A high-yielding, generic fed-batch cell culture process for production of recombinant antibodies

Sauer, Paul W.; Burky, John E.; Wesson, Mark C.; Sternard, H.; Qu, Limin

doi:10.1002/(sici)1097-0290(20000305)67:5<585::aid-bit9>3.3.co;2-8

Cited by 32 publications

(47 citation statements)

References 24 publications

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“…Sauer et al, (2000) reported 7.9 fold increase in average final mAb concentration developed the fedbatch process based on post-feed glucose concentration. According to Sauer et al [13], different post-feed glucose concentration result in producing different final mAb product titer, which is in accordance with our findings. The viability dropped significantly from day 5 to day 6 for Run #5, in spite of the feeding performed on day 5, indicating that the cells have entered the death phase of the cell cycle.…”

Section: Fed-batch Runsmentioning

confidence: 86%

“…Prior to cell counting, samples were diluted 2 to 10-fold with 0.4% trypan blue solution (GIBCO, USA) depending on the cell density. From the VCD measurement, IVCC was calculated in the same manner as described by Sauer et al [13].…”

Section: Methodsmentioning

confidence: 99%

“…Post-feed target glucose concentrations ranged from 2-8 g/l. The volume of feed medium (Vfeed) to be added was calculated using the following equation, as described by Sauer et al, [13], whereas the post feed L-glutamine concentration was maintained at 2 mM [13].…”

Section: Feeding Strategy and Feeding Mediummentioning

confidence: 99%

“…Fed batch cultures have been developed with the objective of achieving maximal increase in the culture viable cell concentrations and prolonging the culture lifetime for increased product concentrations [3,5,[11][12][13][14][15] Strategies such as development of the feeding solutions, feeding rate control, maintaining low residual glucose and/or glutamine concentrations, employing dialysis membranes to remove low molecular weight components from the culture, feeding based on Oxygen UptakeHence, based on the hypothesis that none of the factors affecting the production process can really be independent, fractional factorial design using design expert software was carried out to find the interaction between the batch (Dissolved Oxygen, Temperature and Seeding Density) and fed-batch (post-feed Glucose concentration) process parameters. The usage of design of experiments also facilitates shorter development time, hence more cost effective.…”

Section: Introductionmentioning

confidence: 99%

“…Inoculation into the bioreactor The high and low levels of parameters were as follows: Postfeed Glucose concentration: 2 g/L(11.11 mmol/L) and 8 g/L (44.44 mmol/L) [13] dissolved oxygen tension (DOT) with respect to medium saturation with air (20% and 60%), seeding density (0.3×10 6 cells/mL and 0.5×10 6 cells/mL), Temperature (34°C and 38°C). pH value was set at 7.20 for all the runs.…”

mentioning

confidence: 99%

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Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

Raja¹,

Anuar²,

Rahman³

et al. 2014

J Bioprocess Biotech

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In conventional fed batch process development approaches, batch operating parameters (such as pH, temperature, seeding density, dissolved oxygen concentration) are kept constant and only feeding parameters such as feeding time, post-feed concentration are manipulated. The batch and fed batch operating parameters are assumed to be independent of each other. This approach to process development ignores any interactions that might exist between the batch and fed-batch operating parameters are therefore not evaluated. However in a complex bioprocess, none of the factors affecting the process can be assumed to be independent of each other and mutually exclusive. Therefore in this study an attempt was made to study the interaction between fed-batch operating parameter-post feed glucose concentration (A) and batch operating parameters-seeding density (B), temperature (C), and dissolved oxygen concentration (D) by their simultaneous manipulation, as well as the effect of these interactions on cell growth and monoclonal antibody (mAb) production. NS0 cell line producing the mAb's against carcino-embryogenic antigen (Anti-CEA) was used. The final mAb concentration, viable cell density and integral of viable cell concentration (IVCC) were the responses evaluated. Statistical analysis experimental data showed that parameter (A) and its interaction with parameter (B) were the main factors affecting both the response variables. In comparison to the batch run which yielded 5.21 mg/L mAb, the developed fed batch process increased the mAb titer by 10 fold (59.40 mg/mL), and the IVCC was increased by 7 fold. The maximum VCD value (3.46×10 6 cells/mL) of the developed fed batch process was 1.25 over fold the value for batch.

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Section: Fed-batch Runsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Feeding Strategy and Feeding Mediummentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

Raja¹,

Anuar²,

Rahman³

et al. 2014

J Bioprocess Biotech

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Implementation of advanced technologies in commercial monoclonal antibody production

Zhou

Tressel

Yang

et al. 2008

Biotechnology Journal

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Process advancements driven through innovations have been key factors that enabled successful commercialization of several human therapeutic antibodies in recent years. The production costs of these molecules are higher in comparison to traditional medicines. In order to lower the development and later manufacturing costs, recent advances in antibody production technologies target higher throughput processes with increased clinical and commercial economics. In this review, essential considerations and trends for commercial process development and optimization are described, followed by the challenges to obtain a high titer cell culture process and its subsequent impact on the purification process. One of these recent technical advances is the development and implementation of a disposable Q membrane adsorber as an alternative to a Q-packed-bed column in a flow-through mode. The scientific concept and principles underlining Q membrane technology and its application are also reviewed.

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The impact of pH inhomogeneities on CHO cell physiology and fed‐batch process performance – two‐compartment scale‐down modelling and intracellular pH excursion

Brunner

Braun

Doppler

et al. 2017

Biotechnology Journal

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Due to high mixing times and base addition from top of the vessel, pH inhomogeneities are most likely to occur during large-scale mammalian processes. The goal of this study was to set-up a scale-down model of a 10-12 m stirred tank bioreactor and to investigate the effect of pH perturbations on CHO cell physiology and process performance. Short-term changes in extracellular pH are hypothesized to affect intracellular pH and thus cell physiology. Therefore, batch fermentations, including pH shifts to 9.0 and 7.8, in regular one-compartment systems are conducted. The short-term adaption of the cells intracellular pH are showed an immediate increase due to elevated extracellular pH. With this basis of fundamental knowledge, a two-compartment system is established which is capable of simulating defined pH inhomogeneities. In contrast to state-of-the-art literature, the scale-down model is included parameters (e.g. volume of the inhomogeneous zone) as they might occur during large-scale processes. pH inhomogeneity studies in the two-compartment system are performed with simulation of temporary pH zones of pH 9.0. The specific growth rate especially during the exponential growth phase is strongly affected resulting in a decreased maximum viable cell density and final product titer. The gathered results indicate that even short-term exposure of cells to elevated pH values during large-scale processes can affect cell physiology and overall process performance. In particular, it could be shown for the first time that pH perturbations, which might occur during the early process phase, have to be considered in scale-down models of mammalian processes.

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A high-yielding, generic fed-batch cell culture process for production of recombinant antibodies

Cited by 32 publications

References 24 publications

Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

Implementation of advanced technologies in commercial monoclonal antibody production

The impact of pH inhomogeneities on CHO cell physiology and fed‐batch process performance – two‐compartment scale‐down modelling and intracellular pH excursion

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