1. Rockville, MD June 2012 Dr. Dragan Momcilovic, Medicated Feeds Specialist Dr. Gabriel Davila, Staff Fellow Food and Drug Administration Center for Veterinary Medicine Division of Animal Feeds Medicated Feeds Team Medicated Feeds Overview

2. Definitions and usages Drug Categories Types of Distribution Medicated Products Pre-approval activities FDA’s new animal drug approval process (basics) –Label review Labeling of medicated products Post-approval activities Current Good Manufacturing Practices (cGMP) Program Monitoring Licensing and Registration Where to look for more information Agenda

3. Drug Categories

4. Category IICategory I

5. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved

6. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved

7. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved Drugs regulated on a “no-residue” basis or with a “zero” tolerance level because of a carcinogenic concern

8. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved Drugs regulated on a “no-residue” basis or with a “zero” tolerance level because of a carcinogenic concern Drugs that are veterinary feed directive

9. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved Drugs regulated on a “no-residue” basis or with a “zero” tolerance level because of a carcinogenic concern Drugs that are veterinary feed directive Level of risk

10. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved Drugs regulated on a “no-residue” basis or with a “zero” tolerance level because of a carcinogenic concern Drugs that are veterinary feed directive Level of risk

11. Less risky Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved Drugs regulated on a “no-residue” basis or with a “zero” tolerance level because of a carcinogenic concern Drugs that are veterinary feed directive Level of risk

12. Drug Categories Category IICategory I Drugs with no withdrawal period required at the lowest use level for each species for which they are approved Drugs with a withdrawal period required at the lowest use level for at least one of the species for which they are approved Drugs regulated on a “no-residue” basis or with a “zero” tolerance level because of a carcinogenic concern Drugs that are veterinary feed directive Level of risk Less riskyMore risky

13. Medicated Feeds are distributed: - Over-The-Counter - Veterinary Feed Directive Types of Distribution

14. Medicated Products Type A medicated article Type B medicated feed Type C medicated feed

15. Medicated Products Type A medicated article is a new animal drug

16. * Federal Food, Drug, and Cosmetic Act Section 201(v)*: - any drug intended for use for animals other than man, including any drug intended for use in animal feed - does not include animal feed A new animal drug is….

17. Medicated Products Type A medicated article is a new animal drug with or without inactive ingredients intended for use in animal feed intended solely for further manufacture

18. Medicated Products Type A medicated article is used to make another Type A medicated article a Type B medicated feed a Type C medicated feed

19. * Federal Food, Drug, and Cosmetic Act Section 201(w)*: –an article intended for use for food for animals other than man –intended for use as a substantial source of nutrients in the diet of the animal –is not limited to a mixture intended to be the sole ration of the animal. Animal feed is...

20. Type A medicated article- DRUG Type B medicated feed- FEED containing DRUG Type C medicated feed- FEED containing DRUG Medicated Products

21. contains a substantial quantity of nutrients originates from:a) a Type A medicated article b) another Type B medicated feed c) an unstandardized drug component (bulk or “drum run”) Type B Medicated Feed

22. intended solely for the manufacture of: - other Type B medicated feed - Type C medicated feed Type B Medicated Feed

23. the maximum concentration of drug(s) is: a) if a Category I drug - 200 X the highest continuous use level b) if a Category II drug - 100 X the highest continuous use level c) if a drug is not approved for continuous use - the highest level used for disease prevention/control Type B Medicated Feed

24. product name purpose or indications for use active ingredients guaranteed analysis ingredients mixing directions warning and caution sections (if any) name and address of manufacturer net weight statement Components of a Type B Blue Bird Label

25. Originates from: a) a Type A medicated article b) a Type B medicated feed c) another Type C medicated feed d) an unstandardized drug component (bulk or drum run) Type C Medicated Feed

26. is intended for feeding as: a) the complete feed b) ‘top dressed’ c) ‘free choice’ Type C Medicated Feed

27. product name purpose or indications for use active ingredients guaranteed analysis ingredients feeding directions warning and caution sections (if any) name and address of manufacturer net weight statement Components of a Type C Blue Bird Label

28. Type C –for feeding –to be fed Labeling – Feeding directions Type B –for further mixing –cannot be fed Labeling – Mixing directions Major differences between Type B and Type C medicated feed labels

29. FDA ’ s animal drug approval process (basics)

30. - Required for: - the manufacture of all Type A medicated articles New Animal Drug Application (NADA)

31. mandates that a new animal drug may not be sold in interstate commerce unless it is the subject of a New Animal Drug Application (NADA) The Federal Food, Drug, and Cosmetic Act

32. What does an approved NADA mean? The Federal Food, Drug, and Cosmetic Act

33. What does an approved NADA mean? The product is safe and effective for its intended use The Federal Food, Drug, and Cosmetic Act

34. What does an approved NADA mean? The product is safe and effective for its intended use The methods, facilities and controls used for the manufacturing, processing and packaging of the drug are adequate to preserve its identity, strength, quality and purity The Federal Food, Drug, and Cosmetic Act

35. Effectiveness Based on substantial evidence consisting of one or more adequate and well controlled investigations, such as - a study in a target species - a study in laboratory animals - a bioequivalence study - an in vitro study The Federal Food, Drug, and Cosmetic Act

36. Safety - Adequate tests by all methods reasonably applicable show that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling The Federal Food, Drug, and Cosmetic Act

37. NADA - is a systematic approach to document evidence that drug products are safe and effective - consists of the drug, the packaging, and the labeling The Federal Food, Drug, and Cosmetic Act

38. Division of Animal Feeds Office of Surveillance and Compliance (OSC), Center for Veterinary Medicine Label review

39. Division of Animal Feeds Office of Surveillance and Compliance (OSC), Center for Veterinary Medicine Pre-approvalPost-approval Label review

40. Division of Animal Feeds Office of Surveillance and Compliance (OSC), Center for Veterinary Medicine Office of New Animal Drug Evaluation (ONADE) Center for Veterinary Medicine Pre-approvalPost-approval Label review

41. Division of Animal Feeds Office of Surveillance and Compliance (OSC), Center for Veterinary Medicine Office of New Animal Drug Evaluation (ONADE) Center for Veterinary Medicine Other units within the OSC Field personnel- FDA State Officials Drug Manufacturers Pre-approvalPost-approval Label review

42. Labeling of Medicated Products

43. 21 CFR 514.1(b)(3)(v) –Labeling for new animal drugs intended for use in the manufacture of medicated feeds shall include: ( a ) Specimens of labeling to be used for such new animal drug with adequate directions for the manufacture and use of finished feeds for all conditions for which the new animal drug is intended, recommended, or suggested in any of the labeling, including advertising, sponsored by the applicant. Ingredient labeling may utilize collective names as provided in §501.110 of this chapter. ( b ) Representative labeling proposed to be used for Type B and Type C medicated feeds containing the new animal drug. NADA Regulation

44. Type A medicated article Type B medicated feed Type C medicated feed Medicated Products

45. Types of labels Type A medicated article BrandBrand Type B medicated feedBlue BirdBrand Type C medicated feedBlue BirdBrand Medicated Product Pre-approvalPost-approval Label Review

46. Drug X/Drug Y Growing Turkey Ration Type B MEDICATED FEED For the prevention of coccidiosis caused by Eimeria meleagrimitis, E gallopavonis, and E. adenoeides and for increased rate of weight gain and improved feed efficiency in growing turkeys. ACTIVE DRUG INGREDIENTS Drug X...........................................................................…….…………….……….....80,000 g/ton Drug Y…………………………………………….……………………….........……………6,000 g/ton GUARANTEED ANALYSIS Crude Protein (min)……………………………………………….........................................…..……….…..______% Lysine (min)………………………………………………………...........................................….….….……..______% Methionine (min)…………………………………………………...........................................….….….……..______% Crude Fat (min)……………………………………………………...........................................………..……..______% Crude Fiber (max)………………………………………………………............................................………..______% Calcium (min)…………...………………………………………………………………………..……..….……..______% Calcium (max)………..…………………………………………………………………………..……..….……..______% Phosphorus (min)…..………………………………………………………………………….……….………..______% Salt (min) 1 ……………..…………………………………………............................................………………..______% Salt (max) 1 ……………..……………………………………...........................................….………...………..______% Sodium (min) 2 …..……..…………………………………….........................................…………........……..______% Sodium (max) 2 ….……..…………………………………..........................................………………....……..______% 1 If added. 2 Shall be guaranteed only when total Sodium exceeds that furnished by the maximum salt guarantee. INGREDIENTS: Ingredients as defined by AAFCO. MIXING DIRECTIONS: Mix 10 pounds of this Type B medicated feed with 1990 lb non ‑ medicated feed ingredients to manufacture one ton of complete turkey feed containing 400 grams of Drug X and 30 grams of Drug Y. CAUTION: Do not feed to breeding turkeys. WARNING: Do not feed five days before slaughter. MANUFACTURED BY: BLUE BIRD FEED MILL Robin, IN 00000 Net Weight____lbs (______kg) Bag or Bulk Blue Bird Label

47. YOUR NAME FEEDS Breeding Swine Ration Medicated For control and treatment of leptospirosis (reducing the incidence of abortion and shedding of leptospirae) caused by Leptospira pomona susceptible to Drug Y Active drug ingredient Drug X…………………….................................400 grams/ton Drug Y……………………….............................400 grams/ton Guaranteed Analysis Crude Protein, minimum............................18.0% Lysine…………………………………………..1.27% Crude Fat, minimum.....................................7.0% Crude Fiber, maximum.................................3.5% Calcium, minimum........................................0.7% Calcium, maximum.......................................1.2% Phosphorus, minimum..................................0.65% Selenium, minimum......................................0.29 ppm Zinc, minimum…………………… ……….2000 ppm Ingredient Statement Grain Products, Plant Protein Products, Whey, Animal Fat (preserved with Ethoxyquin), Vitamin A Supplement, D-Activated Animal Sterol (source of Vitamin D 3 ), Vitamin E Supplement, Folic Acid, Biotin, Ascorbic Acid, Copper Sulfate, Manganous Oxide, Zinc Oxide, Ferrous Sulfate, Cobalt Carbonate, Calcium Iodate, Sodium Selenite, Sodium Silico Aluminate, Natural and Artificial Flavors. FEEDING DIRECTIONS Feed continuously for not more than 14 days as the sole ration to provide 10 mg/lb body weight per day of each of the two drugs. CAUTION: Consult your veterinarian if abortions continue to occur at an unacceptable level. WARNING: Withdraw 5 days before slaughter. YOUR NAME FEEDS City, State Zip NET WT 50 LB (22.67 kg) Brand Label

48. YOUR NAME FEEDS Breeding Swine Ration Medicated For control and treatment of leptospirosis (reducing the incidence of abortion and shedding of leptospirae) caused by Leptospira pomona susceptible to Drug Y Active drug ingredient Drug X…………………….................................400 grams/ton Drug Y……………………….............................400 grams/ton Guaranteed Analysis Crude Protein, minimum............................18.0% Lysine…………………………………………..1.27% Crude Fat, minimum.....................................7.0% Crude Fiber, maximum.................................3.5% Calcium, minimum........................................0.7% Calcium, maximum.......................................1.2% Phosphorus, minimum..................................0.65% Selenium, minimum......................................0.29 ppm Zinc, minimum…………………… ……….2000 ppm Ingredient Statement Grain Products, Plant Protein Products, Whey, Animal Fat (preserved with Ethoxyquin), Vitamin A Supplement, D-Activated Animal Sterol (source of Vitamin D 3 ), Vitamin E Supplement, Folic Acid, Biotin, Ascorbic Acid, Copper Sulfate, Manganous Oxide, Zinc Oxide, Ferrous Sulfate, Cobalt Carbonate, Calcium Iodate, Sodium Selenite, Sodium Silico Aluminate, Natural and Artificial Flavors. FEEDING DIRECTIONS Feed continuously for not more than 14 days as the sole ration to provide 10 mg/lb body weight per day of each of the two drugs. CAUTION: Consult your veterinarian if abortions occur at an unacceptable level. WARNING: Withdraw 5 days before slaughter. YOUR NAME FEEDS City, State Zip NET WT 50 LB (22.67 kg) Drug X/Drug Y Growing Turkey Ration Type B MEDICATED FEED For the prevention of coccidiosis caused by Eimeria meleagrimitis, E gallopavonis, and E. adenoeides and for increased rate of weight gain and improved feed efficiency in growing turkeys. ACTIVE DRUG INGREDIENTS Drug X....................................................................…….…………….……….....80,000 g/ton Drug Y……………………………………….……………………….........……………6,000 g/ton GUARANTEED ANALYSIS Crude Protein (min)……………………………………………….........................................…..……….…..______% Lysine (min)………………………………………………………...........................................….….….……..______% Methionine (min)…………………………………………………...........................................….….….……..______% Crude Fat (min)……………………………………………………...........................................………..……..______% Crude Fiber (max)………………………………………………………............................................………..______% Calcium (min)…………...………………………………………………………………………..……..….……..______% Calcium (max)………..…………………………………………………………………………..……..….……..______% Phosphorus (min)…..………………………………………………………………………….……….………..______% Salt (min) 1 ……………..…………………………………………............................................………………..______% Salt (max) 1 ……………..……………………………………...........................................….………...………..______% Sodium (min) 2 …..……..…………………………………….........................................…………........……..______% Sodium (max) 2 ….……..…………………………………..........................................………………....……..______% 1 If added. 2 Shall be guaranteed only when total Sodium exceeds that furnished by the maximum salt guarantee. INGREDIENTS: Ingredients as defined by AAFCO. MIXING DIRECTIONS: Mix 10 pounds of this Type B medicated feed with 1990 lb non ‑ medicated feed ingredients to manufacture one ton of complete turkey feed containing 400 grams of Drug X and 30 grams of Drug Y. CAUTION: Do not feed to breeding turkeys. WARNING: Do not feed five days before slaughter. MANUFACTURED BY: BLUE BIRD FEED MILL Robin, IN 00000 Net Weight____lbs (______kg) Bag or Bulk Blue Bird v Brand label

49. SectionBlue BirdBrand Product nameGenericBrand Indications for useAs regulation saysSame Active ingredients As regulation saysSame Guaranteed analysisBlank levelsSpecific levels Ingredients AAFCO statementList ingredients Directions for useAs regulation saysMostly same Warning sectionAs regulation saysSame Caution sectionAs regulation saysSame Manufacturer informationGenericExact information Net weight statementGenericExact Comparison between Blue Bird and Brand labels