/* These are the FDA standards for the treatment of blood products, parts 606-current good manufacturing practice for blood and blood components; and 607-establishment registration and product listing for manufacturers of human blood and blood products. This file concludes with excerpts from CFR part 610, concerning blood screening, and part 640, blood donor donor screening. */
PART 606-CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD COMPONENTS
Subpart A-General Provisions
Sec.
606.3 Definitions.
Subpart B Organization and Personal
606.20 Personnel.
Subpart C-Plant and Facilities
606.40 Facilities.
Subpart D-Equipment
606.60 Equipment.
606.65 Supplies and reagents.
Subpart E-[Reserved]
Subpart F-Production and Process Controls
606.100 Standard operating procedures.
606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
Subpart G-Finished Product Control
606.120 Labeling, general requirements.
606.121 Container label.
606.122 Instruction circular.
Subpart H-Laboratory Controls
606.140 Laboratory controls.
606.151 Compatibility testing.
Subpart I-Records and Reports
606.160 Records.
606.165 Distribution and receipt; procedures and records.
606.170 Adverse reaction file.
Subpart A-General Provisions
606.3 Definitions.
As used in this part:
(a) Blood means whole blood collected from a single donor and processed either for transfusion or further manufacturing.
(b) Unit means the volume of blood or one of its components in a suitable volume of anticoagulant obtained from a single collection of blood from one donor.
(c) Component means that part of a single-donor unit of blood separated by physical or mechanical means.
(d) Plasma for further manufacturing means that liquid portion of blood separated and used as material to prepare another product.
(e) Plasmapheresis means the procedure in which blood is removed from the donor, the plasma is separated from the formed elements and at least the red blood cells are returned to the donor. This process may be immediately repeated, once.
(f) Plateletpheresis means the procedure in which blood is removed from the donor, a platelet concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor.
(g) Leukapheresis means the procedure in which blood is removed from the donor, a leukocyte concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor.
(h) Facilities means any area used for the collection, processing, compatibility testing, storage or distribution of blood and blood components.
(i) Processing means any procedure employed after collection and before compatibility testing of blood and includes the identification of a unit of donor blood, the preparation of components from such unit of donor blood, serological testing, labeling and associated recordkeeping.
(j) Compatibility testing means the in vitro serological tests performed on donor and recipient blood samples to establish the serological matching of a donor's blood or blood components with that of a potential recipient.
606.20 Personnel.
(a) A blood establishment shall be under the direction of a designated, qualified person who shall exercise control of the establishment In all matters relating to compliance with the provisions of this subchapter. This person shall also have the authority to represent the establishment in all pertinent matters with the Center for Biologics Evaluation and Research and to enforce, or direct the enforcement of, discipline and the performance of assigned functions by employees engaged in the collection, processing, compatibility testing, storage and distribution of blood and blood components. The designated director shall have an understanding of the scientific principles and techniques involved in the manufacture of blood products and shall have the responsibility for ensuring that employees are adequately trained in standard operating procedures and that they are aware of the application of the pertinent provisions of this chapter to their respective functions.
(b) The personnel responsible for the collection, processing, compatibility testing, storage or distribution of blood or blood components shall be adequate in number, educational background, training and experience, including professional training as necessary, or combination thereof, to assure competent performance of their as-signed functions, and to ensure that the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. All personnel shall have capabilities commensurate with their as-signed functions, a thorough understanding of the procedures or control operations they perform, the necessary training or experience, and adequate information concerning the application of pertinent provisions of this part to their respective functions.
(c) Persons whose presence can adversely affect the safety and purity of the products shall be excluded from areas where the collection, processing, compatibility testing, storage or distribution of blood or blood components is conducted.
Subpart C-Plant and Facilities
606.40 Facilities.
Facilities shall be maintained in a clean and orderly manner, and shall be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operations. The facilities shall:
(a) Provide adequate space for the following when applicable:
(1) Private and accurate examinations of individuals to determine their suitability as blood donors.
(2) The withdrawal of blood from donors with minimal risk of contamination, or exposure to activities and equipment unrelated to blood collection.
(3) The storage of blood or blood components pending completion of tests.
(4) The quarantine storage of blood or blood components in a designated location pending repetition of those tests that initially gave questionable serological results.
(5) The storage of finished products prior to distribution.
(6) The quarantine storage, handling and disposition of products and reagents not suitable for use.
(7) The orderly collection, processing, compatibility testing, storage and distribution of blood and blood components to prevent contamination.
(8) The adequate and proper performance of all steps in plasmapheresis, plateletpheresis and leukapheresis procedures.
(9) The orderly conduction of all packaging, labeling and other finishing operations.
(b) Provide adequate lighting, ventilation and screening of open windows and doors.
(c) Provide adequate, clean, and convenient handwashing facilities for personnel, and adequate, clean, and convenient toilet facilities for donors and personnel. Drains shall be of adequate size and, where connected directly to a sewer, shall be equipped with traps to prevent back-siphonage.
(d) Provide for safe and sanitary disposal for the following:
(1) Trash and items used during the collection, processing and compatibility testing of blood and blood components.
(2) Blood and blood components not suitable for use or distribution.
Subpart D-Equipment
/*For the accompanying chart, please refer to file 606D in the .PCX menu.*/
606.60 Equipment.
(a) Equipment used in the collection, processing, compatibility testing, storage and distribution of blood and blood components shall be maintained in a clean and orderly manner and located so as to facilitate cleaning and maintenance. The equipment shall be observed, standardized and calibrated on a regularly scheduled basis as prescribed in the Standard Operating Procedures Manual and shall perform in the manner for which it was designed so as to assure compliance with the official requirements prescribed in this chapter for blood and blood products.
(b) Equipment that shall be observed, standardized and calibrated with at least the following frequency, include but are not limited to:
(c) Equipment employed in the sterilization of materials used in blood collection or for disposition of contaminated products shall be designed, maintained and utilized to ensure the destruction of contaminating microorganisms. The effectiveness of the sterilization procedure shall be no less than that achieved by an attained temperature of 121.5' C (251' F) maintained for 20 minutes by saturated steam or by an attained temperature of 170' C (338' F) maintained for 2 hours with dry heat.
606.65 Supplies and reagents. All supplies and reagents used in the collection, processing, compatibility testing, storage and distribution of blood and blood components shall be stored in a safe, sanitary and orderly manner.
(a) All surfaces coming in contact with blood and blood components intended for transfusion shall be sterile, pyrogen-free, and shall not interact with the product in such a manner as to have an adverse effect upon the safety, purity, potency or effectiveness of the product. All final containers and closures for blood and blood components not intended for transfusion shall be clean and free of surface solids and other contaminants.
(b) Each blood collecting container and its satellite container(s), if any, shall be examined visually for damage or evidence of contamination prior to its use and immediately after filling. Such examination shall include inspection for breakage of seals, when indicated, and abnormal discoloration. Where any defect is observed, the container shall not be used, or, if detected after filling, shall be properly discarded.
(c) Representative samples of each lot of the following reagents or solutions shall be tested on a regularly scheduled basis by methods described in the Standard Operating Procedures Manual to determine their capacity to perform as required:
Reagent or solution Frequency of testing
Anti-human serum Each day of use.
Blood grouping serums Do.
Lectins Do.
Antibody Screening and
reverse grouping cells. Do.
Hepatitis test reagents Each Run.
Syphilis serology reagents Do.
Enzymes Each day of use.
(d) Supplies and reagents that do not bear an expiration date shall be stored in such a manner that the oldest is used first.
(e) Supplies and reagents shall be used in a manner consistent with instructions provided by the manufacturer.
(f) Items that are required to be sterile and come into contact with blood should be disposable whenever possible.
Subpart E-(Reserved]
Subpart F-Production and Process Controls
606.100 Standard operating procedures.
(a) In all instances, except clinical investigations, standard operating procedures shall comply with published additional standards in part 640 of this chapter for the products being processed; except that. references in part 640 relating to licenses, licensed establishments and submission of material or data to or approval by the Director, Center for Biologics Evaluation and Research are not applicable to establishments not subject to licensure under section 351 of the Public Health Service Act.
(b) Written standard operating procedures shall be maintained and shall include all steps to be followed in the collection, processing, compatibility testing, storage and distribution of blood and blood components for homologous transfusion, autologous transfusion and further manufacturing purposes. Such procedures shall be available to the personnel for use in the areas where the procedures are performed, unless this is impractical. The written standard operating procedures shall include, but are not limited to, descriptions of the following, when applicable:
(1) Criteria used to determine donor suitability, including acceptable medical history criteria.
(2) Methods of performing donor qualifying tests and measurements, including minimum and maximum values for a test or procedure when a factor in determining acceptability.
(3) Solutions and methods used to prepare the site of phlebotomy to give maximum assurance of a sterile container of blood.
(4) Method of accurately relating the product(s) to the donor.
(5) Blood collection procedure. including in-process precautions taken to measure accurately the quantity of blood removed from the donor.
(6) Methods of component preparation, including any time restrictions for specific steps in processing.
(7) All tests and repeat tests performed on blood and blood components during processing, including testing for hepatitis B surface antigen as prescribed in 610.40 of this chapter.
(8) Pretransfusion testing, where applicable, including precautions to be taken to identify accurately the recipient blood samples and crossmatched donor units.
(9) Procedures for investigating ad-verse donor and recipient reactions.
(10) Storage temperatures and methods of controlling storage temperatures for all blood products and reagents as prescribed in 600.15 and 610.53 of this chapter.
(11) Length of expiration dates, if any, assigned for all final products as prescribed in 610.53 of this chapter.
(12) Criteria for determining whether returned blood is suitable for reissue.
(13) Procedures used for relating a unit of blood or blood component from the donor to its final disposition.
(14) Quality control procedures for supplies and reagents employed in blood collection, processing and pretransfusion testing.
(15) Schedules and procedures for equipment maintenance and calibration.
(16) Labeling procedures, including safeguards to avoid labeling mixups.
(17) Procedures of plasmapheresis, plateletpheresis, and leukapheresis, if performed, including precautions to be taken to ensure reinfusion of a donor's own cells.
(18) Procedure for preparing recovered (salvaged) plasma, if performed, including details of separation, pooling, labeling, storage and distribution.
(c) All records pertinent to the lot or unit maintained pursuant to these regulations shall be reviewed before the release or distribution of a lot or unit of final product. The review or portions of the review may be performed at appropriate periods during or after blood collecting, processing, compatibility testing and storing. A thorough investigation, including the conclusions and followup, of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications shall be made and recorded.
(d) In addition to the requirements of this subpart and in conformity with this section, any facility may utilize current standard operating procedures such as the manuals of the following organizations, as long as such specific procedures are consistent with, and at least as stringent as, the requirements contained in this part.
(1) American Association of Blood Banks.
(2) American National Red Cross.
(3) Other organizations or individual blood banks, subject to approval by the Director, Center for Biologics Evaluation and Research.
606.110 Plateletpheresis, leukapheresis, and plasmapheresis.
(a) The use of plateletpheresis and leukapheresis procedures to obtain a product for a specific recipient may be at variance with the additional standards for specific products prescribed in this part provided that: (1) A physician has determined that the recipient must be transfused with the leukocytes or platelets from a specific donor, and (2) the procedure is performed under the supervision of a qualified licensed physician who is aware of the health status of the donor, and the physician has certified in writing that the donor's health permits plateletpheresis or leukapheresis.
(b) Plasmapheresis of donors who do not meet the donor requirements of 640.63. 640.64 and 640.65 of this chapter for the collection of plasma containing rare antibodies shall be permitted only with the prior approval of the Director, Center for Biologics Evaluation and Research.
Subpart G-Finished Product Control
606.120 Labeling, general requirements.
(a) Labeling operations shall be separated physically or spatially from other operations in a manner adequate to prevent mixups.
(b) The labeling operation shall include the following labeling controls:
(1) Labels shall be held upon receipt, pending review and proofing against an approved final copy, to ensure accuracy regarding identity, content, and conformity with the approved copy.
(2) Each type of label representing different products shall be stored and maintained in a manner to prevent mixups, and stocks of obsolete labels shall be destroyed.
(3) All necessary checks in labeling procedures shall be utilized to prevent errors in translating test results to container labels.
(c) All labeling shall be clear and legible.
606.121 Container label.
(a) The container label requirements are designed to facilitate the use of a uniform container label for blood and blood components (except Source Plasma) by all blood establishments. Single copies of an FDA guideline entitled "Guideline for the Uniform Labeling of Blood and Blood Components" are available upon request (under Docket No. 80N-0120) from the Dockets Management Branch (HFA-305), Food and Drug Administration, Rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857 (copies of the guideline are available also from the American Blood Commission, 1901 North Ft. Myer Drive, Suite 300, Arlington, VA 22209).
(b) The label provided by the collecting facility and the initial processing facility shall not be removed, altered, or obscured, except that the label may be altered to indicate the proper name and other information required to identify accurately the contents of a container after blood components have been prepared.
(c) The container label shall include the following information, as well as other specialized information as required in this section for specific products:
(1) The proper name of the product in a prominent position, and modifier(s), if appropriate.
(2) The name, address, registration number, and, if a licensed product, the license number of each manufacturer.
(3) The donor, pool, or lot number relating the unit to the donor.
(4) The expiration date, including the day, month, and year, and, if the dating period for the product is 72 hours or less, the hour of expiration.
(5) If the product is intended for transfusion, the appropriate donor classification statement, i.e., "paid donor" or "volunteer donor", in no less prominence than the proper name of the product.
(I) A paid donor is a person who receives monetary payment for a blood donation.
(II) A volunteer donor is a person who does not receive monetary payment for a blood donation.
(III) Benefits, such as time off from work, membership in blood assurance programs, and cancellation of nonreplacement fees that are not readily convertible to cash, do not constitute monetary payment within the meaning of this paragraph.
(6) For Whole Blood, Plasma, Platelets, and partial units of Red Blood Cells, the volume of the product, accurate to within 110 percent; or optionally for Platelets, the volume range within reasonable limits.
(7) The recommended storage temperature (in degrees Celsius).
(8) If the product is intended for transfusion, the statements:
(i) "Caution: Federal law prohibits dispensing without prescription."
(ii) "See circular of information for indications, contraindications, cautions, and methods of infusion."
(iii) "Properly identify intended recipient."
(9) The statement: "This product may transmit infectious agents."
(10) Where applicable, the name and volume of source material.
(11) The statement: "Caution: For Manufacturing Use Only", when applicable.
(12) If the product is intended for transfusion, the ABO and Rh groups of the donor shall be designated conspicuously. For Cryoprecipitated AHF, the Rh group may be omitted. The Rh group shall be designated as follows:
(i) If the test using Anti-D Blood Grouping Serum is positive, the product shall be labeled: "Rh positive."
(ii) If the test using Anti-D Blood Grouping Serum is negative but the test for DU is positive, the product shall be labeled: "Rh positive."
(iii) If the test using Anti-D Blood Grouping Serum is negative and the test for DU is negative, the product shall be labeled: "Rh negative."
(13) The container label may bear encoded information in the form of machine-readable symbols approved for use by the Director, Center for Biologics Evaluation and Research (HFB-l).
(d) Except for recovered plasma in-tended for manufacturing use or as otherwise approved by the Director. Center for Biologics Evaluation and Research (HFB-l), the paper of the container label shall be white and print shall be solid black, with the following additional exceptions:
(1) The Rh blood group shall be printed as follows:
(i) Rh positive: Use black print on white background.
(ii) Rh negative: Use white print on black background.
(2) The proper name of the product, any appropriate modifier(s), the donor classification statement, and the statement "properly identify intended recipient" shall be printed in solid red.
(3) The following color scheme may be used optionally for differentiating ABO Blood groups:
Blood group color of label paper
0 Blue.
A Yellow.
B Pink.
AB White.
(4) Ink colors used for the optional color coding system described in paragraph (d)(3) of this section shall be a visual match to specific color samples designated by the Director, Center for Biologics Evaluation and Research (HFB-1).
(5) Special labels, such as those described in paragraphs (h) and (i) of this section, may be color coded using the colors recommended in the guideline (see paragraph (a) of this section), or colors otherwise approved for use by the Director, Center for Biologics Evaluation and Research (HFB-1).
(e) Container label requirements for particular products or groups of products.
(1) Whole Blood labels shall include:
(i) The volume of anticoagulant.
(ii) The name of the applicable anticoagulant immediately preceding and of no less prominence than the proper name and expressed as follows: (a) ACD, (b) CPD, (c) Heparin, (d) CPDA1, (e) CP2D, or by other nomenclature approved for use by the Director, Office of Biologics Research and Review (HFN-800), Center for Drugs and Biologics.
(iii) If tests for unexpected antibodies are positive, blood intended for transfusion shall be labeled: "Contains (name of antibody)."
(2) Except for frozen, deglycerolized, or washed Red Blood Cell products, red blood cell labels shall include:
(i) The volume and kind of Whole Blood, including the type of anticoagulant, from which the product was prepared.
(ii) If tests for unexpected antibodies are positive and the product is intended for transfusion, the statement: "Contains (name of antibody)."
(3) Labels for products with a dating period of 72 hours or less, including any product prepared in a system that may compromise sterility, shall bear the hour of expiration.
(4) If tests for unexpected antibodies are positive, Plasma intended for transfusion shall be labeled: "Contains (name of antibody)."
(5) Recovered plasma labels shall include:
(i) In lieu of an expiration date, the date of collection of the oldest material in the container.
(ii) The statement: "Caution: For Manufacturing Use Only"; or "Caution: For Use in Manufacturing Noninjectable Products Only", as applicable.
(iii) For recovered plasma not meeting the requirements for manufacture into licensable products, the statement: "Not for Use in Products Subject to License Under Section 351 of the Public Health Service Act."
(f) Blood and blood components determined to be unsuitable for transfusion shall be prominently labeled: "NOT FOR TRANSFUSION", and the label shall state the reason the unit is considered unsuitable. The provision does not apply to recovered plasma labeled according to paragraph (e)(5) of this section.
(g) As required under 610.40 of this chapter, labels for blood and blood components that are reactive for Hepatitis B Surface Antigen, but that are Intended for further manufacturing, shall state conspicuously that the material is reactive when tested for hepatitis B surface antigen and may transmit viral hepatitis or, as applicable, that blood was collected from a donor known to be reactive for hepatitis B surface antigen and is presumed to be infectious, although confirmatory hepatitis testing has not been done.
(h) The following additional information shall appear on the label for blood or blood components shipped in an emergency, prior to completion of required tests, in accordance with 640.2(f) of this chapter:
(1) The statement: "FOR EMERGENCY USE ONLY BY _____
(2) Results of any tests prescribed under 610.40, 610.45, and 640.5 (a), (b), or (c) of this chapter completed before shipment.
(3) Indication of any tests prescribed under 610.40, 610.45, and 640.5 (a), (b), or (c) of this chapter and not completed before shipment.
(i) The following additional information shall appear on the label for Whole Blood or Red Blood Cells intended for autologous infusion:
(1) Information adequately identifying the patient, e.g., name, blood group, hospital, and identification number.
(2) Date of donation.
(3) The statement: "FOR AUTOLOGOUS USE ONLY."
(4) In place of the blood group label, each container of blood intended for autologous use and obtained from a donor who fails to meet any of the donor suitability requirements under 640.3 of this chapter or who is reactive in the hepatitis tests prescribed under 610.40 of this chapter shall be prominently and permanently labeled: "FOR AUTOLOGOUS USE ONLY."
(5) Units of blood originally intended for autologous use, except those labeled as prescribed under paragraph (i)(4) of this section, may be issued for homologous transfusion provided the container label complies with all applicable provisions of paragraphs (b) through (e) of this section. In such case, the special label required under paragraph (i) (1), (2), and (3) of this section shall be removed or otherwise obscured.
(j) A tie-tag attached to the container may be used for providing the information required by paragraph (e) (1 )(i), (2)(ii), and (4), (h), or (i)( 1), (2), and (3) of this section.
606.122 Instruction circular.
An instruction circular shall be available for distribution if the product is intended for transfusion. The instruction circular shall provide adequate directions for use, including the following information:
(a) Instructions to mix the product before use.
(b) Instructions to use a filter in the administration equipment.
(c) The statement "Do Not Add Medications" or an explanation concerning allowable additives.
(d) A description of the product, its source, and preparation, including the name and proportion of the anticoagulant used in collecting the Whole Blood from each product is prepared.
(e) Statements that the product was prepared from blood that was negative when tested for antibody to Human Immunodeficiency Virus (HIV) and nonreactive for hepatitis B surface antigen by FDA required tests and nonreactive when tested for syphilis by a serologic test for syphilis (STS).
(f) The statements: "Warning. The risk of transmitting hepatitis is present. Careful donor selection and available laboratory tests do not eliminate the hazard."
(g) The names of cryoprotective agents and other additives that may still be present in the product,
(h) The names and results of all tests performed when necessary for safe and effective use.
(i) The use of the product, indications, contraindications, side effects and hazards, dosage and administration recommendations,
(j) (Reserved)
(k) For Red Blood Cells, the instruction circular shall contain:
(1) Instructions to administer a suitable plasma volume expander if Red Blood Cells are substituted when Whole Blood is the indicated product.
(2) A warning not to add Lactated Ringer's Injection U.S.P. solution to Red Blood Cell products.
(1) For Platelets, the instruction circular shall contain:
(1) The approximate volume of plasma from which a sample unit of Platelets is prepared.
(2) Instructions to begin administration as soon as possible, but not more than 4 hours after entering the container.
(m) For Plasma, the instruction circular shall contain:
(1) A warning against further processing of the frozen product if there is evidence of breakage or thawing.
(2) Instructions to thaw the frozen product at a temperature between 30 and 37 'C.
(3) When applicable, instructions to begin administration of the product within 6 hours after thawing.
(4) Instructions to administer to ABO-group-compatible recipients.
(5) A statement that this product has the same hepatitis risk as Whole Blood; other plasma volume expanders without this risk are available for treating hypovolemia.
(n) For Cryoprecipitated AHF, the instruction circular shall contain:
(1) A statement that the average potency is 80 or more International Units of antihemophilic factor.
(2) The statement: "Usually contains at least 150 milligrams of fibrinogen"; or, alternatively, the average fibrinogen level determined by assay of representative units.
(3) A warning against further processing of the product if there is evidence of breakage or thawing.
(4) Instructions to thaw the product for no more than 15 minutes at a temperature of 37 C.
(5) Instructions to store at room temperature after thawing and to begin administration as soon as possible but no more than 4 hours after entering the container or after pooling and within 6 hours after thawing.
(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is the preferred diluent.
(7) Adequate instructions for pooling to ensure complete removal of all concentrated material from each container.
(8) The statement: "Good patient management requires monitoring treatment responses to Cryoprecipitated AHF transfusions with periodic plasma factor VIII or fibrinogen assays in hemophilia A and hypofibrinogenemic recipients, respectively."
Subpart H-Laboratory Controls
606.140 Laboratory controls.
Laboratory control procedures shall include:
(a) The establishment of scientifically sound and appropriate specifications, standards and test procedures to assure that blood and blood components are safe, pure, potent and effective.
(b) Adequate provisions for monitoring the reliability, accuracy, precision and performance of laboratory test procedures and instruments.
(c) Adequate identification and handling of all test samples so that they are accurately related to the specific unit of product being tested, or to its donor, or to the specific recipient, where applicable.
606.151 Compatibility testing.
Standard operating procedures for compatibility testing shall include the following:
(a) A method of collecting and identifying the blood samples of recipients to ensure positive identification.
(b) The use of fresh recipient serum samples less than 48 hours old for all pretransfusion testing.
(c) The testing of the donor's cells with the recipient's serum (major crossmatch) by a method that will demonstrate agglutinating, coating and hemolytic antibodies, which shall include the antiglobulin method.
(d) A provision that, if the unit of donor's blood has not been screened by a method that will demonstrate agglutinating, coating and hemolytic antibodies, the recipient's cells shall be tested with the donor's serum (minor crossmatch) by a method that will so demonstrate.
(e) Procedures to expedite transfusions in life-threatening emergencies. Records of all such incidents shall be maintained, including complete documentation justifying the emergency action, which shall be signed by the physician requesting the procedure,
Subpart I-Records and Reports
606.160 Records.
(a)( 1) Records shall be maintained concurrently with the performance of each significant step in the collection, processing, compatibility testing, storage and distribution of each unit of blood and blood components so that all steps can be clearly traced. All records shall be legible and indelible, and shall identify the person performing the work, include dates of the various entries, show test results as well as the interpretation of the results, show the expiration date assigned to specific products, and be as detailed as necessary to provide a complete history of the work performed.
(2) Appropriate records shall be available from which to determine lot numbers of supplies and reagents used for specific lots or units of the final product.
(b) Records shall be maintained that include, but are not limited to, the following when applicable:
(1) Donor records:
(i) Donor selection, including medical interview and examination and where applicable, informed consent.
(ii) Permanent and temporary deferrals for health reasons including reason(s) for deferral.
(iii) Donor adverse reaction complaints and reports, Including results of all investigations and followup.
(iv) Therapeutic bleedings, including signed requests from attending physicians, the donor's disease and disposition of units.
(v) Immunization, including informed consent, identification of the antigen, dosage and route of administration.
(vi) Blood collection, including identification of the phlebotomist.
(2) Processing records:
(I) Blood processing, including results and interpretation of all tests and retests.
(ii) Component preparation, including all relevant dates and times.
(iii) Separation and pooling of recovered plasma.
(iv) Centrifugation and pooling of source plasma.
(v) Labeling, including initials of
person(s) responsible,
(3) Storage and distribution records:
(i) Distribution and disposition, as appropriate, of blood and blood products,
(ii) Visual inspection of whole blood and red blood cells during storage and immediately before distribution.
(iii) Storage temperature, including
initialed temperature recorder charts.
(iv) Reissue, including records of proper temperature maintenance.
(v) Emergency release of blood, including signature of requesting physician obtained before or after release.
(4) Compatibility test records:
(i) Results of all compatibility tests, including crossmatching, testing of patient samples, antibody screening and identification.
(ii) Results of confirmatory testing.
(5) Quality control records:
(i) Calibration and standardization
of equipment.
(ii) Performance checks of equipment and reagents.
(iii) Periodic check on sterile technique.
(iv) Periodic tests of capacity of shipping containers to maintain proper temperature in transit.
(v) Proficiency test results.
(6) Transfusion reaction reports and complaints, including records of investigations and followup.
(7) General records:
(i) Sterilization of supplies and reagents prepared within the facility, including date, time interval, temperature and mode.
(ii) Responsible personnel, (iii) Errors and accidents. (iv) Maintenance records for equipment and general physical plant.
(v) Supplies and reagents, including name of manufacturer or supplier, lot numbers, expiration date and date of receipt.
(vi) Disposition of rejected supplies and reagents used in the collection, processing and compatibility testing of blood and blood components.
(c) A donor number shall be assigned to each accepted donor, which relates the unit of blood collected to that donor, to his medical record, to any component or blood product from that donor's unit of blood, and to all records describing the history and ultimate disposition of these products.
(d) Records shall be retained for such interval beyond the expiration date for the blood or blood component as necessary to facilitate the reporting of any unfavorable clinical reactions. The retention period shall be no less than 5 years after the records of processing have been completed or 6 months after the latest expiration date for the individual product, whichever is a later date. When there is no expiration date, records shall be retained indefinitely,
(e) A record shall be available from which unsuitable donors may be identified so that products from such individuals will not be distributed.
606.165 Distribution and receipt; procedures and records.
(a) Distribution and receipt procedures shall include a system by which the distribution or receipt of each unit can be readily determined to facilitate its recall, if necessary.
(b) Distribution records shall contain information to readily facilitate the identification of the name and address of the consignee, the date and quantity delivered, the lot number of the unit(s), the date of expiration or the date of collection, whichever is applicable, or for crossmatched blood and blood components, the name of the recipient.
(c) Receipt records shall contain the name and address of the collecting facility, date received, donor or lot number assigned by the collecting facility and the date & expiration or the date of collection, whichever is applicable.
606.170 Adverse reaction file.
(a) Records shall be maintained of any reports of complaints of adverse reactions regarding each unit of blood or blood product arising as a result of blood collection or transfusion. A thorough investigation of each reported adverse reaction shall be made. A written report of the investigation of adverse reactions, including conclusions and followup, shall be prepared and maintained as part of the record for that lot or unit of final product by the collecting or transfusing facility. When it is determined that the product was at fault in causing a transfusion reaction, copies of all such written reports shall be forwarded to and maintained by the manufacturer or collecting facility.
(b) When a complication of blood collection or transfusion is confirmed to be fatal, the Director, Office of Compliance, Center for Biologics Evaluation and Research, shall be notified by telephone or telegraph as soon as possible; a written report of the investigation shall be submitted to the Director, Office of Compliance, Center for Biologics Evaluation and Research, within 7 days after the fatality by the collecting facility in the event of a donor reaction, or by the facility that performed the compatibility tests in the event of a transfusion reaction.
PART 607-ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS
Subpart A-General Provisions
Sec.
607.3 Definitions.
607.7 Establishment registration and product listing of blood banks and other firms manufacturing human blood and blood products.
Subpart I-Procedures for Domestic Blood Product Establishments
607.20 Who must register and submit a blood product list.
607.21 Times for establishment registration and blood product listing.
607.22 How and where to register establishments and list blood products.
607.25 Information required for establishment registration and blood product listing.
607.35 Notification of registrant; blood product establishment registration number and NDC Labeler Code,
607.37 Inspection of establishment registrations and blood product listings.
607.39 Misbranding by reference to establishment registration or to registration number.
Subpart C-Procedures for Foreign Blood Product Establishments
607.40 Blood product listing requirements for foreign blood product establishments.
Subpart D-Exemptions
607.65 Exemptions for blood product establishments.
Subpart A-General Provisions
607.3 Definitions.
(a) The term act means the Federal Food, Drug, and Cosmetic Act approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C. 301-392).
(b) Blood and blood product means a drug which consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma or serum, hereinafter referred to as "blood product,"
(c) Establishment means a place of business under one management at one general physical location. The term includes, among others, human blood and plasma donor centers, blood banks, transfusion services, other blood product manufacturers and independent laboratories that engage in quality control and testing for registered blood product establishments,
(d) Manufacture means the collection, preparation, processing or compatibility testing by chemical, physical, biological, or other procedures of any blood product which meets the definition of a drug as defined in section 201(g) of the act, and including manipulation, sampling, testing, or control procedures applied to the final product or to any part of the process. The term includes packaging, labeling, repackaging or otherwise changing the container, wrapper, or labeling of any blood product package in furtherance of the distribution of the blood product from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.
(e) Commercial distribution means any distribution of a blood product except pursuant to the investigational use provisions of part 312 of this chapter, but does not include internal or interplant transfer of a bulk product substance between registered domestic establishments within the same parent, subsidiary, and/or affiliate company.
(f) Any material change includes but is not limited to any change in the name of the blood product, in the quantity or identity of the active ingredient(s) or in the quantity or identity of the inactive ingredient(s) where quantitative listing of all ingredients is required pursuant to 607,31(a)(2) and any significant change in the labeling of a blood product. Changes that are not significant include changes in arrangement or printing or changes of an editorial nature.
(g) Bulk product substance means any substance that is represented for use in a blood product and when used in the manufacturing of a blood product becomes an active ingredient or a finished dosage form of such product.
(h) Advertising and labeling include the promotional material described in 202.1(1) (1) and (2) of this chapter, respectively.
(i) The definitions and interpretations contained in sections 201 and 510 of the act shall be applicable to such terms when used in this part 607.
607.7 Establishment registration and product listing of blood banks and other firms manufacturing human blood and blood products.
(a) All owners or operators of establishments that engage in the manufacturing of blood products are required to register, pursuant to section 510 of the Federal Food, Drug, and Cosmetic Act. Registration and listing of blood products shall comply with this part. Registration does not permit any blood bank or similar establishment to ship blood products in interstate commerce.
(b) Forms for registration of an establishment are obtainable on request from the Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892 or at any of the Food and Drug Administration district offices.
(c) The completed form should be mailed to the Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892.
Subpart B-Procedures for Domestic Blood Product Establishments
607.20 Who must register and submit a blood product list.
(a) Owners or operators of all establishments, not exempt under section 510(g) of the act or subpart D of this part 607, that engage in the manufacture of blood products are required to register and to submit a list of every blood product in commercial distribution (except that listing information may be submitted by the parent, subsidiary, and/or affiliate company for all establishments when operations are conducted at more than one establishment and there exists joint ownership and control among all the establishments), whether or not the output of such blood product establishment or any particular blood product so listed enters interstate commerce.
(b) Preparatory to engaging in the manufacture of blood products, owners or operators of establishments who are submitting an establishment license application to manufacture blood products are required to register before the establishment license application is approved.
(c) No registration fee is required. Establishment registration and blood product listing do not constitute an admission or agreement or determination that a blood product is a "drug" within the meaning of section 201(g) of the act.
607.21 Times for establishment registration and blood product listing.
The owner or operator of an establishment entering into an operation defined in 607.3(d) shall register such establishment within 5 days after the beginning of such operation and submit a list of every blood product in commercial distribution at the time. If the owner or operator of the establishment has not previously entered into such operation (defined in 607.3(d)) for which a license is required, registration shall follow within 5 days after the submission of an establishment and product license application in order to manufacture blood products. Owners or operators of all establishments so engaged shall register annually between November 15 and December 31 and shall update their blood product listing information every June and December.
607.22 How and where to register establishments and list blood products.
(a) The first registration of an establishment shall be on Form FD-2830 (Blood Establishment Registration and Product Listing) obtainable on request from the Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892, or from Food and Drug Administration district offices. Subsequent annual registration shall also be accomplished on Form FD-2830 which will be furnished by the Food and Drug Administration before November 15 of each year to establishments whose product registration for that year was validated pursuant to 607.35. The completed form shall be mailed to the above address before December 31 of that year.
(b) The first list of blood products and subsequent June and December updatings shall be on Form Fl)-2830, obtainable upon request as described in paragraph (a) of this section. In lieu of Form Fl)- 2830, tapes for computer input may be submitted if equivalent in all elements of information as specified in Form FD-2830. All formats proposed for such use will require initial review and approval by the Office of Compliance, Center for Biologics Evaluation and Research, Food and Drug Administration.
607.25 Information required for establishment registration and blood product listing.
(a) Form FD-2830 (Blood Establishment Registration and Product Listing) requires furnishing or confirming registration information required by the act. This information includes the name and street address of the establishment, including post office ZIP code; all trade names used by the establishment; the kind of ownership or operation (that is, individually owned partnership, or corporation); and the name of the owner or operator of such establishment. The term "name of the owner or operator" shall include in the case of a partnership the name of each partner, and in the case of a corporation the name and title of each corporate officer and director and the name of the State of incorporation. The information required shall be given separately for each establishment, as defined in 607.3(c).
(b) Form FD-2830 also requires furnishing blood product listing information required by the act as follows:
(1) A list of blood products, Including bulk product substances as well as finished dosage forms, by established name as defined in section 502(e) of the act and by proprietary name, which are being manufactured for commercial distribution and which have not been included in any list previously submitted on Form FD-2830 (Blood Establishment Registration and Product Listing) or Form FD-2250 (National Drug Code Directory Input).
(2) For each blood product so listed which is subject to section 351 of the Public Health Service Act, the license number of the manufacturer issued by the Center for Biologics Evaluation and Research, Food and Drug Administration.
(3) For each blood product listed, the registration number of every blood product establishment within the parent company at which it is manufactured.
607.26 Amendments to establishment registration.
Changes in individual ownership, corporate or partnership structure location or blood-product-handling activity, shall be submitted on Form Fl)-2830 (Blood Establishment Registration and Product Listing) as amendment to registration within 5 days of such changes. Changes in the names of officers and directors of the corporations do not require such amendment but must be shown at time of annual registration.
(a) After submission of the initial blood product listing information, every person who is required to list blood products pursuant to 607.20 shall submit on Form FD-2830 (Blood Establishment Registration and Product Listing) during each subsequent June and December, or at the discretion of the registrant at the time the change occurs, the following information:
(1) A list of each blood product introduced by the registrant for commercial distribution which has not been included in any list previously submitted. All of the information required by 607.25(b) shall be provided for each such blood product.
(2) A list of each blood product formerly listed pursuant to 607.25(b) for which commercial distribution has been discontinued, including for each blood product so listed the identity by established name and proprietary name, and date of discontinuance. It is requested but not required that the reason for discontinuance of distribution be included with this information.
(3) A list of each blood product for which a notice of discontinuance was submitted pursuant to paragraph (a)(2) of this section and for which commercial distribution has been resumed, including for each blood product so listed the identity by established name as defined in section 502(e) of the act and by any proprietary name, the date of resumption, and any other information required by 607.25(b) not previously submitted.
(4) Any material change in any information previously submitted.
(b) When no changes have occurred since the previously submitted list, no listing information is required.
(a) In addition to the information routinely required by 607.25 and 607.30, the Commissioner may require submission of the following information by letter or by FEDERAL REGISTER notice:
(1) For a particular blood product so listed, upon request made by the Commissioner for good cause, a copy of all advertisements.
(2) For a particular blood product so listed, upon a finding by the Commissioner that it is necessary to carry out the purposes of the act, a quantitative listing of all ingredients.
(3) For each registrant, upon a finding by the Commissioner that it is necessary to carry out the purposes of the act, a list of each listed blood product containing a particular ingredient.
(b) It is requested but not required that information concerning the quantity of blood product distributed be submitted in conjunction with the annual registration in the format prescribed in a section of Form FD-2831 (Blood Establishment Resource Summary), for each blood product currently listed.
607.35 Notification of registrant; blood product establishment registration number and NDC Labeler Code.
(a) The Commissioner will provide to the registrant a validated copy of Form FD-2830 (Blood Establishment Registration and Product Listing) as evidence of registration. This validated copy will be sent only to the location shown for the registering establishment. A permanent registration number will be assigned to each blood product establishment registered in accordance with these regulations.
(b) If a registered blood product establishment has not previously participated in the National Drug Code system, or in the National Health Related Items Code system, the National Drug Code (NDC) numbering system shall be used in assigning the first five numeric characters, otherwise known as the Labeler Code, of the 10-character NDC Code. The Labeler Code identifies the manufacturer.
(c) Although establishment registration and blood product listing are required as described in 607.20, validation of registration and the assignment of a NDC Labeler Code do not, in themselves, establish that the holder of the registration is legally qualified to deal in such products.
607.37 Inspection of establishment registrations and blood product listings,
(a) A copy of the Form FD-2830 (Blood Establishment Registration and Product Listing) filed by the registrant will be available for inspection pursuant to section 510(f) of the act, at the Department of Health and Human Services, Food and Drug Administration, Office of Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD 20892. In addition, there will be available for inspection at each of the Food and Drug Administration district offices the same information for firms within the geographical area of such district office. Upon request and receipt of a self-addressed stamped envelope, verification of registration number, or location of a registered establishment will be provided. The following information submitted pursuant to the blood product listing requirements is illustrative of the type of information that will be available for public disclosure when it is compiled:
(1) A list of all blood products.
(2) A list of all blood products manufactured by each establishment.
(3) A list of blood products discontinued.
(4) All data or information that has already become a matter of public knowledge,
(b) Requests for information regarding blood establishment registrations and blood product listings should be directed to the Department of Health and Human Services, Food and Drug Administration, Office of Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD 20892.
607.39 Misbranding by reference to establishment registration or to registration number.
Registration of an establishment or assignment of a registration number or assignment of a NDC number does not in any way denote approval of the firm or its products, Any representation that creates an impression of official approval because of establishment registration or possession of registration number or NDC number is misleading and constitutes misbranding.
Subpart C-Procedures for Foreign Blood Product Establishments
607.40 Blood product listing requirements for foreign blood product establishments,
(a) Every foreign establishment shall comply with the blood product listing requirements contained in Subpart B of this part, unless exempt under Subpart D of this part, whether or not it is also registered.
(b) No blood product may be imported from a foreign establishment into the United States except a blood product imported or offered for import pursuant to the investigational use provisions of part 312 of this chapter, unless it is first the subject of a blood product listing as required in Subpart B of this part. The blood product listing information shall be in the English language.
(c) Foreign establishments shall submit, as part of the blood product listing, the name and address of the establishment and the name of the individual responsible for submitting blood product listing information. Any changes in this information shall be reported to the Food and Drug Administration at the intervals specified for updating blood product listing information in 607.30(a).
Subpart D-Exemptions
607.65 Exemptions for blood product establishments,
The following classes of persons are exempt from registration and blood product listing in accordance with this part 607 under the provisions of section 510(g) (1), (2), and (3) of the act, or because the Commissioner has found, under section 510(g)(4), that such registration is not necessary for the protection of the public health.
(a) Pharmacies that are operating under applicable local laws regulating dispensing of prescription drugs and that are not manufacturing blood products for sale other than in the regular course of the practice of the profession of pharmacy including the business of dispensing and selling blood products at retail. The supplying by such pharmacies of blood products to a practitioner licensed to administer such blood products for his use in the course of his professional practice or to other pharmacies to meet temporary inventory shortages are not acts which require such pharmacies to register.
(b) Practitioners who are licensed by law to prescribe or administer drugs and who manufacture blood products solely for use in the course of their professional practice.
(c) Persons who manufacture blood products which are not for sale, rather, are solely for use in research, teaching, or analysis, including laboratory samples.
(d) Carriers, by reason of their receipt, carriage, holding, or delivery of blood products in the usual course of business as carriers,
(e) Persons who engage solely in the manufacture of in vitro diagnostic blood products and reagents not subject to licensing under section 351 of the Public Health Service Act (42 U.S.C. 262). This paragraph does not exempt such persons from registration and listing for medical devices required under part 807 of this chapter.
(f) Transfusion services which are a part of a facility approved for Medicare reimbursement and engaged in the compatibility testing and transfusion of blood and blood components, but which neither routinely collect nor process blood and blood components. The collection and processing of blood and blood components in an emergency situation as determined by a responsible person and documented in writing, therapeutic collection of blood or plasma, the preparation of recovered human plasma for further manufacturing use, or preparation of red blood cells for transfusion are not acts requiring such transfusion services to register,
(g) Clinical laboratories that are approved for Medicare reimbursement and are engaged in the testing of blood products in support of other registered blood establishments.
/* This section is listed under Subpart E, hepatitis requirements. */
610.45. Human Immunodeficiency Virus (HIV) requirements.
(a) Testing requirements. (1) Each donation of human blood or blood components intended for use in preparing a product shall be tested for antibody to HIV by a test approved for such use by FDA, except as otherwise approved in writing by FDA. When the test for antibody to HIV is required, blood and blood products nay be issued before the results of the test for antibody to HIV are available only in dire emergency situations or as otherwise approved in writing by FDA and, provided the test required by this paragraph is performed as soon as possible after issuance of the blood or blood product.
(2) Tests approved by FDA for the screening of blood and blood components for evidence of HIV may only be used in place of a test for antibody to HIV to satisfy the requirements of this section and related sections if so specified by FDA.
(b) Testing responsibility. The test for antibody to HIV shall be performed by the collection facility, by personnel of an establishment licensed to manufacture blood or blood derivatives under section 351 (a) of the Public Health Service Act (42 USC 262(a)), or by a clinical laboratory which meets the standards of the Clinical Laboratory Improvement Act of 1967 (CLIA) (42 USC 263a), provided the establishment or clinical laboratory is qualified to perform the test.
(c) Restrictions on use (1) Blood, plasma, or other blood components that are repeatably reactive to a test for antibody to HIV or that were collected from a donor whose blood is known to be repeatably reactive to a test for antibody to HIV, shall not be shipped or sued to prepare any product, including products not subject to licensure; except that such blood and blood components shall be shipped or used only for purposes and under conditions specifically approved in writing by FDA.
(2) The restrictions on use contained in this paragraph shall not apply in the following cases:
(i) Blood and blood components testing repeatably reactive or from a donor whose blood is known to be repeatable reactive that are shown to be negative for evidence of HIV infection by a method or process approved for such use by FDA;
(ii) The distribution of blood, plasma, or serum samples, except when intended for use in the manufacture of a product;
(iii) The in-house use of blood and blood components for research purposes; or
(iv) the distribution of blood and blood components for research purposes, if not distribution by sale, barter, or exchange.
(53 FR 116, Jan. 5, 1988)
/* The following excerpt is taken from 21 CFR Chapter 1, Part 640 -- Additional standards for Human Blood and Blood Products. */
Section 640.3 Suitability of Donor.
(a) Method of determining. The suitability of a donor as a source of Whole Blood shall be determined by a qualified physician or by persons under his supervision and trained in determining suitability. Such determination shall be made on the day of collection from the donor by means of medical history, a test for hemoglobin level, and such physical examination as appears necessary to a physician who shall be present on the premises when examinations are made, except that the suitability of donors may be determined when a physician is not present on the premises, provided the establishment (1) maintains on the premises, and files with the Center for Biologics Evaluation and Research, a manual of standard procedures and methods, approved by the Director of the Center for Biologics valuation and Research, that shall be followed by employees who determine suitability of donors, and (2) maintains records indicating the name and qualifications of the person immediately in charge of the employees who determine the suitability of donors when a physician is not on the premises.
(b) Qualifications of donor; general. Except as provided in paragraph (f), a person may not serve as a source of Whole Blood more than once in 8 weeks. In addition, donors shall be in good health, as indicated in part by:
(1) Normal temperature;
(2) Demonstration that systolic and diastolic blood pressures are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of this section;
(3) A blood hemoglobin level which shall be demonstrated to be no less than 12.5 gm. of hemoglobin per 100 ml. of blood;
(4) Freedom from acute respiratory diseases;
(5) Freedom from any infectious skin disease at the site of phlebotomy and from any such disease generalized to such an extent as to create a risk of contamination of the blood;
(6) Freedom from any disease transmissible by blood transfusion, insofar as can be determined by history and examinations indicated above; and
(7) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics.
(c) Additional qualifications of donors; viral hepatitis. No individual shall be used as a source of Whole Blood if he has --
(1) A history of viral hepatitis;
(2) A history of close contact within six months of donation with an individual having viral hepatitis;
(3) A history of having received within six months human blood, or any derivative of human blood which the Food and Drug Administration has advised the licensed establishment is a possible source of viral hepatitis.
(d) Therapeutic bleedings. Blood withdrawn in order to promote the health of a donor otherwise qualified under the provisions of this section, shall not be used as a source of Whole Blood unless the container label conspicuously indicates the donors disease that necessitated withdrawal of blood.
(e) Immunized donors. Blood withdrawn from donors known to have been immunized to human blood cell antigens shall not be used for Whole Blood unless the container label conspicuously indicates such information.
(f) Qualifications; donations within less than 8 weeks. A person may serve as a source of Whole Blood more than once in 8 weeks only if at the time of donation the person is examined and certified by a person to be in good health, as indicated in part in paragraph (b) of this section.
640.5 Testing the blood.
***
(f) test for antibody to HIV. Whole Blood shall be tested for antibody to HIV as prescribed in 610.45 of this chapter.
/* The above requirements for whole blood also apply generally to all blood products. */
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