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Vaccine Production: Navigating Scale-Up Challenges

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The ongoing COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has claimed over 3.1 million lives worldwide. It has also had a humongous impact on the global economy. Limited success in designing new drugs and repurposing existing drugs to treat COVID-19, has led to a research focus on preventives, which includes vaccines. Thereby, many researchers are working at record speed to develop COVID-19 vaccines, and to date, many new vaccines have received emergency use authorization (EUA) from global regulatory bodies, such as the US Food and Drug Administration (FDA), the Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA).  

After a new vaccine is designed, the main challenge that the manufacturers face is scaling up its production. In the current situation, an added challenge is achieving large-scale production at a rapid pace. Although pharmaceutical companies have been able to manufacture hundreds of millions of doses of COVID-19 vaccines in a short period, demand continues to increase. To vaccinate the global population, the world needs billions of vaccine doses, quickly. The transition from manufacturing vaccines in smaller quantities required for academic research to the mass production that is required to protect the global population can be a daunting task.

Challenges in the large-scale production of vaccines

Typically, more than 200 individual components are required for the production of a vaccine. These components, such as glass vials, syringes, filters, tubing, stabilizing agents and disposable bags, are often 
produced in different countries. In a summit of manufacturers and policymakers, Richard Hatchett, chief executive of the Coalition for Epidemic Preparedness Innovations, pointed out that if the supply of one of the components falls short, the production of the vaccine can be delayed. According to Duke University’s Andrea Taylor, leader of global innovation programs on evaluation, scaling and adaptation of healthcare innovations to address critical access and quality challenges, a break in the supply chain can occur owing to various reasons, such as the exporting countries threatening to block vaccine component shipments. Such an incident occurred recently when India and the European Union announced restrictions on vaccine exports. Before the ongoing COVID-19 pandemic, there was a lack of established networks of contract manufacturers. This problem was further exacerbated owing to the massive global demand for large-scale production of vaccines currently.

Scientists believe that the large-scale production of COVID-19 vaccines is
limited owing to the highly concentrated state of global vaccine manufacturing capacity. At present, very few countries have the domestic capacity to manufacture COVID-19 vaccines. “Scaling up vaccine production is challenging and the lack of sufficient manufacturing plants is hampering the global vaccine supply,” said Zoltán Kis, a chemical engineer at the Future Vaccine Manufacturing Hub at Imperial College London. Kis’ expertise lies in the area of vaccine manufacturing; he works to design novel technologies capable of producing large amounts of vaccines against known and unknown pathogens. More recently, he has been focused on COVID-19 vaccine production processes based on rapid-response technologies, such as the RNA vaccine platform.

Dr Kis further said that “there is a lack of optimization at various stages of manufacturing for two key reasons, because these are newly designed vaccines and because they have been developed in such a short timeframe. However, this limitation is expected to be mitigated as manufacturers become more familiar with each vaccine and as processes are optimized.”

Another key 
challenge is to develop vaccines that are affordable to low- and middle-income countries (LMICs). Several companies, such as AstraZeneca and Johnson & Johnson, which rely on public-sector investments, have claimed to sell their vaccine globally at a low cost during the pandemic to improve accessibility. However, the cost of vaccines, post-pandemic, is yet to be determined. 

Overcoming key challenges related to vaccine scale up

As outlined in a
special report published in Nature, researchers explain that to accelerate vaccine production, collaboration is extremely important. It is essential to collaborate with multiple supply partners and analytical testing sites, in different countries. Recently, Martin Friede, head of vaccine development at the World Health Organization (WHO) stated that WHO has identified several organizations worldwide and is providing matchmaking services by connecting producers of vaccine components and major manufacturing companies. One of the world’s leading companies in the area, AstraZeneca, has collaborated with multiple manufacturing facilities across the world to support each stage of production. The manufacturing processes are transferred to the respective facilities and each of these facilities is governed and technically guided, throughout the manufacturing process, by the “parent” company. 

Widespread transfer of
technology and data across manufacturers, around the world, is vital when there are pressing challenges related to scaling up vaccine production. In the current COVID-19 pandemic, many vaccine manufacturing companies have united to cater to the global demand for vaccines and this initiative should actively continue.

In many organizations, across multiple industries, data sharing remains a key issue – and pharma is no exception. This lack of transparency can lead to the generation of data silos. An isolated approach to data storage can have several disadvantages, for example, it can lead to a duplication of work effort, slows down data analysis and can stunt innovation. Besides clinical trial data on vaccine candidates, epidemiological modeling studies and reports on monoclonal antibodies should be shared widely among biopharmaceutical companies in advanced countries as well as LMICs.

The pharmaceutical industry is recognizing the importance of “connecting” siloed data and is taking steps towards solving the problem.

WHO and its partners have undertaken an initiative to bolster the vaccine production capability of LMICs by establishing a multiple technology transfer hub. The main aim of this initiative is to provide training and knowhow, to interested companies in LMICs, regarding mRNA vaccine technology. In the future, the plan is to extend this technology transfer to other vaccine development processes.     

For scaling up vaccine production, developers have enlisted 53 manufacturing sites in Europe. This number is gradually increasing as more partnerships are being formed between vaccine developers and manufacturing organizations. Kis stated that “increasing the number of manufacturing plants is one of the most effective ways to increase vaccine production and meet the global demand.” However, scientists are wary that a diversion of resources to developing COVID-19 vaccines may hamper the production of vaccines for other diseases, such as cancer.

Optimization and quality checking is another area that can help in bringing about a rapid increase in the scale of vaccine manufacturing. Environmental conditions, such as heat, light and radiation, can affect the quality and purity of vaccines. Different technologies are being used to evaluate vaccine quality. For example, polymerase chain reaction (PCR) is used to analyze the adenoviral vector that carries the spike protein’s genetic code and the viral titer is measured using high-performance liquid chromatography (HPLC). HPLC helps to remove multiple contaminants from in vitro-transcribed RNA and eliminates immunogenicity. While there are several approaches that can be employed to ensure purity, anion exchange chromatography (AEX) is typically the most widely used. This is because the isoelectric point of the majority of viruses is below six. Owing to this property, the viruses can efficiently attach themselves to anion exchange matrixes at neutral pH. The separation of viruses, from impurities, is brought about by selective elution, because many impurities also bind to the anion exchangers at neutral pH. The use of affinity chromatography in vaccine purification helps to enhance the yield and analyze the purity of the vaccine. This technique also helps in reducing numbers of downstream process operations. Researchers will continue to assess and refine storage and handling conditions, at each phase of the vaccine production, to ensure stability, shelf life and safety. In the current scenario where production rate is extremely high, quality and stability testing are being carried out simultaneously with the manufacturing process. 

As mentioned earlier, large-scale manufacturing of affordable vaccines is a challenge. According to Martin Friede, intensifying the process of vaccines and biologics production, in terms of its magnitude, may play a key role in making vaccines 
affordable. This might also have positive spillovers to other vaccines. While the COVID-19 pandemic has provided strain to existing production processes, in the process of meeting the unprecedented demand for vaccines, manufacturers have had the opportunity to innovate and streamline vaccine production on a large scale. Such optimization may yield rich dividends in the future regarding the manufacture vaccines more broadly.