Experimental verification and comparison of model predictive, PID and model inversion control in a Penicillium chrysogenum fed-batch process

Recent advances in the development of Aspergillus for protein production.

Filamentous fungi serve as production host for a number of highly relevant biotechnological products, like penicillin. In submerged culture, morphology can be exceptionally diverse and is influenced by several process parameters, like aeration, agitation, medium composition or growth rate. Fungal growth leads to several morphological classes encompassing homogeneously dispersed hyphae and various forms of hyphal agglomerates and/or clump structures. Eventually, the so-called pellet structure can be formed, which represents a hyphal agglomerate with a dense core. Pellet structures can hinder oxygen and substrate transport, resulting in different states of viability, which in turn affects productivity and process control. Over the years, several publications have dealt with methods to either gain morphological insight into pellet structure or determine biomass viability. Within this contribution, we present a way to combine both in a flow cytometry-based method employing fluorescent staining. Thereby, we can assess filamentous biomass in a statistically sound way according to (i) morphology and (ii) viability of each detected morphological form. We are confident that this method can shed light on the complex relationship between fungal morphology, viability and productivity-in both process development and routine manufacturing processes.

/pdf/the-filamentous-fungus-penicillium-chrysogenum-analysed-via-cz8edqf478.pdf

The filamentous fungus Penicillium chrysogenum analysed via flow cytometry-a fast and statistically sound insight into morphology and viability.

Digitalization in the form of Big Data and Digital Twin inspired applications are hot topics in today’s bio-manufacturing organizations. As a result, many organizations are diverting resources to these applications. In this manuscript, a targeted survey was conducted amongst individuals from the Danish biotech industry to understand both the current state and perceived future obstacles in implementing digitalization concepts in bio-tech production processes. The survey consisted of questions on current level of (a) Big Data analytics and (b) Digital Twins applications and obstacles to expanding these applications. Overall, 33 individuals responded the survey, a group spanning from bio-chemical to bio-pharmaceutical production. With over 73% of the respondents indicating their organization had an enterprise-wide level plan for digitalization, it can be concluded that the digitalization drive in the Danish bio-tech industry is well under way. However, only 30% of the respondents reported that there was a well-established business case for the digitalization applications in their organization. This is a strong indication that the value proposition for digitalization applications is somewhat ambiguous in view of the significant implementation costs. Further, digital applications (58%) were more widely used in industry than Big Data analytic tools (37%). On top of the lack of a business case, organizational readiness was identified as a key hurdle that needs to be overcome for both Digital Twin and Big Data applications. Infrastructure was another key hurdle for implementation with only 6% of the respondents stating that their production processes were 100% covered by advanced process analytical technologies.

/pdf/towards-digitalization-in-bio-manufacturing-operations-a-1dr5mo5h1q.pdf

Towards Digitalization in Bio-Manufacturing Operations: A Survey on Application of Big Data and Digital Twin Concepts in Denmark

Aims The present study was aimed at design of experiments (DoE)- and artificial intelligence-based culture medium optimization for high level extracellular production of a novel recombinant human interferon alpha 2b (huIFNα2b) in glycoengineered Pichia pastoris and its characterization. Methods and results The artificial neural network-genetic algorithm model exhibited improved huIFNα2b production and better predictability compared to response surface methodology. The optimized medium exhibited a fivefold increase in huIFNα2b titre compared to the complex medium. A maximum titre of huIFNα2b (436 mg l-1 ) was achieved using the optimized medium in the bioreactor. Real-time capacitance data from dielectric spectroscopy were utilized to model the growth kinetics with unstructured models. Biological characterization by antiproliferative assay proved that the purified recombinant huIFNα2b was biologically active, exhibiting growth inhibition on breast cancer cell line. Conclusions Culture medium optimization resulted in enhanced production of huIFNα2b in glycoengineered P. pastoris at both shake flask and bioreactor level. The purified huIFNα2b was found to be N-glycosylated and biologically active. Significance and impact of the study DoE-based medium optimization strategy significantly improved huIFNα2b production. The antiproliferative activity of huIFNα2b substantiates its potential scope for application in cancer therapy.

High level extracellular production of recombinant human interferon alpha 2b in glycoengineered Pichia pastoris: culture medium optimization, high cell density cultivation and biological characterization

With increasing bioreactor volumes, the mixing time of the reactor increases as well, which creates an inhomogeneous environment for the cells. This can result in impaired process performance in large-scale production reactors. Particularly the addition of base through the reactor headspace can be problematic, since it creates an area, where cells are repeatedly exposed to an increased pH. The aim of this study is to simulate this large-scale phenomenon at lab-scale and investigate its impact. Two different cell lines were exposed to pH amplitudes of a maximal magnitude of 0.05 units (pH of 6.95). Both cell lines showed similar responses, like decreased viable cell counts, but unaffected lactate levels. However, cell line B showed an initially increased specific productivity in response to the introduced amplitudes, whereas cell line A showed a consistently lower specific productivity. Furthermore, the time point at which base addition is started influences the impact, which pH amplitudes have on process performance. When pH control was started earlier in the process, maximal viable cell counts decreased and the lactate metabolic shift was less pronounced. These results show that the potential negative impact of pH amplitudes can be minimized by strategic process design.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/elsc.202000034

Investigation of cell line specific responses to pH inhomogeneity and consequences for process design.

Controlling the specific growth rate via biomass trend regulation in filamentous fungi bioprocesses

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Investigation of cell line specific responses to pH inhomogeneity and consequences for process design.

Controlling the specific growth rate via biomass trend regulation in filamentous fungi bioprocesses