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ISSUE no.17 NOVEMBER 2011

BiONEWS
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Changes in Dowsntream Processing The biopharmaceutical industry relies on change to make progress in a commercial environment that simultaneously demands higher productivity, higher quality, and lower costs. Recombinant protein titers have improved from tens of milligrams to more than 10 grams per liter during the past 20 years, and at the same time, batch volumes have increased so that industry faces the real prospect of batch yields exceeding 100 kg of protein in the next decade. Over the same period, regulatory demands have become more onerous, and the pressure to reduce costs has increased as more biopharmaceuticals come off patent and overseas manufacturers begin to take an interest in Western markets. There is no doubt that progress in the industry has been impressive [...]. Most of the increases in productivity that have been achieved in previous decades have resulted from improvements in the upstream production phase, with (1) more efficient bioreactors, (2) better media formulations and (3) cell lines that are intrinsically more productive due to the development [...]. Downstream processing is now routinely found to be the bottleneck in biopharmaceutical manufacturing because its capacity has not kept pace with upstream production. [...] Whereas upstream production can be scaled up almost indefinitely by increasing the productivity of cells growing in a bioreactor, downstream processing has limits imposed by physics and chemistry. Downstream processing is driven by the mass of product. If one makes more product per batch, one needs correspondingly larger volumes of buffer, larger storage tanks, preparation areas, larger filters, and most importantly, larger amounts of chromatography media. [...] How can this productivity dilemma be addressed? [...] Three solutions are currently being considered by manufacturers: a) the streamlining of existing processes, b) the revisiting of simple technology solutions currently employed in the bulk-chemical industry and c) the use of innovative technologies from the biopharmaceutical research sector. a) Antibody manufacturing provides an excellent example of the application of process redesign and streamlining principles to increase productivity, cut costs, and maintain product quality: Most manufacturers use three chromatography steps for antibody purification: Anion exchange (AEX) chromatography step to extract negatively charged contaminants Cation exchange (CEX) chromatography or hydrophobic interaction chromatography (HIC) to remove positively charged residual contaminants and product related impurities

Protein A capture step

[...] Pfizer [...] introduced two types of process modifications, one in which the order of the polishing steps was reversed and another in which different separation technologies were used to increase process capacity (i.e., using membrane absorbers). These changes increased the efficiency of purification to such an extent that, for some antibody products, the cation-exchange step became unnecessary, reducing the process from three columns to two columns or even a single column. Not only did this save the direct costs of column resin and buffers, but also reduced the process time by > 45% which doubled the productivity in terms of batch processing. b) Precipitation is widely used as a purification approach in the bulk-chemical industry [...] Precipitation has therefore been used to remove soluble impurities from the feed stream during antibody manufacturing, and these solids can then be trapped by filtration or pelleted by centrifugation leaving a clear feed stream relatively enriched for the target protein. [...] c) Innovative technologies from the biopharmaceutical research sector would include membrane chromatography, disposable technology... which would allow to switch to new campaigns rapidly and to produce multiple products and hence might be the answer to the new biopharmaceutical paradigm.
Refer the complete article / references from Biopharm September 2011

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OVERVIEW OF BIOPHA ARMACEUTICAL PRODU UCTION

5 WEEKS
Theo sessions ory e Introduction to the biopharma sector Share Market S Product ts Prospec cts Drug De evelopment P Processes Steps in Pharma-Bio n otech Produc ction Microbial Fermenta ation tor es Ferment Principle & Design Aeration & Agitation and KLa Es n n stimation Inoculum Development m Microbia growth al lture Cell Cul d e Good laboratory and cell culture practices y Primary cultures to established cell lines Nutritio onal requirem ments of cult tured cells Cryopre eservation pr rinciples and cell banking g Downstream Proces ssing fugation Principles of Centrif ntial Flow Filtration Principles of Tangen sics Chromatography bas Protein quantification methods Steriliza ation & Filtr ration Techn niques Heat Steriliza ation Principles of Moist H eat Principles of Dry He Sterilization erilization by filtration y Cold ste Filter In ntegrity Testing Operation of industrial sterilizers (DHS and ave) Autocla Steriliza ation In Place for process vessel Steriliza ation of Media by Steriliz zing grade filters IT of hy ydrophobic and hydrophilic filters ation of cell broth Clarifica Protein concentration Protein purification n Protein quantification Aseptic techniques in cell culture Cell qua antitation an examinati nd ion Sub-cult turing of mo onolayer cult tures Establis shment and m monitoring of Suspension culture o n Cryopre eservation an revival of frozen cells nd f s m Inoculum build up Fermentor inoculati ion g Fermentor sampling Growth rate estimation Fermentor harvest a cleaning and g Pr ractical sess sions

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