Flexible Vaccine Manufacturing: Collaborations Bringing Localized Solutions

View PDF

The COVID-19 pandemic has become the most recent reminder of how accessibility to drugs and vaccines depends heavily on geographical location and a country’s economic health. Some countries continue to lack the infrastructure, regulatory support, and trained workforce necessary for establishing a viable bioindustry. Unizima, part of the Univercells Group, is a team of experts, scientists, and engineers that partners with public and private companies and other organizations to help build biomanufacturing capabilities in low- and middle-income countries (LMICs).

We spoke with Hala Audi (chief executive officer at Unizima) and David Honba (head of business development at Unizima) about how the company is addressing the limitations and difficulties of working in such regions. To her current position, Audi has brought her experience in construction and infrastructure procurement in government and her experience in UK government policy on global health and antimicrobial resistance. Honba is an experienced biotechnology engineer, formerly working in vaccines manufacturing at GlaxoSmithKline.

Discussion
With what regions does Unizima work, and what challenges are unique to those places?

Audi: We’re finding that modular and offsite constructions are enabling a real paradigm shift in how we build biomanufacturing infrastructures for biologics — both vaccines and biosimilars. For vaccines, both the biomanufacturing engineering and construction engineering present opportunities to regionalize and democratize production because a company does not need to invest in large-scale facilities. Of the regions we are working with, two places come to mind. The first is the African continent, which has had quite a bruising pandemic. There’s been a “political wake-up call” about how it is the only populated continent not currently producing vaccines at any scale. African countries have been left at the back of the queue during this pandemic. There’s a big realization that the next pandemic might be even more difficult in terms of its health impact. That is not something that some African political and business leaders want to accept.

There’s also been a big wake-up call in Asia. We work with Malaysia and other countries that want to build autonomy and the ability to produce vaccines for themselves. We believe our technology opens the door to making that possible and commercially sustainable in a way that may not have been the case 10 years ago.

It’s important to note that although we are in those regions to help, our work should not be considered as “assistance.” Countries are building for themselves and partner with organizations that they think are the right partners for them. I hope that we will be one of their main partners, and certainly on the African continent that has started well. We are working hand in hand with authorities and pharmaceutical sector leaders to address specific challenges they face. That includes offering industrial training so that they can build the workforce needed to build and operate biomanufacturing facilities. We also work with international financial institutions, development agencies, and philanthropies to inform the product strategy and the business case for future facilities so that they generate a sustainable return over the long term.

What considerations go into constructing a vaccine production facility? How might those requirements differ from what you would need for a facility for other kinds of biopharmaceutical modalities?

Honba: For both vaccines and biosimilars, manufacturing control and all good manufacturing practice (GMP) aspects are related to international regulations, including those from the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO). For injectable products, manufacturing control and all GMP aspects are important, but they are the same as with other biologics. What is probably more important in terms of design is first to understand clearly the needs or market demands of a country or area. Of course, one factor when designing a facility is whether it will serve a region with low or high demand. That determines whether a facility will need one or several filling lines. That’s how I would structure it and narrow down the choices to reach the proper design for a facility.

In a pandemic, a vaccine manufacturer might need to make a product rapidly and maintain enough capacity. How do you design or renovate a facility with the flexibility to reach those goals quickly?

Audi: That’s the heart of the matter. When you consider how the Coalition for Epidemic Preparedness Innovations (CEPI) is thinking through that and how all the best minds in global health are thinking about that as well, it’s all about resilience. Resilience comes from flexibility and from preventing single points of failure, of which — as we’ve seen during the pandemic — there have been plenty. Our approach is well placed to support that resilience. Much investment starts with fill–finish operations because those are important to have regionally and locally. That’s where the highest demand is now, certainly on the African continent. That capability provides a region the flexibility to be supplied with bulk drug substance, and fill–finish operations can happen regionally.

We use modular, containerized facilities that can be implemented relatively quickly and can be increased in size over time. A choice in the equipment lines also is available.

That’s the ethos and the engineering philosophy that we bring to increase resilience through flexibility. Other aspects are drug supply and the production of bulk drug substance. That comes from technology developed by Univercells Group, including viral vectors, viral cell production lines, and bioreactors developed by Univercells Technology (e.g., the scale-X small-scale bioreactor and NevoLine upstream platform). They have a small footprint and low capital expenditure (CapEx). Thus, those technologies bring flexibility, enabling users to shift products quickly and at lower costs than large traditional facilities.

How does a facility design change when there is limited infrastructure to work with?

Audi: Water is a problem in many of the countries where we’re working. The stability of electric supply is a problem, as are the transport, infrastructure, logistics of the supply chain, and the human infrastructure that also needs to be built.

National regulators need to be certified Level 3 by the World Health Organization (WHO) to be able to qualify a facility as being GMP compliant. That’s incredibly important. There’s a huge effort in many countries right now to learn from each other and to reach that Level 3 designation from regulators. The other piece is human capital — the people you need to operate facilities, from technicians to the senior experts that you need on site.

There is no “silver bullet” solution. We are in awe of the project that David is working on in Senegal. Weekly, we have people sent there to support the delivery of a project, and they deal with all sorts of problems that I don’t think would be an issue in a European or American context, including water supply, electricity supply, and supply-chain logistics challenges. How you deal with those is through inventiveness, creativity, and determination to just get the job done and reach GMP with whatever terrain you’re given.

With the human-capital issue, that’s something that we’ve structured into Unizima. As part of our offer of services — which we describe as going from soft services to hard equipment and buildings — we have workforce training with our clients in country. We can work with a government that wants a national program of upskilling for biomanufacturing.

For example, what Rwanda is doing at the moment is incredibly impressive. The government has created a Regional Center of Excellence for vaccine, immunization, and health supply-chain management. That center is taking cohorts of students from all East Africa through new modules that focus on biomanufacturing and industrialization. When you see such efforts at a national level, it’s really impressive. We listen to and survey people about their needs. If there are learning modules that we can produce ourselves and bring to students as a service, or a product that we offer, then we do that.

Our offer of technology transfer is end to end. For example, if you want to buy a fill–finish facility for a COVID-19 vaccine, we will support that with project setup, delivery, design, build, operations, validation, and qualification all the way to transferring the facility to you. But all of that won’t work if you don’t have the people to run the facility. As part of our technology transfer service, we integrate an offer for training people we tailor to each client’s needs.

Again, all of that is achieved through partnerships in Belgium and in Europe with the best institutions. Some universities are happy to partner with us, as are some public–private research institutions in Europe that are set up to upscale European workers from jobs that aren’t in Belgium anymore. Belgium is ambitious about expanding its biotechnology sector. We work with an institution called the EU Biotech Campus, which is built for Belgium and other regions in Europe. It incorporates the same quality, standards, and offer of services that are made available to our projects in LMICs for training assistance.

Honba: One of Hala’s examples was water accessibility. When you design a facility in an environment or an ecosystem with limited infrastructure or resources, you have two ways to overcome those issues, and you have to find the right balance. As Hala pointed out, you can implement a modular facility based on high yields, low CapEx costs, and so on. The second approach (already under way in some projects in Africa) is to externalize services, which derisks a project or supply issue. For example, water-for-injection (WFI) supply is externalized, so it can be ordered to arrive when you need it. WFI also can be produced on site, reducing procurement risk and making its production part of the initial facility design.

A decontamination process is another example. If you have hazardous materials, you could externalize some or all of that service, or you could put in place some decontamination process on-site.

Audi: Reducing the amount of subcontracting and relying on external suppliers that might not exist locally or have the capability to work at the level that you need in those countries is a way to work around some of the issues that the projects are having.

Cold-chain capabilities also would either need to be developed locally or in a decentralized way. What solutions are possible for cold-chain capabilities in these regions?

Audi: We have cold-chain needs in mind from the outset, when we start with conceptual design and investment. We have an expert on my team who’s built many vaccine fill–finish facilities for a big pharmaceutical company in different emerging markets. You can tell that this is first and foremost on his mind when he’s talking to clients from the beginning. Our sister company Quantoom Biosciences is developing an mRNA production platform, which is led by Univercells cofounder Jose Castillo. He is developing an mRNA production platform and lowering the cold chain requirements at its heart from the beginning. Then there’s real innovation in cold-chain management. Ziccum in Sweden is working on a powder formulation, but it’s expensive to test that technology and product.

Such solutions are promising. The problem is that they add another layer of cost and time when you’re developing a product. In European and American markets, you don’t need to add that layer because they have the infrastructure deal with cold-chain requirements. When LMICs invest in biomanufacturing, they have an incentive for the products to work in their own context. That is why I think we will see innovation around cold-chain management that will come from the building of infrastructure in regions where the logistics of cold chain are an issue.

Honba: I cannot agree more. It’s true that in Western healthcare environments, there is an increasing number of liquid products (e.g., mRNA and viral vector vaccines), whereas the market had lyophilized products that were stable at higher temperatures or at least could be stored at 2–8 °C. Indeed, development could be improved, although improving your process or adding steps is not always what you’re needing, especially during a pandemic. I also agree that the ecosystem will emerge out of all efforts to implement vaccine capacities.

We talked about the training aspect and how important that is for making these pieces work. How much training and of what kind do facilitators need to provide?

Honba: The key areas include operations, manufacturing of both drug substances and drug products, fill–finish, and all quality aspects. Those are the main pillars. That’s the way we develop our workforce package at Unizima. It starts from GMP basics, depending on the country where you’re working. Training could span from basic GMP and basic manufacturing to more complex training aspects.

Audi: We always will need trained people to operate facilities. But moving toward modular, standardized facilities with automation and digital tools should reduce the number of people that are needed. I was impressed by how thoughtful the Rwandan government was about that and how it is planning to invest in biomanufacturing where BioNTech will provide the bulk supply for a COVID vaccine. Rwanda’s government also wants to build a diversified, thriving biosector over the long term and is thinking about which kind of facilities it will buy and how automated to make them because of difficulties in obtaining a workforce. The other training aspect that’s close to my heart — maybe because I have a background in working in government — is that the regulators need good people. You need the right workforce to qualify facilities and products. So training regulators is a big piece of making everything work as an ecosystem.

There’s an interesting move in the African continent toward creating an African medicine agency that could harmonize and standardize requirements for vaccines. For me, that is key to the investment and business case for companies, because if even one company produces vaccines in one country, it’s still a significant investment. Each pharmaceutical company must be able to sell at least regionally, if not continentally. If separate regulations are established in every African country, working with them all will increase costs and lower returns. So regulatory harmonization is incredibly important. But we’re seeing a commitment from the African Union, from the Africa Center for Disease Control and Prevention, and the current leadership of the African Medicine Agency to upskill regulators in a way that is coherent and cohesive. The hope is that those efforts will help regulators collaborate and not pitch them into competition with each other. We want to be part of this movement that shows that the point is to make the “cake” bigger for everyone, and then it can become a commercially sustainable venture for more companies. If the continent sticks to national regulation and too many differences arise among the countries, then the result might not work for anyone. No single country would be enough in a market.

How do you deal with regulations that are unique to the region?

Audi: We would need a more in-depth conversation on this, but I think there shouldn’t be too many differences among regions. I’m an optimist, but it shouldn’t be impossible to have some collaboration because the regulations are based on WHO, FDA, and EMA rules. Those are the predominant regulations, so there’s no built-in reason why deviations should arise. Look at what we’ve done during this pandemic in different countries with a bit of will. I don’t want to believe that we can’t overcome regulatory differences and have a system that is harmonized enough.

How does a company such as Unizima facilitate some of those conversations? How do you work with local stakeholders to ensure that they’re not only getting what they need, but that they’re building the resilience and autonomy that you mentioned earlier?

Audi: It requires much partnering and taking a certain approach to how we do business. That work is driven partly by the personalities and the leadership of the Univercells Group. Its motto is “Biologics for All,” and the mission of the group is to deliver on that motto. Before I left the career I had in government and joined this adventure, one of my questions was, “How serious are we as a group about this?” The answer was, “progress in global health and building a commercially sustainable business that will deliver more affordable, more available biologics” — that is our business model.

It’s not like Unizima is a “sideshow” that is trying to do something nice in LMICs. The entire group is built on the notion that there is a paradigm shift that’s coming and driven by engineering and biotechnology. It’s also enabled by modernization and digitalization of the construction industry. Those two things together with the right partnering approach will allow a paradigm shift that’s at a high level.

It helps to have people who are familiar with partnering across cultures and across public and private sectors. Our two cofounders bring that experience, but our chief investment officer also is a specialist in blended finance and has worked across public and private models over her career. My experience working in government with ministers and senior officials makes me comfortable working with people who set policy. In the end, that commitment and those investments will come, then need to trickle down into commercially sustainable businesses and private-sector pharmaceutical companies that need to thrive on that. I think our group’s ability to work across cultures, geographies, and the public–private sector is key. I hope that will help us make progress quickly — because it’s needed.

Brian Gazaille is associate editor at BioProcess International; brian.gazaille@informa.com; Maribel Rios is managing editor at BioProcess International; maribel.rios@informa.com.