21 C.F.R. PART 610—GENERAL BIOLOGICAL PRODUCTS STANDARDS
Title 21 - Food and Drugs
Title 21: Food and Drugs
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PART 610—GENERAL BIOLOGICAL PRODUCTS STANDARDS
Section Contents
Subpart A—Release Requirements
§ 610.1 Tests prior to release required for each lot.
§ 610.2 Requests for samples and protocols; official release.
Subpart B—General Provisions
§ 610.9 Equivalent methods and processes.
§ 610.10 Potency.
§ 610.11 General safety.
§ 610.11a Inactivated influenza vaccine, general safety test.
§ 610.12 Sterility.
§ 610.13 Purity.
§ 610.14 Identity.
§ 610.15 Constituent materials.
§ 610.16 Total solids in serums.
§ 610.17 Permissible combinations.
§ 610.18 Cultures.
Subpart C—Standard Preparations and Limits of Potency
§ 610.20 Standard preparations.
§ 610.21 Limits of potency.
Subpart D—Mycoplasma
§ 610.30 Test for Mycoplasma.
Subpart E—Testing Requirements for Communicable Disease Agents
§ 610.40 Test requirements.
§ 610.41 Donor deferral.
§ 610.42 Restrictions on use for further manufacture of medical devices.
§ 610.44 Use of reference panels by manufacturers of test kits.
§ 610.46 “Lookback” requirements.
§ 610.47 “Lookback” notification requirements for transfusion services.
Subpart F—Dating Period Limitations
§ 610.50 Date of manufacture.
§ 610.53 Dating periods for licensed biological products.
Subpart G—Labeling Standards
§ 610.60 Container label.
§ 610.61 Package label.
§ 610.62 Proper name; package label; legible type.
§ 610.63 Divided manufacturing responsibility to be shown.
§ 610.64 Name and address of distributor.
§ 610.65 Products for export.
§ 610.67 Bar code label requirements.
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
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§ 610.1 Tests prior to release required for each lot.
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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.
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(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 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) 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.
[40 FR 31313, July 25, 1975, as amended by 49 FR 23834, June 8, 1984; 50 FR 10941, Mar. 19, 1985; 55 FR 11013 and 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14984, Mar. 24, 2005]
Subpart B—General Provisions
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§ 610.9 Equivalent methods and processes.
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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.
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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 General safety.
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A general safety test for the detection of extraneous toxic contaminants shall be performed on biological products intended for administration to humans. The general safety test is required in addition to other specific tests prescribed in the additional standards for individual products in this subchapter, except that, the test need not be performed on those products listed in paragraph (g) of this section. The general safety test shall be performed as specified in this section, unless: Modification is prescribed in the additional standards for specific products, or variation is approved as a supplement to the product license under §610.9.
(a) Product to be tested. The general safety test shall be conducted upon a representative sample of the product in the final container from every final filling of each lot of the product. If any product is processed further after filling, such as by freeze-drying, sterilization, or heat treatment, the test shall be conducted upon a sample from each filling of each drying chamber run, sterilization chamber, or heat treatment bath.
(b) Test animals. Only overtly healthy guinea pigs weighing less than 400 grams each and mice weighing less than 22 grams each shall be used. The animals shall not have been used previously for any test purpose.
(c) Procedure. The duration of the general safety test shall be 7 days for both species, except that a longer period may be established for specific products in accordance with §610.9. Once the manufacturer has established a specific duration of the test period for a specific product, it cannot be varied subsequently, except, in accordance with §610.9. Each test animal shall be weighed and the individual weights recorded immediately prior to injection and on the last day of the test. Each animal shall be observed every working day. Any animal response including any which is not specific for or expected from the product and which may indicate a difference in its quality shall be recorded on the day such response is observed. The test product shall be administered as follows:
(1) Liquid product or freeze-dried product which has been reconstituted as directed on the label. Inject intraperitoneally 0.5 milliliter of the liquid product or the reconstituted product into each of at least two mice, and 5.0 milliliters of the liquid product or the reconstituted product into each of at least two guinea pigs.
(2) Freeze-dried product for which the volume of reconstitution is not indicated on the label. The route of administration, test dose, and diluent shall be as approved in accordance with §610.9. Administer the test product as approved on at least two mice and at least two guinea pigs.
(3) Nonliquid products other than freeze-dried product. The route of administration, test dose, and diluent shall be as in accordance with §610.9. Dissolve or grind and suspend the product in the approved diluent. Administer the test product as approved on at least two mice and at least two guinea pigs.
(d) Test requirements. A safety test is satisfactory if all animals meet all of the following requirements:
(1) They survive the test period.
(2) They do not exhibit any response which is not specific for or expected from the product and which may indicate a difference in its quality.
(3) They weigh no less at the end of the test period than at the time of injection.
(e) Repeat tests—(1) First repeat test. If a filling fails to meet the requirements of paragraph (d) of this section in the initial test, a repeat test may be conducted on the species which failed the initial test, as prescribed in paragraph (c) of this section. The filling is satisfactory only if each retest animal meets the requirements prescribed in paragraph (d) of this section.
(2) Second repeat test. If a filling fails to meet the requirements of the first repeat test, a second repeat test may be conducted on the species which failed the test: Provided, That 50 percent of the total number of animals in that species has survived the initial and first repeat tests. The second repeat test shall be conducted as prescribed in paragraph (c) of this section, except that the number of animals shall be twice that used in the first repeat test. The filling is satisfactory only if each second repeat test animal meets the requirements prescribed in paragraph (d) of this section.
(f) [Reserved]
(g) Exceptions—(1) The test prescribed in this section need not be performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF, Platelets, Plasma, or Cellular Therapy Products.
(2) For products other than those identified in paragraph (g)(1) of this section, a manufacturer may request from the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in §600.2 of this chapter), an exemption from the general safety test. The manufacturer must submit information as part of a biologics license application submission or supplement to an approved biologics license application establishing that because of the mode of administration, the method of preparation, or the special nature of the product a test of general safety is unnecessary to assure the safety, purity, and potency of the product or cannot be performed. The request must include alternate procedures, if any, to be performed. The Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, upon finding that the manufacturer's request justifies an exemption, may exempt the product from the general safety test subject to any condition necessary to assure the safety, purity, and potency of the product.
[41 FR 10891, Mar. 15, 1976, as amended at 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 19403, Apr. 20, 1998; 63 FR 41718, Aug. 5, 1998; 68 FR 10160, Mar. 4, 2003; 70 FR 14984, Mar. 24, 2005]
§ 610.11a Inactivated influenza vaccine, general safety test.
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For inactivated influenza vaccine, the general safety test shall be conducted in the manner indicated in §610.11 of this chapter except that, with reference to guinea pigs, the test shall be satisfied if the product provides satisfactory results using either the subcutaneous or intraperitoneal injection of 5.0 milliliters of inactivated influenza vaccine into each guinea pig. The requirements for general safety for inactivated influenza vaccine shall not be considered to be satisfied unless each lot of influenza vaccine is assayed for endotoxin in comparison to a reference preparation provided by the Food and Drug Administration, and such lot is found to contain no more endotoxin than the reference preparation.
[39 FR 40016, Nov. 13, 1974]
§ 610.12 Sterility.
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Except as provided in paragraphs (f) and (g) of this section, the sterility of each lot of each product shall be demonstrated by the performance of the tests prescribed in paragraphs (a) and (b) of this section for both bulk and final container material.
(a) The test. Bulk material shall be tested separately from final container material and material from each final container shall be tested in individual test vessels as follows:
(1) Using Fluid Thioglycollate Medium—(i) Bulk and final container material. The volume of product, as required by paragraph (d) of this section (hereinafter referred to also as the “inoculum”), from samples of both bulk and final container material, shall be inoculated into test vessels of Fluid Thioglycollate Medium. The inoculum and medium shall be mixed thoroughly and incubated at a temperature of 30 to 35 °C for a test period of no less than 14 days and examined visually for evidence of growth on the third, fourth, or fifth day, and on the seventh or eighth day, and on the last day of the test period. Results of each examination shall be recorded. If the inoculum renders the medium turbid so that the absence of growth cannot be determined reliably by visual examination, portions of this turbid medium in amounts of no less than 1.0 milliliter shall be transferred on the third, fourth, or fifth day of incubation, from each of the test vessels and inoculated into additional vessels of the medium. The material in the additional vessels shall be incubated at a temperature of 30 to 35 °C for no less than 14 days. Notwithstanding such transfer of material, examination of the original vessels shall be continued as prescribed above. The additional test vessels shall be examined visually for evidence of growth on the third, fourth, or fifth day of incubation, and on the seventh or eighth day, and on the last day of the incubation period. If growth appears, repeat tests may be performed as prescribed in paragraph (b) of this section and interpreted as specified in paragraph (c) of this section.
(ii) Final container material containing a mercurial preservative. In addition to the test prescribed in paragraph (a)(1)(i) of this section, final container material containing a mercurial preservative shall be tested using Fluid Thioglycollate Medium following the procedures prescribed in such subparagraph, except that the incubation shall be at a temperature of 20 to 25 °C.
(2) Using Soybean-Casein Digest Medium. Except for products containing a mercurial preservative, a test shall be made on final container material, following the procedures prescribed in paragraph (a)(1)(i) of this section, except that the medium shall be Soybean-Casein Digest Medium and the incubation shall be at a temperature of 20 to 25 °C.
(b) Repeat tests. If growth appears in any of the test media during testing of either bulk or final container material, the test may be repeated to rule out faulty test procedures as follows:
(1) Repeat bulk test. Only one repeat bulk test may be conducted. The volume of inoculum to be used for the repeat bulk test shall be as prescribed in paragraph (d)(1) of this section. The repeat test shall be performed using the procedure prescribed in paragraph (a)(1)(i) of this section.
(2) First repeat final container test. The number of test samples and the volumes of product used for the first repeat test shall be as prescribed in paragraph (d)(2) of this section. For products that do not contain a mercurial preservative, the repeat test shall be performed, using both Fluid Thioglycollate Medium and Soybean-Casein Digest Medium, following the procedures prescribed in paragraphs (a)(1)(i) and (a)(2), respectively, of this section. If the product contains a mercurial preservative, the repeat test shall be performed using Fluid Thioglycollate Medium and the procedures prescribed in paragraphs (a)(1) (i) and (ii) of this section.
(3) Second repeat final container test. If growth appears in any of the first repeat final container tests, all tests of the first repeat final container test shall be repeated, provided there was no evidence of growth in any test of the bulk material. The test samples used for the second repeat final container test shall be twice the number used for the first repeat final container test.
(c) Interpretation of test results. The results of all tests performed on a lot shall be considered in determining whether or not the lot meets the requirements for sterility, except that tests may be excluded when demonstrated by adequate controls to be invalid. The lot meets the test requirements if no growth appears in the tests prescribed in paragraph (a) of this section. If repeat tests are performed, the lot meets the test requirements if no growth appears in the tests prescribed in paragraph (b)(2) or (3) of this section, whichever is applicable.
(d) Test samples and volumes—(1) Bulk. Each sample for the bulk sterility test shall be representative of the bulk material and the volume tested shall be no less than 10 ml. (Note exceptions in paragraph (g) of this section.)
(2) Final containers. The sample used for each test medium or each incubation temperature of a test medium for the final container and first repeat final container test shall be no less than 20 final containers from each filling of each lot, selected to represent all stages of filling from the bulk vessel. If the amount of material in the final container is 1.0 milliliter or less, the entire contents shall be tested. If the amount of material in the final container is more than 1.0 milliliter, the volume tested shall be the largest single dose recommended by the manufacturer or 1.0 milliliter, whichever is larger, but no more than 10 milliliters of material or the entire contents from a single final container need be tested. If more than 2 filling machines, each with either single or multiple filling stations, are used for filling one lot, no less than 10 filled containers shall be tested from each filling machine for each test medium or each incubation temperature condition, but no more than 100 containers of each lot need be tested. The items tested shall be representative of each filling assembly and shall be selected to represent all stages of the filling operation. (Note exceptions in paragraph (g) of this section.)
(e) Culture medium—(1) Formulae. (i) The formula for Fluid Thioglycollate Medium is as follows:
Fluid Thioglycollate Medium 1-cystine 0.5 gm.Sodium chloride 2.5 gm.Dextrose 5.5 gm. (C6H12O6·H2)O) Granular agar 0.75 gm. (less than 15% moisture by weight)Yeast extract 5.0 gm. (water- soluble)Pancreatic 15.0 gm. digest of caseinPurified water 1,000.0 ml. Sodium 0.5 gm. thioglycollate (or thioglycolic acid_0.3 ml)Resazurin (0.10% solution, 1.0 ml. freshly prepared)pH after sterilization 7.1±0.2 .
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(ii) The formula for Soybean-Casein Digest Medium is as follows:
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Soybean-Casein Digest Medium Pancreatic 17.0 gm. Digest of CaseinPapaic Digest 3.0 gm. of Soybean MealSodium Chloride 5.0 gm.Dibasic 2.5 gm. Potassium PhosphateDextrose 2.5 gm. (C6H12O6·H2O) Purified water 1,000.0 ml.pH after sterilization 7.3±0.2 .
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(2) Culture media requirements—(i) Definition of a lot of culture medium and test requirements. A lot of culture medium is that quantity of uniform material identified as having been thoroughly mixed in a single vessel, dispensed into a group of vessels of the same composition and design, sterilized in a single autoclave run, and identified in a manner to distinguish one lot from another. Each lot of culture medium shall be tested for its growth-promoting qualities unless it meets the exception for dehydrated culture medium described in this subpart. The growth-promoting quality test shall be performed on the smallest sized vessel used in an autoclave run. When using a single batch of dehydrated culture medium, a manufacturer need not perform growth-promoting tests on each lot of prepared liquid medium, provided that a validation program exists for autoclaves used to sterilize the culture medium, and the manufacturer has received approval for this practice from the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research.
(ii) Test organisms, strains, characteristics, identity, and verification. Two or more strains of microorganisms that are exacting in their nutritive and aerobic/anaerobic requirements shall be used to test the growth-promoting qualities of each lot of test medium. When using Fluid Thioglycollate medium, both an aerobic and an anaerobic test microorganism shall be chosen. When using Soybean Casein Digest Medium, the yeast, Candida albicans, shall be one of the two test microorganisms chosen. Manufacturers shall choose the strains of microorganisms from the chart in this paragraph.
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------------------------------------------------------------------------ Incubation Medium Test microorganisms temperature------------------------------------------------------------------------ Spore-formersFluid Thioglycollate........... 1. Bacillus subtilis 30 to 35 (ATCC No. 6633). °C. 2. Clostridium Do. sporogenes (ATCC No. 11437). Non-spore-formers 3. Candida albicans Do. (ATCC No. 10231). 4. Micrococcus luteus Do. (ATCC No. 9341). 5. Bacteroides Do. vulgatus (ATCC No. 8482). Spore-formersSoybean-Casein Digest.......... 1. Bacillus subtilis 20 to 25 (ATCC No. 6633). °C. Non-spore-formers 2. Candida albicans Do. (ATCC No. 10231). 3. Micrococcus luteus Do. (ATCC No. 9341).------------------------------------------------------------------------
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ATCC strains of microorganisms described in this section are available from the American Type Culture Collection, 10801 University Blvd., Manassas, VA 20110. Periodic tests shall be performed to verify the integrity of the test organisms in accordance with §610.18 (a) and (b). The results of these periodic tests shall be recorded and retained in accordance with §600.12(b) of this chapter.
(iii) Storage and maintenance of cultures of test organisms. Cultures of the test organisms used to determine the growth-promoting qualities of the medium shall be stored in a manner that will prevent cross contamination or loss of identity, at a temperature and by a method that will retain the initial characteristics of the organisms and ensure freedom from contamination and deterioration. If the test organisms are stored in the freeze-dried state, or frozen, they shall be reconstituted or thawed, whichever is applicable, and plated periodically to verify the colony count of the suspension. If the test suspensions are stored in a state other than freeze-dried or frozen, they shall be plated, and a colony count shall be performed at the time of each growth-promoting quality test to assure that not more than 100 organisms are used per test vessel. The results of tests for verification of the colony count shall be recorded and retained in accordance with §600.12(b) of this chapter.
(iv) Storage and condition of media. A medium shall not be used if the extent of evaporation affects its fluidity, nor shall it be reused in a sterility test of the product. Fluid Thioglycollate Medium shall be stored in the dark at room temperature if the vessels are unsealed. Sealed vessels shall be stored at the manufacturer's specified storage temperature. Fluid Thioglycollate Medium shall not be used if more than the upper one-third of the medium has acquired a pink color. The medium may be restored once by heating on a steam bath or in free-flowing steam until the pink color disappears. The design of the test vessel for Fluid Thioglycollate Medium shall provide favorable aerobic and anaerobic conditions for growth of the microorganisms throughout the test period. Soybean-Casein Digest Medium shall be stored in the dark at 20 to 25 °C. Unsealed vessels of either medium may be stored for more than 10 days at the proper temperature, provided they are tested monthly for growth-promotion and found to be satisfactory. Sealed vessels of either medium may be stored at the proper temperature for a period of time not to exceed 1 year, provided they are tested for growth-promotion every 3 months and found to be satisfactory. The results of such testing shall be recorded and retained in accordance with §600.12(b) of this chapter.
(v) Criteria for a satisfactory growth-promoting quality test. (a) One hundred or fewer organisms of each strain tested shall be used. The test is satisfactory if evidence of growth appears within 7 days in all vessels inoculated. If a lot of medium fails to support the growth of any test organism, or if the test results show that more than 100 organisms of a strain were used or are necessary to promote growth in the lot of medium being tested, or if the growth is not a pure culture of the test organism, a second test may be performed. If it fails the second test, the lot of medium shall be rejected.
(b) Inoculated Fluid Thioglycollate Medium shall be incubated at 30 to 35 °C for 7 days. If the test medium is to be used in determining the sterility of a product containing a mercurial preservative, a second test shall be performed in accordance with paragraph (e)(2)(v)(a) of this section, except that the test shall be incubated at 20 to 25 °C for 7 days. Inoculated Soybean-Casein Digest Medium shall be incubated at 20 to 25 °C for 7 days. The sterility of each lot of medium shall be confirmed by the incubation of uninoculated control test vessels for 7 days at the temperature(s) for that particular medium. The lot of medium is satisfactory if no growth is observed in the control test vessels within the incubation period. The tests for growth-promoting qualities of culture media may be performed simultaneously with sterility testing of biological products, provided the sterility test is considered invalid if the test medium shows no growth response.
(vi) Volume of culture medium. The volume of each culture medium shall be determined for each bulk and final container sterility test required for each product. The ratio of the volume of inoculum to the volume of culture medium shall result in a dilution of the product that is not bacteriostatic or fungistatic, except for products to be tested by membrane filtration. The volume of inhibitors or neutralizers of preservatives added should be considered in determining the proper ratio of inoculum/medium. Vessels of the product-medium mixture(s) and control vessels of the medium shall be inoculated with dilutions of cultures of bacteria or fungi which are viable in the product being tested, and incubated at the appropriate temperature for no less than 7 days.
(f) Membrane filtration. Bulk and final container material or products containing oil products in water-insoluble ointments may be tested for sterility using the membrane filtration procedure set forth in the United States Pharmacopeia (23d Revision, 1995), section entitled “Test Procedures Using Membrane Filtration,” pp. 1689 to 1690, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, or available for inspection at the Center for Drug Evaluation and Research's Division of Medical Library, 5600 Fishers Lane, rm. 11B–40, Rockville, MD, or at the National Archives and Records Administration (NARA). (For information on the availability of this material at NARA, call 202–741–6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.php). Except that:
(1) The test samples shall conform with paragraph (d) of this section; and
(2) In addition, for products containing a mercurial preservative, the product shall be tested in a second test using Fluid Thioglycollate Medium incubated at 20 to 251/2C in lieu of the test in Soybean-Casein Digest Medium.
(g) Exceptions. Bulk and final container material shall be tested for sterility as described above in this section, except as follows:
(1) Different sterility tests prescribed. When different sterility tests are prescribed for a product in this subchapter.
(2) Alternate incubation temperatures. Two tests may be performed as prescribed in paragraph (a)(1)(i) of this section, one test using an incubation temperature of 18 to 22 °C, the other test using an incubation temperature of 30 to 37 °C, in lieu of performing one test using an incubation temperature of 30 to 35 °C, provided that growth-promoting quality tests have been performed at these temperatures.
(3) [Reserved]
(4) Test precluded or not required. (i) The tests prescribed in this section need not be performed for Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping Reagent.
(ii) Where a manufacturer submits data which the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, finds adequate to establish that the mode of administration, the method of preparation, or the special nature of the product precludes or does not require a sterility test or that the sterility of the lot is not necessary to assure the safety, purity, and potency of the product, the Director may exempt a product from the sterility requirements of this section subject to any conditions necessary to assure the safety, purity, and potency of the product.
(5) Number of final containers more than 20, less than 200. If the number of final containers in the filling is more than 20 or less than 200, the sample shall be no less than 10 percent of the containers.
(6) Number of final containers—20 or less. If the number of final containers in a filling is 20 or less, the sample shall be two final containers, or the sample need be no more than one final container, provided (i) the bulk material met the sterility test requirements and (ii) after filling, it is demonstrated by testing a simulated sample that all surfaces to which the product was exposed were free of contaminating microorganisms. The simulated sample shall be prepared by rinsing the filling equipment with sterile 1.0 percent peptone solution, pH 7.1 ±0.1, which shall be discharged into a final container by the same method used for filling the final containers with the product.
(7) Samples—large volume of product in final containers. For Albumin (Human) and Plasma Protein Fraction (Human), when the volume of product in the final container is 50 milliliters or more, the final containers selected as the test sample may contain less than the full volume of product in the final containers of the filling from which the sample is taken: Provided, That the containers and closures of the sample are identical with those used for the filling to which the test applies, and the sample represents all stages of that filling.
(8) Diagnostic biological products not intended for injection. For diagnostic biological products not intended for injection, (i) only the Fluid Thioglycollate Medium test incubated at 30 to 35 °C is required, (ii) the volume of material for the bulk test shall be no less than 2.0 milliliters, and (iii) the sample for the final container test shall be no less than three final containers if the total number filled is 100 or less, and, if greater, one additional container for each additional 50 containers or fraction thereof, but the sample need be no more than 10 containers.
(9) Immune globulin preparations. For immune globulin preparations, the test samples from the bulk material and from each final container need be no more than 2.0 ml.
(h) Records. The records related to the testing requirements of this section shall be prepared and maintained as required by §§211.167 and 211.194 of this chapter.
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 41 FR 10428, Mar. 11, 1976; 44 FR 11754, Mar. 2, 1979; 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 44906, Dec. 15, 1986; 53 FR 12764, Apr. 19, 1988; 55 FR 11013, Mar. 26, 1990; 62 FR 48175, Sept. 15, 1997; 67 FR 9587, Mar. 4, 2002; 69 FR 18803, Apr. 9, 2004; 70 FR 14985, Mar. 24, 2005]
§ 610.13 Purity.
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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.
[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.
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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.
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(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 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.
[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]
§ 610.16 Total solids in serums.
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Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids.
§ 610.17 Permissible combinations.
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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.
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(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.
[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]
Subpart C—Standard Preparations and Limits of Potency
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§ 610.20 Standard preparations.
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Standard preparations made available by the Center for Biologics Evaluation and Research shall be applied in testing, as follows:
(a) Potency standards. Potency standards shall be applied in testing for potency all forms of the following:
Antibodies
Botulism Antitoxin, Type A.
Botulism Antitoxin, Type B.
Botulism Antitoxin, Type E.
Diphtheria Antitoxin.
Histolyticus Antitoxin.
Oedematiens Antitoxin.
Perfringens Antitoxin.
Antipertussis Serum.
Antirabies Serum.
Sordellii Antitoxin.
Staphylococcus Antitoxin.
Tetanus Antitoxin.
Vibrion Septique Antitoxin.
Antigens
Cholera Vaccine, Inaba serotype.
Cholera Vaccine, Ogawa serotype.
Diphtheria Toxin for Schick Test.
Pertussis Vaccine.
Tuberculin, Old.
Tuberculin, Purified Protein Derivative.
Typhoid Vaccine.
Blood Derivative
Thrombin.
(b) Opacity standard. The U.S. Opacity Standard shall be applied in estimating the bacterial concentration of all bacterial vaccines. The assigned value of the standard when observed visually is 10 units. The assigned value of the standard when observed with a photometer is (1) 10 units when the wavelength of the filter is 530 millimicrons, (2) 10.6 units when the wavelength of the filter is 650 millimicrons, and (3) 9 units when the wavelength of the filter is 420 millimicrons.
[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 10429, Mar. 11, 1976; 41 FR 18295, May 3, 1976; 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]
§ 610.21 Limits of potency.
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Link to an amendment published at 70 FR 75028, Dec. 19, 2005.
The potency of the following products shall be not less than that set forth below and products dispensed in the dried state shall represent liquid products having the stated limitations.
Antibodies
Diphtheria Antitoxin, 500 units per milliliter.
Tetanus Antitoxin, 400 units per milliliter.
Tetanus Immune Globulin (Human), 50 units of tetanus antitoxin per milliliter.
Antigens
Cholera Vaccine, 8 units each of Inaba and Ogawa serotype antigens per milliliter.
Pertussis Vaccine, 12 units per total human immunizing dose.
Typhoid Vaccine, 8 units per milliliter.
[41 FR 10429, Mar. 11, 1976, as amended at 41 FR 18295, May 3, 1976]
Subpart D—Mycoplasma
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§ 610.30 Test for Mycoplasma.
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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 CO2 in N2. Aerobic incubation shall be for a period of no less than 14 days and the broth in the two tubes shall be tested after 3 days and 14 days, at which times 0.5 ml. of broth from each of the two tubes shall be combined and subinoculated on to no less than 4 additional plates and incubated aerobically. Anaerobic incubation shall be for no less than 14 days and the broth in the two tubes shall be tested after 3 days and 14 days, at which times 0.5 ml. of broth from each of the two tubes shall be combined and subinoculated onto no less than four additional plates and incubated anaerobically. All inoculated plates shall be incubated for no less than 14 days, at which time observation for growth of Mycoplasma shall be made at a magnification of no less than 300×. If the Dienes Methylene Blue-Azure dye or an equivalent staining procedure is used, no less than a one square cm. plug of the agar shall be excised from the inoculated area and examined for the presence of Mycoplasma. The presence of the Mycoplasma shall be determined by comparison of the growth obtained from the test samples with that of the control cultures, with respect to typical colonial and microscopic morphology. The virus pool is satisfactory for vaccine manufacture if none of the tests on the samples show evidence of the presence of Mycoplasma.
[38 FR 32056, Nov. 20, 1973, as amended at 63 FR 16685, Apr. 6, 1998]
Subpart E—Testing Requirements for Communicable Disease Agents
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§ 610.40 Test requirements.
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(a) Human blood and blood components. Except as specified in paragraphs (c) and (d) of this section, you, an establishment that collects blood or blood components, must test each donation of human blood or blood component intended for use in preparing a product, including donations intended as a component of, or used to prepare, a medical device, for evidence of infection due to the following communicable disease agents:
(1) Human immunodeficiency virus, type 1;
(2) Human immunodeficiency virus, type 2;
(3) Hepatitis B virus;
(4) Hepatitis C virus;
(5) Human T-lymphotropic virus, type I; and
(6) Human T-lymphotropic virus, type II.
(b) Testing using one or more approved screening tests. To test for evidence of infection due to communicable disease agents designated in paragraph (a) of this section, you must use screening tests that the Food and Drug Administration (FDA) has approved 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 communicable disease.
(c) Exceptions to testing for allogeneic transfusion or further manufacturing use—(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:
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------------------------------------------------------------------------ Donor Testing Status Label------------------------------------------------------------------------Tests negative Label as required under § 606.121Tested negative within the last 30 ``DONOR TESTED WITHIN THE LAST 30 days DAYS''------------------------------------------------------------------------
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(2) Source Plasma. You are not required to test donations of Source Plasma for evidence of infection due to the communicable disease agents listed in paragraphs (a)(5) and (a)(6) of this section.
(3) 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 communicable disease agents listed in paragraphs (a)(5) and (a)(6) of this section 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.”
(4) 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 communicable disease agents listed in paragraph (a) of this section or by a serological test for syphilis under paragraph (i) 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:
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---------------------------------------------------------------------------------------------------------------- Donor Testing Status Label----------------------------------------------------------------------------------------------------------------Untested ``DONOR UNTESTED''Tests negative Label as required under § 606.121Reactive on current collection/reactive in the last 30 ``BIOHAZARD'' legend in § 610.40(h)(2)(ii)(B) daysTested negative within the last 30 days ``DONOR TESTED WITHIN THE LAST 30 DAYS''----------------------------------------------------------------------------------------------------------------
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(e) Further testing. You must further test each donation, including autologous donations, found to be reactive by a screening test performed under paragraphs (a) and (b) of this section, whenever a supplemental (additional, more specific) test has been approved for such use by FDA, except:
(1) For autologous donations, you must further test under this paragraph, at a minimum, the first reactive donation in each 30-day period; or
(2) If you have a record for that donor of a positive result on a supplemental (additional, more specific) test approved for such use by FDA, you do not have to further test an autologous donation.
(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 Health Care Financing Administration 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 communicable disease agents designated in paragraphs (a) and (i) 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 communicable disease agents 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 a communicable disease agent(s) designated in paragraphs (a) and (i) 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 a communicable disease agent(s) designated in paragraphs (a) and (i) 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 communicable disease agent(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, or §640.70 of this chapter, and with the “BIOHAZARD” legend;
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(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 communicable disease agent(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:
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---------------------------------------------------------------------------------------------------------------- Type of Medical Device Label----------------------------------------------------------------------------------------------------------------A medical device other than an in vitro diagnostic ``Caution: For Further Manufacturing Use as a Component reagent 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''----------------------------------------------------------------------------------------------------------------
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(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 communicable disease agent(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 suitable 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 (i) of this section if, consistent with §640.5 of this chapter, 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 §610.40(i) of this chapter, if the donor meets the requirements of §640.65(b)(2) of this chapter.
(i) Syphilis testing. In addition to the testing otherwise required under this section, you must test by a serological test for syphilis under §§640.5(a), 640.14, 640.23(a), 640.33(a), 640.53(a), and 640.65(b)(2) of this chapter.
[66 FR 31162, June 11, 2001]
§ 610.41 Donor deferral.
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(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 communicable disease agent(s) listed in §610.40(a) or reactive for a serological test for syphilis under §610.40(i), 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 or II, on only one occasion. When a supplemental (additional, more specific) test for anti-HBc or anti-HTLV, types I and II, has been approved for use under §610.40(e) by FDA, such a donor must be deferred;
(2) A deferred donor who tests reactive for evidence of infection due to a communicable disease agent(s) listed in §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 suitable;
(4) A deferred donor, who otherwise is determined to be suitable 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 communicable disease agent(s) described under §610.40(a) or reactive with a serological test for syphilis under §610.40(i), may serve as an autologous donor under §610.40(d).
(b) A deferred donor subsequently may be found to be suitable 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.
[66 FR 31164, June 11, 2001]
§ 610.42 Restrictions on use for further manufacture of medical devices.
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(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) or reactive for syphilis under §610.40(i), 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 communicable disease agent(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]
§ 610.44 Use of reference panels by manufacturers of test kits.
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(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 communicable disease agents listed in §610.40(a); and
(2) Human immunodeficiency virus (HIV) test kit approved for use in the diagnosis, prognosis, or monitoring of this communicable disease agent.
(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]
§ 610.46 “Lookback” requirements.
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(a) Quarantine and notification. (1) All blood and plasma establishments are required to take appropriate action when a donor of Whole Blood, blood components, Source Plasma and Source Leukocytes tests repeatedly reactive for antibody to human immunodeficiency virus (HIV), or otherwise is determined to be unsuitable when tested in accordance with §610.45. For Whole Blood, blood components, Source Plasma and Source Leukocytes collected from that donor within the 5 years prior to the repeatedly reactive test, if intended for transfusion, or collected within the 6 months prior to the repeatedly reactive test, if intended for further manufacture into injectable products, except those products exempt from quarantine in accordance with §610.46(c), the blood establishment shall promptly, within 72 hours:
(i) Quarantine all such Whole Blood, blood components, Source Plasma and Source Leukocytes from previous collections held at that establishment; and
(ii) Notify consignees of the repeatedly reactive HIV screening test results so that all Whole Blood, blood components, Source Plasma and Source Leukocytes from previous collections they hold are quarantined.
(2) Consignees notified in accordance with paragraph (a)(1)(ii) of this section shall quarantine Whole Blood, blood components, Source Plasma and Source Leukocytes held at that establishment except as provided in paragraph (c) of this section.
(b) Further testing and notification of consignees of results. Blood establishments that have collected Whole Blood, blood components, Source Plasma or Source Leukocytes from a donor as described in paragraph (a) of this section shall perform a licensed, more specific test for HIV on the donor's blood, and in the case of distributed products, further shall notify the consignee(s) of the results of this test, within 30 calendar days after the donor's repeatedly reactive test. Pending the availability of a licensed, more specific test for HIV–2, a second, different screening test for antibody to HIV–2 shall be used along with a licensed, more specific test for HIV–1.
(c) Exemption from quarantine. Products intended for transfusion need not be held in quarantine if a determination has been made that the Whole Blood, blood components, Source Plasma or Source Leukocytes was collected more than 12 months prior to the donor's most recent negative antibody screening test when tested in accordance with §610.45. Pooled Source Plasma and Source Leukocytes are exempt from quarantine.
(d) Release from quarantine. Whole Blood, blood components, Source Plasma and Source Leukocytes intended for transfusion or further manufacture which have been quarantined under paragraph (a) of this section may be released if the donor is subsequently tested for antibody to HIV as provided in paragraph (b) of this section and the test result is negative, absent other informative test results.
(e) Actions under this section do not constitute a product recall as defined in §7.3(g) of this chapter.
[61 FR 47423, Sept. 9, 1996]
§ 610.47 “Lookback” notification requirements for transfusion services.
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(a) Transfusion services that are not subject to the Health Care Financing Administration's regulations on conditions of Medicare participation for hospitals (42 CFR part 482) are required to take appropriate action in accordance with paragraphs (b) and (c) of this section when a recipient has received Whole Blood or blood components from a donor determined to be unsuitable when tested for human immunodeficiency virus (HIV) infection in accordance with §610.45 and the results of the additional tests as provided for in §610.46(b) are positive.
(b) Notification of recipients of prior transfusion. If the transfusion service has administered Whole Blood or blood components as described in paragraph (a) of this section, the transfusion service shall notify the recipient's attending physician (physician of record) and ask him or her to inform the recipient of the need for HIV testing and counseling. If the physician is unavailable or declines to notify the recipient, the transfusion service shall notify the recipient and inform the recipient of the need for HIV testing and counseling. The notification process shall include a minimum of three attempts to notify the recipient and be completed within a maximum 8 weeks of receipt of the result of the licensed, more specific test for HIV. The transfusion service is responsible for notification, including basic explanations to the recipient and referral for counseling, and shall document the notification or attempts to notify the attending physician or the recipient, pursuant to §606.160 of this chapter.
(c) Notification to legal representative or relative. If the transfusion recipient has been adjudged incompetent by a State court, the transfusion service or physician must notify a legal representative designated in accordance with State law. If the transfusion recipient is competent, but State law permits a legal representative or relative to receive the information on the recipient's behalf, the transfusion service or physician must notify the recipient or his or her legal representative or relative. If the transfusion recipient is deceased, the transfusion service or physician must continue the notification process and inform the deceased recipient's legal representative or relative. Reasons for notifying the recipient's relative or legal representative on his or her behalf shall be documented pursuant to §606.160 of this chapter.
[61 FR 47423, Sept. 9, 1996]
Subpart F—Dating Period Limitations
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§ 610.50 Date of manufacture.
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The date of manufacture shall be determined as follows:
(a) For products for which an official standard of potency is prescribed in either §610.20 or §610.21, or which are subject to official potency tests, the date of initiation by the manufacturer of the last valid potency test.
(b) For products that are not subject to official potency tests, (1) the date of removal from animals, (2) the date of extraction, (3) the date of solution, (4) the date of cessation of growth, or (5) the date of final sterile filtration of a bulk solution, whichever is applicable.
[38 FR 32056, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977]
§ 610.53 Dating periods for licensed biological products.
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(a) General. The minimum dating periods in paragraph (c) of this section are based on data relating to usage, clinical experience, or laboratory tests that establish the reasonable period beyond which the product cannot be expected to yield its specific results and retain its safety, purity, and potency, provided the product is maintained at the recommended temperatures. The standards prescribed by the regulations in this subchapter are designed to ensure the continued safety, purity, and potency of the products and are based on the dating periods set forth in paragraph (c) of this section. Package labels for each product shall recommend storage at the stated temperatures.
(b) When the dating period begins. The dating period for a product shall begin on the date of manufacture, as prescribed in §610.50. The dating period for a combination of two or more products shall be no longer than the dating period of the component with the shortest dating period.
(c) Table of dating periods. In using the table in this paragraph, a product in column A may be stored by the manufacturer at the prescribed temperature and length of time in either column B or C, plus the length of time in column D. The dating period in column D shall be applied from the day the product leaves the manufacturer's storage, provided the product has not exceeded its maximum storage period, as prescribed in column B or C. If a product is held in the manufacturer's storage beyond the period prescribed, the dating period for the product being distributed shall be reduced by a corresponding period.
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---------------------------------------------------------------------------------------------------------------- A B C D---------------------------------------------------------------------------------------------------------------- Dating period after Manufacturer's storage Manufacturer's storage leaving manufacturer's Product period 1 to 5 °C period 0 °C or storage when stored at 2 (unless otherwise colder (unless to 8 °C (unless stated) otherwise stated) otherwise stated)----------------------------------------------------------------------------------------------------------------Adenovirus Vaccine Live Oral....... 6 months............... Not applicable........ 6 months.Albumin (Human).................... 3 years................ ......do.............. (a) 5 years. ......do............... ......do.............. (b) 3 years, provided labeling recommends storage at room temperature, no warmer than 37 °C. Not applicable......... ......do.............. (c) 10 years, if in a hermetically sealed metal container and provided labeling recommends storage between 2 and 8 °C.Allergenic Extracts labeled ``No U.S. Standard of Potency'': 1. With 50 percent or more 3 years................ ......do.............. 3 years. glycerin. 2. With less than 50 percent 18 months.............. ......do.............. 18 months. glycerin. 3. Products for which cold Not applicable......... ......do.............. 18 months (from date of storage conditions are manufacture), provided inappropriate. labeling recommends storage at 30 °C or colder. 4. Powders and tablets......... ......do............... ......do.............. 5 years (from date of manufacture), provided labeling recommends storage at 30 °C or colder. 5. Freeze-dried products: a. Unreconstituted........... ......do............... ......do.............. 4 years (from date of manufacture). b. Reconstituted............. ......do............... ......do.............. 18 months (cannot exceed 4- year unreconstituted dating period plus an additional 12 months).Allergenic Extracts, Alum 18 months.............. ......do.............. 18 months. Precipitated labeled ``No U.S. Standard of Potency''.Anthrax Vaccine Adsorbed........... 2 years................ ......do.............. 1 year.Antibody to Hepatitis B Surface Antigen: 1. Antibody to Hepatitis B 6 months............... ......do.............. 6 months. Surface Antigen. 2. Lyophilized coated red blood ......do............... ......do.............. Do. cells. 3. Enzyme conjugated products.. ......do............... ......do.............. Do.Iodinated (\125\l) products........ Not applicable......... ......do.............. 45 days (from date of manufacture).Antihemophilic Factor (Human)...... ......do............... ......do.............. 1 year (from date of manufacture).Anti-Human Globulin Liquid......... ......do............... ......do.............. 2 years.Anti-Inhibitor Coagulant Complex... ......do............... ......do.............. Do.Antirabies Serum................... 1 year................. ......do.............. Do.Antivenin (Crotalidae) Polyvalent.. ......do............... ......do.............. 5 years with an initial 10 percent excess of potency, provided labeling recommends storage at 37 ° C or colder.Antivenin (Latrodectus Mactans).... ......do............... ......do.............. 5 years with an initial 10 percent excess of potency.Antivenin (Micurus fulvius)........ ......do............... ......do.............. Do.Asparaginase....................... Not applicable......... ......do.............. 18 months from the date of the last valid potency test.BCG Vaccine........................ 1 year................. Not applicable........ 6 months.Blood Grouping Reagents 1. Liquid...................... Not applicable......... Not applicable........ 2 years. 2. Dried....................... 1 year................. 2 years............... 5 years.Blood Group Substance AB........... ......do............... ......do.............. 2 years.Blood Group Substance A............ ......do............... ......do.............. Do.Blood Group Substance B............ ......do............... ......do.............. Do.Botulism Antitoxin................. ......do............... Not applicable........ 5 years with an initial 20 percent excess of potency.Cholera Vaccine.................... ......do............... ......do.............. 18 months.Coccidioidin....................... ......do............... ......do.............. 3 years.Collagenase........................ Not applicable......... ......do.............. 4 years (from date of manufacture), provided labeling recommends storage at 37 °C or colder.Cryoprecipitated AFH............... ......do............... ......do.............. 12 months from the date of collection of source blood, provided labeling recommends storage at -18 °C or colder.Diphtheria Antitoxin: 1. Liquid...................... 1 year................. ......do.............. 5 years with an initial 20 percent excess of potency. 2. Dried....................... ......do............... 2 years............... 5 years with an initial 10 percent excess of potency.Diphtheria and Tetanus Toxoids and ......do............... Not applicable........ 18 months. Pertussis Vaccine Adsorbed.Diphtheria and Tetanus Toxoids, ......do............... ......do.............. 2 years. Adsorbed.Diphtheria Toxin for Schick Test... ......do............... ......do.............. 1 year.Diphtheria Toxoid.................. ......do............... ......do.............. 2 years.Diphtheria Toxoid Adsorbed......... ......do............... 2 years............... Do.Diphtheria Toxoid-Schick Test Not applicable......... Not applicable........ 1 year. Control.Factor IX Complex.................. ......do............... ......do.............. 1 year (from date of manufacture).Fibrinolysin (Human)............... 1 year................. 2 years............... 2 years.Fibrinolysin and Desoxyribonuclease ......do............... ......do.............. 3 years, provided labeling Combined (Bovine). recommends storage at 30 °C or colder.Fibrinolysin and Desoxyribonuclease ......do............... ......do.............. Do. Combined (Bovine) with Chloramphenicol.Hepatitis B Surface Antigen: 1. Unlyophilized coated red Not applicable......... ......do.............. 14 days (from date of blood cells. manufacture). 2. Iodinated (\125\ l) product. ......do............... ......do.............. 45 days (from date of manufacture). 3. Enzyme conjugated product... 6 months............... ......do.............. 6 months.Histoplasmin....................... 1 year................. Not applicable........ 2 years.Immunoglobulins: 1. Hepatitis B Immune Globulin Not applicable......... ......do.............. 1 year. (Human). 2. Immune Globulin (Human)..... 3 years................ ......do.............. 3 years. 3. Immune Globulin Intravenous Not applicable......... ......do.............. 1 year. (Human). 4. Lymphocyte Immune Globulin, ......do............... Not applicable........ 2 years. Anti-Thymocyte Globulin (Equine). 5. Pertussis Immune Globulin 3 years................ ......do.............. 3 years from date the (Human). dried or frozen bulk product is placed in final solution. 6. Rabies Immune Globulin 1 year................. ......do.............. 1 year. (Human). 7. Rho(D) Immune Globulin 6 months............... ......do.............. 6 months. (Human). 8. Tetanus Immune Globulin 1 year................. ......do.............. 3 years with an initial 10 (Human). percent excess of potency. 9. Vaccinia Immune Globulin 3 years................ ......do.............. 3 years. (Human). 10. Varicella-Zoster Immune Not applicable......... ......do.............. 1 year. Globulin (Human).Hepatitis B Vaccine................ 2 years at 2 to 8 Not applicable........ 3 years. °C.Influenza Virus Vaccine............ 1 year................. ......do.............. 18 months.Limulus Amebocyte Lysate........... Not applicable......... Not applicable........ 18 months (from date of manufacture).Measles, Mumps, and Rubella Virus ......do............... 1 year (-20 °C or 1 year. Vaccine Live. colder).Measles and Mumps Virus Vaccine ......do............... ......do.............. 1 year. Live.Measles and Rubella Virus Vaccine ......do............... ......do.............. Do. Live.Measles Live and Smallpox Vaccine.. Not applicable......... ......do.............. 1 year (from date of manufacture).Measles Virus Vaccine Live......... ......do............... ......do.............. 1 year.Meningococcal Polysaccharide Vaccine Group A: 1. Final bulk powder........... ......do............... 2 years (-20 °C or Not applicable. colder). 2. Final container............. Not applicable......... 3 years (-20 °C or 2 years. colder).Meningococcal Polysaccharide Vaccine Group C: 1. Final bulk powder........... ......do............... 2 years (-20 °C or Not applicable. colder). 2. Final container............. ......do............... 3 years (-20 °C or 2 years. colder).Meningococcal Polysaccharide Vaccine Groups A and C combined: 1. Final bulk powder........... ......do............... 2 years (-20 °C or Not applicable. colder). 2. Final container............. ......do............... 3 years (-20 °C or 2 years. colder).Meningococcal Polysaccharide Vaccine Groups A, C, Y, and W135 combined: 1. Final bulk power............ ......do............... 2 years (-20 °C or Not applicable. colder). 2. Final container............. ......do............... 3 years (-20 °C or 2 years. colder).Mumps Skin Test Antigen............ 6 months............... Not applicable........ 18 months.Mumps Virus Vaccine Live........... Not applicable......... 1 year (-20 °C or 1 year. colder).Normal Horse Serum................. 1 year................. 2 years............... 5 years.Pertussis Vaccine.................. ......do............... Not applicable........ 18 months.Pertussis Vaccine Adsorbed......... ......do............... ......do.............. Do.Plague Vaccine..................... ......do............... ......do.............. Do.Plasma products: 1. Fresh Frozen Plasma......... Not applicable......... ......do.............. 1 year from date of collection of source blood (-18 °C or colder). 2. Liquid Plasma............... ......do............... ......do.............. (a) 26 days from date of collection of source blood (between 1 and 6 °C). (b) 40 days from date of collection of source blood only when CPDA-1 solution is used as the anticoagulant (between 1 and 6 °C). 3. Plasma...................... ......do............... ......do.............. 5 years from date of collection of source blood (-18 °C or colder). 4. Platelet Rich Plasma........ ......do............... ......do.............. 72 hours from time of collection of source blood, provided labeling recommends storage (20 to 24 °C or between 1 and 6 °C). 5 days if certain approved containers are used (20 to 24 °C). 5. Source Leukocytes........... ......do............... ......do.............. In lieu of expiration date, the collection date shall appear on the label. 6. Source Plasma............... ......do............... ......do.............. 10 years (at the recommended storage temperature stated on the label). 7. Therapeutic Exchange Plasma. ......do............... ......do.............. 10 years.Plasma Protein Fraction (Human).... 1 year................. ......do.............. (a) 5 years. (b) 3 years provided labeling recommends storage at room temperature, no warmer than 30 °C).Platelets.......................... Not applicable......... ......do.............. 72 hours from time of collection of source blood, provided labeling recommends storage at 20 to 24 °C or between 1 and 6 °C. 5 days if certain approved containers are used (20 to 24 °C).Pneumococcal Vaccine Polyvalent: 1. Final bulk powder........... ......do............... 24 months after Not applicable. potency assay (-20 °C or colder). 2. Final container............. ......do............... Not applicable........ 2 years (from date of manufacture).Poliovirus Vaccine Inactivated..... 1 year................. ......do.............. 1 year.Poliovirus Vaccine Live Oral Trivalent: 1. Frozen...................... Not applicable......... 1 year (-10 °C or 1 year, provided labeling colder). recommends storage at a temperature which will maintain ice continuously in a solid state. 2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling recommends storage between 2 and 8 °C and container has been unopened.Poliovirus Vaccine Live Oral Type I: 1. Frozen...................... ......do............... 1 year (-10 °C or 1 year, provided labeling colder). recommends storage at a temperature which will maintain ice continuously in a solid state. 2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling recommends storage between 2 and 8 °C and container has been unopened.Poliovirus Vaccine Live Oral Type II: 1. Frozen...................... ......do............... 1 year (-10 °C or 1 year, provided labeling colder). recommends storage at a temperature which will maintain ice continuously in a solid state. 2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling recommends storage between 2 and 8 °C and container has been unopened.Poliovirus Vaccine Live Oral Type III: 1. Frozen...................... ......do............... 1 year (-10 °C or 1 year, provided labeling colder). recommends storage at a temperature which will maintain ice continuously in a solid state. 2. Liquid...................... ......do............... Not applicable........ 30 days, provided labeling recommends storage between 2 and 8 °C and container has been unopened.Polyvalent bacterial antigens with 1 year................. ......do.............. 18 months. ``No U.S. Standard of Potency'' liquid.Polyvalent bacterial vaccines with ......do............... ......do.............. Do. ``No U.S. Standard of Potency'' liquid.Rabies Vaccine: 1. Dried....................... ......do............... 2 years............... Do. 2. Liquid...................... 3 months............... Not applicable........ 6 months.Reagent red blood cells............ Not applicable......... Not applicable........ Thirty-five days from earliest date of collection if kept in liquid form (indefinite storage of reagent red blood cell source material at -65 °C or colder).ACD Red Blood Cells................ ......do............... ......do.............. (a) 21 days from date of collection of source blood, provided labeling recommends storage between 1 and 6 °C and the hermetic seal is not broken during processing. (b) 24 hours after plasma removal, provided labeling recommends storage between 1 and 6 °C and the hermetic seal is broken during processing.CPD Red Blood Cells................ ......do............... ......do.............. (a) 21 days from date of collection of source blood, provided labeling recommends storage between 1 and 6 °C and the hermetic seal is not broken during processing. (b) 24 hours after plasma removal, provided labeling recommends storage between 1 and 6 °C and the hermetic seal is broken during processing.CPDA-1 Red Blood Cells............. ......do............... ......do.............. (a) 35 days from date of collection of source blood, provided labeling recommends storage between 1 and 6 °C and the hermetic seal is not broken during processing. (b) 24 hours after plasma removal, provided labeling recommends storage between 1 and 6 °C and the hermetic seal is broken during processing.Red Blood Cells Deglycerolized..... ......do............... ......do.............. 24 hours after removal from storage at -65 °C or colder, provided labeling recommends storage between 1 and 6 °C.Red Blood Cells Frozen............. ......do............... ......do.............. 3 years from date of collection of source blood, provided labeling recommends storage at -65 °C or colder.Rubella and Mumps Virus Vaccine ......do............... 1 year (-20 °C or 1 year. Live. colder).Rubella Virus Vaccine Live......... ......do............... ......do.............. Do.Skin Test Antigens for Cellular 6 months............... Not applicable........ Do. Hypersensitivity.Smallpox Vaccine: 1. Liquid...................... Not applicable......... 9 months (-10 °C 3 months, provided or colder, if product labeling recommends is maintained as storage at 0 °C or glycerinated or colder. equivalent vaccine in bulk or final containers). 2. Dried....................... 6 months............... Not applicable........ 18 months.Streptokinase...................... Not applicable......... ......do.............. Do.Tetanus and Diphtheria Toxoids 1 year................. ......do.............. 2 years. Adsorbed for Adult Use.Tetanus Antitoxin: 1. Liquid...................... ......do............... ......do.............. 5 years with an initial 20 percent excess or potency. 2. Dried....................... ......do............... 2 years............... 5 years with an initial 10 percent excess or potency.Tetanus Toxoid..................... ......do............... Not applicable........ 2 years.Tetanus Toxoid Adsorbed............ ......do............... ......do.............. Do.Thrombin........................... ......do............... 2 year................ 3 years.Thrombin Impregnated Pad........... Not applicable......... Not applicable........ 1 year, or 6 months at 20 to 24 °C.Tuberculin: 1. Purified Protein Derivative, 6 months............... ......do.............. 1 year. diluted. 2. Old or Purified Protein 1 year (not to exceed ......do.............. 2 years, provided labeling Derivative dried on multiple 30 °C; do not recommends storage at a puncture device. refrigerate). temperature not to exceed 30 °C. Do not refrigerate. 3. Old on multiple puncture ......do............... ......do.............. Do. device.Typhoid Vaccine.................... 1 year................. ......do.............. 18 months.ACD Whole Blood.................... Not applicable......... ......do.............. 21 days from date of collection, provided labeling recommends storage between 1 and 6 °C.CPD Whole Blood.................... ......do............... ......do.............. Do.CPDA-1 Whole Blood................. ......do............... ......do.............. 35 days from date of collection, provided labeling recommends storage between 1 and 6 °C.Heparin Whole Blood................ ......do............... ......do.............. 48 hours from date of collection, provided labeling recommends storage between 1 and 6 °C.Yellow Fever Vaccine............... ......do............... 1 year (-20 °C or 1 year, provided labeling colder). recommends storage at 5 °C or colder.----------------------------------------------------------------------------------------------------------------
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(d) Exemptions. Exemptions or modifications shall be made only upon written approval, in the form of a supplement to the biologics license application, issued by the Director, Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research.
[50 FR 4134, Jan. 29, 1985, as amended at 51 FR 15607, Apr. 25, 1986; 51 FR 19750, June 2, 1986; 52 FR 37450, Oct. 7, 1987; 53 FR 12764, Apr. 19, 1988; 62 FR 15110, Mar. 31, 1997; 64 FR 56453, Oct. 20, 1999; 70 FR 14985, Mar. 24, 2005]
Subpart G—Labeling Standards
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§ 610.60 Container label.
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(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.
[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.
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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.
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(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.
§ 610.63 Divided manufacturing responsibility to be shown.
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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.
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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.
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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.
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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]
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