Vaccines against sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are designed to elicit immune responses that prevent recipients from getting — or becoming seriously ill or dying from — novel coronavirus disease (COVID-19). Two available COVID-19 vaccines are based on genetically engineered messenger RNA (mRNA). After administration, such molecules give muscle cells “instructions” for how to make target proteins — e.g., the SARS-CoV-2 spike (S) protein. Immune-system detection of those proteins prompts creation of neutralizing antibodies. Immediately upon delivery of the instructions, mRNA is broken down. It never enters the nucleus, where a cell keeps its DNA.
Chinese biopharmaceutical company Walvax Biotechnology Co., Ltd., is helping to advance the global development of mRNA vaccines to fight current and future COVID strains. With Suzhou Abogen Biosciences, the company obtained regulatory approval in 2021 to conduct phase 3 clinical trials for its ARCoV mRNA vaccine in China, Indonesia, Mexico, and Nepal (1–4). The ARCoV candidate is one of several vaccines in Walvax’s portfolio, which also includes blood products and therapeutic proteins.
To realize its ambitions for the ARCoV vaccine product, Walvax initiated discussions with American manufacturing-technology supplier Honeywell to explore state-of-the-art automation and process-control solutions for a new production facility. The collaboration soon led to the construction of China’s first mRNA vaccine facility in Yuxi, a city in the central part of the Yunnan province. Situated over five floors, the Yuxi facility houses two manufacturing lines for mRNA-based vaccines and one line for vaccines based on adenovirus vectors. When the facility goes online late in 2022, it will have the capacity to produce enough bulk drug substance for 400 million vaccine doses per year.
Ensuring Safety, Quality, and Consistency
Honeywell and Walvax initially worked together to develop a pilot supervisory control and data acquisition (SCADA) system. Following the success of that effort, Walvax’s project engineering team, supported by Honeywell experts both on and off site, gradually began to implement Honeywell’s intelligent manufacturing technologies to enable digital operations at the facility.
Several automation technologies were implemented at the Yuxi site to ensure high product quality and safety, promote process consistency and reliability, and shorten timelines to commercial manufacturing. Experion batch-process control technology will play a critical role within the facility because it enables automation of all factory processes, such as those involving culture-media dispensers, bioreactor systems, and ultrafiltration/diafiltration (UF/DF) skids. Thus, each batch — from the simplest sequence to the most complex recipe — can be monitored and controlled efficiently. Furthermore, Experion batch processing technology combines distributed control, batch automation, and proprietary batch-visualization systems to optimize equipment availability, productivity, and reliability.
Honeywell also supplied Walvax with systems for building management, energy management, quality management, and manufacturing execution. Those systems came with appropriate servers and network equipment, input/output (I/O) modules, cybersecurity protection, and other such supports to meet good manufacturing practice (GMP) requirements and good automated manufacturing practice (GAMP 5) guidelines for computer-system verification (9). Dynamic-modeling tools and virtualized development environments (digital twins) were implemented to visualize production processes and assets.
To help ensure a smooth launch for the Yuxi site, Honeywell is providing Walvax with virtual- and augmented-reality technologies to enhance operator training. Other digital tools are being applied to facilitate site maintenance and bolster critical support functions such as management of production alarms and distributed control system (DCS) loops.
|Manufacturing Requirements for Production of mRNA Vaccines
The process for manufacturing mRNA vaccines follows the same overall pattern as that for monoclonal antibodies (MAbs) and other protein-based drugs, with steps for upstream production, downstream purification, formulation, fill–finish, and packaging. However, mRNA’s distinctive requirements can influence facility needs significantly.The nucleotide component of an mRNA-based vaccine can be synthesized in a chemical reactor or transcribed using a DNA template. A common approach is to perform in vitro transcription (IVT) of a linearized DNA template obtained from a bacterial plasmid (5). If developers use that strategy, then the mRNA manufacturing workflow typical involves• plasmid production and preparation — host cells (e.g., Escherichia coli) are fermented, harvested by centrifugation, and lysed; their plasmids are clarified, then linearized (5).• mRNA production — linearized plasmids undergo an IVT reaction in the presence of specified oligonucleotides, RNA polymerases, and reagents; special reagents sometimes are applied at this stage for 5′ capping and
3′ polyadenylation of the resulting mRNA strands (6).
• downstream processing — mRNA strands are concentrated, purified chromatographically, conditioned with a suitable buffer, and filtered for sterility.
• encapsulation — electrostatic interactions are leveraged to introduce purified mRNA into a lipid nanoparticle, lipid-like particle, or protein derivative (7).
• sterile filtration, formulation, and fill–finish.
Along with such complexities, a facility design must account for the small scale of mRNA production (relative to what can be achieved for MAbs) and the use of solvents and other chemicals that generally are not required for production of other biopharmaceuticals (8).
Benefits of Digital Technologies
“Open” technologies enable seamless integration with most modern equipment from all manufacturers. Walvax and Honeywell are leveraging a breadth of virtual and cloud-based solutions. Examples include industry-4.0–ready virtual-engineering sandboxes, virtual factory acceptance tests (FATs), virtualized control as a service, data-center configuration for remote management of installed assets, tools for remote collaboration, and remote control monitoring. Embedding end-to-end cybersecurity solutions from the outset of operations provides the best protection against unauthorized access to process and facility data.
“Lean” Implementation: A lean execution solution enhances automation-implementation services to decrease associated timelines and costs. Such benefits are reaped by leveraging standardized builds, parallel path development, and automated engineering transfer such that configuration is automatic, remote, and instantaneous (because setup does not require technicians to wait for last-minute design changes). For instance, technology developers can increase implementation efficiency and flexibility by delivering standardized equipment cabinets along with open tools for virtualization, cloud engineering, and automated device commissioning. Honeywell estimates that a large capital project can realize up to 30% capital savings in automation infrastructure and up to a 25% decrease in startup time simply by leveraging lean automation project execution (10).
Reduced Validation Effort: An easy and quick transition from recipe testing to execution reduces qualification efforts. Enhanced simulation reduces testing and qualification time while streamlining overall validation of a biomanufacturing process. Configurations can be tested in a digital twin and then uploaded to a production environment without needing to be changed or reassigned, moving control strategies into manufacturing effortlessly.
Batch Control: Batch execution using a process controller reduces the engineering effort needed to design, modify, and configure a system to perform without shutting down. Using a controller also decreases requirements for recipe maintenance through implementation of equipment-independent master recipes. Such features can help biomanufacturers to produce multiple vaccine products rapidly and cost-effectively.
Remote Autonomy: Using the industrial internet of things (IIoT), a vaccine manufacturer can consolidate data and move control to a centralized (local or remote) data center in a private cloud. The resulting digital twin of the control process makes possible offline testing of new recipes and qualification of changes to the automation system. Process controllers enable this capability.
Flexible I/Os: By decoupling data I/O units from a specific controller using a highly integrated virtualized environment, I/Os for each piece of process equipment can be connected to virtual data- center controllers. Such connectivity enables personnel to modify production processes remotely. A control system can assign controller power to any I/O as needed. That reduces the number of I/O units needed and helps a system to perform simply, efficiently, and flexibly. “Smart” assignment of control can be used in addition to universal I/O modules, which can be adjusted to a digital or analog configuration remotely and instantly without requiring changes or additions to equipment. That feature provides for late binding of automation strategy at the I/O and equipment levels.
Visualization technologies in batch systems can display current and future operations in intuitive ways and with timeline overviews. Operators can obtain insights into upcoming events and potential delays, making it easier for them to conduct multiple tasks simultaneously, take appropriate actions quickly, and adjust subsequent steps accordingly. Progressive workflow messaging and intuitive displays enable easy troubleshooting, helping users to anticipate and respond to process deviations and equipment failures.
Manufacturing Execution Interfaces: Integrating a manufacturing execution system (MES) and a process automation system brings activities such as weigh-and-dispense for buffer preparation into a unified process view. A universal adapter between the process automation and MES is critical to ensuring seamless interactions. A significant advantage of such integration is that recipe changes made using an automation system can be recorded automatically in a linked MES, significantly reducing revalidation effort.
Integrated Data: An integrated interface for data from across a business can leverage process automation and controls alongside artificial intelligence to visualize production processes and yield predictive insights into operations. Such a solution can help to minimize regulatory risks, increase operational efficiencies, and accelerate product delivery while reducing waste and incidence of batch failures. Integrated data platforms also support the transition to paperless operations.
Reaping the Benefits of Digitalization
Working with Honeywell has helped Walvax to enhance production conditions for its ARCoV vaccine against SARS-CoV-2. Walvax is proud to be contributing to digitalization of the wider vaccine industry. For Honeywell, the mRNA vaccine facility in Yuxi represents a key milestone in the company’s expanding reach within the life-sciences industry.
1 Ma J. Domestic Clinical Trials Planned for China’s mRNA COVID-19 Vaccine. South China Morning Post 22 July 2021; https://www.scmp.com/news/china/science/article/3142084/domestic-clinical-trials-planned-chinas-mrna-covid-19-vaccine.
2 Esposito A. Mexico to Start Late-Stage Clinical Trial for China’s mRNA COVID-19 Vaccine. Reuters 11 May 2021; https://www.reuters.com/business/healthcare-pharmaceuticals/mexico-start-phase-iii-clinical-trials-chinas-walvax-covid-vaccine-2021-05-11.
3 Pinghui Z. Indonesia, Mexico Approve Phase 3 Trials of Chinese mRNA Vaccine Hopeful. South China Morning Post 1 September 2021; https://www.scmp.com/news/china/science/article/3147168/coronavirus-indonesia-mexico-approve-late-stage-trials-chinese.
4 Babu J. Nepal Approves Late-Stage Trials for Chinese mRNA Vaccine Candidate. Reuters 27 August 2021; https://www.reuters.com/article/health-coronavirus-nepal-china-idCNL4N2PY3V7.
5 Whitford WG. mRNA Vaccine Production and Facility Design. Cell Culture Dish 21 January 2021; https://cellculturedish.com/mrna-vaccine-production-and-facility-design.
6 Beckert B, Masquida B. Synthesis of RNA By In Vitro Transcription. Meth. Molec. Biol. 703, 2011: 29–41; https://doi.org/10.1007/978-1-59745-248-9_3.
7 Hou X, et al. Lipid Nanoparticles for mRNA Delivery. Nature Rev. Materials 6, 2021: 1078–1094; https://doi.org/10.1038/s41578-021-00358-0.
8 Center A, et al. mRNA: Revisiting a Technology That Has Skyrocketed into Success. BioProcess Int. 19(4) 2021 (eBook); https://bioprocessintl.com/manufacturing/emerging-therapeutics-manufacturing/ebook-mrna-drug-products-revisiting-a-technology-that-has-rocketed-into-success.
9 Good Automated Manufacturing Practice 5: A Risk-Based Approach to Compliant GxP Computerized Systems. 1st edition. International Society for Pharmaceutical Engineering: North Bethesda, MD, 2008.
10 Hand A. Honeywell Makes LEAP in Project Execution. Automation World 5 June 2014; https://www.automationworld.com/home/blog/13311811/honeywell-makes-leap-in-project-execution.
Shawn Opatka is vice president and general manager of the life sciences division of Honeywell Process Solutions, 2101 Citywest Boulevard, Houston, TX 77048; 1-832-252-3500.