Smith, Helen Elizabeth; (2002) Systematic selection of downstream processing techniques. Masters thesis (M.Phil), UCL (University College London).

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Abstract

This project began as an extension of the work undertaken by Harrison, (1996) which looked at the large-scale downstream processing of antibody fragments. After this preliminary work a change was made to the structure of research, whereby I began to look at the theoretical basis for the systematic selection of downstream processing techniques. This thesis examines the reports of protein recovery in the literature as an attempt to create a means of choosing the most appropriate process. The work described focuses on the selection of downstream processing techniques for the purification of therapeutic proteins. Analysing the data collected from 96 protein purification papers published in 1994, attempted to find a factor that could be used to combine yield and purification factor, thereby generating an Operational Effectiveness. This is described as the fraction of contaminant removed for a 95% yield. A review of the most frequently used chromatography steps and the sequence for their use was also undertaken. The order of effectiveness for the steps was given as affinity chromatography = hydrophobic interaction chromatography > ion exchange = gel filtration > precipitation. The major costs of the production of therapeutic proteins incurred during downstream processing are also investigated. This was aided by communications with a number of European biotechnology companies, who provided costings from their companies for the manufacture of therapeutic protein drugs. The overall cost for the production of 100g of a monoclonal antibody was estimated at £100,000. The good manufacturing practice (GMP) requirements for antibody fragment production were also assessed, and shown to require at least 3 chromatography stages to meet the regulatory agencies.

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