Bioreactor Process Parameter Screening Utilizing a Plackett-Burman Design for a Model Monoclonal Antibody

Agarabi, Cyrus; Schiel, John E.; Lute, Scott; Chavez, Brittany; Boyne, Michael T.; Brorson, Kurt; Khan, Mansoor A.; Read, Erik K.

doi:10.1002/jps.24420

Cited by 33 publications

(38 citation statements)

References 47 publications

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“…Cells cultivated in OptiCHO and cell line B were more affected by the condition applied to reduce aggregation. It is important to obtain a balance between cell culture performance and critical product quality attributes (Agarabi et al, 2015). This shows that mathematical models of one biological system cannot easily be transferred to another system, since they lack transferability to other systems even if they are closely related (Koutinas, Kiparissides, Pistikopoulos, & Mantalaris, 2012).…”

Section: Figurementioning

confidence: 99%

“…In all these approaches only soluble aggregates were analyzed, mostly by size exclusion chromatography after a Protein A capturing step. Bioprocess optimization using DoE was mainly performed on protein glycosylation and not on protein aggregation (Agarabi et al, 2015;Grainger & James, 2013;St Amand, Tran, Radhakrishnan, Robinson, & Ogunnaike, 2014). Moreover, a comprehensive screening of cell culture conditions influencing protein aggregation in mammalian cell culture has never been performed before to our knowledge.…”

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confidence: 99%

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Identification of process conditions influencing protein aggregation in Chinese hamster ovary cell culture

Paul

Handrick

Ebert

et al. 2018

Biotech & Bioengineering

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Protein aggregation of monoclonal antibodies (mAbs) is a common phenomenon associated with the production of these biopharmaceuticals. These aggregates can lead to adverse side effects in patients upon administration, thus expensive downstream processing steps to remove the higher molecular weight species are inevitable. A preferable approach is to reduce the level of aggregation during bioprocessing by a careful adjustment of critical process parameters. Recently, new analytical methods enabled characterization of mAb aggregation during bioprocessing of mammalian cells. Furthermore, rapid and efficient bioprocess optimization has been performed using design of experiments (DoE) strategies. In this work, we describe a DoE-based approach for the analysis of process parameters and cell culture additives influencing protein aggregation in Chinese hamster ovary (CHO) cell cultures. Important bioprocess variables influencing the aggregation of mAb and host cell proteins were identified in initial screening experiments. Response surface modeling was further applied in order to find optimal conditions for the reduction of protein aggregation during cell culture. It turned out that a temperature-shift to 31 °C, osmolality above 420 mOsm/kg, agitation at 100 rpm and 0.04% (w/v) antifoam significantly reduced the level of aggregates without substantial detrimental effects on cell culture performance in our model system. Finally, the aggregation reducing conditions were verified and applied to another production system using a different bioprocess medium and another CHO cell line producing another mAb. Our results show that protein aggregation can be controlled during cell culture and helps to improve bioprocessing of mAbs, by giving insights into the protein aggregation at its origin in mammalian cell culture.

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Section: Figurementioning

confidence: 99%

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confidence: 99%

Identification of process conditions influencing protein aggregation in Chinese hamster ovary cell culture

Paul

Handrick

Ebert

et al. 2018

Biotech & Bioengineering

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“…Application of statistical tools for screening and optimisation studies helps to analyse the results with less experiments and time. PlackettBurman (PB) design is a useful method for screening significant variables from a large number of variables with fewer experiments [21][22][23][24]. Response surface methodology (RSM) is a collection of statistical tools used to optimise, develop and improve Nutrafoods (2015) where Y is the dependent variable, α 0 and α i are regression coefficients for the intercept and linear effects respectively and X i is coded independent variables.…”

Section: Fermentation Conditionsmentioning

confidence: 99%

Red pigment production by Monascus purpureus using sweet potato-based medium in submerged fermentation

Srivastav

Yadav

Sharmila³

et al. 2015

Nutrafoods

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“…Requisite control parameters such as critical feed components and bioreactor settings may be identified and optimized via design of experiments studies. For example, a Placket-Burman design of experiments screened the contribution of 11 process variables to identify cell culture temperature and non-essential amino acids supplementation effects on glycan identity of an IgG3 28 . An emerging field of process/product attribute correlation and more informative real-time feedback show promise for improved predictability of optimum conditions and reduces the risk for out of specification batches 29 .…”

Section: Discussionmentioning

confidence: 99%

Heterologous recombinant expression of non-originator NISTmAb

Kashi

Yandrofski

Preston

et al. 2018

mAbs

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The successful development and regulatory approval of originator and biosimilar therapeutic proteins requires a systems approach to upstream and downstream processing as well as product characterization and quality control. Innovation in process design and control, product characterization strategies, and data integration represent an ecosystem whose concerted advancement may reduce time-to-market and further improve comparability and biosimilarity programs. The biopharmaceutical community has made great strides to this end, yet there currently exists no pre-competitive monoclonal antibody (mAb) expression platform for open innovation. Here, we describe the development and initial expression of an intended copy of the NISTmAb using three non-originator murine cell lines. It was found that, without optimization and in culture flasks, all three cell lines produce approximately 100 mg mAb per liter of culture. Sodium dodecyl sulfate polyacrylamide gel electrophoresis, size-exclusion chromatography, nuclear magnetic resonance spectroscopy, intact mass spectrometry, and surface plasmon resonance were used to demonstrate that the products of all three cell lines embody quality attributes with a sufficient degree of sameness to the NISTmAb Reference Material 8671 to warrant further bioreactor studies, process improvements and optimization. The implications of the work with regard to pre-competitive innovation to support process design and feedback control, comparability and biosimilarity assessments, and process analytical technologies are discussed.

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Bioreactor Process Parameter Screening Utilizing a Plackett-Burman Design for a Model Monoclonal Antibody

Cited by 33 publications

References 47 publications

Identification of process conditions influencing protein aggregation in Chinese hamster ovary cell culture

Identification of process conditions influencing protein aggregation in Chinese hamster ovary cell culture

Red pigment production by Monascus purpureus using sweet potato-based medium in submerged fermentation

Heterologous recombinant expression of non-originator NISTmAb

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