Perspectives on integrated continuous bioprocessing—opportunities and challenges

Zydney, Andrew L.

doi:10.1016/j.coche.2015.07.005

Cited by 103 publications

(75 citation statements)

References 36 publications

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“…The abbreviation MoBiDiK means modular bioproduction, being disposable and continuous. For further information, the reader is recommended to overviews of the availability of continuous bioprocessing technology [29,30] and current opinions on the future of bioprocessing [31,32]. Case studies for the applicability of the SPI cont might, therefore, arise soon.…”

Section: Discussionmentioning

confidence: 98%

Production Rate‐Dependent Key Performance Indicators for a Systematic Design of Biochemical Downstream Processes

Brandt

Schembecker

2016

Chem Eng & Technol

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Key performance indicators have become a common tool in bioprocess development, as they allow an objective and independent rating and ranking of process alternatives screened. A disadvantage of all key performance indicators developed so far is their strong focus on costs, which makes them neglect the influence of the production rate on the profit of the process. But, since both production costs and production rate have an equally strong impact, both should be considered when decisions have to be made. Therefore, two new key performance indicators are introduced in this work, one for batch and one for continuous processing. They combine product yield, purity performance, variable manufacturing costs, and production rate to one objective. Thereby, misguided trade-offs between these four individual measures can be replaced by one key performance indicator. This ensures a systematic development of biochemical downstream processes.

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Section: Discussionmentioning

confidence: 98%

Production Rate‐Dependent Key Performance Indicators for a Systematic Design of Biochemical Downstream Processes

Brandt

Schembecker

2016

Chem Eng & Technol

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“…This last constraint enabled straight-through, integrated bioprocesses to be identified using our tool, addressing a major objective in industrial downstream bioprocessing (Ghose, Jin, Liu, & Hickey, 2009;Klutz et al, 2015;Walther et al, 2015;Warikoo et al, 2012;Xenopoulos, 2015;Zydney, 2015). The software was constrained to search for three-step purification processes that contained a single flowthrough step.…”

Section: Purification Process Synthesis Using An In Silico Toolmentioning

confidence: 99%

An impurity characterization based approach for the rapid development of integrated downstream purification processes

Timmick

Vecchiarello

Goodwine

et al. 2018

Biotech & Bioengineering

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In this study, we describe a new approach for the characterization of process-related impurities along with an in silico tool to generate orthogonal, integrated downstream purification processes for biological products. A one-time characterization of process-related impurities from product expression in Pichia pastoris was first carried out using linear salt and pH gradients on a library of multimodal, salt-tolerant, and hydrophobic charge induction chromatographic resins. The Reversed-phase ultra-performance liquid chromatography (UPLC) analysis of the fractions from these gradients was then used to generate large data sets of impurity profiles. A retention database of the biological product was also generated using the same linear salt and pH gradients on these resins, without fraction collection. The resulting two data sets were then analyzed using an in silico tool, which incorporated integrated manufacturing constraints to generate and rank potential three-step purification sequences based on their predicted purification performance as well as whole-process "orthogonality" for impurity removal. Highly ranked sequences were further examined to identify templates for process development. The efficacy of this approach was successfully demonstrated for the rapid development of robust integrated processes for human growth hormone and granulocyte-colony stimulating factor.

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“…Despite the high potential of continuous downstream processing, it is still rarely applied in the manufacturing of biologics. Other industries such as the food and chemical sector, have already successfully implemented integrated processes which create highly flexible and efficient production [6,7]. In continuous operation equipment size can be down scaled, which reduces not only investment costs but also operating costs due to buffer savings [8,9].…”

Section: Biotechnology Journalmentioning

confidence: 99%

Continuous desalting of refolded protein solution improves capturing in ion exchange chromatography: A seamless process

Walch

Jungbauer

2017

Biotechnology Journal

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Truly continuous biomanufacturing processes enable an uninterrupted feed stream throughout the whole production without the need for holding tanks. We have utilized microporous anion and cation exchangers into which only salts, but not proteins, can penetrate into the pores for desalting of protein solutions, while diafiltration or dilution is usually employed for feed adjustments. Anion exchange and cation exchange chromatography columns were connected in series to remove both anions and cations. To increase operation performance, a continuous process was developed comprised of four columns. Continuous mode was achieved by staggered cycle operation, where one set of columns, consisting of one anion exchange and one cation exchange column, was loaded during the regeneration of the second set. Refolding, desalting and subsequent ion exchange capturing with a scFv as the model protein was demonstrated. The refolding solution was successfully desalted resulting in a consistent conductivity below 0.5 mS/cm from initial values of 10 to 11 mS/cm. With continuous operation process time could be reduced by 39% while productivity was increased to 163% compared to batch operation. Desalting of the protein solution resulted in up to seven-fold higher binding capacities in the subsequent ion exchange capture step with conventional protein binding resins. www.biotechnology-journal.com Biotechnology Journalwww.advancedsciencenews.com Biotechnol. J. 2017, 12, 1700082 for IB resolubilization to unfold the protein followed by a dilution step to reduce the chaotropic conditions which initiates protein folding. However, such refolding buffers commonly require also elevated salt concentrations [5] which therefore results in feed streams being high in conductivity, making ion exchange chromatography an unsuitable option for the next unit operation. Ion exchange chromatography is attractive for industry due to the costefficient resins with high capacities. Hence, additional process steps such as dilution or diafiltration have to be introduced to reduce salt concentration in the solution and allow efficient binding of the protein to the ion exchange resins [6]. Despite the high potential of continuous downstream processing, it is still rarely applied in the manufacturing of biologics. Other industries such as the food and chemical sector, have already successfully implemented integrated processes which create highly flexible and efficient production [6,7]. In continuous operation equipment size can be down scaled, which reduces not only investment costs but also operating costs due to buffer savings [8,9]. Additionally optimized cycle times improve also productivity [10,11]. Not only FDA has addressed this topic [12,13], it also raised the interest of numerous researchers in both academia and industry [14,15]. Even it is not realized on a large production scale yet, various different strategies for continuous biomanufacturing have been developed in recent years [8,[16][17][18][19][20][21].In this work, we describe a novel alternati...

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Perspectives on integrated continuous bioprocessing—opportunities and challenges

Cited by 103 publications

References 36 publications

Production Rate‐Dependent Key Performance Indicators for a Systematic Design of Biochemical Downstream Processes

Production Rate‐Dependent Key Performance Indicators for a Systematic Design of Biochemical Downstream Processes

An impurity characterization based approach for the rapid development of integrated downstream purification processes

Continuous desalting of refolded protein solution improves capturing in ion exchange chromatography: A seamless process

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