regulatory affairs and risk assessment · adequate quality control of products entering the market....

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Regulatory affairs and risk assessment

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Session 4: Biopesticide registration

Alison Hamer

Regulatory Project ManagerJSC International Ltd

HarrogateUK

www.jsci.co.uk

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Session 4: Biopesticide registration

1. Review of the principles of biopesticide registration

2. Review of biopesticide registration frameworks within and beyondAfrica

3. Review of data requirements and risk assessment

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Summary of Session 41. The principles of biopesticide registration

Comparison of “conventional” chemicals and “alternative” biopesticidesGeneral principles which commonly apply to biopesticide regulation

2. Biopesticide registration frameworks within and beyond AfricaZone by zone assessment of regulatory systems

3. The data requirements for registration of biopesticidesData on the active substance/micro-organism and the formulationTechnical and biological properties, Effects on humans, Residues, Environmental fate and behaviour, Effects on non-target organisms, Efficacy

4. An introduction to risk assessment for biopesticidesHazard Exposure Risk assessmentRisk management

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Session 4 - Part 1

1. The principles of biopesticide registrationComparison of “conventional” chemicals and “alternative” biopesticidesGeneral principles which commonly apply to biopesticide regimes

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“Conventional” chemical pesticidesPlant protection products containing chemical active substancesInsecticides, herbicides, fungicides, rodenticides, plant growthregulatorsMature regulatory procedures have developed following many yearsexperience of use in agriculture, horticulture, forestry and home gardenRigorous criteria for risk assessment and risk management must be met to ensure safety and to allow global trade of treated commoditiesUsually patented synthetic substances (xenobiotics) with a mode of action that is well understood and usually toxic to the target pest or diseaseHigh levels of efficacy are required and expected by farmers to ensure successful production of high quality cropsA third less chemicals are used today in the UK compared with 1983 but their availability remains essential for the supply of foodDominated by less than ten major companies world wide

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“Alternative” biopesticidesNo consistent regulatory definition exists yet between different countriesUsing living agents to control pest or disease e.g. pathogenicity, parasitisationBiorational compounds discovered in the environment or crops andapplied at elevated levels to mimic naturally occurring processesExtracts from plants or animal products which are found in nature, applied in a novel mannerDevelopments from by a small industry into relatively small marketsMarket developments driven by organic sector and retailer-led initiatives to undercut chemical MRLsMore commonly used on niche crops of high-valueLevels of efficacy may be lower than those demanded for a conventional chemical, commonly used in IPM

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Biopesticide categories include

Micro-organismsMacro-organismsNematodesSemiochemicalsBiochemicalsPlant extractsPlant strengthenersPlant incorporated protectants

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Micro-organisms

The active substance is a viable micro-organismMicrobiological entities, cellular or non-cellular, capable of replication or of transferring genetic materialBacteria, fungi, protozoa, viruses and viroidsSpecial regulatory approaches for the active organism and formulated product have been developed – more later

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Macro-organisms / Nematodes

For example beneficial arthropodsGenerally not regulated under pesticide legislation FAO code of conduct ‘International standards for Phytosanitary Measures: Code of conduct for the import and release of exotic biological control agents’ (1996)Assessed at country level focusing on the likelihood of establishment and the potential impact on ecosystems. OECD 21 ‘Guidance for Information Requirements for Regulation of Invertebrates as Biological Control Agents’ (2004)

Nematodes are generally not regulated in many countriesIn Kenya macro-organisms are registered in order to ensure adequate quality control of products entering the market

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Semiochemicals• Pheromones are semiochemicals produced by individuals of

a species that modify the behaviour of other individuals of the same species

• Semiochemicals “… chemicals emitted by plants, animals, and other organisms - and synthetic analogues of such substances - that evoke a behavioural or physiological response in individuals of the same or other species”

• Straight-chained lepidopteran pheromones (SCLPs) …unbranched aliphatics having a chain of 9-18 carbons, containing < 3 double bonds, ending in an alcohol, acetate or aldehyde functional group. This structural definition encompasses the majority of known pheromones produced by insects in the order Lepidoptera, which includes butterflies and moths.

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Biochemicals / Plant extractsSome reduced data requirements have been allowed for certain plants and plant extracts based on long term experience of use and an existing well-known knowledge baseLow risk status applies to those simple extracts which are mixed with water and those which are ethanol/water basedSemiochemicals could be included in this category of products as they are naturally occurring and may be extracted from plants

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Plant strengtheners

EU: Plant strengtheners are substances and micro-organisms intended to protect plants against harmful organisms by activating the defences of the plant through:

stimulating resistance/defence mechanisms in the plant, orthe competition of the plant strengthener with harmful organisms for space and food-substances in the phyllosphere or rhizosphere

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Plant incorporated protectants

US: Pesticidal substances produced by plants and the genetic material necessary for the plant to produce the substanceIntroducing the gene for a Bt pesticidal protein into the plant’s genetic material. The plant manufactures the pesticidal protein that controls the pest when it feeds on the plant

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There is a wide range of product types that are considered to be biopesticides

But it is easy to understand that the industry get confused, in view of the numerous definitions which are not legally harmonised between countries

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GRAS

Generally Regarded as SafeMany substances having a known long-term history of use with a database indicating the absence of hazardous propertiesGRAS substances have been included on lists to indicate their low risk status Some biopesticide companies only utilise such substances in their products, as

active substancesco-formulants

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Why are all these groups considered to pose a lower risk?

Generally speaking this is the case (always exceptions) Some general characteristics of biopesticides make them suitable for streamlined regulatory assessment This may be due to their high specificity, existing natural emissions and presence in the environmentThere may be existing and acceptable exposure to them through other routes e.g. in food or in cosmeticsRegulatory authorities require special systems to allow more effective registration of these products – to be explored in more detail through the presentations

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Political issues

In addition to the scientific justifications for a different regulatory regime for biopesticides, there are also policy considerationsMany companies producing these products are small to medium sized enterprises (SMEs) which may be relying on just one product to sustain their business – payback of the registration costs takes many yearsThe retailers and public in some countries are asking for lower chemical residue levels (trade considerations)

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Financial comparison

Average cost to generate a study package and prepare a dossier in Europe

For a conventional chemical new active substance: £6-8 millionFor a typical biopesticide new active substance: £1 million

Because a number of data points for biopesticides can be addressed without long term and expensive GLP studies

The market turnover is low for biopesticides

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Therefore

The general regulatory position is that products with active substances in these groups are considered as low risk with characteristics requiring a regulatory approach that is:Specific to the special characteristics of the products

andUsually much less extensive than for conventional chemicals, resulting in a smaller data package

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Questions or Comments?

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Session 4 - Part 2

2. Biopesticide registration frameworks within and beyond AfricaZone by zone assessment of regulatory systems

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Summary of biopesticide registration in other countries

In the context of the registration of plant protection products:

EuropeUS EPACanada

= OECD

South AfricaKenya

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Europe

Under Directive 91/414/EEC active substances are considered as:Chemicals

Data requirements listed in Annex IIA and IIIASpecial guidance documents now appearing for low-risk chemical substances

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Microbial biopesticides Data requirements listed in Annex IIB and IIIB

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US EPA Office of Pesticide Programs

Biochemical PesticidesNaturally-occurring substances that have a non-toxic mode of action against the target pest e.g. insect pheromonesThe lack of toxicity to humans and other non-target organisms is not assumed

Microbial PesticidesBased on use of microorganisms as diseases or competitors to control pests

Plant Incorporated Protectants

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Organisation for Economic Co-operation and Development

European and OECD CountriesAustralia Austria BelgiumCanada Czech Republic DenmarkEuropean Union Finland FranceGermany Greece HungaryIceland Ireland ItalyJapan Korea LuxembourgMexico Netherlands New ZealandNorway Poland PortugalSlovakia Spain SwedenSwitzerland Turkey United KingdomUnited States

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OECD

The OECD are facilitating much beneficial activity to harmonise and streamline world wide registration requirements for biocontrol products Outside of Africa the OECD regulatory framework will be the required system for all members and associated countriesTherefore non-African countries are either compliant, or becoming compliant, with OECD regulatory criteria

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South Africa

Data requirements are in place for microbiological products There are several product registrations in place for MPCAsIndustry consider the South African system to be successful

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Kenya

Registration for Biocontrol Agents in Kenya – a workshop held at Nakuru, Kenya in May 2003Involving key officials in the regulatory processThis initiated the creation of a regulatory framework for biopesticides in Kenya with the potential for use more broadly in AfricaKenyan registration guidance tailored to local agriculture and based on the pragmatic selection of relevant key areas following appraisal of systems in other countries, including OECD

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KenyaRegistration guidance is now available on applications for:

Registration of microbial pest control productsRegistration of macrobial pest control productsRegistration of biochemical pest control products

Documents available for each of these three groups are:

Application formDossier index:• active ingredient• pest control productGuideline on the components of the dossier and application form

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KenyaDefinitions of each group:

Microbial pest control products… naturally occurring bacteria, protozoa, fungi, viruses, rickettsia

Macrobial pest control products… naturally occurring predators, parasitoids and entomopathogenicnematodes

Biochemical pest control products… the chemical products (growth regulators, pheromones, botanicalproducts, etc.) of naturally occurring organisms (bacteria, protozoa, fungi, viruses, plants, animals, etc.)

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Registration status of fungal biopesticides – available data packages

Fungus Europe USA AfricaAmpelomyces quisqualis √ √ ?

Aschersonia aleyrodis √ x ?

Beauveria spp. √ √ ?

Conithyrium minitans √ √ ?

Gliocladium catenulatum √ √ ?

Metarhizium anisopliae √ √ √

Paecilomyces fumosoroseus √ √ √

Phlebiopsis gigantea √ √ ?

Trichoderma spp. √ √ √

Verticillium spp √ √ √

Etc.

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Discussion points for Workshop 1Which groups of biopesticides need to be regulated in Ghana?What is the priority for each group? Where do we start?A proposal is to start with guidance on microbial products and biochemicals in the first instanceA proposal is to base the system on the Kenyan modelAre the needs of stakeholders outside of this workshop taken into account?What should we include in the second workshop?Any other points?

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Session 4 - Part 3

3. The data requirements for registration of biopesticidesData on the active substance/organism and the formulationTechnical and biological properties, Effects on Humans, Residues, Environmental Fate and Behaviour, Effects on Non-target organisms, Efficacy

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Areas of expertise needed in registration

Physical chemistryAnalytical methodsToxicologyMicrobiological characteristicsOperator exposure and risk assessmentPlant and livestock metabolismResidue chemistry & Consumer risk assessmentEnvironmental fate & EcotoxicologyEnvironmental risk assessmentExposure modellingRegulatory proceduresProject management

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How to address data requirements?

Components of the dossier used in risk assessment; hazard or exposure information about the product

Scientific investigations by the applicant or contract laboratories, possibly to GLP standardField trials to measure the persistence, residue behaviour or efficacy of an active substancePublished papers which contain findings relevant to answering the regulatory question – either single papers or the ‘weight of evidence’ Specific pieces of information e.g. “The product will be applied to cereals”Waivers, also known as scientific justifications, where it is explained that the question is not relevant to this particular question because of a specific reason – essential for biopesticides

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Data requirements and their part in risk assessment and product registration

Users, bystanders and workers in the cropConsumers, if food crops are to be treatedAll exposed environmental compartments and non-target speciesEfficacy

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Data requirements for the active substance/micro-organism

• Identity and purity• Physical and chemical properties (biological properties)• Analytical methods• Toxicology (infectivity and pathogenicity)• Residues in the plant• Ecotoxicology• Behaviour in environment

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Data requirements for the formulated product

• Identity and composition of the formulation• Physical and chemical properties• Labelling and packaging• Analytical methods• Efficacy data• Toxicology• Effects on non-target organisms

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Overview of micro-organism data requirements

Key sections of the dossierCharacterisation and identification of the micro-organism and its properties is the core of the dossier and supports all other sectionsA good set of documentation and understanding in this area helps address many other parts of data package and assists a straightforward evaluation

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Overview of semiochemical data requirements

• Reduced data requirements and use of waivers encouraged. Published requirements available for SCLPs

• Arthropod semiochemicals pose lower risk to human health and environment than conventional pesticides because:

• act by modifying behaviour of the pest species rather than killing it

• more target specific than conventional insecticides

• effective at very low rates at concentrations close to those in nature

• generally volatile, dissipate rapidly in the environment minimising residues in crops and exposure of non-target organisms

• end use products may be used in dispensers that result in littledirect exposure to humans and non-target organisms

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Session 4 - Part 4

4. An introduction to risk assessment for biopesticidesHazardExposureRisk assessmentRisk management

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Regulation in OECD is a risk-benefit analysis

RISKUsers, bystanders and workers in the cropConsumers, if food crops are to be treatedAll exposed environmental compartments and non-target species

BENEFITEfficacy - control of threat to food supply

What is procedure in Ghana?

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Risk assessmentHazard x Exposure = Risk

Four interacting parts to the regulatory decision making process, refinement is possible in each part

Hazard informationExposure profileRisk assessmentRisk management and labelling

What is procedure in Ghana?

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Risk assessment criteria and characteristics of concern

The two main product groups where regulatory system is sufficiently developed to allow general statements to be made about the use of waivers and principles of regulatory acceptance are micro-organisms and semiochemicalsWe are covering generally accepted thinking about risk assessmentsIt is important to keep these principles under constant review to ensure relevance to Ghana

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Micro-organisms

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Key sections of the dossierCharacterisation and identification of the micro-organism and its properties is the core of the dossier and supports all other sectionsA good set of documentation and understanding in this area helps address many other parts of data package and assists a straightforward evaluation

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Identity of the organismIdentity of species and criteria usedCharacterisation of strainCulture collection numberDescription of available technology used

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Nature of the materialTechnical specification; a.s. purity and contaminant/impurity profileFormulation detailsIf material not comparable to that commercially available is used in the studies, this may affect their acceptability

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Properties of the organismMode of action on the relevant crops/targetsSurvival at body temperatureAbility to colonise or cause damageExisting knowledge of the organism and its relativesBioassay - units of activity and w/w

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Metabolites/Toxins/Biochemical products

Why and when does the microbe produce them and how is this controlled?Are they responsible for the efficacy of the biopesticide?Are they of toxicological or environmental significance?

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Intended uses of the productCrop(s)Formulation typeApplication method, rate and volumeNumber of and interval between applicationsGrowth stage and seasonPre-harvest interval (PHI)

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Properties of the product

Packaging and method of application - LABELFormulation, technical specification (purity) and QCPhysical propertiesBiological properties e.g. bioassay

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Risk assessment

Performed by combining the exposure profile and hazard assessments

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CONSUMER risk assessment

Assess risk of consuming residues of:viable or non-viable cellular materials

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Consumer exposure

Residues on edible crops and processed food consumed by humans or livestockIs the product applied to soil, foliage or edible parts?Quantify residues on edible parts of the crop, how do they relate to background levels?How to estimate dietary intake?

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Consumer hazard

Based on toxicology data requirementsA tiered approach is followed based on current knowledge, published literature and toxicology studies

For biochemicals:There may be information on substances approved for other uses (such as medicines, food additives, additives in animal feedstuffs, cosmetics or materials intended to come into contact with foods)Along with information on current human exposure this is valuable with respect to the setting of the acceptable daily intake (ADI)

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Toxicology Active agent and/or technical grade

TIER 1Medical surveillance of manufacturing plant and agricultural workers e.g. occurrence of hypersensitivity/allergiesAcute oral LD50 (rat/rabbit)Inhalation LC50 (rat/rabbit)Mutagenicity/genotoxicity (when metabolites of concern)Intraperitoneal injection for infectivity (fungi and protozoa) Intravenous injection for infectivity (others)Discussion of the effects of repeated human exposure

TIER 2 dependent on outcome of Tier 1Sub-chronic toxicity 28 day NOEL

TIER 3 dependent on outcome of Tier 2Chronic, carcinogenicity, neurotoxicity, teratogenicity, reproductive toxicity

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Toxicology Formulated product

Acute oral LD50 ratAcute dermal LD50 ratInhalation LC50 ratSkin irritation rabbitEye irritation rabbitSkin sensitisation in guinea pigWHO classificationSummary of other mammalian toxicological studies e.g. livestock, wildlife, poultry, pets

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OPERATOR risk assessment

UsersMixing, loading, applying, cleaning

BystandersPresent but not using the product

WorkersEntering the crop after application

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Operator exposureAffected by formulation typeAffected by application method and situationPhysical properties of the PPP e.g. dust formation, particle size, spore concentration

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Operator hazard

• Based on toxicology data requirements

• Consider the relevant life stage of the micro-organism

• Sensitisation is a key concern, personal protective equipment may always be recommended.

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ENVIRONMENTAL risk assessment

Birds, Reptiles, Mammals, BeesAquatic life (fish, invertebrates, algae, plants)Non-target arthropods, termites, earthwormsMicrobial processesNon-target terrestrial plantsBiological methods of sewage treatment

Select the appropriate test species based on host specificity, mode of action and ecology specific to the country’s ecology

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Environmental exposure

Fate and behaviourEcological data - does it multiply in soil, air and water?What happens to its metabolites around or away from the crop?Can compare with natural populations but consider dose, activity and life stage relevant to the product in use

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Non-target species exposure

Outdoor - incorporation to soil reduces exposureDirect exposure by overspray of non-target species, spray driftIndirect - consumption of contaminated vegetation or insects/earthworms

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Semiochemicals

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Semiochemicals including pheromones

Examples of pragmatic approaches used in the regulatory assessment

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SemiochemicalsToxicology

If long-term exposure above background levels can be excluded or if a substance is a member of a well-characterised chemical group (e.g. SCLPs); studies of subchronic exposure can be waived

Dietary, Occupational, and Bystander ExposureIf detectable residues on the consumable commodity are unlikely, or unlikely to exceed natural levels, and the residues are not toxic; applicants may present scientific arguments to waive residue data

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SemiochemicalsEnvironmental Risks

Application rates < 375 g SCLP/ha/yr are generally understood to result in exposures comparable to natural emissions and safe for non-target speciesIf application rates are comparable to natural emissions; applicants may request waivers of environmental testing Compared to conventional pesticides, fewer tests are required for semiochemicals and the number of organisms per test are reducedFor fixed point dispensers applied over land; aquatic testing is not required If formulations might be ingested, e.g. granules; avian dietary toxicity data may be justified

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SemiochemicalsEnvironmental Fate

If ecotoxicity data or public literature indicate a hazard to biota; data on the persistence of a semiochemical and its transport from the site of application to another site may be required

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Risk management

Can controls be placed on the conditions of product approval?Limitations to certain crops e.g non-edible crops onlyProduct classification criteria in placeLabel recommendations for personal protective equipment in cases of acute hazard e.g. IRRITANTAn iterative process is enabled: refine the risk assessment, request more data or develop the risk management strategy to conclude the evaluationRisk management will only work if focused on real growing practices and if it can be enforced

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Thank you for your kind attention