Towards process automation in upstream biopharmaceutical processing
File(s)
Author(s)
Kavanagh, Thomas Wayne
Type
Thesis
Abstract
Monoclonal antibodies (mAbs) continue to show significant clinical and commercial success in treating major diseases including heart diseases, cancers, and Alzheimer’s. However, the great costs of biologics, and the development of biosimilars, have driven demand for high-performing and lower-cost manufacturing methods. Process automation can unlock such benefits, but its application to biopharmaceutical processes is impeded by challenges including a lack of inexpensive sensors and difficulty controlling the complex process dynamics. This thesis employs process systems engineering to overcome these barriers advancing towards process automation of biopharmaceutical processes. Firstly, modelling workflows are demonstrated capable of elucidating the behaviour of highly complex processes in instances of limited and expensive data. From this, one can gain an in-depth understanding whilst alleviating the experimental burden of process development. To that end, several experiments were performed characterizing a commercial biopharmaceutical cell culture process under varying feeds of glucose. Next, a mechanistic mathematical model designed for real-time deployment was postulated to describe Chinese hamster ovary (CHO) cell growth and metabolism and subsequently applied to devise an optimal operating strategy. Finally, multiple novel process control strategies were developed and demonstrated experimentally both during a major process deviation and during normal operation. Namely, in an attempt to recover a batch during a major process deviation, reactive scheduling and non-linear model predictive control (NLMPC) were deployed. Further, during normal operation, open-loop optimisation was compared to NLMPC. The control objective of all demonstrations was identical and included maximising product titre whilst minimising exposure to lactate, a metabolic by-product that adversely affects cell culture performance. Here, NLMPC satisfied the control objective achieving superior performance. Overall, this research aims to pave the way towards more advanced process control and automation of biopharmaceutical production processes with the overarching goals of increasing process performance and robustness, reducing process development timelines, and improving process economics.
Version
Open Access
Date Issued
2024-05-12
Date Awarded
01/12/2024
License URL
Advisor
Kontoravdi, Cleo
Papathanasiou, Maria
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Publisher Department
Chemical Engineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)