Integrated Continuous Downstream Processing of Biopharmaceuticals
(2025)- Abstract
- Biopharmaceuticals, of which monoclonal antibodies are a mainstay, have revolutionized healthcare by enabling treatments with high precision and efficacy. However, their established manufacturing processes, particularly the downstream process, are complex, resource-intensive, and expensive, limiting global access to these drugs. This thesis examines how a more efficient, sustainable, and thus less costly downstream process for generating monoclonal antibodies can be achieved.
Such a process can be obtained by transitioning from traditional batch-wise purification to integrated continuous downstream processing, which provides such benefits as improved product quality, lower buffer consumption, better equipment utilization, and... (More) - Biopharmaceuticals, of which monoclonal antibodies are a mainstay, have revolutionized healthcare by enabling treatments with high precision and efficacy. However, their established manufacturing processes, particularly the downstream process, are complex, resource-intensive, and expensive, limiting global access to these drugs. This thesis examines how a more efficient, sustainable, and thus less costly downstream process for generating monoclonal antibodies can be achieved.
Such a process can be obtained by transitioning from traditional batch-wise purification to integrated continuous downstream processing, which provides such benefits as improved product quality, lower buffer consumption, better equipment utilization, and enhanced economic efficiency. In Papers I and II, a continuous downstream process was developed on a lab scale and later operated on a pilot scale for 17 days, around the clock. The pilot-scale process effected recovery yields of approximately 90% and productivity close to 1 g purified antibody per L bioreactor volume and day, accompanied by efficient impurity removal. Paper III presents the implementation of another lab-scale process that was operated for over 5 days and yielded an average monomer content of 94%, with an overall yield above 90%.
An essential component of integrated continuous downstream processes, often involving multiple process systems and complex steps, is the automation, control, and monitoring of these processes. In this work, these aspects were facilitated by a supervisory control and data acquisition software program
that was developed in house, called Orbit. Quality monitoring was conducted by automated at-line product collection and high-performance liquid chromatography, as described in Paper III, reducing manual labor inputs and enabling near real-time monitoring of product quality, supporting the quality by
design concept.
Given the use of large buffer volumes in monoclonal antibody purification and the growing focus on sustainability, this thesis also investigates methods of enhancing buffer management and reducing buffer consumption. Paper IV describes the development of a buffer management system that can manage
buffer orders from multiple process systems and prepare and deliver the buffers. This system was integrated with the processes that are detailed in Papers I and III, providing all necessary buffers. Further, the concept of buffer recycling was introduced during one step of the downstream process, as described in Paper V, the implementation of which lowered buffer consumption during this step by nearly 50%, demonstrating significant improvements in sustainability.
This thesis highlights the benefits of integrated continuous downstream processing, in combination with buffer intensification, supporting the transition from batch production to sustainable integrated continuous biomanufacturing with optimized buffer use. To realize these benefits fully and support global access to biopharmaceuticals, a holistic approach to optimizing their manufacture is essential. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/30d11714-b846-42b4-8361-67da8137b563
- author
- Isaksson, Madelène LU
- supervisor
- opponent
-
- Assoc. Prof. Azevedo, Ana, University of Lisbon, Portugal.
- organization
- publishing date
- 2025-02-28
- type
- Thesis
- publication status
- published
- subject
- keywords
- Biopharmaceuticals, Monoclonal antibodies, Integrated continuous downstream processing, Automation and control, Quality monitoring, Buffer management,, Buffer recycling
- pages
- 83 pages
- publisher
- Department of Process and Life Science Engineering, Lund University.
- defense location
- Lecture Hall Stora hörsalen, IKDC, Klas Anshelms väg 20, Faculty of Engineering LTH, Lund University, Lund.
- defense date
- 2025-02-28 09:00:00
- ISBN
- 978-91-8096-096-0
- 978-91-8096-097-7
- project
- VINNOVA - BMS 3
- VINNOVA - AutoADD
- European Union’s Horizon 2020 research and innovation programme - CODOBIO
- language
- English
- LU publication?
- yes
- id
- 30d11714-b846-42b4-8361-67da8137b563
- date added to LUP
- 2025-01-23 11:53:56
- date last changed
- 2025-04-04 13:57:27
@phdthesis{30d11714-b846-42b4-8361-67da8137b563,
abstract = {{Biopharmaceuticals, of which monoclonal antibodies are a mainstay, have revolutionized healthcare by enabling treatments with high precision and efficacy. However, their established manufacturing processes, particularly the downstream process, are complex, resource-intensive, and expensive, limiting global access to these drugs. This thesis examines how a more efficient, sustainable, and thus less costly downstream process for generating monoclonal antibodies can be achieved. <br/><br/>Such a process can be obtained by transitioning from traditional batch-wise purification to integrated continuous downstream processing, which provides such benefits as improved product quality, lower buffer consumption, better equipment utilization, and enhanced economic efficiency. In Papers I and II, a continuous downstream process was developed on a lab scale and later operated on a pilot scale for 17 days, around the clock. The pilot-scale process effected recovery yields of approximately 90% and productivity close to 1 g purified antibody per L bioreactor volume and day, accompanied by efficient impurity removal. Paper III presents the implementation of another lab-scale process that was operated for over 5 days and yielded an average monomer content of 94%, with an overall yield above 90%. <br/><br/>An essential component of integrated continuous downstream processes, often involving multiple process systems and complex steps, is the automation, control, and monitoring of these processes. In this work, these aspects were facilitated by a supervisory control and data acquisition software program <br/>that was developed in house, called Orbit. Quality monitoring was conducted by automated at-line product collection and high-performance liquid chromatography, as described in Paper III, reducing manual labor inputs and enabling near real-time monitoring of product quality, supporting the quality by <br/>design concept. <br/><br/>Given the use of large buffer volumes in monoclonal antibody purification and the growing focus on sustainability, this thesis also investigates methods of enhancing buffer management and reducing buffer consumption. Paper IV describes the development of a buffer management system that can manage <br/>buffer orders from multiple process systems and prepare and deliver the buffers. This system was integrated with the processes that are detailed in Papers I and III, providing all necessary buffers. Further, the concept of buffer recycling was introduced during one step of the downstream process, as described in Paper V, the implementation of which lowered buffer consumption during this step by nearly 50%, demonstrating significant improvements in sustainability. <br/><br/>This thesis highlights the benefits of integrated continuous downstream processing, in combination with buffer intensification, supporting the transition from batch production to sustainable integrated continuous biomanufacturing with optimized buffer use. To realize these benefits fully and support global access to biopharmaceuticals, a holistic approach to optimizing their manufacture is essential.}},
author = {{Isaksson, Madelène}},
isbn = {{978-91-8096-096-0}},
keywords = {{Biopharmaceuticals; Monoclonal antibodies; Integrated continuous downstream processing; Automation and control; Quality monitoring; Buffer management,; Buffer recycling}},
language = {{eng}},
month = {{02}},
publisher = {{Department of Process and Life Science Engineering, Lund University.}},
school = {{Lund University}},
title = {{Integrated Continuous Downstream Processing of Biopharmaceuticals}},
url = {{https://lup.lub.lu.se/search/files/206780382/Thesis_for_electronic_nailing.pdf}},
year = {{2025}},
}