6.3 Industrial Cell Culture Process Scale-up Strategies and Considerations

Hu, Weiwei; Wiltberger, Kelly

doi:10.1515/9783110278965.455

Cited by 3 publications

(2 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Through the course of bioprocess development and final commercial production, the process has to be properly scaled to avoid late‐stage campaign failure. However, mammalian scale‐up is still challenging and deviations between the small‐scale and large‐scale performances nowadays have been mostly attributed to unavoidable inhomogeneities in large‐scale . One prominent example are pH gradients which can occur due to base or feed addition, resulting in a serious scale‐up problem .…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…To meet the increased demand for recombinant therapeutics, many of the early, low-titer processes for mAbs required bioreactor capacities of greater than 10,000 L, causing manufacturers to invest heavily in increasing production capacity. Large-scale manufacturing facilities were constructed throughout the 2000s, including facilities with bioreactor sizes ranging from 10,000 L to 25,000 L and total capacities up to 200,000 L (75). By 2009, manufacturers were routinely achieving mAb titers of 1-5 g/L from 7-14-day fed-batch processes (76).…”

Section: Upstream Process Development: Increasing Culture Scale and T...mentioning

confidence: 99%

Biopharmaceutical Manufacturing: Historical Perspectives and Future Directions

Szkodny

Lee

2022

Annu. Rev. Chem. Biomol. Eng.

View full text Add to dashboard Cite

This review describes key milestones related to the production of biopharmaceuticals—therapies manufactured using recombinant DNA technology. The market for biopharmaceuticals has grown significantly since the first biopharmaceutical approval in 1982, and the scientific maturity of the technologies used in their manufacturing processes has grown concomitantly. Early processes relied on established unit operations, with research focused on process scale-up and improved culture productivity. In the early 2000s, changes in regulatory frameworks and the introduction of Quality by Design emphasized the importance of developing manufacturing processes to deliver a desired product quality profile. As a result, companies adopted platform processes and focused on understanding the dynamic interplay between product quality and processing conditions. The consistent and reproducible manufacturing processes of today's biopharmaceutical industry have set high standards for product efficacy, quality, and safety, and as the industry continues to evolve in the coming decade, intensified processing capabilities for an expanded range of therapeutic modalities will likely become routine. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering, Volume 13 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

show abstract