Report for the Eighth Asian National Control Laboratory Network meeting in 2023: Self-sufficiency strategy of plasma-derived medicinal products and regulatory harmonisation

Abstract

The Eighth Asian National Control Laboratory (NCL) Network meeting, entitled “Biological Products Quality Control and Self-Sufficiency Strategy focusing on plasma-derived medicinal products (PDMPs)” was held in Seoul on 31 August 2023. The participants were NCL experts from Indonesia, Japan, Malaysia, the Philippines, Vietnam, and the Republic of Korea. Special lectures included the PDMPs self-sufficiency strategies of the World Health Organization (WHO) and Indonesian Food and Drug Authority, and a case study on Global Benchmarking Tool (GBT) assessment for vaccines by the Korea Ministry of Food and Drug Safety. The NCL delegates shared their current experiences with national lot releases and biological standardisation. The meeting contributed to a mutual understanding of the progress of the PDMPs self-sufficiency among Asian countries, the WHO's support strategies, and the NCL's plan for the preparation of the WHO GBT assessment. In the panel discussion, all participants agreed that building capacity in blood safety in the Asian region and harmonisation of relevant international regulatory requirements will support appropriate emergency preparedness, particularly source materials in the region, and will build the foundation for resolving the PDMPs supply insecurity that has worsened after the COVID-19 pandemic in some countries.

Highlights

• •Asian national control laboratory experts gathered in Korea.
• •Plasma-derived medicinal products quality is responsibility of multiple groups.
• •Cooperation is crucial to support self-sufficiency in Asian countries.
• •The participants agreed to harmonise regulatory requirements.
• •The participants agreed to collaborate to enhance the vaccine regulatory system.

Abbreviations

BCG

Bacillus Calmette-Guérin

COVID-19

Coronavirus disease 2019

ECBS

Expert Committee on Biological Standardization

FDA

Food and Drug Administration

GBT

Global Benchmarking Tool

GMP

Good Manufacturing Practice

LMICs

Low- and middle-income countries

MFDS

Ministry of Food and Drug Safety

NCL

National control laboratory

NCLBP

National Control Laboratory for Biological Products

NICVB

National Institute for Control of Vaccines and Biologicals

NIFDS

National Institute of Food and Drug Safety Evaluation

NIID

National Institute of Infectious Diseases

NLR

National lot release

NPRA

National Pharmaceutical Regulatory Agency

NQCLDF

National Quality Control Laboratory of Drug and Food

NRA

National regulatory authority

OCABR

Official Control Authority Batch Release

PDMPs

Plasma-derived medicinal products

SP

Summary Protocol

vCJD

variant Creutzfeldt-Jakob Disease

WHA

World Health Assembly

WHO

World Health Organization

WLA

WHO Listed Authorities

1. Introduction

Plasma-derived medicinal products (PDMPs) are life-saving therapeutics of great importance for the prevention and treatment of several chronic and acute life-threatening diseases [1]. PDMPs include products such as1) albumin used for hypoalbuminaemia and haemorrhagic shock, 2) immunoglobulin used for Guillain-Barre syndrome and Kawasaki disease, and 3) coagulation factors used for the prevention and treatment of haemophilia. Albumin, immunoglobulins, and coagulation factors are classified in the World Health Organization (WHO) Model Lists of Essential Medicines, and the demand for PDMPs continues to increase worldwide [2]. However, only 42 countries manufacture at least one of the four PDMPs, albumin, intravenous immunoglobulin, factor VIII, and factor IX, by fractionation within the country or through contract fractionation, and 91 countries import all PDMPs, whereas 16 countries have no experience using PDMPs [3]. The self-sufficiency of blood and PDMPs from voluntary non-remunerated healthy donors is endorsed by the WHO and is currently the basis for blood collection in most countries [4]. Human plasma, used as a raw material for the production of PDMPs, is recognized as a public and national concern, and ensuring a safe, sufficient, and ethically secured supply of PDMPs is an important public health responsibility of all national regulatory authorities (NRAs) [5]. Nevertheless, in many low- and middle-income countries (LMICs), essential PDMPs are not in sufficient supply, which prevents patients with severe congenital and acquired disabilities from receiving appropriate treatment [6]. To solve this problem, many countries are collaborating with global PDMPs manufacturers to introduce manufacturing facilities and technologies, and are working to strengthen the capabilities of the NRA and the national control laboratory (NCL) by conducting education/training in cooperation with the WHO and PDMPs manufacturing countries. Asia is no exception to the recent need for self-sufficiency in PDMPs. As the demand for PDMPs increases in Asia, cooperation between NCLs in charge of quality control, including national lot release (NLR), is also urgent.

The meeting reported here was held on August 31, 2023 in Seoul, Republic of Korea, entitled “Biological Products Quality Control and Self-Sufficiency Strategy focusing on PDMPs”. The meeting was hosted by the National Institute of Food and Drug Safety Evaluation (NIFDS) of the Ministry of Food and Drug Safety (MFDS) and brought together NCL representatives from Indonesia, Japan, Malaysia, the Philippines, Vietnam, and the Republic of Korea. Three speakers delivered the special lectures: Dr. Yuyun Siti Maryuningsih (WHO), Mr. Bayu Wibisono (Indonesian Food and Drug Authority), and Dr. Jong Won Kim (NIFDS). Subsequently, recent issues regarding NLR and biological standardisation were shared by the NCLs of the six member states. Finally, a panel discussion was conducted with Dr In Soo Shin (NIFDS). The objectives of this meeting were to: 1) share the PDMPs self-sufficiency strategies of the WHO and Indonesian Food and Drug Authority and the MFDS's experience with the Global Benchmarking Tool (GBT) assessment for the WHO Listed Authorities (WLA) listing approval; 2) share NLR issues and plans for biological standardisation of each country; 3) discuss strategies and agendas for NCL collaboration; and 4) strengthen the regulatory capacities of regulators.

2. Opening remarks and special lectures

2.1. Opening remarks

The meeting officially opened with a warm welcome by Dr. Youngju Choi (Director General of the Biopharmaceutical & Herbal Medicine Evaluation Department of the NIFDS). With the advancements in medical technologies, the demand for blood and PDMPs is expanding, and their market size is increasing accordingly. As the demand for PDMPs is expected to increase in Asia, there is a strong need to enhance cooperation for regulatory capacity building at the regional level. Dr. Choi emphasised that this changing landscape highlights the essential responsibilities of the NRAs and NCLs in ensuring the quality, safety, and availability of PDMPs. Dr. Choi hopes that this meeting will yield meaningful results. Furthermore, it is her wish that the participating countries and Korea further enhance the existing frameworks for close cooperation across the areas and take the current relationships fostered in biological standardisation to the next level. After Dr. Choi opened and explained the objectives of the meeting, Dr. Yuyun Siti Maryuningsih, Mr. Bayu Wibisono, and Dr. Jong Won Kim started the first session of special lectures.

2.2. WHO Policies regarding blood establishment and self-sufficiency support in LMICs (Dr. Yuyun Siti Maryuningsih, WHO)

The WHO has designated blood products as essential medicines; however, they carry inherent biological and process-related hazards that can lead to serious or fatal consequences. Therefore, it is essential that blood be used only when clinically needed and should be used appropriately. Plasma not used for transfusion can be used for the production of PDMPs; however, the data showed that approximately 9 million litres of plasma from LMICs was discarded. It is known and deplored that in most LMICs, the supply of appropriate PDMPs is highly insufficient, almost absent. The reasons are insufficient plasma volume for the efficient production of PDMPs, the quality of plasma does not meet the standards, there are few fractionators that are able to run contract plasma fractionation and transfer technology in the African, Southeast Asian, and Western Pacific regions, and establishing local plasma fractionation requires significant investment.

WHO responses to these situations are directed by World Health Assembly (WHA) Resolutions 63.12 (2010) on Availability of Safe and Quality Blood, Blood Components, and PDMPs, which aim to achieve self-sufficiency of blood products; WHA 67.20 (2014) on Regulatory System Strengthening, which aim to achieve at least maturity level 3 of the regulatory system; WHA 72.6 (2019) on Global Action on Patient Safety, which aims to promote patient safety; and WHA 76.5 (2023) on Strengthening Diagnostic Capacity, which aims to establish regulation, assessment, and management of diagnostics.

The strategies to achieve these WHA resolutions are as follows: 1) ensuring the availability, safety, and quality of blood products by implementing Good Manufacturing Standards for Blood Establishments; 2) strengthening the blood regulatory system to maturity level 3 by implementing GBT plus blood; 3) promoting patient safety through the implementation of clinical use of blood and patient blood management practices; and 4) controlling the quality and safety of medical devices and in vitro diagnostic devices used for blood services and transfusion.

Moreover, to achieve self-sufficiency of PDMPs in LMICs, the WHO has published guidelines on increasing the supply of PDMPs in LMICs through the fractionation of domestic plasma. The guidelines describe a three-step approach to improving the supply of PDMPs at the national level. First, when the volume of recovered plasma for fractionation at the national level is insufficient, the country can begin preparing pathogen-reduced plasma protein fractions, resulting in safer products. In the second step, when recovered plasma meeting quality and quantity requirements for fractionation is available at the national level, blood establishments have an auditable qualification system based on current Good Manufacturing Practice (GMP), blood and blood component demand is fully satisfied, and the country can initiate a program for the fractionation of recovered plasma (e.g. contract fractionation). And the last step is that when the volume of plasma for fractionation produced at the national level is sufficient and the country has capacity, a national or regional facility for fractionation can be considered.

To assist countries in implementing these three-step options, the WHO, in collaboration with the International Society of Blood Transfusion, a non-State actor in official relations with the WHO, developed a collaboration agreement to run a project aimed at assisting countries in increasing their access to safe plasma protein products. This project is currently being piloted at the Dakar National Blood Centre in Senegal.

2.3. Self-sufficiency strategies for PDMPs of Indonesian Food and Drug Authority (Mr. Bayu Wibisono, Indonesian Food and Drug Authority)

Currently, blood products are being imported in Indonesia. As there were governmental policies for local production, the Indonesian Food and Drug Authority collaborated with relevant stakeholders to conduct a national program to ensure the quality and safety of blood and plasma that will be used for plasma fractionation to produce PDMPs.

The presentation gave a short experience of how the Indonesian Food and Drug Authority collaborated with the Ministry of Health, the Indonesian Red Cross started GMP implementation in Blood Transfusion Units, and shared information related to the preparation of self-sufficiency strategies for PDMPs in Indonesia. The initial steps involved developing regulations and guidelines and increasing staff competencies.

2.4. MFDS's GBT case studies for WLA listing approval (Dr. Jong Won Kim, NIFDS)

On November 29, 2022 the WHO announced that the MFDS had achieved maturity level 4, the highest level in the WHO classification of regulatory authorities for the regulation of medicines and vaccines based on the WHO's recent independent and objective assessment with the GBT. The Republic of Korea achieved maturity level 4 for medicines and vaccines following a WHO benchmark conducted in the country in May 2022 and is working closely with the WHO to implement the recommendations made by the team of international regulatory experts.

The Vaccines Division of the NIFDS is in charge of the NLR and laboratory tests for vaccines. Especially regarding lot release and laboratory tests, the MFDS has collaborated with the WHO as follows: 1) WHO Global Learning Opportunities Centre since 2016; 2) WHO-NCL Network for Biologicals for exchange of quality and technical information on WHO Prequalified vaccines since 2018; and 3) NCL contracted by the Technical Service Agreement with the WHO for vaccine tests to assess the quality of vaccines purchased by international organisations, including UNICEF, since 2006. Currently, 15 laboratories are operating in 15 countries; 4) the WHO Collaboration Centre regarding the Standardisation of Biologicals since 2011. The MFDS worked to achieve maturity level 4 for lot release and laboratory testing of vaccines. To become a member of the WLA, the MFDS plans to cooperate with WHO.

3. Country presentations

3.1. Laboratory readiness to support the independency of PDMPs production by local pharmaceutical industry (Mr. Dio Ramondrana, Indonesian Food and Drug Authority)

The National Quality Control Laboratory of Drug and Food (NQCLDF) is part of the Indonesian Food and Drug Authority and is responsible for post-market product control. To support this function, the NQCLDF has five laboratories and three technical units, one of which is the National Control Laboratory for Biological Products (NCLBP), which is responsible for ensuring the quality and safety of biological products such as vaccines, blood products, and biosimilar products. The NCLBP is a WHO-accredited laboratory and is one of the laboratories contracted by the WHO for Diphtheria-Tetanus-Pertussis potency testing. The NCLBP has two main responsibilities for vaccine control: laboratory testing and lot release. Some improvements have been made in the NCLBP, such as the acceleration of the lot release evaluation timeline and the development of digital service systems for lot releases. Thus far, the NCLBP has mostly focused on vaccine products, but the laboratory is moving forward with conducting laboratory tests for other biological products. For instance, the NCLBP has developed analytical methods for biosimilar products. Next, we explain the strategies and legal frameworks applied in the NCLBP.

Based on Decree of the Indonesian Food and Drug Authority No. 23 Year 2020, the NCLBP is a technical unit under the NQCLDF which is responsible for ensuring the safety and quality of biological products. In terms of vaccines, the NCLBP follows the decree of the Indonesian Food and Drug Authority No. 1 Year 2023 on guidelines for vaccine lot release as well as the Regulation of Indonesian Food and Drug Authority No. 1 Year 2023 on certification of vaccine batch/lot release. Lot release is the system used to check the appearance of the vaccine sample, as well as the document evaluation of every vaccine batch/lot for both domestic and imported. The evaluated document consisted of a Summary Protocol (SP), a certificate of analysis, and raw data. For domestic vaccines, the NCLBP conducts laboratory tests for 10% of the total annual vaccine production. Based on data from 2020 to 2022 to the number of vaccines lots released in Indonesia will range from 700 to 1200. In addition to lot release, the NCLBP conducts laboratory testing for post-market surveillance of vaccines. The provincial unit of the Indonesian Food and Drug Authority performs vaccine sampling, and the samples are sent to the NCLBP for testing. Post-market surveillance is important to check whether there are any falsified, substandard products and to observe the vaccine cold chain system.

Regarding blood products, there several regulations issued by the Indonesian Food and Drug Authority and Ministry of Health. The regulations issued by the Indonesian Food and Drug Authority focus on GMP guidelines for an establishment of blood transfusion and plasmapheresis centres, whereas blood transfusion unit standards, blood transfusion services, and the administration of plasma fractionation are regulated by the Ministry of Health. The PDMP is a new blood product in Indonesia. Because the source of blood in Indonesia is abundant, some international investors are interested in manufacturing PDMPs in Indonesia. Therefore, NCLBP must be prepared to strengthen control of PDMPs. Similar to vaccines, PDMPs are categorised as high-risk products because they are sourced from human blood. All processes, including blood collection, plasma fractionation, and PDMP manufacturing, must be GMP certified. Both pre- and post-market surveillance should be conducted. Supported by the WHO, a workshop on the quality assurance of blood products was conducted in June 2023. From the workshop, the NCLBP has a wide knowledge of the strategies of PDMP control applied by other NRA from South Korea, Germany, and Australia. After the workshop, the NCLBP created a roadmap for the development of the PDMPs laboratory capacity.

In conclusion, the NCLBP has applied strategies for quality and safety assurance of vaccines. The NCLBP also always strives for improvement, especially for other biological products such as blood products and biosimilar products.

3.2. Systems biology approaches enable evaluation of adjuvant vaccine safety and quality (Dr. Takuo Mizukami, National Institute of Infectious Diseases (NIID))

An update on the complete removal of abnormal toxicity testing from the Minimum Requirements for Biological Products by 2023 has been summarised. Recent progress in the development of new tests to assess vaccine quality and safety using in vitro biomarkers has also been reported. They demonstrated that in vitro testing ensured the safety and lot-to-lot consistency of adjuvanted influenza vaccines. They validated in vitro methods for quality control of seasonal influenza vaccines.

3.3. Lot release for biological products in Malaysia (Ms. Azraini Abdul Samat, National Pharmaceutical Regulatory Agency (NPRA))

The requirements for lot release in Malaysia for imported vaccines and PDMPs, which include reviewing the SP, cold chain inspection, and physical appearance testing, are shared. Lot release will be implemented in phases for the vaccines and PDMPs manufactured in Malaysia. Similar to the imported vaccines and PDMPs, all phases require a review of the SP. Phase 1 occurs when the expertise and facilities to conduct tests are not fully established in the NPRA, for which reviewing the finished product test reports and physical appearance testing are required. Phase 2 is when the facilities and expertise to conduct tests are established. Physical appearance and other tests as recommended by the WHO or European Union Official Control Authority Batch Release (OCABR) will be conducted. In Phase 3, the quality of the product is confirmed through consistent test results for the chosen parameters obtained from Phase 2; therefore, the selected tests are conducted using a risk-based approach.

Considering the pandemic situation, the Drug Control Authority has allowed coronavirus disease 2019 (COVID-19) vaccines to be registered through fast-track conditional registration, as stated in the Guidance and Requirements on Conditional Registration for Pharmaceutical Products During Disasters. This mechanism aims to provide immediate access to pharmaceutical products for treatment or prevention using a risk-based approach without neglecting product quality, safety, and effectiveness. The requirements for lot release of conditionally registered vaccines are as follows: batch release certificate from the NRA/NCL of the country of origin, cold chain inspection, and physical appearance testing. However, in February 2021, the Drug Control Authority granted an exemption from physical appearance testing for all COVID-19 vaccines.

The NPRA has developed a test method for the determination of aluminum content and potency tests for Hepatitis B vaccines. Other divisions under the Ministry of Health Malaysia are collaborating to develop potency test methods for vaccines for surveillance purposes.

Finally, the NPRA aims to become a global standard NRA by achieving maturity level 4 for the WHO GBT NRA Assessment scheduled for November 20–24, 2023.

3.4. National lot release system in the Philippines (Ms. Caren Mangorangca, Food and Drug Administration (FDA) Philippines)

In summary, this presentation provides an overview on how vaccines are lot certified. The Philippines is a procuring country; thus, Lot Release Certification focuses primarily on the review of summary lot protocols and the recognition/acceptance of lot release certificates from the responsible NRA and/or NCL. Three-year data from 2020 to mid-2023 of the National Lot Released Annually showed an increase in the submission of biological products in 2021, in which the bulk of applications were monoclonal antibodies and PDMPs. The FDA Philippines encountered challenges in review/evaluation, as there was limited information and guidelines for these products. Considering the latter, the FDA Philippines issued an advisory (FDA Advisory 2021–2023) to streamline the process of Lot Release Certification and clarify the scope to vaccines, toxoids, and immunoglobulins. During the Asian NCL meeting, it was recommended that a guideline be established to harmonise the regulation of PDMPs. The FDA Philippines is in the process of establishing its own Vaccine Testing Laboratory, and while this is ongoing, it has been requesting technical assistance and collaboration to capacitate the staff for the testing of vaccines. As for the COVID-19 vaccine, currently only one product has been registered, while some are still under evaluation. All emergency use authorisation products in the Philippines were exhausted for one year from the date of lifting the State of Public Health Emergency based on Presidential Proclamation No. 297 dated July 21, 2023.

3.5. Recent issues on national lot release & biological standardization in Vietnam (Dr. Dung Luu Thi, National Institute for Control of Vaccines and Biologicals (NICVB))

This presentation discusses the legal framework related to the current registration and release of batches of vaccines and biological products in Vietnam. Data on the lot release of vaccines and biological products in the 3 years from 2020 to 2022 show that every year, approximately 1000 batches were tested by the NICVB, including imported and domestic products. For COVID-19 vaccines, batch release is applied within two working days, including testing and document review, according to the WHO instructions. In approximately 3 years, nearly 500 batches of COVID-19 vaccines were released in Vietnam. Until now, the number of imported batches was predicted to be less than 10 in 2023. The number of imported batches of biological products by 2022 tends to decrease slightly owing to the impact of the COVID-19 epidemic and war. The quantity of human albumin Baxter was the largest imported biological product within 3 years. In particular, 100% of the therapeutic biological products originate from human blood, serum, and plasma imported from other countries. The small amount of snake venom antitoxin produced from horse serum is likely to show a sharp decline in production by 2022. Vietnam does not manufacture biological products from human blood or a corresponding national standard sample suitable for quality assessment. Therefore, the availability and self-sufficiency of biological products are limited. Vietnam is establishing more specific regulations applicable to biological products derived from human blood in the near future. Testing of biological products originating from human blood, serum, and plasma will require increased technical support in the near future.

4. Panel discussion and recommendations

4.1. Self-sufficiency strategy and international regulatory harmonisation on blood and PDMPs

The panel discussion was chaired by Dr. In Soo Shin with all meeting participants. Blood and source materials for PDMPs are restricted in cross-border movement; therefore, surplus source materials in LMICs are often discarded rather than used for PDMPs production owing to a lack of plasma fractionation facilities and technology, such as viral validation. However, particularly during the COVID-19 pandemic, many countries experienced a growing demand driven by the need for immunoglobulins and an overall decline in plasma donations [7]. The WHO established the Action Framework for Blood Products 2020–2023 to support the strengthening of national blood systems in LMICs through the development of guidelines, technical assistance, and education/training. Currently, the Indonesian Food and Drug Authority is promoting the self-sufficiency of PDMPs, and to strengthen NCL capacity, it held a workshop on testing and analysis to assure the quality of blood products in June 2023 with the WHO, inviting experts from the MFDS, Paul-Ehrlich-Institute, and Therapeutic Goods Administration. Indonesia is working with Korean PDMPs manufacturers to establish manufacturing facilities and transfer technology, and Mr. Dio Ramondrana expressed interest in the MFDS's safety management of source materials and the NLR system and wanted to cooperate in education/training. In addition, because securing safe blood is important for the manufacture of PDMPs, Indonesia is promoting continuous cooperation with the Korean Red Cross. Dr. Yuyun Siti Maryuningsih suggested that the MFDS could play a significant role in this area, including education/training in Asian countries, in line with that Korea is a WHO Global Training Hub for Biomanufacturing since February 2022. The MFDS agreed with the WHO's suggestion, noting that Korea's commitment to international cooperation in the blood sector could further contribute to regulatory harmonisation in the region. Representatives from Indonesia, the Philippines, and Vietnam also agreed with the WHO and MFDS opinions, and Dr. Yuyun Siti Maryuningsih welcomed the promotion of regional cooperation aimed at PDMPs self-sufficiency, planning to report the outcome of this meeting to the Expert Committee on Biological Standardisation (ECBS).

In 2022, the United States FDA issued new guidance regarding variant Creutzfeldt-Jakob Disease (vCJD) that eliminates the deferral for those who spent time in the United Kingdom, Ireland, and France at certain periods of time [8]. Australia also decided to remove the geographical deferral of blood and plasma donors from the United Kingdom based on a risk model assessment, and discussions are underway in Korea, where source materials are imported from the United States [9]. Currently, the major countries exporting source materials from paid donors are the United States, Germany, Austria, Hungary, and the Czech Republic, which are responsible for nearly 90% of the total global supply; Asian countries import source materials from these countries [10]. Different blood management standards across countries could lead to management difficulties, an increase in the amount of discarded source materials, shortage of source material supply, price increases, and an increased incidence of look-back. These predicted issues will lead to increased anxiety and distrust of the national blood system among people who use PDMPs as essential medicines. In response, Dr. In Soo Shin suggested that the WHO should take the leadership in standardising vCJD-related donor deferral regulations, as many scientific studies support that the current risk of transmission of vCJD by blood and blood components is negligible [[11], [12], [13]]. Representatives from six countries also agreed on the need for international harmonisation of the standards, and Dr. Yuyun Siti Maryuningsih said that the WHO is monitoring this situation regarding blood safety and vCJD through expert consultations, harmonisation of related regulations is expected, and will try to further discuss this issue on the ECBS, if needed.

4.2. Sharing the MFDS's experience on WLA evaluation and continuous cooperation in vaccines

The WHO promotes the WLA designation on behalf of existing Stringent Regulatory Authorities through an independent assessment of regulatory functions of NRAs [14]. Listed countries will be eligible for the WHO Prequalification exception when pharmaceutical companies bid for drug procurement from United Nations agencies and can also negotiate with governments to be included as a reference country for drug licensing/review. The WHO has recognized the MFDS for its excellent regulatory capacity by achieving a maturity level of 4, which is the highest rating in the GBT assessment for the regulation of medicines and vaccines. At the meeting, Dr. Jong Won Kim, who is in charge of vaccine lot release and laboratory testing, shared the MFDS's GBT assessment cases, noting that the process of transparently sharing NLR procedures and results with stakeholders, facilities, personnel, and equipment, was crucial to the assessment. To this end, the MFDS discloses information to the public on its website and publishes annual reports and articles to share NLR-related information with stakeholders [15,16]. Dr. Jong Won Kim said that the Vaccines Division of the NIFDS would like to express openness and willingness for all participating countries in this meeting to continuously work and cooperate internationally to strengthen the regulatory system of vaccines, especially regarding lot releases and laboratory tests.

4.3. NLR system and biological standardization activities

According to the WHO guidelines, a protocol review is essential for lot release, testing by NCLs is not always necessary, and testing for reduced percentages of lots is acceptable if good consistency is achieved over a significant period [17]. Canada, China, and the United States are known for conducting lot release testing at a frequency of less than 100%, and the testing frequencies of each product are determined by these organisations using risk assessments based on several factors [18]. Of the countries represented at the meeting, Japan, Korea, Malaysia, and Vietnam applied a risk-based approach to NLR for vaccines and PDMPs; Indonesia applied NLR for vaccines only; and the Philippines applied NLR for vaccines, toxoids, and immunoglobulins (Table 1). Dr. In Soo Shin suggested sharing detailed procedures for risk-based approaches by country as a topic for the next meeting, noting that such information-sharing could help countries in the region make decisions or policies to introduce risk-based approaches to the NLR.

Table 1.

Introduction status of risk-based approaches for NLR.

Country	Vaccines	PDMPs, antitoxins, and others
Indonesia	Introduced in 2001, lot release is required for both domestic and imported vaccines. Vaccine lot release includes appearance test, vaccine vial monitoring, label, leaflet, packaging review, SP, and certificate of analysis.	Lot release is not introduced for PDMPs, but the GMP of those products are strengthened. However, the guidelines for lot release of PDMPs is going to be discussed.
Japan	Introduced in 2009 (Reduction of test items based on risk assessment). It is under discussion to introduce reduction of testing frequency based on risk assessment.	Not introduced for PDMPs. However, the elimination of double-checking at the NCL in each test item is introduced based on past test results, the status of accuracy control such as availability of standard and reference products, and situation of standardization of each test item as appropriate.
Korea	Introduced in 2016 (Risk level 1, 2a, 2b, and 3)	Introduced in 2016 (Risk level 1, 2a, 2b, and 3)
Malaysia	Introduced in 2021, lot release requirements for locally manufactured vaccines (Phase 1, 2, and 3) include review of SP/test report and physical appearance test/other tests in OCABR/selected tests.	Introduced in 2021, lot release requirements for locally manufactured PDMPs (Phase 1, 2, and 3) include review of SP/test report and physical appearance test/other tests in OCABR/selected tests.
Philippines	Introduced in 2023 under FDA Order No. 2023-0302 (for plan testing of vaccines). Review of SP, Recognition/Acceptance of lot release from responsible NRA/NCL. All vaccines are procured/imported and mostly WHO prequalified.	Not introduced. Lot release certification covers only vaccines, toxoids, and immunoglobulins.
Vietnam	Introduced in 2019 (Risk level 1, 2, and 3) Review SP, inspect cold chain, and perform test in specification following yearly testing policy approved by NCL.	Introduced in 2019 (Risk level 1, 2, and 3) Review SP, inspect cold chain, and perform test in specification following yearly testing policy approved by NCL.

While the 2022 Asian NCL Network meeting shared some of the participating NCLs’ NLR statistics, including those of Japan, Korea, and Vietnam in 2022, this 2023 meeting provided NLR statistics for vaccines, PDMPs, and other preparations from 2020 to 2022 for all six participating countries (Table 2). All participating countries showed a significant increase in the NLR number of vaccines by 2021, driven by an increase in the number of emergency-use approvals for COVID-19 vaccines. Despite the recent development of advanced biotherapeutics and medicines, PDMPs still play a critical role in maintaining the public health system, especially in the initial period of unknown infectious diseases, including COVID-19; therefore, the role of manufacturing countries, including Korea and Japan, is important in emergency preparedness in the area of PDMPs, where similar levels of NLR have been reported each year. Additionally, the NLR is expected to increase in other countries as the demand for PDMPs increases and self-sufficiency is promoted. In Korea, botulinum preparations account for the majority of NLR in the antitoxins category. Korea has designated botulinum preparations as biologicals for NLR and performs NLR for every lot.

Table 2.

NLR numbers per country during the 2020–2022 period.

Country	Vaccines (COVID-19 vaccines)			PDMPs			Antitoxins and others
	2020	2021	2022	2020	2021	2022	2020	2021	2022
Indonesia	714	1241	983	–	–	–	–	–	–
Japan	388	635	570	368	388	399	4	2	6
	(5)	(298)	(219)				(including Purified Tuberculin)
Korea	865	1115	843	1110	1000	980	449	459	717
	(0)	(256)	(83)				(including Botulinum toxins)
Malaysia	243 (0)	2332 (1926)	794 (618)	168	143	143	–	–	–
Philippines	297	360	305	40	208	50	–	–	–
Vietnam	595 (0)	832 (364)	679 (123)	225	177	130	22	30	19

As the use of biologicals increases and self-sufficiency is promoted, the role of the NCL in conducting testing becomes more important, and the number of domestic and international biological standardisation activities required by the NCL increases. Table 3 shows the plans for biological standardisation by the participating countries. Most participating countries that provided plans continued to promote the establishment of national standards and development/improvement of test methods related to the NLR. In particular, Indonesia is developing test methods for the NLR of PDMPs, and Malaysia and the Philippines are working towards the recognition of the GBT maturity level for NRA assessment by the WHO. In addition, Indonesia and Korea are planning to develop a monocyte activation test to replace the rabbit pyrogen test, which is expected to contribute to the harmonisation of test methods in the region and improve the reliability of the developed test methods through collaborative studies.

Table 3.

Plans for biological standardization by the participating countries.

Countrya	Plans
Indonesia	Development of testing methods for PDMPs (2024–2026).
	Development of testing methods for biosimilar products, such as Heparin injection, Epoetin alfa, and Filgrastim (2024–2028).
	Development of monocyte activation test as a replacement of rabbit pyrogen test (2025–2027).
	Development of biological reference standards (2025–2030).
Korea	Improvement of the in-vivo potency assay for Botulinum toxin (2023).
	Establishment of a national standard for anti-thrombin concentrate, 2nd (2023).
	Improvement of the potency assay for Bacillus Calmette-Guérin (BCG) vaccine (2023–2024).
	Development of alternative potency assays for haemorrhagic fever with renal syndrome vaccine (2023–2024).
	Development of monocyte activation tests as a replacement of rabbit pyrogen test (2023–2025).
	Improvement of quantitative assays for Meningococcal conjugate vaccine (2024–2025).
	Improvement of testing methods for PDMPs using analytical quality by design (2024–2026).
Malaysia	Development of potency assays for Meningococcal (NPRA), Influenza, and Human papillomavirus vaccines (National Public Health Laboratory) (2023–2024).
	Attainment of WHO GBT maturity level 4 for NRA assessment (2023).
Philippines	Establishment of a Vaccine Laboratory (2024).
	Attainment of WHO GBT maturity level 3 for NRA assessment (October 2023).
Vietnam	Establishment of national standards for Rota, Rubella, Measles, Diphtheria, Tetanus, Haemophilus influenza type b, Typhoid, Japanese encephalitis (Beijing strain), Acellular pertussis, Inactivated Poliovirus, BCG, Rabies, Whole-cell pertussis, Hepatitis B recombinant, Recombinant Hepatitis B MC, and Nakayama Japanese encephalitis vaccines.

^aOnly countries that submitted information were included.

5. Closing remarks and conclusions

The meeting ended with closing remarks from Dr. In Soo Shin by acknowledging the speakers, especially the active discussions from all the participants, who asked for suggestions on topics for special lectures and areas for cooperation between NCLs to prepare for the next meeting in 2024. Dr. Shin said that it is not always possible to prevent a crisis from happening, but we can turn crises into opportunities in the spirit of solidarity and cooperation. He hoped that this meeting and networking would be remembered as the momentum to deliver successful international cooperation through the expertise of the participants.

In conclusion, special lecture speakers, NCL representatives, and all onsite and virtual participants agreed on the need to continue meetings among Asian NCLs, expand the number of participating countries, and strengthen cooperation. The MFDS will continue to cooperate with WHO member states in the Asian region, and small educational workshops or hands-on training programs in this region for quality control and lot release of vaccines and PDMPs might be organised in the near future.

Funding

This meeting was financially supported by the MFDS of the Republic of Korea.

Declarations of interest

The authors declare no potential conflicts of interest.

Author contributions

Chan Woong Choi and In Soo Shin wrote a meeting report with contributions from the meeting participants. All authors revised and approved the final version of the manuscript.

List of meeting participants

Yuyun Siti Maryuningsih.

Blood and Other Product of Human Origin, Health Products Policy and Standards Department, World Health Organization Headquarters, Switzerland.

Bayu Wibisono, Dio Ramondrana, and Desilia Rachmawati

Indonesian Food and Drug Authority, Indonesia.

Takuo Mizukami and Masaki Ochiai.

National Institute of Infectious Diseases, Japan.

Youngju Choi, In Soo Shin, Jong Won Kim, Kyung Hee Sohn, Sun Bo Shim, Su Kyoung Seong, In Yeong Hwang, Joon Ik Ahn, Suk Bae Lee, Chan Woong Choi, Myoung Jun Kim, Hyun Jung Koh, Seong Jae Kim, Yun Su Bang, and Yoo Jung Yi.

National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Korea.

Azraini Abdul Samat, Winnie Huang Mee Eng, Nee Yuan Qi, and Ng Siaw Wee.

National Pharmaceutical Regulatory Agency, Malaysia.

Caren Mangorangca, Jocelyn Balderrama, and Stella Marie Escober

Food and Drug Administration Philippines, Philippines.

Dung Luu Thi and Hung Pham Van.

National Institute for Control of Vaccines and Biologicals, Vietnam.