3.3.2.5 Sterility test It complies with the test for sterility (1101), 3.3.2.6 HBsAg The result shall be negative, detected with the approved diagnostic kit. 3.3.2.7 Additional tests shall be performed depending on the virus inactivation methods used. If tributylphosphate and polysorbate 80 are used, their residual contents shall be tested. (1) Residual tributylphosphate content ‘The residual tributylphosphate content shall be not more than 10 ye/me (3205). (2) Residual polysorbate 80 content The residual polysorbate 80 content shall be not more than 100 4g/mg (3203). 4 Diluent 4.1 Diluent of human fibrinogen for external use The manufacture and control test of diluent shall meet the approved requirement. 4.2. Diluent of human thrombin for external use ‘The manufacture and control test of diluent shall ‘meet the approved requirement, 5. Storage, shipping and validity period Store and ship the product at 2-8, protected from light. The approved validity period shall be the shortest validity period of the component, starting from the date when final bulk is made, 6 Package inserts The Requirements for Packaging of Biologics and the approved contents shall apply. Human Prothrombin Complex Human prothrombin complex is a freeze-dried preparation made from plasma of healthy donors by cold ethanol fractionation or other approved separation methods, followed by viral removal and inactivation. The preparation contains a suitable stabilizer, but free of preservatives and antibiotics, 1. Basic requirements ‘The facilities, source materials and excipients, water, apparatus and animals used for production and control tests shall comply with the requirements set forth in the General Notices. Preservatives or antibiotics shall not be used in the production process. 2 Manufacturing 2.1 Source plasma 2.1.1 Collection and the quality of plasma shall Human Prothrombin Complex comply with the Requirements for Human Source Plasma for Blood Products. 2.1.2 The plasma shall be free of fibrin, lipid or hemolysis a an sma, plasma dep! cxyoprecipitate ao oar ox acon I prep may be used for production. 2.1.4 Fraction Il precipitate shall be stored frozen at or below —20°C. The storage period shall not exceed 6 months. from clot, precipitate 2.2 Bulk 2.2.1 The bulk can be prepared by gel adsorption or cold ethanol and polyethylene glycol fractionation followed by gel adsorption, or by other approved methods. 2.2.2 The fraction after purification, ultrafiltration ‘and sterilization by filtration is regarded as the balk human prothrombin complex. 2.2.3 Control tests on bulk See Section 3. 1. 2.3 Final bulk 2.3.1 Formulation It shall be formulated according to the specifications of final product. A suitable stabilizer can be added to the preparation, If heparin is added, its content shall not exceed 0.5 TU per IU of factor IX. 2.3.2 Control test on final bulk See Section 3. 2. 2.4 Final product 2.4.1 Defining batches The Requirements for Defining Batches of Biologics shall apply. 2.4.2 Filling and lyophilization The Requirements for Filling and Lyophilization of Biologics and (0102) shall apply. ‘The preparation shall be frozen as soon as possible after fi ling, The temperature of fees during lyophilization shall not higher than 35°C, The final containers shal be sealed under vacuum, nel e204 “= 24.3. Strengths Each bottle contains 100 TU, 200 TU, respectively, 2.4.4 Packaging The Requirements for (0102) shall apply, 25° Viral removal and inactivation tae Process for removal and inactivation Virus shall bot TYS OF non-lipid-enveloped © employed in production, If viral human coagulation factor IK 300 TU, 400 TU, 1000 IU; Packaging of Biologics andinactivation agent (solvent, detergent) is useds the limit of the residual agent shall be defined. 3, Control tests 3.1 Control tests on bulk 3.1 pH ‘The pH shall be 6.5-7.5 (0631). 3.1.2. Potency of factor I ‘The potency of factor DX shall be not less than 10 [U/ml (3519). 3.1.3 Protein content It complies with determination of protein content (0731 method 1) . 3.14 Specific activity of factor IX ‘The specific activity shall be not less than 0.5 TU/mg of protein, ‘The tests described above may also be performed oon final bulk. 3.2 Control tests on final bulk 3.2.1 Pyrogen test It complies with the test for pyrogen (1142). The jecting dose of the product shall be 30 TU of factor [X/kg of rabbit body weight. 3.2.2. Sterility test It complies with the test for sterility (1101). 3.3. Control tests on final product Other than the tests for vacuum, reconstitution time, moisture content, weight variation, residual PEG, activated coagulation factor, residual tributylphosphate content and residual polysorbate 80 content, sterile water for injection shall be ‘added as stated on the label, and the reconstituted product shall be subject to the following tests. 3.3.1 Identity test Carry out the test for identity by double immunodiffusion (3403). There shall be only « precipitation line with anti-human serum or plasma, but no precipitation line with anti-horse ig or antisheep serum or anti-bovine, anti-pit plasma. 3.3.2 Physical inspection 3.3.2.1 Appearance The product looks like a white or arayish-green Huet ihe reconstituted product shall be = dat eae ‘olourless, light blue or yellowish green in color. Slight opalescence may occur. ‘Vacuum detection he 22 at shall be tested with a high frequency he cea detector anal the blue pulps glow shall be seen in the final container. tution time 3.3.2.3 Reconstitution 0 = The product shall be reconstituted with 2 volun | of sterile water for injection at 20-30 accord the stated value. It shall be reconstituted completely within 15 minutes on shaking gently. 3.3.2.4 Test for visible particles It complies with the test for visible particles (0904). 3.3.2.5 Determination of osmolality ‘The approved specification of osmolality shall apply (0632) 3.3.2.6 Weight variation Tt complies with the test for weight variation (0102). 3.3.3. Chemical test 3.3.3.1 Moisture content ‘The residual moisture content shall be not more than 3.0% (0832). 3.3.3.2 pH The pH shall be 6. 5-7.5 (0631). 3.3.3.3 Sodium content It shall be not more than 160 mmol/L (3110). 3.8.3.4 Citrate comtent ‘The citrate content shall be not more than 25 mmol/L (3108). 3.3.3.5 Residual polyethylene glycol content If polyethylene glycol is used for preparation, dilute the human coagulation factor [X to 20 TU/ml with diluent, the residual content shall be not ‘more than 0.5 g/L (3202), 3.8.3.6 Sugar content If sugar is used as stabilizer, it shall comply with the approved requirements (3120). 3.3.3.7 Amino acid content If amino acid is used as stabilizer, it shall comply with the approved requirements (3123). 3.3.4 Potency test 3.3.4.1 Human coagulation factor IX ‘The estimated potency of factor [X shall be 80%- 140% of the stated value, calculated with the potency (IU/ml) of factor IX (3519) and the labeled value. The specific activity shall be not less than 0.3 IU/mg of protein, based on the protein content (0731, method 1) and the potency (IU/ml) of factor K. 3.3.4.2 Human coagulation factor I ‘The estimated potency shall be not less than 80% of the stated value, calculated with the potency (U/ml) of factor [I (3517) and the labeled value, 3.3.4.3 Human coagulation factor VI ‘The estimated potency shall be not less than 80% of the stated value, calculated with the potency (IU/ml) of factor WH (3518) and the labeled value, 3.3.4.4 Human coagulation factor X ‘The estimated potency shall be not less than 80%Anti-human T Lymphocyte Porcine Immunoglob of the stated value, calculated with the potenc (TU /ml) of factor X (3520) and the Taine aloe 3.3.5 Human thrombin activity It complies with (3422), 3.3.6 Heparin content ae more than 0.5 TU per IU of factor 3.3.7 Activated coagulation factor When the test sample is diluted to the human coagulation factor [X of 20 TU/ml, the activated coagulation factor it complies with (3423). 3.3.8 HBsAg The result shall be negative, detected with the approved diagnostic kit, 3.3.9 Sterility test It complies with the test for sterility (1101), 3.3.10 Test for abnormal toxicity It complies with the test for abnormal toxicity (1142), The injecting dose of the test sample (containing 10 TU of factor [X/ml) shall be 5 ml per guinea pig and 0.5 ml per mouse, 3.3.11 Pyrogen test It complies with the test for pyrogen (1143), The injecting dose shall be 30 TU of factor X/kg of rabbit body weight. 3.3.12 Additional control tests shall be performed depending on the methods used for virus inactivation. If tributylphosphate and polysorbate 80 are used, dilute the human coagulation factor IX of 20 1U/ml with diluent, their residuel contents shall be tested. 3.3.12.1 Residual tributylphosphate content ‘The residual tributylphosphate content shall be not more than 10 pg/ml (3205). 3. 3.12.2 Residual polysorbate 80 content ‘The residual polysorbate 80 content shall be not more than 100 ug/ml (3203). 4 Dilvent The diluent is sterile water for injection and the manufacture of diluent shall meet the approved requirement. The sterile water for injection shall comply with the specification set forth in Volume TI of the Chinese Pharmacopoeia, 5 Storage, shipping and validity period Store and ship the product at or below 8, protected from light. The approved validity period Thal apply, starting from the date when finel bulk is made. 6 Package inserts : ; ‘The Requirements for Packaging of Biologics and the approved contents shall apply. Beet Anti-human T~ Lymphocyte Porcine Immunoglobulin pphoeyte Poscine Irmanobon 5 rion made from plasma of pigs a wih human T lymphocyte by rae verreher antibodies, purification and conoentaton, followed by viral removal and inactivation. The preparation contains a suitable stabilizer, but fee syatives and antibiotics. ‘Anti-human T Lym of prese 1. Basie requirements ‘The facilities, source materials and excipients, water, apparatus and animals used for production and control tests shall comply with the requirements set forth in the General Notices, 2 Manufacturing 2.1 Immunization of plasma 2.1.1 Antigen used for immunization ‘The antigen used for immunization shall be the human thymocyte or human T lymphocyte isolated from the blood of healthy donors in accordance with the Requirements for Human Source Plasma for Blood Products. The thymocyte donor shall be serologically negative for HBsAg. anti-HCV, anti-HIV-1/HIV-2 and syphilis. The isolated T lymphocyte count and the erythrocyte count shall be not less than 90% and not more than 5% of the total cell count, respectively, 2.1.2 Animal used for immunization ‘The pigs to be immunized shall be healthy and free from porcine pestis virus, porcine parvovirus, pseudore virus, foot-and-mouth disease virus and Japanese encephalitis virus. The body weigh! of the pig shall be 50-60 kg. 2.1.3 Immunization method The approved immunization schedule shall appl 2.1.4 Blood collection and plasma separation After booster immunization, the blood shall be collected when the titer determined by Exo forming inhibition test is not less than 1* ‘The separated plasma shall be stored at or belo¥ —20C. The storage period shall not ee 24 months, 2.2 Bulk 2.2.1. The titer of pooled plasma deteinel bf rosette forming inhibition test shall be not les 1+ 1000. The titer determined by lymphocytotoo™"