key: cord-0814358-l4psd36z authors: Aspland, Avrill M; Douagi, Iyadh; Filby, Andrew; Jellison, Evan R.; Martinez, Lola; Shinko, Diana; Smith, Adrian L; Tang, Vera A.; Thornton, Sherry title: Rising to the challenge: Overcoming Shared Resource Laboratory biosafety challenges during a pandemic date: 2020-12-02 journal: Cytometry A DOI: 10.1002/cyto.a.24280 sha: b926a8781571d9c7c997050d7cbc8c98efd097bc doc_id: 814358 cord_uid: l4psd36z Biosafety has always been an important aspect of daily work in any research institution, particularly for cytometry Shared Resources Laboratories (SRLs). SRLs are common‐use spaces that facilitate the sharing of knowledge, expertise, and ideas. This sharing, inescapably involves contact and interaction of all those within this working environment on a daily basis. The current pandemic caused by SARS‐CoV‐2 has prompted the re‐evaluation of many policies governing the operations of SRLs. Here we identify and review the unique challenges SRLs face in maintaining biosafety standards, highlighting the potential risks associated with not only cytometry instrumentation and samples, but also the people working with them. We propose possible solutions to safety issues raised by the COVID‐19 pandemic and provide tools for facilities to adapt to evolving guidelines and future challenges. Biohazardous materials are commonly encountered in flow cytometry SRLs. As with any laboratory setting, the standard approach to safety when working with potential hazards is to perform a thorough risk assessment on the infectious agents, reagents, standard operating procedures (SOPs) and the instrumentation proposed for use. Protocols are put in place to help reduce these inherent risks, managed through the implementation of primary controls such as; engineering controls, personal protective equipment (PPE) and SOPs (1) . Biosafety considerations when handling samples before, during, and post-acquisition have always been front of mind in flow cytometry SRLs, particularly related to droplet-based cell sorters. The SRL, by its definition, handles a wide variety of samples and hosts users from many laboratories, universities, institutions and companies. Considering that the current pandemic is spread via respiratory transmission and remains viable on surfaces for prolonged periods (2) , the actions of one individual can impact many with wide-spread downstream consequences. In times of epidemics, pandemics and emerging disease, the potential risks Accepted Article associated with working within an SRL are evolving, giving cause for re-evaluation of our practices to accommodate these new challenges. The SRL, by its nature, is a multi-user environment that facilitates interaction between different members of a research community including SRL staff and users. In the case of COVID-19, a vaccine is currently unavailable against the causative agent (SARS-CoV-2), and it is currently not feasible to perform screening for asymptomatic or pre-symptomatic individuals. This pandemic has necessitated significant changes in the working environment and management of the workforce, with increased expectations put on staff and users. As a result of these changes, added attention needs to be given to the human contribution to the risks associated when working within the context of a shared-use space. With respect to biosafety risks, staff and users must now be included in this assessment and operational guidelines should be identified. For most institutions, these expectations are defined by the level of biosafety threat to individuals and the specific institution's approach to risk (1) . We review below some simple strategies that can be employed to maintain a safe and healthy SRL working environment. tech approaches that use purpose-built programs for self-assessment, to low-tech paper versions (4, 5) . More detailed screening methods, from sampling of body temperatures, as well as polymerase chain reaction and serological tests, have also been employed. Institutional and regional policies will dictate when this type of testing is warranted and provide guidelines regarding periods for self-isolation or quarantine. In many institutions, once a positive case has been identified, contact tracing is undertaken to identify individuals at risk so that they may follow the recommended procedures for testing and self-isolation (6) . SRL facility management systems can help to quickly determine who should be contacted when a user or staff member tests positive (7) . Some SRLs have access to high-tech methodologies that enable contact tracing such as badge scanners at the door of the SRL. Low-tech solutions should also be considered including having a sign-in/sign-out log. This manual system is important for users who come to the SRL for purposes other than to utilise an instrument, such that usage would not be recorded in instrument booking systems. For further details on possible booking systems and visitor tracking options please refer to Table 1 . Additional consideration should be given to those who must enter the SRL to provide specialist services, such as instrument maintenance and installation. Prior to their arrival these individuals should be informed of the institution's screening process, escort rules, and other relevant guidelines for working within the facility. In the case where they are arriving from another country or region, government travel regulations must be considered and adhered to. While every effort can be made to identify all potential contacts of a positive case, this may not always be all-encompassing. Thus, having in place a policy that assumes anyone may be infectious (similar to standard precautions when handling biological samples), is crucial to ensure a safe SRL working environment. This article is protected by copyright. All rights reserved. Many facilities have put in place operational policies that help to control the spread of SARS-CoV-2. Although the specific policies and recommendations may vary between institutions, they all serve to reduce transmission through: 1. physical distancing of individuals, 2. improved decontamination of common workspaces, and 3. the use of PPE. 1. Physical Distancing: There are different methods that can be employed to physically distance users and operators within an SRL. If space is not an issue, instruments can be relocated to other spaces or moved further apart to facilitate physical distancing. Rotating shifts for both core facility staff and users can help to reduce the number of persons in a given lab at one time. To complement this, strategies should be employed to minimize possible overlap of users and the number of users in a space by preventing the simultaneous booking of instruments in close proximity. The companion manuscript on regulatory measures (7) covers these issues in detail. Remote support can further reduce physical contact, while maintaining training and support. These same software solutions can also be employed by users who often will work side-by-side on an instrument to demonstrate data acquisition to new colleagues. These strategies can be encouraged to allow for mentoring to continue, while taking place remotely. There are a number of easy-to-use software platforms (see Table 1 ) that can be used to facilitate remote sessions between SRL users and staff alike, as reviewed in detail by Daniels et al. (8) . 2. Environmental Decontamination Procedures: Cleaning procedures will vary between facilities; however, these typically include cleaning protocols for high-touch surfaces such as instrument keyboards, mouse, webcams, headsets, as well as all surface areas of the instrument contacted by a user (9) (10) (11) (12) (13) (14) . A list of surface disinfectants shown to This article is protected by copyright. All rights reserved. be effective against SARS-CoV-2 can be found in Table 2 . Enhancement of ventilation in SRL spaces is also recommended to further reduce the risk of environmental contamination (15, 16 The need for physical distancing means the majority of SRLs are operating with some level of remote support. There are added pressures at this time as research groups must keep working, often on rotating shifts, and under the expectation they will not exceed booking times in order to maintain compliance with room occupancy restrictions. This extra pressure may potentially impact users' abilities to correctly follow protocols. Thus, added precautions should be implemented to not only limit the frequency of potential errors, but also to limit their impact. For example, additional training time in the form of remote support by SRL staff can be included in the first few sessions a new user runs on their own. This also means that users should be trained to follow all new procedures and consistent communication should be implemented to support users in these new policies (1). This article is protected by copyright. All rights reserved. The strategies reviewed here aim to reduce person-to-person contact and subsequent spread of disease while maintaining interactions between members of an SRL. For SRLs, the challenge is to implement working policies that both safeguard the health and well-being of all staff and users, while maintaining a high level of support to ensure continuity of research services. This is a delicate balance as the measures put into place to reduce person-to-person contact can potentially also reduce the ability for SRL staff to provide support to their users. An example of a risk assessment for working with a SARS-CoV-2 infected user in an SRL setting is attached in Appendix I. Historically, facilities have effectively managed inherent risks by implementing "Standard Precautions" in laboratories in line with their biosafety containment level. Standard Precautions are such that all human specimens are assumed potentially infectious, and protective measures are implemented to reduce the risk of transmission (19) . These precautions include the use of protective barriers such as: hand hygiene, gloves, gowns, masks, and protective eyewear or face shields. If procedures are likely to result in a higher risk of transmission, e.g. producing droplets or aerosols, it is recommended that a Class II Biological Safety Cabinet (BSC) or physical barrier is used (19 respiratory nature of SARS-CoV-2 transmission, this means we must maintain heightened awareness of all processes that may result in the generation of droplets and aerosols. A number of factors interplay to determine the final risk associated with running a particular sample on a specific instrument. Effective communication between investigator, shared resource laboratory and safety officer is critical to ensure a cohesive approach when defining a safety assessment in the context of an SRL (Figure 1 ). It is recommended that the SRL, along with their biosafety officer, perform a biological safety assessment for each laboratory group and their specific samples (20, 21) . A template for such a risk assessment has been It is at this point that engineering controls, appropriate PPE and SOPs can start to be applied to control for these risks. The ISAC Biosafety committee has written extensively on the assessment of aerosols created by droplet cell sorters and the dangers posed to the sort operator (22) . In summary, prior to any cell sorting, a risk assessment needs to be performed that will help identify and mitigate It should also be noted that a number of microfluidic and chip based flow cytometry cell sorters have been brought to market in the last 5-10 years. Aerosol generation by these cell sorters is kept to a minimum due to their design; however, there is still a need to validate the sorting safety of these instruments in each environment and with individual users. The ISAC Biosafety Committee has published standards for testing of aerosol management and these standards should be used and adapted to fit each individual situation and instrumentation. The SRL may decide that only facility staff will operate sorters and room requirements may dictate that only one person can be present. In this context, contact-free sorting can be facilitated by thorough documentation encompassing critical parameters such as the reagents This article is protected by copyright. All rights reserved. and remote control software (Table 1) are effective for the required interactions such as gate confirmation (8). As discussed above, the operation of cell sorters is well classified due to the significant risk of aerosol generation, with SRL staff trained to ensure safe operation in line with well developed, evidence based SOPs. The use of analyzers is generally considered low risk due to their enclosed systems and low pressures. However, there appears to be little empirical evidence to support this (28, 29) . While analyzers can be considered a lower risk than cell sorters, at this time they pose an uncharacterized risk, often operated by a large volume of users with varying levels of experience. As such it is important that strategies are implemented to reduce the risk associated with pathogenic and human samples in the SRL setting (30) . These strategies can be subdivided into two main areas: standard operating procedure controls and engineering controls. Utilising fixation as a SOP control allows facilities to minimise the risk of running hazardous and potentially hazardous samples in their SRL space. The most common inactivation process utilised for flow cytometry analysis is the use of formaldehyde solution in various concentrations. Incorporating a fixation protocol into the preparation of samples is a procedure familiar to many users, making this a straightforward process for controlling risk. Fixation is often performed with the primary goal of stabilising samples for downstream assays (e.g. intracellular staining). However, fixation protocols designed for stabilisation may not necessarily result in pathogen inactivation and special care is needed in the assessment This article is protected by copyright. All rights reserved. and development of fixation protocols (14, 22, (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) . Commercial products, both within and across companies, often contain varying concentrations of fixative. This information is often not immediately obvious, and it is therefore necessary to reference the Material Safety Data Sheets (MSDS) along with the protocol when performing fixation protocol assessments. It is important to note that there is inherent variability in the response of pathogen infectivity to inactivation. There is extensive literature detailing pathogen inactivation by varying compounds and this should be reviewed when determining the suitability of a fixation protocol (36, 40, (42) (43) (44) (45) (46) . We are now seeing literature emerging detailing inactivation of SARS-CoV-2 with formaldehyde solution (47) (48) (49) (50) , this is summarized in Table 2 . In instances where pathogens are emerging or classified as Risk Group 3/4 all fixation and inactivation protocols are recommended to be validated by the laboratory undertaking the research rather than relying solely on literature (24) . Viral inactivation validation protocols vary and literature should be reviewed, and local safety officers consulted, when developing protocols for the local context. Viral inactivation validation protocols can be found in these references (36, 40, (42) (43) (44) (45) (46) (47) (48) (49) (50) . In all fixation protocols it is imperative to consider the (i) fixative used, (ii) how fresh this fixative is, (iii) the concentration of the fixative, (iv) the time of incubation and, (v) the temperature maintained during incubation (36, 38, 39, 43, 45) . Critically, it has been demonstrated in a number of publications that fixation at low temperatures, for example at 4 o C, often results in insufficient inactivation of pathogens (38, 39, 43, 45) . It is important that protocols are reviewed and any required changes are identified. Implementing changes in policy can be met with reluctance on the part of the users due to fear of potential impacts on existing work. Facilities can ameliorate this concern by demonstrating that protocol changes do not impact results in any significant manner. Staining protocols, particularly for intracellular markers, may be impacted by additional fixation steps This article is protected by copyright. All rights reserved. if not implemented with care. Some guidance on staining protocols can be found in this methodology publication (51) . Preliminary data from a high-dimensional panel indicates that various fixation protocols do not necessarily alter signal intensity or interpretation of data ( Figure 2 ). Results showed that fixation with a 4% formaldehyde solution (freshly prepared from paraformaldehyde (PFA)) under different incubation conditions did not alter the forward versus side scatter plots (FSC-A vs SSC-A; Figure 2A Significant value lies in testing fixation protocols to determine potential impact on assays. It should be acknowledged that some protocols will not function on fixed samples. The situation may necessitate examination of alternative assays, for example an apoptosis assay that allows for fixation (52) or a move to implementing engineering controls for such samples. Due to the pandemic we are now working in an environment with significant inherent risks, so stakeholders will now be seeking out protocols and reagents that facilitate a reduction of this risk. This is an area in which manufacturers have the opportunity to expand their market by identifying new protocols, taking into account viral inactivation and identifying stability of their reagents after fixation. While some engineering controls already exist on instruments, the most effective control for facilities looking to run unfixed hazardous samples may be (as per standard precautions) to enclose an analyzer and any potential aerosols inside a BSC (30, 53) . Historically this was not This article is protected by copyright. All rights reserved. possible due to the size of instrumentation (30) , but this is no longer the case with many benchtop analyzers (Figure 3 ). The ability to enclose a benchtop analyzer in a BSC opens up options for users in the types of protocols and samples that can be run while maintaining biosafety containment. However, a number of factors need to be carefully considered before moving down this path: • Biological safety assessment: Determine if a BSC is required for the types of samples handled within the facility. • Frequency of live hazardous samples: Depending on how frequently a facility encounters live hazardous samples, the use of a cell sorter contained within a BSC may be sufficient to accommodate user needs. • Accommodation of instrument within BSC: Sufficient air flow around instrument within standard BSC for both heat dispersion and maintaining functional containment. Custom BSC options may need to be explored. • Thermal load: Instrument specifications, such as number of lasers, should be considered. For example, the more lasers, the more heat produced and the less stable the system may be. • Training: Adequate training must be provided for appropriate use of the instrument inside the BSC to ensure containment of hazards is maintained. • Accessories: components such as vortex, pipettes and tube racks will be needed within the BSC to ensure ease of use and reinforcement of safe behaviours. Placement of an analyzer inside a BSC increases the burden on facility staff due to the need for additional sample handling training for users and ensuring continued compliance with This article is protected by copyright. All rights reserved. these behaviours. Additional costs are also associated with the initial BSC purchase and continued certification. The need for such a set-up is limited and unlikely to be necessary for many SRLs if other measures can be effectively implemented. Inactivation of instrument waste is an important consideration for SRLs. Recommendations state that waste containers should hold enough bleach to result in a "10% final concentration of bleach" when the waste tank is full (30, 22) . Local regulations and institution guidelines vary considerably and must be considered when developing a protocol for biohazardous waste disposal. A number of publications detailing wastewater pathogen inactivation are available and may be used as a guide when developing local protocols (54, (56) (57) (58) (59) . It should be noted that the stability of bleach is impacted by a number of factors including, but not limited to, pH, temperature, exposure to light and dilution (59) . The management of waste in SRLs should be structured to ensure that waste is exposed to bleach for a sufficient period of time, at an adequate concentration of free chlorine (54) . In some situations, such as in BSL-3 laboratory waste streams, autoclaving flow cytometry waste may be considered (22) . However, this introduces some complexity due to the potential generation of hazardous gases, such as from wastewater containing formaldehyde or bleach solutions (60) . This article is protected by copyright. All rights reserved. The SRL is a hub for scientific activity, creating a centralized resource that investigators rely on for specialized equipment and technical expertise. The ability to pivot operational structures in response to a pandemic, communicate changed practices, and facilitate continued access, has played an essential role not only for research in general, but also in developing our understanding of SARS-CoV-2. Every day we are seeing the emergence of new COVID-19 research, bringing with it potential changes in our understanding and subsequent changes to the safety measures implemented by SRLs. Biological safety assessment needs to consider not only samples and reagents but also the SRL staff, users and visitors as potential risks. Ensuring and maintaining adherence to standard precautions at all times while working within the SRL space will significantly reduce the risk for each individual and subsequently to the wider research community with whom they associate. This article is protected by copyright. All rights reserved. The ability of an SRL to rapidly respond to the emergence of a new pathogen centers on having established biological safety assessment procedures in place (3, 21, 30) , along with a human risk assessment (Appendix I). At this time literature is starting to form a consensus around the stability and inactivation of SARS-CoV-2 (14, (34) (35) (36) (39) (40) (41) (47) (48) (49) (50) . Exactly how these inactivation methods are applied in SRLs will relate directly to the sample type and the level of risk posed. Samples infected with cultured virus should be treated with significant caution, followed by SARS-CoV-2 positive human tissues known to generate propagative virus, and then those tissues not known to carry propagative virus (30, (61) (62) (63) (64) (65) (66) (67) (68) (69) (70) . Standard precautions apply to all human samples, with a biological safety assessment utilised to help guide the application of additional control measures relative to the local context (1) (Supplementary Table 1 ). Facilitating a safety conversation with users should be the foundation of safety within the SRL. Engaging those who must practice safety measures in the SRL space in these conversations encourages ownership and supports a culture of safety (1). Once a biological safety assessment ( Figure 1 ) and human risk assessment (Appendix I) has been completed and measures put in place, it is then the role of the SRL to ensure effective communication, and thus support users in their ability to comply with these measures. Communication is the key component in ensuring safety during a pandemic. This article is protected by copyright. All rights reserved. Figure 1 . Effective communication between investigator, shared resource laboratory and safety officer ensures a cohesive approach when defining biological safety assessment in the context of an SRL. As in everything we do, our ability to identify the risks, assess them and then go on to manage them is limited by our ability to communicate with all involved parties. It is in the framing of these biosafety discussions that SRL staff can have the most impact, where the focus is understanding, communicating perceived risks, followed by collaborating to determine an appropriate safety response. While compromise may not always be possible, there are invariably instances where inclusion of users leads to innovative solutions and new approaches to safety. There is a certain amount of trust required between users and SRL staff. This trust is developed by having ongoing discussions around safety, developing a cultural expectation of safety and continued inclusive discussions. There is a significant mental and This article is protected by copyright. All rights reserved. time burden to the maintenance and communication of appropriate biological risk management. However, it is imperative, especially during pandemics, that SRLs have effective processes in place to ensure the safety of everyone who uses their space. This article is protected by copyright. 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All rights reserved. This procedure has been developed as an illustrative example to help aid in the assessment of new risks that are now being experienced. Consideration needs to be given to the local context in which this will be applied, including: regional regulation, prevalence of the agent (e.g. SARS-CoV-2), the number of users moving through the space, what measures can be