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The Codex View on
Veterinary Drug Residues
4th International Symposium on Food Safety
Sao Paulo, SP
June 13-14, 2005
Richard Ellis, Ph.D. FDA-CVM
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
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
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)
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)
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)
Codex Committees & Task Forces
• Ad hoc Intergovernmental 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)
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
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 28th CAC) 393
Veterinary drugs without ADI:
29
Codex Publications
• http://www.codexalimentarius.net/web/index_en.jsp
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
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
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
Codex Provisions Recognized by TBT
• Food labeling
• Quality provisions
• Nutritional requirements
• Methods of analysis and sampling
National Regulations and Codex
• National regulations that are
consistent with Codex standards
meet the requirements of the SPS
and TBT measures
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
Role of Science in CodexStatements 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
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
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
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
Determination of
ADI and MRLs
CAC approves new
work
JECFA receives
request for evaluation
JECFA Secretariats
invite experts
CCRVDF reviews and
decides on MRLs
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)
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
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
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
Residue Depletion and MRLs
C
O
N
C
E
N
T
R
A
T
I
O
N
liver
kidney
fat
muscle
TIME
From an ADI to MRLs
ADI
MRLT
If MRLU > MRLT
If MRLU < MRLT
If MRLM > MRLU
If MRLM ≤ MRLU
and MRLM < MRLT
Use MRLU
No MRL
recommended
use MRLM
If MRLT ≥ MRLM
If MRLT < MRLM
use MRLT
No MRL
recommended
JECFA Publications
http://www.codexalimentarius.net/web/jecfa.jsp
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
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)
Current Matters of CCRVDF Interest
• Report of 15th 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
MRLs Recommended for 28th 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)
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
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)
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
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
Veterinary Drugs Without ADI and MRLs
• Growing concern with significant consequences
With no ADI/MRL:
National action levels based on detection limits
Increased prevalence of residues of concern
Significant increases in detection capabilities
Rejection of imported products
Increased dependence on MS and LC-MS/MS
A technology imbalance between primarily
import and export countries
Result: International Trade Disruption
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
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
Analytical Methods Impact on Trade
• National action levels based
on detection limits
• National action limits based
on hazard or risk estimates
• Detection capabilities based
on best science and latest
technology
• “Best” (and costly)
instrumentation
• Detection capability based
on hazard or risk
• Development of methods in
a regional laboratory
• Availability of methods
across laboratories
• Instrumentation to
accomplish regulatory need
Management of Risk - No ADI/MRLs
Toxicological data did
not support an ADI
Use conditions
not consistent
with ADI
No suitably validated
analytical method
No ADI/MRL
Good agricultural
practice could result in
exceeding possible MRL
No valid sponsor
Residue data are
insufficient to support
an MRL
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
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
JECFA Risk Assessments - Current Scenario
Developed
countries
Large number
of substances
currently used
in veterinary
medicine
No
ADI/MRL
No sponsor
no data
Major uses
ADI and MRLs
recommended
Minor uses?
Developing country needs?
Regional needs?
Substances
evaluated by
JECFA
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
Regulatory Lessons Learned
• No ADI/MRL – “No detectable residues”
Analytical
technology
Public
policy
Public health
• Risk communication: Difficulties with managing
perceptions of foods not being “legal”, yet of
low risk to public health and safety
Regulatory Framework Discussions
Data and
information
systems
Suitable
analytical
methods
Public health
objectives
Legislation,
regulations and
guidance documents
Regulatory
framework
components
Effective
surveillance and
compliance
Adequate
technical
resources
Risk based residue
control program
Status quo: Framework capacity differs significantly between countries
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
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
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
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
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
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
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
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
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
16th 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