A lot of recent discussions focus on how to expand COVID-19 vaccine manufacturing capacity in low- and middle-income countries (LMICs). The conversations highlight the importance of technology transfer and the capability of the tech transfer receiving sites (the facilities in these countries that would then produce vaccines locally), including having specialized equipment and personnel. However, to ensure the safety, efficacy, and quality of vaccines manufactured in LMICs, national regulatory authorities (NRAs) in the country of manufacturing will play an irreplaceable role, especially in assuring product quality. Unfortunately, the World Health Organization (WHO) estimates that only 30 percent of NRAs among its member states have the capacity to effectively regulate medical products in their countries. Expanding vaccine manufacturing without guaranteeing adequate regulatory capacity in the countries where manufacturing will take place can lead to poor product quality, which may cause harm and could seriously undermine public trust.
The irreplaceable role of NRAs in securing vaccine quality
The quality of vaccines cannot be assured merely by inspecting and testing finished products. Assuring quality requires a series of interlinked activities that must occur throughout the lifecycle, from clinical development to commercial manufacturing to post approval surveillance. In particular, NRAs are required to:
Assure adequate starting materials: the NRA should assure that starting materials (e.g., cells, seed viruses, etc.) are homogenous, well characterized, and compliant with approved specifications. Because these materials are in shortage or it remains unclear if new LMIC manufacturers will have access to cell lines in the originators’ process, NRAs will need superior analytical expertise to assure that starting materials from non-established suppliers are adequate.
Confirm current good manufacturing practices (cGMP), including robust process validation and manufacturing consistency: the NRA should evaluate the adequacy of the manufacturer’s facilities and ensure that each step of the manufacturing process is controlled to assure that the finished product meets all quality attributes (e.g., purity, strength, etc.). This is not a small task since manufacturers might perform somewhere between 100 and 1,000 quality controls at each step of the manufacturing process.
In the case of COVID vaccines, short supply of key materials such as single use bioreactors might lead to use of fixed equipment from existing lines and sometimes manufacturing of more than one COVID vaccine in the same site, requiring very stringent review of manufacturing steps including cleanup between successive batches to reduce the risk of cross contamination and ensure product quality and safety. This is not a one-time activity; licensed manufacturing sites will have to be inspected regularly and any post licensure manufacturing changes will have to be evaluated thoroughly.
Perform lot release testing and regulatory protocol: the NRA should independently assess each lot of a licensed vaccine before it is release onto the market to confirm it meets the specifications in the emergency use authorization (EUA) or the marketing authorization. The type and extent of confirmatory lot testing may vary depending on factors such as the specific vaccine manufacturing platform and may change over time as the product/ platform demonstrates a record of continued safety, purity, and potency.
Conduct post marketing surveillance: After the vaccine is placed on the market, the NRA should monitor the quality of the product and ensure compliance with marketing authorization and good practice guidelines. Also, NRAs should monitor for unwelcome side effects.
Even though stringent regulatory authorities might have identified and studied quality and safety issues linked to some COVID vaccines manufactured in their territories, surveillance in LMICs is essential to detect additional events that might be linked to variations in the manufacturing process used in LMICs.
The WHO prequalification program (PQ) or Emergency Use Listing Procedure are no substitutes for the role the NRA in the country of manufacturing needs to play. These programs do carry out a thorough and rigorous evaluation, including for manufacturing process and manufacturing quality risks, but they rely on the NRA responsible for the regulatory oversight of the vaccine. In fact, a prerequisite for the PQ program is that the NRA responsible for the product is "functional" as per assessment performed using the WHO established indicators.
Currently, only 13 LMICs (Argentina, Brazil, China, Cuba, Colombia, Ghana, India, Indonesia, Iran, Mexico Serbia, Russia, and Tanzania) have a functional, stable regulatory authority according to assessments conducted by WHO or its regional offices. (This list includes NRAs of Regional Reference in the region of the Americas, those that have achieved maturity level 3 or 4 following evaluation using the WHO Global Benchmarking Tool (GBT), and functional NRAs assessed against the WHO Vaccines Assessment Tool before introduction of the GBT in 2016.) Many of these countries are not vaccine producers and/or are not currently producing any WHO prequalified vaccine (e.g., Colombia, Ghana, Iran, Mexico, and Tanzania). Additionally, some are already manufacturing COVID vaccines as part of a voluntary licensing arrangement or are developing their own vaccine candidates. This leaves very few LMIC with prior experience of manufacturing a WHO-PQ vaccine located in countries with a functional NRA.
Four areas for urgent action
These challenges should not discourage us from expanding manufacturing capacity. But we need a much more pragmatic look at where and how capacity should be built. In particular, we propose four specific areas for urgent action:
1. In the short run, global discussions around vaccine manufacturing capacity expansion should prioritize manufacturers located in countries with a functional NRA.
Regulatory capacity in receiving countries needs to be looked at with equal importance to other more traditional elements, such as the capability of the tech transfer receiving sites, in all discussions regarding expansions of vaccine manufacturing capacity. Functional NRAs ensure the technical capacity, scientific competence, transparency, and independence needed to guarantee product quality. Donors should closely examine any remaining manufacturing capacity that can be repurposed, upgraded, or created in the 13 LMICs with functional, stable regulatory authorities.
2. Any long-term plan to expand global vaccine manufacturing capacity in LMICs should also include a regulatory element to strengthen NRAs in the country of manufacturing.
G-20 and other efforts for long-term scale-up of global vaccine manufacturing capacity and broader financing plans for pandemic preparedness should include clear plans for strengthening NRAs incorporating both adequate funding and technical assistance/technology transfer to NRAs in the country of manufacturing. As part of these, stringent regulatory authorities from high-income countries should increase their support and partner with their LMICs counterparts to conduct joint inspections, twinned regulatory reviews, etc. This support should also include the establishment of strategic regulatory hubs and support for regional or continental initiatives such as the African Medicines Agency designed to harmonize medicines regulation, promote cooperation and mutual recognition of regulatory decisions, as well as pool expertise and capacities for optimal use of the limited resources available.
3. LMIC governments should fully support and adhere to the WHO Global Benchmarking Tool process to strengthen their NRAs in a systematic manner.
LMIC governments should adequately fund NRAs and engage in the WHO GBT process. The GBT offers a unique opportunity to the global health community because it answers the fundamental question of how to measure and strengthen regulatory capacity. The inclusion of an institutional development plan in the GBT methodology provides context-specific actionable steps countries can take to advance their system’s functionality and maturity. The GBT facilitates coordination, improves the effectiveness of regulatory strengthening efforts, promotes good regulatory practices, and facilitates reliance and harmonization, all of which build trust in NRAs and medical products, including vaccines.
4. The WHO should establish an information-sharing and cooperation platform for NRAs in vaccine-producing countries to exchange essential regulatory data such as batch consistency protocols, cGMP inspection reports, etc.
The WHO should revive, expand, and strengthen the Developing Country Vaccine Regulators’ Network established in 2004. The current network only includes nine NRAs from vaccine-producing countries (Brazil, China, Cuba, India, Indonesia, Iran, Republic of Korea, South Africa, and Thailand). It focuses mainly on vaccine clinical trials and only meets once a year; the last meeting took place a few years ago. The renewed network should guarantee a secure platform for continuous exchange of confidential information and should examine, and learned from, other NRA platforms, such as AVAREF in Africa and MDSAP and RISE in the Americas.
We need a systematic plan to boost national regulatory capacity, now
Expanding COVID-19 vaccine manufacturing and building a sustainable global network of vaccine manufacturing capacity in the long run requires functional NRAs in the countries of manufacture. These regulators play an irreplaceable role in ensuring that facilities, manufacturing processes, and finished vaccines meet international quality standards. Their work is essential to avoid harm, waste, and lack of public confidence in COVID vaccines. As multilateral development banks, bilateral donors, and development financing institutions draw out plans for financing the expansion of COVID-19 vaccine manufacturing capacity in LMICs, they need to include a practical and actionable plan for building regulatory capacity, now.