Study On The Preparation Procedure Of Human Immunoglobulin For Intravenous Injection

Intravenous immunoglobulin(IVIG)is manufactured from pooled human plasma with different purification steps and the main compositon is IgG.IVIG is used for the treatment of primary immunoglobulin deficiency,secondary immunoglobulin deficiency and autoimmune disease(eg.primary thrombocytopenic purpura,kawasaki disease).Now,as people have more knowledge on IVIG,the clinical indications are increasing.IVIG has been approved for the treatment of chronic demyelinating multiple neuroinflammation,rheumatoid arthritis and retinal related diseases.The IVIG products that have been approved for market in China are typically manufactured by the Cohn ethanol fractionation method.This process has a long production cycle,requires low-temperature operation environment.The product quality is also somewhat lower than that in foreign countries.The residual protein impurity IgA from low-temperature ethanol process leads to the allergic reaction of IgA deficient patients and the added maltose stabilizer leads to renal failure and other clinical side effects.Only one virus inactivation method is adopted.Therefore,considering the production process,product quality and safety,this thesis investigated the fourth-generation IVIG process named caprylic acid-tomographic technology to produce high-purity,safer and more effective injectable IVIG products.After laboratory research,a caprylic acid-chromatography process preparation route for IVIG product was identified.Ethanol with low temperature was added into the pooled plasma,and components ?+?+? precipitation were acquired after filtration.Then fraction ?+?+? was dissolved and preliminary purification was carried out with octylic acid precipitation method.The supernatant was obtained by filtration.After adjusting the pH and conductivity of the supernatant,the anion exchange chromatography was performed to remove albumin and part IgA and the fluid passage was collected.Then anion exchange chromatography was performed again to obtain high purity IgG.Ultrafiltration concentration and desalination were performed after pH adjustment of the fluid through two chromate graphy.According to the protein content,an appropriate amount of glycine was added and the pH was adjust to 3.4?4.4.The lipid enveloped virus was inactivated after incubation at 24±1? for 21 days.After incubation,20 nm membrane filtration was used to intercept all kinds of virus molecules to avoid or remove the virus.According to the determined process route,the pilot scale was carried out in GMP workshop,and three batches of products were successively trial-produced.The three batches of products were all qualified according to the registration standard.The long-term and accelerated stability of three batches of pilot-scale products were investigated.Accelerated testing after 6 months and 12 months showed that all the test index in the observation period were qualified.Compared to the products of IVIG using caprylic acid-tomographic process,from LFB and using low temperature ethanol methods,we could find that the quality characteristics were the same.The content of IgA and FXI/FXIa of the IVIG products prepared by the caprylic acid-tomographic process was significantly lower than that of the low-temperature ethanol process IVIG products.The risk for side effect was lower and the the product was safer.