The seminar on Problem Formulation for the Risk Assessment of Biopesticides stemmed from a previous CRP-sponsored event on Innovating Microbial Pesticide Testing that identified the need for an overarching guidance document to determine when in vivo tests are necessary. Problem Formulation, a common practice in pesticide risk assessment, was highlighted as a useful approach for addressing uncertainties in data requirements for biopesticides. The seminar featured presentations from various perspectives, including industry, regulatory bodies, and academia. Topics included the history and principles of Problem Formulation, industry perspectives on Problem Formulation and how it is applied internally for microbial pesticides, regulatory approaches, and specific case studies. The seminar provided an overview of the challenges, considerations, and potential solutions in harmonising Problem Formulation for biopesticide risk assessment. It emphasised the need for collaboration and discussion to develop Problem Formulation guidance for biopesticides.

1. Vive Crop Protection
PROPRIETARY AND CONFIDENTIAL

2. General Principles for Tier 0/Tier 1 NGRA for
Microbials
Tier 0 – Collate all relevant existing information on organism of concern (i.e.
microbial AI) and proposed use scenario(s)
What is the AI loading, proposed application rate and method, and timing of application (for each
pest/crop combination)?
Will the AI be subject to co-occurrence with pesticides in formulation or in the field?
Identify genome, sequences of interest and determine similarity to other organisms
Identify potential for contaminants and secondary metabolites
Identify existing hazard information (including any analogs and other germane data for read-across and
bridging)
Identify appropriate existing test methods as well as “data gaps” (limitations of existing methods and
potential for NAMs)
Make predictions regarding toxicity and exposure to support exposure-based waivers
Tier 1 – Generate hypothesis on how/what data will be used in the risk
assessment
Describe WOE method, data generation tools to be used, and how that data can be used in a RA context
to support the product decision (e.g. define the IATA)

3. Vive Crop Protection
PROPRIETARY AND CONFIDENTIAL
Example -- NGRA Problem Formulation
Gilmour et al (2020) Reg Tox Pharmacol.

4. 1. Identify the microbial use scenario(s)
How and where will the product be used?
How does the microbial MOA factor into
product use?
What about consortium products?
How does the biology of the microbe(s) in
the enviroment factor into product use?
Heat killed fermentation broth? Living microbe?
What about consortium products?
Consider a conceptual site model
approach
Guidance for the Development of Conceptual Models for a Problem Formulation
Developed for Registration Review | US EPA

5. 2. Characterize the microbe
Identify distribution data for microbe as well as host range of occurrence
Characterize and analyze the organism sequence
Is 16S rRNA analysis sufficient to provide taxonomic resolution? (Evaluation of 16S rRNA gene
sequencing for species and strain-level microbiome analysis - PMC (nih.gov))
Is the sequence/genome related to a pathogenic organism?
Characterize potential for contaminants from the production method
Characterize the strain-specific potential for secondary metabolite
production
Is there any relevance to proposed use pattern beyond efficacy? Antagonism, etc.? (Mode of Action
of Microbial Biological Control Agents Against Plant Diseases: Relevance Beyond Efficacy - PMC
(nih.gov))
See Working Document on the Risk Assessment of Secondary Metabolites of Microbial Biocontrol
Agents (oecd.org)

6. 3. Identify existing hazard information
Analyze existing in vivo, in chemico and in
vitro literature
Identify validated/in scope prediction tools for
hazard properties (i.e. appropriate in silico
tools)
Understand how interaction/compatibility
with other pesticides impacts hazard from
directed use
Understand how manufacturing and
production steps impacts hazard
Verify whether in vitro experiments
identifying secondary metabolites of concern
are reproduced under in situ conditions

7. 4. Identify and analyze suitability of analogs, etc.
Are there decisions/data on closely-related strains that could be
leveraged?
Are there limitations to the existing data (previously identified) or “data
gaps” from the prescribed chemical-based test guidelines?
Could NAMs fill these gaps? Will Member State use these data for product risk assessment?
See Report of the 9th Biopesticides Expert Group Seminar on Test Methods for Micro-organisms
(2019)
i.e. Next Generation Sequencing and metagenomics/metabolomics/etc.
See Report of the 10th Biopesticides Expert Group Seminar on Bioinformatics and Regulation of
Microbial Pesticides (2020)
Potential for microbial AI to colonize in the wild?
Are there any beneficial effects (e.g. plant health benefits, soil benefits) of
note? How are these considered by the regulator?

8. 5. Explore exposure-based waivers (EBWs)
EBWs were developed for REACH ~ 2011 and may be appropriate if:
exposure is absent (= exposure excluded) or not significant throughout the whole life cycle of the
substance for manufacture and all identified uses or
when strictly controlled conditions apply throughout the life cycle of the substance for manufacture
and all uses and
no releases from the article life cycle stage (and subsequent waste life stage) is to be expected and
consequently there is a negligible likelihood of exposure. This only applies to substances
incorporated into articles.
Criteria exist for defining low-risk pesticidal substances
IBMA working with EC to establish draft legislation for MBCAs – include
specific EBWs based on anticipated exposure, lower toxicity profile, … ?
How compatible is EBW with European governing philosophy?

9. 6. Generate hypotheses on need for/use of data for
risk assessment
1081c8869b7cb02b4e2998e6d75f11e81e23b400.pdf
(unilever.com)
Taken from Unilever NGRA coumarin/skin sensitization NGRA framework

10. Vive Crop Protection
PROPRIETARY AND CONFIDENTIAL
Accelerating the paradigm shift to NGRA
What is needed?
➢ Greater scientific exchange between industry and Agency scientists to
exchange knowledge and establish necessary adaptations to
reguilatory frameworks & guidance
➢ A focus on confidence-building and validation of NGRA methods and
approaches to ensure protectiveness is maintained.
➢ Greater harmonization of methods and data requirements through
the OECD EGs, BIAC, Agencies, etc.
Shamelessly reproduced from the Unilever presentation

11. Vive Crop Protection
PROPRIETARY AND CONFIDENTIAL
Thank you!
Erik R. Janus
Senior Regulatory Manager
Vive Crop Protection Inc.
Contact the Vive Regulatory team at
regulatory@vivecrop.com