Economic Drivers and Trade-Offs in Antibody Purification Processes - The future of therapeutic MAbs lies in the development of economically feasable downstream processes. - BioPharm International


Economic Drivers and Trade-Offs in Antibody Purification Processes
The future of therapeutic MAbs lies in the development of economically feasable downstream processes.

BioPharm International Supplements

DSP Economic Drivers at High Titers

Efforts to lower COG/g must be targeted at decreasing the overall batch costs (e.g., reducing raw material costs) or increasing the overall productivity (e.g., increasing process yields). This section discusses specific downstream processing (DSP) drivers, which are of prime importance when handling multigram per liter titers.

As titers increase to 10–15g/L, it is expected that this will have a profound effect on reducing COG/g, as long as the purification costs do not negate the cell culture gains. With increasing titers, the ratio of upstream to downstream costs shifts so that the downstream costs become more dominant. For example, Sommerfeld and Strube calculated that increasing the fermentation titer 10-fold from 0.1 to 1 g/L caused the ratio of upstream to downstream costs in their process to drop from 55:45 to 30:70. This shift reflects the fact that the upstream costs are inversely proportional to titer but the same is not true for the downstream processing costs.9 Increasing the titer to satisfy larger market demands increases the protein load on chromatography steps resulting in an increase in the number of cycles or additional investment in larger columns; this also produces larger volume loads on any subsequent filtration steps leading to longer filtration times or a need for larger areas.

All these factors increase the downstream operating costs per batch. However, the overall COG/g can still fall if the increase in overall productivity outweighs the increase in downstream costs. Accordingly, as titers increase further, the downstream processing steps will become major contributors to the overall COG/g and offer greater potential for improvements and cost savings. Consequently, the downstream yield and material costs become significant cost drivers. DSP bottlenecks can lead to increased investment in larger equipment and longer batch durations. This results in increased running costs and decreased productivity and suboptimal COG/g values.

Overall DSP Yield

The overall DSP yield is a function of the individual step yields and the number of downstream processing steps, as has often been demonstrated using the plot in Figure 2. Improvements in step yields and the reductions in the number of steps have contributed to typical overall process yields increasing from 40 to 75% in recent years, with savings in cost of goods and investment, and allowing for higher facility throughputs.10,11

Figure 2. Overall yield as a function of individual step yields and the number of steps
The impact of increasing step yields has been illustrated by Sommerfeld and Strube where increasing the average step yield in a seven-step downstream process from 85 to 95%, which increases the overall yield from ~30 to 70%, results in a 40% reduction in the downstream COG/g.9 Increasing step yields actually increases the equipment size or number of cycles required and, hence, the cost of the DSP steps, because each step needs to handle a larger load (chromatography) or volume (filtration). However, because more product is produced per batch, the COG/g typically falls with increasing yields.

To maximize productivity and minimize investment and running costs, it is advisable to keep the number of downstream processing steps to a minimum.10,12,13 For antibody processes, this has encouraged the elimination of buffer exchange steps (diafiltration) that add little purification value by designing each chromatography step so that it can take the material eluted from the previous step where possible.10,14,15 Some companies have recently adopted processes that use only two chromatography steps while maintaining the desired purity levels.16 This requires an anion-exchange step to have additional selectivity to replace the intermediate purification and polishing steps. In cases where the contaminant profile, pH, and conductivity provide the opportunity to adopt this simpler process, time and cost savings can be achieved.

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