Food and Drug Administration, HHS § 640.21

Pt. 640 21 CFR Ch. I (4–1–20 Edition)

relevant transfusion-transmitted infec- reasonable attempts to notify the phy- tion(s) that were a basis for deferral sician. under § 610.41 of this chapter, including [66 FR 31176, June 11, 2001. Redesignated and results of further testing as required in amended at 80 FR 29898, May 22, 2015] § 610.40(e) of this chapter; and, (4) Where appropriate, information PART 640—ADDITIONAL STAND- concerning medical followup and coun- seling. ARDS FOR HUMAN BLOOD AND (c) Time period for notification. You BLOOD PRODUCTS must make reasonable attempts to no- Subpart A—Whole Blood tify the donor within 8 weeks after determining that the donor is deferred or Sec. determined not to be eligible for dona- 640.1 Whole Blood. tion as described in paragraph (a) of 640.2 General requirements. this section. You must document that 640.4 Collection of the blood. 640.5 Testing the blood. you have successfully notified the 640.6 Modifications of Whole Blood. donor or when you are unsuccessful that you have made reasonable at- Subpart B—Red Blood Cells tempts to notify the donor. (d) Autologous donors. (1) You also 640.10 Red Blood Cells. 640.11 General requirements. must provide the following information 640.12 Eligibility of donor. to the referring physician of an 640.13 Collection of the blood. autologous donor who is deferred based 640.14 Testing the blood. on the results of tests for evidence of 640.15 Segments for testing. infection with a relevant transfusion- 640.16 Processing. transmitted infection(s) or whose 640.17 Modifications for specific products. platelets indicate evidence of a bac- Subpart C—Platelets terial infection that is endogenous to the bloodstream of the donor as de- 640.20 Platelets. scribed in paragraph (a) of this section: 640.21 Eligibility of donors. (i) Information that the autologous 640.22 Collection of source material. 640.23 Testing the blood. donor is deferred based on the results 640.24 Processing. of tests for evidence of infection due to 640.25 General requirements. relevant transfusion-transmitted infection(s), as required under § 610.41 of this Subpart D—Plasma chapter, and the reason for that deci- 640.30 Plasma. sion; 640.31 Eligibility of donors. (ii) Where appropriate, the types of 640.32 Collection of source material. donation of blood or blood components 640.33 Testing the blood. that the autologous donor should not 640.34 Processing. donate in the future; and (iii) The results of tests for evidence Subpart E [Reserved] of infection due to relevant trans- Subpart F—Cryoprecipitate fusion-transmitted infection(s), that were a basis for deferral under § 610.41 640.50 Cryoprecipitate AHF. of this chapter, including results of fur- 640.51 Eligibility of donors. ther testing as required in § 610.40(e) of 640.52 Collection of source material. this chapter. 640.53 Testing the blood. 640.54 Processing. (2) You must make reasonable at- 640.55 U.S. Standard preparation. tempts to notify the autologous do- 640.56 Quality control test for potency. nor’s referring physician within 8 weeks after determining that the Subpart G—Source Plasma autologous donor is deferred as described in paragraph (a) of this section. 640.60 Source Plasma. 640.64 Collection of blood for Source Plas- You must document that you have suc- ma. cessfully notified the autologous do- 640.65 Plasmapheresis. nor’s referring physician or when you 640.66 Immunization of donors. are unsuccessful that you have made 640.67 Laboratory tests.

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640.68 Processing. as blood collected from human donors 640.69 General requirements. for transfusion to human recipients. 640.71 Manufacturing responsibility. 640.72 Records. [38 FR 32089, Nov. 20, 1973, as amended at 50 640.73 Reporting of fatal donor reactions. FR 4138, Jan. 29, 1985] 640.74 Modification of Source Plasma. 640.76 Products stored or shipped at unac- § 640.2 General requirements. ceptable temperatures. (a) Manufacturing responsibility. All Subpart H—Albumin (Human) manufacturing of Whole Blood, including donor examination, blood collec- 640.80 Albumin (Human). tion, laboratory tests, labeling, storage 640.81 Processing. and issue, shall be done under the su- 640.82 Tests on final product. pervision and control of the same li- 640.83 General requirements. 640.84 Labeling. censed establishment except that the Director, Center for Biologics Evalua- Subpart I—Plasma Protein Fraction tion and Research, may approve ar- (Human) rangements, upon joint request of two or more licensed establishments, which 640.90 Plasma Protein Fraction (Human). he finds are of such a nature as to as- 640.91 Processing. sure compliance otherwise with the 640.92 Tests on final product. 640.93 General requirements. provisions of this subchapter. 640.94 Labeling. (b) Blood container. The blood container shall not be entered prior to Subpart J—Immune Globulin (Human) issue for any purpose except for blood collection or when the method of proc- 640.100 Immune Globulin (Human). 640.101 General requirements. essing requires use of a different con- 640.102 Manufacture of Immune Globulin tainer. The container shall be (Human). uncolored and transparent to permit 640.103 The final product. visual inspection of the contents and 640.104 Potency. any closure shall be such as will maintain a hermetic seal and prevent con- Subpart K [Reserved] tamination of the contents. The con- Subpart L—Alternative Procedures tainer material shall not interact with the contents under the customary con- 640.120 Alternative procedures. ditions of storage and use, in such a manner as to have an adverse effect Subpart M—Definitions and Medical upon the safety, purity, or potency of Supervision the blood. 640.125 Definitions. (c) Reissue of blood. Blood that has 640.130 Medical supervision. been removed from storage controlled by a licensed establishment shall not AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264. be reissued by a licensed establishment unless the following conditions are ob- SOURCE: 38 FR 32089, Nov. 20, 1973, unless served: otherwise noted. (1) The container has a tamper-proof CROSS REFERENCES: For U.S. Customs seal when originally issued and this Service regulations relating to viruses, se- seal remains unbroken; rums, and toxins, see 19 CFR 12.21–12.23. For U.S. Postal Service regulations relating to (2) A segment is properly attached the admissibility to the United States mails and has not been removed, except that see parts 124 and 125 of the Domestic Mail blood lacking a properly attached seg- Manual, that is incorporated by reference in ment may be reissued in an emergency 39 CFR part 111. provided it is accompanied by instruc- tions for sampling and for use within 6 Subpart A—Whole Blood hours after entering the container for sampling; § 640.1 Whole Blood. (3) The blood has been stored con- The proper name of this product shall tinuously at 1 to 6 °C and shipped be- be Whole Blood. Whole Blood is defined tween 1 and 10 °C;

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(4) The blood is held for observation (1) One or more segments shall be until a significant inspection con- provided with each unit of blood when sistent with the requirements of issued or reissued except as provided in § 640.5(e) can be made. § 640.2(c)(2) and all segments shall be [38 FR 32089, Nov. 20, 1973, as amended at 41 from the donor who is the source of the FR 4015, Jan. 28, 1976; 42 FR 59878, Nov. 22, unit of blood. 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, (2) All samples for laboratory tests Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR performed by the manufacturer and all 4138, Jan. 29, 1985; 53 FR 116, Jan. 5, 1988; 55 segments accompanying a unit of blood FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, shall be collected at the time of filling 1998; 64 FR 45371, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, June 11, 2001; 66 FR the original blood container. 40889, Aug. 6, 2001; 67 FR 9587, Mar. 4, 2002] (3) All containers for all samples shall bear the donor’s identification be- § 640.4 Collection of the blood. fore collecting the samples. (a) [Reserved] (4) All segments accompanying a unit (b) The donor center. The pertinent re- of blood shall be attached to the whole quirements of §§ 600.10 and 600.11 of this blood container before blood collection, chapter shall apply at both the blood in a tamperproof manner that will con- establishment and at any other place spicuously indicate removal and re- where the bleeding is performed. attachment. (c) Blood containers. Blood containers (5) Segments for compatibility test- and donor sets shall be pyrogen-free, ing shall contain blood mixed with the sterile and identified by lot number. appropriate anticoagulant. The amount of anticoagulant required (h) Storage. Whole Blood must be for the quantity of blood to be col- placed in storage at a temperature be- lected shall be in the blood container tween 1 and 6 °C immediately after col- when it is sterilized. In addition, all lection unless the blood is to be further container and donor set surfaces that processed into another component or come in contact with blood used in the the blood must be transported from the processing of Heparin Whole Blood donor center to the processing labora- shall be water repellent. tory. If transported, the blood must be (d) The anticoagulant solution. The placed in temporary storage having anticoagulant solution shall be sterile sufficient refrigeration capacity to and pyrogen-free. Anticoagulant solu- cool the blood continuously toward a tions shall be compounded and used ac- ° cording to a formula approved by the temperature range between 1 and 10 C Director, Center for Biologics Evalua- until arrival at the processing labora- tion and Research. tory. At the processing laboratory, the (e) Donor identification. Each unit of blood must be stored at a temperature ° blood shall be so marked or identified between 1 and 6 C. Blood from which a by number or other symbol as to relate component is to be prepared must be it to the individual donor whose iden- held in an environment maintained at tity shall be established to the extent a temperature range specified for that necessary for compliance with § 630.10 component in the directions for use for of this chapter. the blood collecting, processing, and (f) Prevention of contamination of the storage system approved for such use blood. The skin of the donor at the site by the Director, CBER. of phlebotomy shall be prepared thor- [38 FR 32089, Nov. 20, 1973, as amended at 42 oughly and carefully by a method that FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, gives maximum assurance of a sterile 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, container of blood. The blood shall be Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR collected by aseptic methods in a ster- 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; ile system which may be closed or may 66 FR 40889, Aug. 6, 2001; 72 FR 45887, Aug. 16, be vented if the vent protects the blood 2007; 73 FR 7464, Feb. 8, 2008; 80 FR 29904, May against contamination. 22, 2015] (g) Samples and segments for laboratory tests. Samples and segments for labora- § 640.5 Testing the blood. tory tests shall meet the following All laboratory tests shall be made on standards: a specimen of blood taken from the

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donor, and these tests shall include the tions as required under § 610.40 of this following: chapter. (a) [Reserved] [38 FR 32089, Nov. 20, 1973, as amended at 50 (b) Determination of blood group. Each FR 4138, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; container of Whole Blood shall be clas- 53 FR 12764, Apr. 19, 1988; 64 FR 45372, Aug. 19, sified as to ABO blood group. At least 1999; 66 FR 1836, Jan. 10, 2001; 66 FR 31165, two blood group tests shall be made June 11, 2001; 66 FR 40889, Aug. 6, 2001; 80 FR and the unit shall not be issued until 29904, May 22, 2015] grouping tests by different methods or with different lots of antiserums are in § 640.6 Modifications of Whole Blood. agreement. Only those Anti-A and Upon approval by the Director, Cen- Anti-B Blood Grouping Reagents liter for Biologics Evaluation and Re- censed under, or that otherwise meet search, of a supplement to the biologics the requirements of, the regulations of license application for Whole Blood a this subchapter shall be used, and the manufacturer may prepare Whole technique used shall be that for which Blood from which the antihemophilic the serum is specifically designed to be factor has been removed, provided the effective. Whole Blood meets the applicable re- (c) Determination of the Rh factors. quirements of this subchapter and the Each container of Whole Blood shall be following conditions are met: classified as to Rh type on the basis of (a) The antihemophilic factor shall tests done on the sample. The label be removed in accordance with para- shall indicate the extent of typing and graphs (a), (b), and (c) of § 640.52. the results of all tests performed. If the (b) Although the closed system be- test, using Anti-D Blood Grouping Rea- tween the red blood cells and plasma gent, is positive, the container may be shall be maintained, the red blood cells labeled ‘‘Rh Positive.’’ If the test is ° negative, the results shall be confirmed shall be maintained between 1 and 6 C by further testing which shall include at all times, including that time when tests for the ‘‘weak D (formerly Du).’’ the plasma is being frozen for removal Blood may be labeled ‘‘Rh Negative’’ if of the antihemophilic factor. further testing is negative. Units test- [38 FR 32089, Nov. 20, 1973, as amended at 49 ing positive after additional more spe- FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, cific testing shall be labeled as ‘‘Rh 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Positive.’’ Only Anti-Rh Blood Group- Sept. 28, 1994; 64 FR 45372, Aug. 19, 1999; 64 FR ing Reagents licensed under, or that 56453, Oct. 20, 1999] otherwise meet the requirements of, this subchapter shall be used, and the Subpart B—Red Blood Cells technique used shall be that for which the reagent is specifically designed to § 640.10 Red Blood Cells. be effective. The proper name of this product shall (d) Sterility test. Whole Blood intended be Red Blood Cells. The product is de- for transfusion shall not be tested for fined as red blood cells remaining after sterility by a method that entails en- separating plasma from human blood. tering the final container before the blood is used for transfusion. [38 FR 32089, Nov. 20, 1973, as amended at 50 (e) Inspection. Whole Blood shall be FR 4138, Jan. 29, 1985] inspected visually during storage and § 640.11 General requirements. immediately prior to issue. If the color or physical appearance is abnormal or (a) Storage. Immediately after proc- there is any indication or suspicion of essing, the Red Blood Cells shall be microbial contamination the unit of placed in storage and maintained at a Whole Blood shall not be issued for temperature between 1 and 6 °C. transfusion. (b) Inspection. The product shall be (f) Test for relevant transfusion-trans- inspected immediately after separation mitted infections. Whole Blood shall be of the plasma, periodically during stor- tested for evidence of infection due to age, and at the time of issue. The prod- relevant transfusion-transmitted infec- uct shall not be issued if there is any

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abnormality in color or physical ap- tend to increase the temperature of the pearance or if there is any indication of blood, or by normal undisturbed sedi- microbial contamination. mentation. A portion of the plasma [38 FR 32089, Nov. 20, 1973, as amended at 41 sufficient to insure optimal cell preser- FR 18292, May 3, 1976; 42 FR 59878, Nov. 11, vation shall be left with the red cells 1977; 50 FR 4139, Jan. 29, 1985] except when a cryoprotective substance or additive solution is added for § 640.12 Eligibility of donor. prolonged storage. Establishments must determine the (b) Sterile system. All surfaces that eligibility of donors of the source blood come in contact with the red cells shall for Red Blood Cells in accordance with be sterile and pyrogen-free. §§ 630.10 and 630.15 of this chapter. (c) Final containers. Final containers [80 FR 29904, May 22, 2015] used for Red Blood Cells shall be the original blood containers unless the § 640.13 Collection of the blood. method of processing requires a dif- (a) The source blood shall be col- ferent container. The final container lected as prescribed in § 640.4. shall meet the requirements for blood (b) Source blood may also be derived containers prescribed in § 640.2(c). At from Whole Blood manufactured in ac- the time of filing, if a different con- cordance with applicable provisions of tainer is used, it shall be marked or this subchapter. identified by number or other symbol [38 FR 32089, Nov. 20, 1973, as amended at 50 so as to relate it to the donor of that FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, unit of red cells. 1999] [38 FR 32089, Nov. 20, 1973, as amended at 43 § 640.14 Testing the blood. FR 34460, Aug. 4, 1978; 50 FR 4139, Jan. 29, 1985; 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Blood from which Red Blood Cells are Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001] prepared shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (b) § 640.17 Modifications for specific and (c). products. [53 FR 117, Jan. 5, 1988, as amended at 66 FR Red Blood Cells Frozen: A 31165, June 11, 2001; 80 FR 29904, May 22, 2015] cryophylactic substance may be added to the Red Blood Cells for extended § 640.15 Segments for testing. manufacturers’ storage at ¥65 °C or Segments collected in integral tub- colder, provided the manufacturer sub- ing shall meet the following standards: mits data considered by the Director, (a) One or more segments shall be Center for Biologics Evaluation and provided with each unit of Whole Blood Research, as adequately demonstrating or Red Blood Cells when issued or re- through in vivo cell survival and other issued. appropriate tests that the addition of (b) Before they are filled, all segments shall be marked or identified so the substance, the materials used and as to relate them to the donor of that the processing methods results in a unit of red cells. final product that meets the required (c) All segments accompanying a unit standards of safety, purity, and po- of Red Blood Cells shall be filled at the tency for Red Blood Cells, and that the time the blood is collected or at the frozen product will maintain those time the final product is prepared. properties for the prescribed dating period. Section 640.11 (a) and (b) do not [66 FR 40890, Aug. 6, 2001] apply while a cryophylactic substance § 640.16 Processing. is present. (a) Separation. Within the timeframe [38 FR 32089, Nov. 20, 1973, as amended at 41 specified in the directions for use for FR 18292, May 3, 1976; 49 FR 23834, June 8, the blood collecting, processing, and 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, storage system used, Red Blood Cells Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998] may be prepared either by centrifugation, done in a manner that will not

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Subpart C—Platelets platelet count indicates that the do- nor’s platelet count is at least 150,000 § 640.20 Platelets. platelets/μL; and (a) Proper name and definition. The (3) You must take appropriate steps proper name of this product shall be to assure that the donor’s intended Platelets. The product is defined as post-donation platelet count will be no platelets collected from one unit of less than 100,000 platelets/μL. blood and resuspended in an appro- (e) Frequency of plateletpheresis collec- priate volume of original plasma, as tion. (1) The donor may donate no more prescribed in § 640.24(d). than a total of 24 plateletpheresis col- (b) Source. The source material for lections during a 12-month rolling pe- Platelets is plasma which may be ob- riod. tained by whole blood collection or by (2) When you collect fewer than 6 × plateletpheresis. 1011 platelets, you must wait at least 2 calendar days before any subsequent [40 FR 4304, Jan. 29, 1975, as amended at 47 plateletpheresis collection. You must FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 72 FR 45887, Aug. 16, 2007] not attempt to collect more than 2 col- lections within a 7 calendar day period. § 640.21 Eligibility of donors. (3) When you collect 6 × 1011 or more (a) Establishments must determine platelets, you must wait at least 7 cal- the eligibility of donors of platelets de- endar days before any subsequent rived from Whole Blood and donors of plateletpheresis collection. platelets collected by plateletpheresis (4) Exception. For a period not to ex- in accordance with §§ 630.10 and 630.15 of ceed 30 calendar days, a donor may this chapter, except as provided in this serve as a dedicated plateletpheresis section. donor for a single recipient, in accord- (b) A plateletpheresis donor must not ance with § 610.40(c)(1) of this chapter, serve as the source of platelets for as often as is medically necessary, pro- transfusion if the donor has recently vided that the donor is in good health, ingested a drug that adversely affects as determined and documented by the platelet function. responsible physician, and the donor’s (c) A Whole Blood donor must not platelet count is at least 150,000 plate- serve as the source of platelets for lets/μL, measured at the conclusion of transfusion if the donor has recently the previous donation or before initi- ingested a drug that adversely affects ating plateletpheresis for the current platelet function unless the unit is la- donation. beled to identify the ingested drug that (f) Deferral of plateletpheresis donors adversely affects platelet function. due to red blood cell loss. (1) You must (d) If you are collecting platelets by defer a donor from donating platelets plateletpheresis, you must assess and by plateletpheresis or a co-collection of monitor the donor’s platelet count. platelets and plasma by apheresis for 8 (1) You must take adequate and ap- weeks if the donor has donated a unit propriate steps to assure that the do- of Whole Blood, or a single unit of Red nor’s platelet count is at least 150,000 Blood Cells by apheresis unless at least platelets per microliter (/μL) before 2 calendar days have passed and the plateletpheresis begins. Exception: If extracorporeal volume of the apheresis you do not have records of a donor’s device is less than 100 milliliters. platelet count from prior donations (2) You must defer a donor from do- and you are not able to assess the donating platelets for a period of 16 nor’s platelet count either prior to or weeks if the donor donates two units of immediately following the initiation of Red Blood Cells during a single the collection procedure, you may col- apheresis procedure. lect platelets by plateletpheresis, but (3) You must defer a donor for 8 you must not collect 9.0 × 1011 or more weeks or more if the cumulative red platelets from that donor. blood cell loss in any 8 week period (2) You must defer from platelet do- could adversely affect donor health. nation a donor whose pre-donation (g) The responsible physician must platelet count is less than 150,000 plate- obtain the informed consent of a lets/μL until a subsequent pre-donation plateletpheresis donor on the first day

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of donation, and at subsequent inter- fied in the directions for use for the vals no longer than 1 year. blood collecting, processing, and stor- (1) The responsible physician must age system approved for such use by explain the risks and hazards of the the Director, Center for Biologics Eval- procedure to the donor; and uation and Research. (2) The explanation must be made in (b) Immediately after collection, the such a manner that the donor may give whole blood or plasma shall be held in consent, and has a clear opportunity to storage between 20 and 24 °C unless it refuse the procedure. must be transported from the collec- [80 FR 29904, May 22, 2015] tion center to the processing laboratory. During such transport, all reason- § 640.22 Collection of source material. able methods shall be used to maintain (a) Whole blood used as the source of the temperature as close as possible to Platelets shall be collected as pre- a range between 20 and 24 °C until it ar- scribed in § 640.4. rives at the processing laboratory (b) [Reserved] where it shall be held between 20 and 24 (c) If plateletpheresis is used, the °C until the platelets are separated. procedure for collection must be as The platelet concentrate shall be sepa- prescribed in §§ 640.21, 640.64 (except paragraph (c)), and 640.65, or as de- rated within 4 hours or within the scribed in an approved biologics license timeframe specified in the directions application (BLA) or an approved sup- for use for the blood collecting, proc- plement to a BLA. essing, and storage system. (d) The phlebotomy shall be per- (c) The time and speed of centrifuga- formed by a single uninterrupted tion must have been demonstrated to venipuncture with minimal damage to, produce an unclumped product, with- and minimal manipulation of, the do- out visible hemolysis, that yields a nor’s tissue. count of not less than 5.5 × 1010 plate- [40 FR 4304, Jan. 29, 1975, as amended at 45 lets per unit in at least 75 percent of FR 27927, Apr. 25, 1980; 49 FR 23834, June 8, the units tested. 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, (d) The volume of original plasma Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR used for resuspension of the platelets 45372, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; shall be determined by the mainte- 72 FR 45887, Aug. 16, 2007; 80 FR 29904, May 22, 2015] nance of a pH of not less than 6.2 during the storage period. The pH shall be § 640.23 Testing the blood. measured on a sample of platelets (a) Blood from which plasma is sepa- which has been stored for the max- rated for the preparation of Platelets imum dating period at the selected shall be tested as prescribed in § 610.40 storage temperature. One of the fol- of this chapter and § 640.5 (b) and (c). lowing storage temperatures shall be (b) The tests shall be performed on a used continuously: sample of blood collected at the time of (1) 20 to 24 °C. collecting the source blood, and such (2) 1 to 6 °C. sample container shall be labeled with (e) Final containers used for Plate- the donor’s number before the con- lets shall be colorless and transparent tainer is filled. to permit visual inspection of the con- [40 FR 4304, Jan. 29, 1975, as amended at 50 tents; any closure shall maintain a her- FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; metic seal and prevent contamination 64 FR 45372, Aug. 19, 1999; 66 FR 1836, Jan. 10, of the contents. The container material 2001; 66 FR 31165, June 11, 2001; 80 FR 29904, shall not interact with the contents, May 22, 2015] under the customary conditions of § 640.24 Processing. storage and use, in such a manner as to have an adverse effect upon the safety, (a) Separation of plasma and platelets and resuspension of the platelets purity, potency, or efficacy of the prod- must be in a closed system. Platelets uct. At the time of filling, the final must not be pooled during processing container shall be marked or identified unless the platelets are pooled as speci-

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by number so as to relate it to the resentative of the Food and Drug Ad- donor. ministration. [40 FR 4304, Jan. 29, 1975, as amended at 42 (2) The licensed Platelets manufac- FR 10983, Feb. 25, 1977; 47 FR 49021, Oct. 29, turer has obtained a written agreement 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, that the testing laboratory will permit Apr. 6, 1998; 64 FR 45372, Aug. 19, 1999; 66 FR an authorized representative of the 1836, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001; 72 Food and Drug Administration to in- FR 45887, Aug. 16, 2007; 73 FR 7464, Feb. 8, spect its testing procedures and facili- 2008] ties during reasonable business hours. § 640.25 General requirements. (3) The testing laboratory will par- (a) Storage. Immediately after re- ticipate in any proficiency testing pro- suspension, Platelets shall be placed in grams undertaken by the Center for storage at the selected temperature Biologics Evaluation and Research, range. If stored at 20 to 24 °C, a contin- Food and Drug Administration. uous gentle agitation of the platelet [40 FR 4304, Jan. 29, 1975, as amended at 47 concentrate shall be maintained FR 49021, Oct. 29, 1982; 49 FR 23834, June 8, throughout the storage period. Agita- 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, tion is optional if stored at a tempera- Mar. 26, 1990; 66 FR 1836, Jan. 10, 2001; 72 FR ture between 1 and 6 °C. 45888, Aug. 16, 2007] (b) Quality control testing. Each month four units prepared from dif- Subpart D—Plasma ferent donors shall be tested at the end of the storage period as follows: § 640.30 Plasma. (1) Platelet count. (2) pH of not less than 6.2 measured (a) Proper name and definition. The at the storage temperature of the unit. proper name of this component is Plas- (3) Measurement of actual plasma ma. The component is defined as: volume. (1) The fluid portion of one unit of (4) If the results of the quality con- human blood intended for intravenous trol testing indicate that the product use which is collected in a closed sys- does not meet the prescribed require- tem, stabilized against clotting, and ments, immediate corrective action separated from the red cells; or shall be taken and a record maintained (2) The fluid portion of human blood of such action. intended for intravenous use which is (c) Manufacturing responsibility. All prepared by apheresis methods as spec- manufacturing of Platelets shall be ified in the directions for use for the performed at the same licensed estab- blood collecting, processing, and stor- lishment, except that the quality con- age system including closed and open trol testing under paragraph (b) of this systems. section may be performed by a clinical (b) Source. (1) Plasma shall be ob- laboratory which meets the standards tained by separating plasma from blood of the Clinical Laboratories Improve- collected from blood donors or by plas- ment Amendments of 1988 (CLIA) (42 mapheresis. U.S.C. 263a) and is qualified to perform platelet counts. Such arrangements (2) Plasma may be obtained from a must be approved by the Director, Cen- unit of Whole Blood collected by an- ter for Biologics Evaluation and Re- other licensed establishment. search, Food and Drug Administration. [42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. Such testing shall not be considered as 29, 1983, as amended at 50 FR 4139, Jan. 29, divided manufacturing, as described in 1985; 72 FR 45888, Aug. 16, 2007] § 610.63 of this chapter, provided the following conditions are met: § 640.31 Eligibility of donors. (1) The results of each test are re- (a) Whole Blood donors must meet ceived within 10 days of the prepara- the criteria for donor eligibility pre- tion of the platelet concentrate, and scribed in §§ 630.10 and 630.15 of this are maintained by the establishment chapter. licensed for Platelets so that they may be reviewed by an authorized rep-

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(b) Collection establishments must blood collecting, processing, and stor- determine the eligibility of plasma- age system unless the product is to be pheresis donors in accordance with stored as Liquid Plasma. §§ 630.10 and 630.15 of this chapter. (b) Fresh Frozen Plasma. Fresh frozen [80 FR 29904, May 22, 2015] plasma shall be prepared from blood collected by a single uninterrupted § 640.32 Collection of source material. venipuncture with minimal damage to (a) Whole Blood must be collected, and minimal manipulation of the do- transported, and stored as prescribed in nor’s tissue. The plasma must be sepa- § 640.4. When whole blood is intended rated from the red blood cells or col- for Plasma, Fresh Frozen Plasma, and lected by an apheresis procedure, and Liquid Plasma, until the plasma is re- placed in a freezer within 8 hours or moved, the whole blood must be main- within the timeframe specified in the tained at a temperature between 1 and directions for use for the blood col- 6 °C or as specified in the directions for lecting, processing, and storage sys- use for the blood collecting, processing, tem, and stored at ¥18 °C or colder. and storage system approved for such (c) Liquid Plasma. Liquid Plasma use by the Director, Center for Bio- shall be separated from the red blood logics Evaluations and Research. cells and shall be stored at a tempera- Whole blood intended for Platelet Rich ture of 1 to 6 °C within 4 hours after Plasma must be maintained as pre- filling the final container or within the scribed in § 640.24 until the plasma is timeframe specified in the directions removed. The red blood cells must be for use for the blood collecting, proc- placed in storage at a temperature be- essing, and storage system. tween 1 and 6 °C immediately after the plasma is separated. (d) Platelet Rich Plasma. Platelet rich (b) Plasma obtained by plasma- plasma shall be prepared from blood pheresis shall be collected as pre- collected by a single uninterrupted scribed in § 640.64 (except that para- venipuncture with minimal damage to graph (c)(3) of § 640.64 shall not apply), and manipulation of the donor’s tissue. and § 640.65. The plasma shall be separated from the red blood cells by centrifugation within [42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980; 50 FR 4139, Jan. 29, 4 hours after completion of the phle- 1985; 64 FR 45372, Aug. 19, 1999; 72 FR 45888, botomy or within the timeframe speci- Aug. 16, 2007; 80 FR 29905, May 22, 2015] fied in the directions for use for the blood collecting, processing, and stor- § 640.33 Testing the blood. age system. The time and speed of the (a) Blood from which plasma is sepa- centrifugation shall have been shown rated shall be tested as prescribed in to produce a product with at least § 610.40 of this chapter and § 640.5 (b) and 250,000 platelets per microliter. The (c). plasma shall be stored at a tempera- (b) Manufacturers of Plasma col- ture between 20 and 24 °C immediately lected by plasmapheresis shall have after filling the final container. A testing and recordkeeping responsibil- gentle and continuous agitation of the ities equivalent to those prescribed in product shall be maintained through- §§ 640.71 and 640.72. out the storage period, if stored at a [42 FR 59878, Nov. 22, 1977, as amended at 44 temperature of 20 to 24 °C. FR 17658, Mar. 23, 1979; 50 FR 4139, Jan. 29, (e) Modifications of Plasma. It is pos- 1985; 53 FR 117, Jan. 5, 1988; 66 FR 31165, June sible to separate Platelets and/or 11, 2001; 80 FR 29905, May 22, 2015] Cryoprecipitated AHF from Plasma. § 640.34 Processing. When these components are to be separated, the plasma shall be collected as (a) Plasma. Plasma shall be separated described in § 640.32 for Plasma. from the red blood cells and shall be (1) Platelets shall be separated as stored at ¥18 °C or colder within 6 hours after transfer to the final con- prescribed in subpart C of part 640, tainer or within the timeframe speci- prior to freezing the plasma. The re- fied in the directions for use for the maining plasma may be labeled as

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‘‘Fresh Frozen Plasma,’’ if frozen with- (3) No preservative shall be added to in 6 hours after filling the final con- the final product. tainer or within the timeframe speci- [42 FR 59878, Nov. 22, 1977, as amended at 43 fied in the directions for use for the FR 34460, Aug. 4, 1978; 48 FR 13026, Mar. 29, blood collecting, processing, and stor- 1983; 50 FR 4139, Jan. 29, 1985; 64 FR 45373, age system. Aug. 19, 1999; 66 FR 1836, Jan. 10, 2001; 66 FR (2) Cryoprecipitated AHF shall be re- 40890, Aug. 6, 2001; 72 FR 45888, Aug. 16, 2007] moved as prescribed in subpart F of part 640. The remaining plasma shall be Subpart E [Reserved] labeled ‘‘Plasma, Cryoprecipitate Re- duced.’’ Subpart F—Cryoprecipitate (3) Plasma remaining after both Platelets and Cryoprecipitated AHF § 640.50 Cryoprecipitated AHF. have been removed may be labeled (a) Proper name and definition. The ‘‘Plasma, Cryoprecipitate Reduced.’’ proper name of this product shall be (f) The final container. (1) The final Cryoprecipitated AHF. The product is container shall have no color added to defined as a preparation of the plastic and shall be transparent to antihemophilic factor, which is ob- permit visual inspection of the con- tained from a single unit of plasma col- tents; any closure shall maintain a her- lected and processed in a closed sys- metic seal and prevent contamination tem. of the contents. (b) Source. The source material for (2) The final container material shall Cryoprecipitated AHF shall be plasma not interact with the contents, under which may be obtained by whole blood the customary conditions of storage collection or by plasmapheresis. and use, in such a manner as to have an adverse effect upon the safety, purity, [42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. potency, and effectiveness of the prod- 29, 1983, as amended at 50 FR 4139, Jan. 29, uct. 1985] (3) Prior to filling, the final con- § 640.51 Eligibility of donors. tainer shall be identified by number so as to relate it to the donor. (a) Whole blood donors must meet (g) The final product. (1) The final the criteria for eligibility prescribed in product shall be inspected immediately §§ 630.10 and 630.15 of this chapter. after separation of the plasma and (b) Collection establishments must shall not be issued for transfusion if determine the eligibility of plasma- there is (i) any abnormality in color or pheresis donors in accordance with physical appearance, or (ii) any indica- §§ 630.10 and 630.15 of this chapter. tion of contamination. [80 FR 29905, May 22, 2015] (2) With the exception of Platelet Rich Plasma and Liquid Plasma the § 640.52 Collection of source material. final product shall be inspected for evi- (a) Whole blood used as a source of dence of thawing or breakage at the Cryoprecipitated AHF shall be col- time of issuance, however, the con- lected as prescribed in § 640.4. Whole tainers need not be stored in a manner blood from which both Platelets and that shows evidence of thawing if Cryoprecipitated AHF is derived shall records of continuous monitoring of be maintained as required under § 640.24 the storage temperature establish that until the platelets are removed. the temperature remained at ¥18 °C or (b) If plasmapheresis is used, the pro- colder. If continuous monitoring of the cedure for collection shall be as pre- product is not available, the final prod- scribed in § 640.64 (except that para- uct shall be stored in a manner that graph (c)(3) of that section shall not will show evidence of thawing and shall apply), and 640.65. not be issued if there is any evidence of [42 FR 21774, Apr. 29, 1977, as amended at 50 thawing. FR 4139, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 80 FR 29905, May 22, 2015]

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§ 640.53 Testing the blood. less and transparent to permit visual (a) Blood from which plasma is sepa- inspection of the contents; any closure rated for the preparation of shall maintain a hermetic seal and pre- Cryoprecipitated AHF shall be tested vent contamination of the contents. as prescribed in § 610.40 of this chapter The container material shall not inter- and § 640.5 (b) and (c). act with the contents under customary (b) The tests shall be performed on a conditions of storage and use in such a sample of blood collected at the time of manner as to have an adverse effect collecting the source blood, and such upon the safety, purity, potency and ef- sample container shall be labeled with fectiveness of the product. At the time the donor’s number before the con- of filling, the final container shall be tainer is filled. identified by a number so as to relate (c) Manufacturers of it to the donor. Cryoprecipitated AHF obtained from [42 FR 21774, Apr. 29, 1977, as amended at 47 plasma collected by plasmapheresis FR 15330, Apr. 9, 1982; 50 FR 4139, Jan. 29, shall have testing and record-keeping 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, responsibilities equivalent to those Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001] prescribed in §§ 640.71 and 640.72. § 640.55 U.S. Standard preparation. [42 FR 21774, Apr. 29, 1977, as amended at 42 A U.S. Standard Antihemophilic Fac- FR 37546, July 22, 1977; 42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. tor (Factor VIII) preparation may be 5, 1988; 66 FR 31165, June 11, 2001; 80 FR 29905, obtained from the Center for Biologics May 22, 2015] Evaluation and Research, (HFM–407) (see mailing addresses in § 600.2 of this § 640.54 Processing. chapter) for use in the preparation of a (a) Processing the plasma. (1) The plas- working reference to be employed in a ma shall be separated from the red quality control potency test of blood cells by centrifugation to obtain Cryoprecipitated AHF. essentially cell-free plasma. [42 FR 21774, Apr. 29, 1977, as amended at 49 (2) The plasma shall be placed in a FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, freezer within 8 hours after blood col- 1985; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, lection or within the timeframe speci- Mar. 24, 2005] fied in the directions for use for the blood collecting, processing, and stor- § 640.56 Quality control test for po- age system. A combination of dry ice tency. and organic solvent may be used for (a) Quality control tests for potency freezing: Provided, That the procedure of antihemophilic factor shall be con- has been shown not to cause the sol- ducted each month on at least four rep- vent to penetrate the container or resentative containers of leach plasticizer from the container Cryoprecipitated AHF. into the plasma. (b) The results of each test are re- (3) Immediately after separation and ceived by the establishment licensed freezing of the plasma, the plasma for Cryoprecipitated AHF within 30 shall be stored and maintained at ¥18 days of the preparation of the °C or colder until thawing of the plas- cryoprecipitated antihemophilic factor ma for further processing to remove and are maintained at that establish- the Cryoprecipitated AHF. ment so that they may be reviewed by (b) Processing the final product. (1) The an authorized representative of the Cryoprecipitated AHF shall be sepa- Food and Drug Administration. rated from the plasma by a procedure (c) The quality control test for po- that has been shown to produce an av- tency may be performed by a clinical erage of no less than 80 units of laboratory which meets the standards antihemophilic factor per final con- of the Clinical Laboratories Improve- tainer. ment Amendments of 1988 (CLIA) (42 (2) No diluent shall be added to the U.S.C. 263a) and is qualified to perform product by the manufacturer prior to potency tests for antihemophilic fac- freezing. tor. Such arrangements must be ap- (3) The final container used for proved by the Director, Center for Bio- Cryoprecipitated AHF shall be color- logics Evaluation and Research, Food

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and Drug Administration. Such testing (d) Donor identification. Each unit of shall not be considered as divided man- blood and plasma shall be so marked or ufacturing, as described in § 610.63 of identified by number or other symbol this chapter, provided the following so as to relate it directly to the donor. conditions are met: (e) Prevention of contamination of the (1) The establishment licensed for blood and plasma. The skin of the donor Cryoprecipitated AHF has obtained a at the site of phlebotomy shall be pre- written agreement that the testing lab- pared thoroughly and carefully by a oratory will permit an authorized rep- method that gives maximum assurance resentative of the Food and Drug Ad- of a sterile container of blood. The ministration to inspect its testing pro- blood shall be collected, the plasma cedures and facilities during reason- separated, and the cells returned to the able business hours. donor by aseptic methods in a sterile (2) The testing laboratory will par- system which may be closed, or may be ticipate in any proficiency testing pro- vented if the vent protects the blood grams undertaken by the Center for cells and plasma against contamina- Biologics Evaluation and Research, tion. Food and Drug Administration. [38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. (d) If the average potency level of 16, 1974, as amended at 41 FR 10768, Mar. 12, antihemophilic factor in the containers 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, tested is less than 80 units of Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR antihemophilic factor per container, 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; immediate corrective actions shall be 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16, taken and a record maintained of such 2007; 80 FR 29905, May 22, 2015] action. § 640.65 Plasmapheresis. [42 FR 21774, Apr. 29, 1977, as amended at 49 (a) Procedure-general. The plasma- FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 45373, pheresis procedure is a procedure in Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001] which, during a single visit to the establishment, blood is removed from a Subpart G—Source Plasma donor, the plasma separated from the formed elements, and at least the red § 640.60 Source Plasma. blood cells returned to the donor. This procedure shall be described in detail The proper name of the product shall in the biologics license application. be Source Plasma. The product is de- (b) Procedures-specific requirements. fined as the fluid portion of human The plasmapheresis procedure shall blood collected by plasmapheresis and meet the following requirements: intended as source material for further (1)(i) Except as provided under § 630.25 manufacturing use. The definition ex- of this chapter, the responsible physi- cludes single donor plasma products in- cian must draw a sample of blood from tended for intravenous use. each donor on the day of the initial [41 FR 10768, Mar. 12, 1976, as amended at 50 physical examination or plasma- FR 4140, Jan. 29, 1985] pheresis, whichever comes first, and at least every 4 months thereafter. A se- § 640.64 Collection of blood for Source rologic test for syphilis, a total plasma Plasma. or serum protein determination, and a (a) [Reserved] plasma or serum protein electro- (b) Blood containers. Blood containers phoresis or quantitative immuno-diffu- and donor sets must be pyrogen-free, sion test or an equivalent test to deter- sterile, and identified by lot number. mine immunoglobulin composition of (c) The anticoagulant solution. The the plasma or serum shall be performed anticoagulant solution must be sterile on the sample. and pyrogen-free. Anticoagulant solu- (ii) A repeat donor who does not re- tions must be compounded and used ac- turn for plasmapheresis at the time the cording to a formula that has been ap- 4-month sample is due to be collected proved for the applicant by the Direc- may be plasmapheresed on the day he tor, Center for Biologics Evaluation appears: Provided, That no longer than and Research. 6 months has elapsed since the last

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sample was collected, and the respon- false-positive reaction is not the result sible physician approves the plasma- of an underlying disorder that would pheresis procedure and so indicates by disqualify the donor from participation signing the donor’s record before such in the plasmapheresis program. If the procedure is performed. The sample for serologic test for syphilis is performed the 4–month tests shall be collected on at a facility other than the plasma- the day of the donor’s return. pheresis center, all applicable provi- (iii) A repeat donor from whom the sions of § 640.71 shall be met. plasmapheresis center is unable to ob- (iv) A donor with a reactive serologic tain a sample for testing as prescribed test for syphilis may be in paragraph (b)(1)(i) of this section for plasmapheresed only to obtain plasma a total period exceeding 6 months shall to be used for further manufacturing be processed as a new donor. into control serum for the serologic (2)(i) Except as provided under § 630.25 test for syphilis: Provided, That the re- of this chapter, the responsible physi- sponsible physician approves the dona- cian must review the accumulated lab- tion, the donor’s file contains a signed oratory data, including any tracings of statement from a physician or clinic the plasma or serum protein electro- establishing that treatment for syphi- phoresis pattern, the calculated values lis has been initiated and that continu- of the protein composition of each ance in the plasmapheresis program component, and the collection records will not interfere with or jeopardize within 14 calendar days after the sam- the treatment of the syphilitic donor. ple is drawn to determine whether or (3) A donor identification system not the donor should be deferred from shall be established that positively further donation. If a determination is identifies each donor and relates such not made within 14 calendar days, the donor directly to his blood and its com- donor must be deferred pending such a ponents as well as to his accumulated determination. The responsible physi- records and laboratory data. Such sys- cian must sign the review. If the pro- tem shall include either a photograph tein composition is not within normal of each donor which shall be used on limits established by the testing lab- each visit to confirm the donor’s iden- oratory, or if the total protein level is less than 6.0 grams per deciliter or tity, or some other method that pro- more than 9.0 grams per deciliter in a vides equal or greater assurance of plasma sample or serum sample, the positively identifying the donor. donor must be deferred from donation (4) The amount of whole blood, not until the protein composition returns including anticoagulant, removed from to acceptable levels. Reinstatement of a donor during a manual plasma- the donor into the plasmapheresis pro- pheresis procedure or in any 2-day pe- gram when the donor’s protein com- riod shall not exceed 1,000 milliliters position values have returned to an ac- unless the donor’s weight is 175 pounds ceptable level must first be approved or greater, in which case the amount of by the responsible physician. whole blood, not including anticoagu- (ii) A donor with a reactive serologic lant, removed from the donor during a test for syphilis shall not be manual plasmapheresis procedure or in plasmapheresed again until the donor’s any 2-day period shall not exceed 1,200 serum is tested and found to be non- milliliters. reactive to a serologic test for syphilis, (5) The amount of whole blood, not except as provided in paragraph (b)(2) including anticoagulant, removed from (iii) and (iv) of this section. a donor during a manual plasma- (iii) A donor whose serum is deter- pheresis procedure within a 7-day pe- mined to have a biologic false-positive riod shall not exceed 2,000 milliliters reaction to a serologic test for syphilis unless the donor’s weight is 175 pounds may be plasmapheresed: Provided, That or greater, in which case the amount of the donor’s file identifies the serologic whole blood, not including anticoagu- test for syphilis and results used to lant, removed from a donor during a confirm the biologic false-positive re- manual plasmapheresis procedure action and indicates that the respon- within a 7-day period shall not exceed sible physician has determined the 2,400 milliliters.

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(6) No more than 500 milliliters of § 640.68 Processing. whole blood shall be removed from a (a) Sterile system. All administration donor at one time, unless the donor’s and transfer sets inserted into blood weight is 175 pounds or greater, in containers used for processing Source which case no more than 600 milliliters Plasma intended for manufacturing of whole blood shall be removed from into injectable or noninjectable prod- the donor at one time. ucts and all interior surfaces of plasma (7) The plasma shall be separated containers used for processing Source from the red blood cells immediately Plasma intended for manufacturing after blood collection. The maximum into injectable products shall be ster- feasible volume of red blood cells shall ile, pyrogen-free, nontoxic, and com- be returned to the donor before another patible with the contents under normal unit is collected. conditions of use. Only Sodium Chlo- (8) The volume of plasma collected ride Injection USP shall be used as a during an automated plasmapheresis red blood cell diluent. If the method of collection procedure shall be con- separation of the plasma intended for sistent with the volumes specifically injectable products involves a system approved by the Director, Center for in which an airway must be inserted Biologics Evaluation and Research, and into the plasma container, the airway collection shall not occur less than 2 shall be sterile and constructed so as to days apart or more frequently than exclude microorganisms and maintain twice in a 7-day period. a sterile system. (b) Final containers. Final containers [38 FR 32089, Nov. 20, 1973, as amended at 41 used for Source Plasma, whether inte- FR 10769, Mar. 12, 1976; 64 FR 45373, Aug. 19, grally attached or separated from the 1999; 64 FR 56453, Oct. 20, 1999; 80 FR 29905, original blood container, shall not be May 22, 2015] entered prior to issuance for any purpose except for filling with the plasma. § 640.66 Immunization of donors. Such containers shall be uncolored and If specific immunization of a donor is hermetically sealed, and shall permit to be performed, the selection, sched- clear visibility of the contents. Final uling and administration of the anti- containers and their components shall gen, and the evaluation of each donor’s not interact with the plasma contents clinical response, shall be by the re- under conditions of storage and use so sponsible physician. Any material used as to alter the safety, quality, purity, for immunization shall be either a or potency of the plasma and shall pro- product licensed under section 351 of vide adequate protection against exter- the Public Health Service Act for such nal factors that may cause deteriora- purpose or one specifically approved by tion or contamination. Prior to filling, the Director, Center for Biologics Eval- the final container shall be marked or uation and Research, Food and Drug identified by number or other symbol Administration. Immunization proce- which will relate it directly to the dures shall be on file at each plasma- donor. pheresis center where immunizations (c) Preservative. Source Plasma shall are performed. not contain a preservative. [38 FR 32089, Nov. 20, 1973, as amended at 49 [38 FR 32089, Nov. 20, 1973, as amended at 41 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, FR 10769, Mar. 12, 1976; 50 FR 4140, Jan. 29, 1990; 80 FR 29905, May 22, 2015] 1985]

§ 640.67 Laboratory tests. § 640.69 General requirements. (a) Pooling. Two units of Source Plas- Each unit of Source Plasma shall be ma from the same donor may be pooled tested for evidence of infection due to if such units are collected during one relevant transfusion-transmitted infec- plasmapheresis procedure: Provided, tions as required under § 610.40 of this That the pooling is done by a procedure chapter. that does not introduce a risk of con- [66 FR 31165, June 11, 2001, as amended at 80 tamination of the red blood cells and, FR 29905, May 22, 2015] for plasma intended for injectable

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products, gives maximum assurance of (4) All samples shall be collected in a a sterile container of plasma. manner that does not contaminate the (1) The pooling of plasma from two or contents of the final container. more donors is not permitted in the (e) Restrictions on distribution. Estab- manufacture of Source Plasma in- lishments must ensure that Source tended for manufacturing into Plasma donated by paid donors not be injectable products. used for further manufacturing into (2) The pooling of plasma from two or injectable products until the donor has more donors by the manufacturer of a record of being found eligible to do- Source Plasma intended for manufac- nate in accordance with § 630.10 of this chapter and a record of negative test turing into noninjectable products is results on all tests required under permitted: Provided, That the plasma § 610.40(a) of this chapter on two occa- from two or more donors is pooled after sions in the past 6 months. the plasma has been removed from the (f) Hold. Source Plasma donated by red blood cells, and after the red blood paid donors determined to be suitable cell containers are sealed. for further manufacturing into (b) Storage. Immediately after filling, injectable products must be held in plasma intended for manufacturing quarantine for a minimum of 60 cal- into injectable products shall be stored endar days before it is released for fur- at a temperature not warmer than ¥20 ther manufacturing. If, after placing a °C, except for plasma collected as pro- donation in quarantine under this sec- vided in § 640.74. Plasma intended for tion, the donor is subsequently de- manufacturing into noninjectable ferred under § 610.41 of this chapter, or products may be stored at tempera- you subsequently determine a donor to tures appropriate for the intended use be ineligible under § 630.10 of this chap- of the final product, provided these ter due to risk factors closely associ- temperatures are included in the ated with exposure to, or clinical evi- Source Plasma license application. dence of, infection due to a relevant (c) Inspection. Source Plasma in- transfusion-transmitted infection, you tended for manufacturing into must not distribute quarantined dona- injectable products shall be inspected tions from that donor for further man- for evidence of thawing at the time of ufacturing use to make an injectable issuance, except that inspection of in- product. dividual plasma containers need not be [38 FR 32089, Nov. 20, 1973, as amended at 41 made if the records of continuous mon- FR 10769, Mar. 12, 1976; 41 FR 14367, Apr. 5, itoring of the storage temperature es- 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, tablish that the temperature remained Apr. 6, 1998; 64 FR 45374, Aug. 19, 1999; 80 FR at ¥20 °C or colder. If there is evidence 29905, May 22, 2015] that the storage temperature has not § 640.71 Manufacturing responsibility. been maintained at ¥20 °C or colder, the plasma may be relabeled and issued (a) All steps in the manufacturing of as provided in § 640.76(a). Source Plasma, including donor examination, blood collection, plasma- (d) Samples. If samples are provided, pheresis, laboratory testing, labeling, they shall meet the following stand- storage, and issuing shall be performed ards: by personnel of the establishment li- (1) Prior to filling, all samples shall censed to manufacture Source Plasma, be marked or identified so as to relate except that testing performed in ac- them directly to the donor of that unit cordance with § 610.40 of this chapter of plasma. and § 640.65(b) may be performed by per- (2) All samples shall be filled at the sonnel of an establishment licensed for time the final product is prepared by blood and blood derivatives under sec- the person who prepares the final prod- tion 351(a) of the Public Health Service uct. Act, or by a clinical laboratory that (3) All samples shall be representa- meets the standards of the Clinical tive of the contents of the final product Laboratories Improvement Amend- or be collected from the donor at the ments of 1988 (CLIA) (42 U.S.C. 263a): time of filling the collection container. Provided, The establishment or clinical

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laboratory is qualified to perform the such information is maintained on the assigned test(s). premises of the plasmapheresis center (b) Such testing shall not be consid- where the donor’s plasma has been col- ered divided manufacturing, which re- lected. quires two biologics licenses for Source (3) The original or a clear copy or Plasma: Provided, That other durable record which may be (1) The results of such tests are main- electronic of the donor’s consent for tained by the licensed manufacturer of participation in the plasmapheresis the Source Plasma whereby such re- program or for immunization. sults may be reviewed by a responsible (4) Records of the medical history physician as required in § 640.65(b)(2) of and physical examination of the donor this chapter and by an authorized rep- conducted in accordance with resentative of the Food and Drug Ad- § 630.15(b)(1) of this chapter and, where ministration. applicable, § 630.15(b)(5) of this chapter (2) The Source Plasma manufacturer must document the eligibility of the has obtained a written agreement that donor as a plasmapheresis donor and, the testing laboratory will permit au- when applicable, as an immunized thorized representatives of the Food donor. and Drug Administration to inspect its (5) If plasma that is reactive to a se- testing procedures and facilities during rologic test for syphilis is issued as reasonable business hours. prescribed in § 640.65(b)(2)(iv), the dis- (3) The testing laboratory will par- tribution records shall indicate by ticipate in any proficiency testing pro- number those units that are reactive. grams undertaken by the Center for (b) Each donor record must be di- Biologics Evaluation and Research, rectly cross-referenced to the unit(s) of Food and Drug Administration. Source Plasma associated with the [41 FR 10770, Mar. 12, 1976, as amended at 49 donor. FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, (c) If a repeat donor is rejected or a 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. donor’s plasma is found unsuitable, the 26, 1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, donor’s record shall contain a full ex- Oct. 20, 1999; 66 FR 1837, Jan. 10, 2001; 80 FR planation for the rejection. 29905, May 22, 2015] (d) If a donor has a reaction while on § 640.72 Records. the plasmapheresis premises, or a donor reaction is reported to the center (a) In addition to the recordkeeping after the donor has left the premises, requirements of this subchapter, the the donor’s record shall contain a full following records shall be maintained: explanation of the reaction, including (1) Documentation shall be available the measures taken to assist the donor to ensure that the shipping tempera- and the outcome of the incident. ture requirements of § 600.15 of this title and of § 640.74(b)(2) are being met [41 FR 10770, Mar. 12, 1976, as amended at 50 for Source Plasma intended for manu- FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; facture into injectable products. 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4, (2)(i) For each donor, establishments 2002; 80 FR 29905, May 22, 2015] must maintain records including a sep- § 640.73 Reporting of fatal donor reac- arate and complete record of initial tions. and periodic examinations, tests, laboratory data, and interviews, etc., as If a donor has a fatal reaction which, required in §§ 630.10 and 630.15 of this in any way, may be associated with chapter and §§ 640.65, 640.66, and 640.67, plasmapheresis the Director of the Cen- except as provided in paragraph ter for Biologics Evaluation and Re- (a)(2)(ii) of this section. search shall be notified by telephone as (ii) Negative results for testing for soon as possible. If the facility is lo- evidence of infection due to relevant cated outside of the continental United transfusion-transmitted infections re- States, notification by cable or tele- quired in § 610.40 of this chapter, and gram shall be acceptable. the volume or weight of plasma with- [41 FR 10770, Mar. 12, 1976, as amended at 49 drawn from a donor need not be re- FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, corded on the individual donor record if 1990]

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§ 640.74 Modification of Source Plas- the unit of Source Plasma Liquid shall ma. not be issued. (a) Upon approval by the Director, [38 FR 32089, Nov. 20, 1973. Redesignated and Center for Biologics Evaluation and amended at 41 FR 10770, Mar. 12, 1976; 49 FR Research, Food and Drug Administra- 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 tion, of a supplement to the biologics FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, license application for Source Plasma, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56454, Oct. 20, 1999; 77 FR 18, Jan. 3, 2012] a manufacturer may prepare Source Plasma as a liquid product for a li- § 640.76 Products stored or shipped at censed blood derivative manufacturer unacceptable temperatures. who has indicated a need for a liquid (a) Storage temperature. (1) Except as product. provided in paragraph (a)(2) of this sec- (b) Source Plasma Liquid shall meet tion, Source Plasma intended for man- all standards of the frozen Source Plas- ufacture into injectable products that ma except: is inadvertently exposed (i.e., an un- (1) Source Plasma Liquid shall be foreseen occurrence in spite of compli- stored in nonleachable containers so ance with good manufacturing prac- that the containers and their compo- tice) to a storage temperature warmer nents will not interact with the plasma than ¥20 °C and colder than + 10 °C contents under conditions of storage may be issued only if labeled as and use so as to alter the safety, qual- ‘‘Source Plasma Salvaged.’’ The label ity, purity, or potency of the plasma shall be revised before issuance, and and shall provide adequate protection appropriate records shall be main- against external factors that may tained identifying the units involved, cause deterioration or contamination. describing their disposition, and ex- (2) Source Plasma Liquid shall be plaining fully the conditions that shipped, stored and labeled for storage caused the inadvertent temperature ex- at a temperature of 10 °C or colder. An posure. exception to the shipping or storage (2) Source Plasma intended for manu- temperature shall be approved by the facture into injectable products that is Director, Center for Biologics Evalua- exposed inadvertently (i.e., an unfore- tion and Research, Food and Drug Ad- seen occurrence in spite of compliance ministration, based upon his receipt of with good manufacturing practice) to substantial evidence to support an- one episode of storage temperature other temperature. Such evidence may fluctuation that is warmer than ¥20 °C be submitted by either the licensed and colder than ¥5 °C for not more manufacturer of the Source Plasma than 72 hours is exempt from the label- Liquid or the manufacturer of the final ing requirements of paragraph (a)(1) of blood derivative product who has re- this section, provided that the plasma quested the Source Plasma Liquid. has been and remains frozen solid. Ap- (3) The label for the Source Plasma propriate records shall be maintained Liquid shall be easily distinguished identifying the units involved, describ- from that of the frozen product. Color ing their disposition, explaining fully coding shall not be used for this pur- the conditions that caused the inad- pose. vertent temperature exposure, and doc- (4) The label affixed to each con- umenting that the episode of tempera- tainer of Source Plasma Liquid shall ture elevation did not exceed 72 hours, contain, in addition to the information that the temperature did not rise to required by § 606.121 of this chapter, but warmer than ¥5 °C in storage, and that excluding § 606.121(e)(5)(ii) of this chap- the plasma remained frozen solid ter, the name of the manufacturer of throughout the period of elevated tem- the final blood derivative product for perature. When requested, copies of the whom it was prepared. records shall be provided to the plasma (5) Source Plasma Liquid shall be in- derivative manufacturer. spected immediately prior to issuance. (b) Shipping temperature. If Source If the color or physical appearance is Plasma for manufacture into injectable abnormal, or there is any indication or products is exposed inadvertently (i.e., suspicion of microbial contamination, an unforeseen occurrence in spite of

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compliance with good manufacturing (b) Processing method. The processing practice) to a shipping temperature method shall not affect the integrity of warmer than ¥5 °C and colder than + 10 the product, and shall have been shown °C, the plasma derivative manufacturer to yield consistently a product which is shall label it ‘‘Source Plasma safe for intravenous injection. Salvaged.’’ Appropriate records shall (c) Microbial contamination. All proc- be maintained identifying the units in- essing steps shall be conducted in a volved, describing their disposition, manner to minimize the risk of con- and explaining fully the conditions tamination from microorganisms, that caused the inadvertent tempera- pyrogens, or other impurities. Preserv- ture exposure. atives to inhibit growth of microorga- (c) Relabeling. If Source Plasma is re- nisms shall not be used during proc- quired to be relabeled as ‘‘Source Plas- essing. ma Salvaged’’ under paragraph (a)(1) or (d) Storage of bulk fraction. Bulk con- (b) of this section, the person respon- centrate to be held more than 1 week sible for the relabeling shall cover the prior to further processing shall be original label with either (1) a com- stored in clearly identified closed ves- plete new label containing the appro- sels at a temperature of ¥5 °C or cold- priate information or (2) a partial label er. Any other bulk form of the product, affixed to the original label and con- exclusive of the sterile bulk solution, taining the appropriate new informa- to be held more than 1 week prior to tion, which covers the incorrect infor- further processing shall be stored in mation regarding storage temperature. clearly identified closed vessels at a temperature of 5 °C or colder. Any bulk [45 FR 80501, Dec. 5, 1980, as amended at 50 fraction to be held one week or less FR 4140, Jan. 29, 1985] prior to further processing shall be stored in clearly identified closed ves- Subpart H—Albumin (Human) sels at a temperature of 5 °C or colder. (e) Heat treatment. Heating of the § 640.80 Albumin (Human). final containers of Albumin (Human) (a) Proper name and definition. The shall begin within 24 hours after com- proper name of the product shall be Al- pletion of filling. Heat treatment shall bumin (Human). The product is defined be conducted so that the solution is as a sterile solution of the albumin de- heated continuously for not less than rived from human plasma. 10, or more than 11 hours, at an at- ± ° (b) Source material. The source mate- tained temperature of 60 0.5 C. ± rial of Albumin (Human) shall be plas- (f) Stabilizer. Either 0.08 0.016 ma recovered from Whole Blood pre- millimole sodium caprylate, or ± pared as prescribed in §§ 640.1 through 0.08 0.016 millimole sodium ± 640.5, or Source Plasma prepared as acetyltryptophanate and 0.08 0.016 prescribed in §§ 640.60 through 640.76. millimole sodium caprylate per gram (c) Additives in source material. Source of protein shall be present as a sta- material shall not contain an additive bilizer(s). Calculations of the stabilizer unless it is shown that the processing concentration may employ the labeled method yields a final product free of value for the protein concentration of the additive to such extent that the the product as referred to in § 640.84(d). continued safety, purity, potency, and (g) Incubation. All final containers of effectiveness of the final product will Albumin (Human) shall be incubated at ° not be adversely affected. 20 to 35 C for at least 14 days following the heat treatment prescribed in para- [42 FR 27582, May 31, 1977, as amended at 50 graph (e) of this section. At the end of FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, this incubation period, each final con- 1999] tainer shall be examined and all containers showing any indication of tur- § 640.81 Processing. bidity or microbial contamination (a) Date of manufacture. The date of shall not be issued. The contents of manufacture shall be the date of final turbid final containers shall be exam- sterile filtration of a uniform pool of ined microscopically and tested for ste- bulk solution. rility. If growth occurs, organisms

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shall be identified as to genus, and the temperature that shall not exceed the material from such containers shall recommended storage temperature of not be used for further manufacturing. the final product prescribed in § 610.53 [42 FR 27582, May 31, 1977, as amended at 50 of this chapter. FR 4140, Jan. 29, 1985; 64 FR 26286, May 14, [42 FR 27582, May 31, 1977] 1999; 65 FR 13679, Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000] § 640.84 Labeling. § 640.82 Tests on final product. In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of Tests shall be performed on the final this chapter, the container and pack- product to determine that it meets the age labels shall contain the following following standards: information: (a) Protein concentration. Final prod- (a) The osmotic equivalent in terms uct shall conform to one of the fol- ± of plasma, and the sodium concentra- lowing concentrations: 4.0 0.25 per- tion in terms of a value or a range in cent; 5.0 ±0.30 percent; 20.0 ±1.2 percent; ± milliequivalents per liter; and 25.0 1.5 percent solution of pro- (b) The cautionary statement placed tein. in a prominent position on the label, (b) Protein composition. At least 96 ‘‘Do Not Use if Turbid. Do Not Begin percent of the total protein in the final Administration More Than 4 Hours product shall be albumin, as deter- After the Container Has Been En- mined by a method that has been ap- tered.’’; proved for each manufacturer by the (c) The need for additional fluids Director, Center for Biologics Evalua- when 20 percent or 25 percent albumin tion and Research, Food and Drug Ad- is administered to a patient with ministration. marked dehydration; (c) pH. The pH shall be 6.9 ±0.5 when (d) The protein concentration, ex- measured in a solution of the final pressed as a 4 percent, 5 percent, 20 per- product diluted to a concentration of 1 cent, or 25 percent solution. percent protein with 0.15 molar sodium chloride. [42 FR 27582, May 31, 1977, as amended at 49 (d) Sodium concentration. The sodium FR 2244, Jan. 19, 1984; 64 FR 26286, May 14, concentration of the final product shall 1999] be 130 to 160 milliequivalents per liter. (e) Potassium concentration. The po- Subpart I—Plasma Protein Fraction tassium concentration of the final (Human) product shall not exceed 2 milliequivalents per liter. SOURCE: 42 FR 27583, May 31, 1977, unless (f) Heat stability. A final container otherwise noted. sample of Albumin (Human) shall remain unchanged, as determined by vis- § 640.90 Plasma Protein Fraction ual inspection, after heating at 57 °C (Human). for 50 hours, when compared to its con- (a) Proper name and definition. The trol consisting of a sample, from the proper name of the product shall be same lot, which has not undergone this Plasma Protein Fraction (Human). The heating. product is defined as a sterile solution [42 FR 27582, May 31, 1977, as amended at 49 of protein composed of albumin and FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, globulin, derived from human plasma. 1985; 55 FR 11013, Mar. 26, 1990; 64 FR 26286, (b) Source material. The source mate- May 14, 1999] rial of Plasma Protein Fraction (Human) shall be plasma recovered § 640.83 General requirements. from Whole Blood prepared as pre- (a) Preservative. The final product scribed in §§ 640.1 through 640.5, or shall not contain a preservative. Source Plasma prepared as prescribed (b) Storage of bulk solution. After all in §§ 640.60 through 640.76. processing steps have been completed, (c) Additives in source material. Source the sterile bulk solution shall be stored material shall not contain an additive in a manner that will ensure the con- unless it is shown that the processing tinued sterility of the product, and at a method yields a final product free of

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the additive to such extent that the (f) Stabilizer. Either 0.08±0.016 continued safety, purity, potency, and millimole sodium caprylate, or effectiveness of the final product will 0.08±0.016 millimole sodium not be adversely affected. acetyltryptophanate and 0.08±0.016 millimole sodium caprylate per gram [42 FR 27583, May 31, 1977, as amended at 64 of protein shall be present as a sta- FR 26286, May 14, 1999] bilizer(s). Calculations of the stabilizer § 640.91 Processing. concentration may employ the labeled value 5 percent for the protein con- (a) Date of manufacture. The date of centration of the product. manufacture shall be the date of final (g) Incubation. All final containers of sterile filtration of a uniform pool of Plasma Protein Fraction (Human) bulk solution. shall be incubated at 20 to 35 °C for at (b) Processing method. The processing least 14 days following the heat treat- method shall not affect the integrity of ment prescribed in paragraph (e) of this the product, and shall have been shown section. At the end of this incubation to yield consistently a product which: period, each final container shall be ex- (1) After the heating prescribed in amined and all containers showing any paragraph (e) of this section does not indication of turbidity or microbial show an increase in the components contamination shall not be issued. The with electrophoretic mobility similar contents of turbid final containers to that of alpha globulin that amounts shall be examined microscopically and to more than 5 percent of the total pro- tested for sterility. If growth occurs, tein. the types of organisms shall be identi- (2) Contains less than 5 percent pro- fied as to genus and the material from tein with a sedimentation coefficient such containers shall not be used for greater than 7.0 S. further manufacturing. (3) Is safe for intravenous injection. [42 FR 27583, May 31, 1977, as amended at 64 (c) Microbial contamination. All proc- FR 26286, May 14, 1999] essing steps shall be conducted in a manner to minimize the risk of con- § 640.92 Tests on final product. tamination from microorganisms, Tests shall be performed on the final pyrogens, or other impurities. Preserv- product to determine that it meets the atives to inhibit growth of microorga- following standards: nisms shall not be used during proc- (a) Protein concentration. The final essing. product shall be a 5.0 ±0.30 percent so- (d) Storage of bulk fraction. Bulk con- lution of protein. centrate to be held more than 1 week (b) Protein composition. The total pro- prior to further processing shall be tein in the final product shall consist stored in clearly identified closed ves- of at least 83 percent albumin, and no sels at a temperature of ¥5 °C or cold- more than 17 percent globulins. No er. Any other bulk form of the product more than 1 percent of the total pro- (exclusive of the sterile bulk solution) tein shall be gamma globulin. The pro- to be held more than 1 week prior to tein composition shall be determined further processing, shall be stored in by a method that has been approved for clearly identified closed vessels at a each manufacturer by the Director, temperature of 5 °C or colder. Any bulk Center for Biologics Evaluation and fraction to be held one week or less Research, Food and Drug Administra- prior to further processing shall be tion. stored in clearly identified closed ves- (c) pH. The pH shall be 7.0 ±0.3 when sels at a temperature of 5 °C or colder. measured in a solution of the final (e) Heat treatment. Heating of the product diluted to a concentration of 1 final containers of Plasma Protein percent protein with 0.15 molar sodium Fraction (Human) shall begin within 24 chloride. hours after completion of filling. Heat (d) Sodium concentration. The sodium treatment shall be conducted so that concentration of the final product shall the solution is heated continuously for be 130 to 160 milliequivalents per liter. not less than 10 or more than 11 hours (e) Potassium concentration. The po- at an attained temperature of 60±0.5 °C. tassium concentration of the final

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product shall not exceed 2 milli- (b) Source material. The source mate- equivalents per liter. rial of Immune Globulin (Human) shall (f) Heat stability. A final container be plasma recovered from Whole Blood sample of Plasma Protein Fraction prepared as prescribed in §§ 640.1 (Human) shall remain unchanged, as through 640.5, or Source Plasma pre- determined by visual inspection, after pared as prescribed in §§ 640.60 through heating at 57 °C for 50 hours, when 640.76. compared to its control consisting of a (c) Additives in source material. The sample, from the same lot, which has source material shall contain no addi- not undergone this heating. tives other than citrate or acid citrate dextrose anticoagulant solution, unless [42 FR 27583, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, it is shown that the processing method 1990; 64 FR 26286, May 14, 1999; 65 FR 13679, yields a product free of the additive to Mar. 14, 2000] such an extent that the safety, purity, and potency of the product will not be § 640.93 General requirements. affected adversely. (a) Preservative. The final product [38 FR 32089, Nov. 20, 1973, as amended at 50 shall not contain a preservative. FR 4140, Jan. 29, 1985; 64 FR 26287, May 14, (b) Storage of bulk solution. After all 1999] processing steps have been completed, the sterile bulk solution shall be stored § 640.101 General requirements. in a manner that will ensure the con- (a) Heat stability test. Approximately 2 tinued sterility of the product, and at a ml. of completely processed material of temperature that shall not exceed the each lot shall not show any visible sign recommended storage temperature of of gelation after heating in a 12 × 75 the final product prescribed in § 610.53 mm. stoppered glass tube at 57 °C for 4 of this chapter. hours. (b) pH. The pH of final container ma- § 640.94 Labeling. terial shall be 6.8 ±0.4 when measured In addition to the labeling require- in a solution diluted to 1 percent pro- ments of §§ 610.60, 610.61, and 610.62 of tein with 0.15 molar sodium chloride. this chapter, the container and pack- (c) Turbidity. The product shall be age labels shall contain the following free of turbidity as determined by vis- information: ual inspection of final containers. (a) The osmotic equivalent in terms (d) Date of manufacture. The date of of plasma, and the sodium concentra- manufacture is the date of initiating tion in terms of a value or a range in the last valid measles or poliomyelitis milliequivalents per liter. antibody test (§ 640.104(b) (2) and (3)) (b) The cautionary statement placed whichever date is earlier. in a prominent position on the label, (e) Labeling. In addition to complying ‘‘Do Not Use if Turbid. Do Not Begin with all applicable labeling required in Administration More than 4 Hours this subchapter, labeling shall indicate After the Container Has Been En- that: tered.’’ (1) There is no prescribed potency for viral hepatitis antibodies. [42 FR 27583, May 31, 1977, as amended at 49 (2) The product is not recommended FR 2244, Jan. 19, 1984; 64 FR 26286, May 14, for intravenous administration. 1999] [38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar. Subpart J—Immune Globulin 29, 1983, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611, (Human) Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999] § 640.100 Immune Globulin (Human). (a) Proper name and definition. The § 640.102 Manufacture of Immune proper name of this product shall be Globulin (Human). Immune Globulin (Human). The prod- (a) Processing method. The processing uct is defined as a sterile solution con- method shall be one that has been taining antibodies derived from human shown: (1) To be capable of concen- plasma. trating tenfold from source material at

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least two different antibodies; (2) not § 640.104 Potency. to affect the integrity of the globulins; (a) Antibody levels and tests. Each lot (3) to consistently yield a product of final product shall contain at least which is safe for subcutaneous and the minimum levels of antibodies for intramuscular injection and (4) not to diphtheria, measles, and for at least transmit viral hepatitis. one type of poliomyelitis. In the event (b) Microbial contamination. Low tem- the final bulk solution is stored at a peratures or aseptic techniques shall be temperature above 5 °C the antibody used to minimize contamination by level tests shall be performed after microorganisms. Preservatives to in- such storage with a sample of the hibit growth of microorganisms shall stored material. not be used during processing. (b) Minimum levels. The minimum (c) Bulk storage. The globulin fraction antibody levels are as follows: may be stored in bulk prior to further (1) No less than 2 units of diphtheria processing provided it is stored in antitoxin per ml. clearly identified hermetically closed (2) A measles neutralizing antibody vessels. Globulin as either a liquid con- level that, when compared with that of centrate or a solid and containing alco- a reference material designated by the hol or more than 5 percent moisture Center for Biologics Evaluation and shall be stored at a temperature of ¥10 Research (CBER), Food and Drug Ad- °C or lower. Globulin as a solid free ministration, as indicated in paragraph from alcohol and containing less than 5 (c) of this section, demonstrates ade- percent moisture, shall be stored at a quate potency. The Director, CBER, temperature of 0 °C or lower. shall notify manufacturers when a new (d) Determination of the lot. Each lot reference material will be used and will of Immune Globulin (Human) shall rep- advise manufacturers of an appropriate resent a pooling of approximately antibody level taking into account a equal amounts of material from not comparison of the new reference mate- less than 1,000 donors. rial to the previous reference material. (e) Sterilization and heating. The final (3) A poliomyelitis Type 1, Type 2, or product shall be sterilized promptly Type 3 neutralizing antibody level after solution. At no time during proc- that, when compared with that of a ref- essing shall the product be exposed to erence material designated by the Cen- temperatures above 45 °C, and after ter for Biologics Evaluation and Re- sterilization the product shall not be search, Food and Drug Administration, exposed to temperatures above 32 °C for as indicated in paragraph (c) of this more than 72 hours. section, demonstrates adequate potency. The Director, CBER, shall no- [38 FR 32089, Nov. 20, 1973, as amended at 50 tify manufacturers when a new ref- FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 26287, May 14, 1999; 65 FR 13679, erence material will be used and will Mar. 14, 2000; 65 FR 52018, Aug. 28, 2000] advise manufacturers of an appropriate antibody level taking into account a § 640.103 The final product. comparison of the new reference material to the previous reference material. (a) Final solution. The final product (c) Reference materials. The following shall be a 16.5 ±1.5 percent solution of reference materials shall be obtained globulin containing 0.3 molar glycine from the Center for Biologics Evalua- and a preservative. tion and Research: (b) Protein composition. At least 96 (1) Reference Immune Globulin for percent of the total protein shall be correlation of measles antibody titers. immunoglobulin G (IgG), as deter- (2) Reference Immune Globulin for mined by a method that has been ap- correlation of poliomyelitis antibody proved for each manufacturer by the titers, Types 1, 2, and 3. Director, Center for Biologics Evalua- tion and Research, Food and Drug Ad- [38 FR 32089, Nov. 20, 1973, as amended at 39 ministration. FR 9661, Mar. 13, 1974; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, [38 FR 32089, Nov. 20, 1973, as amended at 64 Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998; 64 FR FR 26287, May 14, 1999] 26287, May 14, 1999]

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Subpart K [Reserved] § 640.125 Definitions. The definitions set out in § 630.3 of Subpart L—Alternative Procedures this chapter apply to the use of those defined terms in this part. § 640.120 Alternative procedures. § 640.130 Medical supervision. (a) The Director, Center for Biologics Evaluation and Research, may issue an The requirements for medical super- exception or alternative to any re- vision established in § 630.5 of this quirement in subchapter F of chapter I chapter supplement the regulations in of title 21 of the Code of Federal Regu- this part. lations regarding blood, blood components, or blood products. The Director PART 660—ADDITIONAL STAND- may issue such an exception or alter- ARDS FOR DIAGNOSTIC SUB- native in response to: STANCES FOR LABORATORY (1) A written request from an estab- TESTS lishment. Licensed establishments must submit such requests in accord- Subpart A—Antibody to Hepatitis B Surface ance with § 601.12 of this chapter; Antigen (2) An oral request from an establishment, if there are difficult cir- Sec. cumstances and submission of a writ- 660.1 Antibody to Hepatitis B Surface Anti- gen. ten request is not feasible. Establish- 660.2 General requirements. ments must follow up such oral request 660.3 Reference panel. by submitting written requests under 660.4 Potency test. paragraph (a)(1) of this section within 5 660.5 Specificity. working days. 660.6 Samples; protocols; official release. (b) To respond to a public health Subpart B [Reserved] need, the Director may issue a notice of exception or alternative to any re- Subpart C—Blood Grouping Reagent quirement in subchapter F of chapter I of title 21 of the Code of Federal Regu- 660.20 Blood Grouping Reagent. lations regarding blood, blood compo- 660.21 Processing. 660.22 Potency requirements with reference nents, or blood products, if a variance preparations. under this section is necessary to as- 660.25 Potency tests without reference prep- sure that blood, blood components, or arations. blood products will be available in a 660.26 Specificity tests and avidity tests. specified location or locations to ad- 660.28 Labeling. dress an urgent and immediate need for blood, blood components, or blood Subpart D—Reagent Red Blood Cells products or to provide for appropriate 660.30 Reagent Red Blood Cells. donor screening and testing. 660.31 Eligibility of donor. (c) If the Director issues such an ex- 660.32 Collection of source material. ception or alternative orally, the Di- 660.33 Testing of source material. rector will follow up by issuing a writ- 660.34 Processing. 660.35 Labeling. ten notice of the exception or alter- 660.36 Samples and protocols. native. Periodically, FDA will provide a list of approved exceptions and alter- Subpart E—Hepatitis B Surface Antigen native procedures on the FDA Center for Biologics Evaluation and Research 660.40 Hepatitis B Surface Antigen. 660.41 Processing. Web site. 660.43 Potency test. [80 FR 29906, May 22, 2015] 660.44 Specificity. 660.45 Labeling. 660.46 Samples; protocols; official release. Subpart M—Definitions and Medical Supervision Subpart F—Anti-Human Globulin 660.50 Anti-Human Globulin. SOURCE: 80 FR 29906, May 22, 2015, unless 660.51 Processing. otherwise noted. 660.52 Reference preparations.

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