Inactivation of Select Agents
FAQ's by Topic
- Due Diligence
- Inactivated Bacillus anthracis
- Legislature, Regulation, and Guidelines
- Personnel Suitability
- Report of the Identification of a Select Agent or Toxin
- Responsible Official
- Restricted Experiments
- Security Risk Assessments
- Select Agents and Toxins
- Theft, Loss, and Release
What information does an inactivation certificate need to include?
Section 17(a)(8)(vii) of the regulation requires a certificate for each sample of a select agent or material containing select agents or regulated nucleic acids that can produce infectious forms of any select agent virus that has been subjected to a validated inactivation procedure or viable select agent removal procedure to include: the date of inactivation or viable select agent removal, a written description of the validated inactivation or viable select agent removal method used, and the name and signature of the Principal Investigator responsible for the select agent, nucleic acids, or material. A copy of this certificate must accompany any transfer of the inactivated select agent, nucleic acids, or material, regardless of to whom it will be transferred or where it will go.
Is there a required format for this certificate?
No specific prescribed format is required; the only requirement is that it is a document containing the information required by the regulations. For example, the information can be added to the inventory log or other documentation. This documentation can be batched and recorded outside of containment. The document must be signed before the samples are removed from the appropriate biocontainment level in registered space, and document used must make it clear that the PI signing the document is certifying to the correctness of the information contained in the document.
What is the role of the Principal Investigator in this process?
As described above and in section 17 (a)(8)(vii) of the regulations, a certificate must contain the name and signature of the Principal Investigator (PI). The name and signature of the PI identifies which PI is responsible for the specific agent, nucleic acids, or material listed on the certificate; that he or she has reviewed the inactivation procedure used and the validation or verification data; and certifies that the inactivation procedure was used correctly. The PI does not have to be present during the actual performance of the inactivation or select agent removal procedure. A certificate should be signed by the PI as close to the date of inactivation as possible; and can be recorded outside of containment. A copy of the certificate must accompany the materials when transferred to another entity. FSAP recommends a certificate of inactivation accompany all transfers of inactivated select agents (includes intra-entity transfers). A PI may not sign an inactivation certificate for a sample in advance of the procedure being performed on that sample.
The PI who signs the certificate is the one individual who is designated by the entity to direct a project or program and who is responsible to the entity for the scientific and technical direction of that project or program (including all inactivation procedures or removal procedures associated with that project). In the absence of that PI, an individual designated by that PI and approved by the entity’s Responsible Official can sign the certificate but only during the duration of the PI’s absence. Each absence of a PI requires a new delegation.
In order for an individual to be the PI’s designee to sign the certificate, a person must:
- Be listed on the entity’s registration
- Have the knowledge and expertise to provide scientific and technical direction regarding the validated inactivation procedure or the procedure for removal of viable select agent to which the certificate refers. If this requirement causes unintended consequences please contact FSAP.
Is the entity that performed the inactivation procedure required to keep the certificate?
Yes. The entity that performed the inactivation procedure must keep the certificate for three years. However, we strongly recommend that the certificate is kept so long as the inactivated sample exists to clearly demonstrate that the material was inactivated.
Is the receiving entity required to retain the inactivation certificate that accompanied the transfer?
No. The entity receiving inactivated material is not required to keep the certificate. However, we strongly recommend that the certificate is kept so long as the inactivated sample exists to clearly demonstrate that the material was inactivated. The entity that performed the inactivation procedure must keep the certificate for three years.
Does a select agent or regulated nucleic acid that was subjected to a validated inactivation procedure prior to March 21, 2017 need to be re-validated as inactivated by the entity?
No. The provisions are to be implemented on any samples inactivated on or after the effective date of the regulations and do not apply retroactively. However, entities should follow prudent practices based on risk assessments.
Is an annual review required by the Responsible Official for the inactivation protocols?
Yes. The review must be conducted annually or after any change in Principal Investigator for those protocols used by that PI, after any change in a validated inactivation procedure or a viable select agent removal method, or after any failure of a validated inactivation procedure or viable select agent removal method. However, the annual review does not mean the procedures have to be revalidated. For example, the RO could review the inactivation procedures and determine that they are still being used as designed and work as intended. In this situation, revalidation would not be necessary.
Do I need to revalidate the inactivation protocol if I plan to use a lower concentration of select agent material being inactivated?
No. However, revalidation would be required if there is a higher concentration of material being inactivated.
If we perform an in-house validation of an inactivation method and verify that the method is successful by testing 100% of the initial sample, do we have to also test 10% of any future samples that we treat using this validated inactivation method?
As long as the validated inactivation method conditions remain consistent for treating future samples, any decisions to verify the inactivation of future samplesshould be made based on the entity’s risk assessment (with the exception of Bacillus anthracis and Bacillus cereus Biovar anthracis, which is subject to the specific requirements in the Inactivated Bacillus anthracis and Bacillus cereus Biovar anthracis policy). In most cases, once an entity has developed and validated an inactivation procedure, they will have to verify the validated procedure depending upon the type of sample. This involves determining a sampling strategy for viability, infectivity, or toxicity testing for subsequent inactivation.
Do I have to develop (and then validate in-house) my own inactivation procedure to meet the requirements or can I validate an existing procedure in-house to meet the regulatory requirements?
An entity can certainly develop and validate their own inactivation procedure, or the entity can use an already developed (commonly accepted or published) inactivation procedure that the entity validates in-house.
To validate an inactivation procedures means an entity has performed a viability testing protocol in-house to confirm the efficacy of the inactivation procedure.
Do I have to validate in-house the methods used for disinfection, decontamination or destruction of select agent waste?
No. Although the regulations require written procedures for each validated method used for disinfection, decontamination or destruction, as appropriate, of all contaminated or presumptively contaminated materials, an entity does not have to validate the method in-house. A validated method is a method that has been shown to render materials safe to handle (i.e., safe in the context of being reasonably free from a risk of disease transmission). The validation of methods for disinfection, decontamination or destruction of select agent waste does not have to occur in-house since this material is not for future use. Further, validation does not have to be performed on select agents but can be performed on surrogates. However, entities must use the concentrations and conditions prescribed by manufacturers, the BMBL, or other government regulations, such as those promulgated by the Environmental Protection Agency (EPA). The inactivation provisions for future use material do not apply to disinfection, decontamination or destruction of select agent waste.
If a laboratory receives a diagnostic sample and extracts nucleic acids for polymerase chain reaction (PCR), do the inactivation requirements found in section 3d(4) and section 4d(4) apply to the extracted nucleic acids?
The inactivation requirements found in section 3d(4) and section 4d(4) do not apply if the purpose of the diagnostic work is not for future use of a known select agent, and the nucleic acids extracted do not meet the definition of regulated nucleic acids:
- Nucleic acids that can produce infectious forms of any of the select agent viruses or
- Recombinant and/or synthetic nucleic acids that encode for the toxic form(s) of any of the 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].
However, if the diagnostic work identifies a select agent, then the original clinical or diagnostic sample would be considered a select agent and must be transferred or destroyed on-site (by a recognized sterilization or inactivation process) within seven calendar days after delivery of patient care by health care professionals has concluded, or put into long term storage inventory (if registered).
It is strongly recommended, but not required, that a clinical or diagnostic laboratory validates their inactivation procedures in-house to reduce the risk of failure of an inactivation procedure. The failure of a clinical or diagnostic laboratory to destroy a select agent or toxin using an inactivation procedure could result in civil and/or criminal penalties.
Are nonregistered clinical or diagnostic laboratories and other entities that possess, use, or transfer a select agent or toxin that is contained in a specimen presented for diagnosis or verification exempt from the inactivation requirements?
Yes, so long as
- Unless directed otherwise by the HHS Secretary, within seven calendar days after identification of the select agent or toxin (except for Botulinum neurotoxin and/or Staphylococcal enterotoxin (Subtypes A–E)), or within 30 calendar days after identification of Botulinum neurotoxin and/or Staphylococcal enterotoxin (Subtypes A–E), the select agent or toxin is transferred in accordance with § 73.16 or destroyed on-site by a recognized sterilization or inactivation process,
- The select agent or toxin is secured against theft, loss, or release during the period between identification of the select agent or toxin and transfer or destruction of such agent or toxin, and any theft, loss, or release of such agent or toxin is reported, and
- Unless otherwise directed by the HHS Secretary, the clinical or diagnostic specimens collected from a patient infected with a select agent are transferred in accordance with § 73.16 or destroyed on-site by a recognized sterilization or inactivation process within seven calendar days after delivery of patient care by health care professionals has concluded, and
- The identification of the agent or toxin is reported to CDC or APHIS, the specimen provider, and to other appropriate authorities when required by Federal, State, or local law by telephone, facsimile, or email. This report must be followed by submission of APHIS/CDC Form 4 to APHIS or CDC within seven calendar days after identification.