Dr. Patrick Osewe
Chief of the Health Sector Group, Asian Development Bank
1. What do we need to know about vaccine manufacturing?
There are a number of important aspects involved in vaccine manufacturing.
First, vaccines are given to healthy people. That is, they are different from clinical trial medications, which are given to sick people. Therefore, bio safety and bio security are critically important, which is why manufacturers must have a state-of-the-art manufacturing facility that adheres to internationally-recognized good manufacturing practices to ensure the development of quality, safe and efficacious products.
Second, highly skilled human resources are required due to the number of steps involved in vaccine manufacturing, each with its own special skills and expertise. For example, biotech scientists are needed to produce the drug substance and many other cadre of staff are required in the process —including those specialized in clinical trials, production, and distribution of vaccines.
A technology partner is also crucial. For example, Kenya, Ghana, or Rwanda, and all the other countries that are trying to manufacturer vaccines now, need to partner with a country that has been doing this for a long time. Given its complexity, vaccine manufacturing is not something that a country can just decide to do. A country can’t just put up a facility and start making vaccines. They must work closely together with a partner who can transfer the technology and provide appropriate training.
A strong national regulator is another component. Without a strong national regulator to oversee compliance with and adherence to good manufacturing practices, the vaccine quality and safety may be called into question, making it difficult to export.
2. What are the competencies for vaccine manufacturing?
There are four key competencies for vaccine manufacturing.
- First, the manufacturer must develop a clear manufacturing process that details how the product is made. This has to be developed and cleared from the outset as every regulator who will be reviewing the product will want to understand the manufacturing process.
- Next, because vaccines are heavily regulated, compliance of the company or organization to good manufacturing practice regulations must be ensured throughout the entire process. Vaccines are treated as biological products, and as such are under rigorous review, to ensure safety, efficacy, purity, and potency at every stage, even when the vaccine goes to market.
- Considerable investments must also be made in terms of testing. This means manufacturers must constantly test the product to ensure that they are getting the results they want and they must be able to start and stop the process immediately they identify any problems.
- Finally, as mentioned earlier, the regulator is crucial to oversee the manufacturing process. Once the vaccine is market-ready, it must also be authorized in order to be released and distributed. WHO has what they call a global benchmarking tool (GBT), which is used to assess regulators’ capacity. Regulators are classified as maturity level 1, 2, 3, and 4. Ultimately, level 4 is the ideal benchmark for countries to reach. At this level, they are a fully-fledged regulator and can regulate any medical product while conferring confidence that they’ve done the best job to ensure quality, efficacy, and safety. It’s not easy to get there. Many countries reach level 3, which is also good as global organizations such as UNICEF can purchase a vaccine from a manufacturer who has reached level 3 or 4. If a regulator is classified below level 3, they are unlikely export vaccines. This is a challenge to any country. Therefore, for any countries considering manufacturing, they should have a level 3 regulator or above. At ADB we are currently working with Bangladesh on regulatory aspects. They would like to produce a COVID-19 vaccine and they are working hard to move their regulator from level 2 to 3. They will likely achieve a level 3 designation within the next 24 months and level 4 within the next 5 years. For any country to do that, they need a strategic plan, including some practical experience with biological products and vaccines. After the vaccine has been produced and is being used, they need to be vigilant and monitor any side effects on those that have been vaccinated. Automation of the regulation functions is also important. A large number of regulators still use manual processes, which can cause delays (e.g., when they sometimes lose documentation submitted by manufacturers, etc.).
3. What is required in developing a well-defined regulatory process for approval?
- First, you have to develop a proof of concept. This involves a lot of elements and knowledge, including the manufacture of clinical materials and toxicology analysis.
- Next, you have to submit the investigational new drug application. The application process itself is not easy, and many countries hire experts to put their dossier together to submit to the regulator.
- You also have to test for safety and effectiveness, which includes the phase 1 to 3 clinical trials.
- Lastly, you must submit the biological license application for final review and licensure
4 .What are the three phases of vaccine manufacturing?
The first phase is fill and finish. This is the relatively easy part, whereby the vaccine comes from a manufacturer like Moderna or the Pfizer. The manufacturer then enters into a partnership with a country—like Kenya, or Nigeria or Morocco—to quickly fill the vaccine so that it can be used in the country or exported at the sub-regional level. Companies utilize this process to rapidly scale up manufacturing across continents and reach wider populations. This process takes about 12 to 16 months and it includes technology transfer, training, and support for the facility that is already manufacturing vaccines or medicines so that they can produce it within the stipulated timeframe. In this case, all the research and the product come from somewhere else.
The second phase is contract manufacturing. This involves using an existing facility that is already manufacturing other vaccines. For example, a company manufacturing polio vaccine now might decide to start manufacturing COVID-19 vaccines. This involves going through the process of pre-formulation, formulation development, and stability studies to ensure that whatever vaccine is being produced at the parent company is the same vaccine at the contracted facility. This process takes slightly longer, around 3 years, and there are many companies in Asia that play a significant role in contract manufacturing. This has created a lot of manufacturing and human resource capacity in some countries, such as India and the People’s Republic of China. By having contract manufacturing in a country, you begin to develop the skills and expertise that are required to make vaccines from scratch (e.g., the biotech scientists, the clinical research team, etc.)
The last phase is full scale bio manufacturing. This usually takes 3 or 5 years, but can sometimes take up to 7 years.
5. What are the aspects you need to consider in vaccine manufacturing?
The vaccine type must be considered.
A whole inactivated vaccine is an active vaccine whereby the virus itself (pathogen) has been inactivated and is essentially dead. In this way, the infectivity is destroyed without destroying the immunogenicity. The challenge with these viruses is that you may require an adjuvant to make it stronger.
A live attenuated virus is actually the virus itself but the part that creates illness has been weakened. It essentially involves giving somebody a live virus that cannot cause disease. This requires a high level of bio safety because the manufacturer is dealing with live viruses, which can be harmful if mishandled. These are usually complex vaccines.
Live activated vaccines produce very high robust immune response because they are a link to the live virus and confer lifelong immunities (e.g., polio and measles vaccine for life and that’s a strong advantage for that.
Viral vectors involve taking part of the virus (e.g., a protein) that then stimulates the immune response.
Vaccines that use genetic material, or the genetic aspects of vaccine (mRNA and DNA) involve taking a small part of the DNA to generate immune response and therefore provide immune protection. Pfizer and Moderna have been very successful in manufacturing this kind of vaccine because the technology has been there for over 20 years, but at a sublevel, since it has not been used before. It’s a new technology and its advantage was that it was very fast to produce. It took about 325 days to produce the vaccine. However, this kind of vaccine has specific requirements, like cold chain storage, that must be maintained in order for it to remain stable—a challenge particularly in developing countries. Beyond COVID-19, mRNA technology has not been commercialized. It’s a very promising technology that most countries have their eye one because of the various other conditions where it may be used, like cancer treatment.
Other things to consider include compliance. Because vaccines are for people who are not sick, compliance with good manufacturing practices, which are very tightly managed and controlled, is critical. Many companies follow WHO standards, with rules that are established globally. Collaboration is also extremely important.
Another consideration with vaccine manufacturing is that sovereign manufacturing might not be a fast solution because it takes years to pass through all the above stages. If the focus is only on manufacturing COVID-19 vaccines, that might present a challenge because though cases are rising in a few countries, the pandemic is beginning to end in most. At some point, it will end completely. So, if you build facilities exclusively for COVID-19 and the pandemic comes to an end, what will happen to those facilities? However, if you build for other vaccines then it’s quite promising.
Finally, as earlier mentioned, another consideration is that you need a strong regulator.
6. What is the potential of vaccine manufacturing in Africa?
A study conducted by the Clinton Health Access Initiative (CHAI) looked at current and potential vaccine manufacturing on the African continent.
In 2021, the estimated production capacity of COVID-19 vaccines was about 825 million doses. The target in 2022 and 2023 is to produce about 3.1 to 3.5 billion vaccines.
South Africa is a country with a lot of manufacturing capacity. Aspen International, for instance, never produced a vaccine before, although it has produced many other pharmaceuticals (e.g., ARVs and products). With financing from the International Finance Cooperation and Johnson and Johnson as technology partner, Aspen was able to strengthen their capacity and produce the Johnson & Johnson vaccine within 6 to 12 months. There are a number of companies in South Africa that are able to produce vaccines.
Despite being small, Senegal also has good capacity. It has been producing the yellow fever vaccine for almost 30 years and Institut Pasteur has a lot of experience producing vaccine. When the pandemic began and companies were looking for collaborators to produce vaccines, the natural partner was Institut Pasteur in Senegal. Also, Senegal’s regulator has reached Level 3.
Rwanda and Ghana
Beyond South Africa and Senegal, there are other companies in several other countries that are trying to produce COVID-19 vaccines through various partnerships across the continent. Rwanda and Ghana have combined forces and partnered to produce vaccines. Rwanda doesn’t have a Maturity Level 3 regulator but Ghana has. In this partnership, manufacturing is being done in Rwanda and the regulatory components are being overseen by the Ghana regulator (FDA).
7. Beyond COVID-19, what is the market like?
Beyond COVID-19, there are opportunities to produce other vaccines. GAVI, the Vaccine Alliance, purchases vaccines for low-income countries and many of these countries are becoming wealthier. GAVI’s requirement is that they only supply to low-income countries and those that are just emerging from the low-income bracket. As countries become richer, the less support they receive from Gavi. By 2026, more countries will stop receiving subsidized vaccines from Gavi. In Kenya, for example, once support from Gavi ends, the treasury will have to allocate funds for the purchase of vaccine.
In East Africa, where several countries have a high birth rate, they require a considerable supply of pediatric vaccines. Millions of children are born annually in Ethiopia (3.6million), DR Congo (3.2million), Tanzania (2.2million), Uganda (1.6million) and Kenya (1.2million). As a result, there is a market for vaccine manufacturing.
8. What is your take away message for African countries before they proceed to vaccine manufacturing?
Countries should conduct a great deal of analysis before they proceed with any vaccine manufacturing process. Upon reflections, at the height of the HIV pandemic, the worst crisis on the continent was in Southern Africa, particularly SADC countries. President Mugabe decided that Zimbabwe would produce a vaccine for the sub-region. A local manufacturer was supported by the government to produce ARVs and Zimbabwe wanted other countries to purchase them. We (I was with the US government at the time) conducted an analysis and given the inefficiencies in the system, if Zimbabwe was to produce the ARVs, it would cost about USD 34 per person per month, while the ARVs that were being produced in India cost about USD 17 per person per month. Assuming you were Botswana, or any other country wanting to purchase ARVs, the cost saving approach would be to purchase from India. Zimbabwe sold ARVs for only two years before the initiative collapsed because no one would purchase them at a higher price.
Countries should also consider the vaccine ecosystem. This includes infrastructure as well as research and development because research capacity in Africa is still limited. However, there is an opportunity for research companies in Africa to partner with the Global North in order to conduct clinical research on the continent. Another consideration is animal research and testing facilities. Before phase 1 of clinical trials, a lot of the research is conducted on animals. Therefore, countries need capacity to do that. The clinical trial framework is another area – countries need biotech scientists and it takes years to train them. Training and development are also key factors. The national immunization technical advisory group is equally important. It should have the relevant expertise to avoid questions or concerns about vaccine safety after manufacture. There is still a lot of vaccine hesitancy around COVID-19 vaccines because many governments on the continent did not engage and educate communities before introducing the vaccines. Health care worker training is also critical in this respect because some healthcare workers themselves are fearful of the vaccine. Thus, it’s very difficult for them to convince someone else to take the vaccine
Countries should consider not only the maturity level of their national regulatory authority (as discussed earlier), but also ways in which they can cooperate with other regulators—both to improve efficiencies and to build their own capacity. We at ADB established a Regional Vaccine Advisory Group (RVAG) at the height of the pandemic to help provide member countries with technical, scientific, and regulatory advice on the quality, safety, and efficacy of COVID-19 vaccines. The RVAG, which includes public health experts, vaccine regulators, and policymakers, has fostered critical information exchange and collaboration around regulatory issues in Asia and the Pacific. This includes accelerating regulatory processes among ADB’s member countries and helping to provide faster access to COVID-19 vaccines. Countries, therefore, should look at the ways in which they can improve the regulatory environment not only domestically, but also with their neighbors through work-sharing, reliance on a stronger regulator’s reports, or joint assessments. This kind of cooperation across borders will serve to create an enabling environment and confidence for vaccine manufacturers and will strengthen regional health security.
Sufficient human resources and a strong lab backup are other considerations.
9. Understanding that vaccine manufacturing is important, in theory, is one thing. Being able to make vaccines or even having the funds/budget to purchase them is another. One of the problems facing African countries is a lack of appreciation of the technology involved in making vaccines – including what is means to get a license for the technology and having the capacity to receive the technology. Another challenge countries face is having the ability to actually pay for vaccines once they are on the market. Could you expand on these?
It’s not easy to manufacture vaccines. Countries must secure the right technology partner and have the capacity to make vaccines that are suitable for people. We have many manufacturers right now and the market is becoming more complicated. At the beginning of the pandemic when vaccines were not readily available, countries opted for any vaccine as long as it was a COVID-19 vaccine app. But now that people have more options, they are choosing vaccines according to their preferences and their underlying health issues.
With regards to market, simply because products are available on the market, it does not mean countries have the ability to pay for that product. And in almost all cases where public goods have been available on the market, African countries have relied on donor partners to buy these goods and provide them to the public free of charge.
Many countries still rely on international financing, and it’s only few countries that have taken over the procurement of life-saving commodities. Countries must consider the health security of their populations and should allocate resources accordingly. For example, countries with large populations of people with HIV should not only rely on external support, because when this support dries up, those living with HIV/AIDS are at danger. The assumptions from these countries that rely on donors is that the donors will always be there to support them to purchase these critical commodities. This is not the case. They must allocate their budget accordingly.
10. Why do you think that animal vaccine facilities can be converted to human vaccine facilities?
Some countries that have been producing animal vaccines have now begun to produce human vaccines, and there are some similarities (e.g., need of a regulator). Certain steps are also the same. But countries cannot just convert facilities used for developing animal vaccines to produce human vaccines. It’s a long process. The regulation, the kind of technology partners, etc. are different. An entire process is needed to convert an animal vaccine facility to a human vaccine facility.
11. Can you give a general take on the cost benefit analysis of vaccine manufacturing – describing whether it makes sense for Africa to manufacturer its own vaccine vis a vis importing from elsewhere?
When doing a cost benefit analysis, one has to look at the cost of production, the various inputs and their costs, the market, other aspects like transportation and the benefit for the continent. Africa is a huge continent with a young and growing population and therefore manufacturing is something central for the continent to achieve health security. Manufacturing should be done in a collaborative manner, not every country can produce its own vaccine.
Companies are thinking beyond COVID-19. If COVID-19 comes to an end, facilities should be able to be used to produce other vaccines (e.g., countries with a high birth rate should be able to produce more pediatric vaccines than any other kind.)
12. Given that the COVID-19 virus appears to slowly fading from view (even if there are still cases), is it economical for African countries to engage COVID-19 vaccine manufacturing, especially since large swathes of the population across the continent are hesitant to take them?
Africa has a large population and of all vaccines used in the continent, only one percent are manufactured locally. Thus, it is vital to increase the capacity to manufacture vaccines as these are public goods. However, the capacity to manufacture vaccines involves many aspects and has several levels—from clinical research, to manufacturing scientists, and regulation. Countries considering manufacturing COVID-19 vaccines should recognize that each of these require massive investments, which ultimately are good for the country. The processes are still the same for other vaccines. But given that COVID-19 is fading away, countries should reflect on whether or not the platforms they have in place are only for the COVID-19 vaccine manufacture or can be converted to produce other vaccines as well. They should also consider their technology partner and whether or not it has global market for vaccines other than COVID-19.
13. Are there other deadly sicknesses in Africa, such as sickle cell, that are rampant and deserve attention from health scientists?
Despite the fact that mRNA technology has been commercialized for COVID-19, it has great potential in terms of emerging diseases. For example, it took 325 days to make the COVID-19 vaccine, compared to malaria which has been with us for a long time. Africa should invest in vaccines that are relevant to its health priorities on the continent, choose the right technology partners, and also lead in certain areas of research.
14. As per your slides, many of the vaccines that are planning to be produced in 2022 and 2023 in Africa utilize mRNA technology. But based on what you have told us, this is a new technology that still lacks pharmacovigilance data, even beyond COVID-19. Could Africa’s excitement at finally manufacturing its own vaccines be premature as, looking down the line, they will be making vaccines that aren’t as effective as the other (biological) COVID-19 vaccines?
mRNA technology has only been commercialized for COVID-19. There has been discussion that it may be useful for cancer and other diseases, but it has not been approved to treat other kinds of conditions. Still, for COVID-19 it has worked well. Countries should choose a platform that can be used beyond COVID-19 and that can treat other illnesses.
15. Are there any vaccine brands that are indigenous to Africa?
There are COVID-19 vaccines that are indigenous to South Africa. The yellow fever vaccine is manufactured in Senegal for the rest of the world
16. What would it take for Africa to manufacture its vaccine starting from scratch, rather than depending on partnerships?
Africa will need to have strong research institutions on the continent, which produce excellent scientists. They are there, but the problem is they don’t know each other. They need to work together and network as they do research and share expertise and knowledge. Partnership is critical – there are many companies in Asia that are interested to partner with African companies.c
17. Can you expound on the automation of regulatory functions?
In the past, if a manufacturer wanted to register in East Africa for example, they had to submit their dossier to each country. This involved paying application fees in each country and slowed registration process. Many companies find this registration process onerous and avoided some markets thereby denying lifesaving medications to the population. The dossier submission process for registration could be made easier through automation.