Digital Twins for Continuous Biologics Manufacturing

Schmidt, A.; Zobel-Roos, Steffen; Helgers, Heribert; Lohmann, Lara; Vetter, Florian Lukas; Jensch, Christoph; Juckers, Alex; Strube, Jochen

doi:10.1002/9783527827343.ch9

Cited by 7 publications

(6 citation statements)

References 130 publications

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“…The kinetic parameters could be determined that are needed for DT-based process optimization and automation. 103 The maximum reaction rate is 0.358 ± 0.001 μM/min for all nucleotides. The second important parameter for modeling the reaction in the process model is the Michaelis–Menten constant, which is 140.4 ± 2.9 μM for ATP, 71.5 ± 1.9 μM for CTP, 101.5 ± 3.8 μM for UTP, and 165.5 ± 6.4 μM for GTP.…”

Section: Discussionmentioning

confidence: 90%

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Digital Twin Fundamentals of mRNA In Vitro Transcription in Variable Scale Toward Autonomous Operation

Hengelbrock,

Schmidt,

Strube

2024

ACS Omega

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The COVID-19 pandemic caused the rapid development of mRNA (messenger ribonucleic acid) vaccines and new RNA-based therapeutic methods. However, the approval rate for candidates has the potential to be increased, with a significant number failing so far due to efficacy, safety, and manufacturing deficiencies, hindering equitable vaccine distribution during pandemics. This study focuses on optimizing the production of mRNA, a critical component of mRNA-based vaccines, using a scalable machine by investigating the key mechanisms of mRNA in vitro transcription. First, kinetic parameters for the mRNA production process were determined. The validity of the determination and the robustness of the model are demonstrated by predicting different reactions with and without substrate limitations as well as different transcripts. The optimized reaction conditions, including temperature, urea concentration, and concentration of reaction-enhancing additives, resulted in a 55% increase in mRNA yield with a 33% reduction in truncated mRNA. Additionally, the feasibility of a segmented flow approach allowed for high-throughput screening (HTS), enabling the production of 20 vaccine candidates within a short time frame, representing a 10-fold increase in productivity, compared to nonsegmented reactions limited by the residence time in the plug flow reactor. The findings presented for the first time here contribute to the development of a fully continuous and efficient manufacturing process for mRNA and other cell and gene therapy drugs/vaccine candidates as presented in our previous work, which discussed the integration of process analytical technologies and predictive process models in a Biopharma 4.0 facility to enable the production of clinical and large-scale doses, ensuring a rapid and resilient supply of critical therapeutics. The results in this study especially highlight that the same machine and equipment can be used for screening and manufacturing different drug candidates in continuous operation. By streamlining production and adhering to quality standards, this approach enhances the industry's ability to respond swiftly to pandemics and public health emergencies, addressing the urgent need for accessible and effective vaccines.

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Section: Discussionmentioning

confidence: 90%

“…The kinetic parameters could be determined that are needed for DT-based process optimization and automation . The maximum reaction rate is 0.358 ± 0.001 μM/min for all nucleotides.…”

Section: Discussionmentioning

confidence: 99%

Digital Twin Fundamentals of mRNA In Vitro Transcription in Variable Scale Toward Autonomous Operation

Hengelbrock,

Schmidt,

Strube

2024

ACS Omega

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“…Continuous manufacturing of pharmaceuticals is regarded as a product quality improvement due to batch harmonization and the reduction in batch lot failures [ 31 ]. Therefore, it starts industrialization with a MIT/Novartis cooperation [ 32 ] on synthetic active pharmaceutical ingredients; many studies have been published recently, trying to transfer such activities into biologics manufacturing [ 34 , 35 , 36 , 37 , 38 , 39 ].…”

Section: Advanced Pharmaceutical Technologymentioning

confidence: 99%

Green Manufacturing for Herbal Remedies with Advanced Pharmaceutical Technology

et al. 2023

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Herbal remedies are in most cases still manufactured with traditional equipment installations and processes. Innovative chemical process engineering methods such as modeling and process intensification with green technology could contribute to the economic and ecologic future of those botanicals. The integration of modern unit operations such as water-based pressurized hot water extraction and inline measurement devices for process analytical technology approaches in traditional extraction processes is exemplified. The regulatory concept is based on the quality-by-design demand for autonomous feed-based recipe operation with the aid of digital twins within advanced process control. This may include real-time release testing to the automatic cleaning of validation issues. Digitalization and Industry 4.0 methods, including machine learning and artificial intelligence, are capable of keeping natural product extraction manufacturing and can contribute significantly to the future of human health.

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“…The multi-objective optimization challenges are methodologically approached with the aid of scalable Digital Twins [58,75]. Distinct in accuracy and precision, process models are validated in laboratory scale experiments [59,76], which are adapted to real-time phenomena of plant operation by sensors within PAT approaches [26,60] in order to predict optimal setpoints for process control which enables autonomous operation [58]. Though it is methodologically and interdisciplinarily complex, it has already verified with proofof-concept studies [71,[77][78][79][80][81].…”

Section: Process Developmentmentioning

confidence: 99%

“…This technology needs to have fast, flexible and modular facilities, and be feasibly operated autonomously, with minimal efforts from personnel [55,56]. Any engineering solution would need to be readily available [57][58][59][60], see Figure 8.…”

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confidence: 99%

Establishment of a Research Focus on Resilient Sustainable Climate Neutral Agricultural Production—Resilient Farming Initiative

et al. 2023

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Efficient and sustainable agricultural production is a pivotal factor in meeting the nutritional needs of an expanding global population. However, it is imperative to optimize national, regional and local effectiveness to support government initiatives towards climate neutrality and resilience, while simultaneously ensuring economic viability for farmers. A significant reduction in the cost of goods must be accompanied by a decrease in their global warming potential contribution to maintain competitiveness in the world market. As such, it is necessary to adopt practices that enhance productivity while minimizing environmental impacts. This paper discusses potential solutions for the sustainable enlargement of botanical product portfolios towards essential oil products and natural extracts for value-added products, such as natural pharmaceuticals, cosmetics, agrochemicals and materials by direct waste valorization. Contributions from the fields of automation and digitalization provide the basic technology for the realization of the approaches presented. Agricultural photovoltaics can contribute to the goal of the reduction of the cost of goods and global warming potential, such as the already established utilization of biogas. The potential of the research initiative described is demonstrated by basic data on key characteristic numbers and costs from the literature. The economic potential for climate neutrality and the reduction of global warming potential contribution is seen in magnitudes of factors 5–10. A research initiative is recommended and exemplified for the industrialization of such integrated processing.

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Digital Twins for Continuous Biologics Manufacturing

Cited by 7 publications

References 130 publications

Digital Twin Fundamentals of mRNA In Vitro Transcription in Variable Scale Toward Autonomous Operation

Digital Twin Fundamentals of mRNA In Vitro Transcription in Variable Scale Toward Autonomous Operation

Green Manufacturing for Herbal Remedies with Advanced Pharmaceutical Technology

Establishment of a Research Focus on Resilient Sustainable Climate Neutral Agricultural Production—Resilient Farming Initiative

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