Table of Contents FIGURES ...................................................................................................................................................... 3 TABLES ........................................................................................................................................................ 3 ACKNOWLEDGEMENTS............................................................................................................................. 4 ABBREVIATIONS AND ACRONYMS ......................................................................................................... 5 EXECUTIVE SUMMARY .............................................................................................................................. 6 INTRODUCTION ........................................................................................................................................... 8 Value Addition of the Project ..................................................................................................................... 8 INDONESIA COUNTRY PROFILE ............................................................................................................... 9 Brief Country Context ................................................................................................................................ 9 The Impact of COVID-19......................................................................................................................... 12 NATIONAL IMMUNIZATION PROGRAM (NIP) AND VACCINE DELIVERY ........................................... 14 National Immunization Program .............................................................................................................. 14 Vaccine Delivery Challenges .................................................................................................................. 15 VACCINE PROCUREMENT PROCESS .................................................................................................... 16 Projected Vaccine Requirements ............................................................................................................ 17 Source: Annual Report PT Bio Farma (2007-2021) ................................................................................ 18 Adverse Events Following Immunization (AEFI) and Pharmacovigilance Systems ............................... 19 ROBUSTNESS OF REGULATORY SYSTEMS......................................................................................... 19 Marketing Authorization Process ............................................................................................................ 21 Regulatory Efforts to Support Innovation and Development of New Vaccines ....................................... 22 DOMESTIC MANUFACTURING AND DISTRIBUTION CAPACITY ......................................................... 23 Existing Capacity ..................................................................................................................................... 23 Potential Vaccine Manufacturers ............................................................................................................ 24 Support, Incentives and Challenges for Domestic Vaccine Manufacturing ............................................ 25 POTENTIAL STRATEGIC PARTNERSHIP BETWEEN INDONESIA AND ASEAN MEMBER STATES IN SUPPORTING ASEAN REGIONAL VACCINE MANUFACTURING CAPACITY ..................................... 27 SWOT ANALYSIS OF POTENTIAL CONTRIBUTION TO REGIONAL VACCINE VALUE CHAIN ......... 29 CONCLUSION ............................................................................................................................................ 31 REFERENCES ............................................................................................................................................ 33 ANNEX 1. Immunization Coverage, nationally and by province .......................................................... 36 ANNEX 2. Proposed New Vaccines to NIP ............................................................................................. 39 ANNEX 3: Vaccine Manufacturer Profiles............................................................................................... 41 ANNEX 4: Domestic Vaccine Manufacturing—National Capacity........................................................ 44 2 Figures Figure 1. Population of the Republic of Indonesia ........................................................................................ 9 Figure 2. Indonesia population by age group, 1970-2020 .......................................................................... 10 Figure 3. Burden of Diseases and Health Cost........................................................................................... 11 Figure 4. COVID-19 cases (i) and coverage of COVID-19 vaccination program (ii) .................................. 12 Figure 5. Forecast of Industrial Vaccine Market in Indonesia (IDR) ........................................................... 18 Figure 6. Key population, education and health indicators in ASEAN ........................................................ 28 Figure 7. Regulations in support of national biological product development ecosystem .......................... 31 Tables Table 1. NIP Responsibilities by Government Level ................................................................................... 14 Table 2. Immunization Financing Realization in 2015-18 by Source and Category (Millions of Rp) .......... 17 Table 3. Differences in Average Growth ..................................................................................................... 18 Table 4. Status of WHO NRA Benchmarking for Vaccine Oversight by BPOM in 2018 ............................ 20 Table 5. Patent Protection (component of vaccine products) owned by of PT. Bio Farma ........................ 27 Table 6. Annual percent change in GDP, ASEAN member states ............................................................. 28 3 Acknowledgements The Indonesia case study was prepared by appreciated. consultants Dra. Lucky Slamet, Apt.MSc., and Bintang Mukhammad Burhanudin Akbar, The Indonesia case study is part of a larger SE.MM., under the leadership of Dr. Pandu regional study with the following components: Harimurti (Senior Health Specialist, World global desk review, private sector landscape Bank-Indonesia) and Dr. Ronald Mutasa analysis, economic analysis, and country (Practice Leader, Human Development). This deep-dive case studies. Partnership and report benefited from technical inputs from Dr. collaboration with the ASEAN Secretariat Ramana Gandham (Technical Advisor/former under the leadership of Dr. Ferdinal Fernando Lead Health Specialist), Dr. Andreas Seiter and Ms. Jennifer Dela Rosa, the UK Foreign, (Technical Advisor/ Industry Expert), Dr. Commonwealth and Development Office, and Achim Schmillen (Practice Leader, Human the Global Financing Facility for Women, Development), Mr. Giles Newmarch (Senior Children and Adolescents was essential to the Investment Officer, IFC), Ms. Ridhi Gupta successful completion of the study. Logistics (Investment Officer, IFC), Ms. Erin Sowers support was provided by Inge Sutardi Tan and (Consultant), and Ms. Zinaida Korableva Mae Myat Moe. The cover and report layout (Operations Analyst). were designed by Kayleigh Ghiot. The information contained in this report draws This report benefited from the valuable heavily from interviews and consultations comments of peer reviewers Dr. Matthew conducted with Indonesia government officials, Downham (Director, CEPI), Ms. Zeynep related experts on vaccine and immunization, Kantur (Global Manager, Health, IFC), Dr. and private sector representatives, including Lombe Kasonde (Senior Health Specialist), vaccine producers and the Indonesian and Dr. Kayla Laserson (Deputy Director, Bill Pharmaceutical Company Association. The and Melinda Gates Foundation). The overall leadership and guidance of Dr. Dra. Lucia technical guidance provided by Daniel Dulitzky Andalucia, Apt., MPharm., MARS., Director (Regional Director for Human Development), General of Pharmaceutical and Medical Farid Fezoua (Global Director, IFC) and Devices, Ministry of Health Indonesia; Prof. dr. Aparnaa Somanathan (Practice Manager, Laksono Trisnantoro, MSc., PhD., Adviser to Health, Nutrition and Population) is gratefully the Minister of Health Indonesia in the field of acknowledged. pharmaceuticals and medical devices resiliency; Dra. Maya Gustina Andarini, Apt., MSc., Deputy Head for Medicine, Narcotics, Precursor and Hazardous Substances Control (Deputy 1 of the Indonesian Food and Drug Authority (BPOM), 2021-2022); Prof. Dr. dr. Sri Rezeki Hadinegoro, SpA(k), Chair of ITAGI (Indonesian Technical Advisory Group on Immunization); Prof. Dr. dr. Hinky Hindra Irawan Satari, SpA(k), Subsp.IPT., M.TropPaed., Chair of the National Committee on AEFI (NC-AEFI); Dr. dr. Julitasari Sundoro, Secretary of NC-AEFI; and officials from the Coordinating Ministry for Maritime and Investments Affairs Indonesia, the National Research and Innovation Agency (BRIN), and the Ministry of Industry Indonesia are greatly 4 Abbreviations and Acronyms AEFI Adverse Event Following Immunization ASEAN Association of Southeast Asian Nations BAPPENAS Badan Perencanaan Pembangunan Nasional (Ministry of National Development Planning) BPJSK Badan Penyelenggara Jaminan Sosial Kesehatan (National Social Health Insurance Agency) BPS Badan Pusat Statistik (Central Bureau of Statistics) BPOM Badan Pengawas Obat dan Makanan (The Indonesia Food and Drug Authority) BPPT Badan Pengkajian dan Penerapan Teknologi (Technology Assessment and Application Agency) CTO Clinical Trial’s Oversight DQS Data Quality Assessment EPI Expanded Program on Immunization EUA Emergency Use Authorization GCP Good Clinical Practice GDP Gross Domestic Product GMP Good Manufacturing Practice GRelP Good Reliance Practice GVAP Global Vaccine Action Plan ITAGI Indonesian Technical Advisory Group on Immunization JACG Joint Assessment Coordinating Group JE Japanese Encephalitis JKN Jaminan Kesehatan Nasional (National Health Insurance Program) LAM Local Area Monitoring LAT Laboratory Access and Testing LIC Licensing Premises LKPP Lembaga Kebijakan Pengadaan Barang/Jasa Pemerintah (Government Goods and Services Procurement Policy Agency) LTR Lot Release MA Marketing Authorization ML Maturity Level MSC Market Surveillance and Control NCD Noncommunicable Disease NIP National Immunization Program NRA National Regulatory Authority NRS National Regulatory System NTB Nusa Tenggara Barat (West Nusa Tenggara) NVI New Vaccination Introduction PCV Pneumococcal vaccine PIC/S Pharmaceutical Inspection Cooperation/Scheme RI Regulatory Inspection RISKESDAS Riset Kesehatan Dasar (Baseline Health Research) RMA Registration and Marketing Authorization RPJMN Rencana Pembangunan Jangka Menengah Nasional (National Medium-Term Development Plan SDG Sustainable Development Goal SEARVAP South-East Asia Regional Vaccine Action Plan SMS Short Service Message SOP Standard Operational Procedure TB Tuberculosis TRIPs Trade-Related Aspects of Intellectual Property Rights VPD Vaccine-Preventable Disease WHO World Health Organization WLA WHO Listed Authority Indonesia Case Study 5 EXECUTIVE SUMMARY Indonesia is the most populous country in ASEAN region, with more than 270 million people comprising more than 40 percent of Indonesia is well- the ASEAN total population. In 2014 the Government introduced the National Public positioned to Health Insurance System (Jaminan Kesehatan Nasional), which has since expanded to cover support the more than 222 million enrollees to date, making development of a it one of the largest public health insurance programs in the world. In Indonesia’s devolved regional vaccine health system, the Central Government provides overall policy and financial support for security ecosystem. health service provision, while sub-national governments manage service delivery. Aligned with regional and global Indonesia first reported cases of development priorities, Indonesia’s National COVID-19 in March 2020; ten months Immunization Program (NIP) has strong later, in January 2021, it launched a backing among Government policy makers vaccination campaign using COVID-19 who have made it a goal to ensure program vaccines imported from China. The sustainability with minimal external financial pandemic has put numerous strains on the support. At present, the NIP includes vaccines health system: Indonesia saw a reduction in for six diseases—BGC, DPT, Polio, Measles, NIP coverage rates, from 84.2 percent in Hepatitis B, Haemophilus Influenza Type B; 2020 to 79.6 percent in 2021, as health four new vaccine introductions—Japanese facilities suspended services and parents Encephalitis (JE) vaccine, Pneumococcal delayed preventive care; the country has vaccine (PCV), HPV vaccine for girls 9-13 also faced challenges in ensuring the years, and Rotavirus vaccine—are planned or availability of affordable COVID-19 vaccines underway. Nearly all NIP vaccines are and sustaining vaccine coverage for primary produced domestically by PT Bio Farma, a and booster doses. To address these issues, globally-significant government-owned the Government has created a National manufacturer. The Indonesian Central Biological Product Ecosystem with broad Government is responsible for procuring stakeholder support, established a new vaccines and overseeing vaccine logistics, national Vaccine Research Center, and while sub-national governments manage pursued comprehensive regulatory service delivery and ensure proper vaccine improvements to support innovation and handling and storage. For a number of reasons development of new vaccines, downstream (e.g. financial, geographic), vaccine delivery to upstream. and distribution is a challenge, with many provinces lacking adequate cold-chain capacity. The Indonesian National Regulatory Authority has achieved WHO Maturity Level 3, indicating that regulatory systems effectively ensure the safety, quality and efficacy of vaccines used and produced in Indonesia. 6 To build domestic capacity for COVID-19 Indonesia is well-positioned to support the vaccine manufacturing, PT Bio Farma has development of a regional vaccine security initiated R&D for a subunit-based COVID- ecosystem. The investment potential of the country is high: its substantial population 19 vaccine and has also signed a fill-and- means strong demand for vaccines now and in finish agreement with the Chinese the future, the regulatory systems for vaccines manufacturer of Sinovac for 250 million have reached ML3 status, and its economy doses of the vaccine per year. In addition, recovered quickly from the effects of COVID- four new vaccine manufacturing companies 19, indicating a stable economic environment. joined the field in 2021-22, all with external There is broad stakeholder and Government strategic partners and plans to utilize new support for scaling up national capacity for R&D vaccine platforms. However, based on and manufacturing for the ASEAN regional information from stakeholders, several market and facilitating communication between important factors should be addressed to the ASEAN regulatory forum and the ASEAN spur domestic vaccine industry growth, vaccine security initiative. Immediate steps for including limited know-how of a coordinated potential partnership between Indonesia and ASEAN member states in supporting ASEAN vaccine ecosystem, and the lack of available, regional vaccine manufacturing capacity may specialized human resources in upstream include, for example, (i) developing a common R&D, cold chain management, and vaccine understanding of vaccine manufacturing among distribution. In addition, government support ASEAN leaders with relevant scientific and is required to build infrastructure and strategic socio-economic perspectives, and (ii) capacitate the regulatory workforce, promote establishing a pilot initiative to strengthen partnerships and support for technology regulatory activities in ASEAN for upstream to transfer, introduce tangible and intangible downstream vaccine product development and incentives to encourage manufacturing supply chain integrity in an environment of investment, and ensure government mitigated risks, in collaboration with non- guarantee as vaccine purchaser. governmental organizations such as the World Bank and others. 7 Introduction COVID-19 has had a devastating effect on the ASEAN region, which has recorded over 27 million cases of the virus. Despite rapid development of a range of COVID-19 vaccines using innovative technologies, access to these vaccines has been a challenge, with manufacturing mostly concentrated in the US and Europe for high-value mRNA vaccines, and China and India for traditional platforms and high-volume production. Countries with domestic COVID-19 vaccine manufacturing capacity prioritized domestic vaccine requirements over foreign needs, putting countries with limited production capabilities at a disadvantage. ASEAN countries, which on the whole have made fairly limited investments in research and development of vaccines and biologicals, were highly dependent on imports, resulting in heightened vulnerability during COVID-19 surges. Despite the existence of an established framework for ASEAN coordination on vaccines, there has been minimal coordination between member states to collectively procure COVID-19 vaccines. Consequently, ASEAN countries have experienced a common set of challenges in navigating the complex global vaccine market to ramp up COVID-19 vaccination. Leaders of ASEAN member states have recognized the need for the region to be self-sufficient in vaccine research and manufacturing to effectively address future pandemics and build regional vaccine security. ASEAN must build regional capacity to develop, test efficacy, and scale up manufacture of vaccines, building on existing country-level strengths and avoiding duplication. While some evidence on regional vaccine manufacturing capacity for ASEAN exists, there has been limited research on the technical, operational, financing and strategic partnership opportunities that exist in the region and might be leveraged to advance regional vaccine security. To address this knowledge gap, the United Kingdom Foreign, Commonwealth and Development Office (UK FCDO) and the World Bank initiated the ASEAN Vaccine Development and Manufacturing Research Project. This project complements the ASEAN Vaccine Security and Self-Reliance (AVSSR) Initiative and the Coalition for Epidemic Preparedness Innovations (CEPI) 2021 plan, and supports the November 2019 declaration of ASEAN leaders on regional vaccine security and self-reliance. Value Addition of the Project This regional analytical activity will contribute to knowledge on the technical, operational, and financial viability and strategic partnership required among ASEAN countries to strengthen coordinated investments on the vaccine value chain. The activity has three major components: i) A deep-dive public sector technical assessment of country and regional level vaccine security, including gaps and opportunities across the value chain from R&D to last mile distribution; ii) A private sector value chain analysis covering upstream and downstream aspects of vaccine manufacturing; and 8 iii) An economic analysis examining the feasibility of coordinated investments across countries to leverage comparative advantage in specific aspects of the vaccine value chain. Five ASEAN members states—Indonesia, Malaysia, Philippines, Thailand and Vietnam—were engaged to conduct detailed analyses of their country’s vaccine system, including current processes related to procurement and distribution, manufacturing capabilities (current or potential), and regulatory systems related to domestic vaccine registration and production. The country teams also consulted with high-level stakeholders from government, regulatory agencies, academia, private sector and civil society to identify relative strengths and critical weaknesses in each country’s technical and human resource capacity to respond to vaccine manufacturing needs in the future. The results of those analyses and consultations make up the succeeding country profiles. Finally, a high-level policy dialogue was facilitated in late-2022 to explore regulatory, financing and institutional reforms required to address the identified challenges to regional vaccine manufacture. Indonesia Country Profile Brief Country Context The Republic of Indonesia is the largest archipelagic country in the world, with an estimated 17,504 islands and a population of more than 270 million‒the fourth largest in the world (Figure 1) and the largest among Association of Southeast Asian Nations (ASEAN) member states. This population includes numerous ethnic, cultural, and linguistic groups, speaking 724 distinct languages and dialects. Even though there is wide variation across countries in ASEAN both in terms of population and economic status, population size plays an important role in industrial and economic development. Indonesia's large population—which makes up 40 percent of the total population of ASEAN and is expected to grow at a rate similar to the global and ASEAN average (approximately 1 percent each year)—gives it an advantage. Figure 1. Population of the Republic of Indonesia 274 272 Population 270 268 266 264 2017 2018 2019 2020 2021 Indonesia 264.7 267.7 270.6 273.5 273.8 Source: World Bank (2020) and Ministry of Home Affairs (2021). 9 One characteristic of the Indonesian population is the uneven distribution and growth between islands and provinces. Most of the country’s population lives on the islands of Java (56 percent) and Sumatra (22 percent), even though the area of Java is less than 7 percent of the total Indonesian land area. However, the proportion of the population living on Java has been gradually decreasing, from about 59.1 percent in 2000 to a predicted 55.5 percent in 2025 (BAPPENAS and Statistics Indonesia, 2021). Indonesia is undergoing a demographic shift: according to the Inter-census Population Survey 1 2015, the population growth rate declined from 1.49 percent annually from 2000 to 2010 to 1.25 percent from 2010 to 2020, and is predicted to fall below one percent between 2020 and 2025. The composition of the population has changed over time, and indicates that Indonesia is heading towards an ageing population structure (Figure 2). The distribution of men and women in the Indonesian population is almost the same (50.58 percent and 49.42 percent, respectively). Figure 2. Indonesia population by age group, 1970-2020 Source: BPS (2021). Indicators of overall health status in Indonesia have improved significantly since the early 2000s. Life expectancy has risen from 69.2 years in 2005 to 72 years in 2015, infant mortality decreased from 32 deaths per 1,000 live births in 2012 to 24 deaths per 1,000 live births in 2017 (Statistics Indonesia, 2015 & 2017), and the stunting prevalence of children under-five dropped from 37.2 percent in 2013 to 30.8 percent in 2018 (UNICEF, 2020). Progress on maternal mortality and communicable diseases has been slower, with maternal mortality remaining high at 305 deaths per 100,000 live births in 2015, 2 and continuing high incidences of tuberculosis (TB) new cases and malaria. At the same time, risk factors for noncommunicable diseases (NCDs), such as high blood pressure, high cholesterol, overweight and smoking, are increasing (BAPPENAS, 2018). According to BPJS-K data 3, these lifestyle diseases continue to be the main contributors to health catastrophic expenditures (Figure 3), accounting for 25 percent of total medical expenses for the 1 SUPAS (Survei Penduduk Antar-Sensus). 2 SUPAS 2015. 3 Social Health Insurance Administration Agency (Badan Penyelenggara Jaminan Sosial Kesehatan: BPJS-Kesehatan or BPJS-K). 10 National Health Insurance Program Jaminan Kesehatan Nasional (JKN) in 2020 and more than 30 percent in 2019, before the COVID-19 pandemic. 4 Figure 3. Burden of Diseases and Health Cost Source: CNBC (2019) Indonesian central government financing supports health service provision, but the responsibility and authority for managing service delivery is held at the sub-national level. Indonesia is comprised of 34 provinces and 514 regencies and cities, which make up the administrative level just below provinces. The backbone of public health service consists of more than 10,000 public primary health care facilities (puskesmas) that are supported by almost 300,000 village health posts (posyandu) and 1,047 public hospitals. Private sector health care plays a significant role in health service delivery, with more than two-thirds of outpatient care services provided by individual physicians, clinics, and pharmacies. NIP implementation relies on puskesmas and the vast network of posyandu in every village, which are run by voluntary health workers. The National Public Health Insurance System (Jaminan Kesehatan Nasional) was introduced in 2014 and has since expanded rapidly, now covering more than 222 million enrollees and making it one of the largest public health insurance programs in the world (Box 1). The introduction of national social insurance reduced direct out-of-pocket payments for health care from 53 to 32 percent of Total Health Expenditure (THE) between 2014 and 2019. The share of government general expenditure for health accounts for 31 percent of THE, with 79 percent of the government share executed at sub-national levels (17 percent at the province level; 62 percent at regency/city level). 4 BPJS Bulletin, edition 104, November 2021 11 ASEAN countries, including Indonesia, are working to build cooperation in various fields—among them health security—with a goal of reducing the impact of COVID-19 and future pandemics as well as regionally endemic and reemerging diseases. The existing ASEAN coordination and cooperation mechanisms carried out in response to the COVID-19 pandemic, and which were formalized in the Declaration of the Special ASEAN Summit on COVID-19 (April 2022), facilitated the availability of important food and health products such as medicines, medical equipment and vaccines. Box 1: Indonesia’s National Health Insurance Program (Jaminan Kesehatan Nasional) Indonesia introduced its social health insurance program, Jaminan Kesehatan Nasional (JKN), in 2014. The new scheme merged four national-level social health insurance schemes and hundreds of local schemes into one national risk pool with a uniform benefit package and a single purchaser of health services, which resulted in the standardization of payment methods, reimbursement rates, and rules for quality of care. As one of the biggest single payer systems in the world, the JKN program covered around 220 million people—or more than 80 percent of Indonesians—in only its fifth year of implementation. The JKN program provides a generous benefit package, covering all medically necessary treatment with no caps or co-payments. Since its introduction, the share of out-of-pocket (OOP) expenditures has decreased by nearly 12 percentage points, though it still remains high at 37 percent. Vaccination for the Government of Indonesia’s Immunization Program is not covered by the JKN Program and is financed by the general government health expenditure. The Impact of COVID-19 Recording of COVID-19 cases in Indonesia began in March 2020, while vaccination started in January 2021; by September 2022, 63.4 percent of the eligible population had been fully vaccinated. The total number of reported COVID-19 cases in Indonesia reached over 5.77 million, with an average recovery rate of 97.3 percent and mortality rate of 2.6 percent (150,430 deaths) as of March 7, 2022. The increase in COVID-19 cases due to the Omicron variant at the beginning of 2022 led to the establishment of a booster vaccination policy. However, only about 14 percent of the eligible population of Indonesia had received booster doses as of April 2022. Trends in reported COVID-19 cases in Indonesia and progress in the implementation of vaccine administration are shown in Figure 4. 12 Figure 4. COVID-19 cases (i) and coverage of COVID-19 vaccination program (ii) Source: https://Covid19.go.id (April 2022) The contraction of Indonesia’s economy due to COVID-19 threatens the availability of fiscal space for the health sector. The country’s GDP contracted by 2 percent in 2020, though it saw modest growth of 3.7 percent in 2021 and is expected to fully rebound in 2022 as consumer and investor demand return and the health situation improves. Indonesia's GDP tripled between 2006 and 2019, from US$364.87 billion to US$1.10 trillion. Conditions decreased slightly to US$1.06 trillion in 2020 due to the COVID-19 pandemic, which resulted in the country being reclassified as a lower-middle-income country. 5 Nevertheless, resumed economic growth has seen Indonesia commit to investing more in its ambitious health transformation agenda, including through building health system resilience. Another impact of COVID-19 on the health sector is the decrease in basic immunization coverage of children, from 84.2 percent in 2020 to 79.6 percent in 2021 (Ministry of Health, 2022), which has led to a resurgence of some vaccine preventable diseases (VPDs), especially in areas already challenged by low immunization coverage. Sixty-five percent of health facilities reported temporarily suspending immunization services during the pandemic (UNICEF, 2021), which is likely behind the decrease in coverage. Other factors include: (i) the preference of parents to delay the immunization schedule for their children during the pandemic (Ministry of Health and UNICEF, 2020); (ii) delaying visits to an immunization center due to transportation difficulties; (iii) fear of being infected with COVID-19 while visiting hospitals and health clinics; (iv) current COVID-19 infection; and (v) high priority given by the health sector to respond to the pandemic at the expense of routine immunizations. A description of the data for basic and advanced immunization coverage nationally and in each province in Indonesia in 2019-20 is presented in Annex 1. Despite the challenges, Indonesia is committed to meeting the goals of the Multi-Year Plan 2020-2024 (Ministry of Health, 2019) and to maintain sound implementation of the NIP during the COVID-19 pandemic, in parallel with efforts to increase the coverage and quality of COVID-19 vaccination (primary and booster). 5World Bank Open Data, indicator: GDP (current US$) – Indonesia. Available online at https://data.worldbank.org/indicator/NY.GDP.MKTP.CD?end=2021&locations=ID&start=2006 13 National Immunization Program (NIP) and Vaccine Delivery National Immunization Program The National Immunization Program (NIP), which includes the Expanded Program on Immunization (EPI), is one of Indonesia’s priority health development programs outlined in the five-year National Medium-Term Development Plan (Rencana Pembangunan Jangka Menengah Nasional: RPJMN). It aligns with the World Health Organization (WHO) Global Vaccine Action Plan (GVAP), South-East Asia Regional Vaccine Action Plan (SEARVAP), Sustainable Development Goals (SDGs), and Immunization Agenda (iA2030). The EPI covers all children under age 5 and has been implemented in Indonesia since 1977 with the aim of reducing morbidity and mortality rates due to VPDs. Vaccines currently included in the EPI are: (i) one dose of BCG vaccine against TB; (ii) three doses of Diphtheria, Pertussis, and Tetanus (DPT) vaccines; (iii) four doses of Injectable Polio vaccine; (iv) one dose of Measles vaccine; (v) three doses of Hepatitis B vaccine; and (vi) three doses of Haemophilus Influenzae Type B (Hib) vaccine. To complete a full basic immunization program, Indonesia has prioritized the addition of four new vaccines to the NIP by 2022/23 (Ministry of Health 2019), namely Japanese Encephalitis (JE) vaccine, Pneumococcal vaccine (PCV), HPV vaccine for girls 9-13 years, and Rotavirus vaccine. Details about initial steps to introduce these vaccines are included in Annex 2. Other vaccines currently being used in community services but not yet included in the NIP are dengue and typhoid vaccines. In 2017, Minister of Health Decree No. 12/2017 on Immunization Implementation was authorized to strengthen the NIP. The decree included updates and improvements on: vaccine distribution; implementation of routine immunization services; service delivery monitoring and treatment of Adverse Events Following Immunization (AEFI); research and development; recording and reporting; and controlling as well as introducing new vaccines based on the recommendation of ITAGI (the Indonesian Technical Advisory Group on Immunization). ITAGI was established in 2006 to support the immunization system in Indonesia by monitoring and assessing vaccine knowledge improvement (technology, production, and new vaccine development), analyzing immunization program achievements to recommend improvements, and coordinating with other institutions and professional organizations at the national and local levels on immunization-related issues. Responsibility for NIP implementation is divided between central, provincial and district governments, as depicted in Table 1. As previously stated, the share of government general expenditure for health accounts is 31 percent of THE, with 79 percent of the government share executed at sub-national levels. However, the commitments from local government for essential health programs such as immunization are not always consistent as they are influenced by changes in local leadership. Table 1. NIP Responsibilities by Government Level Central Government Local Government Primary Health Centre (Puskesma) guided District Health Office • Procuring vaccines and • Supporting implementation • Main deliverer of public overseeing vaccine logistics in their respective geographic immunization services in their throughout the country, areas, area. 14 • Developing guidelines and • Ensuring adequate budgetary • Submit vaccination data to standards, support for incentives, their respective DHOs • Engaging in program transportation, • Compile and transmit it to the planning, • Program operations, Ministry of Health for • Monitoring and evaluation, • Cold-chain monitoring and national-level tracking of ensuring a functional cold- maintenance, immunization coverage. chain, • Community awareness • Training health workers, generation, • Overseeing VPD surveillance. • VPD surveillance. Even before the COVID-19 pandemic, national immunization coverage rates showed a declining trend: Baseline Health Research (Riset Kesehatan Dasar: RISKESDAS) data from 2013-18 show that the percentage of children with complete immunization coverage decreased from 59.2 percent in 2013 to 57.9 percent in 2018. The largest declines occurred in Gorontalo (19 percent), Aceh (18.8 percent), and Riau (17.8 percent) provinces, as described in Annex 1. Explanations for these declines include vaccine hesitancy/community distrust of vaccines, insufficient operational costs, and logistics and/or planning challenges. The decreasing trend for all EPI vaccines was amplified during the COVID-19 pandemic, as previously discussed. Vaccine Delivery Challenges Vaccine storage and distribution require special attention because vaccines are biological preparations susceptible to changes in environmental temperatures. Vaccines, therefore, require a cold-chain mechanism using specialized equipment in order to remain efficacious. Based on Minister of Health Decree No. 12/2017 on Immunization Implementation, the vaccine cold-chain mechanism requires different equipment and operational standards for each administrative region. The total equipment needs and related budgets for cold-chain monitoring are forecasted at the central level annually based on reports from each province and district on the availability and status of cold chain equipment. Despite the minimum requirements stated in the Minister of Health Decree, cold-chain equipment is lacking in many provinces. A recent cold-chain capacity assessment report showed that as of October 2020, only about one-third—or 12 out of 34 provinces—have vaccine- compatible storage facilities, most of which are concentrated on the island of Java. Furthermore, 10 percent of puskesmas lack functional cold chain equipment (Ministry of Health, 2019; 2020). These limitations hamper effective dissemination of vaccines, especially those requiring ultra- cold chain for transport, such as the mRNA (−70°C) COVID-19 vaccine. However, drawing from experience gained from the COVID-19 pandemic, the Indonesian Government recently developed technical guidelines as a reference for vaccine distribution, which include factors to consider in distribution, namely capacity and connectivity, facilities and infrastructure, and safety and security. 6 7 6http://farmalkes.kemkes.go.id/unduh/kmk-no-hk-01-07-menkes-4638-2021-ttg-juknis-pelaksanaan-vaksinasi-dalam-rangka- penanggulangan-pandemi-covid-19/ 7 For ultra-cold chain (UCC) facilities, in particular, Indonesia has been supported by COVAX, GAVI, and donor countries‒for example, In August 2021, UNICEF delivered 17 UCC freezers to Indonesia on behalf of COVAX. 15 Vaccine Procurement Process There are three main methods of procuring medicines in Indonesia, including vaccines and medical devices for hospitals and clinics: national tenders; online e-Katalog; and hospital tenders (BAPPENAS, 2019). National public procurement tenders are used for products of similar specifications that can be supplied by multiple distributors. The national e-Katalog online procurement system is used by public and private hospitals and clinics to procure specialized medicines, including vaccines and medical devices for which there is only one or very few suppliers. Until 2022, the e-Katalog was managed by the Government Goods and Services Procurement Policy Agency (Lembaga Kebijakan Pengadaan Barang/Jasa Pemerintah: LKPP); it is now managed by MOH. Finally, individual hospitals conduct procurement tenders, usually for more highly specialized products that are only used at that hospital. The e-Katalog online procurement system lists the technical specifications and prices of specialized products from various providers. In 2019, the total procurement transaction value was US $462 million for pharmaceutical products (including vaccines) and US$2.2 billion for medical devices 8. There are eligibility criteria for products to be included in the e-Katalog, such as current regulatory approval from the Indonesian Food and Drug Authority 9 (Badan Pengawas Obat dan Makanan: BPOM) and inclusion in the Ministry of Health’s list of products eligible for enrollment in the e-Katalog. Under LKPP management, products that were listed needed to re- enroll annually to remain as such (International Trade Administration), but now that the e- Katalog is under MOH management, registration remains open for the entire year and may expand to accommodate multiyear procurement agreements. 10 Prior to 2022, prices were negotiated between LKPP staff and the local Marketing Authorization (MA) holders; however, specific price negotiations are no longer a feature of this system, as the Ministry of Health and LKPP have developed reference prices, and applications must include the price structure. If the price in the application does not meet the reference price, the application will not be accepted. 11 For imported products, prices are negotiated based on the import transfer price plus an additional percentage to allow for local distribution costs, post-marketing surveillance costs, and a profit margin. Under Ministry of Industry Regulation No. 16/2020, medical products that are certified by the Ministry of Industry as having high local content will be given priority over otherwise similar imported products in e-Katalog procurement. Indonesia allows for a 20-year patent period, which protects innovative medicines from local competition, 12 provided such products have been listed under Indonesian Law No. 13/2016 on Patents. A Presidential Regulation updated in 2020 restricts compulsory licensing to situations where there is a clear public health emergency. From past experience prior to 2022, as LKPP‘s responsibility covers a wide range of public 8 Indonesia Medical Procurement System: https://trade.gov/market-intelligence/Indonesia-medical-procurement-system 9 Indonesian Food and Drug Authority, based on Keputusan Kepala BPOM year 2020 10 Result of interview with Director General of Pharmaceutical and Medical, April 2022 and https://farmalkes.kemkes.go.id Kebijakan Katalog Sektoral Kesehata 11 https://e-katalog.lkpp.go.id and https://farmalkes.kemkes.go.id Kebijakan Katalog Sektoral Kesehatan 12 Patent (Innovated) Medicine Industry based on the Presidential Regulation No 44/2016 on List of Business Fields that are closed to and Business that are open with condition to investment  foreign capital ownership max 85%. All applicants for Marketing Authorization for now is only submitted by pharmaceutical industry only 16 procurement areas, LKPP’s staff do not necessarily have in-depth specialized knowledge of the medical field. This results in a greater emphasis during price negotiations on short-term cost reduction and less emphasis on how innovative products may contribute to improved quality of life. There are no price incentives for innovative medical products that have not been used previously in clinical practice in Indonesia. The budget allocation for the immunization program covers vaccine procurement, cold-chain equipment, personnel, other routine recurrent costs, other capital costs, and vaccine campaign costs. Immunization financing realization in 2015-18 is shown in Table 2. The estimated share of public sector financing for the NIP has been more than 80 percent for many years, with the majority coming from the Central level 13. GAVI has been the largest source of external financing for immunization activities in Indonesia, though its assistance has decreased since 2017 as Indonesia’s economic status has improved. GAVI continues to provide support, however, especially when it comes to introducing new and underutilized vaccines. Table 2. Immunization Financing Realization in 2015-18 by Source and Category (Millions of Rp) Category 2015 2016 2017 2018 Govt Donors Govt Donors Govt Donors Govt Donors Program 472,406 98,891 618,621 104,835 1,731.683 697,802 126,159 114,539 Management Vaccines 61,086 6,306 78,172 5,250 122,248 30,014 1,991,947 139,148 Injection 182,462 30,533 404,573 77,382 322,855 42,505 288,968 6,855 equipment (AD Syringes and Safety box) Total by Source 715,954 135,730 1,101,366 187,467 2,176,786 770,321 2,407,074 260,542 Total Financing 851,684.88 1,288,833.06 2,947,108.04 2,667,615.72 Source: Ministry of Health 2019. Projected Vaccine Requirements Forecasting the long-term need for vaccines in Indonesia is important for both the central government and the vaccine industry, as it allows for strategic planning and budget projection. From the vaccine market perspective, estimated market growth is based on financial statements from vaccine companies from 2007-2021 and specifically considers 1) sales of vaccine products, 2) manufacturing costs for vaccine products, and 3) research and development (R&D) costs. As shown in Table 3, the average growth from 2007 to 2020 (12.96 percent) differs greatly from the average from 2007 to 2021 (59.55 percent). This difference was primarily due to product sales, which increased by 727 percent or Rp 15.60 trillion, due to COVID-19 vaccine requirements (specifically the realization of sales of the COVID-19 Bio Farma vaccine and bulk nOPV2). The responsibility for planning of program pharmaceuticals and supplies including NIP vaccines lies mainly within the Immunization Directorate of MOH. Forecasting for vaccine needs is conducted through a top-down (central to local government) or bottom-up (from public health facilities, to district level, then to central government) approach, or a combination of both, using the target population size (e.g. number of children under age 5, newborns, pregnant women, 13The public financing system has not been able to capture the size of sub national financing. However, from a study in five districts, indicated that the share of sub national financing for immunization is quite small. 17 etc.). There are also non-standardized methods for forecasting of vaccines such as historical requirements. The sub-national level is also expected to forecast vaccine needs, including for buffer and backup (district level forecasts for two months plus one month of buffer, while puskesmas forecast for one month plus one week of backup). The COVID-19 pandemic created an anomaly in vaccine demand. The spike in demand due to the COVID-19 vaccination program began in 2021 and may be sustained depending on additional demand for more regular vaccination in the future (Figure 5). The same data showed that PT Bio Farma continues to grow R&D from year to year, with costs reaching 2-4 percent of total sales. This value is likely to change due to several factors, including a) the entry of new companies into the vaccine industry, b) capacity building of existing companies, and c) protection from other countries as a result of domestic policies. Figure 5. Forecast of Industrial Vaccine Market in Indonesia (IDR) 20,000,000,000,000 15,000,000,000,000 10,000,000,000,000 5,000,000,000,000 - 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 -5,000,000,000,000 Sales Forecast Lower Bound Upper Bound Source: Annual Report PT Bio Farma (2007-2021) Table 3. Differences in Average Growth for PT Bio Farma, 2007-2020 versus 2007-2021 Category 2007-2020 2007-2021 Total Sales Vaccine 9.74% 60.97% Total Cost Manufacture 10.79% 96.17% Cost R&D 18.34% 21.51% Average 12.96% 59.55% Source: Annual Report PT Bio Farma (2007-2021) Learning from the pandemic, the Government of Indonesia accelerated its vision to build self- reliance in vaccine availability, as well as for treatment and diagnostics. The country demonstrated this aspiration even before the pandemic occurred, with the issuance of Presidential Instruction No 6, 2016 for The Acceleration of the Development of the Pharmaceutical and Medical Devices Industry. Recently, MOH launched a health sector transformation agenda that includes a pillar on strengthening pharmaceutical resilience for health security. The government provides support and facilities for investing in pharmaceutical companies to establish factories in Indonesia. 18 Adverse Events Following Immunization (AEFI) and Pharmacovigilance Systems The National Committee on AEFI (NC-AEFI) was established in 1997 to develop and oversee a system for tracking, investigating, documenting, recording, and reporting any AEFI. The NC-AEFI is an independent professional organization that supports the NIP; its membership is renewed every four years per Minister of Health decree. All provinces are mandated to establish provincial-level AEFI committees (PC-AEFI). The Manual for Vaccine Management in Health Service Facilities includes a five-stage process for handling AEFI cases. The process stipulates: (i) every AEFI reported by officers and by the public must be tracked, recorded, and responded to by the immunization officers in charge; (ii) AEFIs must be reported by the immunization officer to an official at a higher administrative level; (iii) for each AEFI, the public has the right to receive an official explanation of the results of the analysis conducted by the Provincial Committee (PC)-AEFI or NC-AEFI; (iv) the results of the AEFI study by the NC-AEFI are used to improve the immunization program; and (v) the central government or local government is responsible for ensuring that financing is in place and that AEFI cases in their area receive prompt access to treatment. Indonesia also has a National Pharmacovigilance Center in BPOM that monitors product-related AEFI and follows-up on AEFI cases in collaboration with the NC-AEFI. AEFI monitoring of COVID-19 vaccines delivered during the vaccination campaign from January 2021 to July 2022 showed an AEFI rate of 54.3 per one million doses. The reported AEFI was considerably lower than for other countries: Brazil, for example, reported an AEFI rate of 105 per one hundred thousand doses in the first seven months of national vaccination rollout. Indonesia used various COVID-19 vaccines including Sinovac and Sinopharm, Astra Zeneca, Pfizer, Moderna, and Johnson & Johnson. The majority of reported AEFIs were non-serious (an AEFI rate of 52.89 per one million doses compared to 1.14 per million doses for serious AEFIs). Based on the WHO field classification on AEFI, among the 453 serious AEFI cases reported, 256 cases were random/coincidental, 38 were related to vaccine reactions, 119 to anxiety (ISRR-Immunization Stress-Related Responses), 21 to indeterminate cases, and 10 to unclassifiable reactions. 14 Robustness of Regulatory Systems The Indonesian Food and Drug Authority or Badan Pengawas Obat dan Makanan (BPOM) is the National Regulatory Authority (NRA) responsible for ensuring the quality, safety, and efficacy of medicines, including vaccines, prior to and after being marketed and distributed throughout the country. It has established, full-spectrum medicinal product oversight and control systems, including law enforcement. Pre-market evaluation is carried out based on evidence of safety, efficacy, and quality submitted by the applicant, the conduct of clinical trials based on Good Clinical Practice (GCP), and the fulfillment of production facilities related to Good Manufacturing Practice (GMP) requirements. Post-market control includes GMP and Good Distribution Practice inspection, product sampling and laboratory testing, advertisement and product labeling monitoring, and marketing surveillance and pharmacovigilance. 14 Result of interview with secretariat of NC-AEFI June 2022 and internal data, January 2021-July 2022 19 The Indonesian regulatory framework adheres to all functions stated in the WHO Global Benchmarking Tool (GBT). This includes: a National Regulatory System (NRS); Registration and Marketing Authorization (RMA); Product Vigilance (PV) program; Market Surveillance and Control (MSC); Licensing Premises (LIC); Regulatory Inspection (RI); Laboratory Access and Testing (LAT); Clinical Trial Oversight (CTO); and NRA Lot Release (LTR). WHO NRA Benchmarking using GBT was conducted in Indonesia in 2018 for vaccine oversight and each function was given a Maturity Level (ML) rating (Table 4). The overall regulatory framework received a rating of ML3. Table 4. Status of WHO NRA Benchmarking for Vaccine Oversight by BPOM in 2018 Source: WHO 2018. Note: Subject to submission and publication of the updated and finalized GMP Guideline and relevant Annexes. A WHO follow-up visit to BPOM was conducted in March 2022 to assess progress on the 2018 findings and to prepare for the upcoming BPOM re-benchmarking in 2023-24. Findings were positive overall and showed a number of improvements, including:15 1. The 2018 Institutional Development Plan has been efficiently implemented for all functions, with follow-up actions taken as required by the WHO. 2. Legal and regulatory provisions that support efficient oversight functions have been renewed and/or enhanced, and a new BPOM directorate has been established to focus on cyber-crime related to medicinal products. The medium-term strategic plan for 2020 - 2024 has also been properly implemented, with Key Performance Indicators adjusted every four years to raise regulatory targets. 3. The number, quality and competence of human resources for health has improved, especially at the provincial and district/city levels. Training protocols have also been implemented. 15 Result of interview with Deputy 1 BPOM and team, April-May 2022 20 4. The Quality Management System is updated and consistent, and BPOM’s laboratory was accredited as a WHO contract laboratory for DTP vaccine in 2020. 5. The BPOM made a significant contribution to the government’s COVID-19 response through: (i) construction of a special BLS-2 laboratory for PCR testing of COVID-19 samples (including genomic sequencing) and plans for the establishment of BLS-3 lab in the future; (ii) accelerated granting of approval of COVID-19 medicines and vaccine with Emergency Use Authorization (EUA) to support timely access to vaccines and therapeutics; and (iii) comprehensive supervision of the development of local COVID-19 vaccines, which are currently in Phase 1 and Phase 2/3 clinical trials. 6. The level of transparency and availability of information for the public has improved. A variety of information is accessible via the BPOM website, including on safety aspects of medicines and vaccines (official Public Assessment Report, Public Warning, Press Releases on Regulatory Issues). BPOM has also met one criterion for inclusion in the transitional WHO Listed Authority (tWLA)16 and as such has been added to the WHO Interim tWLA List. BPOM is preparing to apply for full WLA status as a priority plan, not only covering vaccines but also expanding to medicines for the scope of benchmarking. An Expression of Interest to WHO to become a fully accredited WLA is in progress. Marketing Authorization Process The decision to grant marketing authorization (MA) or registration of medicines, including vaccines, is based on an in-depth, scientific evaluation of quality, safety, and efficacy standards and practices, which are included in the MA dossier that is submitted to BPOM. 17 BPOM follows the common global regulatory procedure for MA or registration of new vaccines, which involves a comprehensive review of: (i) quality (Chemistry Manufacturing and Control - CMC); (ii) clinical and nonclinical data; (iii) GMP compliance; (iv) testing of Lot Release; (v) evaluation of Package Insert/Summary of Product Characteristics/Label; and (vi) the Risk Management Program. The mechanism for granting MA in Indonesia also includes: (a) evidence of a regulated timeline, including expedited registration for products for life-saving and health program with “clock- off/clock-on” system; (b) special consideration of the need to access new vaccines, and major variation of existing vaccines, without compromising quality, safety, and efficacy requirements; and (c) a reliance scheme based on WHO Good Reliance Practices (GRelP). The reliance scheme in the Indonesian registration system covers, for example: (i) type of product eligible for reliance mechanism (that is, new medicines and biologicals), including vaccines and their major variations approved by at least one mature agency; (ii) time line of 120 working days after completing data submission; and (iii) reference countries with established systems (European Medicine Agency – 16A WHO Listed Authority (WLA) is a regulatory authority or a regional regulatory system (RRS) which has been documented to comply with all the relevant indicators and requirements specified by WHO for the requested scope of listing based on an established benchmarking and performance evaluation process. ( Source : WHO Evaluating and Publicly Designating Regulatory Authorities as WHO Listed Authority : Policy Document, Geneva, WHO 2021, License CCBY-NC-SA3.TGO 17 Peraturan BPOM No 24 /2017 tentang Kriteria dan Tata Laksana Registrasi Obat 21 EMA, United States Food and Drug Administration, United Kingdom’s Medicines and Healthcare products Regulatory Agency, Health Canada, Australia’s Therapeutic Goods Administration, and Japan’s Pharmaceuticals and Medical Devices Agency) and WHO’s Pre-qualified or Emergency Use Listing (EUL) products. In response to the COVID-19 pandemic and the need for quick access to new COVID-19 vaccines, BPOM stipulated a new regulation in the Emergency Use Authorization (EUA) mechanism. 18 This regulation allowed for flexibility on the MA procedure (for example, allowing rolling submissions), a shortened approval timeline of 20 working days after submission of documents, and decisions based on interim report rather than the full dossier with regards to the WHO Guidance on COVID-19 vaccine quality, safety, and efficacy. As of June 2022, there are EUAs for thirteen COVID-19 vaccines (for people 18 years of age and over) for primary vaccination, six COVID-19 vaccines (18 years of age and over) for booster vaccination, and two COVID-19 vaccines for children age 6-18 years for primary vaccination. Regulatory Efforts to Support Innovation and Development of New Vaccines Due to the global COVID-19 pandemic, many countries, including Indonesia, began working to develop their own vaccines to meet domestic vaccine requirements. To support COVID-19 vaccine development, the Indonesian Government plans to build a National Biological Product Development Ecosystem in collaboration with stakeholders from academia, research organizations, businesses, and government agencies. In addition, the National Research and Innovation Agency or Badan Riset dan Inovasi Nasional (BRIN) is currently building a vaccine research center with a GMP standard. These efforts are in line with the Indonesian Government’s pathway toward self-reliance in biological products, including vaccines, in accordance with the Presidential Instruction No. 6/2016 on the Acceleration of Industrial Development for Pharmacy and Medical Devices. Indonesia is also taking preliminary steps to manufacture several additional NIP vaccines locally. PCV and HPV vaccines are included among the vaccines that are listed for future domestic manufacture. In addition, PT. Bio Farma has developed a typhoid Vi-DT vaccine, for which the non-clinical study and phases 1, 2 and 3 clinical trials were conducted in Indonesia. This new vaccine is now in the final stage of the regulatory process for MA. Within this context, regulatory efforts to support innovation and development of new vaccines are done comprehensively, downstream to upstream. These efforts include: (i) development of a Self-Assessment Tool for research centers on domestic vaccine development; (ii) providing regulatory assistance to develop clinical trial protocols; (iii) conducting inspection on GCP; (iv) simplification and acceleration of registration and MA processes without compromising quality, safety, and efficacy requirements; (v) maintaining GMP based on international standards; and (vi) increasing vaccine manufacturing capacity and efficiencies (for example, facility-sharing for fill-and-finish activities). Other important efforts include strengthening cross-sectoral cooperation and coordination, and supporting capacity building by providing technical guidance and training to improve competencies related to GMP requirements for vaccine manufacturing personnel. 18Peraturan BPOM No 27/2020 tentang perubahan kedua, dan Peraturan BPOM No 13/2021 tentang perubahan ketiga atas Peraturan Kepala BPOM No 24/2017 tentang Kriteria dan Tata Laksana Registrasi Obat 22 The regional harmonization policy, which was developed by the Pharmaceutical Products Working Group (PPWG) of the ASEAN Consultative Committee for Standards & Quality (ACCSQ), includes a number of important milestones. For example, it introduces the ASEAN Common Technical Dossier, and encourages sharing of inspection reports among ASEAN NRAs through a Mutual Recognition Agreement (MRA) on GMP. It also develops ASEAN Standard Guidelines on stability, bioavailability/bioequivalence, and validation, and establishes a number of joint sectoral committees (JSC) to support sectoral MRA, for example on GMP inspection and bio- availability/bio-equivalence of medicinal products. Despite these achievements, challenges remain in the implementation of regional harmonization protocols. For example, there are still many country-specific requirements, and there is no harmonization for vaccine registration or for including vaccines as priority products within the Joint Assessment Coordinating Group (JACG). To support and enhance oversight for vaccine manufacturing domestically and among ASEAN member states, additional efforts should be made to build capacity in the areas of review and evaluation, inspection of manufacturing sites for new vaccines, including COVID-19 vaccines using new platforms, and on developing stable and structured Institutional Development Plans that include organizational financing schemes. As Indonesia is also planning to domestically manufacture new upstream COVID-19 vaccines and New Vaccine Introductions (NVI) for NIP, there is also a need to strengthen upstream regulatory activities from product development to nonclinical and clinical trial regulatory oversight of new vaccines. Efforts are also required to bridge specific gaps, such as barriers to sharing information, which should also be done among ASEAN regulators with a goal of developing a future policy on vaccine security in the ASEAN region. Domestic Manufacturing and Distribution Capacity Existing Capacity Almost all vaccines in the Indonesian NIP are currently produced by PT. Bio Farma, a government-owned vaccine manufacturer. 19 PT. Bio Farma has the upstream production capacity for OPV, Measles, TT, BCG, DT, DTP-HB-Hib, Td, and DTP-HB vaccines, and downstream capacity for HB and seasonal flu vaccine. In terms of production capacity (finished products), PT. Bio Farma produces 146 million doses of bacterial vaccine, 310 million doses of OPV, 432 million doses of nOPV, and 33 million doses of measles vaccine annually. PT. Bio Farma is also assigned to import several new vaccines that are not yet domestically produced, such as IPV, MR, PCV, HPV, and JE vaccines. The national storage facility is housed within the company, and it is responsible for distributing all NIP vaccines to provincial stores, as it has sophisticated knowledge and cold-chain management capacity. Many of the vaccines produced by PT. Bio Farma are WHO Pre-Qualified Vaccines, specifically: DTP, DT, TT, DTP-HB, m/b/tOPV, Measles and TT, HB in Uniject, Td and PENTABIO; additionally, one vaccine is a WHO EUL Vaccine (nOPV2). PT. Bio Farma has vast export experience: in 2020, it exported vaccines to 82 countries, while in 2021 it exported to sixty-five. It was recently 19 https://www.biofarma.co.id/media/image/originals/uploads/2019/09/Riwayat-Sangkat-Perusahaan.pdf 23 appointed by WHO through the Government of Indonesia to build a production hub for COVID- 19 mRNA vaccine. 20 Besides the plan to implement technology transfer from WHO for a COVID-19 mRNA vaccine, PT. Bio Farma currently has a fill-and-finish agreement with the Chinese manufacturer of Sinovac for inactivated vaccine platform, with a production capacity of 250 million doses per year; it is also working to develop its own subunit-based COVID-19 vaccine in collaboration with Baylor College of Medicine (BCM). The seed and initial antigen process research were developed at Texas Children’s Hospital in Houston, Texas and subsequently transferred to PT. Bio Farma for further development in early 2021. Phase 1 and 2 clinical trials were completed in mid-2022 and resulted in one formulation strategy for Phase 3 clinical trial, which was initiated in June 2022 and has enrolled 4050 subjects in designated sites in Indonesia. It is expected that BPOM will issue Emergency Use Authorization (EUA) for the vaccine by the end of 2022. 21 The COVID-19 pandemic has transformed the vaccine manufacturing landscape and distribution capacity in Indonesia. In the pre-COVID-19 era, vaccine manufacturing was mostly driven by NIPs targeting children under 5 years of age, which ensured long-term demand for manufacturers. During COVID-19 pandemic and endemic phases, vaccine manufacturing should prioritize responding to emerging challenges in order to ensure the availability of new COVID-19 vaccines, for example by: (i) building capacity and capability to manufacture both downstream (i.e. fill and finish) and upstream; (ii) rapidly developing and scaling up new and effective vaccine platforms; (iii) demonstrating willingness to transfer production technology to LMICs for scaling domestic production and ensuring equity; (iv) providing safety and efficacy assurance from limited nonclinical and clinical trials; and (v) minimizing costs and delivering a relatively low-cost vaccine. Potential Vaccine Manufacturers As the requirements to manufacture vaccines are among the most rigorous and highly regulated, the ability to manufacture vaccines of assured quality, safety, and efficacy is built on four competencies: choice of manufacturing process; compliance with procedures to successfully complete the process; testing of the product and supporting operations; and regulatory authorization to release and distribute the product (Gomez and Robinson, 2018). In the operational stage, based on information gleaned during interviews with key stakeholders from April to June 2022, many other important factors also need to be considered, including: (a) tangible (i.e. land, infrastructure, equipment) and intangible capital; (b) liquidity; (c) existence of partnerships and technology transfer; (d) availability of labor according to industry needs; (e) regulations and incentives; and (f) supply chains. Lessons learned from the success stories of China and India in developing their pharmaceutical industries point to other critical factors needed for development of a domestic vaccine industry, including: government support or political will; technology and automation; logistics infrastructure and cost; raw material availability; sustainable land reform; favorable labor cost; reduced utility cost; and economies of scale (Cherian et al., 2021). 20 Result of interview with PT. Bio Farma at the end of April 2022 and internal data provided. 21 Internal data provided by PT Bio Farma, June 2022 24 Despite the rigor of these requirements, there are several new entrants to the vaccine manufacturing industry in Indonesia. 22 These companies are using COVID-19 vaccine production as a starting point but have plans to produce a broader set of vaccines. One of these, PT. Biotis Pharmaceutical Industry, has been granted GMP certification from BPOM and is developing an inactivated COVID-19 vaccine in collaboration with the University of Airlangga; phase 1 and 2 clinical trials have been completed, with phase 3 trials underway. 23 Two other vaccine manufacturers are preparing their facilities for GMP certification: PT. Etana Biotechnology Indonesia, which is developing a COVID-19 mRNA vaccine in collaboration with Yuxi Walvax;24 and PT. Jakarta Biopharmaceutical Industry (J-Bio), which plans to produce a protein subunit COVID-19 vaccine in collaboration with Anhui Zhifei Longcorn Pharmaceutical. Finally, potential vaccine manufacturer PT. Kalbio Global Medika, a subsidiary of PT. Kalbe Farma Tbk, has included in its strategic planning a vaccine venture in collaboration with external partner Genexine (Republic of Korea), but to date there has been no realization in vaccine manufacturing. 25 Short profiles of PT. Bio Farma, PT. Biotis Pharmaceutical Industry, PT. Etana Biotechnology Industry, and PT. Jakarta Biopharmaceutical Industry are included in Annex 3, and their predictive national manufacturing capacity is presented in Annex 4. Support, Incentives and Challenges for Domestic Vaccine Manufacturing The Government of Indonesia recognizes that competition exists in the vaccine manufacturing industry among domestic products as well as between domestic and imported products, and has issued a number of policies and regulations to encourage domestic efforts. It also realizes that industry development happens in stages and that strategic plans with specific, delineated steps can be helpful to guide and/or facilitate these efforts. To this end, it has established a strategic development plan for the domestic vaccine industry with short- and long-term components: o The short-term strategy (2-3 years) is mainly related to a company's status as a start-up in a mature industry. It targets ongoing company operations, utilization of facilities, and development of a product portfolio with a domestic market orientation. Some of the strategies undertaken relate to: • Product development, namely of those that have a large national market size, support government programs, and have a long life cycle. • Building efficient operations (cost leadership) to gain competitiveness, through cooperative arrangements or partnerships. • Integration and alignment in product development to accelerate development time and commercialization. • Building an industrial ecosystem by encouraging government policies and instruments that favor the domestic industry. o The long-term strategy (3-5 years) relates to building business fundamentals and increasing competitiveness of the domestic vaccine industry with foreign companies. Strategies in this phase include: 22 Result of interview with BPOM, end of April 2022. 23 Result of interview with PT. Biotis Pharmaceutical Industry, early April 2022. 24 Result of interview with PT. Etana Biotechnology Indonesia (EBI), early April 2022. 25 Result of interview with PT. Kalbio Global Medika, June 2022. 25 • Strengthening business fundamentals/foundations through the development of various quality systems, corporate governance, HR capabilities and R&D capabilities. • Sustaining market development efforts towards the goal of increasing domestic market coverage and global market penetration. In terms of economic incentives, the Government of Indonesia has implemented tax reduction policies—including a tax holiday for investments above IDR 500 billion, tax allowance for investment of IDR 100–500 billion, and super tax deduction for successful research and development only 26—as well as exemptions from import duties 27 and market-related policies aimed at protecting domestic companies. 28 In 2015 the Government of Indonesia issued a policy to facilitate the import of machinery, goods and materials for industrial construction and development. The exemption from import duty is intended for industrial development and is valid for a period of two years. 29 Despite these incentives, comprehensive government support is lacking in some areas, namely in addressing the high costs of building and maintaining manufacturing plants; there is also a lack of commitment to grow market certainty by identifying long-term reliable buyers, including from regional markets. 30 Other critical challenges relate to limited human resources with experience and knowledge of industry needs, 31 and the lack of a government policy granting incentives for land access, 32 though in 2020 the Government of Indonesia did build an Integrated Industrial Estate in Batang District, Central Java, by offering land prices below the average for other industrial lands. 33 The vaccine manufacturing industry is also influenced by the condition of the market. Sales data in 2020 indicates that the government market for vaccines is Rp 1,032.44 billion (approximately US$ 66 million) and the private market is Rp 743.81 billion (approximately US$ 48 million), while exports were valued at Rp 1,031.79 billion (US$ 66 million) with an average growth rate of 9.7 percent. These market data indirectly illustrate the potential market that could be targeted by the current and emerging vaccine industry in Indonesia. 26 Regulation of the Minister of Finance of the Republic of Indonesia No. 130 /PMK.010/2020 concerning Regulation of the Ministry of Finance (PMK) regarding the Provision of Corporate Income Tax Reduction Facilities. 27 Ministry of Finance Regulation (PMK) No. 188/PMKK.010/2015 concerning the Second Amendment to the Regulation of the Minister of Finance No. 176/PMK.011/2009 concerning Exemption of Import Duties on the Import of Machinery and Goods and Materials for Industrial Development or Development in the Framework of Investment. 28 Government Regulation of the Republic of Indonesia No. 9/2021 concerning Tax Treatment to Support the Ease of Doing Business. 29 https://jdih.kemenkeu.go.id/fulltext/2015/188~PMK.010~2015Per.pdf 30 Result of interview with Directorate General of Pharmaceutical and Medical Devices, MoH, early April 2022. 31 Result of interview with industry stakeholders. 32 https://www.bkpm.go.id/images/uploads/ppid/file_upload/Renstra_BKPM_2020-2024_%28final%29.pdf 33https://www.cnnindonesia.com/ekonomi/20200916121210-92-547107/bkpm-tawarkan-investor-tanah-rp500-ribu-per-square- meter-di-batang 26 Patent protection regulations in Indonesia are based on Law No. 13/2016 on Patents, which takes into account national need, international requirements (Trade-Related Aspects of Intellectual Property Rights: TRIPs), and patent law. 34 This law allows for flexibility in TRIPs in cases of public health need specifically related to parallel imports, compulsory license, and government use. The “government use” option has been implemented for the availability of several medicines which are of public health importance and/or for emergency situations, such as for HIV/AIDs (antiviral, and antiretroviral) 35 and COVID-19 treatment (remdesivir, favipiravir). 36 Regarding vaccine development, a working group has been in place since 2012 for vaccine research and development of TB, dengue, and avian influenza vaccines, however, the extent of the patent process is unknown. As of 2018, PT. Bio Farma had five patents for components of vaccine products (Table 5). Table 5. Patent Protection (component of vaccine products) owned by of PT. Bio Farma No Patent Patent ID 1 The use of Recombinant Trypsin for virus activation in rotavirus vaccines P00201200470 production process 2 Overexpression of Macaca Fascicularis sialyltransferase gen in vero cell lines P00201300277 3 Trachea cell culture of Macaca Fascicularis as the virus substrate candidate P00201300276 4 Recombinant Plasmid as a expression vector to overproduce surface P00201407051 hepatitis B antigen (HBsAg) in Honsenula polymorphia 5 Production of surface Hepatitis B small antigen (HBsAg) virus particle-like in P00201504908 Pichia pastoris Source: Badan Pengkajian dan Penerapan Teknologi (Technology Assessment and Application Agency 2018) Potential Strategic Partnership between Indonesia and ASEAN Member States in Supporting ASEAN Regional Vaccine Manufacturing Capacity The overall profile of ASEAN member states in terms of population size, literacy (a marker of education), and immunization coverage against measles and DPT is varied, as shown in the following infographics (Figure 6). Over the past 40 years (1980-2020), the ASEAN population has increased by 1.3 percent each year, though some countries have experienced considerably more growth than others. Education is an important part of the development agenda because its impact is related to overall population welfare. In general, the adult literacy rate has been relatively stable or shown increases in every ASEAN country except Myanmar. With regards to child immunization coverage against measles and DPT (which may indicate awareness of health information), coverage rates have been stable or shown an increasing trend in most ASEAN 34 https://peraturan.bpk.go.id/Home/Details/37536/uu-no-13-tahun-2016 35 Presidential Regulation No. 76/2012 on Implementation of Patent by Government for antiviral and antiretroviral. 36 Presidential Regulation No. 100/2021 on Implementation of Patent by Government for remdesivir; Presidential Regulation No. 101/2021 on Implementation of Patent by Government for favipiravir. 27 member states. Indonesia alone accounts for more than forty percent of the total population of ASEAN, providing an enormous potential vaccine market and indicating market stability, something potential investors prioritize; education and health indicators also suggest demand for vaccines in Indonesia will continue to grow. Figure 6. Key population, education and health indicators in ASEAN Source: ASEAN Key Figures, 2020 A description of the economic situation in terms of annual percent change in GDP is an important part of understanding Indonesia's resilience in supporting the development of the vaccine industry in ASEAN, as can be seen in the Table 6. Since 2010, Indonesia has seen relatively stable economic growth without dramatic fluctuations that might threaten the stability of the vaccine industry. It rebounded quickly from the COVID-19-related economic contraction in 2020, showing positive GDP growth in 2021. Table 6. Annual percent change in GDP, ASEAN member states 2000 2005 2010 2015 2018 2019 2020 2021 Brunei 2.85 0.39 2.60 -0.39 0.05 3.87 1.13 -1.59 Cambodia 4.92 5.69 6.22 4.88 5.17 5.02 -2.07 3.69 Indonesia 9.99 13.25 5.96 6.97 7.47 7.05 -3.10 3.03 Laos 5.80 7.11 8.53 7.27 6.25 5.46 0.50 2.53 Malaysia 8.86 5.33 7.42 5.09 4.84 4.41 -5.53 3.09 Myanmar 12.42 13.57 10.07 3.28 6.40 6.75 3.17 -17.91 Philippines 4.38 4.94 7.33 6.35 6.34 6.12 -9.52 5.70 Singapore 9.04 7.37 14.52 2.98 3.66 1.10 -4.14 7.61 Thailand 4.46 4.19 7.51 3.13 4.22 2.15 -6.20 1.53 28 Vietnam 6.79 7.55 6.42 6.99 7.46 7.36 2.87 2.56 ASEAN 6.95 6.94 7.66 4.65 5.19 4.93 -2.29 1.02 Source: World Bank, 2021 The investment potential of Indonesia goes beyond population and economic factors. The Government of Indonesia has prioritized making improvements to the vaccine value chain, as demonstrated through a number of policies and collaborations with vaccine stakeholders. And, Indonesia is rich in natural and human resources that can be harnessed to support industry development needs. SWOT Analysis of Potential Contribution to Regional Vaccine Value Chain As discussed in the previous sections, Indonesia is positioned to contribute to the vaccine value chain through its vaccine manufacturing capacity. Therefore, this SWOT analysis is focused on the following: STRENGTHS 1. Strong political will of the Government to financially sustain the National Immunization Program (80 percent) with minimal external support (20 percent) and to support development of the domestic pharmaceutical industry, including vaccine development, with the stipulation of a coordination and other regulations (Presidential Instruction No. 6/2016, Ministry of Health and BPOM regulations). 2. Substantial population contributing to 40 percent of the population of ASEAN as a potential market share. 3. Prioritization of NIP for national health development in line with GVAP, SEARVAP, SDGs, and Immunization Agenda (IA)2030. Policies, guidelines, technical assistance, and supervision structures for immunization program implementation are in place, such as EVM tools, Data Quality Assessment, Short Service Messages, Supportive Supervision and LAM (Local Area Monitoring) to ensure effective vaccine delivery and governance. 4. The NRA achievement of WHO Maturity Level 3 in 2018 and successful WHO follow-up visit in 2022. 5. Existing vaccine manufacturer (PT. Bio Farma) with sufficient capacity to source and/or produce EPI vaccines (basic immunization) and support logistics to provincial stores. It also has fill and finish experience with a COVID-19 vaccine, and substantial export experience. 6. Proven ability to deliver vaccines during pandemics and health emergencies in difficult geographic terrain. 7. Economic incentives—including tax holiday, tax allowance, Master List Free Entry, R&D super deduction tax and patent protection—to encourage investment in manufacturing and R&D and market incentives (domestic component rate). 8. The existence of an independent ITAGI to provide advice and recommendations to the immunization program, including monitoring the routine immunization program, and the national and subnational committees on AEFI to ensure necessary and timely response to adverse events. 29 WEAKNESSES 1. No comprehensive strategic plan of action or resilience policy for vaccine manufacturing that ensures strong sectoral government coordination in implementing existing regulations and guidelines. 2. High capital investments in buildings and maintenance of vaccine manufacturing plants, which weakens interest among vaccine companies. 3. Limited government support for investment and collaboration in transfer of technology for vaccine manufacturing, as the current practice is mostly done as business-to- business schemes. 4. No specific incentives to develop new domestic manufacturers, for example by offering concessional land, low interest capital, or subsidized utilities. 5. No long term government commitment or guarantee as vaccine purchaser. 6. No extensive know-how to build ecosystems required to support vaccine manufacturing in a coordinated manner. 7. Limited specialized and capable human resources for (i) upstream R&D of vaccine manufacturing, and (ii) managerial and technical capacity at distribution points, particularly for cold-chain monitoring and related activities to follow guidelines and SOPs. OPPORTUNITIES 1. Intention to introduce four new and underutilized vaccines in the NIP (HPV, JE Vaccine, PCV, Rotavirus Vaccine) which have been included in the National Strategic Development Plan and are supported by various laws and regulations at the national and subnational levels. 2. Introduction of vaccines for new and emerging diseases in the NIP‒for example, COVID- 19‒which is supported by potential external parties to provide technical and financial assistance. 3. The existence of at least four new vaccine manufacturers that have pursued collaborative arrangements with external strategic partners (business-to-business model), which demonstrates the potential to build an extensive vaccine market in Indonesia. 4. A government procurement policy that favors domestically manufactured products 5. Intention of BPOM to pursue the WHO Listed Authority. 6. Existence of Research and Development Centre of Excellence established by the government to support vaccine development in several research units (universities and agencies). 7. Established, in-country vaccine manufacturing capacity to produce vaccines at a cost advantage, which can support vaccine security in ASEAN. 30 THREATS 1. Challenges in ensuring financing of high vaccine prices and implementation costs of New Vaccine Introductions (NVI). 2. Uncertainty of local governments’ commitment to prioritize the implementation of immunization and ensure sustainability of funding after the reduction of external financial support. 3. Potential competition from imported vaccines produced by manufacturers in other ASEAN countries. 4. Potential increase of vaccine hesitancy due to community misperceptions, lack of awareness, negative rumors, and refusals related to religious beliefs and culture. 5. Other critical factors beyond the health system, such as the unexpected occurrence of disasters and emergencies that could influence vaccination coverage, and unstable economic and political environments that may influence the vaccine business scale. Conclusion Strong political will to grow vaccine manufacturing capacity is one of the most important contributions Indonesia can make to the regional vaccine value chain. This is reflected in the series of technical and economic regulations stipulated by the Government of Indonesia to support a national biological product development ecosystem, as shown in the following diagram (Figure 7). Figure 7. Regulations in support of national biological product development ecosystem Road Map for Master Plan of Exemption of Import Duties Development of the Development of National Industrial on the Import of Machinery Pharmaceutical and Medicinal Raw Development 2015 and Goods and Materials for Medical Devices Materials Industrial Development (MoF (Regulation of the -2034 (Government Industry (Economic Minister of Health Regulation No. 15 Regulation /PMK No. Policy Package XI No. 87 of 2013) of 2014) 188/PMKK.010/2015) 2016) Development of Regulation Tax Action Plan for the Procedures for the regarding the Treatment to Development of the Calculation of Pharmaceutical Provision of Support the Pharmaceutical and Domestic Content and Medical Corporate Income Ease of Doing Medical Devices Levels of Devices Industry Tax Reduction Business(GOI Industry (MoH Pharmaceuticals (Presidential (MoF of the RI No. Regulation of Regulation No. 17 of (GOI Regulation Instruction No. 6 of 130 the RI No. 2017) No. 16 of 2020) 2016) /PMK.010/2020) 9/2021) Indonesia is well-positioned to contribute to the ASEAN vaccine ecosystem, but in order to achieve the goal of ASEAN regional vaccine security and self-reliance, there are proposed elements that must be established by all ASEAN member states, including: stronger government 31 support and economic incentives to grow the vaccine industry, tightening of upstream regulations, domestic market guarantees, and strengthening of NRA capacity by linking with the current ASEAN technical working group of pharmaceuticals (the ACCSQ PPWG – the ASEAN Consultative Committee for Standard and Quality – Pharmaceutical Product Working Group). In addition, ASEAN member states should work together to elaborate and adopt a future policy on vaccine security in the ASEAN region. 32 References ASEAN. 2020. ASEAN Key Figures 2020. Jakarta (ID) : ASEAN. Badan Pengkajian dan Penerapan Teknologi. 2018. Outlook teknologi kesehatan 2018 “Iniasiatif Pengembangan Teknologi dan Industri Biofarmasi. Jakarta (ID) : Pusat Pengkajian Industri Proses dan Energi. Badan Perencanaan Pembangunan Nasional. 2019. Kajian Sektor Kesehatan, Penyediaan Obat, Vaksin dan Alat Kesehatan. Jakarta(ID) : Badan Perencanaan Pembangunan Nasional. BAPPENAS (Ministry of National Development Planning). 2018. Consolidated Health Sector Review Report. BAPPENAS. 2019. Kajian sektor Kesehatan, Penyediaan Obat, Vaksin dan Alat Kesehatan. BAPPENAS. 2022. Buku putih reformasi sistem kesehatan nasional. Jakarta (ID): Ministry of National Development Planning. BAPPENAS and Statistics Indonesia. 2021. Kajian sektor kesehatan penyediaan obat, vaksin dan alat kesehatan. Jakarta (ID): Direktorat Kesehatan dan Gizi Masyarakatkedeputian Pembangunan Manusia, Masyarakat dan Kebudayaan. Bio Farma. 2008. Annual Report 2008. Jakarta (ID). https://www.biofarma.co.id/id/annual-report Bio Farma. 2010. Annual Report 2010. Jakarta (ID). https://www.biofarma.co.id/id/annual-report Bio Farma. 2012. Annual Report 2012. Jakarta (ID). https://www.biofarma.co.id/id/annual-report Bio Farma. 2014. Annual Report 2014. Jakarta (ID). https://www.biofarma.co.id/id/annual-report Bio Farma. 2016. Annual Report 2016. Jakarta (ID). https://www.biofarma.co.id/id/annual-report Bio Farma. 2018. Annual Report 2018. Jakarta (ID). https://www.biofarma.co.id/id/annual-report Bio Farma. 2018. Annual Report 2020. Jakarta (ID). https://www.bioarma.co.id/id/annual-report BPJS. 2021. Jumlah penduduk menurut kelompok umur dan jenis kelamin 2021. https://www.bps.go.id/indikator/indikator/view_data_pub/0000/api_pub/YW40a21pdTU1cnJxOGt6dm43 ZEdoZz09/da_03/1 BPOM. 2021. Written response from Bio Farma on Questions and presentation of BPOM. BPS. 2021. Jumlah penduduk hasil proyek menurut provinsi dan jenis kelami (ribu jiwa). https://www.bps.go.id/indicator/12/1886/1/jumlah-penduduk-hasil-proyeksi-menurut-provinsi-dan-jenis- kelamin.html 33 Cherian, J., S. Sarkar, M. Rahi, and S. Selvaraj. 2021. “India’s Road to Independence in Manufacturing Active Pharmaceutical Ingredients: Focus on Essential Medicines.” Economies 9 (71). CNBC. 2019. BPJS Kesehatan Untuk & 8 Penyakkit Kronis yang bikin tekor. https://www.cnbcindonesia.com/news/20200731070057-4-176656/bpjs-kesehatan-untung-8-penyakit- kronis-yang-bikin-tekor Coherent Market Insight. 2022. Vaccine Market Analysis. Access 6 August 2022. https://www.coherentmarketinsights.com/market-insight/vaccines-market-4914 Emergence Research. 2022. Vaccine Market By Type (Monovalent Vaccine, Multivalent Vaccine), By Patient Type (Adult, Pediatric), By Disease (Human Papillomavirus (HPV), Pneumococcal Disease, Hepatitis), By Technology and By Region Forecast to 2030. Accessed on 6 August 2022. Available online at: https://www.emergenresearch.com/industry-report/vaccine-market Gomez PL and JM Robinson. 2018. “Vaccine Manufacturing.” Plotkin’s Vaccines 2018: 51-60.e1. Imarc. 2022. Vaccine Market: Global Industry Trend, Share, Size, Growth, Opportunity and Forecast 2022- 2027. Accessed on 6 August 2022. Available online at: https://www.imarcgroup.com/vaccine-market International Trade Administration. 2020. Indonesia Medical Procurement System. https://trade.gov/market-intelligence/Indonesia-medical-procurement-system Investor.id. 2022. “Transfer Teknologi, 1 Juta Dosis Vaksin Zifivax Diproduksi di Indonesia.” Ministry of Health. 2019. Comprehensive Multi Year Plan: National Immunization Program Indonesia, 2020-2024. Jakarta (ID) : Ministry of Health. Ministry of Health. 2020. Profil Kesehatan Indonesia 2020. Jakarta (ID) : Ministry of Health Indonesia. Ministry of Health. 2020. Rencana aksi program Tahun 2020 – 2024. Jakarta (ID): Direktorat Jenderal Pencegahan dan Pengendalian Penyakit. Ministry of Health. 2020. Situasi dan analisis imunisasi. Jakarta (ID): Ministry of Health. Ministry of Health Indonesia and UNICEF. 2020. Routine Immunization for Children during the COVID-19 Pandemic in Indonesia: Perceptions of Parents and Caregivers. Available online at https://www.unicef.org/indonesia/media/6066/file/Routine. Pambudi W, Nataprawira SMD, Atzmardina Z, Regina S. 2021. Profil capaian imunisasi dasar/ lanjutan pada baduta sebelum dan selama pandemi covid-19. Jurnal muara medika dan psikologi klinis. 1(1): 2021: 17-23 Presentation by NC-AEFI on Safety of COVID-19 Vaccination during Ramadhan, May 2022. Research and Market. 2022. Global Adult Vaccine Market, Size, Forecast 2022-2027, Industry Trend, Growth, Impact of Covid-19, Opportunity Company Analysis. Accessed on 6 August 2022. Available online at: https://www.researchandmarkets.com/reports/5546195/global-adult-vaccine-market-size-forecast- 34 2022?utm_source=BW&utm_medium=PressRelease&utm_code=wngxst&utm_campaign=1661906+- +Global+Adult+Vaccine+Industry+Trends+and+Opportunities%2C+2022-2027&utm_exec=joca220prd S&P. 2022. COVID-19 May Accelerate Disruption in the Global Vaccine Market. Accessed on 6 August 2022. Available online at: https://www.spglobal.com/ratings/en/research/articles/200803-covid-19-may- accelerate-disruption-in-the-global-vaccine-market-11568238. Statistics Indonesia. 2015. Demographic and Health Survey of Indonesia (Survei Kesehatan dan Demografi Indonesia: SKDI). Statistics Indonesia. 2017. Demographic and Health Survey of Indonesia (Survei Kesehatan dan Demografi Indonesia: SKDI). UNICEF. 2020. The State of Children in Indonesia—Trends, Opportunities, and Challenges for Realizing Children’s Rights. Jakarta: UNICEF Indonesia. UNICEF. 2021. Impact of COVID-19 on Routine Immunization in Indonesia. Available online at https://www.unicef.org/indonesia/reports/impact-covid-19-routine-immunization-indonesia. World Bank. 2021. World Bank Open Data. Link: https://data.worldbank.org/indicator/NY.GDP.MKTP.KD.ZG?locations=ID-MY-SG-PH-TH-VN-LA-MM 35 Annex 1. Immunization Coverage, nationally and by province Table A.1. Immunization Achievement in Indonesia (2019-20) (%) Immunization Achievement Change 2019 2020 Basic Hepatitis B 94.5 83.2 -11.3 OPV 1 95.5 82.0 -13.5 BCG 96.5 83.1 -13.4 OPV 2 97.2 83.6 -13.6 DPT-HB-Hib 1 98.2 83.5 -14.7 OPV 3 95.9 81.7 -14.2 HB-Hib 1 97.1 81.7 -15.4 OPV 4 94.2 79.5 -14.7 IPV 77.0 30.9 -46.1 DPT-HB-Hib 2 96.5 80.5 -16.0 Measles 95.2 79.6 -15.6 Advanced DPT-HB-Hib 75.9 62.7 -13.2 Measles 72.7 60.0 -12.7 Source: The National Immunization Program, Ministry of Health (2020), and Pambudi et al. (2021). 36 Figure A.1. Profile of Basic Immunization (i) and Advanced Immunization (ii), by province, 2019- 2020 Source: Ministry of Health (2020) and Pambudi et al. (2021). Table A.2. Percentage of children fully vaccinated, by province, 2013-2018 NO PROVINCE 2013 2018 CHANGE 1 Aceh 38.3 19.5 (-) 18.8 2 North Sumatra 39.1 32.7 (-) 6.4 3 West Sumatra 39.7 38.7 (-) 1.0 4 Riau 52.2 34.4 (-) 17.8 5 Jambi 60.3 62.6 (+) 2.3 37 NO PROVINCE 2013 2018 CHANGE 6 South Sumatra 48.3 48.3 - 7 Bengkulu 62.1 62.6 (+) 0.5 8 Lampung 62.4 67.3 (+) 4.9 9 Bangka Belitung 67.7 75.2 (+) 7.5 10 Riau Islands 71.6 71.2 (-) 0.4 11 DKI Jakarta 64.5 68.0 (+) 3.5 12 West Java 56.6 58.3 (+) 1.7 13 Central Java 76.9 75.0 (-) 1.9 14 DI Yogyakarta 83.1 83.7 (+) 0.6 15 East Java 74.5 69.2 (-) 5.3 16 Banten 45.8 47.0 (+) 1.2 17 Bali 80.8 92.1 (+) 11.3 18 West Nusa Tenggara 75.4 70.8 (-) 4.6 19 East Nusa Tenggara 50.3 51.6 (+) 1.3 20 West Kalimantan 47.4 48.0 (+) 0.6 21 Central Kalimantan 42.0 47.5 (+) 5.5 22 South Kalimantan 52.0 68.7 (+) 16.7 23 East Kalimantan 65.9 73.6 (+) 7.7 24 North Kalimantan - 73.3 (+) 73.3 25 North Sulawesi 60.9 56.9 (-) 4.0 26 Middle Sulawesi 47.1 47.9 (+) 0.8 27 South Sulawesi 49.5 60.8 (+) 11.3 28 Southeast Sulawesi 47.3 45.6 (+) 1.7 29 Gorontalo 80.6 61.6 (-) 19.0 30 West Sulawesi 52.4 50.2 (-) 2.2 38 NO PROVINCE 2013 2018 CHANGE 31 Maluku 29.7 33.1 (+) 3.4 32 North Maluku 42.6 38.1 (-) 4.5 33 West Papua 35.6 47.6 (+) 12.0 34 Papua 29.2 29.2 - Indonesia 59.2 57.9 (+) 1.3 Sources: Baseline Health Research (RISKESDAS) 2013, 2018. Annex 2. Proposed New Vaccines to NIP In order to further reduce childhood mortality rates due to VPDs, Indonesia has prioritized the addition of the four new vaccines to the NIP by 2022/23. Current efforts towards this goal include: (a) Japanese Encephalitis (JE) vaccine to protect against JE virus infection. Vaccination was initiated in Bali province in March 2018, with Supplementary Immunization Activity (SIA) targeting children 9 months – 15 years, followed by JE vaccination at 10 months through routine immunization. (b) Pneumococcal vaccine (PCV) to protect against pneumonia, an infection that kills 25,000 children under five years of age in Indonesia each year. Reducing the under-5 mortality rate to at least as low as 25 per 1,000 live births would be an important step towards achieving SDG No. 3 in Indonesia. The introduction of the PCV vaccine as a demonstration project was carried out in 2017 in West and East Lombok districts in West Nusa Tenggara (Nusa Tenggara Barat: NTB) province. By 2019, PCV had protected 86,884 children each year from pneumococcal diseases, as the coverage was expanded to all districts in NTB and Bangka Belitung. Starting 2022, PCV is projected to be made available nationwide. (c) HPV vaccine for girls aged 9-13 years to prevent cervical cancer. This was started in 2016 as a pilot in DKI Jakarta and expanded to 131 districts in eight provinces in 2022. 37 The HPV vaccine is delivered through school-based immunization for girls in 5th (1st doses) and 6th class (2nd dose). (d) Rotavirus vaccine to protect against rotavirus infection, which is the leading cause of severe diarrhea and one of the main causes of death among young children under five years old. A Phase 3 clinical trial (using RV3-BB, a locally produced vaccine candidate) is underway under the collaborative work of PT. Bio Farma and the University of Gadjah Mada in Klaten and Sleman. 37 Four Java provinces (Jakarta, DI Yogyakarta, Central Java, and East Java), and four others outside of Java (Bali, North Sulawesi, Southeast Sulawesi, and Gorontalo) 39 40 Annex 3: Vaccine Manufacturer Profiles PT. Bio Farma PT Bio Farma is the first vaccine manufacturing company in Indonesia. The area of land used for production, research and development, marketing, administration, breeding and maintenance of laboratory animals and the production of materials of animal origin as raw materials for the production of sera reaches 379,499 square meters with a total asset of IDR 40.41 trillion. It has an overall production capacity of more than 3.2 billion vaccine doses per year. In 2020, PT Bio Farma succeeded in exporting as many as 263 million vaccine doses to 82 countries, while in 2021 it exported as many as 477 million doses to 65 countries. The company has upstream and downstream capacity to produce DTP, DT, TT, Td, DTP-HB-Hib, m/w/tOPV, HB in Uniject, and OPV – nOPV2 vaccines, while BCG, MR and Measles, and COVID-19 vaccines are still imported, either as bulk or finished products (Table A.1). Table A.1. Upstream and downstream vaccine manufacturing capacity On-site vaccine Manufacturing Type of Vaccine/ Upstream Downstream sources of bulk or fill - finish Yes No Yes No DTP (In-house bulk) V V DT (In-house bulk) V V TT (In-house bulk) V V Td (In-house bulk) V V DTP-HB-Hib (In-house bulk, V V bulk Hep B Korea) m/b/tOPV V V HB in Uniject (bulk Korea) V V OPV – nOPV2 (In-house bulk) V V IPV (Bulk France – Sanofi) V V COVID 19: Inactivated Virus, “COVID-19 V V Bio” (Bulk China – Sinovac) COVID 19 : Inactivated Virus, Sinovac V V (Coronavac), Sinopharm (Finished Product-China) COVID 19 : - Protein Subunit “Covovac” V V (Finished Product- SII India) Other: BCG (Finished Product- V V SII India), MR (Finish Product – 41 On-site vaccine Manufacturing Type of Vaccine/ Upstream Downstream sources of bulk or fill - finish Yes No Yes No SII India), Measles (Finish Product) PT. Bio Farma's work has been recognized at the global level. Since 1997, it has been one of about 30 vaccine manufacturers in 22 countries that have received WHO pre-qualification and are trusted to meet vaccine needs in more than 150 countries. In collaboration with global international networks, research institutes, regional professional organizations, and multinational companies, PT. Bio Farma is actively involved in promoting global public health‒ either directly by providing vaccines or through supporting government or private industry initiatives to implement health policies that are beneficial to the community. PT Bio Farma has been a member of the Developing Country Vaccine Manufacturing Network (DCVMN) since the establishment of this network in 2001. In 2018, PT Bio Farma was officially named a Center of Excellence (CoE) of the Organization of Islamic Cooperation (OIC). Current partners of PT Bio Farma for research and development include: • Bill & Melinda Gates Foundation (USA) for nOPV • IVI (Korea) for Typhoid Conjugate vaccine • Lipotek (Australia) for new TB vaccine • Baylor College of Medicine (USA) for COVID-19 vaccine • Murdoch Children’s Research Institute (Australia) for Rotavirus vaccine • Biken Institute (Japan) for sIPV • Artes (Germany) for HPV vaccine • Bionet Asia (Thailand) for Penta-aP vaccine • Dynavax (USA) for adjuvant development • Future Research Vaccine Hub (UK) for Dengue vaccine • University of Manchester (UK) for mRNA seed construct • Afrigen Biologics & Vaccines (South Africa) for capacity building in mRNA vaccine PT. Biotis Pharmaceutical Industry PT. Biotis is located in Gunung Sindur District, Bogor Regency, West Java Province. Ground breaking for the factory began in July, 2016. Initially, the factory was created to produce Avian Influenza and Newcastle Disease vaccines. The total investment to build this vaccine factory over three years was US$100 million. PT. Biotis has a composition of ownership as follows: Pharmally International holds 69 percent of Biotis shares, Harbin Veterinary Research Institute-Chinese Academy of Agricultural Sciences (CAAS) owns 10 percent, and the remaining 21 percent is controlled by strategic partners from Taiwan and Indonesia. GMP certification on vaccine production was granted to PT Biotis by BPOM in August 2021. 42 PT. Biotis is also one of the pharmaceutical companies working to produce the Red and White COVID-19 inactivated virus-based vaccine, which is being developed with the University of Airlangga. Vaccine development is in the Phase 3 clinical trial stage. “Biotis to life” was the shared vision of Pharmtech, Pharmbac, and Harbin Weike Biotechnology in developing sustainable biotechnology intended to discover, develop, manufacture, and commercialize safe and high-quality vaccines. Striving to be a benchmark in the vaccine industry, PT. Biotis has employed the most advanced technologies in production, quality control, and detection segment to provide healthy and quality medication options that meet strict international quality standards. PT. Etana Biotechnologies Indonesia PT. Etana Biotechnologies Indonesia (PT. EBI) was established in 2014 and obtained a GMP Certificate from BPOM in 2019. PT. EBI is a new producer of high-quality, affordable, and innovative biopharmaceutical products to treat various metabolic, autoimmune, and life- threatening diseases, including cancer, as well as vaccines. It has a storage area of 1,000 square meters and a production building of 3,600 square meters, with a separate R&D building. PT. EBI plays an important role in the health service ecosystem. It collaborates with governments and private institutions such as the Ministry of Health, BPJS Health, BPOM, and other research institutions to develop production capacity of Indonesian domestic medicinal raw materials. In addition, PT. EBI also collaborates with educational institutions at universities such as IMERI, and the Faculty of Medicine at the University of Indonesia. PT. EBI’s strategic plan to develop products is based on the strategic direction articulated in the Ministry of Health’s 2022-2025 resilience policy on medicines including raw material and vaccines 38, and includes the conduct of clinical trials in several research institutes. PT. EBI has registered products of Epoetin alfa and Bevacizumab and is in the process of developing: (i) Monoclonal Antibody (MAB): Tocilizumab, Adalimumab, Rituximab, PD-1; and (ii) COVID-19 Vaccine (mRNA) with Yuxi Walvax and COVID-19 Vaccine (Ad5-nCoV) with CanSino Biologics Inc. With regards to the development of the mRNA-based COVID-19 vaccine, phase 1 and 2 clinical trials done in China, and the phase 3 clinical trial done in Indonesia (with approximately 9000 subjects), showed good safety, immunogenicity profiles, and vaccine efficacy for the prototype antigen. Phase 3 trials were also conducted in Mexico and the Philippines. PT. EBI and Yuxi- Walfax will continue their research and trans-technology for COVID-19 m-RNA based vaccine for modified omicron and delta variant (Bivalent vaccine). PT Jakarta Biopharmaceutical In 2020, PT Jakarta Biopharmaceutical Industry (JBio) initiated construction of a factory to produce drugs and vaccines. The factory stands on an area of 14,850 square meters in the 38 For example, expanding local manufacturing capacities for the development of (i) 6 out of 10 of the most used Active Pharmaceutical Ingredients (candesartan, bisoprolol, amlodipine, lansoprazole, cefixime, ceftriaxone), (ii) Biological Products (erythropoietin EPO, Insulin, monoclonal antibody) (iii) Vaccine ( Measles, Rubella, Rotavirus, Tuberculosis, HPV, PCV, IPV, JE) and (iv) viral-vector and nucleic-acid based vaccines 43 Modern Industrial Estate, Serang, Banten Province, Java; construction costs totaled Rp 500 billion. For the construction of facilities for vaccine production, PT JBio began with the construction of fill-and-finish facilities (in vial and prefilled syringes) with a long-term plan to build capacity for upstream-downstream vaccine production. Completion of the fill-and-finish facility is anticipated for the end of 2022. PT JBio plans to produce several types of vaccines, namely the COVID-19 Vaccine (sub-unit protein based), Tuberculosis Vaccine, and Meningitis Vaccine. The sub-unit protein-based COVID-19 vaccine is under development in partnership with Anhui Zhifei Longcorn Pharmaceutical, China. PT JBio plans to target the domestic Indonesian vaccine market as well as that of other developing countries. The capacity of the factory each year is predicted to be 150 million vaccines. Annex 4: Domestic Vaccine Manufacturing—National Capacity Name of Company Manufacturing Capacity Upstream (L) Downstream (L) Formulation (L) Fill to Vial (Doses) PT Bio Farma 500 500 800 140 mio (10 doses per vial PT Biotis* 1000 1000 200 240 mio (10 doses per vial) PT Etana Biotech * 10 10 15-50 11 mio (PFS) PT JBio * 200 200 200 100 mio (10 doses per vial) PT Kalbe (Kalbio 50 50 200 50 mio (10 doses Global Medika) * per vial) Source : Presentation of MoH, 2022: ”Strategic Priority of Indonesia Preparedness for Emerging Infectious Diseases (EID).” *Predicted capacity for new entrant for domestic vaccine manufacturers 44 45