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Artikel: Triple Space-Time Yield in Discontinuous Antibody Biomanufacturing by Combination of Synergetic Process Intensification Strategies.

Reger, Lucas Nik / Saballus, Martin / Kampmann, Markus / Wijffels, Rene H / Martens, Dirk E / Niemann, Julia

2023 Band 10, Heft 12

Abstract: Monoclonal antibodies are the workhorse of the pharmaceutical industry due to their potential to treat a variety of different diseases while providing high specificity and efficiency. As a consequence, a variety of production processes have been ... ...

Abstract	Monoclonal antibodies are the workhorse of the pharmaceutical industry due to their potential to treat a variety of different diseases while providing high specificity and efficiency. As a consequence, a variety of production processes have been established within the biomanufacturing industry. However, the rapidly increasing demand for therapeutic molecules amid the recent COVID-19 pandemic demonstrated that there still is a clear need to establish novel, highly productive, and flexible production processes. Within this work, we designed a novel discontinuous process by combining two intensification strategies, thus increasing inoculation density and media exchange via a fluidized bed centrifuge, to fulfill the need for a flexible and highly productive production process for therapeutic molecules. To establish this new process, firstly, a small-scale experiment was conducted to verify synergies between both intensification strategies, followed by a process transfer towards the proof-of-concept scale. The combination of these two-process intensification measures revealed overall synergies resulting in decreased process duration (-37%) and strongly enhanced product formation (+116%) in comparison to the not-intensified standard operation. This led to an impressive threefold increase in space-time yield, while only negligible differences in product quality could be observed. Overall, this novel process not only increases the ways to react to emergency situations thanks to its flexibility and possible short development times, but also represents a possible alternative to the current established processes due to high increases in productivity, in comparison to standard fed-batch operations.
Sprache	Englisch
Erscheinungsdatum	2023-12-05
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
DOI	10.3390/bioengineering10121391
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Transcriptomic analysis reveals mode of action of butyric acid supplementation in an intensified CHO cell fed-batch process.

Schulze, Markus / Kumar, Yadhu / Rattay, Merle / Niemann, Julia / Wijffels, Rene H / Martens, Dirk E

Biotechnology and bioengineering

2022 Band 119, Heft 9, Seite(n) 2359–2373

Abstract: Process intensification is increasingly used in the mammalian biomanufacturing industry. The key driver of this trend is the need for more efficient and flexible production strategies to cope with the increased demand for biotherapeutics predicted in the ...

Abstract	Process intensification is increasingly used in the mammalian biomanufacturing industry. The key driver of this trend is the need for more efficient and flexible production strategies to cope with the increased demand for biotherapeutics predicted in the next years. Therefore, such intensified production strategies should be designed, established, and characterized. We established a CHO cell process consisting of an intensified fed-batch (iFB), which is inoculated by an N-1 perfusion process that reaches high cell concentrations (100 × 10
Mesh-Begriff(e)	Animals ; Batch Cell Culture Techniques ; Bioreactors ; Butyric Acid ; CHO Cells ; Cricetinae ; Cricetulus ; Dietary Supplements ; Immunoglobulin G/genetics ; Immunoglobulin G/metabolism ; Transcriptome
Chemische Substanzen	Immunoglobulin G ; Butyric Acid (107-92-6)
Sprache	Englisch
Erscheinungsdatum	2022-06-24
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.28150
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Boosting Productivity for Advanced Biomanufacturing by Re-Using Viable Cells.

Reger, Lucas Nik / Saballus, Martin / Matuszczyk, Jens / Kampmann, Markus / Wijffels, Rene H / Martens, Dirk E / Niemann, Julia

Frontiers in bioengineering and biotechnology

2023 Band 11, Seite(n) 1106292

Abstract: Monoclonal antibodies (mAb) have gained enormous therapeutic application during the last decade as highly efficient and flexible tools for the treatment of various diseases. Despite this success, there remain opportunities to drive down the manufacturing ...

Abstract	Monoclonal antibodies (mAb) have gained enormous therapeutic application during the last decade as highly efficient and flexible tools for the treatment of various diseases. Despite this success, there remain opportunities to drive down the manufacturing costs of antibody-based therapies through cost efficiency measures. To reduce production costs, novel process intensification methods based on state-of-the-art fed-batch and perfusion have been implemented during the last few years. Building on process intensification, we demonstrate the feasibility and benefits of a novel, innovative hybrid process that combines the robustness of a fed-batch operation with the benefits of a complete media exchange enabled through a fluidized bed centrifuge (FBC). In an initial small-scale FBC-mimic screening, we investigated multiple process parameters, resulting in increased cell proliferation and an elongated viability profile. Consecutively, the most productive process scenario was transferred to the 5-L scale, further optimized and compared to a standard fed-batch process. Our data show that the novel hybrid process enables significantly higher peak cell densities (163%) and an impressive increase in mAb amount of approximately 254% while utilizing the same reactor size and process duration of the standard fed-batch operation. Furthermore, our data show comparable critical quality attributes (CQAs) between the processes and reveal scale-up possibilities and no need for extensive additional process monitoring. Therefore, this novel process intensification strategy yields strong potential for transfer into future industrial manufacturing processes.
Sprache	Englisch
Erscheinungsdatum	2023-02-16
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2719493-0
ISSN	2296-4185
ISSN	2296-4185
DOI	10.3389/fbioe.2023.1106292
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: A novel hybrid bioprocess strategy addressing key challenges of advanced biomanufacturing.

Reger, Lucas Nik / Saballus, Martin / Kappes, Annika / Kampmann, Markus / Wijffels, Rene H / Martens, Dirk E / Niemann, Julia

Frontiers in bioengineering and biotechnology

2023 Band 11, Seite(n) 1211410

Abstract: Monoclonal antibodies (mAb) are commonly manufactured by either discontinuous operations like fed-batch (FB) or continuous processes such as steady-state perfusion. Both process types comprise opposing advantages and disadvantages in areas such as plant ... ...

Abstract	Monoclonal antibodies (mAb) are commonly manufactured by either discontinuous operations like fed-batch (FB) or continuous processes such as steady-state perfusion. Both process types comprise opposing advantages and disadvantages in areas such as plant utilization, feasible cell densities, media consumption and process monitoring effort. In this study, we show feasibility of a promising novel hybrid process strategy that combines beneficial attributes of both process formats. In detail, our strategy comprises a short duration FB, followed by a fast media exchange and cell density readjustment, marking the start of the next FB cycle. Utilizing a small-scale screening tool, we were able to identify beneficial process parameters, including FB interval duration and reinoculation cell density, that allow for multiple cycles of the outlined process in a reproducible manner. In addition, we could demonstrate scalability of the process to a 5L benchtop system, using a fluidized-bed centrifuge as scalable media exchange system. The novel process showed increased productivity (+217%) as well as longer cultivation duration, in comparison to a standard FB with a significantly lower media consumption per produced product (-50%) and a decreased need for process monitoring, in comparison to a perfusion cultivation. Further, the process revealed constant glycosylation pattern in comparison to the perfusion cultivation and has strong potential for further scale-up, due to the use of fully scalable cultivation and media exchange platforms. In summary, we have developed a novel hybrid process strategy that tackles the key challenges of current biomanufacturing of either low productivity or high media consumption, representing a new and innovative approach for future process intensification efforts.
Sprache	Englisch
Erscheinungsdatum	2023-06-30
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2719493-0
ISSN	2296-4185
ISSN	2296-4185
DOI	10.3389/fbioe.2023.1211410
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: First continuous marine sponge cell line established.

Hesp, Kylie / van der Heijden, Jans M E / Munroe, Stephanie / Sipkema, Detmer / Martens, Dirk E / Wijffels, Rene H / Pomponi, Shirley A

Scientific reports

2023 Band 13, Heft 1, Seite(n) 5766

Abstract: The potential of sponge-derived chemicals for pharmaceutical applications remains largely unexploited due to limited available biomass. Although many have attempted to culture marine sponge cells in vitro to create a scalable production platform for such ...

Abstract	The potential of sponge-derived chemicals for pharmaceutical applications remains largely unexploited due to limited available biomass. Although many have attempted to culture marine sponge cells in vitro to create a scalable production platform for such biopharmaceuticals, these efforts have been mostly unsuccessful. We recently showed that Geodia barretti sponge cells could divide rapidly in M1 medium. In this study we established the first continuous marine sponge cell line, originating from G. barretti. G. barretti cells cultured in OpM1 medium, a modification of M1, grew more rapidly and to a higher density than in M1. Cells in OpM1 reached 1.74 population doublings after 30 min, more than twofold higher than the already rapid growth rate of 0.74 population doublings in 30 min in M1. The maximum number of population doublings increased from 5 doublings in M1 to at least 98 doublings in OpM1. Subcultured cells could be cryopreserved and used to inoculate new cultures. With these results, we have overcome a major obstacle that has blocked the path to producing biopharmaceuticals with sponge cells at industrial scale for decades.
Mesh-Begriff(e)	Animals ; Porifera ; Cell Line ; Geodia ; Cell Culture Techniques
Sprache	Englisch
Erscheinungsdatum	2023-04-08
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-32394-x
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Automation of high CHO cell density seed intensification via online control of the cell specific perfusion rate and its impact on the N-stage inoculum quality

Schulze, Markus / Lemke, Johannes / Pollard, David / Wijffels, Rene H / Matuszczyk, Jens / Martens, Dirk E

Journal of biotechnology. 2021 July 20, v. 335

2021

Abstract: Current CHO cell production processes require an optimized space-time-yield. Process intensification can support achieving this by enhancing the productivity and improving facility utilization. The use of perfusion at the last stage of the seed train (N- ... ...

Abstract	Current CHO cell production processes require an optimized space-time-yield. Process intensification can support achieving this by enhancing the productivity and improving facility utilization. The use of perfusion at the last stage of the seed train (N-1) for high cell density inoculation of the fed-batch N-stage production culture is a relatively new approach with few industry applicable examples. Within this work, the impact of the cell-specific perfusion rate (CSPR) of the N-1 perfusion and the relevance of its control for the quality of generated inoculation cells was evaluated using an automated perfusion rate (PR) control based on online biomass measurements. Precise correlations (R² = 0.99) between permittivity and viable cell counts were found up to the high densities of 100⋅10⁶ c·mL⁻¹. Cells from N-1 perfusion were cultivated at a high and low CSPR with 50 and 20 pL·(c·d)⁻¹, respectively. Lowered cell growth and an increased apoptotic reaction was found as a consequence of the latter due to nutrient limitations and reduced uptake rates. Subsequently, batch cultivations (N-stage) from the different N-1 sources were inoculated to evaluate the physiological state of the inoculum. Successive responses resulting from the respective N-1 condition were uncovered. While cell growth and productivity of approaches inoculated from high CSPR and a conventional seed were comparable, low CSPR inoculation suffered significantly in terms of reduced initial cell growth and impaired viability. This study underlines the importance to determine the CSPR for the design and implementation of an N-1 perfusion process in order to achieve the desired performance at the crucial production stage.
Schlagwörter	apoptosis ; automation ; biomass ; biotechnology ; cell growth ; cell viability ; industry ; inoculum ; physiological state
Sprache	Englisch
Erscheinungsverlauf	2021-0720
Umfang	p. 65-75.
Erscheinungsort	Elsevier B.V.
Dokumenttyp	Artikel
ZDB-ID	843647-2
ISSN	1873-4863 ; 0168-1656 ; 1389-0352
ISSN (online)	1873-4863
ISSN	0168-1656 ; 1389-0352
DOI	10.1016/j.jbiotec.2021.06.011
Datenquelle	NAL Katalog (AGRICOLA)

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Artikel ; Online: Triple Space-Time Yield in Discontinuous Antibody Biomanufacturing by Combination of Synergetic Process Intensification Strategies

Reger, Lucas Nik / Saballus, Martin / Kampmann, Markus / Wijffels, Rene H. / Martens, Dirk E. / Niemann, Julia

Bioengineering

2023 Band 10, Heft 12

Abstract	Monoclonal antibodies are the workhorse of the pharmaceutical industry due to their potential to treat a variety of different diseases while providing high specificity and efficiency. As a consequence, a variety of production processes have been established within the biomanufacturing industry. However, the rapidly increasing demand for therapeutic molecules amid the recent COVID-19 pandemic demonstrated that there still is a clear need to establish novel, highly productive, and flexible production processes. Within this work, we designed a novel discontinuous process by combining two intensification strategies, thus increasing inoculation density and media exchange via a fluidized bed centrifuge, to fulfill the need for a flexible and highly productive production process for therapeutic molecules. To establish this new process, firstly, a small-scale experiment was conducted to verify synergies between both intensification strategies, followed by a process transfer towards the proof-of-concept scale. The combination of these two-process intensification measures revealed overall synergies resulting in decreased process duration (−37%) and strongly enhanced product formation (+116%) in comparison to the not-intensified standard operation. This led to an impressive threefold increase in space-time yield, while only negligible differences in product quality could be observed. Overall, this novel process not only increases the ways to react to emergency situations thanks to its flexibility and possible short development times, but also represents a possible alternative to the current established processes due to high increases in productivity, in comparison to standard fed-batch operations.
Schlagwörter	CHO cell culture ; discontinuous biomanufacturing ; fluidized bed centrifuge ; intermediate harvest ; monoclonal antibodies ; process intensification
Thema/Rubrik (Code)	660
Sprache	Englisch
Erscheinungsland	nl
Dokumenttyp	Artikel ; Online
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Automation of high CHO cell density seed intensification via online control of the cell specific perfusion rate and its impact on the N-stage inoculum quality.

Schulze, Markus / Lemke, Johannes / Pollard, David / Wijffels, Rene H / Matuszczyk, Jens / Martens, Dirk E

Journal of biotechnology

2021 Band 335, Seite(n) 65–75

Abstract	Current CHO cell production processes require an optimized space-time-yield. Process intensification can support achieving this by enhancing the productivity and improving facility utilization. The use of perfusion at the last stage of the seed train (N-1) for high cell density inoculation of the fed-batch N-stage production culture is a relatively new approach with few industry applicable examples. Within this work, the impact of the cell-specific perfusion rate (CSPR) of the N-1 perfusion and the relevance of its control for the quality of generated inoculation cells was evaluated using an automated perfusion rate (PR) control based on online biomass measurements. Precise correlations (R² = 0.99) between permittivity and viable cell counts were found up to the high densities of 100⋅10
Mesh-Begriff(e)	Animals ; Automation ; Batch Cell Culture Techniques ; Bioreactors ; CHO Cells ; Cell Count ; Cricetinae ; Cricetulus ; Perfusion
Sprache	Englisch
Erscheinungsdatum	2021-06-04
Erscheinungsland	Netherlands
Dokumenttyp	Journal Article
ZDB-ID	843647-2
ISSN	1873-4863 ; 0168-1656 ; 1389-0352
ISSN (online)	1873-4863
ISSN	0168-1656 ; 1389-0352
DOI	10.1016/j.jbiotec.2021.06.011
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Rapid intensification of an established CHO cell fed-batch process.

Schulze, Markus / Niemann, Julia / Wijffels, Rene H / Matuszczyk, Jens / Martens, Dirk E

Biotechnology progress

2021 Band 38, Heft 1, Seite(n) e3213

Abstract: Currently, the mammalian biomanufacturing industry explores process intensification (PI) to meet upcoming demands of biotherapeutics while keeping production flexible but, more importantly, as economic as possible. However, intensified processes often ... ...

Abstract	Currently, the mammalian biomanufacturing industry explores process intensification (PI) to meet upcoming demands of biotherapeutics while keeping production flexible but, more importantly, as economic as possible. However, intensified processes often require more development time compared with conventional fed-batches (FBs) preventing their implementation. Hence, rapid and efficient, yet straightforward strategies for PI are needed. In this study we demonstrate such a strategy for the intensification of an N-stage FB by implementing N-1 perfusion cell culture and high inoculum cell densities resulting in a robust intensified FB (iFB). Furthermore, we show successful combination of such an iFB with the addition of productivity enhancers, which has not been reported so far. The conventional CHO cell FB process was step-wise improved and intensified rapidly in multi-parallel small-scale bioreactors using N-1 perfusion. The iFBs were performed in 15 and 250 ml bioreactors and allowed to evaluate the impact on key process indicators (KPI): the space-time yield (STY) was successfully doubled from 0.28 to 0.55 g/L d, while product quality was maintained. This gain was generated by initially increasing the inoculation density, thus shrinking process time, and second supplementation with butyric acid (BA), which reduced cell growth and enhanced cell-specific productivity from ~25 to 37 pg/(cell d). Potential impacts of PI on cell metabolism were evaluated using flux balance analysis. Initial metabolic differences between the standard and intensified process were observed but disappeared quickly. This shows that PI can be achieved rapidly for new as well as existing processes without introducing sustained changes in cellular and metabolic behavior.
Mesh-Begriff(e)	Animals ; Batch Cell Culture Techniques ; Bioreactors ; CHO Cells ; Cell Count ; Cricetinae ; Cricetulus
Sprache	Englisch
Erscheinungsdatum	2021-09-25
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	165657-0
ISSN	1520-6033 ; 8756-7938
ISSN (online)	1520-6033
ISSN	8756-7938
DOI	10.1002/btpr.3213
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Rapid intensification of an established CHO cell fed-batch process

Schulze, Markus / Niemann, Julia / Wijffels, Rene H. / Matuszczyk, Jens / Martens, Dirk E.

Biotechnology Progress

2022 Band 38, Heft 1

Abstract	Currently, the mammalian biomanufacturing industry explores process intensification (PI) to meet upcoming demands of biotherapeutics while keeping production flexible but, more importantly, as economic as possible. However, intensified processes often require more development time compared with conventional fed-batches (FBs) preventing their implementation. Hence, rapid and efficient, yet straightforward strategies for PI are needed. In this study we demonstrate such a strategy for the intensification of an N-stage FB by implementing N-1 perfusion cell culture and high inoculum cell densities resulting in a robust intensified FB (iFB). Furthermore, we show successful combination of such an iFB with the addition of productivity enhancers, which has not been reported so far. The conventional CHO cell FB process was step-wise improved and intensified rapidly in multi-parallel small-scale bioreactors using N-1 perfusion. The iFBs were performed in 15 and 250 ml bioreactors and allowed to evaluate the impact on key process indicators (KPI): the space–time yield (STY) was successfully doubled from 0.28 to 0.55 g/L d, while product quality was maintained. This gain was generated by initially increasing the inoculation density, thus shrinking process time, and second supplementation with butyric acid (BA), which reduced cell growth and enhanced cell-specific productivity from ~25 to 37 pg/(cell d). Potential impacts of PI on cell metabolism were evaluated using flux balance analysis. Initial metabolic differences between the standard and intensified process were observed but disappeared quickly. This shows that PI can be achieved rapidly for new as well as existing processes without introducing sustained changes in cellular and metabolic behavior.
Schlagwörter	CHO cell culture ; N-1 perfusion ; butyric acid ; intensified fed-batch ; process intensification
Thema/Rubrik (Code)	670
Sprache	Englisch
Erscheinungsland	nl
Dokumenttyp	Artikel ; Online
ZDB-ID	165657-0
ISSN	1520-6033 ; 8756-7938
ISSN (online)	1520-6033
ISSN	8756-7938
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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