Fitoterapia 81 (2010) 462–471

Contents lists available at ScienceDirect

Fitoterapia
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / f i t o t e

Review

Herbal drugs: Standards and regulation

Niharika Sahoo a, Padmavati Manchikanti a,⁎, Satyahari Dey b
a
Rajiv Gandhi School of Intellectual Property Law, IIT Kharagpur, Kharagpur-721302, West Bengal, India
b
Department of Biotechnology, IIT Kharagpur, Kharagpur-721302, West Bengal, India

a r t i c l e i n f o a b s t r a c t

Article history: The use of herbal drugs for the prevention and treatment of various health ailments has been in
Received 18 September 2009 practice from time immemorial. Generally it is believed that the risk associated with herbal
Accepted in revised form 2 February 2010 drugs is very less, but reports on serious reactions are indicating to the need for development of
Available online 13 February 2010 effective marker systems for isolation and identification of the individual components.
Standards for herbal drugs are being developed worldwide but as yet there is no common
Keywords: consensus as to how these should be adopted. Standardization, stability and quality control for
Herbal drug herbal drugs are feasible, but difficult to accomplish. Further, the regulation of these drugs is
Drug regulation not uniform across countries. There are variations in the methods used across medicine
Traditional medicine
systems and countries in achieving stability and quality control. The present study attempts to
Herbal drug harmonization
identify the evolution of technical standards in manufacturing and the regulatory guideline
development for commercialization of herbal drugs.
© 2010 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
2. Effect of herbal drugs on human health: adulteration, heavy metal, pesticide and microbial contamination . . . . . . . . . 463
3. Standardization of herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
3.1. Complexity and characterization: marker based analysis of herbal drugs . . . . . . . . . . . . . . . . . . . . . . 465
3.2. Quality control of herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
4. Regulatory norms development for herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
5. International harmonization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470

1. Introduction estimated that about 25% of the drugs prescribed worldwide

The use of plants, parts of plants and isolated phytochem-
icals for the prevention and treatment of various health
ailments has been in practice from time immemorial. It is
⁎ Corresponding author. Tel.: + 91 3222 281736; fax: + 91 3222 282238.
E-mail addresses: mpadma@rgsoipl.iitkgp.ernet.in,
padmavati@gmail.com (P. Manchikanti).
are derived from plants and 121 such active compounds are in
use. Of the total 252 drugs in WHO's essential medicine list,
11% is exclusively of plant origin [1]. Nearly 80% of African and
Asian population depends on traditional medicines for their
primary healthcare [2]. In India, about 80% of the rural
population uses medicinal herbs or indigenous systems of
medicine [3]. About 960 plant species are used by the Indian
herbal industry of which 178 are of high volume exceeding

0367-326X/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.fitote.2010.02.001
 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471
100 metric tonnes a year [4]. Indian herbal market is
registering a significant growth and is likely to reach Rs
145,000 million by 2012 and exports to Rs 90,000 million
with a CAGR of 20% and 25% respectively (ASSOCHAM, 2008).
Based on nature of the active metabolites herbal drugs are
of three types. Drugs used in crude form are the first category.
The active constituents isolated after the processing of plant
extracts represent the second category of herbal drugs. These
are pure molecules and generally pharmacologically more
active. The third type of herbal drugs for which data on acute
and chronic toxicity studies in animals is available [5].
In 2003, a classification system for herbal drugs was
recommended in the regional workshop on the regulation of
the herbal medicines, organized by WHO regional office for
South East Asia. Herbal drugs have been broadly categorized
into four groups such as indigenous herbal medicines, herbal
medicines in systems, modified herbal medicines and
imported products with an herbal medicine base [6].
Indigenous herbal medicines are well known in terms of
their composition, treatment and dosage due to their age old
use in a local community. Herbal medicines in systems
(Ayurveda, Unani and Siddha) have been in use for a long
time and therefore, for local use assessments of efficacy are
not required. Modified herbal medicines represent modifica-
tion of the form of indigenous herbal medicine or herbal
medicine in systems either in shape or dosage form, mode of
administration, herbal medicinal ingredients, methods of
preparation and medical indications. These should meet the
national regulatory requirements of safety and efficacy. Pre-
clinical data and clinical data may or may not be required
depending on the modification(s). Imported herbal medi-
cines (that include raw materials and products) must be
registered and marketed in the countries of origin. Safety and
efficacy data have to be submitted to the national authority of
the importing country. Good manufacturing practices (GMP)
compliance of the last two categories of herbal drugs is more
critical. Apart from standardized herbal extract and raw
material India is known to export herbal medicines in system
such as ayurvedic drugs to different parts of the world. While
there is increased usage of herbal drugs throughout the
world, reports on side effects and adulteration of herbal drugs
have raised concerns on their wide use and are affecting their
commercialization. Further, regulatory procedures of these
drugs are also not uniform across different countries. The
present study attempts to identify development of technical
standards in herbal drug manufacturing as well as the
regulatory framework for commercialization of these drugs.
2. Effect of herbal drugs on human health: adulteration,
heavy metal, pesticide and microbial contamination
Herbal products are not completely free from side effects.
Well-controlled randomized clinical trials have revealed that
undesirable side effects are possible in the use of herbal drugs.
Cardiovascular problems with use of ephedra, hepatotoxicity
by kava-kava consumption, anticholinergic effects leading to
reduced visceral activity associated with asthma medicine
containing Datura metel, water retention by liquorice are few
examples of herbal drug side effects [7,8]. Due to increased
reports on adverse effects regulatory/monitoring agencies in
many countries have brought out alerts on herbal drugs. In
463
1993, the American Herbal Products Association (AHPA)
issued an alert to restrict the use of comfrey, a herbal
medicine that contains pyrrolizidine alkaloids (PAs) for
external applications. In 2001, hepatotoxicity reported from
use of comfrey led US Food and Drug Administration (USFDA)
to recall it from all dietary supplements. Cardiovascular
events reported with the use of Chinese herb containing
ephedra used to promote weight loss in the US led to its ban
by USFDA in 2004. In 2007, the Medicines and Healthcare
Products Regulatory Agency (MHRA) of the UK advised all
herbal interest groups to withdraw all unlicensed proprietary
products that may contain hepatotoxic PAs from Senecio
species. The use of three herbal medicines that contain
aristolochic acids (AAs), namely Radix Aristolochiae Fangchi
(Guangfangji), Caulis Aristolochiae Manshuriensis (Guanmu-
tong) and Radix Aristolochiae (Qingmuxiang), has been banned
in China since 2004 due to the potential risk of nephrotoxicity
[9].
The WHO database has over sixteen thousand suspected
herbal case reports. The most commonly reported adverse
reactions are hypertension, hepatitis, face oedema, angio-
dema, convulsions, thrombocytopenia, dermatitis and death
[10]. In 1992, a list of about 33 herbal drugs with serious risks
prepared by the Committee for Proprietary Medicinal
Products (CPMP) was published by the European Commis-
sion. This list included some plants such as Aconitum (all
species), Aristolochia (all species), Claviceps purpurea (FR)
TULASNE, Convovulus scamonia L., Ocimum basilicum L.,
Strychnus nux-vomica L., Vinca minor L. etc. [11]. In the UK,
certain potentially hazardous plant species are restricted to
use by medical practitioners by the Prescription Only
Medicines (Products Other than Veterinary Drugs) Order
1997. The Medicines (Retail Sale or Supply of Herbal
Remedies) Order 1977 lists 25 plants which can be supplied
only via a pharmacy and includes toxic species such as Areca,
Crotalaria, Dryopteris and Strophanthus. Following reports of
serious cases of renal toxicity and evidence of substitution of
certain ingredients in traditional Chinese medicines (TCM),
‘The Medicines (Aristolochia and Mu Tong etc) (Prohibition)
Order 2001’ was enacted to prohibit unlicensed medicines of
Aristolochia species and a number of other herbal ingredients
which can be confused with Aristolochia [12].
The effects of herbal drugs on metabolism have been
studied predominantly for ginkgo, kava and St. John's wort
[13]. Components of a number of commonly used herbal
products inhibit human drug metabolizing enzymes in vitro.
Constituents of Ginkgo biloba (ginkgolic acids I and II), kava
(desmethoxyyangonin, dihydromethysticin, and methysti-
cin), garlic (allicin), evening primrose oil (cis-linoleic acid)
and St. John's wort (hyperforin and quercetin) could
potentially inhibit the metabolism of co-administered med-
ications whose primary route of elimination is via cyto-
chrome P450 [14].
Undeclared chemical or synthetic substances or other
active ingredients are the adulterants which are common in
raw material trade of medicinal plants. Adverse event reports
are often due to the presence of unintended herbs and this
has affected the promotion of herbal products. Adulteration of
herbal drugs with one or more synthetic drugs is reported
from different parts of the world. Forty-one products out of
3320 Chinese Proprietary Medicines (CPM) screened by
464 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471
Health Science Authority (HSA) Singapore, between 1990 and
2001were found to contain nineteen synthetic drugs. In
twelve out of nineteen CPM manufactured in China claimed
to be tonics for the treatment of sexual dysfunction in males
had sildenafil as adulterant and other such over the counter
(OTC) drug products were found to be adulterated with
sildenafil, tadalafil, vardenafil and their structurally modified
analogues [15,16]. “Tung Shueh Pills” from Taiwan that
caused acute renal failure was found to be adulterated.
“Tung ShuehWan”, used for pain relief sampled from
Singapore market was found to contain the four undeclared
drugs, caffeine, diazepam, indomethacin and prednisolone,
which have potential to cause mental depression, bone loss,
spontaneous fractures, intestinal bleeding and even coma.
“Gu Ben Wan” used for the treatment of dry cough was found
to contain six undeclared drugs. “Wonder Pills” used for
reducing fats from body was found to contain phenformin, a
drug banned in Singapore since 1977 [16].
Substitution involves intentional replacement with an-
other plant species or intentional addition of a foreign
substance to increase the weight or potency of the product
or to decrease its cost. The use of fake or wrong herbs has
generated serious questions about the safety and efficacy of
herbal products. Many popular and expensive Chinese herbs
are in short supply and inferior substitutes or fake crude
herbs have been found in the UK market [17]. Substitution of
Aristolochia fangchi instead of the Chinese herb Stephania
tetrandra was found to lead to nephritis. It was subsequently
discovered in 1994 that one of the herbs which should have
been from the Stephania genus was unintentionally replaced
with an herb of Aristolochia genus, as both shared the
transliterated name of Fangchi [17]. Cases of substitution are
reported in Indian traditional system of medicine. In
Ayurveda, ‘Parpatta’ refers to Fumaria parviflora. In Siddha
‘Parpadagam’ refers to Mollugo pentaphylla. These two herbs
are often interchanged or substituted as they are similar
sounding. Shankhapushpi is equated with Canscora decussata,
Evolvulus alsinoides and Clitoria ternate in specific regions of
India. Lack of knowledge about the authentic plant can also
lead to unintentional adulteration. Mesua ferrea is available
throughout the Western Ghats and parts of Himalayas and is
an authentic source of ‘Nagakesar’. Samples are adulterated
with flowers of Calophyllum inophyllum due to lack of
knowledge as well as restriction on collection. Hypericum
perforatum is cultivated and sold extensively in European
markets. Due to limited availability the species H. patulum is
sold in the name of H. perforatum. It is reported that similarity
in morphology and or aroma is the reason for unintended
adulteration of Mucuna prurien with M. utilis (sold as white
variety) and M. deeringiana (sold as bigger variety), M.
cochinchinensis, Canavalia virosa and C. ensiformis. Parmelia
perforate, P. cirrhata and Usnea sp. are found to be admixed in
samples of Parmelia perlata commonly used in Ayurveda,
Unani and Siddha [18].
American ginseng and Asian ginseng that have contrasting
properties are morphologically similar. Cases of misidentifi-
cation of ginsengs based on traditional methods of authen-
tication via morphology have been documented [19]. The
replacements of roots of Cholorophytum borivilianum with
Asparagus racemosus, gum resin of Commiphora wightii with
gum of Acacia arabica and Boswellia serrata, Swertia chirata
substituted with Andrographis paniculata, American ginseng
(Radix Panacis Quinquefolii) with ginseng (Radix Ginseng) are
some of examples of substitution of high priced material with
a cheaper plant material [20].
Another common problem with use of herbal medicines is
the intentional or accidental presence of toxic heavy metals in
more than the permissible limit set by national regulatory
authorities. Toxic contaminants are reported at all steps
beginning from collection of raw materials to manufacturing
[17,21]. The first published case of heavy metal poisoning
related to ayurvedic medicines was in 1978 in UK. So far there
are over 50 published reports on heavy metal poisoning from
different areas in the world including the Indian subconti-
nent, North America, the Middle East, Western Europe and
Australasia [22]. Lead, mercury, copper and arsenic are the
predominant contaminants. Thirty-one ayurvedic formula-
tions were analyzed for their mercury content. It was found
that with the exception of one remedy, all exceeded the legal
limits of 1 ppm mercury and 16 preparations exceeded the
limits by more than two orders magnitude. Huge variability of
mercury content was also observed within one identical
remedy manufactured by different companies indicating to
the lack of product uniformity and the associated risks [23].
Accumulation of heavy metals namely Pb, Cd, Cu and Zn was
found in Indian herbal drugs derived from nine plants beyond
the WHO permissible limits [24].
In 2003, a study from US on heavy metal content of
ayurvedic drugs manufactured in India and Pakistan reported
that nearly 20% of the herbal drugs contained high concen-
tration of lead, arsenic and mercury than the prescribed limit
by US Pharmacopeia. It is not yet confirmed whether the
contamination is intentional [25]. Another study published in
2008 also reported 21% of ayurvedic medicines manufactured
and distributed by US and Indian companies via the internet
contained high concentration of lead, mercury or arsenic [26].
Ten Chinese crude herbal drugs marketed in Italy were
analyzed for foreign matter, total ash, microbial and heavy
metal contamination. The level of ash was found to be higher
than the permissible limit in three samples. For one sample,
lead and total viable aerobic count were found to be higher
than the limits set by the European or Italian Pharmacopoeias.
Of these only Rhizoma coptidis showed an amount of lead
three times higher than the maximum level allowed. Parasite
contamination was found in two samples [21].
Out of 3320 CPM marketed from 1990 to 2001 in
Singapore, 138 were found to contain toxic heavy metals in
amounts exceeding the limits set by Singapore Medicines
Order, 1995. Of the 138 CPM products tested, 51.4% was
detected to contain mercury in excess, 34.8% with arsenic,
14.5% with lead and 0.7% with copper [16]. In Malaysia, when
a total of 100 different Eugenia dyeriana herbal preparations
were analyzed for lead contamination using atomic absorp-
tion spectrophotometry, 22% of the products showed 10.15–
13.20 ppm of lead (10 ppm being the maximum permissible
limit) [27]. The permissible limit for some heavy metals in
different regulatory systems is shown in Table 1.
The presence of pesticide residues in herbal materials has
seriously affected the development and process of interna-
tionalization of traditional herbal medicine. Contamination of
crude medicinal plants as well as their products/preparation
(infusion, decoctions, tinctures and essential oils) has
 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471
Table 1
Permissible limit for some heavy metal in herbal drugs.
Test for heavy/toxic WHO US Food and Drug
metals Administration (FDA)
Lead 10.0 ppm 10.0 ppm
Mercury 1.00 ppm 1.00 ppm
Arsenic 10.0 ppm 10.0 ppm
increasingly been reported. A study with 280 samples of 30
different TCMs for pesticides residues showed that 75.8% of
samples contained at least one organochlorine pesticides
(OCPs) such as PCNB, aldrin, BHC or DDT [28]. Another study
with 300 kinds of TCMs revealed that all the samples had
hexachlorocyclohexanes (HCH) residues [29]. Similarly iso-
mers of HCH were found in all the 40 samples of single crude
drugs of Dashmoola, a popular herbal formulation with
immunomodulator and febrifugal properties [30]. OCPs such
as DDT has been restricted or even banned in many countries
due to their persistence in humans and their effects. The use
of pesticides in medicinal plants is regulated in many
countries. The WHO has established maximum residue limit
(MRL) for these pesticides in cultivated or wild medicinal
plants as well as appropriate methodologies for their
detection [31]. Pharmacopoeias of different nations have
assay methods and residual limits for the organochlorine
pesticides. Use of highly sensitive analytical methods for
qualitative and quantitative determinations of multiple
pesticide residues is needed to ensure safety of herbal
medicines. GC, HPLC, GC/MS, HPLC/MS, SFC, capillary elec-
trophoresis (CE), and enzyme linked immunosorbent assay
(ELISA) are the basic analytical methods used for determina-
tion of pesticide residues. Due to the complex compositions of
herbal medicines and diversity in the types of pesticide
residues it is quite difficult to find a method for the removal of
pesticide residues in herbal medicines without loss of active
ingredients and without secondary pollution caused by the
organic solvent.
Practices used in harvesting, handling, storage, production
and distribution can result in contamination by various fungi.
Evaluation of ninety-one medicated herbal samples for the
presence of predominant mycoflora and the extent of fungal
contamination showed that 54.9% of the samples exceeded
the limit determined by the US Pharmacopoeia (2 × 102 CFU/g
of the product is the maximum fungal contamination limit).
The genus Aspergillus was the most dominant genus recov-
ered (179 isolates) followed by Penicillium (44 isolates) and
these two genera were found in 90.1% and 39.6% of the
samples analyzed. Most of the identified moulds have been
reported to have ability to produce mycotoxins [32].
Wide and unsustainable harvesting of plant species is
leading to their depletion and thereby availability of the
herbal drugs. For instance, the African cherry (Pygeum or
Prunus africanum) widely used for the treatment of benign
prostate hyperplasia is facing severe ecological threat due to
its indiscriminate harvesting in Africa. The bark of the tree
used for medicinal preparation is entirely wild-collected.
Since 1995, it has been included in Appendix II of Convention
of International Trade in Endangered Species (CITES), as an
endangered species [33]. Further, this was also included on
the IUCN Red List of Threatened Species. However, initiatives
465
Department of Ayurveda, Unani, Sidhha and Health Science Authority (HSA)
Homoeopathy (AYUSH) India Singapore
10.0 ppm 20 ppm
1.00 ppm 0.5 ppm
10.0 ppm 5 ppm
have been taken by some of the companies to cultivate
Pygeum and harvest it sustainably. Sandalwood (Santalum
spp.) grown in Southern Asia, Indonesia, Australia and the
South Pacific for timber and fragrant oil production, has been
similarly listed. Santalum spp. has self-incompatibility within
the genus. Self-incompatible populations pose a threat to the
plant species as the lack of genetic variability within remnant
populations may result in sexual reproductive failure. This
can have important conservation consequences for this type
of clonal plant species. Development of Santalum stands with
a range of genotypes is proposed to provide self-sustaining
populations, capable of sexual reproduction [34].
These reports on adulteration, contamination with heavy
metals, pesticides and microbes in herbal drugs and their
effects on health have necessitated the development of
effective identification systems for herbal materials and
their components. Methods that ensure the quality and safety
of these products have to be developed in order to ensure the
quality and purity of herbal drugs.
3. Standardization of herbal drugs
3.1. Complexity and characterization: marker based analysis of
herbal drugs
Herbal medicines have distinctive characteristics that
make them different from synthetic drugs. They contain
more than one active compound and the active principle is
frequently unknown. For instance the Chinese medicinal
plant Huang-qin (Scutellaria baicalensis) has over 2000
compounds [35].The chemical profiles of medicinal plants
are affected by conditions of cultivation, manufacturing,
marketing, and distribution. Physiological, genetic, and
environmental variables (photoperiod, climate, soil condi-
tions, nutrient availability and moisture) affect the biochem-
ical profiles and secondary metabolite production in plants.
Secondary metabolite content is also dependent on time of
harvesting, storage, drying, extraction and processing for final
packaging. The development of plant based medicines
requires comprehensive understanding of plant systems
including biological, chemical, genetic, and agronomic
aspects. Chemical consistency at all stages of manufacturing
processes such as extraction, stability, shelf-life and purity is
of utmost importance to ensure medicinal efficacy and
consumer safety. Substantive evidence is lacking with respect
to the unique physiology of medicinal plants and their
bioactive constituents. The different steps for development
of herbal medicines starting from collection of raw materials
to isolation of active ingredients are shown in Fig. 1.
Several markers such as taxonomic, chemical, genomic,
proteomic markers aid in identification of herbal drug
components. Such methods encompass morphological
466 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471
Fig. 1. Steps involved in phytomedicine development.
identification (macroscopic identification), anatomical iden-
tification (microscopic identification), chemical analysis such
as TLC, HPLC, capillary electrophoresis, LC/MS, HPLC/MS,
protein analysis and the use of molecular markers. The EMEA
defines chemical markers as chemically defined constituents
or groups of constituents of an herbal medicinal product
which are of interest for quality control purposes regardless
whether they possess any therapeutic activity. Chemical
markers are categorized into analytical markers and active
markers. Analytical markers are the constituents or groups of
constituents that serve solely for analytical purposes, where-
as active markers are the constituents or groups of constitu-
ents that contribute to therapeutic activities. In cases, where
no active constituent or marker can be defined for a herbal
drug, the percentage extractable matter with a solvent may
be used. A total of 282 chemical markers are listed in the
Chinese Pharmacopoeia (2005 edition) for the quality control
of Chinese herbal medicines. They are helpful for identifica-
tion of the adulterants, differentiation of herbal medicines
with different sources, stability testing of proprietary pro-
ducts. Toxic components may be used as chemical markers in
screening methods [9]. At present, some herbs do not have
markers for quality control. According to the Chinese
Pharmacopoeia, only 281 out of 551 herbs have one or two
chemical markers for quality control. Shortage of chemical
markers, purity levels of available markers are major
hindrances in assuring quality control of herbal drugs.
Secondary metabolites as markers have been extensively
used in quality control and standardization of botanical drugs.
As the genetic composition is unique for each species and is
not affected by age, physiological conditions and environ-
mental factors DNA based markers are also used in identifi-
cation of inter- and intra-species variation. Random amplified
polymorphic DNA (RAPD) based molecular markers have
been found to be useful in differentiating different accessions
of Taxus wallichiana, Neem, Juniperus communis L., Codonopsis
pilosula, Allium schoenoprasum L, A. paniculata collected from
different geographical regions [36]. Marker based analysis has
limitations as the markers are not single compounds and
often a combination of methods become necessary for herbal
component detection.
The safety and efficacy of herbal drugs are established
through their long historical use. Though randomized clinical
trials are reported for herbal drugs, well-controlled double
blind thorough clinical and toxicological studies are lacking.
An assessment of the clinical trial information for Liv.52, an
ayurvedic drug useful for chronic liver ailments reveals the
need for well selected end points to be adopted during
randomized controlled clinical trial [37].
3.2. Quality control of herbal drugs
Quality control of herbal medicines has a direct impact on
their safety and efficacy. Environmental and agricultural
practices are important in collecting herbal materials. The
WHO has developed a series of technical guidelines and
documents relating to the safety and quality assurance of
medicinal plants and herbal materials. WHO had published
the ‘Quality Control Methods for Medicinal Plant Materials’, a
collection of recommended test procedures for assessing the
identity, purity, and content of medicinal plant materials to
assist national laboratories engaged in drug quality control
[38]. In 2003, WHO published the ‘Guidelines on good
agricultural and collection practices (GACP) for medicinal
plants’ and in 2007, a new guideline ‘WHO guidelines for
assessing quality of herbal medicines with reference to
contaminants and residues’ was formulated [39]. The Euro-
pean Union, China and Japan have developed regional and
national guidelines for good agricultural and collection
practices for medicinal plants which ensure that soil and
irrigation water used for herbal material cultivation and
propagation are within the limits or free from harmful heavy
metals, pesticides, herbicides and toxicologically hazardous
substances [31].
Quality assurance of botanicals and herbal preparations is
the prerequisite of clinical trials. The certification for this is
based on parameters such as identification, water content,
chemical assay of active ingredients, inorganic impurities
(toxic metals), microbial limits, mycotoxins, pesticides and
others. For herbal preparations, in addition to these tests,
disintegration, dissolution, hardness/friability and uniformity
of dosage unit should also be presented [40]. The chemistry,
manufacturing and control (CMC) documentation that should
be provided for botanical drugs is often different from that for
synthetic or highly purified drugs, whose active constituents
can be more readily chemically identified and quantified. In
the US, it is not essential for the manufacturer of a botanical
drug to identify the active constituents at the investigational
new drug (IND) stage.
 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471
Due to the variations and inherent complexities of herbal
drugs, conventional quality control, botanical techniques are
insufficient as the sole means for identifying or authenticating
properties, safety and/or efficacy. This is true for a marker
alone approach. A multi-technique approach is necessary in
order to authenticate the link between the components and
the traditional use. The concept of ‘Phytoequivalence’ was
developed in Germany in order to ensure consistency of
herbal products, where a chemical profile, such as a
chromatographic fingerprint for an herbal product is con-
structed and compared with the profile of a clinically proven
reference product [41].
4. Regulatory norms development for herbal drugs
The first international recognition of the role of traditional
medicine and use in primary health care was in The
Declaration of Alma-Ata. It states, inter alia, that “…Primary
health care relies, at local and referral levels, on health
workers, including physicians, nurses, midwives, auxiliaries
and community workers as applicable, as well as traditional
practitioners as needed…” [42]. The safety problems emerg-
ing with herbal medicinal products are due to a largely
unregulated growing market where there is a lack of effective
quality control.
Lack of strict guidelines on the assessment of safety and
efficacy, quality control, safety monitoring and knowledge on
traditional medicine/complementary and alternative medi-
cine (TM/CAM) are the main aspects which are found in
different regulatory systems. Under some regulatory systems
plant may be defined as a food, a functional food, a dietary
supplement or a herbal medicine. As per WHO, herbal
medicines include herbs, herbal materials, herbal prepara-
tions and finished herbal products that contain as active
ingredients parts of plants, or other plant materials, or
combinations. Similarly in the EU, the EMEA defines herbal
drugs as the whole, fragmented or cut, plants, parts of plants,
algae, fungi, lichen in an unprocessed state usually in dried
form or afresh. Unprocessed exudates are also considered as
herbal drugs. When herbal drugs are subjected to treatments
such as extraction, distillation, expression, fractionation,
purification, concentration or fermentation, they are known
as herbal drug preparations. This includes powdered herbal
drugs, tinctures, extracts, essential oils, expressed juice or
process exudates. Virtually all herbal products sold in the US
are treated as dietary supplements and therefore as foods. A
botanical product which is derived from one or more plants,
algae, or macroscopic fungi and prepared from botanical raw
materials by one or more of the processes such as pulveri-
zation, decoction, expression, aqueous extraction, ethanolic
extraction, or other similar process, intended for use as a drug
is known as Botanical Drug Product (Section 201(g)(1)(B),
Federal Food, Drug, and Cosmetic Act).
The safety of herbal medicines is a global concern and
national health authorities have developed mandates to
ensure the safe use of herbal medicines. In 2001, WHO
initiated a global survey in 191 member states on national
policies on TM/CAM and regulation of herbal medicines.
Research data, appropriate control mechanisms, education of
providers and expertise are identified to be most important
for the field of regulation of herbal medicine [43]. The survey
467
revealed that till 2003, 37% of member states had laws and
regulations for herbal medicine, out of this 42% member
states had separate laws and regulation. Further it was found
that nearly 68% of member countries sell herbal medicines as
Over the Counter (OTC) drugs and about 35% of member
states treat herbal medicines as prescription medicines.
Medical claims, health claims and nutrients content claims
are the most common types of claims with which herbal
medicine may legally be sold. Only 24% of responding
countries indicated that national pharmacopoeia for herbal
drug existed and in use and 18% countries indicated that such
a document was in preparation. Fifty one percent countries
indicated that the same GMP rules as for conventional
pharmaceuticals are also applicable to manufacturing of
herbal drugs. Out of the total 142 responded member states
only 15% members have herbal medicines included in their
essential medicine list. China reported highest 1242 herbal
medicines in the essential medicine list [44].
Some of the parameters that help in understanding the
development of herbal drug regulation in a given nation are
general policy structure, drug registration system, develop-
ment of pharmacopoeia, national monographs, inclusion in
essential medicine list and drug type (OTC or prescription).
Using these parameters we have compared the herbal drug
regulation in South East Asian and some Western Pacific
countries (Table 2). Of the eighteen countries studied, except
Bhutan, Sri Lanka and Maldives, all countries have herbal drug
regulation and registration system. Nine countries (Korea,
Indonesia, India, Myanmar, Sri Lanka, Thailand, China,
Malaysia, and Vietnam) have their National Monographs for
herbal drugs. In Bhutan, Nepal and Philippines the develop-
ment of monographs are in progress. Pharmacopoeias for the
herbal medicines are developed in fifteen countries (except
for Maldives, Malaysia and Singapore). In seven countries,
Bhutan, India, Thailand, China, Philippines, Republic of Korea
and Vietnam, the essential medicine list includes herbal
drugs. Philippines has the highest number included in the list
with 2000 herbal drugs followed by China with 1242 herbal
drugs. India has separate essential medicine lists for the
traditional herbal drugs such as Ayurveda and Unani. Except
Bhutan in all other countries, the herbal drugs are available as
OTC drugs. In Bhutan, where no separate regulation for herbal
drugs is available, these are sold as prescription medicines
only.
There are varied requirements for registration and
marketing authorization of herbal drugs in the EU, US and
India (Table 3). The Committee on Herbal Medicinal Products
(HMPC) established within the European Medicines Agency
(EMEA), has introduced a simplified registration procedure
for traditional herbal medicinal products in EU member
states. The simplified procedure allows the registration of
herbal medicinal products without requiring particulars and
documents on tests and trials on safety and efficacy, provided
that there is sufficient evidence of the medicinal use of the
product throughout a period of at least 30 years, including at
least 15 years in the Community (Article 16c (1) (c) of
Directive 2001/83/EC). EMEA has several guidelines related to
quality, clinical safety and efficacy and nonclinical aspects of
herbal drugs [45].
In the US, herbal medicines have been regulated under the
Dietary Supplement Health and Education Act of 1994. A
468 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471

Table 2
Herbal drug regulation in selected countries.

Country Regulation on Herbal drug National monograph Pharmacopoeia Inclusion in essential Drug type
herbal drug registration medicine list
(year) system

Bangladesh 1992 Yes No Bangladesh national Not available Prescription

formularies on unani and and OTC
ayurvedic medicine
Bhutan No No In development In development 103(till 1998) Prescription
Democratic People's 1999 Yes Korean herbal medicine Pharmacopoeia of the Not available Prescription
Republic of Korea monographs (1986) Democratic People's Republic and OTC
of Korea (1996)
India 1940 Yes Yes Ayurvedic pharmacopoeia of Ayurveda (2001)–315, Prescription
India and the Unani Unani (2000)–244, and OTC
pharmacopoeia of India Siddha (2001)–98
Indonesia 1993 Yes Materia medika Indonesia Farmakope Indonesia No OTC
(246 monographs)
Maldives No No No No No OTC
Myanmar 1996 Yes Monograph of Myanmar In development In development OTC
medicinal plants(2000)
Nepal 1978 Yes In development In development Not available Prescription
and OTC
Sri Lanka No No Compendium of medicinal plants Ayurveda pharmacopoeia No Prescription
( 100 monographs) (1979) and OTC
Thailand 1967 Yes Yes, 21 monographs Thai herbal pharmacopoeia, 16 herbal preparation Prescription
traditional formularies of and OTC
herbal medicines (5
volumes)
Australia 1989 Yes No British pharmacopoeia is No OTC
used
China 1963 Yes Yes, 92 monographs Chinese pharmacopoeia 1242 Prescription
(1963) and OTC
Japan 1960 Approval No Japanese pharmacopoeia Not available Prescription
system and OTC
Malaysia 1984 Yes Malaysian herbal monograph No No OTC
(1999)
Philippines 1984 Yes In development In development 2000 OTC
Republic of Korea 1986 Yes No Korea pharmacopoeia (1959) 515 OTC
Singapore 1998 No No No No OTC
Vietnam 1989 Yes Vietnam medicinal plants Vietnam pharmacopoeia 267 Prescription
and OTC

Source: 1st WHO global Survey on National Policy and regulation of TM/CAM, 2005.

botanical drug product may be marketed in the United States
as an OTC drug monograph or as an approved NDA or ANDA
(21 CFR parts 331–358). The manufacturer would need to
submit a petition in accordance with 21 CFR 10.30 to amend
the monograph to add the botanical substance as a new active
ingredient [46].In India, Department of Ayurveda, Yoga &
Naturopathy, Unani, Siddha and Homoeopathy (AYUSH)
established in 1995 under the Ministry of Health & Family
Welfare is responsible for the regulation of herbal medicines.
The Drugs & Cosmetics Act of 1940 lays down the various
rules for production and marketing of Ayurveda, Siddha and
Unani (ASU) drugs. Schedule T of Drugs & Cosmetics Act,
1940, specifically deals with the GMP for ASU drugs. Most of
the herbal products do not have to demonstrate their safety
and efficacy by clinical trials.
Among the Latin American countries Brazil, Argentina and
Mexico are the major players in herbal market. Herbal drug
regulation exists in Brazil since 1967. Herbal medicines are
sold as both prescription based and OTC drug. Legal
requirements for phytopharmaceutical drug registration in
Brazil are described in Directive 6, issued in 1995 by the
Brazilian Drug Division (DIMED) which enforces drug
regulation. The fourth version of regulation RDC/48/2004
was published in 2004. As per the directive complete
documentation of efficacy, safety and constant defined
quality are required as a condition for the registration of
phytopharmaceutical products. Efficacy and safety test results
in humans, in conformity with the guidelines of Directive 116
published by Federal Health Agency are also required for
registration. Scientific documentation from the literature may
be submitted, instead of controlled clinical trials or animal
tests, if they already exist for the proposed preparation. The
national pharmacopoeia and monographs are legally binding
for the manufacturers [47]. In Mexico a large proportion of
the population relies heavily on traditional practitioners and
medicinal plants to meet primary health care needs. Herbal
medicines are available as both prescription and OTC drugs. In
Argentina laws and regulations on TM/CAM, specifically on
phytotherapeutic medicines and vegetable drugs were
established in 1998 in the Resolution 144/98. They are
regulated as prescription medicines, over the counter
medicines and dietary supplements. The relevant regulatory
requirements for manufacturing include adherence to infor-
mation in pharmacopoeias and monographs and special GMP
rules. In both Mexico and Argentina safety assessment
requirements include traditional use without demonstrated
 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 469

Table 3
Herbal medicine regulation in EU, US and India.

Country Regulatory authority Description Regulation/Act

EU European Medicines Agency (EMEA): The Establishment of HMPC and regulation of Directive 2004/24/EC (Traditional Herbal Medicinal
Committee on Herbal Medicinal Products herbal medicine Products Directive) and Regulation (EC) No 726/2004.
(HMPC) Registration Procedure for traditional Articles 16a to 16i of Directive 2001/83/EC
herbal medicinal products
US USFDA: Center for Drug Evaluation and Botanical drug definition 201(g)(1)(B), Federal Food, Drug, and Cosmetic Act
Research (CDER) Regulation of herbal product Dietary Supplement Health and Education Act of 1994
(DSHEA)
Procedure for marketing of Botanical 21 CFR 10.20, 10.30, 312, 314, 321, 324, 330, 331–358
drug as OTC drug
Center for Biologics Evaluation and Research Regulation of Allergenic extracts and Section 351 of the Public Health Service Act (42 U.S.C.
(CBER) vaccines that contain botanical 262).
ingredients
India Department of Ayurveda, Yoga & Naturopathy, Production and marketing of ASU drugs Drugs & Cosmetics Act, 1940 Drugs & Cosmetics Rules,
Unani, Siddha and Homoeopathy (AYUSH) 1945
GMP for ASU drugs Schedule T, Drugs & Cosmetics Act, 1940

harmful effects, reference to documented scientific research
on similar products, toxicological studies when traditional
use cannot be demonstrated and submission of a full
toxicological and pharmacological dossier. Compliance with
these requirements is ensured by regular inspections [44].
Herbal medicines are the most commonly used type of
traditional medicine in the Eastern Mediterranean Region. In
Iran, herbal medicines are produced locally and a large
population depends on them for primary health care. In other
countries, such as the United Arab Emirates, the majority of
herbal products are obtained from the United States, Europe
or Asia. In this region herbal medicines are generally
categorized as ‘traditional herbal medicines’ that have been
widely used, supported by well-established safety and
efficacy data, or have been used within the local community
for a minimum period of fifteen years. ‘New herbal medicines’
are those used for only a short period of time and to a very
small extent (few uses in a small number of patients), or used
in a new combination of herbal substances never combined
before. Only few countries in the region have regulations for
ensuring quality. A recent survey in this region also showed
that there is a necessity for proper handling and licensing of
herbal medicines [48] Important data related to safety,
efficacy and quality control are often either insufficient or
not available. In most countries, either no safety monitoring
system exists or the existing system excludes herbal
medicines. The Eastern Mediterranean Drug Regulatory
Authorities Conferences in 1999 and 2001 provided a general
guidance to drug regulatory authorities in the development
and implementation of preliminary regulatory systems for
herbal medicines. In 2006 WHO developed the Guidelines on
minimum requirements for the registration of herbal medic-
inal in the Eastern Mediterranean Region Products [49]. This
guideline gives an overview of general requirements for
safety and efficacy for traditional as well as new herbal
medicinal products, quality control aspects, pharmacovigi-
lance and control of advertisements for herbal medicines.
Standards for medicinal plants are being developed
worldwide but as yet there is no consensus as to how these
should be adopted. Several publications, United States
Pharmacopoeia, British Herbal Compendium, British Herbal
Pharmacopoeia, Chinese Pharmacopoeia, and Physician's
Desk Reference (PDR) for herbal medicines, Ayurvedic
Pharmacopoeia of India have monographs for herbal raw
materials to which respective countries adhere, but there is
no interlinking of these monographs. For a given plant the
monograph may vary in different publications. Different
country standards with respect to a single formulation create
difficulties for manufacturers in herbal drug trade.
5. International harmonization
Harmonizing efforts have been initiated on pharmaco-
poeial specifications, standardization and classification of
herbal drugs to ensure uniformity of quality, safety and
efficacy of the same herbal medicines across countries. The
pharmacopoeias of Korea, Japan and China list similar herbal
medicines, but their specifications are somewhat different.
The same crude plant material may be described but the
family or species of the original plant may be different.
Further, the same crude plant material may be specified but
the name expressed by the Chinese letter or Latin binomial
pharmacopoeia name or the part used for the herbal medicine
is different [50]. The Western Pacific Regional Forum for the
Harmonization of Herbal Medicine (FHH) tried to harmonize
the crude drug monographs in the pharmacopoeias of six
Asian countries (Japan, China, Korea, Singapore, Vietnam, and
Hong Kong) in order to help in promoting commercialization
of safe and effective herbal drugs across countries. Among the
American countries harmonization of process requirements
and herbal product registration was initiated in the year 2000.
The working group on Medicinal Plant of the Pan American
Network of Drug Regulatory Harmonization (PANDRH) is
working to promote a common understanding on the types of
herbal products, definition of terms used, identification of
procedures and the minimum requirements for registration
of herbal products [51].
The ‘WHO International Standard Terminologies on
Traditional Medicine in the Western Pacific Region’ has
been prepared with international standard terminology that
will help in defining a common scientific basis across
different traditional medicine systems [52]. This compilation
470 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471
has about 4000 traditional medicine terms. It is suggested
that this would help in developing evidence-based clinical
practice guidelines on traditional medicine. A system for
Anatomical Therapeutic Chemical (ATC) classification of
herbal remedies which is fully compatible with the general
medicines has been proposed. With a few modifications this
system has now been adopted and published in the Guide-
lines for Herbal ATC Classification and Herbal ATC Index [10].
India has nearly eight thousand herbal drug companies, of
which about five thousand have GMP compliant manufac-
turing units and majority of them are of small and medium
size. Seventy percent of the Indian exports from the herbal
sector consist largely of raw materials and thirty percent
consist of finished products including herbal extracts [53].
There are fifty five major herbal drug exporting companies in
India. We have carried out a preliminary study based on
twenty five point questionnaire to identify the challenges
these companies face with respect to manufacturing and
exporting of herbal drugs. Compliance to different national
regulatory standards is identified as one of the major
hindrances for commercialization. Thirty-three percent of
the industries surveyed stated achieving regulatory compli-
ance to different country standards is very difficult and time
consuming and sixty-six percent of them feel the need for
development/adoption of a Common Technical Document
(CTD) for marketing authorization application in different
countries.
6. Conclusions
Advances in detection and quantitation of herbal drug
components have increased the understanding of the relation
between the specific component(s) and effects. There is a
widespread concern on the unintended/harmful effects of
herbal drugs with greater number of studies carried out on
herbal drug reactions in the developed countries. This is
challenging the notion that long traditional use is an
indication for safety of herbal medicines. Manufacturers,
particularly in South East Asia, face the challenge of proving
the authenticity and purity of herbal drug preparations
during commercialization. Marker based standards are
becoming popular for the identification/authentication of
herbal drug components. However, as herbal drugs are plant
extracts based the need for adoption of multi-marker system
and effect of storage conditions are important points to be
considered. A general comparison of the pharmacopoeial
standards reveals that there is a wide variation in plant
specific parameters, quality standards such as permissible
limits for heavy metal, pesticide and microbial contamination
in different countries. Country specific standards as well as
regional guidelines have been evolved some of which only
have been adopted. The development of a CTD is an important
lead with respect to unification but so far there is no
consensus on use of a single unified approach either system
wise or drug wise. With respect to South East Asia India is
among the leading countries with respect to development of
pharmacopoeial standards as well as modification of existing
regulatory guidelines. Evidence-based submissions for regu-
latory approval and interlinking of various pharmacopoeial
and/monographs would help herbal manufacturers gain
greater access to regulated markets across the world.
Conflict of interest statement
We have no conflicts of interest that are directly relevant
to the content of this review.
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