45 Part 606—Current Good Man- Ufacturing Practice

Food and Drug Administration, HHS Pt. 606

a presentation. The presiding officer ucts approved under § 601.91, the re- may, as a matter of discretion, permit strictions would no longer apply when questions to be submitted to the pre- FDA determines that safe use of the bi- siding officer for response by a person ological product can be ensured making a presentation. through appropriate labeling. FDA also (f) Judicial review. The Commissioner retains the discretion to remove spe- of Food and Drugs’ decision constitutes cific postapproval requirements upon final agency action from which the ap- review of a petition submitted by the plicant may petition for judicial re- sponsor in accordance with § 10.30 of view. Before requesting an order from a this chapter. court for a stay of action pending review, an applicant must first submit a PART 606—CURRENT GOOD MAN- petition for a stay of action under § 10.35 of this chapter. UFACTURING PRACTICE FOR BLOOD AND BLOOD COMPO- [67 FR 37996, May 31, 2002, as amended at 70 NENTS FR 14984, Mar. 24, 2005]

§ 601.93 Postmarketing safety report- Subpart A—General Provisions ing. Sec. Biological products approved under 606.3 Definitions. this subpart are subject to the postmarketing recordkeeping and safety Subpart B—Organization and Personnel reporting applicable to all approved biological products. 606.20 Personnel.

§ 601.94 Promotional materials. Subpart C—Plant and Facilities For biological products being consid- 606.40 Facilities. ered for approval under this subpart, unless otherwise informed by the agen- Subpart D—Equipment cy, applicants must submit to the agency for consideration during the 606.60 Equipment. preapproval review period copies of all 606.65 Supplies and reagents. promotional materials, including promotional labeling as well as advertise- Subpart E [Reserved] ments, intended for dissemination or Subpart F—Production and Process publication within 120 days following Controls marketing approval. After 120 days following marketing approval, unless oth- 606.100 Standard operating procedures. erwise informed by the agency, the ap- 606.110 Plateletpheresis, leukapheresis, and plicant must submit promotional ma- plasmapheresis. terials at least 30 days prior to the intended time of initial dissemination of Subpart G—Additional Labeling Standards the labeling or initial publication of for Blood and Blood Components the advertisement. 606.120 Labeling, general requirements. § 601.95 Termination of requirements. 606.121 Container label. 606.122 Circular of information. If FDA determines after approval under this subpart that the require- Subpart H—Laboratory Controls ments established in §§ 601.91(b)(2), 601.92, and 601.93 are no longer nec- 606.140 Laboratory controls. essary for the safe and effective use of 606.145 Control of bacterial contamination a biological product, FDA will so no- of platelets. tify the applicant. Ordinarily, for bio- 606.151 Compatibility testing. logical products approved under § 601.91, these requirements will no Subpart I—Records and Reports longer apply when FDA determines 606.160 Records. that the postmarketing study verifies 606.165 Distribution and receipt; procedures and describes the biological product’s and records. clinical benefit. For biological prod- 606.170 Adverse reaction file.

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606.171 Reporting of product deviations by (j) Compatibility testing means the licensed manufacturers, unlicensed reg- procedures performed to establish the istered blood establishments, and trans- matching of a donor’s blood or blood fusion services. components with that of a potential re- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, cipient. 360, 360j, 371, 374; 42 U.S.C. 216, 262, 263a, 264. (k) Distributed means: SOURCE: 40 FR 53532, Nov. 18, 1975, unless (1) The blood or blood components otherwise noted. have left the control of the licensed manufacturer, unlicensed registered Subpart A—General Provisions blood establishment, or transfusion service; or § 606.3 Definitions. (2) The licensed manufacturer has As used in this part: provided Source Plasma or any other (a) Blood means a product that is a blood component for use in the manu- fluid containing dissolved and sus- facture of a licensed biological product. pended elements which was collected (l) Control means having responsi- from the vascular system of a human. bility for maintaining the continued (b) Unit means the volume of blood or safety, purity, and potency of the prod- one of its components in a suitable vol- uct and for compliance with applicable ume of anticoagulant obtained from a product and establishment standards, single collection of blood from one and for compliance with current good donor. manufacturing practices. (c) Blood component means a product [40 FR 53532, Nov. 18, 1975, as amended at 64 containing a part of human blood sepa- FR 45370, Aug. 19, 1999; 65 FR 66635, Nov. 7, rated by physical or mechanical means. 2000; 66 FR 1835, Jan. 10, 2001; 66 FR 40889, (d) Plasma for further manufacturing Aug. 6, 2001; 72 FR 45886, Aug. 16, 2007; 80 FR means that liquid portion of blood sep- 29894, May 22, 2015] arated and used as material to prepare another product. Subpart B—Organization and (e) Plasmapheresis means the proce- Personnel dure in which blood is removed from the donor, the plasma is separated § 606.20 Personnel. from the formed elements and at least (a) [Reserved] the red blood cells are returned to the (b) The personnel responsible for the donor. collection, processing, compatibility (f) Plateletpheresis means the proce- testing, storage or distribution of blood dure in which blood is removed from a or blood components shall be adequate donor, a platelet concentrate is sepa- in number, educational background, rated, and the remaining formed ele- training and experience, including pro- ments are returned to the donor along fessional training as necessary, or com- with a portion of the residual plasma. bination thereof, to assure competent (g) Leukapheresis means the proce- performance of their assigned func- dure in which blood is removed from tions, and to ensure that the final the donor, a leukocyte concentrate is product has the safety, purity, po- separated, and the remaining formed tency, identity and effectiveness it pur- elements and residual plasma are reports or is represented to possess. All turned to the donor. personnel shall have capabilities com- (h) Facilities means any area used for mensurate with their assigned func- the collection, processing, compat- tions, a thorough understanding of the ibility testing, storage or distribution procedures or control operations they of blood and blood components. perform, the necessary training or ex- (i) Processing means any procedure perience, and adequate information employed after collection, and before concerning the application of pertinent or after compatibility testing of blood, provisions of this part to their respec- and includes the identification of a tive functions. unit of donor blood, the preparation of (c) Persons whose presence can ad- components from such unit of donor versely affect the safety and purity of blood, serological testing, labeling and the products shall be excluded from associated recordkeeping. areas where the collection, processing,

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compatibility testing, storage or dis- (9) The orderly conduction of all tribution of blood or blood components packaging, labeling and other finishing is conducted. operations. (b) Provide adequate lighting, ven- [40 FR 53532, Nov. 18, 1975, as amended at 49 tilation and screening of open windows FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997] and doors. (c) Provide adequate, clean, and con- venient handwashing facilities for per- Subpart C—Plant and Facilities sonnel, and adequate, clean, and con- venient toilet facilities for donors and § 606.40 Facilities. personnel. Drains shall be of adequate Facilities shall be maintained in a size and, where connected directly to a clean and orderly manner, and shall be sewer, shall be equipped with traps to of suitable size, construction and loca- prevent back-siphonage. tion to facilitate adequate cleaning, (d) Provide for safe and sanitary dis- maintenance and proper operations. posal for the following: The facilities shall: (1) Trash and items used during the (a) Provide adequate space for the collection, processing and compat- following when applicable: ibility testing of blood and blood com- (1) Private and accurate examina- ponents. tions of individuals to determine their (2) Blood and blood components not eligibility as blood donors. suitable for use or distribution. (2) The withdrawal of blood from do- [40 FR 53532, Nov. 18, 1975, as amended at 80 nors with minimal risk of contamina- FR 29895, May 22, 2015] tion, or exposure to activities and equipment unrelated to blood collec- Subpart D—Equipment tion. (3) The storage of blood or blood com- § 606.60 Equipment. ponents pending completion of tests. (a) Equipment used in the collection, (4) The quarantine storage of blood or processing, compatibility testing, stor- blood components in a designated loca- age and distribution of blood and blood tion pending repetition of those tests components shall be maintained in a that initially gave questionable sero- clean and orderly manner and located logical results. so as to facilitate cleaning and mainte- (5) The storage of finished products nance. The equipment shall be ob- prior to distribution. served, standardized and calibrated on (6) The quarantine storage, handling a regularly scheduled basis as pre- and disposition of products and re- scribed in the Standard Operating Pro- agents not suitable for use. cedures Manual and shall perform in (7) The orderly collection, processing, the manner for which it was designed compatibility testing, storage and dis- so as to assure compliance with the of- tribution of blood and blood compo- ficial requirements prescribed in this nents to prevent contamination. chapter for blood and blood products. (8) The adequate and proper perform- (b) Equipment that shall be observed, ance of all steps in plasmapheresis, standardized and calibrated with at plateletpheresis and leukapheresis pro- least the following frequency, include cedures. but are not limited to:

Equipment Performance check Frequency Frequency of calibration

Temperature recorder .... Compare against thermometer ...... Daily ...... As necessary. Refrigerated centrifuge .. Observe speed and temperature ...... Each day of use Do. Hematocrit centrifuge ...... Standardize before initial use, after repairs or adjustments, and annually. Timer every 3 mo. General lab centrifuge ...... Tachometer every 6 mo. Automated blood-typing Observe controls for correct results ..... Each day of use. machine. Hemoglobinometer ...... Standardize against ...... do. cyanmethemoglobin standard. Refractometer ...... Standardize against distilled water ...... do.

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Equipment Performance check Frequency Frequency of calibration

Blood container scale .... Standardize against container of known ...... do ...... As necessary. weight. Water bath ...... Observe temperature ...... do ...... Do. Rh view box ...... do ...... do ...... Do. Autoclave ...... do ...... Each time of use Do. Serologic rotators ...... Observe controls for correct results ..... Each day of use Speed as necessary. Laboratory thermom- ...... Before initial use. eters. Electronic thermometers ...... Monthly. Vacuum blood agitator .. Observe weight of the first container of Each day of use Standardize with container of known blood filled for correct results. mass or volume before initial use, and after repairs or adjustments.

(c) Equipment employed in the steri- Where any defect is observed, the con- lization of materials used in blood col- tainer shall not be used, or, if detected lection or for disposition of contami- after filling, shall be properly dis- nated products shall be designed, main- carded. tained and utilized to ensure the de- (c) Representative samples of each struction of contaminating microorga- lot of the following reagents or solu- nisms. The effectiveness of the steri- tions shall be tested on a regularly lization procedure shall be no less than scheduled basis by methods described that achieved by an attained tempera- in the Standard Operating Procedures ture of 121.5 °C (251 °F) maintained for Manual to determine their capacity to 20 minutes by saturated steam or by an perform as required: attained temperature of 170 °C (338 °F) maintained for 2 hours with dry heat. Reagent or solution Frequency of testing [40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. Anti-human globulin ...... Each day of use. Blood grouping reagents ...... Do. 2, 1975, as amended at 45 FR 9261, Feb. 12, Lectins ...... Do. 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Antibody screening and re- Do. Apr. 13, 1992] verse grouping cells. Hepatitis test reagents ...... Each run. § 606.65 Supplies and reagents. Syphilis serology reagents .... Do. Enzymes ...... Each day of use. All supplies and reagents used in the collection, processing, compatibility (d) Supplies and reagents that do not testing, storage and distribution of bear an expiration date shall be stored blood and blood components shall be in such a manner that the oldest is stored in a safe, sanitary and orderly used first. manner. (e) Supplies and reagents shall be (a) All surfaces coming in contact used in a manner consistent with in- with blood and blood components instructions provided by the manufac- tended for transfusion shall be sterile, turer. pyrogen-free, and shall not interact (f) Items that are required to be ster- with the product in such a manner as ile and come into contact with blood to have an adverse effect upon the safe- should be disposable whenever possible. ty, purity, potency or effectiveness of the product. All final containers and [40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994] closures for blood and blood components not intended for transfusion shall be clean and free of surface solids Subpart E [Reserved] and other contaminants. (b) Each blood collecting container Subpart F—Production and and its satellite container(s), if any, Process Controls shall be examined visually for damage or evidence of contamination prior to § 606.100 Standard operating proce- its use and immediately after filling. dures. Such examination shall include inspec- (a) In all instances, except clinical tion for breakage of seals, when indi- investigations, standard operating pro- cated, and abnormal discoloration. cedures shall comply with published

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additional standards in part 640 of this ent blood samples and crossmatched chapter for the products being proc- donor units. essed; except that, references in part (9) Procedures for investigating ad- 640 relating to licenses, licensed estab- verse donor and recipient reactions. lishments and submission of material (10) Storage temperatures and meth- or data to or approval by the Director, ods of controlling storage temperatures Center for Biologics Evaluation and for all blood products and reagents as Research, are not applicable to estab- prescribed in §§ 600.15 and 610.53 of this lishments not subject to licensure chapter. under section 351 of the Public Health (11) Length of expiration dates, if Service Act. any, assigned for all final products as (b) Establishments must establish, prescribed in § 610.53 of this chapter. maintain, and follow written standard (12) Criteria for determining whether operating procedures for all steps in returned blood is suitable for reissue. the collection, processing, compat- (13) Procedures used for relating a ibility testing, storage, and distribu- unit of blood or blood component from tion of blood and blood components for the donor to its final disposition. allogeneic transfusion, autologous (14) Quality control procedures for transfusion, and further manufacturing supplies and reagents employed in purposes; for all steps in the investiga- blood collection, processing and tion of product deviations related to § 606.171; and for all steps in record- pretransfusion testing. keeping related to current good manu- (15) Schedules and procedures for facturing practice and other applicable equipment maintenance and calibra- requirements and standards. Such pro- tion. cedures must be available to the per- (16) Labeling procedures, including sonnel for use in the areas where the safeguards to avoid labeling mixups. procedures are performed. The written (17) Procedures of plasmapheresis, standard operating procedures must in- plateletpheresis, and leukapheresis, if clude, but are not limited to, descrip- performed, including precautions to be tions of the following, when applicable: taken to ensure reinfusion of a donor’s (1) Criteria used to determine donor own cells. eligibility, including acceptable med- (18) Procedures for preparing recov- ical history criteria. ered plasma, if performed, including (2) Methods of performing donor details of separation, pooling, labeling, qualifying tests and measurements, in- storage, and distribution. cluding minimum and maximum values (19) Procedures under §§ 610.46 and for a test or procedure when a factor in 610.47 of this chapter: determining acceptability. (i) To identify previously donated (3) Solutions and methods used to blood and blood components from a prepare the site of phlebotomy to give donor who later tests reactive for evi- maximum assurance of a sterile con- dence of human immunodeficiency tainer of blood. virus (HIV) infection or hepatitis C (4) Method of accurately relating the virus (HCV) infection when tested product(s) to the donor. under § 610.40 of this chapter, or when a (5) Blood collection procedure, in- blood establishment is made aware of cluding in-process precautions taken to other reliable test results or informa- measure accurately the quantity of tion indicating evidence of HIV or HCV blood removed from the donor. infection; (6) Methods of component prepara- (ii) To quarantine in-date blood and tion, including any time restrictions blood components previously donated for specific steps in processing. by such a donor that are intended for (7) All tests and repeat tests per- use in another person or further manu- formed on blood and blood components facture into injectable products, except during manufacturing. pooled components intended solely for (8) Pretransfusion testing, where ap- further manufacturing into products plicable, including precautions to be that are manufactured using validated taken to identify accurately the recipi- viral clearance procedures;

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(iii) To notify consignees to quar- as stringent as, the requirements con- antine in-date blood and blood compo- tained in this part. nents previously donated by such a (1) American Association of Blood donor intended for use in another per- Banks. son or for further manufacture into (2) American National Red Cross. injectable products, except pooled com- (3) Other organizations or individual ponents intended solely for further blood banks, subject to approval by the manufacturing into products that are Director, Center for Biologics Evalua- manufactured using validated viral tion and Research. clearance procedures; [40 FR 53532, Nov. 18, 1975, as amended at 49 (iv) To determine the suitability for FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, release, destruction, or relabeling of 1990; 61 FR 47422, Sept. 9, 1996; 64 FR 45370, quarantined in-date blood and blood Aug. 19, 1999; 66 FR 31176, June 11, 2001; 72 FR components; 48798, Aug. 24, 2007; 80 FR 80651, Dec. 28, 2015; (v) To notify consignees of the re- 80 FR 29895, May 22, 2015] sults of the HIV or HCV testing performed on the donors of such blood and § 606.110 Plateletpheresis, leukapheresis, and plasmapheresis. blood components; (vi) To notify the transfusion recipi- (a) The use of plateletpheresis and ent, the recipient’s physician of record, leukapheresis procedures to obtain a or the recipient’s legal representative product for a specific recipient may be that the recipient received blood or at variance with the additional stand- blood components at increased risk of ards for specific products prescribed in transmitting HIV or HCV, respectively. this part provided that: (1) A physician has determined that the recipient must (20) Procedures for donor deferral as be transfused with the leukocytes or prescribed in § 610.41 of this chapter. platelets from a specific donor, and (2) (21) Procedures for donor notification the procedure is performed under the and notification of the referring physi- supervision of a responsible physician cian of an autologous donor, including who is aware of the health status of the procedures for the appropriate followup donor, and the physician has deter- if the initial attempt at notification mined and documented that the do- fails, as prescribed in § 630.40 of this nor’s health permits plateletpheresis or chapter. leukapheresis. (22) Procedures to control the risks of (b) Plasmapheresis of donors who do bacterial contamination of platelets, not meet the donor requirements of including all steps required under §§ 630.10, 630.15, 640.64 and 640.65 of this § 606.145. chapter for the collection of plasma (c) All records pertinent to the lot or containing rare antibodies shall be per- unit maintained pursuant to these reg- mitted only with the prior approval of ulations shall be reviewed before the the Director, Center for Biologics Eval- release or distribution of a lot or unit uation and Research. of final product. The review or portions of the review may be performed at ap- [40 FR 53532, Nov. 18, 1975, as amended at 49 propriate periods during or after blood FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 80 FR 29895, May 22, 2015] collecting, processing, compatibility testing and storing. A thorough investigation, including the conclusions and Subpart G—Additional Labeling followup, of any unexplained discrep- Standards for Blood and ancy or the failure of a lot or unit to Blood Components meet any of its specifications shall be made and recorded. § 606.120 Labeling, general require- (d) In addition to the requirements of ments. this subpart and in conformity with (a) Labeling operations shall be sepa- this section, any facility may utilize rated physically or spatially from current standard operating procedures other operations in a manner adequate such as the manuals of the organiza- to prevent mixups. tions, as long as such specific proce- (b) The labeling operation shall in- dures are consistent with, and at least clude the following labeling controls:

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(1) Labels shall be held upon receipt, (4)(i) The expiration date, including pending review and proofing against an the day, month, and year, and, if the approved final copy, to ensure accuracy dating period for the product is 72 regarding identity, content, and con- hours or less, including any product formity with the approved copy. prepared in a system that might com- (2) Each type of label representing promise sterility, the hour of expira- different products shall be stored and tion. maintained in a manner to prevent (ii) If Source Plasma intended for mixups, and stocks of obsolete labels manufacturing into noninjectable shall be destroyed. products is pooled, the expiration date (3) All necessary checks in labeling for the pool is determined from the col- procedures shall be utilized to prevent lection date of the oldest unit in the errors in translating test results to pool, and the pooling records must container labels. show the collection date for each unit (c) All labeling shall be clear and leg- in the pool. ible. (5) For Whole Blood, Plasma, Plate- lets, and partial units of Red Blood [50 FR 35469, Aug. 30, 1985] Cells, the volume of the product, accurate to within ±10 percent; or option- § 606.121 Container label. ally for Platelets, the volume or vol- (a) The container label requirements ume range within reasonable limits. are designed to facilitate the use of a (6) Where applicable, the name and uniform container label for blood and volume of source material. blood components intended for use in (7) The recommended storage tem- transfusion or further manufacture by perature (in degrees Celsius). all blood establishments. (8) If the product is intended for (b) The label provided by the col- transfusion, the statements: lecting facility and the initial proc- (i) ‘‘Rx only.’’ essing facility must not be removed, al- (ii) ‘‘See circular of information for tered, or obscured, except that the indications, contraindications, cau- label may be altered to indicate the tions, and methods of infusion.’’ proper name of the product, with any (iii) ‘‘Properly identify intended re- appropriate modifiers and attributes, cipient.’’ and other information required to iden- (iv) ‘‘This product may transmit in- tify accurately the contents of a con- fectious agents.’’ tainer after blood components consid- (v) The appropriate donor classifica- ered finished products have been pre- tion statement, i.e., ‘‘paid donor’’ or pared. ‘‘volunteer donor,’’ in no less promi- (c) The container label must include nence than the proper name of the the following information, as well as product. other specialized information as re- (A) A paid donor is a person who required in this section for specific prod- ceives monetary payment for a blood ucts: donation. (1) The proper name of the product in (B) A volunteer donor is a person who a prominent position, with any appro- does not receive monetary payment for priate modifiers and attributes. a blood donation. (2) The name, address, unique facility (C) Benefits, such as time off from identifier, and, if a licensed product, work, membership in blood assurance the license number of each manufac- programs, and cancellation of non- turer; except the container label for replacement fees that are not readily blood and blood components for further convertible to cash, do not constitute manufacture is not required to include monetary payment within the meaning a unique facility identifier. of this paragraph. (3) The donor or lot number relating (9) If the product is intended for the unit to the donor. If pooled, all transfusion or as is otherwise appro- donor numbers, all donation numbers, priate, the ABO group and Rh type of or a pool number that is traceable to the donor must be designated conspicu- each individual unit comprising the ously. For Cryoprecipitated pool. Antihemophiliac Factor (AHF), the Rh

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type may be omitted. The Rh type chine-readable information label re- must be designated as follows: quirement in this section. (i) If the test using Anti-D Blood (iii) What information must be ma- Grouping Reagent is positive, the prod- chine-readable? Each label must have uct must be labeled: ‘‘Rh positive.’’ machine-readable information that (ii) If the test using Anti-D Blood contains, at a minimum: Grouping Reagent is negative, but the (A) A unique facility identifier; test for weak D (formerly Du) is posi- (B) Lot number relating to the donor; tive, the product must be labeled: ‘‘Rh (C) Product code; and positive.’’ (D) ABO and Rh of the donor, except (iii) If the test using Anti-D Blood as described in paragraphs (c)(9) and Grouping Reagent is negative and the (i)(5) of this section. (iv) How must the machine-readable in- test for weak D (formerly Du) is negative, the product must be labeled: ‘‘Rh formation appear? The machine-read- negative.’’ able information must: (10) If the product is not intended for (A) Be unique to the blood or blood transfusion, a statement as applicable: component; ‘‘Caution: For Manufacturing Use (B) Be surrounded by sufficient blank Only,’’ or ‘‘Caution: For Use in Manu- space so that the machine-readable in- facturing Noninjectable Products formation can be scanned correctly; Only,’’ or other cautionary statement and as approved by the Director, Center for (C) Remain intact under normal con- Biologics Evaluation and Research ditions of use. (CBER). (v) Where does the machine-readable in- (11) If the product is intended for fur- formation go? The machine-readable in- ther manufacturing use, a statement formation must appear on the label of listing the results of all the tests for any blood or blood component which is relevant transfusion-transmitted infec- or can be transfused to a patient or tions required under § 610.40 of this from which the blood or blood compo- chapter for which the donation has nent can be taken and transfused to a been tested and found negative; except patient. that the container label for Source (d) Unless otherwise approved by the Plasma is not required to list the nega- Director, CBER, the container label for tive results of serological syphilis test- blood and blood components intended ing under § 640.65(b) of this chapter. for transfusion must be white and print (12) The blood and blood components must be solid black, with the following must be labeled in accordance with additional exceptions: § 610.40 of this chapter, when the dona- (1) The ABO and Rh blood groups tion is tested and demonstrates evi- must be printed as follows: dence of infection due to a relevant (i) Rh positive: Use black print on transfusion-transmitted infection(s). white background and use solid black (13) The container label of blood or or other solid color for ABO. blood components intended for trans- (ii) Rh negative: Use white print on fusion must bear encoded information black background for Rh and use black in a format that is machine-readable outline on a white background for and approved for use by the Director, ABO. CBER. (2) The proper name of the product, (i) Who is subject to this machine-read- with any appropriate modifiers and at- able requirement? All blood establish- tributes, the donor classification statements that manufacture, process, re- ment, and the statement ‘‘properly pack, or relabel blood or blood compo- identify intended recipient’’ may be nents intended for transfusion and reg- printed in solid red or in solid black. (3) The following color scheme may ulated under the Federal Food, Drug, be used for differentiating ABO Blood and Cosmetic Act or the Public Health groups: Service Act. (ii) What blood products are subject to Blood group Color of this machine-readable requirement? All label blood and blood components intended O ...... Blue for transfusion are subject to the ma- A ...... Yellow

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noninjectable products, this statement Blood group Color of label may be replaced by a statement of the B ...... Pink temperature appropriate for manufac- AB ...... White ture of the final product to be prepared from the plasma. (4) Special labels, such as those de- (iii) The total volume or weight of scribed in paragraphs (h) and (i) of this plasma and total quantity and type of section, may be color-coded. anticoagulant used. (e) Container label requirements for (iv) When plasma collected from a particular products or groups of prod- donor is reactive for a serologic test for ucts. syphilis, a statement that the plasma (1) Whole Blood labels must include: is reactive and must be used only for (i) The name of the applicable anti- the manufacturing of positive control coagulant approved for use by the Di- reagents for the serologic test for rector, CBER. syphilis. (ii) The volume of anticoagulant. (v) Source Plasma diverted for (iii) If tests for unexpected antibodies Source Plasma Salvaged must be re- are positive, blood intended for trans- labeled ‘‘Source Plasma Salvaged’’ as fusion must be labeled: ‘‘Contains prescribed in § 640.76 of this chapter. (name of antibody).’’ Immediately following the proper (2) Except for frozen, deglycerolized, name of the product, with any appro- or washed Red Blood Cell products, Red priate modifiers and attributes, the la- Blood Cell labels must include: beling must prominently state as appli- (i) The type of anticoagulant, and if cable, ‘‘STORAGE TEMPERATURE applicable, the volume of Whole Blood EXCEEDED ¥20 °C’’ or ‘‘SHIPPING and type of additive solution, with TEMPERATURE EXCEEDED ¥5 °C.’’ which the product was prepared. (vi) A statement as to whether the (ii) If tests for unexpected antibodies plasma was collected from normal do- are positive and the product is in- nors, or from donors in specific collec- tended for transfusion, the statement: tion programs approved by the Direc- ‘‘Contains (name of antibody).’’ tor, CBER. In the case of specific col- (3) If tests for unexpected antibodies lection programs, the label must state are positive, Plasma intended for the defining characteristics of the plas- transfusion must be labeled: ‘‘Contains ma. In the case of immunized donors, (name of antibody).’’ the label must state the immunizing (4) Recovered plasma labels must in- antigen. clude: (f) Blood and blood components de- (i) In lieu of an expiration date, the termined to be unsuitable for trans- date of collection of the oldest mate- fusion must be prominently labeled rial in the container. ‘‘NOT FOR TRANSFUSION,’’ and the (ii) For recovered plasma not meet- label must state the reason the unit is ing the requirements for manufacture considered unsuitable. The provision into licensable products, the state- does not apply to blood and blood com- ment: ‘‘Not for Use in Products Subject ponents intended solely for further to License Under Section 351 of the manufacture. Public Health Service Act.’’ (g) [Reserved] (iii) The type of anticoagulant with (h) The following additional informa- which the product was prepared. tion must appear on the label for blood (5) Source Plasma labels must in- and blood components shipped in an clude the following information: emergency prior to completion of re- (i) The cautionary statement, as quired tests, in accordance with specified in paragraph (c)(10) of this § 610.40(g) of this chapter: section, must follow the proper name (1) The statement: ‘‘FOR EMER- with any appropriate modifiers and at- GENCY USE ONLY BY ll .’’ tributes and be of similar prominence (2) Results of any tests prescribed as the proper name. under §§ 610.40 and 640.5(b) or (c) of this (ii) The statement ‘‘Store at ¥20 °C chapter completed before shipment. or colder,’’ provided, that where plas- (3) Indication of any tests prescribed ma is intended for manufacturing into under §§ 610.40 and 640.5(b) or (c) of this

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chapter not completed before ship- (a) Instructions to mix the product ment. before use. (i) The following additional informa- (b) Instructions to use a filter in the tion must appear on the label for blood administration equipment. and blood components intended for (c) The statement ‘‘Do Not Add Medi- autologous transfusion: cations’’ or an explanation concerning (1) Information adequately identi- allowable additives. fying the patient, e.g., name, date of (d) A description of the product, its birth, hospital, and identification num- source, and preparation, including the ber. name and proportion of the anticoagu- (2) Date of donation. lant used in collecting the Whole Blood (3) The statement: ‘‘AUTOLOGOUS from each product is prepared. DONOR.’’ (e) A statement that the product was (4) The ABO and Rh blood group and prepared from blood that was found type, except as provided in paragraph negative when tested for relevant (c)(9) of this section. transfusion-transmitted infections, as (5) Each container of blood and blood required under § 610.40 of this chapter component intended for autologous use (include each test that was performed). and obtained from a donor who fails to (f) The statement: ‘‘Warning: The meet any of the donor eligibility re- risk of transmitting infectious agents quirements under § 630.10 of this chap- is present. Careful donor selection and ter or who is reactive to or positive for available laboratory tests do not elimi- one or more tests for evidence of infec- nate the hazard.’’ tion due to relevant transfusion-trans- (g) The names of cryoprotective mitted infections under § 610.40 of this agents and other additives that may chapter must be prominently and per- still be present in the product. manently labeled ‘‘FOR AUTOLOGOUS USE ONLY’’ and as otherwise required (h) The names and results of all tests under § 610.40 of this chapter. Such performed when necessary for safe and units also may have the ABO and Rh effective use. blood group and type on the label. (i) The use of the product, indica- (6) Units of blood and blood compo- tions, contradications, side effects and nents originally intended for hazards, dosage and administration autologous use, except those labeled as recommendations. prescribed under paragraph (i)(5) of this (j) [Reserved] section, may be issued for allogeneic (k) For Red Blood Cells, the circular transfusion provided the container of information must contain: label complies with all applicable pro- (1) Instructions to administer a suit- visions of paragraphs (b) through (e) of able plasma volume expander if Red this section. In such case, the special Blood Cells are substituted when Whole label required under paragraphs (i)(1), Blood is the indicated product. (i)(2), and (i)(3) of this section must be (2) A warning not to add Lactated removed or otherwise obscured. Ringer’s Injection U.S.P. solution to (j) A tie-tag attached to the con- Red Blood Cell products. tainer may be used for providing the (l) For Platelets, the circular of in- information required by paragraphs formation must contain: (e)(1)(iii), (e)(2)(ii), and (e)(3), (h), or (1) The approximate volume of plas- (i)(1), (i)(2), and (i)(3) of this section. ma from which a sample unit of Plate- [77 FR 16, Jan. 3, 2012, as amended at 80 FR lets is prepared. 29895, May 22, 2015] (2) Instructions to begin administration as soon as possible, but not more § 606.122 Circular of information. than 4 hours after entering the con- A circular of information must be tainer. available for distribution if the product (m) For Plasma, the circular of infor- is intended for transfusion. The cir- mation must contain: cular of information must provide ade- (1) A warning against further proc- quate directions for use, including the essing of the frozen product if there is following information: evidence of breakage or thawing.

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(2) Instructions to thaw the frozen Subpart H—Laboratory Controls product at a temperature appropriate for the product. § 606.140 Laboratory controls. (3) When applicable, instructions to Laboratory control procedures shall begin administration of the product include: within a specified time after thawing. (a) The establishment of scientif- (4) Instructions to administer to ically sound and appropriate specifica- ABO-group-compatible recipients. tions, standards and test procedures to (5) A statement that this product has assure that blood and blood compo- the same risk of transmitting infec- nents are safe, pure, potent and effec- tious agents as Whole Blood; other tive. plasma volume expanders without this (b) Adequate provisions for monitoring the reliability, accuracy, preci- risk are available for treating sion and performance of laboratory hypovolemia. test procedures and instruments. (n) For Cryoprecipitated AHF, the (c) Adequate identification and han- circular of information must contain: dling of all test samples so that they (1) A statement that the average po- are accurately related to the specific tency is 80 or more International Units unit of product being tested, or to its of antihemophilic factor. donor, or to the specific recipient, (2) The statement: ‘‘Usually contains where applicable. at least 150 milligrams of fibrinogen’’; or, alternatively, the average § 606.145 Control of bacterial contamination of platelets. fibrinogen level determined by assay of representative units. (a) Blood collection establishments (3) A warning against further proc- and transfusion services must assure essing of the product if there is evi- that the risk of bacterial contamina- dence of breakage or thawing. tion of platelets is adequately con- trolled using FDA approved or cleared (4) Instructions to thaw the product devices or other adequate and appro- for no more than 15 minutes at a tem- priate methods found acceptable for ° perature of between 30 and 37 C. this purpose by FDA. (5) Instructions to store at room tem- (b) In the event that a blood collec- perature after thawing and to begin ad- tion establishment identifies platelets ministration as soon as possible but no as bacterially contaminated, that es- more than 4 hours after entering the tablishment must not release for trans- container or after pooling and within 6 fusion the product or any other compo- hours after thawing. nent prepared from the same collec- (6) A statement that 0.9 percent So- tion, and must take appropriate steps dium Chloride Injection U.S.P. is the to identify the organism. preferred diluent. (c) In the event that a transfusion (7) Adequate instructions for pooling service identifies platelets as to ensure complete removal of all con- bacterially contaminated, the trans- centrated material from each con- fusion service must not release the tainer. product and must notify the blood col- (8) The statement: ‘‘Good patient lection establishment that provided the platelets. The transfusion service management requires monitoring must take appropriate steps to identify treatment responses to the organism; these steps may include Cryoprecipitated AHF transfusions contracting with the collection estab- with periodic plasma factor VIII or lishment or a laboratory to identify fibrinogen assays in hemophilia A and the organism. The transfusion service hypofibrinogenemic recipients, respec- must further notify the blood collec- tively.’’ tion establishment either by providing [50 FR 35470, Aug. 30, 1985, as amended at 53 information about the species of the FR 116, Jan. 5, 1988; 64 FR 45371, Aug. 19, 1999; contaminating organism when the 77 FR 18, Jan. 3, 2012; 80 FR 29895, May 22, transfusion service has been able to 2015] identify it, or by advising the blood collection establishment when the

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transfusion service has determined processing, compatibility testing, stor- that the species cannot be identified. age and distribution of each unit of (d) In the event that a contaminating blood and blood components so that all organism is identified under paragraph steps can be clearly traced. All records (b) or (c) of this section, the collection shall be legible and indelible, and shall establishment’s responsible physician, identify the person performing the as defined in § 630.3(i) of this chapter, work, include dates of the various en- must determine whether the contami- tries, show test results as well as the nating organism is likely to be associ- interpretation of the results, show the ated with a bacterial infection that is expiration date assigned to specific endogenous to the bloodstream of the products, and be as detailed as nec- donor, in accordance with a standard essary to provide a complete history of operating procedure developed under the work performed. § 606.100(b)(22). This determination may (2) Appropriate records shall be avail- not be further delegated. able from which to determine lot num- [80 FR 29895, May 22, 2015] bers of supplies and reagents used for specific lots or units of the final prod- § 606.151 Compatibility testing. uct. Standard operating procedures for (b) Records shall be maintained that compatibility testing shall include the include, but are not limited to, the fol- following: lowing when applicable: (a) A method of collecting and identi- (1) Donor records: fying the blood samples of recipients to (i) Donor selection, including medical ensure positive identification. interview and examination and where (b) The use of fresh recipient serum applicable, informed consent. or plasma samples less than 3 days old (ii) Permanent and temporary defer- for all pretransfusion testing if the re- rals for health reasons including rea- cipient has been pregnant or transfused son(s) for deferral. within the previous 3 months. (iii) Donor adverse reaction com- (c) Procedures to demonstrate incom- plaints and reports, including results of patibility between the donor’s cell type all investigations and followup. and the recipient’s serum or plasma (iv) Therapeutic bleedings, including type. signed requests from attending physi- (d) A provision that, if the unit of do- cians, the donor’s disease and disposi- nor’s blood has not been screened by a tion of units. method that will demonstrate aggluti- (v) Immunization, including informed nating, coating and hemolytic anti- consent, identification of the antigen, bodies, the recipient’s cells shall be dosage and route of administration. tested with the donor’s serum (minor (vi) Blood collection, including iden- crossmatch) by a method that will so tification of the phlebotomist. demonstrate. (vii) Records to relate the donor with (e) Procedures to expedite trans- the unit number of each previous dona- fusion in life-threatening emergencies. tion from that donor. Records of all such incidents shall be (viii) Records concerning the fol- maintained, including complete docu- lowing activities performed under mentation justifying the emergency §§ 610.46 and 610.47 of this chapter: Quar- action, which shall be signed by a phy- antine; consignee notification; testing; sician. notification of a transfusion recipient, [40 FR 53532, Nov. 18, 1975, as amended at 64 the recipient’s physician of record, or FR 45371, Aug. 19, 1999; 66 FR 1835, Jan. 10, the recipient’s legal representative; 2001; 66 FR 40889, Aug. 6, 2001] and disposition. (ix) The donor’s postal address pro- Subpart I—Records and Reports vided at the time of donation where the donor may be contacted within 8 weeks § 606.160 Records. after donation. (a)(1) Records shall be maintained (x) Records of notification of donors concurrently with the performance of deferred or determined not to be eligi- each significant step in the collection, ble for donation, including appropriate

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followup if the initial attempt at noti- cluding date, time interval, tempera- fication fails, performed under § 630.40 ture and mode. of this chapter. (ii) Responsible personnel. (xi) Records of notification of the re- (iii) Biological product deviations. ferring physician of a deferred (iv) Maintenance records for equip- autologous donor, including appro- ment and general physical plant. priate followup if the initial attempt (v) Supplies and reagents, including at notification fails, performed under name of manufacturer or supplier, lot § 630.40 of this chapter. numbers, expiration date and date of (2) Processing records: receipt. (i) Blood processing, including results (vi) Disposition of rejected supplies and interpretation of all tests and and reagents used in the collection, retests. processing and compatibility testing of (ii) Component preparation, includ- blood and blood components. ing all relevant dates and times. (c) A donor number shall be assigned (iii) Separation and pooling of recov- to each accepted donor, which relates ered plasma. the unit of blood collected to that (iv) Centrifugation and pooling of donor, to his medical record, to any source plasma. component or blood product from that (v) Labeling, including initials of the donor’s unit of blood, and to all records person(s) performing the procedure. describing the history and ultimate (3) Storage and distribution records: disposition of these products. (i) Distribution and disposition, as (d) Records shall be retained for such appropriate, of blood and blood prod- interval beyond the expiration date for ucts. the blood or blood component as nec- (ii) Visual inspection of whole blood essary to facilitate the reporting of and red blood cells during storage and any unfavorable clinical reactions. You immediately before distribution. must retain individual product records (iii) Storage temperature, including no less than 10 years after the records initialed temperature recorder charts. of processing are completed or 6 (iv) Reissue, including records of months after the latest expiration date proper temperature maintenance. for the individual product, whichever is (v) Emergency release of blood, in- the later date. When there is no expira- cluding signature of requesting physi- tion date, records shall be retained in- cian obtained before or after release. definitely. (4) Compatibility test records: (e) Records of deferred donors. (1) Es- (i) Results of all compatibility tests, tablishments must maintain at each including crossmatching, testing of pa- location a record of all donors found to tient samples, antibody screening and be ineligible or deferred at that loca- identification. tion so that blood and blood compo- (ii) Results of confirmatory testing. nents from an ineligible donor are not (5) Quality control records: collected and/or released while the (i) Calibration and standardization of donor is ineligible or deferred; and equipment. (2) Establishments must maintain at (ii) Performance checks of equipment all locations operating under the same and reagents. license or under common management (iii) Periodic check on sterile tech- a cumulative record of donors deferred nique. from donation under § 610.41 of this (iv) Periodic tests of capacity of ship- chapter because their donation tested ping containers to maintain proper reactive under § 610.40(a)(1) of this temperature in transit. chapter for evidence of infection due to (v) Proficiency test results. HIV, HBV, or HCV. In addition, estab- (6) Transfusion reaction reports and lishments other than Source Plasma complaints, including records of inves- establishments must include in this cu- tigations and followup. mulative record donors deferred from (7) General records: donation under § 610.41 of this chapter (i) Sterilization of supplies and re- because their donation tested reactive agents prepared within the facility, in- under § 610.40(a)(2) of this chapter for

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evidence of infection due to HTLV or fault in causing a transfusion reaction, Chagas disease. copies of all such written reports shall (3) The cumulative record described be forwarded to and maintained by the in paragraph (e)(2) of this section must manufacturer or collecting facility. be updated at least monthly to add do- (b) When a complication of blood col- nors newly deferred under § 610.41 of lection or transfusion is confirmed to this chapter due to reactive tests for be fatal, the Director, Office of Compli- evidence of infection due to HIV, HBV, ance and Biologics Quality, CBER, or HCV, and, if applicable, HTLV or must be notified by telephone, fac- Chagas disease. simile, express mail, or electronically (4) Establishments must revise the transmitted mail as soon as possible. A cumulative record described in para- written report of the investigation graph (e)(2) of this section to remove must be submitted to the Director, Of- donors who have been requalified under fice of Compliance and Biologics Qual- § 610.41(b) of this chapter. ity, CBER, by mail, facsimile, or elec- [40 FR 53532, Nov. 18, 1975, as amended at 61 tronically transmitted mail (for mail- FR 47422, Sept. 9, 1996; 64 FR 45371, Aug. 19, ing address, see § 600.2(a) of this chap- 1999; 65 FR 66635, Nov. 7, 2000; 66 FR 31176, ter), within 7 days after the fatality by June 11, 2001; 72 FR 48798, Aug. 24, 2007; 80 FR the collecting facility in the event of a 80651, Dec. 28, 2015; 80 FR 29895, May 22, 2015] donor reaction, or by the facility that § 606.165 Distribution and receipt; pro- performed the compatibility tests in cedures and records. the event of a transfusion reaction. (a) Distribution and receipt proce- [40 FR 53532, Nov. 18, 1975, as amended at 49 dures shall include a system by which FR 23833, June 8, 1984; 50 FR 35471, Aug. 30, the distribution or receipt of each unit 1985; 55 FR 11014, Mar. 26, 1990; 64 FR 45371, can be readily determined to facilitate Aug. 19, 1999; 67 FR 9586, Mar. 4, 2002; 77 FR its recall, if necessary. 18, Jan. 3, 2012; 80 FR 18092, Apr. 3, 2015] (b) Distribution records shall contain information to readily facilitate the § 606.171 Reporting of product deviations by licensed manufacturers, identification of the name and address unlicensed registered blood estab- of the consignee, the date and quantity lishments, and transfusion services. delivered, the lot number of the unit(s), the date of expiration or the date of (a) Who must report under this section? collection, whichever is applicable, or You, a licensed manufacturer of blood for crossmatched blood and blood com- and blood components, including ponents, the name of the recipient. Source Plasma; an unlicensed reg- (c) Receipt records shall contain the istered blood establishment; or a trans- name and address of the collecting fa- fusion service who had control over the cility, date received, donor or lot num- product when the deviation occurred, ber assigned by the collecting facility must report under this section. If you and the date of expiration or the date arrange for another person to perform of collection, whichever is applicable. a manufacturing, holding, or distribution step, while the product is in your § 606.170 Adverse reaction file. control, that step is performed under (a) Records shall be maintained of your control. You must establish, any reports of complaints of adverse maintain, and follow a procedure for reactions regarding each unit of blood receiving information from that person or blood product arising as a result of on all deviations, complaints, and ad- blood collection or transfusion. A thor- verse events concerning the affected ough investigation of each reported ad- product. verse reaction shall be made. A written (b) What do I report under this section? report of the investigation of adverse You must report any event, and infor- reactions, including conclusions and mation relevant to the event, associ- followup, shall be prepared and main- ated with the manufacturing, to in- tained as part of the record for that lot clude testing, processing, packing, la- or unit of final product by the col- beling, or storage, or with the holding lecting or transfusing facility. When it or distribution, of both licensed and is determined that the product was at unlicensed blood or blood components,

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including Source Plasma, if that event PART 607—ESTABLISHMENT REG- meets all the following criteria: ISTRATION AND PRODUCT LIST- (1) Either: ING FOR MANUFACTURERS OF (i) Represents a deviation from cur- HUMAN BLOOD AND BLOOD rent good manufacturing practice, applicable regulations, applicable stand- PRODUCTS AND LICENSED DE- ards, or established specifications that VICES may affect the safety, purity, or potency of that product; or Subpart A—General Provisions (ii) Represents an unexpected or un- Sec. foreseeable event that may affect the 607.1 Scope. safety, purity, or potency of that prod- 607.3 Definitions. uct; and 607.7 Establishment registration and product listing of blood banks and other (2) Occurs in your facility or another firms manufacturing human blood and facility under contract with you; and blood products. (3) Involves distributed blood or blood components. Subpart B—Procedures for Domestic Blood (c) When do I report under this section? Product Establishments You should report a biological product 607.20 Who must register and submit a blood deviation as soon as possible but you product list. must report at a date not to exceed 45- 607.21 Times for establishment registration calendar days from the date you, your and blood product listing. agent, or another person who performs 607.22 How to register establishments and a manufacturing, holding, or distribu- list blood products. tion step under your control, acquire 607.25 Information required for establish- information reasonably suggesting ment registration and blood product listing. that a reportable event has occurred. 607.26 Amendments to establishment reg- (d) How do I report under this section? istration. You must report on Form FDA–3486. 607.30 Updating blood product listing infor- (e) Where do I report under this section? mation. You must send the completed Form 607.31 Additional blood product listing in- FDA 3486 to the Center for Biologics formation. 607.35 Blood product establishment registra- Evaluation and Research (CBER), ei- tion number. ther in paper or electronic format. 607.37 Public disclosure of establishment (1) If you make a paper filing, send registration and blood product listing in- the completed form to the CBER Docu- formation. ment Control Center (see mailing ad- 607.39 Misbranding by reference to estab- dress in § 600.2(a) of this chapter), and lishment registration, validation of reg- identify on the envelope that a BPDR istration, or to registration number. (biological product deviation report) is Subpart C—Procedures for Foreign Blood enclosed; or Product Establishments (2) If you make an electronic filing, send the completed Form FDA3486 elec- 607.40 Establishment registration and blood tronically using CBER’s electronic product listing requirements for foreign Web-based application. blood product establishments. (f) How does this regulation affect other Subpart D—Exemptions FDA regulations? This part supplements and does not supersede other provisions 607.65 Exemptions for blood product estab- of the regulations in this chapter. All lishments. biological product deviations, whether Subpart E—Establishment Registration and or not they are required to be reported Product Listing Of Licensed Devices under this section, should be inves- tigated in accordance with the applica- 607.80 Applicability of part 607 to licensed ble provisions of parts 211, 606, and 820 devices. of this chapter. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374, 381, 393; 42 U.S.C. 262, 264, 271. [65 FR 66635, Nov. 7, 2000, as amended at 70 FR 14984, Mar. 24, 2005; 80 FR 18092, Apr. 3, SOURCE: 40 FR 52788, Nov. 12, 1975, unless 2015] otherwise noted.

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