Inspections, Compliance, Enforcement, and Criminal Investigations
SUBCHAPTER 5.9 - VETERINARY MEDICINE
The Center for Veterinary Medicine website contains; a listing of current and planned Guidance Documents; and on-line access to the "Animal Drug@fda" database listing new animal drug approvals. There is a "search" feature allowing you to search for documents containing various words or phrases. The website also contains organizational information for the Center and an explanation of the various laws and regulations which the Center enforces. Information on the website can provide guidance for inspectional efforts related to CVM obligations.
CVM is responsible for inspections of therapeutic and production drugs, and Active Pharmaceutical Ingredients (APIs). Therapeutic drugs are used in the diagnosis, cure, mitigation, treatment or prevention of disease. Production drugs are used for economic enhancement of animal productivity. Examples include: growth promotion, feed efficiency and increased milk production.
Preapproval inspections are conducted pursuant to pending NADA or ANADA applications.
Post approval inspections of veterinary drugs are conducted to determine compliance with the Current Good Manufacturing Practices (CGMPs) for Finished Pharmaceuticals under 21 CFR Part 211. These cGMPs apply to both human and veterinary drugs. Information on veterinary drugs approved can be found in the "Green Book" database accessed through CVM's website.
APIs are active pharmaceutical ingredients. Many of the APIs used to manufacture dosage form drugs are imported from foreign countries. The intended source for an API must be indicated in NADA/ANADA submissions for new animal drug approvals. Any change in a source for an API would require a supplement to the application.
Extra label drug use refers to the regulations in 21 CFR Part 530 codified as a result of the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994. These regulations set forth the requirements that veterinarians must meet to prescribe extra label uses of FDA approved animal and human drugs. The regulations describe what is a valid veterinary-client-patient relationship as well as what is considered illegal extra label use. 21 CFR Part 530 addresses issues regarding extra label use in non-food as well as food producing animals. 21 CFR 530.41 contains a list of drugs that cannot be used in an extra label manner in food-producing animals. During an inspection or investigation if you encounter any situations on suspected illegal extra label use of any FDA approved animal or human drugs or those prohibited for extra label use in food animals, you should contact CVM's Division of Compliance (HFV-230) (240-276-9200).
21 CFR Part 530 also addresses compounding of products from approved animal or human drugs by a pharmacist or veterinarian. The regulations clearly state compounding is not permitted from bulk drugs. This would include APIs. CVM has an existing CPG on Compounding of Drugs for Use in Animals (CPG 608.400). A copy can be found on CVM's website. The Division of Compliance (HFV-230) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding. You should contact the Division of Compliance (HFV-230) at 240-276-9200 to report instances of compounding or to seek guidance on inspectional issues, or regulatory and enforcement policies.
Animal feed is defined under section 201(w) of the FD&C Act [21 U.S.C. 321 (w)]. CVM is responsible for control of medicated and non-medicated animal feeds, Type A medicated articles and pet foods.
The regulations for animal food labeling are in 21 CFR Part 501. The regulations for medicated feed mill licensure are in 21 CFR Part 515. The cGMPs for Medicated Feeds are in 21 CFR Part 225. The cGMPs for Type A Articles are in 21 CFR Part 226.
Inspections are routinely conducted of medicated feed mills and manufacturers of Type A Medicated Articles.
If you have questions related to cGMPs and enforcement policies and strategies concerning Medicated Feeds and Type A Articles you should contact the CVM/Division of Compliance (240-276-9200).
Guidance on pet food labeling requirements can be found on CVM's website.
CVM is responsible for FDA's industry education and regulatory activities involving BSE and animal feed. BSE is "Bovine Spongiform Encephalopathy" and is often referred to as "mad cow disease." There are two BSE-related feed regulations: 21 CFR 589.2000, entitled “Animal Proteins Prohibited in Ruminant Feed" which was adopted in 1997, addresses the feeding of ruminant animals. A second rule, 21 CFR 589.2001, entitled “Cattle Materials Prohibited in Animal Food or Feed to Prevent the Transmission of Bovine Spongiform Encephalopathy” was adopted in 2009. 21 CFR 589.2001 prohibits the use of certain cattle-origin materials in the feed of all animals and is aimed primarily at rendering operations.
CVM has Guidance Documents in place dealing with BSE. The guidance documents address renderers, protein blenders, feed manufacturers, distributors and on farm feeders. The Compliance Program Guidance Manual and the inspection checklist are available on the CVM website, as are a variety of other BSE information, including a database containing a summary of the most recent inspection of each firm.
Questions on inspectional assignments and regulatory activities in the BSE area should be addressed to the CVM/Division of Compliance (HFV-230) at 240-276-9200.
The presence of violative drug residues in food from slaughtered animals is a human health concern. Tissue residue inspections are performed in response to reports of violative drug residue levels found in tissue sampled at slaughter by the USDA/Food Safety Inspection Service (FSIS).
Tissue residues are commonly caused by medicating animals prior to marketing and failure to follow the drug’s approved label directions. When a new animal drug is approved the approval is very specific in how the drug should be used, the dosage it should be given, route of administration, frequency of use and reason for use. A drug manufacturer conducts studies to determine withdrawal times and these times must be followed. Established tolerances for drug residues of new animal drugs in food can be found in 21 CFR Part 556.
Tissue residue investigations are unique in comparison to other fieldwork. Although your investigation may begin at the USDA slaughter establishment or person named on the USDA/FSIS “Violation Notification Letter,” you may inspect and/or visit more sites as part of your overall investigation. You may have to visit an auction barn, dealer, trucker, veterinarian, drug supplier, slaughter facility (USDA firm management or State personnel), etc. One or more of these establishments may be responsible for the tissue residue. Thus, each establishment's activities may warrant a recommendation for regulatory action such as Warning Letter, Injunction, etc. when involvement with residue violations is documented.
Upon receipt of a FACTS assignment from CVM to conduct a tissue residue follow-up investigation, the district may also create additional operations, linked to the original CVM assignment, which will include all operations required to complete the CVM assignment. This could include multiple inspections, sample collections and/or investigations. You may not be aware of all the establishments you will visit prior to beginning your investigation. Appropriate operations should be added to or deleted from the district assignment.
Each site visit is unique and each produces its own set of unique documents and evidence requiring individual reporting by establishment. You should use good judgment during case development to assure you document your investigation thoroughly. Explain the chain of events and evidence, from the initial tissue residue report, and how other establishments were involved. Collect samples (usually DOC samples) as appropriate. Consultation with your supervisor and/or compliance branch during these operations is essential to assure all evidence necessary to develop a quality case is obtained and submitted in an appropriate format.
Following completion of all operations, you should prepare a Memo of Investigation referencing the FACTS assignments for your supervisor’s endorsement to the district Compliance Branch, with a copy to the originating CVM office. This Memo will summarize each site visit (EI or Investigation), sample(s) collected and relevance to the overall CVM assignment. A copy of the memo will be routed to each appropriate factory file.
The individual operations will then stand alone and/or may be used together to build one or multiple cases.
For example, a site visit to a slaughter facility may obtain information on the animal from the USDA inspection personnel on site; and obtain verification from management the establishment ships in interstate commerce. Information obtained at the slaughter facility or other establishments may be documented in an affidavit from each individual providing salient information. A site visit to a veterinarian may be important to establish whether the drugs which caused the tissue residue(s) were prescribed and, if so, how they were prescribed. When there is reason to believe off-label use or other activities have occurred which may warrant a recommendation for regulatory action, an establishment inspection should be conducted and your evidence included with your report. Refer to the Compliance Program 7371.006, “Illegal Residues in Meat, Poultry, Seafood and other Animal Derived Foods” for in depth instructions on how to conduct a tissue residue inspection.
For information on tissue residue violations and activities you should contact the CVM/Division of Compliance (HFV-230, 240-276-9200).
Medical devices for animal/veterinary use are not subject to the premarket approval requirements like human medical devices. Once an animal use device is marketed the Center is concerned with safety and efficacy of the veterinary device. CVM often recommends firms use the human device GMPs in controlling the manufacturing of animal use devices. CVM also suggests labeling be sent in for review by the Division of Compliance (HFV-230) to avoid misbranding. Regulatory questions for veterinary/animal use devices should be directed to the CVM/Division of Compliance (HFV-230).
Grooming aids for animals formulated and labeled only to cleanse or beautify the animal are not cosmetics within the meaning of Section 201(i) and not subject to the Federal Food, Drug, and Cosmetic Act. Where animal grooming aids are labeled to contain an active drug ingredient or otherwise suggest or imply therapeutic benefit, they may be considered to be drugs and/or new animal drugs as defined by Section 201(v) of the Act (see CPG 653.100).
Questions on labeling and regulatory concerns should be directed to the Division of Compliance (HFV-230) at 240-276-9200.
CVM issues assignments to the field to conduct BIMO inspections of animal drug studies, including both therapeutic and production drugs. Currently, there is no requirement for animal drug studies to be controlled by any sort of institutional review board (IRB). See IOM 5.5.6.