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.
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
Table 1. Example of downstream process economic trade-offs
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
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, firstname.lastname@example.org
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