good pharmacopoeial practices draft chapter on monographs on herbal medicines · working document...

Working document QAS/15.621/Rev.4

7 September 2017

Draft

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GOOD PHARMACOPOEIAL PRACTICES 4

Draft chapter on monographs on herbal medicines 5

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(DISCUSSED 7

during the 8th international meeting of world pharmacopoeias, 8

terminology added 7/9/2017) 9

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© World Health Organization 2017 14

All rights reserved. 15

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. 16 The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or 17 in whole, in any form or by any means outside these individuals and organizations (including the organizations' 18 concerned staff and member organizations) without the permission of the World Health Organization. The draft should 19 not be displayed on any web site. 20

Please send any request for permission to: 21

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Regulation of 22 Medicines and other Health Technologies, Department of Essential Medicines and Health Products, World Health 23 Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: [email protected]. 24 25 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 26 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or 27 area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent 28 approximate border lines for which there may not yet be full agreement. 29

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 30 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 31 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 32

All reasonable precautions have been taken by the World Health Organization to verify the information contained in 33 this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. 34 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 35 Organization be liable for damages arising from its use. 36

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 37

Please address any comments on this proposal by 5 October 2017 to Dr S. Kopp, Group Lead, Medicines

Quality Assurance, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or

email: [email protected] with a copy to [email protected]

.

mailto:[email protected]

mailto:[email protected]


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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.621: 39

GOOD PHARMACOPOEIAL PRACTICES – CHAPTER ON MONOGRAPHS ON 40

HERBAL MEDICINES/DRUGS 41

Need for good pharmacopoeial practices (GPhP) stated during

first international meeting of world pharmacopoeias, Geneva,

and other related events with stakeholders

28 February–1 March 2012

7–8 October 2012

9–12 October 2012

21–22 October 2012

First draft of good pharmacopoeial practices (GPhP) sent out

for comment (QAS/12.516)

17 October 2012

Compilation of feedback and comments received November–December 2012

Circulation of GPhP to drafting group on GPhP with

comments, as well as Concept paper on scope and background

(QAS/13.518)

18 January 2013

Formation of initial drafting group (IDG), including

representatives from each pharmacopoeia, as per self-

nomination, to review draft concept paper via teleconference

call

February 2013

Preparation of new skeleton and first draft with more detailed

structure

February 2013

Mailing to world pharmacopoeias for additional feedback,

preparation of draft chapters by drafting group

February–March 2013

Compilation of feedback April 2013

Discussion of draft working document on good

pharmacopoeial practices at second international meeting of

world pharmacopoeias, New Delhi, India

18–19 April 2013

Revised version of GPhP prepared and mailed out for

comments to all pharmacopoeias, for feedback to be provided

to lead pharmacopoeias for each chapter

28 May 2013

Discussion of feedback during informal consultation to

discuss new medicines, quality control and laboratory

standards

12–14 June 2013

Revision of each chapter by each GPhP lead pharmacopoeia 28 June 2013

Mailing of each chapter to WHO for compilation into a

revised working document

July 2013–December 2013

Presentation to forty-eighth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical Preparations

October 2013

Compilation of all various chapters received from the lead

pharmacopoeias and mailing out to all world pharmacopoeias

January 2014

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Compilation of all comments received March 2014

Discussion during the 3rd international meeting of world

pharmacopoeias in London, United Kingdom

10–11 April 2014

Revised version of GPhP prepared and mailed out for

comments to all pharmacopoeias, for feedback to be provided

to each chapter

July 2014

Compilation of all comments received 22 September 2014

Following feedback and discussions during two telephone

conference calls of the subgroup working on the Technical

Annex to the future GPhP the European Pharmacopoeia

Secretariat prepared a significantly shortened draft which is

circulated for comments

23 September 2014

Compilation of all comments received 30 September 2014

Discussion during the 4th international meeting of world

pharmacopoeias in Strasbourg, France

8–10 October 2014

Briefing on progress to forty-ninth meeting of the WHO

Expert Committee on Specifications for Pharmaceutical

Preparations

13–17 October 2014

Continuation of consultation process with world

pharmacopoeias

October 2014–January 2015

Continuation of consultation process with world

pharmacopoeias and worldwide

Mid-January–mid-March 2015

GPhP Chapter 5.4.2: Monographs on Herbals

medicines/drugs drafted by the Indian Pharmacopoeia

Committee (IPC)

April 2013

Comments received by pharmacopoeias and track change

proposals made by USP

2014

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Additional feedback received from various pharmacopoeias to

GPhP Chapter 5.4.2: Monographs on herbals

___________________________

March 2015

Comments reviewed and feedback added by IPC April 2015

Working document sent out to all pharmacopoeias for

comments and feedback

May 2015

Compilation of comments received August 2015

Discussion of feedback during the 6th international meeting

of world pharmacopoeias

September 2015, dates tbc with

the Chinese Pharmacopoeia

Commission


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Presentation to the fiftieth meeting of the WHO Expert


12–16 October 2015

Comments reviewed and feedback added by IPC April 2016



May–June 2016

Compilation of comments received and inclusion of proposed

changes by WHO Secretariat + mailing of feedback and new

draft to all pharmacopoeias

July–August 2016



13–14 September 2016



September 2016

Presentation to the fifty-first meeting of the WHO Expert


17–21 October 2016

Working document sent out (Rev. 2) to all pharmacopoeias

for comments and feedback

November 2016

Compilation of comments received March–May 2017



11–12 July 2017

Circulation to world pharmacopoeias and for public feedback,

addition of glossary after the Third WHO consultation on

quality control of herbal medicines planned to be held in

Hong Kong SAR, China, 4-6 September 2017, during which

the Good Herbal Processing Practices with related

terminology will be discussed – added 7/9/2017

July–September 2017

Presentation to the fifty-second meeting of the WHO Expert


16–20 October 2017

Any follow-up action as necessary

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MONOGRAPHS ON HERBAL MEDICINES 54

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1. INTRODUCTION 56

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Pharmacopoeial monographs for herbal medicines should contain information in the 58

definition that is consistent with the monograph title followed by specifications for 59

quality including identity, purity and content. Individual monographs describe test 60

procedures together with the corresponding specifications. The monograph may include: 61

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an official title; 63

a definition; 64

an identification section; 65

a test section covering, for example, physicochemical tests and, where 66

appropriate, tests on contaminants; 67

an assay section determining constituents with known therapeutic activity, active 68

or analytical markers. 69

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Further sections providing information on labelling and storage may also be provided. 71

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2. GENERAL CHAPTER 73

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The general testing methods and other specifications that are common for herbal 75

medicines may be described in a General Chapter. 76

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3. INDIVIDUAL MONOGRAPHS ON HERBAL MEDICINES 78

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3.1 Monograph title 80

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The title of the monograph may include the Latin name, or the well-established common 82

local name and English common name, if available, in addition to the scientific name. 83


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This is followed by the name of plant part(s) or plant material (e.g. resin, gum-resin) and 84

where applicable, its state and type of herbal preparation (e.g. liquid extract, dry extract) 85

and its dosage form (tablet, capsule, etc.). Individual pharmacopoeias may apply their 86

own nomenclature policies that meet regulatory needs and reflect the common names in 87

commerce, as appropriate. 88

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3.2 Definition 90

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The definition provides details about the subject of the monograph and includes the Latin 92

binomial name and the taxonomic authority (abbreviation if used should be according to 93

internationally-accepted rules), the plant family name if required by national legislations, 94

the well-established common local name and English common name (if available, in 95

addition to the scientific name), and well-recognized synonyms, the plant part(s) (i.e. 96

aerial parts, root, leaves, flowers, rhizome, etc.), plant material (e.g. resin, gum-resin and 97

where applicable, its state and type of herbal preparation (e.g. liquid extract, dry extract) 98

and its dosage form (tablet, capsule, etc.). When necessary, as dictated and supported by 99

data, the definition also states the season or period in which plant material should be 100

harvested according to Good Agricultural and Collection Practices (GACP). If more than 101

one species is included in the monograph the definition should include, for each of the 102

species, the requirements listed above. The definition should include the chemical names, 103

and/or molecular formulas of relevant known constituents, for which there is a specified 104

range or minimum content, in percentage, usually calculated on the basis of the dry 105

weight of the herbal medicines. Where a monograph applies to the herbal medicines in 106

different states or stages of processing (DEFINE “STATES” IN GLOSSARY, 107

including…), this is stated in the definition. 108

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3.3 Identification 110

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The purpose of the Identification section is to ensure that the herbal medicine under 112

examination is in agreement with what is stated in the Definition section. It is only 113

necessary to include those techniques that are applicable for the identification of specific 114

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herbal medicines. Macroscopic and microscopic descriptions of a herbal medicine may be 115

supported by illustrations. Identification tests should be specific for the herbal medicine. 116

Typically, several identification tests, using independent approaches, are required in 117

order to confirm the identity of the herbal medicine. The tests given in the identification 118

section are not designed to give a full confirmation of the chemical structure or 119

composition of the herbal medicine. They are intended to give confirmation, with an 120

acceptable degree of assurance, that the herbal medicine is the one stated on the label. 121

Test methods, if applicable, should be able to detect substitutes or adulterants that are 122

likely to be found. 123

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[Note from Secretatriat: 126

Definition for “Adulterant” in TRS 1003, Annex 1: 127

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Adulterant is herbal material, a herbal constituent or other substance that is either 129

deliberately or non-intentionally (through cross-contamination or contamination) added 130

to a herbal material, herbal preparation, or finished herbal product.] 131

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3.3.1 Macroscopic characters 134

The important macroscopic botanical characteristics of the herbal materials are specified 135

to permit a clear identification. Where two or more species of a genus or subspecies are 136

included in the definition, the differences, if any, between them should be indicated. 137

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3.3.2 Microscopic characters 139

The microscopic examination of herbal materials is useful in determining the identity of 140

herbal materials. Histological characters, such as microscopic characters of a transverse 141

or longitudinal section may support the identification. For herbal materials where 142

macroscopic identification cannot be performed (for example, powdered herbal 143

materials), the microscopic characters are important to determine the identity. 144

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3.3.3 Chemical tests 146

Chemical tests, such as colour tests, can also be useful in determining the presence of 147

substitution, adulteration or other foreign matters. Non-specific chemical tests must be 148

avoided. Phytochemical screening tests that recognize general classes of compounds such 149

as alkaloids, flavonoids, terpenes, steroids, saponins, tannins, etc., must be avoided unless 150

they provide a means to differentiate potential adulteration due to species 151

substitution/adulteration. 152

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3.3.4 Fingerprinting 154

Chromatographic or spectroscopic patterns, often referred to as “fingerprints”, may be 155

used for identification as appropriate. The fingerprints should ideally be able to 156

distinguish the herbal materials from other species that constitute both intentional and 157

unintentional adulterations. 158

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Fingerprints may be obtained, for example, by thin-layer chromatography (TLC), high-160

performance thin-layer chromatography (HPTLC), high-performance liquid 161

chromatography (HPLC), ultra-high performance liquid chromatography (UHPLC), 162

capillary electrophoresis (CE) or gas chromatography (GC) methods. The methods 163

should include all of the information required to perform the test, for example, 164

preparation of sample and reference solutions, nature of plates/columns, testing 165

conditions, mobile phase preparation, flow rate, method of detection/detectors. 166

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The results of such testing to be considered must contain a description of the critical 168

features of the fingerprint chromatograms such as the presence of specific peaks or 169

bands/spots, relative retentions or relative retention values, retardation or retention factor 170

(RF or Rf), their order of elution and, where applicable, their relative abundance. A colour 171

image of a typical reproducible TLC fingerprint may be provided as a guide for users. 172

Pharmacopoeias may consider providing reference standards (RS) to be used for 173

fingerprint testing. 174

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3.3.5 DNA-based tests 177

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The DNA-based tests, such as PCR and DNA sequencing, can be useful in identifying 179

specific herbal materials or detecting adulteration with either related or unrelated species 180

that are difficult to distinguish with other methods. 181

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3.4 Assay 183

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Where the constituent(s) responsible for therapeutic activity of the herbal medicine is/are 185

known, its/their quantitative determination should be included. In herbal medicine where 186

the chemical constituent(s) responsible for known pharmacological/therapeutic activity 187

is/are not known, the pharmacopoeia may include testing for determination of the 188

chemical constituent that act as analytical marker(s). Individual pharmacopoeias may 189

include an assay procedure for one or more marker compounds. Where an assay of one or 190

more chemical constituents is carried out, assay limits are specified either as a minimum 191

content or as a percentage content range. Where constituents are present in a herbal 192

medicine which are known to degrade (e.g. due to improper drying, storage under high 193

temperatures or extended storage), those constituents may be used as analytical markers 194

to control the quality of the herbal medicine. 195

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Stability-indicating chromatographic procedures that are validated for routine quality 197

control work should be used. Individual pharmacopoeias may adopt either requirement 198

for validation of assay methods on lines similar to those adopted for chromatographic 199

procedures for synthetic drugs or developing assay methods. Development of assay 200

methods through a collaborative process involving several laboratories, or other suitable 201

approaches, may be adopted. 202

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3.5 Tests for contaminants/impurities 204

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3.5.1 General 206

Tests for the following parameters should be included and limits specified as appropriate: 207


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foreign matter; 209

elemental contaminants/impurities (for, e.g. toxic metals such as lead, cadmium, 210

mercury and arsenic); 211

microbiological quality: national pharmacopoeias may consider specifying 212

requirements for total aerobic microbial count (TAMC) and total combined 213

yeast/moulds count (TYMC) as well as for specified microorganisms, for 214

example, bile-tolerant gram negative bacteria, Escherichia coli and Salmonella; 215

mycotoxins; 216

toxic/harmful substances (such as pesticide residues, radionuclides and natural 217

toxins); 218

residual solvents. 219

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3.5.2 Specific 221

An individual herbal medicine may require specifications that are peculiar to that item, 222

especially when patient safety is an issue. Limits should be set on certain constituents of 223

the herbal medicines that may be considered undesirable “negative markers”, negative 224

botanic characteristics or histological parameters. Impact on safety/description may form 225

the basis for such test and limits are specified. 226

227

For some individual herbal medicines, there could be risk of adulteration by herbal 228

medicines that have a related morphological appearance or are marketed under similar 229

common names. In such cases, additional tests as appropriate may be specified to detect 230

and determine such adulterants. Where appropriate, tests on compounds (like alkaloids or 231

cardiotonic steroids, etc.) that may impact the safety of the herbal medicines may be 232

included in the monograph. 233

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3.6 Physicochemical tests 235

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Physicochemical tests can serve as a valuable source of information and provide 237

appropriate characterization standards to establish the quality of herbal medicines. Such 238

evaluations may include: 239

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water and/or alcohol extractable matter; 241

total ash content; 242

water soluble ash; 243

alcohol-soluble ash; acid-insoluble ash; 244

loss on drying; 245

water content; 246

volatile oils, etc. 247

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3.7 Other tests 249

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The following tests may be included as appropriate: 251

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swelling index; 253

bitterness values; 254

particle size; or 255

any other test(s) found appropriate to the particular herbal medicine or material. 256

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Taste and/or odour as definitions or test procedures may be inappropriate for user safety 258

reasons and should be avoided. 259

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3.8 Additional information 261

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3.8.1 Packaging, labelling and storage 263


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Labelling requirements consistent with applicable national/regional legislation may be 264

provided. Storage conditions may be provided when considered necessary to prevent 265

contamination and/or are necessary to minimize possible deterioration. Guidance 266

statements specifying the packaging may be included in the monograph, in specific cases, 267

where applicable, for example, oils or oleoresins or distilled oils. 268

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3.8.2 Reference standards 270

The pharmacopoeias may describe the use of reference standards in the analysis of 271

individual herbal medicines. RS may be authentic pure compounds or extracts of herbal 272

materials or powdered herbal materials used for comparison. The RS established by 273

individual pharmacopoeias are suitable for testing purposes. 274

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GLOSSARY 276

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[Note from the Secretariat: 278

The following terms relating to herbal medicines have been redefined in connection with 279

the development of new WHO guidelines in the area of good practices for herbal 280

medicines. The following may serve for the Glossary, but were not yet agreed upon by the 281

world pharmacopoeias during the 2016 meeting in Tokyo, Japan. 282

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During the 8th meeting in Brasilia it was agreed to add the glossary after the Third 284

WHO consultation on quality control of herbal medicines planned to be held in Hong 285

Kong SAR, China, 4–6 September 2017 – during which the Good Herbal Processing 286

Practices and related terminology will be discussed – and recirculate the text thereafter. 287

7/9/2017, please find the terminology agreed upon in that meeting included below] 288

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Herbal medicines include herbs and/or herbal materials and/or herbal preparations 291

and/or finished herbal products in a form suitable for administration to patients. 292

[WHO, 2017] 293

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Note: In some countries herbal medicines may contain, by tradition, natural 294

organic or inorganic active ingredients that are not of plant origin (e.g. animal and 295

mineral materials, fungi, algae, lichens, etc). 296

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Herbs [WHO, 2000] 298

Herbs include crude plant materials such as leaves, flowers, fruit, seed, stems 299

wood, bark, roots, rhizomes or other plant parts, which may be entire, fragmented 300

or powdered. 301

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Herbal materials [WHO 2000]* 303

Herbal materials include, in addition to herbs, fresh juices, gums, fixed oils, 304

essential oils, resins, and dry powders of herbs. In some countries, these materials 305

may be processed by various local procedures, such as steaming, roasting, or stir-306

baking with honey, alcoholic beverages or other plant materials. 307

* The participants of the 3rd

WHO consultation on quality control, held in Hong 308

Kong SAR, China from 4 to 6 September 2017 recommended that latex and 309

exudates can be included. 310

311

Herbal preparations [WHO, 2000] 312

Herbal preparations are the basis for finished herbal products and may include 313

comminuted or powdered herbal materials, or extracts, tinctures and fatty oils of 314

herbal materials. They are produced by extraction, fractionation, purification, 315

concentration, or other physical or biological processes. They also include 316

preparations made by steeping or heating herbal materials in alcoholic beverages 317

and/or honey, or in other materials. 318

319

Finished herbal products [WHO, 2017] 320

Finished herbal products consist of one or more herbal preparations made from 321

one or more herbs (i.e. from different herbal preparations made of the same plant 322

as well as herbal preparations from different plants. Products containing different 323

plant materials are called “mixture herbal products”). 324


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Finished herbal products and mixture herbal products may contain excipients in 326

addition to the active ingredients. However, finished products or mixture herbal 327

products to which chemically defined active substances have been added, 328

including synthetic compounds and/or isolated constituents from herbal materials, 329

are not considered to be “herbal”. 330

331

Herbal dosage forms 332

Herbal dosage forms are the physical form (liquid, solid, semi-solid) of herbal products 333

produced from herbs, with or without excipients, in a particular formulation (such as 334

decoctions, tablets, and ointments). They are produced either from herbal materials (such 335

as dried roots or fresh juices) or herbal preparations (such as extracts). 336

337

Medicinal plants are plants (wild or cultivated) used for medicinal purposes [WHO, 338

2003a]; [WHO, 2006; WHO, 2007a]. 339

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Medicinal plant materials: see Herbal materials 341

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State [QAS/15.621/Rev.2] 343

The state of the herbal material means whole, fragmented, peeled, cut, fresh or dried. 344

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