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DRIED FACTOR IX FRACTION

Human Coagulation Factor IX; Factor IX Concentrate

Category Human blood and blood products (coagulant; antihemorrhagic agent).

          Dried Factor IX Fraction is a freeze-dried plasma protein fraction containing coagulation Factor IX, prepared by a method that effectively separates Factor IX from other prothrombin complex factors (factors II, VII and X). The activities of factor II, VII and X shall be shown to be not more than 5 per cent of the activity of factor IX. It is obtained from human plasma that complies with the requirements stated under Plasma for Fractionation, p. 193. Heparin, antithrombin and other auxiliary substances such as a stabilizer may be added. It contains no antimicrobial preservative.

          The specific activity is not less than 50 IU of factor IX1 per mg of total protein, before the addition of any protein stabilizer. The potency of the preparation, reconstituted as stated on the label, is not less than 20 IU of factor IX per ml.

Description White or pale yellow powder or friable solid.

Strengths available 250, 500, 1000, 1250, and 1500 IU.

Dose Slow intravenous infusion, as prescribed by the physician. The rate of administration of factor IX should be individualized according to the specific product and the response and comfort of the patient.


The potency of factor IX is expressed in terms of the International Units (IU) as defined by the World Health Organization Standard. One unit of factor IX is defined as the average factor IX activity present in 1 ml of normal fresh pooled plasma less than 1 hour old. 

Warning

          1. Fever, chills and urticaria may occur.

          2. Rapid administration may cause nausea, vomiting, headache, or flushing.

          3. Caution should be exercised if large or frequently repeated doses are given to individuals with blood groups A, B, and AB since it may cause hemolysis due to the trace amounts of blood groups A and B isohemagglutinins.

          4. It should be used with caution in neonates since there is a risk of hepatitis.

Expiration date When stored under the prescribed condition, the expiration date is not later than 2 years from the date of the last satisfactory test for potency.

Packaging and storage Dried Factor IX Fraction shall be kept in tightly closed containers, protected from light and stored at a temperature of 2º to 8º.

Labelling Complies with the “General Information for Biological Products”, p. 177. In addition, the label on the container states (1) the number of IU of coagulation factor IX in the container; (2) the concentration of protein in g per litre of the solution constituted as directed; (3) where appropriate, the number of IU of heparin in the container; (4) the name and amount of any other added substance; (5) the volume of Sterile Water for Injection necessary for reconstitution; (6) that if solution is not complete or if a gel forms on reconstitution, the preparation shall not be used; (7) that the solution should be used within 3 hours after reconstitution and any unused solution discarded; (8) that a filter is to be used in the administration set.

      Before carrying out the identification, the tests (except those for constituted solution and water) and the assay, immediately reconstitute the   preparation to be examined as stated on the label​

 

Identification

          A. Using a suitable range of species-specific antisera, carry out precipitation tests on the preparation to be examined. It is recommended that the tests be carried out using antisera specific to the plasma proteins of each species of domestic animal commonly used in the preparation of materials of biological origin in the country concerned. The preparation is shown to contain proteins of human origin and gives negative results with antisera specific to plasma proteins of other species.

          B. The assay for coagulation factor IX contributes to the identification of the preparation.  

pH 6.5 to 7.5 (Appendix 4.11).

Osmolality Not less than 240 mOsmol/kg (Appendix 4.35).

Solubility test Reconstitute the solution as stated on the label or on the leaflet. The preparation dissolves completely under gentle swirling within 10 minutes, giving a clear or slightly opalescent, colourless solution.

Water Not more than 3.0 per cent w/w (Karl Fischer Method, Appendix 4.12). Add a suitable volume of anhydrous methanol to the container of the preparation being examined, shake, allow to stand and carry out the determination on a known volume of the supernatant liquid.

Total protein (Note For some products, especially those without a protein stabilizer such as albumin, this method may not be applicable. Another validated method for protein determination must therefore be performed.) If necessary, dilute the solution with saline TS to produce a solution containing about 15 mg of protein in 2 ml. To 2.0 ml of the resulting solution in a round-bottomed centrifuge tube, add 2 ml of a 7.5 per cent w/v solution of sodium molybdate and 2 ml of a solution containing 1 volume of nitrogen-free sulfuric acid in 30 volumes of water. Shake, centrifuge for 5 minutes, decant the supernatant liquid, and allow the inverted tube to drain on filter paper. Using the residue thus obtained, carry out the determination as described in the “Determination of Nitrogen” (Method II, Appendix 6.7). Calculate the content of protein by multiplying the result by 6.25.

Heparin If heparin has been added, the preparation being examined contains not more than the amount of heparin stated on the label and in any case not more than 0.5 IU of heparin per IU of factor IX (Appendix 14.2.1).

Activated coagulation factor For each of the dilutions, the coagulation time is not less than 150 seconds. If necessary, dilute the preparation to be examined to contain 20 IU of factor IX per ml.

          Where applicable, determine the amount of heparin present and neutralize the heparin by addition of protamine sulfate (10 μg of protamine sulfate neutralizes 1 IU of heparin). Prepare 1 to 10 and 1 to 100 dilutions of the preparation being examined using tris- (hydroxymethyl)aminomethane buffer solution pH 7.5. Place a series of polystyrene tubes in a water-bath at 37º and add to each tube 0.1 ml of platelet-poor plasma and 0.1 ml of a suitable dilution of cephalin TS or platelet substitute. Allow to stand for 60 seconds. Add to each tube either 0.1 ml of one of the dilutions or 0.1 ml of the buffer solution (control tube). To each tube add immediately 0.1 ml of 0.025 M calcium chloride (previously warmed to 37º) and measure, within 30 minutes of the original dilution, the time that elapses between addition of the calcium chloride solution and the formation of a clot. The test is not valid unless the coagulation time measured for the control tube is 200 to 350 seconds.

Pyrogens Complies with the “Pyrogen Test” (Appendix 8.2), using a volume of the solution containing equivalent to not less than 50 IU of factor IX per kg of the rabbit’s weight.

Sterility Complies with the “Sterility Test” (Appendix 10.1).

Assay Carry out the “Biological Assay of Human Coagulation Factor IX” (Appendix 15.1.4). The estimated potency is not less than 80 per cent and not more than 125 per cent of the stated potency. The confidence limits (P = 0.95) are not less than 80 per cent and not more than 125 per cent of the estimated potency.


The potency of factor IX is expressed in terms of the factor IX component. One unit of factor IX is defined as the average factor IX activity present in 1 ml of normal fresh pooled plasma less than 1 hour old. 

MONOGRAPHS • DRIED FACTOR IX FRACTION
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หมายเหตุ / Note : TP II 2011 PAGE 203-205