Animal Feed GRAS Notifications Geoffrey K. Wong, M.S. Division of Animal Feeds Center for Veterinary Medicine Pet Food Institute Pet Food Institute October

Animal Feed GRAS Animal Feed GRAS NotificationsNotifications

Geoffrey K. Wong, M.S.Geoffrey K. Wong, M.S.Division of Animal FeedsDivision of Animal Feeds

Center for Veterinary MedicineCenter for Veterinary Medicine

Pet Food Institute Pet Food Institute October 15, 2009October 15, 2009

PFI October 2009PFI October 2009 22

Ingredient Safety TeamIngredient Safety Team

Geoff Wong, MS (Team Leader) C. George Chang, DVM, PhD, DABT Tom Hendricks, PhD, MPH Marla Luther, PhD Becky Muir, PhD


GRAS NotificationGRAS Notification

What is GRAS?!?What is GRAS?!?


What is GRAS?What is GRAS? GRAS – Generally Recognized As SafeGRAS – Generally Recognized As Safe 1958 Food Additives Amendment to 1958 Food Additives Amendment to

Federal Food, Drug and Cosmetic ActFederal Food, Drug and Cosmetic Act Defined “food additive”Defined “food additive” Required premarket approval of food Required premarket approval of food

additivesadditives Established standards for safety and Established standards for safety and

reviewreview Created exemption to food additive Created exemption to food additive

definitiondefinition GRAS status for a specific use of substanceGRAS status for a specific use of substance


GRAS ExemptionGRAS Exemption Any substance intentionally Any substance intentionally

added to an animal feed must added to an animal feed must be used in accordance with a be used in accordance with a food additive regulation for that food additive regulation for that use use unlessunless

the substance is GRAS among the substance is GRAS among experts qualified by scientific experts qualified by scientific training and experience to training and experience to evaluate its safety under the evaluate its safety under the conditions of its intended useconditions of its intended use


GRAS Exemption GRAS Exemption (cont.)(cont.)

What does this mean in practical terms?What does this mean in practical terms? General recognition of safety is for a General recognition of safety is for a

substance for an substance for an intendedintended use use Two pointsTwo points

Substances are not GRAS, it is a particular use Substances are not GRAS, it is a particular use of a substance that is GRASof a substance that is GRAS

Feed use of substances varies with the animal Feed use of substances varies with the animal species, thusspecies, thus

Feed GRAS determinations must address Feed GRAS determinations must address intended use in the intended animal intended use in the intended animal speciesspecies


Food Additive vs. GRASFood Additive vs. GRAS Food additives require FDA Food additives require FDA

premarket approval, a petition premarket approval, a petition processprocess 21 CFR 571.121 CFR 571.1

GRAS status is an exemption to food GRAS status is an exemption to food additive definitionadditive definition FDA involvement is not requiredFDA involvement is not required Firms can do their own determination Firms can do their own determination

for whether requirements for GRAS for whether requirements for GRAS status are metstatus are met


What Uses can be GRAS?What Uses can be GRAS? Food additive definition is very Food additive definition is very

broad, but it does NOT include:broad, but it does NOT include: PesticidesPesticides Color additivesColor additives

Approved under another FDA premarket Approved under another FDA premarket processprocess

Drugs and new animal drugsDrugs and new animal drugs Some substances approved under Some substances approved under

specific laws administered by USDAspecific laws administered by USDA These substances cannot be GRASThese substances cannot be GRAS


GRAS StatusGRAS Status There are two parts to establish that There are two parts to establish that

a use of a substance is GRASa use of a substance is GRAS Safety - Defined in 21 CFR 570.3(i)Safety - Defined in 21 CFR 570.3(i) General recognition - Addressed in 21 General recognition - Addressed in 21

CFR 570.30CFR 570.30 Fair evaluation of the data…Fair evaluation of the data…

Need to address all data and Need to address all data and informationinformation Cannot ignore the “inconvenient” or Cannot ignore the “inconvenient” or

contradictorycontradictory


GRAS Status GRAS Status (cont.)(cont.) Safety Safety – same as food additive– same as food additive

Reasonable certainty of no harmReasonable certainty of no harm 21 CFR 570.3(i) lists factors to be 21 CFR 570.3(i) lists factors to be

consideredconsidered ConsumptionConsumption Cumulative effect\exposureCumulative effect\exposure Appropriate safety factors Appropriate safety factors

For food animal species, need to For food animal species, need to consider possibility of tissue consider possibility of tissue residuesresidues


GRAS Status GRAS Status (cont.)(cont.)

General RecognitionGeneral Recognition Information needed for GRAS Information needed for GRAS

determinationdetermination Must be generally availableMust be generally available Must be generally accepted by Must be generally accepted by

qualified expertsqualified experts Information needed to establish Information needed to establish

GRAS status of an intended use of GRAS status of an intended use of substance cannot be confidentialsubstance cannot be confidential


InformationInformation Generally available data and Generally available data and

information information Usually means published studiesUsually means published studies Can include information in text booksCan include information in text books

Availability allows review by any Availability allows review by any experts qualified by scientific experts qualified by scientific experience and training to evaluate experience and training to evaluate the safety of substances added to foodthe safety of substances added to food

Consensus among experts about these Consensus among experts about these data and information establishes GRAS data and information establishes GRAS status of intended use of substancestatus of intended use of substance


Basis for GRAS Basis for GRAS DeterminationsDeterminations

Experts may base safety Experts may base safety conclusions on:conclusions on:

1)1) Experience based on common Experience based on common use in animal food before 1958use in animal food before 1958

Data and information must be Data and information must be generally availablegenerally available

Need to show Need to show commoncommon use use

OROR


Basis for GRAS Basis for GRAS (cont.)(cont.)

2)2) Scientific proceduresScientific procedures Most frequently usedMost frequently used Requires same quantity and quality of Requires same quantity and quality of

scientific evidence as required to obtain scientific evidence as required to obtain approval of a food additive regulationapproval of a food additive regulation

Scientific evidence must be generally availableScientific evidence must be generally available

GRAS status is GRAS status is more difficultmore difficult to to establish than a food additive establish than a food additive regulation due to requirement for regulation due to requirement for general recognitiongeneral recognition


Safety EvaluationsSafety Evaluations Addressing animal safety is complexAddressing animal safety is complex

Difficult to do cross-species comparisons Difficult to do cross-species comparisons of toxicity dataof toxicity data

Recent NRC report found insufficient data Recent NRC report found insufficient data to support extrapolation across species to support extrapolation across species

Animal safety studies in the individual Animal safety studies in the individual target species are often necessarytarget species are often necessary

Human food safety may also need to Human food safety may also need to be addressed, dependent on intended be addressed, dependent on intended useuse


GRAS NotificationGRAS Notification Proposed rule published in 1997Proposed rule published in 1997

Changing from petition to notification Changing from petition to notification processprocess

Publication date of final rule is unclearPublication date of final rule is unclear CVM implementing pilot programCVM implementing pilot program

Resources are still an issueResources are still an issue Will be announced in the Federal RegisterWill be announced in the Federal Register Anticipated start dateAnticipated start date

Late 2009Late 2009


GRAS Notification GRAS Notification (cont.)(cont.) Pilot program based on 1997 proposalPilot program based on 1997 proposal VoluntaryVoluntary

Firms can conduct a GRAS determination Firms can conduct a GRAS determination without notifying FDAwithout notifying FDA

Notice informs FDA of Notice informs FDA of notifier’s notifier’s determinationdeterminationthat a use of a substance is GRASthat a use of a substance is GRAS Notifier’s determination and responsibilityNotifier’s determination and responsibility Summary document, not raw data/complete Summary document, not raw data/complete

reportsreports FDA responds by letterFDA responds by letter

Notifier can withdraw notice at any time, Notifier can withdraw notice at any time, stops FDA reviewstops FDA review


Highlights of NoticeHighlights of Notice Talk to CVM as putting notice togetherTalk to CVM as putting notice together Summary of notifier’s determinationSummary of notifier’s determination GRAS notice should include:GRAS notice should include:

Statement of GRAS determinationStatement of GRAS determination Detailed information about identity of substanceDetailed information about identity of substance

Chemical identificationChemical identification Method of manufacture, exclude trade secret Method of manufacture, exclude trade secret

informationinformation Source of substanceSource of substance Characteristic propertiesCharacteristic properties SpecificationsSpecifications

Utility – Intended Uses, Levels, Target Animal Utility – Intended Uses, Levels, Target Animal SpeciesSpecies


Highlights of Notice Highlights of Notice (cont.)(cont.) Comprehensive discussion of basis for Comprehensive discussion of basis for

GRAS determinationGRAS determination Consideration of Food and Water ExposureConsideration of Food and Water Exposure Safety – reasonable certainty of no harmSafety – reasonable certainty of no harm Animal and, potentially human food, safetyAnimal and, potentially human food, safety

Favorable and unfavorable data/informationFavorable and unfavorable data/information Basis for GRAS status in light of both Basis for GRAS status in light of both

favorable and unfavorable informationfavorable and unfavorable information- fair evaluation- fair evaluation

Other administrative informationOther administrative information


Types of FDA ResponseTypes of FDA Response No questionsNo questions

Based on the information provided by Based on the information provided by [notifier], … the agency has no questions at [notifier], … the agency has no questions at this time regarding [notifier’s conclusion that this time regarding [notifier’s conclusion that [substance] is GRAS under the intended [substance] is GRAS under the intended conditions of use. The agency has not, conditions of use. The agency has not, however, made its own determination however, made its own determination regarding … GRAS statusregarding … GRAS status

No basisNo basis FDA has evaluated the information in [the FDA has evaluated the information in [the

GRAS Notice]…as well as other available GRAS Notice]…as well as other available data and information. Your notice does not data and information. Your notice does not provide a sufficient basis for a determination provide a sufficient basis for a determination that [substance] is GRAS under the that [substance] is GRAS under the conditions of its intended use.conditions of its intended use.


GRAS Notification GRAS Notification (cont.)(cont.) Inventory of GRAS notices and FDA Inventory of GRAS notices and FDA

responses on the Internetresponses on the Internet Notices available under Freedom of Notices available under Freedom of

Information Act (FOIA)Information Act (FOIA) May also be posted on InternetMay also be posted on Internet General recognition means information that General recognition means information that

establishes safety cannot be confidentialestablishes safety cannot be confidential CVM’s process will be similar to CFSAN’s CVM’s process will be similar to CFSAN’s

on-going pilot programon-going pilot program Information about CFSAN pilot program at Information about CFSAN pilot program at http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm

..

http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm



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Animal Feed GRAS Notifications Geoffrey K. Wong, M.S. Division of Animal Feeds Center for Veterinary Medicine Pet Food Institute Pet Food Institute October