Biosafety Management Based Upon Risk Assessment and Monitoring: Perspectives from a Clinical Laboratory, China

Introduction

Risk assessment is the foundation of managing biosafety. Biosafety risks are associated with factors such as personnel, safety facilities or equipment, operating processes, disinfectants, experimental waste, emergency plans, etc. However, response measures are only developed and implemented for risks that exceed the acceptable limits of the laboratory. Therefore, accurately assessing the hazard degree of risks is crucial for developing appropriate risk response measures or avoiding excessive protection.¹ However, many institutional biosafety committees (IBC) only focused on the risks associated with operation processes, and the risk evaluation was also relatively superficial, which led to inadequate risk identification and inappropriate risk response measures. In addition, biosafety management should be a continuous improvement process based on risk monitoring and review of biosafety indicators. Risk monitoring is of great significance in identifying unidentified risks, improving risk response measures, avoiding excessive protection, and responding to emerging infectious diseases.¹ The factors that determine the risk-hazard degree in clinical laboratories include the types of pathogens that may be exposed and their biological characteristics (such as virulence, transmission ability, and transmission routes), operating procedures, and sample types. Once any factor changes, using the initial risk-response measures will inevitably lead to excessive protection or an ineffective response. However, the reality is that many laboratories are not aware of the importance of risk monitoring at all.² In recent years, biosafety incidents related to Brucella in laboratories in China, as well as the SARS CoV-2 infection among laboratory staff in Wuhan during the early stages of the COVID-19 pandemic in 2019, exposed the deficiencies in risk monitoring in these laboratories.³ In response to these issues, we retrospectively summarize our successful experience in fully identifying risks, accurately evaluating risks, effectively responding to risks, maintaining risk monitoring, establishing and regularly reviewing safety indicators before and during the COVID-19 pandemic, explore the establishment of a procedure for continuously improving biosafety management based on the experience, and evaluate its value in responding to emerging infectious diseases or avoiding excessive protection. In this study, we will share the experiences and the procedure.

Methods

This study was conducted in the clinical laboratory of a designated hospital for COVID-19 patients in Chongqing City, China in 2021. Our research team collected qualitative data on fully identifying risks, accurately assessing the hazard degree of risk, maintaining risk monitoring, updating risks and adjusting control measures before and during the COVID-19 pandemic in 2019. Taking our experience in implementing safety management as an example, we summarized the procedures for the activities associated with the above data, such as procedures on adequate and accurate risk assessment, procedures on effective and non-excessive risk control, procedures on appropriate risk monitoring, and procedures for continuously improving biosafety management, and evaluated their implementation effect.

Risk Assessment

Determine the Scope of the Experiment

Firstly, determine the scope of all experimental activities conducted in the clinical laboratory.

Collection of Biological Information on Potential Exposed Pathogenic Microorganisms

We collected information on pathogenic microorganisms that we might be exposed to during all laboratory activities. This information included disease pathogenicity, transmission route, infection dose, infection symptoms, incubation period, infection host, diagnostic means, stability in the environment, whether there were effective preventive measures and therapeutic drugs, and sequelae of infection. SARS-CoV-2 was used as an example to gather its biological information.

(Due to the wide variety of potentially exposed pathogenic microorganisms, in order to avoid lengthy manuscripts, we only used SARS-CoV-2 as an example to introduce the biological information of pathogenic microorganisms that should be collected).

Risk Identification

We defined a laboratory biosafety incident as any inadvertent occurrence resulting in actual harm during experimental activities, such as infection, illness, injury to humans, or environmental contamination. We used fishbone diagrams to fully identify biosafety risks in experimental activities from factors such as personnel, equipment, facilities, disinfectants, experimental waste, and operation processes (Figure 1).

Figure 1 The fishbone diagram of risk identification.

Risk Evaluation

The hazard degree of each biosafety risk identified was evaluated:

Risk hazard degree = risk severity × probability of risk occurrence.

The risk severity was quantified as follows:⁴

Score 4: very serious consequences, such as death.

Score 3: Causing widespread human infection or having very serious irreversible effects on the human body, with sequelae after treatment.

Score 2: Relatively serious injury, but recovery is possible after treatment.

Score 1: Slight harm that generally does not require special treatment.

Zero score: No harm.

The probability of risk occurrence was quantified as follows:

Score 4: Certain to happen (100% probability).

Score 3: Frequent occurrence (20%≤ probability < 100%).

Score 2: Occasional occurrence (1% < probability < 20%).

Score 1: Rare occurrence (0 < probability ≤1%).

Zero: score: Never happen (the probability of incident happening is zero).

Risk Response

First, the acceptable range of the risk-hazard degree should be determined. For risks with a hazard degree higher than the acceptable range, risk response measures should be considered, including eliminating risk sources, avoiding risks, controlling risks, and transferring risks. Risk control should be achieved by reducing the severity and/or occurrence probability of risk.

Risk Monitoring and Continuous Improvement of Biosafety Management

We established a risk monitoring approach based on internal or external review, analysis of biosafety incidents, employee recommendations, external information, reflection on internal incidents and warning from external incidents, and timely input the risk monitoring results into management review. Through management review, we decided whether to restart risk assessment or update risk response.

At the same time, we also established annual biosafety indicators such as number of biosafety incidents, personnel training rate, number of failures in biosafety equipment and facilities occupational exposure frequency, number of improper personal protective measures, number of spills, unqualified rate of ultraviolet intensity, and the inefficiency rate of disinfectants. The biosafety indicators were reviewed annually, and the review results were input into the management review. Through management review, improvement measures and their required resources were output (Figure 2).

Figure 2 Flow charts for continuous improvement of biosafety management.

Statistical Analysis

The laboratory safety administrator should conduct annual statistics on annual statistics and analysis of safety indicators. The statistical methods were as follows:

Rate of personnel training = number of participants / number of expected participants ×100%.

Unqualified rate of ultraviolet intensity = Number of ultraviolet lamps with unqualified ultraviolet intensity / The total number of ultraviolet lamps ×100%.

The inefficiency rate of disinfectants = number of ineffective disinfectant monitoring times / number of disinfectant monitoring times ×100%.

Every year, the statistical safety indicators should be compared with the pre-set limits in the laboratory to identify non conformities and opportunities for improvement.

Results

Determine the Scope of the Experiment

The clinical experimental activities conducted in our laboratory include sample reception, sample transport, sample handling before testing, the testing process, sample preservation, and disposal of experimental waste. The testing process also included clinical blood testing, clinical body fluid testing, clinical microbial testing, clinical chemical testing, and nucleic acid testing.

Biological Information of Potential Exposed Pathogenic Microorganisms

SARS-CoV-2

The source of infection is those infected with SARS-CoV-2, and the main route of transmission is through the respiratory tract and close contact. The dosage of the infection has not been reported yet. The main symptoms after infection include fever, muscle pain, a dry or sore throat, and loss of taste. Humans are generally susceptible to infection, and vaccination can reduce infection and morbidity. Infection can be prevented by wearing masks and practicing hand hygiene. The incubation period after infection is 2 to 4 days. The diagnostic method is nucleic acid and antigen testing. SARS-CoV-2 is sensitive to ultraviolet light, high temperatures, organic solvents (ether, 75% or 70% ethanol, H₂O₂, chloroform), 1 to 5% Hypochlo- rite bleach and CaviCide disinfectant, and chlorine-containing disinfectants. There are effective medicines and vaccines.^5–7

Risk Assessment

We determined ≤ 1 as an acceptable range on hazard level of biosafety risk. Therefore, we had identified a total of 30 unacceptable risks, of which there were no risks that need to be avoided, received, or transferred. Then, we had developed and implemented appropriate risk control measures for these 30 risks (Table 1-3). Of course, We also reviewed and analyzed the suitability of risk assessment and the effectiveness of risk control. Prior to the COVID-19 pandemic, there were no biosafety incidents in our laboratory, which proved that our risk assessment was adequate and appropriate, and risk control was effective.

Table 1 Risk Identification

Table 2 Risk Assessment

Table 3 Risk Control

Risk Monitoring and Continuous Improvement of Biosafety Management

After identifying and responding to these risks, we maintained risk monitoring, and timely input the results of the risk monitoring into the management review. During the COVID-19 pandemic, we had twice updated risk identification and risk control through risk monitoring to address emerging risks or avoid excessive protection. At the beginning of COVID-19 in 2019, our laboratory undertook the task of laboratory testing for COVID-19 patients. Given the emergence of new potentially exposed pathogenic microorganisms in the experimental activities, we initiated risk monitoring before conducting laboratory testing. Based on the biological characteristics of SARS-CoV-2 and its distribution in various types of samples, as well as the upcoming experimental activities, the basis of the original risk assessment, we identified ten new risks and three ineffective risk control measures. These new risks exist in the processes of doffing PPE, removal of experimental waste from biosafety cabinets, nucleic acid extraction, and so on. Three ineffective risk control measures included risk control measures for sample reception, risk control measures for bacterial liquid configuration, and PPE. Based on this, we had developed appropriate risk control measures for these newly identified risks and improved these ineffective risk control measures. During the COVID-19 pandemic, no laboratory staff were exposed and we achieved favorable outcomes. In April 2019, China fully began using nucleic acid preservation solutions containing virus inactivators. After obtaining this information, we restarted the risk assessment. The result showed that, except for the unacceptable exposure risks that still existed during the sample reception process, the hazard degree of other risks identified in the early stages of the epidemic was acceptable Based on this, we promptly adjusted our risk control measures to avoid excessive protection.

Through reviewing safety indicators, we concluded that the established safety goals had been met, but we also identified opportunities for improvement in the effective rate of disinfectants and the number of spills. Then, through management review, we increased the limits of these two quality indicators.

Discussion

The clinical laboratory managers should conduct a risk assessment before starting experimental activities and develop risk response measures based on the risk assessment. The biosafety risks in clinical laboratories come from laboratory engineering controls, personnel, safety facilities and equipment, operations, disinfectants, experimental waste, and emergency plans. Unreasonable engineering controls, such as unreasonable division of laboratory areas, unreasonable configuration of safety facilities, and unreasonable negative pressure differentials, can also pose exposure risks to laboratory staff. Therefore, adequate risk identification is a prerequisite for clinical laboratories to effectively respond to risks.

For identified risks that cannot be controlled or eliminated in experimental activities, IBC can avoid or transfer risks by not conducting or outsourcing the experimental activity. For risks that can be controlled, IBC should develop appropriate risk control measures. These risk control measures include reasonable laboratory design, the establishment of management systems and SOPs, the configuration of appropriate safety equipment and facilities, the selection and management of appropriate personal protective equipment, and suitable disinfectants, and so on. The purpose of risk control is to reduce the probability of risk occurrence and/or the severity of risk to a acceptable level, rather than necessarily eliminating the risk source. Of course, the best result of risk control is to eliminate the risk source, but sometimes eliminating the risk source is impossible, or will pay a huge price, which is also unnecessary. For laboratories, the risk with a low hazard degree and low frequency of occurrence is acceptable Therefore, we considered a hazard degree of “≤1” as the acceptable range. Additionally, risk control measures should also be appropriate to the hazard degree of risk. For the same pathogenic microorganism, the risk is not the same for different experimental activities. For example, the inactivation of the Ebola virus needs to be carried out in the BSL-3 laboratory, while the nucleic acid extraction and amplification of the Ebola virus can be carried out in the BSL-2 laboratory.¹⁵ Similarly, for the same pathogenic microorganism, different sample disposal methods before testing result in different risks during the testing process. For example, the risk of detecting samples that have undergone virus inactivation treatment is inconsistent with detecting samples that have not undergone virus inactivation. Therefore, the 2021 fourth edition of the WHO Laboratory Biosafety Manual removed the concept of biosafety levels for laboratories, emphasizing the need to develop effective and non-excessive risk control measures based on the economic conditions of the country and the risk assessment of the laboratory.⁴ Excessive risk control not only affects work efficiency and wastes limited resources but also increases the risk of infection.¹⁶ For example, during the COVID-19 pandemic, there was no longer an exposure risk in the SARS-CoV-2 nucleic acid testing process after the use of nucleic acid preservation solutions containing virus extinguishing agents. However, in China, almost all laboratory staff still wore PPE with Level 3 biosafety protection, which not only wasted resources but also reduced work efficiency. Although the Chinese government issued corresponding guidelines in April 2021 to correct this situation,¹⁴ the above excessive protective measures were still implemented in many laboratories until outbreak control was lifted. If laboratory managers had maintained risk monitoring, restarted risk assessment and adjusted risk control measures accordingly, the above excessive protection could have been avoided.

Every risk assessment is not perfect. In clinical trial activities, factors associated with biosafety risks may change. Therefore, after each risk assessment, there may still be new or unidentified risks in the experimental activities, and initially established risk control measures may not always be effective. For example, the Ebola outbreak in West Africa in 2014–2016 expanded to unprecedented levels due to inadequate control measures put in place by medical institutions, which led to multiple chains of transmission.¹⁷ Therefore, it is necessary to continuously improve biosafety management through risk monitoring to respond to emerging infectious diseases.¹⁸

Risk monitoring can be achieved through various means, with employee suggestions and external information being particularly important. Employee suggestions often arise from observations made during laboratory activities, such as unidentified risks or inappropriate control measures, while external information includes information from sentinel laboratories,¹⁹ current epidemiological information in the region or elsewhere, safety incidents in other laboratories, official reports, changes in the biological characteristics of pathogenic microorganisms, changes in relevant laws and regulations, and so on. For example, in the early days of the COVID-19 in Wuhan, China, in 2019, the local health management department did not listen to the feedback from medical staff that pneumonia of unknown origin may be a new infectious disease with strong infectivity, and did not further strengthen risk control, leading to infection of some medical staff.³ A similar incident of ignoring external information also occurred in Dallas County, Texas, USA. If local medical institutions had noticed the Ebola outbreak information in Guinea, Liberia, and Sierra Leone at that time and taken targeted protective measures, these two nurses might not have been infected with the Ebola virus when receiving fever patients from Liberia.²⁰ Conversely, the successful case of valuing external information and updating risk control measures was the World Health Organization’s timely reduction of risk levels and updating of control measures based on SARS-CoV-2 mutation information.

The focus of risk monitoring should be on changes in experimental activities, such as potential exposed pathogenic microorganisms, the amount of pathogenic microorganisms used, sample types, and sample processing methods. These changes may increase or decrease the number of risks, or alter the hazard level of the risk, so that the initial risk assessment and control measures are no longer applicable, resulting in ineffective or excessive protection.²¹ In the early stages of the outbreak in Wuhan, China, we maintained risk monitoring and implemented stricter risk control measures before testing sputum and fecal samples from COVID-19 patients, achieving good control results. During this period, no laboratory staff were infected.²²

The review of safety indicators is an effective way to analyze the reasons why safety indicators have not reached the limit, evaluate the suitability of laboratory safety indicators, and identify improvement opportunities. Therefore, the establishment and regular review of safety indicators are also effective ways to continuously improve biosafety management. Inputting the results of regular reviews into management reviews is an effective means of achieving continuous improvement.

Conclusions

Adequate risk identification and accurate risk evaluation are particularly important for effectively controlling risks. Therefore, when implementing risk assessment, it is necessary to fully consider the risk sources from engineering control, personnel, PPE, equipment and facilities, emergency plans, disinfectants, experimental waste, operational processes, and quantitatively evaluate their hazard degree.

Effective control measures for risks include developing SOPs, employee training, immunization, the use of effective disinfectants, maintaining the normal functioning of safety equipment and facilities, and developing appropriate emergency plans. Among them, immunization and employee training should also be implemented before employees engage in experimental activities, and SOPs should comply with ethics and local laws and regulations. The continuous improvement of biosafety management is of great significance in reducing the occurrence of safety incidents, responding to emerging infectious diseases, and avoiding excessive protection. The mechanism for continuously improving biosafety management is as follows: implement risk monitoring through various channels to evaluate the suitability and adequacy of risk assessment, as well as the effectiveness of control measures, and analyze high-risk sources. Meanwhile, identify opportunities for improvement through the review of safety indicators. Then the evaluation results, high-risk sources, and improvement opportunities were input into the management review, and improvement measures and the resources required for implementing these measures are output through the management review.

The improvement measures include correcting the reason why the biosafety indicator does not meet the limit value, improving risk assessment and risk response (such as identifying new or unidentified risks, correcting inappropriate risk evaluations, improving response measures for risks). Reviewing safety indicators and risk monitoring are the ways to continuously improve biosafety management, and management review is the means to achieve continuous improvement (Figure 2).