Control of pH in large-scale, free suspension animal cell bioreactors: Alkali addition and pH excursions

Langheinrich, Ch.; Nienow, Alvin W.

doi:10.1002/(sici)1097-0290(1999)66:3<171::aid-bit5>3.0.co;2-t

Cited by 90 publications

(81 citation statements)

References 10 publications

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“…h m values indicate the end point of mixing but not the local spatial and temporal variations in concentration associated with the whole time that it takes to achieve mixing. Probes can do so and therefore pH homogeneity was investigated in the same 8 m 3 (T = 2 m) bioreactor and in a transparent, geometrically similar, scaled-down vessel of 0.61 m diameter (Langheinrich and Nienow 1999). In addition, other work on chemical reactors has shown distinct advantages from feeding close to impellers when chemical reactions, especially involving acid or base, are under consideration (Nienow et al 1997;Assirelli et al 2005).…”

Section: Ph Controlmentioning

confidence: 99%

“…Cytotechnology (2006) 50:9-33 21 operation (pH = 7.3) whilst a second smaller one had predetermined pH variations imposed on it using 2 M NaOH pulse with CO 2 sparging, mimicking approximately those fluctuations shown in the earlier study (Langheinrich and Nienow 1999). This work showed that when cells were subjected to 100 perturbations of 200 s at a cycle time of 6 min up to pH 8, cell death was increased by about 30% compared to a control with similar changes only in osmolarity.…”

Section: Ph Controlmentioning

confidence: 99%

“…Thus, some concern for cell damage would seem to be justified. (Langheinrich and Nienow 1999) However, cells grew well with agitation up tõ 0.25 W kg )1 at 50% dO 2 using headspace aeration (Kioukia et al 1996). Also, as with mammalian cells, addition of Pluronic F 68 at 0.1% by weight essentially eliminated any reduction in performance pre-infection under sparged conditions, even leading to a modestly higher growth rate compared to the best available with only headspace aeration.…”

Section: Insect Culture Post-infectionmentioning

confidence: 99%

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Reactor Engineering in Large Scale Animal Cell Culture

2006

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This article mainly addresses the issues associated with the engineering of large-scale free suspension culture in agitated bioreactors >10,000 L because they have become the system of choice industrially. It is particularly concerned with problems that become increasingly important as the scale increases. However, very few papers have been written that are actually based on such large-scale studies and the few that do rarely address any of the issues quantitatively. Hence, it is necessary very often to extrapolate from small-scale work and this review tries to pull the two types of study together. It is shown that 'shear sensitivity' due to agitation and bursting bubbles is no longer considered a major problem. Homogeneity becomes increasingly important with respect to pH and nutrients at the largest scale and sub-surface feeding is recommended despite 'cleaning in place' concerns. There are still major questions with cell retention/recycle systems at these scales, either because of fouling, of capacity or of potential and different 'shear sensitivity' questions. Fed-batch operation gives rise to cell densities that have led to the use of oxygen and enriched air to meet oxygen demands. This strategy, in turn, gives rise to a CO 2 evolution rate that impacts on pH control, pCO 2 and osmolality. These interactions are difficult to resolve but if higher sparge and agitation intensities could be used to achieve the necessary oxygen transfer, the problem would largely disappear. Thus, the perception of 'shear sensitivity' is still impacting on the development of animal cell culture at the commercial scale. Microcarrier culture is also briefly addressed. Finally, some recommendations for bioreactor configuration and operating strategy are given.

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Section: Ph Controlmentioning

confidence: 99%

Section: Ph Controlmentioning

confidence: 99%

Section: Insect Culture Post-infectionmentioning

confidence: 99%

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Reactor Engineering in Large Scale Animal Cell Culture

2006

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“…The inherent inertia in such a system can lead to over feeding of the pH controlling agent and therefore zones of high and low pH, again with temporal fluctuations superimposed on the spatial ones. Indeed, such regions of fluctuating high and low pH have now been measured in 8 m 3 bioreactors for animal cell culture (Langheinrich and Nienow, 1999).…”

Section: B Operational Constraints At the Large-scalementioning

confidence: 99%

The scale-up of microbial batch and fed-batch fermentation processes

Hewitt

Nienow

2007

Journal of Biotechnology

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“…Mammalian cell culture systems have a number of characteristic features that are important to consider in scaling-up [2,[10][11][12]. Cell culture protocols use expensive and sensitive culture media whereas volumetric product titres are modest.…”

Section: Introductionmentioning

confidence: 91%

Scale‐up of cell culture bioreactors using biomechatronic design

Mandenius

Björkman

2012

Biotechnology Journal

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An alternative approach for scale-up of cell culture bioreactors based on biomechatronic design methodology is suggested.The approach differs from traditional biochemical engineering methodology by applying a sequential design procedure where the needs of the users and alternative design solutions based on the biological and technical functions of the scaled-up bioreactor are derived in functional maps, concept generation charts and scoring and interaction matrices. Basic reactor engineering properties, such mass and heat transfer and kinetics are integrated in the procedure. Examples are provided from production of monoclonal antibody and recombinant protein.

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Control of pH in large-scale, free suspension animal cell bioreactors: Alkali addition and pH excursions

Cited by 90 publications

References 10 publications

Reactor Engineering in Large Scale Animal Cell Culture

Reactor Engineering in Large Scale Animal Cell Culture

The scale-up of microbial batch and fed-batch fermentation processes

Scale‐up of cell culture bioreactors using biomechatronic design

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