European Animal Health Regulations

Table of Contents

CHAPTER 1 LEGAL FRAMEWORK

• 1.1 European Union legislation
• 1.2 European Pharmacopoeia
  • 1.2.1 Guidelines
  • 1.2.2 Notice to applicants
  • 1.2.3 Sources of legal texts, notice to applicants and guidelines
    • .....Marketing Authorization

CHAPTER 2 PRINCIPLE LEGAL TEXTS ON REGULATORY PROCEDURES IN THE EU

• 2.1 Directive 2001/82/EC as amended by 2004/28/EC
• 2.2 Council Regulation 726/2004
  • 2.2.1 Main provisions of Council Regulation 726/2004 of interest
• 2.3 Centralised Procedure
• 2.4 European Medicines Agency
  • .....Procedures for obtaining a MA of a VMP in the EU
  • .....Annex I of Directive 2001/82/EC: Data requirements

CHAPTER 3 PROCEDURES FOR OBTAINING AUTHORIZATIONS ISSUED BY MEMBER STATES

• 3.1 National Procedure
• 3.2 Decentralised Procedure
  • .....Coordination Group
• 3.3 Mutual Recognition Procedure
• 3.4 The effect of the new Directive
  • .....Variations to MA obtained in the DP and MRP
  • .....Key issues in the DP and MRPs
  • .....Arbitration by CVMP
  • .....Common Summary of Product Characteristics

CHAPTER 4 PROCEDURE FOR OBTAINING COMMUNITY AUTHORIZATIONS

• 4.1 Centralised Procedure
• 4.2 Candidature for the Centralised Procedure
  • 4.2.1 Before submission
  • 4.2.2 Assessment
  • 4.2.3 The Committee for Medicinal Products for Veterinary Use' s opinion
  • 4.2.4 Authorization in the European Commission
    • .....Variations to MAs obtained in the CP

CHAPTER 5 EUROPEAN DRUG MASTER FILE AND CERTIFICATE OF SUITABILITY

• 5.1 European Drug Master File
• 5.2 Certificate of Suitability

CHAPTER 6 OTHER ISSUES

• 6.1 Establishment in the Community
• 6.2 Selecting your procedure
• 6.3 Assessment Reports
• 6.4 Fees

CHAPTER 7 RENEWALS

• 7.1 Requirements of Directive 2004/28/EC
  • 7.1.1 Marketing authorizations from National Procedures
    • .....Missing the deadline
  • 7.1.2 Mutual Recognition Procedure
  • 7.1.3 Centralised Procedure
• 7.2 Suspension or revocation
  • .....‘Pharmaceutical Review' continues
• 7.3 The new approach to ‘renewals'

CHAPTER 8 VARIATIONS AND EXTENSIONS

• 8.1 Changes to marketing authorizations from national procedures
• 8.2 Changes to marketing authorizations obtained in the Mutual Recognition Procedure
  • 8.2.1 Type I Minor Variations
  • 8.2.2 Procedure for Type 1 variations
• 8.3 Type II Major Variations
  • 8.3.1 Procedure for Type II Major Variations
• 8.4 Extensions
  • 8.4.1 Procedure for extensions
• 8.5 Changes to marketing authorizations obtained in the Centralised Procedure

CHAPTER 9 BATCH RELEASE IN EUROPE

• 9.1 Manufacture and sale within the EU
• 9.2 Manufacture outside the EU for sale within the EU

CHAPTER 10 PHARMACOVIGILANCE

• 10.1 Legislative framework
  • 10.1.1 Detailed guidance
• 10.2 Key players in veterinary pharmacovigilance
  • 10.2.1 Reporter
  • 10.2.2 Qualified Person
  • 10.2.3 Competent Authorities
• 10.3 Reports to be communicated to the authorities
  • 10.3.1 Adverse Reactions
  • 10.3.2 Periodic Safety Update Reports
• 10.4 Approaching changes in the legislation

CHAPTER 11 PHARMACOPOEIAS

• 11.1 European Pharmacopoeia
• 11.2 National Pharmacopoeias
• 11.3 Hierarchy of pharmacopoeias in Europe
  • 11.3.1 European Pharmacopoeia
  • 11.3.2 National Pharmacopoeia
  • 11.3.3 No monograph
• 11.4 Application of the European Pharmacopoeia

CHAPTER 12 EUROPEAN CO-OPERATION ON HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF VETERINARY MEDICINAL PRODUCTS GUIDELINES

• 12.1 CVMP guidelines
• 12.2 Quality guidelines
• 12.3 Safety guidelines
• 12.4 Efficacy guidelines
• 12.5 Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products
  • .....Guidelines

CHAPTER 13 EUROPEAN GOOD MANUFACTURING PRACTICE

• .....Manufacturing facilities approved by the FDA

CHAPTER 14 GOOD LABORATORY PRACTICE REQUIREMENTS IN EUROPE

• 14.1 What is good laboratory practice?
  • .....Target species tolerance studies

CHAPTER 15 GOOD CLINICAL PRACTICE

CHAPTER 16 MAXIMUM RESIDUE LIMITS

• 16.1 VETERINARY PRODUCTS USED IN FOOD-PRODUCING ANIMALS
  • 16.1.1 Historical perspective
  • 16.1.2 Major and minor species
  • 16.1.3 Regulation 2377/90
  • 16.1.4 Substances considered ‘out of scope'
    • .....Pharmacological activity
  • 16.1.5 Checking MRL status of components of a veterinary medicinal product
  • 16.1.6 How can I find out what MRLs have already been established?
• 16.2 DATA REQUIREMENTS FOR MRLs
  • 16.2.1.1 Safety File: No Observable Effect Level and Acceptable Daily Intake
    • .....Safety Factor
  • 16.2.1.2 Residues file and the MRLs
  • 16.2.1.3 Regulatory analytical method
  • 16.2.1.4 Extrapolating MRLs between different target species 69
• 16.3 MRL PROCEDURE
  • 16.3.1 Before submission
  • 16.3.2 Presentation of the dossier
  • 16.3.3 Fees
  • 16.3.4 Validation
  • 16.3.5 Assessment
  • 16.3.6 The CVMP opinion
  • 16.3.7 Authorization in the European Commission
  • 16.3.8 Extensions of MRLs
    • .....Data protection and different applicants in the maximum residue limit procedure
• 16.4 CRITICAL ISSUES IN OBTAINING MRLs
  • 16.4.1 Setting the No Observable Effect level
    • 16.4.2 4.2 Setting the safety factor
    • 16.4.3 4.3 Determining the marker residue
    • 16.4.4 4.4 Injection site residues
    • 16.4.5 4.5 Regulatory analytical method
    • 16.4.6 4.6 Annex II substances

CHAPTER 17 GENERIC VETERINARY MEDICINES

• 17.1 LEGAL FRAMEWORK IN EUROPE
  • 17.1.1 Article 13.1
  • 17.1.2 Article 13.2
  • 17.1.3 Article 13.5
  • 17.1.4 Article 13.6
  • 17.1.5 Indications and conditions of use for the generic product
  • 17.1.6 Recent changes
• 17.2 ‘BIBLIOGRAPHIC APPLICATIONS' IN EUROPE
  • 17.2.1 Article 13a: Bibliographic applications
    • 17.2.1.1 Article 13a 1
    • 17.2.1.2 Article 13a 2
    • 17.2.1.3 Article 13a as ‘legal base' for marketing authorization application
• 17.3 REGULATORY PROCEDURES FOR GENERIC APPLICATIONS IN THE EU

CHAPTER 18 USEFUL WEBSITES

• Table 1.1: Volumes and CHAPTERs of the Notice to Applicants and Guidelines that apply to veterinary medicinal products
• Table 5.1: Contents of European Drug Master File
• Table 8.1: Variations and Extensions in Regulation 1085/2003
• Table 10.1: Abbreviations in pharmacovigilance
• Table 16.1: Food-producing animal species
• Table 16.2: Are maximum residue limits required?
• Table 16.3: Part III of the marketing authorization application compared with the MRL dossier
• Table 16.4: Content of MRL dossier
• Table 16.5: Extrapolation between animal species

• Figure 3.1: Decentralised Procedure
• Figure 3.2: Mutual Recognition Procedure
• Figure 4.1: Centralised Procedure
• Figure 4.2: Candidature of products for the Centralised Procedure
• Figure 4.3: Centralised Procedure up to day 120
• Figure 4.4: Centralised Procedure after day 210
• Figure 8.1: Procedure for Type IA Variation
• Figure 8.2: Procedure for Type II Variation
• Figure 16.1: Consumption figures of edible tissues
• Figure 16.2: Basis of calculation of MRLs
• Figure 16.3: Maximum residue limit procedure

CHAPTER 1 FRAMEWORK OF MARKETING AUTHORIZATION APPLICATION

• 1.1 Description
• 1.1.1 Part I Summary of the Dossier
• 1.1.2 Part II Quality documentation
• 1.1.3 Part III Safety and residues documentation
• 1.1.4 Part IV Efficacy documentation

CHAPTER 2 PART II: QUALITY

• 2.1 IIA Composition
  • 2.1.1 A.1 Composition
  • 2.1.2 A.2 Container
  • 2.1.3 A.3 Formulation used in clinical trials
  • 2.1.4 A.4 Development pharmaceutics
• 2.2 Part IIB Description of manufacturing method
  • 2.2.1 B.1 Manufacturing formula
  • 2.2.2 B.2 Manufacturing process and controls
    • .....Manufacturing flow chart
    • .....Description of each stage of manufacture
    • .....In-process control tests
  • 2.2.3 B.3 Process validation
• 2.3 Part IIC Control of starting materials
  • 2.3.1 C.1 Active substance(s)
  • 2.3.2 C.2 Excipients
  • 2.3.3 C.3 Primary packaging
    • 2.3.3.1 Part IID Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
    • 2.3.3.2 Part IIE Control tests on intermediate products
    • 2.3.3.3 Part IIF Control tests on the finished product
    • 2.3.3.4 Part IIG Stability
      • .....Analytical methods
    • 2.3.3.5 Part IIH Genetically modified organisms
    • 2.3.3.6 Part IIQ Other information

CHAPTER 3 PART I IIA: SAFETY

• 3.1 Annex 1 of Directive 2001/82/EC and Regulation 2377/90
• 3.2 Part IIIA
  • 3.2.1 Data requirements
    • 3.2.1.1 A.1 Precise identification of the product concerned by the application
    • 3.2.1.2 A.2 Pharmacological studies
    • 3.2.1.3 A.3 Toxicological studies
      • .....VMP for use in non food-producing animals
      • .....VMP for use in food-producing animals
      • .....VMP for use in non food-producing animals
      • .....VMP for use in food-producing animals
    • 3.2.1.4 A.4 Other requirements
    • 3.2.1.5 A.5 User Safety
    • 3.2.1.6 A.5 Environmental Risk Assessment
    • .....Phase I
    • .....Phase II

CHAPTER 4 PART I IIB: RESIDUES

• 4.1 Annex 1 of Directive 2001/82/EC and Regulation 2377/90
• 4.2 Part IIIB description
• 4.3 Part IIIB data requirements: Residues
  • 4.3.1 B.1 Precise identification of the product concerned by the application
  • 4.3.2 B.2 Residue studies
    • 4.3.2.1 B.2.1 Pharmacokinetics
    • 4.3.2.2 B.2.3 Elaboration of Maximum Residue Limits
    • 4.3.2.3 B.2.4 Establishment of withdrawal periods
  • 4.3.3 B.3 Analytical method
    • 4.3.3.1 B.3.1 Description of the method
    • 4.3.3.2 B.3.2 Validation of the method

CHAPTER 5 PART IV: EFFICACY

• 5.1 Preclinical and clinical documentation
  • 5.1.1 1.A Preclinical documentation
    • 5.1.1.1 A.1 Pharmacodynamics
      • .....Mode of action
      • .....Data from animal models
    • 5.1.1.2 A.2 Pharmacokinetics
  • 5.1.2 I.B Target species tolerance
    • 5.1.2.1 General safety
    • 5.1.2.2 Local safety
    • 5.1.2.3 Field studies
    • 5.1.2.4 Pharmacovigilance
  • 5.1.3 I.C: Resistance
• 5.2 Clinical documentation
  • .....Dose selection

CHAPTER 6 LAYING OUT THE MARKETING AUTHORIZATION APPLICATION

• 6.1 Master table of contents
• 6.2 Headers, footers and pagination
• 6.3 Appendices in each part
• 6.4 Electronic submissions

CHAPTER 7 PART I IN DEPTH

• 7.1 Part I.A Application Form
  • .....Declaration and signature
  • 7.1.1 Application
• 7.2 Part I.B Summary of Product Characteristics, label and package insert
• 7.3 Writing Part I.B
• 7.4 Part I.C Expert Reports
  • .....Languages
  • 7.4.1 Objectivity
  • 7.4.2 Internal and External Experts
    • .....Separate Expert Reports needed?
    • .....Personal approach and personal opinion

CHAPTER 8 PART II IN DEPTH

• 8.1 Table of contents
• 8.2 The written summary
• 8.3 The appendices
  • .....Active ingredient
  • .....Finished product
  • .....Appendices

CHAPTER 9 PART I IIA IN DEPTH

• 9.1 Table of contents
• 9.2 The written summary
• 9.3 The appendices
• 9.4 Order of presentation of the appendices
• 9.5 Risk assessments
  • .....VMPs for use in non food-producing animals
  • .....VMPs for use in food-producing animals
  • .....VMPs for use in non food-producing animals
  • .....VMPs for use in food-producing animals
  • .....Phase I
  • .....Phase II

CHAPTER 10 PART I IIB IN DEPTH

• 10.1 B.1 Precise identification of the product concerned in the application
• 10.2 B.2 Residue studies
  • 10.2.1 B.2.1 Pharmacokinetics
  • 10.2.2 B.2.2 Depletion of residues
  • 10.2.3 B.2.3 Elaboration of Maximum Residue Limits
  • 10.2.4 B.2.4 Establishment of withdrawal periods
• 10.3 B.3 Analytical method

CHAPTER 11 PART IV IN DEPTH

• 11.1 Table of contents
• 11.2 The written summary
• 11.3 The appendices
  • 11.3.1 Order of presentation of the appendices
    • .....Field studies
    • .....Pharmacovigilance

CHAPTER 12 ASSEMBLING THE MARKETING AUTHORIZATION APPLICATION

• 12.1 Electronic marketing authorization applications
• 12.2 Copying
• 12.3 Binding

CHAPTER 13 DATA REQUIREMENTS FOR GENERIC APPLICATIONS

• 13.1.1 Part I
• 13.1.2 Part II
  • .....True generic products (Article 13a)
  • .....‘Branded generic' products (Article 13b)
• 13.1.3 Article 13: Parts III and IV
• 13.1.4 Article 13a: Parts III and IV
• 13.1.5 Benefit of citing Article 13a as legal base of application
  • .....Maximum residue limit dossier and the marketing authorization application

• Table 2.1 Example of table composition
• Table 2.2 Example of table of manufacturing formula
• Table 4.1 Edible tissues that are assayed for residues
• Table 7.1 Contents of each Expert Report

• Figure 2.1 Example of stability study of finished product
• Figure 4.1 Example of residue depletion study: results of assay of liver
• Figure 5.1 Example of bioequivalence study
• Figure 6.1 Dossier structure according to Annex I Directive 2001/82/EC