Vaccine manufacturing: Introduction to the process from development to large-scale production

Vaccine manufacturing is a complex journey, merging scientific breakthroughs with global necessity. From the identification of antigens to large-scale production and the use of cutting-edge solutions, this journey reflects the continuous pursuit of creating effective vaccines for a healthier world.

Vaccines rank among the most cost-effective health interventions against pathogens and infectious diseases, annually saving millions of lives. However, growing global demand presents significant challenges for vaccine manufacturers. As the array of new vaccine types and manufacturing methods expands, the establishment of robust processes that could enhance overall efficacy, safety, and cost-effectiveness is hindered.

Efficient production, marked by flexibility and easy scalability, becomes increasingly crucial. In this article, we will give an introduction to vaccine manufacturing, the stages from development to large-scale production, explore challenges faced by manufacturers, and examine potential solutions and future prospects.

What is vaccine manufacturing?

Vaccine manufacturing is the complex and highly regulated process of producing vaccines, which are biological products designed to stimulate the immune system and provide protection against specific diseases. Vaccine development involves several stages, including vaccine research and development, production of raw materials, formulation, and quality control.

Read more: What is meant by vaccine production? | Steps in vaccine manufacturing

Vaccine development

Vaccine development begins at a small-volume stage – with the identification of antigens, where scientists select the key components that will trigger an immune response. The subsequent stage involves pre-clinical research, where the chosen antigens undergo extensive testing to ensure safety and efficacy.

Clinical trials assess vaccine performance in humans, focusing on immune response and vaccine safety. Regulatory bodies such as the Food and Drug Association (FDA), the European Medicines Agency (EMA) with its Committee for Medicinal Products for Human Use (CHMP), and World Health Organization (WHO) closely scrutinize these trials before granting approval, emphasizing the stringent processes in place to guarantee the production of high-quality vaccines.

Collaborations and partnerships between developers, research institutions, and 
regulatory authorities streamline the development pipeline. These alliances enhance efficiency and uphold global regulatory standards, contributing to collective efforts in achieving immunization goals.

The overarching goal is to address the urgent health needs. A prominent example was the development of COVID-19 vaccines in the fight against infectious diseases. These groundbreaking efforts showcase the intersection of scientific innovation, regulatory compliance, and global collaboration in the pursuit of creating effective vaccines that can withstand the demands of public health emergencies.¹ 

Vaccine production

Vaccine production commences with the implementation of various manufacturing techniques, including cell culture, recombinant methods, viral vectors, and RNA-based approaches. The need for respective techniques depends on the vaccine type that is to be produced: The more complex the product, the more elaborate are the processes involved.²

This distinction becomes important when deciding whether to establish a production line for small-molecule or large-molecule vaccines, the latter of which require far more precise solutions, e.g. in cold chain management, due to their increased sensibility.² 

Manufacturing processes involved

The heart of vaccine production lies in diverse manufacturing techniques and processes, each playing a crucial role.

• Cell culture methods involve cultivating cells to generate the necessary components for the vaccine.
• Recombinant techniques utilize genetic engineering to produce specific proteins, contributing to the vaccine's effectiveness.
• Viral vector methods and RNA-based approaches harness cutting-edge technologies to create vaccines with unique mechanisms of action.

Large-scale production

Moving beyond the confines of the laboratory, large-scale production marks a significant phase in vaccine manufacturing. Scaling up vaccine production and increasing manufacturing capacity to meet global demand requires intense planning and execution.

This phase ensures that the developed vaccines transition seamlessly from small-scale prototypes to mass-produced, high-quality immunization solutions.

The confluence of the different manufacturing techniques enables the creation of diverse vaccines that cater to various diseases and health challenges. The commitment to large-scale production reflects the collective dedication to making vaccines widely accessible for the betterment of global public health.

Vaccine manufacturing companies

Vaccine manufacturing companies, including prominent players like Pfizer, Moderna, and AstraZeneca, alongside innovative biopharmaceutical firms such as Novavax, have assumed a crucial role in global public health.

Many of these manufacturers gained prominence, experiencing significant turnovers, particularly due to their contributions during the COVID-19 pandemic. Leveraging advanced technologies and collaborating extensively, these companies drive the development, production, and distribution of vaccines.³

Top 10 vaccine manufacturing companies by turnover 2021:

• Pfizer
• BioNTech
• Sinovac
• Moderna
• Merck
• GSK
• Sanofi 
• Zhifei
• AstraZeneca
• Johnson & Johnson

Source: ³ 

Vaccine platforms

Just as there are multiple pathogens, each demanding a tailored approach, diverse vaccine technologies come into play for effective immunization. Depending on the targeted pathogen—be it a bacteria or virus—various vaccine platforms are harnessed to stimulate a potent immune response.

From traditional methods like live attenuated and inactivated vaccines to cutting-edge advancements like mRNA vaccines, the arsenal of vaccine platforms continues to expand, and can be divided into small molecule vaccines and the more complex and sensitive large molecule vaccines, requiring more elaborate cold chain management:

Small molecule vaccine technology platforms:

• Live Attenuated Vaccines: Utilizing weakened forms of the pathogen to induce a robust immune response.
• Inactivated Vaccines: Employing killed pathogens to stimulate an immune response without causing illness.
• Toxoid Vaccines: Using inactivated toxins to generate an immune response, particularly effective against bacterial diseases.

Large molecule vaccine technology platforms:

• Subunit Vaccines: Focusing on specific components of the pathogen to elicit a targeted immune response.
• mRNA Vaccines: Leveraging genetic material to instruct cells to produce antigens, prompting an adaptive immune response.
• Virus-Like Particle Based Vaccines: Mimicking the structure of viruses without the genetic material, inducing an immune response.
• Viral Vector Vaccines: Harnessing other viruses as vectors to deliver genetic material, stimulating an immune response against the target pathogen.

Sources: ^4 5 

History of vaccine manufacturing

The history of vaccine manufacturing reflects a journey from ancient variolation practices to modern breakthroughs. In the 19th century, Edward Jenner's pioneering smallpox vaccine marked a turning point, laying the foundation for systematic vaccine development. Louis Pasteur extended this paradigm with the first rabies vaccine in 1885.

The 20th century witnessed mass vaccine production, enabling global immunization efforts. A significant triumph occurred in 1980 with the eradication of smallpox, showcasing the profound impact of global vaccine supply on public health.

The 1980s brought forth recombinant DNA technology, allowing precise manipulation of antigens. In the 21st century, mRNA vaccines emerged as a game-changer, exemplified by their response to the COVID-19 pandemic.

In this historical journey is the collaborative effort to combat specific diseases such as polio, addressing challenges faced by diverse populations, including those in African countries and China. The continuous evolution, from traditional vaccines to innovative solutions like the influenza vaccine, demonstrates the resilience and adaptability of vaccine manufacturing in safeguarding global health and reducing hospitalization rates.

Read more: How were vaccines developed in the past? | Benefits of vaccine production

Source: ⁶ 

Challenges in vaccine development and manufacturing

A considerable challenge in vaccine manufacturing comes with the adequate handling of different substances. The individual components need to be cultivated, stored and processed with high accuracy and under sterile conditions in order to provide patients with safe and effective vaccine products, which have to be dealt with equally carefully.

Another critical factor in vaccine development and manufacturing are the associated costs, spanning from research and development in laboratories to large scale manufacturing and subsequent distribution. Balancing the financial aspects while maintaining affordable vaccine accessibility poses a continuous challenge.⁷ 

Efficiency

In order to limit both costs and time expenses involved in vaccine development and manufacturing, process efficiency is key. Streamlining production processes, minimizing wastage, and optimizing resource utilization contribute to addressing this challenge. Additionally, efforts have to be taken to enhance product viability and avoid product loss, as this can be bound to delays and considerable costs. However, enhancing efficiency not only impacts the cost-effectiveness of vaccine manufacturing but also ensures a more sustainable and scalable approach.

Cold Chain Challenges

From the initial stages of development in laboratories to the final distribution, maintaining an unbroken cold chain is crucial. Cold chain challenges encompass the need for consistent temperature control, especially for vaccines that are sensitive to temperature variations, such as mRNA vaccines Maintaining product viability is of utmost importance and, especially when dealing with large molecules, demands dedicated manufacturing solutions.

The transition from research and development settings to large-scale manufacturing facilities and eventual distribution to diverse geographical locations introduces complexities in sustaining the required cold chain conditions.

Innovation in cold chain solutions, such as advanced plate freezing technologies, safe and flexible ultra-cold storage solutions and temperature-monitoring systems, becomes imperative. As an expert in the field of fluid management Single Use Support is supplying vaccine manufacturers from laboratory heads to process managers with solutions for a seamless cold chain management.

cGMP regulations in vaccine production

Good Manufacturing Practice (GMP) and Current Good Manufacturing Practice (cGMP) regulations serve as a cornerstone to ensure the safety, quality, and consistency of vaccine manufacturing processes. These regulatory requirements, set by the FDA, establish a comprehensive framework that vaccine manufacturers must adhere to during every stage of production.

The cGMP regulations for vaccine manufacturing encompass various facets, including facility design, equipment validation, personnel training, and documentation practices. These guidelines are designed to minimize the risks of contamination or quality deviations during vaccine production, ensuring that each batch meets the required specifications and is safe for public consumption.⁸ 

Solutions for efficient vaccine manufacturing

Enhancing efficiency in vaccine manufacturing is a critical goal that involves addressing challenges in various stages of the production and distribution process. Several innovative solutions contribute to making the fluid management process of vaccines more efficient whilst ensuring their quality.

Cold chain solutions

Maintaining the integrity of vaccines during storage and transportation is an important aspect of the cold chain. Implementing advanced cold chain solutions for vaccine development involves employing cutting-edge freeze-thaw technologies, ultra low temperature storage and temperature-monitoring systems. These solutions based on single-use technologies play a crucial role in preventing inadequate cooling that could compromise the efficacy of vaccines, especially those sensitive to environmental conditions.

Single Use Support takes the individual fluid management spectrum in vaccine manufacturing into consideration to provide tailored end-to-end solutions ranging from automated filling into single-use bags to freezing with plate freezers. Notably, the plate-based freezing technology employed by Single Use Support is a flagship solution in terms of the quality of the freezing and thawing process. Covered in single-use shells, the single-use bioprocess containers undergo rapid and controlled rate freezing. The controlled freezing rates based on product characteristics prevents unwanted effects that potentially reduces product viability, such as cryoconcentration or crystallization.

Ultra low temperature storage of vaccines

To further enhance the preservation of frozen substances, Single Use Support’s solution for ultra low temperature storage of vaccines, RoSS.FRDG, comes into play. This solution allows precise temperature control during storage and transportation.

Such modular innovative storage solutions have emerged as a game-changer in the production and supply chain of vaccines as well as raw materials for vaccine production. Vaccines, especially those utilizing advanced technologies like mRNA, often require storage at extremely low temperatures. Ultra-low temperature storage solutions provide a reliable and efficient means of preserving the potency of these vaccines, ensuring they remain viable during production, distribution and administration, without the need to build large walk-in freezers.

Single-use technologies in vaccine manufacturing

The adoption of single-use technologies in vaccine manufacturing offers notable advantages. This approach replaces traditional stainless-steel equipment with disposable components, streamlining the manufacturing process and reducing the risk of cross-contamination.

Single-use technologies enhance flexibility, scalability, and efficiency in vaccine production, allowing for more rapid production scale-up and responsiveness to evolving demands. Additionally, they allow manufacturers to maintain crucial parameters along different scales in production, e.g. the freezing curve that had been established at lab scale and has to be mimicked at larger scales.

Furthermore, in environments where production lines change regularly, or multiple production processes run in parallel, single-use systems provide a versatile platform that can be efficiently adopted to varying requirements.

These solutions collectively contribute to efficient vaccine manufacturing by addressing logistical challenges, optimizing storage conditions, and streamlining production processes. Operating on single-use technology, all the fluid management solutions from Single Use Support facilitate flexible and scalable handling of vaccines—from laboratory development to large-scale production.

Novel methods & trends in vaccine production

The landscape of vaccine production is continually evolving, with emerging technologies driving innovation. Novel vaccine manufacturing methods such as recombinant DNA technology, mRNA vaccines, and viral vector methods are at the forefront. These technologies open new possibilities for creating vaccines with enhanced efficacy and less side effects.

The future of vaccine manufacturing involves envisioning a landscape characterized by increased collaboration, streamlined processes, and broader accessibility. A shift towards increased utilization of single-use technologies brings notable advantages, encompassing manufacturing efficiency, contamination safety, and enhanced scalability and flexibility based on demand.

Future trends in vaccine development suggest a continued focus on personalized therapeutics, tailoring immunization strategies to individual needs. Additionally, advancements in data analytics, artificial intelligence and Pharma 4.0 are likely to play a pivotal role in optimizing production processes and accelerating vaccine development.

In conclusion, the dynamic and innovative field of vaccine manufacturing remains a critical force in safeguarding global health. From historical milestones to cutting-edge technologies, the journey of vaccines reflects humanity's ongoing commitment to preventing infectious diseases and ensuring a healthier future for all.