Development and future ofbiopharmaceutical processes Downstream processing by designJohnCurling课件.pptVIP

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Development and future ofbiopharmaceutical processes Downstream processing by designJohnCurling课件.ppt

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Development and future ofbiopharmaceutical processes Downstream processing by designJohnCurling课件

John Curling Senior Advisor ProMetic BioTherapeutics, Inc. John Curling Consulting AB, Uppsala, Sweden. Advancing innovations in the research, development, manufacture and commercialization of therapeutic proteins Promoting the safety, cost effectiveness and reliable supply of plasma proteins Increasing access to high quality medicinal products which fulfill unmet patient needs on a global basis. Biologics – 1900 - 1959 Biologics – 1960 - 1980 Biologics before rDNA Animal and human tissue sources Bovine blood Equine blood (immunized) Human blood Equine urine Human urine Bovine pancreas Porcine pancreas Lung Pituitaries (human cadaver) Cocks combs/bovine testicle Fruit Bacteria (endogenous protein) Mammalian cells (endogenous protein) Pepsin process Insulin purification from pancreas Aqueous-ethanol extraction + precipitation of non-insulin proteins at their pI Ether extraction of lipids (Banting, 1923) Aqueous extraction + isoelectric precipitation of insulin (pH 4 - pH 7) (Walden, 1924) Cold acid + Solvent extraction + ethanol fractionation (parenteral product) (Murlin, 1925) Differential salting out with sodium chloride, 25% then 15% (Lautenschlager, 1948) Crystallization of zinc complex in presence of citric acid (Petersen, 1953) Separation of proinsulin from insulin not resolved Insulin purification Insulin purification Gel filtration Sephadex? G-50 KS 370 Stack column 6 sections (96 litres) 450 grams ammonium insulin load 0.5M acetic acid, 0.01 M NaCl eluent 5°C operation Cohn fractionation (1946) Cohn fractionation – unit operations First biologics approvals 1982-1989 Chromatographic media development Timeline: chromatography on agarose supports Conceptual purification of recombinants Early recombinant processes (tPA) Similar issues – similar solutions Recombinants expressed in E coli etc. Intracellular expression: expressed as inclusion bodies Cell disruption Need refolding Removal of proteases Removal of endotoxins Removal of DNA Adventitio