1. The Codex View on Veterinary Drug Residues 4 th International Symposium on Food Safety Sao Paulo, SP June 13-14, 2005 Richard Ellis, Ph.D. FDA-CVM

2. A view of Codex, CCRVDF and Food Safety Codex principles and objectives Codex Committee on Residues of Veterinary Drugs in Food (CCRVDF) –Terms of reference and working principles CCRVDF Risk Analysis - CCRVDF and JECFA roles Current areas of interest in CCRVDF – Substances without ADI and MRLs

3. Codex Alimentarius Commission (CAC) The Joint FAO/WHO Food Standards Program Three objectives Consumer protection Fair practices in food trade Co-ordination of all food standards work 172 Member Governments (>98% world population) Meets annually Adopts draft Codex standards Reviews the Program of Work Reviews the budget

4. FOOD & AGRICULTURE ORGANIZATION OF THE UNITED NATIONS ECONOMIC & SOCIAL DEPARTMENT FOOD & NUTRITION DIVISION FOOD QUALITY & STANDARDS SERVICE FOOD STANDARDS GROUP (CODEX) FOOD QUALITY LIAISON GROUP (JECFA )

5. Codex General Subject Committees General Principle (France) Import/Export Inspection and Certification Systems (Australia) Food Labeling (Canada) Methods of Analysis & Sampling (Hungary) Food Hygiene (USA) Residues of Veterinary Drugs in Food (USA) Pesticide Residues (Netherlands) Food Additives & Contaminants (Netherlands)

6. Active Commodity Committees Nutrition and Foods for Special Dietary Uses (Germany) Fats and Oils (UK) Fish and Fishery Products (Norway) Milk and Milk Products (New Zealand) Fresh Fruits and Vegetables (Mexico) Cocoa Products & Chocolate (Switzerland) Meat Hygiene (New Zealand) Processed Fruits and Vegetables (USA)

7. Codex Committees & Task Forces Ad hoc Inter- governmental Task forces –Fruit and Vegetable Juices (Brasil) –Food Derived from Biotechnology (Japan) –Animal Feeding (Denmark) Regional Coordinating Committees –Asia (Korea) –Africa (Morocco) –Europe (Slovak Republic) –Latin America and Caribbean (Dominican Republic) –Near East (Jordan) –North America & Southwest Pacific (Samoa)

8. Codex Standard Development Process Always initiated by CAC Normal Procedure: –Eight (8) Steps –2 rounds of written comments –1 round of comments can be omitted (by vote) Accelerated Procedure: –Five (5) Steps –1 round of written comments 1. Decision of CAC 2. Proposed draft standard 3. Request for written comments 4. Amendments/Session 5. Adoption of draft standard 6. Request for written comments 7. Amendments/Session 8. Adoption as a Codex standard

9. Major Codex (CAC) Accomplishments Food standards for commodities: 237 Codes of hygienic/technology practice: 41 Food Additives evaluated: 1005 Guidelines for contaminants: 25 Pesticides evaluated: 185 Pesticide MRLs: 3274 Veterinary drugs evaluated (1986-date): 80 Veterinary drug MRLs: (39 to 28 th CAC) 393 Veterinary drugs without ADI: 29

10. Codex Publications http://www.codexalimentarius.net/web/index_en.jsp

11. GATT, WTO and Codex 1994 General Agreement on Tariffs and Trade attached significant importance to food safety agreements –Referenced specific steps to protect the sanitary status of member countries and reduce barriers to trade –Elaborated food safety agreements for the Sanitary and Phytosanitary (SPS) and Technical Barriers to Trade (TBT) measures –Established the World Trade Organization

12. Implications of WTO Agreements SPS Measures: –Discourage the use of SPS measures as barriers to international trade –Recognizes Codex as a reference on food safety –Codex may be used to settle trade disputes –Calls for harmonization based on Codex (standards) TBT Measures: –Prevents the use of technical requirements as barriers to trade –Covers all consumer protections not covered by SPS –Places emphasis on international standards for foods

13. Food Safety Provisions Recognized by SPS Maximum residue limits for pesticides and veterinary drugs Maximum level of use of food additives Maximum levels of contaminants Food hygiene requirements of Codex standards

14. Codex Provisions Recognized by TBT Food labeling Quality provisions Nutritional requirements Methods of analysis and sampling

15. National Regulations and Codex National regulations that are consistent with Codex standards meet the requirements of the SPS and TBT measures

16. Codex Committee Residues of Veterinary Drugs in Food CCRVDF established 1986, 15 sessions to date CCRVDF has four responsibilities –Priorities for veterinary drug residues in food –Recommend maximum residue levels –Consider methods of analysis and sampling –Develop codes of practice CCRVDF has three ad hoc working groups –Priorities, methods of analysis and sampling and drugs without ADI and MRLs Role of Science and scientific principles

17. Role of Science in Codex- Statements of Principle Food standards based on scientific analysis and evidence to assure quality and safety of foods Regard other legitimate factors relevant to health protection of consumers Food labeling is important for protection of consumers and promoting fair food trade practices When members agree on level of protection but differ on other concerns, they may abstain from but not prevent decisions by Codex

18. Statement of Codex Principle on Role of Food Safety Risk Analysis CCRVDF endorses the statements of principle in standards development (MRLs and codes of practice): –Health and safety aspects of Codex decisions and recommendations should be based on a risk analysis appropriate to the circumstances –The risk analysis should be soundly based on science and incorporate the four steps of the risk assessment process and documented in a transparent manner –There should be a functional separation of risk assessment and risk management recognizing pragmatic interactions

19. Major & New CCRVDF Accomplishments Codex Alimentarius Volume 3: Residues of Veterinary Drugs in Food (parts being revised) –List of MRLs (1995) –Code of practice for control of use of veterinary drugs –Guidelines for establishing a regulatory program for control of veterinary drug residues (methods and sampling guidelines) –Glossary of terms and definitions Code of practice to minimize antimicrobial resistance (at step 8) New initiative on substances without an ADI or MRLs (new working group established) New risk management policy under development Revision on analytical methods sections in Volume 3 Revision of guidelines for residue control programs

20. CCRVDF Risk Assessment & Risk Management Risk assessment expert advice provided by JECFA – Joint FAO/WHO Expert Committee on Food Additives CCRVDF proposes vet drug for MRLs CAC approves new work JECFA receives request for evaluation JECFA Secretariats invite experts Determination of ADI and MRLs CCRVDF reviews and decides on MRLs

21. JECFA - The Risk Assessors Members are invited by WHO and FAO as experts in their independent, personal capacity Meetings are ad hoc, meeting only when needed For reasons of confidentiality and prevention of external influences, meetings are closed sessions –Results are made public immediately thereafter Provide scientific advice on specific issues for: –FAO and WHO member countries –FAO and WHO governing bodies –Codex Alimentarius Commission and subsidiary Codex Committees (e.g., CCRVDF)

22. First Things First – The ADI Adverse systemic effects Reproduction and developmental effects Mutagenic effects Carcinogenic effects Effects on human intestinal flora Immunologic effects Pharmacological properties Endocrine effects

23. Specific Considerations -ADI The extent of data needed depends on dietary exposure Determine if residues are normally present in edible tissues If drug is also used in humans, data from human case reports and epidemiological studies Special studies to investigate specific effects of mechanisms of toxicity An effect and no-effect dose level should be determined from these studies and tests

24. Studies for Recommending MRLs Chemical identity and properties Uses and recommended doses in food animals Pharmacokinetic, metabolism and pharmacodynamic data Total residue (radiolabel) studies Residue depletion studies in food animals Available routine method of analysis including method performance Special studies on residue effects as necessary

25. Residue Depletion and MRLs T I M E CONCENTRATIONCONCENTRATION muscle fat kidney liver

26. From an ADI to MRLs ADI MRL T If MRL U < MRL T If MRL M > MRL U and MRL M < MRL T use MRL M If MRL M ≤ MRL U Use MRL U If MRL U > MRL T No MRL recommended If MRL T ≥ MRL M use MRL T If MRL T < MRL M No MRL recommended

27. JECFA Publications http://www.codexalimentarius.net/web/jecfa.jsp

28. CCRVDF Recommendation Process CCRVDF receives JECFA recommendation at Step 3 and proceeds through Step 8 with a recommendation to Codex Alimentarius 1. Decision of CAC 2. Proposed draft standard 3. Request for written comments  4. Amendments/Session 5. Adoption of draft standard 6. Request for written comments 7. Amendments/Session 8. Adoption as a Codex standard

29. Codex Alimentarius Commission Options Adopt CCRVDF recommendation as a standard Hold the recommendation pending additional information from CCRVDF or JECFA Request CCRVDF reconsideration based on CAC comments on matters of concern (e.g., new scientific studies) Reject CCRVDF recommendation (e.g., due to a lack of consensus)

30. Current Matters of CCRVDF Interest Report of 15 th Session Alinorm 05/28/31 http://www.codexalimentarius.net/web/reports.jsp?lang=en MRLs from JECFA recommendations Code of Practice to Minimize and Contain Antimicrobial Resistance Revised guidelines for establishing a regulatory program for control of veterinary drug residues in food Revised General considerations on analytical methods Rounding of ADIs for veterinary drugs Veterinary drugs without ADI/MRL

31. MRLs Recommended for 28 th CAC Step 8 –Cyhalothrin: cattle, pigs, sheep –muscle, liver, kidney, fat and cattle milk –Flumequine: cattle, pig, chicken, sheep – muscle, liver, kidney, fat and trout muscle –Neomycin: cattle – liver, kidney and milk –Dicyclanil: sheep – muscle, liver, kidney and fat Step 5/8 –Imidocarb: cattle – muscle, liver, kidney, fat and milk (recommended MRLs in sheep withdrawn)

32. CCRVDF – Antimicrobial Resistance Responsibilities of regulatory authorities –Assessment of efficacy and safety, surveillance, distribution, advertising, training, research, etc. Responsibilities of veterinary pharmaceutical industry –Marketing authorization, export, advertising, etc. Responsibilities of wholesale/retail distributors Responsibilities of veterinarians –Off-label use, records, training Responsibilities of producers

33. CCRVDF Revised Guidelines Regulatory Program Revision of current Codex Volume 3 regulatory control guidelines (published 1995) needed Current document precedes Codex adoption of HACCP food safety principles CCRVDF scope will be a more holistic approach –Risk based approaches to regulatory programs –Residue control programs for food producing animals and food producing animal products (e.g., milk) Early in development (Step 2)

34. CCRVDF – Methods of Analysis Similar activity for Codex Volume 3 - review and amend Part II on General Considerations Coordinated by ad hoc Working Group – Methods of Analysis and Sampling Update following the recent Codex decisions on analytical method performance –e.g., method validation procedures Expand compendia of analytical methods for review by ad hoc working group

35. CCRVDF – Risk Management Issue Rounding of JECFA ADIs Potential differences with ADI calculation by JECFA and member governments ( e.g., very small ADI ) –JECFA rounding ADI to one significant figure –Numerous examples - 11 higher, 14 lower Related issue with differences in MRLs Three recommendations considered –preferences: –JECFA: use calculated ADI, round ADI for publication of JECFA recommendation –CCRVDF: use calculated ADI and publish the calculated ADI as the JECFA recommendation  CCRVDF will apply to future evaluations and recalculations of substances already considered by JECFA case-by-case

36. Veterinary Drugs Without ADI and MRLs Growing concern with significant consequences National action levels based on detection limits Significant increases in detection capabilities Increased dependence on MS and LC-MS/MS A technology imbalance between primarily import and export countries Increased prevalence of residues of concern Rejection of imported products With no ADI/MRL: Result: International Trade Disruption

37. CCRVDF and FAO/WHO Response Seriousness of issue raised primarily by developing countries highly dependent on export trade at CCRVDF –Thailand and Argentina highlighted issues with emphasis on nitrofuran and chloramphenicol in food products CCRVDF and FAO/WHO agreed to hold a technical workshop on the issue –Held in Bangkok in September 2004

38. Bangkok Consultation Risk assessments/Analytical methodologies –Progress of analytical methods and impact on international trade –Analysis and management of risk of low level residues –Risk assessments by JECFA Regulatory framework/Capacity building –Regulatory framework at the national and regional level –International regulatory framework provided by Codex and WTO –Capacity building

39. Analytical Methods Impact on Trade National action levels based on detection limits Detection capabilities based on best science and latest technology “Best” (and costly) instrumentation Development of methods in a regional laboratory National action limits based on hazard or risk estimates Detection capability based on hazard or risk Instrumentation to accomplish regulatory need Availability of methods across laboratories

40. Management of Risk - No ADI/MRLs No ADI/MRL Toxicological data did not support an ADI No suitably validated analytical method Good agricultural practice could result in exceeding possible MRL No valid sponsor Residue data are insufficient to support an MRL Use conditions not consistent with ADI

41. Management of Risk - Low Level Residues In the absence of an ADI and MRLs: –National authorities may regulate to no detectable residues –The prevalence of residues of concern changes as analytical method detection capability improves Changes in technology and improved detection capability results in previously non-detectable residues becoming reportable Change in reported amounts of residues is independent of toxicological risk

42. CCRVDF and JECFA Critical Issue of Managing Risk of Low Levels of Residues Considering the close relationship between the nature and extent of available data and the ability to establish an ADI and MRLs: What data does JECFA need to establish an ADI and MRLs? How does JECFA obtain the necessary data to establish an ADI and recommend MRLs? Need alternate approaches to evaluate data for an ADI Need alternate approaches to an ADI to evaluate risk and safety

43. JECFA Risk Assessments - Current Scenario Large number of substances currently used in veterinary medicine ADI and MRLs recommended No ADI/MRL Developed countries Major uses No sponsor no data Minor uses? Developing country needs? Regional needs? Substances evaluated by JECFA

44. Regulatory Framework/Capacity Building 12 of the 23 discussion papers addressed regulatory frameworks on six continents Three had unique features and many others provided general nature details – the unique: –Margin of Exposure concept –Positive lists for agricultural chemicals in food –Spectrum of residue control programs and capability within a continent

45. Regulatory Lessons Learned No ADI/MRL – “No detectable residues” Risk communication: Difficulties with managing perceptions of foods not being “legal”, yet of low risk to public health and safety Public policy Analytical technology Public health

46. Regulatory Framework Discussions Regulatory framework components Data and information systems Public health objectives Legislation, regulations and guidance documents Suitable analytical methods Effective surveillance and compliance Risk based residue control program Adequate technical resources Status quo: Framework capacity differs significantly between countries

47. Identified Regulatory Framework Weaknesses Lack of high commitment to national policies Low priority commitment to national food safety measures Inadequate resources for food safety programs Lack of coordination among relevant stakeholders Stakeholders not always involved in developing food safety programs Limited numbers of safe veterinary drugs with Codex MRLs for adoption by national governments Inadequate enforcement to ensure judicious use of veterinary drugs

48. Measures to Facilitate Improvement Improved awareness and commitment to public health protection and international trade Designing capacity building to meet specific national needs Encourage stakeholder involvement in food safety programs Improve coordination and communication among competent authorities for food safety programs Implement mentoring programs with countries having comprehensive food safety programs Improve good veterinary drug practices especially at the farm level

49. Promising Factors to Improve Food Safety Programs Marketing access and economic factors Consumer demand for safer foods Export market access increases demand and need for safer and higher quality food Ending international trade and market disruptions Increasing attention to substances without an ADI or MRL Better attention to WTO/SPS obligations Recognizing that developing countries are not receiving full benefit of the SPS provisions

50. Codex and WTO Problems and Gaps Codex (CCRVDF) has not fulfilled its mandate to evaluate all veterinary drugs posing a potential significant threat to health and consumer risk Where JECFA has evaluated but not established and ADI or MRLs, these substances are “forgotten” and disappear from adoption procedures WTO notification procedures seem to be inadequate, not assuring sufficient consultation and involvement of exporting countries Summary: No comprehensive set of standards for implementation by member governments results in a patchwork of national solutions

51. Capacity Building: Issues and Approaches Building capacity is frequently driven by growth of consumer demand for safer food Lack awareness of roles and responsibilities of international agencies (e.g., FAO) and organizations (e.g., Codex) that impedes capacity development Ability to provide needed expertise is limited by developing country resources and commitment Effective capacity building requires a global vision and commitment at the highest levels Needs to be approached in a holistic manner Should be directed to the most appropriate sector in recipient countries

52. Bangkok Recommendations Five blocks of recommendations –To CCRVDF on risk management –To JECFA on issues related to risk assessment –To governments –To FAO, WHO and other international organizations –To organizations addressing capacity building

53. Highlight Recommendations CCRVDF and JECFA should develop a list of substances not to be used as veterinary drugs (and not condone their illegal use) Develop an approach to prepare a comprehensive list of MRLs covering all substances used as veterinary drugs within the next ten years CCRVDF should facilitate creation of a list of drugs that are seen as important to developing countries CCRVDF should complete development of its risk management policy and update its guidance documents

54. Highlight Recommendations (2) Develop approaches for using techniques providing dose-response characteristics and estimates of risk when no ADI or MRL Develop new approaches to the risk analysis of low level residues Develop a holistic approach to capacity building with international organizations

55. CCRVDF Establishes a New Working Group CCRVDF agreed to a Circular Letter to collect necessary information on –1) all substances with no Codex MRLs used at the national level; 2) substances that raise health concerns; 3) substances that create trade problems; 4) substances for inclusion on a negative list; 5) national or regional MRLs; and 6) information on analytical methods detection or determination CCRVDF defined the specific tasks –1) establish lists to circular letter request; 2) prioritize listed compounds for future consideration; 3) develop recommendations on how to proceed with priorities; 4) develop risk management options; and 5) develop a timetable for action

56. 16 th CCRVDF and Beyond “The future is not some place we are going to, but one we are creating…The paths are not to be found, but made, and the activity of making them changes both maker and the destination”. »JOHN SCHAAR, philosopher