7 September 2017 Draft 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 GOOD PHARMACOPOEIAL PRACTICES Draft chapter on monographs on herbal medicines (DISCUSSED during the 8th international meeting of world pharmacopoeias, terminology added 7/9/2017) Please address any comments on this proposal by 5 October 2017 to Dr S. Kopp, Group Lead, Medicines Quality Assurance, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or email: kopps@who.int with a copy to finnertyk@who.int World Health Organization 2017 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Regulation of Medicines and other Health Technologies, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: kopps@who.int. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
page 2 38 39 40 41 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.621: GOOD PHARMACOPOEIAL PRACTICES CHAPTER ON MONOGRAPHS ON HERBAL MEDICINES/DRUGS Need for good pharmacopoeial practices (GPhP) stated during first international meeting of world pharmacopoeias, Geneva, and other related events with stakeholders 28 February 1 March 2012 7 8 October 2012 9 12 October 2012 21 22 October 2012 17 October 2012 First draft of good pharmacopoeial practices (GPhP) sent out for comment (QAS/12.516) Compilation of feedback and comments received November December 2012 Circulation of GPhP to drafting group on GPhP with 18 January 2013 comments, as well as Concept paper on scope and background (QAS/13.518) Formation of initial drafting group (IDG), including February 2013 representatives from each pharmacopoeia, as per selfnomination, to review draft concept paper via teleconference call Preparation of new skeleton and first draft with more detailed February 2013 structure Mailing to world pharmacopoeias for additional feedback, February March 2013 preparation of draft chapters by drafting group Compilation of feedback April 2013 Discussion of draft working document on good pharmacopoeial practices at second international meeting of 18 19 April 2013 world pharmacopoeias, New Delhi, India Revised version of GPhP prepared and mailed out for 28 May 2013 comments to all pharmacopoeias, for feedback to be provided to lead pharmacopoeias for each chapter Discussion of feedback during informal consultation to 12 14 June 2013 discuss new medicines, quality control and laboratory standards Revision of each chapter by each GPhP lead pharmacopoeia 28 June 2013 Mailing of each chapter to WHO for compilation into a revised working document Presentation to forty-eighth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Compilation of all various chapters received from the lead pharmacopoeias and mailing out to all world pharmacopoeias July 2013 December 2013 October 2013 January 2014
page 3 Compilation of all comments received March 2014 Discussion during the 3rd international meeting of world 10 11 April 2014 pharmacopoeias in London, United Kingdom Revised version of GPhP prepared and mailed out for July 2014 comments to all pharmacopoeias, for feedback to be provided to each chapter Compilation of all comments received 22 September 2014 Following feedback and discussions during two telephone 23 September 2014 conference calls of the subgroup working on the Technical Annex to the future GPhP the European Pharmacopoeia Secretariat prepared a significantly shortened draft which is circulated for comments Compilation of all comments received 30 September 2014 Discussion during the 4th international meeting of world pharmacopoeias in Strasbourg, France Briefing on progress to forty-ninth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Continuation of consultation process with world pharmacopoeias Continuation of consultation process with world pharmacopoeias and worldwide 8 10 October 2014 13 17 October 2014 October 2014 January 2015 Mid-January mid-march 2015 GPhP Chapter 5.4.2: Monographs on Herbals April 2013 medicines/drugs drafted by the Indian Pharmacopoeia Committee (IPC) Comments received by pharmacopoeias and track change proposals made by USP 2014 Additional feedback received from various pharmacopoeias to GPhP Chapter 5.4.2: Monographs on herbals March 2015 Comments reviewed and feedback added by IPC April 2015 Working document sent out to all pharmacopoeias for May 2015 comments and feedback Compilation of comments received August 2015 Discussion of feedback during the 6th international meeting of world pharmacopoeias September 2015, dates tbc with the Chinese Pharmacopoeia Commission 3
page 4 Presentation to the fiftieth meeting of the WHO Expert 12 16 October 2015 Committee on Specifications for Pharmaceutical Preparations Comments reviewed and feedback added by IPC April 2016 Working document sent out to all pharmacopoeias for May June 2016 comments and feedback Compilation of comments received and inclusion of proposed July August 2016 changes by WHO Secretariat + mailing of feedback and new draft to all pharmacopoeias Discussion of feedback during the 7th international meeting 13 14 September 2016 of world pharmacopoeias Working document sent out to all pharmacopoeias for September 2016 comments and feedback Presentation to the fifty-first meeting of the WHO Expert 17 21 October 2016 Committee on Specifications for Pharmaceutical Preparations Working document sent out (Rev. 2) to all pharmacopoeias November 2016 for comments and feedback Compilation of comments received March May 2017 Discussion of feedback during the 8th international meeting of world pharmacopoeias Circulation to world pharmacopoeias and for public feedback, addition of glossary after the Third WHO consultation on quality control of herbal medicines planned to be held in Hong Kong SAR, China, 4-6 September 2017, during which the Good Herbal Processing Practices with related terminology will be discussed added 7/9/2017 Presentation to the fifty-second meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations 11 12 July 2017 July September 2017 16 20 October 2017 Any follow-up action as necessary 42 43 44 45 46 47 48 49 50 51 52
page 5 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 MONOGRAPHS ON HERBAL MEDICINES 1. INTRODUCTION Pharmacopoeial monographs for herbal medicines should contain information in the definition that is consistent with the monograph title followed by specifications for quality including identity, purity and content. Individual monographs describe test procedures together with the corresponding specifications. The monograph may include: an official title; a definition; an identification section; a test section covering, for example, physicochemical tests and, where appropriate, tests on contaminants; an assay section determining constituents with known therapeutic activity, active or analytical markers. Further sections providing information on labelling and storage may also be provided. 2. GENERAL CHAPTER The general testing methods and other specifications that are common for herbal medicines may be described in a General Chapter. 3. INDIVIDUAL MONOGRAPHS ON HERBAL MEDICINES 3.1 Monograph title The title of the monograph may include the Latin name, or the well-established common local name and English common name, if available, in addition to the scientific name. 5
page 6 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 This is followed by the name of plant part(s) or plant material (e.g. resin, gum-resin) and where applicable, its state and type of herbal preparation (e.g. liquid extract, dry extract) and its dosage form (tablet, capsule, etc.). Individual pharmacopoeias may apply their own nomenclature policies that meet regulatory needs and reflect the common names in commerce, as appropriate. 3.2 Definition The definition provides details about the subject of the monograph and includes the Latin binomial name and the taxonomic authority (abbreviation if used should be according to internationally-accepted rules), the plant family name if required by national legislations, the well-established common local name and English common name (if available, in addition to the scientific name), and well-recognized synonyms, the plant part(s) (i.e. aerial parts, root, leaves, flowers, rhizome, etc.), plant material (e.g. resin, gum-resin and where applicable, its state and type of herbal preparation (e.g. liquid extract, dry extract) and its dosage form (tablet, capsule, etc.). When necessary, as dictated and supported by data, the definition also states the season or period in which plant material should be harvested according to Good Agricultural and Collection Practices (GACP). If more than one species is included in the monograph the definition should include, for each of the species, the requirements listed above. The definition should include the chemical names, and/or molecular formulas of relevant known constituents, for which there is a specified range or minimum content, in percentage, usually calculated on the basis of the dry weight of the herbal medicines. Where a monograph applies to the herbal medicines in different states or stages of processing (DEFINE STATES IN GLOSSARY, including ), this is stated in the definition. 3.3 Identification The purpose of the Identification section is to ensure that the herbal medicine under examination is in agreement with what is stated in the Definition section. It is only necessary to include those techniques that are applicable for the identification of specific
page 7 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 herbal medicines. Macroscopic and microscopic descriptions of a herbal medicine may be supported by illustrations. Identification tests should be specific for the herbal medicine. Typically, several identification tests, using independent approaches, are required in order to confirm the identity of the herbal medicine. The tests given in the identification section are not designed to give a full confirmation of the chemical structure or composition of the herbal medicine. They are intended to give confirmation, with an acceptable degree of assurance, that the herbal medicine is the one stated on the label. Test methods, if applicable, should be able to detect substitutes or adulterants that are likely to be found. [Note from Secretatriat: Definition for Adulterant in TRS 1003, Annex 1: Adulterant is herbal material, a herbal constituent or other substance that is either deliberately or non-intentionally (through cross-contamination or contamination) added to a herbal material, herbal preparation, or finished herbal product.] 3.3.1 Macroscopic characters The important macroscopic botanical characteristics of the herbal materials are specified to permit a clear identification. Where two or more species of a genus or subspecies are included in the definition, the differences, if any, between them should be indicated. 3.3.2 Microscopic characters The microscopic examination of herbal materials is useful in determining the identity of herbal materials. Histological characters, such as microscopic characters of a transverse or longitudinal section may support the identification. For herbal materials where macroscopic identification cannot be performed (for example, powdered herbal materials), the microscopic characters are important to determine the identity. 7
page 8 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 3.3.3 Chemical tests Chemical tests, such as colour tests, can also be useful in determining the presence of substitution, adulteration or other foreign matters. Non-specific chemical tests must be avoided. Phytochemical screening tests that recognize general classes of compounds such as alkaloids, flavonoids, terpenes, steroids, saponins, tannins, etc., must be avoided unless they provide a means to differentiate potential adulteration due to species substitution/adulteration. 3.3.4 Fingerprinting Chromatographic or spectroscopic patterns, often referred to as fingerprints, may be used for identification as appropriate. The fingerprints should ideally be able to distinguish the herbal materials from other species that constitute both intentional and unintentional adulterations. Fingerprints may be obtained, for example, by thin-layer chromatography (TLC), highperformance thin-layer chromatography (HPTLC), high-performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UHPLC), capillary electrophoresis (CE) or gas chromatography (GC) methods. The methods should include all of the information required to perform the test, for example, preparation of sample and reference solutions, nature of plates/columns, testing conditions, mobile phase preparation, flow rate, method of detection/detectors. The results of such testing to be considered must contain a description of the critical features of the fingerprint chromatograms such as the presence of specific peaks or bands/spots, relative retentions or relative retention values, retardation or retention factor (R F or R f ), their order of elution and, where applicable, their relative abundance. A colour image of a typical reproducible TLC fingerprint may be provided as a guide for users. Pharmacopoeias may consider providing reference standards (RS) to be used for fingerprint testing.
page 9 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 3.3.5 DNA-based tests The DNA-based tests, such as PCR and DNA sequencing, can be useful in identifying specific herbal materials or detecting adulteration with either related or unrelated species that are difficult to distinguish with other methods. 3.4 Assay Where the constituent(s) responsible for therapeutic activity of the herbal medicine is/are known, its/their quantitative determination should be included. In herbal medicine where the chemical constituent(s) responsible for known pharmacological/therapeutic activity is/are not known, the pharmacopoeia may include testing for determination of the chemical constituent that act as analytical marker(s). Individual pharmacopoeias may include an assay procedure for one or more marker compounds. Where an assay of one or more chemical constituents is carried out, assay limits are specified either as a minimum content or as a percentage content range. Where constituents are present in a herbal medicine which are known to degrade (e.g. due to improper drying, storage under high temperatures or extended storage), those constituents may be used as analytical markers to control the quality of the herbal medicine. Stability-indicating chromatographic procedures that are validated for routine quality control work should be used. Individual pharmacopoeias may adopt either requirement for validation of assay methods on lines similar to those adopted for chromatographic procedures for synthetic drugs or developing assay methods. Development of assay methods through a collaborative process involving several laboratories, or other suitable approaches, may be adopted. 3.5 Tests for contaminants/impurities 3.5.1 General Tests for the following parameters should be included and limits specified as appropriate: 9
page 10 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 foreign matter; elemental contaminants/impurities (for, e.g. toxic metals such as lead, cadmium, mercury and arsenic); microbiological quality: national pharmacopoeias may consider specifying requirements for total aerobic microbial count (TAMC) and total combined yeast/moulds count (TYMC) as well as for specified microorganisms, for example, bile-tolerant gram negative bacteria, Escherichia coli and Salmonella; mycotoxins; toxic/harmful substances (such as pesticide residues, radionuclides and natural toxins); residual solvents. 3.5.2 Specific An individual herbal medicine may require specifications that are peculiar to that item, especially when patient safety is an issue. Limits should be set on certain constituents of the herbal medicines that may be considered undesirable negative markers, negative botanic characteristics or histological parameters. Impact on safety/description may form the basis for such test and limits are specified. For some individual herbal medicines, there could be risk of adulteration by herbal medicines that have a related morphological appearance or are marketed under similar common names. In such cases, additional tests as appropriate may be specified to detect and determine such adulterants. Where appropriate, tests on compounds (like alkaloids or cardiotonic steroids, etc.) that may impact the safety of the herbal medicines may be included in the monograph.
page 11 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 3.6 Physicochemical tests Physicochemical tests can serve as a valuable source of information and provide appropriate characterization standards to establish the quality of herbal medicines. Such evaluations may include: water and/or alcohol extractable matter; total ash content; water soluble ash; alcohol-soluble ash; acid-insoluble ash; loss on drying; water content; volatile oils, etc. 3.7 Other tests The following tests may be included as appropriate: swelling index; bitterness values; particle size; or any other test(s) found appropriate to the particular herbal medicine or material. Taste and/or odour as definitions or test procedures may be inappropriate for user safety reasons and should be avoided. 3.8 Additional information 3.8.1 Packaging, labelling and storage 1
page 12 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 Labelling requirements consistent with applicable national/regional legislation may be provided. Storage conditions may be provided when considered necessary to prevent contamination and/or are necessary to minimize possible deterioration. Guidance statements specifying the packaging may be included in the monograph, in specific cases, where applicable, for example, oils or oleoresins or distilled oils. 3.8.2 Reference standards The pharmacopoeias may describe the use of reference standards in the analysis of individual herbal medicines. RS may be authentic pure compounds or extracts of herbal materials or powdered herbal materials used for comparison. The RS established by individual pharmacopoeias are suitable for testing purposes. GLOSSARY [Note from the Secretariat: The following terms relating to herbal medicines have been redefined in connection with the development of new WHO guidelines in the area of good practices for herbal medicines. The following may serve for the Glossary, but were not yet agreed upon by the world pharmacopoeias during the 2016 meeting in Tokyo, Japan. During the 8th meeting in Brasilia it was agreed to add the glossary after the Third WHO consultation on quality control of herbal medicines planned to be held in Hong Kong SAR, China, 4 6 September 2017 during which the Good Herbal Processing Practices and related terminology will be discussed and recirculate the text thereafter. 7/9/2017, please find the terminology agreed upon in that meeting included below] Herbal medicines include herbs and/or herbal materials and/or herbal preparations and/or finished herbal products in a form suitable for administration to patients. [WHO, 2017]
page 13 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 Note: In some countries herbal medicines may contain, by tradition, natural organic or inorganic active ingredients that are not of plant origin (e.g. animal and mineral materials, fungi, algae, lichens, etc). Herbs [WHO, 2000] Herbs include crude plant materials such as leaves, flowers, fruit, seed, stems wood, bark, roots, rhizomes or other plant parts, which may be entire, fragmented or powdered. Herbal materials [WHO 2000]* Herbal materials include, in addition to herbs, fresh juices, gums, fixed oils, essential oils, resins, and dry powders of herbs. In some countries, these materials may be processed by various local procedures, such as steaming, roasting, or stirbaking with honey, alcoholic beverages or other plant materials. * The participants of the 3 rd WHO consultation on quality control, held in Hong Kong SAR, China from 4 to 6 September 2017 recommended that latex and exudates can be included. Herbal preparations [WHO, 2000] Herbal preparations are the basis for finished herbal products and may include comminuted or powdered herbal materials, or extracts, tinctures and fatty oils of herbal materials. They are produced by extraction, fractionation, purification, concentration, or other physical or biological processes. They also include preparations made by steeping or heating herbal materials in alcoholic beverages and/or honey, or in other materials. Finished herbal products [WHO, 2017] Finished herbal products consist of one or more herbal preparations made from one or more herbs (i.e. from different herbal preparations made of the same plant as well as herbal preparations from different plants. Products containing different plant materials are called mixture herbal products ). 1
page 14 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 Finished herbal products and mixture herbal products may contain excipients in addition to the active ingredients. However, finished products or mixture herbal products to which chemically defined active substances have been added, including synthetic compounds and/or isolated constituents from herbal materials, are not considered to be herbal. Herbal dosage forms Herbal dosage forms are the physical form (liquid, solid, semi-solid) of herbal products produced from herbs, with or without excipients, in a particular formulation (such as decoctions, tablets, and ointments). They are produced either from herbal materials (such as dried roots or fresh juices) or herbal preparations (such as extracts). Medicinal plants are plants (wild or cultivated) used for medicinal purposes [WHO, 2003a]; [WHO, 2006; WHO, 2007a]. Medicinal plant materials: see Herbal materials State [QAS/15.621/Rev.2] The state of the herbal material means whole, fragmented, peeled, cut, fresh or dried. ***