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DRIED PROTHROMBIN COMPLEX

Prothrombin Complex Concentrate (PCC); Factor IX Complex Concentrate

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

          Dried Prothrombin Complex is a sterile, freezedried powder consisting of partially purified Factor IX fraction as well as concentrated factors II, VII and X fractions. 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 0.6 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 slightly coloured powder or friable solid. Very hygroscopic.

Strengths available 400 to 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.

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

See also under Dried Factor IX Fraction, p. 204.

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

Packaging and storage Dried Prothrombin Complex 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, factor II, and factor X per container; (2) where applicable, the number of IU of factor VII per container; (3) the concentration of protein in g per litre of the solution constituted as directed; (4) where appropriate, the number of IU of heparin per container; (5) the name and amount of any other added substance; (6) the name and the volume of the liquid to be used for reconstitution; (7) that if solution is not complete or if a gel forms on reconstitution the preparation shall not be used; (8) that the solution should be used within 3 hours after reconstitution and any unused solution discarded; (9) 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 activity and, where applicable, those for factors II, VII, and X contribute 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 solution that may be coloured.

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 to be 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 and 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 to be 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.

Thrombin No coagulation occurs in the tubes containing the preparation to be examined. Coagulation occurs within 30 seconds in the tube containing thrombin.

          Where applicable, determine the amount of heparin present and neutralize the heparin by addition of protamine sulfate (10 g of protamine sulfate neutralizes 1 IU of heparin). In each of two test-tubes, mix equal volumes of the reconstituted preparation and a 0.3 per cent solution of fibrinogen. Keep one of the tubes at 37º for 6 hours and the other at room temperature for 24 hours. In the third tube, mix a volume of the fibrinogen solution with an equal volume of a solution containing 1 IU per ml of human thrombin and place the tube in a water-bath at 37º.

Pyrogens Complies with the “Pyrogen Test” (Appendix 8.2), using a volume of the solution containing equivalent to not less than 30 IU of coagulation factor IX per kg of the rabbit’s weight.

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

Assay

          FOR FACTOR IX 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. FOR

          FACTOR II Carry out the “Biological Assay of Human Coagulation Factor II” (Appendix 15.1.7). 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 90 per cent and not more than 111 per cent of the estimated potency. FOR FACTOR VII If the label states that the preparation contains factor VII, carry out the “Biological Assay of Human Coagulation Factor VII” (Appendix 15.1.8). 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.

          FOR FACTOR X Carry out the “Biological Assay of Human Coagulation Factor X” (Appendix 15.1.5). 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 90 per cent and not more than 111 per cent of the estimated potency.

MONOGRAPHS • DRIED PROTHROMBIN COMPLEX
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หมายเหตุ / Note : TP II 2011 PAGE 205-207