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Topic #1 – Breaking the Bottleneck: Advances in Chromatography to Accelerate Biomanufacturing

Advances in upstream processing have increased protein yields per unit volume coming from bioreactors. Unfortunately, the capacity of bioprocessing operations designed years ago may struggle to accommodate the protein titers that can be produced today. Antibody expression levels now routinely exceed 1 g/L whereas levels of 100 mg/L were commonplace in the not so distant past. Successful efforts to maximize bioreactor titer levels have put significant pressure on downstream processes, shifting production bottlenecks from upstream to downstream unit operations.

Our experts describe how the latest advances in chromatography are helping to overcome production bottlenecks.

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2 Comments for this entry

Michael Lu
November 30th, 2011 on 3:28 pm

The operational effectiveness of bioseparations is measured according to four characteristics: speed, efficiency, recovery and loading capacity. However, existing bioseparations media for are inadequate for optimizing all four of these characteristics simultaneously. Conventional soft gel media for biomolecular separation might have good recovery and loading capacity, but they lack speed and resolution. Synthetic polymeric media might have rigidity, porosity and pore sizes that can achieve speed and resolution in the separations, but they are very hydrophobic and non-biocompatible. This can create recovery problems, especially in the protein separation and other large scale of biomolecular separation and production. The best solution is to use hybrid media of rigid synthetic polymers and biocompatible soft gels that offer both advantages.
Biopharmaceutical analysis and purification use biocompatible, natural polymers such as polysaccharides and celluloses in the production of separation media. These materials are biocompatible, friendly to biomacromolecules, such as high-molecular-weight therapeutics, recombinant proteins, antibodies, vaccines, complex biologics and biosimilars. These media are biocompatible and have large flexible pore sizes suitable for applications in biomacromolecular analysis and separation. The media can provide good recovery and loading capacity. However, most of these media can only be used under low pressure or gravitational force separation and analysis. They cannot be used for high pressure and high speed applications. They fall short on two key characteristics for modern bioseparations: speed and efficiency. This deficiency creates a bottleneck in downstream biopharmaceutical production and manufacturing. The media cannot be pressurized in large scale production. The media must be able to be pressurized in the separation to achieve speed, high efficiency, and resolution, which means that natural biocompatible polymers have limited applications in biopharmaceutical development and production.
Rigid polymer beads can be produced with high porosity and large pore size that can be operated under high pressure to provide high speed and high efficiency separation for macromolecular analysis and purification. Macroporous polymer beads can be produced with high porosity and at pore sizes greater than 1500 Ǻ. Their densities are around 0.3 to 0.4 grams per milliliter. They can be used directly as reversed phase media to analyze and purify biomolecules from small peptides, polypeptides, insulin up to more than 290 KDa. molecular weight of proteins and enzymes. This application can save significant development time and expense in early stage drug discovery and development. However, the synthetic, rigid polymeric beads are very hydrophobic and non-biocompatible. Unless the materials have adequate biocompatible coating to reduce their hydrophobicity or the materials have the specially created porosity, pore size and pore structure, the direct application of polymeric beads for biomolecular separation can result in recovery issues, especially in large-scale preparative and process application

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Jack Vicalvi
December 1st, 2011 on 11:38 am

First, Michael is spot on in his assessment of our current dilemma in downstream process development. Fortunately, new membrane and resin technologies are going to explode onto the scene in 2012, allowing for more manageable processing times at a reduced cost.
Second, in your poll question adsorptive membranes are a disposable technology. And as mentioned above, new advances in resin technologies will place these into the disposable category as well.

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