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U.S.F.D.A. Regulatory Approach for Control of Residues of Veterinary Drugs

Richard Ellis, FDA, CVM, USA

1. Introduction

The FDA Center for Veterinary Medicine (CVM) is a consumer protection organization that aids public and animal health by approving safe and effective products for animals and by enforcing other applicable provisions of the Federal Food, Drug, and Cosmetic Act and other authorities. The FDA is responsible for ensuring that all animal drugs and medicated feeds are safe and effective for their intended uses. When the drug is for use in food-producing animals, not only must the safety and efficacy to the animal be demonstrated, but also the safety of food products derived from the treated animals that are intended for human consumption.

Virtually all animal drugs are "new animal drugs" within the meaning of the term in the Federal Food, Drug, and Cosmetic Act. A new animal drug is deemed unsafe unless there is an approved new animal drug application. The CVM Office of New Animal Drug Evaluation (ONADE) has major responsibility to review information submitted by drug sponsors who desire to obtain approval to manufacture and market animal drugs. Before a new animal drug receives FDA approval, it must be clinically tested for effectiveness and safety in the target animal. It must also be tested for safety to human consumers, and the edible animal products must be free of unsafe drug residues. It is the responsibility of the drug sponsor (the individual or firm seeking FDA approval of the drug product) to conduct all the necessary tests. The product sponsor also must develop analytical methods to detect and measure drug residues in edible animal products.

ONADE performs the following tasks in their review of applications:

There are two main processes involved in regulating the interstate shipment of animal drug products. The first process, the Investigational New Animal Drug exemption (INAD), involves the interstate shipment of experimental drugs used for testing in animals. This testing may require drugs be given to animals that will later be used to produce human food products. FDA must ensure that the food products derived from these experimental animals will be safe for human consumption. The second process is the New Animal Drug Application NADA review. It includes the evaluation of data regarding an animal drug's safety to the target animal and to humans who might consume products from the treated animal; the review also evaluates effectiveness for the purposes claimed. To be legally marketed, a new animal drug must be approved under a NADA.

For veterinary medicines intended for use in food producing animals, the human food safety group evaluates the safety of the residues from use of the veterinary drug for the consuming public, the user of the veterinary drug (e.g., a producer or veterinarian), analytical methods, withdrawal times, and provides the drug tolerances so that safe residue levels and conditions of use are provided to the public. The manufacturing chemistry group evaluates the manufacturing processes, quality control and environmental safety. The biometrics group provides statistical support to ONADE and the rest of the Center.

The general information and guidance for the comprehensive review of a potential veterinary drug is published in two general documents - the Code of Federal Regulations, Chapter 21 (and subsequent parts, e.g., parts 500-599) and in Guidance for Industry (GFI). The Code of Federal Regulations may be found at http://frwebgate.access.gpo.gov/cgi-bin/multidb.cgi. The GFIs may be found on the FDA-CVM website (http://www.fda.gov/cvm/default.html). The general principles for evaluating the safety of compounds used in food producing animals are described in Guidance No. 3, initially published approximately 20 years ago. GFI No. 3 may not always reflect the contemporary procedures applied in practice because of the continual evolution of regulatory toxicology, microbiology and analytical chemistry and international developments of harmonized protocols, but the basic framework remains scientifically sound and the foundation for safety evaluation for veterinary drugs in FDA. An example of international guidance documents referenced above, are those developed through the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH), a tri-lateral programme aimed at harmonising technical requirements for veterinary product registration. Three recent GFIs on microbial food safety complement GFI No. 3 in FDA's food safety assessments.

One of FDA's highest priorities is assuring the safety of the food supply through elimination of violative residues in meat and milk. For this reason, a cooperative effort of FDA and the U.S. Department of Agriculture (USDA) Food Safety Inspection Service (FSIS) is an integral part of the overall food safety programme for control of residues of veterinary medicines. The role of FSIS will be reviewed subsequently.

2. Good Laboratory Practices

Because of the critical nature of the quality of information required for conducting a comprehensive evaluation of efficacy and human food safety, FDA established guidelines for good laboratory practice (GLP) about 1978 and has amended these regulations as appropriate since that time. The GLP regulations are published annually in the U.S. Code of Federal Regulations, Chapter 21, part 58. They are for use in non-clinical laboratory studies on all aspects of veterinary medicine development and registration. These studies are intended to support applications for research or marketing permits for products regulated by the FDA. Compliance with these regulations helps to assure the quality and integrity of the safety data filed with FDA for registration of all veterinary medicine products. The details of GLPs are beyond the scope of this paper. Briefly, they address the following areas: general provisions, organization and personnel, facilities, equipment, testing facilities operation procedures, test and control articles, protocols for the conduct of a non-clinical laboratory study, records and reports and procedures for disqualification of testing facilities and their reinstatement. Guidance for conducting inspections and regulatory actions regarding compliance with the GLPs is an integral part of FDA's regulatory approval procedures.

3. Regulatory review - GFI No. 3, 52, 152 and 159

FDA's guidance documents do not establish legally enforceable responsibilities. They describe the Agency's current thinking on a topic and are only suggested or recommended but not required procedures unless specific regulatory or statutory requirements are cited.

GFI No. 3, General principles for evaluating the safety of compounds used in food-producing animals, contains eight individual sections and serves as the introduction to the descriptive components of FDA's regulatory review. GFI No. 52, 152 and 159 are complementary documents that address specific microbiological toxicology review. For brevity, only highlights of the principle assessment considerations will be addressed. Specific components of GFI No. 3 are:

The overlying principle for FDA in regulating veterinary drugs is that the review is based upon the foundation of a scientific risk assessment using a benchmark of "reasonable certainty of no harm". In considering approval of a veterinary drug, FDA does not consider a benefit assessment as part of the decision making process.

3.1. Toxicology

The toxicology review process for human food safety begins with acceptance of study data. Included in this consideration is whether the studies provide assurance of GLP compliance. A thorough protocol has to be included as well as individual animal or in vitro test data. Study reports need to be complete. In the toxicology review, any effect seen is considered a toxic effect - whether it is tissue and/or system injury, transient, reversible or pharmacological. Laboratory studies must address lifetime exposure in test animals and due consideration to extrapolation from animal data to humans (that is, the test models must be relevant to humans). There is substantial consideration on repeat-dose toxicity studies generally applying consideration of a reviewers' template for such studies. Reviews consider the analysis and interpretation of individual toxicology reports. Attention is given to clinical chemistry and haematology parameters, with emphasis in dose-response relationships or biological drift from control values. Effects observed should be correlated with other manifestations of toxicity. Coupled with the above information, organ weights and histopathology are relevant. The general types of toxicological endpoints, in accord with the specific class of drug, include genetic, reproductive, developmental, neurological, central nervous system, cardio/pulmonary, immunologic, hormonal, allergenicity and microbiological toxicity. Carcinogenicity studies are a mainstay for toxicological assessment; however, carcinogenicity studies are rarely used to establish a no observed effect level (NOEL). There are provisions in U.S. food safety laws and regulations for carcinogenic substances that will be addressed below.

Intestinal flora toxicity assessment has become a significant consideration in determining the most appropriate end-point study for a NOEL and subsequently, an acceptable daily intake (ADI). As indicated above, there are three GFI documents relative to microbiological toxicity. GFI 52, Assessment of the effects of antimicrobial drugs - Residues from food of animal origin on the human gut intestinal flora, provides a pathway approach for determining the need for a microbiological based ADI. GFI 152, Evaluating the safety of antimicrobial new animal drugs with regard to their antimicrobial effects on bacteria of human health concern, provides a qualitative risk assessment approach for evaluating the microbial food safety of antimicrobial new animal drugs. The format for the guidance is based on the Office of International Epizooties (OIE) model. That is, it addresses "release assessment", as the probability of emergence or selection for resistant bacteria in food -producing animals as a result of the use of an antimicrobial drug; "exposure assessment", as the probability that humans consuming animal-derived foods will be exposed to resistant bacteria of public health concern or resistant determinants; and a "consequence assessment", as the probability that human exposure to resistant bacteria results in an adverse health consequence. This assessment takes into account, in particular, the importance of the antimicrobial drug for use in human therapy.

Within the context of risk assessment, many possible mechanisms to address the development of antimicrobial resistance resulting from the use of antimicrobial new animal drugs in food-producing animals are available to the sponsor. If a sponsor can identify an alternative process that may be more appropriate to a particular drug and its intended conditions of use, it may be used to characterize the microbial food safety of that drug.

Recently harmonized protocols for toxicological food safety assessment have been agreed upon by VICH and are becoming the international standard for this purpose. As a result of VICH Guidance 36, FDA has developed GFI 159, Studies to evaluate the safety of residues of veterinary drugs in human food - A general approach to establish a microbiological ADI. This guidance document develops a step-wise approach and proposes models that can be used for determining a microbiological ADI. Specific reference to these guidance documents can be found on the FDA website (http://www.fda.gov/cvm/guidance/published.htm).

3.2. Residue Chemistry and Metabolism

The toxicological assessment of a veterinary drug establishes the basis for identifying the most appropriate in vitro or in vivo study upon which a NOEL and, subsequently, an ADI can be established. Based on the quantity and quality of the data and the scientific interpretation of that data, a safety factor is applied to the NOEL to establish the ADI. The second major component described in GFI No. 3 in regards to safety evaluation is exposure to humans from consumption of residues of toxicological concern in tissues (and milk and eggs, as appropriate). That process begins with metabolism and radiolabelled residue studies in the target animals. The three principle components of this endeavour include comparative metabolism in the toxicological species, total radiolabelled residue and metabolism studies in the food-producing animal, and residue depletion studies to establish the pre-slaughter withdrawal period and when needed, the milk withdrawal and discard time.

The total residue and metabolism study provides the necessary information to determine the appropriate marker residue (the compound used to monitor the depletion of total residue in a food-animal tissue) and to determine the target tissue (generally, the edible tissue from which residue deplete most slowly). Additional information derived from these studies includes 1) establishing the marker residue to total residue ratio that eventually will be used to calculate the tolerance (maximum residue limit) in the target tissue; and 2), a metabolism profile in the food-producing animal for comparison with the metabolism profile of the toxicological species. Residue depletion studies using non-radiolabelled drug provide additional information necessary for developing tolerances and withdrawal times.

3.3. Tolerance setting

For FDA, and following the GFI No. 3, when the tolerance is based on a toxicological end-point, the concentration of the marker residue in the target tissue at the time the total radiolabelled residues in the target tissue has depleted to less than the target tissue safe concentration, it is the target tissue tolerance. When the ADI is based on a microbiological end-point, a similar approach is used, however, only residues of microbiological concern are considered. In the FDA approach, when the concentration of the marker residue in the target tissue is less than the target tissue tolerance, total residues in all the edible tissues are less than their respective safe concentrations (i.e., the entire food animal carcass is safe).

Safe concentrations of residues in the animal tissues are related to the ADI and food consumption factors. FDA uses the same food consumption factors as used in the Joint FAO/WHO Expert Committee for Food Additives (JECFA); however, they are applied differently. FDA assumes that if a person consumes 300g of muscle tissue, they will not consume an allocation of liver or kidney tissue but may consume a full allocation of milk and eggs. The food allocation is 300g muscle, 100g for liver, 50g for kidney and fat, 1500g for milk and 100g for eggs. Therefore, for a safe concentration in muscle tissue for a 60kg consumer, the ADI (in mg/kg, for example) is multiplied by 60kg and that value divided by 0.3kg. For liver, the denominator will be 0.1kg and for kidney and fat the denominator will be 0.05kg. For milk the denominator is 1.5kg and for eggs, it is 0.1kg.

One other significant difference in developing tolerances (maximum residue limits) from the ADI for mitigating the hazard from consumption of residues in food animal tissues is that FDA allows consideration of portioning the ADI between food animal tissues and milk and eggs. As this is considered a risk management issue, the drug sponsor may make a recommendation on the distribution of the ADI. Therefore, if a sponsor intends to use the product in dairy cows and they want to have a short withholding period for milk discard, they may suggest a large portion of the ADI be set for milk and consequently a small portion for residues in tissues because feedlot cattle can be held for longer withholding periods. Hypothetically, a sponsor may suggest 70% of the ADI be allocated to milk and 30% for tissue residues. In this case, if an ADI is 0.1mg/kg per day, then for determining a safe concentration in milk, FDA will use 0.07mg/kg per day to calculate the safe concentration for residues in milk and use 0.03mg/kg per day to calculate the safe concentration for residues in food animal tissues. If a sponsor defers the allocation of the ADI, then FDA will make an allocation of the ADI. If at some time point in the future, the sponsor indicates that use of the veterinary drug will change, then the allocation may be revised, and accordingly, the safe concentrations and tolerances.

For establishing a tolerance, as indicated above, FDA will use the safe concentration value and the results from residue depletion studies using the marker residue and target tissue. The latter two factors can be readily determined because the definition of a marker residue indicates that it has a relatively "fixed" ratio with the total residues. An estimate can be made for when tissues (and milk or eggs, as appropriate) deplete to the required concentration. In selecting a withdrawal period for food animal products, FDA applies a conservative value based on the 99th percentile of residue values from controlled studies applying a 95% confidence limit to the 99th percentile residue value. If the calculated value is an intermediate value between five and six days, the withholding period would be rounded up to six days. The same concept applies to milk withholding periods; however, because the sampling protocols are different than collecting animal tissue, a specific statistical programme has been developed for this purpose. FDA requires that there is a zero day withdrawal for eggs, that is, residues must be below the safe concentration at the earliest sampling time after drug treatment. All treatment regimes and tolerances are listed in the Code of Federal Regulations (CFR), Chapter 21 (section 520 for oral dosage products, section 522 for injectable products, section 524 for topical and ophthalmic products, section 526 for intramammary products and section 558 for medicated feeds. Tolerances are listed in section 556).

There is a unique feature in U.S. food law that is worth comment. That feature is legislative language regarding the regulation of carcinogens in foods. It is based on three significant pieces of legislation - the so-called "Delaney clause", the DES Proviso, and the SOM (sensitivity of the method). They may be applied to veterinary drugs; however, it has been done so in very limited situations. The Delaney clause in the U.S. Food, Drug and Cosmetic Act addresses unsafe food additives. The salient feature of the language is that "no additive is deemed safe...if it induces cancer in man or animals". The DES Proviso may be applied to veterinary drugs. It states that the Delaney clause does not apply to substances added to animal feeds if it does not adversely affect the food-producing animals and no residue of the substance is found in any food derived from the animal. The SOM legislation defines the concept of "no residue" (based on analytical measurement). In many ways, parallel to the ADI/safe concentration/tolerance setting process, the SOM approach has similar but different terminology. The legislation requires that a concentration of the carcinogen in the total diet of test animals must correspond to a maximum lifetime risk of cancer in the (toxicology) test animals of no more than one-in-a-million risk (SO). FDA assumes that residues at or below this value correspond to a concentration of residues of carcinogenic concern in the total human diet that represents no significant increase in the risk of cancer to people. The equivalent concept of safe concentrations is identified as SM and residue tolerance as RM. Under SOM, the limit of detection for the method must be less than or equal to the RM. The outcome of application of this concept results in analytical method requirements usually at ng/kg concentrations. In this type of food safety assessment, calculations are derived also for any carcinogenic metabolite and the molecule with the lowest RM is applied. In accord with these values, corresponding withholding periods may be derived. As expected, these are usually in excess of 45 days.

3.4. Regulatory surveillance and compliance

Once a new veterinary drug is approved, the sponsor is obligated to conduct pharmacovigilance surveys and report results to FDA on a regular basis. These data are provided to the Office of Surveillance and Compliance. The information is carefully reviewed to verify the safety and efficacy in broad animal production. If it is determined that there are sufficient concerns on safety and efficacy, the sponsor will be requested to adequately amend the use, formulations, labelling, etc., to correct the noted deficiency. Field inspections are a regular part of follow-up activities when violative residues in food animal products are found to determine to the extent possible the use and practices by authorized individuals in treatments of food producing animals. In cooperation with FSIS a database is maintained for repeat residue violators accessible by staff at CVM and FSIS. This interactive database is updated on a frequent basis. The data in the residue databases are used also to make decisions on the type and frequency of residue testing for individual products or food animal abattoirs for defined time periods to assure that residue control practices are in a state of control (see section 5).

4. Import tolerances

As could be expected, not all veterinary drugs used in food producing animals in countries that export to the United States are approved in the United States. To address the potential implications of these situations, legislation was enacted to address this gap in food safety regulation. The Animal Drug Availability Act of 1996 authorized FDA to establish import tolerances for imported food products of animal origin for drugs that are used in other countries, but that are unapproved new animal drugs in the U.S. The working concept was that food products of animal origin that are in compliance with the import tolerance would not be considered adulterated under the Federal Food, Drug and Cosmetic Act and could be imported into the United States.

To address the appropriate framework for import tolerances, FDA asked the Veterinary Medicine Advisory Committee (VMAC) to provide guidance to FDA. VMAC considered two possible approaches - good agricultural use and food safety. Setting tolerances applying good agricultural practices requires adequate information on "Good Agricultural Practices" to be taken into account. Therefore, the tolerance in this approach would be a reflection of how the drug is used. In its final analysis, VMAC indicated that import tolerances should be based on a food safety approach similar to that applied to domestic veterinary drug regulation. FDA has opted for this conservative approach to only have one tolerance for a veterinary drug or drug - product combination. Accordingly, these tolerances are established following evaluation of toxicity, metabolism and residue depletion studies similar to the manner domestic drug approvals take place. The only significant difference in establishing an import tolerance is that studies regarding withholding periods are not required. Efforts are made to harmonize import tolerances, particularly where there may be an international standard, e.g., Codex.

5. Residue control programmes

The second integral part of control of veterinary drug residues is the National Residue Program (NRP) administered by the USDA Food Safety and Inspection Service. There are two basic components to the NRP - the domestic residue sampling programme and the import residue sampling programme. While many similarities exist regarding sampling plans, there is one substantial difference between the two components. The FSIS domestic NRP provides a variety of sampling plans to verify and ensure that slaughter establishments are fulfilling their responsibilities under the Hazard Analysis and Critical Control Point (HACCP) regulation, and in accordance with FDA and the Environmental Protection Agency (EPA) regulations, to prevent the occurrence of violative residues in food producing animals. The import residue testing program is primarily a verification programme to determine that an exporting countries' residue control programme is operating in a state of control. An exporting country's residue control programme is a major feature of an inspection system that must be determined to be equivalent to the U.S. system before a country becomes eligible to export to the U.S. After a foreign country is determined to have an equivalent system of inspection and becomes eligible to export product to the U.S., FSIS relies on the country's national inspection authorities to certify that establishments meet all applicable standards. FSIS performs periodic audits of the foreign inspection systems. The frequency and extent of audits depends on the country's performance history. If a country does not maintain an inspection system equivalent to the U.S. system, it is not permitted to export product to the U.S.

One of the critical control points under HACCP is absence of violative residues in fresh product. The domestic NRP collects and uses national data on chemical residue to support risk assessment, enforcement and educational activities. All residue data are collected and stored in computer databases. Detailed information on residue violations is immediately transferred to the Residue Violation Information System (RVIS) to facilitate regulatory follow-up on violations and tracking residue violators by FSIS and FDA.

The type of sampling for the two programmes is similar. They contain: 1) monitoring plans to provide information about the occurrence of residue violations on an annual basis, based on statistical sampling; 2) surveillance plans designed to investigate and control the occurrence of residue violations in animal populations and may be either random sampling or directed sampling to control residue problems where they exist. The domestic program also includes: 1) exploratory projects often intended to be information gathering for future programs and the test results normally are not used to take regulatory action; and 2) enforcement testing on animals that appear suspicious to inspectors based on herd history or ante-mortem or post-mortem inspection. Enforcement testing is also performed to detect individual animals with violative residues. The import programme has components of 1) increased monitoring when FSIS finds a violation in a country; as well as 2) surveillance testing and exploratory testing with similar objectives as the domestic programme.

Development of the NRP is an inter-governmental endeavour consisting of FDA, the Centers for Disease Control and Prevention, the Environmental Protection Agency and four agencies in USDA. A risk management approach is used to select the compounds to be included in the NRP. In an evolutionary manner, an algorithm has been developed based on the integration and weighting of several parameters including:

The candidate veterinary drugs of concern selected for the import monitoring plan are the same as those designated in the domestic plan. Ranking of priority compounds is likewise similar. However, if there is reason to believe that a compound is being misused in a foreign country then FSIS would add that compound/country pair to the import monitoring programme.

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