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

Alternatives to Chromatography

Research into alternatives for column chromatography focuses on methods that have the potential to effectively handle increased amounts of both the product and impurities (e.g., host cell proteins and antibody aggregates or isomers). Ideally, these alternatives should achieve a separation power equal to that of column chromatography while reducing the COG/g.33 When assessing the cost-effectiveness of these alternatives, it is important to consider not only the equipment sizes and resource consumption, but also the development and validation costs required.

Table 1. Example of downstream process economic trade-offs
Membrane chromatography operating in flow-through mode is emerging as a popular alternative to anion-exchange chromatography steps in MAb purification,11,26,34–36 because of its rapid operation, ease of scale-up, and cost savings (Table 1). The dominant component in the distribution of raw material costs shifts from buffer costs in packed-bed chromatography to membrane costs; a membrane suitable for processing a batch of several thousand liters can cost several thousands of dollars and is disposable and not reusable. The key process economic trade-offs for anion-exchange applications therefore depends on whether the savings in buffer, labor, and overheads outweigh the high cost of the membranes. Critical variables that will affect the outcome of this cost comparison are the relative differences in the handling capacities assumed between anion-exchange membranes and resins, which dictate the sizes required, and the assumed WFI and buffer costs; higher values of these variables increase the economic attractiveness of membrane chromatography.26 The pace at which resin and membrane capacities improve will contribute to which operation secures its place in future platform processes. In cases where packed-bed and membrane chromatography offer similar COG/g, the real cost advantages may be in the development and validation costs that are significantly reduced with membrane chromatography because there is no column packing or cleaning validation.26

Summary and Outlook

As demand and titers continue to increase for MAbs, the DSP costs will become an increasingly dominant proportion of the COG/g with the DSP handling capacity representing a potential bottleneck that could reduce productivity. These factors have encouraged a shift in development efforts towards new DSP solutions that improve the process economics and alleviate bottlenecks. Consequently, the industry is taking advantage of improvements that affect the critical process economic drivers by looking to: improve the overall DSP yield and reduce the batch duration using platform processes based on two chromatography operations without intermediate buffer exchange steps; increase DSP capacity by taking advantage of improvements in chromatography resins that allow increased throughput over shorter times; and lower buffer demands and validation costs using new technologies such as membrane chromatography.

These improvements will be important for facilities that already have large bioreactor capacities installed, and also for newer facilities that will probably be built with smaller capacities with flexibility in mind to allow rapid turnaround between campaigns for multiple products. Furthermore, if cheaper and faster expression technologies, such as glycoengineered Pichia pastoris, become more widespread, there will be an even greater spotlight on DSP costs. Although new DSP approaches may present complex and challenging problems to tackle, it is anticipated that this line of enquiry will dominate studies in the near future so that more cost-effective MAb platform technologies can evolve. However, with each of these new approaches there are trade-offs and potential risks that need to be evaluated to assess the impact on process economics. The capacity to cost such alternatives provides a common basis for such decision-making and will prove a vital tool for bioprocess designs in the future. Process economics can also be dramatically improved if the potency of MAbs is increased; recent efforts in this area are an encouraging sign for the future. BP

This is an excerpt from the chapter entitled "Process Economic Drivers in Industrial Monoclonal Antibody Manufacture" in the forthcoming John Wiley and Sons book Process Scale Purification of Antibodies edited by Uwe Gottschalk.

SUZANNE S. FARID, PhD, is a lecturer (assistant professor) at the Advanced Centre for Biochemical Engineering, Department of Biochemical Engineering, University College London, London, UK, +44 20 7679 4415,


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