Fixed Bed Reactors for the Cultivation of Mammalian Cells: Design,
Performance and Scale-Up

Pörtner, Ralf; Platas, Oscar B; Fassnacht, D.; Nehring, Dirk; Czermak, Peter; Märkl, Herbert

doi:10.2174/1874070700701010041

Cited by 29 publications

(18 citation statements)

References 43 publications

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“…This effect is even pronounced for carriers with smaller diameters, as the width of the channels between the carriers is smaller in this case and can be blocked by growing cells. Similar effects have been observed for mammalian cells grown in fixed bed reactors [19]. It was decided to use a larger fraction of 8 mm mean diameter of the VitraPOR ® carrier for the following experiment in the 1 L-fixed-bed bioreactor for reasons mentioned in the material section.…”

Section: Fixed-bed Cultures On Different Scalesmentioning

confidence: 69%

“…The radius corresponds to the height of the axial-flow fixed-bed bioreactors introduced above. For more details see [19]. Here the borosilicate carrier (VitraPOR ® , ROBU ® GlasfilterGeräte GmbH) with a mean diameter of 8 mm was used because the smaller size would fall through the mesh of the of the wire-cage.…”

Section: L-fixed-bed Bioreactormentioning

confidence: 99%

“…Even if this is probably not the final industrial scale, the reactor system already has the main characteristics of a large-scale system, mainly the radius. For further increase of the volume, just the height has to be increased [19]. Fig.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Fixed-Bed Cultures with Immobilized Lactococcus Lactis ssp. Lactis on Different Scales

Faschian¹,

Eren²,

Minden³

et al. 2017

TOBIOTJ

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Fixed-bed processes, where cells are immobilized within macroporous carriers, are a promising alternative to processes with suspended cells. A scale-up concept is presented in order to evaluate the performance as part of process design of fixed-bed processes. Therefore, Lactococcus lactis cultivation in chemostat and batch mode was compared to fixed bed cultures on three different scales, the smallest being the downscaled Multiferm with 10 mL fixed bed units, the second a 100 mL fixed-bed reactor and the third a pilot scale reactor with 1 L fixed bed volume. As expected, the volume specific lactate productivity of all cultivations was dependent on dilution rate. In suspension chemostat culture a maximum of 2.3 g·L -1 ·h -1 was reached. Due to cell retention in the fixed-beds, productivity increased up to 8.29 g·L -1 ·h -1 at a dilution rate of D = 1.16 h -1 (corresponding to 2.4·µ max ) on pilot scale. For all fixed bed cultures a common spline was obtained indicating a good scale-up performance.

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Section: Fixed-bed Cultures On Different Scalesmentioning

confidence: 69%

Section: L-fixed-bed Bioreactormentioning

confidence: 99%

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Evaluation of Fixed-Bed Cultures with Immobilized Lactococcus Lactis ssp. Lactis on Different Scales

Faschian¹,

Eren²,

Minden³

et al. 2017

TOBIOTJ

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“…Many authors described a broad variety of different materials for carriers including dextran, collagen, polymers, glass, and ceramic, among others [73,85,86]. In addition, several shapes are also accessible, such as fibres, flat discs, woven discs, cubes, and sphere (Figure 6.2.6).…”

Section: Carriers For Cell Immobilizationmentioning

confidence: 99%

6.2 High Cell Density Cultivation Process

Ceaglio¹,

Bollati-Fogolín²,

Oggero³

et al. 2014

Animal Cell Biotechnology

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Since human tissue plasminogen activator (tPA) became the first approved biotherapeutic obtained from mammalian cells using recombinant DNA technology in 1987 [1], the biopharmaceutical market rapidly expanded based on a development pipeline of several mammalian cell culture-derived drugs. Even more, mammalian cells are still the dominant recombinant protein production systems for clinical applications [2].In this scenario, high-throughput production processes of therapeutics, expressed in mammalian cells, are necessary to fulfil the market demands. The success of a process depends both on cell productivity (defined as the quantity of the interest protein produced by cell) and the viable cell density in the culture. Considering these parameters, one of the applied strategies to obtain a high recombinant protein yield is the development of culture systems that reach high cell densities and sustain cell viability, leading to an increment of the volumetric productivity.Animal cells can be grown using different modes of operation, and the maximum cell density that can be achieved will depend on that selection. The method of cultivation defines the environmental and nutritional conditions under which cells will proliferate and synthesize the protein of interest, determining the success of attaining high viable cell density and, consequently, high concentration of the desired product. A general classification distinguishes discontinuous modes (batch, repeated batch and fed-batch) and continuous ones (without cell retention or chemostat, or cell retention, also known as perfusion).Despite the fact that suspension cultures are by far the most common cell culture format for recombinant protein expression in mammalian cells [3], anchoragedependent cell lines are also used in the industry for the mentioned purpose. Consequently, the scaling up of a process where cells grow in adherence can be carried out by cultivating them as monolayer in static or gently agitated surfaces or by growing cells attached to polymers spheres that are introduced in bioreactors to maintain them in suspension at high density cultures.The present chapter comprehensively describes theapproaches for high cell density cultivation of animal cells taking into account strategies to grow them in suspension or immobilized into proper supports.

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“…[ 1 ] A carrier must contain a high surface‐to‐volume ratio; be simple, stabilizable, and nontoxic; provide optimal diffusion from the bulk phase to the center of the carrier; and keep the mechanical and pH stability. [ 2 ] Medium flows through the bed providing oxygen and nutrients for the cells typically in the low‐shear manner. Different immobilized cells, such as bacteria, yeast, or mammalian cells, have been used in many biosynthesis processes over the decades, such as production of enzymes, e.g., glutamic acid, coenzyme A, or β‐lactamase, or antibiotics such as penicillin.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Single‐Use Fixed‐Bed Bioreactors in Scalable Virus Production

Lesch¹,

Valonen

Karhinen

2020

Biotechnology Journal

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The accelerating development of gene therapy from research towards clinical trials and beyond has elevated the demand for practical viral vector‐manufacturing solutions. The use of disposable upstream technology is gaining traction in clinical manufacturing. Packed‐bed or fixed‐bed reactors, where column is packed with immobilized biocatalyst particles providing surface to constrain the cells in a particular region of the reactor, have been widely used in bioprocessing applications since mid‐1900s. However, the world's first single‐use, fully integrated, high cell density, fixed‐bed bioreactor was launched only approximately a decade ago. By now, several single‐use, fixed‐bed technology solutions have been developed in a small scale. Scaling‐up the manufacturing can be challenging and for commercial‐scale manufacturing, there is practically only one single‐use, good manufacturing practice‐compliant option available. This study reviews the latest, fully disposable, fixed‐bed bioreactors; compares the virus production in the different systems; and discusses important manufacturing cost‐related topics. It is predicted that single‐use, fixed‐bed bioreactors will receive even more attention in the field of viral vector manufacturing and commercialization, especially with the need for higher virus titers and virus yields.

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Fixed Bed Reactors for the Cultivation of Mammalian Cells: Design, Performance and Scale-Up

Cited by 29 publications

References 43 publications

Evaluation of Fixed-Bed Cultures with Immobilized Lactococcus Lactis ssp. Lactis on Different Scales

Evaluation of Fixed-Bed Cultures with Immobilized Lactococcus Lactis ssp. Lactis on Different Scales

6.2 High Cell Density Cultivation Process

Evaluation of the Single‐Use Fixed‐Bed Bioreactors in Scalable Virus Production

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