Establishment of a mink enteritis vaccine production process in stirred-tank reactor and Wave® Bioreactor microcarrier culture in 1–10L scale

Hundt, Boris; Best, C.; Schlawin, N.; Kassner, Helmut; Genzel, Yvonne; Reichl, Udo

doi:10.1016/j.vaccine.2007.02.061

Cited by 42 publications

(21 citation statements)

References 19 publications

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“…In particular, this would be critical in viral vaccine manufacturing when virus replication is linked to the status of the cell cycle. 35 Furthermore, an early growth inhibition also decreases the scale-up factor, an essential property of process economy. In contrast, lower initial cell numbers result in a smaller disparity in distributions, but decrease the attachment efficiency and increase the cultivation time.…”

Section: Attachment Behaviormentioning

confidence: 99%

Growth behavior of number distributed adherent MDCK cells for optimization in microcarrier cultures

Böck

Sann

Schulze‐Horsel

et al. 2009

Biotechnology Progress

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An assay for measuring the number of adherent cells on microcarriers that is independent from dilution errors in sample preparation was used to investigate attachment dynamics and cell growth. It could be shown that the recovery of seeded cells is a function of the specific rates of cell attachment and cell death, and finally a function of the initial cell-to-bead ratio. An unstructured, segregated population balance model was developed that considers individual classes of microcarriers covered by 1-220 cells/bead. The model describes the distribution of initially attached cells and their growth in a microcarrier system. The model distinguishes between subpopulations of dividing and nondividing cells and describes in a detailed way cell attachment, cell growth, density-dependent growth inhibition, and basic metabolism of Madin-Darby canine kidney cells used in influenza vaccine manufacturing. To obtain a model approach that is suitable for process control applications, a reduced growth model without cell subpopulations, but with a formulation of the specific cell growth rate as a function of the initial cell distribution on microcarriers after seeding was developed. With both model approaches, the fraction of growth-inhibited cells could be predicted. Simulation results of two cultivations with a different number of initially seeded cells showed that the growth kinetics of adherent cells at the given cultivation conditions is mainly determined by the range of disparity in the initial distribution of cells on microcarriers after attachment.

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Section: Attachment Behaviormentioning

confidence: 99%

Growth behavior of number distributed adherent MDCK cells for optimization in microcarrier cultures

Böck

Sann

Schulze‐Horsel

et al. 2009

Biotechnology Progress

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show abstract

“…Various examples can be found for the cultivation of animal cells using bioreactors with wave-induced motion, demonstrating the possibility of adapting classical processes that use either roller bottles or stirred tank bioreactors to the cellbag method (Hundt et al, 2007;Lohr et al, 2009;Okonkowski et al, 2007;Tang et al, 2007;Weber et al, 2002). For the cultivation of adherent Madin-Darby canine kidney (MDCK) cells in an influenza vaccine production process, it has been observed that higher maximum cell densities can Correspondence concerning this article should be addressed to D. Thévenin at thevenin@ovgu.de.…”

Section: Introductionmentioning

confidence: 99%

Experimental characterization of flow conditions in 2‐ and 20‐l bioreactors with wave‐induced motion

Kalmbach

Bordás

Öncül

et al. 2011

Biotechnology Progress

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Quantifying the influence of flow conditions on cell viability is essential for a successful control of cell growth and cell damage in major biotechnological applications, such as in recombinant protein and antibody production or vaccine manufacturing. In the last decade, new bioreactor types have been developed. In particular, bioreactors with wave-induced motion show interesting properties (e.g., disposable bags suitable for cGMP manufacturing, no requirement for cleaning and sterilization of cultivation vessels, and fast setup of new production lines) and are considered in this study. As an additional advantage, it is expected that cultivations in such bioreactors result in lower shear stress compared with conventional stirred tanks. As a consequence, cell damage would be reduced as cell viability is highly sensitive to hydrodynamic conditions. To check these assumptions, an experimental setup was developed to measure the most important flow parameters (liquid surface level, liquid velocity, and liquid and wall shear stress) in two cellbag sizes (2 and 20 L) of Wave Bioreactors®. The measurements confirm in particular low shear stress values in both cellbags, indicating favorable hydrodynamic conditions for cell cultivation.

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“…These bioreactors are now widely applied in many scientific laboratories and industrial companies (e.g. Eibl and Eibl (2006), Genzel et al (2006), Genzel and Reichl (2007), Hundt et al (2007), Palazón et al (2003), Singh (1999)) due to their attractive design and process advantages (Singh 1999). The employed flexible, disposable PET-bags (called wave-bags or cellbags depending on the manufacturer) can be shaken in different modes (Eibl and Eibl 2006;Singh 2001).…”

Section: Introductionmentioning

confidence: 99%

Flow Characterization in Wave Bioreactors Using Computational Fluid Dynamics

Öncül

Genzel

Reichl

et al. 2011

Proceedings of the 21st Annual Meeting of the European Society for Animal Cell Technology (ESACT), Dublin, Ireland, June 7-10,

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Quantifying and optimizing the flow conditions in cultivation systems is essential for successful cell growth in major biotechnological applications, like vaccine production processes. Recently, disposable wave bioreactors have been proposed for manufacturing of biologics, leading to markedly different mixing properties compared to stirred tank reactors, i.e. lower shear stress. To describe accurately the conditions in wave bioreactors using numerical simulations, it is first necessary to compute the unsteady flow employing Computational Fluid Dynamics (CFD). Simultaneously, the Volume of Fluid (VOF) method is employed to simulate motion of the free liquid surface. Experimental measurements have been carried out in order to determine liquid surface height, flow velocity and shear stress, which are used as a validation of CFD simulations. The obtained results confirmed low shear stress levels, well below known threshold values leading to cell damage. Recent simulations take additionally into account microcarriers through Population Balance Model (PBM), needed for adherent cell growth. Nomenclature

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Establishment of a mink enteritis vaccine production process in stirred-tank reactor and Wave® Bioreactor microcarrier culture in 1–10L scale

Cited by 42 publications

References 19 publications

Growth behavior of number distributed adherent MDCK cells for optimization in microcarrier cultures

Growth behavior of number distributed adherent MDCK cells for optimization in microcarrier cultures

Experimental characterization of flow conditions in 2‐ and 20‐l bioreactors with wave‐induced motion

Flow Characterization in Wave Bioreactors Using Computational Fluid Dynamics

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