Practical Considerations for Navigating Withdrawal from the Federal Select Agent Program

Abstract

Introduction:

Clear guidance is provided by the Federal Select Agent Program (FSAP) to assist registered entities in nearly all facets of compliance with the Federal select agent regulations (7 CFR Part 331; 9 CFR Part 121; 42 CFR Part 73). If a registered entity chooses to discontinue its registration, detailed instructions for registration withdrawal are deeply embedded within a document entitled “eFSAP Form 1 Amendment Instructions,” which is found on the FSAP website within the electronic Federal Select Agent Program (eFSAP) Resource Center.

Methods:

Using the information found within the eFSAP Form 1 Amendment Instructions, as well as extensive written and verbal guidance provided by the lead assigned entity point of contact at the FSAP, we completed the FSAP withdrawal process during a 12-month period between 2022 and 2023.

Discussion:

This commentary shares our recent professional experiences navigating the FSAP withdrawal process at the University of Texas Health Science Center at Houston (UTHealth Houston). Successes, challenges, and lessons learned are shared so that others planning or considering withdrawing may benefit from our experience.

Conclusion:

The resources provided for withdrawal within the eFSAP Form 1 Amendment Instructions are relatively basic, and additional details are not currently found in other FSAP guidance documents. Therefore, direct communication and support from the FSAP to the entity Responsible Officials are imperative to ensure a safe, secure, and compliant withdrawal.

Introduction

Clear guidance is provided by the Federal Select Agent Program (FSAP) to assist registered entities in nearly all facets of compliance with the Federal select agent regulations (7 CFR Part 331,¹ 9 CFR Part 121,² 42 CFR Part 73³). Various guidance documents, checklists, and frequently asked questions have been developed and are conveniently available on the FSAP webpage for reference when needed for program development, implementation, and maintenance.⁴ The FSAP also communicates effectively to the regulated community about new guidance or changes or improvements to existing guidance. However, if a registered entity chooses to discontinue its registration, instructions for the withdrawal of the registration are not found in a readily obvious location. At the time of writing, both the regulatory code and the various compliance guidance documents provided by the FSAP are devoid of information on entity withdrawal.

Rather, the only written instructions are deeply embedded in a document entitled “eFSAP Form 1 Amendment Instructions,”⁵ which is found in the electronic Federal Select Agent Program (eFSAP) system Resource Center on the FSAP website. We suggest that a distinct path to these instructions and inclusion in both the compliance documents and FAQs on the FSAP webpage should be considered, as there have been, on average, 13 withdrawals per year since 2015.^6–12 In addition to utilizing these instructions, we found it necessary to repeatedly communicate directly with our lead assigned entity point of contact at the FSAP who provided additional written and verbal instructions and guidance on the withdrawal process as we navigated through the various steps of the process.

This commentary shares our recent professional experiences navigating the withdrawal process at the University of Texas Health Science Center at Houston (UTHealth Houston), which relied heavily on guidance provided by our entity's lead assigned point of contact at the FSAP to safely, securely, and compliantly withdraw. Successes, challenges, and lessons learned are shared so that other entities planning or considering withdrawing may benefit from our experience.

Background

Following the “Amerithrax” anthrax attacks of 2001 that resulted in five deaths, the U.S. Congress significantly strengthened oversight of select biological agents and toxins by introducing and passing the USA PATRIOT Act in 2001¹³ and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002¹⁴ requiring Health and Human Services (HHS) and the United States Department of Agriculture (USDA) to publish regulations for the possession, use, and transfer of regulated select agents and toxins (Select Agent Regulations: 7 CFR Part 331,¹ 9 CFR Part 121,² 42 CFR Part 73,³ effective February 7, 2003).¹⁵

On July 2, 2010, President Barrack Obama signed Executive Order 13546 entitled Optimizing the Security of Biological Select Agents and Toxins in the United States that directed the HHS and USDA, as a part of an ongoing review, to both tier and consider the reduction of the select agent list, as well as establish physical security standards for select agents and toxins with the highest risk of misuse.¹⁶ A final rule published on October 5, 2012, designated “Tier 1” select agents and toxins, reduced the number of agents on the select agent and toxins list, and established physical security and information security standards for Tier 1 agents. The subset of select agents and toxins designated as Tier 1 present the greatest risk of deliberate misuse with significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence.^3,15

Research activities at UTHealth Houston involving a regulated select biological agent have been conducted since the early 1990s, before modern select agent regulations began. Registration and approval under the new select agent and toxin rules were granted, and the registration was upgraded to Tier 1 when the new requirements were implemented in 2012. The registered select agent laboratory space for Tier 1 research activities included a 1000 square foot Biosafety Level 3 (BSL-3) containment facility, containing an anteroom, main laboratory area, and inner Animal Biosafety Level 3 (ABSL-3) vivarium space. Collectively, this registered space was dedicated solely for one principal investigator (PI) and one single regulated select biological agent requiring BSL-3 and ABSL-3 containment.

After many years of operating safely, securely, and compliantly with the Federal select agent regulations, in September 2021, the select agent PI notified the entity's Responsible Official (RO) and Alternative Responsible Officials (AROs) of the intent to retire from the institution within the next 12–18 months. Rather than pass the research efforts to another faculty member with similar interests and expertise, the intent was communicated to shut down the laboratory and withdraw from the FSAP.

Methods

To determine the steps required to initiate the entity withdrawal process, we first referenced the prevailing Federal Select Agent and Toxin regulations, specifically 42 CFR Part 73, since this was the designated regulation applicable to the entity registration. The regulatory code provides the following regarding entity withdrawal in section 73.7(k): “A certificate of registration will be terminated upon the written request of the entity if the entity no longer possesses or uses any select agents or toxins and no longer wishes to be registered.”³ Given that this language does not provide descriptive details, the associated compliance guidance documents on the FSAP webpage were consulted. However, detailed information on the withdrawal process was not identified in the existing compliance documents which we reviewed. Therefore, we then proceeded to consult the eFSAP Resource Center on the FSAP website for more information.¹⁷

When clicking on the eFSAP Resource Center hyperlink, there is a section titled “Using eFSAP,” which provides training materials, reference guides, and answers to frequently asked questions to assist eFSAP users. Once this hyperlink is selected, the “Resources for Using the APHIS/CDC Forms” menu appears—and the “Form 1—Registration and Amendments” tab must be selected. At this juncture, you are taken to a page entitled “APHIS/CDC Form 1: Application for Registration for Possession, Use and Transfer of Select Agents and Toxins.” Within this webpage, the document entitled “eFSAP Form 1 Amendment Instructions” can be found, and detailed instructions for “Withdrawal Requests” start on page 37.⁵

Next, we contacted our entity's assigned lead primary point of contact at the FSAP to verify the steps described in the eFSAP Form 1 Amendment Instructions and determine additional necessary steps for the withdrawal process (Table 1). The primary instructions indicate that the first step is to document in writing the intent to withdraw from the registration within the eFSAP and to construct a list of tasks necessary to decommission the laboratory. These tasks may include, but are not limited to, transfer or destruction of any remaining regulated select agent or toxin stocks, destruction or removal of any laboratory supplies and consumables, equipment decontamination to safely remove reusable laboratory equipment, whole room decontamination inclusive of any related ductwork and high efficiency particulate air (HEPA) filter banks within the facility's heating, ventilation and air conditioning system, and to verify success of the whole room and equipment decontamination processes.

Table 1.

Comparison of the electronic Federal Select Agent Program Instructions for withdrawal and UTHealth Houston tasks

Form 1 Instructions for withdrawal 5	UTHealth Houston steps	UTHealth Houston timeline
General discussion board on the home page, provide a statement indicating that the entity is requesting to withdraw its registration from the FSAP	Document the intent to withdraw and reason from the registration in eFSAP comments section	October 2021
The request should state the wish to withdraw from the FSAP, the reason for withdrawal, the disposition of agents/toxins, and the decontamination of registered space and equipment	Provide a list of tasks to decommission the laboratory
Disposition of select agent/toxin
Verification of inventory audit	Documentation of stock destruction All inventory logs scanned to secure site	October 2021 June 2022 December 2022
Confirmation that no select agents or toxins remain	After destruction of stocks and transfer, the laboratory was prepared for decontamination, including all equipment where BSAT material could be present	February 2023
Destroyed/inactivated—provide documentation (e.g., autoclave records and statement signed by witness)	Destruction of stocks with the method listed in Biosafety Plan; verified with BIs and documented	December 2022 February 2023
Transferred—provide the APHIS/CDC Form 2	Transfer of one stock; Form 2 processed	February 2023
	Destruction of all consumable supplies	December 2022–February 2023
Documentation that effective decontamination appropriate to the use of the suite(s)/room(s) must be provided	CURIS System's HHP™ Reports with pictures of BI results Vendor decontamination of ductwork and HEPA filter banks	February 2023–March 2023
	Submission of Amendment by RO for withdrawal in the eFSAP	March 2023
Upload supporting documentation to the eFSAP	• Timeline of steps taken, including the responsible parties • Pictures of stock destruction and BIs • All documents associated with the transfer and shipment of select agent stock • Room decontamination reports provided by CURIS; map and results of BIs for room decontamination • Invoices (third party) from ductwork and HEPA bank decontamination	March 2023
Remove all strains and serotypes from Section 7B	Completed after instruction from primary contact	March 2023
Remove all personnel, except the RO and PIs from Section 4	Completed after instruction from primary contact	March 2023
On approval, the FSAP will update the entity's status to Withdrawn; perform the changes in Sections 3, 7A, and 7C; withdraw the RO and PIs; and request the inactivation of all entity SAMS accounts. The RO will receive an email from the FSAP POC confirming the finalization of the withdrawal request.	Received	April 2023
Discontinuation of security controls, occupational health program for select agents	Notified security, Occupational health/hospital, locksmith	April 2023

APHIS, Animal Plant Health Inspection Service; BI, biological indicator; BSAT, biological select agents and toxins; CDC, Centers for Disease Control and Prevention; eFSAP, electronic Federal Select Agent Program; FSAP, Federal Select Agent Program; HEPA, high efficiency particulate air; HHP™, Hybrid Hydrogen Peroxide™; PI, principal investigator; POC, point of contact; RO, responsible official; SAMS, secure access management services.

Following these instructions, we formally submitted an amendment in the eFSAP indicating the request for withdrawal and listing the anticipated steps necessary to safely and securely decommission our registered laboratory. The RO, not the AROs, must submit this amendment. The entity's FSAP lead primary point of contact quickly confirmed that the request was received within the eFSAP and acknowledged that we could proceed with the list of tasks for decommissioning. The response also clearly indicated that we must document all steps completed during the laboratory decommissioning process, and all associated documentation must be uploaded to the eFSAP for review and verification before granting withdrawal. In addition, a reminder was provided to indicate that all security measures within the registered facility must remain in place and remain active until official approval for withdrawal is granted in writing by the FSAP.

At this time, to ensure communication to key stakeholders at UTHealth Houston, the RO and AROs provided notification to institutional leadership, Occupational Health, Campus Police, Facilities Management, and the Institutional Biosafety Committee (IBC) regarding the PIs notification of intent to retire, the anticipated steps to be taken for withdrawal, and a promise to keep all stakeholders apprised of decommissioning activities and progress.

Decommissioning Tasks

Once the PI made the intent to retire known, there was a significant decrease in active laboratory work, funding for the associated research, and the total number of authorized laboratory staff was significantly reduced. Particularly, the resulting staffing conditions necessitated the remaining security risk assessment (SRA)-approved personnel to have a more hands-on role during the decommissioning to conduct the necessary work. Besides the PI, these personnel consisted of the RO, AROs, and biological safety professionals, all of whom were already SRA-approved and served to support the registered laboratory.

The initial step in decommissioning was to determine which select agent strains would be intrinsically valuable to the scientific community and should be transferred to other registered entities or a national repository. The PI was responsible for evaluating which stock strains would be suitable to be maintained and which institutions would be available to receive the transfer. Several strains were selected for transfer, and Form 2 transfers were necessary. Although this is a normally straightforward process, as the PIs funding and authorized personnel were reduced, an additional funding source was necessary to pay for the shipment and the AROs were required to directly assist the PI with the select agent transfer since no other authorized staff trained on infectious substance shipping regulations were available.

All remaining stocks not transferred were then destroyed as defined in our biosafety plan and verified with biological indicators. All consumables were destroyed in a similar process. All records maintained inside the laboratory on paper, such as inventory logs, were scanned to a secure file storage site, and the original paper documents were destroyed. Once again, these steps would normally be conducted by authorized laboratory staff, but due to the reduction in funding and staff, the AROs were required to assist the PI in these processes due to lack of available personnel who were authorized to enter the laboratory space unescorted.

After all select agents were removed (transferred or destroyed) from the laboratory, the laboratory was prepared for whole-room decontamination. Freezers were thawed, and all large equipment remaining in the laboratory, such as incubators and centrifuges, were opened to allow for gaseous decontamination. Air supply and exhaust serving the laboratory, as well as doors, were sealed, and the laboratory rooms were decontaminated using the CURIS System's Hybrid Hydrogen Peroxide™ (HHP™) technology (CURIS Decontamination). Apex biological indicators (Mesa Labs) were strategically placed throughout the rooms and equipment, collected after decontamination, and incubated for 7 days to verify successful decontamination.

This decontamination process, from set-up to verification, took 2 weeks. In addition, the ductwork and HEPA banks serving this laboratory were decontaminated with formaldehyde by a third-party vendor. This ductwork and HEPA filter bank decontamination process took an additional 3 days for decontamination, neutralization, and return to normal ventilation status. Both room and ductwork decontaminations required the assistance of several key institutional stakeholders, including the AROs and biosafety program staff, as well as Facilities Maintenance.

Another step required to decommission the laboratory involved the removal of laboratory equipment after decontamination. Since the PI was retiring, decontaminated equipment was removed from the registered laboratory space and turned over to the research department to be evaluated for reuse or transfer to surplus.

Decommissioning Documentation

An amendment to withdraw the registration was submitted through the eFSAP by the RO to start the withdrawal process. Since the FSAP clearly communicated that documentation of the decommissioning processes would be required for the withdrawal to be approved, we compiled and submitted the following documentation through the eFSAP with our withdrawal request:

• Summary of the overall timeline of steps taken, including the responsible parties for each step (this was an internal document used to project manage the withdrawal process, but it was decided that this could be shared with the FSAP to serve as a record of the processes followed).

• Completed Form 2 and all associated documentation related to the select agents transfers, including photographs of the actual stock transfer process.

• All associated documentation of the select agent stock destruction process, including photographs of the actual stock destruction process, photographs of the biological indicators used to verify successful destruction, and the completed autoclave logs.

• Photographs of the decontamination of consumable supplies from the laboratory.

• All associated documentation of the whole room decontamination process (conducted using Curis HHP), including the printed decontamination reports provided by the Curis unit and a room map indicating the results of biological indicators used to verify successful decontamination.

• All associated documentation and invoices from ductwork and HEPA bank decontamination process (conducted using formaldehyde).

• Photographs of the removal of decontaminated equipment from the laboratory.

• Verification that all security controls for the registered laboratory space remained in place during the decommissioning process and further until authorization of withdrawal is granted by the FSAP.

Final Steps and Withdrawal Approval

The above-listed documentation was uploaded to the eFSAP as part of the amendment request. Before withdrawal approval, as a final culminating step, we were required to remove any remaining authorized (SRA-approved) personnel, except the PI and the RO. This included the removal of the AROs, so the timing of this removal was important due to the role served by the AROs to assist with the decommissioning process as previously described. Once all other individuals were successfully removed in eFSAP, only the PI and RO remained on the authorized personnel list. The FSAP then administratively removed both the PI and the RO to complete the steps of the withdrawal process.

To formally complete the entire process, the FSAP issued a letter indicating that the entity had successfully withdrawn and an effective date was included in the communication. The letter also provided specific instructions to maintain all records created under the select agent regulations for a period of 3 years from the date of their creation. Entity records maintained in the laboratory anteroom, such as visitor logs, select agent inactivation records, and autoclave logs used during the course of research during the entity's registration, were removed to the secure long-term storage location defined in our written select agent program plans.

Once the withdrawal letter was issued, security was notified in writing by the RO and AROs that all associated security measures described in the written security plan could be stepped down and discontinued. This included the 15-min response time by security personnel, laboratory door alarms, camera coverage, badge and key access, and other security features previously in place. Facilities Maintenance personnel were also engaged to change the unique key lockset on the laboratory doors so that the department could reclaim the space for other future use.

Discussion

Submitting and processing a FSAP entity registration withdrawal request may be a once-in-a-career activity for biological safety professionals. Each circumstance leading to a withdrawal request will likely differ—in our case, the select agent work was discontinued and not handed off to another research investigator or maintained in any way. An outgoing retiring PI wishing to withdraw the select agent registration posed some unique challenges for our entity, so some of the considerations described be our experience may not necessarily be applicable to all entities.

Given our circumstances of an outgoing retiring PI, resources and staffing were a significant consideration. As mentioned previously, the PI indicated the intent to retire ∼1 year in advance of their departure. It is not unusual for a retiring PI to have a decreased workload, fewer graduate students and staff, and a decline in funding as grants are discontinued. Within non-select agent laboratories, it is often relatively easy to find laboratory staff or students from other areas, or even Environmental Health and Safety personnel, to assist with laboratory cleanouts and closures. However, for a registered select agent laboratory that must follow strict safety and security requirements under the Federal regulations, this significantly limits the total number of individuals who can assist with laboratory decommissioning activities.

For us, this resulted in the AROs and biological safety program staff taking a large portion of the responsibility for decommissioning and hands-on laboratory cleanout. Not only did the AROs serve as project managers for the decommissioning process, they were also required to physically conduct many of the described tasks themselves. This may take significant effort and commitment and should be anticipated for those entities who find themselves in similar circumstances.

Also, the funding necessary for various tasks, including shipping costs for select agent transfers (which are notably expensive since many businesses have discontinued transferring select agents and toxins),¹⁸ decontamination services and associated supplies (e.g., equipment, chemical decontaminant, biological indicators), and other costs, should be accounted for and communicated in advance to the PI and the institution to ensure that sufficient support is provided. We recommend that resources and manpower be forecasted and discussed with the PI and/or organizational leadership as soon as the intent to retire is given to avoid deviation from plans, or possible significant delays, due to these obstacles.

Another important consideration for the withdrawal process is the anticipated timeline of events. Despite best intentions, delays should be anticipated and sufficient time buffers should be incorporated into the timeline for decommissioning activities. Note that entity FSAP registration expiration dates are in effect until the official FSAP letter of withdraw is provided. Also, you may encounter situations where authorized (SRA-approved) personnel are required to renew their SRA approvals concurrent with the decommissioning activities. We recommend informing the PI of the registration renewal date and any associated SRA renewal dates that fall within the decommissioning timeline. Within the time period of submitting our intent to withdraw and completion of the withdraw request, our PI and RO were due for renewal of security clearance. Failure to act on these renewals in a timely manner could be problematic for continued entity compliance and/or progress with decommissioning activities.

Based on our experience, frequent and timely updates on the withdrawal process should be routinely communicated to the IBC and other institutional stakeholders as appropriate. This not only provides assurance to the institution that the appropriate steps are being followed during this unique process, but it also can help to ensure that necessary manpower or resources are allocated to the decommissioning process.

Conclusion

The resources provided for withdrawal within the eFSAP Form 1 Amendment Instructions are relatively basic, and additional details are not currently found in other FSAP guidance documents. Therefore, direct communication and support from the FSAP to the entity RO and ARO(s) are imperative to ensure a safe, secure, and compliant withdrawal. In sharing our experience navigating the withdrawal process from the FSAP, we hope to clarify the actions needed to successfully and compliantly withdraw. Although other entity's experience will likely vary based on the entity's needs and unique circumstances, we have experienced that a registered entity can withdraw from the FSAP within a reasonable time frame.

Presentation Details

The information contained within this article has been accepted for poster presentation at the forthcoming ABSA International Annual Biosafety and Biosecurity Conference in Omaha, Nebraska.

Authors' Contributions

Each author contributed equally to the creation, writing, and editing of this article.

Authors' Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.