Roundtable 2 Pharmaceutical Summary Report

THE AfCFTA AND TRANSFORMATIVE INDUSTRIALISATION ROUND TABLESERIES ROUNDTABLE SERIES

ROUNDTABLE 2

THE OPPORTUNITIES FOR DRUG SUBSTANCE MANUFACTURING IN AFRICA – CREATING REGIONAL VALUE CHAINS THROUGH LOCALISATION

SUMMARY REPORT 2022 Cape Town

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Contents 1. Background and Context .......................................................................................................................... 2 2. Roundtable Objectives..............................................................................................................................4 3. Summary of Presentations........................................................................................................................ 5 SESSION ONE: Drug Substance Development & Manufacturing Processes ................................. 6 Dr Simon Agwale: .............................................................................................................................. 6 Prof Petro Terblanche: ...................................................................................................................... 6 Mr Youssef Gaabouri: ........................................................................................................................ 8 SESSION TWO: Country Plans in Africa – Morocco & Senegal......................................................... 9 Dr Sam Machour: ............................................................................................................................... 9 Mr David Lindholm: ........................................................................................................................... 9 4. Policy considerations................................................................................................................................ 11 5. Conclusion................................................................................................................................................... 11

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1. Background and Context This roundtable was the second in the series of roundtable discussions hosted by the Nelson Mandela School of Public Governance at the University of Cape Town (UCT), to make policy recommendations for the development of regional value chains in the healthcare and pharmaceutical sector across Africa through leveraging opportunities presented by the implementation of the African Continental Free Trade Agreement (AfCFTA).

Global vaccine purchase data indicates potential supply security challenges in two key areas: 1) very few suppliers of individual vaccines or vaccine components and 2) countries limiting their available choices by relying predominantly on supply from certain manufacturers or manufacturer groups.1 The monopoly of the small number of manufacturers in just a few countries producing health tools needs to be broken. Protectionist approaches to manufacturing and trade will only aid the spread of the COVID-19 virus.

Instead, we must act globally to ensure that tools such as vaccines can be produced worldwide if we are to end the acute stage of this pandemic. As WHO Director-General Dr Tedros Adhanom Ghebreyesus puts it: “No other event like the COVID-19 pandemic has shown that reliance on a few companies to supply global public goods is limiting, and dangerous.”2 The first roundtable discussion focused on the formulation aspects of the vaccine manufacturing process, which most of the vaccine manufacturing initiatives and partnerships in Africa have focused on to date. This focus is very much needed and a necessary step towards developing local African vaccine manufacturing capacity – however, this does not alleviate the external dependency since the ‘drug substance’ (DS) or active ingredient for

the vaccines still needs to be imported.

Access to the DS remains a challenge due to intellectual property arrangements as well as limited capacity to manufacture it in Africa.

Recently, however, an announcement made by Moderna regarding the first mRNA manufacturing facility to be established in Kenya looks to change the manufacturing landscape. It is unclear at this stage as to what the practical arrangements will be and what the benefits to the market will be in terms of local capacity building. The facility will focus on manufacturing vaccine drug substances, with potential plans to expand its capacity to also include the filling of vaccine vials “as early as 2023, subject to demand.”3 It also announced a new initiative “that will offer researchers use of Moderna’s mRNA technology to explore new vaccines against emerging or neglected infectious diseases.”

This will allow researchers globally access to the company’s “preclinical manufacturing capabilities and research and development expertise.”4 The manufacturing of vaccines is a complex process that is very different to that of small molecules used in medicines. The drug substance/API production stage is commonly described as a two-phase process. Upstream processing includes cell isolation and cultivation (in some cases a process of direct DNA synthesis is adopted at this stage), followed by the cell banking and culture expansion steps using bioreactors. The second phase (downstream) includes the cell harvesting and purification steps, which entails the cell disruption, purification and polishing steps.5 Vaccines are often produced using raw materials that are obtained from biological production processes (e.g., yeast extract, natural or

1 WHO. (Dec, 2019). Global Vaccine Market Report 2 Dr Alakija, A. (2022, March 10). Opinion: It’s time to smash the bottlenecks to global health care. https://www.devex.com/ news/opinion-it-s-time-to-smash-the-bottlenecks-to-global-health-care-102795#:~:text=https%3A//www.devex,Find%20 a%20service 3 Green, A. (2022, March 10). The looming COVID-19 treatment equity gap. https://www.devex.com/news/the-loomingcovid-19-treatment-equity-gap-102816#.YjB2FcGI7Ks.twitter 4 Green, A. (2022, March 10). The looming COVID-19 treatment equity gap. https://www.devex.com/news/the-loomingcovid-19-treatment-equity-gap-102816#.YjB2FcGI7Ks.twitter 5 Sarkis et al., 2021; Alzahrani & Harris, 2020; Puetz & Wurm, 2019

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The Opportunities for Drug Substance Manufacturing in Africa • SUMMARY REPORT

recombinant enzymes). These materials add inherent biological variability to the manufacturing or analytical processes. Due to their specialized nature, these raw materials may be limited in supply, and subject to shortages or process changes as suppliers change methods to increase productivity or their bottom line.6 Plotkin, et al.7 argue that equipment and skilled labour that are not available in low-resource countries will need to be imported, and maintained or replaced, for years if not decades. Countries seeking to augment or localize vaccine supply will need to invest heavily in facilities, equipment, skilled labour and ongoing quality management with a long time horizon – requiring ‘‘patient capital” and development of in-house technical skills. Countries or companies must also carefully weigh the systemic risks and inherent difficulties in high-quality vaccine manufacturing and be prepared that returns may only accrue in the long-term, if at all.

that are required in the vaccine production process. Many of these production inputs are common across different vaccine platforms and therefore opportunities for localisation would need to be investigated. The Futures report also identified various opportunities across the vaccine value chain, both in terms of production and service inputs, that could be potentially localized.

Some would argue that African countries should not even pursue developing DS manufacturing capabilities at all due to the level of complexity and the late stage that the continent would be entering these industries.

In this roundtable discussion, key questions were asked to understand the actual processes involved in DS manufacturing from entrepreneurs and experts who are involved in this area as well as experts involved in developing manufacturing equipment for DS manufacturing.

The first roundtable discussion revealed that there are at least 150-200 production inputs

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Adapted from Plotkin, S. et al. (2017). The complexity and cost of vaccine manufacturing – an overview. Vaccine.

Adapted from Plotkin, S. et al. (2017). The complexity and cost of vaccine manufacturing – an overview. Vaccine.

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2. Roundtable Objectives The key objective was to understand the processes involved in developing capabilities in Africa for DS manufacturing in more detail, and secondly how to create localisation opportunities for both manufacturing and non-manufacturing countries in Africa to contribute towards the development of regional value chains through the provision of either essential goods or services required.

Specific questions posed to the panellists during the roundtable focused on the following areas: 1. Creating an understanding of the DS production process?

2. Should Africa be pursuing developing DS manufacturing capacity? How will this be beneficial?

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3. How the production of vaccines is different from traditional pharmaceutical manufacturing?

4. Manufacturing equipment required and what it takes to move from active ingredients to scale-up of production?

5. How DS manufacturing processes are interlinked and how these processes can be optimized to ensure seamless vaccine production and delivery?

6. Large scale vaccine manufacturing projects in Africa and how plants/facilities are developed?

7. Country vaccine manufacturing plans – Morocco and Senegal.

The Opportunities for Drug Substance Manufacturing in Africa • SUMMARY REPORT

3. Summary of Presentations Introduction and opening remarks by Ms Kirti Narsai: Ms Narsai welcomed all the participants, stating that this webinar forms part of a broader series on transformative industrialization, being convened by the Nelson Mandela School.

This series focuses on vaccine manufacturing, in terms of creating regional value chains under the AfCFTA through localisation. Ms Narsai clarified that this webinar would focus on the earlier part of the value chain, specifically drug substance (DS) manufacturing; the previous webinar focused on formulation manufacturing.

During the first webinar, the experts/speakers shared that there are more than 150-200 production inputs that are required in the entire vaccine manufacturing process. There are potential localisation opportunities that can be explored in terms of the sourcing of these production inputs, especially in instances where there are commonalities in requirements across various vaccine platforms.

The speakers for this webinar included the following: Speaker Name

Title, Organisation CEO, Innovative Biotech Nigeria

Dr Simon Agwale Managing Director of Afrigen Biologics (Pty) Ltd

Prof Petro Terblanche Associate Director, Head of Sales Middle East and Africa with BioProcess Division

Mr Youssef Gaabouri Executive Vice President and Chief Quality Officer, Samsung Biologics

Dr Sam Machour Global business development at KeyPlants

Mr David Lindholm

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SESSION ONE: Drug Substance Development & Manufacturing Processes Dr Simon Agwale: Dr Agwale indicated that he would be sharing his experience from the last 15 years of producing vaccine candidates for the unique diseases that affect the African continent. According to recent announcements, Africa currently has facilities that can produce 4.5 billion doses of vaccines per annum (referring to the finished product); the question is how we feed these facilities (with active drug substance, which is currently mostly being imported).

The goal is to have Africa produce 60% of its own vaccines by 2040 (African CDC target); which translates to 1.5 billion doses per annum.

Therefore, there are major plans to put facilities on the ground. In terms of distribution, in South Africa alone there are four major initiatives: Aspen aims to produce 500 million doses per annum, NAT SA will be producing one billion doses per annum, Afrigen’s target is 250 million doses per annum and Biovac aims to produce 100 million doses per annum.

Morocco aims to produce 500 million doses, Egypt is targeting 300 million doses and Senegal is aiming for 250 million doses per annum.

This demonstrates that Africa has the capacity to fill-finish 4.5 billion doses per annum. The key question is where the drug substance will come from; the business case needs to be considered.

Dr Agwale went on to stress the importance of choosing which vaccine platform the continent will use. He shared how the arrival of COVID-19 catalysed the building of vaccine manufacturing facilities in Nigeria; his team is currently in the process of developing a second-generation vaccine for COVID-19. He added that to build a vaccine production facility, a process is required; without the process, the development of a vaccine cannot be designed.

For this industry to thrive and be sustainable, one should not only look at the availability of vaccines but the business case and then build infrastructure based on the products that will help to sustain the industry; he however noted that a pandemic situation may require a different approach. The production of the product/

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vaccine must sustain the facility; there must be a market/demand for the vaccine, and the venture must be viable and relevant.

Dr Agwale then went on the share his experience in developing an HBV vaccine which will provide more protection/coverage for people living in Africa (more impactful), at a reduced cost (cheaper). He concluded by reiterating that there should be justification for going into a venture; we need to carefully look at what exists and what the gaps are, and then try to produce vaccines that will fill those gaps.

Dr Agwale also shared that a critical consideration when building a business case is consulting financial experts who can do the modelling to see whether the venture is profitable. Investors will want to see that the business case is viable.

Prof Petro Terblanche: Prof Terblanche indicated that she would share Afrigen’s experience in creating an mRNA vaccine and what it took to make this process successful; a case study that provides both learnings and is aligned to a strategy of drug substance manufacturing. The African continent currently produces one per cent of the vaccines it uses/needs and uses 25% of the vaccines produced globally. Pre-2020 there was very little capacity on the continent for drug substance production and insufficient capacity for fill-finish. Prof Terblanche reiterated Dr Agwale’s question – the African continent is currently over-capacitated in terms of fill-finish; how do we feed this?

Prof Terblanche shared that Afrigen developed an end-to-end vaccine manufacturing facility without a business plan; they proceeded based on the knowledge that there would be a need and opportunity for the production of their vaccines. With the arrival of COVID-19 and the Covax Initiative, there soon came the realization that for the sake of pandemic preparedness and global survival, low and middle-income countries need to be able to produce their own vaccines. These countries did not get a sufficient supply of the COVID-19 vaccine when it became available and were not able to meet the needs of their populations. The mRNA was the most versatile platform to help these countries produce their own vaccines. Prof Terblanche added that leveraging public-private partnerships is a key success factor in having an end-to-end value chain established.

The Opportunities for Drug Substance Manufacturing in Africa • SUMMARY REPORT

In the absence of technology transfer, Afrigen and WITS University (as part of the mRNA Hub) worked together using the resources available in the public domain (the sequence of the Moderna vaccine published by Stanford University) to develop a vaccine candidate. They now have a lab-scale proof of concept vaccine candidate, which they are preparing to take through clinical development. She added that when using platforms like mRNA, intellectual property considerations are of immense importance; this is less so in the case of fill-finish. Prof Terblanche argued that the continent needs to look at the reformation of its patent laws if it wants to build a vertically integrated drug substance industry.

Another important factor in building drug substance capacity creation and manufacturing, is access to technology; particularly technology transfer. Over the last 18 months, there were 37 tech transfer deals in the COVID-19 space globally, 19 of which were in Africa; however, most of these focused on fill-finish tech transfers. The continent must make the conscious decision to create an enabling environment that will allow it to be able to do tech transfer, license and use a combination of methods for its own development for drug substance manufacturing.

A crucial component in this process is research and development (R&D) and directed research orientation. The R&D capabilities that sit within South Africa’s universities have significantly enabled the fast-tracking of the mRNA hubs production of a vaccine candidate. Through R&D the continent needs to focus on improving its ability to produce relevant vaccines, as well as creating second-generation vaccines; considering thermostability, payload and affordability of the vaccines.

Prof Terblanche shared that there will be five companies who will receive tech transfers from Afrigen for mRNA vaccine production. They will establish a platform to establish the proof of concept for new vaccines. This will form an R&D pipeline of development for vaccines of importance for the burden of disease in Africa with multiple partners to ensure that these end-to-end facilities have sustainability beyond COVID. She stressed the importance of having a bankable model; facilities that can produce multiple products, have versatility and can be operated at low cost.

Link to Slides

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Mr Youssef Gaabouri: Mr Gaabouri began his presentation by clarifying that he is part of Merck Life Sciences, and there is no relation to the company Merck Sharpe & Dohme which is a separate pharmaceutical company.

Mr Gaabouri shared that vaccines in the biologic space are quite unique compared to older biotherapeutics (which have a well-known manufacturing template). The technology and process that will be used have to be considered when developing a strategy for local manufacturing and capacity building, as this will determine the type of equipment used. Another consideration is biosafety for the operators, especially when producing viral vaccines that are inactivated.

Mr Gaabouri went on to share some terminology: USP (upstream processing), DSP (downstream processing), and formulation and final fill; these are the main process steps for sequencing drug substances when it comes to value chain fallbacks in manufacturing. He then proceeded to share the difference between the mRNA vaccine and the inactive process template, noting that the process one selects will determine the number of steps in your vaccine production.

He also shared some of the equipment used for upstream and downstream processes. In

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Africa, most pharma players tend to choose classical pharma production methods (injectable and non-injectable products) where the number of the process steps are significantly reduced compared to the biological space.

There are several considerations that need to be made when determining the equipment that will be needed and the design of the plant and processes.

Mr Gaabouri shared some insights on the shifts in technology in the vaccine space, particularly the biologic space; there is a shift to single-use technologies (plastic and silicone) to try and reduce the footprint and costs of the manufacturing process. Another shift relates to time and the ability to produce a vaccine in a very short time – big manufacturers like Moderna and Pfizer now claim to be able to produce and bring to market a vaccine in 2-3 years.

He concluded by saying that although Africa is well equipped to run classic pharma facilities, we have to ask whether we have qualified people to run large drug substance manufacturing (and the related devices). Therefore tech transfer and collaboration initiatives are imperative for success.

Link to slides

The Opportunities for Drug Substance Manufacturing in Africa • SUMMARY REPORT

SESSION TWO: Country Plans in Africa – Morocco & Senegal Dr Sam Machour: Dr Machour shared that the initiative in Morocco for vaccines is fill-finish, with DS manufacturing to only be established in the future.

Morocco currently manufacturers more than 500 million doses of vaccines for veterinary use and zero for human use; it imports 100% of human vaccines needed annually and has been doing so for a long time. Despite having one of the most established pharmaceutical industries on the continent, Morocco currently does not manufacture a single dose of vaccine for human use.

With the arrival of COVID-19, Morocco spent more than $800 million on vaccine procurement; much of which was not delivered. Hence the business case for building vaccine capabilities in the country was quite straightforward.

Dr Machour highlighted four reasons that supported Morocco’s business case for doing so: 1. The directive to build manufacturing facilities came directly from the King; it was a top-down initiative built on the basis of national security and not profitability.

2. Morocco could have built four plants with the $800 million that was wasted on undelivered vaccines.

3. Morocco is next to Europe and can deliver fill-finish vaccines by truck, if needed.

4. The desire and the instruction came from the King to support Africa and to connect the dots with the self-sufficiency momentum that is being built in Africa.

Further to the country’s involvement in the PAVM and African CDC, the Moroccan vaccine project was given 12 months to start manufacturing vaccines; this would be done through licensing, as the country was not going to develop its own novel vaccines.

At the start of the project, the country did not have any capacity for the production of fill-finish vaccines for humans. This meant that within

a year Morocco had to build the manufacturing plants (with all the engineering, technical and safety requirements that come with it). The plan will go live in July 2022 with the initial capacity of 150 million doses of fill-finish vaccines, and the goal of reaching 500 million doses by 2023 and 900 million in 2025.

The business model of the plant in Morocco is twofold: • The vast majority of the capacity will be used utilized as a contract manufacturer, (CMO).

Since the plant is built based on EU and US FDA requirements and will be licensed as such, Morocco is working with different states and pharmaceuticals to discuss with them potential fill-finish outsourcing and using that capacity for fill-finish.

• Public-Private Partnerships and Tech transfer – Morocco is in the process of signing an agreement for 20 vaccines (both fill-finish and vaccines manufacturing) with a company called Bioinvest, to license their vaccine portfolio. The government will give preference to locally manufactured vaccines, over vaccines that have previously been imported.

Dr Machour emphasized that R&D will be imperative; manufacturing alone will not provide Morocco (or Africa) with self-sufficiency. It will also be important to cooperate with other countries on the continent, to avoid duplication of efforts.

Link to slides

Mr David Lindholm: Dr Lindholm shared the experience of KeyPlants in building a first-of-its-kind vaccine manufacturing filling facility in Senegal – Project MADIBA, “Vaccines in Africa for Africa”. The aseptic filling facility was designed and manufactured

by KeyPlants in less than 8 months and was shipped from their workshop in Sweden, arriving in Senegal in April 2022.

The facility will be able to produce 300 million COVID-19 vaccine doses annually. The initial facility will be used for aseptic filling of COVID-19 vaccines, however, it is designed to be modular and flexible to adapt to changing health needs; multi-suite drug substance and

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drug product capabilities are planned.

Dr Lindholm concluded his presentation with some key considerations for establishing local manufacturing capabilities: • GMP (Good Manufacturing Practice) expertise is key when designing any facility.

• Safety and quality assurance is always important even more so for vaccines as they are given to a healthy population, often infants.

• Pharmaceuticals are typically produced through chemical synthesis; vaccines are biological products defined by their process.

• Establishing vaccine and biologics manufacturing processes requires technology transfer, extensive process validation, stability studies and often clinical trials.

Further considerations, similar to those presented by the other speakers, include: Link to slides

Thank you and Closing Remarks by Ms Kirti Narsai: Ms Narsai thanked the speakers for sharing their knowledge and insights. Some critical questions were raised, which the Nelson Mandela School will endeavour to answer through this ongoing webinar series.

Some of those critical questions and key learnings from the session include: • How do we go about developing talent?

• How do we connect the dots and develop this ecosystem that is already thriving?

• The IP regime and regulated systems that need to be developed?

• We have amazing capabilities on this continent already, but we need to do a better job of collaborating and leveraging those capabilities and bringing them to commercialization.

• The importance of a business case and the different ways of thinking about what is important in terms of the critical elements that make up a business case; what works and what doesn’t work in terms of our context.

• The importance of the PAVM as a convener of Africa Inc. and how we should be using that as the key platform for developing the sector going forward.

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The Opportunities for Drug Substance Manufacturing in Africa • SUMMARY REPORT

4. Policy considerations • If Africa is to truly become self-sufficient in developing vaccine manufacturing capabilities on the continent, then there has to be a concerted effort made towards supporting and developing capabilities in drug substance manufacturing.

• Business cases, whether led by political leadership, the private sector or individual entrepreneurs, need to be well thought through and focus on long-term sustainability, capacity building and benefits to local populations from a public health perspective.

• Vaccine manufacturing processes are complex and bespoke based on the type of vaccine platforms utilised – talent development and training initiatives should support human resource development for employment in the vaccine value chain.

• Provisions should be made for adequate

access to finance from local sources for African entrepreneurs to pursue business opportunities in the vaccine value chain, to ensure business sustainability and longevity.

• Technology transfer and innovative partnership agreements are going to be key to succeeed in developing infrastructure and capabilities in local African markets – however, these will be of little value if they are not coupled with local talent development and capacity building which will ensure longterm sustainability and self-sufficiency.

• As mentioned previously, not all markets in Africa will become vaccine manufacturing countries, therefore regional coordination and collaboration, where these countries are able to also participate in the vaccine value chain, will become important in establishing regional value chains and leveraging further opportunities for localisation.

5. Conclusion 1. True self-sufficiency in vaccine manufacturing for Africa will only come if capabilities are developed for developing drug substance manufacturing in addition to ‘fill & finish’ capabilities. This will avert the need to import drug substances (DS) from foreign sources as is currently the case.

2. Recent developments on the continent have shown pockets of excellence in the scientific development of novel vaccines, which indicates the potential to grow further R&D capabilities – this will be explored further in upcoming roundtable discussions.

3. Entrepreneurial activities also indicate a similar potential for further developing the sector, should an enabling environment be created with associated financing – another area which will be further explored in upcoming roundtable discussions.

4. Lastly, talent development and retention will be critical to the functioning and further development of the sector – this critical element, including focusing on the gender and youth elements of talent development will require a separate discussion.

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