Evaluation of the financial and technical impacts of changing commercial-scale pharmaceutical manufacturing processes.

Growing pressures in the pharmaceutical industry are driving the need to optimise processes used for the manufacture of drugs at commercial-scale, in order to improve cost of goods, product throughput and production times. Evaluating the impacts of process optimisation upon these metrics presents a challenge due to complexities and trade-offs that are often encountered when developing a typical bioprocess. Such factors have resulted in a range of novel simulation- and experimental- based techniques being developed which enable rapid, accurate and cost effective assessment of manufacturing options for commercial-scale production. This thesis proposes a combination of modelling and experimental methods for evaluating the business- and process-related impacts of implementing changes to pre-existing commercial-scale pharmaceutical manufacturing processes. The approaches are illustrated through an industrial case study, focusing upon a process operated by Protherics U.K. Limited for the manufacture of the FDA-approved rattlesnake anti-venom CroFab (Crotalidae Polyvalent Immune Fab (Ovine)). The novel methods developed and illustrated in this thesis include: Investigating the effects of process changes upon calculated yields and processing times within the production framework for a pre-existing FDA-approved bio-manufacturing process Evaluating the impacts of both developing and implementing process changes, combining output metrics into a single value to simplify the assessment Developing a multi-layered simulation methodology for the rapid and efficient evaluation of bio- manufacturing process options Applying advanced sensitivity analysis techniques to identify the most critical factors that influence product yield and throughput Evaluating a novel synthetic Protein A matrix for the recovery and purification of polyclonal antibodies from hyperimmunised ovine serum Developing decision-support software to aid the design of chromatography steps for antibody purification at industrial scale Demonstrating the utility of such models by application to data and constraints derived from a full-scale industrial facility.