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U.S. Department of Health and Human Services

CFR - Code of Federal Regulations Title 21

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Help | More About 21CFR
[Code of Federal Regulations]
[Title 21, Volume 7]
[Revised as of April 1, 2013]
[CITE: 21CFR640]





TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER F--BIOLOGICS
 
PART 640ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
 

Subpart G--Source Plasma

Sec. 640.60 Source Plasma.

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

[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]

Sec. 640.61 Informed consent.

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

Sec. 640.62 Medical supervision.

A qualified licensed physician shall be on the premises when donor suitability is being determined, immunizations are being made, whole blood is being collected, and red blood cells are being returned to the donor.

[66 FR 1837, Jan. 10, 2001]

Sec. 640.63 Suitability of donor.

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

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

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

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

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

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

(1) Normal temperature;

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

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

(4) A normal pulse rate;

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

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

(7) Freedom from acute respiratory diseases;

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

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

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

(11) Freedom from a history of viral hepatitis after the 11th birthday;

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

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

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

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

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

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

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

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10768, Mar. 12, 1976; 43 FR 9805, Mar. 10, 1978; 43 FR 12311, Mar. 24, 1978; 46 FR 57480, Nov. 24, 1981; 50 FR 4140, Jan. 29, 1985; 64 FR 45373, Aug. 19, 1999; 66 FR 1837, Jan. 10, 2001; 66 FR 40890, Aug. 6, 2001]

Sec. 640.64 Collection of blood for Source Plasma.

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

(b)Blood containers . Blood containers and donor sets must be pyrogen-free, sterile, and identified by lot number.

(c)The anticoagulant solution . The anticoagulant solution must be sterile and pyrogen-free. Anticoagulant solutions must be compounded and used according to a formula that has been approved for the applicant by the Director, Center for Biologics Evaluation and Research.

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

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

[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at 41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56453, Oct. 20, 1999; 72 FR 45888, Aug. 16, 2007]

Sec. 640.65 Plasmapheresis.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 64 FR 45373, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999]

Sec. 640.66 Immunization of donors.

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

[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

Sec. 640.67 Laboratory tests.

Each unit of Source Plasma shall be tested for evidence of infection due to communicable disease agents as required under 610.40 of this chapter.

[66 FR 31165, June 11, 2001]

Sec. 640.68 Processing.

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

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

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

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 50 FR 4140, Jan. 29, 1985]

Sec. 640.69 General requirements.

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

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

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

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

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

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

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

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

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

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

[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998; 64 FR 45374, Aug. 19, 1999]

Sec. 640.71 Manufacturing responsibility.

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

(1) The test for hepatitis B surface antigen.

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

(3) The serologic test for syphilis.

(4) A test for antibody to HIV.

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

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

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

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

[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 64 FR 45374, Aug. 19, 1999; 64 FR 56453, Oct. 20, 1999; 66 FR 1837, Jan. 10, 2001]

Sec. 640.72 Records.

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

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

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

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

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

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

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

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

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

[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 64 FR 45374, Aug. 19, 1999; 67 FR 9587, Mar. 4, 2002]

Sec. 640.73 Reporting of fatal donor reactions.

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

[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]

Sec. 640.74 Modification of Source Plasma.

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

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

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

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

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

(4) The label affixed to each container of Source Plasma Liquid shall contain, in addition to the information required by 606.121 of this chapter, but excluding 606.121(e)(5)(ii) of this chapter, the name of the manufacturer of the final blood derivative product for whom it was prepared.

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

[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998; 64 FR 56454, Oct. 20, 1999; 77 FR 18, Jan. 3, 2012]

Sec. 640.76 Products stored or shipped at unacceptable temperatures.

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

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

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

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

[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.
Source: 38 FR 32089, Nov. 20, 1973, unless otherwise noted.

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