Guidelines for the

Regulation Of Herbal
Medicines
in the South-East Asia
Region

1
 Guidelines for the
Regulation Of Herbal
Medicines
in the South-East Asia
Region

2
Preface

 Traditional medicine and

complementary/alternative medicine
(TM/CAM) have been used, through the ages,
in all countries of the WHO South-East Asia
Region (SEAR).

Many countries in this Region have extensive

systems of TM within existing health services.

3
Preface …

In the rural areas of countries such as India,

Indonesia, Nepal and Sri Lanka, a large
proportion of the population use traditional
medicines to meet their primary health care
needs.
Due to this long history, the roles of TM and its
practitioners have been recognized by the
governments in this Region, with national
policies and regulations on TM being
implemented in many of these countries.

4
Preface …
 Governments in the South-East Asia Region
are encouraging medical doctors to work with
traditional practitioners at the hospital level,
and to support research on TM.
For example, in India there are 2860 hospitals
providing Ayurvedic medicines.
In Bhutan, in the national health centre,
patients can receive both conventional and
TM treatments based on their needs.

5
Preface …

 Used as self-care or as an alternative form of

treatment to conventional medicines, there is
a large market and demand for medicinal
plants and herbal products.

Many countries in SEAR need expertise and

guidance to develop national regulations and
safety monitoring systems.

6
Preface …

According to the WHO global survey on the

national policy and regulation of TM, there
are three common difficulties and challenges:
lack of information sharing;
lack of safety monitoring for herbal
medicines; and
lack of methods to evaluate their safety
and efficacy.

7
Preface …
 To address the above-mentioned needs and the
WHO Regional Office for South-East Asia
organized a regional workshop on the
‘Regulation of Herbal Medicines’ at Bangkok on
24–26 June 2003.
 To support Member States in renewing or
updating their regulations on traditional
medicines, and to meet technical requirements
for evaluating the safety, efficacy and quality
control of herbal medicines, these Regional
Guidelines for the Regulation of Herbal
Medicines in the South-East Asia Region were
developed.
8
 1.Objectives
The objective of these guidelines is to propose
to Member States a framework for facilitating
the regulation of herbal medicines/products
used in TM.
The proposed framework, which has a regional

perspective, should help accelerate the

establishment of appropriate mechanisms for
registration and regulation of herbal medicines
within SEAR, based on criteria for:
-safety of use,
-therapeutic efficacy,
-quality control and
-pharmacovigilance. 9
1.Objectives …
 Traditional medicine involves not only the
use of herbal medicines, but also use of
animal parts and minerals.

As herbal medicines are the most widely used

of the three, and as the other types of
materials involve other complex factors,
this document will concentrate on herbal
medicines.

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1.1 General objective

 This document aims to facilitate the

registration and regulation of herbal
medicines by establishing the foundation
for a harmonized regulatory standard to
meet the common demands of the Region.

11
1.2 Specific objectives
 To propose a classification for herbal
medicines;
 To propose regulatory requirements for the

registration of each category of herbal

medicines;
 To set up minimum requirements for

registration and regulation of herbal

medicines.

12
2.Classification of herbal medicines
 For practical purposes, herbal medicines can
be classified into four categories, based on
their origin, evolution and the forms of current
usage.

While these are not always mutually exclusive,

these categories have sufficient distinguishing
features for a constructive examination of the
ways in which safety, efficacy and quality can
be determined and improved.

13
Category 1: Indigenous herbal
medicines
This category of herbal medicines is historically used
in a local community or region and is very well
known through long usage by the local population in
terms of its composition, treatment and dosage.
Detailed information on this category of TM, which
also includes folk medicines, may or may not be
available. It can be used freely by the local
community or in the local region.
However, if the medicines in this category enter the
market or go beyond the local community or region
in the country, they have to meet the requirements
of safety and efficacy laid down in the national
regulations for herbal medicines.
14
Category 2: Herbal medicines in
systems
Medicines in this category have been used for
a long time and are documented with their
special theories and concepts, and accepted
by the countries.
For example, Ayurveda, Unani and Siddha
would fall into this category of TM.

15
Category 3: Modified herbal
medicines
 These are herbal medicines as described
above in categories 1 and 2, except that they
have been modified in some way–either
shape, or form including dose, dosage form,
mode of administration, herbal medicinal
ingredients, methods of preparation and
medical indications. They have to meet the
national regulatory requirements of safety
and efficacy of herbal medicines.

16
Category 4: Imported products with a
herbal medicine base
 This category covers all imported herbal
medicines including raw materials and
products.
 Imported herbal medicines must be registered

and marketed in the countries of origin.

 The safety and efficacy data have to be

submitted to the national authority of the

importing country and need to meet the
requirements of safety and efficacy of
regulation of herbal medicines in the recipient
country.
17
18
3.Minimum requirements for
assessment of safety of herbal
medicines
3.1 Safety category
 A drug is defined as being safe if it causes no

known or potential harm to users.

 There are three categories of safety that need

to be considered, as these would dictate the

nature of the safety requirements that would
have to be ensured.

19
 3.Minimum requirements for
assessment of safety of herbal
medicines …
 Category 1: safety established by use over long
time
 Category 2: safe under specific conditions of use

(such herbal medicines should preferably be

covered by well-established documentation)
 Category 3: herbal medicines of uncertain safety

(the safety data required for this class of drugs

will be identical to that of any new substance)

20
3.Minimum requirements for
assessment of safety of herbal
medicines …
 Data will be required on the following:
◦ Acute toxicity
◦ Long-term toxicity

 Data may also be necessary on the following:

◦ Organ-targeted toxicity
◦ Immunotoxicity
◦ Embryo/fetal and prenatal toxicity
◦ Mutagenicity/genotoxicity
◦ Carcinogenicity
21
 3.2 General considerations for assessment of
safety of herbal medicines

 Any assessment of herbal medicines must be

based on unambiguous identification and
characterization of the constituents.
 A literature search must be performed.
 This should include the general literature such

as:
◦ handbooks specific to the individual form of
therapy, modern handbooks on phytotherapy,
phytochemistry and pharmacognosy,
◦ articles published in scientific journals, official
monographs such as WHO monographs, national
monographs and other authoritative data related to 22
 3.2 General considerations for assessment of
safety of herbal medicines …

◦ if available, database searches in online or offline

databases, e.g. WHO adverse drug reaction database,
National Library of Medicine’s Medline, etc.

 The searches should not only focus on the

specific herbal medicinal preparation, but
should include different parts of the plant,
related plant species and information
originating from chemotaxonomy.
Toxicological information on single
ingredients should be assessed for its
relevance to the herbal medicines. 23
3.2.1 Specific requirements for assessment of
safety of four categories of herbal
medicines

 Before any category of herbal medicine listed

above is introduced into the market, the
relevant safety category needs to be reviewed
and the required safety data obtained, based
on that particular safety category.

24
Category 1: Indigenous herbal medicines

 These can be used freely by the local

community or region, and no safety data
would be required. However, if the medicines
in this category are introduced into the market
or moved beyond the local community or
region, their safety has to be reviewed by the
established national drug control agency.
 If the medicines belong to safety category 1,

safety data are not needed. If the medicines

belong to safety category 2, they have to meet
the usual requirements for safety of herbal
medicines. Medicines belonging to safety 25
Category 2: Herbal medicines in systems
 The medicines in this category have been
used for a long time and have been officially
documented.
Review of the safety category is necessary. If
the medicines are in safety categories 1 or 2,
safety data would not be needed.
If the medicines belong to safety category 3,
they have to meet the requirements for safety
of ‘herbal medicines of uncertain safety’.

26
Category 3: Modified herbal medicines
 The medicines in this category can be
modified in any way including dose, dosage
form, mode of administration, herbal
medicinal ingredients, methods of preparation,
or medical indications based on categories 1
and 2.
The medicines have to meet the requirements
of safety of herbal medicines or requirements
for the safety of ‘herbal medicines of uncertain
safety’, depending on the modification.

27
Category 4. Imported/exported products with a herbal
medicine base

 Exported products shall require safety data,

which have to meet the requirements for
safety of herbal medicines or requirements
for safety of ‘herbal medicines of uncertain
safety’, depending on the safety requirement
of the importing/recipient countries.

28
3.3 Literature review of herbal medicines

 Member States in the South-East Asia Region

should share information from reliable
sources. In assessing these bibliographic data,
particular attention should be paid to the
following aspects:
◦ · The characteristics and type of preparation
described in the literature: Does the literature refer to
the same herbal preparation? Can the data be
extrapolated?
◦ · The extent of time and use of the herbal medicines:
Can the use have generated sufficient experience on
safety? Is it plausible that the risks would have been
recognized empirically?
29
3.3 Literature review of herbal medicines …

 The need for additional data or new tests should be

considered in the light of the information
requirements for new substances. Many of the tests
required for new substances may be replaced by
documented experience. However, it should be
carefully considered if all the questions on toxicology
raised for new substances could be answered
sufficiently and in a plausible way by the available
general knowledge. A specific focus should be given
to effects that cannot be detected or are very difficult
to detect empirically, e.g. genotoxicity.
 The assessment should determine if there is sufficient
information to guarantee safe use in vulnerable
populations, such as pregnant or lactating women,
and in children. For the assessment of safety in 30
4.Minimum requirements for assessment of the
efficacy of herbal medicines
4.1 Claims categories

 Disease
◦ · Acute disease: Diseases that have a rapid onset
and a relatively short duration.
◦ · Chronic disease: Diseases that have a slow onset
and last for long periods of time.
 Diseases of acute onset could also progress
to a chronic state.

31
4.1 Claims categories …
 In most cases, severe diseases refer to a life-
threatening illness or those diseases in which delayed
treatment will lead to deterioration of the disease
state or loss of capability to cure them. For example,
severe cardiovascular, gastrointestinal, endocrine,
haematological diseases, and immune disorders and
diseases fall into this group.
◦ · Health condition: Problems related to health
conditions are those which, with time, could recover
spontaneously, even without any medical
intervention, e.g. loss of appetite, hay fever,
menopause, etc. The efficacy for this category could
be supported by data in existing well-established
documents such as national pharmacopoeia and
monographs as well as other authoritative 32
 Table 1. Summary of the efficacy data requirements
for the three types of disease and conditions

.
Type of disease Pre-clinical data of Clinical data of Other data or
efficacy efficacy information
required
Acute Needed Control trial needed
Chronic May be needed Clinical data may or
may not be needed
Health condition May not be needed May not be needed Supported by
wellestablished
documents such as
national
pharmacopoeia and
monographs

33
Table 2. Requirements data for the evaluation of
efficacy of traditionally used herbal medicines with
limited modifications
. Traditionally used herbal medicines with Pre-clinical data Clinical data of
wellestablished documentation of efficacy efficacy
No change based on traditional use Not needed May not be
needed
Dose May be needed Needed
Dosage form May be needed Needed
Mode of administration May or may not Needed
be needed
Changes Medical indication Needed Needed
Herbal Addition Needed Needed
medicinal Deletion May or may not be May or may not
ingredients needed be needed
New combination Needed Needed
Part of medicinal plant used Needed Needed
Methods of preparation Needed Needed

34
4.2 Explanation of terms used in tables
 General efficacy data requirements are
given in Table 1.
 The herbal medicines that are used with

well-established documents, but with

changes in medical indication, dosage
form, mode of administration, clinical and
pre-clinical efficacy data are given in Table
2.
 The efficacy should be proven by clinical

trials or well established documentation. If

the changes will modify the
pharmacodynamics, pre-clinical studies 35
4.2 Explanation of terms used in tables …

 The following are terms related to the tables:

◦ · Pre-clinical data: These include efficacy of
laboratory test and data regarding the standard
dose and dosage form;
◦ · Clinical data of efficacy: This refers to ‘clinical
research’ in WHO General Guidelines for
Methodologies on Research and Evaluation of
Herbal Medicines;
◦ · Addition: This means the addition of one or
more plants or ingredients into traditionally used
formulas;
◦ · Deletion: This refers to the deletion of one or
more plants or ingredients from traditionally used
formulas;
36
4.3 Minimum requirements for assessment of
the efficacy of herbal medicines
 · The assessment of efficacy for herbal
medicines in categories 1 and 2 are not
required if they are used locally;
 · For medicines in category 3, pre-clinical

data and clinical data may or may not be

required depending on the modification(s),
which are given in Table 2;
 · For medicines in category 4, efficacy data

are required.

37
38
5. Quality assurance of herbal medicinal
products
 Quality assurance of herbal medicinal products
is the shared responsibility of manufacturers
and regulatory bodies.
National drug regulatory authorities have to
establish guidelines on all elements of quality
assurance, evaluate dossiers and data
submitted by the producers, and check post-
marketing compliance of products with the
specifications set out by the producers as well
as compliance with Good Manufacturing
Practices (GMP).

39
5. Quality assurance of herbal medicinal
products …
 The manufacturers have to adhere to Good
Agricultural and Collection Practices (GACP),
GMP and Good Laboratory Practice (GLP)
standards, establish appropriate specifications
for their products, intermediates and starting
materials and compile a well-structured,
comprehensive documentation on
pharmaceutical development and testing. The
producers should make continued efforts to
improve standards and adapt them to the
present state of knowledge. A cooperative
approach between different manufacturers, 40
5.1 Coordinating quality control
 A coordinating agency on GACP should be established to
facilitate the availability of good quality herbal medicines
to the market by giving training and advice to small
producers and farmers. To encourage implementation of
GACP, incentives should be given to producers of botanical
raw materials. These include giving technical and logistic
support in the selection of appropriate sites for agricultural
production, providing seeds and seedlings, selecting
fertilizers and pesticides, providing or giving advice on
machinery for harvesting and primary processing. The
government should honour efforts by issuing certificates
to producers and farmers who adhere to the GACP, based
on the country situation. Implementation of such
requirements is only possible if the production and
marketing of herbal medicines is subject to an adequate
registration scheme by a drug regulatory authority.
41
5.2 Quality assurance

 Elements of quality assurance are:

◦ · adherence to GACP, GMP and GLP guidelines;
◦ · setting specifications; and
◦ · quality control measures.

42
5.3 Quality control for herbal medicinal
products
 All herbal-based medicinal products should
meet the requirements for safety, efficacy
and quality, as per the Categories of Herbal
Medicines (see the section on Minimum
requirements for assessment of safety of
herbal medicines).
 All imported herbal medicinal products

need to meet the requirements for safety,

efficacy and quality control regulations in
the importing countries. To control the
quality of imported herbal medicinal
products, the following requirements 43
5.3.1 Licensing authority
 Licensing for importers, wholesalers,
manufacturers and assemblers of herbal
medicinal products should be issued by the
national drug regulatory authority. Dealers of
imported herbal medicinal products need to
apply for one or more of the licences
depending on the type of business involved,
such as licence of importers, wholesalers,
manufacturers and assemblers.

44
 5.3.2 Import licence
 The responsibility of applying for an import
licence shall rest with local companies which are
approved by the licensing authority to import
herbal medicinal products and sell them in the
importing countries.
 The following information related to the

importing company is required for the

application of an import licence:
◦ · Particulars of the company;
◦ · Particulars of the person making the application on
behalf of the company;
◦ · Certificate of company/business registration;
◦ · Layout plan of the store.
45
 5.3.2 Import licence …
 Importers are required to provide information on each
imported herbal medicinal product they deal with, and
will be allowed to deal in approved products only.
Detailed requirements for each imported herbal
medicinal product are as follows:
◦ · Full product formula (in the languages of the
importing and exporting countries);
◦ · A set containing labels, pamphlet, carton and
specimen sales pack (in the languages of the
importing and exporting countries, if necessary);
◦ · Particulars of manufacturer(s) and assembler(s);
◦ · Manufacturer’s licence or certificate from the drug
regulatory authority of the manufacturing country of
origin. Pre-export Notification and Certificate of Free
Sale of the herbal medicinal product should be 46
5.4 Guidelines related to Good Agricultural and
Collection Practices (GACP) and Good
Manufacturing Practices (GMP)
 The coordinating agency should adhere to the principles
set out in the WHO Guidelines on Good Agricultural and
Collection Practices for Medicinal Plants (for GACP) and
manufacturers and assemblers should follow WHO Good
Manufacturing Practices (for GMP). Manufacturers of
herbal medicines should obtain a licence and register
their products. The quality control system for
production should be in place. The implementation of a
credible concept of quality assurance, e.g. identifying
and eliminating potential sources of contamination,
should be a primary goal of the manufacturers rather
than the implementation of all individual technical
aspects.

47
5.4 Guidelines related to Good Agricultural and
Collection Practices (GACP) and Good
Manufacturing Practices (GMP) …

 The following areas should be considered

while studying the WHO guidelines:
◦ · Control of raw materials (refer to the GACP and
Quality Control Methods for Medicinal Plant
Products);
◦ · Control of starting materials and intermediate
substances;
◦ · In-process control (Standard Operating Procedure
for Processing Methods should be mentioned);
◦ · Finished product control (It should be performed
with reference to the control of raw materials,
starting materials and intermediate substances).
48
 5.5 Guidelines related to quality control

 The purpose of quality control is to ensure quality of the

products by adhering to appropriate specifications and
standards. Information on appropriate standards can be
found in official pharmacopoeias, monographs,
handbooks, etc.
 In choosing analytical methods, the availability,
robustness and validity of the methods must be
considered, such as microscopic identification, thin layer
chromatography (TLC), titration of active substance and, if
possible, a full validation of more sophisticated methods,
such as high-performance liquid chromatography (HPLC),
gas chromatography (GC), and gas chromatography-mass
spectrometry (GC-MS). If such advanced methods are
used, a full validation for each test would be necessary.
49
5.6 Product information for registration
 This should include all necessary information on the
proper use of the product. The detailed information of
the herbal medicinal products should include the
following requirements for registration:
◦ · Quantitative list of ingredients; if this is difficult, it
could be replaced by including the plant names and
plant parts used (i.e. Latin name);
◦ · Full product formula for imported herbal-based
medicinal products (in the language of the importing
and exporting countries);
◦ · A set containing labels, pamphlet, carton and
specimen sales pack;
◦ · Particulars of manufacturer(s) and assembler(s);
50
5.6 Product information for registration …

◦ · Manufacturer’s licence or certificate from the drug

regulatory authority. Pre-export notification and
Certificate of Free Sale of the herbal-based medicinal
product should be obtained from the concerned
authority;
◦ · Brand name of product;
◦ · Dosage form;
◦ · Indications;
◦ · Dosage;
◦ · Mode of administration;

51
5.6 Product information for registration …

◦ · Mode of administration;
◦ · Duration of use;
◦ · Adverse effects, if any;
◦ · Contraindications, warnings, precautions and
major drug interactions, if possible;
◦ · Date of manufacture;
◦ · Expiry date of product;
◦ · Lot/Batch number;
◦ · Storage condition.

52
 6.Pharmacovigilance of herbal medicinal
products
 The national government needs to strengthen capacity
building in setting up and running such systems
through training programmes etc. While developing a
national programme to monitor the safety of medicinal
products, care should be taken to ensure that this will
include:
◦ · Establishing a national pharmacovigilance centre for
monitoring the safety of medicinal products including herbal
medicinal products;
◦ · Training staff who will be included in the reporting system;
◦ · Setting up necessary equipment;
◦ · Developing the reporting forms;
◦ · Setting up a multidisciplinary advisory committee to review
and analyse the collected data.
53
6.1 Adverse drug reaction report
 Pharmacovigilance units or national
pharmacovigilance centres are necessary to collect
and assess information on adverse drug reaction
(ADR) relating to medicinal products including
herbal medicines. Where such units/centres exist,
they should include herbal medicines in the current
scope of their activities.
 Each ADR report should be evaluated and assessed
on the causality with the suspected herbal
medicines. Health professionals should be
encouraged to ask their patients about the use of
herbal products and herbal medicines, including
‘medicinal foods/health food/dietary supplement’
and any other medicines, and to include
information on concomitant use in their ADR.
54
6.1 Adverse drug reaction report …
 Each herbal medicine should be clearly
identified by its constituents, brand name (if
applicable) and dosage. If such information
is missing in the ADR, the
pharmacovigilance unit/centre should
immediately try to gather complete
information, e.g. by asking the reporting
health professional.
 To avoid the missing vital information,

national drug regulation on herbalmedicines

and herbal medicines should include all the
necessary information on registered herbal
55
 6.1 Adverse drug reaction report …
 In analysing ADR reports the following aspects should be
considered:
(1) A literature search on the herbal product, its
constituents and any co-medication should be
performed;
(2) The time–ADR relationship must be assessed:
◦ · When did the ADR occur?
◦ · Did the symptom occur when the herbal medication
was started?
◦ · Has any co-medication been used before the use of
the herbal medicines without side-effect?
◦ · Did the ADR occur when the co-medication was
added to the herbal treatment?
◦ · Did the ADR stop when the herbal medicines were 56
6.1 Adverse drug reaction report …
(3) The dosage used should be compared with the
traditional dosage described in the literature:
◦ · Did the patient use a higher dose than
recommended? Would it be intoxication rather
than an ADR?
◦ · Is the dosage so low compared to the
traditional dose that a link is not plausible?
However, be aware of allergic reactions!
◦ · Were there any signs of allergic reactions such
as: rashes, asthma, eosinophilia, angio-oedema?
(4) How common is the symptom with other
diseases?
◦ · What is the prevalence of diseases with the
same symptoms, e.g. hepatitis?
57
6.1 Adverse drug reaction report …
(5) Search databases for similar case reports for
association with the same or similar herbal
medicines or combination products. In the case of
suspicious files, go to original reports, because the
database file may not be complete and additional
information may be found in the original report;
(6) If no association was found in literature, or if an
association is not plausible because of the low
dose, there could be a problem related to the
product’s quality. Check for possible adulteration,
substitution or contamination, e.g. by mycotoxins,
heavy metals, etc.
 The assessment should be done in cooperation

with an expert panel comprising experts in

58
6.2 How to set up or expand the reporting system on
adverse events relating to herbal medicinal products

 To begin with, the report will be voluntary. If

possible, the report should be mandatory later. The
following actions should be taken into account
when setting up a reporting system, or including
providers of herbal medicinal products in a pre-
existing reporting system:
◦ · Provide education and awareness for the
public/consumers and professionals including
doctors, pharmacists, herbal medicine
practitioners, etc.;
◦ · Establish a proper regulatory system for herbal
medicines;
◦ · Activate medicine information centres in health
authorities for the establishment of special 59
6.2 How to set up or expand the reporting
system on adverse events relating to herbal
medicinal products…
◦ · Use existing tools (for conventional drugs) to collect
and analyse data supported by a computerized
system;
◦ · Emphasize the scientific use of herbal medicines;
◦ · Solve existing problems in the reporting systems by
using advanced database programmes;
◦ · Ask for WHO assistance in establishing an ADR
reporting system;
◦ · Encourage manufacturers, the public/consumers
and professionals including doctors, pharmacists,
practitioners of herbal medicine, etc. who produce,
prescribe or use herbal medicines, to report ADR to
relevant authorities. 60
7.Control of advertisements of herbal
medicinal products
 The national authorities responsible for the
regulation of herbal medicinal products and
practices should approve every advertisement
before it reaches the public.
 The regulatory authority should issue
advertisement permits after satisfactory evaluation
of the contents of each advertisement to ensure
that the public gets the correct information about
the product, devoid of ambiguous or fraudulent
claims. The print and electronic media should be
notified to ensure that every advertiser of herbal
medicinal products obtains the permit from the
national authority before such an advertisement is
published. 61
8. Recommendations
 Member States should:
◦ · Develop national regulations on herbal
medicines based on the WHO guidelines;
◦ · Establish a national advisory committee for
herbal medicines;
◦ · Adopt requirements for the registration of
herbal medicines as proposed during this
workshop;
◦ · Establish coordination agencies to implement
GACP;
◦ · Establish an ADR monitoring centre and system
for conventional medicines and herbal medicines,
and develop necessary linkages with other ADR
monitoring centres in the Region and with WHO 62
8. Recommendations …

◦ · Work to strengthen the regional network in all

possible aspects of herbal medicines, particularly
with regard to their safety, efficacy and ADR;
◦ · Develop and strengthen herbal medicine
education and training, practice and research;
◦ · Work at facilitating harmonization among those
countries that have common systems of herbal
medicine.

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