One of FDA’s highest priorities is to ensure the safety of animal-derived foods for human consumption. As part of the approval process of a drug for a food-producing animal, the agency sets the drug’s tolerance level. Marketing animals for food with drug residues above the established tolerance is illegal and causes the food to be adulterated. FDA’s compliance program objectives for violative residue include:
- Identifying on-farm husbandry practices and animal drug use patterns leading to violative residue -- for program analysis, identifying educational needs, and policy and guidance development.
- Correcting farm practices that lead to violative residues through voluntary or enforcement action.
FDA actively investigates the misuse of veterinary drugs in food animals. Violative residues in edible tissues are a common trigger for follow-up investigations and for sending Warning Letters to all responsible parties in the animal production and marketing chain. If continued violations occur, FDA can recommend enforcement actions such as injunctions, contempt of injunction, and prosecutions.
Leadership in Coordination with US Department of Agriculture (USDA) and the Environment Protection Agency (EPA)
CVM was instrumental in forming an Inter-Agency Executive Level Steering Committee with leaders from FDA, USDA and EPA. The committee’s purpose is to resolve long-standing issues related to residues in food animals. One key accomplishment is a proposal for sponsors to work more closely with USDA and its Food Safety Inspection Service on methods to detect and avoid residues prior to drug approval. Residue control is a collaborative interagency effort in which EPA and FDA have statutory authorities for establishing residue tolerances or action levels. The steering committee meets as needed to hear concerns from the Interagency Residue Control Group (IRCG) and others involved in tissue residue avoidance and enforcement. This interagency coordination is a vital part of improving food safety.
CVM’s Division of Compliance processed recommendations for four injunctions, three contempt of injunction actions (for violation of injunctions), and 76 warning letters related to tissue residue violations. Three examples of injunctions put into place during the year are:
Michigan Dairy Farm. On November 1, 2011, the U.S. District Court for the Western District of Michigan enjoined a dairy farm from selling cows for slaughter until the FDA certifies that the dairy is in compliance with federal law and the requirements of the court’s injunction. The dairy owned approximately 10,000 dairy animals at three sites. The firm had a long history of illegal animal drug residues found in tissues of dairy animals culled for slaughter as human food, and FDA on a number of occasions notified the firm of the violations. The illegal residues included neomycin, penicillin, and sulfadimethoxine.
Wisconsin livestock dealer/producer. In July, 2012 the U.S. District Court for the Eastern District of Wisconsin signed a consent decree of permanent injunction against a livestock dealer/producer who purchased calves from local farms and feeder cattle from various sale barns, either reselling them or taking them to his farm to raise for later marketing. The FDA Minneapolis District had conducted several inspections over a period of years, following up on USDA/FSIS reported tissue residue violations, to confirm the identification of the responsible party and to determine the causes for the residues. Reinspection following issuance of an FDA Warning Letter revealed continuing deficiencies including the sale and distribution of veterinary prescription drugs without a license, food and drug adulterations related to the misuse of the drugs and resulting residue, and failure to maintain treatment records.
Idaho dairy farm complex. Following USDA reports of tissue residue violations found in several adult cows and calves from Idaho dairy farms, FDA investigators found that the farms were linked to other dairies in the area; a total of seven dairies were listed under three limited liability corporations (LLC’s) owned by five individuals. In December 2011, the U.S. District Court for the District of Idaho entered a consent decree against one of the LLCs and three individuals for violations based on illegal drug residues found in edible animal tissue, and drug adulteration related to the misuse of the drugs and resulting residue. This case represents the first time the Agency has taken action against an LLC for tissue residue violations.
Research on New Methods for Detecting Antibiotic Residue in Animal Food Products
Tetracyclines and ceftiofur are antibiotic drugs that are widely used for treating and preventing infectious diseases in food-producing animals such as cattle. If these drugs are used improperly, residues of the drugs can remain in the food products and can cause health problems in consumers. The current regulatory methods for detecting unsafe tetracycline and ceftiofur drug residues were developed years ago and are now obsolete. The methods are difficult to use, cannot distinguish between multiple drugs in a sample, and require equipment that is no longer available. CVM’s Office of Research made considerable progress during the fiscal year developing new methods for detecting residues of these drugs in edible tissues in the following four studies.
Incurring Residues for Bridging of Chemical and Microbiological Detection Methods. The purpose of the study is to provide tissues with incurred drugs to chemists and microbiologists who are conducting studies to compare the new and old methods (bridging). As of June 2012, residue-incurred animal tissue for the bridging studies of oxytetracycline and chlortetracycline had been provided. The final reports had been written. Work to generate tissue with incurred levels of tetracycline was underway.
Bridging of new method for detecting residues of the tetracyclines. A new and more efficient method has been developed to detect oxytetracycline, tetracycline, and chlortetracycline in bovine kidney. In the bridging study conducted during the year, samples were concurrently analyzed by both the new and old methods to establish a correlation. The bridging of each individual drug has been completed and three methods have been validated separately for each of the tetracyclines. Validation of the method for detecting all three drugs when they are combined was being completed at the end of the year.
Once the bridging study is completed, the new method will replace the obsolete regulatory method in surveillance and compliance activities. The new method will also be the reference method to which future analytical methods will be bridged.
Developing and validating a new method for detecting ceftiofur residues. We have completed the laboratory work to develop a new LC/MS/MS-based method to replace the regulatory HPLC UV method. We have written an interim report and are reviewing experimental data. We have also published a paper describing a chemical method for detecting ceftiofur.
Bridging the new method for detecting ceftiofur residues. This study is entitled, “Bridging of a Quantitative and Confirmatory LC-MS/MS Method to the Regulatory HPLC Method Used to Determine Ceftiofur in Bovine Kidney.” We completed the laboratory phase and wrote an interim report during the year, and at year’s end were reviewing the report and experimental data.
These studies will improve FDA's and USDA’s ability to prevent unsafe food products from entering into the consumer market.
Leadership in Residue Related Training
During the year, CVM staff members served as instructors at tissue residue training courses in Wisconsin, New York, and California for FDA investigators, state inspectors, supervisors, and compliance officers. Participants acquired skills and knowledge in gathering, developing, and documenting evidence during tissue residue investigations. Upon completion of the course, participants were also able to recognize animal diseases, types of drugs used to treat these diseases, animal management practices for the various food-animal production classes, the causes of drug residues, and the development and implementation of prevention strategies.
CVM staff members also aided in developing and implementing an Animal Medicinal Drug Use Clarification Act (AMDUCA) training course in Nashville, Tennessee for FDA investigators, state inspectors, compliance officers, and supervisors. (AMDUCA is the law that governs extra-label use of animal drugs including compounding). The course included instruction on the laws, regulations and policies pertaining to compounding of animal drugs and the extra-label drug use of veterinary and human drugs in animals. Participants in the course learned about the regulations and guidance documents that address the proper use of animal drugs; the compounding of drugs for use in animals; the extra- label use of drugs in animals; appropriate investigative and data gathering techniques for conducting investigations of compounding pharmacies, veterinarians, and food animal producers; and correct completion of the documentation required for the development of a successful enforcement action.
Milk Sampling Assignment for Drug Residues
USDA/FSIS reports of violative drug residues in dairy cattle tissues have been associated with poor on-farm practices. The same poor practices that lead to tissue residues (for example, inadequate record keeping and lack of a valid veterinary-client-patient relationship) may also lead to residues in milk. After extensive meetings with industry and other stakeholders, FDA developed a milk sampling survey to see if targeted farms, with known tissue residue violations, were more likely to have milk residues than non-targeted farms. In order to prevent disruption to the milk industry, this survey was conducted using blinded samples that were only identified as “targeted” or “non-targeted.” Sampling was initiated in January 2012 and was completed by January 2013.
Incurring is the spiking of untreated tissue with known amounts of a substance, e.g., a drug, for use in research.
Liquid chromatography - mass spectrometry
High-performance liquid chromatography - ultra violet.