#3 General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food-Producing Animals Guidance for Industry Submit comments on this guidance at any time. Submit electronic comments to https://www.regulations.gov/. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number FDA–2005–D–0155. For further information regarding this document, contact [email protected]. Additional copies of this guidance document may be requested from the Policy and Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, and may be viewed on the Internet at either https://www.fda.gov/AnimalVeterinary/default.htm or https://www.regulations.gov/. U.S. Department of Health and Human Services Food and Drug Administration Center for Veterinary Medicine June 2018 Contains Nonbinding Recommendations Table of Contents I. Introduction and Scope ............................................................................................................. 4 II. Legal Authority.................................................................................................................. 5 III. Overview of the Human Food Safety Evaluation .............................................................. 5 IV. Microbial Food Safety (Antimicrobial Resistance) ........................................................... 6 V. Toxicology ......................................................................................................................... 7 A. Introduction .................................................................................................................... 7 B. Generally Recommended Testing Approach ................................................................. 8 C. Evaluation of Non-traditional New Animal Drugs ........................................................ 9 D. Evaluation of Endogenous Sex Steroid Hormones - Permitted Incremental Increases 10 E. Additional or Specialized Toxicological Studies ......................................................... 10 F. Establishing the Acceptable Daily Intake (ADI), Acute Reference Dose (ARfD), and Safe Concentrations................................................................................................................ 11 1. Determination of the Toxicological Acceptable Daily Intake ................................ 11 2. Effects of Antimicrobial Drug Residues on the Human Intestinal Flora - Determining the Microbiological Acceptable Daily Intake (mADI) .................................. 12 3. Establishing the Final ADI...................................................................................... 12 4. Determining the Acute Reference Dose (ARfD) .................................................... 13 5. Partitioning of the ADI ........................................................................................... 13 6. Food Consumption Values for Edible Tissues........................................................ 14 7. Calculation of the Safe Concentrations................................................................... 14 a. Safe concentrations for total residues in edible tissues ........................................... 14 b. Safe concentration for total residues in muscle injection sites ............................... 15 VI. Residue Chemistry ........................................................................................................... 16 A. Introduction .................................................................................................................. 16 B. Total Residue and Metabolism Study .......................................................................... 16 C. Comparative Metabolism Study ................................................................................... 17 D. Selection of Target Tissue and Marker Residue .......................................................... 17 E. Assignment of Tolerance ............................................................................................. 18 F. Tissue Residue Depletion Study .................................................................................. 19 G. Analytical Methods for Residues ................................................................................. 20 1. Introduction ............................................................................................................. 20 2. Evaluation Criteria .................................................................................................. 20 a. Determinative Procedure ........................................................................................ 20 2 Contains Nonbinding Recommendations (1) Calibration Range and Linearity ......................................................................... 21 (2) Bias (Systematic Error) ....................................................................................... 21 (3) Precision and Accuracy ....................................................................................... 21 (4) Limit of Detection (LOD) and Lower Limit of Quantitation (LLOQ) ............... 22 (5) Robustness and Ruggedness................................................................................ 22 (6) Specificity and Selectivity ................................................................................... 22 (7) Parallelism ........................................................................................................... 23 (8) Stability ............................................................................................................... 23 (9) System Suitability ............................................................................................... 23 (10) Additional Criteria ........................................................................................... 24 (11) Confirmatory Procedure .................................................................................. 24 (12) Adaption of a Previously Validated Method ................................................... 24 3. Specific Data Needed .............................................................................................. 25 a. Sponsor's Submission ............................................................................................. 25 b. Inter-laboratory Study ............................................................................................. 26 H. Establishing a Withdrawal Period ................................................................................ 27 I. Statistical Analysis of the Residue Data .......................................................................... 28 1. Theory ..................................................................................................................... 28 2. Statistical Software: Residues in Tissue and Milk ................................................. 31 VII. Carcinogenic Compounds ............................................................................................ 32 VIII. References .................................................................................................................... 33 3 Contains Nonbinding Recommendations General Principles for Evaluating the Human Food Safety of New Animal Drugs Used in Food-Producing Animals Guidance for Industry This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page. I. Introduction and Scope This guidance describes the type of information that the Food and Drug Administration’s (FDA’s) Center for Veterinary Medicine (CVM) recommends sponsors provide to address the human food safety of new animal drugs used in food-producing animals. The human food safety evaluation of new animal drugs used in food-producing animals helps ensure that food derived from treated animals is safe for human consumption. Sponsors are required to furnish to CVM scientific data or information necessary to demonstrate that residues of the new animal drug in the edible tissues of treated animals are safe (see section 512(b)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act)). In general, studies conducted to provide this information must be conducted in accordance with FDA’s Good Laboratory Practice (GLP) regulations. See Title 21, Code of Federal Regulations, part 58 (21 CFR part 58). FDA conducts a human food safety assessment of new animal drugs for use in food-producing animals through hazard identification, hazard characterization, exposure assessment, and mitigation of human exposure to drug residues in food derived from treated animals. CVM developed this guidance to inform sponsors of the scientific data and/or information that may provide an acceptable basis to determine that the residue of a new animal drug in or on food, when consumed, presents a reasonable certainty of no harm to humans. This guidance describes a recommended approach for providing human food safety scientific data and/or information. CVM acknowledges that alternate approaches also may be appropriate