Performance of high intensity fed‐batch mammalian cell cultures in disposable bioreactor systems

Smelko, John Paul; Wiltberger, Kelly; Hickman, Eric Francis; Morris, Beverly Janey; Blackburn, Tobias; Ryll, Thomas

doi:10.1002/btpr.634

Cited by 43 publications

(15 citation statements)

References 34 publications

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“…Cell‐specific perfusion rates were between 2.3 and 2.8 pL/(cell h) and within values reported in literature during cultivation 25. The cell densities and viabilities achieved were comparable to those described for several retention devices using CHO cells in the literature at significantly smaller scales 15, 18, 22–36. A decline in viability from 99 to 90% was observed during the course of the culture.…”

Section: Resultssupporting

confidence: 78%

Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors

Pohlscheidt

Jacobs

Wolf

et al. 2013

Biotechnology Progress

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Increasing capacity utilization and lowering manufacturing costs are critical for pharmaceutical companies to improve their competitiveness in a challenging environment. Development of next generation cell lines, improved media formulations, application of mature technologies and innovative operational strategies have been deployed to improve yields and capacity utilization. This article describes a large-scale perfusion strategy for the N-1 seed train bioreactor that was successfully applied to achieve higher inoculation cell densities in the production culture. The N-1 perfusion at 3,000-L scale, utilizing a inclined settler, achieved cell densities of up to 158 × 10(5) cell mL(-1) at perfusion rates of 2950 L day(-1) and a retention efficiency of >85%. This approach increased inoculation cell densities and decreased cultivation times by ~20% in a CHO-based, fed-batch antibody manufacturing process while providing comparable culture performance, productivity, and product quality. The strategy therefore yielded significant increase in capacity utilization and concomitant cost improvement in a large scale cGMP facility. Details of the strategy, the cell retention device, and the cell culture performance are described in this article.

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Section: Resultssupporting

confidence: 78%

Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors

Pohlscheidt

Jacobs

Wolf

et al. 2013

Biotechnology Progress

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“…Adoption of single‐use systems (SUS) for biopharmaceutical manufacturing, such as flexible plastic containers for cell culture and other fluid mixing or storage operations, promises numerous advantages, both economic and environmental . However, the introduction of a large new set of materials into process streams demands careful consideration of the suitability of those materials, and the consequences of any impacts to process performance, product titer, quality, and safety .…”

Section: Introductionmentioning

confidence: 99%

A cytotoxic leachable compound from single‐use bioprocess equipment that causes poor cell growth performance

Hammond

Marghitoiu

Lee

et al. 2014

Biotechnology Progress

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A current trend in the production of biopharmaceuticals is the replacement of fixed stainless steel fluid-handling units with disposable plastic bags. Such single-use systems (SUS) offer numerous advantages, but also introduce a new set of materials into the production process and consequently expose biomanufacturers to a new set of risks related to those materials, not to mention reliance on an entirely new supply chain. In the course of developing and conducting a cell-growth-based test for suitability of disposable plastic components destined for use in cell culture operations, we discovered that the cytotoxic compound bis(2,4-di-tert-butylphenyl)phosphate (bDtBPP) leaches out of certain bags and into cell culture media in concentrations that are deleterious to cell growth. Specifically, media held in certain bags for several days at 37°C was found to contain bDtBPP, and use of those held-media samples in cell growth experiments provides data that overlap neatly with cell growth experiments using media spiked directly with bDtBPP, proving that bDtBPP leaching is responsible for the reduced growth attributable to those SUS bags. Overall, this issue represents a risk to the production of biopharmaceuticals in SUS, a risk that must be managed by diligent collaboration among companies along the entire supply chain for SUS components.

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“…Lower degrees of CO 2 stripping and differences in cellular metabolism at large scale can lead to raised lactate concentrations (Abu-Absi et al 2014). Smelko et al (2011) and others report highest lactate levels in 15,000 L reactors when comparing a NS0 fed batch process across scales.…”

Section: Parameters and Technologies: Metabolic Parameters And Recombmentioning

confidence: 94%

Monitoring of Cell Culture

2014

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Cell culture monitoring is essential for the continuous characterisation of cultivated cells. This helps us to understand each cell line's growth and metabolism properties and to establish and ensure reproducible cell cultivations. Monitoring not only comprises biological parameters, like cell count and viability, but also physiological parameters, like substrate, metabolite and possibly product concentrations. Furthermore, a large set of physicochemical parameters such as pH, temperature and osmolarity is routinely monitored in cell culture applications. A multiplicity of monitoring technologies exists. Often, there are several methods for one monitoring parameter to choose from and the choice depends on application and process needs. Moreover, new methods are developed at ever increasing speed. Today, cell culture processes and regulatory agencies demand detailed process understanding, which extensive monitoring is a prerequisite for. In this chapter, the current state of monitoring technologies and applications is reviewed. Particular emphasis is placed on biological parameters, i.e. cell density and viability as well as substrates, metabolites, and product concentration but also on cell stress and apoptosis. Furthermore, promising exploratory technologies are surveyed. Lastly, the chapter is meant to bridge the gap between existing technology-driven and more biologyoriented publications in this field.

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Performance of high intensity fed‐batch mammalian cell cultures in disposable bioreactor systems

Cited by 43 publications

References 34 publications

Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors

Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors

A cytotoxic leachable compound from single‐use bioprocess equipment that causes poor cell growth performance

Monitoring of Cell Culture

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