion, the requirements at § 606.121(c)(13) of this chapter apply instead. [69 FR 9171, Feb. 26, 2004] § 610.68 Exceptions or alternatives to labeling requirements for biological products held by the Strategic National Stockpile. (a) The appropriate FDA Center Director may grant an exception or alternative to any provision listed in paragraph (f) of this section and not explicitly required by statute, for specified lots, batches, or other units of a biological product, if the Center Director determines that compliance with such labeling requirement could adversely affect the safety, effectiveness, or availability of such product that is or will be included in the Strategic National Stockpile. (b)(1)(i) A Strategic National Stockpile official or any entity that manufactures (including labeling, packing, relabeling, or repackaging), distributes, or stores a biological product that is or will be included in the Strategic National Stockpile may submit, with written concurrence from a Strategic National Stockpile official, a written request for an exception or alternative described in paragraph (a) of this section to the Center Director. (ii) The Center Director may grant an exception or alternative described in paragraph (a) of this section on his or her own initiative. (2) A written request for an exception or alternative described in paragraph (a) of this section must: (i) Identify the specified lots, batches, or other units of the biological product that would be subject to the exception or alternative; (ii) Identify the labeling provision(s) listed in paragraph (f) of this section that are the subject of the exception or alternative request; (iii) Explain why compliance with such labeling provision(s) could adversely affect the safety, effectiveness, or availability of the specified lots, batches, or other units of the biological product that are or will be included in the Strategic National Stockpile; (iv) Describe any proposed safeguards or conditions that will be implemented so that the labeling of the product includes appropriate information necessary for the safe and effective use of the product, given the anticipated circumstances of use of the product; (v) Provide a draft of the proposed labeling of the specified lots, batches, or other units of the biological product subject to the exception or alternative; and (vi) Provide any other information requested by the Center Director in support of the request. (c) The Center Director must respond in writing to all requests under this section. (d) A grant of an exception or alternative under this section will include any safeguards or conditions deemed appropriate by the Center Director so that the labeling of product subject to the exception or alternative includes the information necessary for the safe and effective use of the product, given the anticipated circumstances of use. (e) If you are a sponsor receiving a grant of a request for an exception or alternative to the labeling requirements under this section: (1) You need not submit a supplement under § 601.12(f)(1) through (f)(2) of this chapter; however, (2) You must report any grant of a request for an exception or alternative under this section as part of your annual report under § 601.12(f)(3) of this chapter. (f) The Center Director may grant an exception or alternative under this section to the following provisions of this chapter, to the extent that the requirements in these provisions are not explicitly required by statute: (1) § 610.60; (2) § 610.61(c) and (e) through (r); (3) § 610.62; (4) § 610.63; (5) § 610.64; (6) § 610.65; and (7) § 312.6. [72 FR 73600, Dec. 28, 2007]