PART 640—ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264. Source: 38 FR 32089, Nov. 20, 1973, unless otherwise noted. Cross References: For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111. Subpart A—Whole Blood § 640.1 Whole Blood. 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. [38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985] § 640.2 General requirements. (a) Manufacturing responsibility. (b) Blood container. (c) Reissue of blood. (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. [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42 FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR 116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 67 FR 9587, Mar. 4, 2002] § 640.4 Collection of the blood. (a) [Reserved] (b) The donor center. (c) Blood containers. (d) The anticoagulant solution. (e) Donor identification. (f) Prevention of contamination of the blood. (g) Samples and segments for laboratory tests. (1) One or more segments shall be provided with each unit of blood when issued or reissued except as provided in § 640.2(c)(2) and all segments 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 segments accompanying a unit of blood shall be collected at the time of filling the original blood container. (3) All containers for all samples shall bear the donor's identification before collecting the samples. (4) All segments 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) Segments for compatibility testing shall contain blood mixed with the appropriate anticoagulant. (h) Storage. [38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8, 2008; 80 FR 29904, May 22, 2015] § 640.5 Testing the blood. All laboratory tests shall be made on a specimen of blood taken from the donor, and these tests shall include the following: (a) [Reserved] (b) Determination of blood group. (c) Determination of the Rh factors. u (d) Sterility test. (e) Inspection. (f) Test for relevant transfusion-transmitted infections. [38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR 40889, Aug. 6, 2001; 80 FR 29904, May 22, 2015] § 640.6 Modifications of Whole Blood. 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. [38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999] Subpart B—Red Blood Cells § 640.10 Red Blood Cells. The proper name of this product shall be Red Blood Cells. The product is defined as red blood cells remaining after separating plasma from human blood. [38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985] § 640.11 General requirements. (a) Storage. (b) Inspection. [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42 FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985] § 640.12 Eligibility of donor. Establishments must determine the eligibility of donors of the source blood for Red Blood Cells in accordance with §§ 630.10 and 630.15 of this chapter. [80 FR 29904, May 22, 2015] § 640.13 Collection of the blood. (a) The source blood shall be collected as prescribed in § 640.4. (b) Source blood may also be derived from Whole Blood manufactured in accordance with applicable provisions of this subchapter. [38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999] § 640.14 Testing the blood. Blood from which Red Blood Cells are prepared shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (b) and (c). [53 FR 117, Jan. 5, 1988, as amended at 66 FR 31165, June 11, 2001; 80 FR 29904, May 22, 2015] § 640.15 Segments for testing. Segments collected in integral tubing shall meet the following standards: (a) One or more segments shall be provided with each unit of Whole Blood or Red Blood Cells when issued or reissued. (b) Before they are filled, all segments shall be marked or identified so as to relate them to the donor of that unit of red cells. (c) All segments accompanying a unit of Red Blood Cells shall be filled at the time the blood is collected or at the time the final product is prepared. [66 FR 40890, Aug. 6, 2001] § 640.16 Processing. (a) Separation. (b) Sterile system. (c) Final containers. [38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001] § 640.17 Modifications for specific products. Red Blood Cells Frozen: A cryophylactic substance may be added to the Red Blood Cells for extended manufacturers' storage at −65 °C or colder, provided the manufacturer submits data considered by the Director, Center for Biologics Evaluation and Research, as adequately demonstrating through in vivo cell survival and other appropriate tests that the addition of the substance, the materials used and the processing methods results in a final product that meets the required standards of safety, purity, and potency for Red Blood Cells, and that the frozen product will maintain those properties for the prescribed dating period. Section 640.11 (a) and (b) do not apply while a cryophylactic substance is present. [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998] Subpart C—Platelets § 640.20 Platelets. (a) Proper name and definition. (b) Source. [40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 72 FR 45887, Aug. 16, 2007] § 640.21 Eligibility of donors. (a) Establishments must determine the eligibility of donors of platelets derived from Whole Blood and donors of platelets collected by plateletpheresis in accordance with §§ 630.10 and 630.15 of this chapter, except as provided in this section. (b) A plateletpheresis donor must not serve as the source of platelets for transfusion if the donor has recently ingested a drug that adversely affects platelet function. (c) A Whole Blood donor must not serve as the source of platelets for transfusion if the donor has recently ingested a drug that adversely affects platelet function unless the unit is labeled to identify the ingested drug that adversely affects platelet function. (d) If you are collecting platelets by plateletpheresis, you must assess and monitor the donor's platelet count. (1) You must take adequate and appropriate steps to assure that the donor's platelet count is at least 150,000 platelets per microliter (/µL) before plateletpheresis begins. Exception: If you do not have records of a donor's platelet count from prior donations and you are not able to assess the donor's platelet count either prior to or immediately following the initiation of the collection procedure, you may collect platelets by plateletpheresis, but you must not collect 9.0 × 10 11 (2) You must defer from platelet donation a donor whose pre-donation platelet count is less than 150,000 platelets/µL until a subsequent pre-donation platelet count indicates that the donor's platelet count is at least 150,000 platelets/µL; and (3) You must take appropriate steps to assure that the donor's intended post-donation platelet count will be no less than 100,000 platelets/µL. (e) Frequency of plateletpheresis collection. (2) When you collect fewer than 6 × 10 11 (3) When you collect 6 × 10 11 (4) Exception. (f) Deferral of plateletpheresis donors due to red blood cell loss. (2) You must defer a donor from donating platelets for a period of 16 weeks if the donor donates two units of Red Blood Cells during a single apheresis procedure. (3) You must defer a donor for 8 weeks or more if the cumulative red blood cell loss in any 8 week period could adversely affect donor health. (g) The responsible physician must obtain the informed consent of a plateletpheresis donor on the first day of donation, and at subsequent intervals no longer than 1 year. (1) The responsible physician must explain the risks and hazards of the procedure to the donor; and (2) The explanation must be made in such a manner that the donor may give consent, and has a clear opportunity to refuse the procedure. [80 FR 29904, May 22, 2015] § 640.22 Collection of source material. (a) Whole blood used as the source of Platelets shall be collected as prescribed in § 640.4. (b) [Reserved] (c) If plateletpheresis is used, the procedure for collection must be as prescribed in §§ 640.21, 640.64 (except paragraph (c)), and 640.65, or as described in an approved biologics license application (BLA) or an approved supplement to a BLA. (d) The phlebotomy shall be performed by a single uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's tissue. [40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 72 FR 45887, Aug. 16, 2007; 80 FR 29904, May 22, 2015] § 640.23 Testing the blood. (a) Blood from which plasma is separated for the preparation of Platelets shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (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. [40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 80 FR 29904, May 22, 2015] § 640.24 Processing. (a) Separation of plasma and platelets and resuspension of the platelets must be in a closed system. Platelets must not be pooled during processing unless the platelets are pooled as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluation and Research. (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 collection center 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 or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system. (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 10 (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 6.2 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. [40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47 FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8, 2008] § 640.25 General requirements. (a) Storage. (b) Quality control testing. (1) Platelet count. (2) pH of not less than 6.2 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. (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. [40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 66 FR 1836, Jan. 10, 2001; 72 FR 45888, Aug. 16, 2007] Subpart D—Plasma § 640.30 Plasma. (a) Proper name and definition. (1) The fluid portion of one unit of human blood intended for intravenous use which is collected in a closed system, stabilized against clotting, and separated from the red cells; or (2) The fluid portion of human blood intended for intravenous use which is prepared by apheresis methods as specified in the directions for use for the blood collecting, processing, and storage system including closed and open systems. (b) Source. (2) Plasma may be obtained from a unit of Whole Blood collected by another licensed establishment. [42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 50 FR 4139, Jan. 29, 1985; 72 FR 45888, Aug. 16, 2007] § 640.31 Eligibility of donors. (a) Whole Blood donors must meet the criteria for donor eligibility prescribed in §§ 630.10 and 630.15 of this chapter. (b) Collection establishments must determine the eligibility of plasmapheresis donors in accordance with §§ 630.10 and 630.15 of this chapter. [80 FR 29904, May 22, 2015] § 640.32 Collection of source material. (a) Whole Blood must be collected, transported, and stored as prescribed in § 640.4. When whole blood is intended for Plasma, Fresh Frozen Plasma, and Liquid Plasma, until the plasma is removed, the whole blood must be maintained at a temperature between 1 and 6 °C or as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluations and Research. Whole blood intended for Platelet Rich Plasma must be maintained as prescribed in § 640.24 until the plasma is removed. The red blood cells must 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 § 640.64 (except that paragraph (c)(3) of § 640.64 shall not apply), and § 640.65. [42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980; 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, Aug. 16, 2007; 80 FR 29905, May 22, 2015] § 640.33 Testing the blood. (a) Blood from which plasma is separated shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (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. [42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, May 22, 2015] § 640.34 Processing. (a) Plasma. (b) Fresh Frozen Plasma. (c) Liquid Plasma. (d) Platelet Rich Plasma. (e) Modifications of 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 within 6 hours after filling the final container or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system. (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. (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. (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. [42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4, 1978; 48 FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 FR 45888, Aug. 16, 2007] Subpart E [Reserved] Subpart F—Cryoprecipitate § 640.50 Cryoprecipitated AHF. (a) Proper name and definition. (b) Source. [42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 50 FR 4139, Jan. 29, 1985] § 640.51 Eligibility of donors. (a) Whole blood donors must meet the criteria for eligibility prescribed in §§ 630.10 and 630.15 of this chapter. (b) Collection establishments must determine the eligibility of plasmapheresis donors in accordance with §§ 630.10 and 630.15 of this chapter. [80 FR 29905, May 22, 2015] § 640.52 Collection of source material. (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 § 640.64 (except that paragraph (c)(3) of that section shall not apply), and 640.65. [42 FR 21774, Apr. 29, 1977, as amended at 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 80 FR 29905, May 22, 2015] § 640.53 Testing the blood. (a) Blood from which plasma is separated for the preparation of Cryoprecipitated AHF shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (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. [42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977; 42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, May 22, 2015] § 640.54 Processing. (a) Processing the plasma. (2) The plasma shall be placed in a freezer within 8 hours after blood collection or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system. A combination of dry ice and organic solvent may be used for freezing: Provided, (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. (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. [42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001] § 640.55 U.S. Standard preparation. A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may be obtained from the Center for Biologics Evaluation and Research, (HFM-407) (see mailing addresses in § 600.2 of this chapter) for use in the preparation of a working reference to be employed in a quality control potency test of Cryoprecipitated AHF. [42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005] § 640.56 Quality control test for potency. (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. [42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001] Subpart G—Source Plasma § 640.60 Source Plasma. 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. [41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985] § 640.64 Collection of blood for Source Plasma. (a) [Reserved] (b) Blood containers. (c) The anticoagulant solution. (d) Donor identification. (e) Prevention of contamination of the blood and plasma. [38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at 41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16, 2007; 80 FR 29905, May 22, 2015] § 640.65 Plasmapheresis. (a) Procedure-general. (b) Procedures-specific requirements. (1)(i) Except as provided under § 630.25 of this chapter, the responsible physician must draw a sample of blood from each donor on the day of the initial physical examination or plasmapheresis, whichever comes first, and at least every 4 months thereafter. 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, (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) Except as provided under § 630.25 of this chapter, the responsible physician must review the accumulated laboratory data, including any tracings of the plasma or serum protein electrophoresis pattern, the calculated values of the protein composition of each component, and the collection records within 14 calendar days after the sample is drawn to determine whether or not the donor should be deferred from further donation. If a determination is not made within 14 calendar days, the donor must be deferred pending such a determination. The responsible physician must sign the review. If the protein composition is not within normal limits established by the testing laboratory, or if the total protein level is less than 6.0 grams per deciliter or more than 9.0 grams per deciliter in a plasma sample or serum sample, the donor must be deferred from donation until the protein composition returns to acceptable levels. Reinstatement of the donor into the plasmapheresis program when the donor's protein composition values have returned to an acceptable level must first be approved by the responsible physician. (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, (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, (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. [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 64 FR 45373, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 80 FR 29905, May 22, 2015] § 640.66 Immunization of donors. If specific immunization of a donor is to be performed, the selection, scheduling and administration of the antigen, and the evaluation of each donor's clinical response, shall be by the responsible physician. 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. [38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 80 FR 29905, May 22, 2015] § 640.67 Laboratory tests. Each unit of Source Plasma shall be tested for evidence of infection due to relevant transfusion-transmitted infections as required under § 610.40 of this chapter. [66 FR 31165, June 11, 2001, as amended at 80 FR 29905, May 22, 2015] § 640.68 Processing. (a) Sterile system. (b) Final containers. (c) Preservative. [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 50 FR 4140, Jan. 29, 1985] § 640.69 General requirements. (a) Pooling. Provided, (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, (b) Storage. (c) Inspection. (d) Samples. (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. (e) Restrictions on distribution. (f) Hold. [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 45374, Aug. 19, 1999; 80 FR 29905, May 22, 2015] § 640.71 Manufacturing responsibility. (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 testing performed in accordance with § 610.40 of this chapter and § 640.65(b) 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, (b) Such testing shall not be considered divided manufacturing, which requires two biologics licenses for Source Plasma: Provided, (1) The results of such tests are maintained by the licensed manufacturer of the Source Plasma whereby such results may be reviewed by a responsible 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. [41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 66 FR 1837, Jan. 10, 2001; 80 FR 29905, May 22, 2015] § 640.72 Records. (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)(i) For each donor, establishments must maintain records including a separate and complete record of initial and periodic examinations, tests, laboratory data, and interviews, etc., as required in §§ 630.10 and 630.15 of this chapter and §§ 640.65, 640.66, and 640.67, except as provided in paragraph (a)(2)(ii) of this section. (ii) Negative results for testing for evidence of infection due to relevant transfusion-transmitted infections required in § 610.40 of this chapter, and the volume or weight of plasma withdrawn from a donor need not be recorded on the individual donor record if 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 or other durable record which may be electronic of the donor's consent for participation in the plasmapheresis program or for immunization. (4) Records of the medical history and physical examination of the donor conducted in accordance with § 630.15(b)(1) of this chapter and, where applicable, § 630.15(b)(5) of this chapter must document the eligibility of the donor as a plasmapheresis donor and, when applicable, as an immunized donor. (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. [41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4, 2002; 80 FR 29905, May 22, 2015] § 640.73 Reporting of fatal donor reactions. 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. [41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990] § 640.74 Modification of Source Plasma. (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 § 606.121 of this chapter, but excluding § 606.121(e)(5)(ii) of this chapter, 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. [38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56454, Oct. 20, 1999; 77 FR 18, Jan. 3, 2012] § 640.76 Products stored or shipped at unacceptable temperatures. (a) Storage temperature. (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. (c) Relabeling. [45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985] Subpart H—Albumin (Human) § 640.80 Albumin (Human). (a) Proper name and definition. (b) Source material. (c) Additives in source material. [42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, 1999] § 640.81 Processing. (a) Date of manufacture. (b) Processing method. (c) Microbial contamination. (d) Storage of bulk fraction. (e) Heat treatment. (f) Stabilizer. (g) Incubation. [42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000] § 640.82 Tests on final product. Tests shall be performed on the final product to determine that it meets the following standards: (a) Protein concentration. (b) Protein composition. (c) pH. (d) Sodium concentration. (e) Potassium concentration. (f) Heat stability. [42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14, 1999] § 640.83 General requirements. (a) Preservative. (b) Storage of bulk solution. [42 FR 27582, May 31, 1977] § 640.84 Labeling. 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. [42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64 FR 26286, May 14, 1999] Subpart I—Plasma Protein Fraction (Human) Source: 42 FR 27583, May 31, 1977, unless otherwise noted. § 640.90 Plasma Protein Fraction (Human). (a) Proper name and definition. (b) Source material. (c) Additives in source material. [42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999] § 640.91 Processing. (a) Date of manufacture. (b) Processing method. (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. (d) Storage of bulk fraction. (e) Heat treatment. (f) Stabilizer. (g) Incubation. [42 FR 27583, May 31, 1977, as amended at 64 FR 26286, May 14, 1999] § 640.92 Tests on final product. Tests shall be performed on the final product to determine that it meets the following standards: (a) Protein concentration. (b) Protein composition. (c) pH. (d) Sodium concentration. (e) Potassium concentration. (f) Heat stability. [42 FR 27583, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, May 14, 1999; 65 FR 13679, Mar. 14, 2000] § 640.93 General requirements. (a) Preservative. (b) Storage of bulk solution. § 640.94 Labeling. 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.” [42 FR 27583, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984; 64 FR 26286, May 14, 1999] Subpart J—Immune Globulin (Human) § 640.100 Immune Globulin (Human). (a) Proper name and definition. (b) Source material. (c) Additives in source material. [38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 64 FR 26287, May 14, 1999] § 640.101 General requirements. (a) Heat stability test. (b) pH. (c) Turbidity. (d) Date of manufacture. (e) Labeling. (1) There is no prescribed potency for viral hepatitis antibodies. (2) The product is not recommended for intravenous administration. [38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar. 29, 1983, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999] § 640.102 Manufacture of Immune Globulin (Human). (a) Processing method. (b) Microbial contamination. (c) Bulk storage. (d) Determination of the lot. (e) Sterilization and heating. [38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000] § 640.103 The final product. (a) Final solution. (b) Protein composition. [38 FR 32089, Nov. 20, 1973, as amended at 64 FR 26287, May 14, 1999] § 640.104 Potency. (a) Antibody levels and tests. (b) Minimum levels. (1) No less than 2 units of diphtheria antitoxin per ml. (2) A measles neutralizing antibody level that, when compared with that of a reference material designated by the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, as indicated in paragraph (c) of this section, demonstrates adequate potency. The Director, CBER, shall notify manufacturers when a new reference material will be used and will advise manufacturers of an appropriate antibody level taking into account a comparison of the new reference material to the previous reference material. (3) A poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody level that, when compared with that of a reference material designated by the Center for Biologics Evaluation and Research, Food and Drug Administration, as indicated in paragraph (c) of this section, demonstrates adequate potency. The Director, CBER, shall notify manufacturers when a new reference material will be used and will advise manufacturers of an appropriate antibody level taking into account a comparison of the new reference material to the previous reference material. (c) Reference materials. (1) Reference Immune Globulin for correlation of measles antibody titers. (2) Reference Immune Globulin for correlation of poliomyelitis antibody titers, Types 1, 2, and 3. [38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999] Subpart K [Reserved] Subpart L—Alternative Procedures § 640.120 Alternative procedures. (a) The Director, Center for Biologics Evaluation and Research, may issue 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. The Director may issue such an exception or alternative in response to: (1) A written request from an establishment. Licensed establishments must submit such requests in accordance with § 601.12 of this chapter; (2) An oral request from an establishment, if there are difficult circumstances and submission of a written request is not feasible. Establishments must follow up such oral request by submitting written requests under paragraph (a)(1) of this section within 5 working days. (b) To respond to a public health need, the Director may issue a notice of 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, if a variance under this section is necessary to assure that blood, blood components, or blood products will be available in a specified location or locations to address an urgent and immediate need for blood, blood components, or blood products or to provide for appropriate donor screening and testing. (c) If the Director issues such an exception or alternative orally, the Director will follow up by issuing a written notice of the exception or alternative. Periodically, FDA will provide a list of approved exceptions and alternative procedures on the FDA Center for Biologics Evaluation and Research Web site. [80 FR 29906, May 22, 2015] Subpart M—Definitions and Medical Supervision Source: 80 FR 29906, May 22, 2015, unless otherwise noted. § 640.125 Definitions. The definitions set out in § 630.3 of this chapter apply to the use of those defined terms in this part. § 640.130 Medical supervision. The requirements for medical supervision established in § 630.5 of this chapter supplement the regulations in this part.