Research Topic

Continuous Biomanufacturing in Microbial Systems

About this Research Topic

While most chemical industrial processes are designed and executed in continuous operation, the biotechnology industry still relies on batchwise production. Due to the multiple variables of complex biological systems, a batchwise approach is often preferred in biotech industry, while continuous cultivation approaches have the need for accurate process analytics and control strategies. Recent data has demonstrated that significant economic advantages lie in continuous biomanufacturing (CBM), which has gained ground on cell culture processes. These perfusion processes often lead to the best scenario of integrated processes, coupled with up- and downstream development. However, the establishment of an integrated process in microbial systems is, by far, more complicated because the targeted product is often located inside the cell. This leads to a limitation in effective recombinant protein production, as an irreversible drop in protein productivity occurs, due to still unknown reasons.

The lack of basic knowledge about the regulatory mechanism during recombinant protein production on a long-term scale prevents the industrial application of continuous biomanufacturing. Continuous processes significantly influence the ecological and economic footprint, as facilities become smaller and versatile with the application of modular design approaches. Recently, different methods have been established to overcome these limitations in the long-term productivity of continuous microbial culturing:

• Understanding of the metabolic or product burden of the host cells. Design of suitable expression strains changed product location from cytoplasm to periplasm or even the extracellular space.
• Uncovering the population dynamics in CMB. Often, different dynamics in subpopulations are believed to cause high variations in process performance.
• Upstream redesigning by decoupling biomass production from induction may help to stabilize long-term productivity.
• Undergoing changes in strain designs, transitioning from plasmid-based systems to genomic integrated genes for long term productivity.

Robust downstreaming (DSP) starts with robust upstreaming in terms of consistent product quality and lean design of DSP unit operations. The research tasks in this Research Topic should be open for all applications of continuous processes, ranging from production of pharmaceutical active compounds to “waste to value” approaches. Special focus should be targeted towards analytical and processing approaches to increase in-depth process understanding.

• New innovative applications of continuous processes using microbial hosts in red, white and green biotechnology.
• Insights into regulatory mechanisms in continuous culturing microbial techniques, using multi-omics technologies and/or new analytical techniques.
• Implementation of new engineered strains using genomic integrations, or deletions or providing new selection markers, to stabilize target product expression at a feasible level. This could include the redesign of existing industrial fed-batch processes towards continuous processes.
• Process analytical technologies (PAT) for monitoring and controlling of continuous processes.

The Research Topic is open for Method Perspectives, Review and Systematic Review articles, as well as Original Research.

Christoph Herwig is founder of Exputec GmbH.


Keywords: Continuous Biomanufacturing, Microbes, Circular Economy, Upstream Development, Integrated


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

While most chemical industrial processes are designed and executed in continuous operation, the biotechnology industry still relies on batchwise production. Due to the multiple variables of complex biological systems, a batchwise approach is often preferred in biotech industry, while continuous cultivation approaches have the need for accurate process analytics and control strategies. Recent data has demonstrated that significant economic advantages lie in continuous biomanufacturing (CBM), which has gained ground on cell culture processes. These perfusion processes often lead to the best scenario of integrated processes, coupled with up- and downstream development. However, the establishment of an integrated process in microbial systems is, by far, more complicated because the targeted product is often located inside the cell. This leads to a limitation in effective recombinant protein production, as an irreversible drop in protein productivity occurs, due to still unknown reasons.

The lack of basic knowledge about the regulatory mechanism during recombinant protein production on a long-term scale prevents the industrial application of continuous biomanufacturing. Continuous processes significantly influence the ecological and economic footprint, as facilities become smaller and versatile with the application of modular design approaches. Recently, different methods have been established to overcome these limitations in the long-term productivity of continuous microbial culturing:

• Understanding of the metabolic or product burden of the host cells. Design of suitable expression strains changed product location from cytoplasm to periplasm or even the extracellular space.
• Uncovering the population dynamics in CMB. Often, different dynamics in subpopulations are believed to cause high variations in process performance.
• Upstream redesigning by decoupling biomass production from induction may help to stabilize long-term productivity.
• Undergoing changes in strain designs, transitioning from plasmid-based systems to genomic integrated genes for long term productivity.

Robust downstreaming (DSP) starts with robust upstreaming in terms of consistent product quality and lean design of DSP unit operations. The research tasks in this Research Topic should be open for all applications of continuous processes, ranging from production of pharmaceutical active compounds to “waste to value” approaches. Special focus should be targeted towards analytical and processing approaches to increase in-depth process understanding.

• New innovative applications of continuous processes using microbial hosts in red, white and green biotechnology.
• Insights into regulatory mechanisms in continuous culturing microbial techniques, using multi-omics technologies and/or new analytical techniques.
• Implementation of new engineered strains using genomic integrations, or deletions or providing new selection markers, to stabilize target product expression at a feasible level. This could include the redesign of existing industrial fed-batch processes towards continuous processes.
• Process analytical technologies (PAT) for monitoring and controlling of continuous processes.

The Research Topic is open for Method Perspectives, Review and Systematic Review articles, as well as Original Research.

Christoph Herwig is founder of Exputec GmbH.


Keywords: Continuous Biomanufacturing, Microbes, Circular Economy, Upstream Development, Integrated


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

29 July 2020 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

29 July 2020 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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