Abstract
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.
Highlights
The second major manufacturing step starts with the transcription of the spike protein encoding gene from the linearized DNA into mRNA, which is the key ingredient substance of the vaccine, and subsequent purification
The first process analytical technology (PAT) results should be followed by detailed investigation at different batches and processing steps in order to implement this strategy for process control and reliable efficient operation
Towards application of the existing digital twin for advanced process control (APC), the PAT study must be concluded in order to reduce off-line quality assurance (QA) testing and enable real time release testing (RTRT)
Summary
Vaccine supply for whole populations in a pandemic crisis has been known from the beginning as a dominating scientific, technical and organizational challenge for any society [1,2,3,4]. It is obvious that speed in time-to-market and sufficient capacities save wellbeing, lives and economic status [5,6]. Decisions need to be—as usual—data-driven and without compromise. To generate data and come to any broadly supported decision in society takes time, in any democracy. Comparing vaccine development to market pathways in different states, there are organizational government systems which function quite well and some which do not. The history of vaccine development [7,8,9,10]
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