A case study on the ecosystem for local production of pharmaceuticals, vaccines and biologicals The Tunisia context A case study on the ecosystem for local production of pharmaceuticals, vaccines and biologicals The Tunisia context A case study on the ecosystem for local production of pharmaceuticals, and biologicals A case study on the ecosystem for local production of pharmaceuticals, vaccines and biologicals The Tunisia context ii A case study on the ecosystem for local production of pharmaceuticals, vaccines and biologicals: the Tunisia context ISBN 978-92-4-009244-0 (electronic version) ISBN 978-92-4-009245-7 (print version) © World Health Organization 2024 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. 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Qatar Red Crescent Society supports the Syria Humanitarian Response. iii Contents Preface ........................................................................................................................................... v Acknowledgements ...................................................................................................................... vi Abbreviations .............................................................................................................................. vii Executive summary ...................................................................................................................... ix Introduction ................................................................................................................................... 1 Part I: Vaccines and biologicals .................................................................................................... 5 1.1 The vaccines and biologics ecosystem .................................................................................... 6 1.1.1 Existing manufacturing capability .................................................................................... 6 1.1.2 Government policies ......................................................................................................... 6 1.1.3 Government incentives ..................................................................................................... 8 1.1.4 Financing conditions ....................................................................................................... 11 1.1.5 The regulatory system .................................................................................................... 15 1.1.6 R&D capabilities ............................................................................................................ 17 1.1.7 The patent system ........................................................................................................... 20 1.1.8 Technology transfer activities......................................................................................... 21 1.2 Drivers, bottlenecks and challenges ...................................................................................... 22 Part II: mRNA vaccines .............................................................................................................. 24 2.1 mRNA vaccine technology ................................................................................................... 25 2.2 mRNA vaccine ecosystem ................................................................................................... 27 2.2.1 Manufacturing capacity .................................................................................................. 27 2.2.2 Government policies and financing ................................................................................ 27 2.2.3 Regulatory system .......................................................................................................... 28 2.2.4 Technology transfer activities......................................................................................... 29 2.3 Drivers, bottlenecks and challenges ...................................................................................... 30 Part III: Vaccine manufacturing capacity ................................................................................... 32 3.1 Production capacity ........................................................................................................... 33 3.2 Vaccine sales, export markets and procurement ................................................................ 35 3.2.1 Export markets ............................................................................................................ 35 3.2.2 Sales and procurement ................................................................................................ 37 Part IV: Recommendations and future directions ....................................................................... 39 4.1 National strategies and initiatives: overview ......................................................................... 40 4.2 Country expectations and objectives ..................................................................................... 41 4.3 Training and assistance needs ............................................................................................... 42 4.3.1 Vaccines and biologicals ............................................................................................. 42 4.3.2 mRNA vaccines .......................................................................................................... 42 iv References ................................................................................................................................... 44 Annexes ....................................................................................................................................... 47 Annex 1: Primary research participants ......................................................................... 48 Annex 2: List of resources consulted as part of the literature review ............................ 48 Annex 3: List of tunisian drug manufacturers ................................................................ 54 Annex 4: List of priority sectors in industry ................................................................. 55 Annex 5: List of incubators, accelerators, seed and start-up funds, business angels, venture capital investment companies and venture capital mutual funds....................... 58 Annex 6: List of banks in Tunisia .................................................................................. 58 Annex 7: Pharmaceutical innovation and healthcare R&D ............................................ 60 Annex 8: A comprehensive academic and vocational training system .......................... 60 Annex 9: African vaccine manufacturers ....................................................................... 61 List of figures Figure 1. Global vaccine market distribution by a) market value (% of total) and b) market volume (% of total), 2019 ………………..………………………………………………………1 Figure 2. Key milestones in the evolution of Tunisia’s pharmaceutical industry and associated regulatory bodies ………………………………………………………………………………15 Figure 3. Public institutions forming the national regulatory authority in Tunisia …………….16 Figure 4. mRNA manufacturing production processes and associated critical parameters….....25 Figure 5. Enoxaparin Medis export distribution by volume, 2021 (number of syringes) …..….35 Figure 6. Enoxaparin Unimed export distribution by volume, 2021 (number of syringes) …... 36 Figure 7. Heparin Medis export distribution by volume, 2021 (number of syringes) ……….…36 Figure 8. Epoetin alfa Medis export distribution by volume, 2021 (number of syringes/vials) ..37 Figure 9. Vaccine procurement, 2019-2021 (million doses per year) ………………….………. 38 Figure 10. Vaccine procurement, by vaccine type ……………………………………….…….. 38 List of tables Table 1. Evaluating Tunisia’s pharmaceutical manufacturing ecosystem: research methods …..4 Table 2. New business financing options ………………………………………………………12 Table 3. International funding sources ……………………………………………...………….14 Table 4. Agencies and programmes promoting R&D and innovation …………….………….. 19 Table 5. Production of sterile products in Tunisia ……………………………………………..34 9 2 4 5 v Preface The Local Production and Assistance (LPA) Unit in the Regulation and Prequalification Department (RPQ), Access to Medicines and Health Products Division (MHP), WHO, supports Member States, particularly low- and middle-income countries (LMICs), to strengthen sustainable local production and technology transfer to improve timely, equitable access to quality, safe and effective essential medical products. The LPA Unit provides assistance and support to Member States with an ecosystem-wide and holistic approach, such as fostering global coordination and partnerships, conducting ecosystem assessments for sustainable, quality local production, developing and implementing strategies/roadmaps, providing comprehensive capacity building and technical assistance, including for WHO Prequalification (PQ)/Emergency Use Listing (EUL), facilitating technology transfer (TT) and developing global resources on local production and TT. A landmark resolution WHA74.6 on strengthening local production of medicines and other health technologies to improve access was adopted in the Seventy-fourth World Health Assembly, signalling globally the important role local production plays in improving access and strengthening health security. Within this mandate, the LPA Unit, developed a series of case studies on the ecosystem for local production of pharmaceuticals, vaccines and biologicals, with a focus on country context in the low- and middle-income countries. These case studies add to the existing repository of resources on strengthening local production and technology transfer of health products for countries to leverage upon when countries embark in these areas. The countries in this series are Bangladesh, Kenya, Nigeria, Pakistan, Senegal and Tunisia. From June to September 2022, a series of interviews and consultative meetings, including a review of available literature, policies and other documents, and administration of a questionnaire, were performed. This case study is intended to report the collated information in areas such as available policies, initiatives, financing, regulatory system, patent protection system, research and development work, markets and capacity and preparedness to uptake local production of quality-assured pharmaceuticals, vaccines (including mRNA vaccines) and biologicals. Stakeholder perspectives on the expectations and needs of countries were also collected and included in the case studies, along with proposed recommendations, for the reader to see various viewpoints towards strengthening sustainable local production and achieving universal health coverage and the Sustainable Development Goals. vi Acknowledgements This case study was developed under the lead and supervision of Jicui Dong, Unit Head of Local Production and Assistance (LPA) Unit, World Health Organization (WHO), with a main contribution by Sameh Ben Tkhayat, WHO consultant, and technical contribution by David Woo, Technical Officer, and Wee Ling Phua, WHO consultant. Particular appreciation is given to WHO Country Office of Tunisia for the support in facilitating the local arrangements, with particular thanks to Ibrahim El-Ziq, WHO Representative to Tunisia, and Ramzi Ouhichi, Public Health Officer, as well as the WHO Regional Office for Eastern Mediterranean and the Government of Tunisia for their support. A special thanks is given to Yukiko Nakatani, Assistant Director-General, Access to Medicines and Health Products Division, WHO, and Rogério Paulo Pinto de Sá Gaspar, Director, Regulation and Prequalification Department, WHO, for their guidance and support. WHO would like to acknowledge those who reviewed this document and sent their comments and suggestions: Hechmi Louzir, Director of Institut Pasteur de Tunis and the focal point of transfer of the technology for the production of mRNA vaccines. WHO would also like to thank the external entities and individuals who have contributed to either the survey, interviews and/or discussions which have informed the development of this case study. This case study was developed under the WHO Local Production and Assistance Unit’s mandates to support Member States in strengthening sustainable local production and technology transfer to improve access to safe, effective, quality and affordable medicines and other health technologies with funding from the Governments of China and France. vii Abbreviations AFD Agence Française de Développement AfDB African Development Bank ANCSEP Agence Nationale de Contrôle Sanitaire et Environnemental des Produits (The National Agency for Sanitary and Environmental Control of Products) APII Agency for the Promotion of Industry and Innovation APRICE Agence de Promotion de la Recherche, de l’Innovation et de Création d’Entreprises (Agency for Promotion of Research, Innovation, and Business Creation) BBIL Bharat Biotech International Limited BCG Bacille Calmette-Guérin BFPME Banque de Financement des Petites et Moyennes Entreprises (Small and Medium Business Corporate Banking) BVMT Bourse des Valeurs Mobilières de Tunis (The Tunis stock exchange) CAGR compound annual growth rate CEPEX Export Promotion Center CNPV Centre National de Pharmacovigilance (The National Pharmacovigilance Centre) COVID-19 coronavirus disease 2019 DIP Direction d’Inspection Pharmaceutique (The Directorate of Pharmaceutical Inspection) DNA deoxyribonucleic acid DPM Direction de la Pharmacie et du Médicament (The Directorate of Pharmacy and Medicine) DSSB Direction des Soins de Santé de Base (Basic Health Care Directorate) EFPIA European Federation of Pharmaceutical Industries and Associations EIB European Investment Bank EMA European Medicines Agency ENP European Neighbourhood Policy EU European Union EUA Emergency Use Authorization FIPA Foreign Investment Promotion Agency Gavi The Global Alliance for Vaccines and Immunization GMP good manufacturing practice GSK GlaxoSmithKline GTP guanosine triphosphate HPV human papillomavirus IEC International Electrotechnical Commission IFC International Finance Cooperation INEAS Institut National d’Evaluation et d’Accréditation en Santé (National Authority for Evaluation and Accreditation in Health) INNORPI Institut National de la Normalisation et de la Propriété Industrielle (The National Institute for Standardization and Industrial Property) viii IPT Institut Pasteur de Tunis (Tunis Pasteur’s Institute) ISO International Organization for Standardization IVT in vitro transcription LMICs low- and middle-income countries LNCM Laboratoire National de Contrôle des Médicaments (National Laboratory for Drug Control) LNP lipid nanoparticle LPA Local Production and Assistance Unit MENA Middle East and North Africa mRNA messenger ribonucleic acid NRA national regulatory authority ONST Observatoire National des Sciences et de la Technologie (National Observatory of Science and Technology) PCT Pharmacie Centrale de Tunisie (The Central Pharmacy of Tunisia) PCV pneumococcal conjugate vaccine PEG polyethylene glycol PFR Program of Federated Research PNRI Program of National Research and Innovation QC quality control SARS severe acute respiratory syndrome SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 SME small- and medium-sized enterprise SII Serum Institute of India SICAR Société d’Investissement à Capital Risque STI Science Technology Innovation TFF tangential flow filtration TIA Tunisia Investment Authority TRIPS Trade-Related Aspects of Intellectual Property Rights UNCTAD United Nations Conference on Trade and Development UNICEF United Nations International Children's Emergency Fund VAT value added tax VCE vaccine capping enzyme VRR Valorization of Results of Research WB The World Bank WHO World Health Organization WIPO World Intellectual Property Organization WTO World Trade Organization ix Executive summary Tunisia, like many other African nations, confronts a pronounced dependency on imported vaccines. This reliance on imports poses critical risks to public health security and economic stability. In order to address this issue, Tunisia aims to fortify its domestic vaccine production capacity to ensure self-sufficiency, bolster healthcare resilience and stimulate socioeconomic development. This report describes Tunisia's progress towards establishing a robust vaccine manufacturing ecosystem, emphasizing the concerted efforts and strategic initiatives that are needed to achieve self-sufficiency in vaccine production. Vaccine ecosystem assessment Tunisia has a nascent vaccine industry which currently manufactures 1% of the 1.3 billion vaccine doses administered annually across the continent. The Tunisian government demonstrates a steadfast commitment to fostering greater vaccine production through multiple strategic policies and incentives, most notably, a legislative framework which offers substantial financial and fiscal support for priority sectors, particularly in biotechnology and pharmaceuticals. A comprehensive financial support system exists, which spans the entire business cycle from project inception through to international market penetration and promotes both public-private partnerships and entrepreneurial endeavours. Regulatory framework and manufacturing expertise While Tunisia’s regulatory standards align with international norms, a specialized framework dedicated to vaccine production remains a pivotal necessity. Encouragingly, local companies proficient in injectable pharmaceutical products have expressed keen interest in diversifying their operations to include messenger ribonucleic acid (mRNA) vaccine manufacturing. Research and development landscape and patent laws The Tunisian pharmaceutical sector boasts maturing research and development (R&D) capabilities and exhibits a favourable environment for innovation and clinical trials. However, limitations persist in intellectual property sharing, inhibiting widespread utilization of mRNA technology. Challenges identified encompass regulatory reinforcement, sustained political dedication, secure commitments to private technology transfer entities, and fostering enhanced research and development capacities. Local production dynamics and global engagement Key local entities such as the Institut Pasteur de Tunis (IPT) alongside several interested manufacturers signify the potential for indigenous vaccine production. While these local products have yet to secure international procurement, Tunisian biosimilars have gained traction in global export markets. Furthermore, those companies aspiring to manufacture vaccines and biologicals have expressed their intentions to expand into African and Middle Eastern markets. x Complexities and training imperatives The intricate nature of vaccine and biologicals manufacturing necessitates sophisticated technology and specialized expertise. Comprehensive training programmes conducted at manufacturing sites, focusing on mRNA vaccine manufacturing, quality control and clinical trials, serve as essential complements to national educational systems. Conclusion Fortifying and growing Tunisia's vaccine manufacturing prowess requires long-term governmental commitment, regulatory enhancements, and collaboration to secure intellectual property sharing and substantial investments in specialized training initiatives. Such strategic interventions are pivotal in positioning Tunisia as a self-reliant contributor to regional health security while propelling economic advancement. 1 Introduction The global vaccine landscape The global vaccine manufacturing landscape is characterized by a concentration of capacity among a small number of major players. A handful of manufacturers – GlaxoSmithKline (GSK), Pfizer, Merck, Sanofi, Serum Institute of India (SII), Bharat Biotech International Limited (BBIL) and Haffkine – dominate the market, managing a significant majority of both market value and production volume. Just four manufacturers account for nearly 90% of the global vaccine market value (Fig. 1a), while 60% of all vaccines by volume are produced by five manufacturers (Fig. 1b). This concentration is a consequence of the cost-intensive and inherently variable and high-risk nature of vaccine production (1). Thus, despite the high unmet global demand for vaccines, only a limited number of manufacturers have been able to thrive in this highly competitive space (2). BBIL, Bharat Biotech International Limited; GSK, GlaxoSmithKline; SII, Serum Institute of India Fig. 1: Global vaccine market distribution by a) market value (% of total) and b) market volume (% of total), 2019 Source: Global Vaccine Market report, 2020 (1) The coronavirus disease 2019 (COVID-19) pandemic, declared a global health crisis by the World Health Organization (WHO) in March 2020, highlighted the need for the global community and individual countries to address challenges in the vaccine ecosystem and to take steps to develop a vaccine ecosystem that is capable of meeting both today’s challenges and tomorrow’s needs. In particular, the pandemic underscored the need for countries to create an environment which allowed for rapid vaccine development and roll out to mitigate associated health and socioeconomic repercussions. Different platforms, including messenger ribonucleic acid (mRNA) vaccines, emerged as pivotal tools in combating the pandemic. The pharmaceutical industry is an important and growing sector for many economies worldwide. In 2020, global revenues from the pharmaceutical sector surpassed US$ 1.3 trillion and are expected to reach US$ 1.6 trillion by 2025 (3). While the sector remains dominated by the United States of America (the USA), the European Union (EU) and Japan (4), there are increasing opportunities for emerging markets. It is widely recognized that for many countries, a stronger pharmaceutical sector can help drive economic development, improve health outcomes and increase overall country resilience in a post COVID-19 era (5). Vaccine manufacturing in Africa is currently very limited, with only 1% of the 1.3 billion vaccines administered each year manufactured locally. However, recent developments – including 2 explicit statements of political commitment by national governments – suggest that multiple African countries have the potential to expand their pharmaceutical sector to include vaccine manufacturing. Several African countries, including Tunisia, have indicated their interest in expanding vaccine manufacturing, both to meet domestic demand and to supply other countries in the continent in the coming years. There are several well recognized socioeconomic and public health benefits to vaccine manufacturing, such as the development of a diversified, value-adding industry (providing skills development and employment opportunities) and improved vaccine supply. Greater self-reliance in terms of vaccine supply is desirable as it can help protect countries against the impacts of future infectious disease outbreaks and pandemics, including Africa-specific diseases (1,6). However, success in this area remains contingent on unlocking barriers and creating an enabling environment which is attractive to potential investors. The vaccine landscape in Tunisia Tunisia currently imports all its vaccines, with the exception of the Bacille Calmette-Guérin (BCG) vaccine which is produced on an intermittent basis by the Institut Pasteur de Tunis (IPT). While Tunisia has a number of public and private institutions that are engaged in pharmaceutical- related activities as well as biomedical research capacity, to date neither have been mobilized to produce vaccines. This poses challenges in managing any future infectious disease outbreak or pandemic such as COVID-19 (3). In the wake of the COVID-19 pandemic, Tunisia has expressed its ambition to counter the risks associated with import dependency by strengthening its domestic vaccine manufacturing capacity. Its goal is to become self-sufficient to meet local demand for vaccines and ensure vaccine safety (1,6). In this regard, WHO’s announcement of its intention to designate Tunisia, alongside five other African countries, as a technology recipient for mRNA vaccines is a positive development. The relatively simple mRNA vaccine manufacturing process, at least compared with conventional vaccines, makes this technology the obvious choice as the basis for extending the country’s vaccine manufacturing capability. Nevertheless, the mRNA technology hub, while primarily set up to address the COVID-19 emergency, offers a gateway for expanding manufacturing capacity for other products, putting recipient countries in the driver’s seat when it comes to making decisions about the kinds of vaccines and other products, they need to address their public health priorities (3). Supporting countries to strengthen vaccine manufacturing capacity Many low- and middle-income countries (LMICs) are looking to build their domestic manufacturing capacity to ensure timely access to quality vaccines and to strengthen national health security, particularly during health emergencies such as the recent COVID-19 pandemic. Increasingly therefore, WHO’s Local Production and Assistance (LPA) Unit has been receiving requests from Member States for support in strengthening their pharmaceutical sector, including their vaccine production capacity, and many perceive technology transfer as an important component of this process. The purpose of this work, an evaluation of the pharmaceutical manufacturing ecosystem in Tunisia, is to provide technical input to the LPA Unit to inform WHO’s programme activities aimed at strengthening domestic production and technology transfer for improving access to quality-assured, safe and effective pharmaceutical products, including vaccines. It is based on 3 the premise that knowing and understanding the vaccine ecosystem in a given country is an important first step towards strengthening and improving it. Indeed, in a post-COVID-19 era, understanding the vaccine ecosystem has become a priority for every country, as well as the global community. Aims and methodology The aim of this evaluation was to describe the existing vaccine ecosystem, to identify opportunities (i.e. drivers) and challenges (i.e. bottlenecks), and to provide pragmatic recommendations to bolster local vaccine manufacturing in Tunisia. The evaluation employed a mix of primary and secondary research methodologies. The primary research methods involved conducting surveys and direct interviews with manufacturing companies and policy-making bodies. This was supplemented by a literature review (secondary research). Information obtained from approaches was amalgamated and synthesized to generate this report. Further details about the research methods adopted are provided in Table 1. A list of participants is attached as Annex 1. A list of the resources that were consulted as part of the literature review is included as Annex 2. The present report is structured as follows. Part I provides a detailed description of Tunisia's vaccine and biologicals ecosystem overall, covering the government policies, financing conditions and incentives as well as the regulatory framework. Part II focuses on the nascent landscape for mRNA vaccines. Part III covers the existing production capacity (vaccines and biologicals/biosimilars) and assesses procurement strategies and export potential. Finally, Part IV provides an overview of Tunisia’s vaccine ecosystem, highlighting current barriers and future needs, and delineating a roadmap that will enable Tunisia to develop its local vaccine manufacturing capabilities and enhance its ability to contribute to regional health security and economic growth. 4 Table 1: Evaluating Tunisia’s pharmaceutical manufacturing ecosystem: research methods Stage Description Primary research Interviews and surveys The primary research involved direct interviews and a written survey. The survey comprised questions covering the three main areas: • the vaccines and biologicals landscape, • the regulatory landscape and value chain, and • government procurement and export. Participant selection The sample comprised 15 participants, including 10 from manufacturing companies and 5 from policy-making bodies or other public entities. The selection aimed to gather diverse perspectives from key stakeholders in the ecosystem. Data collection period The survey was conducted from 1 June 2022 to 9 August 2022. Data analysis Quantitative analysis: Survey responses were analysed quantitatively to derive statistical insights and trends, especially when there were numerical or rating- based questions. Qualitative analysis: Open-ended responses and interview transcripts were subjected to qualitative analysis. This involved categorizing and interpreting responses, identifying recurring themes and extracting key insights. Secondary research Literature review An extensive review of the existing literature and recent market research studies was conducted. This involved gathering information from academic papers, industry reports, published articles and any available data sources relevant to the evaluation's focus areas in Tunisia. Data synthesis and report generation Integration of findings The data collected from both primary and secondary research streams were synthesized. Similarities, discrepancies or complementary information between primary survey results and secondary research findings were identified. Cross verification Information obtained from primary and secondary sources was cross-checked to ensure consistency and reliability. Report compilation The synthesized data was then compiled, structured, and organized into a cohesive report format. This involved presenting key findings, insights, recommendations, and any actionable points derived from the evaluation. 5 Part I: Vaccines and biologicals 6 1.1 The vaccines and biologicals ecosystem As noted in the Introduction, Tunisia has made strengthening its vaccines and biologicals ecosystem a priority. However, before taking steps to increase vaccine manufacturing capabilities, which at present are limited to BCG vaccines and selected related products, it is important to first know and understand the existing vaccines and biologicals landscape. Below, the vaccine and biologicals manufacturing ecosystem in Tunisia is described. Material is presented under the following subheadings: • existing manufacturing capability • government policies • government incentives • financing conditions • the regulatory system • research and development (R&D) capabilities • the patent system • technology transfer activities. 1.1.1 Existing manufacturing capability Tunisia is home to 41 drug manufacturing companies, some operating as joint ventures with international firms to produce medicines for human use, mainly generic medicines but also some under-licence products, vaccines and biosimilars (Annex 3). Most drug manufacturing companies were founded by Tunisian professionals following the sector’s privatization in the 1990s and the introduction of favourable tax incentives, including exemption from import duties, tax breaks and improved conditions for public bids (see also Financing conditions). The market environment has changed rapidly over the past decade, as growing competition has prompted drug manufacturers to launch new products. Moreover, Tunisia has encouraged the local production of generic medicines to reduce its health care costs and provide the population with better access to medicines. Generics now account for two thirds of local production, with the remainder being licensed medicines (7). Between 2014 and 2019, domestic sales of medicines grew by more than 30% and now provide around half (51%) of Tunisia’s domestic consumption (8–10). The rapid growth in Tunisia’s domestic manufacturing capabilities, coupled with the government efforts to promote exports, has translated into a surge in exports of medicines – which have nearly tripled over recent years – confirming Tunisia’s potential as a regional export hub toward Europe, Middle East and sub-Saharan Africa (8–10). See also Part III. 1.1.2 Government policies The evaluation identified four key policies which are relevant to the development of an expanded pharmaceutical sector in Tunisia: • National Health Policy 2030, • Industrial Strategy and Innovation to 2035, • Three-year Development Plan 2023–2025, • National Pharmaceutical Policy. 7 The Tunisian government approved its National Health Policy 2030 on 7 April 2021 (11). This policy was developed through societal dialogue and has as its core tenets and objectives: • family and community health at the heart of the health system; • a package of essential services for all; • a unified basic plan for all; • a public sector equipped with the necessary means to deliver health equity, training and research; • protection of the health of citizens. Tunisia’s industrial strategy for 2035 was developed at the request of the Ministry of Industry with the assistance of a consulting firm and funding from the African Development Bank (AfDB). It was finalized in July 2022. The Industrial Strategy and Innovation for 2035 aims to design and introduce the necessary changes to strengthen Tunisia’s position as an attractive space for investment and co-production of goods and services with national and international manufacturers (12). Within this broader strategy: • The pharmaceutical industry was identified as a promising candidate as part of the strategic action, "Encouragement of the development of the industry in the carrier niches". • The "biological drugs" sector was identified as one of several promising sectors within the framework of the strategic action, "Development of collaborative projects in sectors of excellence", that the State can develop with private economic actors. The Ministry of Industry subsequently drafted a policy document entitled, “The pact for the development of the competitiveness of the pharmaceutical sector” in late 2022. This policy initiative aims to mobilize and coordinate the actions of the public and private sectors, accelerate the pace of sectoral development, increase national coverage, promote investment, and job creation, and support the development of exports with higher added value. Drug development from biotechnology was identified as one of the policy’s priority axes that was considered achievable by 2027. Two further government policies mention vaccines and biologicals. The Three-year Development Plan 2023–2025, which was approved by the Ministry of Health in June 2022, includes the promotion of the production of vaccines and biologicals and strengthening the field of R&D (13). Likewise, the National Pharmaceutical Policy, currently under development under the auspices of the Ministry of Health, also makes provision for the promotion of the production of vaccines and biologicals. The National Pharmaceutical Policy is expected to be approved before the end of 2022. The Ministry of Health has also been working since the beginning of the pandemic to constitute a clear and futuristic strategy to promote vaccine manufacturing. In June 2021, the ministry decided to establish a working group to develop a strategy for the manufacture of vaccines in Tunisia and to monitor its implementation. The working group was also tasked with preparing the specifications for the vaccine manufacturing projects. This group, which is chaired by the Minister of Health and whose secretariat is provided by the Directorate of Pharmacy and Medicine (DPM), has held periodic meetings since its creation. 8 1.1.3 Government incentives In September 2016, the Tunisian government established a new legislative framework as part of a national effort to increase investment. This framework provides for a range of fiscal incentives for investors in projects of “national interest” and in “priority sectors”, the latter of which includes the biotechnology and pharmaceutical industries as well as clinical R&D centres (see Annex 4). The new framework is comprised of the following legal instruments (14,15): • Investment Law: Law n°71 of 2016, promulgated on the 30th of September 2016; • Fiscal Incentives Law: Law n°8 of 2017, promulgated on the 14th of February 2017; • Financial Incentives Decree: Decree n°389 of 2017, promulgated on the 9th March 2017. The framework is intended to promote investment by: • setting clear and transparent rules regarding the list of administrative authorizations required for market access, including those governing the procedures, conditions and the period of their issuance; • establishing a common legal framework which includes the definition of terms related to investment operations and the governance authorities with responsibilities for investments; • improving governance by creating new governance institutions and investment incentives; • clarifying an investor’s Guarantees and Obligations and introducing the principle of equality between Tunisian and foreign investors; • reinforcing the principle of free international transfer of funds for foreign investors. The Investment Law 2016-71 announced the creation of the Tunisia Investment Authority (TIA), a public body attached to the government ministry in charge of investment. The TIA ensures the permanent secretariat of the Higher Council of Investment. TIA is the unique interlocutor for local and foreign investors. With its network of partners, it is positioned as the facilitator for the realization of investment projects through reliable information, fluid procedures and customized support. See also Box 1. The financial incentives that apply to the pharmaceutical industry (14,15) that were introduced by the 2016 legislative framework, specifically the 2016 Investment Law, are articulated in Articles 19 and 20: • Under Article 19 (applies to projects whose investment value is < 50 million Tunisian dinars and/or have an employability capacity of < 500 jobs): - a premium for the increase in value-added and competitiveness under the achievement of direct investment operations in priority sectors set at 15% of the approved investment cost with a ceiling of 1 million Tunisian dinars, or - a regional development premium set at 15% of the approved investment cost with a maximum of 1.5 million Tunisian dinars or 30% of the approved investment cost with a maximum of 3 million Tunisian dinars, or - a premium of development of the employability capacity for the assumption of responsibility by the State of the employer's contribution to the legal system of social security (for the first 3–10 years from the date of entry into actual activity); 9 • Under Article 20 (applies to projects of national interest): - an investment premium within the limit of the third of the investment cost including the expenses of the intramural infrastructure works, with a maximum of 30 million Tunisian dinars, or - a premium of development of the employability capacity for the assumption of responsibility by the State of the employer's contribution to the legal system of social security (for the first 10 years from the date of entry into actual activity), or - deduction of profits from the corporate tax base for up to 10 years. 10 Box 1: Tunisia Investment Authority (TIA) The TIA was created to fulfil the following functions: • to act as the unique interlocutor for investors; • to take an active role in developing investment strategy and policy reforms; • to foster interagency coordination. www.tia.gov.tn TIA services may be summarized as follows: - assisting the investor during their investment experience by providing unique interlocutor services; - resolving investors’ queries; - coordinating the investment promotion agencies to ensure consistency in fostering private sector investment - issuing the investment declaration certificates for the projects whose investment amount exceeds 15 million Tunisian dinars; - evaluating applications for granting bonuses and incentives for projects whose investment amount exceeds 15 million Tunisian dinars and/or are of national interest; - assessing and evaluating projects of national interest; - providing post launch support services to investors; - receiving and guiding the investor in the process of legal incorporation of the company and obtaining authorizations. TIA works in close coordination with Tunisia’s investment agencies, namely: • The Agency for the Promotion of Industry and Innovation (APII): industrial and service projects including pharmaceutical projects www.tunisieindustrie.nat.tn • The Foreign Investment Promotion Agency (FIPA): prospection and accompaniment of foreign investors www.investintunisia.tn www.cepex.nat.tn • The Export Promotion Center (CEPEX): Commercial Single Desk: accompaniment of Tunisian companies for expanding into international marks 11 To be considered as a project of “national interest”, projects must contribute to the realization of at least one of the following four national economic priorities: • an increase in the value-added, competitiveness, export capacity and technological content of the Tunisian economy at the regional and international levels, as well as the development of priority sectors; • creation of jobs and enhancement of human resources skills; • inclusive regional development; • sustainable development. In addition, projects of national interest must fulfil at least one of the following criteria: • minimum investment value of 50 million Tunisian dinars; • creation of a minimum of 500 jobs over a 3-year period (from the date of the commencement of the operation of the project). For investment projects whose investment value exceeds 15 million Tunisian dinars and/or are of national interest, the TIA (Ministry of Economy) is tasked with assessing and evaluating applications for granting bonuses and incentives. For other projects, this role falls to the Agency for the Promotion of Industry and Innovation (APII) (Ministry of Industry). Other incentives which apply to the pharmaceutical industry, and thus to vaccines, biologicals and other pharmaceutical products (3), include: • Law N° 94-127 dated 26 December 1994: the finance law for the year 1995 stipulates the exemption of customs duties on the import of raw materials and other items necessary for the manufacture of medicines that have no locally manufactured equivalent. • Governmental decree n° 2017-419 dated 10 April 2017 (fixing the list of equipment and conditions that are eligible for incentives stipulated by articles 3, 4 and 5 of law n° 2017- 8 dated 14 February 2017, amending the tax benefit system): stipulates an exemption from customs duties and value-added tax (VAT) payments for imported equipment that has no locally manufactured equivalent and suspension of VAT for locally manufactured equipment. • Decree n° 2014-1039 dated 13 March 2014 (regulating public procurement): in the event of a tender or call for products, accords domestic products a 10% advantage over international tenders. In sum, while there are financial incentives for investors in the pharmaceutical sector, they are no different to those offered to investors in other priority sectors. Tunisia does not currently offer specific incentives to the pharmaceutical sector and is weakly positioned on the financing of R&D. 1.1.4 Financing conditions Financing instruments and funding The Tunisian financing system includes a wide range of financial support mechanisms and instruments that cover all stages of the development of a business or company, starting from 12 the initial concept, through to the creation of the company, its operation and growth, and finally its expansion into international markets. The available financing mechanisms cover all types and sizes of businesses and are managed by public and private structures or nongovernmental organizations (16). Table 2 describes the range of domestic funding sources that are available to support vaccine and biologicals manufacturing projects in Tunisia. This table includes both private and public (state) funding mechanisms and describes how in principle these could support new R&D or manufacturing projects; a full list of incubators and accelerators, seed and start-up funds, business angels and venture capital investment companies and mutual funds is given in Annex 5. Funding is also available from private and public banks, of which there are around 20 (Annex 6), including the Banque de Financement des Petites et Moyennes Entreprises (BFPME), a public bank (Table 2). Other public sources of funding listed in Table 2 include The Tunisian Investment Fund (17) and various guarantee funds (18). International funding sources are listed in Table 3. Table 2: New business financing options Funder Description Private Incubators and accelerators These are structures that help entrepreneurs by supporting them in the creation of their business and during the first months of their launch. They offer a wide range of services such as the organization of workshops, personalized coaching, help with drafting the business plan, legal advice and help in raising start-up funds from financial institutions. Some incubators offer young entrepreneurs a workspace or access to research laboratories, as well as access to a network of professionals. Others provide financial support by conducting market research, or patent filing for companies selling new products. This support is in the form of repayable advances. Seed and start- up funds These funds are available to investors, before the legal incorporation of the company, to finance R&D, prototypes, business plans, legal advice, etc. Business angels The term “business angel” is widely used to describe a person (natural or legal) who intervenes in the launch phase of the company with a contribution to the capital and a contribution in knowledge, experience and networking. The organization grouping together business angels in Tunisia is the Carthage Business Angels Association. Venture capital investment companies and mutual funds The role of the venture capitalist and mutual funds is to strengthen investment opportunities, equity and quasi-equity of companies established in Tunisia and not listed on the Bourse des Valeurs Mobilières de Tunis, the Tunisian stock exchange. They intervene by helping with subscription or acquisition of ordinary shares, investment certificates, contributing securities, bonds convertible into shares and generally any other category relating to equity or quasi-equity. Public The Tunisian Investment Funda The Tunisian Investment Fund ensures the release of bonuses provided for by the Investment Law and the subscription to venture mutual funds, venture capital funds and seed funds in a direct or indirect way. The resources of the fund are made up of resources from the state budget, loans and donations granted from within and outside the country and other resources (17). 13 Table 2: continued Funder Description Small and medium business corporate bankingb The Banque de Financement des Petites et Moyennes Entreprises, a public bank, can participate in a business launch by granting participatory loans in order to strengthen the equity capital of small- and medium-sized enterprises in the creation or expansion phase. The bank finances the initial tangible or intangible investment or any activity of production of goods or services. It is a medium/long-term loan co-financed by the local banks, with the option of full funding. Funding covers investment projects with increased asset costs. Net fixed assets are between 100 000 and 15 million Tunisian dinars. Guarantee funds Guarantee funds contribute by guaranteeing the capital of certain companies benefiting from certain categories of loans granted by credit institutions to small- and medium-sized enterprises in industry and services and certain categories of holdings of venture capital companies, mutual venture funds and seed funds. The management of those funds is entrusted to Société Tunisienne de Garantie. The resources of the guarantee funds are: the grants from the Tunisian State and other donors, the investment income of the balances of the guarantee funds, the contribution of the beneficiaries of the credits accepted to the guarantee and the contribution of the Société d’Investissement à Capital Risque, the Fonds Communs de Placements à Risque and the Fonds d'Amorçage (18). Available guarantee funds vary according to the risks covered, their conditions, eligibility criteria and their method of intervention. a Eligibility criteria: to benefit from the resources of the Tunisian Investment Fund, companies must fulfil the following cumulative conditions: participate in priority sectors (e.g. pharmaceutical sector) and activities benefiting from regional development bonuses and be an established company with investments not exceeding 15 million Tunisian dinars (including working capital). The Fund also covers expansion investments up to a value of 15 million Tunisian dinars, including fixed assets. b Extension and restructuring loans are available to small- and medium-sized enterprises that have benefited from a medium- and long-term loan from the Banque de Financement des Petites et Moyennes Entreprises. Loans of up to 60% are available, with a limit of 300,000 Tunisian dinars for projects located in regional development zones and 200,000 Tunisian dinars for projects located outside the regional development zones. There is a 10-year maximum reimbursement period and a maximum 4-year grace period. Foreign investments and currency regulations Tunisia’s financial systems are generally supportive of foreign investment by allowing the free movement of money from current transactions and profits gained from selling previous investments made in foreign currency (24,25). However, any other financial actions or obligations, including the paying of debts to other countries do require permission. The movement of assets between Tunisia and other countries must be done through the Central Bank of Tunisia. Alternatively, authorized financial intermediaries approved by the Minister of Finance, upon the recommendation of the Governor of the Central Bank of Tunisia, can also handle these transactions. 14 Table 3: International funding sources Funding source Description European Investment Bank www.eib.org The European Investment Bank (EIB) has worked with Tunisia since 1979. The Bank operates in Tunisia in the framework of the European Neighbourhood Policy (ENP) and other EU bilateral agreements. In cooperation with local Tunisian banks, investment funds and microfinance institutions, EIB supports micro, small and medium-sized enterprises creating jobs and boosting growth. Local companies have been able to benefit from financing agreements, signed with several Tunisian intermediary banks, dedicated to small and medium-sized enterprises, with disbursements reaching €320 million (19). International Finance Corporation www.ifc.org The International Finance Corporation (IFC) is a member of the World Bank Group and advances economic development and improves the lives of people by encouraging the growth of the private sector in developing countries. IFC’s lending activities are mainly funded through a very wide range of benchmark and bespoke debt products in various currencies. Investors in IFC’s bonds are invariably supporting the achievement of the Sustainable Development Goals. As part of the World Bank Group, IFC has two overarching goals—ending extreme poverty by 2030 and boosting shared prosperity—that are aligned with the Sustainable Development Goals. Through direct investments and advisory services, IFC provides private sector solutions that lay the foundation for sustainable and inclusive economic growth (20). Agence Française de Développement www.afd.fr The Agence Française de Développement (AFD) Group funds, supports and accelerates the transition to a fairer and more sustainable world. AFD has funded more than 4,000 projects in France’s overseas departments and territories and 115 other countries (21), the majority of which have a focus on climate, biodiversity, peace, education, urban development, health and governance. African Development Bank www.afdb.org The overarching objective of the African Development Bank (AfDB) Group is to spur sustainable economic development and social progress in its regional member countries, thus contributing to poverty reduction. In the area of vaccine manufacturing, the objective is to finance 2-3 manufacturing projects per year in the next 5 years (22,23). The AfDB can invest US$ 3 billion to 2030 to implement its part of this continental vision, including developing infrastructure that would have benefits well beyond the pharmaceutical industry. Through its diverse finance products, the AfDB is articulating a focused Pharmaceutical Industry Development Action Plan and aims to mobilize, on average, US$ 100 million per year directly to finance the development of the industry and US$ 200 million per year to support infrastructure development. Implementing the strategy through multi-sectorial self-reinforcing programmes could enable AfDB and other players to achieve faster and more transformative impact. Tunisia’s financial systems also permit resident companies to borrow freely from non-residents in a foreign currency. The amount that can be borrowed is however limited to 10 million Tunisian dinars per calendar year for lending institutions and 3 million Tunisian dinars for the other companies. When granted for a period of more than 12 months, these loans are borrowed freely and without a limit for the amount for the lending institutions and within a limit of 10 million Tunisian dinars per year for the other companies. However, the lending institutions must be 15 subject to a prior voluntary assessment from a rating agency or listed on the stock exchange market. Transfers related to reimbursement in principal and interest payment of these borrowing are free. Transfers regarding current transactions are also free. This applies to trade transactions, transactions related to corporate production, transport, insurance, capital income, operations concerning banking and financial expenditures, personal operations, public sector operations, and general operations such as subscriptions, advertising, entertainment and show contracts. 1.1.5 The regulatory system The evolution of the regulatory environment surrounding medicines and pharmaceutical products in Tunisia is summarized in Fig. 2. Currently, the pharmaceutical sector is regulated and controlled by the Ministry of Health and a number of public institutions, namely: • The Directorate of Pharmacy and Medicine (DPM), • The National Laboratory for Drug Control (LNCM), • The Directorate of Pharmaceutical Inspection (DIP), • The National Pharmacovigilance Centre (CNPV), • The National Agency for Sanitary and Environmental Control of Products (ANCSEP). Fig. 2: Key milestones in the evolution of Tunisia’s pharmaceutical industry and associated regulatory bodies Source: TIA, 2022 (26) 16 Responsibility for the regulatory oversight of the distribution of medicines and pharmaceutical products rests with the Central Pharmacy of Tunisia (PCT)1, while the National Authority for Evaluation and Accreditation in Health (INEAS) 2 supervises the accreditation of health establishments and the evaluation of technologies and health interventions. These bodies are jointly responsible for monitoring and guaranteeing the quality, efficacy and safety of medicines and pharmaceutical products in the country (Fig. 3). ANCSEP, National Agency for Sanitary and Environmental Control of Products; CNPV, The National Pharmacovigilance Centre; DIP, The Directorate of Pharmaceutical Inspection; LNCM, The National Laboratory for Drug Control; PCT, Central Pharmacy of Tunisia Fig.3: Public institutions forming the national regulatory authority in Tunisia Source: The Directorate of Pharmacy and Medicine In 2022, the Minister of Health announced the government’s intention to replace the existing regulatory bodies with a single body to oversee the regulation of medicines and other pharmaceutical products including vaccines. It is anticipated that this switch to a single agency will take place in the near future with the government indicating that it plans to pass the necessary legislation before the end of 2022. The new Agency for Medicines and Health Products will provide increased fluidity, facilitating the adoption of more efficient administrative procedures which in turn will enhance user satisfaction, engender international recognition of locally manufactured products and support the development of the national pharmaceutical industry. The creation of the new agency is part of Tunisia’s efforts to upgrade its regulatory system and to attain a national regulatory agency (NRA) maturity level 3 certification. Tunisia has regulations covering the manufacturing and registration of medicines and pharmaceutical products (Fig. 2) that date back to the 1980s, and which are in line with international standards. While there is a 2018 guideline covering the registration of biosimilars, specific guidelines for vaccines are lacking and will need to be produced. To align with international standards, these guidelines will need to cover the manufacturing process, clinical 1 www.phct.com.tn 2 www.ineas.tn 17 trials and registration of vaccines. Given the biological nature of vaccines, there is a system in place for the supervision of quality control of all the steps from production to supply. A batch- by-batch release system has been in place for several years. This is equally applicable to both imported and locally produced vaccines. 1.1.6 R&D capabilities Tunisia’s pharmaceutical sector is supported by a maturing ecosystem marked by the emergence of regional leaders in the fields of R&D and healthcare innovation, including BiotechPôle Sidi Thabet and the Institut Pasteur de Tunis (8). See Box 2. In addition to R&D capabilities (Box 2), Tunisia has several well-established government- supported public agencies that have been set up to promote technology and innovation, including the Agency for Promotion of Research, Innovation, and Business Creation (APRICE), the National Observatory of Science and Technology (ONST) and the APII (Table 4). In addition, there are a number of programmes which have been created to foster and support collaborative research and technological innovation projects between research structures, industry and technical centres, such as the Programme of Federated Research (Table 4). With a total of 14 research centres, and more than 18 000 researchers (full-time equivalent), Tunisia ranks among the countries with the best capacity in science technology innovation (STI). Its R&D capability however is less well developed and would benefit from a stronger knowledge commercialization cycle with better integration of technology and scientific research achievements. Currently, researchers are focusing on their academic careers and are spread over a large spectrum of public R&D institutions (28). Tunisia’s favourable environment for pharmaceutical industries is also reflected at the clinical investigation level as Tunisia is now recognized as a major destination for clinical trials in Africa thanks to the availability of infrastructure, researcher expertise, and established regulatory and ethics structures. Over the last few years, Tunisia has succeeded in attracting a number of global clinical research organizations such as Quintiles, PRA Health Sciences Inc. and Parexel, which have conducted several clinical trials. Furthermore, several regional clinical research organizations, including, for example, MCT-CRO and Eshmoun have established their headquarters in Tunisia. (see also Annex 7). The Tunisian government has set up a training system aimed at meeting the country’s human resource needs in several high-quality pharmaceutical and paramedical specialities (see also Annex 8). 18 Box 2: Key leaders in the field of pharmaceutical R&D The Institut Pasteur de Tunis (IPT) is a publicly-funded scientific research establishment, and member of the Institut Pasteur International Network. Established in 1893, and now operating across 18 laboratories (some of which are regional reference centres), its main roles are: • Conducting investigations, missions, analyses and scientific research of human or animal public health relevance; • Developing biological products such as serums and vaccines; IPT is the only producer in Africa of the BCG vaccine and its immunotherapeutic form used for bladder cancer; • Training of students and young researchers, as well as industry employees. www.pasteur.tn The BiotechPôle Sidi Thabet is a technopole fully dedicated to the biotechnology, pharmaceutical and para-pharmaceutical industries, as well as applied health engineering. Its main functions are: www.BiotechPôle.tn • Developing and producing biologicals locally via a dedicated public- private biotech production platform; • Fostering the emergence of strategic collaborative R&D projects based on a “triple helix” innovation model; • Stimulating and managing technology transfers and valuing R&D results; • Encouraging the creation of innovative health-tech companies via dedicated incubation programmes; • Developing highly skilled human resources in the field of biotech & health tech through training and coaching. The Biotechnology Center of Sfax was created in 1983 to promote innovation and the field of biotechnology. It currently operates seven research laboratories and one special unit and employs 30 researchers and nearly 50 engineers and technicians. It supports innovation in the bio-industry sector by: www.cbs.rnrt.tn • Positioning itself in the region as an active player in the industry thanks to 50 cooperation projects, including four European projects; • Realizing under contract studies for the industry (16 agreements signed with manufacturers); • Providing incubation services for innovative health-tech companies. 19 Table 4: Agencies and programmes promoting R&D and innovation Organization Description Agencies promoting technological innovation Agency for Promotion of Research, Innovation, and Business Creation (APRICE) www.anpr.tn APRICE is a governmental agency whose primary mission is providing services to professionalize the management of research activities in partnership with socioeconomic operators. It strives to achieve national priorities in technological innovation by identifying promising research areas and promoting companies that can advance those areas. National Observatory of Science and Technology (ONST) www.tunisieindustrie.nat.tn ONST undertakes projects for clients interested in identifying and strategizing policy and programme development related to research and innovation. Agency of Promotion of Industry and Innovation (APII) www.tunisieindustrie.nat.tn APII is a governmental agency responsible for the implementation of government policies related to the promotion of the industrial sector and innovation. APII provides support services to entrepreneurs and enterprises. Its mission is to spread the culture of innovation among businesses by promoting capacity building and incentivization mechanisms. It plays a crucial role in interfacing and supporting the implementation of the R&D valorization process and the transfer of research results. It promotes investment in industrial development. Programmes fostering collaboration The Valorisation of Results of Research (VVR) The VVR programme was established in 1992 as a means of strengthening the partnership between research structures and the socioeconomic fabric such as technical centres, companies and professional groups. Projects are funded by the Ministry of Higher Education and Scientific Research following an "open" call for proposals. Beneficiaries are public research structures (e.g. research centres, research laboratories, research units) with the possibility of partnership with economic enterprises. Projects are typically of 3 years duration (27). VRR projects aim to bring the results obtained by the research laboratories to market usually through: • The development of prototypes of new systems designed in research structures or the substantial improvement of a system, a process, a device or a product. This type of valorization will have to lead to a protection of the intellectual property, in the form of patent or copyright. • The promotion of the transfer of research results from research structures to the productive system. To this end, and in cases when a partner company is involved, that partner company must part finance the project (at least 10%). 20 Table 4: Continued Programme Description Program of Federated Research (PFR) The PFR was set up by the Ministry of Higher Education and Scientific Research in 2002. Projects are funded by the Ministry of Higher Education and Scientific Research following a call for proposals. Each PFR project is piloted and managed by a Project Carrier Structure which is a public structure with a vocation to support and sustain research and technological development. The typical duration of a PFR project is 4 years. The PFR aims to mobilize skills and the creation of synergies between research structures (laboratories and research units) and socio- economic partners, both public or private, whether companies, specialized organizations, associations, or others, in order to provide concrete solutions to targeted problems in connection with the socio- economic development of the country (27). Program of National Research and Innovation (PNRI) The PNRI is a programme that finances R&D, innovation projects, improvements in industrial capacities, and modernization of production processes, through the consolidation of the cooperation and the partnership between industrial companies, the research structures and the technical centres. The programme is under the supervision of the ministry in charge of industry. To be eligible for funding, a project must associate an industrial company with a technical centre and a public research organization (centre, laboratory or research unit) for 2 years at maximum. It must also demonstrate significant innovation and a minimum contribution of the industrial partner of 20% of the project cost (27). 1.1.7 The patent system Tunisia is a member of the World Intellectual Property Organization (WIPO), a signatory to the Patent Cooperation Treaty, and party to the Madrid Protocol for the International Registration of Marks. Tunisia is also a signatory of the Paris Convention for the Protection of Industrial Property and the Paris Convention Regarding Trademarks, as revised in The Hague, London and Stockholm and is a signatory of the United Nations Conference on Trade and Development (UNCTAD) agreement on the protection of patent and trademarks. Tunisia has a long history of protecting inventions by patents, which dates back to the Paris Convention of 1883 on the protection of industrial property of which Tunisia is a founding member. Patent legislation and laws have been in place since 1888 (the beylical decree of December 26, 1888) and have been the subject of regular revisions to ensure that Tunisia’s laws are compatible with the requirements of the World Trade Organization (WTO) Agreement and in particular the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). This is the basis of current legislation (law N° 2000-84 of 24 August 2000) on patents and its application decrees (29). Article 78 of the Patent Law provides that in order to meet the needs of the national economy, safeguarding environment, defence or national security, the minister in charge of the relevant 21 industry can put the owners of patents on notice to undertake their exploitation. Also, Article 78 provides that if the interests of public health require it, patents granted for medicines may, under certain circumstances (e.g. if the medicines in question are only available to the public in insufficient quality or quantities or at abnormally high prices), be subjected, at the request of the minister responsible for public health, to the system of compulsory licensing by order of the minister responsible for industry. In practice, these measures are necessary in order to facilitate and promote access to medicines for all. These provisions are inspired by the provisions of the TRIPS Agreement and in particular Article 30 (29). The agency responsible for patents and trademarks in Tunisia is the National Institute for Standardization and Industrial Property (INNORPI) (see Box 3). Tunisia’s various intellectual property laws enshrine the equal treatment of foreign registrants and Tunisian nationals. Registration and maintenance requirements for Tunisian patents, trademarks and copyrights are straightforward and relatively inexpensive in comparison to similar requirements in, for example, the USA. In 2016, Tunisia signed an agreement with the EU that allows automatic patent protection in Tunisia for European patent applications through the European Patent Organization. The agreement came into effect in December 2017 (30). Box 3: The National Institute for Standardization and Industrial Property The National Institute for Standardization and Industrial Property (INNORPI) is the agency responsible for patents and trademarks: www.innorpi.tn • issues patents, registers trademarks, service marks and industrial designs; • receives and registers all acts affecting industrial property rights; • maintains the central trade register; • represents Tunisia at the International Organization for Standardization (ISO), the International Electrotechnical Commission (IEC) and the WIPO. 1.1.8 Technology transfer activities A number of Tunisian companies have already established successful collaborations with international partners which involve technology transfers. To date, these have mainly supported the manufacture of biosimilars. Medis laboratories have marketing authorizations for biosimilar drugs based on erythropoietin, insulin glargine and human insulin. The production of these drugs has been the subject of a technology transfer with various partners specialized in the manufacture of biosimilar products, including the Argentinean laboratory, Biosidus and the Indian laboratory, Biocon. Unimed laboratories have submitted a marketing authorization application, which is currently being studied by the NRA, for human insulin with a technology transfer with Emirati laboratories (Julphar). Teriak and Dorcas have in turn technology transfer projects for the manufacture and 22 registration in Tunisia of some biosimilar drugs with Iranian laboratories (Aryogen Pharma), Argentine laboratories (Biosidus) and Mexican laboratories (Probiomed).3 1.2 Drivers, bottlenecks and challenges The key features – in terms of existing structures and strategic policy directions – of Tunisia’s vaccine and biologicals manufacturing ecosystem which have emerged from the present analysis are summarized in Box 4. Although several programmes and projects are still in the study or design stage, the overall level of activity demonstrates the country's commitment to promoting the manufacture of vaccines and biotechnology products. Box 4: Key features of the vaccine and biologicals landscape in Tunisia • About 40 manufacturing companies are currently operating in Tunisia (some as joint ventures with international firms) and producing medicines for human use (mainly generic medicines but also under-licence products, including vaccines and biosimilars). • Several manufacturers with the prerequisites for manufacturing sterile products have expressed an interest in producing vaccines and biological products. • Tunisia has created a new legislative framework to incentivize investment in projects of “national interest” and “priority” sectors which include the biotechnology and pharmaceutical industries as well as clinical R&D. • The Tunisian financing system offers a wide range of financial support instruments that cover all stages of the development of a company. • Tunisia has regulations for manufacturing and registration that date back to the 1880s and are in line with current international standards. There is a specific guideline for biosimilars registration, but specific guidelines for vaccines will need to be created and published in line with international standards. • Tunisia is working actively to upgrade its national regulatory system and to succeed in reaching maturity level 3. • Tunisia’s pharmaceutical sector is supported by a maturing ecosystem, one in which companies such as BiotechPôle Sidi Thabet and Institut Pasteur de Tunis are emerging as regional leaders in the fields of R&D and healthcare innovation. • Tunisia’s favourable environment for pharmaceutical industries is also demonstrated by the fact that Tunisia is now a major destination for clinical trials in Africa, thanks to the availability of infrastructure, researcher expertise, and regulatory and ethics structures, including well-established patent legislation. The ecosystem analysis highlighted several areas of strength which offer opportunities for expanding the country’s capacity to manufacture pharmaceutical products, including vaccines. Most notably: • Several local manufacturers have the potential to adopt biotechnology based on their current expertise and experience in sterile products. Six manufacturers have expressed their interest in producing vaccines and their readiness to start with fill and finish 3 Source: Expert interview. 23 steps,(4) four of which are already licensed to manufacture biosimilars and two have marketing authorization for biosimilars. • Several international tech partners are interested in collaborations for technology transfer in Tunisia: Quantoom, Univercells and Unizima, Big pharma players such as Pfizer and Moderna are possible technology transfer partners (3,31). The analysis identified the following as priority areas for further development and improvement: • Regulatory system strengthening: Tunisia needs to attain maturity level 3 for its NRA. There also a need to elaborate specific guidelines for vaccines in line with international standards. These guideline documents should cover the manufacturing, clinical trials, and registration of vaccines. • Investment: Experts identified continued political commitment in Tunisia as a significant challenge, given the high risks associated with vaccine capability development which is both time and investment-intensive. • Technology transfer: Volume guarantee by the government to private tech transfer entities is necessary for sustaining high levels of investment and to incentivise private partners to engage in technology transfer projects. • R&D: While capability in R&D exists, it needs to be strengthened, especially concerning the upstream and downstream processes that are involved in the manufacture of drug substances for vaccines and biologicals. 4 Source: Expert interview. 24 Part II: mRNA vaccines 25 2.1 mRNA vaccine technology On 11 March 2020, WHO declared the outbreak of COVID-19 to be a pandemic, prompting the rapid development and scale-up of COVID-19 vaccines which proved to be critical to reducing the morbidity, mortality and economic damage associated with the pandemic. Different platforms were used to produce COVID-19 vaccines, including mRNA vaccines (32). mRNA vaccine technology offers several advantages that make it an attractive alternative to traditional vaccines or even deoxyribonucleic acid (DNA) vaccines. Unlike attenuated or inactivated vaccines, mRNA vaccines will only express a specific antigen and induce a directed immune response. Additionally, they promote both humoral and cellular immune responses and induce the innate immune system. The flexible nature of the mRNA vaccine platform is also advantageous from the manufacturing perspective since it is possible to change the encoded antigen without affecting the physical– chemical characteristics of the mRNA backbone. This allows production to be standardized. Additionally, since production is based on an in vitro cell-free transcription reaction, safety concerns regarding the presence of cell-derived impurities and viral contaminants commonly found in other platforms are minimized. The manufacture of mRNA vaccines comprises a series of steps. These can be grouped into upstream processing, which comprises the enzymatic generation of mRNA, and downstream processing, which includes the unit operations required to purify the mRNA product (33). The final part of the process is generally referred to as the fill-and-finish steps, which include dilution, sterile filtration, filling in containers, capping, sealing, labelling and packaging (34). Fig. 4: mRNA manufacturing production processes and associated critical parameters Source: reference (34). Upstream Downstream 26 Fig. 4 shows the key steps involved in the manufacture of mRNA vaccines in more detail. First, a plasmid DNA template for the mRNA drug substance is produced via biological fermentation, and then an enzyme-catalysed in-vitro transcription process produces the mRNA drug substance that codes for the desired protein, in this case, the spike protein. The latter stages of the upstream processing involve subjecting the raw mRNA to a series of further chemical reactions (capping and stabilization) to render it biologically active. In the downstream processing steps mRNA is formulated as lipid nanoparticles (LNPs) which are formed by mixing with a blend of lipids, including cholesterol and cationic or PEGylated lipids. Once the mRNA drug substance is formulated into LNPs, it undergoes fill-and-finish as well as quality assurance and quality control in the same manner as the other vaccines. The complexity of the processes described above and the biological nature of critical steps make vaccine manufacturing at times unpredictable and even the most advanced production systems can experience failure. Quality control and quality management are therefore highly sophisticated and a critical component of every vaccine production system (35). Key points to note about the upstream processing steps, which include the in vitro transcription (IVT) step and capping, are as follows: • The purpose of the IVT step is to synthesize multiple copies of full-length, uncapped RNA from a DNA template (plasmid) which is produced in advance, usually by linearization of a purified plasmid or by amplification of the region of interest using a polymerase chain reaction (PCR). • The reaction only takes a few hours in contrast with the time-consuming processes used to manufacture conventional vaccines. In general, milligrams of mRNA per millilitre of reaction can be obtained. Additionally, the production process can be standardized as it is not dependent on the antigen encoded in the template. • mRNA capping can be performed during the IVT reaction step by substituting a part of the guanosine triphosphate (GTP) substrate for a cap analogue. Alternatively, mRNA can be capped in a second enzymatic reaction using the vaccinia capping enzyme (VCE) and a methyl donor as a substrate. Although the capping efficiency of this method is higher (100% compared to 60–80% obtained with the use of a cap analogue), the process with cap analogues is faster as it does not require the set-up of a second enzymatic reaction. However, due to their price, cap analogues can have an impact on production costs, especially if large-scale manufacturing is considered. In terms of the downstream processing steps, which comprise the operations required to purify the mRNA product, important features to note include: • Once the mRNA is generated by IVT, it must be isolated and purified from the reaction mixture using multiple purification steps to achieve clinical purity standards. Current setups are composed of a combination of a tangential flow filtration (TFF), followed by a chromatographic step and a second TFF. • Following this, the production enters its second phase: the RNA formulation. This stage is currently based on the mixing of a liquid stream containing the four lipids in ethanol [or three, as polyethylene glycol (PEG)-lipid can be subsequently added] with another stream containing RNA in an aqueous low-pH buffer. Two options are the most appropriate for current good manufacturing practice manufacturing: microfluidics and jet mixing. Finally, LNPs are concentrated and purified using a final TFF. 27 2.2 mRNA vaccine ecosystem The first part of this report provides an overview of the vaccine and biologicals manufacturing ecosystem in Tunisia, summarizing existing government policies, financing systems and incentives, and legislative frameworks that are relevant to the pharmaceutical sector including vaccines and biologicals. The picture that emerges is one of a maturing ecosystem and one that reflects Tunisia’s commitment to further developing its pharmaceutical sector by strengthening its capacity to produce vaccines and biologicals. This part focuses on those features of the ecosystem that are specific to mRNA vaccines, in particular the policy and strategic developments around technology transfer. This is especially relevant following the announcement that Tunisia is one of the six African countries that will receive training and mRNA technical know-how from the global mRNA technology transfer hub based in South Africa. A discussion with an overview of the areas of strength and areas where there is room for improvement given Tunisia’s stated aim to develop its vaccine manufacturing capacity will be presented towards the end. 2.2.1 Manufacturing capacity After it was announced that Tunisia would be one of six countries to receive training and technical know-how on how to produce mRNA vaccines from the global mRNA technology transfer hub based in Cape Town, South Africa, some Tunisian companies expressed their interest in producing mRNA vaccines. These are manufacturers with several years’ worth of expertise in the manufacture of injectable products with aseptic processes (Annex 3). 2.2.2 Government policies and financing As detailed in Part I, Tunisia has developed or is in the process of developing, a range of policies and projects designed to strengthen the country’s pharmaceutical sector. Most of these policies and strategies apply to the sector as a whole and are not specifically aimed at vaccines and other biotechnology products. Furthermore, traditionally Tunisia has not offered specific financial incentives to the pharmaceutical sector and so investors in the pharmaceutical sector typically benefit from the same incentives as other “priority” sectors. Tunisia can also be described as only “weakly positioned” in terms of the financing of R&D (see also Part I). More recently, however, and following the outbreak of COVID-19 in 2020, the government has initiated a project to develop and implement a national strategy for manufacturing vaccines. To this end, the Ministry of Health – through the IPT and BiotechPôle Sidi Thabet – have requested the support and involvement of WHO. Moreover, a letter of interest was sent to WHO in May 2021 expressing Tunisia’s interest in hosting a technology transfer hub for mRNA vaccines. Tunisia also sought support from the World Bank, requesting technical assistance to the Ministry of Health with the development of its national vaccine manufacturing strategy and help with conducting a feasibility study for the vaccine manufacturing project. The World Bank agreed to provide technical assistance to the Ministry of Health with a United Kingdom of Great Britain and Northern Ireland trust fund of US$ 240 000. After the selection of a consulting firm by the 28 World Bank, the study began in early March 2022 and the report was submitted to the Ministry of Health at the end of June 2022 (3). Further details of these projects are provided in Box 5. Box 5: Key milestones in the development of Tunisia’s national vaccine manufacturing strategy WHO support: technology transfer hub On 17 February 2022, it was confirmed that the application of Tunisia was retained by the General Director of WHO to be among the six African countries that will benefit from technical support to manufacture mRNA through cooperation with the global centre for technology transfer for mRNA vaccines. Within this framework, the Ministry of Health sent five candidates to participate in the training on biomanufacturing in the Republic of Korea in July 2022. The candidates were industry personnel as well as regulators. As part of the public-private partnership, the private sector has been involved in this project. World Bank support: technical assistance and feasibility study The support provided by the World Bank focused on: • The conducting of a benchmarking study on the recent experiences of the strategies of implementation of vaccine manufacturing including mRNA vaccines on the African continent, the Middle East and North Africa (MENA) Region and Latin America, and the benchmarks related to the successful strategies of development of vaccine export and identification of barriers to the export of vaccine manufactured in Tunisia. • Establishment of recommendations with risk and success factors, presentation of a short, medium- and long-term action plan and assistance in its implementation and success. • Feasibility study of the implementation of an mRNA-based vaccine production platform. The recommendations from this study have been shared with the vaccine manufacturing steering committee. The next step is the operationalization of the action plan proposed by the study office. This is a very important step for the realization of the vaccine manufacturing project in Tunisia and will probably be supported by the IFC. 2.2.3 Regulatory system Tunisia, relative to the other five countries selected by WHO for mRNA technology transfer, has limited regulatory maturity. South Africa’s technology transfer hub is facilitated for mRNA vaccines. Egypt has achieved maturity level 3 for vaccine regulation (both locally produced and imported vaccines). Nigeria’s NRA has also achieved maturity level 3 for imported vaccines. Senegal has a WHO pre-qualified vaccine and Kenya received regulatory support as part of the Moderna investment package. Tunisia is currently working to upgrade its regulatory system and to succeed in reaching maturity level 3. Indeed, a self-assessment workshop for NRAs of medicines and vaccines, organized by WHO and the WHO Regional Office of the Eastern Mediterranean, was scheduled for the end of September 2022 in Tunisia. The main objective of this workshop was to strengthen the regulatory system through self-assessment using the WHO global benchmarking tool. As well as identifying strengths and weaknesses of regulatory systems, this tool allows NRAs to better understand the principles and requirements of a functional regulatory authority. This workshop 29 will be followed by a formal evaluation by WHO, which is scheduled to take place in the first quarter of 2023. Despite the relative immaturity of Tunisia’s NRA, evaluators were able to grant around 10 Emergency Use Authorizations (EUAs) for vaccines against COVID-19 during the period, January– August 2021, with exceptional timelines ranging from 4–65 days. Two of these EUAs concerned mRNA vaccines. These authorizations were granted after an evaluation of the submitted dossiers in accordance with international guidelines, in particular those of the European Medicines Agency (EMA) and the WHO, both for the evaluation of the quality modules and the evaluation of the preclinical and clinical studies modules (36). There is also a quality control system in place which covers all steps in the vaccine production process, including supply, and which applies to imported and locally produced vaccines. Patent protection laws limit the widespread use and adoption of mRNA technology. This means that the sharing of intellectual property and know-how, as well as voluntary licensing, will be key to facilitating the effective technology transfer and the scale-up of mRNA production capacity. 2.2.4 Technology transfer activities As noted in Part I, several Tunisian pharmaceutical companies have already participated in technology transfer projects with a range of partners, typically those with expertise in the manufacture of biosimilar products. Moreover, and as also previously noted, a number of manufacturers have expressed their interest in taking advantage of mRNA technology transfer opportunities which will allow them to expand their vaccine manufacturing capabilities and produce mRNA vaccines. Responses from survey participants suggest that the optimal investment model for establishing a new vaccine/biologicals plant in Tunisia would be a step-wise one. One respondent expressed the view that initiating a "fill-and-finish" project was “a prudent initial step”. The advantage of adopting this strategy is that it would allow for rapid operationalization within a few months. This could then be followed by a comprehensive process transfer, enabling the establishment of suitable facilities that would be capable of scaling up and integrating the entire vaccine production process. It was envisaged that such initiatives would most likely succeed if they were executed through a consortium or in collaboration with the public sector and with suitable access to the market.(5) In this regard, 2022 saw some welcome developments. IPT concluded a contract with Moderna to conduct preclinical studies for mRNA-based vaccine development studies for leishmaniasis and rabies. These studies will start in late 2022 or early 2023. The contract is for a period of 2 years. These studies are funded by the Merieux Institute. 5 Source: Expert interview. 30 2.3 Drivers, bottlenecks and challenges In this section, we explore the drivers, bottlenecks and challenges around mRNA technology and technology transfer readiness of Tunisia. In terms of the mRNA vaccine manufacturing process, the key drivers are: • mRNA manufacturing is advantageous when compared to the production of most biologicals since it does not require the use of cell cultures (33). • Owing to its fast reaction time, the risk of contamination is lower than what is observed with other complex vaccine manufacturing processes. • Additionally, the non-integrative nature and the transient expression inside the cells favour the mRNA safety profile. • mRNA vaccines can be manufactured within weeks, which is a huge advantage during a public health emergency. • They can be adjusted relatively quickly to combat variants of the virus when they arise. mRNA vaccines have been tested as therapeutic agents in oncology (37). The growing number of clinical trials for cancer therapies and infectious diseases demonstrates an increased interest from the industry to release these types of vaccines to the market. • mRNA vaccines are precise, safe and flexible, and can be easily manufactured on a large scale for clinical grade applications. These vaccines can be an answer to quickly respond to epidemic outbreaks in terms of manufacturing. • Possible continuous (sequential) processing would be advantageous as it leads to lower costs. The relative simplicity of mRNA manufacturing makes the process well suited for continuous processing, and in particular, at a microfluidic scale, the use of expensive reagents can be minimized, and cascade reactions can be compartmentalized easily. Regarding Tunisia’s mRNA vaccine ecosystem and technology transfer readiness: • Local manufacturers have the potential to adopt mRNA technology based on their current expertise and experience in sterile products. Nine manufacturers have expressed their interest in producing mRNA vaccine and their readiness to start with the fill-and-finish steps.(6) • IPT’s collaboration with Moderna for mRNA leishmaniasis vaccine development and with WHO for mRNA technology transfer are positive steps for Tunisia to develop the necessary know-how.(7) • There are international tech partners that are interested in collaborations for technology transfer in Tunisia (Quantoom, Univercells, Unizima). Big pharma players, such as Pfizer and Moderna, can collaborate as technology transfer partners (3,31). However, the ecosystem analysis revealed some areas which currently represent barriers to the development of mRNA vaccine production capacity in Tunisia and where there would need to be some action taken to overcome these barriers: • There is a need to strengthen the regulatory system. More specifically, Tunisia’s NRA needs to attain maturity level 3. There is also a need to elaborate guidelines for specific vaccines in line with international standards. These guidelines should cover the manufacturing process, as well as clinical trials and vaccine registration. 6 Source: Expert interview. 7 Source: Expert interview. 31 • Continued strong high-level political commitment to vaccine capability development will be essential, given that such development is time and investment-intensive. • Tunisia does not offer specific incentives to the pharmaceutical sector and is weakly positioned on the financing of R&D. • Volume guarantees will be necessary to sustain private sector investment in technology transfer. • R&D capability will need to be strengthened to deliver the necessary expertise in the manufacture of drug substance for mRNA vaccines and bioproduction. • The sharing of intellectual property and know-how, voluntary licensing and effective technology transfer are essential to facilitate the rapid scale-up of production capacity (38). 32 Part III: Vaccine manufacturing capacity 33 In this Part, we describe Tunisia's vaccine and biological product manufacturing capacities. Led by IPT and bolstered by emerging manufacturers like Medis and Unimed, Tunisia has developed state-of-the-art facilities adhering to international standards. These facilities not only produce vaccines but also supply a range of biological products, contributing to Tunisia's position as a key player in global healthcare manufacturing and distribution. 3.1 Production capacity Tunisia is among one of five African countries with existing capacity to manufacture vaccines (2; Annex 9). This capacity resides within IPT which produces intradermal BCG vaccine, fresh BCG vaccine for bladder cancer immunotherapy and therapeutic sera (anti-viperine, anti-scorpionic and anti-rabies). BCG vaccine is a live attenuated vaccine (38). The Institut Pasteur de Tunis is a public health institution under the guardianship of the Ministry of Public Health. It is mandated to carry out all inquiries, missions, analyses and research activities pertaining to human and animal health. It produces vaccines, sera and antigens for the domestic market and contributes to higher education at both the national and regional levels. Internationally, IPT is well established and collaborates with several foreign scientific institutions. The Institut Pasteur de Tunis is also a member of the Institut Pasteur International Network, which consists of 32 institutes throughout the world (38). See also Part I: Box 2. The Institut Pasteur de Tunis currently produces vaccines and serums for the domestic market. Its premises (700 m² for production and 1000 m2 for storage) are in accordance with international standards of good manufacturing practices. The capacity of that production is: • 70 000 vials of 20 adult doses of BCG vaccine (lyophilized intradermal) • 70 000 vials of solvent for BCG vaccine • 15 000 vials of BCG Immun Fresh 75mg/ml • 8000 ampoules of anti-scorpionic serum GAMMA SCORP • 2500 ampoules of anti-viperine serum GAMMA VIP • 4000 ampoules of anti-rabies serum GAMMA RAB. The Institut Pasteur de Tunis has the capability for both upstream and downstream manufacturing activities. It has two filling lines; the first is used exclusively for the manufacture of BCG vaccine, while the second is used for the manufacture of therapeutic serums (and is equipped with a filling machine that flame seals ampoules). In addition, IPT has a third line composed of a filling machine with a capping station and a capper with a blowing roof. This third line has a high output but needs to be installed in a class B area. At the end of 2022, IPT signed a 2-year contract with Moderna to begin a series of preclinical studies to pave the way for the development of mRNA-based vaccine against leishmaniasis and rabies. These studies are funded by Merieux Institute. BiotechPôle Sidi Thabet also has expertise in biologicals manufacturing and is in the process of setting up a platform for the production of monoclonal antibodies (elementary stage). The production phase is expected to start at the end of 2023. BiotechPôle Sidi Thabet is a public organization managed by the Ministry of Higher Education and Scientific Research (see also Part I: Box 2). 34 Besides IPT and BiotechPôle Sidi Thabet, seven other manufacturers have expressed their interest in manufacturing vaccines, including rDNA, vectored and recombinant protein vaccines, as well as mRNA vaccines. These companies are Teriak, Medis, Neapolis Pharma, Steripharm, Dorcas, Cytopharma and Unimed. These companies are already authorized to manufacture sterile forms under aseptic production conditions (Table 5). Three manufacturers (Steripharm, Medis and Unimed) have stated that they initiated a dialogue with vaccine manufacturers in 2021 to start the transfer of technology process which would allow them to undertake the fill- to-finish steps of COVID-19 vaccine manufacturing process (Medis with Moderna and Cansino; Steripharm and Unimed with Gamaleya). These negotiations have not yet been successful as a commitment from the government has been requested. Unimed and Medis have also been in contact with HIPRA in order to be an alternative site for manufacturing of their potential COVID- 19 vaccine under approval by the EMA. Three of the seven companies have a European Good Manufacturing Practice Certificate. These are Cytopharma, Unimed and Medis. In addition, Teriak has declared to be working on the European good manufacturing practice (GMP) certificate and WHO prequalification for some chemical products. Cytopharma, Medis and Unimed are interested in the prequalification for some chemical products. Table 5: Production of sterile products in Tunisia Company Production capacity Cytopharma 5 million vials per year Dorcas 1 – 5 million per year Medis 10 – 15 million vials per year Neapolis Pharma 3000 vials per hour Steripharm 6 million ampoules per year Teriak Syringe (0.5 ml): 4.4 million per year Syringe (1 ml): 2.2 million per year Carpule (3 ml): 3.4 million per year Vial (10 ml): 4.7 million per year Vial (20 ml): 3.6 million per year Vial (50 ml): 1.9 million per year Unimed Syringe line:15 million syringes per year Vial line: 3.5 million bottles per year (20 million bottles per year by 2023) Source: Expert interviews. 35 3.2 Vaccine sales, export markets and procurement 3.2.1 Export markets The vaccines and biosimilars produced locally in Tunisia have not been procured by international agencies (e.g. Gavi, UNICEF). The Institut Pasteur de Tunis does not export its BCG vaccine. However, biosimilars produced by Tunisian companies (Medis and Unimed) are exported to different countries around the world. Figures 5–7 show the destination of Tunisia’s heparin and enoxaparin exports (which totalled over 2 million syringes in 2021), and Fig. 8 shows the destination of epoetin alfa exports. With regards to the Medis biosimilars: • Heparin and enoxaparin were exported to Lebanon, Libya, Morocco, sub-Saharan Africa and some European countries in 2021. • Enoxaparin has just been registered in Saudi Arabia and will be launched at the end of 2022 with an important share of the market. Medis is the first biosimilar company in this market. • Epoetin alfa is being exported to some African countries. • Insulins are being registered in some African countries. Regarding the biosimilars manufactured by Unimed: • Enoxaparin is registered and exported to Iraq, Jordan, Libya and Morocco. • Enoxaparin is under registration in the Qatar and United Arab Emirates. The interviewed companies that have expressed their interest to produce vaccines and biologicals intend to export the manufactured products to African and MENA countries.8 Fig. 5: Enoxaparin Medis export distribution by volume, 2021 (number of syringes) Sources: The Directorate of Pharmacy and Medicine; Expert interview 8 Source: Expert interviews. 35220 6000 6426 249518 276706 1200 20000 447234 263854 130356 140000 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 Q u an ti ty ( sy ri n ge s p er y ea r) Country Total quantity per year: 1 576 514 36 Fig. 6: Enoxaparin Unimed export distribution by volume, 2021 (number of syringes) Sources: The Directorate of Pharmacy and Medicine; Expert interviews. Fig. 7: Heparin Medis export distribution by volume, 2021 (number of syringes) Sources: The Directorate of Pharmacy and Medicine; Expert interviews. 452876 72602 257290 160000 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 Iraq Jordan Libya Sudan Q u an ti ty ( sy ri n ge s p er y ea r) Country Total quantity per year: 942 768 870 1100 12000 749 9700 567 0 2000 4000 6000 8000 10000 12000 14000 Côte d'Ivoire Iraq Lebanon Libya Morocco Senegal Q u an ti ty ( sy ri n ge s p er y ea r) Country Total quantity per year: 24 986 37 Fig. 8: Epoetin alfa Medis export distribution by volume, 2021 (number of syringes/vials) Sources: The Directorate of Pharmacy and Medicine; Expert interviews. 3.2.2 Sales and procurement All vaccines and biologicals are procured by PCT by tender or by auction on a self-financing basis; Tunisia is not Gavi-supported. The Central Pharmacy of Tunisia has a monopoly on the importation of medicines and vaccines in Tunisia. The number of vaccine doses procured by Tunisia have steadily increased between 2019 and 2021 at a compound annual growth rate of 11% (Fig. 9). Along with the overall increase, the public sector share of procured vaccines also increased significantly, by 12% (from 70% in 2019 to 82% in 2021). According to the 2022/2023 tender data, SII is the leading supplier of vaccines to Tunisia by volume and value. Pentavalent, pneumococcal conjugate vaccine (PCV-10) and hepatitis A (paediatric) accounted for 51% of overall vaccine sales in 2021 in Tunisia. In contrast, within the private sector, influenza and BCG vaccines accounted for 51% of 2021 sales (Fig. 10). Based on historic data and future needs estimated by the Direction des Soins de Santé de Base (DSSB), estimated 2022 vaccine demand is 3.3 million doses which represents a value market of US$ 16.7 million. Currently, human papillomavirus (HPV) vaccine procurement in Tunisia is zero. However, based on Tunisia’s HPV prevalence and expected future inclusion of HPV in the country’s routine immunization schedule, demand for this vaccine is expected to increase in Tunisia. Also, both doses of COVID-19 vaccine are currently administered to only 53% of the population and its further deployment to meet the current need and routine usage is likely to increase domestic market size (3). 2520 90 360 2700 0 500 1000 1500 2000 2500 3000 Burkina Faso Cameroon Chad Libya Q u an ti ty ( sy ri n ge s o r vi al s p er y ea r) Country Total quantity per year: 5670 38 Fig. 9: Vaccine procurement, 2019–2021 (million doses per year) Sources: The Directorate of Pharmacy and Medicine; Expert interviews. PCV, pneumococcal conjugate vaccine Fig. 10: Vaccine procurement, by vaccine type Sources: The Directorate of Pharmacy and Medicine; Expert interviews. 0 500 1000 1500 2000 2500 3000 2019 2020 2021 720 700 540 1680 2100 2460 Q u an ti ty ( '0 0 0 d o se s p er y ea r) Year Private sector Public sector Pentavalent , 17.50% PCV-10 , 17.30% Hepatitis A (Pediatric) , 16.20% Influenza (Flu) - tetravalent , 8.60% Injectable polio vaccine, 10.60% 39 Part IV: Recommendations and future directions 40 In this final Part, we provide an overview of the key policy initiatives and national strategies that are underpinning Tunisia’s efforts to increase its domestic vaccine production with a view to not only becoming self-reliant in vaccine supply but also to contribute to broader economic and health benefits for the region. It also describes Tunisia’s roadmap for achieving its goals and outlines what are perceived to be the most critical training and assistance needs. 4.1 National strategies and initiatives Tunisia currently imports all its vaccines, with the exception of the BCG vaccine which it manufactures on an occasional basis. The COVID-19 pandemic has however highlighted the risks to health security posed by an over reliance on vaccine imports and has prompted many countries, including Tunisia, to invest in developing their own vaccine manufacturing industries. July 2022 saw the launch of Tunisia’s Industrial Strategy and Innovation to 2035. The project to develop this strategy was spearheaded by the Ministry of Industry and was conducted with the assistance of a consulting firm with funding from the African Development Bank (see Part I). The development of the Industrial Strategy and Innovation to 2035 will design and introduce the changes necessary to strengthen the productive structure and the positioning of Tunisia as an attractive space for investment and co-production of goods and services, including vaccines and biologicals with national and international manufacturers. A parallel initiative coordinated by the Ministry of Industry, which is focused on the development of the competitiveness of the pharmaceutical sector, is expected to be validated before the end of 2022. This project aims to mobilize and coordinate the actions of the public and private sectors to accelerate the pace of sectoral development, increase national coverage, and promote investment, job creation and the development of exports with higher added value. The development of drugs from biotechnology was identified as one of the priority axes achievable by 2027. At the same time, the Ministry of Health has been working on a national vaccine manufacturing strategy. The World Bank was asked to support the Ministry of Health in developing this strategy, and to this end, a consulting firm was recruited in March 2022 for a three-month mission. The objectives of the commissioned study were: • To conduct a benchmarking study on the recent experiences of the strategies of implementation of vaccine manufacturing including mRNA vaccines on the African continent, the MENA Region and Latin America, and the benchmarks related to the successful strategies of development of vaccine export and identification of barriers to the export of vaccine manufactured in Tunisia; • To make recommendations (with risk and success factors) and to develop a short-, medium- and long-term action plan and assist in its implementation; • To conduct a feasibility study of the implementation of an mRNA-based vaccine production platform. At the end of July 2022, the recommendations from this study were shared with Tunisia’s vaccine manufacturing steering committee. These recommendations can be summarized in three steps: • Setting the basis for successful technology transfer: to include achieving maturity level certification of the NRA; finding technology transfer partners and market guarantees. 41 • Establishment of an organization to receive mRNA technology and create an environment conducive to manufacturing: to include fund-raising and company creation; modernization and political reforms. • Supporting the R&D pipeline, local know-how and complementarities with other countries for the longevity of vaccine development: to include capacity building, international and regional cooperation. The next logical step for Tunisia is the operationalization of the action plan proposed by the consulting firm. To achieve this, the steering committee was advised to prioritize the following actions: 1. To create a project team responsible for: "the implementation of an operational strategy for the promotion of the production of biologicals" with the identification of a focal point that leads the implementation of the operational plan and coordinates with different stakeholders, including communication; 2. To publish the strategy and make it known (government document with expected results and timeline); 3. To have a formal commitment at the highest level of the State that also engages the different departments concerned (health, industry, economy and planning, research); 4. To accelerate the operationalization of the National Agency for Medicines and its maturity level 3 certification; and 5. To put in place a series of accompanying measures including i. legislative (research, ethics, others), ii. additional support measures (e.g. export promotion, tax and customs incentives, tendering policy and price definition), iii. preparation and publication of guides and other regulatory documents (guide for vaccines, in particular). The operationalization of the action plan is a very important step for the realization of the vaccine-manufacturing project in Tunisia and will probably be supported by the IFC. 4.2 Country expectations and objectives When asked about what Tunisia might gain from expanding its vaccine manufacturing industry, and in particular from being a spoke in the mRNA technology transfer hub , interview participants generally gave positive answers, reflecting a high level of support for action in this area. Specific examples of response include: “The selection of Tunisia as a spoke of the mRNA technology transfer hub will enable the development of the value chain, upgrading of skills not only at the level of the private sector but also at the level of the regulatory body. It also will ensure the creation of jobs, responding to health needs and creation of value.” “With regard to the objectives of being a spoke of mRNA technology transfer hub, first, they are related to national security and foreign independence and secondly, they are regional, in fact, this will make it possible to ensure the supply of the North African region. The selection of Tunisia as a spoke of the mRNA technology transfer hub will offer market sizes supporting development of sustainable production capacity. Diplomacy actions are important to ensure access of such products to foreign countries.” 42 “The role of WHO in the next steps is very important to give assistance to the country to succeed this project.” 4.3 Training and assistance needs 4.3.1 Vaccines and biologicals The manufacturing process for vaccines and biologicals (upstream, downstream, fill-to-finish) are highly complex and characterized by cutting-edge science and technologies. Given this complexity, even the most advanced systems could experience challenges. Different platforms can be used: viral vector, protein subunits, live-inactivated virus, recombinant protein, and each platform has its specificities, but there are some common steps. Some platforms are used also for biologicals (35). Although Tunisia has some experience in the manufacturing of biosimilars, as this evaluation has revealed, this is limited to a small number of manufacturers at the fill-to-finish and quality control stage. Indeed, only four manufacturers have authorization for the manufacture of biosimilars (Medis, Unimed, Neapolis Pharma and Teriak) and only two companies have market authorizations for biosimilars (Medis and Unimed). Interviewed manufacturers identified a number of key areas where there was a need for specialist training and assistance to support Tunisia’s ambitions to expand its vaccine manufacturing base; these areas include bioproduction, upstream and downstream processes, technology transfer, clinical trials and regulatory framework. The need for WHO’s support in implementing the action plan/road map of the national vaccine manufacturing strategy, in terms of both regulatory and production aspects, was also acknowledged. 4.3.2 mRNA vaccines Although mRNA vaccines have several advantages over traditional vaccines, at least in terms of their manufacture, the production process is nevertheless complex and involves multiple steps (see Part II). Once the mRNA drug substance has been formulated into LNPs, it still needs to go through fill-to-finish processes, as well as quality assurance and quality control, in the same manner as other vaccines. The complexity of the processes involved and the biological nature of the critical steps make vaccine manufacturing at times unpredictable and even the most advanced production systems can experience failure. Quality control and quality management are therefore highly sophisticated and a critical component of every vaccine production system, and in this regard, mRNA vaccines are no different (35). The precise nature of quality control processes that need to be carried out and thus the facilities required depend on the drug substance and drug product. Most vaccines require a combination of biological and immunological tests (for identity, potency and impurities); some may require animal tests. Viral vaccines will require virological testing; newer vaccines may require molecular biology laboratories. These tests are generally not required for chemical, sterile products. In order to be able to perform mRNA vaccines to sufficient standards, the personnel responsible for the manufacturing and quality control processes must be adequately trained. This applies 43 especially at the level of the bioproduction, production of the mRNA, the manufacture of plasmids, the mastery of replication platforms, the formulation in nanoemulsion and the mastery of the stability of these products. Equally important is the need for training in the mastery of quality control of vaccines, microbiology control, aseptic process, environment monitoring and clinical trials. Training courses at sites that produce RNA vaccines, other types of vaccines and biologicals are important to complement the theoretical training acquired through the national training system. 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Tunis: Agency for the Promotion of Industry and Innovation; 2022 (http://www.tunisieindustrie.nat.tn/en/home.asp, accessed 7 July 2022). 15. Law N°2016-71 related to investment law. Tunis: JORT, September 2016 (https://wipolex- res.wipo.int/edocs/lexdocs/laws/en/tn/tn080en.html, accessed 21 July 2022). 45 16. Principaux mécanismes de financement en Tunisie. Tunis: Tunisia Health Authority; 2022 (https://guide.tia.gov.tn/uploads/Mecanismes_de_Financement-en.pdf, accessed 13 October 2022). 17. Ayari K. Les nouvelles réformes d’investissement en Tunisie [in French]. Tunis: Ministère du développement, de l’investissement et de la coopération internationale; Juin 2018 (http://bvmt.com.tn/sites/default/files/actualites/mltql-hwl-ltr-lqnwny-llstthmr-fy-fy-twns.pdf, accessed 13 October 2022). 18. Amélioration de l’accès au financement des PME- Programme d’Appui à l’Accord d’Association et au Plan d’Action Voisinage (P3A-II). Tunis: Banque de Financement des Petites et Moyennes Entreprises (https://twinning.msz.gov.pl/media/1064/fiszka_tunezja2.doc, accessed 13 October 2022). 19. Tunisia and the European Investment Bank. Luxembourg: European Investment Bank; 2022 (https://www.eib.org/en/projects/regions/med/tunisia/index.htm, accessed 23 July 2022). 20. IFC. Washington, DC: International Finance Corporation; 2022 (https://www.ifc.org/wps/wcm/connect/CORP_EXT_Content/IFC_External_Corporate_Site/Abo ut+IFC_New/, accessed 23 July 2022). 21. AFD. Paris: Agence Française de Développement; 2022 (https://www.afd.fr/en, accessed 23 July 2022). 22. AfDB. Abidjan: African Development Bank; 2022 (https://www.afdb.org/en, accessed 23 July 2022). 23. A new frontier for the African pharmaceutical manufacturing industry. Abidjan: African Development Bank Group; 2022. (https://www.afdb.org/en/documents/new-frontier-african- pharmaceutical-manufacturing-industry, accessed 23 July 2022) 24. Exchange regulation. Tunis: Banque Centrale de Tunisie; 2022 (https://www.bct.gov.tn/bct/siteprod/page.jsp?id=67null&la=AN, accessed 23 July 2022). 25. Exchange regulation. Washington, DC: International Trade Administration; 2022 (https://www.trade.gov/country-commercial-guides/tunisia-trade-financing, accessed 23 July 2022). 26. Guide de l’investisseur. Tunis: Tunisian Health Authority; 2022 (https://guide.tia.gov.tn/PHARMACEUTICAL_INDUSTRY, accessed 7 June 2022). 27. Programmes nationaux. Tunis: Agence Nationale de la Promotion de la Recherche Scientifique; 2022 (http://www.anpr.tn/programmes-nationaux/, accessed 25 July 2022, link no longer available). 28. National Technology Development and Transfer System in Tunisia. Tunis: National Agency for Scientific Research Promotion; 2018 (https://www.unescwa.org/sites/default/files/event/materials/national_technology_development_ and_transfer_system_in_tunisia.pdf, accessed 25 July 2022). 29. Law N° 84 -2000 in respect of patents of inventions. Tunis: JORT; August 24, 2000. (not published, not publicly available) 30. Country commercial guides. Tunisia - Protecting intellectual property. US: International Trade Administration; 2022 (https://www.trade.gov/country-commercial-guides/tunisia-protecting- intellectual-property, accessed 10 August 2022). 31. IQVIA/World Bank. Report on implementation considerations and best practices pertaining to mRNAs and other vaccine production. Tunis: Ministry of Health; 2022. (not published, not publicly available) 32. Yamey G, Schäferhoff M, Pate M, Chawla M, Ranson K, Zhao F et al. Funding the development and manufacturing of COVID-19 vaccines: Background paper for the World Bank/CEPI financing COVID-19 vaccine development consultation on February 20, 2020. The Center for Policy Impact in Global Health. Duke Global Working Paper Series: number 20, March 2020 46 (https://centerforpolicyimpact.org/wp-content/uploads/sites/18/2020/03/COVID-19-funding-and- manufacturing-working-paper-1.pdf, accessed 16 July 2022). 33. Rosa SS, Prazeres DMF, Azevedo AM, Marques MPC. mRNA vaccines manufacturing: Challenges and bottlenecks. Vaccine. 2021;39(16):2190-2200. doi: 10.1016/j.vaccine.2021.03.038. Epub 2021 Mar 24. PMID: 33771389; PMCID: PMC7987532. 34. Daniel S, Kis Z, Kontoravdi C, Shah N. Quality by Design for enabling RNA platform production processes. Trends in Biotechnology. 2022;40(10):1213–28. doi: 10.1016/j.tibtech.2022.03.012. 35. Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2022;6:1078–1094 (2021). doi.org/10.1038/s41578-021-00358-0. 36. Liste des médicaments. Tunis: The Directorate of Pharmacy and Medicine; 2022 (http://www.dpm.tn/medicament/humain/liste-des-medicaments, accessed 7 June 2022). 37. Towards a stronger vaccine ecosystem : building resilience beyond COVID-19. New York, NY: The Economist Group; 2021 (https://impact.economist.com/health/vaccineecosystem/framework/, accessed 7 August 2022). 38. World Local Production Forum. Enhancing access to medicines and other health technologies. Report of the first World Local Production Forum, 21–25 June 2021. Geneva: World Health Organization; 2021 (https://www.who.int/initiatives/world-local-production-forum, accessed 9 August 2022). 47 Annexes 48 Annex 1: Primary research participants Interviewed organizations Government and public authorities Interviewees Central Pharmacy of Tunisia (PCT) Feten Lemkecher DRM (Directorate of Medical Research) Myriam Khrouf Tunisia investment Authority (TIA) Abir Chaouachi Yousra Hamrouni General Direction of the Manufacturing industries (DGIM ) Manel Hanafi Syndicates Interviewees National Chamber of Pharmaceutical industry (CNIP) Tarek Hammami Tunisian Health Alliance (THA) Olfa Gam Manufacturers Interviewees Adwya Tarek Hammami BiotechPôle de Sidi Thabet Abderrahmen Ayadi Cytopharma Olfa Gam Dorcas Ymen Zgarni Institut Pasteur de Tunis Hechmi Louzir Les laboratoires Medis Lassaad Boujbel Neapolis Pharma Lassaad Boujbel Steripharm Ramzi Sandi Teriak Sara Masmoudi Unimed Nabil Saadaoui 49 Annex 2: List of resources consulted as part of the literature review Abiodun T, Andersen H, Mamo LT, Sisay O(2021). Vaccine Manufacturing in Africa: What It Takes and Why It Matters. London: Tony Blair Institute for Global Change (https://assets.ctfassets.net/75ila1cntaeh/5yvAe6KGMmxqSJBgmNuXRQ/b750f97ab0db3d464b69606d 7d0c80d8/Vaccine-Manufacturing-in-Africa-What-It-Takes-and-Why-It-Matters.pdf, accessed 18 February 2024). Africa CDC (2021). Partnership for African Vaccine Manufacturing (PAVM): ‘From Aspiration to Action’. Progress made so far on implementing the partnerships for vaccine manufacturing in Africa. Concept note: Kigali: Africa Centers for Disease Control and Prevention (https://africacdc.org/wp- content/uploads/2021/11/ENGLISH_PAVM_Public-Stakeholder-Engagement_Concept-note_Final- version.pdf, accessed 23 July 2022). Africa CDC (2022). Partnerships for African Vaccine Manufacturing PAVM: Framework for Action. Adis Ababa: Africa Centers for Disease Control and Prevention (https://africacdc.org/download/partnerships- for-african-vaccine-manufacturing-pavm-framework-for-action/, accessed 18 February 2024). African Development Bank (2022). Supporting the pharmaceutical industry sector – Concept note “Pharmaceutical Continental Vision 2030 and Implications for Tunisia”. Tunis: African Development Bank; 2022. AVMI (2017). VMPA Study. Vaccine manufacturing and procurement in Africa. Cape Town: African Vaccine Manufacturing Initiative; 2017 (https://www.avmi-africa.org/wp- content/uploads/2017/09/VMPA-Study-e-book.pdf, accessed 29 August 2022). CEPI (2022). Towards vaccinating the world- landscape of current COVID-19 supply chain and manufacturing capacity, potential challenges, initial responses, and possible “solution space”. A discussion document. Oslo: Coalition for Epidemic Preparedness Innovations (https://cepi.net/wp- content/uploads/2021/03/Landscape_of_current_C19_supply_chain_manufacturing_capacity.pdf, accessed 16 July 2022). Chtourou S (2020). Analyse des stratégies & politiques publiques favorisant l’accès aux bio thérapeutiques [Analysis of strategies and public policies promoting access to bio-therapeutics]. Tunis: Biotechnopole. Chtourou S (2021). Projet création CDV BIOTHERAPIES: Session de clôture de la mission [Creation project of CDV BIOTHERAPIES: Closing session of the mission]. Tunis: GIZ/Biotechnopole. Dolgin ES (2022). The tangled history of mRNA vaccines. Nature, 597:318–324 (https://media.nature.com/original/magazine-assets/d41586-021-02483-w/d41586-021-02483-w.pdf, accessed 16 July 2022). EFPIA (2022). The Pharmaceutical Industry in Figures. Key data 2021. Brussels: European Federation of Pharmaceutical Industries and Associations (https://www.efpia.eu/publications/downloads/efpia/the- pharmaceutical-industry-in-figures-2021/, accessed 05 June 2022). FIPA (2021). Pharmaceutical industries in Tunisia. Tunis: Foreign Investment Promotion Agency (https://www.investintunisia.tn/En/publications_21_196_D6, accessed 7 June 2022). 50 Fu X, Buckley PJ, Sanchez-Ancochea D. et al. (2022). The world has a unique opportunity: Accelerating technology transfer and vaccine production through partnerships. J Int Bus Policy. 5:406–415. doi: 10.1057/s42214-021-00124-7. Giersing B, Shah N, Kristensen D, Amorij JP, Kahn AL, Gandrup-Marino K, et al. (2021). Strategies for vaccine-product innovation: Creating an enabling environment for product development to uptake in low- and middle-income countries. Vaccine. 39(49):7208–19. doi: 10.1016/j.vaccine.2021.07.091. Health Policy Watch (2022). BioNTech to ship modular mRNA vaccine facilities in containers to African countries to jump-start production. Geneva: Health Policy Watch (https://healthpolicy- watch.news/biontech-to-set-up-modular-mrna-vaccine-production-facilities-in-africa/, accessed 16 June 2022). Health Policy Watch (2022). Even if Moderna declines – other pharma partners now poised to join South African mRNA Vaccine Hub Initiative. Geneva: Health Policy Watch (https://healthpolicy- watch.news/has-south-africa-made-modernas-vaccine-scientists-are-not-yet-sure-because-there-has- been-no-tech-transfer/, accessed 23 July 2022). Ilin I, Levina A, Frolov K. Innovative ecosystem model of vaccine lifecycle management. Journal of Open Innovation: Technology, Market, and Complexity. 8(1):5. doi:10.3390/joitmc8010005. IQVIA (2020). Realizing biosimilar potential in the Middle East & Africa. White paper. Dubai: IQVIA (https://www.iqvia.com/locations/middle-east-and-africa/library/white-papers/realizing-biosimilar- potential-in-the-middle-east-and-africa. Accessed 18 February 2024). Malvolti S, Malhame M (2020). Effective vaccine ecosystem. London: Welcome Trust (https://cms.wellcome.org/sites/default/files/2021-10/effective-vaccine-ecosystem-equipped-to-meet- challenges-of-future-infectious-disease-threats.pdf, accessed 25 July 2022). Mavolti S, Feiden K (2021). Understanding the vaccine ecosystem: Structure and challenges. Washington, DC: The Sabin-Aspen Vaccine Science & Policy Group (https://www.sabinaspengroup.org/understanding-the-vaccine-ecosystem-structure-and-challenges/, accessed 25 July 2022). Ministry of Health/IQVIA/World Bank (2022). Regional vaccine demand. Supply analysis and benchmarking. Tunis: Ministry of Health/IQVIA/World Bank. OECD (2021). Access to COVID-19 vaccines: Global approaches in a global crisis. Paris: Organisation for Economic Co-operation and Development (https://read.oecd-ilibrary.org/view/?ref=1069_1069384- ewmqrw9sx2&title=Access-to-COVID-19-vaccines-Global-approaches-in-a-global-crisis, accessed 16 July 2022). UNIDO (2018). White paper. Commercializing vaccines: A methodology to identify potential market opportunities and conduct outline assessments. Case study: South Africa. Vienna: United Nations Industrial Development Organization (https://www.unido.org/sites/default/files/files/2018- 12/Commercialising_Vaccines_Identifying_Market_Opportunities.pdf, accessed 18 February 2024). Whiteshield Partners Limited (2013). Knowledge economy assessment of Tunisia: Identifying and addressing capability and innovation gaps in the Southern and Eastern Mediterranean region (SEMED). London: Whiteshield Partners Limited (https://www.ebrd.com/downloads/news/tunisia-knowledge- report.pdf, accessed 7 June 2022). WHO (2011). Pharmaceutical production and related technology transfer: Landscape report. Geneva: World Health Organization (https://www.who.int/publications/i/item/9789241502351, accessed 18 February 2024). 51 WHO (2021). Virtual cGMP Training marathon for vaccine manufacturing: Questions & Answers. Geneva: World Health Organization (https://www.who.int/publications/i/item/WHO-MHP-RPQ-LPA-2022.1, accessed 16 July 2022). WHO (2022). COVID-19 Research and innovation powering the world’s pandemic response – now and in the future. Geneva: World Health Organization (https://cdn.who.int/media/docs/default-source/blue- print/achievement-report-_grif_web_finalversion15.pdf?sfvrsn=39052c73_9&download=true, accessed 16 July 2022) World Bank (2016). Sectorial PPDs in Tunisia: Experiences and lessons learned- Pharmaceutical sector. Tunis: World Bank (http://www.publicprivatedialogue.org/workshop%202017/PPD%20Sectorial%20- %20Tunisia.pdf, accessed 5 June 2022). 52 Annex 3: List of Tunisian drug manufacturers Manufacturers Biologicals Vaccine/ sera Sterile forms Aerosols Soft capsules Semi- solids Suppositories /ova Oral dry forms E×ternal liquid Internal liquid Radiopharma- ceuticals DPI ACT Pharma × Advans Pharma × Adwya × × × × × × Alliance Pharma × Berg Life Sciences × Cytopharma × Dar Essaydali × × × × × Dorcas × × × Galien Pharmaceuticals × Galpharma × × × × Ibn Al Baytar × Industries Pharmaceutiques SAID × × × × × Infomed pharma × Institut Pasteur de Tunis FP × Medicef × Medis F&F × × × Neapolis Pharma 1/Neapolis Pharma 2 (DPI) F&F × × × Lino Pharma × Opalia Pharma × × × × × × Pfizer Pharmaceuticals Tunisie × Pharmacare × × 53 Manufacturers Biologica ls Vaccine/ sera Sterile forms Aerosols Soft capsules Semi- solids Suppositories/ ova Oral dry forms E×ternal liquid Internal liquid Radiopharma- ceuticals DPI Pharmaderm × × × Pharmaghreb × × × × × Pharmavera × Pharmin × Philadelphia Pharma × Pierre Fabre Medicament Production Tunisie × SAIPH × × × × Sanofi Aventis Pharma Tunisie × SIMED × × × × × SIPHAT × × × × × × SISORA × × Steripharm × Synbioz × Taha Pharma × × TERIAK Site El Fejja/TERIAK Site Jbel El Ouest F&F × × × × × × × Thera × Unimed F&F × Vaga Laboratories × West Pharma × × × × Winthrop Pharma Tunisie × DPI, dry powder inhaler; FP, full process (drug substance and drug product); F&F, fill & finish Reference Etat des établissements de fabrication des médicaments à usage humain. Tunis: The Directorate of Pharmacy and Medicine; 2022 (http://www.dpm.tn/images/pdf/etat_fab_med_hum.pdf, accessed 23 July 2022). 54 Annex 4: List of priority sectors in industry Priority sectors Definition: Sectors characterized by their strategic nature and their ability to raise the growth pattern or have high employment capacity and priority according to the development plans. List of priority sectors in industry and services (1): o Primary transformation of agricultural and fishery products o Nanotechnology industry o Biotechnology industrya o Weaving and clothing industry o Electronics industries o Engineering plastics and composites o Automotive, aircraft and ship components manufacturing o Medical supplies and pharmaceutical industrya o Clinical research and development centresa o Industrial equipment manufacturing o Military industries o Cultural and creative industries o Collection, valorization, recycling and treatment of solid and liquid waste o Biodiversity valorization and protection and desertification prevention projects o Renewable energy manufacturing o Information and communication technologies o Logistic services provided in logistic activity zones o Sports and entertainment centres a Denotes sector related to the pharmaceutical industry. Reference List of priority sectors in industry. Tunis: Agency for the Promotion of Industry and Innovation; 2022 (http://www.tunisieindustrie.nat.tn/en/doc.asp?mcat=12&mrub=209#1, accessed 16 July 2022). 55 Annex 5: List of incubators, accelerators, seed and start -up funds, business angels, venture capital investment companies and venture capital mutual funds Incubators Website/e-mail Essect Ensit Business Incubator (E²BI) www.essect.rnu.tn essect@essect.rnu.tn Smart 216 www.smart216.com contact@smart216.com B@Labs www.biatlabs.com contact@biatlabs.com Business Intelligence Center www.bicenter.tn bintelcenter@gmail.com CEED Tunisie www.ceed-tunisia.tn bwennes@ceed-tunisia.org Le 15 www.le15.org Contact@Le15.org NetworkLab www.linkedin.com/company/networklab-tech/ Ping@networklab.tech WIKI START UP www.wikistartup.tn info@wikistartup.tn Lab'ess www.labess.tn contact@labess.tn Accelerators Website/e-mail Flat6Labs Tunis www.flat6labs.com tunis@flat6labs.com Fondation BIAT pour la jeunesse (BIAT Youth Foundation) www.fondationbiat.org.tn Founder Institute www.fi.co fitunis@gmail.com Impact Partner www.impactpartner.co contact@impactpartner.co Open Startup Tunisia www.open-startup.org Start Act www.startact.tn startactbusinessaccelerator@outlook.fr Start-up Space By Enpact Tunisia www.enpact.org/entrepreneurial-support/startup-haus National-mentoring@enpact.org The Next Society (Company) www.thenextsociety.co welcome@thenextsociety.co Seed and start-up funds Website/e-mail Ikdam management/ IKDAM II Fund www.cmf.tn/sites/default/files/pdfs/epargne/prospectu s/Prospectus_IKDAM_I I_fr.pdf 56 Ikdam.gestion@hexabyte CAPITAL Lease Seed Fund II www.cba.tn www.ugfsnorthafrica.com.tn contact@ugfsnorthafrica.com.tn IntilaQ Innovation www.intilaq.tn contact@intilaq.tn Sages Capital/ Spin off funds www.sagescapital.com info@essaimage-sagescapital.com Business Angels Website/e-mail Carthage Business Angels Association www.cba.tn Fund management companies Website/e-mail UGFS Nord Africa www.ugfsnorthafrica.com.tn contact@ugfsnorthafrica.com.tn AfricInvest www.africinvest.com contact@africinvest.com CDC Gestion www.cdcgestion.tn contact@cdcgestion.tn Alternative Capital Partners/ACP www.alter-cap.com info@alter-cap.com Investment companies in risk capital (SICAR) Website/e-mail Sages Capital www.sagescapital.com info@essaimage-sagescapital.com Sodis SICAR www.sodis-sicar.tn sodis.sicar@planet.tn Sidco SICAR www.sidco-sicar.com sidco.sicar@gnet.tn Sodino SICAR sodino.sicar@ hexabyte.tn F.R.D.C.M. SICAR www.frdcm.tn frdcgafsa@tunet.tn Sodicab SICAR sodicab@planet.tn Sodek SICAR sodek.sicar@ hexabyte.tn Innovest www.innovest.tn contact@innovest.tn Investment Participation And Promotion Company info@sppi.fin.tn STB SICAR www.stbsicar.com.tn info@stbsicar.com.tn BH Equity www.bhequity.tn contact@bhequity.tn Sicar Invest (BNA) www.bna.tn Sicar.invest@planet.tn BTE SICAR www.bte.com.tn habib.benhadj@bte. com.tn 57 BT SICAR www.bt.com.tn mehdi.elbah@ bt.com.tn Global Invest SICAR (UBCI) www.ubci.tn ugf@ubci.com.tn nabil.lakhoua@ bnpparibas.com Univers Invest SICAR (BTK) www.btknet.com uis@planet.tn International SICAR (UIB) www.uib.com.tn sicar.uib@planet.tn Attijari SICAR www.attijaribank.com.tn Ali.saidi@attijaribank.com.tn Reference Principaux mécanismes de financement en Tunisie. Tunis: TIA; 2022 (https://guide.tia.gov.tn/uploads/Mecanismes_de_Financement-en.pdf, accessed 13 October 2022). 58 Annex 6: List of banks in Tunisia Conventional banks Alubaf International Bank-Tunis Avenue de la Bourse, les Berges du LacII-1053-Tunis Tel : +216 70 015 600/ Fax+ 216 71 198 000 alub@alubaf.com.tn www.alubaf.com.tn ATB 9, Rue Hédi Nouira 1001 Tunis Tel : +216 71 351 155/Fax : +216 71 342 852 atbbank@atb.com.tn http://www.atb.tn BNA Rue Hédi Nouira 1001 Tunis Tel : +216 71 831 000 / 71 831 200/ Fax : +216 71 830 117 bna@bna.tn http://www.bna.com.tn Attijari Bank Rue Hédi Karray centre Urbain nord Tunis 1082 Tel : +216 70 012 000/Fax :+216 70 235 636 courrier@attijaribank.com.tn http://www.attijaribank.com.tn BT 2, rue de Turquie 1000 Tunis Tel : +216 71 125 500 / 71 332 188/ Fax : +216 71 349 477 / 71 125 401 finance@bt.com http://www.bt.com.tn Amen Bank Avenue Mohamed V 1002 Tunis Tel : +216 71 148 000/ Fax :+216 71 833 517 amenbank@amenbank.com.tn http://www.amenbank.com.tn BIAT 70/72 Avenue Habib Bourguiba – Tunis Tel : +216 71 340 733/Fax :+216 71 340 680 webmaster@biat.com.tn http://www.biat.com.tn STB Rue Hédi Nouira, 1001 Tunis Tel : +216 70 140 000/Fax : +216 71 340 009 / 71 348 400 stb@stb.com.tn http://www.stb.com.tn UBCI 139, Avenue de la Liberté 1002 Tunis Tel : +216 81 100 000/Fax : +216 71 841 583 ubci.contact@ubcinet.tn http://www.ubci.tn UIB 65, Avenue Habib Bourguiba 1000 Tunis Tel : +216 81 10 20 20 / 71 218 000/Fax : +216 71 218 009 / 71 218 458 UIBCONTACT@uib.com.tn http://www.uib.com.tn BH 18, Avenue Mohamed V Tunis Tel : +216 71 126 000/Fax : +216 71 784 417 / 71 337 957 banquehabitat@bh.fin.tn http://www.bh.com.tn CITIBANK 55, Avenue Jugurtha Belvédère 1002 Tunis Tel : +216 71 113 300/Fax : +216 71 785 556 http://www.citigroup.com 59 BTK 10 bis Avenue Mohamed V – 1001 Tunis Tel : +216 71 204 000/Fax : +216 71 343 106 contact@btknet.com http://www.btknet.com TSB 32, Rue hédi Karray – cité mahragène 1082 Tunis – P.O Box 20 – 1002 Tunis Tel : +216 70 243 000/Fax : +216 71 753 233 / 233 843 contact@tsb.com.tn http://www.tsb.com.tn QNB Rue cité des sciences centre Urbain Nord Tunis Tel : +216 71 750 000/Fax : +216 71 713 111 / 71 235 611 http://www.qnb.com.tn BTE 5 bis, Rue Mohamed Badra 1002 Tunis Tel : +216 71 112 000 / 783 756 / 783 600/Fax : +216 71 783 756 bte@bte.com.tn http://www.bte.com.tn BTL Avenue de la terre Centre urbain nord Tel : +216 70 131 700/Fax : +216 71 902 808 / 902 837 / 903 197 btl@gnet.tn http://www.btl.com.tn BANK ABC ABC Building – Rue du Lac d’Annecy – 1053 Les Berges du Lac Tel : +216 71 861 861/Fax : +216 71 860 921 abc.tunis@bank-abc.com http://www.bank-abc.com NAIBANK Avenue Kheireddine Pacha Ennassim Montplaisir, 1002 Tunis – Tunisia – PO BOX 485 – 1080 Tunis Cedex Tel : + 216 71 950 800/Fax : +216 71 950 840 naib@naibank.com http://www.naibbank.com/ Islamic banks Albaraka Bank 88, avenue Hédi Chaker 1002 Tunis Tel : +216 71 790 000/Fax : +216 71 780 235 albarakamail@albarakabank.com.tn http:///www.albarakabank.com.tn Banque Ezitouna 2, Boulevard qualité de la vie 2015 le Kram – Tunisie. Tel : +216 81 105 555/Fax : + 216 71 165 000 contact@banquezitouna.com. http://www.banquezitouna.com Wifak Bank Siège Social : Av H. Bourguiba Médenine – Médenine 4100 Centre D’affaires: Zone d’activités Kheireddine – les Berges du Lac 3- Tunis 2015 Tel : +216 70 259 000 / 70 259 259/Fax : +216 70 254 000 info@wifakbank.com http://www.wifakbank.com/ Reference Principaux mécanismes de financement en Tunisie. Tunis: TIA; 2022 (https://guide.tia.gov.tn/uploads/Mecanismes_de_Financement-en.pdf, accessed 13 October 2022). 60 Annex 7: An enabling ecosystem for pharmaceutical innovation and healthcare R&D Reference Pharmaceutical sector: Tunisia value proposition. Tunis: Tunisia Investment Authority; 2021. (not published nor publicly available) Annex 8: A comprehensive academic and vocational training system Reference Pharmaceutical sector: Tunisia value proposition. Tunis: Tunisia Investment Authority; 2021. (not published nor publicly available) 61 Annex 9: African vaccine manufacturers Reference Vaccine manufacturing in Africa: External Tunisia Country Pack. London: UKaid; April 2021. 62 For more information, please contact: World Health Organization Local Production & Assistance Unit Innovation and Emerging Technologies Department Access to Medicines and Health Products Division 20 Avenue Appia 1211 Geneva 27 Switzerland Email: localproduction@who.int Website: https://www.who.int/teams/regulation-prequalification/lpa www.who.int
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A case study on the ecosystem for local production of pharmaceuticals, vaccines and biologicals: the Tunisia context
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