Working Group on Harmonization of Standards and Regulatory Framework of Herbal Medicines, Seoul, Republic of Korea, 27 - 30 November 2001 : report

(WP)TLRIICP/HRF/001/RB/2000 Report series number: RS/2001/GE/29(KOR)

English only

REPORT

WORKING GROUP ON HARMONIZATION OF STANDARDS AND REGULATORY FRAMEWORK OF HERBAL MEDICINES

Convened by: WORLD HEALTH ORGANIZATION REGIONAL OFFICE FOR THE WESTERN PACIFIC Seoul, Republic of Korea 27-30 November 2001

Not for sale Printed and distributed by: World Health Organization Regional Office for the Western Pacific Manila, Philippines January 2002

NOTE

The views expressed in this report are those of the participants in the Working Group on Hannonization of Standards and Regulatory Framework of Herbal Medicines and do not necessarily reflect the policy of the World Health Organization.

This report has been prepared by the Regional Office for the Western Pacific of the World Health Organization for governments of Member States in the Region and for the participants in the Working Group on Hannonization of Standards and Regulatory Framework of Herbal Medicines held in Seoul, Republic ofKorea from 27-30 November 2001.

CONTENTS

SUMMARY .............. ,.._..... ................................................................ ........... ..... ................. .... 1 I. INTRODUCTION ............................ ... ............ .. .......................... ............... ...... ......... ....... 3 1.1 1.2 1.3 1.4 2. Objectives of the meeting .. .......................... ...... .. ........ ......................... ................. .. . 4 Participants ........................ ......... ............... ...... ... ... ................. ... ...... ....................... .. 4 Organization ...................... .............................................. ........................ .. ............... 4 Opening ceremony ............. .... .... ... ...................................................... ............. ....... .. 5

PROCEEDINGS ...................... .. ..................... ... ..... ..... .................. ..... ... .. ....... .. ................ 5 2.1 Initial presentations ................................................................................. ... .............. 5 2.2 Country reports ........................................................................................ ... ... ........... 7 2.3 Working groups and plenary sessions ...................................................... ............... 14 2.4 Closing ceremony ...................................................................................... .......... ... 14

3. 4.

CONCLUSIONS .... ..... ... .. ......................... ........................... .... ........... ........................... 14 RECOMMENDATIONS ........... .. ....... .. .. .. ......... .. ........................ .. ......... .. ......... ............. 23 ANNEXES: ANNEX 1 LIST OF TEMPORARY ADVISERS, CONSULT ANT, OBSERVERS AND SECRETARIAT ....................................... ... .......... 27 COUNTRY REPORTS .......................................................... ....... ......... 35 AUSTRALIA ........................................................................ ....... ......... 35 PEOPLE'S REPUBLIC OF CHINA .......................................... .... ......... 41 HONG KONG (CHINA) ........................................................ ..... .......... 53 JAPAN ................................ .................................................................. 55 REPUBLIC OF KOREA ....... .... ...................... ....................................... 61 SINGAPORE ........................ ................................................................. 65 VIETNAM ............................ ..... .. ...... .. ...... .......................................... 73 Keywords

ANNEX 2

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Medicine, Herbal- standards I Drug and quality control I Korea

SUMMARY

The Working Group on Harmonization of Standards and Regulatory Framework of Herbal Medicines met in Seoul, Republic of Korea, from 27 to 30 November 2001. The main objectives of the meeting were: ( 1) to share expenences ot regulatory measures to control the quality of herbal medicines; (2) to identify issues relating to collaboration within and among participating countries on quality and standards of herbal medicine; (3) to identify practical mechanisms for harmonizing herbal medicines, particularly regulatory requirements, quality and standard of herbal medicines; (4) to define the areas of collaboration and the role of each of the participating countries; and medicine; and (5) to develop a plan on harmonizing herbal medicines among participating and other interested countries in the Region. The meeting was attended by 20 temporary advisers, a consultant, and a member of the Secretariat from the WHO Western Pacific Region. There were also a number of observers from the People's Republic of China, Japan, and the Republic of Korea in attendance. Country reports on the status, quality control, and regulatory aspects were presented by temporary advisers from Australia, China, Hong Kong (China), Japan, the Republic of Korea, Singapore and VietNam. Subsequently, the Working Group was divided into two groups to examine the issues of quality standards and technical requirements ofherbal medicines. Given the increased use and trade of herbal medicine and some reports of adverse reactions and the lack of common standards and regulations among the Member States, the Working Group concluded that in order to ensure the uniformity of quality, safety and efficacy of the same herbal medicines in these and other Member States in the Region, there is a need for cooperation and harinonization of the standards and regulatory requirements. As a step toward harmonization, the Working Group identified issues, priorities, activities and mechanisms for harmonization, and proposed the formation of an organization to facilitate this work. The Working Group recommended that: (I)

a Forum in the WHO Western Pacific Region be formed with the aims of: • promoting health by recognizing and developing common regulatory requirements and guidelines that aim to ensure the quality, safety and efficacy of herbal medicines in the Region; and harmonizing regulatory requirements and guidelines to lead to a greater mutual acceptance of herbal medicines;

•

the Forum be known as the "Western Pacific Regional Forum for the Harmonization of (2) Herbal Medicines (FHH)"; the Forum consist of representatives of regulatory authorities and research institutes. Later, (3) industry associations from interested Member States will also be invited;

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( 4)

the first priorities of the Forum shall consist ofthe following items: • harmonization of nomenclature related to herbal medicines (plants, preparation and use); harmonization of methods and guidelines for the registration and regulation of herbal medicines, including the development of standards and monographs; harmonization of agricultural (GAP) and field collection practice (GFCP) procedures, including standard operating procedures (SOPs) on the use of pesticides, harvest, storage, and other protocols to insure consistent quality of the starting source materials; and establishment of a system for dissemination and communication of information relating to the regulation of herbal medicine;

•

•

•

(5) the appointed Preparation Committee, in collaboration with the WHO Western Pacific Regional Office, convene a further meeting in 2002 to establish the Forum and the organizational structure to fulfill the above aims and priorities; (6) funding in support of the Forum be sought from interested Member States, industry associations and other organizations; (7) the Working Group participants, wherever possible, brief the appropriate government policy and decision makers and other interested parties and stake holders on the deliberations and recommendations of this Working Group and initiate activities to implement the above priorities; and (8) to facilitate the above identified tasks, and to provide immediate contact, two representatives, one each from the regulatory authority and a research institute from each of the participating Member States are to be nominated from among the participants of the present Working Group as temporary focal points.

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1. INTRODUCTION

Over the past decade, there has been increased global interest in the use of traditional systems of medicine, especially herbal medicinal product,. In developing countries, they are most often used in primary healthcare, whereas, in developed countries, these medical modalities, designated as complementary and alternative medicine (CAM), are often used concomitantly with conventional medicine in medical treatments. The use of CAM in the United States of America increased from 34% in 1990 to 42% of adults in 1997, and American consumers spent an estimated US$5.1 bill ion on herbal medicines in 1997. 1 In the same year, the global market for herbal products was estimated to be approximately US$20 billion. 2•3 More recently, the global trade in herbal medicine has been estimated to total US$ 43 billion. 4 Regionally, there has been an increased production, use and international trade of herbal medicine among the Member States of the Western Pacific Region. Herbal medicine production in China amounted to US$ 2.3 billion in 1995; total annual sales of herbal medicine in the Republic of Korea exceeded US$ 500 million in 1996; annual herbal medicine products sales in Japan approximate US$ 1.5 billion (according to data available in 1992); and the import of Chinese herbal medicine into Australia has increased four-fold in as many years. 5 Despite the dramatic increase in the use and commerce of herbal medicine, the quality of these products, which can affect their efficacy and/or safety, vary greatly from product to product, and from country to country. The factors contributing to these quality variations may be due to the lack or inconsistent use of good agricultural or field collection practices; intentional or unintentional substitution adulteration with other plant or pharmaceutical materials; the contamination by microbes, microtoxins, synthetic drugs and/or other noxious chemicals; the lack of good manufacturing and laboratory practices; the lack ofpharmaco-toxicological evaluations; and the absence of, or lack of uniform regulatory requirements among the producer and/or user nations. 6 The prescribing, sale and use of inferior or questionable quality herbal medicines could represent a public heath problem. Historically, the production, and registration of pharmaceutical products containing single active chemical compounds also varied from country to country. In 1990, interested parties in the European Community, Japan, and the United States of America initiated an International Conference on Harmonization ofTechnical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which has since harmonized many guidelines to insure the production of the drugs having the same quality, safety and efficacy for registration in these countries. 7 Theoretically, harmonization of the production and regulation of herbal medicines would bring forth similar beneficial effects to public health. To date, except for some proposed guidelines on the quality control of single herb products by the European Agency for the Evaluation of Medicinal Products, there have been no concerted effort in the harmonization of herbal medicines, especially multi-component herbal formulae commonly found in Member States ofthe Western Pacific Region. One of the problems associated with harmonization of multi-component herbal medicines may be ascribed to the differences among various traditional systems of medicine, such as Traditional Chinese, Ayuverdic, and Jammu. Harmonization of herbal medicines based on one single system may be feasible. Although known by different names, Kampa, Korean and Vietnamese, traditional medicine systems and traditional Chinese medicine all share common roots. Thus, similar herbal medicines are used in the People's Republic of China, Hong Kong (China), Japan, Republic of Korea, Singapore, VietNam and other countries/areas in the Region, and are traded among these countries. However, the quality standards and technical requirements vary from country to country. To ensure the uniformity of quality, safety and efficacy of the same herbal medicines in these and other

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Member States in the Region, cooperation and harmonization of the standards and regulatory requirements are needed. As a first step to achieving harmonization, a consultation of the most affected Member States would be appropriate. Toward that end, the WHO Regional Office for the Western Pacific organized the present "Working Group on Harmonization of Standards and Regulatory Framework of Herbal Medicines" meeting in Seoul, Republic of Korea, 27-30 November 2001. The Consultation proposed to identify key issues and areas for cooperation and harmonization, and to identify possible mechanisms for implementation among interested Member States and areas in the Region. 1.1 Objectives ofthe meeting ( 1) to share experiences of regulatory measures to control the quality of herbal medicines;

(2) to identify issues relating to collaboration within and among participating countries on quality and standards of herbal medicine; (3) to identify practical mechanisms for harmonizing herbal medicines, particularly regulatory requirements, quality and standard of herbal medicines; ( 4) to define the areas of collaboration and the role of each of the participating countries; and medicine; and (5) to develop a plan on harmonizing herbal medicines among participating and other interested countries in the Region. 1.2 Participants

Temporary advisers from Australia, Hong Kong (China), Japan, People's Republic of China, Republic of Korea, Singapore, and VietNam attended the consultation. There were also observers from Japan, People's Republic of China, and the Republic of Korea in attendance. In addition, there was a consultant, and a member of the Secretariat from the WHO Western Pacific Region. The list of participants is attached as Annex 1. 1.3 Organization

To preside over the meeting, a chairperson, a vice-chairperson and two rapporteurs were elected. Dr Ren Dequan from the People's Republic of China served as chairperson. The vice-chairperson was Dr II-Moo Chang from the Republic of Korea. The two rapporteurs were Dr David Briggs from Australia and Dr Leung Ting-hung from Hong Kong (China). To facilitate the proceedings, three working sessions were held in addition to plenary sessions. For the first two working sessions, the participants were divided into two smaller working groups, one consisted principally of research scientists and the second composed of drug regulatory officials. In the third working session, the participants were divided into three groups according to their areas of expertise and discussion focus. Each of the working groups chose its own chairpersons and rapporteurs.

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1.4

Opening ceremony

The Working Group on Harmonization of Standards and Regulatory Framework ofHerbal Medicines consultation was opened by Mr Joel A. Vanderburg, WHO Country Liaison Officer for the Republic of Korea. Mr Vanderburg expressed his conviction that herbal medicine is very important in the healthcare ofthe people ofthe Region and that if it is most appropriate to sustain and develop its position as a therapeutic agent. Dr 11-Moo Chang, Director of the WHO Collaborating Centre for Traditional Medicine, the Natural Products Research Institute, Seoul National University, extended his welcome as venue host. Following a round of introductions, Dr Chen Ken, Regional Adviser in Traditional Medicine, Laboratories and Research, WPRO, who is the Responsible Officer for the consultation, welcomed the participants and presented an outline of working format and timetable for the sessions.

2. PROCEEDINGS

2.1

Initial presentations

2.1.1 "Welcome to the Regional Working Group on Harmonization of Quality Standards and Regulatory Framework of Herbal Medicine" Dr Chen Ken, Responsible Officer, WHO Western Pacific Regional Office, presented the background on events that led to the present consultation. He noted that the issue of a need for the harmonization of herbal medicine in the Region was raised by several participants over the last few years based on their experience and expertise; that it is an important issue; bilateral talks on harmonization has already begun between China and Japan, China and the Republic of Korea, and Australia and Singapore; and that WHO could play a role in bringing everyone together for discussions leading to multi-national harmonization of herbal medicines. The purpose of this meeting is for participants to share their experiences in regulatory measures to control the quality of herbal medicines; to identify issues relating to collaboration in the harmonization of herbal medicines; and to identify possible mechanisms and to identify the role(s) of the participating parties in the harmonization process. The expected outcome of the consultation is to achieve the objectives and reach agreement on areas requiring harmonization; devise mechanisms for harmonization; define the roles of affected parties; devise methods for evaluation and compliance monitoring; and to construct a work plan for collaboration among the participating Member States. Dr Chen also informed the participants that representatives were invited from countries/areas where herbal medicines based on similar systems of traditional medicine are used; traded among each other; have existing systems for the regulation of herbal medicines; have similar experiences; and exhibited willingness for collaboration. Further, Dr Chen reminded the participants that the working method for the consultation will consist of country reports, breakout working group sessions, plenary session discussion, conclusions, recommendations and future work plans.

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2.1.2 "Traditional Medicine and Regional Strategy: for a safer, more effective herbal medicine with a better quality" In a second presentation, Dr Chen Ken, Responsible Officer, WHO Western Pacific Regional Office, reviewed the current usage and economic values of traditional medicine. He noted that traditional medicine is still used by a large percentage of the population, and that the involvement of the academic/research community and industries is increasing. It has also attracted increasing interest of governments. Further, the use of herbal medicine is increasing m the mdustrahzed countries. W1thin the WHO Western Pacific Region, there are presently more countries/areas with policies on traditional medicine; community-based traditional medicine projects; technical standard/guidelines; training of healers; research; comprehensive programme on traditional medicine; manufacturing in accordance with good manufacturing practices (GMP); reports on adverse reaction/herbal medicines; publications; and regional networks. With the increased use of herbal medicines, there arose a number of challenges. The academic/research community is demanding evidence; the government sector needs to promulgate policies and regulations to ensure proper use; and the public needs safe, efficacious medicine of good quality. In addition to the questions of safety, efficacy and quality, there are the challenges of cultural context; single plants versus mixtures; changes in practice sites from community to hospital settings; their use in other lands; and concomitant use with modern medicine. In recognition of these challenges and issues, the Regional Strategy for Traditional Medicine in the Western Pacific was endorsed by the Western Pacific Regional Committee, the Governing Body of WHO Western Pacific Region, in Brunei (WPRIRC52.R4 Sep. 2001). The seven strategic directions are to: develop a national policy for traditional medicine; promote public awareness of and access to traditional medicine; evaluate the economic potential of traditional medicine; establish appropriate standards for traditional medicine; encourage and strengthen research into evidence-based practice of traditional medicine; foster respect for the cultural integrity of traditional medicine; and formulate policies on the protection and conservation of health In establishing standards of traditional medicine, proper directions should be pursued. The scope of the standardization of traditional medicine materials should be defined; proper mechanisms to regulate traditional medicine materials should be set up; and the quality of traditional medicine products should be improved. Actions needed to achieve these objectives require the setting up of national capacity for standard setting, promulgation of regulations, and international cooperation. 2.1.3 "Harmonization of Herbal Medicine: Quality, Safety and Efficacy"

Professor Harry H.S. Fong, Consultant, indicated in his presentation that the harmonization of herbal medicine involves the interrelated issues of quality, safety and efficacy. Quality is the paramount issue since it can affect the efficacy and/or safety of the herbal products being used. Current product quality ranges from very high to very low according to recent analytical reports. The quality of the source medicinal plants may be due to intrinsic, extrinsic and/or regulatory factors. Intrinsically, species differences, organ specificity, diurnal and seasonal variations can affect the qualitative and quantitative accumulation of active chemical constituents in the source medicinal plants. Extrinsically, environmental factors; field collection methods; cultivation, harvest, post harvest transport and storage; manufacturing practices; inadvertent contamination and substitution; and intentional adulteration are contributing factors to the quality of herbal medicinal products. Contamination with microbes, microbial toxins, environmental pollutants, or heavy metals must be minimized in source plant materials. Plants containing toxic pyrrolizidine alkaloids possessing a 11 1' 2-unsaturated rings and aristolochic acid-I should not be employed in herbal medicine. Finished products adulterated with foreign toxic plants or synthetic

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pharmaceutical agents have led to adverse events. Herb-drug interactions can contribute to issues of safety. Current data on efficacy are available only for a small number of herbal medicines. Herbal medicine quality, safety and efficacy can also be attributed to regulatory practices. In a number of countries, herbal medicines are unregulated, which has led to product quality differences. Product quality improvement can only be achieved by implementing control measures from the point of medicinal plant procurement under good sourcing practices (GSP), good laboratory practice (GLP), good manufacturing practices (GMP), and good clinical practice (GCP), plus post-marketing quality assurance surveillance. These measures, however, can come about only through harmonization of regulatory requirements by participating Member States. 2.1.4 "ICH: A Model for the Harmonization of Herbal Medicine ?"

The Consultant, Professor Harry H.S. Fong, reviewed the history, structure, administration and process ofthe International Conference on Harmonization ofTechnical Requirements for Registration of Pharmaceuticals for Human Use (ICH) as a potential model for the harmonization of herbal medicine. The ICH is a joint initiative involving both regulators and the pharmaceutical industry as equal partners in the technical aspects of product registration. Structurally, the ICH is composed of six parties, a regulatory agency plus an industrial association from each of three regions (European Union, Japan and the United States of America), where most of the pharmaceutical drugs are produced. In addition, there are three observer organizations, and the Secretariat office is housed in the offices of the International Federation of Pharmaceutical Manufacturers Association. The major aim of the ICH is to harmonize the technical requirements covering the issues of quality, safety and efficacy of new pharmaceutical products containing a single active constituent for registration in each of the three regions. The harmonization process begins with deliberations on a selected topic by an expert working group under the auspices of the ICH Steering Committee. Agreement by the Steering Committee releases the draft document for wider deliberation, followed by regulatory consultation in the three regions. Agreement on a harmonized ICH guideline leads to adoption by regulators and final implementation. More than 40 ICH guidelines have been adopted and a Common Technical Document (CTD) process has been agreed to recently. The CTD can be a model for the harmonization of herbal medicine. A harmonized medical dictionary for regulatory activities is another useful ICH model for adoption. In addition to the ICH model, the European Union has been involved in the harmonization of single plant herbal products. It has published a number of guidelines by the European Agency for the Harmonization of Medicinal Products (EMEA), which can also serve as models for the harmonization of herbal medicines in the Western Pacific Region. 2.2 Country reports

Country reports on the standards of herbal medicines and accompanying regulatory frameworks were presented by the temporary advisers and are summarized below. The text of these reports are included in Annex 2. 2.2.1 Australia

Dr David Briggs reported that in Australia, herbal medicines are included in a group of medicines collectively referred to as complementary medicines, which are regulated under the therapeutics goods legislation. The Therapeutic Goods Administration (TGA), a Division of the Commonwealth Department of Health and Aged Care, is responsible for administering the provisions of the Act. The overall objective ofthe Act is to ensure the quality, safety and efficacy of therapeutic goods, including medicines and medical devices. While the Act provides a substantially uniform national system of controls over

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therapeutic goods, other Commonwealth and State and Territory legislation may also apply. The Australian Register of Therapeutic Goods (ARTG), a database maintained by the TGA, includes details of all therapeutic goods that are imported into, supplied in, or exported from Australia. It is a legal requirement, unless specifically exempt or excluded, that all therapeutic goods be included in the ARTG prior to their supply. Only therapeutic goods that have been assessed or evaluated by the TGA are included in the ARTG. The evaluation or assessment process undertaken depends on the type of therapeutic good and its indications and claims. The present regulatory system for complementary medicines uses a risk-based approach to determine an appropriate level of both pre-market evaluation/assessment and post-market activity for complementary medicines. This approach has resulted in a two tiered regulatory system based on risk. Medicines assessed as having a higher level of risk are included in the ARTG as registered medicines. Medicines of low risk are included in the ARTG as listed medicines. Most, but not all, complementary medicines are listed medicines. The risk associated with therapeutic goods, including complementary medicines, is managed through three main processes: licensing of manufacturers; pre-market assessment of products; and post-market regulatory activity. Consistent with their low risk, listed complementary medicines may only carry certain indications and claims. The claims and indications for a listed medicine are not evaluated by the TGA before the product enters the market. However, the Act requires that sponsors hold appropriate evidence to support the indications and claims made at the time the product is included in the ARTG. Claims and indications for listed medicines may be supported by scientific evidence or evidence of traditional use. Where there is a public health or safety concern about the claim for a product or the claim appears to be wilfully misleading or in response to a complaint about the product, the TGA may call upon sponsors to provide the evidence they hold to support the claim(s). In order to facilitate compliance with the requirement to hold appropriate evidence to support particular claims, the TGA and the Complementary Medicines Evaluation Committee (an independent expert statutory committee established to advise the TGA) have developed guidelines to assist sponsors in determining what constitutes appropriate evidence to support various types of therapeutic claims and indications (Therapeutic Goods Administration, 2001 ). Details on indications and claims, data necessary to support safety evaluation, examples of complementary medicine, pre- and post-marketing requirements, are presented in the full report in Annex 2. 2.2.2 People's Republic of China

Dr Ren Dequan and Dr Lin Rui-Chao reported on the traditional medicine situation in the People's Republic of China. Traditional Chinese Medicine (TCM) refers to crude drugs, processed plant products, and manufactured preparations; and the TCM sector include agriculture, commerce and industry. Although China is in the process of economic development and modernization, with modern medicine being readily available, the use ofTCM has entered into a new period of growth due to its unique characteristics for health care and protection and its being available in new dosage forms, packaging and greater product quality. A pre-market approval system has been established that requires that new TCM preparations be approved and registered before their entry into the market. For new TCM crude drugs that have not been previously recorded or used by the people, marketing authorizations is required. TCM is being classified into prescription and non-prescription medicines, and national standards have been established for market access. In addition, local drug regulatory authorities stipulate standards for those medicine not under national standards. Local authorities are also responsible for setting up specifications for processing ofTCM products. The manufacturers ofTCM preparations and processed products are regulated under a licensing system, requiring production under GMP and GSP. A post market sampling system has been established according to national and local standards for the control ofTCM crude drugs, preparations, and the processed products, as well as a tracking system on adverse drug reactions.

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Imported TCM products are registered and approved according to the rules and regulations for the importation of pharmaceutical drugs. Provisions for the Approval ofNew TCM Preparations was issued in 1986, in line with the basic requirements for ensuring the safety, efficacy and quality of drugs and on the basis of valuing and carrying on traditional characteristics, and encouraging the combination with modern science and technology. New TCM preparations are required to be approved and registered before being placed on the market. TCM preparations marketed prior to 1986 have been re-evaluated with those traditional drugs, which were generally recognized by the public, being issued registration numbers; and those TCM preparations that have never been recorded in the classical medicine books were evaluated by experts according to the TCM theory and clinical trial for potential registration and market. The major elements of the TCM product examination and approval management include (I) classification, (2) procedure, and (3) application for new drug (TCM Preparations). Quality control ofChinese Materia Medica involves the issues of standardization, reference substances, and research activities. Standardization requirements, methods and procedures are described in the Chinese Pharmacopeia, Propharmacopeia and Regional Standards. There are presently 992 herbal medicines described in the Chinese Pharmacopoeia (2000 edition). Product description, quality rubrics, tests and assay methods, and reference substance and reference drug specifications are specified in the Pharmacopoeia. Research activities on the quality control of Chinese Materia Medica include a Five-Year Plan sponsored by the Ministry of Scientific Technology (MOST) and the State Administration of Traditional Chinese Medicine (SA TCM). Other research sponsors include the State of Drug Administration (SDA), Natural Scientific Fund of China (NSFC), pharmaceutical industries and research institutes. 2.2.3 Hong Kong (China)

According to Dr Ting-hung Leung, the dominant health care system in Hong Kong (China) has been Western medicine. At the same time, Chinese medicine has been widely used for many years, both as an alternative and a complement to Western medicine with about 22% of the outpatient medical consultations being provided by Chinese medicine practitioners, and up to 60% of Hong Kong people use Chinese medicine either for treatment of diseases or for health maintenance. It is estimated that there are a total of about 3800 retailers, wholesalers and manufacturers of Chinese medicines, which included proprietary Chinese medicines and herbs, estimated to include about 2000 kinds of herbs and about 6600 types of proprietary Chinese medicines. As a first step in the development of Chinese medicines, the Government is committed to establishing a sound regulatory framework for Chinese medicine, covering both the practice of Chinese medicine practitioners as well as the use, sale and manufacture of Chinese medicines. The Chinese Medicine Council of Hong Kong (Council) is responsible for devising measures and setting standards to regulate the practice of Chinese medicine practitioners and the use, trading and manufacture of Chinese medicines. The regulatory measures of Chinese medicine practitioners include a system of professional examination, registration and discipline. In the future, only registered Chinese medicine practitioners will be allowed to practise Chinese medicine in Hong Kong (China). The Chinese Medicine Board, established under the Council, is mainly responsible for implementing regulatory measures for Chinese medicines. These measures include a licensing system for traders and manufacturers of Chinese medicines and a registration system for proprietary Chinese medicines based on the criteria of safety, quality and efficacy. All retailers, wholesalers and manufacturers of Chinese herbs and proprietary Chinese medicines have to demonstrate that the hygienic conditions and facilities in warehouses, shops and factories satisfy the regulatory requirements before they will be granted a license. Proper packaging,

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labelling and keeping of sales record are also required to facilitate audit trail and recall in case of adverse medical reactions. In order to upgrade the standard ofpractice ofthe traders and manufacturers of Chinese medicines, the Chinese Medicine Board is devising practising guidelines for each type of license holder. All proprietary Chinese medicines need to be registered before they are allowed to be on sale or manufactured in Hong Kong (China). A gradual and incremental approach is preferred, recognizing the historical development of Chinese medicine in Hong Kong (China), and the complexity of issues involved. The Chinese Medicine Board is now finalizing registration criteria for the different categories of proprietary Chinese medicines. 2.2.4 Japan

Dr Motoyoshi Satake reviewed the history of the Japanese Pharmacopoeia, which had its roots in the Pre-Pharmacopoeia ("Wazaikyokuhou") first published in II 00 AD. The first edition of the Japanese Pharmacopoeia was published in July 1888 and contained 468 monographs, including 97 crude drugs. The current (14th edition, 2001) contain 172 crude drugs. The Pharmacopoeia provides definitions and establishes quality standards and purity rubrics, tests and assays for crude drugs. Example monographs including monographs on Rhubarb, Ginseng, Glycyrrhiza, Ephedra herb and Magnolia bark. Detailed information can be found in Annex 2. In his presentation, Professor Ushio Sankawa indicated that of the 2 I 0 KAMPO prescriptions covered under the Japanese Social Health Insurance, 147 are being produced as Ethical KAMPO Preparations. KAMPO prescriptions are regarded as medicinal drugs and concomitant use with synthetic drugs is possible. The efficacy of KAMPO medicine has been subjected to clinical studies. The manufacture ofKAMPO medicine under GMP is controlled by self-imposed regulation of the Japan Kampa Medicine Manufacturers Association (JKMA), not by government mandate. Identification and analysis according to the l4 1h edition of the Japanese Pharmacopoeia (JP 14) or the non-Pharmacopoeial Crude Drug Standard (non-JP Crude Drug Standard) are required for each crude drug used in the manufacture of ethical and over-the-counter (OTC) Kampa extract preparation. Thin-layer chromatographic profiles and HPLC analysis of the main constituents of more than two crude drugs contained in the final Kampo extract preparation are required. There are 120 crude drugs and 51 powder items described in JP I4, and there are 75 crude drugs and eight powders in the non-JP Crude Drug Standard. In addition to being a drug, botanical preparations can be also be classified as a specified functional health food, a nutraceutical supplement, or a food/health food. A specified functional health food is required to list the active ingredient, the specific function supported by clinical evidence, and a cautionary statement on the label. 2.2.5 Republic of Korea

Dr Soo Chun-Park reported that traditional Korean medicines are governed by the Pharmaceutical Affairs Law, which stipulates matters pertaining to the production, dispensing, appraisal, safekeeping, import and sale of oriental and Western medicines or other things concerning pharmaceutical skills. Regulations on the quality control of medicines are covered by Korean Pharmacopoeia and Medicinal Herbs Standards, which stipulate methods of production, nature, effects, quality and methods of storage. These regulations are controlled by the Central Pharmacists Deliberations Commission. The Oriental Medicines Bureau ofthe Ministry of Health and Welfare (MOHW) is directly in charge of matters concerning traditional Korean medicines. The Korea Food and Drug Administration (KFDA) Herbal Medicine Evaluation Department is in charge of the enactment of standards for herbal medicines, investigation and research concerning harmful materials contained in herbal medicines, production of standard herbal medicines, and quality standardization ofherbal medicines.

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On the issue of medicinal herbs standards, a system for standardization of medicinal herbs is being implemented. The standards applied to all medicinal herbs are specified in the Korean Pharmacopoeia and Medicinal Herb Standards. In the production of medicinal herbs, a commercial enterprise specializing in medicinal herbs require a permit granted by the relevant local office ofKFDA. Some 69 important medicinal herbs, including dried ginger (Zinger officina/e), rhubarb (Rhuem palmatum), and pueraria root (Pueraria lobata), are allowed to be handled only by authorized commercial enterprises. 2.2.6 Singapore

Aspects oftraditional medicine and control of Chinese medicine materials in Singapore were presented by Dr Chris Cheah Hean-Aun and Mr Yee Shen Kuan. Although Western medicine is generally recognized and accepted as the main form ofhealthcare in Singapore, traditional medicine still enjoys considerable popularity. Traditional medicinal materials popularly in use include: Chinese herbal medicines from China, Jamu from Indonesia and Malaysia, and Ayurveda from India. Traditional Indian medicine or Ayurveda is generally practised among the Indian segment of the population and migrant workers from the Indian subcontinent while traditional Malay medicine is practiced by traditional Malay herbalists (bomoh) and midwives (bidan), whereas TCM is the most widely practised of the traditional medicines in Singapore. A survey conducted by the Ministry of Health in 1994 revealed that almost half ofthe population (45%) had consulted a TCM practitioner in the past. TCM practice is restricted to outpatient service in Singapore. It is estimated that about 10 000 persons (12%) visit TCM clinics each day compared to 74 000 persons who visit Western medical clinics. The Committee on TCM appointed by the Minister for Health to review the practice ofTCM and recommend measures to safeguard patient interest and safety, and to enhance the standard of training of TCM practitioners recommend: (I) a phased approach to the regulation ofTCM in Singapore, with self-regulation by the TCM community first, followed by statutory regulation later; (2) ways to upgrade the standard of training ofTCM practitioners; and (3) control of Chinese medicinal materials in Singapore. As a result, an umbrella body representing eight local TCM organizations, known as the Singapore TCM Organizations Coordinating Committee, was formed to facilitate self-regulation and to act as a channel of communication between the TCM community and the Ministry of Health. Presently, there is a TCM Practitioners Board set up to register TCM practitioners, starting with acupuncturists. The regulatory control of Chinese medicinal materials (CMM), which include Chinese herbs and medicinal materials obtained from animal and mineral sources, can be grouped into two categories: Raw CMM (materials in natural states or undergone simple processing, e.g. cutting and drying, (used in the practice ofTCM); and Chinese Proprietary Medicines (CPM, preparations in final dosage forms, e.g. tablets, pills, liquid preparations, used in the practice ofTCM). CPM control, mandated by various legislation, was implemented in three phases from 1 September 1999 to 1 September 2001 based on various dosage forms. Phase I consisted of tablets, Phase 2 dealt with liquid preparations, and Phase 3 concerned other dosage fonns such as pills, granules and powders. Under CPM control, all local CPM importers, wholesale dealers, manufacturers andre-packers must be licensed in order to upgrade their standards and make them fully accountable for safety and quality of their products. As of November 2001, there were 189 licensed importers, 258 licensed wholesale dealers, 22 licensed manufacturers and 31 licensed re-packers. In addition, CPM products must be approved before they could be imported, manufactured and sold in Singapore. This is to ensure product safety and quality by eliminating sub-standard, fake, imitation and adulterated products as well as to ensure consistency in labelling and removal of misleading and exaggerated claims. The CPM approval criteria include: product must not be adulterated with Western drugs or synthetic active substances; must not contain naturally occurring, potentially toxic substances controlled under the Poisons Act; must not contain toxic heavy metals (mercury, arsenic, copper and lead) and microbial counts beyond the legal limits; must fulfill the labelling requirements in

- 12 -

English, including batch number, expiry date, particulars of manufacturer and importer; product label must not make any reference for usage on serious medical conditions or diseases stipulated in the Medicines Act, e.g. cancer, diabetes and impotency; and the product manufacturer must be licensed and product must be freely sold in the country of manufacture. Furthermore, licensed CPM importers are required to submit toxic heavy metal and microbial test reports for each consignment at the point of import in order to ensure product quality and safety of each imported consignment. The advertisements and sales promotions ofCPM products must be approved by the Ministry of Health to ensure the public is protected against misleading and exaggerated advertisements and sales promotions. Even with these mandatory requirements, there are still current concerns on the quality of CMM, and future strategies are required to upgrade the standard of local CMM dispensers, with the aim of registration in the future. 2.2.7 VietNam

Associate Professor LeVan Truyen and Dr Trinh Van Quy authored papers on the standardization of medicinal plants and traditional medicines in VietNam and on the standardization of herbal medicines in VietNam - current situation and experience. The Ministry of Health has defined traditional medicines as herbal medicines in crude form or processed, or their preparations which are prepared according to the method of traditional medicine from one or more kinds of drugs derived from animals, plants and/or minerals with efficacy in disease treatment or with benefit for human health. According to this definition, traditional medicines include "Chinese medicinal herbs", "Vietnamese medicinal herbs", and "traditional national medicines", and emphasizes the traditional methods of preparation. In general, herbal medicines are also required to ensure quality as in the case of modern medicines. The Ministry of Health has issued a regulation on the evaluation ofthe effectiveness and safety of traditional medicine. Unfortunately, a large number of oriental medicines of low or no efficacy, and/or harmful are still available. Another problem with the quality of oriental medicaments presently is that some producers have mixed active ingredients of Western medicine with finished products without declaring or labelling them approximately. To ensure the production of quality herbal medicines meeting requirements for quality, stability, safety, and efficacy, it is necessary to standardize them from starting materials to processing techniques; production processes, and production management. The VietNam Pharmacopoeia Commission was established in 1963 to implement the standardization in the field of pharmaceutical products, and edit the VietNam Pharmacopoeia, which is legal and promulgated by the Ministry of Health. The VietNam Pharmacopoeia consists of standards stipulated by the state regulating the definition, quality rubrics, and the methods of analysis. The current edition contains 312 monographs on medicinal plants. Quality management organizations, drug quality control and assurance system, processing units, pharmaceutical manufacturer, pharmaceutical trading companies and hospital pharmacy departments, are required to follow the VietNam Pharmacopoeia's standards. Standards of Manufacturer are required to be equal to, or higher than those described in the VietNam Pharmacopoeia. VietNam Pharmacopoeia's standard system is applied in every production unit in the country including 320 pharmaceutical manufacturers and companies with 1566 herbal finished products that were registered in the pharmaceutical market in VietNam in 2001. In addition to the above country reports, a brief survey of the participants was conducted during the course of the meeting. Specifically, the survey requested information on the quality control measures and regulatory processes in effect in each Member State. In the procurement of starting plant materials, most Member States do not have mandated good agricultural or good field collection practices. Most countries have, or are in the process of implementing, quality control (chemical); good manufacturing, good

- 13 -

laboratory, and good clinical practices; labelling; and safety, registration and post-market surveillance measures. Responses to this survey are presented in Table I. Table I. Summary of Status of Herbal Medicine in Participating Member States Herbal medicine activity/status Established agricultural practices (eg GAP) Established field collection practices (eg GFCP) Identification/authentication of raw (source) herbal material Established quality standards of raw herbal materials Post-harvest treatment (established processing procedures) Established quality standards of processed herbal materials Established manufacturing standards (eg GMP) Licensing of manufacturers Chemical quality control (analytical chemistry) Pharmaceutical quality control (eg stability) Established series of safety studies Established laboratory methods (eg GLP) Laboratory accreditation Established series of effectiveness studies (eg GCP) Established labelling requirements Established product registration system Established post-market surveillance system Regulation of herbal practitioners Regulation of herbal dispensers Regulation of herbal wholesalers

Australia X X Y (OTC) N (herbs) Y (OTC) N (herbs) X

China AI AI

Hong Kong Japan X X

Republic of Korea X X

Singapore VietNam X X X

AI

c y

X

y

AI&

y

c

c c X

y

y

X

y

y

c c c y y y y y AI

y

X

y

X

Y (OTC) N (herbs)

c y y y y y y y y

X

c y y y y

c y y y y y y y y

y

y y y y y X X

AI AI AI AI AI AI AI AI

y y

c c c y y

c y X

y

y

c y C (only listing) y AI AI

y y

y y

y y y y y y

AI AI AI

y y y X

y y y y y y

y y AI

c AI&C AI&C X

y AI AI

y

y y

c c

y

Key: X = no, Y = yes, AI = awaiting implementation, C =conditional or some aspects only

- 14 -

2.3

Working groups and plenary sessions

Three smaller working group sessions were held in addition to the plenary sessions. In the first working group session, two teams of participants were assigned the task of identifying the potential issues relating to the harmonization of standards for herbal medicines that may be effectively addressed through future collaboration between participating countries. The objectives of the second working group session were to identify the organization, mechanisms and shared responsibilities for collaboration on prioritized issues in order to develop a consensus proposal for each issue. The third and final working group session was devoted to developing a realistic timetable of activities, along with methods for monitoring activities and evaluating the outcomes. Following each group session, the rapporteur or chair from each team reported the recommendations and plans of action to the plenary session for further deliberation and adoption. The period of articulated small group and plenary sessions was designed to deliver clear proposals on the harmonization issues identified. During the course of these deliberations, the Working Group identified and prioritized issues for harmonization; developed a series of mechanisms; identified activities; proposed an organizational structure and formulated strategies to implement the harmonization of herbal medicines in the Western Pacific Region. 2.4 Closing ceremony

The consultation ofthe Working Group on Harmonization of Standards and Regulatory Framework of Herbal Medicines was brought to a close on 30 November 2001 with remarks by Dr Soo-Chun Park, Director, Oriental Medicine Division, Ministry of Health and Welfare, Republic of Korea; Dr Chen Ken, Responsible Officer, WHO Western Pacific Regional Office; Dr Ren Dequan, the Working Group chairperson; and Dr 11-Moo Chang, the Working Group vice-chairperson.

3. CONCLUSIONS

3.1

Conclusions

Herbal medicines form an important and integral part of most traditional systems of medicine in the Western Pacific Region. According to the Regional Strategy for Traditional Medicine in the Western Pacific (2001), traditional systems of medicine vary from being highly developed and well documented in such countries as China, Japan, Malaysia and Republic of Korea, to much simpler systems found within small and isolated ethnic groups, especially in the island regions. A common element of all of these systems is the significant role herbal medicine has played in protecting the health of the people living in the Region. Interestingly, many of the developed TRM systems are based on or derived from TCM. For example, the Kampa Medicine of Japan, the Korean Traditional Medicine, the Vietnamese Traditional Medicine and TCM all share similar roots. In addition, TCM is employed widely in areas of Australia, Hong Kong (China), and Singapore. The use ofTRM in these selected seven countries/areas of the Region ranged from 45% in Singapore to 90% in China. The present Working Group on Harmonization of Standards and Regulatory Framework of Herbal Medicines Consultation, organized by the WHO Regional Office for the Western Pacific, reviewed the status of herbal medicines among the participating countries and areas and noted that similar herbal medicines are used in the People's Republic of China, Hong Kong (China), Japan, Republic of Korea, Singapore, and other countries/areas in the Region, and that they are traded among these countries. However, the country reports from the participants showed that the quality standards and technical requirements vary from country to country. Given the increased use and trade of herbal medicine and periodic literature reports of adverse reactions and the lack of

- 15 -

common standards and regulations among the Member States, the Working Group concluded that in order to ensure the uniformity of quality, safety and efficacy of the same herbal medicines in these and other Member States in the Region, there is a need for cooperation and harmonization of the standards and regulatory requirements. As a step toward harmonization, the Working Group identified and prioritized issues for harmonization; developed a series of mechanisms; identified activities; proposed an organizational structure and formulated strategies to implement the harmonization of herbal medicines in the Western Pacific including the establishment of"Westem Pacific Regional Forum for the Harmonization of Herbal Medicines (FHH)". 3.1.1 Issues for harmonization

A range of issues were identified as being important for harmonization of herbal medicines. These covered the entire spectrum of herbal medicine production starting from crude drugs (include animal and mineral materials) to finished herbal drug products and herbal medicine practitioners: • • Harmonize of nomenclature related to herbal medicines (plants, preparation and use). Harmonize agricultural practices, employing where possible, good agricultural (GAP) and good field collection practice (GFCP) procedures, including standard operating procedures (SOPs) on the use of pesticides, harvest, storage, and other protocols to insure consistent quality of the starting source materials. Harmonize the protocols for species authentication, including the use of botanical standard reference materials for macroscopic, microscopic, electron microscopic DNA, and other methods of analysis. Harmonize standards of pharmacopoeia and monographs on common limits on heavy metal (including the definition of"heavy metal" and individual and/or total limits); microbial and pesticide and other impurities contaminations. Harmonize standards of pharmacopoeia and monographs on analytical methods, format, and taxonomy. Standardize methods of processing herbal medicine into appropriate dosage forms, such as cutting, drying, baking, frying. Standardize the method of extraction and the extraction solvents used. Harmonize manufacturing practices by GMP methods in processing, authentication and identification, and packaging of the manufactured preparation. Standardize where possible, products with the same formula name, but with different quantities of ingredients. Standardize the methods and guidelines for assessing efficacy (including clinical trial) of traditional and new herbal formulations, where appropriate. Documented traditional usage are used as a basis for assessing efficacy in some countries. Standardize the allowable ranges of constituents in finished products to ensure consistency of the product to enable correlations with the clinical outcome.

•

•

•

•

• •

•

•

•

- 16 -

•

Develop and standardize the methods to assess the stability (expiration dating) ofherbal drug products. Standardize packaging and labelling of herbal products. Where possible, the full labelling of all herbal ingredients in the preparation, therapeutic claims, and contraindications. Evaluation of quality of finished products (chemical and pharmaceutical, sampling methods, and contamination). Requirements for animal toxicity data for both herbal material and finished products (acute, chronic, reproductive, mutagenic, immuno-toxic), and human case data for previously used and new formulations. Standardization of dosage ranges, forms and indications. Studies, access to data on contraindications; herb-food, herb-herb, and herb-drug interactions. Standardize requirements for supporting pharmacological evidence (mechanisms, absorption, metabolism, excretion on single and multi-component herbal formulae). Research on synergistic herb-herb interactions. Harmonize the requirements for registration of herbal products (as herbal drugs, as health products). Establish post-market surveillance system(s) (phase IV requirements). Regulation of standards of practice (practitioners, dispensers, traders). Resolution of intellectual property issues. Establish a system for dissemination and communication of information relating to the regulation of herbal medicine. Acknowledge the issue of food/drug interface problems within countries and between countries. Priority issues

•

•

•

• • •

• •

• • • •

•

3.1 .2

Four issues were identified as being of the highest priority for harmonization consideration: • • harmonization of nomenclature related to herbal medicines (plants, preparation and use); harmonization of methods and guidelines for the registration and regulation of herbal medicines, including the development of standards and monographs; harmonization of agricultural (GAP) and field collection practice (GFCP) procedures, including standard operating procedures (SOPs) on the use of pesticides, harvest, storage, and other protocols to insure consistent quality of the starting source materials; and

•

- 17 -

•

establishment of a system for dissemination and communication of information relating to the regulation of herbal medicine.

In addition, the participants identified two major issues that merit future consideration: • • regulation of standards of practice (practitioners, dispensers, traders); and labelling of herbal products. Where possible, the ti.JII labelling of all active herbal ingredients in the preparation, therapeutic claims, and contraindications or restricted uses. Specific mechanisms to achieve priorities

3.1.3

The mechanisms and shared responsibilities for collaboration in order to achieve a consensus proposal for each issue, and to develop a realistic timetable of activities, along with methods for monitoring progress and evaluating the outcomes of the harmonization process is presented in the following table (Table 2).

Table 2 . Summary of Mechanisms to Achieve Priorities for Harmonization of Herbal Medicines

Priority issue

Scope of activity

Proposed mechanisms

Proposed participants (from participating countries) Botanists, Pharmacognosists Natural product chemists Natural product information scientists Members of pharmacopoeial commissions

Deliverables

Methods of monitoring and evaluation Number of countries adopting thf nomenclature system in tlreir pharmacopc eia or standards

Estimated timelines Three to four years to develop the method, and implementation of nomenclature harmonization

Harmonization of nomenclature related to herbal medicines (plants, preparation and use)

Nomenclature of l. medicinal plants (standardize botanical names of plant species and parts referred to in native language) 2. Review and standardize the nomenclature of the procedures associated with the preparation and uses of herbal medicines

Ia. Form Subcommittee for nomenclature I b. Select the most suspect/confusing herbs to start 1c. Collate information related to these herbs from each country's pharmacopoeia I d. Determine best method for achieving consistency in assigning and adopting nomenclatures I e. Establish related reference materials and databases 2a. Preparation of a series of definitions related to the preparation and use 2b. Comparison and standardization of definitions

Recommendations on a series of harmonized names for plants and preparations for specific herbs Lists of herbs Recommended method of nomenclature

Priority activity

Scope of activity

Proposed mechanisms Form Subcommittee for regulations and monographs Collate technical requirements associated with herbal product registration and regulation from each participating country Collate monographs associated with herbs and herbal products from each participating country Review differences and suggest, where possible, methods for standardizing technical requirements and monographs

Proposed participants (from participating countries) Regulators and experts on quality control; on safety, quality and efficacy assessment Participants may include experts from industries of participating countries

Deliverables

Methods of monitoring and evaluation Validation of methodology and standards for their intended purposes Changes to the methods and guidelines foc- the registration and regulation of herbal medicines in participating countries Identify problems associated with the implementation of standards

Estimated timelines Six months for collation and comparison of pharmacopoeia, monographs and standards One year for the identification and prioritization of areas for harmonization

Harmonization of methods and guidelines for the registration and regulation of herbal medicines including the development of standards and monographs

Identify differences 1. in guidelines, regulations and standards, which have impacts on quality, safety and efficacy of herbal medicines between participating countries To identify and agree 2. on areas of harmonization and undertake feasibility evaluations to determine impact of harmonization in participating countries To determine the 3. priority areas for the development of harmonization of guidelines, regulations and standards

Comparison of pharmacopoeia or monograph standards of herbal medicines in each participating country Identify and prioritize areas for harmonization To agree upon the methodology to be used for quality control To identify relevant reference materials (pure chemicals, crude drugs standards) for quality control To make recommendations to participating countries for implementation of areas identified for harmonization

Priority activity

Scope of activity

Proposed mechanisms

Proposed participants (from participating countries) Subcommittee of experts Botanists, pharmacognosists, agriculturalists, horticulturists Natural product chemists Natural product information scientists Members of pharmacopoeial commissions Environmental scientists

Deliverables

Methods of monitoring and evaluation Completion af recommendations . Number of countries recognizing and adopting guidelines.

Estimated timelines Within two years

Harmonization of good agricultural and field collection practice procedures to ensure consistent quality of the source materials

1. Harmonization of GAP

Form Subcommittee Form one Expert Workgroup Data collection, comparison and proposals for harmonization Documentation/report writing

• •

A series of SOPs Based on existing similar documents (EMEA& WH02002)

A regional GAP guideline A regional GFCP guideline A regional raw herb verification guideline

2. Harmonization of GFCP • Based on existing similar documents (EMEA& WH02002) 3. Harmonization of verification protocols for raw herbs • Labeling requirements • Source identification • Cultivation period/grade • Storage conditions • Export certificate • Analysis certificate

N

0

I

Priority activity

Scope of activity

Proposed mechanisms

Proposed participants (from participating countries) Regulators, representatives from associations of industry

Deliverables

Methods of monitoring and evaluation Number of website visit()rs

Estimated timelines Two years

Establish a system for dissemination and communication of information relating to the regulation of herbal medicines

Additional general information not covered by the other three Subcommittees, such as: - adverse events and misuse -restriction of use - drug-herb/herb-herb interaction -extent of use of herbal medicines (e.g. volumes and sales)

Form Subcommittee for information dissemination Collate relevant information from each participating country Compile reports on specific issues Internet chat room/email (restricted access)

System established (e.g. paper and/or electronic reports on specific issues; website)

- 22 -

3 .1.4

Intra-Regional Communication on the Harmonization of Herbal Medicines

As part of the strategy on harmonization, the Working Group participants, wherever possible, shall brief their appropriate government policy and decision makers as well as other interested parties and stake holders on the deliberations of this consultation and recommend the initiation of activities to implement the harmonization of herbal medicines. To facilitate information on the identified tasks, and to provide immediate and interim communication among the Member States present in the current meeting on harmonization of herbal medicine and related matters, two participants from each country or area were nominated from among the participants to serve as focal points or contact persons. This interim communication group consists of Drs Alan Bensoussan and David Briggs (Australia), Dr Ting-hung Leung and Mr Thomas Cheung (Hong Kong, China); Drs Motoyoshi Satake and Yukihiro Goda (Japan); Drs Ren Dequan and Lin Ruichao (People's Republic of China); Drs II-Moo Chang and Soo Chun Park (Republic of Korea); Drs Yee shen Kuan and Chris Cheah (Singapore); Drs LeVan Truyen and Trinh Van Guy (VietNam). 3.1.5 Western Pacific Regional Forum for the Harmonization of Herbal Medicines

The Working Group proposed the formation of a forum for the harmonization of herbal medicines in the Western Pacific Region. The aims of this forum are for the promotion of health by recognizing and developing common regulatory requirements and guidelines that aim to ensure the quality, safety and efficacy of herbal medicines in the Region and the harmonization of regulatory requirements and guidelines leading to a greater mutual acceptance of herbal medicines. This forum is to be known as the "Western Pacific Regional Forum for the Harmonization of Herbal Medicines" with the acronym of"FHH". Membership in the Forum shall consist of representatives of regulatory authorities and research institutes. Industry associations from interested Member States will be invited in the future. A summary of the goals and objectives, membership, funding and organizational structure ofthe Forum follows: ( 1) Goals and objectives of the forum (1.1) Goals • to promote public health by recognizing and developing common regulatory requirements and guidelines that aim to ensure the quality, safety and efficacy of herbal medicines in the Western Pacific Region; and to harmonize regulatory requirements and guidelines leading to a greater mutual acceptance of herbal medicines.

•

( 1.2) Objectives • • • to identify issues for harmonization consideration; to identify procedures and mechanisms for implementation of harmonization issues; and to propose an organizational structure, membership and funding for the harmonization of herbal medicines in the Region.

(2) Organizational structure of the Western Pacific Regional Forum for the Harmonization of Herbal Medicines (FFH) The organizational structure of the forum for the harmonization of herbal medicines in the Western Pacific Region shall consist of a Steering Committee (SC) as the governing body. Subcommittees (SubC) are designated for specific topics such as nomenclature, regulation, quality control

- 23 -

and information. The work of the Sub-committees shall be carried out by Expert Working Groups (EWG). The organizational structure is presented in Figure 1. Figure I. Organization Structure of Proposed Forum

(3)

Membership

Membership in the Forum shall consist of representatives of regulatory authorities, research institutes and industry associations from interested Member States. (4) Funding

Funding to support the functions and activities of the Forum will be sought from interested Member States, industrial associations and other organizations. (5) Preparation Committee

To effect the formation of the "Western Pacific Regional Forum for the Harmonization of Herbal Medicines (FHH)" and implementation of the work of this forum, a "FHH Preparation Committee" composed of individuals from among the current participants or others upon consultation with governmental authorities of interested Member States was formed. It was recommended that this Committee, in collaboration with WHO Western Pacific Regional Office, convene a further meeting in 2002 to establish the Forum and the organizational structure to fulfill the aims, objectives and implementation of action on the priorities identified. The initial membership in the FHH Preparation Committee is composed of representatives from the People's Republic of China (Drs Ren Dequan and Lin Ruichao), Hong Kong, China (Dr Margaret Chan, Dr Ting-hung Leung and Mr Sik-Yiu Kwan), Japan (Drs Motoyoshi Satake and Yukihiro Goda), and Republic of Korea (Drs 11-Moo Chang, Sao Chun Park and Keum-Ryon Ze). The Committee members present agreed to hold their first organizational meeting in Beijing, in March 2002, in conjunction with the regularly scheduled bilateral talks on the harmonization of herbal medicines between the People's Republic of China and Japan.

4. RECOMMENDATIONS

The Working Group on Harmonization of Standards and Regulatory Framework of Herbal Medicines proposes the following recommendations to the WHO, Member States, and participants for implementation: (I) The formation of a Forum in the WHO Western Pacific Region with the aims of:

- 24 -

•

the promotion of health by recognizing and developing common regulatory requirements and guidelines that aim to ensure the quality, safety and efficacy of herbal medicines in the Region; and the harmonization of regulatory requirements and guidelines leading to a greater mutual acceptance of herbal medicines.

•

(2) The Forum be known as the "Western Pacific Regional Forum for the Harmonization of Herbal Medicines (FHH)". (3) The Forum consist of representatives of regulatory authorities, research institutes and industry associations from interested Member States. (4) The first priorities ofthe Forum shall consist ofthe following items: • harmonization of nomenclature related to herbal medicines (plants, preparation and use); harmonization of methods and guidelines for the registration and regulation of herbal medicines, including the development of standards and monographs; harmonization of agricultural (GAP) and field collection practice (GFCP) procedures, including standard operating procedures (SOPs) on the use of pesticides, harvest, storage, and other protocols to insure consistent quality of the starting source materials; and establishment of a system for dissemination and communication of information relating to the regulation of herbal medicine.

•

•

•

(5) The appointed Preparation Committee, in collaboration with the WHO Western Pacific Regional Office, convene a further meeting in 2002 to establish the Forum and the organizational structure to fulfill the above aims and priorities. (6) Funding in support of the Forum be sought from interested Member States, industry associations and other organizations. (7) The Working Group participants, wherever possible, brief the appropriate government policy and decision makers and other interested parties and stake holders on the deliberations and recommendations of this Working Group and initiate activities to implement the above priorities. (8) To facilitate the above identified tasks, and to provide immediate contact, two representatives, one each from the regulatory authority and a research institute from each of the participating Member States are to be nominated from among the participants of the present Working Group as temporary focal points.

- 25 -

References 1. Eisenberg D.M., Davis, R.B., Ettner, S.L., Appel, S., Wilkey, S., Van Rompay, M., & Kessler, R.C. ( 1998) Trends in alternative medicine use in the United States, 1990-1997. Results of a follow-up national survey. JAMA 280:1569-1575. 2. Dev S. Ethnotherapeutics and modern drug development: the potential of Ayurveda. Current sczence. 1997, 73:909-9:LH. 3. Dev S. Ancient-modern concordance in Ayurvedic plants: some examples. Environmental healthperspectives. 1999, 107:783-789. 4. Secretariats of the Convention on Biological Diversity (CBD) 2000. 5. Bensoussan A. and Myers S.P. Towards a safer choice, the practice of traditional Chinese medicine in Australia. Macarthur, University of Western Sydney, November 1996. 6. Mahady GB, Fong HHS, Farnsworth NR. Botanical dietary supplements: Quality, safety and efficacy. Lisse, Swets & ZeitI inger Publishers, 200 I. 7. http:://www.ifpma.org/ICH

- '2.6 -

- 27 Annex I

LIST OF TEMPORARY ADVISERS, CONSULTANT, OBSERVERS AND SECRETARIAT

1. TEMPORARY ADVISERS Dr Alan Bensoussan Associate Professor and Head Chinese Medicine Unit University of Western Sydney Locked Bag 1797 Perth South DC, NSW 1797 Australia Tel. no.: 612-0772-6363 FAX: 612-9773-0998 E-mail: a.bensoussan@uws.edu.au Dr David Briggs Manager Scientific Programs Office of Complementary Medicine Therapeutic Goods Administration P.O. Box 100 Woden, ACT 2606 Australia Tel. no. 61 2 6232 8439 FAX: 61 2 6232 8577 E-mail: david.briggs@health.gov.au Pharm. Cao Thi Mai Phuong Head, Office of VietNam Pharmacopoeia Commission 48 Hai Ba Trung Street HaNoi VietNam Tel. no: (844) 8256905 FAX: (844) 9343547 Professor 11-Moo Chang Head WHO Collaborating Centre for Traditional Medicine Natural Products Research Institute Seoul National University #28, Yungun-dong Jong-ro-ku Seoul 11 0-160 Republic of Korea Tel. no: 82-2-740 8721 FAX: 82-2-745-1015 E-mail: changim@snu.ac.kr

- 28 Annex 1

Dr Chris Cheah Hean-Aun Assistant Head Traditional and Complementary Medicine Department Ministry of Health 3 Second Hospital Avenue Institute of Health Singapore 168937 Tel. no: 065-2361990 FAX: 065-2361947 E-mail: chris_CHEAH@moh.gov.sg. Mr Thomas Cheung Senior Pharmacist Chinese Medicine Division Department of Health The Government of the Hong Kong Special Administrative Region Wu Chung House, 32"d Floor 213 Queen's Road East Wan Chai Hong Kong Tel. no: 852 2126 5110 FAX: 852 2123 9566 Dr Ren Dequan Deputy Director-General State Drug Administration A38 Beilishilu Beijing 100810 People's Republic of China Tel. no: 86 I 0 88372259 FAX: 86 10 68310909 Dr Yukihiro Goda Head Division of Pharmacognosy and Phytochemistry National Institute of Health Sciences 1- I 8-1, Kamiyoga, Setagaya-ku Tokyo 158-8501 Japan Tel. no: 81-3-3700-9154 FAX: 81-3-3707-6950 E-mail: goda@nihs.go.jp

- 29 -

Annex 1

Professor Huang Luqi Director Institute of Chinese Materia Medica China Academy of Traditional Chiinese Medicine 18 Beixincang, Dongzhimennei Beijing 100700 People's Republic of China Tel. no: 86-10-64014411-2853 FAX: 86-10-6401-3996 E-mail: huangluqi@263.com Dr Ho-Cheol Kim Director Department of Pharmacology & Drug Development Team Kyung Hee University Graduate School of East-West Medical Science Seoul 130-701 Republic of Korea Tel. no: 82-2-961-0419 FAX: 82-2-964-0325 E-mail: hckim@khu.ac.kr Professor Hyo Jung Kim Director General Efficacy and Safety Research Centre for Traditional Oriental Medicines Kyungsan University Kyongbuk Technopark 165 Sangdong, Suseongku Daegu 706-060 Republic of Korea Tel. no: 82-53-770-2299 FAX: 82-53-762-1263 E-mail: hyokimm@yahoo.co.kr hyokim@kyungsan.ac.kr Mr Sik-Yiu Kwan Chief Chemist Government Laboratory 7IF, 88 Chung Hau Street Homantin Kowloon Hong Kong Tel. no. (852) 2762 3895 FAX: (852) 2714 4083 E-mail: sykwan@govtlab.gov.hk

- 30 Annex I

Dr Leung Ting-hung Assistant Director of Health and Head, Chinese Medicine Division The Government of the Hong Kong Special Administrative Region Wu Chung Hou!le, 32"d Floor 213 Queen's Road East Wan Chai Hong Kong Tel. no: (852) 2126 5100 FAX: (852) 2123 9566 E-mail: t_h_leung@dh.gov.hk Dr Lin Ruichao Director Division of Chinese Materia Medica and Natural Products National Institute of Control for the Pharmaceutical and Biological Products State Drug Administration 2 Tiantan Xili Beijing 100050 People's Republic of China Tel. no. 8610 670 17755-307; 67023650 FAX: 8610 67023650 Dr Soo-chun Park Director Oriental Medicine Division Ministry of Health and Welfare 1, JoongAng-Dong Kwacheon City Kyunggi-Do 427-721 Republic of Korea Tel. no: 82-2-211 0-6044; 6045 FAX: 82-2-503-7541 E-mail : scpark@mohw.go.kr Professor Trinh Van Qm: Director National Institute of Drug Quality Control 48 Hai Ba Trung Street HaNoi VietNam Tel. no: 844 825 5341 FAX: 844 825 6911 E-mail: quyvkn@hn.vnn.vn

- 31 -

Annex 1 Dr Ushio Sankawa Director International Research Center for Traditional Medicine Toyama International Health Complex 151 Tomosugi Toyama 939-8224 Japan Tel. no: 81-76-493-0830 FAX: 81-76-493-0834 E-mail: sankawa@toyama-pref-ihc.or.jp Dr Motoyoshi Satake Japan Pharmacist Education Center Toranomon 19 Mori BLD. 3F, 1-2-20 Toranomon, Minato-ku Tokyo Japan Tel. no: 81-3-5251-9951 FAX: 81-3-3592-1665 Dr Shilin Yang Researcher and Director Institute of Medicinal Plant Development Hai Dian District Xi Bei Wang Beijing I 00094 People's Republic of China Tel. no: FAX: 86 10 6289 4335 Professor Le Van Truyen Vice Minister of Health Ministry of Health 138A Giang Yo Street HaNoi VietNam Tel. no: 844-48453303 FAX: 844-8464051 Mr Y ee Shen Kuan Deputy Director (Product Evaluation and Registration) Deputy Director (Surveillance and Enforcement) Centre for Pharmaceutical Administration Health Sciences Authority Deputy Head (Chinese Medicinal Materials) Traditional & Complementary Medicine Department Ministry of Health 2 Jalan Bukit Merah Singapore 169547 Tel. no: 65 2213014 FAX: 65 2226797 E-mail: yee_shen_kuan@hsa.gov.sg

- 32 Annex 1

Dr Keum-Ryon Ze Section Chief Herbal Medicine Standardization Division Korea Food and Drug Administration 5, Nokbun-Dong Eunpyung-Uu Seoul 122-704 Republic ofKorea Tel. no: 82-2-2646-7330 FAX: 82-2-385-0297 E-mail: keumryon@kfd a.go.kr

2. CONSULTANT Dr Harry H.S. Fang Professor of Pharmacognos y WHO Collaborating Centre for Traditional Medicine PCRPS (M/C 877), College of Pharmacy University of Illinois at Chicago 833 S. Wood Street Chicago, Illinois 60612 United States of America Tel. no. 1-(630) 469-7158 FAX: 1-(312) 413-5894 E-mail: Hfong@uic.ed u

3. OBSERVERS

Professor Norio Aimi Graduate School of Pharmaceutica l Sciences Chiba University Chiba 263-8522 Japan FAX: 81 43 2902901 E-mail: aimi@p.chiba- u.ac.jp Dr Kwang-Won Ha Director Department of Herbal Medicine Evaluation Korea Food and Drug Administration 5, Nokbun-Dong Eunpyong-Gu Seoul 122-704 Republic of Korea Tel. no: 82-2-3463-608 2 FAX: 82-2-385-0297 E-mail: hakw@kfda.go .kr

- 33 -

Annex 1 Dr Lee Jong-kyu Oriental Medicines Division Ministry of Health and Welfare l Jeong-Dong Gwacheon City Kyunggi-Do 427-721 Republic ofKorea Tel. no.: 82-2-211 0-6044; 6045 FAX: 82-2-503-7541 E-mail: npobby@mohw.go.kr Dr Park Sang-Pya Deputy Director Oriental Medicines Division Ministry of Health and Welfare 1 Jeong-Dong Gwacheon City Kyunggi-Do 427-721 Republic ofKorea Tel. no.: 82-2-2110-6044; 6045 FAX: 82-2-503-7541 E-mail: dangun99@mohw.go.kr Dr Sang-Y ong Park Researcher Department of Herbal Medicine Evaluation Korea Food and Drug Administration 5, Nokbun-Dong Eunpyong-Gu Seoul 122-704 Republic of Korea Tel. no: 82-2-380-1730-2 FAX: 82-2-385-0297 Dr Setsuko Sekita Director Tsukuba Medicinal Plant Research Station National Institute of Health Sciences 1 Hachimandai, Tsukubashi lbaraki 305-0843 Japan Tel. no.: 81-298-38-0571 FAX: 81-298-38-0575 E-mail: sekita@nihs.go.jp

- 34 Annex 1

Dr Rack-Seon Seong Senior Researcher Department of Herbal Medicine Evaluation Korea Food and Drug Administration 5, Nokbun-Dong EunpyongwG\1 Seoul 122-704 Republic ofKorea Tel. no: 82-2-380-1730-2 FAX: 82-2-385-0297 Dr Kazuo Toriizuka Associate Professor Laboratory of Pharmacognosy and Phytochemistry School of Pharmaceutical Sciences Showa University Tokyo 142-8555 Japan FAX: 81 3 3784 8191 Mrs Wang Qian Institute of Chinese Materia Medica China Academy of Traditional Chinese Medicine Beijing 100700 People's Republic of China FAX: 861 0-640 13 996 E-mail: zhongyaosuo@I63.com

4. SECRETARIAT Dr Chen Ken (Responsible Officer) Regional Adviser in Traditional Medicine, Laboratories and Research WHO Western Pacific Regional Office United Nations Avenue, Ermita, Manila Philippines Tel. no.: (63 2) 528-9844 FAX: (63 2) 521-1036 E-mail: chenk@wpro.who.int

- 35 Annex2

THE REGULATION OF COMPLEMENTARY MEDICINES IN AUSTRALIA by Dr David Briggs Managitr, Scientific ProgrnmG Office of Complementary Medicine Therapeutic Goods Administration Australia Introduction In Australia, herbal medicines are included in a group of medicines collectively referred to as complementary medicines. Other complementary medicines include vitamins, minerals, nutritional supplements, aromatherapy oils and homoeopathic medicines. The Regulatory Framework for Therapeutic Goods in Australia Complementary medicines in Australia are regulated under therapeutics goods legislation. The Therapeutic Goods Act 1989 (the Act) (Commonwealth of Australia, 200la) came into effect in 1991. The Therapeutic Goods Administration {TGA), a Division of the Commonwealth Department of Health and Aged Care, is responsible for administering the provisions of the Act. The overall objective of the Act is to ensure the quality, safety and efficacy of therapeutic goods, including medicines and medical devices. Australia is a federation of states with a Commonwealth (Federal) Government and six State and two Territory governments. While the Act provides a substantially uniform national system of controls over therapeutic goods, other Commonwealth and State and Territory legislation may also apply. The Australian Register of Therapeutic Goods (ARTG) is a database maintained by the TGA. It includes details of all therapeutic goods that are imported into, supplied in, or exported from Australia. It is a legal requirement, unless specifically exempt or excluded, that all therapeutic goods be included in the ARTG prior to their supply. Only therapeutic goods that have been assessed or evaluated by the TGA are included in the ARTG. The evaluation or assessment process undertaken depends on the type of therapeutic good and its indications and claims. Australia has a unique regulatory system for complementary medicines, the latest developments of which are based on a regulatory reform package introduced into legislation in 1999. The reforms use a risk-based approach to determine an appropriate level of both pre-market evaluation/assessment and post-market activity for complementary medicines. This approach has resulted in a two tiered regulatory system based on risk. Medicines assessed as having a higher level of risk are included in the ARTG as Registered medicines. Medicines of low risk are included in the ARTG as Listed medicines. Most, but not all, complementary medicines are Listed medicines. Managing risk The risk associated with therapeutic goods, including complementary medicines, is managed through three main processes: • • • licensing of manufacturers; pre-market assessment of products; and post-market regulatory activity.

- 36 Annex2

Licensing of manufacturers: Manufacturers who are seeking to manufacture for the Australian market must meet certain standards. They must demonstrate to the Australian government, through the TGA, that they are manufacturing medicines under conditions that contribute to ensuring the safety and quality of the goods. Standards for the manufacture of therapeutic goods are delivered through Good Manufacturing Practice (GMP). Manufacturers must be licensed and their manufacturing processes are su~ject to inspection and audit by the TGA. Medicines imported into Australia must also meet Australian GMP requirements for manufacture before they can be legally marketed. Pre-market assessment: The pre-market assessment process for a new medicine depends on the relative risk associated with the medicine. In determining risk, a number of factors are taken into consideration, including: the toxicity of the ingredients; whether the medicine is intended to be used to treat, cure, manage or prevent a serious condition, disease or disorder; • whether the use of the medicine is likely to result in significant side effects; and • whether there may be adverse effects from prolonged use or inappropriate self-medication. Medicines that are assessed to be of higher risk are individually evaluated for safety, quality and efficacy before they are released onto the market. Once approved for supply, these products are included in the ARTG as Registered products and carry an identifying AUST R number on the label. Registered medicines include both prescription and non-prescription medicines. Depending on their ingredients and proposed indications, some complementary medicines require evaluation as Registered medicines. A different assessment process is applied to low risk products which include most complementary medicines. In this streamlined approach, low risk products are individually assessed by the TGA for compliance with legislation, but they are not evaluated before they are released onto the market. However, all ingredients from which these products are formulated must have undergone pre-market evaluation for safety and quality. Products may only be supplied if they contain substances previously approved by the TGA as suitable for use in low risk medicines. Once approved for supply, these products are included in the ARTG as Listed products and carry an identifying AUST L number on the label. Consistent with their low risk, Listed complementary medicines may only carry certain indications and claims (see Table I). Table I. Indications and claims permitted for Listed (low risk) complementary medicines (Therapeutic Goods Administration, 200 I). Health maintenance; Health enhancement; Nutritional support; Symptomatic relief of non-serious diseases, disorders and conditions; May aid or assist in the management of non-serious diseases, disorders and conditions; and Reduction in the risk of a particular non-serious disease d isorder, condition, symptom or ailment. The claims and indications for a Listed medicine are not evaluated by the TGA before the product enters the market. However, the Act requires that sponsors hold appropriate evidence to support the indications and claims made at the time the product is included in the ARTG. Claims and indications for Listed medicines may be supported by scientific evidence or evidence of traditional use. Where there is a public health or safety concern about the claim for a product or the claim appears to be wilfully misleading or in response to a complaint about the product, the TGA may call • •

- 37 Annex 2 upon sponsors to provide the evidence they hold to support the claim(s). In order to facilitate compliance with the requirement to hold appropriate evidence to support particular claims, the TGA and the Complementar y Medicines Evaluation Committee (an independent expert statutory committee established to advise the TGA) have developed guidelines to assist sponsors in determining what constitutes appropriate evidence to support various types of therapeutic claims and indications (Therapeutic Goods Administration , 200 I). In addition to limits on ingredients and indications/clai ms for Listed medicines, there are a number of other ways that the risk associated a medicine can be controlled. This includes, but is not limited to, the use of label advisory information, limits on dose, mode of administration, use of particular plant parts, method of preparation and container type. The data used to support the evaluation of new complementary medicine substances, for use in Listed medicines and the objectives of the data are outlined in Table 2. Table 2. Data and objectives to support the safety evaluation of new complementary medicine substances for use in Listed medicines (Cumming, F. 200 I). Data Characterisatio n ofthe complementary medicine substance. History and mode and patterns of previous human use. Reports of adverse reactions.

Objective To unambiguously define the compositional characteristics of the substance. To determine the conditions, if any, under which the substance has been used by humans in the past. To determine the nature, severity and frequency of adverse reactions where there has been a history of use of the substance. To describe the role the substance in human metabolism . To describe what is known about and where possible, quantify, potential risk associated with the use ofthe substance. To report the results of use of the substance by humans under clinical trial conditions to identify risks from the experience of use in humans.

Biological activity Toxicology

Clinical trials

Where a herbal ingredient is a fresh or dry herb, essential oil, tincture, decoction, infusion or extract and it has been previously included in a therapeutic good included in the ARTG; and it is not subject to specific regulatory restrictions (for example, because of the toxicity associated with a particular chemical component, plant part or concentration); then the ingredient is generally eligible to be included in a Listed medicine without further evaluation by the TGA. Herbal ingredients that have not previously included in a therapeutic good included in the ARTG, and which are not subject to other specific regulatory restrictions, may be eligible to be included in Listed medicines following evaluation as a new complementary medicine substance. Where regulatory restrictions apply to a particular herbal ingredient that precludes its use in Listed medicines, it may be eligible to be included in a Registered medicine. The ingredients or kind of ingredients designated as complementary medicine ingredients are shown in Table 3 (Commonweal th of Australia, 200lb).

- 38 Annex 2 Table 3. Ingredients or kind of ingredients designated as complementary medicine ingredients (Commonwealth of Australia, 2001 b). an amino acid charcoal a cholint! salt

an essential oil plant or herbal material (or a synthetically produced substitute for material of that kind), including plant fibres, enzymes, algae, fungi, cellulose and derivatives of cellulose and chlorophyll a homoeopathic preparation a microorganism, whole or extracted, except a vaccine a mineral including a mineral salt and a naturally occurring mineral a mucopolysaccharide non-human animal material (or a synthetically produced substitute for material of that kind) including dried material, bone and cartilage, fats and oils and other extracts or concentrates a lipid, including an essential fatty acid or phospholipid a substance produced by or obtained from bees, including royal jelly, bee pollen and propolis a sugar, polysaccharide or carbohydrate a vitamin or provitamin Quality of herbal medicines An important determinant in evaluating a new complementary medicine substance, and the suitability of a complementary medicine for registration, is the quality of the starting material and the finished product. The Act defines the quality standards applicable to all therapeutic goods. For regulatory purposes the British Pharmacopoeia (BP) is the source of official standards. The BP is supplemented by Therapeutic Goods Orders (TGOs) which are developed through a process of industry consultation in response to a particular need, such as where there is no coverage by the BP or where Australian-specific requirements are relevant. Examples are TGO 69 which sets out requirements for labels for therapeutic goods and TGO 56 which describes the tests and acceptance criteria to be applied to tablets, capsules and pills in those cases where there is no specific BP monograph . Quality standards for specific starting materials and products may also be established through the Listing/Registration process. In this situation, reference may be made to other national pharmacopoeias or recognised texts. Herbal medicines usually contain complex mixtures of chemical components and, because of this, their analysis can be rather challenging. For this reason, the quality of herbal medicines is best assured by controlling the quality of all steps in their production. This begins with a rigorous characterisation ofthe herb from which the medicine is produced. Growing, harvesting, drying, agricultural practices and processing of the herb should all be controlled to obtain optimal and reproducible quality. Likewise, production of herbal preparations, such as extracts, should be performed under conditions ofGMP with measures in place to ensure processes are well controlled. Where appropriate, attention should be given to controlling impurities arising from extraction solvents, breakdown products or contaminants such as toxic metals and mycotoxins. Microbial load also requires control. Where the therapeutic activity of a herbal substance can be assigned unambiguously to a particular component or group of components, then the levels of these components should be measured as part of quality control testing. In cases where therapeutic activity can not be directly

- 39 Annex2 linked to any particular herbal constituent or group of constituents then the common practice is to use levels of phytochemical markers as a means of monitoring batch-to-batch consistency. Chromatographic profiling is also useful for assisting in providing reproducible quality of herbal preparations as well as being an aid in the identification of herbal materials. Post-market regulatory activity The streamlined approach to assessment for low risk complementary medicine products (Listed medicines) addresses the need to improve market access to quality new complementary medicines while maintaining public health and safety. It allows for timely market access with a level of premarket evaluation of the components of each medicine that provides an assurance of the safety and quality of the product. To support this assurance, the TGA undertakes a range of post-market regulatory activities that includes: targeted and random desk-based audits of Listed products; monitoring of adverse reactions to complementary medicines; targeted and random laboratory testing or products and ingredients; targeted and random surveillance in the market place; an effective, responsive and timely recalls procedure; audit of good manufacturing practice (GMP); and effective controls for the advertising of therapeutic goods. Overall, this allows for the timely identification and appropriate regulatory response to problems with the formulation, manufacture, labelling and advertising of complementary medicines. Conclusion The recent reforms to the regulation of complementary medicines in Australia build on the existing regulatory system to provide a sound risk-based management system to: • • ensure a level of regulation commensurate with the risk of complementary medicines; and meet the need to improve market access to quality new products while maintaining public health and safety. • • • • • • •

References Commonwealth of Australia, (2001a). Therapeutic Goods Act 1989 as amended. Commonwealth of Australia, (2001 b). Schedule 14, Therapeutic Goods Regulations as amended. Cumming, F., (2001). Personal communication, Office of Complementary Medicines, Therapeutic Goods Administration, PO Box 100 Woden, ACT, 2609, Australia Therapeutic Goods Administration, (2001). Guidelines on Levels and Kinds of Evidence to Support Indication and Claims, Canberra, Australia

- 40 Annex2

- 41 -

Annex2 CHINESE TRADITIONAL MEDICINE, GENERAL INTRODUCTION, ADMINISTRATION AND QUALITY CONTROL by Dr Ren Dequan and Dr Lin Ruichao State Drug Administration Beijing, China

General information on Traditional Chinese Medicines and Traditional Chinese Medicines Sector Traditional Chinese Medicine (TCM) refers to crude drugs, processed plant products, and manufactured preparations. The TCM sector include agriculture, commerce and industry. In 1978, the total sales of TCM products of all types were approximately RMB 2.1 bi Ilion. In the year 2000, the total sales ofthese products were over RMB 61.2 billion. The growth rate for manufactured TCM preparations was 20% /year. The previous dominant dosage fonns of the preparations, such as pills, powders, plasters and pellets have evolved to tablets, capsules, pellets and oral liquids. Additionally, there are now injections, powders for injection, and bulk solutions being available. Twenty years ago, the annual sales of the largest TCM product manufacturer totaled RMB I 0 million. Presently there are up to 120 such manufacturers, with annual sales of more than RMB 100 million. There are 11 manufacturers with annual sales records of US$ 100 million. Although China is in the process of economy development and modernization, including the availability of modern medicines, TCM use has not declined. In fact, it has entered into a new period of high growth. This is mainly due to two reasons: first, it is because TCM has its unique characteristics for health care and protection; second, the modernization ofTCM medicine has further enabled it to meet the society's progressive need/demand for new dosage forms, packaging and product quality. Regulation on TCM in China A pre-market approval system has been established that requires new TCM preparations be approved and registered before their entry into the market. For new TCM crude drugs that have never been recorded in the history or used by the people, the marketing authorizations are also required. TCM is being classified into prescription and non-prescription medicines, and national standards for TCM preparations have been established for market access. National standards have also been established for a number ofTCM crude drugs. Local drug regulatory authorities have stipulated standards for those not under national standards. Local authorities are also responsible for setting up specifications for processing ofTCM products. The manufacturers ofTCM preparations and processed products are regulated under a licensing system. The licensing to TCM preparation manufacturers has been linked to production under GMP, and, together with GSP, the system is implemented so as to regulate the distribution, including retails and wholesales, ofTCM preparations and the processed products ofTCMs. A market sampling system has been established according to national and local standards for the control ofTCM crude drugs, preparations, and the processed products. A tracing system on Adverse Drug Reactions has also been implemented.

- 42 Annex2 Imported TCM products are registered and approved according to the rules and regulations for the importation of pharmaceutical drugs. Registration of TCM products in China In September of 1984, the standing committee ofthe National People's Congress promulgated the Drug Administration Law, and according to the law, the Provisions for the Approval ofNew TCM Preparations was issued in 1986, in line with the basic requirements for ensuring the safety, efficacy and quality of drugs and on the basis of valuing and carrying on traditional characteristics, and encouraging the combination with modern science and technology. From then on, any new TCM preparations should be approved and registered before its access to the market. Meanwhile, TCM preparations which were marketed prior to 1986 have been re-evaluated. Those traditional drugs, which were generally recognized by the public, such as "Niu Huang Qing Xin Wan, Liu Wei Di Huang Wan" were issued registration numbers and continue production and sales on the basis of standardized specifications. Those TCM preparations, which have never been recorded in the classical medicine books, were evaluated and sorted out by experts according to the TCM theory and clinical trial. Those TCM preparations with theoretic rationality, safety as well as efficacy, after improving the quality standards, were granted the approval number and recognized as state-approved products in the market. The major elements of the TCM product Examination and Approval Management are as follows: A. Classification of new TCM products Class 1: (I) Artificial alternatives of Chinese crude drugs. (2) Newly discovered Chinese crude drugs and their preparations. (3) Active constituents extracted from Chinese crude drugs and their preparations. (4) Active constituents extracted from the composite formulation of traditional Chinese medicines. Class 2: (1) Injection oftraditional Chinese medicines. (2) New medicinal parts used of Chinese crude drugs and their preparations. (3) Effective fractions extracted from Chinese crude drugs or natural drugs and their preparations. (4) Chinese crude drugs artificially developed in animal body and their preparations. (5) Effective fractions extracted from composite formulation. Class 3: (l) New composite formulation oftraditional Chinese medicines. (2) Composite preparation of traditional Chinese medicines and chemical drug with the main efficacy played by traditional Chinese medicines. (3) Domestically cultivated or bred crude drugs originally imported and commonly used in China, and their preparations. Class 4: (I) Preparation with a change of dosage form or route of administration. (2) Botanical crude drugs acclimated from their origin, or crude drugs from domesticated wild animal in China.

- 43 Annex2

Class 5: Marketing drugs with new indications or syndromes.

B. Procedures of approval of new TCM products Drug administration at provincial level

Review process (Preliminary review, on-site inspection)

Be approved

I Not be approved ~

~

State Drug Administration

I I

lr

rl ~r-

Department of Drug Registration, SDA

l

I

Center of Drug Evaluation, SDA

J

I Expert Committee of Drug Evaluation, SDA

...

I

I

Evaluation

I 1,.. I~

lr

I

Manufacturer

- 44 Annex2 C. Application items for new drug (TCM Preparations) Part I. General data I. Introduction of research and development of the preparation. 2. Name (including name in Chinese, the Chinese phonetics, Latin name) and the reason for nomenclature. 3. Source of the formulation, purpose and reason for the subject selected and a review of relevant literature. 4. Sample of insert sheet (on probation) and explanation for drafting. It should include name ofthe preparation, its principal ingredients, description, pharmacological effect, function and indications, administration and dosage, adverse drug reactions, contraindication, warning, specification, storage, expiry date, manufacturer, approval number, etc. Properties of the packaging materials, sample of labeling and the explanation. Marks for specially controlled drugs and drugs for external use must be clearly presented on the package and in the insert sheet.

Part II. Pharmaceutical data 5. Preparation process and its research data. 6. Research data and literature of the physical and chemical properties related to quality. 7. Draft of quality specification for the preparation in clinical trial and quality specifications for materials (including Chinese crude drugs) used for the preparation, and explanation for drafting. 8. Data of preliminary stability testing for the preparation to be used in clinical trial and relevant literature. 9. Samples (three times of that required for a complete analysis) ofthe preparation to be used in clinical trial, quality and hygienic testing reports. 10. Quality specifications and explanation for drafting of the raw material (crude drug), final products, reference substances and relevant data (for preliminary review). 11. Data of stability test, conclusions and research data concerning expiry date of the preparations, and relevant literature. 12. At least three consecutive batches of samples (from pilot products), quality and hygienic testing reports (the amount of the sample for each batch should be three times of that required for a complete analysis). Part III. Pharmacological and toxicological data 13. 14. 15. 16. 17. 18. 19. Data and Data and Data and Data and Data and Data and Data and literature of principal pharmacodynamics relevant to its function and indication. literature of general pharmacological study. literature of acute toxicity test. literature of long-term toxicity test. literature of mutagenicity test. literature of carcinogenicity test. literature of reproductive toxicity test.

Part IV. Clinical data 20. Formulation, function and indication, interpretation ofthe pathogenic factors, pathogenesis, methods of treatment of the indications, and formulation by theory of traditional Chinese medicine. 21. Design and protocol of clinical trial and results and review of pharmacological and toxicological study as references for clinical investigators. 22. Final report of clinical trial written by the principal investigator, and individual clinical trial reports provided by each clinical trial site.

- 45 Annex2

Table 1 Application items for New Drug (Chinese Crude Drug) Item General Data Pharmaceutical Data Data Number 1 2 3# 4 5 6 7 8 9 1011 11"' 1211 13 14 15 16 17 18 19 20 21 22"' Classification ofNew Drubs Class 2 Class 3 Class 1 Class 4

Pharmacological and Toxicological Data

Clinical Data

+ + + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + +

+ + + + + + + + + + + + +

+ + + + + + + + + + + ±

± ±

+ ±

+ + +

-

-

+ + +

+ + +

Notes : I. 2. 3. 4.

+ : dare must be submitted. ± : experimental data or detailed literature should be submitted.

- : not required. # : data required when applying for production.

- 46 Annex2

Table 2 Application items for New Drug (Traditional Chinese Drug Preparation) Item Data Number I 2 3 4# 5 6 7 8 9 IO# If# I2# 13 14 15 I6 17 18 19 20 21 22# Classification ofNew Drubs Class 4 Class 2 Class 3

Class 1

Class 5

General Data

Pharmaceutical Data

Pharmacological And Toxicological Data

Clinical Data

+ + + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + +

+ + + + + + + + + + + + +

+ + + + + ±

+ + + + ± ±

+ + + + + + ±

+ + + + + + +

+ + -

± ±

+ + +

+ + +

+ + +

-

+ + +

Notes: 1. 2. 3. 4.

+ : i data must be submitted. ± : experimental data or detailed literature should be submitted.

- : not required. # : data required when applying for production.

- 47 Annex2

Table 3 Application items for Clinical Study of New Drugs (Traditional Chinese Medicines) Clinical Trial Classification ofNew Drubs Phase No. ofCases Class 3 Class 1 Class 4 Class 2 of Test Group 20-30 +J I + + "'2 II ::::too + + + + ;?:300 m + + + *1 *2 N ::::2000 + +

Class 5

.4-J

+

-

Notes : 1. + : data must be submitted. 2. - : not required. 3. * : with a number: see the text of corresponding number in the Explanation attached. 4. Number of cases denotes number of trial cases in test group, requirements for control group f each phase indicated in "Technical Requirements for study on New Traditional Chinese Medicines". Explanation: 1. For Class 3 drugs containing crude drugs with toxicity or drug incompatibility existing in the preparation (18 FAN, I9WEI), Phase I clinical trial is required, and Phase IV trail might be carried out depending on individual situation. 2. If manufacturing process of a drug is changed significantly in the change of dosage form, and it turns to a drug of active fractions, phase I clinical trail is required in general, and Phase IV trail might be carried out depending on individual situation. 3. Phase I clinical trial must be performed for the drugs adding new indications, increasing dose, prolonging the duration of treatment and containing toxic crude drugs in the formulation. 4. New measures to perfect the management and to promote the development ofTCM preparations A. The revised Drug Administration Law was drafted by SDA, adopted by the State Council, and promulgated by the Standing Committee ofNational People's Congress, which clarifies the implementation of Approval Number system on Crude Medicines and processed products. In another words, the market access of Crude Medicines and processed products would be regulated as that of TCM preparations. B. The revised Drug Administration Law also clarifies that all TCM preparation manufacturers should meet the standards ofGMP and pass the GMP certification. After the deadline, those who fail to pass the GMP certification will be deprived of their license. C. GAP for the production of herbal material is formulated and punished to promote the standardization and centralization of the herbal material production, to guarantee the quality of herbal material and to advocate ecotype herbal material and green herbal material.

D. High Inner quality standards are required. The quality standards oftraditional medicine injection must be set up with dactyloscopy technology. The quality standards of prepared herbal medicine and herbal materials are required to set up as far as possible with spectrum and chromatogram technologies when applying the number of registration.

- 48 Annex2

E. To strengthen the links with the drug administrations of all the countries in the world and promote the international exchanges on the problems in the application of the traditional Chinese medicine. The important point now is exchange about the registration and standards of the market entering of TCM, and its harmful effects. To combine the characteristic ofTCM with scientific administration and technology meanwhile to let the world knowing its characteristic. Quality Control of Chinese Materia Medica Quality control of Chinese Materia Medica involves the issues of standardization, reference substances, and research activities. I. 0 Standardization

Standardization requirements, methods and procedures are described in the Chinese Pharmacopeia, Propharmacopeia and Regional Standards. The number of official herbal medicines in seven editions of the Chinese Pharmacoepoeia are as follows:

.. Edllto/1

1953 1963 1977 1985 1990 1995 2000

Crud D rugs 65 446 882 506 509 522 534

p

TCM . reparatwns 46 197 270 207 275 398 458

Totalnumhers Ill

643 1152 713 784 920 992

A breakdown ofthe types ofTCM medicines in the 2000 edition ofthe Pharmacopoeia is as follows: · ·_,

Types Pills Powders

Sum 210 50 29 58 2 4 3 9 I

Types Mixtures Dripping Pills Capsules Medicinal Wines Tinctures Liquid Extracts and Extracts Plasters Adhesive Plasters Ointments · -· = = ~ ~ · ~~ = = = = = :: ::

Sum 26 2 15 5 5 10 1 6 3 .::=:..-:::;:: := := :.

Types Medicinal Distillates Medicinal Teas Injections Liniments Suppositories Nasal Drops Eye Drops Aerosols and Sprays -··~ "====··=··

Sum I

2 2 I I I

. ;

Granules Tablets

, Troches Concentrated Decoctions Glues Syprus Cataplasms

1 2

- 49 Annex 2 The first edition of the Propharmacopoeia was published in 1991 and contained 101 crude drugs. Twenty volumes describing 4,052 TCM preparations have been published thus far. New approved herbal drugs will be added in the Propharmacopoeia following a two-year testing period.

General Guideline for the Quality Control of Chinese Materia Medica include the following items: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. The origin of medicinal plant, animal or mineral The part used for pharmaceutical purpose The appropriate season for collection The processing method of crude drugs Storage and transportation Description and action of crude drugs Determination of total ash, water and acid- insoluble ash. Determination of ethanol-soluble or ether-soluble extractives Compounds and single ingredient identification and determination, such as: Volatile oil, Flavonoids, Alkaloids, Saponins etc. Methods: HPLC, TLC, GC,etc. Impurities Pesticide residue, such as: organic chlorine or phosphorus Test of heavy metal, such as: Arsenic, Mercury, Plumbum, Cadmium, Cuprum.etc. Measurement and determination of radioactive substance Microbiological assay and determination, such as: Aflatoxin, Bacteria etc.

The quality ofTCM preparations is controlled by the following measures: 1. Description: Form (Appearance or shape), size, color, odor and taste 2. Identification: Specificity, accuracy and sensitivity must be considered. The methods may include: ( 1) Microscopic identification (2) Chemical identification (3) Chromatography analysis (TLC, GC, HPLC, etc.) 3. Tests:

(1) Lose on drying, total ash, disintegration tests, size of granules, uniformity, dispensability, ethanol content (2) Toxic component, including brucine, aconitine and heavy metal (Hg, Cu, Pb, Cd etc.) (3) Pesticide residue and microbial contamination. 4. Assay: The assay is designed to measure the content of active or single representative composition or some chemical compositions or total compositions. Assay methods should be carefully set up employing a marker or active component as the quality indicator because the variation of content always be encountered with plant materials collected in different seasons, cultivation in different regions, and by different processing methods. The specification of the content of certain ingredient or maker compound or compounds should be established based on a large quantity of research data.

- 50 Annex2

2.0 Reference substances Reference substances refer to two types of materials: • • Chemical Reference Substances (CRS) refers to pure chemical compounds used for assay and identification. Reference of Crude Drugs (RCD) refers to intact plant material or milled powder, which have been identified and authenticated for use as reference in identifying other material medicine and its finished products.

There are 200 CRS and 150 RCD materials listed in the Propharmacopoeia, Pharmacopoeia and Regional Standards. Technical Directions for CRS are: l. General requirements 2. Description 3. Confirmation of structure 4. Purity 5. Content 6. Storage Technical Directions for RCD are: I. General requirements 2. Characteristics 3. Identification 4. Assay 5. Storage and packaging 6. Stability The RCD is very useful and cannot be replaced in the identification (microscopy and TLC) of Chinese Materia Medica and TCM Preparations, especially in the following conditions: • The ingredients in the drug are not clear. • The ingredient is cannot be easily isolated. • The ingredient is unstable. • Two different Chinese medicinal plants have the same single ingredient which cannot be distinguished by CRS. • RCD can also be used for originative identification of Chinese medicinal plants. • RCD can provide more chemical constituent information, in some degree, the information provided by SRM can also be looked as rudimental fingerprint.

- 51 Annex 2

Official CRS and RCD materials in the past editions of the Chinese Pharmacopoeia are as follows:

Edition

CRS

RCD

1985 1990 1995 2000

60

16

100

39

143

94

203

152

300 Research Activities Research activities on the quality control of Chinese Materia Medica include: I. Five Year Plan Sponsored by Ministry of Scientific Technology (MOST), State Administration of Traditional Chinese Medicine (SATCM) The most current Five Year Plan was in the 1986-2000 period: No p enot1 S pomwro\ o 0

p rtl)i!cl o

A c,uevements ,. I The book of Species Systematization and Quality Evaluation of Commonly Used Chinese Traditional Drugs, NorthChina Edition, Vol. 1, 2, 30 0

19861990

SATCM

19911995

SATCM

19962000

MOST SATCM

Species Systematization and Quality Evaluation of Commonly Used Chinese Traditional Drugs Species Systematization and Quality Evaluation of Commonly Used Chinese Traditional Drugs Quality Control and Standardization of Commonly Used Chinese Traditional Drugs

20 The book of Species Systematization and Quality Evaluation of Commonly Used Chinese Traditional Drugs, SouthChina Edition, Vol. I, 20

70 species of Commonly Used Chinese Traditional Drugs have been studied and much progress gained

- 52 Annex2

2. Other sponsors by national departments such as State of Drug Administration (SDA), State Administration of Traditional Chinese Medicine (SATCM) and Natural Scientific Fund of China (NSFC). They all have paid much attention to research works of Chinese Materia Medica. 3. Many pharmaceutical industries and research institutes have being taken great efforts to study the Chinese Materia Medica, and much progress has been gained. 4. For the quality control of drug materials of Chinese Materia Medica, Chinese SDA are promoting Good Agriculture Programs (GAP), Which is considered as guarantee of high quality (safety, efficacy, consistency, and controllability) of Chinese Materia Medica. 5. Strengthen International Cooperation

- 53 Annex 2 REGULATION AND QUALITY CONTROL OF CHINESE MEDICINE IN HONG KONG (CHINA) by Dr Leung Ting-hung Assistant Director of Health and Head, Chinese Medicine Division Hong Kong (China)

1.

Background

The dominant health care system in Hong Kong, China has been Western medicine. This notwithstanding, Chinese medicine has been widely used for many years, both as an alternative and a complement to Western medicine. According to the General Household Survey conducted in 1999, about 22% of the outpatient medical consultations in Hong Kong, China were provided by Chinese medicine practitioners. An earlier survey also showed that up to 60% of Hong Kong people had used Chinese medicine either for treatment of diseases or for health maintenance. It is estimated that there are a total of about 3800 retailers, wholesalers and manufacturers of Chinese medicines which included proprietary Chinese medicines and herbs in Hong Kong, China. Traders of Chinese medicines estimated that there are about 2000 kinds of herbs and about 6600 types of proprietary Chinese medicines sold in Hong Kong, China. There were about 8000 applications for registration of Chinese medicine practitioners under the transitional arrangements at the end of 2000. To pave the way for the development of Chinese medicine in Hong Kong, the then Secretary for Health and Welfare in 1989 and 1995 appointed two working groups respectively to review the use and practice of Chinese medicine in Hong Kong and make recommendations for its future development. 2. Regulatory framework

The Chief Executive announced and reaffirmed in his Policy Addresses in 1997 and 1998 his priority to develop Chinese medicine. As a first step, the Government is committed to establishing a sound regulatory framework for Chinese medicine, covering both the practice of Chinese medicine practitioners as well as the use, sale and manufacture of Chinese medicines. This approach underlines the recognition of their inter-relatedness and the need to address them in parallel. In July 1989, the Chinese Medicine Ordinance was enacted. The Chinese Medicine Council of Hong Kong (Council), established under the Ordinance in September 1999, is responsible for devising measures and setting standards to regulate the practice of Chinese medicine practitioners and the use, trading and manufacture of Chinese medicines. The regulatory measures of Chinese medicine practitioners include a system of professional examination, registration and discipline. In future, only registered Chinese medicine practitioners are allowed to practise Chinese medicine in Hong Kong, China. 3. Quality control and regulatory measures of Chinese medicines

The Chinese Medicine Board, established under the Council, is mainly responsible for implementing regulatory measures for Chinese medicines. These measures include a licensing system for traders and manufacturers of Chinese medicines and a registration system for proprietary Chinese medicines based on the criteria of safety, quality and efficacy.

- 54 Annex2 All retailers, wholesalers and manufacturers of Chinese herbs and proprietary Chinese medicines need to obtain license. They have to demonstrate that the hygienic conditions and facilities in warehouses, shops and factories satisfy the regulatory requirements before they will be granted a license. Proper packaging, labelling and keeping of sales record are also required to facilitate audit trail and recall in case of adverse medical reactions. In order to upgrade the standard of practice of the traders and manufacturers of Chinese medicines, the Chinese Medicines Board is devising practising guidelines for each type of license holder. Transitional arrangements are provided for traders and manufacturers of Chinese medicines. Any trader or manufacturer who carried on their business on or before 3 January 2000 can apply for provisional licenses. A fully license would only be issued when all the licensing requirements and practising conditions as stipulated under the Ordinance are met. All proprietary Chinese medicines need to be registered before they are allowed to be on sale or manufactured in Hong Kong, China. A gradual and incremental approach is preferred, recognizing the historical development of Chinese medicine in Hong Kong, China, the complexity of issues involved, and balancing the livelihood of the trade and the protection of public health. Furthermore, there are practical reasons for a pragmatic solution to the regulation of herbal medicine-based products where its understanding and technology for testing and evaluation are still evolving. The Chinese Medicines Board is now finalizing registration criteria for the different categories of proprietary Chinese medicines. Proofs of quality, safety and efficacy are required. As a first step, the Chinese Medicines Board demands that each proprietary Chinese medicine must have satisfied the following requirements before they will be considered for registration: • • • • Heavy metals contents are within limits; Pesticides residues are within limits Microbial counts are within limits The use of herbs as raw materials are in compliance with the Animals and Plants (Protection of Endangered Species) Ordinance, and There is no adulteration of Western medicines.

•

Initially, provision for transitional registration of proprietary Chinese medicines would also be made. Any proprietary Chinese medicine sold or manufactured in Hong Kong, China on or before 1 March 1999 may apply to the Chinese Medicines Board within specified time for registration. On receipt of such application, the proprietary Chinese medicine should be deemed to have been registered and could continue to be sold or manufactured in Hong Kong, China. Upon submission of the necessary documents and evidence for registration, they will be granted a "full" registration. The subsidiary legislation for the regulation of Chinese medicines will be introduced to the Legislative Council of Hong Kong, China shortly. Upon its enactment, licensing oftraders and manufacturers will begin in 2002, to be followed by the registration of proprietary Chinese medicines. 4. Conclusion

Chinese medicine, notwithstanding its contribution to the health of millions of people over thousands of years, has much room for growth, research and development. To this end, a sound regulatory framework for medicinal herbs, couple with the development and harmonization of standards based on scientific principles and evidence is of utmost importance. In this way, herbal medicines would be more widely recognized or accepted by drug regulatory authorities.

- 55 Annex 2 JAPANESE PHARMACOPOEIA, REGULATION AND QUALITY CONTROL OF TRM PHARMACEUTICAL PRODUCTS by Dr Motoyoshi Satake .T::~p;m Ph::~rm::~r.ist

F.clur.atinn r.r:ntr:r

and Dr Ushio Sankawa Director, International Research Center for Traditional Medicine Japan I. History of Japanese Pharmacopoeia Prior to the appearance of the Japanese Pharmacopeia, a document known as the PrePharmacopoeia or the WAZAIKYOKUHOU, was published in 1100 AD and was used by the Shyogun Tokugawa Ieyasu onto the 17 century. In 1835, Rouan Udagawa translated the Nederland Pharmacopoeia into the Japanese language. After the Meiji revolution in 1868, the quality control of medicine was carried out using the European Pharmacopoeial method in Tokyo (1873), Kyoto (1875) and Yokohama (1876). For example, the quality control on Digitalis, Cinchona bark, Ipecac, morphine, atropine and quinine was carried out according to the methods described therein. The pharmacists were educated in the Osaka and Kobe Drug Laboratory. The Japanese Pharmacopoeia was started by Drs.Geerts and. Dwars in 1883. The first edition ofthe Japanese Pharmacopoeia was published in July 1888 and contained 468 monographs, including 97 crude drugs. Twenty five monographs from the first edition are still official in the fourteenth edition, 2001. They are: Acacia, Amomum seed, Bearberry leaf, Benzoin, Bitter orange peel, Calumba, Cinnamon bark, Clove, Digitalis, Fennel, Gambir, Japanese gentiana, Ginger, Glycyrrhiza, Honey, Ipecac, Valerian, Mentha herb, Nux vomica, Powdered opium, Rhubarb, Saffron, Senega, Senna leaf, and Tragacanth The second edition ( 1891) of the Japanese Pharmacopoeia contained 91 crude drugs, from which three monographs (Coptis Rhizome, Apricot Kernel, Scopolia Rhizome) are still found in the 2001 edition. The third edition (1906) contained 135 crude drugs, and four monographs (Cundurango, Gentiana, Immature Orange, Zedoary) are in the 2001 edition. The fourth edition (1920): 120 crude drugs , from which four monographs (Pharbitis seed, Platycodon root, Polyglot root, Swertia herb) were official in the 1996 edition. The fifth edition (1932): 98 crude drugs, which afforded four monographs (Catalpa, Potato starch, Rice starch, Wheat starch) in the 1996 edition. Of the 87 crude drugs found in the sixth edition ( 1949), the following nine monographs are still in the 1996 edition: Atractylodes lancea rhizome , Atractylodes Rhizome, Corn starch , Geranium herb, Peony root, Phellodendron bark, and Ginseng.

- 56 Annex2

The seventh edition (1961) contained 176 crude drugs, 47 ofwhich were found in the 1996 edition: From the seventh edition (I96I) (Part I): Achyranthes root, Anemarrhena rhizome, Asiasarum root, Astragalus root, Cassia seed, Belladonna root, Bupleurum root, Cimicifuga rhizome, Cnidium rhizome, Cyperus rhizome, Evodia frUit, Gardema trUit, Glehnia root, Gypsum, Houttuyinia herb, Imperata rhizome, Japanese angelica root, Jujube, From the seventh edition (I961) (part 2): Houttuyinia herb, Imperata rhizome, Japanese angelica root, Jujube, Lithospermum root, Magnolia bark, Montan bark, Moms bark, Nuphar rhizome, Ophiopogon tuber, Oriental bezoar, Oyster shell, Panax rhizome, Peach kernel, Plantago herb, Plantago seed, Polyporus sclerotum, Poria sclerotum, Prunella spike, Red ginseng, Rehmannia root, Rose fruit, Safflower, Saposhnikovia root, Schisandra fruit, Scutelaria root, Smilax rhizome, Sophora root, Sweet hydrangea leaf, Trichosanthes root The eighth edition (197I): the same I76 crude drugs found in the seventh edition. The ninth edition (1976): I69 crude drugs, with the following 10 monographs remained in the 1996 edition: Schizonepeta spike, Comus fruit, Dioscorea rhizome, Perilla leaf, Citrus unshiu peel, Mentha herb, Angelica dahurica, Saposhnikovia root, Longgu, and Forsythia fruit. The tenth edition ( I981 ): I66 crude drugs, whereas, the 1I th edition (1986) contained 165 crude drugs with musk being excluded. The twelfth edition (199I ): 165 crude drugs. The thirteenth edition ( I996): I72 crude drugs with following new monographs being added: Mallotsu bark, Artemisia capillaris flower, Powder of Fennel, Powder ofDioscorea rhizome, Powder ofPolyporus sclerotum, Powder of Peach kernel, Powder of Ginseng. The fourteenth edition (200 I) also contain 172 crude drugs. 2. General rules for Crude Drugs and Crude Drugs Test (I) General rule for Crude Drugs a) Crude drugs are usually used in the forms of whole crude drug, cut or powdered. b) Unless otherwise specified, crude drugs are used in the dried form. The drying is usually carried out at a temperature not exceeding 60°C. c) Stored in a clean and hygienic state. d) The description in each monograph of crude drug usually covers the crude drug derived from its typical original plant or animal and includes statement of characteristic properties of the crude drug. e) Crude drugs are preserved in well-closed containers unless otherwise specified.

- 57 Annex2

(2) Crude Drug Tests a) Sampling: Sampling should be taken by one of three categories. • • • 50-250g sample for small-size or powder, 250-SOOg for large-size not less than 5 pieces, the weight of each piece not less than 500 g.

b) Preparation of the test sample for analysis: Preparation is to be made by mixing the sample well. Powdered drugs should be used as they are, and in the case of unpowdered drugs, unless otherwise specified, grind the sample into powder. If the sample cannot be ground into powder, reduce it as finely as possible, spread it out in a thin layer, and withdraw a typical portion for analysis. If necessary, preserve the test sample in a tight container. c) Loss on drying: 2-6g of the test sample for analysis. Drying at 105°C for 5 hours. Continue the drying at 105°C, and weight accurately at 1-hour intervals. When the weight of the sample becomes constant, the loss of weight represents the percentage of loss of drying (% ). When the period of time for drying is specified, weight accurately after drying for the period of time specified, and determine the % loss on drying. d) Total ash: Heating to a temperature between 500-550°C. for more than 4 hours. e) Acid-insoluble ash: Add dilute hydrochloric acid to the total ash, boil for 5 minutes. f)

Extraction: Dilute ethanol-soluble extract, water-soluble extract, and ether-soluble extract.

g) Essential oil content: The essential oil content in the crude drugs is performed as directed in the essential oil determination. h) Microscopic examination: Apparatus, preparation for microscopic examinations, and observation of components in the description. (1) Apparatus Use an optical microscope with objectives of 10 and 40 magnifications and an ocular of 10 magnifications. (2) Preparation for microscopic examination a) Section: To a section on a slide glass add 1 to 2 drops of a mounting agent, and put a cover glass on it, taking precaution against inclusion of bubbles. Usually use section 10 to 20 ~Min thickness. b) Powder: Place about 0.1 g of powdered sample in a watch glass containing 2 to 3 drops of swell agent, stir well with a small rod preventing inclusion ofbubbles, and allow to stand for more than 10 minutes to swell the sample. Smear, using a small glass rod, the slide glass with a small amount of the swollen sample, add 1 drop of the

- 58 Annex2 mounting agent, and put a cover glass on it so that the issue sections spread evenly without overlapping each other, taking precaution against inclusion of bubbles. Unless otherwise specified, use a mixture of Glycerin and water ( 1: 1) as mounting agent and swelling agent. c) Observation of components in the Description In each monograph, description is usually given of the outer portion and the inner portion of a section in this order, followed by a specification of cell contents. Observation should be made in the same order. In the case of a powdered sample, description is given of a characteristic component or matter present in large amount, rarely existing matter, and cell contents in this odor. Observation should be mad in the same odor. 3. Sample monographs Rhubarb:

Rheum palmate, Rheum tanguticum, Rheum officinale, Rheum coreanum or their interspecific hybrids. It contains not less than 0.25% of sennosides A. Purity; raponticin, Loss on drying; not more than 13.0%, Total ash; not more than 13.0% Extractable content (Dilute ethanol-soluble extract); not less than 30.0% Ginseng:

Panax ginseng Identification; ginsenoside Rg1 by TLC Total ash, not more than 4.2% Extractable content (Dilute ethanol-soluble extract); not less than 14.0%,. Purity (1) Foreign matter, (the amount ofthe stem and other foreign matter contained does not exceed 2.0%) (2) Heavy metals (not more than 15 ppm) (3) Arsenic (not more than 2 ppm) (4) Total BHC's and total DDT's (not more than 0.2ppm) Glycyrrhiza:

Glycyrrhiza uralensis and Glycyrrhiza glabra It contains not less than 2.5% of glycyrrhizic acid.

Loss on drying, not more than 12.0%; Total ash, not more than 7.0%; Acid-insoluble ash, not more than 2.0%; Extractable content (Dilute ethanol-soluble extract), not less than 25.5%

- 59 Annex2 Ephedra herb:

Ephedra sinica, Ephedra intermedia and Ephedra equisetina It contains not less than 0.7% oftotal ephedrine as ephedrine and pseudoephedrine. Identification; ephedrine by TLC Total ash; not more than II.O% Acid-insoluble; not more than 2.0% Extractable content (Dilute ethanol-soluble extract); not less than I4.0%. Purity; woody stem and foreign matter Magnolia bark:

Magnolia obovata, Magnolia officina/is, Magnolia officina/is var. biloba It contains not less than 0.8% of magnolol Total ash; not more than 6.0%, Extractable content (Dilute ethanol-soluble extract); not less than 25.5% 4. The standard compounds Example reference standard compounds for the crude drug assay are: barberine for Coptis Rhizome and Phellodendron bark; paeniflorin for Peony root; baicalin for Scutalleria root; sennoside A for Rhubarb; sennoside B for Rhubarb and swertiamarin for Swertia Herb. 5. General Information (I) Aristolochic acid; Assay Method

(2) Microbial Attributes ofNon-sterile Pharmaceutical Products (Microbial contamination limits for herbal drugs) Target limits of microbial contamination for herbal drugs and herbal drug containing preparations are two categories. Category I indicates herbal drugs and their preparations to which boiling water is added before use, and category 2 indicates other herbal drugs and other gram-negative bacteria, Escherichia coli, Salmonella, and Staphylococcus aureus are mentioned as specified microorganisms, but other microorganisms such as certain species of Bacillus cereus, Clostridia, Pseudomonas, Burkholderia, Asperigillus and Enterobacter species are also necessary to be tested depending on the origin of the herbal drug raw materials or the preparation method of the preparations. Category I Aerobic bacteria Molds and yeasts Category 2

107 I 04

105 104

- 60 Annex2

Japan Report #2: 6. Regulation and quality control ofTRM pharmaceutical products in Japan The use of KAMPO medicine in medical care today include 14 7 prescriptions being produced for Ethical KAMPO Preparations, which are in the list of 210 KAMPO Prescriptions covered by the Social Health Insurance. Each KAMPO preparation is assigned its efficacy and effect on indication. The names of diseases should be assigned with those of modern medicine, but not by KAMPO medicine. It should be noted that KAMPO prescriptions are regarded as medicinal drugs and concomitant use with synthetic drugs is possible. While the expenditures on modern prescription and over the counter drugs remained essentially unchanged in the 1988-1998 period, the expenditures for KAMPO medicines rose from approximately Yen 100 billion in 1988 to a high of approximately Yen 170 billion in I 992. The total expenditure for KAMPO medicines in I 998 was approximately the same as it was in I988. In 1997, a total of 4.39 million kg ofKAMPO medicine was produced. The efficacy ofKAMPO medicine has been subjected to clinical studies. For example, "Shosaiko-to" was evaluated for its clinical effect on hepatitis. Improvement was shown in 55% treated compared to 46% in the placebo group. The efficacy of"Dalo-kanzo-to" in the treatment of constipation was treatment group (73%), placebo group (48%). "Sho-seiryu-to", treatment of perennial nasal allergy: treatment group (45%), placebo group (18%). "Choto-san", treatment of vascular dementia: treatment group (75%), placebo group (50%). The regulation for the manufacturing control of KAMPO medicine under GMP is under the self-imposed regulation of the Japan Kampo Medicine Manufacturers Association (JKMA), not a governmental mandate. The identification and analysis are required for each crude drug used in the 1 manufacture of ethical and over-the-counter (OTC) Kampo extract preparation according to the 14 h edition of the Japanese Pharmacopoeia (JP I4) or the non-Pharmacopoeial Crude Drug Standard (nonJP Crude Drug Standard). Thin-layer chromatographic profiles and HPLC analysis of the main constituents of more than two crude drugs contained in the final Kampo extract preparation are required. It should be noted that there are I 20 crude drugs and 51 powder items described in JP 14, and there are 75 crude drugs and 8 powders in the non-JP Crude Drug Standard. In the manufacturing process, it is overseen by a Medicinal Drug Administrator, under whom are two divisional managers: a manufacturing control manager (Manufacturing division), and a quality control manager (Quality Control Division). Reporting to the quality control manager is a crude drug (herbal) control manager. Educationally, there is a Training Course of Kampo Drugs and Crude Drugs by Pharmacist Training Centre, the objectives ofwhich are to gain basic knowledge ofKampo medicine; to learn about up-to-date studies on crude drugs, natural medicines, and others; and to understand the regulation and law relating to Kampo medicine and extract preparation. Botanical preparations can be classified as a drug, a specified functional health food, a nutraceutical supplement, or a food/health food. A specified functional health food is required to list the active ingredient, the specific function supported by clinical evidence, and a cautionary statement on the label.

- 61 -

Annex2 INTRODUCTION TO STANDARDS OF TRADITIONAL KOREAN MEDICINE by Dr Soo-chun Park Director, Oriental Medicine Division Ministry of Health and Welfare Republic of Korea 1. Relevant laws and regulations • Traditional Korean medicines are governed by the Pharmaceutical Affairs Law.

The Law stipulates matters pertaining to production, dispensation, appraisal, safekeeping, import, sale of oriental and Western medicines or other things concerning pharmaceutical skills. • 0 Regulations on quality control Regulations on quality control of medicines are covered by Korean Pharmacopoeia and Medicinal Herbs Standards.

They stipulate methods of production, nature, effects, quality and methods of storage. The 514 kinds of medicinal herbs are comprised of 428 vegetable by-products, 55 animal byproducts, and 31 mineral by-products. The regulations are controlled by the Central Pharmacists Deliberations Commission. 0 There are regulations on tests for medicinal herbs, such as tolerance limits of heavy metals in medicinal herbs and test methods, tolerance limits of residual chemicals in medicinal herbs and test methods.

2.

Relevant institutions and organizations • 0 The Ministry of Health and Welfare (MOHW) A General Director for Oriental Medicines Bureau is the official directly in charge of matters concerning traditional Korean medicines.

Oriental Medicine Bureau is comprised of the Oriental Medicine Policy Division and the Oriental Medicines Division 0 Related organization

The Pharmaceutical and Food Policy Division ofMOHW is in charge of general pharmaceutical affairs.

- 62 Annex2 3. KFDA (Korea Food and Drug Administration) • KFDA is in charge of implementation of safety management, and test and inspection of medicines and foods.

Pharmaceutical Safety Department is in charge of permits and clinical management concerning medicines. Pharmaceutical Management Department is in charge of removal of problematic pharmaceuticals and overall supervision of pharmaceuticals. Herbal Medicine Evaluation Department is in charge of enactment of standards for herbal medicines, investigation and research concerning harmful materials (such as residual chemicals and heavy metals) contained in herbal medicines, production of standard herbal medicines, and quality standardization of herbal medicines. Six local government offices assume the role of instruction and supervision. 4. Central Pharmacists Deliberations Commission • Organization

A chairman is Vice Minister ofMOHW and deputy chairmans are two persons including KFDA Deputy President. The Commission shall consist of 100 members or less appointed by the Minister ofMOHW at the recommendation of the heads of organizations related to pharmaceutical matters. • The Commission's function is to give consultation at the request of the Minister of MOHW and KFDA President

The major function is as follows: 5. Enactment of, and amendment to, Korean Pharmacopoeia Matters concerning the standards of pharmaceuticals Matters concerning investigation, research and appraisal of safety and effects Matters concerning methods of remedy against harmful side effects of pharmaceuticals

Medicinal Herbs Standards • • System for standardization of medicinal herbs is being implemented The regulation for supply and distribution of oriental medicines supports medicinal herbs standards Only those complying with specifications for methods of production, nature, effects, quality and method of storing are allowed to be used. Only those made by authorized commercial enterprise specializing in medicinal herbs can be distributed in principle.

•

•

- 63 Annex2 • The standards apply to all medicinal herbs specified in Korea Pharmacopeia and Medicinal Herbs Standards ( 514 kinds).

6.

Production of Medicinal Herbs • Source of regulations is the Pharmaceutical Affairs Law A commercial enterprise specializing in medicinal herbs require a permit granted by the relevant local office ofKFDA. Requirements for commercial enterprises specializing in medicinal herbs The following conditions shall meet the requirements stipulated in the Decree for Facility Standards for Pharmacy and Businesses of Production, Import and Sale of Pharmaceuticals - A place of production - A laboratory for quality control of raw materials and products - A storage place for raw materials and products - Facilities and equipment needed for quality control and production D One shall have a staff member (a Western or Oriental pharmacist) in charge of supervision of production There are 170 commercial enterprises specializing in medical herbs in Korea. 69 important medicinal herbs including dried ginger (Zinger officina/e), rhubarb (Rhuem palmatum), and pueraria root (Pueraria lobata) are allowed to be handled only by authorized commercial enterprise specializing in medicinal herbs. The business of oriental medicine preparations requires a permit granted by KFDA under the same requirements as other medicines.

D

• D

• •

•

7.

Supervision • Matters concerning preparation and production of medicinal herbs are under the supervision ofthe relevant local office ofKFDA. Matters subject to supervision by the authorities are as follows - Result of quality tests for products - Report of records of production - Whether one is engaged in production of unapproved medicinal herbs - Compliance with the system for standardization - Whether one is engaged in production or sale of medicinal herbs not reported as an item or production to the authorities

•

- 64 Annex2 - Whether one has installed and maintains required facilities for production and quality control - Compliance with specifications for production management and product standards

- 65 Annex2 THE REGULATION OF TRADITIONAL MEDICINE IN SINGAPORE by Dr Chris Cheah Hean-Aun Assistant Head, Traditional and Complementary Medicine Dept. Ministry of I Iculth, Singuporo and Mr Y ee Shen Kuan Deputy Director (Production Evaluation and Registration) Centre for Pharmaceutical Administration Health Sciences Authority Singapore

Current Status ofTraditional Medicine Singapore's total population of 3.8 million is composed essentially of the three main races of Chinese (77%), Malay (14%) and Indian (7%). Although Western medicine is generally recognised and accepted as the main form of healthcare here, traditional medicine comprising the historical healing methods of the three main races still enjoys considerable popularity. 2 Traditional medicinal materials popularly in use include: a) b) c) Chinese herbal medicines from China Jamu from Indonesia and Malaysia, and Ayurveda from India.

Traditional Indian medicine or Ayurveda is generally practised among the Indian segment of 3 the population and migrant workers from the Indian subcontinent while traditional Malay medicine is practiced by traditional Malay herbalists (bomoh) and midwives (bidan). Traditional Chinese medicine (TCM) is the most widely practised of the traditional medicine 4 in Singapore.

Traditional Chinese Medicine

A survey conducted by the Ministry of Health (MOH) in 1994 revealed that almost half of the 5 population (45%) had consulted a TCM practitioner in the past. They comprised: a) b) c) 54% of the Chinese, 16% of the Indians, and 8% ofthe Malays.

TCM practice is restricted to outpatient service in Singapore. It is estimated that about 10,000 6 persons (12%) visit TCM clinics each day compared to 74,000 persons who visit Western medical clinics.

- 66 Annex 2 7 A list published by the local TCM community in 1997 listed 1,807 TCM practitioners in Singapore. Most of them were above 40 years old. Half of them practised TCM on a full-time basis, a third practised part-time and the remainder was not practising at the time of the listing.

REGULATORY POLICY ON TRADITIONAL CHINESE MEDICINE 8 In July 1994, a Committee on TCM was appointed by the Minister for Health to review the practice ofTCM and recommend measures to safeguard patient interest and safety, and to enhance the standard oftraining ofTCM practitioners. 9 The Committee published its report in October 1995. The main recommendations of the Committee include: a) A phased approach to the regulation of TCM in Singapore - self-regulation by the TCM community first, followed by statutory regulation later; Ways to upgrade the standard of training ofTCM practitioners in Singapore; and The control of Chinese medicinal materials (CMM) in Singapore.

b) c)

REGULATION OF TCM PRACTITIONERS 10 An umbrella body representing eight local TCM organisations, known as the Singapore TCM Organisations Coordinating Committee (STCMOCC), was formed in 1996 to facilitate self-regulation and to act as a channel of communication between the TCM community and MOH.

Self Regulation 11 As part of the effort to implement self-regulation of TCM in Singapore, MOH has been working closely with STCMOCC to achieve the following: a) Listing ofTCM Practitioners STCMOCC published a listing of 1, 807 TCM practitioners in 1997 with details on their practice address, training background and years of experience. b) Standardised TCM Training Course A new standardised six-year part-time TCM training course was adopted by the two largest local TCM training schools in 1996. The course is open only to persons with at least a full GCE A-level certificate or its equivalent. c) Ethical Code and Disciplinary Process With guidance from MOH, STCMOCC drew up an ethical code and a disciplinary process for TCM practitioners in 1997. The ethical code includes guidelines for professional behaviour, advertising, use of titles, qualifications and clinic names, and consultation fees.

- 67 Annex 2

Statutory Regulation 12 The TCM Practitioners Act 2000 was passed on 14 Nov 2000 and a TCM Practitioners Board was set up to register TCM practitioners, starting with acupuncturists. The registration of acupuncturists was started on 8 Feb 2001. About 1,600 acupuncturists applied for registration. 13 Passing the Common Acupuncture (Jualifying Examination (CAQE) is a mandatory requirement for the registration of acupuncturists. However, about 63% of the acupuncturists who were practising in Singapore at the time registration came into effect were fully exempted from CAQE as their qualifications and practise experience were recognised by the Board. 14 About 7% ofthe acupuncturists with minimal or no qualifications or experience were required to enroll in the Acupuncture Upgrading Training Course (AUTC) to upgrade their skills before they were allowed to sit for the CAQE. 15 About 22% of the acupuncturists were partially exempted from CAQE as they had some qualifications and practise experience. They were registered after they passed an Acupuncture Appraisal (AA) examination. 16 The remaining 8% of the applicants either withdrew their applications or had their applications rejected by the Board. 17 To date, about 1,300 acupuncturists have been registered by the TCM Practitioners Board. By 1 Jan 2002, a person who wishes to practice acupuncture in Singapore will need to be registered with the Board.

REGULATION OF CHINESE MEDICINAL MATERIALS (CMM) CATEGORIES OF CMM 18 Chinese medicinal materials (CMM) include Chinese herbs and medicinal materials obtained from animal and mineral sources. CMM can be grouped into the following 2 categories: (a) RawCMM These are CMM in natural states or undergone simple processing (e.g. cutting, drying) which are used in the practice of Traditional Chinese Medicine. (b) Chinese Proprietary Medicines (CPM) These are CMM preparations in final dosage forms (e.g. tablets, pills, liquid preparations) which are used in the practice ofTCM. REGULATORY POLICY ON CMM 19 In line with the national regulatory policy on TCM, the Committee on TCM appointed by the Minister for Health in July 1994 made the following recommendations for the regulation of CMM m its 1995 report: (a) Strengthen the control of CPM quality and safety by a product approval system and licensing of dealers

- 68 Annex2 (b) Establish a CPM advisory committee to advise the Ministry of Health on CPM matters Set up a CPM Unit to carry out CPM product approvals and licensing of dealers In the interest of the public, CMM dispensers should be adequately trained. In the future, CMM dispensers may also be required to receive formal training and be registered.

(c) (d)

Control of Raw CMM 20 Currently, the control of raw CMM is minimal. They must not contain natural occurring, potentially toxic substances listed under the Poisons Act. e.g. strychnine, aconitine and tetrahydropalmitine. 21 The usage oftoxic raw CMM will be reviewed by the Ministry of Health after the registration ofTCM practitioners and CMM dispensers. Control of CPM 22 CPM control was implemented in 3 phases from 1 Sep 1999 to 1 Sep 2001 based on various dosage forms. Phase 1 consisted of tablets and capsules which was implemented on 1 Sep 1999 followed by Phase 2 (liquid preparations) on I Sep 2000 and Phase 3 (other dosage forms such as pills, granules and powders) on 1 Sep 2001. 23 From 1 Sep 2001 onwards, the entire 3 phases of CPM control was successful implemented and CPM products available in Singapore (about 8800 products in total till Nov 2001) had obtained product approvals. Legislation 24 CPM control is accomplished under the following legislations: (a) (b) Medicines Act 1975 Medicines (Traditional Medicines, Homoeopathic Medicines and Other Substances) (Exemption) (Amendment) Order 1998 Medicines (Chinese Proprietary Medicines) (Exemption) Order 1998 Medicines (Labelling of Chinese Proprietary Medicines) Regulations 1998 Medicines (Licensing, Standard Provisions and Fees) (Amendment) Regulations 1998 Medicines (Prohibition of Sale and Supply) (Amendment) Order 1998

(c) (d) (e) (f)

Principles adopted in CPM control 25 When implementing CPM control in Singapore, the differences in the concepts of the TCM system of the therapeutics as compared to Western medicines were taken into careful consideration.

- 69 Annex 2 A practical and balanced concept of control was adopted, i.e. on one hand meeting the 26 objective of safeguarding public health and on the other hand, did not impose too many restrictions on the local CPM trade and development. The emphasis of CPM control is to ensure product safety and quality, which have direct 27 effects on the health of local consumers.

A Summary of CPM Control Requirements Under CPM control, all local CPM importers, wholesale dealers, manufacturers and re28 packers must be licensed in order to upgrade their standards and make them fully accountable for safety and quality of their products. Till Nov 2001, there were 189 licensed importers, 258 licensed wholesale dealers, 22 licensed manufacturers and 31 licensed re-packers. In addition, CPM products must be approved before they could be imported, manufactured 29 and sold in Singapore. This is to ensure product safety and quality by eliminating sub-standard, fake, imitation and adulterated products as well as to ensure consistency in labeling and removal of misleading and exaggerated claims. The CPM approval criteria include: (a) (b) Product must not be adulterated with Western drugs or synthetic active substances. Product must not contain naturally occurring, potentially toxic substances controlled under the Poisons Act. Product must not contain toxic heavy metals (mercury, arsenic, copper and lead) and microbial counts beyond the legal limits. Product must fulfill the labeling requirements in English, including batch number, expiry date, particulars of manufacturer and importer. The product label must not make any reference for usage on serious medical conditions or diseases stipulated in the Medicines Act e.g. cancer, diabetes and impotency. The product manufacturer must be licensed and product must be freely sold m country of manufacture.

(c)

(c)

(d)

(f)

Furthermore, licensed CPM importers are required to submit toxic heavy metal and microbial 30 test reports for each consignment at the point of import in order to ensure product quality and safety of each imported consignment. The advertisements and sales promotions of CPM products must be approved by the Ministry 31 of Health to ensure the public is protected against misleading and exaggerated advertisements and sales promotions.

AREAS OF CONCERN IN CMM REGULATION Contamination Although the CPM control had resulted in a significant reduction of sub-standard products in 32 the local market, cases of CPM products exceeding the legal toxic heavy metal limits and microbial counts were still encountered during the Ministry's post marketing quality surveillance programme.

- 70 Annex2

Sub-standard products, lack of standardization and batch variation.

33 During the Ministry's post marketing quality surveillance programme, a small percentage of CPM products were usually found to be adulterated with western drugs e.g. NSAIDS, antihistamines, a net se:cllltive:s. Dnrine ?.001, there were several cases of CPM products and medicated wines found to be adulterated with sildenafil (active ingredient ofViagra). FAKE I IMITATION PRODUCTS

34 Fake or imitation CPM products are usually targeted at famous and expensive items such as Yunnan Paiyao and Pien Tze Huang. The implementation ofCPM control had resulted in the removal of such items in the market but they could still be imported through illegal means. CMM Misidentification & Non-Traditional I Inappropriate Use

35 The misidentification and substitution of CMM is of great concern, especially among CMM of almost similar names and appearances. For example in 1992, the erroneous substitution of stephania tetrandra with aristolochia fangchi (due to the similarity of the Chinese names) in slimming products in Belgium had resulted in significant cases of severe nephrotoxicity. Aristolochia fangchi is documented to contain the nephrotoxin and carcinogen known as aristolochic acid which is not documented in stephania tetrandra. 36 Another great concern is the non-traditional and inappropriate use of CMM resulting in adverse reactions. For example, ephedra sinensis (rna huang) is commonly used in TCM as an exterior relieving herb mainly for dispersing wind-cold. Its traditional use in TCM is very different from the inappropriate use in slimming products which have resulted in adverse reactions reported in the US. In another example, the nephrotoxicity adverse reports of aristolochia (see paragraph 36) were associated with long term use in slimming (a non-TCM way of usage). On the other hand, the use of aristolochia in TCM involves small quantities of herbs in combination with other CMM for a short duration of TCM treatment. Labelling

37 The CPM control had resulted in a significant improvement in the consistency of product labelling, with removal of exaggerated and objectionable claims. However, CPM labels still contain claims on the treatment of some serious medical conditions such as hepatitis and bronchitis. This area would be looked into when the Ministry of Health explores on efficacy assessment of CPM in the future. FUTURE PLANS

38

The future plans in the regulation in CMM are as follows: (a) Upgrade the standard of local CMM dispensers, with the aim of registration in the future. With the upgrading ofTCM standard in Singapore, constant review of the regulations will be made to ensure that the control meets international standards.

(b)

- 71 -

Annex 2 (c) Further improve the safety and quality standard of CPM in addition to the existing requirements. Explore on efficacy assessment when the clinical and scientific data are more established. Reference would be made from established overseas regulatory agencies such as US FDA and Australia TGA. Impose tighter control on other forms of traditional medicines such as Jamu and Ayuverda. Facilitate CMM research and development in Singapore as part of the nation's life sciences project. Strengthen co-operation with overseas regulatory agencies (e.g. WHO, China's SDA, US FDA, Australia TGA, Asian countries) in the area ofCMM.

(d)

(e)

(f)

(g)

- 72 -

Annex2

- 73 Annex 2 THE STANDAR DIZATION OF MEDICINA L PLANTS AND TRADITIO NAL MEDICINES IN VIETNAM by Associate Professor Le Van Truyen Vice Minister ot Health Ministry of Health and Professor Trinh Van Quy Director National Institute of Drug Quality Control

I.

lnroduction

As defined in the regulation on evaluating safety and effectiveness of traditional medicines by the Ministry of Health, "traditional medicines are herbal medicines in crude form or processed, or their preparations which are prepared according to the method of traditional medicine from one or more kinds of drugs derived from animals, plants, mineral with efficacy in disease treatment or with benefit for human health". According to this definition, traditional medicines include both "Chinese medicinal herbs", "Vietnames e medicinal herbs", and "Traditional national medicines", and emphasizes the traditional methods of preparation, which include: Mechanical: slicing, eroding, grinding, sieving. Physio-chemical: dehydrating, steaming, drying on a fire, grilling, burning, heating, keeping warm, soaking, stewing, extracting, and distilling. These processing methods are to eradicate or reduce poisonous substances or to change effect of medicines. Traditional processing methods usually create simple dosage forms such as balsams, pills, remedies for concoction. However, there are also available presently a large number of medicines derived from traditional origin but prepared in modern dosage forms such as tablets, capsules, and others. Therefore, the term "Herbal medicines" is used to define all traditionally originated medicines which have or have not been modernized: "Herbal medicines are all kinds of medicines derived from plants, animals, minerals, which are basically prepared according to traditional methods and consisting of complex elements in which the main active constituents may be, but usually are not known. However, according to traditional experience, they show effectivenes s in curing or improving health in conformity with general action mechanism of the theory of oriental medicine".

Characteristics of herbal medicines • • • Herbal medicines have natural origins. They are basically prepared in accordance with the traditional method. The chemical constituents are very complex, consisting of main constituent(s), minor constituent(s), supplemented constituent(s), their chemical nature are generally unknown. This complexity increases many-fold when the formula includes many different herbs (up to 50)

- 74 Annex 2 • The effect of these medicines displays slowly, according to general mechanism based on the theory of the oriental medicine.

Classification of oriental medicines • Ancient oriental medic.ines are medicine.s utilize.ci in conformity with ancient books, noting the number of herbs, the amount of each, method of preparation, dosage, mode of use and indications. Modified oriental medicines are medicines different from ancient medicines in the number of herbs, amount of each kind, preparation method, usage, dosage based on the theory of dialectic therapy, but still based on the ancient core. New traditional medicines are completely different from the ancient ones in the number of herbs, amount of each kind, form of medicines, dosage, and indications; Regional oriental medicines are medicinal remedies known in certain region and are handed down from ancestors passed by tradition from one generation to another in the family.

•

• •

2.

Quality of oriental medicines

In general, herbal medicines are also required to ensure quality as for modern medicines/ pharmaceuticals in terms of quality, safety and efficacy. In order to meet this requirement, the Ministry of Health (Decision N° 3 71/BYT- QD dated 12/3/1996) issued a regulation on evaluating the effectiveness and safety of traditional medicine. This regulation is applied to the traditional medicines known as modified ancient prescription, prescription handed down from ancestors, and new traditional medicines. The evaluation criteria include: • • • • • • Formula Processing method Quality standards for medicinal plants and finished products; Pharmacological effect Toxicity Clinical trials:

Unfortunately, a large number of oriental medicines of low or no efficacy, and/or harmful are still available, due to the fact that these medicines are not prepared in accordance with the formula and the traditional method; and most of them are new traditional medicines or modified ancient oriental medicaments that are not well researched and evaluated properly according to regulations. Another problem in the quality of oriental medicaments presently is that some producers have mixed active ingredients of Western medicine with finished products without declaring or labelling them. These products should be considered as counterfeit belonging to neither traditional nor western medicines.

- 75 Annex 2 3. The Standardization ofTraditional medicines quality

To ensure the production of quality herbal medicines (Traditional remedies or modified oriental medicine) meeting requirements on effectiveness and safety, it is necessary to standardize them from starting materials to processing techniques; production processes, and production management: Medicinal plant standardization : Medicinal plants are required to be correct, pure/clean and good.

+

Correct: A correct medicinal plant is one which has the correct botanical (Latin) name, correct species, and correct part for use. It meets the specific macroscopic characters, microscopic features, and chemical reactions of active or marker ingredients for this medicinal plant.

+

Good: A good medicinal plant is one which has been grown under G.A.P (Good Agricultural Practice) requirements, gathered on time, dried and processed properly, not moldy, rotten, eaten by insects, and meets the requirements on specifications, content of active ingredients or specific substance, content of solvent extractables. Pure/clean: Freed of impurities such as sand, soil, other/incorrect medicinal plants or plant parts. The pure medicinal plant also means to be maintained in safe humidity. Standardization of medicinal plant process ing method : As the processing methods can affect considerably the quality, safety and efficacy of the medicines, it is necessary to evaluate and standardize them. Standardization of finished products: The standardization of products from processed medical plants must also satisfy three requirements: correct, good and pure.

+

+ Correct: The number of processed medicinal herbs and quality of each must be according to the formula. Standardization can be accomplished by botanical/pharmacognostical, examination, chemical or physico-chemical methods. appearance

+ Good : Quality requirements also relate to quantification of active ingredients or specific substances of each medicinal plant.

+ Pure: Medicines cannot be contaminated and mixed with impurities. Biological contamination and abnormal toxicity should be tested. Quality standardization criteria for medicinal plants and finished traditional medicines are summarized in table I and table II. ·

- 76 -

Annex2

Table 1: Necessary criteria of quality for crude herbal medicines and their finished products Requirement Crude herbs Correct - Botanical: + Outside features + Microscopic characteristics + Powder examination - Chemical: Identification reaction (if possible) -Size - Chemical identification - Content of solvent extractables - Content of active/specific substance(s) - Moisture content - Impurities content - Ash content -Toxicity Criteria Finisht:u pwuuds Combination of several methods: appearance examination, powder examination with microscope, chemical reactions, instrumental method especially chromatograph y - Identification - Content of active/specific substance(s) - Specifications of respective galenic forms (see Table 2) - Moisture content - Impurities content (heavy metals) - Biocontamination -Toxicity

Good

Clean/Pure

Table 2: Requirements for production control of galenic forms Criteria Galenic Forms Liquid Powder extract

Liquor

Pills

Granules

Tablets

Syrup

Appearance Hardness Particle size Specific volume Size uniformity Color uniformity Clarity Total solid content Density Moisture Ethanol content Disintegration time Weigh uniformity Packing weigh/volume error

+ +

+

+

+

+ +

+ +

+

+ + + + + + + + + + + + + + + + + + + + + +

+

+

+

- 77 Annex2

4.

The VietNam Pharmacopo eia

The VietNam Pharmacopo eia Commission was established in 1963 to implement the standardization in the field of pharmaceutical products, taking charge of editing the VietNam Pharmacopoeia, which is legal and promulgated by the Ministry of Health. The VietNam Pharmacoput:ia Cuuuuission consists of a Chairman, u Vice Chairman and special committees: Permanent committee, Secretariat committee, Subcommitt ee of chemica- pharmaceut icals, Subcommittee of pharmaceutical preparations, Subcommittee of medicinal plants, Subcommit tee of vaccines and sera, Subcommitt ee of traditional medicines, Subcommitt ee of analytical methods, reagents and reference substances, Subcommitt ee of nomenclature and pharmaceut ical regulations, Subcommittee on biological analytical methods and Editorial board. The VietNam Pharmacopo eia consists of standards stipulated by the state regulating the quality and the methods of analysis for medicines for human use. Over the past 30 years, standardization has been enhanced and developed, and the VPC has compiled and published many volumes of VietNam Pharmacopoeia. A summary of the VietNam Pharmacopoeia Commission edited standards are as follows: Nr.Of monographs ofVNPC 740 284 828 Medicinal plants and traditional medicines monographs 224 141 312 (%)

Publishing First edition Second edition Third edition 5.

The year 1971 - 1983 1984- 1994 1995-2001

30,3 49,6 37,7

Process of formulating monographs of standards for medici nal plants and traditional medicines

The schedule to formulate and edit monograph standards is implemented according to the following steps: 5.1 Establishing the traditional medicines committee and medicinal plants committee. The Component of the Committee for traditional medicines and medicinal plants are as follows: Head and Deputy- Head of the committee Recruited committee members who are pharmacists, traditional medical doctors, eminent and experienced healers and practitioners, scientists and researchers working at National Institute of Drug Quality Control, National Institute of Materia Medica, pharmaceut ical manufacture rs and medicinal plant trading companies and pharmaceutical colleges in Hanoi and Ho Chi Minh City, Vietnam Oriental medicine association.

5.2

Selecting medicinal plants and finished products to put in to VPC: Principles for selection: Common medicinal plants normally used in writing out prescription. Medicinal plants commonly grown in medicinal gardens of hamlets, communes.

- 78 Annex2 Acclimatized - medicinal plants and domestic medicinal plants. Medicinal plants nonnally imported from overseas to serve prescription writing - out. Medicinal plants listed in the Essential Medicinal Plants List (200 plants) issued by the Ministry of Health. Medicinal plants usually used in manufacturing and processing traditional medicines. Traditional phannaceutical finished products have been used widely and effective in treatment and health care.

-

5.3 5.3.1

Requirements for standard For medicinal plants I. Name (Latin name, Vietnamese name, local name ) 2. Macroscopic description 3. Microscopic description 4. Microscopic determination of powder 5. Identification 6. Assay, extractives (Alcohol extractive and water- extractive) 7. 7- Content of water 8. Total ash, acid- insoluble ash 9. Foreign matter I 0. Crumb rate I I. Processing I2. Preparation 13. Storage I4. Action 15. Indications, therapeutic uses 16. Usage and dosage 17. pharmacological incompatibility

- 79 Annex2 5.3.2 For traditional medicines: 1. 2. 3. Name (Vietnamese name) Formula and ingredients Procedure of preparation Description Other requirements Identification Assay Storage Action, therapeutic uses Usage and dosage Pharmacological incompatibility

4. 5.

6. 7. 8. 9. 10.

11.

Due to specific requirements, these standards may consist of all or some criteria of the above standards. 5.4 Preparation:

In order to prepare for the first edition, VNPC has organized to formulate and publish a VietNam Pro-Pharmacopoeia stating 415 medicinal plants, of which 74 medicinal plants were imported from overseas, the remaining are domestic and acclimatized medicinal plants. In the pro-Pharmacopoeia, treatises include some criteria such as: Names of medicinal plants (scientific names and names in Vietnamese), part of using, describing plants and part of using, property effectiveness, dosage and usage. 5.5 Organizing compilation and consulting relevant organizations.

Through the above point of view, the committee chose the list to work out compilation by applying quality criteria and technical requirements such as index 2.3 on VietNam Pharmacopoeia. The compilation organization is carried out basing on the research in Universities' Laboratories, National Institute of Drug Quality Control and pharmaceutical manufacturer and trading company and reference of official domestic and external documents. The monographs after compilation are printed in draft form and circulated to many pharmacists, doctors, specialists, and healers over the country to collect their comment as feed back. This is an important step to have accurate, scientific and practically suited documents.

- 80 Annex2 5.6 Monograph completion and approving submission for promulgation.

The editing board ofVNPC considers the suggestions, implements reconsideration and perfects standards. The monographs then are submitted to the Minister of Health for issuance of decision allowing the promulgation of standards and official application to the whole sector. 6. VietNam Pharmacopoeia, third edition (200 I)

The number of contained monographs consists of both VietNam and imported medicinal plants. Domestic medicinal plants are compiled based on practical researches in VietNam, especially elaborated and scientific ones from Master or Doctor thesis. In comparison with previous publications, the Third Edition of VietNam Pharmacopoeia has higher quality requirement and modern analytical techniques adopted extensively in the requirement of monographs to strengthen the examination and management of medicinal plants and traditional medicines' quality. 7. The implementation ofVietNam Pharmacopoeia

Quality management organizations, drug quality control and assurance system, processing manufacturer, pharmaceutical trading companies and hospital pharmacy pharmaceutical units, departments, all apply following the VietNam Pharmacopoeia's standards. Standards of Manufacturer are required to be equal or higher than those of VietNam Pharmacopoeia. VietNam Pharmacopoeia's standard system is applied in every production units in the country including 320 pharmaceutical manufacturers and companies with 1566 herbal finished products that are registered in the pharmaceutical market in VietNam to 2001. 8. Conclusion

In order to develop and modernize traditional medicine, it is necessary and important to consider the standardization of medicinal plants quality and traditional medicines quality with the aim to create products of higher quality, stability, safety, and efficacy in utilization. The application of VietNam Pharmacopoeia's standards in the past few decades has brought management, production, quality testing and business of medicine in to orderly routine, gaining effectiveness and has improved the quality requirement of medicines in production, distributing circulation and using. In the process of integration, harmonization of regulations on management and quality standards of traditional drugs is really a pressing issue as this will promote strong and effective cooperation and contribute to reaffirm the status of Asian traditional medicines into the cause of people's health care and protection.