processes
Article
A Framework for the Development of Integrated and
Computationally Feasible Models of Large-Scale
Mammalian Cell Bioreactors
Parham Farzan and Marianthi G. Ierapetritou *
Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey,
98 Brett Road, Piscataway, NJ 08854, USA; parham.farzan@rutgers.edu
* Correspondence: marianth@soemail.rutgers.edu; Tel.: +1-848-445-2971
Received: 5 May 2018; Accepted: 26 June 2018; Published: 29 June 2018
Abstract: Industrialization of bioreactors has been achieved by applying several core concepts of
science and engineering. Modeling has deepened the understanding of biological and physical
phenomena. In this paper, the state of existing cell culture models is summarized. A framework
for development of dynamic and computationally feasible models that capture the interactions of
hydrodynamics and cellular activities is proposed. Operating conditions are described by impeller
rotation speed, gas sparging flowrate, and liquid fill level. A set of admissible operating states
is defined over discretized process parameters. The burden on a dynamic solver is reduced
by assuming hydrodynamics at its fully developed state and implementation of compartmental
modeling. A change in the conditions of operation is followed by hydrodynamics switching
instantaneously to the steady state that would be reached under new conditions. Finally, coupling
the model with optimization solvers leads to improvements in operation.
Keywords: bioreactor integrated modeling; CFD simulation; compartmental modeling; reduced-order
model; bioreactor operation optimization
1. Introduction
1.1. The Importance of Reliable Unit Operation Models
Global sales of biopharmaceutical products reached $228 billion in 2016 [1]. Compared to microbial
and yeast-based production systems, mammalian cells possess the cellular machinery to manufacture
and secrete large proteins with the necessary post-translational modifications. Mammalian cell cultures
are responsible for half of the revenue generated by the biotechnology industry, which is expected to
grow by 15% annually [2].
The average commercial-scale titer for mammalian-expressed products has increased by 10-fold
since the early 1990s and reached 2.5 g/L in recent years [3]. This has mainly been achieved via clone
selection, cell line screening, host cell engineering, improving vectors, and gene amplification. At the
same time, the demand and regulations for production of therapeutic proteins from mammalian cells
have also been increasing. As a result, the delivery of affordable products at consistent quality is
still a challenge for the industry. The industry has responded to this challenge by expanding the
manufacturing capacity and improving the operational agility and efficiency of the supply chain.
Bioreactors as large as 25,000 L are used, which has increased the capacity of manufacturing sites up to
200,000 L [4]. However, scale-up methodologies have remained based on the overall characterization
of the components of the system such as aeration and agitation mechanisms. Considering the total
cost of launching an asset and net cash inflow an asset is forecast to deliver, the return on innovation,
as the engine of the industry, has been declining. Deloitte Center for Health Solutions monitored the
Processes 2018, 6, 82; doi:10.3390/pr6070082
www.mdpi.com/journal/processes
114
Article
A Framework for the Development of Integrated and
Computationally Feasible Models of Large-Scale
Mammalian Cell Bioreactors
Parham Farzan and Marianthi G. Ierapetritou *
Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey,
98 Brett Road, Piscataway, NJ 08854, USA; parham.farzan@rutgers.edu
* Correspondence: marianth@soemail.rutgers.edu; Tel.: +1-848-445-2971
Received: 5 May 2018; Accepted: 26 June 2018; Published: 29 June 2018
Abstract: Industrialization of bioreactors has been achieved by applying several core concepts of
science and engineering. Modeling has deepened the understanding of biological and physical
phenomena. In this paper, the state of existing cell culture models is summarized. A framework
for development of dynamic and computationally feasible models that capture the interactions of
hydrodynamics and cellular activities is proposed. Operating conditions are described by impeller
rotation speed, gas sparging flowrate, and liquid fill level. A set of admissible operating states
is defined over discretized process parameters. The burden on a dynamic solver is reduced
by assuming hydrodynamics at its fully developed state and implementation of compartmental
modeling. A change in the conditions of operation is followed by hydrodynamics switching
instantaneously to the steady state that would be reached under new conditions. Finally, coupling
the model with optimization solvers leads to improvements in operation.
Keywords: bioreactor integrated modeling; CFD simulation; compartmental modeling; reduced-order
model; bioreactor operation optimization
1. Introduction
1.1. The Importance of Reliable Unit Operation Models
Global sales of biopharmaceutical products reached $228 billion in 2016 [1]. Compared to microbial
and yeast-based production systems, mammalian cells possess the cellular machinery to manufacture
and secrete large proteins with the necessary post-translational modifications. Mammalian cell cultures
are responsible for half of the revenue generated by the biotechnology industry, which is expected to
grow by 15% annually [2].
The average commercial-scale titer for mammalian-expressed products has increased by 10-fold
since the early 1990s and reached 2.5 g/L in recent years [3]. This has mainly been achieved via clone
selection, cell line screening, host cell engineering, improving vectors, and gene amplification. At the
same time, the demand and regulations for production of therapeutic proteins from mammalian cells
have also been increasing. As a result, the delivery of affordable products at consistent quality is
still a challenge for the industry. The industry has responded to this challenge by expanding the
manufacturing capacity and improving the operational agility and efficiency of the supply chain.
Bioreactors as large as 25,000 L are used, which has increased the capacity of manufacturing sites up to
200,000 L [4]. However, scale-up methodologies have remained based on the overall characterization
of the components of the system such as aeration and agitation mechanisms. Considering the total
cost of launching an asset and net cash inflow an asset is forecast to deliver, the return on innovation,
as the engine of the industry, has been declining. Deloitte Center for Health Solutions monitored the
Processes 2018, 6, 82; doi:10.3390/pr6070082
www.mdpi.com/journal/processes
114