Advanced monitoring and control in biopharmaceutical production

Z.I.T.A. Soons

Research output: Thesisinternal PhD, WU


Bioprocesses are characterised by natural variability in raw materials, initial conditions, human intervention, and varying properties of the micro-organism. In traditional biopharmaceutical production quality of the product is currently tested at the end of the production process only. Recently the Food and Drug Administration (FDA) released guidelines on process analytical technology (PAT) aiming at reducing variability in the end-products by introducing timely measurement and control of quality variables during the manufacturing process.
This thesis intends to be a step forward towards the introduction of real-time feedback control within the frame of PAT by combining several techniques from a multidisciplinary field of systems and control theory, biology, and chemometrics. The dual substrate cultivation of Bordetella pertussis for the production of bulk whole cell whooping cough vaccine was chosen as test case.
A software sensor was developed to reconstruct biomass and specific growth rate from easy to obtain measurements during cultivation. The software sensor accurately monitors biomass growth over the whole range from low to high biomass concentrations during different types of cultivation (batch, fed-batch, and continuous cultivations). It has also been investigated how near infra red spectra can be used to yield an alternative measurement of biomass. In the current state of development the software sensor is the preferred choice when it comes to feed-back control.
A model-reference based controller was derived that adapts its settings in response to the time-varying conditions in order to control the specific growth rate during fed-batch cultivation, thus obtaining higher bulk vaccine concentrations compared to the standard production process. Two methods to automate controller tuning were proposed and have successfully been implemented.
To obtain an indication which controller set-points are needed to obtain the best vaccine quality, the effect of specific growth rate on the formation of virulence factors has been investigated. The data and a proposed preliminary model are in favour of choosing the highest feasible growth rate.
Finally, with some precautions the monitoring and control tools developed on lab-scale using headspace aeration turned out to be transportable to medium size pilot-scale cultivation using sparger aeration.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
  • van Straten, Gerrit, Promotor
  • van Boxtel, Ton, Co-promotor
Award date13 Jun 2008
Place of Publication[S.l.
Print ISBNs9789085049333
Publication statusPublished - 2008


  • new drugs
  • drug development
  • quality controls
  • sensors
  • bioprocess engineering
  • process control

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