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Abstract

Introduction:

Although the United States and other countries have implemented comprehensive legislation, regulations, and policies to support biosafety and biosecurity of high- and maximum-containment laboratories, Brazil's legislation has notable gaps and inconsistencies.

Objective:

To evaluate the Brazilian approach to ensuring nationwide biosafety and biosecurity oversight and governance of high- and maximum-containment laboratories.

Methods:

A systematic gap analysis was conducted to compare Brazilian biosafety and biosecurity legislation, regulations, and policies with their international counterparts, with a particular focus on the oversight and governance of high- and maximum-containment laboratories.

Results:

We found that Brazilian biosafety and biosecurity legislation, regulations, and policies have relevant gaps. Governance and regulatory oversight of Brazil's high- and maximum-containment laboratories are decentralized with variable levels of adherence to commonly accepted global biosafety and biosecurity compliance standards. These findings represent a limitation not only to governance but also to the preparedness to face current and future challenges related to emergent infectious diseases in Brazil. Enhancing the Brazilian legal framework on laboratory biosafety and biosecurity is necessary and urgent. Reviewing the lessons learned and regulations applied in the United States and other international frameworks helped identify potential areas for improving Brazil's ability to inventory and manage its diverse biocontainment laboratory capabilities and assure these valuable resources align with national needs and priorities.

Conclusion:

The Brazilian government has an opportunity to revise and improve upon a national set of legislation, regulations, and policies for its high- and maximum-containment laboratories, taking advantage of legislation and guidelines published by other countries.

Introduction

United Nations Security Council Resolution (UNSCR) 15.40 was adopted unanimously in 2004 regarding the nonproliferation of weapons of mass destruction. Countries can comply with UNSCR 15.40 by implementing laboratory biosecurity measures that secure biological weapons source materials in bioscience facilities.¹

The World Health Organization (WHO) defines laboratory biosafety as containment principles, technologies, and practices implemented to prevent unintentional exposure to biological agents or their inadvertent release, whereas biosecurity aims to prevent their unauthorized access, loss, theft, misuse, diversion, or release. The combination of physical design parameters and operational practices that protect personnel, the immediate work environment, and the community from exposure to biological agents is known as “biocontainment.”²

The Brazilian Standard for Public Health Laboratory approved by the Ministry of Health (Ministério da Saúde; MS) through Ordinance 3,204/2010,³ defines biosafety level (BSL) as the level of containment required for working with biological agents and handling animals in a way that is safe for humans, animals, and the environment. The General Guidelines for Work in Containment with Biological Agents,⁴ a complimentary document of Ordinance 3,204/2010, addresses the requirements for four BSLs, with BSL-3 and BSL-4 considered as high- and maximum-biocontainment laboratories, respectively.

The nature and scope of the regulatory arrangements for assuring laboratory biosafety and biosecurity are extremely diverse worldwide. Some countries have highly developed regulatory systems, with detailed legislation backed up by robust regulatory bodies and stakeholders, each with well-defined responsibilities and processes.⁵ In other countries, there are gaps in regulations and shortfalls in the technical and financial resources required to maintain an adequate biosafety and biosecurity infrastructure.⁶

The Brazilian regulatory framework on high- and maximum-containment laboratories has relevant gaps, including the absence of definitions and requirements related to laboratory biosecurity.^7–10 In contrast, the United States, Canada, Australia, and the European Union (E.U.) deployed comprehensive legislation, regulations, and policies that could serve as possible models to be adapted to the Brazilian context.

This study aimed to evaluate Brazilian regulations on high- and maximum-containment laboratory biosafety and biosecurity to identify the main gaps and opportunities while considering the legal frameworks established in the United States and other countries.

Methods

A thorough gap analysis was conducted to compare Brazilian biosafety and biosecurity regulations with those of other countries, focusing on the oversight and governance of high- and maximum-containment laboratories. In addition to examining legislation and complementary documents obtained from governmental websites and official reports, valuable insights were gathered through a comprehensive literature review. The current study does not require submission for Institutional Review Board review, since it does not involve human participant interactions.

Legal Framework for Biosafety and Biosecurity in Brazilian High- and Maximum-Containment Laboratories

The Brazilian “Biosafety Law” and related regulations^11–13 internalized the Cartagena Protocol on Biosafety to the Convention on Biological Diversity, establishing biosafety rules and ways to inspect the activities related to Genetic Modified Organisms (GMOs). Furthermore, it created the National Council for Biosafety, restructured the National Technical Committee for Biosafety, and defined the National Biosafety Policy. The current policy does not acknowledge or consider the myriad of biosafety and biosecurity risks beyond GMOs, nor does it explicitly offer guidance defining policies or practices to promote broader laboratory biosafety and biosecurity across Brazil.^7,8,10,14

The ordinance that addresses the broader issue of governing biosafety and biosecurity risks was released by the MS in 2010 and established the Brazilian Standard for Public Health Laboratories.³ It requires that laboratories have an Internal Biosafety Commission (IBC) and a Biosafety Policy outlined in a Biosafety Manual. In addition, public health laboratories are expected to establish the appropriate BSL based on a thorough risk assessment and in compliance with the General Directives for Containment Work with Biological Agents.⁴ This document is considered a normative reference, as the standard stipulates that all policies and procedures related to laboratory biosafety must align with this guideline or any other document that may replace it. MS has also published a translated version of the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories (BMBL) 4th Edition,¹⁵ but this document does not have a normative role.

Considering that both the ordinance and the guideline were released in 2010, they do not integrate into the most recent concepts and recommendations from the 4th edition of the WHO Laboratory Biosafety Manual (2020),² the 6th Edition of the BMBL (2020),¹⁶ or other relevant international guides and standards.

Another relevant MS Ordinance classifies biological agents into four risk groups, highlighting that there is not always a direct correlation between the microorganism risk group and the BSL required to handle it since some procedures may require higher or lower containment.¹⁷ For example, no proliferative diagnostic methods for Mycobacterium tuberculosis (a risk group 3 pathogen) can be carried out in a BSL-2 laboratory, whereas handling significant volumes of Trypanosoma cruzi (a risk group 2 pathogen) requires a BSL-3 laboratory. It is worth mentioning that risk groups are typically attributed to the “risk to humans.” Some agricultural (or plant) pathogens can belong to a low-risk group to humans, but their environmental, animal health, or potential for adverse trade consequences demand a higher containment level.

The MS regulation and guidelines related to laboratory biosafety do not apply to veterinary laboratories, as they are overseen by the Ministry of Agriculture (Ministério da Agricultura e Pecuária; MAPA). The MAPA released a list of notifiable diseases,¹⁸ but unlike the MS, it has not defined the pathogens' risk groups. The only law that addresses veterinary laboratory biosafety and biosecurity requirements is for handling foot-and-mouth disease (FMD) virus.¹⁹ This is the most comprehensive national regulation on laboratory biosafety and biosecurity, including infrastructure, equipment, and procedural requirements. It serves as the legal framework for MAPA's inspections of Brazilian facilities that manufacture FMD vaccines.

The Brazilian Government (BRG) has internalized the Biological and Toxin Weapons Convention commitments and the UNSCR 15.40. However, the legal framework related to biodefense^20–22 does not explicitly address high- and maximum-containment laboratories biosafety and biosecurity in Brazil. The current legislation defines a procedure to monitor the export of biological, chemical, and radiological materials of concern determined by the BRG and equipment related to their proliferation.^23,24

The Ministry of Science, Technology, and Innovation (Ministério da Ciência, Tecnologia e Inovação; MCTI) is in charge of elaborating guidelines and other documents related to this issue, including a list of controlled biological agents, which is available on the MCTI website.²⁵ Although this is similar to the American biological select agents and toxins list, it is not used to regulate laboratories' operations but only for transit control. Other national regulations related to biological laboratories include the transportation of biological agents, waste treatment, occupational health, and animal care (Table 1).

Table 1.

Primary legislation and guidelines relating to biosafety and biosecurity in the United States, Canada, and Brazil

Subject	Brazil	The United States	Canada
Select Agent Program	—	7 CFR Part 3319 CFR Part 12142 CFR Part 73	Canadian Biosafety Standard (2022)—SSBA program
Laboratory Biosafety and Biosecurity and Good Laboratory Practice	Law 11,105/2005Decree 5,591/2005Ordinance 3,204/2010—Ministry of HealthGeneral Guidelines for Work in Containment with Biological Agents (2010)—Ministry of HealthNormative 5/2012—Ministry of Agriculture	21 CFR 58NIH Guidelines (2019)BMBL (2020)	Human Pathogens and Toxins ActHuman Pathogens and Toxins RegulationsCanadian Biosafety Standard (2022)Canadian Biosafety Guideline—Pathogen Risk Assessment (2018)Canadian Biosafety Guideline—Conducting a Biosecurity Risk (2018)
Construction requirements for high-biocontainment laboratories	—	ARS Facilities Design Standards (2002)NIH Biosafety Level 3 Laboratory Certification Requirements (2006)NIH Design Requirements Manual (2016)	Canadian Biosafety Handbook (2016)Containment Standards for Facilities Handling Plant Pests (2014)Containment Standards for Facilities Handling Aquatic Animal Pathogens (2013)
Risk Group Classification	Ordinance 3,398/2021—Ministry of Health	NIH Guidelines (2019)BMBL (2020)	Human Pathogens and Toxins Act https://health.canada.ca/en/epathogen https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment.html
Dual use research	—	P3CO policyNRC Responsible research with biological select agents and toxins (2009)NIH Tools for the Identification, Assessment, Management, and Responsible Communication of Dual Use Research of Concern (2014)	Plan for Administrative Oversight for Pathogens and Toxins in a Research Setting—Required Elements and Guidance
Transportation of biological agents	Resolution RDC 20/2014—ANVISA/Ministry of HealthGeneral Guidelines for Work in Containment with Biological Agents (2010)—Ministry of HealthSupplementary instruction 175-004D approved by Ordinance 4,497/SPO/2021—ANAC/Ministry of TransportationDangerous Goods Regulations—IATA	49 CFR 171-18042 CFR 71.54USDA Guideline 11257 CFR Part 3319 CFR Part 12142 CFR Part 73Dangerous Goods Regulations—IATA	Transportation of Dangerous Goods Act/1992 and RegulationsDangerous Goods Regulations—IATA
Export/import of biological agents	Normative 29/2010—Ministry of AgricultureLaw 13,123/2015Decree 8,772/2016Resolutions RDC 81/2018 and 208/2018—ANVISA/Ministry of Health	15 CFR 738, 742, 745 and 774	Human Pathogens and Toxins ActHuman Pathogens and Toxins RegulationsHealth of Animals ActHealth of Animals Regulations
Bioterrorism preparedness and biodefense	Decree 77,374/1976Law 9,112/1995Decree 2,977/1999Decree 7,722/2012Decree 9,573/2018Decree 10,569/2020Decree 11,200/2022Normative 2,312/2023 (Ministry of Defense)	Public Law 107-56 (2001)Public Law 107–188 (2002)Homeland Security Directive9 (2004)National Biodefense Strategy (2018)	Plan for Administrative Oversight for Pathogens and Toxins in a Research Setting—Required Elements and GuidanceBiological Weapons Convention Meeting of States PartiesNovember 2021—National Statement of CanadaFederal/Provincial/Territorial Public Health Response Plan for Biological Events
Waste treatment	Law 12,305/2010Resolution CONAMA 430/2011—Ministry of EnvironmentResolution RDC 222/2018—ANVISA/Ministry of Health	NIH Guidelines (2019)BMBL (2020)29 CFR 1910.1030	Canadian Biosafety Standard (2022)
Occupational health	Ordinance 485/2005, approving the Regulatory Standard 32—Ministry of Employment	29 CFR 1910.120, 132, 133, 134, 136, 138, 1030, 1200, 1450	Canada Occupational Health and Safety Regulations (SOR/86-304)
Animal care	Law 11,794/2008	Guide for the Care and Use of Laboratory Animals (2011)Guide for the Care and Use of Agricultural Animals in Research and Teaching (2020)	Provinces' legislations

ANVISA, Brazilian Health Regulatory Agency; BMBL, Biosafety in Microbiological and Biomedical Laboratories; CFRs, Code of Federal Regulations; CONAMA, National Environment Council; NIH, National Institutes of Health; NRC, National Research Council; P3CO, Potential Pandemic Pathogen Care and Oversight; SSBAs, Security Sensitive Biological Agents.

The Brazilian legal framework has critical gaps that need to be addressed. It is outdated and mainly focuses on GMOs. There are no oversight mechanisms in place beyond self-regulation. There is currently no official data available regarding laboratories that handle high-risk pathogens, nor is there an inventory in place that would allow the BRG to be aware of which pathogens are stored in these laboratories and who is responsible for their handling. The Standard for Public Health Laboratories only applies to the National System of Public Health Laboratories, which supports national health surveillance programs. There is little emphasis on capacity-building programs. The legal framework does not address the IBC competencies, such as reviewing risk assessments. There is little emphasis on laboratory biosecurity. Finally, the risk group classification is limited to human pathogens, and toxins are omitted.

The Brazilian regulation lacks governance mechanisms pertaining to Dual Use Research of Concern (DURC), such as those addressing pathogen gain-of-function, as well as any framework for monitoring laboratories handling high-risk pathogens, including those with pandemic potential.

Despite the regulatory limitations, BRG is demonstrating a commitment to Biosafety and Biosecurity. The primary evidence is the inclusion of this matter in the list of priority areas for Brazilian strategic critical infrastructures, together with Energy, Financial, Telecommunication, Transport, and Water, to be overseen by the Foreign Affairs and National Defense Board, chaired by the Institutional Security Office of the Presidency of the Republic.²⁶ One of the advancements achieved since then was the elaboration of a National Policy for Biosafety and Biosecurity (to be released) and the decision to build a National BSL-4 laboratory.²⁷ The National Safety Plan for Critical Facilities was also launched, requiring the MS to create a safety plan and strategic actions for laboratories. This plan should include a capacity-building plan and mechanisms to oversee and protect high- and maximum-containment facilities.²⁸

Legal Framework for High- and Maximum-Containment Laboratory Biosafety and Biosecurity in Other Countries

The United States

The Federal Select Agent Program (FSAP), which was first established within the Antiterrorism and Effective Death Penalty Act of 1996, is one of the fundamental regulations for laboratory biosafety and biosecurity in the United States. The 2001 terrorist attacks increased the United States Government's (USG) interest in the threat of bioterrorism. Congress enacted the USA PATRIOT Act and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, which increased restrictions on handling pathogens and toxins identified as possessing the most significant potential for malicious use.²⁹ More details on this legal framework's motivations, deployment, and evolution are available in the literature.^30,31

The FSAP is detailed in the following Code of Federal Regulations (CFRs): 7 CFR Part 331,³² 9 CFR Part 121,³³ and 42 CFR Part 73³⁴ focused on plant health, animal health, and human health, respectively, and identifying the most dangerous pathogens as “Tier 1.” Some overlapping pathogens associated with zoonotic diseases are listed in the 9 CFR Part 121 and 42 CFR Part 73. According to the regulations, any individual or entity intending to possess, use, or transfer a biological select agent and toxin must obtain a certificate of registration from either the Centers for Disease Control and Prevention (CDC) Division of Select Agents and Toxins for human pathogens and toxins or the Animal and Plant Health Inspection Service of the United States Department of Agriculture (APHIS/USDA) Division of Agricultural Select Agents and Toxins for animal pathogens and toxins.

In the case of overlap agents, it is possible for entities to be jointly overseen by both agencies if they are registered with one lead agency but also hold registration for an agent or toxin regulated solely by the other agency. Each entity registered with the FSAP must designate a responsible official as the person responsible for assuring compliance with all FSAP requirements on behalf of the institution.

The process for obtaining and then maintaining FSAP registration is complex and requires institutional support from the top leadership. Each registered entity must develop and implement a written biosafety plan. Other requirements present in the regulations include an occupational health program for individuals with access to “Tier 1” biological select agents and toxins; a security plan to be designed according to a site-specific risk assessment; a written incident response plan (with more detailed information for “Tier 1” agents); training on biocontainment, biosafety, security, and incident response; authorization provided by FSAP to transfer a biological select agent or toxin; keeping complete records, including inventory for each biological select agent or toxin; immediate notification of theft, loss, or release of a biological select agent or toxin. The regulations state that the U.S. Department of Health and Human Services (HHS) and APHIS can inspect the sites and records without prior notification.

Overall, most of the 233 entities registered with FSAP comply with the regulations, as evidenced by the small number of compliance issues identified in the 2021 report. In addition, none of the releases resulted in illness, death, or transmission among workers or outside of a laboratory into the surrounding environment or community. With oversight from FSAP, entities continue to work as safely and securely as possible.^35,36

Nevertheless, the FSAP has limitations, for example, high- and maximum-containment laboratories that do not handle biological select agents and toxins are omitted. Other criticisms from the scientific community include the regulatory burden on researchers and institutions, especially related to the accurate inventory of individual vials containing biological select agents and toxins, the red tape to transfer biological materials, and the requirement to develop and maintain a skilled workforce.³⁷ Therefore, the laboratory has substantial additional costs.

The USG released a policy for DURC based on the premise that certain types of research conducted for legitimate purposes can be utilized for both benevolent and harmful purposes. The DURC policy delineates the roles and responsibilities of government funding agencies, research institutions, and scientists. It provides requirements and performance standards for reviewing life sciences research, identifying potential DURC, and developing and implementing risk mitigation measures for DURC, where applicable. Noncompliance with this policy may result in suspension, limitation, or termination of USG funding.³⁸ This kind of initiative is encouraged by WHO, which stated: “Robust biorisk management relies on three core pillars: biosafety, laboratory biosecurity and the oversight of DURC.”³⁹

The USG created the National Science Advisory Board for Biosecurity (NSABB), a Federal advisory committee that addresses issues related to biosecurity and DURC at the USG's request. The NSABB provides advice on and recommends strategies for the efficient and effective oversight of federally conducted or supported DURC, considering national security concerns and the research community's needs to foster continued progress in public health and agricultural research.⁴⁰

In 2017, the HHS released the Potential Pandemic Pathogens Care and Oversight (P3CO) policy, requiring that an HHS panel review any National Institutes of Health (NIH)-funded study with the potential to generate an enhanced version of a pathogen that is highly virulent, highly transmissible, and might cause a pandemic. In February 2022, NIH asked NSABB to broaden an existing review of the P3CO policy.⁴¹ NSABB recognized that the P3CO framework is more flexible than DURC policy and allows for the identification of research involving enhanced potential pandemic pathogens from a much broader swath of life sciences research. However, the absence of a list circumscribing the oversight scope similar to the approach applied in the DURC policies has the potential to introduce a degree of uncertainty as to what is covered.⁴²

Other regulations and guidelines related to activities carried out in biological laboratories include certification and construction standards for high-biocontainment laboratories (e.g., the NIH Design Requirements Manual⁴³ and the USDA ARS Facilities Design Standards⁴⁴), transportation, export, and import of biological agents, waste treatment, occupational health, and animal care (Table 1).

Canada

The Human Pathogens and Toxins Act,⁴⁵ the Human Pathogens and Toxins Regulations,⁴⁶ the Health of Animals Act,⁴⁷ and the Health of Animals Regulations⁴⁸ are the primary legislation related to the handling of pathogens and toxins in Canada, and they are complemented by guidelines and manuals.

According to this legal framework, possessing, handling, using, producing, storing, permitting access, transferring, importing, exporting, releasing, and disposing of a human pathogen (risk group 2 or higher) or toxin is considered a controlled activity that requires a license issued by the Federal government. Accessing risk groups 3 and 4 pathogens require an individual security clearance. Licensed facilities shall designate a biosafety officer.

The license also permits the importation and subsequent transfer of indigenous terrestrial animal pathogens under the Health of Animals Act. The government designates inspectors, who may examine the laboratory and any material or equipment, among other activities carried out during the audits.

The Canadian Biosafety Standard⁴⁹ is used by the human and animal health authorities to verify the ongoing compliance of regulated facilities and individuals with applicable legislation, supporting license applications, renewals, animal pathogen import permit applications, and, where applicable, facility certification and recertification of containment laboratories. The Canadian Biosafety Handbook⁵⁰ is a companion document to the Canadian Biosafety Standard that provides core information and guidance as to how the biosafety and biosecurity requirements can be achieved.

All license applicants looking to conduct scientific research with pathogens and toxins must submit a Plan for Administrative Oversight describing how biosafety and biosecurity risks will be managed. The plan should demonstrate how institutions or organizations identify, assess, and manage research activities with dual-use potential.⁵¹

As of March 2019, there were 986 licenses issued (916 for risk group 2 pathogens, 65 for risk group 3, 2 for risk group 4, and 3 for toxins) and 439 people with a security clearance required to work with the risk groups 3 and 4 pathogens.⁵²

The Canadian Biosafety Standard defines Security Sensitive Biological Agents (SSBAs) as human pathogens and toxins that pose an increased biosecurity risk due to their inherent dual-use potential. SSBAs are all risk group 3 and 4 human pathogens that also appear on the List of Human and Animal Pathogens and Toxins for Export Control, published by the Australia Group, except for Duvenhage virus, Rabies virus and all other members of the Lyssavirus genus, Vesicular stomatitis virus, and Lymphocytic choriomeningitis virus. A similar criterion is applied to toxins. There are unique requirements for SSBAs and toxins at any containment level.⁴⁹ Information regarding risk groups and SSBAs for humans and animals is online available.^53,54

The main shortcoming of the Canadian legal framework is the excessive number of facilities involved in the oversight process, which can be addressed by adopting a risk-based approach and implementing prioritization criteria.

Other countries

In the E.U., Directive 2000/54/EC⁵⁵ is widely used as a reference document for the definition of policies and procedures related to laboratory biosafety and biosecurity as well as certain CEN Workshop Agreement (CWA) documents (e.g., CWA 16335—Biosafety professional competence). However, some countries have established complementary instructions, resulting in a lack of harmonization in the implementation of the guidelines. Some countries have adopted additional references such as the U.S. BMBL and Canadian manuals.⁵⁶

Among E.U. countries, Germany and Switzerland have the most comprehensive legislation on laboratory biosafety and biosecurity. German directives provide detailed construction requirements and establish minimum criteria to be met by the principal investigator and biosafety officer. Laboratories are required to submit an annual report to the government, which conducts annual inspections and certifications.⁵⁶

In Switzerland, laboratories that handle pathogens of risk group 2 must notify their activities to the government, whereas those handling risk group 3 and 4 agents must apply for an operating license.⁵⁶

The United Kingdom carries out systematic monitoring of high- and maximum-containment laboratories through Great Britain's Health and Safety Executive, which is the only regulatory body in the country for laboratory biosafety and biosecurity. This brings benefits in terms of standardization of procedures and legislation and avoids duplication of control, resulting in less bureaucracy for laboratories handling pathogens of human and veterinary interest. Inspections are prioritized according to a risk analysis that considers the degree of risk of the pathogen, how it is handled in the laboratory, and the impact of a possible incident. In this sense, diagnostic laboratories are audited less frequently than research laboratories.⁵⁷

Australia has its SSBA program established according to the National Health Security Act.⁵⁸ The list of sensitive biological agents is available online.⁵⁹ The Federal government maintains a National Register of SSBA, which includes the identification of each entity, the agents handled, and the purpose of possessing each SSBA. The SSBA Standard⁶⁰ are requirements for nonexempt entities to ensure the oversight of biological agents of security concern in Australia. These standards set out the physical, personnel, transport, information management, inactivation, and decontamination security requirements for nonexempt entities when handling SSBAs and biological agents suspected of being SSBAs. The registered laboratories are inspected according to the premises stated in the National Health Security Act and to the requirements described in the SSBA Standards.

Lessons to Be Applied to the Brazilian Scenario

Table 1 summarizes the primary legislation and guidelines on biosafety and biosecurity in the United States, Canada, and Brazil. Some topics such as transportation, import, and export of biological agents, waste treatment, occupational health, and animal care seem to be well addressed in all scenarios. Brazilian regulations should be updated and improved, taking advantage of experiences from other countries that could be adapted to the national context, to strengthen laboratory biosafety and biosecurity measures, standardizing definitions and requirements, minimizing the risks of laboratory-acquired infections and other accidents that could result potentially lead to the release of high-risk pathogens with severe implications for public and animal health.

The main gaps are detailed in Table 2. Considering that the BRG is preparing a security plan and strategic actions for Laboratory Biosafety and Biosecurity, the time is suitable to address crucial gaps, especially the lack of high- and maximum-containment laboratory oversight. In this sense, the following questions must be addressed in establishing a national biological laboratory monitoring program.⁶¹

Table 2.

Opportunities to improve the Brazilian legal framework on laboratory biosafety and biosecurity

Element	Legislation			Main gaps	Possible models from other regulatory frameworks
Element	Type/number	Source	Coverage	Main gaps	Possible models from other regulatory frameworks
The National Biosafety Policy	Law 11,105/2005	National Congress	Overall	Limited to Genetic Modified OrganismsBiosecurity is not addressed	Canadian Human Pathogens and Toxins RegulationsU.S. Federal Select Agent ProgramAustralian SSBA
Biocontainment Laboratories Oversight	Ordinance 3,204/2010 and complimentary guideline	MS	Public Health Laboratories	Out of dateLimited to public health laboratoriesLittle emphasis on biosecurityTechnical staff capacity-building is not addressed.Little emphasis on the Internal Biosafety Commission's competencies	U.S. BMBLAustralian SSBA StandardsCanadian Biosafety StandardCanadian Biosafety HandbookCanadian Biosafety Guideline—Pathogen Risk AssessmentCanadian Biosafety Guideline—Conducting a Biosecurity RiskE.U. Directive 2000/54/EC
Risk Group Classification	Ordinance 3,398/2021	MS	Overall	Limited to human pathogensToxins are omitted.	Canadian pathogen safety data sheet
Veterinary Biocontainment Laboratories	Normative 5/2012	Ministério da Agricultura e Pecuária	FMD virus handling	Out of dateLimited to FMD virus	U.S. BMBLAustralian SSBA StandardsCanadian Biosafety StandardE.U. Directive 2000/54/EC
Biodefense	Decree 2,977/1999 and correlated legislation	Presidency of Republic	Overall	DURC is omitted.	U.S. P3CO policyU.S. Policy for Institutional Oversight of DURC
National Safety Plan for Critical Facilities	Decree 11,200/2022	Presidency of Republic	Overall	Regulation for high- and maximum-containment laboratories biosafety and biosecurity is needed.	U.S. BMBLAustralian SSBA StandardsCanadian Biosafety StandardCanadian Biosafety HandbookE.U. Directive 2000/54/ECISO 35,001:2019

DURC, dual use research of concern; E.U., European Union; FMD, foot-and-mouth disease; MS, Ministério da Saúde; SSBA, security-sensitive biological agent.

Who should do the monitoring? Is there critical infrastructure support for a monitoring program?

Although the MS is responsible for the creation of a security plan and strategic actions for Laboratory Biosafety and Biosecurity in Brazil, a multidisciplinary and interinstitutional approach should be considered since there are biosafety experts not just in this service, but also in other governmental bodies, such as MAPA, MCTI, Ministry of Defense, Federal Police, Brazilian Intelligence Agency, and Public Universities.

Representatives from these organizations have the potential to make valuable contributions to the MS in developing the regulatory framework and can also actively participate as inspectors in the monitoring program.

The number of professionals and the amount of time they would dedicate to the program should be addressed. Taking this as a reference, the CDC had 51 inspector positions for FSAP in 2017, whereas APHIS had 11 at that time.⁵⁷

What should be the program focus, and who should be monitored?

The U.S. FSAP and Australian SSBA programs are based on microorganisms that can be used as bioweapons and/or of potential agricultural and trade impact, as seen in many other countries, although the list of biological select agents and toxins varies between them.¹ A limitation of this approach is that not all high- and maximum-containment laboratories are included in the monitoring program. The Canadian legal framework does not have such limitations as it covers all risk group 2 or higher pathogens. However, to prevent excessive burden on the system, the monitoring criteria vary for different risk groups, for example, facilities and personnel that handle SSBAs are subjected to more stringent requirements.

Given that bioterrorism seems not to be a great concern to the Brazilian context^8,62 (although this threat should not be underestimated), an approach that could be feasible is focusing the program on critical infrastructures, including the high- and maximum-containment laboratories themselves, instead of specific biological agents. Creating a comprehensive list of such facilities and gaining an understanding of the activities conducted within them is a crucial step in comprehending risks and the overall landscape and establishing criteria and oversight procedures.

In this strategy, the number of facilities to be registered and monitored would be higher than those that only handle pathogens that could be used as bioweapons. However, the frequency and kind of inspection should be defined according to a risk assessment, considering the risk group of microorganisms stored, laboratory purpose and scope, volume of samples received and/or supplies produced (e.g., vaccines and reagents), methods and equipment in use, complaints recorded by employees or customers, facility's age and size, location, usage of animal testing models, and so on. Ideally, the program would require that new or remodeled facilities be inspected before launching.

BRG should define if participation in the program would be voluntary or not. If voluntary, the benefits should be attractive, for example, restricting public grants to registered laboratories only.

Considering the successful experience of the United Kingdom in having the monitoring program centralized in one body and considering that the Brazilian MS was designated to elaborate the national safety plan and strategic actions for laboratories,²⁸ this body could create a working group with representatives from other ministries, especially MAPA, MCTI, and the Ministry of Defense to establish a central line of authority for the monitoring process.

How extensive should the monitoring be? What standards and requirements should be used?

Although on-site inspections are usually more comprehensive, one of the lessons learned during the COVID-19 pandemic was the benefit of remote work. Owing to travel restrictions, FSAP implemented hybrid inspections, including on-site (focused on laboratory and facility reviews) and remote inspections (focused on document review). U.S. FSAP will continue to refine the hybrid inspection process and expects this will become the primary method of inspecting facilities in the future. Of the 206 inspections conducted in 2021, 19 were on-site, 106 were remote, and 81 were hybrid, with an overall average length of 3 business days.³⁵

The extensive monitoring will depend on its aims (assessing compliance, initial registration, periodic regular inspections, etc.), the facility's complexity, and inspectors' availability. The success of an inspection depends on the expertise and training of the inspectors and their ability to follow the audit schedule.

Another aspect to be addressed is the availability and source of financial resources. In the fiscal year 2016, for instance, the CDC's budget to manage its component of the FSAP was about US$ 21 million, and APHIs' was about US$ 5.5 million.⁵⁷ It is essential to highlight that the number of entities registered in FSAP is more than two times the estimated number of self-declared BSL-3 laboratories in operation in Brazil—no more than 100.¹⁰ BRG should consider creating a specific budget source linked, for example, to MS or MCTI to meet the costs related to regulatory oversight.

Inspections must be based on objective criteria and/or comprehensive checklists, which is not well established in Brazilian legislation (except for FMD vaccine manufacturers). Although the country does not have its own guidelines and checklists, international references may be an acceptable alternative.

Another possible approach is focusing the monitoring program on evaluating the risk assessment carried out by the laboratories instead of emphasizing specific biological agents and toxins or structural features. The BRG could take advantage of ISO 35,001:2019,⁶³ incorporating it into the national legal framework and requiring the laboratories to follow it. The benefit of this approach is addressing the facilities and research specificities, which can demand higher or lower biosafety and biosecurity requirements beyond those considered in the traditional four laboratory BSLs.⁶⁴ In contrast, this approach requires a high level of training on risk assessment for both auditors and those being audited. Standardizing the monitoring process and avoiding subjective assessments would be more difficult. Another challenge would be defining criteria to decide which institutions should participate in the oversight program.

What are the consequences if a laboratory does not meet the requirements or is unwilling to comply?

For serious noncompliance, U.S. FSAP may refer entities to the HHS Office of Inspector General (OIG) or APHIS Investigative and Enforcement Services (IES) for further investigation and possible civil monetary penalties. The HHS-OIG can levy civil money penalties (for an individual up to US$250,000 and for an entity up to US$500,000 for each violation) or recommend criminal enforcement. Since 2015, three to seven entities have been referred to either HHS OIG or APHIS IES each year, except for 2019 and 2020, when only one entity was referred. In 2021, no entity was referred. FSAP notifies the Federal Bureau of Investigation (FBI) of any security-related issue identified and any report of a loss of a select agent. The FBI investigates the incidents to determine whether there is a criminal threat.³⁵

Great Britain, Canada, France, and Switzerland can pursue criminal prosecution in response to severe violations of their laws or regulations governing high- and maximum-containment laboratories. In Canada, penalties for severe violations can include up to 10 years in prison.⁵⁷

Brazilian authorities should define whether the monitoring process would focus on punitive sanctions (once compatible with the broader legal framework) or an educational approach (focused on providing capacity-building tools and guidance rather than punishments), assessing the pros and cons of each strategy. It is essential to highlight that depending on the requirements, restrictions, burden, and sanctions forced by the regulations, the cost and effort to operate a high- and maximum-containment laboratory can culminate in the discouragement of researchers from studying relevant infectious diseases, as observed in France, where many scientists have redirected their research to the study of attenuated strains that are not listed as controlled microorganisms.⁶⁵

Conclusions

BRG must establish a regulatory and monitoring program for high- and maximum-containment laboratories, considering the pillars of biorisk management: biosafety, biocontainment, and biosecurity. By strengthening the regulatory framework, the risks of laboratory-acquired infections would be minimized, as well as the occurrence of accidents that could potentially lead to the release of high-risk pathogens with significant implications for public and animal health.

The fundamental step in this pathway is to establish the minimum requirements to be followed by the high- and maximum-containment laboratories. The BMBL, WHO manual, or other international standards and guidelines can be used as a reference for this purpose. After that, it will be necessary to define if the country prefers adopting a biological select agents and toxins program, such as the U.S. FSAP or Australian SSBA, or a wider approach, including all biocontainment laboratories in the monitoring process, as established by the Canadian legal framework. Regardless, it is advisable to emphasize the relevance of risk assessment in biorisk management and the adoption of ISO 35,001:2019, or another international guideline, as a national standard.

The increasing private research on infectious diseases worldwide (and likely in Brazil) and the possible construction of a BSL-4 laboratory in the country reinforce the need to prove reliability to the international community. Having a more comprehensive regulation is an appropriate step for that. Enhancing the Brazilian legal framework on laboratory biosafety and biosecurity is necessary and urgent. Taking advantage of the lessons learned and regulations applied in other countries can be helpful if adjusted to the national context and priorities. The WHO “Guidance on implementing regulatory requirements for biosafety and biosecurity in biomedical laboratories”⁵ could be another powerful tool that the BRG can take advantage of during this regulatory improvement process.

The recent deployment of the Brazilian National Safety Plan for Critical Facilities marked a crucial milestone on the path toward strengthening the regulatory framework for high- and maximum-containment laboratories. However, the effectiveness of subsequent actions hinges on adopting a multidisciplinary and interinstitutional approach.

This approach should actively involve the scientific community and civil society throughout the entire process. It is essential to establish a balanced legal framework that ensures effective oversight without overwhelming institutions or discouraging research on high-risk pathogens.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research has been supported by the Project “Management and Governance in Biosafety,” Procad-Defesa, an initiative of the Coordination of Superior Level Staff Improvement (CAPES), and the Ministry of Defense, Brazil (Grant no. CAPES 88881.682224/2022-01).

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Comparison of Brazilian High- and Maximum-Containment Laboratories Biosafety and Biosecurity Regulations to Legal Frameworks in the United States and Other Countries: Gaps and Opportunities