The rules governing medicinal products in the European Union Volume 4 Good manufacturing practices Medicinal products for human and veterinary use 1998 Edition EUROPEAN COMMISSION Directorate General III Industry Pharmaceuticals and cosmetics
THE RULES GOVERNING MEDICINAL PRODUCTS IN THE EUROPEAN UNION Volume 1 Pharmaceutical legislation Medicinal products for human use Volume 2 Notice to applicants Medicinal products for human use Volume 3 Guidelines Medicinal products for human use Volume 4 Good manufacturing practices Medicinal products for human and veterinary use Volume 5 Pharmaceutical legislation Veterinary medicinal products Volume 6 Notice to applicants Veterinary medicinal products Volume 7 Guidelines Veterinary medicinal products Volume 8 Maximum residue limits Veterinary medicinal products Volume 9 Pharmacovigilance Medicinal products for human and veterinary use
FOREWORD The Pharmaceutical Industry of the European Community maintains high standards of Quality Assurance in the development, manufacture and control of medicinal products. A system of Marketing Authorisations ensures that all medicinal products are assessed by a Competent Authority to ensure compliance with contemporary requirements of safety, quality and efficacy. A system of Manufacturing Authorisations ensures that all products authorised on the European market are manufactured only by authorised manufacturers, whose activities are regularly inspected by the Competent Authorities. Manufacturing Authorisations are required by all pharmaceutical manufacturers in the European Community whether the products are sold within or outside of the Community. Two directives laying down principles and guidelines of good manufacturing practice (GMP) for medicinal products were adopted by the Commission in 1991, the first for medicinal products for human use (Directive 91/356/EEC), the second one for veterinary use (Directive 91/412/EEC). Detailed guidelines in accordance with those principles are published in the Guide to Good Manufacturing Practice which will be used in assessing applications for Manufacturing authorisations and as a basis for inspection of manufacturers of medicinal products. The principles of GMP and the detailed guidelines are applicable to all operations which require the authorisation referred to in Article 16 of Directive 75/319/EEC and in Article 24 of Directive 81/851/EEC as modified. They are also relevant for all other large scale pharmaceutical manufacturing processes, such as that undertaken in hospitals, and for the preparation of products for use in clinical trials. All Member States and the Industry itself are agreed that the GMP requirements applicable to the manufacture of veterinary medicinal products are the same as those applicable to the manufacture of medicinal products for human use. Certain detailed adjustments to the GMP guidelines are set out in two annexes specific to veterinary medicinal products and to immunological veterinary medicinal products. The Guide is presented in chapters, each headed by a principle. Chapter 1 on Quality Management outlines the fundamental concept of Quality Assurance as applied to the manufacture of medicinal products. Thereafter each chapter has a principle outlining the Quality Assurance objectives of that chapter and a text which provides sufficient detail for manufacturers to be made aware of the essential matters to be considered when implementing the principle. In addition to the general matters of Good Manufacturing Practice outlined in the 9 chapters of this guide, a series of annexes providing detail about specific areas of activity is included. For some manufacturing processes, different annexes will apply simultaneously (e.g. annex on sterile preparations and on radiopharmaceuticals and/or on biological medicinal products). iii
Foreword A glossary of some terms used in the Guide has been incorporated after the annexes. The first edition of the Guide was published in 1989, including an annex on the manufacture of sterile medicinal products. The second edition was published in January 1992; including the Commission Directives 91/356 of 13 June 1991 and 91/412 of 23 July 1991 laying down the principles and guidelines on good manufacturing practice for medicinal products for human use as well as for veterinary medicinal products. The second edition also included 12 additional annexes. The basic requirements in the main guide have not been modified. 14 annexes on the manufacture of medicinal products have been included in this third edition. Annex 1 on the manufacture of sterile medicinal products has been modified. Annex 13 on the manufacture of investigational medicinal products, which was not included in the second edition of the Guide, has been modified and included in this version. Annex 14 on the manufacture of products derived from human blood or human plasma, which was not included in the second edition of the Guide, has been included in this version and a revision is scheduled for 1998. The Guide is not intended to cover security aspects for the personnel engaged in manufacture. This may be particularly important in the manufacture of certain medicinal products such as highly active, biological and radioactive medicinal products, but they are governed by other provisions of Community or national law. Throughout the Guide it is assumed that the requirements of the Marketing Authorisation relating to the safety, quality and efficacy of the products, are systematically incorporated into all the manufacturing, control and release for sale arrangements of the holder of the Manufacturing Authorisation. The manufacture of medicinal products has for many years taken place in accordance with guidelines for Good Manufacturing Practice and the manufacture of medicinal products is not governed by CEN/ISO standards. Harmonised standards as adopted by the European standardisation organisations CEN/ISO may be used at industry s discretion as a tool for implementing a quality system in the pharmaceutical sector. The CEN/ISO standards have been considered but the terminology of these standards has not been implemented in this third edition of the Guide. It is recognised that there are acceptable methods, other than those described in the Guide, which are capable of achieving the principles of Quality Assurance. The Guide is not intended to place any restraint upon the development of any new concepts or new technologies which have been validated and which provide a level of Quality Assurance at least equivalent to those set out in this Guide. It will be regularly revised. iv
TABLE OF CONTENTS Foreword... DIRECTIVES... 1 Commission Directive 91/356/EEC of 13 June 1991 laying down the principles and guidelines of good manufacturing practice for medicinal products for human use... 3 Commission Directive 91/412/EEC of 23 July 1991 laying down the principles and guidelines of good manufacturing practice for veterinary medicinal products... 11 iii GOOD MANUFACTURING PRACTICES... 19 BASIC REQUIREMENTS... 21 CHAPTER 1: QUALITY MANAGEMENT... 23 Principle... 23 Quality Assurance... 23 Good Manufacturing Practice for Medicinal Products... 24 Quality Control... 25 CHAPTER 2: PERSONNEL... 27 Principle... 27 General... 27 Key Personnel... 27 Training... 29 Personnel Hygiene... 29 CHAPTER 3: PREMISES AND EQUIPMENT... 31 Principle... 31 Premises... 31 General... 31 Production Area... 31 Storage Area... 32 Quality Control Area... 33 Ancillary Areas... 33 Equipment... 34 CHAPTER 4: DOCUMENTATION... 35 Principle... 35 General... 35 Documents Required... 36 Specifications... 36 Specifications for starting and packaging materials... 36 Specifications for Intermediate and Bulk Products... 36 v
Table of contents Specifications for Finished Products... 36 Manufacturing Formulae and Processing Instructions... 37 Packaging Instructions... 37 Batch Processing Records... 38 Batch Packaging Records... 39 Procedures and Records... 39 Receipt... 39 Sampling... 40 Testing... 40 Other... 40 CHAPTER 5: PRODUCTION... 43 Principle... 43 General... 43 Prevention of Cross-contamination in Production... 44 Validation... 45 Starting Materials... 45 Processing Operations: Intermediate and Bulk Products... 46 Packaging Materials... 46 Packaging Operations... 46 Finished Products... 48 Rejected, Recovered and Returned Materials... 48 CHAPTER 6: QUALITY CONTROL... 49 Principle... 49 General... 49 Good Quality Control Laboratory Practice... 49 Documentation... 50 Sampling... 50 Testing... 51 CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS... 53 Principle... 53 General... 53 The Contract Giver... 53 The Contract Acceptor... 54 The Contract... 54 CHAPTER 8: COMPLAINTS AND PRODUCT RECALL... 55 Principle... 55 Complaints... 55 Recalls... 55 CHAPTER 9: SELF INSPECTION... 57 Principle... 57 vi
Table of contents ANNEXES... 59 Annex 1 Manufacture of sterile medicinal products... 61 Principel... 61 General... 61 Isolator technology... 64 Blow/fill/seal technology... 64 Terminally sterilised products... 65 Aseptic preparation... 65 Personnel... 65 Premises... 67 Equipment... 68 Sanitation... 68 Processing... 68 Sterilisation... 70 Sterilisation by heat... 70 Moist heat... 71 Dry heat... 71 Sterilisation by radiation... 71 Sterilisation with ethylene oxide... 72 Filtration of medicinal products which cannot be sterilised in their final container... 73 Finishing of sterile products... 73 Quality control... 74 Annex 2 Manufacture of biological medicinal products for human use... 75 Scope... 75 Principle... 75 Personnel... 76 Premises and equipment... 77 Animal quarters and care... 78 Documentation... 78 Production... 78 Starting materials... 78 Seed lot and cell bank system... 79 Operating principles... 79 Quality control... 80 Annex 3 Manufacture of radiopharmaceuticals... 81 Principle... 81 Personnel... 81 Premises and equipment... 81 Production... 82 Quality control... 82 Distribution and recalls... 82 Annex 4 Manufacture of veterinary medicinal products other than immunologicals... 83 Manufacture of premixes for medicated and feedingstuffs... 83 Manufacture of ectoparasiticides... 84 Manufacture of veterinary medicinal products... 84 Retention of samples... 84 vii
Table of contents Sterile veterinary medicinal products... 84 Annex 5 Manufacture of immunological veterinary medicinal products... 85 Principle... 85 Personnel... 85 Premises... 86 Equipment... 88 Animals and animal houses... 90 Disinfection Waste disposal... 90 Production... 90 Starting materials... 90 Quality control... 93 Annex 6 Manufacture of medicinal gases... 95 Principle... 95 Personnel... 95 Premises and equipment... 95 Production and quality control... 96 Labelling... 98 Storage Release... 98 Annex 7 Manufacture of herbal medicinal products... 99 Principle... 99 Premises... 99 Storage areas... 99 Production area... 99 Documentation... 99 Specifications for starting materials... 99 Processing instructions... 100 Sampling... 100 Quality control... 100 Annex 8 Sampling of starting and packaging materials... 103 Principle... 103 Personnel... 103 Starting materials... 103 Packaging material... 104 Annex 9 Manufacture of liquids, creams and ointments... 105 Principle... 105 Premises and equipment... 105 Production... 105 Annex 10 Manufacture of pressurised metered dose aerosol preparations for inhalation... 107 Principle... 107 General... 107 Premises and equipment... 107 Production and quality control... 107 viii
Table of contents Annex 11... Computerised systems 109 Principle... 109 Personnel... 109 Validation... 109 System... 109 Annex 12 Use of ionising radiation in the manufacture of medicinal products... 113 Introduction... 113 Responsibilities... 113 Dosimetry... 114 Validation of the process... 114 Commissioning of the plant... 115 General... 115 Gamma irradiators... 115 Electron beam irradiators... 116 Re-commissioning... 117 Premises... 117 Processing... 117 Gamma irradiators... 117 Electron beam irradiators... 118 Documentation... 118 Microbiological monitoring... 118 Annex 13 Manufacture of investigational medicinal products... 119 Introduction... 119 Glossary... 120 Quality management... 121 Personnel... 121 Premises and equipment... 121 Documentation... 122 Order... 122 Product Specification File... 122 Manufacturing Formulae and Processing Instructions... 122 Packaging instructions... 123 Labelling Instructions... 123 Manufacturing and packaging batch records... 124 Production... 124 Starting materials... 124 Manufacturing operations... 124 Principles applicable to comparator product... 125 Randomisation code... 125 Quality control... 125 Release of batches... 126 Free movement... 126 Contract manufacture and contract analysis... 126 Complaints... 126 Recalls and returns... 127 Shipping Returns Destruction... 127 Shipping... 127 ix
Table of contents Returns... 127 Destruction... 128 Annex 14 Manufacture of products derived from human blood or human plasma... 129 Principle... 129 Quality management... 130 Premises and equipment... 130 Blood collection... 130 Production and quality control... 131 Fractionation/purification procedures... 132 a) Precipitation methods... 132 b) Solid phase and filtration methods... 133 Retention of samples... 133 Cellular products and whole blood... 133 GLOSSARY... 136 x