Development of ultra scale-down shear filtration system and modelling of large scale diafiltration system

• Main Author: Ma, G.
• Published: University College London (University of London) 2010
• Subjects: 660.6
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.625330

Ultra scale-down (USD) approach is a powerful tool to predict large-scale process performance by using very small amounts of material. A new USD membrane tool for mimicking large scale crossflow filtration (CFF) would allow preliminary evaluation to be conducted at the early stages of process development to give an indication of the processability of the biomaterials, and provide crucial data for identifying optimal operating parameters with lower development cost. This thesis reports the development of an ultra scale-down shear device, method for USD mimicking, method for large scale performance prediction as well as method of verification based on an industrial relevant and complex feed material, E. coli lysate containing antibody fragment (Fab’). The Pellicon 2 labscale system (Millipore Corporation, Bedford, MA) is used as the benchmark for the mimic evaluation which can readily be scaled to small pilot or industrial scale. Large scale CFF was attempted to be scaled down with a rotating disc filter in recycle mode previously. However, the volume of feed material required cannot be reduced effectively, and the resulting loading ratio of the feed volume to the membrane area was large, which led to long experimental time. In addition, the operating conditions such as transmembrane pressure were hard to maintain due to the small size of membrane and the inaccurate monitor of the permeate flow, hence the accurate operation at USD cannot be achieved. A new mimicking method has overcome these difficulties. Adopted from the pulsed sample injection technique by Ghosh and Cui (2000), the rotating disc filter has been modified by building in inserts to allow the flexibility of the chamber volume, so that a large volume reduction can be achieved and only 1.5 mL of processing material is required for each diafiltration experiment. The USD mimicking method uses the modified rotating disc filter operated in dead-end mode, processing material is prefilled in the shear chamber and only buffer is pumped in through inlet port. The new set-up is much simpler and accurate control of operating conditions has been achieved. As the establishment of shear rate correlation between USD and labscale is essential, a specific correlation between shear rate on membrane surface and disc rotating speed for USD has been generated by CFD simulations with high accuracy and validated by Laser Doppler Velocimetry. The correlation between wall shear rate on the membrane and the inlet flow rate in labscale cassette is based on the developed analytical models, which can be readily modified and used for membrane cartridge systems of different designs and scales. Flux model regarding TMP and shear rate has been established using USD mimicking method based on E. coli lysate. Recognising the difference of system configuration between USD and large scale, e.g., the existing of screen on both side of the membrane in cassette, a new flux prediction method is developed firstly to accurately calibrate the system resistance in large scale CFF with water flux tests, and secondly to predict large scale performance accurately with USD model inputs. The important benefit is that the method allows accurate predictions with a simple procedure, so it can be widely applied. The transmission prediction method has also been developed based on mass balance technique. It has been found that the transmembrane pressure and shear rate do not show significant impact on the transmission of antibody fragment, but the ionic strength of the solution has strong influence on the observed transmission. Predicted transmission data agrees well with the experimental results of a labscale diafiltration.