Chapter 10: Federal Select Agent Program

The U.S. Department of Health and Human Services (DHHS) and the U.S. Department of Agriculture’s (USDA) regulations require institutions that possess, use, or transfer certain biological agents and toxins (known as “select agents”) be registered and approved by the Federal Select Agent Program (FSAP). The FSAP have identified specific biological agents and toxins they consider to be a severe threat to public health and safety because of their potential use as bioterrorism agents. These materials are referred to as “Select Agents”. Their transfer, possession, use, and disposal are strictly regulated. On December 4, 2012, the CDC and APHIS (now the FSAP) implemented the amendment to the regulation and identified certain select agent and toxins as Tier I. These Tier I agents have additional requirements on security, biosafety and occupational health.

This chapter will refer to all these agents as “Select Agents.” The current list of select agents is provided at the end of this chapter. Because the list of select agents may be revised, it is recommended that the Federal Select Agent Program website be checked before acquiring pathogenic agents and biological toxins.

The regulations associated with select agents are very complex and strict, and significant monetary fines and criminal penalties are associated with non-compliance. The information in this chapter is a summary of the select agent regulations; it is not a complete description of the regulatory requirements. Investigators must review and understand the select agent regulations and their responsibilities prior to acquiring or working with any select agent (for regulatory information, see the CDC website).

Responsible Official and Authorization

Responsible Official (RO)

Select agent regulations require that a RO be designated for each institution that possesses and uses select agents.

The RO has institutional responsibility for the biosafety, security, and regulatory compliance of select agents, and as such, must be contacted prior to obtaining any select agents.

Authorization to Possess and Use Select Agents

Prior to personnel obtaining any select agent, the IBC must review and approve any proposed work. In addition, PIs who want to acquire, possess, or use any biological agent or toxin listed as a select agent must be registered and approved with the FSAP prior to obtaining the agent(s) or toxin(s).

The FSAP must approve both the institution and the individual laboratory. Investigators who want to possess and use select agents must contact the RO for assistance with the registration application process. Approval by the FSAP can take several months, and PIs should plan research projects accordingly.

The select agent regulations contain very strict requirements regarding biosafety, training, emergency response, security and accountability, as well as other requirements. Investigators wanting to acquire select agents should thoroughly review the Federal select agent regulations before initiating the registration application process.

Exemptions and Exclusions

Diagnostic labs that do not maintain select agents are largely excluded from the Federal select agent regulations; however, notification and possession time limits and other requirements do apply. Additionally, the FSAP can grant exclusions for temporary public health emergency situations and other special circumstances. Consequently, any laboratory that conducts diagnostic or verification testing for any select agent must identify itself by contacting the RO as soon as possible. Identification of any select agent in a specimen or isolate must be reported to the RO immediately. The RO will assist the diagnostic laboratory with reporting to FSAP immediately after identification. Laboratories must fill out and submit “Report of the Identification of a Select Agents or Toxin” (Form 4) within 7 days of the identification. Form 4 can be found on the FSAP website.

Several specific select agent microbial strains and toxin forms have been determined not to present a severe threat to public health and safety and are therefore excluded from the Federal select agent regulations. The list of excluded biological agents and toxins is dynamic and the most current list is available on the FSAP select agent website. Permissible amounts of the listed biological toxins do not fall under the regulation as long as they meet the threshold quantities. Laboratories maintaining these exempt quantities of select agent toxins must register their toxin with the IBC and keep an accurate inventory of toxin amounts to verify that total quantities are below the threshold.

Security, Incident response and Biocontainment requirements

Each select agent laboratory must develop and implement three written plans: security; incident response; and biosafety; that address safety issues associated with that specific select agent.

Security Requirements

Each select agent laboratory must have a written security plan that addresses the following topics:

• Site-specific security risk assessment
• Information system security control
• Storage control and inventory audits of select agents
• Select agent shipping and transfers
• Roles and responsibilities and training
• Reporting of unauthorized persons, suspicious activities and missing materials
• Access control and escort provisions for cleaning, maintenance, and repairs

Any theft or loss of select agents must be immediately reported to the RO, BU Police and EHS, which will notify the FSAP. In addition, the BPHC will be notified of such events. BU in collaboration with City Agencies (BPHC, Boston Fire Department, Boston Police Department and EMS) has developed an Emergency Notification and After-Action Guideline High Risk Materials Matrix outlining the list of agencies and events for which they will be notified.

This plan must be available and up-to-date during a CDC inspection.

The Department of Justice must approve all persons who will have access to any select agent. Approval requires that each individual successfully pass a background security check (conducted by the FBI in accordance with the USA Patriot Act) and submit fingerprints to the FBI. Anyone who has not been approved for access to select agents must be denied access unless escorted by an approved person. Everyone who enters a laboratory where select agents are accessible must have security approval or be accompanied by an approved person. This includes visiting scientists (on or off-campus), maintenance workers, custodians, and vendors.

Please see the CDC/USDA Security Plan Guidance document for more information.

Incident Response Plan

Each laboratory that possesses or uses select agents must develop a written emergency plan that is laboratory specific and coordinated with department, building, and Institutional emergency plans. The plan must address the following:

• Loss, theft, or release of a select agent or toxin
• Inventory discrepancies
• Security breaches (including information systems access controls to select agents and toxins)
• Severe weather and other natural disasters
• Workplace violence
• Bomb threats and suspicious packages
• Emergencies such as fire, gas leak, explosion, or power outage
• Planning and coordination with emergency responders
• Building evacuation, site security, and control
• Decontamination and emergency medical treatment, and other emergency response issues

Any exposure or potential exposure should be reported immediately, and the BU Incident Response Plan for Select Agent Laboratories and the Biological Spill Response Plan for Select Agent Laboratories implemented.

Affected personnel should immediately contact the ROHP for medical evaluation and treatment by calling (617) 358-7647(ROHP).

Please see the CDC/USDA Incident Response Plan document for more information.

Laboratory personnel should become familiar with these plans.

Biocontainment
All persons approved for access to select agents must receive documented training covering the following:

• Hazardous characteristics of select agents and their safe handling, use, and disposal
• Safeguards for protecting against exposure to select agents, requirements and procedures
• Biological safety and personal protective equipment (PPE) requirements
• Disinfection, decontamination or destruction of select agents
• Handling select agents and in shared spaces

For more information on biocontainment, please see the CDC and USDA’s Select Agents and Toxins Biosafety/Biocontainment Plan Guidance.

Training of Personnel

Training in all aspects of delineated in the Security, Incident Response and Biosafety Plans is required before beginning work with select agents and annually thereafter.

Transfers of Select Agents

Select agents can only be transferred to, or between, entities that are currently approved by the FSAP to possess and use select agents. All transfers of select agents require prior approval of the FSAP.

Both the sender and recipient must complete a common transfer form (Form 2), and the recipient must submit the form 2 request to the FSAP for approval. Form 2 requires the signature of the RO at both the sender and recipient facilities. When the select agent is consumed or destroyed, the recipient must notify FSAP through an update of their registration.

Inventory and Disposal of Select Agents

An accurate record of all select agents, from receipt to destruction or disposal, must be maintained.
The inventory must include specific information on individual containers and vials, as well as a record of each use, and ultimate disposal. The select agent inventory must be verified twice a year to account for all quantities and containers of select agents. Any discrepancies between the inventory record and the actual inventory must be reported immediately to the RO.

For more information, please see Guidance on the Inventory of Select Agents and Toxins.

Records Required for Select Agents

Select agent regulations require that several records be maintained, including the following:

• Biocontainment certifications
• Laboratory notebooks
• Institutional Biosafety and Animal Use Committees minutes
• Records associated with occupational health and suitability programs
• Training records
• Transfer documents (Form 2)
• Safety and security incident reports

Each laboratory/institution is responsible for maintaining these records. The recordkeeping requirements are complex, and therefore the FSAP regulations should be reviewed for a complete description of the recordkeeping requirements.

Recordkeeping for Select Agent Laboratories

The following is a list of required recordkeeping for all select agent inventory and access records, per FSAP regulations.

Inventory Records

The Logbook Inventory must contain the following elements:

• Name, characteristics, designation data;
• Quantity acquired, source, date;
• Where stored (e.g., building, room, and freezer);
• Quantity, volume, used, purpose of use, destroyed or disposed of date, individual;
• Transfers: quantity, date, individual;
• Current quantity held;
• Lost, unaccounted for, stolen;
• Written explanation of any discrepancy.

Access Records

Access Records must contain the following elements:

• Access to SA: Name, SA, date Access to Area: Name, date, and time entered and left area; uncleared individuals must be accompanied by approved individuals and recorded as such.

Records are reviewed routinely by the RO and EHS to ensure that they are being maintained and updated appropriately. Records must be maintained for three (3) years.

Further information regarding select agents and records will be given to laboratories working with select agents in specialized safety training by laboratory personnel authorized to work with such agents.

Procedures for Select Agent Procurement and Receipt

Procedure Description

The BSL3 / BSL4 Transportation Plan establishes the BU procedures to be followed when obtaining biological agents and toxins that have been designated as “Select Agents” under Federal Regulation (42 CFR 73.0, 7 CFR 331, 9 CFR 121).

For the transportation of Select Agents, Boston University follows the regulations of other international, federal, state, and local authorities including the Department of Transportation, the FSAP/CDC, International Air Transportation Authority, and World Health Organization on the transportation of Select Agents to ensure pathogens are safely shipped to and from the labs. The general requirements are issued by the US Department of Transportation, which sets down strict requirements for packaging, labeling, and documentation of the materials, and requires training for employees involved in shipping.

All transportation of Select Agents will involve Department of Transportation (DOT) compliant triple packaging and will be placed in a non-crushable, liquid-tight, solid container for an added layer of safety. These packages will be transported via exclusive-use vehicles and will be secured in the transport vehicle away from potential impact on outer walls. In addition, shippers will adhere to pre-determined travel routes and strictly defined schedules for pick-ups and deliveries, and both package and vehicle will be monitored by BU and local emergency responders using GPS.

For more information, please see the Boston Public Health Commission website.

The FSAP/CDC also regulates the shipment of Select Agents. Qualified carriers must meet all federal, state and local regulations to transport select agent materials. There will be notifications to the Boston Public Health Commission, Boston Police and Fire Departments, and Boston Emergency Medical Services in advance of shipments and GPS monitoring of the vehicle and package. The transportation of Select Agents is tightly controlled, and BU has worked closely with city, state, and federal authorities to ensure that our transportation plan complies with all regulations. Boston University’s Select Agent transportation plan significantly exceeds requirements and standards in place.

This SOP incorporates the requirements of the BU Materials Transportation Management Policy.
The BU Select Agent Transportation Plan outlines the procedures for the transfer of select agents between BSL-4 laboratories. For more information about select agent transportation contact the BSO.

Approval and Transportation Process

Initial Request for Select Agent

• PI notifies the BUBSO that a select agent needs to be ordered at least two weeks before anticipated use date.
• PI obtains any applicable USDA permits that may be required for the interstate transport of the select agent, and provides permits to RO.

BSO’s Review

Upon receipt of request to acquire select agent, the BSO:

• Confirms that the PI is an authorized select agent user.
• Confirms that IBC approvals, training, and inspection status are valid and current.
• Confirms that appropriate laboratory and storage facilities are available.

RO’s Approval

• RO or Alternate RO completes Section 1 of the Form 2 requesting the transfer of select agents and submit it for approval by the Federal Select Program (FSAP).
• For imported select agents, the RO or Alternate RO works with the PI to obtain any needed CDC Import permit, USDA and/or U.S. Public Health Service (PHS) permit.

Federal Approval

• APHIS/CDC issues an approval authorization number that is good for 30 days. Faxes approved Form 2 to Recipient (BU RO) and Sender RO.

Shipping Process

Order Placement

• BSO designates a transporter to be used who meets the selection criteria of the BU Materials Transportation Policy described in Chapter 11.
• The BSO, upon approval of Form 2 and authorization number from the RO, coordinates transport of the select agent with the shipper to use a method that tracks the movement of the select agent being shipped and is in accordance with the BU Materials Transportation Policy. Coordinates shipment details and tracking with transporter.
• Sender RO/ARO complete Section 2 of the Form2 and coordinates shipment details with BU RO and BSO. Packages, labels, and ships select agent in accordance with all federal regulations.

Notifications

The BSO notifies the following of shipment, date, and time of delivery:

• RO
• PI/Authorized User (Recipient)
• Executive Director of Public Safety
• City of Boston and Boston Public Health Commission
• Manager of Emergency Planning and Response

Transportation

• Transporter accepts, stores, loads and delivers package(s) to the approved location, using approved access routes.
• Transporter reports any and all violations of law, regulation, and/or policy.
• Transporter will contact BSO for any problem or incident that may occur during transit with select agents.

Receipt

Steps Prior to Arrival

• RO, BSO, and PI verify that appropriate laboratory and/or storage facilities are available.
• RO and Executive Director of Public Safety or designee review security procedures for receipt and transfer prior to the day of scheduled arrival, which includes the means for securing of the loading dock.
• The Executive Director of Public Safety or designee will ensure that a BU public safety officer provides escort for the RO and subject materials package.

Arrival and Receipt

• Upon the transporter’s arrival, the RO and Executive Director of Public Safety or their designee(s) verify identity of drivers and accuracy of the shipping papers.
• RO or designee instructs drivers to wait until the package contents are verified.
• The public safety officer will escort the RO or designee to the approved select agent laboratory.

The actual course of action will depend on whether or not there is any sign of obvious leakage, the extent of the damage or suspicion that the integrity of the internal packaging container has been compromised. The action taken may include:

• Over-packing of the package and removal to the laboratory to check the contents to check the integrity of the inner package
• Leaving the container in place for further evaluation by public agencies for additional course of action
• Containment of any leakage within the transport vehicle will be achieved by use of appropriate (i.e. effective for the agent) absorbent materials and disinfectants.

Verification of Shipment

• After donning appropriate personal protection equipment and following established laboratory procedures, the PI and RO or their designee(s) take the unopened package to a previously designated biological cabinet (in a laboratory appropriate for a select agent).
• The PI and RO or their designee(s) examine the package for any signs of tampering, damage, or leakage and then open the package and verify contents.
• The public safety officer will wait outside the laboratory while verification of the shipment occurs.
  If all is in order (no non-conformities) and the contents are verified, the RO or designee finalizes the transporter’s shipping papers.

Notification and Documentation

• The RO then completes Section 3 of Form 2 within 24 hours of receipt, and submit it to the FSA.
• The PI enters the select agent into inventory per established procedure.

Discrepancies

Notification

In the event of non-conformity with the shipment, the RO will immediately notify:

• The Executive Director of Public Safety to hold the transporter.
• FSAP, BPHC and local law enforcement and the Department of Justice in the event of theft or loss.
• RO/ARO complete and transmit a loss or release of select agent Form3 to the FSAP.

References

• APHIS/CDC Guidance Document for Report and Transfer of Select Agents and Toxins (APHIS/CDC Form 2)
• APHIS/CDC Guidance Document for the Report of Theft, Loss or Release of Select Agents and Toxins (APHIS/CDC Form 3)
• Federal Select Agent website
• BU Materials Transportation Management Policy

List of Select Agents

HHS and USDA Select Agents and Toxins

The following biological agents and toxins have been determined to have the potential to pose a severe threat to both human and animal health, to plant health, or to animal and plant products. An attenuated strain of a select agent or an inactive form of a select toxin may be excluded from the requirements of the Select Agent Regulations. Excluded agents and toxins are listed separately.

1. Abrin [6]
2. Bacillus cereus Biovar anthracis [1]
3. Botulinum neurotoxins [1][6]
4. Botulinum neurotoxin producing species of Clostridium [1]
5. Conotoxins (Short, paralytic alpha conotoxins containing the following amino acid sequence X1CCX2PACGX3X4X5X6CX7) [6]
6. Coxiella burnetii
7. Crimean-Congo haemorrhagic fever virus
8. Diacetoxyscirpenol [6]
9. Eastern Equine Encephalitis virus [4][5]
10. Ebola virus [1]
11. Francisella tularensis [1]
12. Lassa fever virus
13. Lujo virus
14. Marburg virus [1]
15. Monkeypox virus [4]
16. Reconstructed replication competent forms of the 1918 pandemic influenza virus containing any portion of the coding regions of all eight gene segments (Reconstructed 1918 Influenza virus)
17. Ricin [6]
18. Rickettsia prowazekii
19. SARS-associated coronavirus (SARS-CoV) [5]
20. SARS-CoV/SARS-CoV-2 chimeric viruses resulting from any deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors
21. Saxitoxin [6]
    South American Haemorrhagic Fever viruses:
22. Chapare
23. Guanarito
24. Junin
25. Machupo
26. Sabia
27. Staphylococcal enterotoxins (subtypes A,B,C,D,E) [6]
28. T-2 toxin [6]
29. Tetrodotoxin [6]
    Tick-borne encephalitis complex (flavi) viruses:
30. Far Eastern subtype [5]
31. Siberian subtype [5]
32. Kyasanur Forest disease virus [5]
33. Omsk hemorrhagic fever virus [5]
34. Variola major virus (Smallpox virus) [1]
35. Variola minor virus (Alastrim) [1]
36. Yersinia pestis [1]
    Overlap Select Agents and Toxins
37. Bacillus anthracis [1]
38. Bacillus anthracis Pasteur strain
39. Brucella abortus
40. Brucella melitensis
41. Brucella suis
42. Burkholderia mallei [1]
43. Burkholderia pseudomallei [1]
44. Hendra virus
45. Nipah virus
46. Rift Valley fever virus
47. Venezuelan equine encephalitis virus [4][5][8]
    USDA Veterinary Services (VS) Select Agents and Toxins
48. African horse sickness virus
49. African swine fever virus
50. Avian influenza virus [4]
51. Classical swine fever virus [5]
52. Foot-and-mouth disease virus [1][5]
53. Goat pox virus
54. Lumpy skin disease virus
55. Mycoplasma capricolum [4]
56. Mycoplasma mycoides [4]
57. Newcastle disease virus [3][4]
58. Peste des petits ruminants virus
59. Rinderpest virus [1]
60. Sheep pox virus
61. Swine vesicular disease virus [5]
    USDA Plant Protection and Quarantine (PPQ) Select Agents and Toxins
62. Coniothyrium glycines (formerly Phoma glycinicola and Pyrenochaeta glycines)
63. Peronosclerospora philippinensis (Peronosclerospora sacchari)
64. Ralstonia solanacearum [7]
65. Rathayibacter toxicus
66. Sclerophthora rayssiae [7]
67. Synchytrium endobioticum
68. Xanthomonas oryzae

<h5>Footnotes</h5>

[1] Denotes Tier 1 Agent
[2] C = Cysteine residues are all present as disulfides, with the 1st and 3rd Cysteine, and the 2nd and 4th Cysteine forming specific disulfide bridges; The consensus sequence includes known toxins a-MI and a-GI (shown above) as well as a-GIA, Ac1.1a, a-CnIA, a-CnIB; X1 = any amino acid(s) or Des-X; X2 = Asparagine or Histidine; P = Proline; A = Alanine; G = Glycine; X3 = Arginine or Lysine; X4 = Asparagine, Histidine, Lysine, Arginine, Tyrosine, Phenylalanine or Tryptophan; X5 = Tyrosine, Phenylalanine, or Tryptophan; X6 = Serine, Threonine, Glutamate, Aspartate, Glutamine, or Asparagine; X7 = Any amino acid(s) or Des X and; “Des X” = “an amino acid does not have to be present at this position.” For example if a peptide sequence were XCCHPA then the related peptide CCHPA would be designated as Des-X.
[3] A virulent Newcastle disease virus (avian paramyxovirus serotype 1) has an intracerebral pathogenicity index in day-old chicks (Gallus gallus) of 0.7 or greater or has an amino acid sequence at the fusion (F) protein cleavage site that is consistent with virulent strains of Newcastle disease virus. A failure to detect a cleavage site that is consistent with virulent strains does not confirm the absence of a virulent virus.
[4] Select agents that meet any of the following criteria are excluded from the requirements of this part: Any low pathogenic strains of avian influenza virus, South American genotype of eastern equine encephalitis virus, west African clade of Monkeypox viruses, any strain of Newcastle disease virus which does not meet the criteria for virulent Newcastle disease virus, all subspecies Mycoplasma capricolum except subspecies capripneumoniae (contagious caprine pleuropneumonia), all subspecies Mycoplasma mycoides except subspecies mycoides small colony (Mmm SC) (contagious bovine pleuropneumonia), and any subtypes of Venezuelan equine encephalitis virus except for Subtypes IAB or IC, provided that the individual or entity can verify that the agent is within the exclusion category.
[5] For determining the regulatory status of nucleic acids that are capable of producing infectious forms of select agent viruses, please reference guidance here.
[6] For determining the regulatory status of Recombinant and/or Synthetic nucleic acids that encode for the toxic form(s) of any select toxins if the nucleic acids (i) can be expressed in vivo or in vitro, or (ii) are in a vector or recombinant host genome and can be expressed in vivo or in vitro; please reference guidance here.
[7] Select agents or toxins that meet any of the following criteria are excluded from the requirements of this part: Any subspecies of Ralstonia solanacearum except race 3, biovar 2 and all subspecies of Sclerophthora rayssiae except var. zeae, provided that the individual or entity can identify that the agent is within the exclusion category.
[8] Modified Venezuelan Equine Encephalitis Virus TC-83(A3G) strain is a select agent.