Chemical Engineering

Formulation of monoclonal antibody (mAb) solutions using membrane fi ltration processing is a critical unit operation in the preparation of antibody therapies. A key constraint in formulation process development, particularly in the early stages of development and when using high protein concentration solutions, is the availability of material for experimental studies. Ultrascale down (USD) technologies use a combination of critical fl ow regime analysis, bioprocess modeling and experimentation at the milliliter scale to enable a more eff ective process development approach signifi cantly reducing process material, cost and time requirements. Th e ability to predict the performance of large-scale (LS) operations, e.g., fl ux profi le characteristics and changes in protein structure will help maximize the value of eventual high cost pilot-scale runs during process development. In this study a USD membrane device, comprising a sheared cell unit with a rotating disc and with an eff ective membrane area of 0.00021 m2 developed at University College London, is used to predict the performance of a LS cross-fl ow membrane cassette of area 0.11 m2. Th e USD set up was designed to mimic the LS in terms of processing volumes, membrane area and process times. Computational Fluid Dynamics (CFD) is implemented to characterize average shear rates as a function of suspension viscosities and disc speed of the USD membrane device. A series of trials at USD scale established the eff ect of average shear rate on fl ux and the rate of fl ux decline during a diafi ltration operation reaching 7 diafi ltration volumes. A series of LS runs were carried out at diff erent cross flow rates covering a similar range of average shear rates as the USD trials. Good correlation was obtained between USD and LS performance using constant average shear rate over the membrane surface as the basis for scale translation between the two scales of operation. Th e predicted eff ect of change in shear rate on fl ux in USD matched that found in LS. Th is scale correlation on performance was additionally verifi ed by studying the eff ect of type and concentration of mAb. Th e comparable process performance was achieved at USD with 520-fold reduction in eff ective membrane area, required process material and diafi ltration buff er for the trial. Future studies will include membrane concentration operations and evaluating sensitivity to stress-related eff ects and the impact of operation at higher protein concentrations.