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 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.

Process analytical technology in continuous manufacturing of a commercial pharmaceutical product

2018 ◽  
Vol 538 (1-2) ◽  
pp. 167-178 ◽  
Author(s):  
Jenny M. Vargas ◽  
Sarah Nielsen ◽  
Vanessa Cárdenas ◽  
Anthony Gonzalez ◽  
Efrain Y. Aymat ◽  
...  
Keyword(s):  
Process Analytical Technology ◽  
Pharmaceutical Product ◽  
Continuous Manufacturing ◽  
Analytical Technology

scholarly journals Process Analytical Technology for continuous manufacturing of solid-dosage forms

2015 ◽  
Vol 67 ◽  
pp. 159-166 ◽  
Author(s):  
Margot Fonteyne ◽  
Jurgen Vercruysse ◽  
Fien De Leersnyder ◽  
Bernd Van Snick ◽  
Chris Vervaet ◽  
...  
Keyword(s):  
Process Analytical Technology ◽  
Dosage Forms ◽  
Continuous Manufacturing ◽  
Solid Dosage Forms ◽  
Solid Dosage ◽  
Analytical Technology

scholarly journals Enhanced Transport Capabilities via Nanotechnologies: Impacting Bioefficacy, Controlled Release Strategies, and Novel Chaperones

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Thomai Panagiotou ◽  
Robert J. Fisher
Keyword(s):  
Controlled Release ◽  
Process Analytical Technology ◽  
Critical Role ◽  
Process Intensification ◽  
Therapeutic Interventions ◽  
Continuous Manufacturing ◽  
Transfer Energy ◽  
Analytical Technology ◽  
The Brain

Emerging nanotechnologies have, and will continue to have, a major impact on the pharmaceutical industry. Their influence on a drug's life cycle, inception to delivery, is rapidly expanding. As the industry moves more aggressively toward continuous manufacturing modes, utilizing Process Analytical Technology (PAT) and Process Intensification (PI) concepts, the critical role of transport phenomena becomes elucidated. The ability to transfer energy, mass, and momentum with directed purposeful outcomes is a worthwhile endeavor in establishing higher production rates more economically. Furthermore, the ability to obtain desired drug properties, such as size, habit, and morphology, through novel manufacturing strategies permits unique formulation control for optimum delivery methodologies. Bottom-up processing to obtain nano-sized crystals is an excellent example. Formulation and delivery are intimately coupled in improving bio-efficacy at reduced loading and/or better controlled release capabilities, minimizing side affects and providing improved therapeutic interventions. Innovative nanotechnology applications, such as simultaneous targeting, imaging and delivery to tumors, are now possible through use of novel chaperones. Other examples include nanoparticles attachment to T-cells, release from novel hydrogel implants, and functionalized encapsulants. Difficult tasks such as drug delivery to the brain via the blood brain barrier and/or the cerebrospinal fluid are now easier to accomplish.

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.

Continuous Manufacturing of a Polymer Stabilized Emulsion Monitored with Process Analytical Technology

2020 ◽  
Vol 21 (5) ◽  
Author(s):  
Pernille Kjærgaard Qwist ◽  
Camilla Sander ◽  
Nils Bostijn ◽  
Vibeke Jessen ◽  
Jukka Rantanen ◽  
...  
Keyword(s):  
Process Analytical Technology ◽  
Continuous Manufacturing ◽  
Polymer Stabilized ◽  
Analytical Technology

scholarly journals Towards Autonomous Operation by Advanced Process Control—Process Analytical Technology for Continuous Biologics Antibody Manufacturing

Processes ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 172
Author(s):  
Heribert Helgers ◽  
Axel Schmidt ◽  
Lara Julia Lohmann ◽  
Florian Lukas Vetter ◽  
Alex Juckers ◽  
...  
Keyword(s):  
Process Control ◽  
Product Quality ◽  
Process Development ◽  
Process Analytical Technology ◽  
Control Process ◽  
Continuous Manufacturing ◽  
Two Phase ◽  
Advanced Process Control ◽  
Vis Spectroscopy ◽  
Analytical Technology

Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In the present study, the applicability of a combination of spectroscopic methods was evaluated to enable Advanced Process Control (APC) in continuous manufacturing by Process Analytical Technology (PAT). In upstream processing (USP) and aqueous two-phase extraction (ATPE), Raman-, Fourier-transformed infrared (FTIR), fluorescence- and ultraviolet/visible- (UV/Vis) spectroscopy have been successfully applied for titer and purity prediction. Raman spectroscopy was the most versatile and robust method in USP, ATPE, and precipitation and is therefore recommended as primary PAT. In later process stages, the combination of UV/Vis and fluorescence spectroscopy was able to overcome difficulties in titer and purity prediction induced by overlapping side component spectra. Based on the developed spectroscopic predictions, dynamic control of unit operations was demonstrated in sophisticated simulation studies. A PAT development workflow for holistic process development was proposed.

Process analytical technology for continuous manufacturing tableting processing: A case study

2019 ◽  
Vol 162 ◽  
pp. 101-111 ◽  
Author(s):  
Victoria Pauli ◽  
Yves Roggo ◽  
Laurent Pellegatti ◽  
Nhat Quang Nguyen Trung ◽  
Frantz Elbaz ◽  
...  
Keyword(s):  
Process Analytical Technology ◽  
Continuous Manufacturing ◽  
Analytical Technology

scholarly journals PAT for Continuous Chromatography Integrated into Continuous Manufacturing of Biologics towards Autonomous Operation

Processes ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 472
Author(s):  
Florian Lukas Vetter ◽  
Steffen Zobel-Roos ◽  
Jochen Strube
Keyword(s):  
Molecular Weight ◽  
Zero Point ◽  
Test System ◽  
Target Component ◽  
Array Detector ◽  
Continuous Manufacturing ◽  
Fluorescence Detector ◽  
Autonomous Operation ◽  
Side Component ◽  
Process Disturbances

This study proposes a reliable inline PAT concept for the simultaneous monitoring of different product components after chromatography. The feed for purification consisted of four main components, IgG monomer, dimer, and two lower molecular weight components of 4.4 kDa and 1 kDa molecular weight. The proposed measurement setup consists of a UV–VIS diode-array detector and a fluorescence detector. Applying this system, a R2 of 0.93 for the target component, a R2 of 0.67 for the dimer, a R2 of 0.91 for the first side component and a R2 of 0.93 for the second side component is achieved. Root mean square error for IgG monomer was 0.027 g/L, for dimer 0.0047 g/L, for side component 1 0.016 g/L and for the side component 2 0.014 g/L. The proposed measurement concept tracked component concentration reliably down to 0.05 g/L. Zero-point fluctuations were kept within a standard deviation of 0.018 g/L for samples with no IgG concentration but with side components present, allowing a reliable detection of the target component. The main reason inline concentration measurements have not been established yet, is the false-positive measurement of target components when side components are present. This problem was eliminated using the combination of fluorescence and UV–VIS data for the test system. The use of this measurement system is simulated for the test system, allowing an automatic fraction cut at 0.05 g/L. In this simulation a consistent yield of >99% was achieved. Process disturbances for processed feed volume, feed purity and feed IgG concentration can be compensated with this setup. Compared to a timed process control, yield can be increased by up to 12.5%, if unexpected process disturbances occur.

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