CVM

1
CVMs Procedure for Setting Tolerances

• Lynn G. Friedlander, Ph. D.
• Division of Human Food Safety
• Residue Chemistry Team

2
Tolerance Setting

• Chemical residues
• Other approaches

3
Tolerance Setting

• Residue
• Any compound present in the edible tissues of
  the target animal which results from the use of
  the sponsored compound, including the sponsored
  compound, its metabolites, and any other
  substances formed in or on food because of the
  sponsored compounds use. 21 CFR 500.82 (b)

4
Tolerance Setting

• Office of New Animal Drug Evaluation
• Division of Human Food Safety
• Toxicity data from the model species
• Microbial safety data
• Residue data from the target food-producing
  species
• Analytical methodology
• Good Laboratory Practices (GLP)

5
Tolerance Setting-Toxicology

• Basic Toxicology Package
• Additional/special toxicology studies
• Calculate the No Observable Effect Level (NOEL)
• Determine the appropriate safety factor
• Calculate the Allowable Daily Intake (ADI)

6
Tolerance Setting-Toxicology
ADI No Observable Effect Level Safety
Factor
7
Tolerance Setting-ToxicologyCalculating the Safe
Concentration
Safe Concentration ADI x 60 kg
consumption factor
8
Tolerance Setting-Toxicology

• The safe concentration is the amount of residue
  that can be eaten in any edible tissue each day
  for an entire lifetime without exposing the
  consumer to residues in excess of the ADI.

9
Tolerance Setting-Residue Chemistry

• Risk Hazard X Exposure
• Mitigates the hazard identified in the toxicology
  safety studies by controlling exposure to the
  hazard through the assigning of tolerances and
  withdrawal periods or milk discard periods, where
  needed.

10
Tolerance Setting-Residue Chemistry

• Basic Studies
• Comparative Metabolism-Toxicology Species
• Total Residue and Metabolism-Target Species
• Analytical Method
• Residue Depletion/Withdrawal-Target Species

11
Tolerance Setting-Residue Chemistry

• Comparative Metabolism Study
• Did the toxicology testing evaluate the right
  compound(s)?
• Qualitative comparison of the metabolic profiles
  in the toxicological and food-producing species
• Ensures that the toxicological species has been
  exposed to the same residues to which humans will
  be exposed when they consume products derived
  from treated food-producing animals
• If profiles are not comparable, more toxicology
  testing may be indicated.

12
Tolerance Setting-Residue Chemistry

• Total Residue and Metabolism Study
• Radiolabeled drug
• 1-1.5X the proposed dose
• Proposed route of administration
• Intended duration of treatment/steady state
• Intended species males and females

13
Tolerance Setting-Residue Chemistry

• Total Residue and Metabolism Study
• Determines the MARKER RESIDUE
• the residue that monitors the depletion of total
  residues in a tissue
• Determines the TARGET TISSUE
• generally, the edible tissue from which residues
  deplete most slowly
• often, liver or kidney
• rarely, muscle or fat

14
Tolerance Setting-Residue Chemistry

• Total Residue and Metabolism Study
• Provides a METABOLISM PROFILE in the
  food-producing animal
• for comparison with the metabolism profile of the
  toxicological species
• Establishes the MARKERTOTAL ratio
• to calculate the tolerance

15
Tolerance Setting-Residue Chemistry

• Analytical Methodology
• Determinative
• measures concentrations of drug residues in
  tissue
• Confirmatory
• verifies the identity of the drug residue
• Screening
• assesses impact the new drug on pre-existing
  residue tests
• not required

16
(No Transcript)
17
Tolerance Setting-Residue Chemistry

• Determine the time at which the concentration of
  total radiolabeled residues in the target tissue
  is less than the target tissue safe concentration
• Determine the concentration of the marker residue
  in the target tissue at that time using the
  proposed analytical methodology

18
Tolerance Setting-Residue Chemistry

• The concentration of the marker residue in the
  target tissue at the time the total radiolabeled
  residue in the target tissue has depleted to less
  than the target tissue safe concentration is the
  target tissue TOLERANCE

19
Tolerance Setting-Residue Chemistry

• Can establish tolerances for more than one
  tissue, i.e., target tissue and muscle
• must have data for the tissue(s) to support the
  tolerance assignment(s)
• often these data are available as part of the
  total residue and metabolism study

20
(No Transcript)
21
Tolerance Setting-Residue Chemistry

• Target tissue tolerance is a monitor for the
  depletion of residues from all the edible tissues
• When the concentration of the marker residue in
  the target tissue is less than the target tissue
  tolerance, total residues in all of the edible
  tissues are less than their respective safe
  concentrations

22
Tolerance Setting-Residue Chemistry

• Non-target tissue tolerance monitors depletion of
  residues only from the specific non-target tissue
• For example, if we assign a muscle tolerance and
  muscle is not the target tissue
• Muscle tolerance monitors the depletion of
  residues from the muscle
• When the concentration of the marker residue in
  the muscle is less than the muscle tolerance, the
  total residues in the muscle are less than the
  muscle safe concentrations
• Muscle tolerance does not monitor any other
  edible tissues

23
Tolerance Setting-Residue Chemistry

• Tolerance
• links the ADI and safe concentrations of total
  radiolabeled residues to cold residues that
  result from the use of the proposed market
  formulation as measured with the regulatory
  analytical method

24
Tolerance Setting-Residue Chemistry
25
Tolerance Setting-Residue ChemistryApplying the
Tolerance

• The preslaughter withdrawal period and, if
  applicable, the milk discard period
• on the product labeling
• in the relevant section of 21 CFR Part 500
• The established tolerance is codified under 21
  CFR 556

26
Tolerance Setting-Residue ChemistryApplying the
ToleranceUS Approvals