Importance of national regulatory agencies and national control laboratories in the face of the COVID-19 pandemic: Experience of Federal Commission for the Protection against Sanitary Risks (COFEPRIS)

Abstract

COVID-19 pandemic has challenged the National Regulatory Agencies (NRAs). One of these challenges is the transfer and validation of new vaccine methodologies so that they are safe, quality, and effective in protecting the population. In this article, we review the process that the Mexican NRA followed for the Vaxzevria and Convidecia vaccines; where communication between manufacturers and NRA allowed the methodological transfer and validation to be carried out before the first batch for application was ready in compliance with WHO guidelines. In this way, the importance of the relationship that must exist between manufacturers and NRAs is manifested to provide an immediate response and provide the population with a means of protection in the event of a public health emergency.

Resumen

La pandemia de COVID-19 ha desafiado las Agencias Nacionales Reguladoras (ARN). Uno de estos desafíos es la transferencia y validación de metodologías de vacunas nuevas para que sean seguras, de calidad y efectivas para proteger a la población. En este artículo, revisamos el proceso que siguió la ARN de México para las vacunas Vaxzevria y Convidecia; en donde la comunicación entre fabricantes y ARN permitió que la transferencia y validación metodológica se realizara antes de que el primer lote para aplicación estuviera listo dando cumplimiento a las directrices de la OMS. De esta manera, se manifiesta la importancia de la relación que debe existir entre los fabricantes y las ARN para dar una respuesta inmediata y brindar a la población un medio de protección ante una emergencia de salud pública.

Introduction

Evidence has shown that vaccines are essential tools for public health systems, since they offer the population protection against infectious diseases that significantly impact health, leading to hospitalisations and even death.^1,2

Regardless of the technology used for their manufacturing and their structural complexity, vaccines must undergo exhaustive description classification and analysis. This implies knowing and carrying out special procedures for their manufacture, control, regulation, authorisation, and release of batches.³

National regulatory agencies (NRAs) are responsible for establishing the necessary procedures to ensure that the manufacturer guarantees that its product, e.g., a vaccine, is of quality, safe, and effective, by reviewing production data and quality control test results. In addition, the NRA can complement this review by carrying out analytical tests, independent from those of the manufacturer, and this allows the results of the reported tests to be verified.⁴

When dealing with the COVID-19 pandemic (disease caused by the SARS-CoV-2 coronavirus), it became necessary to carry out expeditious analysis and release of vaccine batches, due to the urgent need to immunise the population. The World Health Organisation (WHO) therefore issued an operational tool for the efficient and effective management of the release of batches of these vaccines, so that they would be available to the population as soon as possible.⁴ This tool recommends that vaccine recipient countries choose the most appropriate approach to batch release, and to the extent possible, apply the concept of “mutual recognition”, i.e., acceptance of the jurisdiction of a regulatory decision made by another national regulatory authority or other trusted institution.⁵

Whether or not this “mutual recognition” is accepted depends on the “maturity level” of the NRAs of the countries involved. Only certificates issued by NRAs that operate with a maturity level 3 (stable, well-functioning, and integrated regulatory system) or 4 (regulatory system that operates at an advanced level of performance and continuous improvement), can be recognised, in accordance with the WHO's comparative assessment of regulatory systems.⁵

The batch release strategy recommended by the WHO was to recognise, accept, and trust the release certificates issued by the NRA or the National Control Laboratory (NCL) with maturity level 3 or 4 of those countries where the manufacturing of vaccines was to take place, aimed at reducing the number of independent tests in each batch.⁶

Release of vaccine batches against COVID-19 in Mexico

The Federal Commission for the Protection against Health Risks (COFEPRIS for its initials in Spanish) is the national regulatory agent in Mexico. It comprises different administrative units, among which is the Commission for Analytical Control and Expansion of Coverage (CCAYAC) where the NCL resides. This is the only authorised laboratory in the country to carry out the official analysis of vaccines that are to be administered in Mexico in both the public and private sectors, thereby guaranteeing their quality, safety and effectiveness, prior to the release of the batches.⁷

Following WHO recommendations, COFEPRIS was responsible for the control of COVID-19 vaccines, recognising the NRA/NCL certificates of the country of origin of the vaccine manufacturers approved by the WHO.⁴ Mexico partially manufactured 2 vaccines: Vaxzevria™, belonging to AstraZeneca, manufactured in Argentina-Mexico and Convidecia®, belonging to CanSinoBio manufactured in China–Mexico.

Since the last manufacturing stage was carried out in Mexico, specifically for these 2 vaccines, COFEPRIS was in-charge of executing the release of the batches. The process involved documentation and analysis, through the review of the summarised manufacturing protocols and with the batch-by-batch analysis carried out by the NCL.⁸ The Vaxzevria™ vaccine was authorised by the WHO at the end of 2021 for emergency use, the first of its kind produced in Latin America.⁹

National control laboratory of Mexico, CCAYAC

The CCAYAC has the necessary infrastructure to carry out the different tests required in the analysis of vaccines and medications. The activities carried out at the CCAYAC are supported by the Quality Management System, implemented under the ISO/IEC 17025:2018 (NMX-EC-17025-IMNC-2018) and ISO 9001:2015 (NMX-CC-9001- IMNC-2015) and complies with the requirements of Good Laboratory Practices issued by the WHO. In addition, it is an associate member of the WHO Network of National Control Laboratories for Biological Products (WHO-NCL Network for Biologicals), which provides technical certainty that the analytical results issued are reliable.⁷

Two groups of analytical methods exist for vaccine analysis: pharmacopeial methods, which are established based on the Pharmacopeia of the United Mexican States (FEUM) or pharmacopoeias of other countries; and non-pharmacopoeial methods, which are developed and validated by the product manufacturers.¹⁰

Pharmacopoeial methods are general methods that do not require validation, but only verify their applicability to the product under the operating conditions of the laboratory and based on the analytical method already implemented, resulting in rapid execution. However, for the implementation of non-pharmacopoeial methods, the method developer is required to perform and document the validation, indicating all the tests performed that support the suitability of the method for their particular needs.¹⁰ The technological transfer of the analytical method is a requirement of validation and this process qualifies a laboratory (the receiving laboratory) to use an analytical method that originated elsewhere (the transferring laboratory), for which close collaboration is required between both entities until acceptance by the receiving laboratory is achieved. The NCL of the CCAYAC is in charge of receiving the methodological transfers from the different manufacturers. This process lasts between 12 and 18 months, between the first contact with the manufacturer and the launch of the first batches.

Importance of the National Control Laboratory of Mexico in the face of the COVID-19 pandemic

The COVID-19 pandemic represented a major challenge for NRAs and NCLs to guarantee the quality, safety, and efficacy of these new vaccines against SARS-CoV-2, in view of the different technological platforms used for their manufacture.

The SARS-CoV-2 vaccines combine platforms that have been used in other existing vaccines, such as inactivated viruses and virus subunit-based vaccines, with the use of newer technologies, such as viral vectors and messenger ribonucleic acids.^11,12 Each type of vaccine requires specific methods for its evaluation.

Faced with this challenge, the NCL of the CCAYAC carried out the implementation of the different test methods for the evaluation of vaccines based on viral vectors, in a short period of time, while continuing to comply with the requirements established by national and international regulations to evaluate the so-called critical quality attributes (CQAs),^13,14 which guarantee that the released product is manufactured correctly. For Mexico, the CQAs are regulatory in nature and are established in the FEUM.¹⁵

The transfer of analytical methodologies for the analysis of vaccines against SARS-CoV-2 involved a series of coordinated actions of a scientific, technical, material, and human nature by the NCL of the CCAYAC, while at the same time, the vaccine manufacturers were still in the process of verification or validation of these methodologies within their own laboratories (Table 1). The joint work between the NCL and the manufacturers was therefore of utmost importance.

Table 1.

Analytical methods transferred to the Commission for Analytical Control and Expansion of Coverage (CCAYAC).

Analytical method	Foundation
AstraZeneca, Vaxzevria™ vaccine
Infectivity	Infectious units in cell line
Spike and Flank gene identity	Quantitative real-time PCR
Viral particle concentration	AEX-HPLC
DNA protein ratio	AEX-HPLC
Polysorbate 80 Concentration Detector	HPLCwith detector (ELSD)
CanSino, Convidecia® Vaccine
Adenoviral vector identity	PCR
Target gene identity	PCR
AAV	PCR
VP	UV spectrophotometry
Target antigen expression	Western Blot
IFU	Infectious units in cell line

AAV: quantification of associated adenovirus; IFU: infectious viral titre; PCR: polymerase chain reaction; UV: ultraviolet; VP: viral particle.

This study consisted of identifying which methods needed to be transferred for the analysis of the finished product, as well as what supplies, equipment, infrastructure, human capital, and training were required to be able to carry out the analysis of these new vaccines. An important factor that had to be resolved was not having established reference materials for quality control of the different vaccines against SARS-CoV-2, so the NCL of the CCAYAC established internal controls to ensure reliability of results. Parameter trend data for each vaccine batch analysed was critical to identifying any changes in product consistency. The COVID-19 pandemic tested the laboratory's response capacity and resilience, as it had to demonstrate its adaptability to new global demands and circumstance, optimising spaces, supplies, personnel, times, processes, and operating procedures. This rapid adaptation was accomplished by taking advantage of the capabilities, experience, knowledge, and skills acquired over time by the laboratory personnel, achieving the analytical transference of 11 methodologies (Table 1). (Vaxzevria™ 5 methodologies and Convidecia,® 6 methodologies) in an average time of 4 months, compared to the 12–18 months that the process routinely lasts. With this decrease in response time, the NCL collaborated to achieve vaccination coverage in the Mexican population, as well as in the population of other Latin American countries through the release of safe, effective, and quality vaccines.¹⁶

The modernisation of test methods for the evaluation of vaccines against SARS-CoV-2 represented a challenge for the NCL of the CCAYAC and COFEPRIS itself, since it required a greater investment of material and human resources, together with scientific and technological updates, and its incorporation into the framework of viral vector vaccines of the FEUM.

The work carried out by the CCAYAC in the face of the COVID-19 pandemic opened new windows of opportunity for technical and technological innovation within the institution. Emerging technologies such as computational modelling and bioinformatics are changing the way analytical methods are designed and validated. In addition to this is the availability of open source protocols, free exchange of appropriate controls/standards to enable comparative evaluation of results between laboratories and the rapid dissemination, and publication of research referring to analytical tools. However, a limitation of these technological platforms is the technical knowledge and infrastructure required to perform these analyses. As a result, training in these areas, increasing availability and access to computer platforms and other specialised equipment foster opportunities for the modernisation and future application of these evaluation methods for other vaccines with the same and/or different technological platforms.

Conclusion

The health emergency generated by the COVID-19 pandemic created several challenges for NRAs and NCLs to guarantee public health. Among these challenges was the transfer and validation of methodologies for the analysis of new vaccines to ensure that they met the safety, quality, and effectiveness requirements that would protect the population. This health emergency caused the appearance of a large number of vaccines for COVID-19 and different methodologies for analysing them, for which a flexible workforce and constant communication with manufacturers was essential to achieve a successful methodological transfer and validation.

The NRAs and NCLs, such as the CCAYAC, have experienced personnel and may make the most of their capabilities, experience, knowledge, and skills acquired over time,. This is essential for shortening technical transfer periods, demonstrating the adaptability that all NCLs must have in order to deliver a timely response. Thus, it is clear that the technical, technological, and knowledge capabilities of laboratories must be strengthened so that the NRAs can provide an immediate response and offer the population with a means of protection in the face of a health emergency such as COVID-19.