Residues and How to Avoid Them: It's Black and White- Mike Apley

Residues and How to Avoid Them: It’s Black and White

Mike Apley, DVM, PhD

Extralabel Penicillin UseYou 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

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.

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.

What are the problems?

Bob Veal Residues

• Neomycin• Oxytetracycline• Gentamicin• Flunixin• Tilmicosin

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TISSUE RESIDUES IN DAIRY CATTLE - RVIS

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

TISSUE RESIDUES IN DAIRY CATTLE - RVIS

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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

DRUG 2005 2006 2007 2008 Total Percent

Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM

TRIMS 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

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TRIMS - Traditional Causes of Residues

Treatment Records Not Maintained

Withdrawal Time Not Followed

Exceeded Approved Dose

Extra Label Use by Laymen

Drugs Given or Fed by Mistake

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Illness88%

Preventive12%

Reason Drug Used - FY08

04/12/2023

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Did they have a Valid VCPR for Use for FY08?

Yes30%

No70%

04/12/2023

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Withdrawal times must be extended in the case of extralabel use

But, under absolutely no circumstances is there justification for shortening a withdrawal period

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

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

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

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.

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

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


• 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)


• 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.

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).”

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.”

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.”

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.”

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)

Education

Residues and How to Avoid Them: It's Black and White- Mike Apley