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 itaccording to your typical dose of 5 cc/100 lbs under theskin. To avoid a residue, which of the following would be yourbest 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.
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 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
Reason Drug Used - FY08 Preventive 12% Illness 88% Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM11/10/2011 11
Yes 30% No 70% Slide courtesy of Drs. Deborah Cera and Randy Arbaugh, FDA/CVM11/10/2011 12
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
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)
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.
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)