Inactivation of Select Agents
FAQs 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 an inactivation certificate must accompany the inactivated material when the inactivated material is transferred externally (from your entity to another entity). It is recommended that an inactivation certificate also accompany the transfer of inactivated material internally (from one PI to another PI at the same registered entity). Additionally, regardless of whether a transfer is made, an entity remains responsible for the record keeping requirements found in section 17(a)(8) of the select agents and toxins regulations. An original certificate must be generated for every sample inactivated regardless of future transfer.
The entity that performed the inactivation or removal procedure must keep the certificate for three years however FSAP recommends that entities retain the inactivation certificate as long as the material is in their possession.
Is there a required format for this certificate?
No specific prescribed format is required; the only requirement is that the document contains 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 the document used must make it clear that the PI signing the document is certifying to the correctness of the information contained in the document. A PI may not sign an inactivation certificate for a sample in advance of the inactivation or removal procedure being performed on that sample.
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 inactivated specific agent, nucleic acids, or material listed on the certificate; that he or she has reviewed the inactivation or removal procedure used and the validation or verification data; and certifies that the 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 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 (RO) 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 or removal procedure must keep the certificate for three years. However, we strongly recommend that the certificate is kept so long as the inactivated or select agent removed 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 or select agent removed material is not required to keep the certificate. However, we strongly recommend that the certificate is kept so long as the material exists to clearly demonstrate that the material was inactivated or no longer contains viable select agent. The entity that performed the 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 samples should 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 or infectivity 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.
Does a nucleic acid extraction procedure performed on a select agent sample meet the requirements found in sections 3d(4) and 4d(4) for the exclusion of that select agent sample from the requirements of the select agent regulations?
The select agent sample would be excluded from the requirements of the select agent regulations if the nucleic acid extraction procedure is used to inactivate the select agent and the procedure had been validated in house by the entity using the procedure. Note, however, that the nucleic acids that result from the extraction may still be regulated. The inactivation requirements found in section 3d(4) and section 4d(4) do apply to the nucleic acid extraction procedure if it is used as a procedure to inactivate a select agent. If so, the procedure would have to be validated in house prior to excluding the material that was subjected to it.
Are nucleic acids extracted for further analysis (such as Polymerase Chain Reaction or sequencing) regulated?
It depends. If the nucleic acids extracted do not meet the definition of regulated nucleic acids (see below) then they are not regulated. If the nucleic acids do meet the definition of regulated nucleic acids then they are regulated.
- 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.
If a nonregistered clinical or diagnostic laboratory uses an “inactivation process” to destroy a select agent or toxin identified in a specimen presented for diagnosis or verification, does the nonregistered clinic or diagnostic laboratory have to use “a validated inactivation procedure that is confirmed through a viability testing protocol” or maintain complete records relating to the “inactivation process” required by section 17 of the select agents and toxins regulations?
Is a registered clinical or diagnostic laboratory that identifies a select agent or toxin contained in a specimen presented for diagnosis or verification exempt from the inactivation and/or the select agent removal requirements?
The Responsible Official must report the identification and final disposition of any select agent contained in a specimen presented for diagnosis or verification pursuant to section 9 (c). Final disposition could include transferring of the select agent material to another registered entity in accord with section 16 of the select agent regulations using the APHIS/CDC Form 2; destroying the select agent material; retaining the select agent (if the entity is registered for that select agent); or inactivating the select agent in accord with sections 3(d)(4) or 4(d)(4), and 17(a)(8).
If a registered entity uses an inactivation procedure to generate material for the identification of a select agent in a specimen presented for diagnosis or verification, the entity does not have to use “a validated inactivation procedure that is confirmed through a viability testing protocol” for the identification or maintain complete records relating to the “inactivation process” because the select agent will not have been excluded from the requirement of the select agent regulations.
However, if a registered entity uses an inactivation procedure to exclude a select agent from the requirements of the select agent regulations pursuant to section 3 (d)(4) or 4 (d)(4), then the entity must meet all of the regulatory requirements found in sections 3(d)(4-5), 4(d)(4-5), and 17(a)(8).