(a) Proper name and definition. The proper name of this product shall be Blood Grouping Reagent and it shall consist of an antibody-containing fluid containing one or more of the blood grouping antibodies listed in § 660.28(a)(4).

(b) Source. The source of this product shall be blood, plasma, serum, or protein-rich fluids, such as those derived from stable immunoglobulin-secreting cell lines maintained either in tissue cultures or in secondary hosts.

(a) Processing method. (1) The processing method shall be one that has been shown to yield consistently a specific, potent final product, free of properties that would affect adversely the intended use of the product throughout its dating period. Stability testing shall be performed on an adequate number of representative samples of each group of products manufactured in the same fashion.

(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. Blood Grouping Reagents may be colored provided the added colorant does not adversely affect the safety, purity, or potency of the product and the colorant is approved by the Director, Center for Biologics Evaluation and Research.

(c) Final containers and dropper assemblies. Final containers and dropper pipettes shall be colorless and sufficiently transparent to permit observation of the contents to detect particulate matter or increased turbidity during use.

(d) Volume of final product. Each manufacturer shall identify the possible final container volumes in the biologics license application.

(e) Date of manufacture. The date of manufacture shall be the date the manufacturer begins the last entire group of potency tests.

(a) Potency requirements. Products for which reference Blood Grouping Reagents are available shall have a potency titer value at least equal to that of the reference preparation.

(b) Reference preparations. Reference Blood Grouping Reagents 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 Blood Grouping Reagents.

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. Blood Grouping Reagents recommended for the test tube methods, including the indirect antiglobulin tests, shall have the following potency titer values, unless other values are approved by the Director, Center for Biologics Evaluation and Research.

(1) For Anti-K, Anti-k , Anti-Jk a, Anti-Fy a, Anti-C w, at least 1 + reaction with a 1:8 dilution of the reagent.

(2) For Anti-S, Anti-s , Anti-P1, Anti-M, Anti-I, Anti-e (saline), Anti-c (saline), and Anti-A1, at least 1 + reaction with a 1:4 dilution of the reagent.

(3) For Anti-U, Anti-Kp a, Anti-Kp b, Anti-Js a, Anti-Js b, Anti-Fy b, Anti-N, Anti-Le a, Anti-Le b, Anti-Lu a, Anti-Lu b, Anti-Di a, Anti-M g, Anti-Jk b, Anti-Co b, Anti-Wr a, and Anti-Xg a, at least 2 + reaction with undiluted reagent.

(b) Products recommended for slide tests or microplate techniques. Blood Grouping Reagent recommended for slide test methods or microplate techniques shall produce clearly positive macroscopic results when both undiluted reagent and reagent diluted with an equal volume of diluent are tested by all methods recommended in the manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the corresponding antigen. The dilution shall be made with an equal volume of compatible serum or approved diluent.

(c) Products recomended for use in an automated system. The manufacturer of Blood Grouping Reagent that is recommended for use in an automated system shall demonstrate that its product when used both undiluted and diluted with an equal volume of diluent satisfactorily performs when tested with cells representing heterozygous or diminished expression of the corresponding antigen.

Specificity and avidity tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research.

(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—(i) Color coding. The final container label of all Blood Grouping Reagents shall be completely white, except that all or a portion of the final container label of the following Blood Grouping Reagents may be color coded with the specified color which shall be a visual match to a specific color sample designated by the Director, Center for Biologics Evaluation and Research. Printing on all final container labels shall be in solid black. 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 the main panel.

(ii) Required information. The proper name “Blood Grouping Reagent” need not appear on the final container label provided the final container is distributed in a package and the package label bears the proper name. The final container label shall bear the following 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. The type size for the specificity of the antibody designation on the labels of a final container with a capacity of less than 5 milliliters shall be not less than 12 point. The type size for the specificity of the antibody designations on the label of a container with a capacity of 5 milliliters or more shall be not less than 18 point.

(iv) Visual inspection. When the label has been affixed to the final container, a sufficient area of the container shall remain uncovered for its full length or no less than 5 millimeters of the lower circumference to permit inspection of the contents. The label on a final product container for antibodies Anti-c, Anti-k, or Anti-s shall display a bar immediately over the specificity letter used in the name, i.e., Anti-c , Anti-k , or Anti-s .

(2) Package label. The following information shall appear either on the package label or on the final container label if it is visible within the package.

(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., turbidity, color change, precipitate, that may indicate possible deterioration of the product.

(3) Package insert. Each final container of Blood Grouping Reagent shall be accompanied by a package insert meeting the requirements of § 809.10. If two or more final containers requiring identical package inserts are placed in a single package, only one package insert per package is required.

(4) Names of 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 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., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope.

(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.