Strategies to Boost Vaccines Manufacturing Capability

Although vaccine doses were rapidly manufactured, the shortage of vaccine manufacturing capacity was one of the bottlenecks for mass production. After the COVID-19 pandemic, several countries have addressed this challenge by developing plans to ensure available manufacturing capacity for future pandemics. Vaccines and nonvaccine manufacturing facilities must adapt to fulfill these plans. This article will evaluate different approaches to improve manufacturing capabilities. A detailed assessment of how vaccine platforms, equipment selection, and regulatory guidelines affect the manufacturing facility design was performed. Different strategies were identified and discussed. These strategies were to improve manufacturing facilities capacity, agility, and flexibility to produce drug products in non-pandemic periods or only vaccines during new infectious disease outbreaks.

BACKGROUND

For more than two centuries, vaccine development has been based on empirical research. Researchers elaborated vaccines by inoculating inactivated cultured microorganisms or purified pathogen components, which have often been combined with natural immunostimulants/adjuvants to enhance immune response1. Strategies for developing vaccines against infectious diseases have progressed significantly in the past couple of decades2. Traditional vaccines, such as inactivated or live attenuated, have shown protective efficacy against several viral infectious diseases but can be limiting for others3, 4. Newer recombinant protein vaccines/recombinant subunit prepared using non-pathogen-defined virus protein antigens have unlocked the potential to advance vaccines for unmet indications4.

During the COVID-19 worldwide pandemic, the vaccine industry responded swiftly to a global health emergency. A new type of vaccine, and associated successful clinical trials, was developed in less than a year; billions of vaccine doses were manufactured and distributed. The first efficient approved COVID-19 vaccines were based on messenger mRNA technology displaying the highest vaccine efficacy and effectiveness compared to adenovirus-based vaccines5, 6, 7, 8. Following years of research and technological development, this innovative type of vaccine was rapidly deployed during the pandemic. Nonetheless, rapid mass production was a challenge to meet worldwide demands. Although it is not unique to vaccines, the lack of capacity was one of the key bottlenecks delaying the swift response to this global pandemic8, 9.

Post-pandemic reviews on how to mitigate COVID-19 challenges have sparked reevaluation of critical public health emergency preparedness for infectious disease emergencies10. Valuable studies in the literature have shown the need to build vaccine capacity, laboratory and diagnostic system capacity, infection prevention and control capacity, financial investment in infrastructure, workforce readiness, and health system capacity10, and to improve vaccine supply chain resilience11. During the pandemic, many countries lacked the manufacturing capacity to mass-produce vaccines9, 10. Since then, several European Union countries, such as Germany, have adopted contract schemes to ensure that manufacturing capacity will be available for future pandemics28.

Vaccines and nonvaccine manufacturing facilities need to adapt to fulfill these government contracts. This article will evaluate different approaches to improve manufacturing capabilities. We will review how vaccine platforms, equipment selection, and regulatory guidelines can impact manufacturing facility design. We will propose different strategies to improve production capacity, improve flexibility, and increase readiness to de-risk vaccine production if new infectious disease epidemics arise.

VACCINE TECHNOLOGY PLATFORMS OVERVIEW

Vaccine manufacturing relies on different technology platforms developed for different types of vaccines2, 12. These vaccines are usually classified as live or non-live/“inactivated” to differentiate vaccines containing attenuated replicating pathogen from those containing only components or killed whole organisms (see Table 1). Several other vaccine platforms have been developed over the past few decades, including viral vectors-derived, nucleic-acid-based RNA and DNA (deoxyribonucleic acid) vaccines, and virus-like particles. In addition, vaccines designed on the pathogens’ antigenic component can be purified proteins from the microorganisms or recombinant proteins and polysaccharide conjugates. Toxoid vaccines are produced using the toxin’s protein purified from the cultivated pathogen inactivated by heat or chemicals (see Table 1).

These diverse types of licensed vaccines require a wide range of manufacturing knowledge and technology platforms that can impact the manufacturing facility’s operational efficiency and flexibility.

COMPARISON OF VACCINE MANUFACTURING PROCESS PLATFORMS

Biological-derived vaccine complex manufacturing processes can be divided into several phases including upstream and downstream (see Figure 1). Upstream manufacturing activities encompass the expansion of mammalian, bacteria, or insect cell lines. Then, either the active substance production is induced, or virus infection occurs. Finally, the active substance or propagated virus produced are harvested. An additional chemical or heat inactivation step is required for live, non-live virus and toxoid vaccines. Downstream operations usually entail chromatography purification of the active substance/specific virus followed by various diafiltration, filtration, and concentration steps. Then, the vaccine is formulated, and a final filtration is performed before vial or syringe fill and sterilization.

For these types of biological-derived vaccines, the manufacturing facility needs to be designed to accommodate the type of organism used to produce the vaccines. If the organism is genetically modified, the potential infectious risks associated with manufacturing must be mitigated appropriately (see Figure 1) through suitable biosafety containment level boundaries in the facility’s design layout. This includes appropriate waste treatment before leaving the biosafety containment zone in accordance with regulatory agencies and local and country regulations.

Regarding nonbiological-derived vaccines such as mRNA vaccines, the unit operations encompass enzymatic reactions to produce mRNAs from plasmid DNA blueprint, chromatography purification steps, encapsulation of mRNAs into lipid nanoparticles (LNPs), purification of mRNAs-LNP complexes, final filtration, and fill and finish steps (see Figure 1). No cells or genetically modified organisms are used to manufacture this type of vaccine from the DNA blueprint starting material. Because mRNA vaccine purification steps may need highly flammable substances such as ethanol, the facility design should incorporate ATEX regulations (ATEX EU directives 114 and 15313, 14 and local and country safety standards.

Also, both biological-derived and nonbiological-derived vaccines facility design needs to comply with GMP local and country regulations. Although mRNA vaccines are potent in their immunological effect and protect against disease, they are typically administered in relatively large doses. This is not characteristic of what would be considered a highly potent drug in a pharmacological sense compared with “high-potency drugs,” such as some chemotherapy agents or hormones. No carcinogenic, mutagenic, and toxicity to reproduction effects have been reported for commercial mRNA vaccines and they are not considered hazardous medicinal products (EudraLex regulations (EC) No 1272/200815).

HEALTH AND SAFETY: CONTAINMENT AND REGULATORY COMPLIANCE

In theory, vaccine production platform technologies offer the possibility to produce multiple vaccine products against different pathogens. Although vaccine regulation may require segregation of vaccine production, if the manufacturing process and technology are similar, production of different vaccines in a campaign mode, following GMP guidelines, would allow time segregation, complying with regulations post–World Health Organization (WHO) approval for certain licensed vaccines.

Local and national health and safety regulations should be applied to ensure safe handling of pathogens, biological materials, and genetically modified organisms. To minimize the risk of pathogen release outside the facility that produces and stores the vaccines, appropriate containment boundary and biosecurity measures should be put in place. Careful consideration should be given to define the primary containment barrier—choice of process equipment used to manufacture the vaccines and the secondary containment—facility architectural design including the heating, ventilation, and air conditioning systems. Also, process waste, either dry or liquid, needs to be inactivated before it leaves the bio-containment boundaries. Dry waste is usually heat inactivated by autoclaving and liquid waste is inactivated using heat or chemical inactivation systems.

In some cases, quality, safety, and efficacy of licensed vaccines production might require dedicated facilities to adhere to regulatory guidelines and WHO recommendations (i.e., BCG vaccine). For example, it would be unlikely for a multivaccine facility to concomitantly produce live attenuated replicating pathogens and toxoid vaccines in unsegregated cleanrooms. Furthermore, depending on the type of organisms or cell lines used to produce different vaccines (i.e., mammalian cells, bacterial cells, yeast, insect cells, chicken embryos), manufacturing unit operations would require physical segregation in a multivaccine facility. Indeed, it is recommended to separate viral-based vaccines (i.e., attenuated, killed, nonreplicating virus vaccines), toxoid vaccines, protein-based vaccines, and nucleic-acid-based vaccine production to control cross-contamination, minimize bioburden, follow containment regulations, and reduce human exposure. The different types of vaccines planned to be concomitantly manufactured will impact the facility design to fulfill regulatory and health and safety regulations.

STRATEGIES TO IMPROVE VACCINE MANUFACTURING CAPACITY, FLEXIBILITY, AND PANDEMIC READINESS

Vaccine Process Platform Selection

In principle, vaccine production platform technologies offer the possibility to produce multiple vaccines against different pathogens. Compared with conventional pathogen-specific production mode, these platforms share similar production process, raw materials, personnel training, and facility requirements, which will significantly increase vaccine manufacturing capacity. In addition, upstream and downstream manufacturing process units can be similar to produce not only different vaccines but also nonvaccine therapeutic products. Therefore, the same production equipment and cleanroom lines can be used alternatively to manufacture different types of products in a campaign mode. This greatly increases the manufacturing facility flexibility and lets the facility scale up one type of vaccine production during a pandemic.

The manufacturing equipment employed on the different platforms can be either single-use or stainless steel. Weighing the two options for agility, sustainability, scale, and costs is crucial for defining what type of vaccines and therapeutic products each facility can produce (see Table 2)16, 17.

Stainless steel plants are custom-built and designed to produce a specific type of vaccine, with fixed unit operations that cannot be easily modified for different manufacturing processes. As a result, stainless steel facility vaccines production flexibility is extremely limited. Also, protein physisorption and irreversible chemisorption to stainless steel equipment surfaces is well established; they require regular stringent cleaning. Using stainless steel equipment can lower production efficiency and increase operational costs 18, 19.

A study reported that deploying single-use equipment decreases the facility footprint by 38%, headcount labor requirements by 21%, water usage by 87%, and energy consumed by 30% compared with a traditional stainless-steel facility20. Single-use equipment can give a multiproduct facility operational flexibility and efficiency (see Table 2). Reconfiguration of the cleanroom unit operation for different product process platforms is rapid. New process technologies can be implemented quickly. Single-use technology components come presterilized, which reduces changeover time between products and drastically decreases the risk of cross-contamination. This is because there is never a contact between the product and the equipment.

Single-use equipment increases operational agility and allows rapid scale-up and customization for a specific product. Additionally, using a continuous manufacturing (CM) production method can significantly increase the facility’s manufacturing efficiency and capability. Compared with traditional batch production, CM requires smaller equipment, which reduces facility footprint, reduces energy needs, decreases single-use dry waste volume, and reduces overall environmental impact. Contaminated single-use plastic waste can be incinerated to produce power and thermal energy. Because single-use equipment does not require clean-in-place activities during changeover and cleaning validation, water and energy consumption as well as waste treatment are significantly reduced. This decreases the facility operational costs and environmental impact substantially16, 20.

Single-Use Equipment Selection

ISPE’s Good Practice Guide: Single-Use Technology29 provides a roadmap for efficiently adopting single-use equipment with minimum disruptions to existing operations. A key advantage of single-use equipment is its flexibility; it can be used by different process manufacturing platforms. Indeed, bioreactors/reactors, mixers, chromatography, and tangential flow filtration systems can be used alternatively for the manufacturing of different types of vaccine, monoclonal antibodies (mAbs), and recombinant therapeutic proteins (see Table 3). Bioreactors’ and fermenters’ unit structure is modular, even for 2000-L-scale (i.e., separate vessel, human–machine interface controller, and temperature control unit) and enables flexible setups and optimized cleanroom footprints. Owing to single-use units’ mobility and simple setup, product-specific process platforms can be easily deployed as needed in cleanrooms, which will make the manufacturing facility more agile and flexible.

SMART MANUFACTURING IMPLEMENTATION

Optimization of vaccine production can be achieved by integrating technologies such as automation, sensors, robotics, and artificial intelligence (AI). Autonomous mobile robots can travel along digital pathways to deliver ingredients and equipment. Automation of repetitive tasks (i.e., picking, placing, mixing, and handling solutions) by deploying cobots (collaborative robots working with humans) can further improve manufacturing quality and performance and can eliminate human error in sterile environments21, 22, 23.

Closed-loop AI-based control systems—in which AI analyzes data from process equipment sensors in real time—can monitor manufacturing continuously and optimize the process without human intervention24, 25, 26. Manufacturing operations can autonomously adapt and optimize, ensuring vaccine production efficiency. By using real-time data from equipment sensors, high-fidelity digital twin-process simulations can let staff control the process outside the cleanroom and identify problems before they occur. Materials can be tracked, bottlenecks can be removed, and tasks can be optimized to improve manufacturing performance23.

Facility Design to Enhance Vaccines Production Capacity

Designing flexible multiproduct cleanrooms is key for improving overall production capacity for vaccines and medicines and for decreasing manufacturing costs. The design must comply with and incorporate environmental, health, safety, and country regulations. Basic design requirements usually include the GMP production area and quality control laboratory plus the clean utilities, the warehouse (i.e., raw material, consumables, and products), the central utilities with non-GMP utilities, and the administration areas.

Vaccine Facility Adjacency Diagram

An adjacency diagram is generally used to identify critical functional relationships among GMP production process activities. These diagrams help plan how to position spaces for different manufacturing processes in relation to one another. Figure 2A illustrates an adjacency diagram for one production line in a multiproduct vaccines’ facility. Facilities must be designed to support the intended production requirements. Unit operations must be placed in the appropriate area classifications, and a strategy must be established for people and materials to enter and exit these areas. To maintain the integrity of environmental classified areas and isolate product-specific operations, appropriate transition spaces will need to be implemented.

VACCINES FACILITY LAYOUT DESIGN

Facility designs and engineering controls must meet current GMP principles, regulatory agency requirements, and industry best practices for transitions into and out of various classified and controlled environments. Based on the adjacency diagram, a GMP facility layout can be developed to accommodate multiproduct manufacturing processes by adding manufacturing line modules as needed (Figure 2B).

Air locks are used to balance air pressure between areas dedicated to manufacturing different products; to establish a barrier zone (i.e., “bubble” or “sink”) when containment is required; and to provide a controlled environment for transferring materials (material airlocks [MALs]) or the transition or gowning of personnel between classified areas (personnel airlocks [PALs]). Areas of operation must be adequately separated, and people and materials must move in one direction to prevent cross-contamination as different products are manufactured concurrently.

For all sterile and aseptic facilities, the flow of people and material between product suites must be controlled to prevent contamination (e.g., environment-to-product, personnel-to-product), cross-contamination (multiproduct) and to ease the manufacturing process flow. Physical segregation between unit operations and minimizing the direct interaction between people and material at different gowning and cleanliness levels and from different production suites helps prevent contamination.

It is recommended to use a facility modular design approach based on the option to produce either concomitantly different vaccines and nonvaccine products or use the entire facility to produce one type of vaccine during a pandemic. Independent media and buffer preparation cleanrooms, and a central temperature-controlled storage area can support several production lines. By centralizing the preparation and holding of media and buffers, facilities can optimize resource use, streamline workflows, and enhance their operations’ overall quality and consistency.

Product transfer between cleanrooms though aseptic transfer ports will allow integrated CM from upstream to downstream operations using single-use equipment. To add flexibility, utilities can be arranged in a generic grid pattern in ceiling panels (i.e., power, gases, data). This includes spare plug-in slots for adding utilities. This will let cleanroom setups adapt to specific types of equipment for different manufacturing processes without interrupting operations. Designing flexible and modular vaccine facilities that are fully digitalized will let facilities respond nimbly and manufacture multiple vaccines and medicines concurrently. It will also allow for the rapid scale-up of vaccine production during pandemics by using the entire manufacturing cleanroom suites.

CONCLUSION

The WHO’s recent adoption of the first international pandemic agreement to improve prevention, preparedness, and response to future pandemics sets out the principles, strategies, and tools to address shortcomings highlighted by the COVID-19 pandemic. This promotes equitable access to vaccines and medical resources, improving coordination and financial mobilization for health emergencies, creating a more resilient and equitable global health framework, increasing the resilience of health workforces and systems, and supporting capacity building for countries in need27. It implies that governments must build regional manufacturing, streamline regulation, and invest in sustainable funding. Resilience of manufacturing pandemic vaccines and health products requires more manufacturing capacity9. Indeed, a focus on improving vaccine manufacturing flexibility, adaptability, and efficiency will help rapidly increase production capabilities and reduce costs.

Strategies to improve manufacturing agility include deploying vaccine platforms, mobile standard single-use process units, and modular facility design. Embracing smart manufacturing, by leveraging advanced technologies and data analytics, will enable real-time process monitoring, analysis, autonomous decision-making, and optimization. This will lead to higher efficiency and operational excellence. Multiproduct facility design approach will let the industry manufacture different vaccines and medicinal products. It will also enable rapid scale-up to increase overall vaccine production capacity during a pandemic.