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The European perspective on regulatory
aspects and experiences with dsRNA-
based products
Achim Gathmann
Federal Office of...
Outline
• Experiences in the EU
• Principles in the authorisation process of Plant Production
Products (PPP) in the EU
• W...
Experiences in the EU
18.04.2019Achim Gathmann, BVL 3
• No dsRNA-based plant protection product is authorised in the EU
ye...
Experiences in the EU
18.04.2019Achim Gathmann, BVL 4
• EFSA (GMO unit)
– organised Workshop in June 2014 (EFSA 2014, EN-7...
Outline
• Experiences in the EU
• Principles in the authorisation process of Plant Production
Products (PPP) in the EU
• W...
Steps placing plant protection products
on the market
Active substances (a.s.):
Assessed on EU level
Approval for at least...
• Approval of a.s. in the EU under lead of EU COM
• Risk assessment a.s.: EFSA and member states (MS)
(EFSA = European Foo...
• Risk management and authorisation of PPP take place on national level
• Zonal cooperation: reporting member state (zRMS)...
• Product chemistry
• Chemical identity
• Physical and chemical properties
• Analytical methods
• Efficacy and application...
• Regulation EC 1107/2009
• Data requirements are provided in law in Regulation
(EC) No 283/2013 and 284/2013 data require...
Quantitative risk assessment
= TER ≥ target value
LC50 /EC50 / NOEC
PEC
The higher the TER, the lower the risk
• According...
• Terrestrial arthropods
• Bees
• Aphidius rhopalosiphi
• Typhlodromus pyri
Fixed set of NTO test organisms :
Example terr...
Legal classification
• dsRNA-base products has to be considered as any other plant
protection product at the moment
• Ther...
Article 77 (EC/1107/2009)
18.04.2019Achim Gathmann, BVL 14
Guidance documents
The Commission may, in accordance with the a...
Adopted requirements for
according Article 77
• Microorganisms
– Guidance Document for the assessment of the equivalence o...
Outline
• Experiences in the EU
• Principles in the authorisation process of Plant Production
Products (PPP) in the EU
• W...
Why ds-RNA-based products
might be useful?
– New mode of action – high value for resistance management
– Potential for env...
Lessons learned from GMO
• History of save use of RNAi silencing
– Many GMOs using the gene silencing mechanism like
• blu...
Differences an d similarities between
GMO and ds-RNA based PPP
–
18.04.2019Achim Gathmann, BVL 19
GMOs dsRNA-based PPP
NTO...
Challenges – adoption of risk assessment
methods
• Methods in risk assessment may need adoption
– Are models used in risk ...
Challenges - formulation
• For efficient application RNAi must be protected from
degradation (RNAse, UV light)
– Possibly ...
Challenges – procedural issues
• Product chemistry
– Does each difference in sequence lead to a new active
substance?
– Se...
Summary
– New product class with new mode of action and possibly lower
environmental harm
– Risk assessment of PPP is esta...
Contact:
Thank you for your attention!
Dr. Achim Gathmann
Federal Office for Consumer Protection and
Food Safety
achim.gat...
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The European perspective on regulatory aspects and experiences with dsRNA-based products - chim Gathmann, Federal Office of Consumer Protection and Food Safety (BVL), German

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10-12 April 2019: The OECD Conference on RNAi based pesticides provided an overview on the current status and future possibilities for the regulation of externally applied dsRNA-based products that are proposed for use as pesticides. The event facilitated exchanges between policy makers, academia, industry on their implications in health, environment, and regulation.

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The European perspective on regulatory aspects and experiences with dsRNA-based products - chim Gathmann, Federal Office of Consumer Protection and Food Safety (BVL), German

  1. 1. The European perspective on regulatory aspects and experiences with dsRNA- based products Achim Gathmann Federal Office of Consumer Protection and Food Safety (BVL)
  2. 2. Outline • Experiences in the EU • Principles in the authorisation process of Plant Production Products (PPP) in the EU • What’s new? - Challenges for the current risk assessment system of PPP • Preliminary remark – Perspective of the BVL – Information is not based on survey or any other coordinated position – Focus is on environmental consideration 18.04.2019 2Achim Gathmann, BVL Jagtap et al. 2011 Science of Nature 98(6):473-92
  3. 3. Experiences in the EU 18.04.2019Achim Gathmann, BVL 3 • No dsRNA-based plant protection product is authorised in the EU yet • Some experiences with GMO using RNAi silencing mechanisms in the EU – e.g. MON87411 and carnation, but only application for import and processing – Therefore environmental risk assessment does not include the full environmental risk assessment
  4. 4. Experiences in the EU 18.04.2019Achim Gathmann, BVL 4 • EFSA (GMO unit) – organised Workshop in June 2014 (EFSA 2014, EN-705) – Initiated a literature review (Christiaens et al. 2018, EN-1424) – Topic on the EFSA conference Science Food Society in 2018 • My impression: ds-based RNA PPP are not really on the agenda of many EU MS member states • Some MSs start to address the topic e.g. NL (Techreport COGEM 2016 & 2018) or DE actively participate on the current OECD activity Experiences are very limited in the EU!
  5. 5. Outline • Experiences in the EU • Principles in the authorisation process of Plant Production Products (PPP) in the EU • What’s new? - Challenges for the current risk assessment system of PPP 18.04.2019 5Achim Gathmann, BVL Jagtap et al. 2011 Science of Nature 98(6):473-92
  6. 6. Steps placing plant protection products on the market Active substances (a.s.): Assessed on EU level Approval for at least 10 years Benalaxyl Fluazinam, Fenamidone , … Product containing one or more a.s.: Company submits application including a risk assessment for national (or zonal) authorization Authorization for specific intended use 18.04.2019Achim Gathmann, BVL 6 Photo: „Folienserie“ BVLU
  7. 7. • Approval of a.s. in the EU under lead of EU COM • Risk assessment a.s.: EFSA and member states (MS) (EFSA = European Food Safety Authority) • a.s. fulfilling following cut-off criteria are not approvable:  Endocrine disruptors  Mutagens  Cancerogens  Toxic for reproduction  Substances with high potential for persistence, bioaccumulation and toxicity EU-approval of active substances (a.s.) according to regulation (EC) N0 1107/2009 18.04.2019Achim Gathmann, BVL page 7
  8. 8. • Risk management and authorisation of PPP take place on national level • Zonal cooperation: reporting member state (zRMS) assesses the application for all MS of one of the three zones • MS are bound on these authorisation • MS can consider national specificities and decide on specific risk management options Zonal authorisation of plant protection products according regulation EC 1107/2009 North: Denmark, Estonia, Finland, Latvia, Lithuania, Sweden Central: Belgium, Germany, Ireland, Luxembourg, Nether Austria, Poland, Rumania, Slovakia, Slovenia, Czech Republic, Hungry, UK South: Bulgaria, France, Greece, Italy, Malta, Portugal, Spain, Cyprus 18.04.2019Achim Gathmann, BVL page 8 Graphic: „Folienserie“ BVL
  9. 9. • Product chemistry • Chemical identity • Physical and chemical properties • Analytical methods • Efficacy and application • Health • Toxicology • Residues in food an feed • Maximum residues levels • Exposure of applicants and bystander • Environment • Fate • Ecotoxicology Areas of concern 18.04.2019Achim Gathmann, BVL page 9
  10. 10. • Regulation EC 1107/2009 • Data requirements are provided in law in Regulation (EC) No 283/2013 and 284/2013 data requirements for the approval of active substances and the authorisation of plant protection products • Regulation (EU) 546/2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products • Noted test protocols are described in different OECD GD and EFSA GD • Defined set of test parameters and endpoints! Legal framework defining data requirements 18.04.2019Achim Gathmann, BVL page 10 Photo: „Folienserie“ BVL
  11. 11. Quantitative risk assessment = TER ≥ target value LC50 /EC50 / NOEC PEC The higher the TER, the lower the risk • According to legal authorisation criteria, the TER must at least achieve a target value which depends on – Organism group (e.g. aquatic organisms, birds etc.) – Toxicity value from acute or longer-term tests The toxicity value relevant for assessment is considered in relation to the expected exposure (Toxicity-Exposure-Ratio, TER) 18.04.2019Achim Gathmann, BVL page 11
  12. 12. • Terrestrial arthropods • Bees • Aphidius rhopalosiphi • Typhlodromus pyri Fixed set of NTO test organisms : Example terrestrial non-vertebrates • Soil organisms • Earthworm • Folsomia candida • Hypoaspis aculeifer 18.04.2019Achim Gathmann, BVL page 12
  13. 13. Legal classification • dsRNA-base products has to be considered as any other plant protection product at the moment • Therefore the whole data package is needed for authorisation as active substance and later on for plant protection products. 18.04.2019Achim Gathmann, BVL 13
  14. 14. Article 77 (EC/1107/2009) 18.04.2019Achim Gathmann, BVL 14 Guidance documents The Commission may, in accordance with the advisory procedure referred to in Article 79(2), adopt or amend technical and other guidance documents such as explanatory notes or guidance documents on the content of the application concerning micro- organisms, pheromones and biological products, for the implementation of this Regulation. The Commission may ask the Authority to prepare or to contribute to such guidance documents.
  15. 15. Adopted requirements for according Article 77 • Microorganisms – Guidance Document for the assessment of the equivalence of technical grade active ingredients for identical microbial strains or isolates approved under regulation (EC) no 1107/2009 (SANCO/12823/2012 –rev. 4,12 December 2014) • Pheromones/Straight Chain Lepidopteran Pheromones (SCLPs) – Guidance Document on semiochemical active substances and plant protection products (SANTE/12815/2014 rev. 5.2 May 2016) – Guidance Document on the assessment of new substances falling into the group of Straight Chain Lepidopteran Pheromones (SCLPs) included in Annex I of Council Directive 91/414/EEC (SANCO/5272/2009 rev. 3 28 October 20101) • Plant extracts/Botanicals – Guidance document on botanical active substances used in plant protection products (SANCO/11470/2012– rev. 8 20 March 2014) • However for dsRNA-based products such guidance documents are not available • There is no initiative on preparation of such GD at the moment Reference for documents: ttps://ec.europa.eu/food/plant/pesticides/approval_active_substances/guidance_documents_en 18.04.2019Achim Gathmann, BVL 15
  16. 16. Outline • Experiences in the EU • Principles in the authorisation process of Plant Production Products (PPP) in the EU • What’s new? - Challenges for the current risk assessment system of PPP 18.04.2019 16Achim Gathmann, BVL Jagtap et al. 2011 Science of Nature 98(6):473-92
  17. 17. Why ds-RNA-based products might be useful? – New mode of action – high value for resistance management – Potential for environmentally safe products • High specificity – minor effects on NTO • Low stability in the environment – low environmental load in soil, surface and ground water • Low risk for vertebrates due to existing physiological barriers But it might depend on the formulation of the product But some data gaps must be filled 18.04.2019Achim Gathmann, BVL 17
  18. 18. Lessons learned from GMO • History of save use of RNAi silencing – Many GMOs using the gene silencing mechanism like • blue carnation, • not browning apples • `Flavr Savr’ tomato • compositionally-modified soybeans and alfalfa (Lucerne), • virus-resistant papaya, squash, plums, potatoes and beans • bruise-resistant potatoes Target is the metabolism of the plant (but none of them are authorised in the EU for cultivation) • New products with target outside of the plant – MON87411 (construct DvSnf7; assessed for import and processing) – Sprayable PPP 18.04.2019Achim Gathmann, BVL 18
  19. 19. Differences an d similarities between GMO and ds-RNA based PPP – 18.04.2019Achim Gathmann, BVL 19 GMOs dsRNA-based PPP NTOs by feeding of plant material or debris by feeding of sprayed plant material, direct or other exposure routes Time of exposure continuously limited Application of ds-RNA in tissue formulated product Degradation balance between degradation and production in plant rapid degradation in the environment strongly dependent on formulation Construct identical Mode of action same Specificity identical
  20. 20. Challenges – adoption of risk assessment methods • Methods in risk assessment may need adoption – Are models used in risk assessment appropriate to model exposure in soil, surface and ground water? – Adaption of ecotoxicological testing schemes? – Do we need additional information to support risk assessment e.g. bioinformatics? • Risk management – Mechanisms of resistance evolution 18.04.2019Achim Gathmann, BVL 20 Photo: „Folienserie“ BVLScreen copy Pelmo
  21. 21. Challenges - formulation • For efficient application RNAi must be protected from degradation (RNAse, UV light) – Possibly new approaches for stabilising RNAi • Improving RNAi efficiency – delivery/uptake of intact RNAi into cells • Methods in discussion – Polymeric nanoparticles e.g. chitosan (Zhang et al. 2010) – Liposomes (Whyard et al. 2009) – Chemical modifications e.g. adding methylgroups on specific parts of the RNAi – ds-RNA plus the biomass debris and spent fermentation medium 18.04.2019Achim Gathmann, BVL 21
  22. 22. Challenges – procedural issues • Product chemistry – Does each difference in sequence lead to a new active substance? – Sequence differences, but matches to the same binding site? – Criteria for identification of the product? – No experience about purity: Have all ds-RNAs in a product the same sequence? – How much variability in RNA sequence is acceptable in a product? – If microbial production system will be used (GMO) – Inactivation of microorganisms might be guaranteed 18.04.2019Achim Gathmann, BVL 22
  23. 23. Summary – New product class with new mode of action and possibly lower environmental harm – Risk assessment of PPP is established but might need regulatory and methodological adoptions – Limited experiences with this new class of products – Data gaps need to be filled – Some unknowns such as formulation strategies – Some procedural aspects need to be clarified 18.04.2019Achim Gathmann, BVL 23
  24. 24. Contact: Thank you for your attention! Dr. Achim Gathmann Federal Office for Consumer Protection and Food Safety achim.gathmann@bvl.bund.de 18.04.2019Achim Gathmann, BVL 24

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