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ation using Autoclave

Plan Execute Test

Changes in Dowsntream Processing

The biopharmaceutical industry relies on change to make progress in a commercial environment thatsimultaneously demands higher productivity, higher quality, and lower costs. Recombinant protein titers haveimproved from tens of milligrams to more than 10 grams per liter during the past 20 years, and at the sametime, batch volumes have increased so that industry faces the real prospect of batch yields exceeding 100 kg ofprotein in the next decade. Over the same period, regulatory demands have become more onerous, and thepressure to reduce costs has increased as more biopharmaceuticals come off patent and overseasmanufacturers 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 productivitythat have been achieved in previous decades have resulted from improvements in the upstream productionphase, with (1) more efficient bioreactors, (2) better media formulations and (3) cell lines that areintrinsically more productive due to the development [...].

Downstream processing is now routinely found to be the bottleneck in biopharmaceutical manufacturingbecause its capacity has not kept pace with upstream production. [...] Whereas upstream production can bescaled up almost indefinitely by increasing the productivity of cells growing in a bioreactor, downstreamprocessing has limits imposed by physics and chemistry. Downstream processing is driven by the mass ofproduct. If one makes more product per batch, one needs correspondingly larger volumes of buffer, largerstorage 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 bymanufacturers: a) the streamlining of existing processes, b) the revisiting of simple technology solutionscurrently employed in the bulk-chemical industry and c) the use of innovative technologies from thebiopharmaceutical research sector.

a) Antibody manufacturing provides an excellent example of the application of process redesign andstreamlining principles to increase productivity, cut costs, and maintain product quality: Most manufacturersuse three chromatography steps for antibody purification:

Protein A capture step

Anion exchange (AEX)chromatography step to

extract negatively chargedcontaminants

Cation exchange (CEX) chromatography or hydrophobicinteraction chromatography (HIC) to remove positively

charged residual contaminants and product relatedimpurities

[...] Pfizer [...] introduced two types of process modifications, one in which the order of the polishing stepswas 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 extentthat, for some antibody products, the cation-exchange step became unnecessary, reducing the process fromthree columns to two columns or even a single column. Not only did this save the direct costs of column resinand buffers, but also reduced the process time by > 45% which doubled the productivity in terms of batchprocessing.

b) Precipitation is widely used as a purification approach in the bulk-chemical industry [...] Precipitationhas 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 streamrelatively enriched for the target protein. [...]

c) Innovative technologies from the biopharmaceutical research sector would include membranechromatography, disposable technology... which would allow to switch to new campaigns rapidly and toproduce multiple products and hence might be the answer to the new biopharmaceutical paradigm.

Refer the complete article / references from Biopharm September 2011

ISSUE no.17NOVEMBER 2011 BiONEWS

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