High-Consequence Infectious Diseases,Bioterrorism,and the Imperative for International and US Biosecurity and Biosafety Frameworks for Biocontainment Clinical Laboratories

Abstract

Introduction

In an increasingly interconnected world, special pathogen diseases, whether naturally occurring or accidentally or deliberately released, pose significant challenges to global health security. High-level isolation units (HLIUs) are specifically designed to care for patients with suspected or confirmed special pathogen diseases (high-consequence infectious diseases [HCIDs]). HLIUs play a critical role not only in caring for and managing patients but also safely containing special pathogens to prevent wider spread. Often housed within designated hospitals, some HLIUs contain dedicated biocontainment clinical laboratories (BCLs) that provide biosafety level (BSL) 2 and 3 capabilities for clinical patient care activities. However, no established international biosecurity and biosafety framework exists for BCLs. This commentary examines this gap and the need for a standard approach to international biosecurity and biosafety BCL frameworks. The authors propose fundamental considerations, including risk assessment, personnel training and clearance, facility design, operational protocols, regulatory oversight, enforcement, and accreditation to help guide laboratories in establishing and strengthening BCL biosecurity and biosafety frameworks.

Role of Biocontainment Clinical Laboratories

BCLs play a pivotal role in the diagnosis and management of patients infected with special pathogens. Special pathogen diseases are acute infectious diseases that are associated with high morbidity and/or mortality; may have a high likelihood of secondary cases (person-to-person spread); can lack an effective vaccine, prophylaxis, or treatment; and pose a significant risk to healthcare personnel.¹ They have been described as HCIDs by other countries and regions using similar definitions/criteria.² Examples of special pathogen diseases include viral hemorrhagic fevers (eg, Ebola virus disease, Marburg virus disease, Lassa fever), severe respiratory diseases (eg, severe acute respiratory syndrome, Middle East respiratory syndrome [MERS]), and other HCIDs, including smallpox. The importance of BCLs has been underscored in the last decade by recent special pathogen disease cases—notably, the Ebola virus cases that were cared for at 4 US HLIUs, where timely and accurate diagnosis and/or ongoing clinical monitoring proved crucial for patient management.

Dedicated BCLs are often housed either within, adjacent to, or near HLIUs that care for patients with suspected or confirmed special pathogens. BCLs are specifically designed to handle and analyze, in a safe and controlled environment, samples from patients suspected or confirmed to be infected with highly pathogenic organisms. Although BCLs primarily function as diagnostic facilities and may not directly engage in research, the laboratory analysis and test results generated by BCLs contribute to research on treatment modalities and outcomes. In addition, BCLs serve as crucial nodes for monitoring the progress of diseases and the efficacy of treatments.

In the United States, BCLs are solely used for direct patient care. They are regulated and subject to requirements outlined by the Clinical Laboratory Improvement Amendments (CLIA) and local state departments of health. BCLs are not subject to the US Government Policy for Oversight of Life Sciences Dual Use Research of Concern³ or the Department of Health and Human Services’ Framework for Guiding Funding Decisions About Proposed Research Involving Enhanced Potential Pandemic Pathogens.⁴ There are no regulations outlining special requirements to work within a BCL, which differs from organizations such as blood banks that require an approved cooperative research and development agreement for material transfer with the Department of Defense. This type of agreement outlines requirements to comply with International Traffic in Arms Regulations,⁵ the United States Munitions List,⁶ and the Arms Export Control Act.⁷ It also requires the establishment of a list of authorized personnel who must meet the criteria for “US persons,” guaranteeing of limited or controlled access, creation of a technology control plan, and attestation by staff. For example, Warrior Panel test kits (BioFire, Salt Lake City, Utah) and controls must be protected, tracked, and autoclaved before disposal. Their state-of-the-art design integrates both engineering controls (eg, negative pressure spaces and specialized ventilation systems) and operational practices (eg, working in biosafety cabinets and wearing personal protective equipment) to prevent the release of or exposure to pathogens and ensure the safety and wellbeing of healthcare and laboratory personnel.⁸

Although no specific regulations address BCLs, a number of organizations have created tools to identify, assess, mitigate, control, and monitor risks. Further, existing regulations covering clinical laboratories address many of the same issues faced by BCLs, albeit to a differing degree. The International Organization for Standardization’s standard for biorisk management for laboratories and other related organizations, ISO 35001:2019, established a framework for continual improvement to assess, control, evaluate, and thereby minimize laboratory-associated infections, inadvertent releases, or other accidents or incidents.⁹ Government agencies, including the US Centers for Disease Control and Prevention and the National Institutes of Health, provide guidance on how to perform a collaborative risk assessment. The US Occupational Safety and Health Administration requires that all laboratories perform an annual risk assessment for each position in the laboratory. Many countries and states also have specific regulations addressing laboratory safety and biosafety, to which a BCL would be required to comply.

US clinical laboratory compliance with regulations is assured via biannual external inspections. Laboratories in the United States are subject to external inspections by many regulatory agencies and accrediting bodies, including the Centers for Medicare and Medicaid Services, Occupational Safety and Health Administration, state departments of health, College of American Pathologists, and the Joint Commission. In addition to external inspections, clinical laboratories are required to perform internal audits to ensure compliance. They also are expected to identify noncompliant practices and implement and sustain corrective actions. Laboratories that fail to comply with regulations risk losing their ability to perform testing. Successful external inspections are required to retain a clinical laboratory permit. Without a CLIA laboratory permit, a US clinical laboratory is not permitted to perform patient testing. When a BCL falls under a facility’s general clinical laboratory permit, it will be inspected along with the other clinical laboratories.

Although the principles of high-(bio)containment facilities in the United States tend to be similar, other countries with BCLs may differ in their operational approaches for laboratory support and services for HCIDs. For example, in the United Kingdom, some Advisory Committee on Dangerous Pathogens Hazard Group 3 HCID pathogens¹⁰ (eg, MERS, influenza A[H7] and A[H9] viruses, clade II mpox virus) can be detected in BSL-3 laboratories operating in hospitals across the United Kingdom (with confirmatory testing at UK Health Security Agency national reference laboratories). This can occur only when appropriately validated commercial detection assays are available, although hospital laboratories may sometimes use their own in-house assays under derogation. Most HCID pathogens in the United Kingdom, and certainly all Advisory Committee on Dangerous Pathogens Hazard Group 4 HCID pathogens,¹⁰ are detected by high-containment laboratories (including BSL-4 laboratories) located within 2 UK Health Security Agency specialist high-containment laboratories in Porton Down and London, England.

During larger, exceptional incidents, such as the 2014-2016 West Africa Ebola virus disease epidemics, temporary derogation may be assigned to hospital BSL-3 laboratories elsewhere in the United Kingdom to run approved detection assays. Otherwise, a centralized approach to the initial detection and subsequent monitoring is followed, which has benefits (eg, strict biocontainment, quality assurance, access to positive control material, concentration of experience and expertise in the pathogens/assays concerned, geographical risk panels that can detect a wide range of travel-associated pathogens) and drawbacks (eg, long distance transport of Category A samples to the laboratory, which can be slow and costly). Routine tests such as hematology and biochemistry assays are performed, with approved and audited biocontainment controls in place, at HCID treatment centers; the principal HLIU in London that manages adult cases of viral hemorrhagic fever has its own en suite high-containment laboratory for this purpose.¹¹ Other HCID centers in the United Kingdom perform routine clinical tests using a mixture of clinical point-of-care tests and tests that can be performed safely—with necessary risk assessments, operating procedures, and approvals in place—in hospital BSL-3 laboratories. The UK Health Security Agency provides guidance to assist hospitals to determine what tests can be performed safely according to the Advisory Committee on Dangerous Pathogens hazard group—for example, for samples from patients with MERS.¹² For samples from patients with viral hemorrhagic fever who are managed at centers other than the London HLIU, the range of tests that can be performed (in a hospital BSL-3 laboratory) is more limited. Additional restrictions may apply to the handling and storage of samples that contain pathogens that are subject to UK counterterrorism legislation.¹¹

The Gap in Biosecurity and Biosafety Frameworks in BCLs

In the United States, 13 regional healthcare facilities are HLIUs and an additional 63 are designated treatment centers.^13,14 As noted previously, not all HLIUs have BCLs. At the international level, it is unclear how many HLIUs and BCLs exist today or whether they are colocated. A 2009 cross-sectional study in 16 European countries identified at least 48 isolation facilities that manage highly infectious disease patients.¹⁵

HLIUs and BCLs play a pivotal role in disease containment and outbreak response and are critical global infrastructures. Without a standardized biosecurity and biosafety framework, however, their safety and effectiveness can be compromised. There have been some US biosecurity guidelines, but they are specific to certain pathogens. For example, the White House Executive Order 13486 established a working group that reviewed current guidance and practices for select agent laboratories^16,17 and the US Centers for Disease Control and Prevention and National Institutes of Health’s Biosafety in Microbiological and Biomedical Laboratories⁸ provides recommendations for biosecurity. Because no specific regulations address BCL and not all clinical laboratories have experience with high-consequence pathogens, it is possible that the inspector or inspection team performing the required biannual external inspection of clinical laboratories in the United States may fail to recognize or identify potential risks. Specially trained inspectors may be required to inspect BCLs to assure biosafety and biosecurity risks are properly judged.

Biosecurity measures are policies and practices implemented to prevent the intentional or negligent loss, theft, or deliberate misuse of biological materials or the acquisition of technology or research-related materials that could be used to cause harm.^8,17 An example of a biosecurity measure within a BCL is the implementation of controlled access systems. This can include card-key access controls or CCTV surveillance. Such measures ensure that only authorized personnel can access certain high-risk areas or sensitive biological materials, reducing the risk of theft, misuse, or intentional release of pathogenic agents.¹⁸ Even within secure areas, access to certain laboratory reagents or specimens containing or possibly containing special pathogens should be limited; this can be achieved using special refrigerators and freezers with locks. Limiting access to clinical information regarding a patient under investigation or confirmed with a special pathogen, while challenging, can be done via computer security levels.

On the other hand, biosafety measures are policies and practices implemented to provide a safe work environment and prevent the accidental release of biological materials.^8,17 An example of a biosafety measure within a BCL is the use of certified biosafety cabinets. Biosafety cabinets are ventilated laboratory equipment designed to protect the laboratory worker and the surrounding environment from biological materials used within the cabinet. All air exhausted from the biosafety cabinet is HEPA-filtered to remove biological agents such as viruses and bacteria, ensuring that only clean air is released into the environment. Proper usage and regular certification of biosafety cabinets are essential to maintain their efficacy and contribute to the safety of the laboratory environment.¹⁹

In the context of BCLs, both biosafety and biosecurity concepts are of paramount importance. Implementing biosafety measures provides assurance that hospital staff, patients, and the surrounding community are safeguarded from accidental infections originating from the BCL. Biosecurity measures safeguard diagnostic specimens (eg, blood or other body fluids or tissues of hospitalized patient with a special pathogen such as Ebola virus). Robust biosecurity and biosafety protocols are vital for the overall safety and security of the healthcare setting given the duration of care for patients with special pathogen diseases, which is often longer and more complex than care for nonspecial pathogen patients, and the ongoing volume and diversity of samples processed in BCLs where special pathogen agents are present.

Key Components of the Proposed Framework

There are many examples of guidance and frameworks for the management of biosafety in laboratories.⁹^,21 -27 However, very few are specifically written for BCLs. The Table offers a stakeholder view of areas that need additional oversight. The proposed considerations for a biosafety and biosecurity framework for BCLs serve as a starting point and should be integrated within existing international guidelines.^24,27 Our framework draws upon best practices, personal experiences, and well-established laboratory biosafety guidance in the United States, such as the Biosafety in Microbiological and Biomedical Laboratories,⁸ and international guidelines, including the World Health Organization’s Laboratory Biosafety Manual²¹; both examples serve as the US and global guidelines for risk assessment in biosafety. In terms of an international framework, it is possible for the principles of the CLIA regulations to be expanded internationally; however, it is important to recognize that the financial costs for this program may not be feasible in some countries with BCLs.

Table.

Key Considerations for US and International Biosecurity and Biosafety Framework for BCLs

Consideration	Description
Personnel management Training Competency Employee vetting/screening policy	Facilities must train and evaluate each staff member to provide them with the knowledge and skills to handle special pathogens safely and effectively. Training should include potential consequences of biosecurity breaches. Competency could be assessed using a variety of training tools; written, verbal, or online exams; and hands-on drills. These drills must include loss or theft, accident, and incident reporting and must be conducted periodically. Employee screening should be conducted to evaluate individuals who will work in the BCL, and periodic employee reviews should be conducted. Employee policies should include access procedures and incident and anonymous reporting.
Physical security Access control and monitoring Layered security system for entry and exit	Facilities should use security measures to prevent unauthorized access to the BCL and surveillance systems to monitor for potential breaches, theft, or misuse of samples. A patient sample logbook should be established to track samples. Security requirements should be established for any patient samples that are kept after the initial sample validation.
Transportation security Security of special pathogens in transit	Policies must outline how clinical samples will be transported from the HLIU to the BCL and within the BCL. In the United States, personnel must have appropriate shipping training that meets all US DOT and IATA requirements for special pathogens. Other countries should have their own equivalent requirements and guidance (eg, the UK Transport of Infectious Substances guidance²⁰).
Culture of safety and trust Open communication channels for reporting concerns Regular safety audits Accountability and transparency in laboratory operations	Facilities should create a culture of safety and trust through continuous training, open channels for reporting concerns, and routine safety audits. They should also ensure operational transparency and accountability. The safety program should be reviewed frequently, particularly after any incident.
Regulatory oversight Regular inspections Accreditations and certifications Enforcement mechanism for noncompliance Accountability	Facilities should establish the following: clear BCL guidelines and standards that include biosafety and biosecurity components, criteria for proper selection of qualified inspectors to audit BCLs, a facility inspection program for each BCL, and a logbook for BCL samples. They also should conduct periodic external inspections, accreditations, and certifications to create a standardized process. Facilities should ensure local and state governmental/public health agencies are involved for transparency and are aware of any suspected or confirmed patient being evaluated. They should ensure timely and proper reporting of any safety, security, or other concern regarding a select agent to the US CDC/APHIS (or the equivalent regulator in another country). Clinical and diagnostic laboratories must report select agents using the CDC/APHIS Form 4. Facilities should enforce the standards using a peer-reviewed system similar to that of AAALAC International. They should evaluate peer institutions, conduct a comprehensive programmatic review, and identify deficiencies and corrective actions. This program should allow for accreditation of each BCL and should be reevaluated for accreditation every 3 years.
Waste management Designated and monitored disposal pathways with specified trained personnel Clear inventory and documentation of all waste generated that may contain infectious material	Facilities should ensure safe management of waste contaminated with special/high-consequence pathogens; in particular, they should have designated disposal routes and dedicated trained personnel using inactivation methods performed either onsite or offsite, with chain of custody documentation of waste and inventory.
Inventory and accountability Documentation Internal storage information security	Facilities should establish a documented chain of custody throughout the lifecycle of each sample collected and stored. This should include immediate reporting mechanisms for any breaches or discrepancies. A facility’s policy should define the materials, records, standard operating procedures, and reporting requirements for the inventory. The policy should also dictate how sensitive electronic information will be protected and secured. BCLs that handle special pathogens that are select agents must comply with all requirements under the US select agent regulations¹⁷ or the relevant regulations in other countries.
Incident response Policies for emergency responders	Facilities should establish policies for how emergency responders should enter the BCL or HLIU during an incident. These policies must recognize the need to prioritize the preservation of human life, health, and safety over laboratory biosecurity and biosafety.
Communication Chain of notification	Facilities should establish how to notify key stakeholders in the event of an incident. This communication protocol should outline the variety of incidents that occur in BCLs and the roles and responsibilities of all stakeholders.

Abbreviations: APHIS, Animal and Plant Health Inspection Service; BCL, biocontainment clinical laboratory; CDC, Centers for Disease Control and Prevention; DOT, Department of Transportation; HLIU, high-level isolation unit; IATA, International Air Transport Association.

The establishment of a robust biosecurity and biosafety framework is paramount to provide a safe workplace and to reduce the risk of accidental release of pathogens to the environment and unauthorized access to special pathogens originating from clinical patient samples. It is critical that BCLs also have a process for corrective action for noncompliance. By integrating the key components (outlined in the Table) of existing BCL biosecurity and biosafety frameworks, current regulations and guidelines will establish clearer accountability guidance to these laboratories.

Conclusion

In summary, we underscore the critical need for a comprehensive biosecurity and biosafety framework for BCLs. In the United States, these laboratories are a critical national resource and must be further fortified with enhanced regulatory and local operating guidelines to be protected. Given the dual threats of special pathogen diseases and potential bioterrorism, such a framework not only fortifies our defense against unintended pathogenic releases but also safeguards against deliberate misuse. Establishing and adhering to robust policies and protocols ensures the safety of both laboratory personnel and the broader community, thus reinforcing the essential role these laboratories play in the broader health security infrastructure.

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