(a) The term act means the Federal Food, Drug, and Cosmetic Act approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C. 301-392).

(b) Blood and blood product means a drug which consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma or serum, hereinafter referred to as “blood product.”

(c) Establishment means a place of business under one management at one general physical location. The term includes, among others, human blood and plasma donor centers, blood banks, transfusion services, other blood product manufacturers and independent laboratories that engage in quality control and testing for registered blood product establishments.

(d) Manufacture means the collection, preparation, processing or compatibility testing by chemical, physical, biological, or other procedures of any blood product which meets the definition of a drug as defined in section 201(g) of the act, and including manipulation, sampling, testing, or control procedures applied to the final product or to any part of the process. The term includes packaging, labeling, repackaging or otherwise changing the container, wrapper, or labeling of any blood product package in furtherance of the distribution of the blood product from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.

(e) Commercial distribution means any distribution of a blood product except pursuant to the investigational use provisions of part 312 of this chapter, but does not include internal or interplant transfer of a bulk product substance between registered domestic establishments within the same parent, subsidiary, and/or affiliate company.

(f) Any material change includes but is not limited to any change in the name of the blood product, in the quantity or identity of the active ingredient(s) or in the quantity or identity of the inactive ingredient(s) where quantitative listing of all ingredients is required pursuant to § 607.31(a)(2) and any significant change in the labeling of a blood product. Changes that are not significant include changes in arrangement or printing or changes of an editorial nature.

(g) Bulk product substance means any substance that is represented for use in a blood product and when used in the manufacturing of a blood product becomes an active ingredient or a finished dosage form of such product.

(h) Advertising and labeling include the promotional material described in § 202.1(l) (1) and (2) of this chapter, respectively.

(i) The definitions and interpretations contained in sections 201 and 510 of the act shall be applicable to such terms when used in this part 607.

(a) All owners or operators of establishments that engage in the manufacturing of blood products are required to register, pursuant to section 510 of the Federal Food, Drug, and Cosmetic Act. Registration and listing of blood products shall comply with this part. Registration does not permit any blood bank or similar establishment to ship blood products in interstate commerce.

(b) Forms for registration of an establishment are obtainable on request from the Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892 or at any of the Food and Drug Administration district offices.

(c) The completed form should be mailed to the Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892.

(a) Every foreign establishment shall comply with the blood product listing requirements contained in Subpart B of this part, unless exempt under Subpart D of this part, whether or not it is also registered.

(b) No blood product may be imported from a foreign establishment into the United States except a blood product imported or offered for import pursuant to the investigational use provisions of part 312 of this chapter, unless it is first the subject of a blood product listing as required in Subpart B of this part. The blood product listing information shall be in the English language.

(c) Foreign establishments shall submit, as part of the blood product listing, the name and address of the establishment and the name of the individual responsible for submitting blood product listing information. Any changes in this information shall be reported to the Food and Drug Administration at the intervals specified for updating blood product listing information in § 607.30(a).

The following classes of persons are exempt from registration and blood product listing in accordance with this part 607 under the provisions of section 510(g) (1), (2), and (3) of the act, or because the Commissioner has found, under section 510(g)(4), that such registration is not necessary for the protection of the public health.

(a) Pharmacies that are operating under applicable local laws regulating dispensing of prescription drugs and that are not manufacturing blood products for sale other than in the regular course of the practice of the profession of pharmacy including the business of dispensing and selling blood products at retail. The supplying by such pharmacies of blood products to a practitioner licensed to administer such blood products for his use in the course of his professional practice or to other pharmacies to meet temporary inventory shortages are not acts which require such pharmacies to register.

(b) Practitioners who are licensed by law to prescribe or administer drugs and who manufacture blood products solely for use in the course of their professional practice.

(c) Persons who manufacture blood products which are not for sale, rather, are solely for use in research, teaching, or analysis, including laboratory samples.

(d) Carriers, by reason of their receipt, carriage, holding, or delivery of blood products in the usual course of business as carriers.

(e) Persons who engage solely in the manufacture of in vitro diagnostic blood products and reagents not subject to licensing under section 351 of the Public Health Service Act (42 U.S.C. 262). This paragraph does not exempt such persons from registration and listing for medical devices required under part 807 of this chapter.

(f) Transfusion services which are a part of a facility approved for Medicare reimbursement and engaged in the compatibility testing and transfusion of blood and blood components, but which neither routinely collect nor process blood and blood components. The collection and processing of blood and blood components in an emergency situation as determined by a responsible person and documented in writing, therapeutic collection of blood or plasma, the preparation of recovered human plasma for further manufacturing use, or preparation of red blood cells for transfusion are not acts requiring such transfusion services to register.

(g) Clinical laboratories that are approved for Medicare reimbursement and are engaged in the testing of blood products in support of other registered blood establishments.

No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. Each applicable test shall be made on each lot after completion of all processes of manufacture which may affect compliance with the standard to which the test applies. The results of all tests performed shall be considered in determining whether or not the test results meet the test objective, except that a test result may be disregarded when it is established that the test is invalid due to causes unrelated to the product.

(a) General. Samples of any lot of any licensed product, except for radioactive biological products, 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. 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) Radioactive biological products. Samples of any lot of a radioactive biological product, as defined in § 600.3(ee) of this chapter, together with the protocols showing results of applicable tests, may at any time be required to be sent to the Food and Drug Administration for official release. Upon notification by the Director, Center for Drug Evaluation and Research, a manufacturer shall not distribute a lot of a radioactive biological product until the lot is released by the Director, Center for Drug Evaluation and Research: Provided, That the Director, Center for Drug Evaluation and Research shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.

Modification of any particular test method or manufacturing process or the conditions under which it is conducted as required in this part or in the additional standards for specific biological products in parts 620 through 680 of this chapter shall be permitted only under the following conditions:

(a) The applicant presents evidence, in the form of a license application, or a supplement to the application submitted in accordance with § 601.12(b) or (c), demonstrating that the modification will provide assurances of the safety, purity, potency, and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified in the general standards or additional standards for the biological product; and

(b) Approval of the modification is received in writing from the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter.

A 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 by the Director, Center for Biologics Evaluation and Research, 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 approved by the Director, Center for Biologics Evaluation and Research, 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) [Reserved]

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.

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, when deemed not necessary for the continued safety, purity, and potency of the product.

(2) Records. Appropriate records for residual moisture under paragraph (a)(1) of this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.

(b) Test for pyrogenic substances. Each lot of final containers of any product intended for use by injection shall be tested for pyrogenic substances by intravenous injection into rabbits as provided in paragraphs (b) (1) and (2) of this section: Provided, That notwithstanding any other provision of Subchapter F of this chapter, the test for pyrogenic substances is not required for the following products: Products containing formed blood elements; Cryoprecipitate; Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts; venoms; diagnostic substances and trivalent organic arsenicals.

(1) Test dose. The test dose for each rabbit shall be at least 3 milliliters per kilogram of body weight of the rabbit and also shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended, but need not exceed 10 milliliters per kilogram of body weight of the rabbit, except that: (i) Regardless of the human dose recommended, the test dose per kilogram of body weight of each rabbit shall be at least 1 milliliter for immune globulins derived from human blood; (ii) for Streptokinase, the test dose shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended.

(2) Test procedure, results, and interpretation; standards to be met. The test for pyrogenic substances shall be performed according to the requirements specified in United States Pharmacopeia XX.

(3) Retest. If the lot fails to meet the test requirements prescribed in paragraph (b)(2) of this section, the test may be repeated once using five other rabbits. The temperature rises recorded for all eight rabbits used in testing shall be included in determining whether the requirements are met. The lot meets the requirements for absence of pyrogens if not more than three of the eight rabbits show individual rises in temperature of 0.6 °C or more, and if the sum of the eight individual maximum temperature rises does not exceed 3.7 °C.

The contents of a final container of each filling of each lot shall be tested for identity after all labeling operations shall have been completed. The identity test shall be specific for each product in a manner that will adequately identify it as the product designated on final container and package labels and circulars, and distinguish it from any other product being processed in the same laboratory. Identity may be established either through the physical or chemical characteristics of the product, inspection by macroscopic or microscopic methods, specific cultural tests, or in vitro or in vivo immunological tests.

(a) Ingredients, preservatives, diluents, adjuvants. All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. Any preservative used shall be sufficiently nontoxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature. Products in multiple-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume in volume (v/v) glycerin. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:

(1) 0.85 milligrams if determined by assay;

(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or

(3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research.

(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.

Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids.

Licensed products may not be combined with other licensed products either therapeutic, prophylactic or diagnostic, except as a license is obtained for the combined product. Licensed products may not be combined with nonlicensable therapeutic, prophylactic, or diagnostic substances except as a license is obtained for such combination.

(a) Storage and maintenance. Cultures used in the manufacture of products shall be stored in a secure and orderly manner, at a temperature and by a method that will retain the initial characteristics of the organisms and insure freedom from contamination and deterioration.

(b) Identity and verification. Each culture shall be clearly identified as to source strain. A complete identification of the strain shall be made for each new stock culture preparation. Primary and subsequent seed lots shall be identified by lot number and date of preparation. Periodic tests shall be performed as often as necessary to verify the integrity of the strain characteristics and freedom from extraneous organisms. Results of all periodic tests for verification of cultures and determination of freedom from extraneous organisms shall be recorded and retained.

(c) Cell lines used for manufacturing biological products—(1) General requirements. Cell lines used for manufacturing biological products shall be:

(i) Identified by history;

(ii) Described with respect to cytogenetic characteristics and tumorigenicity;

(iii) Characterized with respect to in vitro growth characteristics and life potential; and

(iv) Tested for the presence of detectable microbial agents.

(2) Tests. Tests that are necessary to assure the safety, purity, and potency of a product may be required by the Director, Center for Biologics Evaluation and Research.

(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.

The presence of Group A streptococcus organisms and derivatives of Group A streptococcus in Bacterial Vaccines and Bacterial Antigens with “No U.S. Standard of Potency” may induce dangerous tissue reactions in humans. Available data demonstrate that they are unsafe as ingredients in products for human use. Group A streptococcus organisms and derivatives of Group A streptococcus are prohibited from Bacterial Vaccines and Bacterial Antigens with “No U.S. Standard of Potency.” Any Bacterial Vaccine or Bacterial Antigen with “No U.S. Standard of Potency” containing Group A streptococcus organisms or derivatives of Group A streptococcus in interstate commerce is in violation of section 351 of the Public Health Service Act (42 U.S.C. 262).

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:

(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.

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.

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:

(a) Test sensitivity. Each donation of blood, plasma, or serum to be used in preparing a biological product shall be tested for the presence of hepatitis B surface antigen by a method of sufficient sensitivity to detect all sera labeled A, (A), B, (B), and C in the Reference Hepatitis B Surface Antigen Panel distributed by the Center for Biologics Evaluation and Research; except that, in emergency situations, a test method of sufficient sensitivity to detect all sera labeled A, (A), and B in the Reference Hepatitis B Surface Antigen Panel may be used and, in dire emergency situations, blood and blood products may be issued without any HB8 Ag testing, provided that a test otherwise required by this paragraph is performed as soon as possible after issuance of the blood and blood product.

(b) Procedures. Only Antibody to Hepatitis B Surface Antigen licensed under this subchapter shall be used in performing the test and the test method(s) used shall be that for which the antibody product is specifically designed to be effective as recommended by the manufacturer in the package insert. The sample of blood, plasma, or serum to be tested shall have been taken from the donor at the time of donation of that unit. The test need not be performed on the day of the withdrawal of the sample. If the radioimmunoassay method is used, it must be performed in one of the following ways:

(1) The complete test is performed at the collection facility.

(2) The test is performed at the collection facility up to the point of counting the radioactivity of the samples, which counting, thereafter, is performed at another facility by personnel from the collection facility or by personnel from the counting facility.

(3) The complete test is performed by the personnel at an establishment licensed to manufacture blood or blood derivatives under section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)), or by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the establishment or the clinical laboratory is qualified to perform radioimmunoassay testing for the presence of hepatitis B surface antigen.

(4) Except as provided in this paragraph (b)(4), a collection facility shall not ship any blood product as a biological product or ship such a blood product where it is intended for use in manufacturing a biological product until the test for hepatitis B surface antigen is completed and the written test results are received by the collection facility. Notwithstanding the provisions of § 610.1 of this chapter, in the case of an emergency, or as otherwise approved in writing by the Director, Center for Biologics Evaluation and Research, a collection facility may ship a blood product before the test for hepatitis B surface antigen is completed. To obtain approval for such shipments, the collection facility shall submit a description of the control procedures to be used by both the collection facility and the manufacturing facility to the Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892. The control procedures to be used by the collection facility and the manufacturing facility shall include, but may not be limited to, a system of communicating the test results to the manufacturing facility, use of specific labeling warnings for the product to ensure that persons handling the shipment know that it may be infectious, procedures for quarantine of the untested or incompletely tested product both at the collection facility and at the manufacturing facility, and a procedure at the manufacturing facility to identify, preclude use of, and dispose of any blood product that is received and later found to be reactive for hepatitis B surface antigen.

(c) Materials in storage. All blood, plasma, or serum in storage which has not been tested for the presence of the hepatitis B surface antigen shall be tested as required in paragraphs (a) and (b) of this section before use as a biological product, or before use in the manufacture of a biological product. All blood, plasma, or serum in storage which has been tested for the presence of the hepatitis B surface antigen by a method of second generation sensitivity may be used as a biological product or in manufacture of a biological product, provided it is used on or before March 15, 1976.

(d) Restrictions on use. Blood, plasma, or serum that is reactive when tested for hepatitis B surface antigen or that was collected from a donor known to be reactive for hepatitis B surface antigen shall not be used in manufacturing biological products except as provided in paragraphs (d) (1) and (2) of this section.

(1) Injectable biological products and licensed in vitro diagnostic biological products. Blood, plasma, or serum that is reactive when tested for hepatitis B surface antigen or that was collected from a donor known to be reactive for hepatitis B surface antigen may be used in manufacturing hepatitis B vaccine and licensed in vitro diagnostic biological products if all of the following conditions are met:

(i) The final product cannot be prepared from blood, plasma, or serum that is nonreactive when tested for hepatitis B surface antigen, due either to the nature or to the scarcity of the final product.

(ii) The label of the source blood, plasma, or serum conspicuously states either that it is reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source blood, plasma, or serum was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.

(iii) The package label of the licensed in vitro diagnostic biological product prepared from such blood, plasma, or serum states conspicuously that either the product was prepared from source material that was reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source material was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.

(iv) The package label of the licensed injectable biological product prepared from such blood, plasma, or serum states that the product has been inactivated.

(v) The Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda MD 20892, is notified in writing at the time of the shipment, or in the case of repetitive shipments, or April 1 and October 1 of each year, of each shipment of source blood, plasma, or serum for manufacture into hepatitis B vaccine or into a licensed in vitro diagnostic biological product. Such shipments shall not be subject to the requirements of paragraph (b)(3) of this section. Each notification shall identify the kind and amount of source material shipped, the name and address of the consignee, the date of shipment, and the manner in which the source material is labeled.

(2) Unlicensed in vitro diagnostic biological products. Blood, plasma, or serum that is reactive when tested for hepatitis B surface antigen or that was collected from a donor known to be reactive for hepatitis B surface antigen may be used in manufacturing unlicensed in vitro diagnostic biological products including clinical chemistry control reagents if all of the following conditions are met:

(i) The final product cannot be prepared from blood, plasma, or serum that is nonreactive when tested for hepatitis B surface antigen, due either to the nature or to the scarcity of the final product.

(ii) The label of the source blood, plasma, or serum states conspicuously that either it is reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source blood, plasma, or serum was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.

(iii) The manufacturer of the source blood, plasma, or serum obtains written assurance from the manufacturer(s) of the final unlicensed product that package labels of all unlicensed products will conspicuously state, as required by § 809.10(a)(4) of this chapter, that the product was prepared from blood, plasma, or serum that was reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source material was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.

(iv) At the time of shipment, the Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, is notified in writing of each shipment of source blood, plasma, or serum signifying the kind and the amount of source material shipped, the name and address of the consignee, the date of shipment, and the manner in which such source material was labeled. Such shipments shall not be subject to the requirements of paragraph (b)(3) of this section.

(e) Manufacturing responsibility. When the radioimmunoassay method for hepatitis B surface antigen testing is performed by personnel other than those of the facility collecting the blood, plasma, or serum, as provided in paragraph (b) of this section, it shall not be considered as divided manufacturing as described in § 610.63, provided the following conditions are met:

(1) The collecting facility has obtained a written agreement that the testing laboratory will permit authorized representatives of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(2) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

(f) The information collection requirements in paragraph (d) of this section were approved by the Office of Management and Budget and assigned OMB control number 0910-0136.

(a) Testing requirements. (1) Each donation of human blood or blood components intended for use in preparing a product shall be tested for antibody to HIV by a test approved for such use by FDA, except as otherwise approved in writing by FDA. When the test for antibody to HIV is required, blood and blood products may be issued before the results of the test for antibody to HIV are available only in dire emergency situations or as otherwise approved in writing by FDA and, provided the test required by this paragraph is performed as soon as possible after issuance of the blood or blood product.

(2) Tests approved by FDA for the screening of blood and blood components for evidence of HIV may only be used in place of a test for antibody to HIV to satisfy the requirements of this section and related sections if so specified by FDA.

(b) Testing responsibility. The test for antibody to HIV shall be performed by the collection facility, by personnel of an establishment licensed to manufacture blood or blood derivatives under section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)), or by a clinical laboratory which meets the standards of the Clinical Laboratory Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the establishment or clinical laboratory is qualified to perform the test.

(c) Restrictions on use. (1) Blood, plasma, or other blood components that are repeatably reactive to a test for antibody to HIV or that were collected from a donor whose blood is known to be repeatably reactive to a test for antibody to HIV, shall not be shipped or used to prepare any product, including products not subject to licensure; except that such blood and blood components shall be shipped or used only for purposes and under conditions specifically approved in writing by FDA.

(2) The restrictions on use contained in this paragraph shall not apply in the following cases:

(i) Blood and blood components testing repeatably reactive or from a donor whose blood is known to be repeatably reactive that are shown to be negative for evidence of HIV infection by a method or process approved for such use by FDA;

(ii) The distribution of blood, plasma, or serum samples, except when intended for use in the manufacture of a product;

(iii) The in-house use of blood and blood components for research purposes; or

(iv) The distribution of blood and blood components for research purposes, if not distributed by sale, barter, or exchange.

(d) For a donor whose test results for antibody to HIV are repeatedly reactive or otherwise determined to be unsuitable when tested in accordance with paragraph (a) of this section, the blood establishment shall comply, as applicable, with §§ 610.46 and 610.47.

(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.

(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.

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.

(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.

(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.

(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: “Caution: Federal law prohibits dispensing without prescription,” for prescription biologicals.

(7) If a Medication Guide is required under part 208 of this chapter, the statement required under § 208.24(d) of this chapter instructing the authorized dispenser to provide a Medication Guide to each patient to whom the drug is dispensed and stating how the Medication Guide is provided, except where the container label is too small, the required statement may be placed on the package label.

(b) Package label information. If the container is not enclosed in a package, all the items required for a package label shall appear on the container label.

(c) Partial label. If the container is capable of bearing only a partial label, the container shall show as a minimum the name (expressed either as the proper or common name), the lot number or other lot identification and the name of the manufacturer; in addition, for multiple dose containers, the recommended individual dose. Containers bearing partial labels shall be placed in a package which bears all the items required for a package label.

(d) No container label. If the container is incapable of bearing any label, the items required for a container label may be omitted, provided the container is placed in a package which bears all the items required for a package label.

(e) Visual inspection. When the label has been affixed to the container a sufficient area of the container shall remain uncovered for its full length or circumference to permit inspection of the contents.

The following items shall appear on the label affixed to each package containing a product:

(a) The proper name of the product;

(b) The name, address, and license number of manufacturer;

(c) The lot number or other lot identification;

(d) The expiration date;

(e) The preservative used and its concentration, or if no preservative is used and the absence of a preservative is a safety factor, the words “no preservative”;

(f) The number of containers, if more than one;

(g) The amount of product in the container expressed as (1) the number of doses, (2) volume, (3) units of potency, (4) weight, (5) equivalent volume (for dried product to be reconstituted), or (6) such combination of the foregoing as needed for an accurate description of the contents, whichever is applicable;

(h) The recommended storage temperature;

(i) The words “Shake Well”, “Do not Freeze” or the equivalent, as well as other instructions, when indicated by the character of the product;

(j) The recommended individual dose if the enclosed container(s) is a multiple-dose container;

(k) The route of administration recommended, or reference to such directions in an enclosed circular;

(l) Known sensitizing substances, or reference to an enclosed circular containing appropriate information;

(m) The type and calculated amount of antibiotics added during manufacture;

(n) The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;

(o) The adjuvant, if present;

(p) The source of the product when a factor in safe administration;

(q) The identity of each microorganism used in manufacture, and, where applicable, the production medium and the method of inactivation, or reference to an enclosed circular containing appropriate information;

(r) Minimum potency of product expressed in terms of official standard of potency or, if potency is a factor and no U.S. standard of potency has been prescribed, the words “No U.S. standard of potency.”

(s) The statement: “Caution: Federal law prohibits dispensing without prescription,” for prescription biologicals.

(a) Position. The proper name of the product on the package label shall be placed above any trademark or trade name identifying the product and symmetrically arranged with respect to other printing on the label.

(b) Prominence. The point size and typeface of the proper name shall be at least as prominent as the point size and typeface used in designating the trademark and trade name. The contrast in color value between the proper name and the background shall be at least as great as the color value between the trademark and trade name and the background. Typography, layout, contrast, and other printing features shall not be used in a manner that will affect adversely the prominence of the proper name.

(c) Legible type. All items required to be on the container label and package label shall be in legible type. “Legible type” is type of a size and character which can be read with ease when held in a good light and with normal vision.

If two or more licensed manufacturers participate in the manufacture of a biological product, the name, address, and license number of each must appear on the package label, and on the label of the container if capable of bearing a full label.

The name and address of the distributor of a product may appear on the label provided that the name, address, and license number of the manufacturer also appears on the label and the name of the distributor is qualified by one of the following phrases: “Manufactured for _____”, “Distributed by ______”, “Manufactured by _____ for _____”, “Manufactured for _____ by ____”, “Distributor: _____”, or “Marketed by _____”. The qualifying phrases may be abbreviated.

Labels on packages or containers of products for export may be adapted to meet specific requirements of the regulations of the country to which the product is to be exported provided that in all such cases the minimum label requirements prescribed in § 610.60 are observed.

The proper name of this product shall be Whole Blood. Whole Blood is defined as blood collected from human donors for transfusion to human recipients.

(a) Manufacturing responsibility. All manufacturing of Whole Blood, including donor examination, blood collection, laboratory tests, labeling, storage and issue, shall be done under the supervision and control of the same licensed establishment except that the Director, Center for Biologics Evaluation and Research, may approve arrangements, upon joint request of two or more licensed establishments, which he finds are of such a nature as to assure compliance otherwise with the provisions of this subchapter.

(b) Final container. The original blood container shall be the final container and shall not be entered prior to issue for any purpose except for blood collection. Such container shall be uncolored and transparent to permit visual inspection of the contents and any closure shall be such as will maintain an hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents under customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, or potency of the blood.

(c) Reissue of blood. Blood that has been removed from storage controlled by a licensed establishment shall not be reissued by a licensed establishment unless the following conditions are observed:

(1) The container has a tamper-proof seal when originally issued and this seal remains unbroken;

(2) A segment is properly attached and has not been removed, except that blood lacking a properly attached segment may be reissued in an emergency provided it is accompanied by instructions for sampling and for use within 6 hours after entering the container for sampling;

(3) The blood has been stored continuously at 1 to 6 °C and shipped between 1 and 10 °C;

(4) The blood is held for observation until a significant inspection consistent with the requirements of § 640.5(e) can be made.

(d) Issue prior to determination of test results. Notwithstanding the provisions of § 610.1 of this chapter, blood may be issued by the manufacturer on the request of a physician, hospital, or other medical facility before results of all tests prescribed in § 640.5, the test for hepatitis B surface antigen prescribed in § 610.40(a) of this chapter, and a test for antibody to Human Immunodeficiency Virus (HIV) prescribed in § 610.45(a) of this chapter have been completed, where such issue is essential to allow time for transportation to ensure arrival of the blood by the time it is needed for transfusion: Provided, That (1) the blood is shipped directly to such physician or medical facility, (2) the records of the manufacturer contain a full explanation of the need for such issue, and (3) the label on each container of such blood bears the information required by § 606.121(h) of this chapter.

(a) Method of determining. The suitability of a donor as a source of Whole Blood shall be determined by a qualified physician or by persons under his supervision and trained in determining suitability. Such determination shall be made on the day of collection from the donor by means of medical history, a test for hemoglobin level, and such physical examination as appears necessary to a physician who shall be present on the premises when examinations are made, except that the suitability of donors may be determined when a physician is not present on the premises, provided the establishment (1) maintains on the premises, and files with the Center for Biologics Evaluation and Research, a manual of standard procedures and methods, approved by the Director of the Center for Biologics Evaluation and Research, that shall be followed by employees who determine suitability of donors, and (2) maintains records indicating the name and qualifications of the person immediately in charge of the employees who determine the suitability of donors when a physician is not present on the premises.

(b) Qualifications of donor; general. Except as provided in paragraph (f) of this section and for autologous donations, a person may not serve as a source of Whole Blood more than once in 8 weeks. In addition, donors shall be in good health, as indicated in part by:

(1) Normal temperature;

(2) Demonstration that systolic and diastolic blood pressures are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of this section;

(3) For allogeneic donors, a blood hemoglobin level which shall be demonstrated to be no less than 12.5 grams (g) of hemoglobin per 100 milliliters (mL) of blood; or a hematocrit value of 38 percent, and for autologous donors, a blood hemoglobin level which shall be demonstrated to be no less than 11.0 g of hemoglobin per 100 mL of blood or a hematocrit value of 33 percent.

(4) Freedom from acute respiratory diseases;

(5) Freedom from any infectious skin disease at the site of phlebotomy and from any such disease generalized to such an extent as to create a risk of contamination of the blood;

(6) Freedom from any disease transmissible by blood transfusion, insofar as can be determined by history and examinations indicated above; and

(7) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics.

(c) Additional qualifications of donor; viral hepatitis. No individual shall be used as a source of Whole Blood if he has—

(1) A history of viral hepatitis;

(2) A history of close contact within 12 months of donation with an individual having viral hepatitis;

(3) A history of having received within 12 months of donation, human blood or any derivative of human blood which the Food and Drug Administration has advised the blood establishment is a possible source of viral hepatitis.

(d) Therapeutic bleedings. Blood withdrawn in order to promote the health of a donor otherwise qualified under the provisions of this section, shall not be used as a source of Whole Blood unless the container label conspicuously indicates the donor's disease that necessitated withdrawal of blood.

(e) [Reserved]

(f) Qualifications; donations within less than 8 weeks. A person may serve as a source of Whole Blood more than once in 8 weeks only if at the time of donation the person is examined and certified by a physician to be in good health, as indicated in part in paragraph (b) of this section.

(a) Supervision. Blood shall be drawn from the donor by a qualified physician or under his supervision by assistants trained in the procedure. A physician shall be present on the premises when blood is being collected, except that blood may be collected when a physician is not present on the premises, provided the establishment (1) maintains on the premises, and files with the Center for Biologics Evaluation and Research, a manual of standard procedures and methods, approved by the Director of the Center for Biologics Evaluation and Research, that shall be followed by employees who collect blood, and (2) maintains records indicating the name and qualifications of the person immediately in charge of the employees who collect blood when a physician is not present on the premises.

(b) The donor center. The pertinent requirements of §§ 600.10 and 600.11 of this chapter shall apply at both the blood establishment and at any other place where the bleeding is performed.

(c) Blood containers. Blood containers and donor sets shall be pyrogen-free, sterile and identified by lot number. The amount of anticoagulant required for the quantity of blood to be collected shall be in the blood container when it is sterilized. In addition, all container and donor set surfaces that come in contact with blood used in the processing of Heparin Whole Blood shall be water repellent.

(d) The anticoagulant solution. The anticoagulant solution shall be sterile and pyrogen-free. Anticoagulant solutions shall be compounded and used according to a formula approved by the Director, Center for Biologics Evaluation and Research.

(e) Donor identification. Each unit of blood shall be so marked or identified by number or other symbol as to relate it to the individual donor whose identity shall be established to the extent necessary for compliance with § 640.3.

(f) Prevention of contamination of the blood. The skin of the donor at the site of phlebotomy shall be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. The blood shall be collected by aseptic methods in a sterile system which may be closed or may be vented if the vent protects the blood against contamination.

(g) Pilot samples for laboratory tests. Pilot samples for laboratory tests shall meet the following standards:

(1) One or more pilot samples shall be provided with each unit of blood when issued or reissued except as provided in § 640.2(c)(2) and all pilot samples shall be from the donor who is the source of the unit of blood.

(2) All samples for laboratory tests performed by the manufacturer and all pilot samples accompanying a unit of blood shall be collected at the time of filling the final container by the person who collects the unit of blood.

(3) All containers for all samples shall bear the donor's identification before collecting the samples.

(4) All containers for pilot samples accompanying a unit of blood shall be attached to the whole blood container before blood collection in a tamperproof manner that will conspicuously indicate removal and reattachment.

(5) When CPDA-1 is used, pilot samples for compatibility testing shall contain blood mixed with CPDA-1.

(h) Storage. Immediately after collection, unless the blood is to be used as a source for Platelets, it shall be placed in storage at a temperature between 1 and 6 °C unless it must be transported from the donor clinic to the processing laboratory. In the latter case, the blood shall be placed in temporary storage having sufficient refrigeration capacity to cool the blood continuously toward a range between 1 and 6 °C until it arrives at the processing laboratory, where it shall be stored at a temperature between 1 and 6 °C. Blood from which Platelets is to be prepared shall be held in an environment maintained at a temperature range 20 to 24 °C until the platelets are separated. The red blood cells shall be placed in storage at a temperature between 1 and 6 °C immediately after the platelets are separated.

All laboratory tests shall be made on a pilot sample specimen of blood taken from the donor at the time of collecting the unit of blood, and these tests shall include the following:

(a) Serological test for syphilis. Whole Blood shall be negative to a serological test for syphilis.

(b) Determination of blood group. Each container of Whole Blood shall be classified as to ABO blood group. At least two blood group tests shall be made and the unit shall not be issued until grouping tests by different methods or with different lots of antiserums are in agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed under, or that otherwise meet the requirements of, the regulations of this subchapter shall be used, and the technique used shall be that for which the serum is specifically designed to be effective.

(c) Determination of the Rh factors. Each container of Whole Blood shall be classified as to Rh type on the basis of tests done on the pilot sample. The label shall indicate the extent of typing and the results of all tests performed. If the test, using Anti-D Blood Grouping Reagent, is positive, the container may be labeled “Rh Positive”. If this test is negative, the results shall be confirmed by further testing which may include tests for the Rho variant (Du) and for other Rh-Hr factors. Blood may be labeled “Rh Negative” if negative to tests for the Rho (D) and Rho variant (Du) factors. If the test using Anti-D Blood Grouping Reagent is negative, but not tested for the Rho variant (Du), the label must indicate that this test was not done. Only Anti-Rh Blood Grouping Reagents licensed under, or that otherwise meet the requirements of, the regulations of this subchapter shall be used, and the technique used shall be that for which the serum is specifically designed to be effective.

(d) Sterility test. Whole Blood intended for transfusion shall not be tested for sterility by a method that entails entering the final container before the blood is used for transfusion.

(e) Inspection. Whole Blood shall be inspected visually during storage and immediately prior to issue. If the color or physical appearance is abnormal or there is any indication or suspicion of microbial contamination the unit of Whole Blood shall not be issued for transfusion.

(f) Test for antibody to HIV. Whole Blood shall be tested for antibody to HIV as prescribed in § 610.45 of this chapter.

Upon approval by the Director, Center for Biologics Evaluation and Research, of a supplement to the biologics license application for Whole Blood a manufacturer may prepare Whole Blood from which the antihemophilic factor has been removed, provided the Whole Blood meets the applicable requirements of this subchapter and the following conditions are met:

(a) The antihemophilic factor shall be removed in accordance with paragraphs (a), (b), and (c) of § 640.52.

(b) Although the closed system between the red blood cells and plasma shall be maintained, the red blood cells shall be maintained between 1 and 6° C at all times, including that time when the plasma is being frozen for removal of the antihemophilic factor.

(a) Proper name and definition. The proper name of this product shall be Platelets. The product is defined as platelets collected from one unit of blood and resuspended in an appropriate volume of original plasma, as prescribed in § 640.24(d).

(b) Source. The source material for Platelets shall be plasma which may be obtained by whole blood collection, by plasmapheresis, or by plateletpheresis.

(a) Whole blood donors shall meet the criteria for suitability prescribed in § 640.3.

(b) Plasmapheresis donors shall meet the criteria for suitability prescribed in § 640.63, excluding the phrase “other than malaria” in paragraph (c)(9). Informed consent shall be required as prescribed in § 640.61.

(c) Plateletpheresis donors shall meet criteria for suitability as described in a biologics license application or a supplement to the biologics license application, and must have the written approval of the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

(a) Whole blood used as the source of Platelets shall be collected as prescribed in § 640.4.

(b) If plasmapheresis is used, the procedure for collection shall be prescribed in §§ 640.62, 640.64 (except paragraph (c)(3)), and 640.65.

(c) If plateletpheresis is used, the procedure for collection shall be as described in a biologics license application or a supplement to a biologics license application, and must have the written approval of the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

(d) The phlebotomy shall be performed by a single uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's tissue.

(a) Blood from which plasma is separated for the preparation of Platelets shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).

(b) The tests shall be performed on a sample of blood collected at the time of collecting the source blood, and such sample container shall be labeled with the donor's number before the container is filled.

(a) Separation of plasma and platelets and resuspension of the platelets shall be in a closed system. Platelets shall not be pooled during processing.

(b) Immediately after collection, the whole blood or plasma shall be held in storage between 20 and 24 °C, unless it must be transported from the donor clinic to the processing laboratory. During such transport, all reasonable methods shall be used to maintain the temperature as close as possible to a range between 20 and 24 °C until it arrives at the processing laboratory where it shall be held between 20 and 24 °C until the platelets are separated. The platelet concentrate shall be separated within 4 hours after the collection of the unit of whole blood or plasma.

(c) The time and speed of centrifugation must have been demonstrated to produce an unclumped product, without visible hemolysis, that yields a count of not less than 5.5×10 1 0 platelets per unit in at least 75 percent of the units tested.

(d) The volume of original plasma used for resuspension of the platelets shall be determined by the maintenance of a pH of not less than 6.0 during the storage period. The pH shall be measured on a sample of platelets which has been stored for the maximum dating period at the selected storage temperature. One of the following storage temperatures shall be used continuously:

(1) 20 to 24 °C.

(2) 1 to 6 °C.

(e) Final containers used for Platelets shall be colorless and transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents, under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, or efficacy of the product. At the time of filling, the final container shall be marked or identified by number so as to relate it to the donor.

(a) Storage. Immediately after resuspension, Platelets shall be placed in storage at the selected temperature range. If stored at 20 to 24 °C, a continuous gentle agitation of the platelet concentrate shall be maintained throughout the storage period. Agitation is optional if stored at a temperature between 1 and 6 °C.

(b) Quality control testing. Each month four units prepared from different donors shall be tested at the end of the storage period as follows:

(1) Platelet count.

(2) pH of not less than 6.0 measured at the storage temperature of the unit.

(3) Measurement of actual plasma volume.

(4) If the results of the quality control testing indicate that the product does not meet the prescribed requirements, immediate corrective action shall be taken and a record maintained of such action.

(c) Manufacturing responsibility. All manufacturing of Platelets shall be performed at the same licensed establishment, except that the quality control testing under paragraph (b) of this section may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a) and is qualified to perform platelet counts. Such arrangements must be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be considered as divided manufacturing, as described in § 610.63 of this chapter, provided the following conditions are met:

(1) The results of each test are received within 10 days of the preparation of the platelet concentrate, and are maintained by the establishment licensed for Platelets so that they may be reviewed by an authorized representative of the Food and Drug Administration.

(2) The licensed Platelets manufacturer has obtained a written agreement that the testing laboratory will permit an authorized representative of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

The use of the plateletpheresis procedure to obtain a product for a specific recipient may be at variance with §§ 640.21(c) and 640.22(c): Provided, That: (a) A licensed physician has determined that the recipient must be transfused with the platelets from a specific donor, and (b) the plateletpheresis procedure is performed under the supervision of a qualified licensed physician who is aware of the health status of the donor and the physician has certified in writing that the donor's health permits plateletpheresis.

(a) Proper name and definition. The proper name of this product shall be Plasma. The product is defined as the fluid portion of one unit of human blood intended for intravenous use which in a closed system, has been collected, stabilized against clotting, and separated from the red blood cells.

(b) Source. (1) Plasma shall be obtained by separating plasma from blood collected from blood donors or by plasmapheresis.

(2) Plasma may be obtained from a unit of Whole Blood collected by another licensed establishment.

(a) Whole blood donors shall meet the criteria for donor suitability prescribed in § 640.3.

(b) Plasmapheresis donors shall meet the criteria for donor suitability prescribed in § 640.63, excluding the phrase “other than malaria” in paragraph (c)(9) of that section. Informed consent shall be required as prescribed in § 640.61.

(a) Whole blood shall be collected, transported, and stored as prescribed in § 640.4. When whole blood is intended for Plasma, Fresh Frozen Plasma, and Liquid Plasma, it shall be maintained at a temperature between 1 and 6 °C until the plasma is removed. Whole blood intended for Platelet Rich Plasma, shall be maintained as prescribed in § 640.24 until the plasma is removed. The red blood cells shall be placed in storage at a temperature between 1 and 6 °C immediately after the plasma is separated.

(b) Plasma obtained by plasmapheresis shall be collected as prescribed in §§ 640.62, 640.64 (except that paragraph (c)(3) of § 640.64 shall not apply), and § 640.65.

(a) Blood from which plasma is separated shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).

(b) Manufacturers of Plasma collected by plasmapheresis shall have testing and recordkeeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.

(a) Plasma. Plasma shall be separated from the red blood cells within 26 days after phlebotomy (within 40 days after phlebotomy when CPDA-1 solution is used as the anticoagulant), and shall be stored at -18 °C or colder within 6 hours after transfer to the final container, unless the product is to be stored as Liquid Plasma.

(b) Fresh Frozen Plasma. Fresh Frozen Plasma shall be prepared from blood collected by a single uninterrupted venipuncture with minimal damage to and minimal manipulation of the donor's tissue. The plasma shall be separated from the red blood cells, frozen solid within 6 hours after phlebotomy and stored at -18 °C or colder.

(c) Liquid Plasma. Liquid Plasma shall be separated from the red blood cells within 26 days after phlebotomy (within 40 days after phlebotomy when CPDA-1 solution is used as the anticoagulant), and shall be stored at a temperature of 1 to 6 °C within 4 hours after filling the final container.

(d) Platelet Rich Plasma. Platelet Rich Plasma shall be prepared from blood collected by a single uninterrupted venipuncture with minimal damage to and manipulation of the donor's tissue. The plasma shall be separated from the red blood cells by centrifugation within 4 hours after phlebotomy. The time and speed of centrifugation shall have been shown to produce a product with at least 250,000 platelets per microliter. The plasma shall be stored at a temperature between 20 to 24 °C or between 1 and 6 °C, immediately after filling the final container. A gentle and continuous agitation of the product shall be maintained throughout the storage period, if stored at a temperature of 20 to 24 °C.

(e) Modifications of Plasma. It is possible to separate Platelets and/or Cryoprecipitated AHF from Plasma. When these components are to be separated, the plasma shall be collected as described in § 640.32 for Plasma.

(1) Platelets shall be separated as prescribed in subpart C of part 640, prior to freezing the plasma. The remaining plasma may be labeled as Fresh Frozen Plasma, if frozen solid within 6 hours after phlebotomy.

(2) Cryoprecipitated AHF shall be removed as prescribed in subpart F of part 640. The remaining plasma shall be labeled “Plasma, Cryoprecipitate Reduced.”

(3) Plasma remaining after both Platelets and Cryoprecipitated AHF have been removed may be labeled “Plasma, Cryoprecipitate Reduced.”

(f) The final container. (1) The final container shall have no color added to the plastic and shall be transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents.

(2) The final container material shall not interact with the contents, under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, and effectiveness of the product.

(3) Prior to filling, the final container shall be identified by number so as to relate it to the donor.

(g) The final product. (1) The final product shall be inspected immediately after separation of the plasma and shall not be issued for transfusion if there is (i) any abnormality in color or physical appearance, or (ii) any indication of contamination.

(2) With the exception of Platelet Rich Plasma and Liquid Plasma the final product shall be inspected for evidence of thawing or breakage at the time of issuance, however, the containers need not be stored in a manner that shows evidence of thawing if records of continuous monitoring of the storage temperature establish that the temperature remained at -18 °C or colder. If continuous monitoring of the product is not available, the final product shall be stored in a manner that will show evidence of thawing and shall not be issued if there is any evidence of thawing.

(3) No preservative shall be added to the final product.

(a) Proper name and definition. The proper name of this product shall be Cryoprecipitated AHF. The product is defined as a preparation of antihemophilic factor, which is obtained from a single unit of plasma collected and processed in a closed system.

(b) Source. The source material for Cryoprecipitated AHF shall be plasma which may be obtained by whole blood collection or by plasmapheresis.

(a) Whole blood donors shall meet the criteria for suitability prescribed in § 640.3.

(b) Plasmaphersis donors shall meet the criteria for suitability prescribed in § 640.63, excluding the phrase “other than malaria” in paragraph (c) (9) of that section. Informed consent shall be required as prescribed in § 640.61.

(a) Whole blood used as a source of Cryoprecipitated AHF shall be collected as prescribed in § 640.4. Whole blood from which both Platelets and Cryoprecipitated AHF is derived shall be maintained as required under § 640.24 until the platelets are removed.

(b) If plasmapheresis is used, the procedure for collection shall be as prescribed in §§ 640.62, 640.64 (except that paragraph (c)(3) of that section shall not apply), and 640.65.

(a) Blood from which plasma is separated for the preparation of Cryoprecipitated AHF shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).

(b) The tests shall be performed on a sample of blood collected at the time of collecting the source blood, and such sample container shall be labeled with the donor's number before the container is filled.

(c) Manufacturers of Cryoprecipitated AHF obtained from plasma collected by plasmapheresis shall have testing and record-keeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.

(a) Processing the plasma. (1) The plasma shall be separated from the red blood cells by centrifugation to obtain essentially cell-free plasma.

(2) The plasma shall be frozen solid within 6 hours after blood collection. A combination of dry ice and organic solvent may be used for freezing: Provided, That the procedure has been shown not to cause the solvent to penetrate the container or leach plasticizer from the container into the plasma.

(3) Immediately after separation and freezing of the plasma, the plasma shall be stored and maintained at −18 °C or colder until thawing of the plasma for further processing to remove the Cryoprecipitated AHF.

(b) Processing the final product. (1) The Cryoprecipitated AHF shall be separated from the plasma by a procedure that has been shown to produce an average of no less than 80 units of antihemophilic factor per final container.

(2) No diluent shall be added to the product by the manufacturer prior to freezing.

(3) The final container used for Cryoprecipitated AHF shall be colorless and transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents under customary conditions of storage and use in such a manner as to have an adverse effect upon the safety, purity, potency and effectiveness of the product. At the time of filling, the final container shall be identified by a number so as to relate it to the donor.

A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may be obtained from the Center for Biologics Evaluation and Research, Food and Drug Administration, for use in the preparation of a working reference to be employed in a quality control potency test of Cryoprecipitated AHF.

(a) Quality control tests for potency of antihemophilic factor shall be conducted each month on at least four representative containers of Cryoprecipitated AHF.

(b) The results of each test are received by the establishment licensed for Cryoprecipitated AHF within 30 days of the preparation of the cryoprecipitated antihemophilic factor and are maintained at that establishment so that they may be reviewed by an authorized representative of the Food and Drug Administration.

(c) The quality control test for potency may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a) and is qualified to perform potency tests for antihemophilic factor. Such arrangements must be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be considered as divided manufacturing, as described in § 610.63 of this chapter, provided the following conditions are met:

(1) The establishment licensed for Cryoprecipitated AHF has obtained a written agreement that the testing laboratory will permit an authorized representative of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(2) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

(d) If the average potency level of antihemophilic factor in the containers tested is less than 80 units of antihemophilic factor per container, immediate corrective actions shall be taken and a record maintained of such action.

The proper name of the product shall be Source Plasma. The product is defined as the fluid portion of human blood collected by plasmapheresis and intended as source material for further manufacturing use. The definition excludes single donor plasma products intended for intravenous use.

The written consent of a prospective donor shall be obtained after a qualified licensed physician has explained the hazards of the procedure to the prospective donor. The explanation shall include the risks of a hemolytic transfusion reaction if he is given the cells of another donor, and the hazards involved if he is hyperimmunized. The explanation shall consist of such disclosure and be made in such a manner that intelligent and informed consent be given and that a clear opportunity to refuse is presented.

(a) Method of determining. The suitability of a donor for Source Plasma shall be determined by a qualified licensed physician or by persons under his supervision and trained in determining donor suitability. Such determination shall be made on the day of collection from the donor by means of a medical history, tests, and such physical examination as appears necessary to the qualified licensed physician.

(b) Initial medical examinations. (1) Each donor shall be examined by a qualified licensed physician on the day of the first donation or no more than 1 week before the first donation and at subsequent intervals of no longer than 1 year.

(2)(i) A donor who is to be immunized for the production of high-titer plasma shall be examined by a qualified licensed physician. The medical examination shall be performed within no more than 1 week before the first immunization injection. The medical examination for plasmapheresis need not be repeated, if the first donation occurs within 3 weeks after the first injection.

(ii) A donor who is an active participant in a plasmapheresis program, and has been examined in accordance with paragraph (b)(1) of this section, need not be reexamined before immunization for the production of high-titer plasma.

(3) Each donor shall be certified to be in good health by the examining physician. The certification of good health shall be on a form supplied by the licensed establishment and shall indicate that the certification applies to the suitability of the individual to be a plasmapheresis donor and, when applicable, an immunized donor.

(c) Qualification of donor. Donors shall be in good health on the day of donation, as indicated in part by:

(1) Normal temperature;

(2) Demonstration that systolic and diastolic blood pressures are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of this section;

(3) A blood hemoglobin level of no less than 12.5 grams of hemoglobin per 100 milliliters of blood or a hematocrit level of 38 percent;

(4) A normal pulse rate;

(5) A total serum or total plasma protein of no less than 6.0 grams per 100 milliliters of blood;

(6) Weight, which shall be at least 110 pounds;

(7) Freedom from acute respiratory diseases;

(8) Freedom from any infectious skin disease at the site of phlebotomy and from any such disease generalized to such an extent as to create a risk of contamination of the plasma;

(9) Freedom from any disease, other than malaria, transmissible by blood transfusion, insofar as can be determined by history and examinations indicated in this section;

(10) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics;

(11) Freedom from a history of viral hepatitis;

(12) Freedom from a history of close contact within 12 months of donation with an individual having viral hepatitis;

(13) Freedom from a history of having received, within 12 months, human blood or any derivative of human blood which the Food and Drug Administration has advised the blood establishment is a possible source of viral hepatitis, except for specific immunization performed in accordance with § 640.66.

(d) General. Any donor who, in the opinion of the interviewer, appears to be under the influence of any drug, alcohol, or for any reason does not appear to be providing reliable answers to medical history questions, shall not be considered a suitable donor.

(e) Failure to return red blood cells. Any donor who has not had the red blood cells returned from a unit of blood collected during a plasmapheresis procedure or who has been a donor of a unit of whole blood shall not be subjected to plasmapheresis for a period of 8 weeks, unless:

(1) The donor has been examined by a qualified licensed physician and certified by the physician to be acceptable for further plasmapheresis before expiration of the 8-week period;

(2) The donor possesses an antibody that is (i) transitory, (ii) of a highly unusual or infrequent specificity, or (iii) of an unusually high titer; and

(3) The special characteristics of the antibody and the need for plasmapheresing the donor are documented.

(a) Supervision. All blood for the collection of Source Plasma shall be drawn from the donor by a qualified licensed physician or by persons under his supervision trained in the procedure.

(b) Blood containers. Blood containers and donor sets shall be pyrogen-free, sterile and identified by lot number. The amount of anticoagulant required for the quantity of blood to be collected shall be in the blood container when it is sterilized.

(c) The anticoagulant solution. The anticoagulant solution shall be sterile and pyrogen-free. One of the following formulas shall be used in the indicated volumes, except that a different formula may be used for plasma for manufacture into noninjectable products if prior written approval is obtained from the Director of the Center for Biologics Evaluation and Research at the time of licensing or in the form of a supplement to the biologics license application for Source Plasma.

(1) Anticoagulant citrate dextrose solution (ACD).

(2) Anticoagulant citrate phosphate dextrose solution (CPD).

(3) Anticoagulant sodium citrate solution.

(d) Donor identification. Each unit of blood and plasma shall be so marked or identified by number or other symbol so as to relate it directly to the donor.

(e) Prevention of contamination of the blood and plasma. The skin of the donor at the site of phlebotomy shall be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. The blood shall be collected, the plasma separated, and the cells returned to the donor by aseptic methods in a sterile system which may be closed, or may be vented if the vent protects the blood cells and plasma against contamination.

(a) Procedure-general. The plasmapheresis procedure is a procedure in which, during a single visit to the establishment, blood is removed from a donor, the plasma separated from the formed elements, and at least the red blood cells returned to the donor. This procedure shall be described in detail in the biologics license application.

(b) Procedures-specific requirements. The plasmapheresis procedure shall meet the following requirements:

(1)(i) A sample of blood shall be drawn from each donor on the day of the first medical examination or plasmapheresis, whichever comes first and at least every 4 months thereafter by a qualified licensed physician or by persons under his supervision and trained in such procedure. A serologic test for syphilis, a total plasma or serum protein determination, and a plasma or serum protein electrophoresis or quantitative immuno-diffusion test or an equivalent test to determine immunoglobulin composition of the plasma or serum shall be performed on the sample.

(ii) A repeat donor who does not return for plasmapheresis at the time the 4-month sample is due to be collected may be plasmapheresed on the day he appears: Provided, That no longer than 6 months has elapsed since the last sample was collected, and the physician on the premises approves the plasmapheresis procedure and so indicates by signing the donor's record before such procedure is performed. The sample for the 4-month tests shall be collected on the day of the donor's return.

(iii) A repeat donor from whom the plasmapheresis center is unable to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of this section for a total period exceeding 6 months shall be processed as a new donor.

(2)(i) The accumulated laboratory data, including tracings, if any, of the plasma or serum protein electrophoresis pattern, the calculated values of each component, and the collection records shall be reviewed by a qualified licensed physician within 21 days after the sample is drawn to determine whether or not the donor may continue in the program. The review shall be signed by the reviewing physician. If the protein composition is not within normal limits established by the testing laboratory, or if the total protein is less than 6.0 grams per 100 milliliters of samples, the donor shall be removed from the program until these values return to normal.

(ii) A donor with a reactive serologic test for syphilis shall not be plasmapheresed again until the donor's serum is tested and found to be nonreactive to a serologic test for syphilis, except as provided in paragraph (b)(2) (iii) and (iv) of this section.

(iii) A donor whose serum is determined to have a biologic false-positive reaction to a serologic test for syphilis may be plasmapheresed: Provided, That the donor's file identifies the serologic test for syphilis and results used to confirm the biologic false-positive reaction and indicates that the physician on the premises has determined the false-positive reaction is not the result of an underlying disorder that would disqualify the donor from participation in the plasmapheresis program. If the serologic test for syphilis is performed at a facility other than the plasmapheresis center, all applicable provisions of § 640.71 shall be met.

(iv) A donor with a reactive serologic test for syphilis may be plasmapheresed only to obtain plasma to be used for further manufacturing into control serum for the serologic test for syphilis: Provided, That the physician on the premises approves the donation, the donor's file contains a signed statement from a physician or clinic establishing that treatment for syphilis has been initiated and that continuance in the plasmapheresis program will not interfere with or jeopardize the treatment of the syphilitic donor.

(3) A donor identification system shall be established that positively identifies each donor and relates such donor directly to his blood and its components as well as to his accumulated records and laboratory data. Such system shall include either a photograph of each donor which shall be used on each visit to confirm the donor's identity, or some other method that provides equal or greater assurance of positively identifying the donor.

(4) The amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure or in any 2-day period shall not exceed 1,000 milliliters unless the donor's weight is 175 pounds or greater, in which case the amount of whole blood, not including anticoagulant, removed from the donor during a manual plasmapheresis procedure or in any 2-day period shall not exceed 1,200 milliliters.

(5) The amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure within a 7-day period shall not exceed 2,000 milliliters unless the donor's weight is 175 pounds or greater, in which case the amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure within a 7-day period shall not exceed 2,400 milliliters.

(6) No more than 500 milliliters of whole blood shall be removed from a donor at one time, unless the donor's weight is 175 pounds or greater, in which case no more than 600 milliliters of whole blood shall be removed from the donor at one time.

(7) The plasma shall be separated from the red blood cells immediately after blood collection. The maximum feasible volume of red blood cells shall be returned to the donor before another unit is collected.

(8) The volume of plasma collected during an automated plasmapheresis collection procedure shall be consistent with the volumes specifically approved by the Director, Center for Biologics Evaluation and Research, and collection shall not occur less than 2 days apart or more frequently than twice in a 7-day period.

If specific immunization of a donor is to be performed, the selection and scheduling of the injection of the antigen, and the evaluation of each donor's clinical response, shall be by a qualified licensed physician or physicians. The administration of the antigen may be performed by a licensed physician or a trained person under his supervision. Any material used for immunization shall be either a product licensed under section 351 of the Public Health Service Act for such purpose or one specifically approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Immunization procedures shall be on file at each plasmapheresis center where immunizations are performed.

(a) Hepatitis B surface antigen. Each unit of Source Plasma shall be nonreactive to a test for hepatitis B surface antigen as prescribed in §§ 610.40 and 610.41 of this chapter, except insofar as permitted in § 610.40(d)(1) and (d)(2) of this chapter.

(b) Antibody to HIV. Each unit of Source Plasma shall be negative by a test for antibody to HIV as prescribed in § 610.45 of this chapter, except as provided in § 610.45(c) of this chapter.

(a) Sterile system. All administration and transfer sets inserted into blood containers used for processing Source Plasma intended for manufacturing into injectable or noninjectable products and all interior surfaces of plasma containers used for processing Source Plasma intended for manufacturing into injectable products shall be sterile, pyrogen-free, nontoxic, and compatible with the contents under normal conditions of use. Only Sodium Chloride Injection USP shall be used as a red blood cell diluent. If the method of separation of the plasma intended for injectable products involves a system in which an airway must be inserted into the plasma container, the airway shall be sterile and constructed so as to exclude microorganisms and maintain a sterile system.

(b) Final containers. Final containers used for Source Plasma, whether integrally attached or separated from the original blood container, shall not be entered prior to issuance for any purpose except for filling with the plasma. Such containers shall be uncolored and hermetically sealed, and shall permit clear visibility of the contents. Final containers and their components shall not interact with the plasma contents under conditions of storage and use so as to alter the safety, quality, purity, or potency of the plasma and shall provide adequate protection against external factors that may cause deterioration or contamination. Prior to filling, the final container shall be marked or identified by number or other symbol which will relate it directly to the donor.

(c) Preservative. Source Plasma shall not contain a preservative.

(a) Pooling. Two units of Source Plasma from the same donor may be pooled if such units are collected during one plasmapheresis procedure: Provided, That the pooling is done by a procedure that does not introduce a risk of contamination of the red blood cells and, for plasma intended for injectable products, gives maximum assurance of a sterile container of plasma.

(1) The pooling of plasma from two or more donors is not permitted in the manufacture of Source Plasma intended for manufacturing into injectable products.

(2) The pooling of plasma from two or more donors by the manufacturer of Source Plasma intended for manufacturing into noninjectable products is permitted: Provided, That the plasma from two or more donors is pooled after the plasma has been removed from the red blood cells, and after the red blood cell containers are sealed.

(b) Storage. Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than −20 °C, except for plasma collected as provided in § 640.74. Plasma intended for manufacturing into noninjectable products may be stored at temperatures appropriate for the intended use of the final product, provided these temperatures are included in the Source Plasma license application.

(c) Inspection. Source Plasma intended for manufacturing into injectable products shall be inspected for evidence of thawing at the time of issuance, except that inspection of individual plasma containers need not be made if the records of continuous monitoring of the storage temperature establish that the temperature remained at −20 °C or colder. If there is evidence that the storage temperature has not been maintained at −20 °C or colder, the plasma may be relabeled and issued as provided in § 640.76(a).

(d) Samples. If samples are provided, they shall meet the following standards:

(1) Prior to filling, all samples shall be marked or identified so as to relate them directly to the donor of that unit of plasma.

(2) All samples shall be filled at the time the final product is prepared by the person who prepares the final product.

(3) All samples shall be representative of the contents of the final product or be collected from the donor at the time of filling the collection container.

(4) All samples shall be collected in a manner that does not contaminate the contents of the final container.

(a) In addition to the labeling requirements of § 610.62 of this chapter, and in lieu of the requirements in §§ 606.121, 610.60, and 610.61 of this chapter, the following information shall appear on the label affixed to each container of Source Plasma:

(1) The proper name of the product.

(2) The statement “Caution: For Manufacturing Use Only” for products intended for further manufacturing into injectable products, or the statement, “Caution: For Use In Manufacturing Noninjectable Products Only”, for products intended for further manufacturing into noninjectable products. The statement shall follow the proper name in the same size and type of print as the proper name.

(3) The statement “Store at −20 °C or colder”: Provided, That where plasma is intended for manufacturing into noninjectable products, this statement may be omitted if replaced by a statement of the temperature appropriate for the final product to be prepared from the plasma.

(4) The total volume or weight of plasma and total quantity and type of anticoagulant used.

(5) The donor number or individual bleed number, or both. If plasma is pooled from two or more donors, either all donor numbers, all bleed numbers, or a pool number that is traceable to each individual unit comprising the pool.

(6) The expiration date of the plasma. If plasma intended for manufacturing into noninjectable products is pooled from two or more donors the expiration date is determined from the collection date of the oldest unit in the pool, and the pooling records shall show the collection date for each unit constituting the pool.

(7) A statement as to whether the plasma was collected from normal donors or from immunized donors. In the case of immunized donors, the label shall state the immunizing antigen.

(8) The test for hepatitis B surface antigen used for the results, or the statement “Nonreactive for HBs Ag by FDA required test”.

(9) When plasma collected from a donor is reactive for the serologic test for syphilis, a statement that the plasma is reactive and must be used only for the manufacturing of positive control reagents for the serologic test for syphilis.

(10) Name, address, and license number of the manufacturer.

(11) The statement “Negative by a test for antibody to HIV”, or equivalent statement.

(b) Source Plasma diverted for Source Plasma Salvaged shall be relabeled “Source Plasma Salvaged” as prescribed in § 640.76. Immediately following the proper name of the product, the labeling shall conspicuously state as applicable, “STORAGE TEMPERATURE EXCEEDED −20 °C” or “SHIPPING TEMPERATURE EXCEEDED −5 °C”.

(a) All steps in the manufacturing of Source Plasma, including donor examination, blood collection, plasmapheresis, laboratory testing, labeling, storage, and issuing shall be performed by personnel of the establishment licensed to manufacture Source Plasma, except that the following tests may be performed by personnel of an establishment licensed for blood and blood derivatives under section 351(a) of the Public Health Service Act, or by a clinical laboratory that meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42 U.S.C. 263a): Provided, The establishment or clinical laboratory is qualified to perform the assigned test(s).

(1) The test for hepatitis B surface antigen.

(2) The total plasma or serum protein and the quantitative test for plasma or serum proteins or for immunoglobulins.

(3) The serologic test for syphilis.

(4) A test for antibody to HIV.

(b) Such testing shall not be considered divided manufacturing, which requires two biologics licenses for Source Plasma: Provided, That

(1) The results of such tests are maintained by the licensed manufacturer of the Source Plasma whereby such results may be reviewed by a licensed physician as required in § 640.65(b)(2) of this chapter and by an authorized representative of the Food and Drug Administration.

(2) The Source Plasma manufacturer has obtained a written agreement that the testing laboratory will permit authorized representatives of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.

(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.

(a) In addition to the recordkeeping requirements of this subchapter, the following records shall be maintained:

(1) Documentation shall be available to ensure that the shipping temperature requirements of § 600.15 of this title and of § 640.74(b)(2) are being met for Source Plasma intended for manufacture into injectable products.

(2) For each donor, a separate and complete record of all initial and periodic examinations, tests, laboratory data, interviews, etc., undertaken pursuant to §§ 640.63, 640.65, 640.66, and 640.67, except that negative test results for hepatitis B surface antigen, negative test results for antibody to HIV, and the volume or weight of plasma withdrawn from a donor need not be kept on the individual donor record: Provided, That such information is maintained on the premises of the plasmapheresis center where the donor's plasma has been collected.

(3) The original or a clear copy of the donor's written consent for participation in the plasmapheresis program or for immunization.

(4) The certification of the donor's good health as prescribed in § 640.63(b)(3).

(5) If plasma that is reactive to a serologic test for syphilis is issued as prescribed in § 640.65(b)(2)(iv), the distribution records shall indicate by number those units that are reactive.

(b) Each donor record must be directly cross-referenced to the unit(s) of Source Plasma associated with the donor.

(c) If a repeat donor is rejected or a donor's plasma is found unsuitable, the donor's record shall contain a full explanation for the rejection.

(d) If a donor has a reaction while on the plasmapheresis premises, or a donor reaction is reported to the center after the donor has left the premises, the donor's record shall contain a full explanation of the reaction, including the measures taken to assist the donor and the outcome of the incident.

If a donor has a fatal reaction which, in any way, may be associated with plasmapheresis the Director of the Center for Biologics Evaluation and Research shall be notified by telephone as soon as possible. If the facility is located outside of the continental United States, notification by cable or telegram shall be acceptable.

(a) Upon approval by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, of a supplement to the biologics license application for Source Plasma, a manufacturer may prepare Source Plasma as a liquid product for a licensed blood derivative manufacturer who has indicated a need for a liquid product.

(b) Source Plasma Liquid shall meet all standards of the frozen Source Plasma except:

(1) Source Plasma Liquid shall be stored in nonleachable containers so that the containers and their components will not interact with the plasma contents under conditions of storage and use so as to alter the safety, quality, purity, or potency of the plasma and shall provide adequate protection against external factors that may cause deterioration or contamination.

(2) Source Plasma Liquid shall be shipped, stored and labeled for storage at a temperature of 10 °C or colder. An exception to the shipping or storage temperature shall be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, based upon his receipt of substantial evidence to support another temperature. Such evidence may be submitted by either the licensed manufacturer of the Source Plasma Liquid or the manufacturer of the final blood derivative product who has requested the Source Plasma Liquid.

(3) The label for the Source Plasma Liquid shall be easily distinguished from that of the frozen product. Color coding shall not be used for this purpose.

(4) The label affixed to each container of Source Plasma Liquid shall contain, in addition to the information required by § 640.70(a) but excluding § 640.70(a)(3), the name of the manufacturer of the final blood derivative product for whom it was prepared.

(5) Source Plasma Liquid shall be inspected immediately prior to issuance. If the color or physical appearance is abnormal, or there is any indication or suspicion of microbial contamination, the unit of Source Plasma Liquid shall not be issued.

(a) Storage temperature. (1) Except as provided in paragraph (a)(2) of this section, Source Plasma intended for manufacture into injectable products that is inadvertently exposed (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to a storage temperature warmer than −20 °C and colder than +10 °C may be issued only if labeled as “Source Plasma Salvaged.” The label shall be revised before issuance, and appropriate records shall be maintained identifying the units involved, describing their disposition, and explaining fully the conditions that caused the inadvertent temperature exposure.

(2) Source Plasma intended for manufacture into injectable products that is exposed inadvertently (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to one episode of storage temperature fluctuation that is warmer than −20 °C and colder than −5 °C for not more than 72 hours is exempt from the labeling requirements of paragraph (a)(1) of this section, provided that the plasma has been and remains frozen solid. Appropriate records shall be maintained identifying the units involved, describing their disposition, explaining fully the conditions that caused the inadvertent temperature exposure, and documenting that the episode of temperature elevation did not exceed 72 hours, that the temperature did not rise to warmer than −5 °C in storage, and that the plasma remained frozen solid throughout the period of elevated temperature. When requested, copies of the records shall be provided to the plasma derivative manufacturer.

(b) Shipping temperature. If Source Plasma for manufacture into injectable products is exposed inadvertently (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to a shipping temperature warmer than −5 °C and colder than +10 °C, the plasma derivative manufacturer shall label it “Source Plasma Salvaged.” Appropriate records shall be maintained identifying the units involved, describing their disposition, and explaining fully the conditions that caused the inadvertent temperature exposure.

(c) Relabeling. If Source Plasma is required to be relabeled as “Source Plasma Salvaged” under paragraph (a)(1) or (b) of this section, the person responsible for the relabeling shall cover the original label with either (1) a complete new label containing the appropriate information or (2) a partial label affixed to the original label and containing the appropriate new information, which covers the incorrect information regarding storage temperature.

(a) Proper name and definition. The proper name of the product shall be Albumin (Human). The product is defined as a sterile solution of the albumin derived from human plasma.

(b) Source material. The source material of Albumin (Human) shall be plasma recovered from Whole Blood prepared as prescribed in §§ 640.1 through 640.5, or Source Plasma prepared as prescribed in §§ 640.60 through 640.76.

(c) Additives in source material. Source material shall not contain an additive unless it is shown that the processing method yields a final product free of the additive to such extent that the continued safety, purity, potency, and effectiveness of the final product will not be adversely affected.

Tests shall be performed on the final product to determine that it meets the following standards:

(a) Protein concentration. Final product shall conform to one of the following concentrations: 4.0±0.25 percent; 5.0±0.30 percent; 20.0±1.2 percent; and 25.0±1.5 percent solution of protein.

(b) Protein composition. At least 96 percent of the total protein in the final product shall be albumin, as determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

(c) pH. The pH shall be 6.9±0.5 when measured in a solution of the final product diluted to a concentration of 1 percent protein with 0.15 molar sodium chloride.

(d) Sodium concentration. The sodium concentration of the final product shall be 130 to 160 milliequivalents per liter.

(e) Potassium concentration. The potassium concentration of the final product shall not exceed 2 milliequivalents per liter.

(f) Heat stability. A final container sample of Albumin (Human) shall remain unchanged, as determined by visual inspection, after heating at 57 °C for 50 hours, when compared to its control consisting of a sample, from the same lot, which has not undergone this heating.

(a) Preservative. The final product shall not contain a preservative.

(b) Storage of bulk solution. After all processing steps have been completed, the sterile bulk solution shall be stored in a manner that will ensure the continued sterility of the product, and at a temperature that shall not exceed the recommended storage temperature of the final product prescribed in § 610.53 of this chapter.

In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter, the container and package labels shall contain the following information:

(a) The osmotic equivalent in terms of plasma, and the sodium concentration in terms of a value or a range in milliequivalents per liter;

(b) The cautionary statement placed in a prominent position on the label, “Do Not Use if Turbid. Do Not Begin Administration More Than 4 Hours After the Container Has Been Entered.”;

(c) The need for additional fluids when 20 percent or 25 percent albumin is administered to a patient with marked dehydration;

(d) The protein concentration, expressed as a 4 percent, 5 percent, 20 percent, or 25 percent solution.

(a) Proper name and definition. The proper name of the product shall be Plasma Protein Fraction (Human). The product is defined as a sterile solution of protein composed of albumin and globulin, derived from human plasma.

(b) Source material. The source material of Plasma Protein Fraction (Human) shall be plasma recovered from Whole Blood prepared as prescribed in §§ 640.1 through 640.5, or Source Plasma prepared as prescribed in §§ 640.60 through 640.76.

(c) Additives in source material. Source material shall not contain an additive unless it is shown that the processing method yields a final product free of the additive to such extent that the continued safety, purity, potency, and effectiveness of the final product will not be adversely affected.

(a) Date of manufacture. The date of manufacture shall be the date of final sterile filtration of a uniform pool of bulk solution.

(b) Processing method. The processing method shall not affect the integrity of the product, and shall have been shown to yield consistently a product which:

(1) After the heating prescribed in paragraph (e) of this section does not show an increase in the components with electrophoretic mobility similar to that of alpha globulin that amounts to more than 5 percent of the total protein.

(2) Contains less than 5 percent protein with a sedimentation coefficient greater than 7.0 S.

(3) Is safe for intravenous injection.

(c) Microbial contamination. All processing steps shall be conducted in a manner to minimize the risk of contamination from microorganisms, pyrogens, or other impurities. Preservatives to inhibit growth of microorganisms shall not be used during processing.

(d) Storage of bulk fraction. Bulk concentrate to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of −5 °C or colder. Any other bulk form of the product (exclusive of the sterile bulk solution) to be held more than 1 week prior to further processing, shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder. Any bulk fraction to be held one week or less prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder.

(e) Heat treatment. Heating of the final containers of Plasma Protein Fraction (Human) shall begin within 24 hours after completion of filling. Heat treatment shall be conducted so that the solution is heated continuously for not less than 10 or more than 11 hours at an attained temperature of 60±0.5 °C.

(f) Stabilizer. Either 0.08±0.016 millimole sodium caprylate, or 0.08±0.016 millimole sodium acetyltryptophanate and 0.08±0.016 millimole sodium caprylate per gram of protein shall be present as a stabilizer(s). Calculations of the stabilizer concentration may employ the labeled value 5 percent for the protein concentration of the product.

(g) Incubation. All final containers of Plasma Protein Fraction (Human) shall be incubated at 20 to 35 °C for at least 14 days following the heat treatment prescribed in paragraph (e) of this section. At the end of this incubation period, each final container shall be examined and all containers showing any indication of turbidity or microbial contamination shall not be issued. The contents of turbid final containers shall be examined microscopically and tested for sterility. If growth occurs, the types of organisms shall be identified as to genus and the material from such containers shall not be used for further manufacturing.

Tests shall be performed on the final product to determine that it meets the following standards:

(a) Protein concentration. The final product shall be a 5.0±0.30 percent solution of protein.

(b) Protein composition. The total protein in the final product shall consist of at least 83 percent albumin, and no more than 17 percent globulins. No more than 1 percent of the total protein shall be gamma globulin. The protein composition shall be determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.

(c) pH. The pH shall be 7.0±0.3 when measured in a solution of the final product diluted to a concentration of 1 percent protein with 0.15 molar sodium chloride.

(d) Sodium concentration. The sodium concentration of the final product shall be 130 to 160 milliequivalents per liter.

(e) Potassium concentration. The potassium concentration of the final product shall not exceed 2 milliequivalents per liter.

(f) Heat stability. A final container sample of Plasma Protein Fraction (Human) shall remain unchanged, as determined by visual inspection, after heating at 57 °C for 50 hours, when compared to its control consisting of a sample, from the same lot, which has not undergone this heating.

(a) Preservative. The final product shall not contain a preservative.

(b) Storage of bulk solution. After all processing steps have been completed, the sterile bulk solution shall be stored in a manner that will ensure the continued sterility of the product, and at a temperature that shall not exceed the recommended storage temperature of the final product prescribed in § 610.53 of this chapter.

In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter, the container and package labels shall contain the following information:

(a) The osmotic equivalent in terms of plasma, and the sodium concentration in terms of a value or a range in milliequivalents per liter.

(b) The cautionary statement placed in a prominent position on the label, “Do Not Use if Turbid. Do Not Begin Administration More than 4 Hours After the Container Has Been Entered.”

(a) The Director, Center for Biologics Evaluation and Research, may approve an exception or alternative to any requirement in subchapter F of chapter I of title 21 of the Code of Federal Regulations regarding blood, blood components, or blood products. Requests for such exceptions or alternatives shall ordinarily be in writing. Licensed establishments shall submit such requests in accordance with § 601.12 of this chapter. However, in limited circumstances, such requests may be made orally and permission may be given orally by the Director. Oral requests and approvals must be promptly followed by written requests and written approvals.

(b) FDA will publish a list of approved alternative procedures and exceptions periodically in the Federal Register.