Hydrodynamic inhomogeneities in large scale stirred tanks – Influence on mixing time

Rosseburg, Annika; Fitschen, Jürgen; Wutz, Johannes; Wucherpfennig, Thomas; Schlüter, Michael

doi:10.1016/j.ces.2018.05.008

Cited by 57 publications

(59 citation statements)

References 35 publications

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“…This is conventionally done by keeping a hydrodynamic state constant, e.g. volumetric power input ( P / V L ) ( Klöckner et al, 2012;Catapano et al, 2009 ), mixing time ( Varley and Birch, 1999;Rosseburg et al, 2018 ), impeller tip speed ( Ju and Chase, 1992;Alsayyari et al, 2018 ) or the volumetric mass transfer coefficient k L a ( Xing et al, 2009;Nienow et al, 1996 ). Therefore, it is recommended to hydrodynamically characterize the bioreactors at each scale (recommendation see Meusel et al, 2016 ).…”

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confidence: 99%

Model uncertainty-based evaluation of process strategies during scale-up of biopharmaceutical processes

Möller

Rodríguez

Müller

et al. 2020

Computers & Chemical Engineering

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Model-assisted design of experiments Quality by design a b s t r a c tReliable scale-up of biopharmaceutical production processes is key in Quality by Design. In this study, a model-based workflow is described to evaluate the bioprocess dynamics during process transfer and scale-up computationally. First, a mathematical model describes the bioprocess dynamics of different state variables (e.g., cell density, titer). Second, the model parameter probability distributions are determined at different scales due to measurement uncertainty. Third, the quantified parameter distributions are statistically compared to evaluate if the process dynamics have been changed. This workflow was tested for the scale-up of an antibody-producing CHO fed-batch process. Significant differences were identified between the process development (30 ml) and implementation (250 ml) scale, and the feeding strategy was validated using model-assisted Design of Experiments. Then, the validated process strategy was successfully scaled up to 2 l laboratory and 50 l pilot scale. In summary, the proposed workflow enables a knowledge-driven evaluation tool for bioprocess development.

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confidence: 99%

Model uncertainty-based evaluation of process strategies during scale-up of biopharmaceutical processes

Möller

Rodríguez

Müller

et al. 2020

Computers & Chemical Engineering

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“…. However, most commonly colorimetry or tracer pulses are used . Furthermore, these types of experiments are utilized to validate CFD simulations.…”

Section: Determining the Extent Of Inhomogeneities In Large‐scale Biomentioning

confidence: 99%

“…However, there are published characterization studies of bioreactors ranging in volume up to 25 000 L . Recently, a transparent 15 000 L cell culture reactor has been used to characterize the occurring flow patterns with the benefit of optical access into the reactor . Computational fluid dynamics (CFD) simulations have also been widely used to characterize the flow fields of large bioreactors and provide information of the mixing dynamics in these reactors .…”

Section: Introductionmentioning

confidence: 99%

Scale‐down simulators for mammalian cell culture as tools to access the impact of inhomogeneities occurring in large‐scale bioreactors

Paul

Herwig

2020

Engineering in Life Sciences

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During the scale-up of a bioprocess, not all characteristics of the process can be kept constant throughout the different scales. This typically results in increased mixing times with increasing reactor volumes. The poor mixing leads in turn to the formation of concentration gradients throughout the reactor and exposes cells to varying external conditions based on their location in the bioreactor. This can affect process performance and complicate process scale-up. Scale-down simulators, which aim at replicating the large-scale environment, expose the cells to changing environmental conditions. This has the potential to reveal adaptation mechanisms, which cells are using to adjust to rapidly fluctuating environmental conditions and can identify possible root causes for difficulties maintaining similar process performance at different scales. This understanding is of utmost importance in process validation. Additionally, these simulators also have the potential to be used for selecting cells, which are most robust when encountering changing extracellular conditions. The aim of this review is to summarize recent work in this interesting and promising area with the focus on mammalian bioprocesses, since microbial processes have been extensively reviewed. K E Y W O R D S 2-compartment system, gradients, inhomogeneity, large-scale bioprocess, scale-upAbbreviations: CFD, computational fluid dynamics; CHO, Chinese Hamster ovary; CS, compartment system; PFR, plug flow reactor; STR, stirred tank reactor; VCC, viable cell count.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. throughput and decrease time lines for process development and characterization [1]. Particularly production processes for monoclonal antibodies (mAbs) that are in high demand, like adalimumab (Humira TM ) [2], are transferred to large-scale production reactors. These bioreactors can reach volumes of up to 25 000 L for mammalian cell culture processes [3]. Furthermore, it has been estimated that approximately 50% of the biologics will continue to be produced in bioreactor volumes of at least 5000 L [4]. There are different approaches Eng Life Sci.

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“…Furthermore, to study the stirring in an industrial scale tank is difficult to carry out by conventional laboratory technics [15], but CFD can be used on an industrial scale, too. In the laboratory, one of the most important tasks is to choose the correct detection system.…”

Section: Introductionmentioning

confidence: 99%

Laboratory and Computational Fluid Dynamics Investigation of Homogenization in a Tank Stirred by External Pump

Bobek¹,

Egedy²,

Rippel-Pethő³

2019

Period. Polytech. Chem. Eng.

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The scope of this study was to investigate the homogenization of a two-layer stratified liquid in a tank where liquid stirring was achieved by carrying out external recirculation. Furthermore, the aim of the research was to observe the effect of the height of the outlet during the time of mixing one. The experimental fluid was two-layer, density stratified liquid. From the perspective of homogeneity, the effect of the height of the outlet was investigated in laboratory. Moreover, the experimental device was modeled in CFD. In simulation examination, laminar - and k-ε-model were used, and the influence of the outlet position was observed. The difference was remarkable in the first part of the measurement caused by the presence of sharp concentration variation in the tank. After the operating time, the expected homogeneity was fulfilled at the outlet in all cases. Regarding of CFD research, the results suggest that the laminar model is more effective to describe the concentration changes at the sampling point in the tank investigated.

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Hydrodynamic inhomogeneities in large scale stirred tanks – Influence on mixing time

Cited by 57 publications

References 35 publications

Model uncertainty-based evaluation of process strategies during scale-up of biopharmaceutical processes

Model uncertainty-based evaluation of process strategies during scale-up of biopharmaceutical processes

Scale‐down simulators for mammalian cell culture as tools to access the impact of inhomogeneities occurring in large‐scale bioreactors

Laboratory and Computational Fluid Dynamics Investigation of Homogenization in a Tank Stirred by External Pump

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