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


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

BioPharm International Supplements

Process Economic Trade-offs for DSP Bottlenecks

Current efforts to avoid downstream processing becoming a bottleneck when handling larger masses include intensifying existing processes by enhancing capacity and speed. Such approaches can mitigate the need for extra investment in equipment and improve the process economics. However, with each of these approaches there are trade-offs and uncertainties that need to be evaluated to assess the impact on overall process economics.

Chromatography Resin Dynamic Binding Capacity

Increasing resin binding capacity reduces column size requirements with concomitant drops in resin volumes required and buffer consumption [for equilibration, washing, elution, regeneration, and clean-in-place (CIP)] per batch. Novel resins have capacities that are more than twice those of the first generation resins.24,31 This can lower consumables costs which are a major component of COG/g at higher titers and demands,9 although the impact on the consumable costs will depend on the price differential between first and second generation resins. Increasing the binding capacity of affinity resins can have a greater influence on COG/g because affinity resins are more expensive than ion-exchange resins. With the cheaper ion-exchange resins, Sommerfeld and Strube highlight that a trade-off exists between the less pronounced drop in consumables cost and the increase in labor costs, which becomes more important at higher binding capacities, because of the longer processing times. However, given that most of the novel resins also allow higher flow rates, this may not be an issue.

Chromatography Flow Rates

The first generation of cell-culture–based MAb processes used compressible chromatography resins. However, these impose severe limits on usable bed heights and flow rates when considering the expected increases in titer and scale.30,32 A move away from compressible resins and towards rigid resins that can handle higher flow rates reduces process cycle times and turnaround time and increases productivity.24,30,31 Flow rates with rigid resins can be three to five times faster than conventional compressible agarose resins.24,31 However, their use can also lead to increased buffer demands, higher pressure drops, packing complications, and shear stresses.30 New ion-exchange resins have recently been developed that can handle high flow rates (700 cm/h) and low back pressures (<3 bar). If the productivity increases outweigh the increased buffer demands, this will positively influence the COG/g.

Chromatography Resin Cycle Limits

As mentioned earlier, resin and filter re-use can have a significant impact on the process economics at higher scales if the materials are expensive, despite the CIP and cleaning validation costs. Re-use also reduces the frequency of column packing which is time-consuming and costly when carried out on a large-scale.31 New resins are becoming available with increased stability when exposed to the harsh chemicals used for CIP; hence, they have longer cycle limits and can contribute to reducing the raw material costs.

Platform Processes

Platform processes provide a generic approach to antibody production that greatly reduces the development time while streamlining the regulatory aspects of processing. They represent a useful starting point for customization depending on the antibody being manufactured. Advances in resin properties have also allowed platform processes to emerge with two rather than three chromatography steps.16,28 This can help to alleviate DSP bottlenecks in existing facilities because a two-chromatography–step process occupies less floor space and consumes less buffer. Through such process intensification methods, Kelley predicted that a platform consisting of two chromatography steps with high capacity resins would be able to handle an annual output of 10 tons.16 Newer resins with the combined attributes of longer lifetimes, higher flow rates, and improved dynamic binding capacities will lead to improved platform processes for antibodies and contribute to significant reductions in downstream costs.28,31

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,because of its rapid operation, ease of scale-up, and cost savings (Table 1).11,26,34–36 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

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