Nanotechnology, Impact on Nanotechnology, Impact on Animal Drugs and FeedsAnimal Drugs and Feeds

Dragan Momcilovic, DVM, PhD, DACTDragan Momcilovic, DVM, PhD, DACTCenter for Veterinary MedicineCenter for Veterinary Medicine

AAFCO AAFCO August 2, 2008August 2, 2008

WASHINGTON WASHINGTON –– Few domestic policy areas that the new administration Few domestic policy areas that the new administration mustmust address will have greater longaddress will have greater long--range consequences than range consequences than nanotechnologynanotechnology —— a new technology that has been compared with the a new technology that has been compared with the industrial revolutionindustrial revolution in terms of its impact on society. If the right decisions in terms of its impact on society. If the right decisions are made, nanotechnology will bring vast are made, nanotechnology will bring vast improvementsimprovements to almost every to almost every area of daily living. If the wrong decisions are made, the Ameriarea of daily living. If the wrong decisions are made, the American can economy, human health and the environment will economy, human health and the environment will suffersuffer. .

http://www.nanotechproject.org/publications/archive/pen13/

Woodrow Wilson Center for International Scholars

There's Plenty of Room at the BottomAn Invitation to Enter a New Field of Physics

by Richard P. Feynman

~2nm

NanogoldNanogold

OutlineOutline

–– IntroductionIntroductionTerminologyTerminologySize that mattersSize that matters

–– DefinitionDefinition–– Examples of Examples of nanoparticlesnanoparticles

–– CVMCVM’’ss roleroleNew animal drug approval processNew animal drug approval process

–– Technical sections for an animal drug approvalTechnical sections for an animal drug approvalAnimal feedsAnimal feeds

–– Technical sections for a food additive petitionTechnical sections for a food additive petition–– Type of product Type of product -- feedsfeeds

–– SummarySummary

TerminologyTerminology

NanotechnologyNanotechnologyThe study of phenomena and manipulation of materials at The study of phenomena and manipulation of materials at atomic, molecular and macromolecular scales, where atomic, molecular and macromolecular scales, where properties differ significantly from those at a larger scaleproperties differ significantly from those at a larger scale

NanoscaleNanoscaleHaving one or more dimensions of the order of 100 nm or lessHaving one or more dimensions of the order of 100 nm or less

NanoparticleNanoparticleParticle with one or more dimensions at the Particle with one or more dimensions at the nanoscalenanoscale..

Size that mattersSize that matters

A nanometer is a billionth of a meter A nanometer is a billionth of a meter –– A human hair is about 80,000 nanometers in A human hair is about 80,000 nanometers in

width width

1x101x10--99m v 1x10m v 1x1099mm

1m

1x101x10-9mm 1x101x109mm

1x101x109mm

0.38x100.38x109mm

1x101x109mm

1x101x10--99m m -- 1x101x10--77mm

nm1 10 20 30 40 50 60 70 80 90 100

Definition:Definition:–– NNI definition: NNI definition: ““Nanotechnology is the Nanotechnology is the

understanding and control of matter at understanding and control of matter at dimensions of roughly 1 to 100 nanometers, dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel where unique phenomena enable novel applicationsapplications…”…”

Size that mattersSize that matters

1x101x10--99m m -- 1x101x10--77mm

nm1 10 20 30 40 50 60 70 80 90 100

1x101x10--99m m -- 1x101x10--77mm

nm1 10 20 30 40 50 60 70 80 90 100

Parvovirus ~26nm Rotavirus ~60-80nmGlucose ~1nm

Examples of Examples of NanoparticlesNanoparticles

nanotubes

Nature 452, 904 (17 April 2008)

Micro-GC nanotube sensor array

Examples of Examples of NanoparticlesNanoparticles

nanotubes

fullerenes quantum dots

Renal clearance of quantum dotsRenal clearance of quantum dots

Choi et al., 2007. Nature Biotechnology. 25:1165-1170

CdSe

ZnS

Organic coating

2.8 – 4.3 nm

4.4 – 8.7 nm

<5.5 nm

>5.5 nm

Kidney elimination

Liver elimination

What does CVM do?What does CVM do?

CVM is responsible for assuring that animal CVM is responsible for assuring that animal drugs and medicated feeds are safe and drugs and medicated feeds are safe and effective and that food from treated animals effective and that food from treated animals is safe to eatis safe to eat

Drug Feed

Medicated Feed

CVMCVM

Animals

Humans

Drug ApprovalDrug Approval

To have an approved animal drug means that:To have an approved animal drug means that:–– Product is safe and effective for intended use Product is safe and effective for intended use –– The methods, facilities, and controls used for the The methods, facilities, and controls used for the

manufacturing, processing, and packaging of the drug manufacturing, processing, and packaging of the drug are adequate to preserve its identity, strength, quality, are adequate to preserve its identity, strength, quality, and purityand purity

NADA = New Animal Drug ApplicationNADA = New Animal Drug Application

The Federal Food, Drug, and Cosmetic ActThe Federal Food, Drug, and Cosmetic Act

•• mandates that a new animal drug may not be mandates that a new animal drug may not be sold in interstate commerce unless it is the sold in interstate commerce unless it is the subject of a New Animal Drug Application subject of a New Animal Drug Application (NADA)(NADA)

Technical sections for an Technical sections for an Animal Drug ApprovalAnimal Drug Approval

EffectivenessEffectivenessTarget Animal SafetyTarget Animal SafetyHuman Food SafetyHuman Food SafetyChemistry, Manufacturing, and ControlsChemistry, Manufacturing, and ControlsEnvironmental AssessmentEnvironmental AssessmentLabelingLabelingFreedom of Information SummaryFreedom of Information Summary

EffectivenessEffectiveness

Same effectiveness criteria as Same effectiveness criteria as ““conventionalconventional””drug: substantial evidence of effectivenessdrug: substantial evidence of effectiveness–– Independent substantiationIndependent substantiation–– Inferential valueInferential value

This may include laboratory and field studiesThis may include laboratory and field studies

Also use information from effectiveness studies Also use information from effectiveness studies for safety evaluationsfor safety evaluations

Target Animal SafetyTarget Animal Safety

Same overall safety criteria Same overall safety criteria –– must show drug is must show drug is safe when used as labeledsafe when used as labeled

Additional variables/procedures in TAS studies Additional variables/procedures in TAS studies may be necessary for a specific product (based may be necessary for a specific product (based on pilot work, published literature on similar on pilot work, published literature on similar product/product/nanomaterialnanomaterial))

User SafetyUser Safety

Any unique concerns to humans who administer Any unique concerns to humans who administer the product to animals?the product to animals?–– Contact with animal drug product before Contact with animal drug product before

administration, during administration, and after administration, during administration, and after administrationadministration

–– Veterinarian, animal owner, and others that may Veterinarian, animal owner, and others that may contact treated animalcontact treated animal

Human Food SafetyHuman Food Safety

If drug for food animal, must show when animal If drug for food animal, must show when animal products are safe for human consumptionproducts are safe for human consumption

May require new detection methods for May require new detection methods for determining tissue residuesdetermining tissue residues

Toxicology Toxicology –– need appropriate assays and need appropriate assays and studiesstudies

Human Food SafetyHuman Food Safety

Slaughter Authorizations (preSlaughter Authorizations (pre--approval)approval)–– Only applies to animals used in studies that will enter Only applies to animals used in studies that will enter

the food supplythe food supply–– Need to provide information to support a requestNeed to provide information to support a request–– Authorizations and withdrawal times based on Authorizations and withdrawal times based on

available dataavailable data

Chemistry, Manufacturing, and Chemistry, Manufacturing, and ControlsControls

Ensure the methods, facilities, and controls used Ensure the methods, facilities, and controls used for the manufacturing, processing, and for the manufacturing, processing, and packaging of the drug are adequate to preserve packaging of the drug are adequate to preserve its identity, strength, quality, and purityits identity, strength, quality, and purity

Need to confirm formulationNeed to confirm formulation

May need new methodsMay need new methods–– Validate methods for determining particle attributes in Validate methods for determining particle attributes in

formulationformulation–– Methods for manufacturing controlsMethods for manufacturing controls

EnvironmentalEnvironmental

May give more consideration to a product before May give more consideration to a product before determining if an EA is necessary or granting categorical determining if an EA is necessary or granting categorical exclusionexclusion

Existing categorical exclusions (from the requirement to Existing categorical exclusions (from the requirement to prepare an EA) may not applyprepare an EA) may not apply

May need more information in decision process May need more information in decision process (formulation and particle sizes)(formulation and particle sizes)

Existing test methods may need to be altered due to Existing test methods may need to be altered due to unique properties of some unique properties of some nanomaterialsnanomaterials

LabelingLabeling

Labeling of FDALabeling of FDA--regulated products must be regulated products must be truthful, not misleading, and containing material truthful, not misleading, and containing material informationinformation

Current state of the science does not indicate Current state of the science does not indicate unique safety concernsunique safety concerns

RecommendationRecommendation–– Address on a productAddress on a product--byby--product basis whether labeling must or product basis whether labeling must or

may contain information on the use of nanomaterialsmay contain information on the use of nanomaterials

Animal FeedsAnimal Feeds

Animal FeedsAnimal Feeds

Generally Recognized as Safe (GRAS)Generally Recognized as Safe (GRAS)

Otherwise Permitted (e.g., AAFCO)Otherwise Permitted (e.g., AAFCO)

Food Additive Petition (FAP)Food Additive Petition (FAP)

Technical Sections for a Technical Sections for a Food Additive PetitionFood Additive Petition

UtilityUtilityTarget Animal SafetyTarget Animal SafetyHuman Food SafetyHuman Food SafetyChemistry, Manufacturing, and ControlsChemistry, Manufacturing, and ControlsEnvironmental SafetyEnvironmental SafetyLabelingLabelingProposed RegulationProposed Regulation

Types of Products Types of Products -- FeedsFeeds

Medicated Feed Articles Medicated Feed Articles –– like drugslike drugs

Feed Additives Feed Additives –– new platformsnew platforms–– Toxin binding Toxin binding –– Matrix with nanomaterialsMatrix with nanomaterials–– Enhanced delivery of vitamins, mineral, and nutrientsEnhanced delivery of vitamins, mineral, and nutrients

PackagingPackaging–– AntimicrobialAntimicrobial–– Longer shelf lifeLonger shelf life

Drug Feed

Medicated Feed

NanoproductNanoproduct

Animals

Humans

““Due to a high surface area, the Due to a high surface area, the nanoparticlesnanoparticles can can interact strongly with all the components of the food interact strongly with all the components of the food matrix.matrix.””

Simon and Joner. 2008. J. Food Nutr. Res. 47:51-59

““Modernising the rules on food additives and Modernising the rules on food additives and labelling of azo dyeslabelling of azo dyes””

NanotechnologyNanotechnology““…… if the production process of an additive is changed, for examplif the production process of an additive is changed, for example e via a change in particle size through nanotechnology, a fresh via a change in particle size through nanotechnology, a fresh authorization process, including a safety evaluation, must be caauthorization process, including a safety evaluation, must be carried rried

out.out.””

http://www.europarl.europa.eu/news/expert/infopress_page/067-33565-189-07-28-911-20080707IPR33563-07-07-2008-2008-false/default_en.htm

SummarySummary

Overall premarket approval process is similar to a Overall premarket approval process is similar to a ““conventionalconventional”” drug, but the use of nanoscale materials drug, but the use of nanoscale materials in animal drugs does present new issuesin animal drugs does present new issues–– New methods, validate existing methodsNew methods, validate existing methods–– Methods may be product specificMethods may be product specific

Current regulations allow CVM to consider the potential Current regulations allow CVM to consider the potential novel properties of products containing nanoscale novel properties of products containing nanoscale materialsmaterials

May issue new guidance as appropriateMay issue new guidance as appropriate

JC Meyer et al. Nature 454, 319-322 (2008) doi:10.1038/nature07094