Maximisation of perfusion systems and process comparison with batch-type cultures

Griffiths, J. B.; Looby, D.; Racher, Andrew J.

doi:10.1007/bf02521726

Cited by 24 publications

(8 citation statements)

References 12 publications

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“…batch, fed‐batch, semicontinuous, continuous, and perfusion). Although some studies have specifically examined the influence of the cultivation mode using the same cell line,12–15 most of these compared only volumetric productivity and/or yield on medium. These parameters are highly dependent on the specific operating conditions employed, such that general conclusions cannot readily be obtained.…”

Section: Introductionmentioning

confidence: 99%

Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures

Henry¹,

Kwok²,

Piret³

2008

Biotechnology Progress

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Perfusion culture optimization in multiple noninstrumented small-scale flasks allows reduced expense and time associated with process development. These cultures normally use a different process mode because at small scales it is not practical to retain the cells for medium perfusion. In this work, the kinetics of growth, nutrient consumption, metabolite, and product formation were compared in spinner cultures operated in batch, semicontinuous, chemostat, and perfusion modes. Fed-batch was also included to provide an added comparison. Using logistic fitting for more reliable specific rate estimates in transient conditions, the growth phase of batch cultures predicted similar kinetics to fed-batch and continuous processes. For daily medium exchange rates up to 50%, the semicontinuous mode also predicted the perfusion process kinetics. Differences between the chemostat and semicontinuous culture results were only observed at higher exchange rates with the greatest daily culture perturbation. Overall, the batch or semicontinuous cultures were shown to readily provide results similar to the far more complex to operate chemostat or perfusion cultures.

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Section: Introductionmentioning

confidence: 99%

Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures

Henry¹,

Kwok²,

Piret³

2008

Biotechnology Progress

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“…The use of microcarriers (macroporous or solid) in different bioreactor types is a good way to increase the available growth area for cells per unit of volume and to attain some of the above goals (6,7). Microcarriers are used routinely in animal cell culture for the growth of anchorage-dependent cells and are among the established technological platforms for industrial production (8).…”

Section: Introductionmentioning

confidence: 99%

Microcarrier Culture of Lepidopteran Cell Lines: Implications for Growth and Recombinant Protein Production

Ikonomou¹,

Drugmand²,

Bastin

et al. 2002

Biotechnology Progress

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Several microcarrier systems were screened with Sf‐9 and High‐Five cell lines as to their ability to support cell growth and recombinant (β‐galactosidase) protein production. Growth of both cell lines on compact microcarriers, such as Cytodex‐1 and glass beads, was minimal, as cells detached easily from the microcarrier surface and grew as single cells in the medium. Cell growth was also problematic on Cytopore‐1 and ‐2 porous microcarriers. Cells remained attached for several days inside the microcarrier pores, but no cell division and proliferation were observed. On the contrary, insect cells grew well in the interior of Fibra‐Cel disks mainly as aggregates at points of fiber intersection, reaching final (plateau) densities of about 4 × 106 (Sf‐9) and 2.7 × 106 (High‐Five) cells mL‐1 (8 × 106 and 5.5 × 106 cells per cm2 of projected disk area, respectively). Their growth was described well by the logistic equation, which takes into account possible inhibition effects. β‐Galactosidase (β‐gal) production of Sf‐9 cells on Fibra‐Cel disks (infected at 3.3 × 106 cells mL‐1) was prolonged (192 h), and specific protein production was similar to that of high‐density free cell infection. Cultispher‐S microcarriers were found to be a very efficient system for the growth of High‐Five cells, whereas no growth of Sf‐9 cells took place for the same system. Concentrations of about 9 × 106 cells mL‐1 were reached within 120 h, with cell growth in both microcarriers and aggregates, appearance of cellular bridges between microcarriers and aggregates, and eventual formation of macroaggregates incorporating several microcarriers. Specific protein productions after β‐gal baculovirus infection at increasing cell concentrations were almost constant, thus leading to elevated volumetric protein production: final β‐gal titers of 946, 1728, and 1484 U mL‐1 were obtained for infection densities of 3.4, 7.2, and 8.9 × 106 cells mL‐1, respectively.

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“…The term “high cell density” was previously defined as any cell concentration in the order of 10 7 cells/mL (Griffiths et al 1992 ). However, authors have often taken as a reference the typical cell concentrations achieved so far for a reference production process (typically batch) for that specific cell line.…”

Section: Virus Production At High Cell Densitiesmentioning

confidence: 99%

Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production

Tapia

Vázquez-Ramírez

Genzel

et al. 2016

Appl Microbiol Biotechnol

123

111

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With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 107 cells/mL or even 108 cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control.

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Maximisation of perfusion systems and process comparison with batch-type cultures

Cited by 24 publications

References 12 publications

Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures

Simpler noninstrumented batch and semicontinuous cultures provide mammalian cell kinetic data comparable to continuous and perfusion cultures

Microcarrier Culture of Lepidopteran Cell Lines: Implications for Growth and Recombinant Protein Production

Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production

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