ASSESSMENT OF PROPOSAL FOR AMENDMENT
Assessment of proposal for amendment under section 67A of the HSNO Act (1996)
Summary
This memo provides the EPA staff assessment and recommendation regarding the proposed amendment to the approval of application APP203137.
Introduction
1. South Pacific Sera Limited was granted an approval in 2017, by the EPA’s Chief Executive under delegation. The approval allows the approval holder to develop, as a project, genetically modified cell lines (for a full list see Table 1 of the decision document) in containment for subsequent use in quality control, commercial and research purposes.
Application proposed to be amended
APP203137
Approval holder South Pacific Sera Limited
Purpose of the approval To develop plasmids and standard non-conjugative mammalian expression plasmid vectors in order to transform low-risk mammalian cell lines to express mammalian proteins, for subsequent use in quality control, commercial and research purposes.
Date of approval 1 March 2017
Amendment number APP204245
Purpose of the amendment To include ‘spike sequence of SARS-Cov-2 virus’ to the list of donors of genetic material
Amendment applicant South Pacific Sera Limited
Date of advice 25 June 2021
2. The current controls for APP203137 require the approval holder to develop cell lines within a containment facility that complies with the MAF/ERMA New Zealand Standard: Facilities for Microorganisms and Cell Cultures 2007a, and The Australian/New Zealand Standard AS/NZS 2243.3:2002 Safety in laboratories: Part 3: Microbiological aspects and containment facilities, and Physical Containment level 1 (PC1) requirements of the above Standards (at minimum) for developments involving non-conjugative plasmid cloning and protein expression vectors, in order to transform cultured mammalian cell lines for subsequent use in quality control of existing products and for research and development purposes.
3. The approval holder is seeking to amend this approval to include: ‘spike sequence of SARS- CoV-2 virus’ to the list of donors of genetic material.
4. The controls proposed for APP203137 mitigate the risk of genetically modified organisms (GMOs) escaping from containment. The controls are prescriptive, specifying a set method by which the outcome must be achieved.
5. The original application was not publicly notified, as it met the criteria for the rapid assessment of projects for low-risk genetic modifications. There is no statutory requirement to publicly notify these low-risk applications.
6. The original decision was made by the Chief Executive of the Environmental Protection Authority, under section 40(1) and 42A of the Hazardous Substances and New Organisms (HSNO) Act 1996, taking into account matters relevant to the purpose of the Act, as specified under Part 2 of the Act and the HSNO (Methodology) Order 1998.
7. The power to make amendments under section 67A has been delegated by the Chief Executive to the Group General Manager Regulatory Systems and Operations and the General Manager Hazardous Substances and New Organisms for approvals within their delegated power to decide.1
8. The proposal was formally received on 09 June 2021.
Legislative criteria and EPA guidance
9. Any approval may be amended under section 67A of the HSNO Act, provided the change is minor in effect or corrects a minor or technical error and is within the scope of what was approved.
10. A “minor error” is likely to be an error (a mistake) that is thought to be comparatively unimportant or insignificant. A “technical error” may include typographical or drafting errors related to a technical aspect of the approval and is not restricted to “minor” technical errors.
Changes that are “minor in effect” may include alterations that do not significantly increase risks, especially those risks that are associated with the organism, and on the parties involved.
1 Refer to the instrument of delegation to staff which took effect on 6 March 2020.
11. Changes cannot go beyond the scope of the approval and this will depend on how narrowly or broadly the approval is drafted.
12. Facilities carrying out research under the Regulations must comply with the controls set out in a HSNO Act approval. These controls specify the approved organisms, the types of development to be undertaken, and the standard to which the containment facility using the HSNO Act approval needs to be approved.
13. Please find the ‘decision path for consideration of amendments to existing approvals under section 67A of the HSNO Act’ in the Appendix of this document.
Consultation
Information from other departments
14. The Ministry for Primary Industries (MPI) and the Department of Conservation (DOC) were consulted regarding the proposed amendment.
15. DOC had no objection to this amendment.
16. MPI did not comment on this amendment proposal.
Māori consultation
17. The original application was considered under section 42A of the HSNO Act which does not require public consultation, including Māori consultation. Since the proposed amendment is minor in effect, no Māori consultation was required.
The amendment proposed and staff analysis
The proposed amendment
18. The APP203137 approval currently allows the development of low-risk mammalian cell lines to express coding and non-coding sequences of mammalian protein-coding genes within PC1 containment level. The applicant wishes to add: ‘spike sequence of SARS-CoV-2 virus’ to the list of donor genetic materials.
19. The expression of ‘spike sequence of SARS-CoV-2 virus’ would also be conducted under the same standard (as above), should the amendment be approved.
Assessment of the proposal
20. The proposal seeks to include ‘spike sequence of SARS-CoV-2 virus, obtained from gene bank’
to the list of donors of genetic material.
21. SARS-CoV-2 virus is pathogenic to humans and is the causative agent of the COVID-19 pandemic. SARS-CoV-2 is a coronavirus which, like other coronaviruses recognises and gains entry to a susceptible host cell via a viral surface glycoprotein, called the spike protein (Huang et al. 2020).
22. The genetic modifications under APP203137 conform to Category A of the HSNO (Low-Risk Genetic Modification) Regulations (the Regulations). As per the Regulations, a category A genetic modification is a modification that—
(a) involves a category 1 host organism, as defined in regulation 7(1); and (b) is carried out under a minimum of PC1 containment; and
(c) does not increase the pathogenicity, virulence, or infectivity of the host organism to laboratory personnel, the community, or the environment; and
(d) does not result in the genetically modified organism having a greater ability to escape from containment than the unmodified host organism.
23. The proposed amendment does not amend the list of host organisms, and therefore, if the amendment is approved, the proposed genetic modifications involve category 1 host organisms.
24. The spike protein mediates host cell entry of the virus. Adding ‘spike sequence of SARS-CoV-2 virus’ to the list of donors of genetic material means that the only gene sequence added to the list of approved donor DNA sequences would be the spike sequence of the SARS-CoV-2 virus for expression in the mammalian host cell lines approved under APP203137. Importantly, this would not include the expression of any other SARS-CoV-2 viral proteins, nor allow for the regeneration of the virus. Therefore, the expression of the spike protein in mammalian host cell lines would not increase the pathogenicity, virulence, or infectivity of the host organisms to laboratory personnel, the community, or the environment.
25. Since the spike protein mediates host cell entry of coronavirus, its expression in mammalian host cell lines would not result in the genetically modified organism having a greater ability to escape from containment than the unmodified host organism.
26. Since the proposed amendment would neither change:
• the risk Category of host organisms, nor increase the pathogenicity, virulence, or infectivity of the host organism to laboratory personnel, the community
• the ability of the host cell lines to escape from containment
the expression of the spike protein in mammalian host cell lines can be conducted under a minimum of PC1 containment.
27. Therefore, the proposed amendment conforms to the Category A genetic modification, as per Section 5(1) of the Regulations (see paragraph 22), and the activities proposed for the
additional donor gene are entirely consistent with those already allowed in the current approval.
28. Consequently, the proposed amendment would not change the risk profile of the application.
29. I therefore assess this amendment as minor in effect.
30. Further, as the relevant control that is proposed to be amended is written in an inclusive way, the change can be regarded as not outside the scope of the approval.
31. To accommodate the requested amendment, we propose to amend the purpose statement of the approval. The current purpose statement is “To develop plasmids and standard non- conjugative mammalian expression plasmid vectors in order to transform low-risk mammalian cell lines to express mammalian proteins for subsequent use in quality control, commercial and research purposes”, which we are proposing to amend it to “To develop plasmids and standard non-conjugative mammalian expression plasmid vectors in order to transform low-risk
mammalian cell lines to express mammalian proteins, and the spike protein from the SARS- CoV-2 virus, for subsequent use in quality control, commercial and research purposes”.
Although the purpose statement will be amended, the scope of the approval will not be changed as explained in this memorandum.
Matters in Part 2 of the Act
32. The proposed amendment relates to an approval for a GM development in containment application. The change proposed by the amendment is minor in effect and will not alter the risks of this research. As such, I do not think that the purpose, principles or matters to be considered (sections 4-8 of the HSNO Act) would be adversely affected by the proposed amendment.
Conclusion and Recommendation
33. In assessing whether the proposed amendment meets the criteria required for an amendment under s67A of the HSNO Act, I conclude that the amendment is minor in effect, as there is no change in the risk posed by including ‘spike sequence of SARS-CoV-2 virus’ to the list of donors of genetic material and the purpose statement of the approval, and the controls provide for suitable containment of the organisms expressing the spike protein.
34. I did not identify any cumulative effects resulting from the current proposed amendment and further, the amendments will not change the risk profile of the original approval.
35. The proposed amendment may be achieved by adding the additional donor of genetic material to the Table 1 of the approval document. The added donor of genetic material is distinguished by tracked changes in the approval document for you to review.
36. I recommend that you approve the amendment of the approval document for application APP203137 under section 67A of the HSNO Act, as the proposed amendment is to include
‘spike sequence of SARS-CoV-2 virus, obtained from gene bank’ to the list of donors of genetic material, and thus the amendment is minor in effect.
25 June 2021 Senior Advisor, New Organisms Date
Hazardous Substances and New Organisms
Appendix: Decision path for consideration of amendments to existing approvals that are ‘minor in effect’ or to correct a ‘minor or technical error’ under section 67A of the HSNO Act, and explanatory notes
For proper interpretation of the decision path it is important to work through the flowchart in
conjunction with the explanatory notes.
Figure 23 Explanatory Notes
Item 1: Review all information on the proposed alterations (including possible consultation) Review all information, including any information provided by other agencies or experts. This should enable the HSNO decision maker to clearly evaluate the proposed alteration(s) against the criteria set out in section 67A for making an amendment, namely whether the HSNO decision maker considers the amendment to be ‘minor in effect’ or to correct a ‘minor or technical error’.
Item 2: Does the proposed alteration correct an error?
Taking each proposed alteration in this category in turn, review whether the alteration corrects an error. An ‘error’ can be described as something done incorrectly because of ignorance or inadvertence: a mistake
Item 3: (if ‘yes’ from item 2) Is the error ‘minor or technical’?
If the proposed alteration is to correct an error, consider whether the error meets the criteria for
‘minor or technical error’, as described with detail in the Key Concepts protocol “‘Minor in effect’
or ‘minor or technical error’”.
Item 4: (if ‘no’ from item 2 or 3) Does the proposed alteration meet the criteria for ‘minor in effect’?
If the proposed alteration does not correct a ‘minor or technical’ error, consider whether the alteration meets the criteria for ‘minor in effect’ as described with detail in the Key Concepts protocol “Minor in effect’ or ‘minor or technical error’”2.
If a proposed alteration meets the criteria for ‘minor in effect’, continue to item 5. If any of the proposed alterations do not meet these criteria move to item 7 and discard the proposed alterations. While these are unable to be considered under section 67A, it may be appropriate for them to be resubmitted as an application under section 63A for hazardous substances (modified reassessment) or section 63 for both hazardous substances and new organisms (full reassessment).
Item 5: (if ‘yes’ from item 4) Include alteration
If the proposed alteration meets the criteria for ‘minor in effect’, include this alteration for final consideration and confirmation in item 9, and continue to item 8.
Item 6: (if ‘yes’ from item 3) Include alteration
If the proposed alteration meets the criteria for correcting a ‘minor or technical error’, include this alteration for final consideration and confirmation in item 9, and continue to item 8.
Item 7: (if ‘no’ from item 4) Discard this proposed alteration
If the proposed alteration did not meet the criteria for correcting a ‘minor or technical error’ or
‘minor in effect’, discard this proposed alteration and do not consider it further.
Item 8: Have all proposed alterations been considered?
Check whether all the proposed alterations for ‘minor in effect’ and to correct a ‘minor or technical error’ have been considered. If not, then return to item 2 and consider the remaining alterations. If all proposed alterations have been considered, continue to item 9.
Item 9: (if ‘yes’ from item 8) Having considered the matters in Part 2 of the Act, the approval may be amended with the alterations to come from items 5 & 6.
Considering each alteration identified in items 5 and 6 that has met the criteria specified in section 67A, review in terms of the matters described in Part 2 of the Act and decide whether to make the alteration, noting that the Authority retains the discretion as to whether or not to make the alteration.
Once consideration has been given to all alterations that have met the criteria, the approval may be amended.
References
Huang Y, Yang C, Xu XF, Xu W, Liu SW 2020. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin 41(9):
1141-1149.
