scholarly journals Digital Twin of mRNA-Based SARS-COVID-19 Vaccine Manufacturing towards Autonomous Operation for Improvements in Speed, Scale, Robustness, Flexibility and Real-Time Release Testing

Processes ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 748
Author(s):  
Axel Schmidt ◽  
Heribert Helgers ◽  
Florian Lukas Vetter ◽  
Alex Juckers ◽  
Jochen Strube
Keyword(s):  
Process Analytical Technology ◽  
Reversed Phase ◽  
Efficient Operation ◽  
Messenger Ribonucleic Acid ◽  
Digital Twin ◽  
Manufacturing Operations ◽  
Autonomous Operation ◽  
Qualified Personnel ◽  
Readiness Level ◽  
Analytical Technology

Supplying SARS-COVID-19 vaccines in quantities to meet global demand has a bottleneck in manufacturing capacity. Assessment of existing mRNA (messenger ribonucleic acid) vaccine processing shows the need for digital twins enabled by process analytical technology approaches to improve process transfers for manufacturing capacity multiplication, reduction of out-of-specification batch failures, qualified personnel training for faster validation and efficient operation, optimal utilization of scarce buffers and chemicals, and faster product release. A digital twin of the total pDNA (plasmid deoxyribonucleic acid) to mRNA process is proposed. In addition, a first feasibility of multisensory process analytical technology (PAT) is shown. Process performance characteristics are derived as results and evaluated regarding manufacturing technology bottlenecks. Potential improvements could be pointed out such as dilution reduction in lysis, and potential reduction of necessary chromatography steps. 1 g pDNA may lead to about 30 g mRNA. This shifts the bottleneck towards the mRNA processing step, which points out co-transcriptional capping as a preferred option to reduce the number of purification steps. Purity demands are fulfilled by a combination of mixed-mode and reversed-phase chromatography as established unit operations on a higher industrial readiness level than e.g., precipitation and ethanol-chloroform extraction. As a final step, lyophilization was chosen for stability, storage and transportation logistics. Alternative process units like UF/DF (ultra-/diafiltration) integration would allow the adjustment of final concentration and buffer composition before lipid-nano particle (LNP) formulation. The complete digital twin is proposed for further validation in manufacturing scale and utilization in process optimization and manufacturing operations. The first PAT results should be followed by detailed investigation of different batches and processing steps in order to implement this strategy for process control and reliable, efficient operation.

scholarly journals Fast and Flexible mRNA Vaccine Manufacturing as a Solution to Pandemic Situations by Adopting Chemical Engineering Good Practice—Continuous Autonomous Operation in Stainless Steel Equipment Concepts

Processes ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1874
Author(s):  
Axel Schmidt ◽  
Heribert Helgers ◽  
Florian Lukas Vetter ◽  
Alex Juckers ◽  
Jochen Strube
Keyword(s):  
Stainless Steel ◽  
Chemical Engineering ◽  
Process Analytical Technology ◽  
Good Practice ◽  
Operation Mode ◽  
Continuous Manufacturing ◽  
Efficient Operation ◽  
Messenger Ribonucleic Acid ◽  
Autonomous Operation ◽  
Analytical Technology

SARS-COVID-19 vaccine supply for the total worldwide population has a bottleneck in manufacturing capacity. Assessment of existing messenger ribonucleic acid (mRNA) vaccine processing shows a need for digital twins enabled by process analytical technology approaches in order to improve process transfer for manufacturing capacity multiplication, a reduction in out-of-specification batch failures, qualified personal training for faster validation and efficient operation, optimal utilization of scarce buffers and chemicals and speed-up of product release by continuous manufacturing. In this work, three manufacturing concepts for mRNA-based vaccines are evaluated: Batch, full-continuous and semi-continuous. Technical transfer from batch single-use to semi-continuous stainless-steel, i.e., plasmid deoxyribonucleic acid (pDNA) in batch and mRNA in continuous operation mode, is recommended, in order to gain: faster plant commissioning and start-up times of about 8–12 months and a rise in dose number by a factor of about 30 per year, with almost identical efforts in capital expenditures (CAPEX) and personnel resources, which are the dominant bottlenecks at the moment, at about 25% lower operating expenses (OPEX). Consumables are also reduceable by a factor of 6 as outcome of this study. Further optimization potential is seen at consequent digital twin and PAT (Process Analytical Technology) concept integration as key-enabling technologies towards autonomous operation including real-time release-testing.

scholarly journals Process Analytical Technology for Precipitation Process Integration into Biologics Manufacturing towards Autonomous Operation—mAb Case Study

Processes ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 488
Author(s):  
Lara Julia Lohmann ◽  
Jochen Strube
Keyword(s):  
Process Control ◽  
Real Time ◽  
Process Analytical Technology ◽  
Measurement Techniques ◽  
Array Detector ◽  
Precipitation Process ◽  
Suitable Model ◽  
Process Data ◽  
Autonomous Operation ◽  
Analytical Technology

The integration of real time release testing into an advanced process control (APC) concept in combination with digital twins accelerates the process towards autonomous operation. In order to implement this, on the one hand, measurement technology is required that is capable of measuring relevant process data online, and on the other hand, a suitable model must be available to calculate new process parameters from this data, which are then used for process control. Therefore, the feasibility of online measurement techniques including Raman-spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), diode array detector (DAD) and fluorescence is demonstrated within the framework of the process analytical technology (PAT) initiative. The best result is achieved by Raman, which reliably detected mAb concentration (R2 of 0.93) and purity (R2 of 0.85) in real time, followed by DAD. Furthermore, the combination of DAD and Raman has been investigated, which provides a promising extension due to the orthogonal measurement methods and higher process robustness. The combination led to a prediction for concentration with a R2 of 0.90 ± 3.9% and for purity of 0.72 ± 4.9%. These data are used to run simulation studies to show the feasibility of process control with a suitable digital twin within the APC concept.

scholarly journals Digital Twin for Lyophilization by Process Modeling in Manufacturing of Biologics

Processes ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 1325
Author(s):  
Leon S. Klepzig ◽  
Alex Juckers ◽  
Petra Knerr ◽  
Frank Harms ◽  
Jochen Strube
Keyword(s):  
Process Design ◽  
Process Model ◽  
Process Analytical Technology ◽  
Downstream Processing ◽  
Pilot Scale ◽  
Digital Twin ◽  
Physical Chemical ◽  
Optimization And Control ◽  
And Control ◽  
Analytical Technology

Lyophilization stabilizes formulated biologics for storage, transport and application to patients. In process design and operation it is the link between downstream processing and with final formulation to fill and finish. Recent activities in Quality by Design (QbD) have resulted in approaches by regulatory authorities and the need to include Process Analytical Technology (PAT) tools. An approach is outlined to validate a predictive physical-chemical (rigorous) lyophilization process model to act quantitatively as a digital twin in order to allow accelerated process design by modeling and to further-on develop autonomous process optimization and control towards real time release testing. Antibody manufacturing is chosen as a typical example for actual biologics needs. Literature is reviewed and the presented procedure is exemplified to quantitatively and consistently validate the physical-chemical process model with aid of an experimental statistical DOE (design of experiments) in pilot scale.

scholarly journals Exploiting Fluorescent Reporter Molecules for Process Analytical Technology (PAT)

2009 ◽  
Vol 63 (3) ◽  
pp. 171-173 ◽  
Author(s):  
Tobias Broger ◽  
Res P. Odermatt ◽  
Pablo Ledergerber ◽  
Bernhard Sonnleitner
Keyword(s):  
Process Analytical Technology ◽  
Fluorescent Reporter ◽  
Analytical Technology

Process analytical technology for bakery industry: A review

2019 ◽  
Vol 42 (5) ◽  
Author(s):  
Rifna E. Jerome ◽  
Sushil K. Singh ◽  
Madhuresh Dwivedi
Keyword(s):  
Process Analytical Technology ◽  
Bakery Industry ◽  
Analytical Technology
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