歐洲動物用藥品相關限制

This report, which has two volumes, is aimed at anyone who needs to understand the basics of the regulations. It provides information on how to plan for the acquisition of a veterinary pharmaceutical product approval in the region in question.

Key coverage:

• Learn the different procedures and processes that you can apply for and how to apply for them.
• Understand how to get a product from the lab to the market effectively and efficiently.
• Use Volume 2 of the report to guide you through the the application processes - with invaluable do' s and don' ts to help make a more favorable impression.
• Examine national market profiles including major market segments and future market prospects.
• Find out the procedures for renewals, variations & extensions, generics and good practice guidelines and more - providing you with a one stop resource.

Key issues

• You will learn that you can submit your application for approval in only one European country, or in any number of territories.
• Alternatively, you can seek a simultaneous approval throughout the EU and not the European Economic Area in the Centralised Procedure (CP).
• You will understand that knowing what your product is, and where your priority markets are, will condition which procedure you select.
• You will have a practical guide to completing an application as Volume 2 talks you through the entire process from start to finish.

Chapters include:

Legal Framework, principle legal texts on regulatory procedures in the EU, procedures for obtaining authorisations issued by member states, procedure for obtaining community authorisations, European drug master file and certificate of suitability, other Issues, renewals variations and extensions, batch release in Europe pharmacovigilance, pharmacopoeias, European good manufacturing practice, good laboratory practice, good clinical practice, Maximum Residue Limits, generic veterinary medicines.

Who should read this report?

• Non-European generics manufacturers
• Drug developers wanting to market their products in Europe
• New member European States

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