pharmaceutical product licensing - gbv · pharmaceutical product licensing requirements for europe...

PHARMACEUTICALPRODUCTLICENSINGRequirements for Europe

Editors

A. C. CARTWRIGHT and BRIAN R. MATTHEWSboth of the Medicines Control AgencyDepartment of Health, London

ELLIS HORWOODNEW YORK LONDON TORONTO SYDNEY TOKYO SINGAPORE

Table of Contents

PREFACE 21References to the European Communities texts — The rulesgoverning medicinal products in the European Community 24

1 INTRODUCTION AND HISTORY OF PHARMACEUTICALREGULATIONAnthony C. Cartwright1.1 Introduction 291.2 A brief history of pharmaceutical regulation 29

1.2.1 Early history to the nineteenth century 291.2.2 The early twentieth century in the UK: beginnings of regulation 311.2.3 The early twentieth century in the USA: early regulation . . . .311.2.4 Thalidomide 321.2.5 Thalidomide: the regulatory aftermath 331.2.6 Thalidomide: implications for chirality requirements . : 34

1.3 The European Community: regulation of proprietary medicinalproducts (1965 to 1987) 341.3.1 Introduction 341.3.2 Directive 65/65/EEC: definitions and requirements 351.3.3 Directive 75/318/EEC: the 'norms and protocols' Directive . . .361.3.4 Directive 75/319/EEC: legal and administrative provisions . . .361.3.5 Decision 75/320/EEC: the Pharmaceutical Committee 371.3.6 Directive 78/25/EEC: approved colouring matters 371.3.7 Commission Communication of 6 May 1982: parallel

importation of medicinal products 381.3.8 Directive 83/570/EEC: amending Directive 391.3.9 Council Recommendation 83/571/EEC: 'guidelines' 391.3.10 Directive 87/19/EEC: the regulatory committee procedure . . .401.3.11 Directive 87/21/EEC: abridged applications for

'copy products' and protection of innovation 40

Table of contents

1.3.12 Directive 87/22/EEC: the high technology/biotechnologyprocedure 41

1.4 The European Pharmacopoeia 411.5 Publication of the Community rules for product registration

in 1989 421.6 Other measures designed to eliminate the remaining barriers to

the establishment of a Single European Market in pharmaceuticalproducts 43

References 44

2 THE EUROPEAN COMMUNITY: ITS STRUCTURE, INSTITUTIONS,AND REGULATIONAnthony C. Cartwright2.1 Introduction 462.2 The Treaty of Rome 462.3 The Member States of the European Economic Community 462.4 The Community institutions 47

2.4.1 The Commission of the European Communities 472.4.2 The Council of Ministers 472.4.3 The European Parliament 492.4.4 The Economic and Social Committee 492.4.5 The European Court of Justice 49

2.5 The legal instruments of the Community 502.5.1 Regulations 502.5.2 Directives 502.5.3 Decisions 512.5.4 Recommendations 512.5.5 Opinions 512.5.6 Communications 51

2.6 The Single European Act and the Single Market 512.7 The European Free Trade Association 522.8 The Nordic Council .52Reference 53

3 NEW CHEMICAL ACTIVE SUBSTANCE PRODUCTS:QUALITY REQUIREMENTSBrian R. Matthews3.1 Introduction 543.2 Sources of information 543.3 Requirements relating to the format of the application 553.4 Part I: The summary of the dossier 56

3.4.1 Introduction 563.4.2 Administrative information 573.4.3 Summary of product characteristics 58

Table of contents 7

3.4.4 Expert Reports 593.5 Part II: The chemical, pharmaceutical, and biological

documentation 603.5.1 Introduction 603.5.2 Description of analytical methods and analytical validation . . .613.5.3 Part IIA: Composition 623.5.4 Part IIB: Method of manufacture of the dosage form 633.5.5 Part IIC: Control of the starting materials 64

3.5.5.1 New active ingredients 64(a) Identity of the material 64(b) Manufacture of the active ingredient 65(c) Quality control during synthesis 65(d) Development chemistry 65(e) Impurities 66(f) Active ingredient specification 66(g) Batch analyses . .67

3.5.5.2 Radiolabelled compounds 673.5.5.3 Other ingredients 67

3.5.6 Part IID: Control tests applied at an intermediate stageof the manufacturing process 68

3.5.7 Part HE: Control tests on the finished product 683.5.8 Part IIF: Stability 69

3.5.8.1 Active ingredients 703.5.8.2 Finished product 70

3.6 Part V: Special particulars 723.6.1 Part VA: Dosage form 723.6.2 Part VB: Samples 733.6.3 Part VC: Manufacturer(s) authorisation(s) 733.6.4 Part VD: Marketing authorisation(s) 73

3.7 Product labelling .73References .75

4 NEW CHEMICAL ACTIVE SUBSTANCE PRODUCTS:PRECLINICAL REQUIREMENTSJames C. Ritchie4.1 Introduction 764.2 Pharmacodynamics .77

4.2.1 EC requirements 774.2.2 EC guidelines 78

4.3 Pharmacokinetics 784.3.1 EC requirements 784.3.2 EC guidelines 78

4.4 Toxicology 794.4.1 EC requirements 794.4.2 EC guidelines 79

4.4.2.1 Single dose toxicity 79

8 Table of contents

4.4.2.2 Repeat dose toxicity 804.5 Reproductive toxicology 80

4.5.1 EC requirements 804.5.2 EC guidelines 81

4.6 Mutagenicity studies 814.6.1 EC requirements 814.6.2 EC guidelines 82

4.7 Carcinogenicity studies 834.7.1 EC requirements 834.7.2 EC guidelines 83

5 NEW CHEMICAL ACTIVE SUBSTANCE PRODUCTS:CLINICAL REQUIREMENTSJ. Alex Nicholson5.1 Introduction 855.2 Clinical trials 85

5.2.1 National requirements for the regulation of clinical drug trials .855.2.2 Good clinical practice 865.2.3 Clinical guidelines 89

5.3 The clinical documentation 895.3.1 Introduction 895.3.2 The index 895.3.3 Part IVA: Clinical pharmacology 895.3.4 Part IVB: Clinical experience 905.3.5 Overall summary 90

5.4 The Clinical Expert Report 915.5 Conclusion 91

6 ABRIDGED APPLICATIONSAnthony C. Cartwright6.1 Introduction 936.2 Abridged applications before July 1987 93

6.2.1 Directive 65/65/EEC 936.2.2 Directive 83/570/EEC 94

6.3 Directive 87/21/EEC 946.3.1 The objectives of the new Directive .946.3.2 Protection of pharmaceutical innovation 946.3.3 Harmonisation of the rules for products which are

copies of established medicinal products 956.3.4 Harmonisation of the rules for combination products 96

6.4 Requirements for information on second applicant products 966.5 Evidence of ten year authorisation and marketing 966.6 Essential similarity 97

6.6.1 The Smith Kline and French judicial review 976.6.2 Essential similarity and the active ingredient 976.6.3 Essential similarity and the finished product 99

Table of contents 9

6.6.4 Essential similarity and the clinical indications 996.7 Second applicant products by detailed reference to the published

scientific literature — Article 4(8)(a)(ii) of 65/65/EEC 996.8 Chemistry and pharmacy of abridged applications 100

6.8.1 Composition/container/development pharmaceutics 1006.8.2 Method of preparation 1016.8.3 Control of starting materials 1016.8.4 Control tests on intermediate products 1016.8.5 Control tests on the finished product 1016.8.6 Stability of the active ingredient and the finished product . . . 102

6.9 Pharmacotoxicological data 1026.10 Clinical data 1026.11 Bioavailability and bioequivalence data 103

6.11.1 Verifiability of bioavailability and bioequivalence studies . . 104References 104

7 DRUG MASTER FILESBrian R. Matthews7.1 Introduction 1067.2 What is a drug master file and when may one be used? 106

7.2.1 In the United Kingdom 1067.2.2 In the European Community 1077.2.3 Comparison with United States Food and Drug

Administration DMFs 1077.3 Assessment procedures for DMFs in the United Kingdom 108

7.3.1 Introduction 1087.3.2 Data requirements 1097.3.3 Experience with DMFs in the United Kingdom 110

7.4 The European drug master file procedure 1107.4.1 Introduction 1107.4.2 The European drug master file procedure I l l7.4.3 Related matters 112

References 113

8 RADIOPHARMACEUTICAL PRODUCTSBrian R. Matthews8.1 Introduction 1148.2 Radiopharmaceutical and related definitions 115

8.2.1 UK definitions 1158.2.1.1 The Medicines Act 1968 1158.2.1.2 The Medicines (Radioactive Substances)

Order 1978 1158.2.2 Relevant European Pharmacopoeia definitions 1168.2.3 Definitions from Directive 89/343/EEC 1168.2.4 Definitions from Directive 65/65/EEC 116

8.3 UK control of radiopharmaceuticals 1178.3.1 Introduction 117

10 Table of contents

8.3.2 Basis of data expectations 1178.3.3 Expert Reports 1188.3.4 Pharmaceutical data requirements 118

8.3.4.1 Composition 1188.3.4.2 Development pharmaceutics 1188.3.4.3 Manufacture 1198.3.4.4 Impurities 1198.3.4.5 Other constituents 1198.3.4.6 Control tests on the finished product 1198.3.4.7 Stability data 120

8.3.5 Preclinical data requirements 1208.3.6 Clinical data requirements 120

8.4 EC involvement in the regulation of radiopharmaceutical products. . 1218.4.1 Introduction 1218.4.2 Predicted data requirements for radiopharmaceuticals

under EC Directives 1228.4.2.1 Introduction 1228.4.2.2 Pharmaceutical, chemical, biological and

microbiological data requirements 122(a) Qualitative particulars 122(b) Quantitative particulars 122(c) Development particulars 122(d) Method of preparation 122(e) Control of starting materials 123(f) Control tests on the finished product 123(g) Dosage form-related points 124(h) Stability testing 124

8.4.2.3 Toxicological and pharmacological datarequirements 124(a) General 124(b) Subacute toxicity studies : 125(c) Mutagenic potential 125(d) Carcinogenic potential 125(e) Reproductive studies 125(f) Pharmacodynamics 125(g) Pharmacokinetics . . 125(h) Radiation dosimetry 125

8.4.2.4 Clinical data requirements 1258.4.3 Labelling and instruction leaflets 126

8.4.3.1 Introduction 1268.4.3.2 Directive 89/343/EEC specific requirements 1268.4.3.3 European Pharmacopoeia requirements 1268.4.3.4 Instruction leaflet 127

9 MEDICATED DEVICESBrian R. Matthews9.1 Introduction 129

Table of contents 11

9.2 The development of the medical device Directives 1299.2.1 Introduction 1299.2.2 The present EC market for medical devices 1299.2.3 Control of medical devices in the Member States of the EC. . 131

9.3 Ideal characteristics for a new system of controls for medicaldevices 133

9.4 'Old approach'and'New approach'Directives 1349.4.1 The role of CEN and CENELEC 1349.4.2 The consultative processes in the EC in the development

of a Directive 1369.4.3 Constituent parts of a'new approach'Directive 137

9.5 Contents of the active implantable medical device Directive 1389.5.1 Article 1: Application, definitions, provision re: medicinal

products, reference to Directive 89/336/EEC 1389.5.2 Article 2: Marketing of custom-made and investigational

devices 1399.5.3 Article 3: Compliance with essential requirements .1399.5.4 Article 4: Member States'obligations and rights 1399.5.5 Article 5: Role of harmonised standards 1409.5.6 Article 6: Unsatisfactory harmonised standards;

implementation and practical application of the Directive —the role of the Standing Committees 140

9.5.7 Article 7: Removal of products from the market 1409.5.8 Article 8: Records of adverse events and withdrawals

from the market 1419.5.9 Article 9: Conformity assessment options 1419.5.10 Article 10: Clinical investigation provisions 1419.5.11 Article 11: Appointment and withdrawal of notified bodies . .1419.5.12 Article 12: Application of the CE mark and notified body's

logo to products 1419.5.13 Article 13: Inappropriate application of the CE mark. ...... 1429.5.14 Article 14: Refused or restricted marketing provisions 1429.5.15 Article 15: Confidentiality 1429.5.16 Article 16: Effective dates 1429.5.17 Article 17: Addressees 1429.5.18 Annex 1: Essential requirements 142

9.5.18.1 Introduction 1429.5.18.2 General requirements 1429.5.18.3 Requirements regarding design and construction . .143

9.5.19 Annex 2: Declaration of conformity (full quality system) . . . 1449.5.20 Annex 3: EC type-examination procedure 1459.5.21 Annex 4: EC verification procedures 1469.5.22 Annex 5: Assurance of production quality in connection

with the EC declaration of conformity to type 1479.5.23 Annex 6: Custom-made devices and devices intended for

clinical investigations 148


9.5.24 Annex 7: Clinical evaluation 1489.5.25 Annex 8: Minimum criteria for inspection bodies

to be notified 1499.5.26 Annex 9: CE mark 149

9.6 The draft Directive on medical devices 1499.6.1 Introduction 1499.6.2 Definitions 1499.6.3 Products containing medicinal substances 1519.6.4 Classification of medical devices 1519.6.5 Provisions which differ from the active implantable medical

devices Directive 1529.6.6 Provisions in common with the active implantable medical

devices Directive 1539.6.7 Essential requirements 154

9.6.7.1 General requirements 1549.6.7.2 Design and construction 154

9.6.8 Conformity assessment procedures 1569.6.9 Statement concerning devices intended for special purposes . 1569.6.10 Classification decision criteria v 157

9.6.10.1 Non-active medical devices 1579.6.10.2 Active medical devices 159

9.6.11 Clinical evaluation 1599.6.12 Criteria to be met with designating inspection bodies to be

notified 1599.6.13 CE mark of conformity 159

9.7 Comments on the medical devices Directives 159

10 CONTACT LENS PRODUCTS AND INTRAUTERINECONTRACEPTIVE DEVICESBrian R. Matthews10.1 Introduction 16210.2 Contact lens care products 162

10.2.1 Contact lenses and contact lens care products in the UK ..16210.2.2 Controls in the EC 16310.2.3 Requirements in the UK 163

10.2.3.1 General requirements .16310.2.3.2 Chemical and pharmaceutical documentation . . 16410.2.3.3 Experimental and biological studies 16510.2.3.4 Studies in humans 16510.2.3.5 Product literature 165

10.3 Intrauterine contraceptive devices 16610.3.1 Introduction 16610.3.2 Data requirements in the UK 166

10.3.2.1 Chemical and pharmaceutical documentation ..16610.3.2.2 Experimental and biological studies 16610.3.2.3 Studies in humans 167


11 EXPERTS AND EXPERT REPORTS IN MARKETINGAUTHORISATION APPLICATIONSAnthony C. Cartwright11.1 Introduction 16811.2 Why are Expert Reports needed? 169

11.2.1 To comply with the requirements of Articles 1 to 3 ofDirective 75/319/EEC 169

11.2.2 To be used in the compilation of assessment reports(for multistate and concertation applications) 169

11.2.3 To provide a summary and overview of the productfor any subsequent action by the authorities on theauthorisation 170

11.2.4 To identify the major issues raised by the data in thedossier for its subsequent consideration nationally orin the Committee for Proprietary Medicinal Products . . . . 170

11.2.5 To ensure that all marketing authorisation applicationshave had critical review 171

11.2.6 To provide the core of the Evaluation Report in theProduct Evaluation Report scheme 171

11.2.7 To provide the core of the assessment/evaluation reportin the future in a wider European or global application . . . 172

11.3 The Expert — legal definitions and practical requirements(training, position, and experience) 17211.3.1 Legal definitions (Directive 75/319/EEC) 172

11.3.1.1 The analyst 17211.3.1.2 The pharmacological/toxicologist 17211.3.1.3 The clinician 17211.3.1.4 Legal requirements as to qualification of Experts 172

11.3.2 The practical requirements as defined in the 1989 editionof the 'Notice to Applicants' 173

11.4 The three Experts: further exploration of their roles . .17311.4.1 The pharmaceutical Expert 17311.4.2 The pharmaco-toxicological Expert 17311.4.3 The clinical Expert 17411.4.4 The three Experts: their role in defining the applicability

of published references (for abridged applications) 17511.5 The Experts: who should they be? 175

11.5.1 Single versus multiple Experts 17511.5.2 The consultant Expert 17611.5.3 The'foreign'Expert versus national Expert 176

11.6 The flow of information — raw data in the laboratory to theExpert Report and the product profile 177

11.7 Links between the three Experts 17711.8 The duties of the Experts 178

11.8.1 To provide the Expert Report 178


11.8.2 To provide a justification for the acceptance of a productin List B ('high technology' procedure ofDirective 87/22/EEC). . . • 179

11.8.3 To be available for consultation with the authorities 18011.8.4 To participate in appeals 180

11.9 The pharmaceutical Expert Report: structure, format, and content. 18011.9.1 Structure of the pharmaceutical Expert Report 18011.9.2 Contents of the pharmaceutical Expert Report 18111.9.3 Evaluation section of the pharmaceutical Expert

Report 18211.10 The pharmacotoxicological Expert Report: structure,

format, and content 18511.10.1 Structure of the pharmacotoxicological

Expert Report 18511.10.2 Contents of the pharmacotoxicological

Expert Report 18511.10.3 Conclusions of the pharmacotoxicological

Expert Report "*. 18511.11 The clinical Expert Report: structure, format, and content 186

11.11.1 Structure of the clinical Expert Report 18611.11.2 Contents of the clinical Expert Report 18611.11.3 Conclusions of the clinical Expert Report 187

11.12 Miscellaneous issues in relation to Expert Reports 18711.12.1 Products outside the Directives 18711.12.2 Clinical trial approval applications 18811.12.3 Cross-referral marketing authorisation applications 188

References 188

12 DEFECTS IN APPLICATIONS — AN ANALYSISDavid B. Jefferys, Brian R. Matthews, and James C. Ritchie12.1 Introduction 19012.2 The clinical dossier 192

12.2.1 Introduction 19212.2.2 Structure of the dossier 19212.2.3 The clinical Expert Report 19312.2.4 Overall summary 19512.2.5 Clinical pharmacology 19512.2.6 Reports of individual clinical trials 196

12.3 The pharmaceutical dossier 19812.3.1 Introduction 19812.3.2 Analysis of deficiencies in UK applications 199

12.3.2.1 Deficiencies relating to the drug substance . . . .19912.3.2.2 Deficiencies relating to the finished product. . . .20112.3.2.3 Points of general applicability 203

12.3.3 Deficiencies in applications referred to CPMP 204


12.3.4 Objections remaining after consideration by advisorycommittees 20512.3.4.1 Introduction 20512.3.4.2 The outcome of additional data consideration

of applications routed via the CPMP 20512.3.4.3 Applications considered by the CSM 205

12.4 The preclinical dossier 20812.4.1 Introduction 20812.4.2 Pharmacology 21012.4.3 Pharmacokinetics 21012.4.4 Toxicology 21012.4.5 Reproduction studies 21112.4.6 Mutagenicity 21112.4.7 Carcinogenicity 212

References 212

13 CPMP AND THE PHARMACEUTICAL COMMITTEEAnthony C. Cartwright

13.1 The Committee for Proprietary Medicinal Products (CPMP)and its activities 213

13.1.1 The original functions of the CPMP 21313.1.2 The chairmanship and vice-chairmanship of the CPMP . . .21313.1.3 The current role of the CPMP 21413.1.4 The future role of the CPMP 21413.1.5 The CPMP working parties 21513.1.6 The Commission working parties 217

13.2 The Pharmaceutical Committee 21713.3 The Committee for the Adaptation to Technical Progress 218

14 CPMP MULTISTATE PROCEDUREAnthony C. Cartwright14.1 Introduction 22014.2 The former CPMP procedure 22114.3 The new rules of the multistate procedure 22214.4 What authorisations can be used in the multistate procedure? . . . . 22214.5 What authorisations cannot be used in the multistate procedure? . . 22314.6 Suitability of products for the multistate procedure 22414.7 Second applicant (abridged) products 22514.8 Changes to the original authorisation ('variations') 22614.9 Multistate applications for products whose authorisations were

granted in the originating (outgoing) Member State some yearspreviously 226

14.10 The multistate procedure and timing 22714.11 The role of the rapporteur and co-rapporteur 22914.12 The assessment report 23014.13 Labels and leaflets 23014.14 Samples of the starting materials and dosage-form 230


14.15 Applications to Portugal 23114.16 The format and language of multistate applications 23114.17 Hearings 23114.18 The 'Euro-SPC 23214.19 Analysis of multistate applications (1986 to 1989) 233Reference 234

15 THE CONCERTATION (HIGH TECHNOLOGY/BIOTECHNOLOGY)PROCEDUREAnthony C. Cartwright15.1 Introduction 23515.2 Protection of innovation 23515.3 Early evaluation of the procedure 23615.4 Biotechnology products — an obligatory procedure 23615.5 Exemption from the obligatory biotechnology procedure 23715.6 The high technology procedure 23715.7 The concertation timetable ^ 23815.8 Appeals 23915.9 The Summary of product characteristics 24015.10 Changes to the marketing authorisation ('variations') 24015.11 Experience with the biotechnology procedure 24015.12 Experience with the high technology procedure 241

16 REGULATORY STRATEGY: THE EC, EFTA, THE PER SCHEMEAnthony C. Cartwright16.1 Regulatory strategy 242

16.1.1 Regulatory strategy in national applications 24316.2 Regulatory strategy in concertation applications for biotechnology

products 24416.2.1 Quality of the dossier 24416.2.2 Choice of the rapporteur country 24416.2.3 Liaison with the rapporteur 24516.2.4 Choice of the Experts for the Expert Report 24516.2.5 Quality of the written response to questions 24516.2.6 Choice of the Experts for hearings 24516.2.7 Response to remaining'subject to'points . .245

16.3 Regulatory strategy in high technology applications 24516.4 Regulatory strategy in the multistate procedure 24616.5 Overall regulatory strategy for the product 24616.6 The PER scheme 247Reference 248

17 THE UNITED KINGDOM'S SYSTEM FOR LICENSINGPHARMACEUTICAL PRODUCTSBrian R. Matthews17.1 Introduction 249


17.2 Sources of information 24917.3 Product licences and clinical trial certificates for pharmaceuticals

for use in humans 25017.3.1 Introductory remarks 25017.3.2 Purpose of an application 25117.3.3 Application forms 25117.3.4 Before submitting the application 25217.3.5 Submitting the application and supporting data 25217.3.6 Registration 25217.3.7 Validation 25317.3.8 Professional assessment 25517.3.9 Reference to advisory bodies 25617.3.10 Other appeal procedures 26017.3.11 The issue of a product licence or clinical trial certificate.". . 26117.3.12 Processing of applications routed via the Committee

for Proprietery Medicinal Products 26117.4 The clinical trial exemption scheme 262

17.4.1 The scope of the scheme 26217.4.2 How the procedure works 262

17.5 Changes to licences, certificates, and exemptions 26317.5.1 Scope 26317.5.2 The procedures 263

17.6 Renewals 26317.6.1 Scope 26317.6.2 The procedures 264

17.7 Legal status and related topics 26417.7.1 Introduction 26417.7.2 Proposed method of sale 26417.7.3 Prescription only medicines 26517.7.4 General sales list products 26517.7.5 The determination of legal status 26617.7.6 Changing legal status 26717.7.7 Examples of special cases 268

17.7.7.1 Radiopharmaceuticals 26811.1.1.2 Breathing gases 26917.7.7.3 Surgical materials .26917.7.7.4 Contact lenses and contact lens care products . . 26917.7.7.5 Topical hydrocortisone creams and ointments . . 270

17.7.8 An outline of the legal status position in the EC 270

18 THE OTHER NATIONAL AUTHORITIES IN THE ECAnthony C. Cartwright18.1 Introduction 28018.2 The EC Member States 28018.3 The organisation of the assessment of marketing

authorisation applications 282


18.4 The role of the national committees of independent experts 28318.5 The appeals procedures 28718.6 The national control laboratories and their involvement in the

premarketing testing of samples of active ingredients,intermediates, and finished products 288

18.7 The names and addresses of national authorities in theEC Member States 290

Reference 293

19 EEC GUIDELINES — QUALITY, SAFETY, EFFICACY, ANDBIOTECHNOLOGYAnthony C. Cartwright19.1 Introduction ^.29419.2 The purpose of guidelines 29519.3 Status of guidelines 29519.4 Working parties and their membership 29519.5 Procedure for drawing up guidelines 29519.6 Revision of existing guideline texts 296Reference 296

20 THE NEW GENERAL DIRECTIVE, IMMUNOLOGICALS,ETC. DIRECTIVESAnthony C. Cartwright20.1 Introduction 29720.2 Directive 89/341/EEC. The new general Directive 297

20.2.1 Implementation date 29720.2.2 Objectives of the Directive 29820.2.3 Change of terminology 29820.2.4 New categories of exemptions from the Directives 29820.2.5 Amendment to the Summary of product characteristics

(SPC) requirements .29820.2.6 Amendment to the labelling requirements 29920.2.7 Labelling of ampoules: batch number added 29920.2.8 Replacement of term 'proprietary medicinal product'

by 'medicinal product' in Directive 75/318/EEC 29920.2.9 Testing of samples .29920.2.10 Mandatory package leaflet 29920.2.11 A manufacturing authorisation required even for export

only products 29920.2.12 Inspections and good manufacturing practice 30020.2.13 Exports and export certificates 30020.2.14 Communicating the results of GMP inspections between

the authorities 30020.2.15 Notification of suspensions and revocations 300


20.3 Directives 89/342/EEC (Immunogicals), 89/343/EEC(Radiopharmaceuticals), and 89/381/EEC (Blood Products) 301

Reference 301

21 THE SINGLE MARKET AFTER 1992: NEW DIRECTIONSAnthony C. Cartwright21.1 Introduction 30221.2 The consultation process 30221.3 Review and adoption of the future system legislative proposals . . .30321.4 The proposals for procedures after 1992 30321.5 Phasing and transitional arrangements for the new procedures . . . .304

21.5.1 National applications 30421.5.2 Centralised applications 304

21.6 Products authorised nationally before 1993 30421.7 The objectives of the new institutions and procedures 305

21.7.1 Public health 30521.7.2 Industrial policy 30521.7.3 EC interests 305

21.8 The European Medicines Evaluation Agency 30621.8.1 Managerial and administrative support 30621.8.2 Administrative board 30721.8.3 Scientific and technical support for the EMEA 30721.8.4 The scientific and technical committees 30721.8.5 The Scientific Council 307

21.9 The centralised procedure 30821.9.1 Products eligible for the procedure 30821.9.2 The working of the centralised procedure 30921.9.3 Appeals in the centralised procedure 309

21.10 The decentralised procedure 31021.10.1 Products eligible for the decentralised procedure 31021.10.2 The working of the decentralised procedure . . . . . . . . .31021.10.3 Appeals in the decentralised procedure 311

21.11 The 'regulatory mechanism' — turning Opinions into Decisions . . 31221.12 The supervisory authority 312Reference 313

APPENDIX: ABBREVIATIONS AND ACRONYMS 314

INDEX 318

pharmaceutical product licensing - gbv · pharmaceutical product licensing requirements for europe...

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