Development of a Scale-Down Model of hydrodynamic stress to study the performance of an industrial CHO cell line under simulated production scale bioreactor conditions

Sieck, Jochen B.; Cordes, Thekla; Budach, W.; Rhiel, Martin; Suemeghy, Zoltan; Leist, C.; Villiger, Thomas K.; Morbidelli, Massimo; Šoóš, Miroslav

doi:10.1016/j.jbiotec.2012.11.012

Cited by 87 publications

(43 citation statements)

References 52 publications

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“…Most commercial miniscale systems provide mechanical mixing but do not address fluid dynamic issues. A scale-down model used 2 l reactors to simulate the hydrodynamic stresses at the large scale by oscillations between high and low agitation rates based on agitation power calculations (Sieck et al 2013). Such studies along with the employment of transcriptome analysis across scales (Jayapal and Goudar 2014), or even extended to metabolomics studies, can provide much insight into the impact of scale up on cellular physiology.…”

Section: Assessment Of Process Performance and Scaledown Modelsmentioning

confidence: 99%

Cell line development for biomanufacturing processes: recent advances and an outlook

et al. 2015

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At the core of a biomanufacturing process for recombinant proteins is the production cell line. It influences the productivity and product quality. Its characteristics also dictate process development, as the process is optimized to complement the producing cell to achieve the target productivity and quality. Advances in the past decade, from vector design to cell line screening, have greatly expanded our capability to attain producing cell lines with certain desired traits. Increasing availability of genomic and transcriptomic resources for industrially important cell lines coupled with advances in genome editing technology have opened new avenues for cell line development. These developments are poised to help biosimilar manufacturing, which requires targeting pre-defined product quality attributes, e.g., glycoform, to match the innovator's range. This review summarizes recent advances and discusses future possibilities in this area.

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Section: Assessment Of Process Performance and Scaledown Modelsmentioning

confidence: 99%

Cell line development for biomanufacturing processes: recent advances and an outlook

et al. 2015

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“…More details about CO 2 -depletion phenomenon and the limitation of carbon dioxide stripping for larger cell culture reactors ([200 L) can be found in Sieblist et al (2011a). Shear force and the impact to cell culture have been discussed in literature by several authors (Cherry 1993;Elias et al 1995;Godoy-Silva et al 2010;Joshi et al 1996;Kretzmer and Schügerl 1991;Nienow 1998;van der Pol and Tramper 1998;Sieck et al 2013;Sorg et al 2011;Yang and Wang 1992). The influence of shear stress and appropriate scaling strategies are as well discussed by Nienow and colleagues (Nienow 2014;.…”

Section: Mass Transfer O 2 /Comentioning

confidence: 99%

“…It is essential to understand and demonstrate similar fluid dynamics for the large scale manufacturing equipment to achieve similar performance within the design space. Recent publications demonstrate the need for enhanced understanding of the fluid dynamics and the impact on cell culture performance for several unit operations in the context of QbD and the associated design space (Broly 2014;Sieck et al 2013;Soos 2014).…”

Section: Introductionmentioning

confidence: 99%

Equipment characterization to mitigate risks during transfers of cell culture manufacturing processes

2015

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The production of monoclonal antibodies by mammalian cell culture in bioreactors up to 25,000 L is state of the art technology in the biotech industry. During the lifecycle of a product, several scale up activities and technology transfers are typically executed to enable the supply chain strategy of a global pharmaceutical company. Given the sensitivity of mammalian cells to physicochemical culture conditions, process and equipment knowledge are critical to avoid impacts on timelines, product quantity and quality. Especially, the fluid dynamics of large scale bioreactors versus small scale models need to be described, and similarity demonstrated, in light of the Quality by Design approach promoted by the FDA. This approach comprises an associated design space which is established during process characterization and validation in bench scale bioreactors. Therefore the establishment of predictive models and simulation tools for major operating conditions of stirred vessels (mixing, mass transfer, and shear force.), based on fundamental engineering principles, have experienced a renaissance in the recent years. This work illustrates the systematic characterization of a large variety of bioreactor designs deployed in a global manufacturing network ranging from small bench scale equipment to large scale production equipment (25,000 L). Several traditional methods to determine power input, mixing, mass transfer and shear force have been used to create a data base and identify differences for various impeller types and configurations in operating ranges typically applied in cell culture processes at manufacturing scale. In addition, extrapolation of different empirical models, e.g. Cooke et al. (Paper presented at the proceedings of the 2nd international conference of bioreactor fluid dynamics, Cranfield, UK, 1988), have been assessed for their validity in these operational ranges. Results for selected designs are shown and serve as examples of structured characterization to enable fast and agile process transfers, scale up and troubleshooting.

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“…Research has been done to investigate maximum allowed power input per volume (W/kg, also called volumetric energy dissipation rate, from here on symbolized as [ε]) for mammalian cells 37,38,165,177,196,214 . The results of these studies indicate that shear generated from agitation is generally well below the critical level of mammalian cells.…”

Section: Shearmentioning

confidence: 99%

“…differences between scales) influence cell physiology and process performance. For example, Sieck et al 32,177 found that transcripts related to DNA damage and repair mechanisms were up-regulated when elevated shear forces from agitation and sparging were applied to a CHO cell culture.…”

Section: Introductionmentioning

confidence: 99%

Scale-down of CHO cell fed-batch cultures

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Development of a Scale-Down Model of hydrodynamic stress to study the performance of an industrial CHO cell line under simulated production scale bioreactor conditions

Cited by 87 publications

References 52 publications

Cell line development for biomanufacturing processes: recent advances and an outlook

Cell line development for biomanufacturing processes: recent advances and an outlook

Equipment characterization to mitigate risks during transfers of cell culture manufacturing processes

Scale-down of CHO cell fed-batch cultures

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