Joseph, AVA; (2017) Scale-down characterisation and modelling of harvest operations in mammalian cell culture processes. Doctoral thesis , UCL (University College London).

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Abstract

Disk-stack centrifugation and depth filtration are often used in combination for the removal of cells and cellular debris during the production of biopharmaceutical products. Process development and characterisation of these unit operations are often conducted at pilot-scale so as to best mimic the performance of commercial-scale equipment. However, this requires large volumes of material and significant levels of effort for successful characterization. This thesis describes scale-down methods for centrifugation and depth filtration that were developed to minimize test volumes when conducting characterization studies. The scale-down method for centrifugation uses a capillary shear device to mimic the shear created in commercial-scale centrifuges. This method consists of a two-stage process in which the culture is exposed to a shear device with a known energy dissipation rate and then separated by a lab-scale centrifuge. Themethodology showed on multiple occasions to create mimic centrates with similar turbidities. The scale-down depth filtration method developed in this thesis uses a model based approach to translates constant pressure data to provide constant flow predictions. Themethod proposed uses constant pressure filter fouling data fitted to common filter fouling models to identify the best fitting model. The best fittingmodel’s optimized coefficients were then correlated with the filter capacities fromconstant flow studies. The developed scale-down method for depth filtration was able to predict constant flow capacity with in an accuracy of ± 15%. Scale-down methods enable drastic reduction in both material and time requirements for process characterisation studies. Additionally, they allow a much wider design space to be tested than is currently possible at pilot-scale for such studies. In the case of the scale-down method developed this thesis for depth filtration there was on average an 80% reduction in processing time and an additional 70% reduction in feed material required when performing depth filter characterisation studies. While the scale-down centrifugationmethod enabled studies to be conducted with few millilitres of material compared to the pilot scalemethod whichmay require tens of hundreds of litres. With scale-down methods for centrifugation and depth filtration developed, these tools were used to quantify the effect of a range of cell culture conditions on the process performance of the harvest sequence.

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