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1 WHO/SDS/TCM 2
Draft WHO guidelines for comments 3 August 2016 4
Distribution: Restricted 5
Draft: 6
WHO guidelines on good herbal processing practices (GHPP) 7
for herbal medicines 8
9
DRAFT FOR COMMENTS 10
11
Please address any comments on this draft guidelines by 20 February 2017, to:
Ms Yukiko Maruyama, Scientist, Traditional and Complementary Medicine, Service Delivery and
Safety Department, World Health Organization, 1211 Geneva 27, Switzerland, at the email address
below:
E-mail: [email protected]
12 Traditional and Complementary Medicine (TCM) 13
Service Delivery and Safety Department (SDS) 14
World Health Organization (WHO) 15 16
TITLE: Draft: WHO guidelines on good herbal processing practices (GHPP) for herbal medicines - Draft 17 for comments, August 2016 18
19 © World Health Organization 2016 20 21 All rights reserved. 22 23 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 24 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in 25 any form or by any means outside these individuals and organizations (including the organizations’ concerned staff and 26 member organizations) without the permission of WHO. The draft should not be displayed on any web site. 27 28 Please send any request for permission to: 29 30 Ms Yukiko Maruyama, Scientist, Traditional and Complementary Medicine, Service Delivery and Safety Department, World 31 Health Organization, 1211 Geneva 27, Switzerland. E-mail: [email protected] 32 33 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 34 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 35 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 36 border lines for which there may not yet be full agreement. 37 38 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 39 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and 40 omissions excepted, the names of proprietary products are distinguished by initial capital letters. 41 42 The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall 43 not be liable for any damages incurred as a result of its use. 44
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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DRAFTDOCUMENT: 45
WHO GUIDELINES FOR GOOD HERBAL PROCESSING PRACTICES FOR HERBAL 46
MEDICINES 47
Need for a WHO technical guidance on processing to produce herbal
materials, and to produce herbal preparations for quality control of herbal
medicines at different stages of their production, was stated during the
WHO informal meeting on methodologies for quality control of finished
herbal products (Ottawa, Canada) as a recommendation to WHO for
development/action.
July 2001
Reported to the 37th session of the WHO Expert Committee on
Specifications for Pharmaceutical Preparations (ECSPP), Geneva, on the
output of the WHO informal meeting (July 2001) and informed the
Committee that WHO planned to develop new technical guidelines on
processing of herbal medicines; the Committee noted the proposal.
22-26 October 2001
Needs for good processing practices for herbal medicines were also stated
during the International Conferences of Drug Regulatory Authorities
(ICDRAs)
Hong Kong SAR, China,
November 2002
Madrid, Spain, February 2004
Drafting of the proposal on the development of WHO guiding document
on good processing practices for medicinal plant materials
2003
Obtained WHO’s internal approval in developing a WHO guiding
document on good processing practices for medicinal plant materials
(title: tentative)
November 2003
Identification, collection, collation and compilation of technical
information and reference materials for formulating draft synopsis and
annotated content table
2008
Development of concept paper on scope and background as well as the
document development plan
2008
Further identification, collection, collation and compilation of technical
information and reference materials for revising draft synopsis and
annotated content table.
2012
Revision of draft concept paper on scope and background as well as the
document development plan
2012-2013
Revision and elaboration of the draft synopsis and content table for
drafting the first working draft guidelines
2012-2013
Meeting proposal development and search for potential host of the
meeting (2nd WHO consultation on quality control of herbal medicines) 2012-2013
Further collection and collation of technical information and reference
materials for the preparation of the first working draft guidelines
2013-2014
Formulating the first working draft WHO guidelines on good processing
practices for herbal medicines
2014
Formation of initial drafting group 2014
Reported on the progress to the 49th session of the WHO ECSPP,
Geneva, October 2014
October 2014
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48
Distribution of the first working draft WHO guidelines to the participants
of the 2nd WHO consultation on quality control of herbal medicines for
discussion at the 2nd WHO consultation meeting
October – November 2014
Reported on the progress to the 37th Annual meetings of national centres
participating in the WHO international drug monitoring programme,
Tianjin, China, October 2014
October 2014
At the 2nd WHO consultation meeting held in Hong Kong SAR, China, in
November 2014, the first working draft WHO guidelines on good
processing practices for herbal medicines were reviewed and discussed;
and the objectives, scope and proposed contents were discussed
intensively, and agreed. The draft synopsis and table of content of the
proposed guidelines were further refined and agreed; it was also agreed to
revise the first working draft WHO guidelines based on the discussion
and agreed guidelines’ objectives, scope, and contents at the 2nd WHO
consultation meeting.
17-19 November 2014
Reported on the progress of the guidelines development at the 7th annual
meeting of International Regulatory Cooperation for Herbal Medicines
(IRCH), Lisbon, Portugal, December 2014
December 2014
Further identification, collection and collation of relevant technical
information for revision of the first working draft guidelines
2015-2016
Revision of the first working draft WHO guidelines 2015-2016
Reported on the progress at the 8th annual meeting of IRCH, Riyadh,
Saudi Arabia, December 2015
8-10 December 2015
Formulation of the draft WHO guidelines on good herbal processing
practices for herbal medicines for a global review
2016
Reported on the progress to the 51st session of the WHO ECSPP, Geneva,
October 2016
17-21 October 2016
Reported on the progress at the 9th annual meeting of IRCH, New Delhi,
India, November 2016
9-11 November 2016
First global review on the draft WHO guidelines on good herbal
processing practices for herbal medicines
December 2016 - February
2017
Meeting proposal development and search for potential host of the
meeting (3rd WHO consultation on quality control of herbal medicines) December 2016 – February
2017
Compilation of comments received and revision of the draft February – April 2017
The second global review on the revised draft May-June 2017
Compilation of comments received and revision of the revised draft June- July 2017
Review and discussion of feedback received at the 3rd WHO consultation
on quality control of herbal medicines
Date to be decided
Finalization of the manuscript based on the discussion at the 3rd WHO
consultation meeting
Date to be identified
Update to the 10th annual meeting of IRCH September 2017
Update to the 52nd session of the WHO ECSPP, Geneva, October 2017 October 2017
Any follow-up action, as needed
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Table of Contents 49 50
1. INTRODUCTION…………………………………………………………………...………………6 51 1.1 Background of guidelines development………………………………………………...…6 52 1.2 Scope………………………………………………………………...…………………….753 1.2.1 Processing of herbs into herbal materials……………………………………...….8 54 1.2.2 Processing of herbal materials into herbal preparations…………………...……8 55 1.2.3 Processing of herbal materials or herbal preparations into herbal dosage forms…8 56 1.3 Objectives of guidelines………………………………………………………...…………9 57 1.4 Glossary/definitions of terms………………………………………………..…….……10 58 1.4.1 Terms relating to herbal medicines…………………………………..….………10 59 1.4.2 Terms related to herbal processing practices……………………….……….…..11 60 1.4.3 Terms related to herbal preparations……………………………………….……12 61 1.4.4 Terms relating to quality control……………………………………………..….13 62 63 2. GOOD HERBAL PROCESSING PRACTICES FOR THE PRODUCTION OF HERBAL 64
MATERIALS…………………………………………………………………………………...….14 65 2.1 General information………………………………………………………………….…..14 66 2.2 Purposes and functions of processing……………………………………………….…...15 67 2.3 Processing techniques and procedures……………………………………………….…..16 68 2.3.1 Preparation of harvested/collected medicinal plant part for processing……...….17 69 2.3.2 Primary processing procedures……………………….…………………………17 70 2.3.3 Secondary processing procedures………………………………….……………20 71 2.3.3.1 Selection of processing method…………………………….…………22 72 2.3.3.2 Temperature…………………………………………………………..23 73 2.3.3.3 Duration of procedure/treatment……………………………………...23 74 2.3.3.4 Use of adjuvants……………………………………………………...23 75 2.3.4 Special processing procedures………………………………………………….23 76 2.3.4.1 Detoxification…………………….…………………………………...23 77 2.3.4.2 Enhancement or modification of therapeutic properties………………24 78 2.3.4.3 Use of adjuvants……………………………..………………………...24 79 2.3.5 Documentation……………………………………….………………………….24 80 81 3. GOOD HERBAL PROCESSING PRACTICES FOR THE PRODUCTION OF HERBAL 82
PREPARATIONS………………………………………………………………………………….25 83 3.1 General information…………………………………….………………………………..25 84 3.2 Extraction……………………………………………….…….………………………….25 85 3.2.1 Common methods of extraction………………………………………….……...26 86 3.2.2 Steps involved in the extraction of medicinal plants………………………….…28 87 3.2.3 Common herbal preparations prepared by extraction……………………….…..28 88 3.2.4 Controlling factors in extracting herbal materials…………………….…………29 89 3.3 Distillation………………………………………………………….…………………….29 90 3.4 Fractionation and purification…………………………….……………………………...30 91 3.4.1 Liquid-liquid partition………………………………………………….………..30 92 3.4.2 Chromatography…………………………………………………………….…...30 93 3.5 Concentration and drying…….…………………………………………………………..31 94 3.6 Fermentation……………………………………………………………….…………….31 95 3.7 Processing techniques and procedures……………………………………………….…..31 96 3.7.1 Preparation of herbal materials for processing………………………….……….31 97 3.7.2 Extraction………………………………………………….…………………….32 98 3.7.2.1 Selection of extraction methods…………………………………….....32 99 3.7.2.2 Extraction conditions and procedures…………………………...…….32 100
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3.7.3 Distillation……………………………………………………………….………33 101 3.7.4 Fractionation and purification……………………………………….…………..33 102 3.7.5 Concentration and drying…………………………………………………….….34 103 3.7.6 Fermentation…………………………………………………………….……….34 104 3.8 Documentation……………………………………………………………….…………..34 105 106 4. GOOD HERBAL PROCESSING PRACTICES FOR THE PRODUCTION OF HERBAL 107
DOSAGE FORMS…………………………………………...…………………………………….35 108 4.1 General information………………………………………………………….…………..35 109 4.2 Extract…………………………………………………………………….……………...35 110 4.3 Fluidextract………………………………………………………….…………………35 111 4.4 Infusion…………………………………………………………………………………..35 112 4.5 Decoction………………………………………………………………………………...36 113 4.6 Herbal tea bag…………………………………………………………………………….36 114 4.7 Tincture and spirit…………………………………………………………………….….36 115 4.8 Aromatic Water……………………………………………………………………….….36 116 4.9 Syrup………………………………………………………………………………….….36 117 4.10 Powder…………………………………….……………………………….……………..36 118 4.11 Granule…………………………………………………………………………….……..36 119 4.12 Pills……………………………………………………………………….………………37 120 4.13 Capsule…………………………………………………………………………….……..37 121 4.14 Tablet……………………………….………………………………………….…………37 122 4.15 Ointment/cream…………………………………………………………………….…….37 123 4.16 Inhalation………………………………………………………………………….…...…37 124 4.17 Plaster and patch…………………………………………………………………….……37 125 126 5. T E C H N I C A L I S S U E S S U P P O R T I N G G O O D H E R B A L P R O C E S S I N G 127
PRACTICES…………………………………………………….………………………………….38 128 5.1 Processing facilities………………………………………………………………….…...38 129 5.2 Packaging and labelling……………………………………………………………….…38 130 5.3 Storage and transportation……………………………………………………….…….…39 131 5.4 Equipment………………………………………………………………………….…….39 132 5.5 Quality assurance and quality control…………………………………………….……...40 133 5.6 Documentation……………………………………………………………….…………..40 134 5.7 Personnel……………………………………….…………………….…………………..40 135 5.7.1 General…………………………………….…………….……………………….40 136 5.7.2 Health, hygiene and sanitation…………………………………….……………..41 137 138 6. OTHER RELEVANT ISSUES………………………………………………………….………….41 139 6.1 Ethical and legal considerations……………………………………………….…………41 140 6.2 Research, research training and information sharing……………………………….……42 141 6.3 Adoption of good herbal processing practices………………….…………….………….42 142 6.4 Intellectual property rights and benefits-sharing……………………...………….………42 143 6.5 Threatened and endangered species……………………………………………………...42 144 145 7. REFERENCES…...…………………………………………………………………………….…..42 146 147 Annex 1: Example of a model format of good herbal processing practices monograph/SOP protocol to 148
produce a herbal material………………………………………..……… . .……44 149 Annex 2: Example of a model format of good herbal processing practices monograph/SOP protocol to 150
produce a herbal preparation…..……………………………………………………….…..47 151 Annex 3: Example of general rules for preparation of dosage forms related to herbal medicines……50 152 Annex 4: Processing facilities…………………….………………………………………….…..…….56 153
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1. INTRODUCTION 154
155
1.1 Background of guidelines development 156
157 Over the past three decades, there has been a constant, and at times, exponential growth in 158
global interest in the use of herbal medicines. This increase in popularity and usage of herbal 159
medicines is evidenced by the global market which also experienced similar growth. Herbal 160
medicines, including not only finished herbal products but also their starting materials for 161
production, such as medicinal plants, herbal materials, and herbal preparations, are moving 162
into international commerce and the global trade arena, which indicates increased economic 163
value and importance. When adverse events are reported to the regulatory authorities in 164
relation to the use of herbal products, a large portion of them are attributable to poor quality 165
of products, which may involve a variety of factors, including those due to natural (e.g. source 166
material) and human (e.g. manufacturing/processing) factors. Hence, the safety and quality of 167
herbal materials, herbal preparations and finished herbal products have become a major 168
concern to health authorities, healthcare providers, the pharmaceutical industry and the public. 169
170
The safety and efficacy of herbal medicines largely depend on their quality. Unlike 171
conventional pharmaceutical products, which are formulated from single molecule chemicals 172
produced synthetically or by isolation from natural source materials employing reproducible 173
methods, herbal medicines consist of simple processed herbs or finished products prepared 174
from source materials containing a multiplicity of chemical constituents, the quality and 175
quantity of which can vary from batch to batch due to intrinsic and extrinsic factors. 176
Consequently, the quality of finished herbal products is greatly influenced by the quality of 177
the raw materials and the intermediates; and the requirements and methods for quality control 178
of finished herbal products, particularly for mixture herbal preparations, are far more complex 179
than those employed for single molecule chemical drugs. 180
181
A number of World Health Assembly (WHA) resolutions relating to traditional medicine has 182
requested WHO to provide technical support to develop methodology to monitor or ensure the 183
quality, efficacy and safety of herbal medicines. The International Conferences of Drug 184
Regulatory Authorities (ICDRAs), and annual meetings of International Regulatory 185
Cooperation for Herbal Medicines (IRCH), as well as the Meetings of the National Centres 186
Participating in the WHO International Drug Monitoring Programme have also requested 187
WHO to develop and continuously update the technical guidelines on quality, safety, and 188
efficacy of herbal medicines. 189
190
Participants of the WHO Informal Meeting on Methodologies for Quality Control of Finished 191
Herbal Products (held in Ottawa, Canada, July 2001) looked at the overall picture of herbal 192
medicines: from raw materials to the distribution and supply of finished herbal products, 193
including key steps where quality control is required. 194
195
One of the main recommendations of the meeting was that WHO should prepare a series of 196
technical guidelines and documents covering quality control issues (from raw materials to 197
finished herbal medicinal products), as well as to update other existing documents. 198
199
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Following the meeting’s recommendations, and as a part of the implementation of relevant 200
WHO strategies (notably, WHO traditional medicine strategies and WHO medicines 201
strategies) and WHA resolutions, WHO undertook the development of four new guidelines 202
and to update other existing documents in order to provide technical guidance for quality 203
control required at key steps in the production of herbal medicines to support Member States 204
in their efforts to ensure the quality of herbal medicines. These cover: 205
206
WHO guidelines on good agricultural and collection practices (GACP) for medicinal 207
plants (published in 2003) [WHO, 2003a]; 208
WHO guidelines on assessing quality of herbal medicines with reference to contaminants 209
and residues (published in 2007) [WHO, 2007b]; 210
WHO guidelines for selecting marker substances of herbal origin for quality control of 211
herbal medicines (in preparation) [WHO, 2017]; and 212
WHO guidelines on good herbal processing practices (GHPP) for herbal medicines 213
(present document). 214
215
WHO has also updated two key technical guiding documents: 216
217
WHO guidelines on good manufacturing practices (GMP) for herbal medicines (published 218
in 2007) [WHO, 2007a]; and 219
Quality control methods for herbal materials (published in 2011) [WHO, 2011], which 220
includes the WHO good practices for pharmaceutical quality control laboratories as an 221
annex. 222
223
GACP for medicinal plants are only the first step in quality assurance. The next important 224
phase involves the GHPP of herbal materials. The processed materials are herbal materials or 225
herbal preparations, which may be used as a starting source material for the GMP production 226
of finished herbal products, or directly employed as herbal medicines in various herbal dosage 227
forms. For this reason, GHPP for herbal medicines is integrally linked to GACP for 228
medicinal plants and GMP for herbal medicines in the quality assurance and control of herbal 229
medicines. 230
231
The present guidelines are intended to complement, and should be read in conjunction with, 232
those guidelines provided in WHO guidelines on GACP for medicinal plants [WHO, 2003a] 233
and WHO guidelines on GMP for herbal medicines [WHO, 2007b]. Altogether, the present 234
guidelines plus the above-mentioned three new and two updated WHO guidelines form the 235
core technical guidance for the overall quality assurance and control of herbal medicines. 236
237
1.2 Scope 238 239
Processing refers to the unique procedures of preparing herbal materials and herbal 240
preparations for therapeutic applications. The process concerns not only ensuring the quality 241
of the herbal materials and preparations produced, but also their safety and efficacy in clinical 242
settings. 243
244
These guidelines will provide technical guidance on good processing practices in the: 245
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(1) processing of herbs into herbal materials; 246
(2) processing of herbal materials into herbal preparations; and 247
(3) processing of herbal materials or herbal preparations into herbal dosage forms. 248
249
In the case of processing herbs into herbal materials, three major categories of processing are 250
involved, namely, the “primary”, “secondary” and “special” processes. In the case of 251
processing of herbal materials into herbal preparations, as well as processing herbal materials 252
or herbal preparations into herbal dosage forms, the processing procedures involve the good 253
practice preparation or GMP production. 254
255
An outline of the major processes and examples of procedures are given below. 256
257
1.2.1 Processing of herbs into herbal materials 258
259 Primary processing encompasses the immediate post-harvest treatments accorded to herbs 260
obtained from cultivation or by wild crafting or field collection intended to free them from 261
foreign matters and other contaminants, and includes, for example, the procedures of garbling 262
(sorting), washing, and drying. For herbal materials that are used without further processing, 263
the primary processing may also include cutting, sectioning, and comminution. 264
265
Secondary processing is the next step concerned with converting the primary processed herbs 266
into herbal materials by various additional procedures, including, for example, 267
aging/sweating; baking/roasting; boiling/steaming; and stir-frying. 268
269
Special processing is an extension of the secondary process, which employs a specialized 270
method to treat selected herbs to reduce their toxicity or to alter and modify their therapeutic 271
activity. Examples of herbs so processed include Aconitum and Euphorbia species. 272
273
1.2.2 Processing of herbal materials into herbal preparations 274
275 The herbal materials described above may serve as crude materials for use as herbal 276
medicines. But in many cases, the herbal materials will undergo further treatment procedures 277
before being used to manufacture the finished herbal products. The active ingredients are 278
usually not purified but rather are obtained along with other components of the medicinal 279
plant part. Sometimes the active ingredients are further concentrated by the removal of 280
inactive and/or undesirable substances. The herbal preparations thus obtained include 281
extracts, decoctions, tinctures, essential oils, and others. The processes involved include 282
extraction, distillation, fractionation, purification, concentration, fermentation, or other 283
chemical/biological methods. 284
285
1.2.3 Processing of herbal materials or herbal preparations into herbal dosage forms 286
287 Depending on the intended use, herbal materials and herbal preparations could be regarded as 288
intermediates in the process of producing finished products or as final dosage forms for 289
clinical applications. In the latter case, it is not uncommon that simple dosage forms are 290
prepared from either herbal materials (such as ground powders of raw herbs) or herbal 291
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preparations (such as dried extracts) ready for administration to the patients. These herbal 292
dosage forms include fluidextract, decoction, tea bags, granules and syrups, among others. 293
294
1.3 Objectives of guidelines 295
296 These new guidelines will provide technical guidance on good herbal processing practices 297
(GHPP) for the production of herbal materials and herbal preparations. Under the overall 298
context of quality assurance and control of herbal medicines, the main objectives of this 299
guidelines are to: 300
301
provide general and specific technical guidance on GHPP for herbal medicines; 302
provide technical information on general as well as specific good herbal processing 303
techniques and procedures applied for the preparation of herbal materials from 304
herbs/medicinal plant; 305
provide technical information on good herbal processing techniques and procedures 306
applied for the production of herbal preparations from herbal materials; 307
provide technical information on good herbal processing techniques and procedures 308
applied for the production of dosage forms of herbal medicines; 309
provide a model for the formulation of national and/or regional good herbal processing 310
practice guidelines and monographs for herbal materials, as well as for herbal 311
preparations, and related standard operating procedures (SOP); and 312
contribute to the quality assurance and control of herbal materials, herbal preparations and 313
herbal dosage forms, and to promote safety, efficacy and sustainability of herbal 314
medicines. 315
316
This guidelines should be considered in conjunction with the existing documents and 317
publications relating to the quality assurance of herbal medicines and medicinal plants (for 318
details, see Bibliography), for example: 319
320
WHO guidelines on good agricultural and collection practices (GACP) for medicinal 321
plants [WHO, 2003a]; 322
WHO guidelines on assessing quality of herbal medicines with reference to contaminants 323
and residues [WHO, 2007b]; 324
WHO guidelines for selection of substances of herbal origin for quality control of herbal 325
medicines [in preparation, WHO, 2017]; 326
WHO guidelines on good manufacturing practices (GMP) for herbal medicines [WHO, 327
2007a]; 328
Quality control methods for herbal materials [WHO, 2011]; 329
WHO monographs on selected medicinal plants, Vol. 1-4 [WHOM-1999, WHOM-2002, 330
WHOM-2007, WHOM-2009]; 331
WHO monographs on selected medicinal plants commonly used in the Newly Independent 332
States (NIS) [WHOM-2010]; and 333
General guidelines for methodologies on research and evaluation of traditional medicine 334
[WHO, 2000]. 335
336
The WHO guidelines on good herbal processing practices (GHPP) for herbal medicines is 337
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one of a series of guidance documents concerned with control measures necessary to produce 338
quality herbal medicines for safe and efficacious use. The present document concerns the 339
assurance of the quality of the herbal materials being prepared through various “processing” 340
of the medicinal plant and its part materials obtained under GACP; and of the herbal 341
preparations being prepared through various “processing” of the herbal materials. Herbal 342
materials can be used directly as herbal medicines or to serve as source materials for the GMP 343
production of finished products. These guidelines are applicable to the processing operations 344
from post-harvest to finished medicinal forms. The processing of medicinal plants or plant 345
parts should meet all applicable national and/or regional quality standards. The guidelines 346
therefore may need to be adjusted according to each Member State’s situation. Each Member 347
State should develop its own national guidelines on good herbal processing practices for 348
herbal medicines that are appropriate to the country’s actual situation. 349
350
1.4 Glossary/definitions of terms 351
352 The terms used in these guidelines are defined below. The terms and their definitions have 353
been selected and adapted from other WHO documents and guidelines that are widely used by 354
WHO Member States, as well as from other reference sources (reference source is indicated 355
with [ ]). These definitions may differ from those included in national regulations, and are 356
therefore, for reference only. 357
358
1.4.1 Terms relating to herbal medicines 359 360
Herbal medicines include herbs and/or herbal materials and/or herbal preparations and/or 361
finished herbal products in a form suitable for administration for patients. [WHO, 2017, in 362
preparation] 363
Note: In some countries herbal medicines may contain, by tradition, natural organic or 364
inorganic active ingredients that are not of plant origin (e.g. animal and mineral 365
materials). [WHO, 2017, in preparation] 366
367
Herbs [WHO, 2017, in preparation] 368
Herbs are crude plant material which may be entire, fragmented or powdered. Herbs 369
include, e.g. the entire aerial part, leaves, flowers, fruits, seeds, roots, barks (stem or 370
root) of trees, tubers, rhizomes or other plant parts. 371
372
Herbal materials [WHO, 2017, in preparation] 373
Herbal materials include, in addition to herbs, other crude plant materials. These other 374
plant materials can be, e.g. gums, resins, balsams, exudates, and other such 375
matters. Herbal materials may also be referred to as “medicinal plant materials”. 376
377
Herbal preparations [WHO, 2017, in preparation] 378
Herbal preparations are produced from herbal materials by physical or biological 379
processes. These processes may be extraction (with water, alcohol, supercritical CO2), 380
fractionation, purification, concentration, fermentation, and other processes. They 381
also include preparations made by processing herbal materials with a natural vehicle 382
or steeping or heating them in alcoholic beverages and/or honey, or in other materials. 383
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Herbal preparations include simply comminuted (fragmented) or powdered herbal 384
materials as well as extracts, tinctures, fatty (fixed) or essential oils, expressed plant 385
juices, decocts, cold and hot infusions, among others. 386
387
Finished herbal products [WHO, 2017, in preparation] 388
Finished herbal products consist of one or more herbal preparations made from one or 389
more herbs (i.e. from different herbal preparations made of the same plant as well as 390
herbal preparations from different plants. Products contained different plant materials 391
are called “mixture herbal products”). 392
393
Finished herbal products and mixture herbal products may contain excipients in 394
addition to the active ingredients. However, finished products or mixture herbal 395
products to which chemically defined active substances have been added, including 396
synthetic compounds and/or isolated constituents from herbal materials, are not 397
considered to be “herbal”. 398
399
Herbal dosage forms 400 Herbal dosage forms are herbal products in the forms in which they are marketed for use or 401
taken by the patient, the production of which typically involve simple preparation procedures 402
using herbal materials (such as packing dried root or leaf powders into capsules or herbal tea 403
bags) or herbal preparations (such as grinding freeze-dried extracts into powders). The herbal 404
dosage forms may contain substances originated from a single herb or a combination of herbs. 405
406
Medicinal plants are plants (wild or cultivated) used for medicinal purposes [WHO, 2003a]; 407
[WHO, 2007a]. 408
409
Medicinal plant materials: see Herbal materials 410
411
1.4.2 Terms related to herbal processing practices 412 413
Processing 414 The processing of herbal materials refers to a series of post-harvest treatments applied to the 415
crude medicinal plant materials. For the purpose of the present guidelines, “processing” 416
includes primary processing, such as sorting, cleaning, and drying as described in the WHO 417
guidelines on GACP for medicinal plants [WHO, 2003a]; it also includes secondary, special, 418
and other processing as defined in the present guidelines. 419
420
Primary processing 421 Primary processing refers to a series of simple preparatory procedures that may be performed 422
at the harvest/collection site, including sorting, garbling, cleaning, and drying. For herbal 423
materials that do not require further processing prior to use as decoction materials or as 424
starting materials for manufacturing of finished products, the primary process may also 425
include cutting, sectioning, or comminution. 426
427
Secondary processing 428 Secondary processing refers to the preparative steps applied to herbs in addition to the 429
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primary processing before they can be used as direct decocting materials for immediate 430
therapeutic treatment or as starting materials for manufacturing of finished products. They 431
are considered important pharmaceutical techniques in the herbal industry, through which, 432
purity of raw herbs is assured (such as removal of foreign matters, prevention of microbial 433
and insect infection/infestation), the therapeutic properties of raw herbs are improved (such as 434
enhancement of efficacy or reduction of toxicity) for clinical applications. The secondary 435
processing procedures may vary from one herbal material to another, depending on the 436
characters of the active ingredients as well as the therapeutic target. These processes are 437
referred to as “specific processing” in the WHO guidelines on GACP for medicinal plants 438
[WHO, 2003a]. 439
440
Special processing 441 Special processing is an extension of the secondary processing in which a set of prescribed 442
procedures is employed to treat a particular herbal material for specific purposes such as 443
detoxification or ensuring clinical effects of that herbal material or resulting herbal 444
preparation. The special processing procedures vary from one herbal material to another, 445
depending on the characters of the active ingredients as well as the therapeutic target intended 446
to be treated. 447
448
Adjuvants 449 Adjuvants are adjunctive substances used during the herbal processing procedures alongside 450
the herbal materials, included for the purpose of altering the pharmacological/therapeutic 451
properties of the herbal preparations or neutralizing/reducing toxicity. Common adjuvants 452
include wine, vinegar, honey, milk and others. 453
454
1.4.3 Terms relating to herbal preparations 455
456
Extraction 457 Extraction is a separation process in which medicinally significant portions of plant chemical 458
constituents and tissues are removed from other plant metabolites and the insoluble cellular 459
marc by using selective solvent(s) (which is sometimes called the menstruum). Herbal 460
extracts include decoctions, infusions, fluidextracts, tinctures, and powdered extracts. The 461
herbal preparation so obtained may be ready for use as a medicinal agent, or it may be further 462
processed to afford finished products such as tablets and capsules. 463
464
Extract 465 Extract is a general description of the concentrated preparation of herbal materials obtained by 466
dissolving the active constituents in a suitable solvent and subsequent evaporation of all or 467
nearly all of the solvent. If the extract is completely freed from the solvent (dried) and 468
obtained either as fine or granular powder, it is called a Powdered Extract. 469
470
Decoction 471 Decoction is a liquid preparation made by boiling herbal materials with water. This is 472
probably the most common method of preparing herbal drugs in many traditional medicine 473
systems. 474
475
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Infusion 476 Infusion is a liquid preparation made by extracting herbal materials with either cold or hot 477
water without boiling. Other solvents such as edible oil or vinegar may be used. 478
479
Fluidextract 480 Fluidextract is a liquid preparation from herbal materials made by maceration or percolation 481
in alcohol or wine. Typically, a fluidextract is made in such a ratio that one part (e.g. one 482
millilitre) of the liquid contains one part (e.g. one gram) of the original herbal materials. 483
484
Tincture 485 Tincture is a dilute alcoholic extract of herbal materials, typically made up of 1 part of herbal 486
material and 5-10 parts of solvent. 487
488
Powder 489 Powder is a form of herbal preparation processed as dry, granulated, or powdered materials. 490
Extracts, tinctures or other liquid preparations can be evaporated to dryness to obtain the 491
powders. 492
493
Essential (volatile) oil 494 Essential (volatile) oil constitutes the odorous principles of the plant from which it is 495
extracted. Each essential oil has its own characteristic colour, odour, and taste. 496
497
1.4.4 Terms relating to quality control 498
499 For a comprehensive list of terms on quality control of herbal medicines, please refer to the 500
Quality control methods for herbal materials [WHO, 2011], WHO guidelines for selection of 501
substances of herbal origin for quality control of herbal medicines [WHO, 2017], and WHO 502
guidelines on GMP for herbal medicines [WHO, 2007a]. The following terms are more 503
directly or indirectly applicable to the present guidelines than others. 504
505
Batch (or lot) [WHO, 2007a – WHO, 2003b]; [WHO, 2014] 506
A defined quantity of starting material, packaging material or product processed in a single 507
process or series of processes so that it is expected to be homogeneous. It may sometimes be 508
necessary to divide a batch into a number of sub-batches which are later brought together to 509
form a final homogeneous batch. In the case of terminal sterilization the batch size is 510
determined by the capacity of the autoclave. In continuous manufacture the batch must 511
correspond to a defined fraction of the production, characterized by its intended homogeneity. 512
The batch size can be defined either as a fixed quantity or as the amount produced in a fixed 513
time interval. 514
515
Batch number (or lot number) [WHO, 2007a – WHO, 2003b]; [WHO, 2014] 516
A distinctive combination of numbers and/or letters which uniquely identifies a batch on the 517
labels, its batch records and corresponding certificates of analysis, etc. 518
519
Contamination [WHO, 2007a – WHO, 2003b]; [WHO, 2014] 520
The undesired introduction of impurities of a chemical or microbiological nature, or of 521
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foreign matter, into or on to a starting material or intermediate during production, sampling, 522
packaging or repackaging, storage or transport. 523
524
Cross-contamination [WHO, 2007a- WHO, 2003b]; [WHO, 2014] 525
Contamination of a starting material, intermediate product or finished product with another 526
starting material or product during production. 527
528
Good manufacturing practice (GMP) [WHO, 2014] 529
GMP is that part of quality management which ensures that products are consistently 530
produced and controlled according to the quality standards appropriate to their intended use 531
and as required by the marketing authorization, clinical trial authorization or product 532
specification. GMP is concerned with both production and quality control. GMP is aimed 533
primarily at managing and minimizing the risks inherent in pharmaceutical manufacture to 534
ensure the quality, safety and efficacy of products. 535
536
In-process control [WHO, 2007a – WHO, 2003b]; [WHO, 2014] 537
Checks performed during production in order to monitor and, if necessary, to adjust the 538
process to ensure that the product conforms to its specifications. The control of the 539
environment or equipment may also be regarded as a part of in-process control. 540
541
Master formula [WHO, 2007a – WHO, 2003b];[WHO, 2014] 542
A document or set of documents specifying the starting materials with their quantities and the 543
packaging materials, together with a description of the procedures and precautions required to 544
produce a specified quantity of a finished product as well as the processing instructions, 545
including the in-process controls. 546
547
Chemical reference substance (or standard) [WHO, 2007c] 548
An authenticated, uniform material that is intended for use in specified chemical and physical 549
tests, in which its properties are compared with those of the product under examination, and 550
which possesses a degree of purity adequate for its intended use. 551
552
Specification [WHO, 2007a – WHO, 2003b]; [WHO, 2014] 553
A list of defined requirements with which the products or materials used or obtained during 554
manufacture have to conform. They serve as a basis for quality evaluation. 555
556
Standard operating procedure (SOP) [WHO, 2007a – WHO, 2003b]; [WHO, 2014] 557
An authorized written procedure giving instructions for performing operations not necessarily 558
specific to a given product or material (e.g. equipment operation, maintenance and cleaning; 559
validation; cleaning of premises and environmental control; sampling and inspection). 560
Certain SOPs may be used to supplement product-specific master and batch production 561
documentation. 562
563
2. GOOD HERBAL PROCESSING PRACTICES FOR THE PRODUCTION OF 564
HERBAL MATERIALS 565
566
2.1 General information 567
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568 “Processing” is a unique process in the preparation of herbal materials from medicinal plant 569
and plant parts and has been practiced as a material specific procedure. Historically, this 570
process is as old as that of the use of medicinal plants for the alleviation of human ailments. 571
572
When the medicinal plant and its parts are obtained through wild collection or cultivation 573
under GACP for medicinal plants [WHO, 2003a], they must be subjected to a series of good 574
practice of post-harvest processing procedures in order to ensure the maximum safety, 575
efficacy and desired therapeutic outcome. The exact processing procedures may vary from 576
one herbal material to another. Some consist of only a few simple steps such as sorting, 577
cleaning and drying, and they are generally referred to as the “primary processing”. For 578
herbal materials that are used without further processing, the primary processing may include 579
cutting, sectioning, and comminution, etc. Others may require some more complicated steps 580
such as aging/sweating, baking/roasting, boiling/steaming, and stir-frying, for the purpose of 581
improving the purity, preventing damage from mould and other microorganisms, detoxifying 582
indigenous toxic ingredients, or enhancing therapeutic efficacy. Such processing procedures 583
are referred to as the “secondary process” in these guidelines. They may have a significant 584
impact on the quality of the resulting herbal materials. 585
586
Special processing is an extension of the secondary process, in which a series of special 587
treatment procedures are applied to the herbs for specific purposes such as reduction of 588
toxicity or alteration/modification of therapeutic properties. Examples of herbs (medicinal 589
plants) so processed include Aconitum and Euphorbia species. 590
591 The safety and efficacy of herbal medicines are intricately dependent on the quality of the 592
starting and processed source materials. To assure their quality, the good practices for 593
processing herbal materials may be considered. In general, good practices for processing 594
herbal materials mirror the good manufacturing practices for herbal medicine as delineated in 595
the WHO guidelines on GMP for herbal medicines [WHO, 2007a], with the first step being 596
the post-harvest handling and preparation of the starting medicinal plant materials under 597
sanitary conditions. All critical equipment for processing must be qualified; all processing 598
methods and procedures are standardized (SOP); master formulae, master and batch records 599
documented; and quality control parameters established and adhered to. GHPP 600
monograph/SOP protocol on specific herbal material should be developed and implemented. 601
602
2.2 Purposes and functions of processing 603
604 Through experiences gained over the centuries, knowledge has been acquired for the 605
development of processing procedures for maximizing the quality and therapeutic value of 606
herbal materials. The final form a herbal medicines takes depends upon the nature of the herb 607
and the nature of the disease to be treated. In general, the processing of herbal materials 608
serves several purposes, such as to improve bioavailability of active components, reducing 609
toxicity and/or side effects, enhancing potency and effectiveness, modifying the therapeutic 610
properties, facilitating storage, and eliminating other undesirable properties. Thus, the major 611
purposes of the processing for herbal materials are: 612
613
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Neutralization of toxicity and diminishing side effects 614 Herbal materials that possess significant levels of toxicity, highly potent pharmacological 615
actions, or severe side effects must be pre-treated in certain specific manners in order to 616
neutralize the toxicity or to reduce the side effects prior to use. Such a detoxifying process is 617
particularly important for those medicinal plants that are known to contain toxic or 618
undesirable chemical components; they must be properly “cured” to remove those unwanted 619
substances. Through the pre-treatment processes such as “steaming” and “frying”, the heat-620
sensitive toxic components will be degraded. In other cases, processes such as “sweating” 621
and “aging” would result in enzymatic degradation of the toxic ingredients. For example, raw 622
aconite (Aconitum species) tuber, containing significant amounts of toxic alkaloids such as 623
aconitine, must be boiled or steamed for hours to hydrolyse aconitine into less toxic 624
derivatives. In the case of cascara (Rhamnus purshiana) bark, they have to be aged for at 625
least one year before use, to allow oxidation reaction to occur, by which the strongly laxative 626
hydroxyanthracene glycosides are converted to oxidized compounds of lower laxative 627
potencies. 628
629
Modification of therapeutic properties 630 Some herbal materials require specific processing to alter their therapeutic properties. For 631
example, rhubarb (Rheum rhabarbarum) in its raw form possesses purgative action and is 632
useful as a cathartic. After processing, however, the purgative action is attenuated and the 633
processed rhubarb can be used for other purposes such as anti-inflammation. 634
635
The specific action of some herbal materials may be reinforced through processing. For 636
example, the unprocessed raw rehmannia (Rehmannia glutinosa) root is used to treat fever, 637
hypertension and skin eruptions; whereas after being cooked in wine, the processed 638
rehmannia is often used for tonic, emmenagogue and anti-aging purposes. 639
640
In the case of ginseng (Panax ginseng) roots, different post-harvest processing procedures 641
give rise to several processed products, such as "white ginseng" and "red ginseng". "White 642
ginseng" is the material dried by the sun or heat, whereas “red ginseng” is made through a 643
series of steaming and cooking steps. These two types of ginseng products have been shown 644
to exert opposite pharmacological actions on human blood pressure, among other differing 645
therapeutic effects. 646
647
Enhancing efficacy and reinforcing therapeutic effects 648 The therapeutic efficacy of certain herbal materials can be augmented through specific 649
methods of preparation. For instance, the pain-relieving property of corydalis (Corydalis 650
yanhusuo) rhizomes is increased when they are stir-fried with rice vinegar. Similarly the 651
honey-treated ephedra (Ephedra species) would possess stronger antitussive and anti-asthma 652
properties than the unprocessed ephedra, which is mostly used as a diaphoretic. 653
654
2.3 Processing techniques and procedures 655
656 Appropriate measures of general processing are dependent on the individual materials. These 657
processes should be carried out in conformity with national and/or regional quality standards, 658
regulations and norms. These protocols should also comply with the regulatory requirements 659
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that apply in the producer and the purchaser countries. The SOP of processing should 660
describe in detail the various operations to be performed on the medicinal plant material, such 661
as sorting, washing, drying, crushing, milling, pulverization and sifting. They should also 662
include the length of time and temperature, among others. As much as possible, the SOP 663
should be adhered to. If modifications are made, they should be justified by adequate test data 664
demonstrating that the quality of the herbal materials is enhanced and/or not compromised. 665
666
2.3.1 Preparation of harvested/collected medicinal plant part for processing 667
668 Prior to general or special processing, the starting raw medicinal plant materials should be 669
inspected and sorted in order to ensure there is no contamination or cross-contamination by 670
untargeted plants, unwanted plant parts, foreign matters, and obvious damages. 671
672
Harvested or collected raw medicinal plant materials should be promptly unpacked upon 673
arrival at the processing facility. Prior to processing, they should be protected from rain, 674
excessive sunlight, moisture and any other conditions that might cause microbial fermentation 675
and thermal degradation. The unprocessed raw medicinal plant materials should be stored in 676
appropriate containers at ambient or lower temperature under well ventilated conditions; as 677
well as protected from insects, rodents, birds, livestock, domestic animals, and other pests. 678
679
Consistent quality for the finished herbal products can only be assured if the starting raw 680
medicinal plant materials are defined in a rigorous and detailed manner. For this reason, the 681
crude/raw medicinal plant materials must be adequately documented prior to the processing 682
procedures to include, as far as possible and at a minimum, the following information; 683
684
Botanical name of the medicinal plant; local name; plant part(s); 685
Source (cultivation/wild growing region); 686
Batch (or lot) number; 687
Collection (harvest) conditions (e.g. season/month and date; plant part; wet/dry 688
environment); 689
Botanical authentication of the source medicinal plant materials; 690
Physical appearance such as colour, odour, form, sharp, size and texture; 691
Suitable identification tests such as TLC or other chromatographic fingerprints; 692
Assay results, where appropriate, of active ingredient(s) or Chemical reference 693
standard(s); 694
Limit tests such as ash value, water content, and extractives; and 695
Determination of possible contaminants such as pesticides and heavy metals, mycotoxins 696
and where and when appropriate, radioactivity. 697
698
2.3.2 Primary processing procedures 699
700 Harvested/collected medicinal plants and/or their parts undergo a series of good practice post-701
harvest (and post-collection) processing procedures, which in the broadest sense include all 702
steps from the immediate on-site primary clean-up of the desired medicinal plant part to its 703
being processed into a form (herbal materials) ready for therapeutic use or as a starting source 704
material for the production of a finished herbal products. While the exact processing methods 705
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may differ from one herbal material to another, the procedures shall be adopted from those 706
good practice protocols specified in the national pharmacopoeia or recommended by other 707
authoritative documents of the end-user’s country. In the event that no acceptable good 708
processing procedures are available, or that modification of existing or reference cited 709
protocols are required, they should be justified by adequate quality control test data that the 710
efficacy of the herbal material is not diminished. In the absence of national/regional 711
procedures or protocols, international guidelines, such as WHO guidelines on GACP for 712
medicinal plants [WHO, 2003a], and the present guidelines, may be consulted. 713
714
Garbling (Sorting) 715
The garbling process serves as the first step to ensure the purity and cleanness of the 716
medicinal plant materials. After the bulk amount of the desired plant part is harvested or 717
collected, all extraneous and unwanted matters including dirt (e.g. soil, dust, mud, rubbles), 718
impurities (e.g. insects, rotten tissues), and residual non-medicinal parts must be separated 719
from the medicinal part(s). The process may involve, depending on the plant material, 720
procedures such as removing dirt and foreign substances, discarding damaged parts, peeling 721
(to separate unwanted plant parts from the medicinal plant parts such as removing unwanted 722
root bark from the roots or collecting stem bark from the stem), sieving, trimming, singeing 723
(to remove hairs or rootlets), removal of residuals of unwanted plant parts (e.g. removing 724
unwanted seeds from fruits and stripping leaves from stems). Although sorting may be done 725
by mechanical means in some cases, it is usually performed by hand operation. Only suitably 726
trained staff should carry out this work. 727
728
Washing 729
After sorting, the medicinal plant materials should be cleaned well to remove remaining soil, 730
dirt, dust, and other unwanted matters from the surface. They, especially roots, rhizomes and 731
tubers, are commonly washed with clean water, dried soon after harvest/collection. During 732
the washing process, scraping and brushing may be necessary. It is generally recommended 733
not to soak the medicinal plant materials in water for an unnecessarily long period of time. 734
Change water frequently as required. 735
736
Parboiling (Blanching) 737
After washing, certain raw medicinal plant materials may undergo a parboiling or blanching 738
process in which they are put into boiling water for a brief period of time without being fully 739
cooked. Such a heating procedure may serve several purposes, such as improving storage life 740
of the processed materials by gelatinizing the starch and preventing mould/insect 741
contamination, and facilitating further processing such as removal of the seed coat of 742
almonds. 743
744
Leaching 745
Some impurities can be removed by the action of running water over the raw medicinal plant 746
materials. The length of leaching has to be controlled in order to prevent excessive loss of 747
other ingredients. 748
749
Drying 750
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Unless used in the fresh state, the raw medicinal plant materials are to be dried after being 751
sorted and washed. In general, they must be dried as soon as possible to remove as much 752
moisture as possible in order to ensure good keeping qualities and to reduce damage from 753
mould and other microbial infestation. Drying will also avoid tissue deterioration and 754
phytochemical alteration caused by the actions of enzymes and microbial organisms; and will 755
also facilitate grinding and milling, and convert the herbal materials into a convenient form 756
for further processing. 757
758
The final moisture content for dried herbal materials varies depending on the tissue structure, 759
but should generally be below 12%. Information on the appropriate moisture content for 760
particular herbal material may be available from pharmacopoeias or other authoritative 761
monographs. 762
763
Proper drying involves three major aspects: control of temperature, humidity and air flow. 764
The drying conditions are determined by the nature of the raw medicinal plant material to be 765
dried (tissue structure and chemical composition) and by the desired appearance of the final 766
form. The drying method used may have considerable impact on the quality of the resulting 767
herbal materials. Hence, the choice of proper operational procedure is crucial. Information 768
on the appropriate drying methods and procedures for particular herbal materials may be 769
available from pharmacopoeias or other authoritative monographs. In general, raw medicinal 770
plant materials are most often dried by sun-drying, shade-drying, or by artificial heat. 771
772
The drying conditions chosen should be appropriate to the type of the medicinal plant 773
material. They are dependent on the character (e.g. volatility, stability) of the active 774
ingredients and the texture of the plant part collected (e.g. root, leaf or flower). In general, the 775
following drying processes can be adapted.; 776
777
Sun-drying 778
Most medicinal plant materials can be dried in open-air under direct sunshine, provided the 779
climate is suitable for such a practice. The duration of the drying process depends largely on 780
the physical structure of the medicinal plant material and the weather condition. 781
782
In the case of natural drying in the open air, medicinal plant materials should be spread out in 783
thin layers on drying frames and kept away from possible contaminations such as vehicle 784
exhaust, heavy dusts, and rain, as well as protected from insects, rodents, birds and other 785
pests, livestock and domestic animals. The drying frames should be located at a sufficient 786
height above the ground. Efforts should be made to achieve uniform drying within the 787
shortest period of time to avoid mould formation. 788
789
Shade-drying 790
Some medicinal plant materials can be dried in the shade with or without artificial air flow to 791
avoid direct exposure to strong sunlight. The drying process is slow, but it is preferred to 792
maintain (or minimize loss of) colour of leaves and flowers. Low temperatures (relative to 793
heat-drying) will also preserve most of the volatile and aromatic components from being 794
evaporated. 795
796
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Drying by artificial heat 797
Drying by artificial heat is more rapid than open-air drying and is often necessary on rainy 798
days or in regions where the humidity is high. Medicinal plant materials may be dried by 799
means of ovens, stoves, belt driers, other heating devices or with open fires. 800
801
For artificial-heat drying, the temperature, humidity and other conditions should be governed 802
by the physical nature of the drug and the physical/chemical properties of its active 803
ingredients. Over-heating may lead to an excessive loss of the volatile components and/or 804
decomposition of chemical ingredients. As much as possible, the temperature should be kept 805
below 60 °C. 806
807
2.3.3 Secondary processing procedures 808
809 In addition to the primary processing, the WHO guidelines on GACP for medicinal plants 810
[WHO, 2003a] also addressed, albeit very briefly, the fact that some herbal materials require 811
“specific” processing to improve their purity and quality. This section highlights the 812
principles and practice of the commonly used secondary processing techniques. In all cases, 813
good in-process control measures must be employed to assure the quality of the end product. 814
Nationally established botanical and chemical quality standards for each processed herbal 815
material must be met. In absence of national standards, regional or international 816
pharmacopoeial standards may be adopted. Guidance for compliance measures can be found 817
in the annex to the Quality control methods for herbal materials [WHO, 2011], WHO 818
guidelines for selection of substances of herbal origin for quality control of herbal medicines 819
[WHO, 2017], WHO guidelines on GMP for herbal medicines [WHO, 2007a], and the present 820
guidelines. An example of a model format of good herbal processing practices 821
monograph/SPO protocol on secondary processing is given as Annex 1. 822
823
The applicable procedures of the secondary processing nature are as follows: 824
825
Cutting, sectioning, and comminution 826
When thoroughly dried, the herbal materials are processed by cutting and sectioning into 827
convenient sizes and shapes for storage, direct use as decoction pieces, and/or further 828
processed for the manufacture of finished herbal products. Where applicable, the herbal 829
materials should be cut or sectioned into specific shapes or forms, or comminuted/pulverized 830
into powder form according to common practice found in herbal medicines. 831
832
Decoction slices or pieces available in many Member States for use as herbal medicines are 833
herbal materials processed only by cutting, sectioning, slicing or comminution/pulverization. 834
White ginseng products presented as root pieces or in powder form prepared from naturally 835
dried roots of Panax ginseng, marketed as herbal medicines, are good examples of herbal 836
materials derived from a simple processing procedure. 837
838
Aging/Sweating 839
The aging process refers to storing the herbal materials for a period of time after being 840
harvested or collected from the field prior to use. It is generally done under the sun or in the 841
shade for up to a year, depending on the specific herbal material. During the process of aging, 842
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excessive water is evaporated and enzymatic reactions (such as hydrolysis of the glycone 843
portion from glycosides) may occur to alter the chemical composition of the herbal material. 844
For example, cascara sagrada (Rhamnus purshiana) bark should be aged for at least one year 845
(or artificially heated to speed up the process) prior to use in medicinal preparations, for the 846
purpose of curtailing the strong irritating effects that may cause vomiting and upset stomach. 847
848
A similar process known as sweating involves keeping the herbal materials at a temperature 849
of 45-65 °C with high humidity for an extended period of time, from one week to a couple of 850
months, depending on the plant species. The herbal materials are usually densely stacked 851
between woollen blankets or other kinds of cloth. The sweating process is considered a 852
hydrolytic and oxidative process in which some of the chemical ingredients within the herbal 853
materials are hydrolysed and/or oxidized. 854
855
For example, vanilla beans (Vanilla planifolia) are well known to undergo repeated sweating 856
between woollen blankets in the sun during the day and packing in wool-covered boxes at 857
night for about two months, during which the vanilla pods lose up to 80% of weight and take 858
on the characteristic colour and odour of the commercial drug. 859
860
Baking/Roasting 861
The baking/roasting process is a dry-heating procedure using indirect, diffused heat, where 862
the herbal materials are put in a heating device, often embedded in bran or magnesium silicate 863
(talc) powder to ensure even heating on the entire surface at an elevated temperature for a 864
period of time. Some herbal materials are wrapped in moistened papers during the roasting 865
process. The exact temperature used and duration of baking/roasting vary from one herbal 866
material to another. Some are baked or roasted until the surface colour turns yellowish 867
brown; some may be further heated until charred. 868
869
For example, the processing procedure of nutmeg (Myristica fragrans) and kudzu (Pueraria 870
lobata) root requires being roasted together with bran. 871
872
Boiling/Steaming 873
The boiling process involves cooking the plant materials in water or another liquid solvent 874
such as vinegar, wine, milk or animal urine. 875
876
In the steaming process, herbal materials are kept separate from the boiling water but have 877
direct contact with the steam, resulting in a moist texture to the herbal materials. Such 878
treatment is often done by placing the herbal materials in a steamer or in a special utensil 879
equipped with a flat frame hanging over boiling water. In some cases, the herbal materials are 880
pre-mixed with excipient substances such as wine, brine, or vinegar before being steamed. 881
The boiling/steaming process serves to soften plant tissues, to denature enzymes present in the 882
herbal materials, and/or to thermally degrade selected chemical constituents. At the same 883
time, the excipient, if used, is absorbed into the plant tissues to become an integral part of the 884
processed herbal materials. 885
886
For example, Polygonum multiforum root is often steamed in the presence of a black-bean 887
decoction in order to enhance its tonic effects. Boiling the rhizome of Acorus calamus in 888
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cow’s urine can enhance its anti-convulsant activity. On the other hand, boiling the raw 889
materials such as Croton tiglium, Abrus precatorius, Nerium indicum, Gloriosa superba, and 890
Semecarpus anacardium in cow’s milk would reduce the levels of their toxic ingredients and 891
thus diminish the toxicity of the herbal materials. 892
893
Stir-frying 894
Stir-frying is a process in which the herbal materials are put in a pot or frying pan, 895
continuously stirred or tossed for a period of time under heating, until the external colour 896
changes, charred, or even carbonized. Depending on the medicinal plant species, the stir-897
drying process may require the addition of adjuvants such as wine, vinegar, honey, saline, and 898
ginger juice, which would be infused into the herbal matrix to become an integral part of the 899
processed herbal material. 900
901
To ensure even heating on the surface of the herbal materials, sand, rice, bran, talc or clay can 902
be admixed with the herbal material during stir-frying. 903
904
For example, liquorice (Glycyrrhiza glabra) root and rhizome and Astragalus 905
membranaceous roots are often stir-fried with honey for the preparation of decoction slides, 906
whereas the Salvia miltiorrhiza root is stir-fried with wine. In the case of ginger, fresh ginger 907
is often stir-fried together with sand until the surface colour turns brown. In other instances, 908
ginger can be further stir-fried over intense fire to a carbonized state. 909
910
Fumigation 911
Fumigation by sulphur dioxide has been employed in post-harvest handling of some 912
medicinal herbs for the purpose of preserving colour, improving fresh-looking appearance, 913
bleaching, preventing the growth of insect and overcoming decays caused by moulds. Thus 914
the process has been frequently applied to herbal materials of light and bright colours to avoid 915
“browning”. Due to concerns about the undesirable residues, such process should be avoided 916
as much as possible. If the process is required, all relevant regulations (e.g. limits on sulphur 917
residue) should be compiled. 918
919
2.3.3.1 Selection of processing method 920
Herbal materials derived from the same species but processed by different methods may show 921
significant differences in quality and therapeutic property, owing to the influence of the 922
treatment process on the chemical composition. 923
924
It is not uncommon to find different processing methods for the same medicinal plant/plant 925
part, depending on intended use. For example, raw (unprocessed) liquorice is used as an 926
antitussive and expectorant; but after being stir-fried with honey and ghee, the processed 927
liquorice becomes a tonic drug to be used for replenishing body strength. 928
929
Prior to processing, consult the national or regional regulatory standards and other literature 930
sources to decide on the most appropriate method to use. Once a method is adopted, adhere to 931
the SOP to ensure batch-to-batch consistency. For industrial production, method validation 932
should be adopted as part of the SOP. 933
934
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Only suitably trained staff should carry out the work, which should be conducted in 935
accordance with the SOP and national and/or regional regulations in both the grower/collector 936
and the end-user countries. 937
938
2.3.3.2 Temperature 939
In processing procedures that involve heating, the temperature used is critical. Make sure the 940
required temperature is achieved during the process. In some cases, pre-heating the 941
equipment (e.g. oven, frying pan and steamer) and/or the additives (such as sand, bran and 942
rice) is required before putting in the herbal materials. When heating equipment (e.g. electric 943
oven) is used, the heating device should be regularly calibrated. 944
945
2.3.3.3 Duration of procedure/treatment 946
It is also critical to control the time of procedure/treatment of the herbal materials. Both over- 947
and under- treatment will affect the quality of the resulting materials. The traditional 948
approach would specify the duration of treatment on the basis of organoleptic alterations such 949
as changes in colour, odour, and texture. If a modern method or instrument is used, the timing 950
should also be accurately controlled. 951
952
2.3.3.4 Use of adjuvants 953
Any adjuvant (e.g. wine, vinegar) used in the processing procedures should be of the 954
required/appropriate quality. The exact amounts and quality of these adjuvants used (the ratio 955
of herbal material and the adjuvant) should also be consistent from batch to batch. 956
957
2.3.4 Special processing procedures 958
959 For herbal materials derived from toxic medicinal plants, general primary and/or secondary 960
processing is insufficient to reduce or attenuate their adverse effects. Such herbal materials 961
require further specific (special) processing procedures before they can be used for 962
therapeutic purpose. These special processing procedures serve as a means to detoxify or 963
neutralize the toxicity, or to reduce the side effects. Such processes are particularly important 964
for those medicinal plant parts that are known to contain toxic or undesirable chemical 965
components; they must undergo proper processes in order to have the unwanted substances 966
degraded. On the other hand, a number of herbal materials require special methods of 967
processing in order to enhance their therapeutic efficacy or to modify their therapeutic 968
properties for the treatment of other disease conditions. The following are examples of 969
special herbal material processing. 970
971
2.3.4.1 Detoxification 972
Aconite (Aconitum species) root, even after having undergone general processing, is an 973
extremely lethal substance and should not be taken in the crude form. Only after proper 974
processing procedure can the toxicity of aconite root be reduced and becomes suitable for 975
use in herbal medicine. The specific process generally involves boiling in water or 976
steaming, or both, to significantly reduce the content of aconitine and related alkaloids. 977
Nux-vomica (Strychnos nux-vomica) seeds are specifically processed by frying or boiling 978
in water or other media such as cow’s milk and ghee to reduce the contents of its toxic 979
ingredients, strychnine and brucine. 980
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Pinellia ternata tuber: To reduce the gastrointestinal irritant property, the raw herb is 981
soaked in a solution containing glycyrrhiza and calcium oxide at a pH ≥ 12. Alternatively, 982
the raw herb is soaked in water together with potassium aluminum sulphate, or boiled in 983
water together with ginger and potassium aluminum sulphate. 984
Arisaema erubescens rhizome: The raw herbal material is first soaked in water together 985
with potassium aluminum sulphate for several days, followed by cooking with ginger and 986
potassium aluminum sulphate to reduce the strong irritant effect on the respiratory and 987
gastrointestinal tracts. An alternate method for processing Arisaema rhizome is by 988
steaming with animal bile. 989
Euphorbia kansui and E. pekinensis herb: Processing by frying with vinegar to degrade 990
the toxic components that cause severe vomiting and diarrhoea, and central nervous 991
system poisoning. 992
Seeds of Xanthium sibircum, Ricinus communis and Croton tiglium are often processed by 993
stir-frying for the purpose of degrading their contained toxic proteins. 994
Cascara sagrada (Rhamnus purshiana) bark: Following primary post-harvest processing, 995
the bark is aged (stored) for at least one year prior to use as a laxative. During the aging 996
period, natural enzymatic action reduces the drastic cathartic potency of its active 997
glycoside constituents to a non-toxic level. 998
999
2.3.4.2 Enhancement or modification of therapeutic properties 1000
Ginseng (Panax ginseng and Panax quinquefolius): Fresh ginseng is converted to red 1001
ginseng through a series of repeated steaming procedures to afford a product with altered 1002
pharmacological actions or differing therapeutic effects. 1003
Corydalis yanhusuo rhizome is stir-fried or cooked with rice vinegar to enhance its pain-1004
relieving property for use as an analgesic agent. 1005
Rehmannia glutinosa root: The unprocessed herbal material is used to treat fever, 1006
hypertension and skin eruptions; whereas after being cooked in wine, the processed 1007
rehmannia is used as a tonic, emmenagogue and anti-aging drug. 1008
1009
2.3.4.3 Use of adjuvants 1010
Common adjuvants used during the special processing procedures include wine (e.g. rice 1011
wine, wheat wine, and sorghum wine), vinegar, honey, ginger juice, liquorice extract, and 1012
brine, etc. Under special circumstances, other auxiliaries such as human/cow urine, cow/goat 1013
milk, animal bile, butter, cow’s ghee, goat fat, black bean extract, and coconut water, etc. 1014
have been used. 1015
1016
The use of animal parts/products in any processing procedures should be evaluated for safety 1017
and contamination prior to use. 1018
1019
2.3.5 Documentation 1020
1021 Good documentation is an essential part of the processing procedures as set out in the Good 1022
Manufacturing Practices for Pharmaceutical Products: main principles [WHO, 2007a – 1023
WHO, 2003b]; [WHO, 2014]. Thus it is important to prepare and keep in record the details 1024
of the entire processing procedures for each batch of herbal materials. 1025
1026
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25
Written processing record should include, but not limited to, the following information; 1027
1028
Botanical (scientific) and the local/common names of the source medicinal plant material; 1029
and plant part(s) being processed; 1030
Site and time of harvesting/collection; 1031
Batch number and any other identification code; 1032
Dates of receipt of the material, processing of the material, and completion of the process; 1033
Name of person in charge of the processing; 1034
General processes that the plant material has already undergone (drying, washing, cutting, 1035
for example., including drying time and temperatures, and size of herbal material); 1036
Gross weight of the plant material before and after processing; 1037
Method used for special processing; 1038
Details of the procedures (master formula), including descriptions of the utensil and 1039
equipment used, steps of operation, amount and quality grade of the auxiliary (e.g. wine, 1040
vinegar) and/or other substances (e.g. sand, bran) used, temperature control, length of 1041
processing time, after-process steps (e.g. cooling, drying, cutting), and other relevant 1042
information; 1043
Batch production detail deviations/modifications of the master formula; 1044
In process control, e.g. organoleptic changes of the plant material after processing (such as 1045
change in colour, shape, texture, odour); and 1046
Quality control parameters and assay results, where appropriate, of active ingredient(s) or 1047
Chemical reference standard(s). 1048
1049
3. GOOD HERBAL PROCESSING PRACTICES FOR THE PRODUCTION OF 1050
HERBAL PREPARATION 1051
1052
3.1 General information 1053
1054 The herbal materials described in Section 2 of these guideline may be ready to serve as the 1055
starting materials for use as herbal medicines. In some cases, they are ground into powder 1056
and used directly as the final dosage form. But in many other cases, the herbal materials will 1057
undergo further treatment processes before being used to manufacture the finished herbal 1058
products. The active ingredients are usually not purified but rather are obtained along with 1059
other components of the medicinal plant part. Sometimes the active ingredients are further 1060
concentrated by the removal of inactive and/or undesirable substances. 1061
1062 Herbal preparations are thus obtained by subjecting the herbal materials to treatments such as 1063
extraction, distillation, fractionation, purification, concentration, fermentation, or other 1064
chemical/biological methods. These include extracts, decoctions, tinctures, essential oils, and 1065
others. 1066
1067
3.2 Extraction 1068 1069
The purpose of extraction of medicinal plant matrix is to eliminate unwanted materials and to 1070
concentrate the active constituents in a soluble form. In some cases, extraction also increases 1071
the shelf life of the product; for example, an alcoholic extract may have a longer shelf life 1072
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compared to raw herbal materials. The resulting extracts are complex mixtures of chemical 1073
substances, which may be ready for use as a medicinal agent, or they may undergo further 1074
purification to obtain the active constituent(s). The extract may also be processed into 1075
finished products such as tablets and capsules. Herbal extracts include decoctions, infusions, 1076
fluidextracts, tinctures, and powdered extracts. 1077
1078
Various techniques are used for medicinal herb extraction, including maceration, infusion, 1079
digestion, percolation, and decoction. Modern separation techniques can also be applied, e.g. 1080
counter-current extraction, microwave-assisted extraction, ultrasonic extraction (sonication), 1081
and supercritical fluid extraction. For the extraction of volatile components of the herbal 1082
materials (such as essential oils), techniques such as hydrodistillation, expression and 1083
enfleurage may be employed. 1084
1085
3.2.1 Common methods of extraction 1086
1087 In order to produce herbal preparations of defined quality, the use of appropriate extraction 1088
technology, extraction solvents, and type of equipment are crucial. Some common methods 1089
of extraction are illustrated below. 1090
1091
Maceration involves the procedures of mixing the properly comminuted herbal materials 1092
with the solvent and allowing the mixture to stand at room temperature for a defined period of 1093
time with frequent agitation. During the maceration process, chemical constituents are 1094
separated from the plant tissues through a dissolution process into the liquid solvent. A 1095
common practice is to put the herbal material in a container and add solvent until the herbal 1096
powder is thoroughly moistened. An additional amount of solvent is then introduced. The 1097
mixture is agitated occasionally for a period of one day, strained, and the marc (the solid 1098
materials) is pressed. All liquids are collected, combined, and filtered. The maceration 1099
process may be repeated if desirable. In the process of maceration, the herbal materials are 1100
macerated in definite quantities of a solvent (at an optimal ratio of the amounts of dried herbal 1101
material and solvent), and a definite period of time should be specified. Exhaustive bulk 1102
extractions can be quite time-consuming and require large volumes of solvent. 1103
1104
In a special case, a modified maceration procedure involves pre-soaking the herbal material in 1105
water for a period to time to induce fermentation. In other cases, maceration can be 1106
performed by gentle heating in order to enhance the extraction efficiency in a process known 1107
as digestion. 1108
1109
Sonication-assisted extraction and microwave-assisted extraction are modified methods of 1110
maceration, in which ultrasound or microwave is utilized to enhance the extraction efficiency, 1111
to reduce the amount of solvent used, and to shorten the extraction time. For sonication, the 1112
herbal material is placed in a container together with a solvent, which is in turn put in an 1113
ultrasonic bath. The ultrasound provides sufficient power to breakdown the cell walls of the 1114
herbal material and facilitates the solubilization of metabolites into the solvent. The 1115
frequency of ultrasound, length of treatment, and temperature of sonication are important 1116
factors affecting the extraction yield. For microwave-assisted extraction, the herbal material is 1117
placed in a container together with water and subjected to microwave treatment. Heat 1118
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generated by the microwave energy facilitates the dissolution of compounds from the herbal 1119
matrix into the solvent. Sonication-assisted and microwave-assisted extraction is rarely 1120
applied to large-scaled extraction; they are used mostly for the initial extraction of a small 1121
amount of material. 1122
1123
Infusion refers to an extraction procedure in which the herbal material is immersed in cold 1124
or hot water for a brief period of time to produce a dilute liquid preparation. Typically, the 1125
herbal material is moistened with water and allowed to stand for 15 minutes. A Sufficient 1126
quantity of cold or hot water is then added and allowed to stand for another 30 minutes or 1127
longer. The mixture is strained and ready for use. In the case of hot infusion, the herbal 1128
material is not subjected to the boiling process, although it is common to pour boiling water 1129
over it. Infusion is commonly employed to make herbal teas. 1130
1131
Percolation is the procedure in which the solvent is allowed to continuously flow through 1132
the powdered herbal material in a percolator (a cone-shaped vessel open at both ends). 1133
Typically, the properly comminuted herbal material is moistened with an appropriate amount 1134
of solvent and allowed to stand (macerate) for a few hours before being packed into the 1135
percolator. Additional solvent is added to totally wet the plant powder for a day or two. The 1136
bottom end of the percolator is then opened, with fresh solvent being replenished from the top 1137
of the percolator to maintain a steady flow of solvent through the bed of herbal materials. The 1138
flowrate of the liquid is controlled by adjusting the valve of the outlet. The extraction liquid 1139
is collected from the bottom outlet of the percolator. When the process is completed, the 1140
marc is pressed and all liquids are pooled to obtain the percolate. In addition to the solvent 1141
used for the extraction, the flow rate and the temperature would influence the extraction yields 1142
and they have to be carefully controlled. Percolation is applicable to both initial and large-1143
scale extraction. 1144
1145
Decoction is the most common method to make herbal preparations in many traditional 1146
medicine systems. It involves boiling the herbal material in water, during which time the 1147
chemical ingredients are dissolved into the hot liquid. This procedure is suitable for 1148
extracting water-soluble and heat-stable ingredients of the medicinal plant. 1149
1150
A special technique of decoction is the hot continuous (Soxhlet) extraction using the Soxhlet 1151
apparatus. Typically, the Soxhlet instrument includes an extraction chamber with reflux 1152
condenser and a collection flask. The chamber is placed between the collection flaks and the 1153
condenser. The herbal powder or pieces are kept inside the extraction chamber. A suitable 1154
solvent is added to the flask and heated under refluxing. The solvent will first be evaporated 1155
up into the condenser, then liquefied and drops into the chamber and covers up the herbal 1156
powder. When the condensed solvent in the chamber reaches a certain height, it is siphoned 1157
back into the flask, and the next cycle of extraction starts. Usually, 50-60 times of recycling 1158
are necessary for an extraction to complete. Due to continuous extraction, this method is 1159
more efficient than simple decoction with less consumption of solvent. However, due to 1160
continuous heating at the boiling point of the solvent used, thermos-labile compounds may be 1161
damaged and/or artefacts may be formed. Besides the laboratory scale setup for continuous 1162
extraction, industrial scale stainless steel extractors and high pressure extraction are 1163
commonly used in many manufacturing facilities. 1164
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1165
Supercritical fluid extraction makes use of the solvating property of a supercritical fluid 1166
(carbon dioxide is the most common supercritical solvent) to dissolve the chemical 1167
constituents in herbal materials. The density of the supercritical fluid (thus its solvating 1168
property) can be adjusted by altering the temperature and pressure, or by the addition of 1169
modifiers (e.g. methanol) to change the polarity of the supercritical fluid. 1170
1171
3.2.2 Steps involved in the extraction of medicinal plants 1172
1173 The following steps are generally involved in the extraction procedures. 1174
1175
Grinding or milling 1176
Prior to extraction, the medicinal plant part is generally dried and reduced to a size between 1177
30-40 mesh (the actual size can be adjusted as the need arises). If fresh material is used for 1178
extraction, it is necessary to perform extraction as soon as possible after the material is 1179
collected to avoid deterioration (microbial fermentation). The purpose of powdering the plant 1180
material is to rupture its tissues and cell structures so that the chemical ingredients are more 1181
readily exposed to the extraction solvent. Moreover, size reduction increases the surface area, 1182
which in turn enhances the mass transfer of chemical ingredients from plant tissue to the 1183
solvent. 1184
1185
Extraction 1186
The extraction process is carried out in the selected solvent at a desirable temperature for an 1187
optimal period of time. Depending on the polarity of the desirable chemical components, 1188
water or other solvents can be used, either at room temperature (“cold” extraction) or at an 1189
elevated temperature (“hot” extraction). 1190
1191
Filtration 1192
After the completion of extraction, the liquid so obtained is separated from the marc by 1193
filtration through a filter cloth or filter paper to remove any particulate insoluble residues. 1194
Other filtering devices may also be used. 1195
1196
Concentration 1197
The enriched extract is often concentrated by the removal of excessive solvent to a thick 1198
concentrated extract or to a solid mass. The concentration procedures may involve 1199
evaporation under reduced pressure (temperature is recommended to below 40 °C) or freeze-1200
drying. 1201
1202
3.2.3 Common herbal preparations prepared by extraction 1203 1204
Decoction is a water-based herbal preparation most commonly utilized in many traditional 1205
medicine systems. It is recommended that only freshly prepared decoctions should be used, 1206
and the amounts of herbal materials and water used, as well as the length of the decocting 1207
process, should be specified. 1208
1209
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Infusion is a dilute solution prepared by steeping the herbal materials in hot water over a short 1210
period of time. Typically, water is boiled and then poured over the herb. The resulting 1211
solution (the infused tea) should be consumed freshly made or stored at low temperature for 1212
future use. Infusions prepared in edible oil or vinegar are also available. 1213
1214
Fluidextract is an aqueous alcoholic preparation typically made in a ratio of one part (e.g. one 1215
millilitre) of liquid to one part (one gram) of herbal materials. When the liquid preparation is 1216
dilute, e.g. 1:5 or 1:10 liquid-to-herb ratio, it is called a Tincture. Tincture can be prepared by 1217
extracting herbal materials with ethanol or a spirit (an alcoholic beverage). 1218
1219
Extract is a preparation of herbal materials made by an extraction process. In some cases, the 1220
extract is completely freed from the solvent (dried) to become fine or granular powder; it is 1221
called Powdered Extract. 1222
1223
Powder is a form of herbal preparation existing as dry, granulated, or ground materials. 1224
Extracts, tinctures or other liquid preparations can be evaporated to dryness to obtain the 1225
powders. 1226
1227
3.2.4 Controlling factors in extracting herbal materials 1228 1229
There are a number of factors that would influence the efficiency and reproducibility of the 1230
extraction process. A few issues to consider include the solvent used to make an extract, 1231
particle size of the herbal material, the herb-to-solvent ratio, extraction time and temperature. 1232
All these factors should be optimized and incorporated into the SOP, and be strictly adhered 1233
to. 1234
1235
3.3 Distillation 1236 1237
Essential (volatile) oil, the odourous principles of certain medicinal plant materials, is usually 1238
obtained by hydrodistillation from the plant matrix. 1239
1240
Water or steam distillation is a method of choice for extracting volatile ingredients from 1241
medicinal plants. In brief, the herbal material is packed in a still, a sufficient amount of water 1242
is added and brought to a boil (water distillation). Alternatively a stream of steam is 1243
introduced to the herbal material pre-soaked in water (water-steam distillation), or a stream of 1244
steam is introduced to fresh medicinal plant materials without water being added (direct steam 1245
distillation). The method of distillation depends on the condition of the herbal materials. 1246
Water distillation is applied to dried medicinal plant material that is heat stable. Water-steam 1247
distillation is best used for either dried or fresh medicinal plant materials that may be 1248
damaged by boiling, while direct steam distillation is often used for fresh medicinal plant 1249
materials. Freed from the plant tissue, the essential oil is carried away with the steam. Upon 1250
condensation, both water and oil are collected in the liquid form, and the latter separates from 1251
the former into two immiscible layers. 1252
1253
The yield and quality of essential oil obtained by distillation is affected by the process 1254
parameters. It is advisable to design the most optimal conditions in order to obtain the best 1255
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results. Among the contributing factors are: mode of distillation, condition of raw medicinal 1256
plant materials, loading of raw medicinal plant materials, steam pressure and temperature, and 1257
length of time for distillation. 1258
1259
For volatile oils that may be decomposed during distillation, they can be obtained by 1260
expression (mechanical pressing) or by the enfleurage process. 1261
1262
3.4 Fractionation and Purification 1263
1264 Fractionation is a separation process in which a mixture is divided into a number of smaller 1265
quantities (fractions) with higher purity. The crude extracts of herbal materials contain 1266
complex mixtures of secondary metabolites with diversified chemical and physical 1267
characteristics. It is often desirable to divide the chemical constituents into different groups 1268
based on their similarities in chemical and physical properties, such as a flavonoid-rich 1269
preparation, total glycosides, or an alkaloid fraction. Fractional separation of an herbal 1270
extract can be achieved by subjecting the extract to a variety of fractionation techniques such 1271
as liquid-liquid partition and various forms of chromatography. The method can be applied to 1272
produce semi-purified preparations in order to enrich pharmacologically active constituents, 1273
to remove inactive constituents, and to deplete toxic components. 1274
1275
3.4.1 Liquid-liquid partition 1276
1277 The liquid-liquid partition (or solvent partition) method involves the use of a series of liquid 1278
solvents. The herbal extract is usually dissolved or suspended in water and partitioned with 1279
organic solvents successively in a sequence of increasing polarities, e.g. n-hexane, 1280
dichloromethane, ethyl acetate, and water-saturated n-butanol. As a result, chemical 1281
compounds possessing different polarities are transferred from the water portion to different 1282
solvent fractions according to the principle of “like dissolves like”. For example, the initial 1283
step of partition using non-polar solvents (such as n-hexane or petroleum ethers) removes 1284
lipophilic substances (such as alkanes, fatty acids, sterols) from the herbal mixture, and such a 1285
process is sometimes referred to as “defatting”. The compounds with intermediate polarity 1286
(such as flavonoids and quinones) will dissolve in the medium-polarity solvents (such as 1287
dichloromethane and ethyl acetate), whereas more polar compounds (such as glycosides, 1288
polyphenols) will be concentrated in the more polar solvents (such as butanol) or retained in 1289
the water phase. The organic portion after each step of partition is then evaporated to dryness. 1290
1291
3.4.2 Chromatography 1292
1293 Further purification of the extract fractions can be achieved by various chromatographic 1294
techniques, of which column chromatography is commonly employed, particularly in the 1295
preparative scale. Column chromatography can be carried out using materials based on 1296
different mechanisms. Common modes are adsorption, partition, size exclusion, and ion-1297
exchange. The most frequently used stationary phases (sorbents) are silica gel and alumina in 1298
adsorption chromatography; in size exclusion and ion-exchange chromatography, polymeric 1299
gels and ion-exchange resins, respectively, are used. A proper column packed with the 1300
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appropriate stationary phase and eluted by a mobile phase with suitable elution power is 1301
crucial to obtain optimized separation of the herbal extract. 1302
1303
3.5 Concentration and drying 1304
1305 The herbal extracts or semi-purified extracts are often concentrated to produce a concentrated 1306
liquid preparation by the removal of excessive solvent. This can be achieved through 1307
evaporation or vaporization. Solvent (single) is generally recovered and may be reused. 1308
Mixed or mixture of solvents cannot be so conserved. The degree of concentration depends 1309
on the desired end product. 1310
1311
Equipment for concentration may include descending film, thin layer or plate concentrators. 1312
Any method used to concentrate the extracts must avoid excessive heat because the active 1313
compounds may be subject to degradation. The liquid preparation so obtained may be used as 1314
is or further processed into a dry powder. 1315
1316
When complete drying is required, the drying process can make use of vacuum freeze dryers, 1317
cabinet vacuum dryers, continuously operating drum or belt dryers, microwave ovens, or 1318
atomizers. The technique for drying depends on the stability of the product and the amount of 1319
moisture that must be removed. The resulting powdered extract is less subject to microbial 1320
contamination than are liquid extracts. 1321
1322
3.6 Fermentation 1323 1324
In some cases, herbal preparation is obtained after undergoing through a fermentation process 1325
of the plant powder or decoction. Fermentation can be either natural (“self-fermentation”) or 1326
by introducing an appropriate microbial organism (e.g. Lactobacillus bacteria). 1327
1328
For natural fermentation, the dry plant powder, a decoction, or infusion of herbal material is 1329
often mixed with the juice of sugarcane, brown sugar or honey, and the mixture is kept in an 1330
airtight utensil for several weeks for anaerobic fermentation to occur. 1331
1332
In some cases, herbal materials are mixed with a small amount of water and shaped to bricks, 1333
followed by microbial cultivation in an incubation room for a week or so, letting the mould 1334
grow on the surface of the herbal materials. 1335
1336
3.7 Processing techniques and procedures 1337
1338 In general, for processes such as extraction, fractionation, purification and fermentation, the 1339
rationale for the guidelines should be established on a case-by-case basis. An example of a 1340
model format of good herbal processing practice monograph/SOP protocol to produce a 1341
herbal preparation is given as Annex 2. The general guidance is provided below. 1342
1343
3.7.1 Preparation of herbal materials for processing 1344
1345 Authentication of herbal materials should be performed prior to extraction. Purity should 1346
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also be ensured. 1347
Proper documentation on the herbal material should be available as recommended in 1348
Section 2.3.5. 1349
The herbal material should be cleaned, dried, and comminuted into an optimal size for 1350
extraction. 1351
The herbal materials should be processed as soon as possible after arrival at the processing 1352
facility. Otherwise they must be properly stored to avoid contamination, damage, and 1353
deterioration. 1354
All operational steps should be reproducible and performed hygienically, forming parts of 1355
the processing SOP. 1356
1357
3.7.2 Extraction 1358
1359 3.7.2.1 Selection of extraction method 1360
The selection of an extraction method is governed by the nature (stability, solubility, etc.) 1361
and amount of material to be extracted. For large amounts, the feasibility of extracting in 1362
bulk scale should be considered. 1363
The extraction method should be as exhaustive as possible, i.e. removing as much of the 1364
desired ingredients as possible from the plant matrix. 1365
It should be fast, simple, economical, environment-friendly, and reproducible. 1366
1367
3.7.2.2 Extraction conditions and procedures 1368
Solvent 1369
Depending on the nature of the active constituents, an appropriate solvent (or solvent 1370
mixture) should be selected for use. Although water is used as a solvent for many 1371
traditional medicines, organic solvents of varying polarities are generally selected in 1372
modern methods of extraction to exploit the various solubilities of plant constituents. 1373
Typically, an aqueous solution of alcohol (e.g. 60-80% aqueous ethanol) can extract the 1374
majority of organic secondary metabolites from herbal materials. Other solvents may 1375
apply for the extraction of specific types of ingredients (such as proteins and 1376
polysaccharides). 1377
When selecting a solvent or solvent mixture, the following factors should be considered: 1378
solubility of the target compounds, stability and reactivity of the solvent, safety (low 1379
toxicity, low flammability, non-corrosiveness), cost, ease of subsequent solvent removal 1380
and solvent recovery (low boiling point), and environmental friendliness. 1381
Before using a solvent, the material safety data sheet (MSDS) should be reviewed and 1382
appropriate protective measures should be used. Precautions must be taken to minimize 1383
the risk of fire and explosion. Care should be taken to reduce environmental 1384
contamination and to protect the workers and other people in the vicinity from exposure to 1385
chemical hazards. 1386
Toxic solvents and those detrimental to the environment, e.g. benzene, toluene, and carbon 1387
tetrachloride, must not be used. Diethyl ether should be avoided as it is highly flammable 1388
and can lead to the formation of explosive peroxides. The use of chlorinated solvents is 1389
discouraged; if used, dichloromethane is preferred to chloroform, the latter being more 1390
toxic. 1391
Solvents of general-purpose grade available in plastic containers are often contaminated by 1392
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plasticizers, and minimizing contamination is especially important when bulk extraction is 1393
carried out requiring large volumes of solvent. It is advisable to distill solvents prior to use. 1394
The ratio of herbal material to the extraction solvent is a decisive factor for the 1395
effectiveness of extraction. Thus, the amounts of solvent used must be optimized to ensure 1396
batch-to-batch conformity. 1397
The quality and specification of solvent used should be specified and controlled. 1398
Solvents should be properly stored in non-plastic containers in a well ventilated, fire and 1399
explosion containable area; and away from direct exposure to sun light. 1400
When solvents are recycled, the purity must be confirmed prior to re-use. 1401
Waste solvents must be disposed safely and properly. Guidelines from national, local, or 1402
institutional regulations of waste solvent disposal must be strictly observed and followed. 1403
1404
Temperature 1405
To avoid thermal degradation of the chemical constituents, extractions are preferably 1406
performed under 40 °C, unless evidence is available for the use of higher temperatures. 1407
For heat stable constituent, Soxhlet extraction or decocting in boiling water can be used. 1408
In any case, higher than required temperature should be avoided. 1409
Temperature during the entire extraction process should be controlled and recorded. 1410
1411
Length of treatment 1412
The length of extraction time depends on the purpose for which the extraction is performed 1413
and the nature of the active constituents. Insufficient time will result in incomplete 1414
extraction, but prolonged extraction will lead to excessive extraction of the unwanted 1415
constituents (e.g. tannins), and/or degradation of active chemical ingredients. 1416
The number of repeated extraction cycles required for the complete removal of the 1417
desirable constituents is as important as the length of time per each extraction. 1418
The length of extraction time and the number of cycles should be controlled and recorded. 1419
1420
3.7.3 Distillation 1421 1422
The distillation apparatus must be set up properly and safely according to the 1423
manufacturer’s instructions. 1424
Distillation should be carried out in a well ventilated room. 1425
Optimum extraction conditions, e.g. heating rate and distilling rate, have to be specified 1426
and controlled. 1427
When distillation is performed on an industrial scale, the equipment employed should be in 1428
conformance with the official safety standards and all procedures must conform to the 1429
operational instructions and safety requirements. 1430
1431
3.7.4 Fractionation and purification 1432
1433 Liquid-liquid partition 1434
The storage, use, and disposal of solvents must be handled with care and in conformance 1435
with the national/local/institutional regulations. 1436
The experimental procedures should be carried out in certified facilities with sufficient 1437
ventilation and safety measures. They are preferably preformed inside exhaustive fume 1438
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hoods. 1439
1440
Chromatography 1441
The choice of stationary phase depends on the polarity, molecular size, or the charge of the 1442
desired ingredients. It should be supported by good rationale. 1443
The choice of mobile phase (solvent system) must be optimized. 1444
Column operation and development procedures (e.g. column size, amount of stationary 1445
phase used, column packing, sample application, elution gradient formation, flow rate, 1446
temperature, fraction collection, and detection method), should be specified and 1447
standardized. 1448
1449
3.7.5 Concentration and drying 1450
1451 The minimization of loss and/or damage to the chemical constituents of interest is critical 1452
to the efficacy of the preparation. Therefore, the preservation of the active ingredients is 1453
of paramount importance during the concentration stage when heat is often applied to 1454
evaporate the solvent. Any concentration process should ensure minimal thermal 1455
decomposition and chemical reactions (such as oxidation) to occur. For organic solvents, 1456
evaporation under reduced pressure at a temperature below 40 °C is preferred. 1457
Solvent removal should be done as soon as possible after extraction. Prolonged exposure 1458
to sunlight should also be avoided. 1459
While evaporation is the most common and the most applied technique for concentration, 1460
other approaches such as membrane technology and freeze concentration are available. 1461
1462
3.7.6 Fermentation 1463
1464 When fermentation is required to produce a herbal preparation, all utensils should be 1465
completely cleaned. A non-corrosive fermentor is required. 1466
The water to be used should not be alkaline and should be free of inorganic matters 1467
(deionized water). 1468
The temperature and length of fermentation should be optimized and controlled. 1469
When fermentation is complete, the solution is filtered and stored in bottles. 1470
1471
3.8 Documentation 1472 1473
The general principles for documentation are set out in the GMP for pharmaceutical 1474
products: main principles [WHO, 2007a – WHO, 2003b]; [WHO, 2014]. 1475
1476
In addition to the data called for in the above guidelines, the specifications for herbal 1477
preparations should as far as possible include, as a minimum, the following information; 1478
1479
Botanical (scientific) and the local/common names of the source medicinal plant material; 1480
and plant part(s) being processed; 1481
Site and time of harvest/collection of the plant; 1482
Batch number and any other identification code; 1483
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Dates of receipt of the herbal material, processing of the material, and completion of the 1484
process; 1485
Name of person in charge of the processing; 1486
Previous processes that the herbal material has already undergone; 1487
Methods used for processing to produce herbal preparation; 1488
Details of the procedures (master formula), including descriptions of the steps of 1489
operation, operational conditions used during the process, and other relevant information; 1490
Batch production detail deviations/modifications of the master formula; and 1491
Quality control parameters and assay results, where appropriate, of active ingredient(s) or 1492
Chemical reference standard(s). 1493
1494
The SOP including all processing steps should be adopted and documented in the Master 1495
Record. Batch records should be kept, particularly in cases of deviation from the SOP. 1496
Name(s) of all operators and the dates on which each step/stage are carried out should be 1497
documented. 1498
1499
4. GOOD HERBAL PROCESSING PRACTICES FOR THE PRODUCTION OF 1500
HERBAL DOSAGE FORMS 1501
1502
4.1 General information 1503
1504 In contrast to pharmaceutical drugs, many herbal materials and herbal preparations may 1505
undergo only simple processes to become suitable dosage forms for administration. 1506
Generally, these dosage forms are produced under good practice procedures, such as those 1507
given in the Japanese Pharmacopoeia (16th Edition) (see Annex 3). This section describes 1508
some common dosage forms of herbal medicines. 1509
1510
4.2 Extracts 1511 1512
Extracts are prepared by concentrating the extractives of herbal materials. There are two 1513
kinds of extracts: concentrated extract and dried extract. 1514
1515
In general, after being pulverized to a suitable size, the herbal material is extracted for a 1516
certain period of time with suitable solvents by means of cold or warm extraction as described 1517
in Section 3.7.2. The solid and liquid are separated by filtration or centrifugation, followed by 1518
concentration by a suitable method to obtain a concentrated extract, or by bringing to 1519
complete dryness to obtain solid extract in the form of solid masses, granules or powder. 1520
1521
4.3 Fluidextracts 1522 1523
Fluidextracts are liquid percolates of herbal materials, usually prepared by maceration or 1524
percolation of coarse powder or cut pieces of herbal materials as described in Section 3.2.1, to 1525
such a concentration that each milliliter contains soluble substances from one gram of the 1526
herbal material. 1527
1528
4.4 Infusions 1529
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1530
Infusions are fluid preparations obtained by macerating herbal materials in water. Herbal 1531
materials are cut into a suitable size and wetted with water (usually using 1 milliliter of water 1532
for each gram of herbal material) for 15 minutes. A larger amount of hot water is then added 1533
and heat for a period of time (usually 5-10 minutes), followed by filtration and cooling to 1534
obtain a clear liquid. 1535
1536
4.5 Decoctions 1537 1538
Decoctions are fluid preparations obtained by macerating herbal materials in water. Herbal 1539
materials are cut into a suitable size and cooked with a sufficient quantity of boiling water in a 1540
decoction apparatus for a period of time, usually until about half of the water is dried. 1541
Additional water can be added to repeat the process if desirable. The decoction is obtained by 1542
decanting or filtration. 1543
1544
4.6 Herbal tea bags 1545 1546
Herbal tea bags are prepared by packing finely ground herbal materials (such as dried roots, 1547
leaves or flowers) into paper or cloth bags. When used, boiling water is poured onto the bag 1548
in order to make an infusion. 1549
1550
4.7 Tinctures and spirits 1551
1552 Tinctures and spirit are liquid preparations, usually prepared by extracting herbal materials 1553
with ethanol or with a mixture of ethanol and water by means of either maceration or 1554
percolation. They should be kept away from open fire or directly under the sun. 1555
1556
4.8 Aromatic Waters 1557 1558
Aromatic waters are water preparations containing saturated essential oils or other volatile 1559
substances. Usually, an essential oil is shaken in water and set aside for 12 hours or longer. 1560
The solution is filtered and made up to a certain volume with water. Aromatic waters have a 1561
characteristic odour of the essential oil or volatile substances used. 1562
1563
4.9 Syrups 1564
1565 Syrups are viscous liquid containing sugars or other sweetening agents. They are prepared by 1566
dissolving, mixing, suspending or emulsifying herbal extracts or decoctions in a solution of 1567
honey, sucrose or other sweetening agents. When necessary, the mixture is boiled and 1568
filtered. 1569
1570
4.10 Powders 1571
1572 Powders are prepared by grinding herbal materials or dried extracts to a suitable particle size. 1573
1574
4.11 Granules 1575
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1576 Granules are dried extracts or decoctions in the form of spherical particles. They are prepared 1577
by adding diluents, binders or other suitable excipients to extract powders, mixed to 1578
homogenize and granulated by a suitable method. Typically, granules are dissolved in hot 1579
water to make a “herbal tea” for administration. 1580
1581
4.12 Pills 1582
1583 Pills are dried extracts or decoctions in the form of small, spherical solids, similar to granules. 1584
They may be prepared by adding suitable excipients to extract powders, mixed to homogenize 1585
and granulated by a suitable method. Typically, pills are swallowed with warm water. 1586
1587
4.13 Capsules 1588
1589 Capsules are prepared by enclosing herbal powder or dried extract in capsule shells or in a 1590
suitable capsule base such as gelatin in a particular shape and size. 1591
1592
4.14 Tablets 1593
1594 Tablets are solid preparations having a defined shape and size. They are usually prepared by 1595
mixing the homogenous herbal powder or dried extract with excipients such as diluents and 1596
binders, followed by compression into a defined shape and size. 1597
1598
4.15 Ointments/creams 1599
1600 Ointments/creams are topical preparations for application to the skin. They are usually semi-1601
solid emulsions dissolved or dispersed in a suitable base. Alongside with the herbal 1602
ingredients, they may contain emulsifiers or thickening agents. 1603
1604
4.16 Inhalations 1605
1606 Inhalations are preparations intended for administration as aerosols to the bronchial tubes or 1607
lungs. They are usually either dry powder inhalers or inhalation liquid preparations. For 1608
administration of inhalations, suitable devices or apparatus are required. 1609
1610
Dry powder inhalers are prepared by pulverizing dried extracts into fine particles. When 1611
necessary, lactose or other suitable excipients are added to make a homogenous mixture. 1612
Inhalation liquid preparations are usually prepared by mixing dried herbal extracts with a 1613
vehicle and suitable pH adjusting agents to make a solution or suspension. Suitable 1614
preservatives may be added to prevent the growth of microorganisms. 1615
1616
4.17 Plasters and Patches 1617
1618 Plasters and patches contain herbal preparations such as dried extracts or decoctions on pieces 1619
of fabric or plastic sheets. When applied topically to the skin, they deliver the herbal 1620
ingredients through the skin to underlying tissues, usually for the relief of pain, backache, or 1621
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sore muscles. 1622
1623
An example of general good practice for the preparation of herbal dosage forms is given in 1624
Annex 3. 1625
1626
5. TECHNICAL ISSUES SUPPORTING GOOD HERBAL PROCESSING 1627
PRACTICES 1628
1629 In the formulation of a good practice protocol for processing herbal materials, a number of 1630
supporting technical issues must be considered and adopted. Since the primary objective is to 1631
produce quality processed herbal materials and preparations, many of the same technical 1632
issues associated with the GACP, GMP and quality control (QC) methods are applicable to 1633
GHPP. 1634
1635
Therefore, these guidelines have been consulted for applicable good practice items for 1636
adoption. Moreover, the same technical issues on the post-harvest processing of cultivated 1637
and collected medicinal plant materials were addressed in section 4 of the WHO guidelines on 1638
GACP for medicinal plants [WHO, 2003a]. Therefore, the applicable good practice 1639
guidelines have been adopted in whole or modified as appropriate for the present guidelines. 1640
1641
5.1 Processing facilities 1642
1643 The ideal design and construction of a herbal material processing facility incorporating the 1644
most appropriate location, buildings, medicinal plant material handling and processing areas, 1645
water supply, effluent and waste disposal, changing facilities and toilets, hand-washing 1646
facilities in processing areas, disinfection facilities, lighting, ventilation, dust and storage of 1647
waste and unusable materials, have already been fully described in Sections 4.1.5 (pages 19-1648
23) of the WHO guidelines on GACP for medicinal plants [WHO, 2003a]. Therefore, they 1649
are adopted for the present guidelines and the descriptions are excerpted and presented in 1650
Annex 4 for easy reference. 1651
1652
5.2 Packaging and labelling 1653
1654 Processed herbal materials or herbal preparations should be packaged as quickly as possible to 1655
preserve their quality by preventing deterioration of the herbal medicines and to protect 1656
against unnecessary exposure to pest infestations and other sources of contamination. 1657
1658
Continuous in-process quality control measures should be implemented to eliminate sub-1659
standard materials, contaminants and foreign matter prior to and during the final stages of 1660
packaging. Processed medicinal plant materials should be packaged in clean, dry boxes, 1661
sacks, breathable bags or other containers in accordance with standard operating procedures 1662
and meeting national and/or regional regulations of the producer and the end-user countries. 1663
Materials used for packaging should be non-polluting, clean, dry and in undamaged condition 1664
and should conform to the quality requirements for the processed herbal materials or herbal 1665
preparations concerned. Fragile medicinal plant materials should be packaged in rigid 1666
containers. Wherever possible, the packaging used should be agreed upon between the 1667
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supplier and buyer. 1668
1669
A label affixed to the packaging should clearly indicate the scientific name, the processed 1670
plant part with date, the processing techniques used, the name and address of the processor, as 1671
well as quantitative information. The label should also contain information indicating quality 1672
approval and compliance with other national and/or regional labelling requirements. The 1673
label should bear a number that clearly identifies the production batch. Additional 1674
information about the production and quality parameters of the medicinal plant materials may 1675
be added in a separate certificate, which is clearly linked to the package carrying the same 1676
batch number. 1677
1678
Records should be kept of batch packaging, and should include the product name, place of 1679
origin, batch number, weight, assignment number and date. The records should be retained 1680
for a period of three years or as required by national and/or regional authorities. 1681
1682
5.3 Storage and transportation 1683
1684 All processed herbal materials or herbal preparations should be properly stored and preserved 1685
before use. They must be protected from microbial and insect contaminations, and rodents 1686
and other pests. Every effort should be tried to use the type of packaging that provides ample 1687
protection against physical damages to the materials and to keep away, as much as possible, 1688
from exposure to moisture, light, heat, and insect attack. 1689
1690
Storage areas should be of sufficient capacity to allow orderly storage of the various types of 1691
processed herbal materials and herbal preparations with proper separation and segregation. In 1692
particular, they should be clean, dry, sufficiently lit and maintained within acceptable 1693
temperature and humidity limits, and controlled, monitored and recorded where appropriate to 1694
ensure good storage conditions. 1695
1696
Conveyances used for transporting processed herbal materials and herbal preparations from 1697
the place of processing to storage should be clean and, where appropriate, well ventilated to 1698
keep an appropriate level of and to prevent condensation. 1699
1700
Fumigation against pest infestation in conveyances and in storage areas should be carried out 1701
only when necessary, and should be carried out by licensed or trained personnel. Only 1702
registered chemical agents authorized by the regulatory authorities of the source country and 1703
the countries of intended end-use should be used. All fumigation, fumigation agents, and 1704
dates of application should be documented. When freezing or saturated steam is used for pest 1705
control, the humidity of the materials should be checked after treatment. 1706
1707
5.4 Equipment 1708
1709 All equipment, including tools and utensils used in the processing of herbal materials and 1710
herbal preparations should be made of materials that do not transmit toxic substances, odour 1711
or taste; are non-absorbent; are resistant to corrosion and are capable of withstanding repeated 1712
cleaning and disinfection. The use of wood and other materials that cannot be adequately 1713
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cleaned and disinfected should be avoided, except when their use would clearly not be a 1714
source of contamination. The use of metals where contact corrosion may occur should be 1715
avoided. 1716
1717
All equipment and utensils should be designed and constructed so as to prevent hygienic 1718
hazards and permit easy and thorough cleaning and disinfection. Where practicable, they 1719
should be accessible for visual inspection. Stationary equipment should be installed in such a 1720
manner as to permit easy access and thorough cleaning. 1721
1722
Containers for unusable materials or waste should be leak-proof, constructed of metal or other 1723
suitable impervious materials, should be easy to clean or be disposable, and should close 1724
securely. 1725
1726
All refrigerated spaces should be equipped with temperature measurement or recording 1727
devices. 1728
1729
5.5 Quality assurance and quality control 1730
1731 Compliance with quality assurance measures should be verified through regular internal 1732
oversight personnel (QC manager) and external auditing visits to processing facilities by 1733
expert representatives of buyers and other stake holders and through inspection by national 1734
and/or local regulatory authorities. 1735
1736
5.6 Documentation 1737
1738 The SOP should be adopted and documented. All methods and procedures involved in the 1739
processing of herbal materials and herbal preparations and the dates on which they are carried 1740
out should be documented. 1741
1742
The types of information that should be collected include the items described in Sections 2.3.5 1743
and 3.8 above. Additionally, documentation on post-processing transportation and storage of 1744
processed products should be prepared. 1745
1746
Where applicable, the results of inspection should be documented in an inspection report 1747
which contains copies of all documents, (QC) analysis reports, and local, national and/or 1748
regional regulations, and which are stored according to their requirements. 1749
1750
5.7 Personnel 1751
1752
5.7.1 General 1753
1754 All personnel should receive proper post-harvest handling and herbal processing training. 1755
1756
All personnel required to handle chemical solvents and adjuvants should receive adequate 1757
training and possess sufficient knowledge and appropriate techniques employed for their safe 1758
handling and proper use. 1759
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1760
Local, national and/or regional regulations governing labour should be respected in the 1761
employment of staff for all phases of herbal processing. 1762
1763
5.7.2 Health, hygiene and sanitation 1764
1765 All personnel involved in the pre-processing and during processing handling of herbal 1766
materials should be trained and perform tasks in compliance with local, national and/or 1767
regional regulations on safety, materials handling, sanitation and hygiene. 1768
1769
All personnel should be protected from contact with toxic or potentially allergenic herbs by 1770
means of adequate protective clothing, including gloves and masks. 1771
1772
Health status 1773
All personnel known, or suspected to be suffering from or to be a carrier of a disease or illness 1774
likely to be transmitted, should not be allowed to enter any processing area, and should 1775
immediately be reported to the management, and suspended from work as deemed medically 1776
appropriate. 1777
1778
Health conditions that should be reported to the management for consideration regarding 1779
medical examination and/or possible exclusion from handling of medicinal plant and 1780
processing/processed herbal materials and associated equipment including but not limited to: 1781
such as jaundice, diarrhoea, vomiting, fever, sore throat with fever, visibly infected lesions 1782
(boils, cuts, among other conditions) and discharges from the ear, nose or eye. Any personnel 1783
who have cuts or wounds and are permitted to continue working should cover their injuries 1784
with suitable waterproof dressings. 1785
1786
Personal hygiene and behaviours 1787
Personnel who handle processing/processed herbal materials should be trained to maintain a 1788
high degree of personal cleanliness, and, where appropriate, wear suitable protective clothing 1789
and gloves, including head/hair covering and footwear. 1790
1791
Personnel should always wash their hands at the start of handling activities, after using the 1792
toilet, and after handling medicinal plant materials or any contaminated material. 1793
1794
Smoking, drinking, and eating should not be permitted in medicinal plant processing areas. 1795
1796
Visitors 1797
Visitors to processing and handling areas should wear appropriate protective clothing and 1798
adhere to all of the personal hygiene provisions mentioned above [WHO, 2003a]. 1799
1800
6. OTHER RELEVANT ISSUES 1801
1802
6.1 Ethical and legal considerations 1803 1804
All herbal processing must be carried out in accordance with applicable legal and 1805
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environmental requirements and with the ethical codes or norms of the community and 1806
country in which the activities take place. 1807
1808
6.2 Research, research training and information sharing 1809
1810 Research to find alternate processing procedures to achieve the same therapeutic efficacy as 1811
traditional or historical methods is needed. Additionally, research to determine the chemical 1812
conversion process and mechanism involved in the qualitative and quantitative alteration of 1813
the biologically active or adjuvant chemical constituents following processing is also needed 1814
and encouraged. 1815
1816
Technical information resulting from processing method research is useful instrument for 1817
promoting technical advancement, and should be shared through publication, conferences or 1818
otherwise conveyed to interested stakeholders. 1819
1820
As in all technical endeavours, education and research training are essential to preserve 1821
technical expertise and to promote innovation in development of new and better techniques 1822
and procedures in herbal processing. 1823
1824
Research to develop good herbal processing practices of each medicinal plant – such as 1825
monographs. 1826
1827
6.3 Adoption of good herbal processing practices 1828 1829
Member States or nations that have not adopted good herbal processing practices for herbal 1830
medicines are encouraged to establish or adopt such practices as part of quality assurance and 1831
control measures, as well as a part of their regulatory requirements for herbal medicines. 1832
1833
6.4 Intellectual property rights and benefits-sharing 1834 1835
Agreements on intellectual property rights and the return of benefits and compensation for the 1836
use of source herbal materials or herbal preparations concluded in writing by the sourcing 1837
contractor, shall be acknowledged and followed by the processor as appropriate. 1838
1839
6.5 Threatened and endangered species 1840 1841
When obtaining medicinal plants that are protected by national and international laws, such as 1842
those listed in national “red” lists, for processing, the processor shall ascertain and obtain 1843
appropriate documentation from the sourcing contractor that said materials were acquired 1844
only by relevant permission according to national and/or international laws, and that the 1845
provisions of the Convention on International Trade in Endangered Species of Wild Fauna 1846
and Flora (CITES) have been complied with. 1847
1848
7. REFERENCES 1849 1850 WHO, 2000:General guidelines for methodologies on research and evaluation of traditional medicine 1851 WHO/EDM/TRM/2000.1, Geneva, World Health Organization, 2000. 1852
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1853 WHO, 2003a:WHO guidelines on good agricultural and collection practices (GACP) for medicinal plants. 1854 Geneva, World Health Organization, 2003. 1855 1856 WHO, 2003b: Good Manufacturing Practices for pharmaceutical products: main principles In: WHO 1857 Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh report. Geneva, 1858 World Health Organization, 2003 (WHO Technical Report Series, N0. 908), Annex 4. 1859 1860 WHO, 2007a: WHO guidelines on good manufacturing practices (GMP) for herbal medicines. Geneva, 1861 World Health Organization, 2007. 1862 1863 WHO, 2007b:WHO guidelines on assessing quality of herbal medicines with reference to contaminants 1864 and residues, Geneva, World Health Organization, 2007. 1865 1866 WHO, 2007c:General guidelines for the establishment, maintenance and distribution of chemical reference 1867 substances. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first 1868 report. Geneva, World Health Organization, 2007 (WHO Technical Report Series, No. 943), Annex 3. 1869 1870 WHO, 2011:Quality control methods for herbal materials. Geneva, World Health Organization, 2011. 1871 1872 WHO, 2014:Good Manufacturing Practices for pharmaceutical products: main principles In: WHO Expert 1873 Committee on Specifications for Pharmaceutical Preparations. Forty-eighth report. Geneva, World Health 1874 Organization, 2014 (WHO Technical Report Series, N0. 986), Annex 2. 1875 1876 WHO, 2017:WHO guideline for selecting marker substances of herbal origin for quality control of herbal 1877 medicines. Geneva, World Health Organization, 2017 (in preparation). 1878 1879 WHOM-1999:WHO monographs on selected medicinal plants, Volume 1, Geneva, World Health 1880 Organization, 1999. 1881 1882 WHOM-2002:WHO monographs on selected medicinal plants, Volume 2, Geneva, World Health 1883 Organization, 2002. 1884 1885 WHOM-2007:WHO monographs on selected medicinal plants, Volume 3, Geneva, World Health 1886 Organization, 2007. 1887 1888 WHOM-2009:WHO monographs on selected medicinal plants, Volume 4, Geneva, World Health 1889 Organization, 2009. 1890 1891 WHOM-2010:WHO monographs on selected medicinal plants commonly used in the Newly Independent 1892 States (NIS), Geneva, World Health Organization, 2010. 1893
1894
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Annex 1: Example of a model format of good herbal processing practices 1895
monograph/SOP protocol to produce a herbal material 1896 1897
TITLE of the monograph/protocol: 1898 1899 Processing of [name of the plant] (Scientific name of the medicinal plant; medicinal plant part) 1900 1901 1. Objective of the SOP Protocol 1902 1903 2. Scope 1904 1905 3. Procedures 1906 1907 3.1 Sampling 1908 1909 Sampling of herbal materials should follow applicable national or regional specifications. In absence 1910 of appropriate specifications, the following method may be considered: When a batch consists of five 1911 containers or packaging units, take a sample from each one. From a batch of 6-50 units, take a sample 1912 from five. In the case of batches of over 50 units, sample 10%, rounding up the number of units to the 1913 nearest multiple of ten (WHO, 2011). 1914 1915 Quality testing of the raw material 1916 Perform morphological identification/validation by macroscopic and microscopic examinations and 1917 physicochemical tests by following the procedures set out in the national pharmacopoeia or other 1918 authoritative documents. 1919 1920 The following requirements must be fulfilled. 1921 Morphology: Conform with the national pharmacopoeial standards 1922 Identification (including microscopic examination, colorimetric and/or chromatographic tests): 1923
Conform with the pharmacopoeial standards 1924 Water content: ≤ xxx % 1925 Total ash: ≤ xxx % 1926 Extractive: ≥ xxx % 1927 1928 3.2 Quality control assay 1929 1930 3.2.1 Marker compound 1931 Compound “Z” is used as the marker compound for plant X..y.. for quality control purpose. Obtain 1932 analytical grade Compound Z (≥ 98% purity) from a reliable source to serve as Chemical reference 1933 substance. 1934 1935 3.2.2 High-performance liquid chromatographic (HPLC) analysis 1936 Set up the HPLC system. Perform system suitability test to ensure suitability of the instrument and 1937 method. 1938 Under the recommended HPLC conditions, establish calibration curves by injecting an appropriate 1939 amount of the chemical reference (marker) standard solution in a series of concentrations. 1940 Obtain HPLC chromatogram of the herbal material. Identify the analyte signal in the chromatogram 1941 by comparing the retention time with that of the peak of the chemical reference substance obtained 1942 under same HPLC conditions. 1943 Calculate the percentage content of the analyte in the sample using the calibration curve. 1944
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Determine the percentage content of the marker compound again after final drying of the processed 1945 herbal material (section 3.10 below). 1946 1947 The following requirement must be fulfilled. 1948 Content of Compound Z before processing: ≥ xxx % calculated with reference to the dry weight of 1949
the starting material 1950 Content of Compound Z after processing: ≥ xxx % calculated with reference to the dry weight of 1951
the processed material 1952 1953 3.3 Testing of the excipient* 1954 1955 Perform tests by following the procedures set out in the SOP document. The following requirements 1956 must be fulfilled. 1957 Appearance: Conform with internal standards 1958 Total excipient content: ≥ xxx % 1959 1960 3.4 Initial sorting of the plant material for processing 1961 1962 The source herbal materials are manually sorted by trained personnel according to the requirements 1963 specified in the SOP. Impurities (e.g. dirt and non-medicinal plant parts) should be removed, and any 1964 materials of non-uniformed sizes should be excluded. 1965 1966 The following requirements must be fulfilled. 1967 Impurity: ≤ xxx % 1968 Size uniformity: ≥ xxx % 1969 Total recovery: ≥ xxx % (Recovery = Weight after sorting / Weight before sorting X 100%) 1970 1971 3.5 Washing 1972 1973 Washing should be performed by following the procedures set out in the SOP document. Pay attention 1974 to the quality of water used, the length of washing time, and any precautions applicable to the specific 1975 herb. 1976 1977 The following requirements must be fulfilled. 1978 Appearance after washing: in conformance with the SOP standard 1979 Recovery: xxx-xxx % (Recovery = Weight after washing/Weight before washing X 100%) 1980 1981 3.6 Steaming (or other treatment) 1982 1983 The procedures set out in the SOP document should be strictly followed. All equipment should be 1984 properly maintained, clean, and performing at optimal and safe conditions. 1985 1986 The following requirements must be fulfilled. 1987 Appearance after steaming/treatment: in conformance with the SOP standard 1988 Recovery: ≥ xxx % (Recovery = Weight after steaming/Weight before steaming X 100%) 1989 1990 3.7 Semi-drying 1991 1992 If required, dry the samples according to SOP guideline, either by sunlight or by artificial heating. 1993 1994 The following requirements must be fulfilled. 1995
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Appearance after semi-drying : in conformance with the SOP standard 1996 Recovery: xxx-xxx% (Recovery = Weight after drying/Weight before drying X 100%) 1997 1998 3.8 Cutting/sectioning/comminuting 1999 2000 The processed material should be comminuted into the required size and shape in conformance with 2001 the SOP standard. 2002 2003 The following requirements must be fulfilled. 2004 Non-conformed pieces: ≤ xxx % 2005 Recovery: ≥ xxx % (Recovery = Weight after cutting/Weight before cutting X 100%) 2006 2007 3.9 Final drying of processed herbal material 2008 2009 The cut materials should be thoroughly dried according to the SOP requirement. 2010 2011 The following requirements must be fulfilled. 2012 Water content of the final product: xxx-xxx % 2013 Recovery: ≥ xxx % (Recovery = Weight after drying/Weight before drying X 100%) 2014 2015 3.10 Final sorting 2016 2017 The dried material should be carefully inspected by trained personnel, with impurities removed, and 2018 sorted into specific grades in accordance with the pharmacopoeial or trading standard. 2019 2020 The following requirements must be fulfilled. 2021 Impurity: ≤ xxx % 2022 Grade-1 pieces: ≥ xxx% 2023 Grade-2 pieces: xxx –xxx% 2024 Recovery: ≥ xxx % (Recovery = Weight after sorting/Weight before sorting X 100%) 2025 2026 3.11 Packaging, labelling, and storage 2027 2028 3.11.1 Packaging 2029 Processed materials should be packaged quickly and appropriately in air-tight, non-corrosive 2030 containers, and protected from light to preserve quality, prevent deterioration and to protect against 2031 contamination. 2032 2033 3.11.2 Labelling 2034 Labels affixed to each package should clearly indicate the scientific name of the medicinal plant, the 2035 plant part, the processing method, the date of processing, the batch number, quality specification and 2036 compliance, quantitative and other relevant information. 2037 2038 3.11.3 Storage 2039 The packaged products must be stored in a clean, dry and well-ventilated area, at a constant 2040 temperature appropriate for the proper maintenance of the final product, and protected against 2041 microbial and other sources of contaminations and free from insects and animal pest attacks. 2042 2043
*This step is not required if excipient(s) are not employed in the processing protocol 2044 2045
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Annex 2: Example of a model format of good herbal processing practices 2046
monograph/SOP protocol to produce a herbal preparation 2047 2048
TITLE of the monograph/protocol 2049 2050
Processing of [name of the plant] (Scientific name of the medicinal plant; medicinal plant part) 2051 2052 1. Objective of the SOP Protocol 2053 The objective of this protocol is to establish a procedure for preparation of the finished product. 2054 2055 2. Scope 2056 This procedure applies to processes required in the preparation of the juice of the herb of X..y... 2057 2058 3. Procedures 2059 This protocol should be carried out in accordance with the standard operating procedures (SOP) for 2060 the processing of material X.. y... as described in this document, the SOP for equipment operation and 2061 maintenance, as well as those for facility management and cleaning. Any other relevant requirements 2062 may also apply. 2063 2064 The protocol should be adhered to in conjunction with relevant internal standards of the processing 2065 facility. 2066 2067 After the completion of each processing step, the products should be inspected by qualified personnel. 2068 All inspection records should be properly filed and retained for a period of three years or as required 2069 by national and/or regional authorities. 2070 2071 4. Plant substance 2072 The identity of the raw plant material should be confirmed using morphological 2073 identification/validation by macroscopic and microscopic examinations and physicochemical tests by 2074 following the procedures set out in the pharmacopoeia or other authoritative documents. 2075 2076 Specifications such as those below should be in place. 2077 2078 Origins of the plant material (natural state/cultivation): Describe appropriate origins of the 2079
plant material 2080 Part plant: Describe the desired plant part/parts (i.e. flowers) 2081 Growing conditions: 2082
o fertilizers: Specify allowable fertilizers in compliance with applicable regulations 2083 o pest controls: Specify allowable pesticides and/or biological pest controls, in compliance 2084
with applicable regulations 2085 o fungicides: Specify allowable fungicides (if any) in compliance with applicable regulations 2086 o fumigants: Specify allowable fumigants (if any) in compliance with applicable regulations 2087
Harvest time: Describe the appropriate months for harvest (i.e. during flowering (June-July) 2088 Harvesting: Describe the process for harvesting (i.e. mechanical process) 2089 Drying conditions: Describe the process for drying, if applicable 2090 Purification: Describe the process for inspection and removal of impurities 2091 Storage conditions: Specify the storage conditions. In general, the plant material should be 2092
stored in a clean, dry and well-ventilated area, at an appropriate constant temperature, protected 2093 against microbial and other sources of contaminations, free from attack by insects and animal 2094 pests 2095
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Transportation conditions: Commercial vehicles should be clean, dry, deprived of any foreign 2096 matter. Conditions should ensure protection against moisture and contamination. Baskets, chests 2097 and jute bags can be used as containers. Each container will be labelled with the name of the 2098 material, date of harvest, harvesting site, net and gross weight and the name of the supplier 2099
2100 5. Processing 2101 Descriptions of the processing facility requirements are included in this section, i.e. certification of the 2102 site as a good practice facility. Details are given for the raw components to be used in the production 2103 of the final herbal preparation. 2104 2105 As an example, raw X...y... material to be processed into X...y... juice are detailed in the table below. 2106 In this example, the plant material is extracted using ethanol 95% (V/V) and water as needed. The 2107 drug extract ratio (DER) is 1:1. 2108 2109
Raw Material Components in the Production of X...y...juice 2110 Raw Materials Function Amount per 100 kg Standard
Fresh X...y... herb Plant material 100.0 kg Standard specification
Ethanol 95% Extraction solvent Xx litres Pharmacopoeia .XYZ
Extraction water Extraction solvent q.s. Pharmacopoeia .XYZ
2111 Raw materials accepted for processing must meet specifications for identity and quality. 2112 Specifications include appearance/description of the plant material(s), the particle size, water content, 2113 total ash, as well as appropriate chemical assays. These criteria may follow criteria detailed in 2114 pharmacopoeial monograph(s). 2115 2116 The steps below describe the preparation of the juice of the herb of X..y.. 2117 Step 1. The fresh fragmented plant material is stabilized with the vapours of boiling 95% ethanol 2118
in an autoclave. The duration, temperature and vapour pressure are specified in the SOP. When 2119 the process is completed, the fluid separates from the plant material. 2120
Step 2. The stabilized plant material is placed in a macerator with post-stabilization fluid and 2121 water. The maceration process lasts for a period of time (n days) specified. At the end of the 2122 extraction process, the extract is separated from the plant matter in a manner specified by the SOP. 2123 The ethanol content of the extract and density of the extract are specified. 2124
Step 3. The resulting extract is stored in a stainless steel container for a minimum time 2125 (days/weeks) specified. The process ensures sedimentation of inorganic residual waste. 2126
Step 4. The extract is filtered using a pressurized process. Both the input pressure and filter size 2127 are specified by the manufacturer. 2128
2129 6. Process controls 2130 Controls for tests conducted during the process should be described. A description of the tests, their 2131 methods and the acceptance criteria should be given. These include appearance (i.e. colour), particle 2132 size (amount expected to pass through a specified sieve size), water or alcohol content, and/or relative 2133 density. 2134 2135 7. Release specifications of final product 2136 Identify criteria that must be met for release of the final product. These criteria generally include 2137 appearance, relative density, and specified quantities for chemical constituent(s), as well as limits for 2138 heavy metals, microbial content and residual matter. 2139 2140 Chemical profile: i.e. TLC/HPLC fingerprint of chemical constituents 2141
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Pharmacopoeial/standard quantitation of chemical markers, where applicable 2142 Heavy metals: limits defined 2143 Microbial: limits defined 2144 Residuals: limits for pesticides, fertilizers, foreign matter, etc. 2145 2146 8. Certificate of analysis 2147 A certificate of analysis will be generated following completion of quality control testing. This 2148 document should include the assay methods as well as the results obtained using those methods. 2149 2150 9. Packaging 2151 The appropriate packaging the containers should be described. Processed materials should be 2152 packaged quickly and appropriately in air-tight, non-corrosive containers, and protected from light to 2153 preserve quality, prevent deterioration and to protect against contamination. 2154 2155 10. Labelling 2156 Labels affixed to each package should clearly indicate the scientific name of the medicinal plant, the 2157 plant part, the processing method, the date of processing, the batch number, quality specification and 2158 compliance, quantitative and other relevant information. 2159 2160 11. Storage conditions 2161 The packaged products must be stored in a clean, dry and well-ventilated area, at a constant 2162 temperature appropriate for the proper maintenance of the final product, and protected against 2163 microbial and other sources of contaminations and free from insects and animal pest attacks 2164 2165 12. Stability 2166 Stability testing should be conducted to determine an appropriate shelf-life. 2167 2168 13. Retained samples 2169 Sufficient materials (raw material and finished goods) must be retained in proper storage conditions to 2170 allow for future verification of identity and quality. 2171 2172
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Annex 3: Example of general rules for preparation of dosage forms related to herbal 2173
medicines 2174 2175 [Reference Source: Japanese Pharmacopoeia 16th edition, Ministry of Health, Labour and Welfare, Mach 2011] 2176
2177
Japanese Pharmacopoeia, 16th Edition (2011): 2178
General Rules for Preparations/Monographs for Preparations Related to Crude Drugs 2179
2180 Monographs for Preparations Related to Crude Drugs 2181
2182 Preparations Related to Crude Drugs 2183 2184 (1) Preparations related to crude drugs are preparations mainly derived from crude drugs. Extracts, 2185 Pills, Spirits, Infusions and Decoctions, Teabags, Tinctures, Aromatic Waters, and Fluidextracts are 2186 included in this category. 2187 2188 Definitions, methods of preparations, test methods, containers and packaging, and storage of these 2189 preparations are described in this chapter. 2190 2191 (2) The descriptions of the test methods and the containers and packaging in this chapter are 2192 fundamental requirements, and the preparation methods represent commonly used methods. 2193 2194 1. Extracts 2195 (1) Extracts are preparations, prepared by concentrating extractives of crude drugs. There are 2196 following two kinds of extracts. 2197
(i) Viscous extracts 2198 (ii) Dry extracts 2199
2200 (2) Unless otherwise specified, Extracts are usually prepared as follows. 2201
(i) Crude drugs, pulverized to suitable sizes, are extracted for a certain period of time with 2202 suitable solvents by means of cold extraction or warm extraction, or by percolation as directed in (ii) 2203 of (2) under 6. Tinctures. The extractive is filtered, and the filtrate is concentrated or dried by a 2204 suitable method to make a millet jelly-like consistency for the viscous extracts, orto make crushable 2205 solid masses, granules or powder for the dry extracts. Extracts, which are specified the content of 2206 active substance(s), are prepared by assaying active substance(s) in a portion of sample and adjusting, 2207 if necessary, to specified strength with suitable diluents. 2208
(ii) Weigh crude drugs, pulverized to suitable sizes, according to the prescription and heat for a 2209 certain period of time after adding 10 ñ 20 times amount of water. After separating the solid and liquid 2210 by centrifugation, the extractive is concentrated or dried by a suitable method to make a millet jelly-2211 like consistency for the viscous extracts, or to make crushable solid masses, granules or powder for the 2212 dry extracts. 2213
2214 (3) Extracts have odour and taste derived from the crude drugs used. 2215 2216 (4) Unless otherwise specified, Extracts meet the requirements of Heavy Metals Limit Test <1.07>
1 2217 (for detail of test methods, procedure, and regents and solutions, see end note of this annex), when 2218 the test solution and the control solution are prepared as follows. 2219 2220 Test solution: Ignite 0.30 g of Extracts to ash, add 3mL of dilute hydrochloric acid, warm, and filter. 2221 Wash the residue with two 5-mL portions of water. Neutralize the combined filtrate and washings 2222
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(indicator: a drop of phenolphthalein TS) by adding ammonia TS until the color of the solution 2223 changes to pale red, filter where necessary, and add 2mL of dilute acetic acid and water to make 2224 50mL. 2225 2226 Control solution: Proceed with 3mL of dilute hydrochloric acid in the same manner as directed in the 2227 preparation of the test solution, and add 3.0mL of Standard Lead Solution and water to make 50mL. 2228 2229 (5) Tight containers are used for these preparations. 2230 2231 2. Pills 2232 (1) Pills are spherical preparations, intended for oral administration. 2233 2234 (2) Pills are usually prepared by mixing drug substance(s) uniformly with diluents, binders, 2235 disintegrators or other suitable excipient(s) and rolling into spherical form by a suitable method. They 2236 may be coated with a coating agent by a suitable method. 2237 2238 (3) Unless otherwise specified, Pills comply with Disintegration Test. 2239 2240 (4) Well-closed or tight containers are usually used for these preparations. 2241 2242 3. Spirits 2243 (1) Spirits are fluid preparations, usually prepared by dissolving volatile drug substance(s) in ethanol 2244 or in a mixture of ethanol and water. 2245 2246 (2) Spirits should be stored remote from fire. 2247 2248 (3) Tight containers are used for these preparations. 2249 2250 4. Infusions and Decoctions 2251 (1) Infusions and Decoctions are fluid preparations, usually obtained by macerating crude drugs in 2252 water. 2253 2254 (2) Infusions and Decoctions are usually prepared by the following method. 2255
Cut crude drugs into a size as directed below, and transfer suitable amounts to an infusion or 2256 decoction apparatus. 2257
Leaves, flowers and whole plants: Coarse cutting 2258 Woods, stems, barks, roots and rhizomes: Medium cutting 2259 Seeds and fruits: Fine cutting 2260
2261 (i) Infusions: Usually, damp 50 g of crude drugs with 50mL of water for about 15 minutes, pour 2262
900 mL of hot water to them, and heat for 5 minutes with several stirrings. Filter through a cloth after 2263 cooling. 2264
(ii) Decoctions: Usually, heat one-day dose of crude drugs with 400 ñ 600mL of water until to 2265 lose about a half amount of added water spending more than 30 minutes, and filter through a cloth 2266 while warm. Prepare Infusions or Decoctions when used. 2267 2268 (3) These preparations have odour and taste derived from the crude drugs used. 2269 2270 (4) Tight containers are usually used for these preparations. 2271 2272
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5. Tea bags 2273 (1) Tea bags are preparations, usually packed one day dose or one dose of crude drugs cut into a size 2274 between coarse powder and coarse cutting in paper or cloth bags. 2275 2276 (2) Teabags are usually used according to the preparation method as directed under 4. Infusions and 2277 Decoctions. 2278 2279 (3) Well-closed or tight containers are usually used for these preparations. 2280 2281 6. Tinctures 2282 (1) Tinctures are liquid preparations, usually prepared by extracting crude drugs with ethanol or with a 2283 mixture of ethanol and purified water. 2284 2285 (2) Unless otherwise specified, Tinctures are usually prepared from coarse powder or fine cuttings of 2286 crude drugs by means of either maceration or percolation as described below. 2287 2288
(i) Maceration: Place crude drugs in a suitable container, and add an amount of a solvent, 2289 equivalent to the same volume or about three-fourths of the volume of the crude drugs. Stopper 2290 container, and allow the container to stand for about 5 days or until the soluble constituents have 2291 satisfactorily dissolved at room temperature with occasional stirring. Separate the solid and liquid by 2292 centrifugation or other suitable methods. In the case where about three-fourths volume of the solvent is 2293 added, wash the residue with a suitable amount of the solvent, and squeeze the residue, if necessary. 2294 Combine the extract and washings, and add sufficient solvent to make up the volume. In the case 2295 where the total volume of the solvent is added, sufficient amounts of the solvent maybe added to make 2296 up for reduced amount, if necessary. Allow the mixture to stand for about 2 days, and obtain a clear 2297 liquid by decantation or filtration. 2298 2299
(ii) Percolation: Pour solvent in small portions to crude drugs placed in a container, and mix well 2300 to moisten the crude drugs. Stopper container, and allow it to stand for about 2 hours at room 2301 temperature. Pack the contents as tightly as possible in an appropriate percolator, open the lower 2302 opening, and slowly pour sufficient solvent to cover the crude drugs. When the percolate begins to 2303 drip, close the opening, and allow the mixture to stand for 2 to 3 days at room temperature. Then, open 2304 the opening, and allow the percolate to drip at a rate of 1 to 3mL per minute. Add an appropriate 2305 quantity of the solvent to the percolator, and continue to percolate until the desired volume has passed. 2306 Mix thoroughly, allow standing for 2 days, and obtain a clear liquid by decantation or filtration. The 2307 time of standing and the flow rate may be varied depending on the kind and amount of crude drugs to 2308 be percolated. 2309 2310 Tinctures, prepared by either of the above methods and specified the content of marker constituent or 2311 ethanol, are prepared by assaying the content using a portion of the sample and adjusting the content 2312 with a sufficient amount of the percolate or solvent as required on the basis of the result of the assay. 2313 2314 (3) Tinctures should be stored remote from fire. 2315 2316 (4) Tight containers are used for these preparations. 2317 2318 7. Aromatic Waters 2319 (1) Aromatic Waters are clear liquid preparations, saturated essential oils or other volatile substances 2320 in water. 2321 2322 (2) Unless otherwise specified, Aromatic Waters are usually prepared by the following process. Shake 2323
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thoroughly for 15 minutes 2mL of an essential oil or 2 g of a volatile substance with 1000 mL of 2324 lukewarm purified water, set the mixture aside for 12 hours or longer, filter through moistened filter 2325 paper, and add purified water to make 1000 mL. Alternatively, incorporate thoroughly 2 mL of an 2326 essential oil or 2 g of a volatile substance with sufficient talc, refined siliceous earth or pulped filter-2327 paper, add 1000 mL of purified water, agitate thoroughly for 10 minutes, and then filter the mixture. 2328 To obtain a clear filtrate repeat the filtration if necessary, and add sufficient purified water passed 2329 through the filter paper to make 1000mL. 2330 2331 (3) Aromatic Waters have odour and taste derived from the essential oils or volatile substances used. 2332 2333 (4) Tight containers are used for these preparations. 2334 2335 8. Fluidextracts 2336 (1) Fluidextracts are liquid percolates of crude drugs, usually prepared so that each mL contains 2337 soluble constituents from 1 g of the crude drugs. Where the content is specified, it takes precedence. 2338 2339 (2) Unless otherwise specified, Fluidextracts are usually prepared from coarse powder or fine cutting 2340 of crude drugs by either of following maceration or percolation. 2341 2342
(i) Maceration: Place a certain amounts of crude drugs in a suitable vessel, add a solvent to cover 2343 the crude drugs, close the vessel, and allow the vessel to stand at room temperature with occasional 2344 stirring for about 5 days or until the soluble constituents have satisfactorily dissolved. Separate the 2345 solid and liquid by centrifugation or other suitable method. Usually, reserve a volume of the liquid 2346 equivalent to about three-fourths of the total volume, and use it as the first liquid. Wash the residue 2347 with appropriate amount of the solvent, combine the washings and the remaining of the first liquid, 2348 concentrate if necessary, mix with the first liquid, and use it as solution (A). To the solution (A) add 2349 the solvent, if necessary, to make equal amount of the mass of the crude drugs. Allow the mixture to 2350 stand for about 2 days, and collect a clear liquid by decantation or filtration. 2351 2352
(ii) Percolation: Mix well 1000 g of the crude drugs with the first solvent to moisten them, close 2353 the container, and allow it to stand for about 2 hours at room temperature. Transfer the content to a 2354 suitable percolator, stuff it as tightly as possible, open the lower opening of the percolator, and slowly 2355 pour the second solvent to cover the crude drugs. Close the lower opening when the solvent begins to 2356 drop, and allow the mixture to stand for 2 to 3 days at room temperature. Open the lower opening, and 2357 allow the percolate to run out at the rate of 0.5 to 1.0mL per minute. Set aside the first 850 mL of the 2358 percolate as the first percolate. Add the second solvent to the percolator, then drip the percolate, and 2359 use it as the second percolate. 2360 2361 The period of standing and the flow rate during percolation may be varied depending on the kind and 2362 the amount of crude drugs used. The flow rate is usually regulated as follows, depending on the using 2363 amount of crude drugs. 2364 2365
Mass of crude drug
Volume of solution running per
minute
Not more than 1000 g
Not more than 3000 g
Not more than 10000g
0.5 - 1.0mL
1.0 - 2.0mL
2.0 - 4.0mL
2366 Concentrate the second percolate, taking care not to lose the volatile substances of the crude drug, mix 2367 with the first percolate, and use it as solution (A). To the solution (A) add the second solvent to make 2368
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1000 mL, and allow the mixture to stand for about 2 days. Decant the supernatant liquid or filter the 2369 liquid to obtain a clear solution. 2370 2371 Fluidextracts for which the content of marker constituent or ethanol is specified are obtained by 2372 adjusting the content with a sufficient amount of the second solvent as required on the basis of the 2373 result of the assay made with a portion of the solution (A). 2374 2375 (3) Fluidextracts have odour and taste derived from the crude drugs used. 2376 2377 (4) Unless otherwise specified, Fluidextracts meet the requirements of Heavy Metals Limit Test 2378 <1.07>
1 when the test solution and the control solution are prepared as follows. 2379
2380 Test solution: Ignite 1.0 g of Fluidextracts to ash, add 3 mL of dilute hydrochloric acid, warm, and 2381 filter. Wash the residue with two 5-mL portions of water. Neutralize the combined filtrate and 2382 washings (indicator: a drop of phenolphthalein TS) by adding ammonia TS until the colour of the 2383 solution changes to pale red, filter if necessary, and add 2 mL of the dilute acetic acid and water to 2384 make 50 mL. 2385 2386 Control solution: Proceed with 3 mL of dilute hydrochloric acid in the same manner as directed in the 2387 preparation of the test solution, and add 3.0 mL of Standard Lead Solution and water to make 50 mL. 2388 2389 (5) Tight containers are used for these preparations. 2390 2391 1Test <1.07> 1.07 Heavy Metal Limit test (JP 16, pp21-23) 2392
Heavy Metals Limit Test is a limit test of the quantity of heavy metals contained as impurities in drugs. The heavy metals 2393 are the metallic inclusions that are darkened with sodium sulfide TS in acidic media, as their quantity is expressed in terms of 2394 the quantity of lead (Pb). In each monograph, the permissible limit for heavy metals (as Pb) is described in terms of ppm in 2395 parentheses. 2396 2397 Procedure: 2398 Add 1 drop of sodium sulfide TS to each of the test solution and the control solution, mix thoroughly, and allow to stand for 5 2399 minutes. Then compare the colors of both solutions by viewing the tubes downward or transversely against a white 2400 background. The test solution has no more color than the control solution. 2401 2402 Solutions and Reagents: 2403 Standard Lead Solution 2404 Measure exactly 10 mL of Standard Lead Stock Solution, and add water to make exactly 100 mL. Each mL of this solution 2405 contains 0.01 mg of lead (Pb). Prepare before use. 2406 2407 Standard Lead Stock Solution 2408 Weigh exactly 159.8 mg of lead (II) nitrate, dissolve in 10 mL of dilute nitric acid, and add water to make exactly 1000 mL. 2409 Prepare and store this solution using glass containers, free from soluble lead salts. 2410 2411 Ammonia solution (28) 2412 NH4OH [K 8085, Ammonia Water, Special class, Density: 0.90 g/mL, Content: 28- 30%] 2413 2414 Ammonia TS 2415 To 400 mL of ammonia solution (28) add water to make 1000 mL (10%). 2416 2417 Acetic acid, dilute 2418 Dilute 6 g of acetic acid (100) with water to make 100 mL (1 mol/L). 2419 2420 Acetic acid (100) 2421 CH3COOH [K 8355, Acetic Acid, Special class] 2422 2423 Dilute acetic acid 2424 See acetic acid, dilute. 2425
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2426 Dilute hydrochloric acid 2427 See hydrochloric acid, dilute. 2428 2429 Hydrochloric acid, dilute 2430 Dilute 23.6 mL of hydrochloric acid with water to make 100mL (10%). 2431 2432 Hydrochloric acid 2433 HCl [K 8180, Special class] 2434 2435 Phenolphthalein TS 2436 Dissolve 1 g of phenolphthalein in 100 mL of ethanol (95). 2437 2438 Phenolphthalein 2439 C20H14O4 [K 8799, Special class] 2440 2441 Ethanol (95) 2442 C2H5OH [K 8102, Special class] 2443 2444 Sodium sulfide enneahydrate 2445 Na2S.9H2O [K 8949,Special class] 2446 2447 Sodium sulfide TS 2448 Dissolve 5 g of sodium sulfide enneahydrate in a mixture of 10 mL of water and 30 mL of glycerin. Or dissolve 5 g of 2449 sodium hydroxide in a mixture of 30 mL of water and 90 mL of glycerin, saturate a half volume of this solution with 2450 hydrogen sulfide, while cooling, and mix with the remaining half. Preserve in well-filled, light-resistant bottles. Use within 3 2451 months. 2452 2453 Sodium hydroxide 2454 NaOH [K 8576, Special class] 2455 2456 Glycerin 2457 C3H8O3 [K 8295, Glycerol, Special class. Same as the monograph Concentrated Glycerin] 2458 2459 Hydrogen sulfide 2460 H2S Colorless, poisonous gas, heavier than air. It dissolves in water. Prepare by treating iron (II) sulfide heptahydrate with 2461 dilute sulfuric acid or dilute hydro chloric acid. Other sulfides yielding hydrogen sulfide with 2462 dilute acids may be used. 2463 2464 Sulfuric acid 2465 H2SO4 [K 8951, Special class] 2466 2467 Sulfuric acid, dilute 2468 Cautiously add 5.7 mL of sulphuric acid to 10 mL of water, cool, and dilute with water to make 100 mL (10%). 2469 2470 Iron (II) sulfate heptahydrate 2471 FeSO4.7H2O [K 8978, Special class] 2472 2473
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Annex 4: Processing facilities 2474
2475 The following is extracted from Section 4.1.5 of the WHO guidelines on good agricultural and collection 2476 practices (GACP) for medicinal plants (WHO, 2003) (pages 19-23). 2477 2478 4.1 Processing facilities 2479 2480 In constructing or designing a processing facility, the following elements should be considered that 2481 will allow the establishment of a quality assurance system adaptable to the different types and steps of 2482 processing to yield the desired end products. 2483 2484 Location 2485 Facilities should preferably be located in areas that are free from objectionable odours, smoke, dust or 2486 other contaminants, and are not subject to flooding or other natural adverse conditions. 2487 2488 Buildings 2489 Buildings should be of sound construction and maintained in good repair. Filthy areas must be isolated 2490 from clean processing areas. All construction materials should be such that they do not transmit any 2491 undesirable substance including toxic vapours to medicinal plant materials. Electrical supply, lighting, 2492 and ventilation should be appropriately installed. 2493 2494 Buildings should be designed to: 2495 provide adequate working space and storage room to allow for satisfactory performance of all 2496
operations; 2497 to ensure the logical flow of materials and personnel; 2498 facilitate efficient and hygienic operations by allowing a regulated flow in processing from the 2499
arrival of the raw medicinal plant materials at the premises to the dispatch of the processed 2500 medicinal plant materials; 2501
permit appropriate control of temperature and humidity; 2502 permit control of access to different sections, where appropriate; 2503 permit easy and adequate cleaning and facilitate proper supervision of hygiene; 2504 prevent the entry of environmental contaminants such as smoke, dust, the entrance and harbouring 2505
of pests, livestock and domesticated animals. 2506 2507 Medicinal plant material handling and processing areas 2508 The layout and design of the work area should be such as to minimize the risk of errors and permit 2509 effective cleaning and maintenance in order to avoid cross contamination, and otherwise avoid any 2510 adverse effect on the quality of the processed product. 2511 2512 Windows and other openings should be constructed so as to avoid accumulation of dirt, and those 2513
that open should be fitted with insect-proof screens. Screens should be easily removable for 2514 cleaning and kept in good repair. Internal window sills, if present, should be sloped to prevent use 2515 as shelves. 2516
Doors should have smooth, non-absorbent surfaces and, where appropriate, be self-closing and 2517 close-fitting. 2518
Overhead structures and fittings should be installed in such a manner as to avoid contamination of 2519 medicinal plant materials (both raw and processed) by condensation and drippings, and should be 2520 protected to prevent contamination in case of breakage. They should be insulated, where 2521 appropriate, and be designed and finished so as to prevent the accumulation of dirt and to 2522 minimize condensation, mould development and flaking. They should be easy to clean. 2523
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- WHO guidelines on good herbal processing practices (GHPP) for herbal medicines -
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Food preparation and eating areas, changing facilities, toilets should be completely separated from 2524 and not open directly onto medicinal plant material processing areas. 2525
2526 Water supply 2527 An ample supply of potable water, under adequate pressure and at suitable temperature, used for 2528
processing medicinal plant materials, should be available with appropriate facilities for its storage, 2529 where necessary, and distribution, and with proper protection against contamination. 2530
Ice should be made from potable water; it should be manufactured, handled and stored so as to 2531 protect it against contamination. 2532
Non-potable water used for steam production, refrigeration, fire control and other similar purposes 2533 not connected with processing should be carried in completely separate pipes, identifiable 2534 preferably by colour, and with no cross-connection with or back siphonage into the system 2535 carrying potable water. 2536
2537 Effluent and waste disposal 2538 Facilities should have an effective effluent and waste disposal system, which should at all times be 2539 maintained in good order and repair; and should be constructed so as to avoid contamination of 2540 potable water supplies. 2541 2542 Changing facilities and toilets 2543 Adequate, suitable and conveniently located changing facilities and toilets should be provided. Hand-2544 washing facilities with warm or hot and cold water, a suitable hand-cleaning preparation and hygienic 2545 means of drying should be provided adjacent to toilets and located so that employees have to pass 2546 them when returning to the processing area. Notices should be posted directing personnel to wash 2547 their hands after using the toilet. 2548 2549 Hand-washing facilities in processing areas 2550 Adequate and conveniently located facilities for hand-washing and a hygienic means of drying should 2551 be provided whenever the process demands. Where appropriate, facilities for hand disinfection should 2552 also be provided. 2553 2554 Disinfection facilities 2555 Where appropriate, adequate facilities for cleaning and disinfection of working implements and 2556 equipment should be provided. These facilities should be constructed of corrosion-resistant materials, 2557 should be easy to clean, and should be fitted with hot and cold water supplies. 2558 2559 Lighting 2560 Adequate natural or artificial lighting should be fitted throughout the facility. Where appropriate, the 2561 lighting should not alter colours of the medicinal plants undergoing processing. 2562 2563 Ventilation 2564 Adequate ventilation should be provided to prevent excessive heat, steam condensation and dust and 2565 to remove contaminated air from both the processing and storage areas/facilities. 2566 2567 Storage of waste and unusable materials 2568 Facilities should be provided for the storage of waste and unusable materials prior to removal from the 2569 premises. 2570