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.
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.
(a) Licensed biological products regulated by CBER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter). Upon notification by the Director, Center for Biologics Evaluation and Research, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Center for Biologics Evaluation and Research: Provided, That the Director, Center for Biologics Evaluation and Research, shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.
(b) Licensed biological products regulated by CDER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter) for official release. Upon notification by the Director, Center for Drug Evaluation and Research, a manufacturer shall not distribute a lot of a biological product until the lot is released by the Director, Center for Drug Evaluation and Research: Provided, That the Director, Center for Drug Evaluation and Research shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.
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.
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.
(a) The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and as approved in the biologics license application or supplement for that product.
(b) Test requirements. (1) The sterility test must be appropriate to the material being tested such that the material does not interfere with or otherwise hinder the test.
(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. Manufacturers must establish, implement, and follow written procedures for sterility testing that describe, at a minimum, the following:
(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. The sample must be appropriate to the material being tested, considering, at a minimum:
(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. (1) For culture-based test methods, studies must be conducted to demonstrate that the performance of the test organisms and culture media are suitable to consistently detect the presence of viable contaminating microorganisms, including tests for each lot of culture media to verify its growth-promoting properties over the shelf-life of the media.
(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. (1) If the initial test indicates the presence of microorganisms, the product does not comply with the sterility test requirements unless a thorough investigation by the quality control unit can ascribe definitively the microbial presence to a laboratory error or faulty materials used in conducting the sterility testing.
(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. The records related to the test requirements of this section must be prepared and maintained as required by §§ 211.167 and 211.194 of this chapter.
(h) Exceptions. Sterility testing must be performed on final container material or other appropriate material as defined in the approved biologics license application or supplement and as described in this section, except as follows:
(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.
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. Each lot of dried product shall be tested for residual moisture and shall meet and not exceed established limits as specified by an approved method on file in the biologics license application. The test for residual moisture may be exempted by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, when deemed not necessary for the continued safety, purity, and potency of the product.
(2) Records. Appropriate records for residual moisture under paragraph (a)(1) of this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.
(b) Test for pyrogenic substances. Each lot of final containers of any product intended for use by injection shall be tested for pyrogenic substances by intravenous injection into rabbits as provided in paragraphs (b) (1) and (2) of this section: Provided, That notwithstanding any other provision of Subchapter F of this chapter, the test for pyrogenic substances is not required for the following products: Products containing formed blood elements; Cryoprecipitate; Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts; venoms; diagnostic substances and trivalent organic arsenicals.
(1) Test dose. The test dose for each rabbit shall be at least 3 milliliters per kilogram of body weight of the rabbit and also shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended, but need not exceed 10 milliliters per kilogram of body weight of the rabbit, except that: (i) Regardless of the human dose recommended, the test dose per kilogram of body weight of each rabbit shall be at least 1 milliliter for immune globulins derived from human blood; (ii) for Streptokinase, the test dose shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended.
(2) Test procedure, results, and interpretation; standards to be met. The test for pyrogenic substances shall be performed according to the requirements specified in United States Pharmacopeia XX.
(3) Retest. If the lot fails to meet the test requirements prescribed in paragraph (b)(2) of this section, the test may be repeated once using five other rabbits. The temperature rises recorded for all eight rabbits used in testing shall be included in determining whether the requirements are met. The lot meets the requirements for absence of pyrogens if not more than three of the eight rabbits show individual rises in temperature of 0.6 °C or more, and if the sum of the eight individual maximum temperature rises does not exceed 3.7 °C.
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.
(a) Ingredients, preservatives, diluents, adjuvants. All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. Any preservative used shall be sufficiently nontoxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature. Products in multiple-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume in volume (v/v) glycerin. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:
(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. Extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection. If serum is used at any stage, its calculated concentration in the final medium shall not exceed 1:1,000,000.
(c) Antibiotics. A minimum concentration of antibiotics, other than penicillin, may be added to the production substrate of viral vaccines.
(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.
Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids.
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.
(a) Storage and maintenance. Cultures used in the manufacture of products shall be stored in a secure and orderly manner, at a temperature and by a method that will retain the initial characteristics of the organisms and insure freedom from contamination and deterioration.
(b) Identity and verification. Each culture shall be clearly identified as to source strain. A complete identification of the strain shall be made for each new stock culture preparation. Primary and subsequent seed lots shall be identified by lot number and date of preparation. Periodic tests shall be performed as often as necessary to verify the integrity of the strain characteristics and freedom from extraneous organisms. Results of all periodic tests for verification of cultures and determination of freedom from extraneous organisms shall be recorded and retained.
(c) Cell lines used for manufacturing biological products - (1) General requirements. Cell lines used for manufacturing biological products shall be:
(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. Tests that are necessary to assure the safety, purity, and potency of a product may be required by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research.
(3) Applicability. This paragraph applies to diploid and nondiploid cell lines. Primary cell cultures that are not subcultivated and primary cell cultures that are subsequently subcultivated for only a very limited number of population doublings are not subject to the provisions of this paragraph (c).
(d) Records. The records appropriate for cultures under this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.
Except as provided otherwise in this subchapter, prior to clarification or filtration in the case of live virus vaccines produced from in vitro living cell cultures, and prior to inactivation in the case of inactivated virus vaccines produced from such living cell cultures, each virus harvest pool and control fluid pool shall be tested for the presence of Mycoplasma, as follows:
Samples of the virus for this test shall be stored either (1) between 2 and 8 °C for no longer than 24 hours, or (2) at −20 °C or lower if stored for longer than 24 hours. The test shall be performed on samples of the viral harvest pool and on control fluid pool obtained at the time of viral harvest, as follows: No less than 2.0 ml. of each sample shall be inoculated in evenly distributed amounts over the surface of no less than 10 plates of at least two agar media. No less than 1.0 ml. of sample shall be inoculated into each of four tubes containing 10 ml. of a semisolid broth medium. The media shall be such as have been shown to be capable of detecting known Mycoplasma and each test shall include control cultures of at least two known strains of Mycoplasma, one of which must be M. pneumoniae. One half of the plates and two tubes of broth shall be incubated aerobically at 36 °C ±1 °C and the remaining plates and tubes shall be incubated anaerobically at 36 °C ±1 °C in an environment of 5-10 percent CO
The definitions set out in § 630.3 of this chapter apply to this subpart.
(a) Human blood and blood components. Except as specified in paragraphs (c) and (d) of this section, you, an establishment that collects blood and blood components for transfusion or for use in manufacturing a product, including donations intended as a component of, or used to manufacture, a medical device, must comply with the following requirements:
(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. To perform testing for evidence of infection due to relevant transfusion-transmitted infections as required in paragraph (a) of this section, you must use screening tests that FDA has licensed, approved, or cleared for such use, in accordance with the manufacturer's instructions. You must perform one or more such tests as necessary to reduce adequately and appropriately the risk of transmission of relevant transfusion-transmitted infections.
(c) Exceptions to testing for dedicated donations, medical devices, and samples. - (1) Dedicated donations. (i) You must test donations of human blood and blood components from a donor whose donations are dedicated to and used solely by a single identified recipient under paragraphs (a), (b), and (e) of this section; except that, if the donor makes multiple donations for a single identified recipient, you may perform such testing only on the first donation in each 30-day period. If an untested dedicated donation is made available for any use other than transfusion to the single, identified recipient, then this exemption from the testing required under this section no longer applies.
(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. (i) You are not required to test donations of human blood or blood components intended solely as a component of, or used to prepare, a medical device for evidence of infection due to the relevant transfusion-transmitted infections listed in § 630.3(h)(iv) of this chapter unless the final device contains viable leukocytes.
(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. You are not required to test samples of blood, blood components, plasma, or sera if used or distributed for clinical laboratory testing or research purposes and not intended for administration to humans or in the manufacture of a product.
(d) Autologous donations. You, an establishment that collects human blood or blood components from autologous donors, or you, an establishment that is a consignee of a collecting establishment, are not required to test donations of human blood or blood components from autologous donors for evidence of infection due to relevant transfusion-transmitted infections listed in paragraph (a) of this section, except:
(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. You must further test each donation, including autologous donations, found to be reactive by a donor screening test performed under paragraphs (a) and (b) of this section using a licensed, approved, or cleared supplemental test, when available. If no such supplemental test is available, you must perform one or more licensed, approved, or cleared tests as adequate and appropriate to provide additional information concerning the reactive donor's infection status. Except:
(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. Required testing under this section, must be performed by a laboratory registered in accordance with part 607 of this chapter and either certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) under 42 CFR part 493 or has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services in accordance with those provisions.
(g) Release or shipment prior to testing. Human blood or blood components that are required to be tested for evidence of infection due to relevant transfusion-transmitted infections designated in paragraph (a) of this section may be released or shipped prior to completion of testing in the following circumstances provided that you label the blood or blood components under § 606.121(h) of this chapter, you complete the tests for evidence of infection due to relevant transfusion-transmitted infections as soon as possible after release or shipment, and that you provide the results promptly to the consignee:
(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 - (1) Reactive screening test. You must not ship or use human blood or blood components that have a reactive screening test for evidence of infection due to relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section or that are collected from a donor with a previous record of a reactive screening test for evidence of infection due to relevant transfusion-transmitted infection(s) designated in paragraph (a) of this section, except as provided in paragraphs (h)(2)(i) through (h)(2)(vii) of this section.
(2) Exceptions. (i) You may ship or use blood or blood components intended for autologous use, including reactive donations, as described in paragraph (d) of this section.
(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(a)(2)(ii) and (b)(1)(i) of this chapter, if the donor meets the requirements of § 640.65(b)(2)(i) through (b)(2)(iv) of this chapter.
(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.
(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.
(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.
(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.
(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.
(a) When the dating period begins. The dating period for a product must begin on the date of manufacture as described in paragraphs (b) and (c) of this section. The dating period for a combination of two or more products must be no longer than the dating period of the component with the shortest dating period.
(b) Determining the date of manufacture for biological products other than Whole Blood and blood components. The date of manufacture for biological products, other than Whole Blood and blood components, must be identified in the approved biologics license application as one of the following, whichever is applicable: The date of:
(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. (1) The date of manufacture for Whole Blood and blood components must be one of the following, whichever is applicable:
(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.
(a) General. Dating periods for Whole Blood and blood components are specified in the table in paragraph (b) of this section.
(b) Table of dating periods. In using the table in this paragraph, when a product in column A is stored at the storage temperature prescribed in column B, storage of a product must not exceed the dating period specified in column C, unless a different dating period is specified in the instructions for use by the blood collection, processing and storage system approved or cleared for such use by FDA. Container labels for each product must include the recommended storage temperatures.
Whole Blood and Blood Components Storage Temperatures and Dating Periods
| A | B | C |
|---|---|---|
| Product | Storage temperature | Dating period |
| ACD, CPD, CP2D | Between 1 and 6 °C | 21 days from date of collection. |
| CPDA-1 | do 1 | 35 days from date of collection. |
| 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
(e.g., deglycerolized, washed) | 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 | 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. |
| 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 | −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 | Temperature appropriate for final product | In lieu of expiration date, the collection date must appear on the label. |
1 The abbreviation “do.” for ditto is used in the table to indicate that the previous line is being repeated.
(a) Full label. The following items shall appear on the label affixed to each container of a product capable of bearing 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. If the container is not enclosed in a package, all the items required for a package label shall appear on the container label.
(c) Partial label. If the container is capable of bearing only a partial label, the container shall show as a minimum the name (expressed either as the proper or common name), the lot number or other lot identification and the name of the manufacturer; in addition, for multiple dose containers, the recommended individual dose. Containers bearing partial labels shall be placed in a package which bears all the items required for a package label.
(d) No container label. If the container is incapable of bearing any label, the items required for a container label may be omitted, provided the container is placed in a package which bears all the items required for a package label.
(e) Visual inspection. When the label has been affixed to the container a sufficient area of the container shall remain uncovered for its full length or circumference to permit inspection of the contents.
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.
(a) Position. The proper name of the product on the package label shall be placed above any trademark or trade name identifying the product and symmetrically arranged with respect to other printing on the label.
(b) Prominence. The point size and typeface of the proper name shall be at least as prominent as the point size and typeface used in designating the trademark and trade name. The contrast in color value between the proper name and the background shall be at least as great as the color value between the trademark and trade name and the background. Typography, layout, contrast, and other printing features shall not be used in a manner that will affect adversely the prominence of the proper name.
(c) Legible type. All items required to be on the container label and package label shall be in legible type. “Legible type” is type of a size and character which can be read with ease when held in a good light and with normal vision.
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.
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.
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.
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.
(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.