PART 660—ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 372; 42 U.S.C. 216, 262, 263, 263a, 264. Cross References: For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111. Subpart A—Antibody to Hepatitis B Surface Antigen § 660.1 Antibody to Hepatitis B Surface Antigen. (a) Proper name and definition. (b) Source. [40 FR 29711, July 15, 1975] § 660.2 General requirements. (a) Processing. (b) Ancillary reagents and materials. (c) Labeling. (i) Indication of the source of the product immediately following the proper name on both the final container and package label, e.g., (ii) Name of the test method(s) recommended for the product on the package label and on the final container label when capable of bearing a full label (see § 610.60(a) of this chapter). (iii) A warning on the package label and on the final container label if capable of bearing a full label (see § 610.60(a) of this chapter) indicating that the product and antigen if supplied, shall be handled as if capable of transmitting hepatitis. (iv) If the product is dried, the final container label shall indicate “Reconstitution date: ___” and a statement indicating the period within which the product may be used after reconstitution. (v) The package shall include a package enclosure providing: (A) Adequate instructions for use; (B) A description of all recommended test methods; and (C) Warnings as to possible hazards, including hepatitis, in handling the product and any ancillary reagents and materials accompanying the product. (2) The applicant may provide the labeling information referenced in paragraph (c)(1) of this section in the form of: (i) A symbol accompanied by explanatory text adjacent to the symbol; (ii) A symbol not accompanied by adjacent explanatory text that: (A) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act; (B) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and (C) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or (iii) A symbol not accompanied by adjacent explanatory text that: (A) Is established in a standard developed by a standards development organization (SDO); (B) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; (C) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act; (D) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and (E) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used. (3) The use of symbols to provide the labeling information referenced in paragraph (c)(1) of this section which do not meet the requirements of paragraph (c)(2) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act. (4) For purposes of paragraph (c)(2) of this section: (i) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, ( i.e., (ii) The term “symbols glossary” means a compiled listing of: (A) Each SDO-established symbol used in the labeling for the device; (B) The title and designation number of the SDO-developed standard containing the symbol; (C) The title of the symbol and its reference number, if any, in the standard; and (D) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard. (d) Final container. (e) Date of manufacture. 125 (f) Retention samples. 125 [38 FR 32098, Nov. 20, 1973, as amended at 40 FR 29711, July 15, 1975; 46 FR 36134, July 14, 1981; 49 FR 1684, Jan. 13, 1984; 81 FR 38924, June 15, 2016] § 660.3 Reference panel. A Reference Hepatitis B Surface Antigen Panel shall be obtained from the Food and Drug Administration, Center for Biologics Evaluation and Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002 and shall be used for determining the potency and specificity of Antibody to Hepatitis B Surface Antigen. [40 FR 29711, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] § 660.4 Potency test. To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent to detect the antigen in the appropriate sera of the reference panel by all test methods recommended by the manufacturer in the package insert. [40 FR 29711, July 15, 1975] § 660.5 Specificity. Each filling of the product shall be specific for antibody to hepatitis B surface antigen, as determined by specificity tests found acceptable by the Director, Center for Biologics Evaluation and Research. [40 FR 29712, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990] § 660.6 Samples; protocols; official release. (a) Samples. 125 125 (2) Unless the Director, Center for Biologics Evaluation and Research, determines that the reliability and consistency of the finished product can be assured with a smaller quantity of sample or no sample and specifically reduces or eliminates the required quantity of sample, each manufacturer shall submit the following samples to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter), within 5 working days after the manufacturer has satisfactorily completed all tests on the samples: (i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section. (ii) One sample at periodic intervals of 90 days, beginning after written notification of official release is no longer required under paragraph (c)(2) of this section. The sample submitted at the 90-day interval shall be from the first lot or filling, as applicable, released by manufacturer, under the requirements of § 610.1 of this chapter, after the end of the previous 90-day interval. The sample shall be identified as “surveillance sample” and shall include the date of manufacture. (iii) Samples may at any time be required to be submitted to the Director, Center for Biologics Evaluation and Research, if the Director finds that continued evaluation is necessary to ensure the potency, quality, and reliability of the product. (b) Protocols. (c) Official release. (2) After written notification of official release is received from the Director, Center for Biologics Evaluation and Research, for at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product, and after the manufacturer receives from the Director, Center for Biologics Evaluation and Research, written notification that official release is no longer required, subsequent lots or fillings may be released by the manufacturer under the requirements of § 610.1 of this chapter. (3) The manufacturer shall not distribute lots or fillings, as applicable, of products that required sample submission under paragraph (a)(2)(iii) of this section until written notification of official release or notification that official release is no longer required is received from the Director, Center for Biologics Evaluation and Research. [48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] Subpart B [Reserved] Subpart C—Blood Grouping Reagent Source: 53 FR 12764, Apr. 19, 1988, unless otherwise noted. § 660.20 Blood Grouping Reagent. (a) Proper name and definition. (b) Source. [53 FR 12764, Apr. 19, 1988, as amended at 65 FR 77499, Dec. 12, 2000; 81 FR 38925, June 15, 2016] § 660.21 Processing. (a) Processing method. (2) Only that material that has been fully processed, thoroughly mixed in a single vessel, and filtered shall constitute a lot. (3) A lot may be subdivided into sublots. If lots are to be subdivided, the manufacturer shall include this information in the biologics license application. The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot. (4) Each lot of Blood Grouping Reagent shall be identified by a lot number. Each sublot shall be identified by that lot number to which a distinctive prefix or suffix shall be added. Final container and package labels shall bear the lot number and all distinctive prefixes and suffixes that have been applied to identify the sublot from which filling was accomplished. (b) Color coding of reagents. (c) Final containers and dropper assemblies. (d) Volume of final product. (e) Date of manufacture. [53 FR 12764, Apr. 19, 1988, as amended at 64 FR 56454, Oct. 20, 1999; 65 FR 77499, Dec. 12, 2000; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005] § 660.22 Potency requirements with reference preparations. (a) Potency requirements. (b) Reference preparations. [53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] § 660.25 Potency tests without reference preparations. Products for which Reference Blood Grouping Reagents are not available shall be tested for potency by a method approved by the Director, Center for Biologics Evaluation and Research. (a) Potency requirements. (1) For Anti-K, Anti-k a a w (2) For Anti-S, Anti-s 1 1 (3) For Anti-U, Anti-Kp a b a b b a b a b a g b b a a (b) Products recommended for slide tests or microplate techniques. (c) Products recomended for use in an automated system. [53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005] § 660.26 Specificity tests and avidity tests. Specificity and avidity tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research. [53 FR 12764, Apr. 19, 1988, as amended at 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005] § 660.28 Labeling. (a) In addition to the applicable labeling requirements of §§ 610.62 through 610.65 and § 809.10 of this chapter, and in lieu of the requirements in §§ 610.60 and 610.61 of this chapter, the following requirements shall be met: (1) Final container label Color coding. Blood grouping reagent Color of Anti-A Blue. Anti-B Yellow. Slide and rapid tube test blood grouping reagents only: Anti-C Pink. Anti-D Gray. Anti-E Brown. Anti-CDE Orange. Anti-c Lavender. Anti-e Green. (ii) Required information. (A) Name of the antibody or antibodies present as set forth in paragraph (a)(4) of this section. (B) Name, address (including ZIP code), and license number of the manufacturer. (C) Lot number, including sublot designations. (D) Expiration date. (E) Source of product if other than human plasma or serum. (F) Test method(s) recommended. (G) Recommended storage temperature in degrees Celsius. (H) Volume of product if a liquid, or equivalent volume for a dried product if it is to be reconstituted. (I) If a dried product, to remind users to record the reconstitution date on the label, the statement “RECONSTITUTION DATE ___. EXPIRES 1 YEAR AFTER RECONSTITUTION DATE.” (iii) Lettering size. (iv) Visual inspection. i.e., (2) Package label. (i) Proper name of the product. (ii) Name of the antibody or antibodies present as set forth in paragraph (a)(4) of this section. (iii) Name, address (including ZIP Code), and license number of the manufacturer. (iv) Lot number, including sublot designations. (v) Expiration date. (vi) Preservative used and its concentration. (vii) Number of containers, if more than one. (viii) Volume or equivalent volume for dried products when reconstituted, and precautions for adequate mixing when reconstituting. (ix) Recommended storage temperature in degrees Celsius. (x) Source of the product if other than human serum or plasma. (xi) Reference to enclosed package insert. (xii) If a dried product, a statement indicating the period within which the product may be used after reconstitution. (xiii) The statement: “FOR IN VITRO DIAGNOSTIC USE.” (xiv) The statement: “MEETS FDA POTENCY REQUIREMENTS.” (xv) If human blood was used in manufacturing the product, the statement: “CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.” (xvi) A statement of an observable indication of an alteration of the product, e.g., (3) Package insert. (4) Names of antibodies. Blood Group Designation for Container Label Anti-A Anti-Jk b Anti-A 1 Anti-Js a Anti-A, B Anti-Js b Anti-A and B Anti-K Anti-B Anti-k Anti-C Anti-Kp a Anti-C w Anti-Kp b Anti- c Anti-Le a Anti-CD Anti-Le b Anti-CDE Anti-Lu a Anti-Co b Anti-Lu b Anti-D Anti-M Anti-DE Anti-M g Anti-Di a Anti-N Anti-E Anti-P 1 Anti-e Anti-S Anti-Fy a Anti-s Anti-Fy b Anti-U Anti-I Anti-Wr a Anti-Jk a Anti-Xg a (b) The applicant may provide the labeling information referenced in paragraph (a) of this section in the form of: (1) A symbol accompanied by explanatory text adjacent to the symbol; (2) A symbol not accompanied by adjacent explanatory text that: (i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act; (ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and (iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or (3) A symbol not accompanied by adjacent explanatory text that: (i) Is established in a standard developed by a standards development organization (SDO); (ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; (iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act; (iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and (v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used. (c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements in paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act. (d) For purposes of paragraph (b) of this section: (1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, ( i.e., (2) The term “symbols glossary” means a compiled listing of: (i) Each SDO-established symbol used in the labeling for the device; (ii) The title and designation number of the SDO-developed standard containing the symbol; (iii) The title of the symbol and its reference number, if any, in the standard; and (iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard. [81 FR 38925, June 15, 2016] Subpart D—Reagent Red Blood Cells Source: 52 FR 37450, Oct. 7, 1987, unless otherwise noted. § 660.30 Reagent Red Blood Cells. (a) Proper name and definition. (b) Source. [52 FR 37450, Oct. 7, 1987, as amended at 64 FR 56454, Oct. 20, 1999] § 660.31 Eligibility of donor. Donors of peripheral blood for Reagent Red Blood Cells must meet all the criteria for donor eligibility under §§ 630.10 and 630.15 of this chapter. [80 FR 29906, May 22, 2015] § 660.32 Collection of source material. Blood for Reagent Red Blood Cells from donors of peripheral blood shall be collected as prescribed under § 640.4 of this chapter, except that paragraphs (c), (d), (g), and (h) of § 640.4 shall not apply. § 660.33 Testing of source material. Except as provided in this section, a sample of each blood incorporated into the Reagent Red Blood Cell product shall be individually tested, with no fewer than two donor sources of each antibody specificity employed, to confirm the identification of all blood group antigens specified in the labeling as present or absent. The manufacturer shall perform at least one of the required tests for each factor. The Reagent Red Blood Cell product may be tested with a single donor source of antibody specificity if only one source of antibody is available, and the Director, Center for Biologics Evaluation and Research, has approved the use of a single donor source of antiserum. Each of these tests shall be conducted and interpreted independently, and any discrepancy between the results of these two tests shall be resolved by testing with at least one additional antiserum before concluding that the antigen is present or absent. Where fewer than three donor sources of an antibody specificity are available, test discrepancies shall be resolved in accordance with the manufacturer's biologics license application. Group O Reagent Red Blood Cells used in the detection or identification of unexpected antibodies shall include at least the following common antigens in each lot of the product: D, C, E, c a b a b a b 1 [52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990; 64 FR 56454, Oct. 20, 1999] § 660.34 Processing. (a) Processing method. (b) Products prepared from pooled red blood cells. (c) Absence of antibodies. (d) Final container. (e) Date of manufacture. (f) Retention samples. [52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002] § 660.35 Labeling. (a) In addition to the items required by § 809.10 of this chapter and other applicable labeling provisions of this chapter, the following information shall be included in the labeling: (1)(i) A logo or company name may be placed on the final container label, however, the logo or company name shall be located along the bottom or end of the label, outside of the main panel. (ii) If washing the cells is required by the manufacturer, the container label shall include appropriate instructions; if the cells should not be washed before use, e.g., (2) The container label of Group O cells shall state: “FOR USE IN DETECTION OF UNEXPECTED ANTIBODIES” or “FOR USE IN IDENTIFICATION OF UNEXPECTED ANTIBODIES” or “NOT FOR USE IN DETECTION OR IDENTIFICATION OF UNEXPECTED ANTIBODIES”. (3) Except as provided in this section, the container and package labels shall state the percentage of red blood cells in the suspension either as a discrete figure with a variance of more than [±] 1 percentage unit or as a range the extremes of which differ by no more than 2 percentage units. If the stated red blood cell concentration is less than 2 percent, the variance shall be no more than [±] 0.5 percentage unit. (4) The words “pooled cells” shall appear on the container and package labels of products prepared from pooled cells. The package label or package insert shall state that pooled cells are not recommended for pre-transfusion tests, done in lieu of a major crossmatch, to detect unexpected antibodies in patients' samples. (5) The package insert of a pooled product intended for detection of unexpected antibodies shall identify the number of donors contributing to the pool. Products designed exclusively for ABO Serum Grouping and umbilical cord cells need not identify the number of donors in the pool. (6) When the product is a multicontainer product, e.g., (7) The package label or package insert shall state the blood group antigens that have been tested for and found present or absent on the cells of each donor, or refer to such information in an accompanying antigenic constitution matrix. Cells for ABO Serum Grouping are exempt from this requirement. The package insert or antigen constitution matrix shall list each of the antigens tested with only one source of antibody. (8) The package label or package insert shall bear the cautionary statement: “The reactivity of the product may decrease during the dating period.” (9) The package insert of a product intended for the detection or identification of unexpected antibodies shall note that the rate at which antigen reactivity ( e.g., (10) The package insert shall provide adequate directions for use. (11) The package insert shall bear the statement: “CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.” (12) The package insert or the antigenic constitution matrix for each lot of product shall specify the date of manufacture or the length of the dating period. (13) Manufacturers shall identify with a permanent donor code in the product labeling each donor of peripheral blood used for detection or identification of unexpected antibodies. (b) The applicant may provide the labeling information referenced in paragraph (a) of this section in the form of: (1) A symbol accompanied by explanatory text adjacent to the symbol; (2) A symbol not accompanied by adjacent explanatory text that: (i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act; (ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and (iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or (3) A symbol not accompanied by adjacent explanatory text that: (i) Is established in a standard developed by a standards development organization (SDO); (ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; (iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act; (iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and (v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used. (c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements of paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act. (d) For purposes of paragraph (b) of this section: (1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, ( i.e., (2) The term “symbols glossary” means a compiled listing of: (i) Each SDO-established symbol used in the labeling for the device; (ii) The title and designation number of the SDO-developed standard containing the symbol; (iii) The title of the symbol and its reference number, if any, in the standard; and (iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard. [81 FR 38926, June 15, 2016] § 660.36 Samples and protocols. (a) The following shall be submitted to the Center for Biologics Evaluation and Research Sample Custodian (see mailing addresses in § 600.2(c) of this chapter), within 30 days after each routine establishment inspection by FDA. (1) From a lot of final product, samples from a cell panel intended for identification of unexpected antibodies. The sample shall be packaged as for distribution and shall have at least 14 days remaining in the dating period when shipped to the Center for Biologics Evaluation and Research. (2) A protocol which shall include the following: (i) Complete test records of at least two donors of the samples submitted, including original and confirmation phenotyping records. (ii) Bleeding records or receipt records which indicate collection date, volume, and HBsAg test results. (iii) Manufacturing records which document all steps involved in the preparation of the product. (iv) Test results which verify that the final product meets specifications. (v) Identity test results. (b) A copy of the antigenic constitution matrix specifying the antigens present or absent shall be submitted to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter), at the time of initial distribution of each lot of Reagent Red Blood Cells for detection or identification of unexpected antibodies. Products designed exclusively to identify Anti-A, Anti-A 1 (c) Except for umbilical cord samples, whenever a new donor is used, a sample of red blood cells from each new donor used in a cell panel intended for the identification of unexpected antibodies shall be submitted by the manufacturer to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter). The sample should contain a minimum volume of 0.5 milliliter of red blood cells. [52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] Subpart E—Hepatitis B Surface Antigen Source: 44 FR 36382, June 22, 1979, unless otherwise noted. § 660.40 Hepatitis B Surface Antigen. (a) Proper name and definition. (b) Source. § 660.41 Processing. (a) Method. (b) Ancillary reagents and materials. (c) Final container. (d) Date of manufacture. 125 [44 FR 36382, June 22, 1979, as amended at 49 FR 1685, Jan. 13, 1984] § 660.43 Potency test. To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the antibody in the appropriate sera of the reference panel by all test methods recommended by the manufacturer in the package insert. § 660.44 Specificity. Each filling of the product shall be specific for Hepatitis B Surface Antigen as determined by specificity tests found acceptable to the Director, Center for Biologics Evaluation and Research. [44 FR 36382, June 22, 1979, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990] § 660.45 Labeling. (a) In addition to the requirements of §§ 610.60, 610.61, and 809.10 of this chapter, the labeling shall bear the following: (1) The “d and y” antigen subtype and the source of the product to follow immediately the proper name on both the final container label and the package label. If the product is intended to identify antibodies to the “r and w” antigen subtype, the antigen subtype designation shall include the “r and w” antigen subtype. (2) The name of the test method(s) recommended for use of the product on the package label and on the final container label, when capable of bearing a full label (see § 610.60(a) of this chapter). (3) A warning on the package label and on the final container label stating that the product is capable of transmitting hepatitis and should be handled accordingly. (4) The package shall include a package insert providing: (i) Detailed instructions for use, (ii) An adequate description of all recommended test methods, and (iii) Warnings as to possible hazards, including hepatitis transmitted in handling the product and any ancillary reagents and materials accompanying the product. (b) The applicant may provide the labeling information referenced in paragraph (a) of this section in the form of: (1) A symbol accompanied by explanatory text adjacent to the symbol; (2) A symbol not accompanied by adjacent explanatory text that: (i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act; (ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and (iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or (3) A symbol not accompanied by adjacent explanatory text that: (i) Is established in a standard developed by a standards development organization (SDO); (ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; (iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act; (iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and (v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used. (c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements of paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act. (d) For purposes of paragraph (b) of this section: (1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, ( i.e., (2) The term “symbols glossary” means a compiled listing of: (i) Each SDO-established symbol used in the labeling for the device; (ii) The title and designation number of the SDO-developed standard containing the symbol; (iii) The title of the symbol and its reference number, if any, in the standard; and (iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard. [81 FR 38928, June 15, 2016] § 660.46 Samples; protocols; official release. (a) Samples. 125 125 (2) Unless the Director, Center for Biologics Evaluation and Research, determines that the reliability and consistency of the finished product can be assured with a smaller quantity of sample or no sample and specifically reduces or eliminates the required quantity of sample, each manufacturer shall submit the following samples to the Director, Center for Biologics Evaluation and Research (see mailing addresses in § 600.2(c) of this chapter), within 5 working days after the manufacturer has satisfactorily completed all tests on the samples: (i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section. (ii) One sample of product at periodic intervals of 90 days, beginning after written notification of official release is no longer required under paragraph (c)(2) of this section. The sample submitted at the 90-day interval shall be from the first lot or filling, as applicable, released by the manufacturer, under the requirements of § 610.1 of this chapter, after the end of the previous 90-day interval. The sample shall be identified as “surveillance sample” and shall include the date of manufacture. (iii) Samples may at any time be required to be submitted to the Director, Center for Biologics Evaluation and Research, if the Director finds that continued evaluation is necessary to ensure the potency, quality, and reliability of the product. (b) Protocols. (c) Official release. (2) After written notification of official release is received from the Director, Center for Biologics Evaluation and Research, for at least five consecutive lots or fillings manufactured after licensure of the products, and after the manufacturer receives from the Director, Center for Biologics Evaluation and Research, written notification that official release is no longer required, subsequent lots or fillings may be released by the manufacturer under the requirements of § 610.1 of this chapter. (3) The manufacturer shall not distribute lots or fillings, as applicable, of products that require sample submission under paragraph (a)(2)(iii) of this section until written notification of official release or notification that official release is no longer required is received from the Director, Center for Biologics Evaluation and Research. [48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, 11014, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] Subpart F—Anti-Human Globulin § 660.50 Anti-Human Globulin. (a) Proper name and definition. (b) Source. [50 FR 5579, Feb. 11, 1985, as amended at 65 FR 77499, Dec. 12, 2000; 81 FR 38928, June 15, 2016] § 660.51 Processing. (a) Processing method. (2) Anti-IgG, -C3d (polyspecific) reagents and anti-IgG products may be colored green. (3) Only that material which has been fully processed, thoroughly mixed in a single vessel, and filtered shall constitute a lot. Each lot shall be identified by a lot number. (4) A lot may be subdivided into sublots which shall be identified by the lot number to which has been added a distinctive prefix or suffix. If lots are to be subdivided, the manufacturer shall include this information in the license application . The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot. (b) Final containers and dropper assemblies. (2) Final containers and dropper pipettes shall be colorless and sufficiently transparent to permit observation of the contents for presence of particulate matter or increased turbidity. (c) Date of manufacture. [50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 65 FR 77499, Dec. 12, 2000; 67 FR 9587, Mar. 4, 2002] § 660.52 Reference preparations. Reference Anti-Human Globulin preparations shall be obtained from the Food and Drug Administration, Center for Biologics Evaluation and Research, Reagents and Standards Shipping, 10903 New Hampshire Ave., Bldg. 75, Rm. G704, Silver Spring, MD 20993-0002, and shall be used as described in the accompanying package insert for determining the potency of Anti-Human Globulin. [50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005; 80 FR 18093, Apr. 3, 2015] § 660.53 Controls for serological procedures. Red blood cells sensitized with complement shall be tested with appropriate positive and negative control antisera. All tests shall be performed in accordance with serological testing procedures approved by the Director, Center for Biologics Evaluation and Research. [50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005] § 660.54 Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties. The following tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research: (a) Potency tests for determining anti-IgG and anti-complement activity. (b) Specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties. [50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 67 FR 9587, Mar. 4, 2002; 70 FR 14986, Mar. 24, 2005] § 660.55 Labeling. (a) In addition to the applicable labeling requirements of §§ 610.62 through 610.65 and § 809.10 of this chapter, and in lieu of the requirements in §§ 610.60 and 610.61 of this chapter, the following requirements shall be met: (1) Final container label Color coding. (ii) Required information. (A) Name of the antibody or antibodies present as set forth in paragraph (a)(4) of this section. Anti-Human Globulin may contain one or more antibodies to either immunoglobulins or complement components but the name of each significant antibody must appear on the final container label ( e.g., (B) Name, address, and license number of the manufacturer. (C) Lot number, including any sublot designations. (D) Expiration date. (E) Source of the product. (F) Recommended storage temperature in degrees Celsius. (G) Volume of product. (H) Appropriate cautionary statement if the Anti-Human Globulin is not polyspecific. For example, “DOES NOT CONTAIN ANTIBODIES TO IMMUNOGLOBULINS” or “DOES NOT CONTAIN ANTIBODIES TO COMPLEMENT COMPONENTS.” (I) If the final container is not enclosed in a package, all items required for a package label shall appear on the container label. (iii) Lettering size. (iv) Visual inspection. (2) Package label. (i) Proper name of the product, and the name of the antibody or antibodies as listed in paragraph (a)(4) of this section. (ii) Name, address (including ZIP code), and license number of the manufacturer. (iii) Lot number, including any sublot designations. (iv) Expiration date. (v) Preservative(s) used and its concentration. (vi) Number of containers, if more than one. (vii) Recommended storage temperature in degrees Celsius. (viii) Source of the product. (ix) Reference to enclosed package insert. (x) The statement: “For In Vitro Diagnostic Use.” (xi) The statement: “Meets FDA Potency Requirements.” (xii) A statement of an observable indication of an alteration of the product, e.g., (xiii) Appropriate cautions. (3) Package insert. (4) Names of antibodies. Antibody designation on Definition (1) Anti-IgG, -C3d; Polyspecific Contains anti-IgG and anti-C3d (may contain other anticomplement and anti-immunoglobulin antibodies). (2) Anti-IgG Contains anti-IgG with no anti-complement activity (not necessarily gamma chain specific). (3) Anti-IgG; heavy chains Contains only antibodies reactive against human gamma chains. (4) Anti-C3b Contains only C3b antibodies with no anti-immunoglobulin activity. Note: (5) Anti-C3d Contains only C3d antibodies with no anti-immunoglobulin activity. (6) Anti-C4b Contains only C4b antibodies with no anti-immunoglobulin activity. (7) Anti-C4d Contains only C4d antibodies with no anti-immunoglobulin activity. (b) The applicant may provide the labeling information referenced in this section in the form of: (1) A symbol accompanied by explanatory text adjacent to the symbol; (2) A symbol not accompanied by adjacent explanatory text that: (i) Is contained in a standard that FDA recognizes under its authority in section 514(c) of the Federal Food, Drug, and Cosmetic Act; (ii) Is used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; and (iii) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used; or (3) A symbol not accompanied by adjacent explanatory text that: (i) Is established in a standard developed by a standards development organization (SDO); (ii) Is not contained in a standard that is recognized by FDA under its authority in section 514(c) or is contained in a standard that is recognized by FDA but is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition; (iii) Is determined by the manufacturer to be likely to be read and understood by the ordinary individual under customary conditions of purchase and use in compliance with section 502(c) of the Federal Food, Drug, and Cosmetic Act; (iv) Is used according to the specifications for use of the symbol set forth in the SDO-developed standard; and (v) Is explained in a paper or electronic symbols glossary that is included in the labeling for the device and the labeling on or within the package containing the device bears a prominent and conspicuous statement identifying the location of the symbols glossary that is written in English or, in the case of articles distributed solely in Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be used. (c) The use of symbols in device labeling to provide the labeling information referenced in paragraph (a) of this section which do not meet the requirements of paragraph (b) of this section renders a device misbranded under section 502(c) of the Federal Food, Drug, and Cosmetic Act. (d) For purposes of paragraph (b) of this section: (1) An SDO is an organization that is nationally or internationally recognized and that follows a process for standard development that is transparent, ( i.e., (2) The term “symbols glossary” means a compiled listing of: (i) Each SDO-established symbol used in the labeling for the device; (ii) The title and designation number of the SDO-developed standard containing the symbol; (iii) The title of the symbol and its reference number, if any, in the standard; and (iv) The meaning or explanatory text for the symbol as provided in the FDA recognition or, if FDA has not recognized the standard or portion of the standard in which the symbol is located or the symbol is not used according to the specifications for use of the symbol set forth in FDA's section 514(c) recognition, the explanatory text as provided in the standard. [81 FR 38928, June 15, 2016]