The importance of choosing the correct chromatography resin
In this case study, the final chromatography step in the purification of a monoclonal antibody (mAb) was proving problematic. The achievement of a robust process with respect to high molecular weight (HMW) contaminant removal was elusive, with significant yield loss (up to 50%) observed across the polishing step. This resulted in a variable manufacturing process that was not commercially viable.
During the purification of a monoclonal antibody (mAb), chromatography steps are employed to capture and purify mAbs and process-related impurities. The final chromatography step is critical to ensure a highly purified product is derived from a robust and commercially viable process. It is difficult to justify a process that struggles in balancing product quality and yield.
A choice must be made as to whether to tweak and optimise multiple, interconnected process parameters or go back to first principles and undertake a complete redesign.
Both approaches have their merit.
Thus, a chromatography purification step with poor yield and variable HMW contaminant clearance can be a significant bottleneck in the development of a robust and viable manufacturing process. A choice must be made as to whether to tweak and optimise multiple, interconnected process parameters or go back to first principles and undertake a complete redesign. Both approaches have their merit. However, it can be difficult to overhaul an established process. At the same time, "optimisation fatigue" (diminishing returns in trying to optimize something that has inherent flaws which render it impossible/unfeasible to make meaningful improvements) can result in wasted time and resources. Alternatively, one can decide to approach the issue with a fresh pair of eyes and a new batch of resins.
A rationale was developed to go ‘back to basics’ and screen alternative chromatography resins to advance development and define a tailored, robust, reliable process.
This approach with ‘fresh eyes’ to screen multiple, alternative chromatography resins, with subsequent upscaling and process characterisation, helped overcome roadblocks in the process development. Although daunting at first, this approach helped identify a resin that ensured a robust, commercially viable purification step and ultimately accelerated the development of the medicine.
Performing a resin screen in 96-well plates and robocolumn format enables the assessment of multiple resin types and a range of process conditions (loading density, pH and salt concentration) with small quantities of process material, buffers and consumables. Resins in plate format are also readily available in columns to facilitate upscaled process development. Furthermore, as resin technologies advance, small scale studies enable the assessment of resins that may not have been available during previous process development campaigns.
In using this ‘back to basics’
approach, coupled with subsequent design of experiments to optimize parameters,
we were able to refine a full process and ultimately define a robust
chromatography purification step.
This did not impact the overall development timelines and avoided the original purification in which there was up to 50% yield loss observed.