Model development and simulation of membrane separation systems for the recovery of intracellular protein products from crude biological feedstocks

The definition of a microfiltration operation for the recovery of protein products from complex biological feedstocks requires an understanding of a large number of operating variables including the permeate flux rate and transmission characteristics of the membrane. This thesis examines the use of computer-based simulation techniques, accompanied with experimental studies, for the rapid design and evaluation of crossflow microfiltration systems for use in the bioprocess industries. The thesis sets out to test the hypothesis that single laboratory tests of permeate flux rate and transmission, accompanied by selected laboratory-scale characterisations, may be used to define the operating characteristics of a membrane separation process and hence allow the evaluation of the effect of a range of operating variables including the recirculation rate and the concentration factor on process performance. The results of single microfiltration experiments have been used to establish a relationship between the rejection of soluble species as a function of their molecular weight and the membrane operating conditions. Verification trials have been conducted to test the accuracy of the model predictions. Microfiltration experiments have also been conducted on biological systems including polyethleneimine flocculated yeast homogenate and Escherichia coli cell lysate. The results of experiments indicate that the use of physical property characterisations as a generic basis for the prediction of membrane performance is limited by the highly specific nature of biological feed-streams and their interaction with the membrane. Simulations studies were conducted on a 3-stage filtration process for the recovery of alcohol dehydrogenase from yeast homogenate. The studies assessed the impact of the recirculation rate, the membrane module length, the starting cell concentration and diafiltration volumes on the product yield and product purity. The benefits of simulation were further illustrated through a realistic case study where the objective was to specify the design and operating conditions for a membrane separation process leading to the lowest overall cost for a fermentation-based product manufactured to a specified level. The work highlighted the high degree of specific interactions between membranes and typical bioprocess feed-streams making statistical modelling approaches most appropriate for describing membrane filtration. The importance of simulation as an efficient tool to aid process development work was also illustrated