FROM THE 2015 FEED ADDITIVE COMPENDIUM
by Dragan Momcilovic
Dr. Dragan Momcilovic is a medicated feeds specialist with the Center for Veterinary Medicine's Division of Animal Feed.
The Federal Food, Drug, and Cosmetic Act (the Act), the basic federal food and drug law in the U.S., prohibits interstate distribution or importation of articles that are adulterated or misbranded. This law is the basis for regulations published in the Code of Federal Regulations, Title 21, Food and Drugs. Parts 500-599 constitute the principal body of regulations concerned with animal drugs, feeds and related products, with Parts 200-299 containing the labeling, registration and current good manufacturing practice (cGMP) regulations for drugs, including Type A medicated articles and Type B and Type C medicated feeds.
The responsibility for determining that veterinary drugs and devices are properly labeled for their intended use, and that animal feeds and food derived from animals are safe, rests with the Center for Veterinary Medicine (CVM). Other Food & Drug Administration units (e.g., Center for Food Safety & Applied Nutrition [CFSAN], Office of Regulatory Affairs [ORA] and Office of Chief Counsel [OCC]) also have an active role in some of these activities.
Organization of CVM
Dr. Bernadette Dunham is the director of CVM and Dr. William Flynn and Ms. Tracey Forfa serve as the deputy directors. Dr. Merton Smith is Special Assistant for International Activities. In addition to the Office of the Center Director, there are five other offices within CVM: Dr. Daniel McChesney is the Director, Office of Surveillance & Compliance, Mrs. Roxanne Schweitzer is the Associate Director of the Office of Management, Dr. Steven Vaughn is the Director of the Office of New Animal Drug Evaluation, Dr. John Graham is the Director of the Office of Research and Dr. Meg Oeller is the Director of the Office of Minor Use & Minor Species (MUMS) Animal Drug Development.
Office of New Animal Drug Evaluation
Section 512 of the Act requires an approved application before a new animal drug can be marketed in interstate commerce. However, Congress showed cognizance of the importance of testing the safety and effectiveness of unapproved drugs by exempting the interstate ban for investigational usage. A sponsor submits a notice of claimed investigational exemption to permit legal interstate shipment of investigational new animal drugs (INAD). The application for approval for general marketing of an animal drug is the new animal drug application (NADA), form FDA-356v.
The Office of New Animal Drug Evaluation is divided into several divisions that are charged with the evaluation of both INAD and NADA submissions. Effectiveness and safety information for target animals is evaluated by three divisions, two that evaluate therapeutic use of new animal drugs (one division for food animals and the other for non-food animals) and one division that evaluates production use of new animal drugs. Additional divisions in the Office are responsible for reviewing other aspects of drug submissions. The Human Food Safety division evaluates the safety to the public, the user (the producer or veterinarian), analytical methods, withdrawal times and determines the drug tolerances. The Manufacturing Technologies division evaluates the manufacturing processes and quality control procedures. The Environmental Safety Team evaluates the safety of new animal drugs introduced into the environment.
When a NADA is approved, a notice appears in the Federal Register authorizing the applicant to market the drug in interstate commerce. Also, Part 558 (New Animal Drugs for Use in Animal Feeds) and, when indicated, Part 556 (Tolerances for Residues of New Animal Drugs in Food) of the Code of Federal Regulations, are amended to include this approval. The Office will also decide whether a drug for use in animal feed will be approved for marketing as an over-the-counter (OTC) drug or as a Veterinary Feed Directive (VFD) drug.
The Nov. 18, 2003, passage of the Animal Drug User Fee Act (ADUFA), which amended the Federal Food, Drug, and Cosmetic Act, permits FDA to assess and collect user fees for certain applications, products, establishments and sponsors. Collected user fees are used to support the review of new animal drugs.
Office of MUMS Animal Drug Development
The Office of MUMS has responsibility for coordinating incentive programs intended to encourage sponsors to submit applications for legal marketing of products for “minor uses” in major species (horses, cattle, pigs, dogs, cats, chickens and turkeys) and for “minor species” (all the rest). These incentives include waiver of user fees and “designation” (exclusive marketing rights and grants). The Office also manages the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the Index). This alternative to the approval process makes drugs legally available for animals like pet birds, ornamental fish, ferrets and zoo animals. The position of FDA Liaison to the U.S. Department of Agriculture’s minor use animal drug program (NRSP-7) also resides in this Office. NRSP-7 conducts research in support of drug approval for minor species of agricultural importance. These data are then made publicly available for use by commercial sponsors seeking approval for these intended uses.
Office of Surveillance & Compliance
Four divisions compose the Office of Surveillance & Compliance: the Divisions of Surveillance, Veterinary Product Safety, Animal Feeds, and Compliance.
Division of Surveillance
The Division of Surveillance evaluates drug product labels and promotion and advertising and recommends action to correct deficiencies or to impose regulatory authority to ensure marketed products are safe and effective. The division maintains and makes available inventory listings of all marketed animals drugs to ensure adequate information is available for regulators, industry, as well as the public. The division reviews and tabulates the reported amounts of drugs marketed, with particular attention to antimicrobials for food animals. The division coordinates with the Division of Compliance, the Division of Animal Feeds and the Division of Veterinary Product Safety to decide jurisdiction, develop enforcement strategies, obtain expert witnesses and work on scientific, compliance and regulatory issues. These divisions work together to review inspection reports, labeling and other investigative data to determine whether regulated products are being marketed in accordance with the Act and agency regulations and policy.
The Division of Surveillance consists of three teams: Marketed Product Information Team, Post-Approval Review Team and Unapproved Drug, Jurisdictional & Hazard Review Team.
The Marketed Product Information Team, led by Ms. Sue Dessai, evaluates drug product labels and recommends action to correct deficiencies to ensure marketed products are safe and effective. The team maintains and makes available inventory listings of all marketed animals drugs to ensure adequate information is available for regulators, industry, as well as the public. The team also reviews and tabulates the reported amounts of drugs marketed, with particular attention to antimicrobials for food animals.
The Post-Approval Review Team, led by Dr. Dottie McAdams, evaluates promotion and advertising as well as labeling and recommends action to correct deficiencies to ensure marketed products are safe and effective. The team also works with other divisions to consult on labels and to develop enforcement strategies for scientific, compliance and regulatory issues.
The Unapproved Drug, Jurisdictional, & Hazard Review Team, led by Dr. Vitolis Vengris, reviews unapproved animal drugs, determines jurisdictional issues of animal drugs, biologics and devices and coordinates scientific, compliance and regulatory issues dealing with hazards and medically necessary veterinary products.
Dr. Neal Bataller is the Division Director.
Division of Veterinary Product Safety
The Division of Veterinary Product Safety (DVPS) in the Office of Surveillance & Compliance supports the Center’s mission to protect human and animal health. DVPS monitors the adverse event database for approved drugs, pet foods, unapproved drugs and veterinary devices to identify safety signals and effectiveness issues of concern. For approved drug products, DVPS evaluates adverse event reports to ensure product labeling contains a current accurate safety profile. It also coordinates with FDA District Offices to receive and evaluate product defect reports for the identification of product safety issues. DVPS also provides surveillance of drug product medication errors. DVPS participates in outreach programs to encourage veterinarians to participate in the pharmacovigilance program. Dr. John Baker is the Division Director. The division has three teams. Dr. Linda Walter-Grimm leads the Adverse Drug Event Review Team, Dr. Lee Anne Palmer leads the Adverse Event Review Team and Dr. Susan Bright leads the Data Management & Analysis Team.
Division of Animal Feeds
The Division of Animal Feeds consists of five teams: Medicated Feeds, Feed Safety, Nutrition & Labeling (Team 1 and Team 2), and Ingredient Safety.
The Medicated Feeds Team in the Division of Animal Feeds is responsible for managing the agency’s medicated feed program. Once a Category II drug has been approved, a feed manufacturer can purchase and use the Type A medicated article only if the manufacturer is licensed with the agency. The license application (form FDA-3448) is designed to provide CVM with information required by the amended section of 512(m) of the Act. The division approves medicated feed mill license applications. The team reviews labels of Type A medicated articles and Type B and C medicated feeds. The team also processes VFD Distributor Notices and Out-of-specification assays. Dr. Dragan Momcilovic is the Center’s medicated feed specialist. Ms. Jo Gulley is the leader of the Medicated Feeds Team.
The Feed Safety Team, led by Dr. Terry Proescholdt, provides scientific opinions about feed safety. This team evaluates the potential health hazards to animals and the potential for toxic tissue residues in food-producing animals that may be unsafe for human consumption. Scientific support for agency-initiated regulatory action concerning the safety of animal feed is an important activity of this team. This team also works with CVM’s Division of Compliance, USDA and the U.S. Environmental Protection Agency to administer the interagency environmental contaminant residue monitoring program and provides scientific and technical expertise in the area of microbiological contamination of animal feed, including pet foods. Scientific expertise for bovine spongiform encephalopathy (BSE) resides in this team and is the focal point for the Center’s activities in this area.
Section 409 of the Act requires that a food additive regulation be established before a food additive can be marketed in interstate commerce. The basis for the regulation is an approved food additive petition (FAP). The two Nutrition & Feed Labeling Teams and the Animal Feed Safety Team are responsible for reviewing information on the nutritional additives and ingredients. Unapproved food additives can be shipped interstate for research purposes provided an Investigational Food Additive (IFA) file has been established and exception for investigational use has been granted by CVM prior to shipment. The Nutrition & Labeling Team 1 is responsible for the review of data and information regarding the intended use of food additives, GRAS substances, and other substances intended for nutritional purposes in animal foods. The team also evaluates pet food labels for compliance with federal regulations, recommends any necessary modifications to label content or format, provides scientific and regulatory oversight for pet food, and collaboratively handles the review of scientific information for color additives for use in animal foods. The acting leader is Dr. William Burkholder, the Center's pet food specialist. The Nutrition & Labeling Team 2, led by Dr. Mika Alewynse, is responsible for the review of data and information regarding the intended use of food additives, GRAS substances, and other novel nutritional substances in animal foods, such as enzymes, fermentation products, amino acids, and minerals. The team also evaluates livestock feed labels for compliance with federal regulations and recommends any necessary modifications to label content or format. Additionally, the team is responsible for the review of genetically modified plants and microorganisms prior to their use in animal feed.
The Feed Safety Team and the two Nutrition & Labeling Teams also determine the food additive status of items added to animal feed.
The Ingredient Safety Team provides scientific evaluation and logistical support for CVM’s GRAS (Generally Recognized as Safe) Notification pilot program. Mr. Geoff Wong is the leader of the Ingredient Safety Team. The team also reviews data and information regarding the intended use of food additives, GRAS substances, and other substances intended for technical effect/purposes in animal foods, and reviews information submitted in support of an ingredient's safety for its intended use and manufacturing data submitted by sponsors of animal food additive petitions to determine if data supports approval.
The Division of Animal Feeds also assists FDA’s district and regional offices, as well as other CVM divisions, in preparing for court cases by obtaining and providing expert witnesses and scientific information to support the government’s case. The director of the division is Dr. Sharon Benz.
Division of Compliance
Mr. Eric Nelson leads the Division of Compliance, which is CVM’s focal point for regulatory activity involving rule development, interpretation and enforcement of the Act. The division works closely with FDA field offices and other agency units in developing legal actions against violative products and/or firms. The division consists of five teams: the Imports/Complaint/Emergency/Recall Team led by acting leader D. April Hodges, the Post-Market Compliance Team led by Mr. Dillard Woody, the Drug Residue Compliance Team led by Dr. Annamaria Castiglia, the Pre-Market Compliance & Administrative Action Team led by Dr. Vernon Toelle and the Programs & Operations Support Team led by Mr. Jeremy Robbi.
The Division of Compliance advises on FDA’s regulatory requirements for all animal drugs, feeds, devices and other CVM-regulated products. It provides technical assistance to FDA’s district offices in handling enforcement actions against violative firms or individuals. The division decides on the drug and new animal drug status of products. It coordinates and prepares replies to inquiries from state governments, Congress and industry regarding regulatory issues. The Division of Compliance also handles CVM’s tissue residue program and imports (iCERT).
Office of Research
The Office of Research conducts applied research in support of current and evolving FDA regulatory issues. A cornerstone of this mission is CVM’s intramural and extramural (outside contracts) research programs. This office’s personnel are located in Laurel, Md.
Three divisions, the Division of Residue Chemistry led by Dr. Philip Kijak, the Division of Applied Veterinary Research led by Dr. Mary Allen, and the Division of Animal & Food Microbiology led by Dr. Maureen Davidson, compose the office. Studies are conducted to aid (1) in evaluating data concerning the safety and effectiveness of animal drugs and food additives, (2) development of analytical methods for assay of drug residues in food and (3) policy development on critical health matters. A significant portion of the office’s research is aimed at supporting the Agency’s food safety initiative. The Office of Research also serves as a resource of scientific expertise for application review and regulatory activities.
Dr. John Graham is the director of the Office of Research.
Medicated Feed Program
The agency’s medicated feed program is multifaceted, including the approval of medicated feed license applications, registering and inspecting feed mills, developing policy, writing regulations and evaluating labeling.
The regulations that define the present framework for medicated feed manufacturing are 21 CFR 558.3 and 558.4. All new animal drugs approved for use in animal feed are placed into one of two categories, Category I and Category II. Those drugs in Category I, with the exception of certain liquid or free-choice feeds, do not require the manufacturer to hold an approved medicated feed mill license before use of a Type A medicated article. The maximum drug concentration for a Category I drug in Type B medicated feed is calculated by multiplying the drug’s highest continuous use level (g/ton) by a factor of 200. For example, if the maximum approved concentration of a Category I drug in a Type C medicated feed is 400 g/ton, the maximum drug concentration for that drug in a Type B medicated feed will be 80,000 g/ton or 40 g/lb. (400 g/ton X 200 = 80,000 g/ton).
Drugs in Category II have a different regulatory scheme. To use a Type A medicated article of a Category II drug to make medicated feed (Type B or C) requires the manufacturers of the medicated feed to have an approved medicated feed mill license. These manufacturers are also required to register annually with the agency as a drug establishment (on form FDA 2656) and are part of the inventory of firms to be inspected at least once every two years. For many years, the agency mailed out registration forms as a reminder to firms to renew its annual registration. However, the agency no longer does that. It is the firm’s responsibility to submit its registration annually. For licensed firms, a set of more stringent cGMP regulations has been established. The use of a Category II drug in a Type B medicated feed concentration in manufacturing other medicated feeds does not require an approved medicated feed mill license. However, a license is required for use of a Category II drug, Type B medicated feed in manufacturing of certain liquid or free-choice medicated feed. The maximum Type B level for each drug is calculated similar to that for a Category I drug, except that the multiplication factor is 100.
Firms using drug products that do not require an approved medicated feed license are not required to register with the agency as a drug manufacturer. Therefore, such firms are not part of the inventory of firms to be inspected once every two years. A less stringent set of cGMP regulations has been established for firms not required to be registered. It is important to be in compliance with these cGMP regulations. In addition to being good business practice, it is the law and failure to comply could be the basis for regulatory action such as in the follow up on a residue violation by FDA or during an inspection by state officials.
Distribution of Type A Medicated Articles
Section 512(a)(1)(C) of the Act states that a new animal drug shall be deemed unsafe for such purposes (any particular use or intended use of such drug) in the event of removal from the establishment by a manufacturer, packer or distributor of such drug for use in the manufacture of animal feed in any state unless at the time of such removal such manufacturer, packer or distributor has an unrevoked written statement from the consignee of such drug, to the effect that, with respect to the use of such drug in animal feed, such consignee (i) is the holder of an approved application under subsection (m) of this section or (ii) will, if the consignee is not a user of the drug, ship such drug only to a holder of an approved application under subsection (m) of this section. This requirement is repeated in 21 CFR 510.7 and allows for two exceptions: (1) where such drugs are intended for export and/or (2) where the use of such drug in the manufacture of a finished feed has been exempted from the requirements of section 512 (m) of the Act, under the conditions specified by regulations published in Part 558 of this chapter.
This means that a distributor of Category II Type A medicated articles must furnish the holder of the approved NADA a written statement that he or she will only sell to the holders of approved medicated feed mill licenses or to other distributors for which he or she has an unrevoked written statement that they will meet the requirements as well. The holder of the NADA has the ultimate responsibility to make sure that all of the paperwork is in order and sale of the article is made only to properly approved feed manufacturers.
Non-Licensed Feed Mills
The adequate manufacture and proper labeling of medicated feed are critically important operations. They must occur to ensure that feed and food safety are uncompromised, regardless of whether the feed mixing takes place in a commercial mill or on the farm. The rules established by FDA apply to all manufacturers of medicated feed.
Section 501(a)(2)(B) of the Act states that a drug is adulterated if its manufacture, processing, packing or holding is not done within cGMP. This applies to medicated feed and is the legal basis for FDA’s medicated cGMP regulations. As indicated previously, FDA has two sets of cGMP regulations, one for facilities registered with FDA, because the facility holds a medicated feed mill license, and another for firms not required to register with FDA. The important point is that, regardless of whether a facility is licensed, the operation is required to be in compliance with cGMP regulations. Failure to be in compliance could disrupt business or could result in legal difficulties. The burden is on the inspection office, FDA or the state, to demonstrate that compliance with the regulations is deficient before regulatory action can be initiated. However, it is the facility’s responsibility to manufacture safe feed.
Feed Manufacturing Compliance Program
The FDA field offices and states, under contract to FDA, conduct inspections of registered medicated feed mills, following guidance from CVM in the feed manufacturing compliance program. This compliance program contains sections covering implementation, inspection, analytical work and regulatory follow up. The inspection classification determination made by the field office is used by CVM in determining whether to approve a medicated feed license application. A classification of Official Action Indicated (OAI) will advise CVM not to approve a firm’s license. An OAI classification usually means that an inspection has uncovered violations demonstrating that the methods, facilities or controls used by the firm present an actual or probable adverse impact on the safety, identity, strength, quality or purity of the finished medicated feed. As a general rule, the violations resulting in an inspection being classified OAI would occur in a pattern rather than being isolated occurrences.
The compliance program requires that OAI firms be notified that failure to be in compliance with the cGMP regulations is a basis for withdrawal of an approved medicated feed license. Additionally, the program asks that these firms be reinspected within 90 days and if found not to be in compliance again, the field is directed to recommend to CVM withdrawal of the firm’s license. If CVM and OCC agree, a notice of opportunity of hearing (NOOH) will be published in the Federal Register, which begins the formal legal process.
The regulation (21 CFR 510.301) and the commitments section of the medicated feed license application require the reporting to CVM of “any failure of one or more distributed batches of the drug to meet specifications established for it in the new animal drug application.” Laboratory results beyond the assay limits may indicate a serious problem either with the feeds, the analysis or analytical methodology. We are seeking this information only where the failure is confirmed, i.e., the assays for the original and reserve samples are outside the assay limits for the drug or follow-up investigation of the original out-of-limits assay determines that an error occurred in the manufacturing process. The reports must be sent to the Division of Animal Feeds, HFV-226, FDA/CVM, 7519 Standish Place, Rockville, Md. 20855.
Food Safety Modernization Act
The Food Safety Modernization Act was signed into law on January 4, 2011. FSMA brings the most extensive change in the manner in which the FDA will regulate human food and animal feed since FDCA was enacted in 1938. FSMA enables FDA to better protect public health by strengthening the food safety system. The main themes in FSMA are prevention, inspection and compliance, imports, and enhanced partnerships. Under FSMA, FDA is shifting the focus to preventing food safety problems rather than relying primarily on reacting to problems after they occur. For the first time, FDA will have a legislative mandate to require comprehensive, science-based preventive controls across the food supply including preventive controls for animal food, preventive controls for human food, and produce safety regulations. FSMA recognizes that preventive control standards improve food safety only to the extent that producers and processors comply with them. Therefore, it will be necessary for FDA to provide oversight, ensure compliance with requirements and respond effectively when problems emerge. To ensure compliance, FSMA provides FDA with a mandatory inspection frequency and new enforcement authorities designed to achieve higher rates of compliance such as mandatory recall authority, access to food safety records, suspension of registration, and administrative detention. FSMA granted FDA unprecedented authority to ensure that imported products meet U.S. standards and are safe for U.S. consumers. For the first time, importers have an explicit responsibility to verify that their foreign suppliers have adequate preventive controls in place to ensure that the food they produce is safe. Several new programs, such as voluntary qualified importer program (VQIP) and Third Party Certification, are being developed under FDA’s implementation of the FSAM imports provisions. Lastly, FSMA recognizes that FDA cannot and should not be responsible for food safety oversight alone. FSMA recognizes the need for enhanced partnerships and builds a formal system of collaboration with other government agencies, both domestic and foreign. In doing so, the statute explicitly recognizes that all food safety agencies need to work together in an integrated way to achieve our public health goals. Building a new food safety system based on prevention will take time.
One of the main FSMA provisions of interest to the animal food industry is the proposed rule for Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for Food for Animals. The proposed rule published in the Federal Register on October 29, 2013. The proposed rule applies to all animal food, including pet food. The proposed rule would require all domestic and foreign facilities required to register under the FDCA to also implement current Good Manufacturing Practices for the manufacture, processing, packing, and holding of animal food. In addition, any facility covered by the rule would be required to conduct a hazard analysis and implement risk-based preventive controls. There are a number of exemptions built into the proposed rule such as:
• Hazard analysis requirements would not apply to smaller firms;
• Firms conducting low-risk farm activities
• Facilities covered by other regulations, such as the “low-acid canned food” or standards for produce safety requirements the FDCA; and
• Facilities solely engaged in storage or raw agricultural commodities (other than fruits and vegetables) or packaged animal food.
The comment period for the proposed regulation on animal food ended March 31, 2014.
FDA is committed to implementing the requirements through an open process with opportunity for input from all stakeholders. For additional information on FSMA, please visit: www.fda.gov/fsma.
Animal Drug User Fee Act, Animal Generic Drug User Fee Act
ADUFA and AGDUFA authorize FDA to collect fees for certain animal drug applications and for the establishments, products and sponsors associated with these and previously approved animal drug applications, in support of the review of animal drugs. These additional resources support FDA’s responsibilities under the Federal Food, Drug, and Cosmetic Act to ensure that new animal drug products are safe and effective for animals as well as for the public with respect to animals intended for food consumption.
This program is similar to the very successful program for human drugs. Like the Prescription Drug User Fee Act and the Medical Device User Fee & Modernization Act, this legislation helps FDA expedite and improve its review of applications for new animal drugs so that safe and effective new products become available more quickly.
Feed Defense and Intentional Contamination
FSMA includes a mandate to protect food against deliberate contamination. The Act enables FDA to better protect public health by strengthening the food and feed safety system. It enables FDA to focus more on preventing problems rather than primarily reacting to problems after they occur. Prevention is the primary principle of the AFSS.
FSMA provides authority to prevent intentional contamination. As a part of the Food Safety Modernization Act, the proposed rule on Focused Mitigation Strategies to Protect Food Against Intentional Adulteration was published in the Federal Register on December 24, 2013 (78 FR 78013). The animal food portion is exempt from the requirements of employing mitigation strategies to protect the food supply against intentional adulteration caused by acts of terrorism. The proposed rule, would require the largest food businesses to have a written food defense plan that addresses significant vulnerabilities in a food operation. The reasoning behind the exception for animal food is based on risk with the highest priorities given to resources for protecting human mortality and human morbidity. Microbial agents and chemical agents placed in animal feed will not gain the results and level of human illnesses and death to be a chosen mechanism by terrorists. Moreover, the clinical signs produced in altered diets of animals are expected to prompt the involvement of veterinarians and State officials, and follow-up regulatory measures to prevent products from these animals from entering the human food supply. The proposed rule has an extended comment period to June 30, 2014.
Under FSMA, food facilities will be required to perform their own assessments and apply mitigation techniques to vulnerabilities detected by the assessment.
Animal Feed Safety System
FDA announced in August 2003 its intention to make its animal feed safety program more risk-based and comprehensive. The modernized Animal Feed Safety System (AFSS) incorporates risk-based, preventive control measures for ensuring the safety of animal feed. To date, FDA has hosted five national public meetings to update the public and seek input and agreement from different segments of the public.
AFSS covers the entire continuum of Agency activities from pre-approval of additives for use in feed, to establishing limits on feed contaminants, providing education and training to FDA, state and industry personnel, conducting research, performing inspections and taking enforcement actions for ensuring compliance with Agency regulations.
AFSS includes oversight of manufacture, labeling, storage, distribution and use of all feed at all stages of feed production, whether at commercial or non-commercial establishments. The AFSS Overview Document, as well as other useful information on this initiative, can be found in the AFSS home page on the CVM website at www.fda.gov/AnimalVeterinary/SafetyHealth/AnimalFeedSafetySystemAFSS/default.htm.
A risk-based, preventive animal feed safety program will require producers and distributors of animal feed to take into consideration hazards whose presence in feeds pose an unacceptable risk to animal or human health and develop a plan to reduce or eliminate those hazards. Thus, under a modernized AFSS, feed producers’ knowledge would improve on how to identify and minimize or eliminate hazards associated with animal feed before those hazards result in decreased production, adverse health consequences to the animal and potential risks to human health. Further, producers of animal feed who understand their own business and technical processes well enough to establish effective control points for naturally occurring and/or accidental hazards are also likely to be more capable of detecting and controlling deliberately introduced hazards in a bioterrorism-related event. The principles under which AFSS operates are consistent with the good manufacturing practice and preventive control rules for animal foods that were proposed on October 25, 2013 as required under FSMA. Further, the AFSS risk-based approach will be important for the implementation of the preventive control rule by FDA, states and industry.
The enactment of the Animal Drug Availability Act (ADAA) of 1996 created a new category of drug for use in animal feed, the Veterinary Feed Directive (VFD) drug (Section 504 of the Act). Before ADAA, there were only two drug distribution categories, over-the-counter (OTC) or prescription (Rx). With only two exceptions, all drugs approved in the last 30 years for use in animal feed have been OTC. Currently, the drugs tilmicosin for use in swine and cattle (21 CFR 558.615) and florfenicol for use in catfish, freshwater-reared salmonids and finfish, and swine (21 CFR 558.261) are the only two drugs approved under the VFD category.
FDA published the final VFD regulation Dec. 8, 2000. The process for using VFD is actually very similar to the process for using Rx veterinary drugs. It is not, however, an Rx drug. A veterinarian, upon examining the producer’s animals under a valid veterinarian-client-patient relationship, decides whether a VFD drug is needed. The veterinarian writes a directive providing the information required by FDA regulations. The producer takes the directive to his/her feed supplier who then sells medicated feed containing the VFD drug to the producer. The veterinarian and the producer maintain copies of the VFD order and the feed supplier (e.g., distributor) maintains the original. All parties are responsible for maintaining the records and making them available to FDA for a period of two years.
A feed manufacturer can only make medicated feeds according to the conditions of use provided in the drug approval regulations. Regulations strictly prohibit extra-label use of a feed containing a VFD drug.
Section 504 requires firms distributing medicated feeds containing VFD drugs to notify FDA when they first begin this practice. This notification must be sent to the Division of Animal Feeds (HFV-226), CVM/FDA, 7519 Standish Place, Rockville, Md. 20855, providing the complete name and full business address of company (including site address if different from mailing), the signature of the most responsible person at the site (additionally, the name of the responsible party should be printed or typed) and a statement that you are notifying FDA that you have begun to distribute feeds containing VFD drugs.
CVM has issued a guidance document (Guidance document #120) in regard to the VFD regulation in 21 CFR 558.6 and revised it recently by introducing the system for distribution of VFD orders electronically by using a system compliant with 21 CFR, Part 11. This document may be found on the CVM website at www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052660. pdf. The major associations that worked on ADAA have also prepared information materials for the feed industry, producers and the veterinary profession to help understand what is expected of each party. This educational effort is critical.
On December 12, 2013, CVM published in the Federal Register a notice titled “Veterinary Feed Directive; Proposed rule.” Changes proposed to the VFD regulation in 21 CFR 558.6 are in concert with FDA's actions on antimicrobial resistance. The proposed rule is intended to apply to all VFD drugs including those that are presently approved as VFD drugs, those that will be approved in the future as VFD drugs, and those antimicrobials that are presently marketed over-the-counter and that will be transitioned as part of the judicious use approach specified in GFI#209 and GFI#213 to the VFD status.
The Minor Use & Minor Species Animal Health Act, also known as the "MUMS Act," was passed in 2004 with the goal of increasing the legal availability of medications for use in treating minor animal species as well as uncommon diseases in the major animal species. Minor animal species are all animal species that are not one of the seven major animal species (dogs, cats, horses, cattle, turkeys, chickens and swine).
The MUMS Act modified the Federal Food, Drug, and Cosmetic Act by introducing drug indexing, designation and conditional drug approval and establishing an Office of Minor Use & Minor Species Animal Drug Development at CVM. Drug indexing allows a pharmaceutical sponsor to request addition of an intended use for a minor species to the legally-marketed unapproved new animal drug index for minor species (the Index) based primarily on a review by an independent panel. This option is limited to intended uses in non food-producing minor species. Drug designation provides incentives including grants to support safety and effectiveness testing and seven years of exclusive marketing rights for new animal drug approvals for minor uses and minor species. The grants program is ongoing and there are generally two open application periods each year.
Conditional approval provides a legal means for a sponsor to market a new animal drug before collecting sufficient effectiveness data to meet the full approval standard. All other components of the New Animal Drug Application must be accepted by the FDA and the sponsor must have shown that the product has a “reasonable expectation of effectiveness.” Conditional approval is handled by the Office of New Animal Drug Evaluation.
The Center has published final regulations and Small Entity Compliance Guides for indexing and designation, and a regulation defining a “small number of animals” for determination of minor use status in each of the major species. More information on the MUMS Act provisions is available at www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/MinorUseMinorSpecies/default.htm.
Reportable Food Registry
As mandated by the FDA Amendments Act of 2007, FDA has established the Reportable Food Registry (the Registry) as an electronic portal for industry to report when there is reasonable probability that an article of food will cause serious adverse health consequences. The Registry helps FDA better protect public health by tracking patterns and targeting inspections. It applies to all FDA-regulated categories of food and feed, except dietary supplements and infant formula. The Registry can be accessed at www.fda.gov/Food/FoodSafety/FoodSafetyPrograms/RFR/default.htm.
Extra-Label Use of Drugs
In addition to the cGMP regulations, there are other regulations that manufacturers of medicated feed are required to adhere. An animal drug must be mixed into feed as provided for by the regulations in 21 CFR 558. Again, this applies regardless of whether the facility is mixing feed for sale or for its own animals. We are receiving reports of the mixing of drugs into feeds at unapproved levels or in unapproved combinations. In most cases, the request for making these illegal medicated feeds is coming from a livestock operator or a veterinary clinic. It really does not matter who requested it; the fact is that the manufacture of illegal feed could get the mill and farm in trouble with their customers and with the law.
The Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994 amended the Act to permit extra-label uses of animal drugs under certain conditions. Although AMDUCA prohibits extra-label use of drugs in medicated feeds, there are some minor species that cannot be practically medicated in any way other than through the use of medicated feeds. Furthermore, minor species such as fish and game birds have very few drugs approved for their use. The Center published a Compliance Policy Guide (Sec. 615.115) for the extralabel use of drugs in certain medicated feeds and under certain conditions for these species. In such situations, a veterinarian may determine that extra-label use of medicated feeds approved for use in other species can be considered when the health of animals is threatened and suffering or death would result from failure to treat the affected animals. In instances of this nature, the agency will not ordinarily consider regulatory action. The Compliance Policy Guide lists all the specific conditions that must exist before regulatory discretion is considered for extra-label use in a feed.
The Association of American Feed Control Officials (AAFCO) is an important component of these programs, both from an educational and a regulatory aspect. AAFCO prepared a compliance program and an inspection form for use by state feed control offices. It is important to note that the stated purpose of AAFCO’s compliance program “is to prevent harmful residues from being introduced into the human food supply through medicated feeds.” The compliance program and the inspection form are published yearly in AAFCO’s Official Publication. A copy of the current year’s edition is available for purchase from AAFCO, 1800 S. Oak St., Suite 100, Champaign, Ill. 61820; phone, (217) 356-4221; fax, (217) 398-4119, or email, firstname.lastname@example.org or on AAFCO’s website at www.aafco.org/Portals/0/AAFCO/2013_op_order_form.pdf?v2.
There is a booklet (updated October 21, 2010) that provides information and answers typical questions about the manufacture of medicated feed by facilities not required to register with FDA. A copy of this booklet, “GMPs for Medicated Feed Manufacturers Not Required to Register and Be Licensed with FDA” (Guidance document #72), is available on CVM’s home page (www. fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052386.pdf) or can be obtained by writing to the Communications Staff (HFV-12), CVM, FDA, 7519 Standish Place, Rockville, Md. 20855, or by calling (240) 276-9300. The material in this booklet should be very helpful; however, additional assistance may be necessary.
As another way to assist its stakeholders, FDA recently posted a video concerning the importance of reading medicated feed labels. The video, which can be accessed at www.youtube.com/watch?v=E_CMQFzMxec, outlines why labels are important, and explains how to read them.
State feed control offices and trade associations have begun to take a more active role in developing additional education information and programs. The National Grain & Feed Association has a comprehensive notebook for non-registered mills and is offering regional training courses. The American Feed Industry Association has prepared a similar document. Further, Kansas State University developed a quality assurance pocket manual for on-the-farm feed manufacturers.
The Center’s website at www.fda.gov/AnimalVeterinary/default.htm provides easy access to information on any number of topics with which the Center is involved. More specifically, there is a safe animal feeds website at www.fda.gov/SafeFeed.
There are a wide variety of topics concerning medicated animal feeds. Animal product registration, feed mill licensing, feed contaminants, pet foods and medicated feed mill registration information are just a few of the subjects available. A repository of representative (blue bird) labels is available at www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/MedicatedFeed/BlueBirdLabels/default.htm.