Scientific and Regulatory Basis for Development, Quality Assurance and Marketing Authorisation Dr. Frauke Gaedcke, Waidesch Dr. Barbara Steinhoff, Konigswinter In collaboration with Dr. Helga Blasius, Remagen With 11 colour photographs, 37 black-and-white figures and 30 tables Scientific Publishers StUttgart 2003 CRC PRESS Boca Raton London New York Washington, DC.
Preface V Abbreviations.. XIII 1 Definitions 1 1.1 Phytotherapy 1 1.2 Herbal medicinal products 1 1.3 Herbal drugs 2 1.4 Herbal drug preparations 3 1.5 Herbal extracts 4 1.5.1 Classification of extracts in terms of their physical state 5 1.5.2 Native and not-native extracts (extract preparations) 6 1.5.3 Adjusted (standardised), quantified and "other" extracts 7 1.6 Preparations of fresh plants 7 1.7 Ratio of the herbal drug to the extraction solvent 8 1.8 Ratio of the herbal drug to the native herbal drug preparation (native extract) (DER native ) 9 1.8.1 Definition of the DER native 9 1.8.2 Calculation of the DER native 10 1.8.3 Calculation of the daily dose (DD) of the herbal drug preparation via the DER native 12 1.9 Ratio of the herbal drug to the herbal extract preparation 12 1.10 Factors influencing the quantity of native herbal drug preparation (native extract) and the DER native 13 1.11 What is meant by standardisation? 15 1.11.1 Measures designed to ensure consistency of a herbal extract 15 1.11.2 Adjustment of a herbal drug preparation to a defined range of therapeutically active constituent(s) 16 1.11.3 Adjustment of a herbal drug preparation to a fixed content of more than one therapeutically active constituent (so-called "double-adjustment").. 19
1.12 Classification of plant constituents and extracts 22 1.12.1 Constituents with known therapeutic activity (therapeutically active constituents) 22 1.12.2 Constituents which contribute to therapeutic efficacy (active constituents) 23 1.12.3 Marker substances 23 1.12.4 Standardised extracts 25 1.12.5 Quantified extracts 25 1.12.6 Other extracts 26 1.13 Refined ("purified", "enriched") extracts 26 1.14 Mixed extracts (extracts of mixtures of herbal drugs, one-pot extracts).. 27 1.15 Mixtures of herbal extracts (multiple-pot extracts) 28 2 Labelling of herbal drug preparations (extracts) 31 2.1 Adjusted (standardised) extracts (siccum extracts) 31 2.2 Quantified extracts (siccum extracts) 32 2.3 Other extracts 32 2.4 Liquid extracts (fluida) 33 2.5 Tinctures 34 2.6 Soft extracts 34 3 Quality assurance of herbal medicinal products 37 3.1 General aspects 37 3.2 Quality assurance of the herbal starting material 41 3.2.1 Identification test 44 3.2.2 Assay 44 3.2.3 Purity tests 45 3.2.4 Reference substances 45 3.3 Quality assurance of the herbal extract 46 3.3.1 Extraction solvent 48 3.3.2 Extraction procedure 48 3.3.3 Evaporation 53 3.3.4 Microbial decontamination 54 3.3.5 Drying 56 3.3.6 Filing of the specification 58 3.4 Quality assurance of the finished herbal medicinal product 59 3.4.1 Development pharmaceutics 59
3.4.2 Disintegration time 63 3.4.3 Release of herbal medicinal products 63 4 Can herbal extracts and herbal medicinal products be "essentially similar"? 67 4.1 Different approaches for the definition of phytoequivalence 68 4.2 Phytoequivalence and pharmaceutical equivalence 69 4.3 Criteria for pharmaceutical equivalence 71 4.3.1 Herbal starting material 72 4.3.2 Type and concentration of extraction solvent 72 4.3.3 Manufacturing procedure 73 4.3.4 Conformity of batches and extracts 74 4.3.5 Dosage form and dosage 75 4.4 How to establish therapeutical equivalence 76 5 The European marketing authorisation system si 5.1 Directives relating to medicinal products 81 5.2 The centralised, decentralised and national procedure 81 5.3 The option of bibliographic applications 84 5.4 Application of the decentralised procedure to herbal medicinal products 85 5.5 The Herbal Medicinal Products Working Party (HMPWP) 85 5.6 The future of marketing authorisation in the EU 88 6 Legal provisions relating to the quality of herbal drugs, herbal drug preparations and herbal medicinal products... 93 6.1 Quality, efficacy and safety as prerequisites for marketing authorisation. 93 6.2 The European Pharmacopoeia 93 6.3 Annex of Directive 2001/83/EC 94 6.3.1 Qualitative and quantitative particulars of the constituents 96 6.3.2 Development pharmaceutics 97 6.3.3 Description of the method of preparation 97 6.3.4 Control of starting materials 97 6.3.5 Control tests in intermediate stages 98 IX
6.3.6 Control tests for the finished product 98 6.3.7 Stability tests 99 6.4 The European Guidelines "Quality of herbal medicinal products" and "Specifications" 102 6.5 Other European and international guidelines 103 6.6 Tests for special impurities 104 6.6.1 Microbiological testing 104 6.6.2 Heavy metals 107 6.6.3 Aflatoxins 108 6.6.4 Plant protection products 109 6.6.5 Ethylene oxide Ill 6.6.6 Radioactivity 112 6.6.7 Residual solvents 112 6.7 Filing of the documentation: Notice to Applicants 113 6.8 Bioavailability 113 7 Legal provisions relating to efficacy and safety of herbal medicinal products 7.1 Evidence of efficacy and safety required for herbal medicinal products including the well-established medicinal use 117 7.2 Attempts to harmonise the assessment criteria 121 7.3 Special requirements for fixed combinations 124 7.4 Marketing authorisation of "traditionally used" herbal medicinal products: the national ways and future European options 124 7.5 Research in phytotherapy 129 in 8 Herbal Medicinal Products Worldwide 131 8.1 The WHO Traditional Medicine Programme 131 8.2 WHO Guidelines for the assessment of herbal medicines 131 8.3 Model monographs of widely used medicinal plants 132 8.4 Further WHO activities 132
Annex I II CPMP/CVMP Note for Guidance on Quality of Herbal Medicinal Products 135 General monographs on herbal drugs, herbal drug preparations and herbal teas (Ph. Eur., Suppl. 2000) 142 III General monograph on extracts (Ph. Eur. 2002, Suppl. 4.3) 145 IV V Monographs on herbal drugs and herbal drug preparations published in the Ph. Eur. 2002, including Suppl. 4.1 to 4.3 149 Monographs and component characteristics published by the German Commission E 151 VI Monographs published by ESCOP 1996-1999 (fascicules 1-6) 166 VII WHO Model Monographs of Widely used Medicinal Plants (including Vol. I, II and III). 170 VIII WHO Publications relating to herbal medicines 171 Index 173 XI