Development and Qualification of a Cell Culture Scale‐Down Model

Khattak, Sarwat F.; Pferdeort, Valerie

doi:10.1002/9783527811410.ch16

Cited by 4 publications

(4 citation statements)

References 46 publications

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“…While the experiment did not achieve a second steady state for these two bioreactors, and a complete dilution rate study was not attempted, it is clear from the limited data that the cascading linked bioreactors system is significantly more productive than the stand‐alone CSTRs for similar operating conditions. Although only modest productivities were achieved while operating as a stand‐alone CSTR without cell retention in the current work, recent public disclosures on standalone CSTRs for cell culture (Khattak et al, 2019) demonstrate the potential for significant improvement with optimization.…”

Section: Resultsmentioning

confidence: 67%

“…Continuous processes operating without cell retention have also been assessed. Originally evaluated decades ago (Hiller et al, 1991) continuous mammalian cell culture processes operating as simple continuous‐flow stirred tank reactors (CSTRs) have recently been found capable of delivering volumetric productivities comparable to fed‐batch with enough optimization (Khattak et al, 2019). Two CSTRs operating in series (or cascade) have also been explored as an option to optimize productivity (Bakker et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Hydrocyclones as cell retention devices for an N‐1 perfusion bioreactor linked to a continuous‐flow stirred tank production bioreactor

Kundu

Hiller

2021

Biotech & Bioengineering

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A continuous Chinese hamster ovary (CHO) cell culture process comprised of a highly proliferative N‐1 perfusion bioreactor utilizing a hydrocyclone as a cell retention device linked to a production continuous‐flow stirred tank reactor (CSTR) is presented. The overflow stream from the hydrocyclone, which is only partially depleted of cells, provides a continuous source of high viability cells from the N‐1 perfusion bioreactor to the 5–20 times larger CSTR. Under steady‐state conditions, this linked‐bioreactor system achieved a peak volumetric productivity of 0.96 g/L/day, twofold higher than the optimized fed‐batch process. The linked bioreactor system using a hydrocyclone was also shown to be 1.8–3.1 times more productive than a dual, cascading CSTR system without cell retention.

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Section: Resultsmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Hydrocyclones as cell retention devices for an N‐1 perfusion bioreactor linked to a continuous‐flow stirred tank production bioreactor

Kundu

Hiller

2021

Biotech & Bioengineering

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“…An approach most commonly followed is to statistically compare a group of runs from a manufacturing scale with a group of runs at a small scale performed at set-point conditions [18][19][20]. Various statistical techniques have been used for scale-down model qualification [21]. A disadvantage of these approaches is that they compare the scales only at set-point conditions and do not provide any insight as to whether the functional relationships between process parameters and quality attributes are the same.…”

Section: Introductionmentioning

confidence: 99%

Temperature Upshifts in Mammalian Cell Culture: A Suitable Strategy for Biosimilar Monoclonal Antibodies?

Marschall,

Gottimukkala,

Kayal

et al. 2023

Bioengineering

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Temperature downshifts are the gold standard when setting up control strategies for mammalian cell culture processes. These shifts are performed to prolong production phases and attain heightened levels of productivity. For the development of biosimilars, however, the bottleneck is in achieving a prespecified product quality. In a late-stage development project, we investigated the impact of temperature shifts and other process parameters with the aim of optimizing the glycosylation profile of a monoclonal antibody (mAb). We applied a design of experiments approach on a 3 L scale. The optimal glycosylation profile was achieved when performing a temperature upshift from 35.8 °C to 37 °C. Total afucosylated glycan (TAF) decreased by 1.2%, and galactosylated glycan species (GAL) increased by up to 4.5%. The optimized control strategy was then successfully taken to the manufacturing scale (1000 L). By testing two sets of set points at the manufacturing scale, we demonstrated that the statistical models predicting TAF and GAL trained with small-scale data are representative of the manufacturing scale. We hope this study encourages researchers to widen the screening ranges in process development and investigate whether temperature upshifts are also beneficial for other mAbs.

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“…This involves using a quality by design (QbD) approach where scaleindependent parameters such as specific power inputs (e.g., power per volume [P/V]) and mass transfer coefficients (k L a) (e.g., oxygen transfer) are conserved in larger bioreactors [10] and scale-down models. [11] Typically, bioprocess scientists choose one of these parameters and then select a bioreactor setting (e.g., stir speed) so that the bioprocess parameter is the same between small-and large-scale bioreactors. This can cause issues when developing a process across multiple scales from process development (e.g., 250 mL) to production (e.g., 2000 L).…”

Section: Introductionmentioning

confidence: 99%

Untitled

2021

BPJ

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The ability to scale a cell culture effectively and efficiently, from lab to manufacturing, is critical to maximizing productivity whilst minimizing the risk of run failures and delays that can cost millions of dollars per month. The task of scaling well, however, is still considered to be a challenge by many upstream scientists, and this can be an exercise in trial and error. Traditionally, scaling has most often been performed using arithmetic in a spreadsheet and/or simple "back of an envelope" calculations. For some, it may even come in the form of support from a team of data scientists using advanced analytical software. This dependency on what some consider to be complex mathematics or statistics has resulted in the common consideration of using just one scaling parameter at a time, one scale at a time. However, it is difficult to determine easily or optimally, from the start, whether a process successfully transfers across scales based on only one process parameter, at one scale.In this article, we describe the benefits of using a risk-based approach to scaling, and the development of a software scaling tool known as BioPAT® Process Insights for predictive scale conversion across different bioreactor scales. BioPAT Process Insights can be used to consider multiple parameters and across multiple scales simultaneously, from the start of a scaling workflow. We briefly describe how it was used in a proof-of-concept scale-up study to allow a faster, more cost-effective process transfer from 250 mL to 2000 L. In summary, using BioPAT Process Insights, in conjunction with a bioreactor range that has comparable geometry and physical similarities across scales, has the potential to help biopharma manufacturing facilities reach 2000 L production-scale volumes with fewer process transfer steps, saving both time and money during scale-up of biologics and vaccines.

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Development and Qualification of a Cell Culture Scale‐Down Model

Cited by 4 publications

References 46 publications

Hydrocyclones as cell retention devices for an N‐1 perfusion bioreactor linked to a continuous‐flow stirred tank production bioreactor

Hydrocyclones as cell retention devices for an N‐1 perfusion bioreactor linked to a continuous‐flow stirred tank production bioreactor

Temperature Upshifts in Mammalian Cell Culture: A Suitable Strategy for Biosimilar Monoclonal Antibodies?

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