This document discusses avoiding drug residues in livestock. It notes that using penicillin purchased from a feed store according to typical doses and routes of administration would result in an illegal residue, as this would constitute extralabel use without veterinary oversight. The best option presented is to consult the drug label for the appropriate withdrawal time. The document emphasizes that extralabel drug use can only be done legally under veterinary guidance within a veterinarian-client-patient relationship.

1. Residues and How to Avoid Them:
It’s Black and White
Mike Apley, DVM, PhD

2. Extralabel Penicillin Use
You purchase procaine Pen G from the feedstore and use it
according to your typical dose of 5 cc/100 lbs under the
skin. To avoid a residue, which of the following would be your
best option.
1.) Consult the label for the appropriate withdrawal time
2.) I would stop because as described above this is an illegal act unless a
veterinarian is involved
3.) This would be fine if I injected the drug intramuscularly because the
subcutaneous (under the skin) route would be off label
4.) I should only purchase this from a route truck because they will be
able to help me with the proper procedure that others are using

3. Residues: It’s Black and White
• Residues occur when detected concentrations
of the marker residue are above the approved
tolerance for that drug in that tissue.
• Residues are monitored in target tissues; the
tissues which hold the residue the longest.
These tissues indicate the status of other
edible tissues in the animal.

4. So…….
• There can be legally acceptable concentrations
of drugs in edible tissues (except for a
carcinogenic parent drug or metabolites) at
slaughter IF there is an established tolerance
in tissues for that animal species.
• For drugs without a label and corresponding
tolerance in a species (including use class and
edible tissue), then any residue detected is
violative.

5. What are the problems?

6. Bob Veal Residues
• Neomycin
• Oxytetracycline
• Gentamicin
• Flunixin
• Tilmicosin

7. DRUG 2005 2006 2007 2008 Total Percent
Amikacin 4 2 0 1 7 0.20%
Ampicillin 6 10 13 8 37 1.04%
Ceftiofur * * * 71 71 1.99%
Dihydrostreptomycin 14 10 8 3 35 0.98%
Florfenicol 1 0 0 0 1 0.03%
Flunixin 121 133 262 233 749 20.99%
Furazolidone 1 1 0 0 2 0.06%
Gentamicin 77 95 58 50 280 7.85%
Kanamycin 2 1 0 0 3 0.08%
Lincomycin 0 0 1 0 1 0.03%
Slide courtesy of Drs. Deborah Cera and Randy Arbaugh,
FDA/CVM 7

8. TISSUE RESIDUES IN DAIRY CATTLE - RVIS
DRUG 2005 2006 2007 2008 Total Percent
Neomycin 22 28 23 21 94 2.63%
Oxytetracycline 31 30 21 32 114 3.20%
Penicillin 301 358 413 304 1376 38.57%
Phenylbutazone 2 0 4 3 9 0.25%
Sulfachlorpyridazine 0 1 0 0 1 0.03%
Sulfadimethoxine 102 158 159 135 554 15.53%
Sulfamethazine 24 33 33 22 112 3.14%
Sulfathiazole 1 2 0 0 3 0.08%
Tetracycline 16 16 7 15 54 1.51%
Tilmicosin 17 27 14 4 62 1.74%
Tylosin 1 0 1 1 3 0.08%
743 905 1017 903 3568
* Prior to July 28, 2008 USDA could not quantitate Ceftiofur
Slide courtesy of Drs. Deborah Cera and Randy Arbaugh,
FDA/CVM 8

9. 9
 An Interactive Database Containing
Information Acquired During FDA/State
Inspections of Firms Involved/Responsible
for Tissue Residue Violations.
 Attachment C Ensures Consistent Data
Collection by both Federal and State
Investigators.
 Attachment C Forms are Entered into
TRIMS
Slide courtesy of Drs. Deborah Cera and
Randy Arbaugh, FDA/CVM

10. 10
 Treatment Records  Drugs Given or
Not Maintained Fed by Mistake
 Withdrawal Time
Not Followed
 Exceeded
Approved Dose
 Extra Label Use by
Laymen
Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM

11. Reason Drug Used - FY08
Preventive
12%
Illness
88%
Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
11/10/2011
11

12. Yes
30%
No
70%
Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM
11/10/2011
12

13. Withdrawal times must be extended
in the case of extralabel use
But, under absolutely no
circumstances is there justification
for shortening a withdrawal period

14. Things that get us in trouble…
• Just blowing off withdrawal times
• No records
• No protocols
• No training of employees on protocols
• Extra-label use (ELDU) without the proper
guidance
– Under the AMDUCA regulations, a veterinarian
MUST be involved in any ELDU in the form of a
VCPR

15. Extralabel use (ELDU)
• Whenever a drug is used other than exactly as
specified on the label
– Dose
– Route
– Duration
– Frequency
– Injection site (location and volume per site)
– Treatment indication
– Animal species and use class

16. Animal Medicinal Drug Use
Clarification Act (AMDUCA)
• The regulations written for this act are what
we really need to understand.
• There is a clear hierarchy of uses in the
AMDUCA regulations
– Use of a labeled product as labeled
– Use of a food animal-labeled product in an
extralabel manner
– Use of a human or non-food animal veterinary
labeled drug
– Use of a compounded drug

17. AMDUCA
• Applies only within the confines of a valid
veterinary-client-patient relationship
• The regulations apply only to products that
are approved for use in either animals or
humans
– For example, solvent grade DMSO is not legal to
put in a food animal at any time. The animal
would be adulterated by using this product.

18. The vets job in ELDU
• Confirm it is legal
• Determine that the use makes sense medically
• Determine the extended withdrawal time
– There must be information available to do this or the
drug cannot be used in this manner
• Assure that the animals are correctly identified for
observation of the extended withdrawal time
• Provide the drug or the prescription

19. Practices that just don’t make sense
• Putting an entire dose of Penicillin G in one
spot
– And what about procaine/benzathine pen G?
• Putting a drug in another injection site than as
labeled
– Moving ceftiofur crystalline free acid to the neck
instead of the ear or base of the ear
– Giving flunixin meglumine intramuscularly

20. Practices that just don’t make sense
• Gentamicin
– There IS a reason why FARAD recommends an 18
month slaughter withdrawal time for this drug.
– It lights up prolonged kidney residues even when
given intramammary
• Using any drug in an extralabel manner
outside the presence of a veterinary-client-
patient relationship (this would be illegal)

21. Practices that just don’t make sense
• Using compounded products outside of
compliance with the AMDUCA regulations
– There is a compliance policy guideline for
compounding. (CPG 608.400)
– The FDA/CVM DOES have the authority to regulate
compounded products just as they do for
approved drugs.

22. CPG 608.400 Excerpts
• “However, FDA is greatly concerned about veterinarians
and pharmacies that are engaged in manufacturing and
distributing unapproved new animal drugs in a manner
that is clearly outside the bounds of traditional pharmacy
practice and that violates the Act (e.g., compounding that
is intended to circumvent the drug approval process and
provide for the mass marketing of products that have been
produced with little or no quality control or manufacturing
standards to ensure the purity, potency, and stability of the
product).”

23. CPG 608.400 Excerpts
• “These activities are the focus of this
guidance. Pharmacies and veterinarians who
engage in activities analogous to
manufacturing and distributing drugs for use
in animals may be held to the same provisions
of the Act as manufacturers.”

24. CPG 608.400 Excerpts
• “With regard to compounding from bulk drug substances,
two Federal Appeals Court decisions, United States v.
Algon Chemical Inc., 879 F.2d 1154 (3d Cir. 1989) and
United States v. 9/1 Kg. Containers, 854 F.2d 173 (7th Cir.
1988), affirmed the FDA position that the Act does not
permit veterinarians to compound unapproved finished
drug products from bulk drug substances, unless the
finished drug is not a new animal drug. The principle
established by the court applies equally to compounding
by pharmacists.”

25. CPG 608.400 Excerpts
• “Neither the Act nor its implementing regulations exempt veterinarians
or pharmacists from the approval requirements in the new animal drug
provisions of the Act, 21 U.S.C. Section 360b. In the absence of an
approved new animal drug application, the compounding of a new
animal drug from any unapproved drug or from bulk drug substances
results in an adulterated new animal drug in violation of section 21
U.S.C. Section 351(a)(5). The compounding of a new animal drug from
an approved human or animal drug also results in an adulterated new
animal drug in violation of 21 U.S.C. Section 351(a)(5), unless the
conditions set forth in 21 CFR 530.13(b) are met.”

26. It all comes down to…
• Develop a treatment protocol
– Case definition
– Regimen (with a qualified veterinarian)
– Outcome definitions
– Animal disposition (animal ID!)
• Adhere to the protocol
• Monitor adherence and outcomes
– Records (and check them before selling an animal)