| Object: To apply the most advanced seperation technologies to our large-scale human albumin manufacturing process, such as filter-pressing technology, chromatography and the automatic control technology of in place cleaning and sterilising system, reaction parameters (temperature, weight, flow rate, pH,etc.), large-scale ultrafiltration system, virus inactivation system and aseptic filling system. Two purposes should be realized by changing the manufacturing process. One is that the application of new technologies should be combined with the the parameters and some common facilities of the old centrifugation technology, so as to reduce the cost, overcome the high labour intensity brought by manual operation, be suitable for large-scale manufacturing process, save energy and increase economic returns. The other is that the changes of the manufacturing process should be approved by SFDA . It should be assured that the Good Manufacturing Practices for Drugs are well carried out. As a result, the product quality can be controlled in the following aspects: safety, efficacy, stablity and controllability.Methods: Several seperation technologies were compared, for the selecting and determinating which should be adopted. The filter-pressing technology is chosen instead of the centrifugation technology; the continuous flow process is combined with filter-pressing technology resulting in a new design for human albumin preperation. The chromatographic technology was introduced into the process for purification to make purity higher, aluminum ion and PKA contents lower.The application of computer in industrial production complies with automatic and precise control. Dehydrating agent could be well-distributed immediately as soon as it got in touch with plasma, decreasing the protein damage and maintaining more bioactivity. The temperature probe made from Pt100 might ensure the precision of±0.2℃range during the automatic viral inactivation. The conductivity can be detected while cleaning the reaction vessels in place, to ensure whether the cleaning is complied or not.We re-arranged layout of the clean room, designed Heating, Ventilation and Air Condition(HVAC), Water for injection, Cleaning In Place(CIP), Virus Inactivation System, to meet the requirement of appendix of Good Manufacture Practices (1998 revision)Result: The conditions of the production process, such as temperature, pH, the concentration of ethanol and the amount of filtration aid and filter sheet, were determined by the study on the filter-pressing process of human albumin preparation. Following the application of the new technologies in industrial production, product quality was improved obviously and the content of aluminum ion per liter was only 30% of the limit in European Pharmacopoeia. The new technologies were applied to the production of IVIG and specific human immunoglobulins, all the testing results of the final products met the requirements of the lastest European Pharmacopoeia, especially the purity, aluminum ion, pyrogen, molecular size distribution, PKA, polymer, absorbance, hepatitis B antibody, Anti-A and B haemagglutinins, etc were quite better than European Pharmacopoeia requirements. Detection online, cleaning in place and virus inactivation system came to true. The changed process was permitted by SFDA in 2005, passed the inspection of GMP for production process on May 18th, 2006, and follow-up inspection of the blood products of GMP on May 13-18, 2007.Conclusion and significance: The technique takes the lead in domestic blood product enterprises. Compared with traditional centrifugation. The online control of the parameters in the process of production is achieved, dehydrating agent can be well-distributed immediately while reaching the plasma and continuous flow reaction is formed by accurate control with computer. Combined with chromatographic technique, products quality is improved perfectly. At present, the technique could be used to isolation, purication, refinement of blood products, for example human albumin, human immunoglobulin, blood coagulation factor, etc..
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