Design and Control of Integrated Continuous Processes for the Purification of Biopharmaceuticals

Joaquin Gomis Fons

Research output: ThesisDoctoral Thesis (compilation)

317 Downloads (Pure)


The production of biopharmaceuticals so far has been based on batch processes that are robust and well-known, but very inefficient and inflexible, causing the products to be very expensive and process development to be slow and costly. The production of biopharmaceuticals is thus changing towards integrated continuous biomanufacturing (ICB) in order to reduce costs and increase flexibility in a constantly changing market. Continuous processing has been successfully implemented in upstream operation through the use of perfusion bioreactors, but the maturity required for the widespread use of ICB on commercial scale has not yet been achieved in integrated continuous downstream processes (ICDPs). The research presented in this thesis provides several tools for the design, optimization, control and scale-up of ICDPs for the purification of biopharmaceuticals with the aim of reducing the technological gap in downstream processing. The feasibility of implementing these processes in general platforms on laboratory and pilot scale has also been demonstrated.
Process control and automation form a central part of the work presented in this thesis, including the development of several control strategies such as controlling the loading phase in the chromatography column, optimal product pooling in the elution phase, and adjusting and monitoring the pressure in an ultrafiltration process. In addition, existing research software has been further developed to enable automation in a number of different applications.
The implementation of an ICDP requires a specific design approach to enable process integration and continuity of the feed from the upstream process. Several design equations were used for process integration. Feed continuity was achieved by employing periodic multi-column chromatography in the capture step. Process scheduling is therefore very important in this case, as the cycle time must be matched to the product recovery time. The effects of different integration approaches on process scheduling, and thus the overall productivity, was studied. Periodic multi-column chromatography not only allows for a continuous feed, but can also lead to increased productivity and resin utilization, as in the case of the periodic counter-current chromatography (PCC) process described in Paper III, where model-based optimization was performed. Another tool used to increase process efficiency in a downstream process was model-aided flow programming (Paper V), where a variable flow rate was used in the loading phase to achieve higher productivity and resin utilization.
The feasibility of ICDPs was demonstrated by implementing them in different applications. Chromatography and ultrafiltration technologies were integrated in a single system (Paper I), and a complete ICB process was developed for the production of monoclonal antibodies (mAbs) (Paper II). Paper III describes the integration of a 3-column PCC capture step in a downstream process for the purification of mAbs. Continuous solvent/detergent-based virus inactivation and continuous capture were combined in an ICDP (Paper IV). The downstream processes described in Papers II and III were further developed to allow for the purification of pH-sensitive mAbs (Paper VI), and this process was coupled with the upstream system and run on pilot scale, demonstrating its feasibility on a larger scale (Paper VII).
The results of this research show that ICDPs outperform traditional manual batch downstream processes. Automation, integration and continuous biomanufacturing lead to higher productivity, shorter process time, more rapid development of biopharmaceuticals, and lower investment costs.
Original languageEnglish
Awarding Institution
  • Division of Chemical Engineering
  • Nilsson, Bernt, Supervisor
  • Andersson, Niklas, Assistant supervisor
Award date2022 Mar 11
ISBN (Print)978-91-7422-862-5
ISBN (electronic) 978-91-7422-863-2
Publication statusPublished - 2022

Bibliographical note

Defence details
Date: 2022-03-11
Time: 09:00
Place: Lecture hall KC:C, Kemicentrum, Naturvetarvägen 14, Faculty of Engineering LTH, Lund University, Lund
External reviewer(s)
Name: Mota, Paulo
Title: Prof.
Affiliation: NOVA University Lisboa, Portugal

Subject classification (UKÄ)

  • Other Chemical Engineering

Free keywords

  • Integrated Continuous Biomanufacturing
  • Downstream Processing
  • Process Design and Optimization
  • Process Control
  • Biopharmaceuticals


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