Larger Pore Size Hollow Fiber Membranes as a Solution to the Product Retention Issue in Filtration‐Based Perfusion Bioreactors

Wang, Samantha B.; Godfrey, Scott; Radoniqi, Flaka; Lin, Henry; Coffman, Jon

doi:10.1002/biot.201800137

Cited by 32 publications

(49 citation statements)

References 19 publications

(25 reference statements)

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“…Our previous study (Pinto, Napoli, & Brower, 2020) showed an integrated continuous bioprocess with practically nonproduct retention when employing macroporous (>1 µm pore size) perfusion membranes. This observation, corroborated by Wang et al (2017) and Wang et al (2019), highlights that microfiltration membranes retain particles within its pore size range, which leads to product sieving. Whereas, submicron particles perfuse through the larger pores of macroporous hollow fiber membranes and thus overcome product sieving.…”

Section: Introductionsupporting

confidence: 70%

Wide‐surface pore microfiltration membrane drastically improves sieving decay in TFF‐based perfusion cell culture and streamline chromatography integration for continuous bioprocessing

Pinto

Brower

2020

Biotech & Bioengineering

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Although several compelling benefits for bioprocess intensification have been reported, the need for a streamlined integration of perfusion cultures with capture chromatography still remains unmet. Here, a robust solution is established by conducting tangential flow filtration-based perfusion with a wide-surface pore microfiltration membrane. The resulting integrated continuous bioprocess demonstrated negligible retention of antibody, DNA, and host cell proteins in the bioreactor with average sieving coefficients of 98 ± 1%, 124 ± 28%, and 109 ± 27%, respectively. Further discussion regarding the potential membrane fouling mechanisms is also provided by comparing two membranes with different surface pore structures and the same hollow fiber length, total membrane area, and chemistry. A cake-growth profile is reported for the narrower surface pore, 0.65-µm nominal retention perfusion membrane with final antibody sieving coefficients ≤70%. Whereas the sieving coefficient remained ≥85% during 40 culture days for the wide-surface pore, 0.2-µm nominal retention rating membrane. The wide-surface pore structure, confirmed by scanning electron microscopy imaging, minimizes the formation of biomass deposits on the membrane surface and drastically improves product sieving. This study not only offers a robust alternative for integrated continuous bioprocess by eliminating additional filtration steps while overcoming sieving decay, but also provides insight into membranes' fouling mechanism.

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Section: Introductionsupporting

confidence: 70%

Wide‐surface pore microfiltration membrane drastically improves sieving decay in TFF‐based perfusion cell culture and streamline chromatography integration for continuous bioprocessing

Pinto

Brower

2020

Biotech & Bioengineering

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“…In another study, the use of ATF in place of an internal spin filter was studied, and it was found to result in higher cell densities, a higher perfusion rate, higher production (50-70%), and a longer run (Bosco et al, 2017). To overcome the product retention problem associated with TFF-and ATF-based perfusion cultures, a large pore size hollow fiber was recently used and drastically reduced product retention (Wang et al, 2019). In another study, temperature was established to be an important parameter in perfusion culture performance optimization (Wolf et al, 2019a).…”

Section: Perfusion Culture Processmentioning

confidence: 99%

Recent Developments in Bioprocessing of Recombinant Proteins: Expression Hosts and Process Development

Tripathi

Shrivastava

2019

Front. Bioeng. Biotechnol.

360

243

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Infectious diseases, along with cancers, are among the main causes of death among humans worldwide. The production of therapeutic proteins for treating diseases at large scale for millions of individuals is one of the essential needs of mankind. Recent progress in the area of recombinant DNA technologies has paved the way to producing recombinant proteins that can be used as therapeutics, vaccines, and diagnostic reagents. Recombinant proteins for these applications are mainly produced using prokaryotic and eukaryotic expression host systems such as mammalian cells, bacteria, yeast, insect cells, and transgenic plants at laboratory scale as well as in large-scale settings. The development of efficient bioprocessing strategies is crucial for industrial production of recombinant proteins of therapeutic and prophylactic importance. Recently, advances have been made in the various areas of bioprocessing and are being utilized to develop effective processes for producing recombinant proteins. These include the use of high-throughput devices for effective bioprocess optimization and of disposable systems, continuous upstream processing, continuous chromatography, integrated continuous bioprocessing, Quality by Design, and process analytical technologies to achieve quality product with higher yield. This review summarizes recent developments in the bioprocessing of recombinant proteins, including in various expression systems, bioprocess development, and the upstream and downstream processing of recombinant proteins.

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“…Hence, the use of PS membranes can be equally important for related perfusion processes where expressed proteins are considered as product, but retained by PES membranes with a nominal cutoff of 0.2 μm (Karst, Serra, Villiger, Soos, & Morbidelli, 2016;Kelly et al, 2014). Alternatively, other studies identified the use of large-pore membranes of 2 μm and larger as a solution for production retention (Pinto, Napoli, & Brower, 2019;S. B. Wang, Godfrey, Radoniqi, Lin, & Coffman, 2019).…”

Section: Membrane Fouling Dynamics and Its Impact On Product Retentionmentioning

confidence: 99%

Virus harvesting in perfusion culture: Choosing the right type of hollow fiber membrane

Nikolay

Grooth

Genzel

et al. 2020

Biotech & Bioengineering

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The use of bioreactors coupled to membrane‐based perfusion systems enables very high cell and product concentrations in vaccine and viral vector manufacturing. Many virus particles, however, are not stable and either lose their infectivity or physically degrade resulting in significant product losses if not harvested continuously. Even hollow fiber membranes with a nominal pore size of 0.2 µm can retain much smaller virions within a bioreactor. Here, we report on a systematic study to characterize structural and physicochemical membrane properties with respect to filter fouling and harvesting of yellow fever virus (YFV; ~50 nm). In tangential flow filtration perfusion experiments, we observed that YFV retention was only marginally determined by nominal but by effective pore sizes depending on filter fouling. Evaluation of scanning electron microscope images indicated that filter fouling can be reduced significantly by choosing membranes with (i) a flat inner surface (low boundary layer thickness), (ii) a smooth material structure (reduced deposition), (iii) a high porosity (high transmembrane flux), (iv) a distinct pore size distribution (well‐defined pore selectivity), and (v) an increased fiber wall thickness (larger effective surface area). Lowest filter fouling was observed with polysulfone (PS) membranes. While the use of a small‐pore PS membrane (0.08 µm) allowed to fully retain YFV within the bioreactor, continuous product harvesting was achieved with the large‐pore PS membrane (0.34 µm). Due to the low protein rejection of the latter, this membrane type could also be of interest for other applications, that is, recombinant protein production in perfusion cultures.

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Larger Pore Size Hollow Fiber Membranes as a Solution to the Product Retention Issue in Filtration‐Based Perfusion Bioreactors

Cited by 32 publications

References 19 publications

Wide‐surface pore microfiltration membrane drastically improves sieving decay in TFF‐based perfusion cell culture and streamline chromatography integration for continuous bioprocessing

Wide‐surface pore microfiltration membrane drastically improves sieving decay in TFF‐based perfusion cell culture and streamline chromatography integration for continuous bioprocessing

Recent Developments in Bioprocessing of Recombinant Proteins: Expression Hosts and Process Development

Virus harvesting in perfusion culture: Choosing the right type of hollow fiber membrane

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