1. Animal Feed GRAS Notifications Geoffrey K. Wong, M.S. Division of Animal Feeds Center for Veterinary Medicine Pet Food Institute Pet Food Institute October 15, 2009

2. PFI October 20092 Ingredient Safety Team Geoff Wong, MS (Team Leader) C. George Chang, DVM, PhD, DABT Tom Hendricks, PhD, MPH Marla Luther, PhD Becky Muir, PhD

3. PFI October 20093 GRAS Notification What is GRAS?!?

4. PFI October 20094 What is GRAS? GRAS – Generally Recognized As Safe GRAS – Generally Recognized As Safe 1958 Food Additives Amendment to Federal Food, Drug and Cosmetic Act 1958 Food Additives Amendment to Federal Food, Drug and Cosmetic Act Defined “food additive” Defined “food additive” Required premarket approval of food additives Required premarket approval of food additives Established standards for safety and review Established standards for safety and review Created exemption to food additive definition Created exemption to food additive definition GRAS status for a specific use of substance GRAS status for a specific use of substance

5. PFI October 20095 GRAS Exemption Any substance intentionally added to an animal feed must be used in accordance with a food additive regulation for that use unless Any substance intentionally added to an animal feed must be used in accordance with a food additive regulation for that use unless the substance is GRAS among experts qualified by scientific training and experience to evaluate its safety under the conditions of its intended use

6. PFI October 20096 GRAS Exemption (cont.) What does this mean in practical terms? What does this mean in practical terms? General recognition of safety is for a substance for an intended use General recognition of safety is for a substance for an intended use Two points Two points Substances are not GRAS, it is a particular use of a substance that is GRAS Substances are not GRAS, it is a particular use of a substance that is GRAS Feed use of substances varies with the animal species, thus Feed use of substances varies with the animal species, thus Feed GRAS determinations must address intended use in the intended animal species Feed GRAS determinations must address intended use in the intended animal species

7. PFI October 20097 Food Additive vs. GRAS Food additives require FDA premarket approval, a petition process Food additives require FDA premarket approval, a petition process 21 CFR 571.1 21 CFR 571.1 GRAS status is an exemption to food additive definition GRAS status is an exemption to food additive definition FDA involvement is not required FDA involvement is not required Firms can do their own determination for whether requirements for GRAS status are met Firms can do their own determination for whether requirements for GRAS status are met

8. PFI October 20098 What Uses can be GRAS? Food additive definition is very broad, but it does NOT include: Food additive definition is very broad, but it does NOT include: Pesticides Pesticides Color additives Color additives Approved under another FDA premarket process Approved under another FDA premarket process Drugs and new animal drugs Drugs and new animal drugs Some substances approved under specific laws administered by USDA Some substances approved under specific laws administered by USDA These substances cannot be GRAS These substances cannot be GRAS

9. PFI October 20099 GRAS Status There are two parts to establish that a use of a substance is GRAS There are two parts to establish that a 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 CFR 570.30 General recognition - Addressed in 21 CFR 570.30 Fair evaluation of the data… Fair evaluation of the data… Need to address all data and information Need to address all data and information Cannot ignore the “inconvenient” or contradictory Cannot ignore the “inconvenient” or contradictory

10. PFI October 200910 GRAS Status (cont.) Safety – same as food additive Safety – same as food additive Reasonable certainty of no harm 21 CFR 570.3(i) lists factors to be considered 21 CFR 570.3(i) lists factors to be considered Consumption Consumption Cumulative effect\exposure Cumulative effect\exposure Appropriate safety factors Appropriate safety factors For food animal species, need to consider possibility of tissue residues For food animal species, need to consider possibility of tissue residues

11. PFI October 200911 GRAS Status (cont.) General Recognition General Recognition Information needed for GRAS determination Information needed for GRAS determination Must be generally available Must be generally available Must be generally accepted by qualified experts Must be generally accepted by qualified experts Information needed to establish GRAS status of an intended use of substance cannot be confidential Information needed to establish GRAS status of an intended use of substance cannot be confidential

12. PFI October 200912 Information Generally available data and information Generally available data and information Usually means published studies Usually means published studies Can include information in text books Can include information in text books Availability allows review by any experts qualified by scientific experience and training to evaluate the safety of substances added to food Availability allows review by any experts qualified by scientific experience and training to evaluate the safety of substances added to food Consensus among experts about these data and information establishes GRAS status of intended use of substance Consensus among experts about these data and information establishes GRAS status of intended use of substance

13. PFI October 200913 Basis for GRAS Determinations Experts may base safety conclusions on: 1)Experience based on common use in animal food before 1958 Data and information must be generally available Data and information must be generally available Need to show common use Need to show common useOR

14. PFI October 200914 Basis for GRAS (cont.) 2) Scientific procedures Most frequently used Most frequently used Requires same quantity and quality of scientific evidence as required to obtain approval of a food additive regulation Requires same quantity and quality of scientific evidence as required to obtain approval of a food additive regulation Scientific evidence must be generally available Scientific evidence must be generally available GRAS status is more difficult to establish than a food additive regulation due to requirement for general recognition

15. PFI October 200915 Safety Evaluations Addressing animal safety is complex Addressing animal safety is complex Difficult to do cross-species comparisons of toxicity data Difficult to do cross-species comparisons of toxicity data Recent NRC report found insufficient data to support extrapolation across species Recent NRC report found insufficient data to support extrapolation across species Animal safety studies in the individual target species are often necessary Animal safety studies in the individual target species are often necessary Human food safety may also need to be addressed, dependent on intended use Human food safety may also need to be addressed, dependent on intended use

16. PFI October 200916 GRAS Notification Proposed rule published in 1997 Proposed rule published in 1997 Changing from petition to notification process Changing from petition to notification process Publication date of final rule is unclear Publication date of final rule is unclear CVM implementing pilot program CVM implementing pilot program Resources are still an issue Resources are still an issue Will be announced in the Federal Register Will be announced in the Federal Register Anticipated start date Anticipated start date Late 2009 Late 2009

17. PFI October 200917 GRAS Notification (cont.) Pilot program based on 1997 proposal Pilot program based on 1997 proposal Voluntary Voluntary Firms can conduct a GRAS determination without notifying FDA Firms can conduct a GRAS determination without notifying FDA Notice informs FDA of notifier’s determination Notice informs FDA of notifier’s determination that a use of a substance is GRAS Notifier’s determination and responsibility Notifier’s determination and responsibility Summary document, not raw data/complete reports Summary document, not raw data/complete reports FDA responds by letter FDA responds by letter Notifier can withdraw notice at any time, stops FDA review Notifier can withdraw notice at any time, stops FDA review

18. PFI October 200918 Highlights of Notice Talk to CVM as putting notice together Talk to CVM as putting notice together Summary of notifier’s determination Summary of notifier’s determination GRAS notice should include: GRAS notice should include: Statement of GRAS determination Statement of GRAS determination Detailed information about identity of substance Detailed information about identity of substance Chemical identification Chemical identification Method of manufacture, exclude trade secret information Method of manufacture, exclude trade secret information Source of substance Source of substance Characteristic properties Characteristic properties Specifications Specifications Utility – Intended Uses, Levels, Target Animal Species Utility – Intended Uses, Levels, Target Animal Species

19. PFI October 200919 Highlights of Notice (cont.) Comprehensive discussion of basis for GRAS determination Comprehensive discussion of basis for GRAS determination Consideration of Food and Water Exposure Consideration of Food and Water Exposure Safety – reasonable certainty of no harm Safety – reasonable certainty of no harm Animal and, potentially human food, safety Animal and, potentially human food, safety Favorable and unfavorable data/information Favorable and unfavorable data/information Basis for GRAS status in light of both favorable and unfavorable information Basis for GRAS status in light of both favorable and unfavorable information - fair evaluation Other administrative information Other administrative information

20. PFI October 200920 Types of FDA Response No questions No questions Based on the information provided by [notifier], … the agency has no questions at this time regarding [notifier’s conclusion that [substance] is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding … GRAS status Based on the information provided by [notifier], … the agency has no questions at this time regarding [notifier’s conclusion that [substance] is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding … GRAS status No basis No basis FDA has evaluated the information in [the GRAS Notice]…as well as other available data and information. Your notice does not provide a sufficient basis for a determination that [substance] is GRAS under the conditions of its intended use. FDA has evaluated the information in [the GRAS Notice]…as well as other available data and information. Your notice does not provide a sufficient basis for a determination that [substance] is GRAS under the conditions of its intended use.

21. PFI October 200921 GRAS Notification (cont.) Inventory of GRAS notices and FDA responses on the Internet Inventory of GRAS notices and FDA responses on the Internet Notices available under Freedom of Information Act (FOIA) Notices available under Freedom of Information Act (FOIA) May also be posted on Internet May also be posted on Internet General recognition means information that establishes safety cannot be confidential General recognition means information that establishes safety cannot be confidential CVM’s process will be similar to CFSAN’s on- going pilot program CVM’s process will be similar to CFSAN’s on- going pilot program Information about CFSAN pilot program at Information about CFSAN pilot program at http://www.fda.gov/Food/FoodIngredientsPackaging/ GenerallyRecognizedasSafeGRAS/default.htmhttp://www.fda.gov/Food/FoodIngredientsPackaging/ GenerallyRecognizedasSafeGRAS/default.htm. http://www.fda.gov/Food/FoodIngredientsPackaging/ GenerallyRecognizedasSafeGRAS/default.htm

22. Questions?

23. PFI October 200923 Thank You enter for eterinary edicine CVMCVM