regulation of herbal products

Regulations for Herbal Products
Abstract: The use of herbal drugs for the
prevention and treatment of various health
ailments has been in practice from time
immemorial. Generally it is believed that
the risk associated with herbal drugs is
very less, but reports on serious reactions
are indicating to the need for development
of 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 consensus as to how
these should be adopted. Standardization,
stability and quality control for herbal
drugs are feasible, but difficult to
accomplish. Further, the regulation of
these drugs is not uniform across
countries. There are variations in the
methods used across medicine systems and
countries in achieving stability and quality
control. The present study attempts to
identify the evolution of technical
standards in manufacturing and the
regulatory guideline development for
commercialization of herbal drugs.
Keywords: survey was conducted to
obtain primary data on challenges faced
during production, commercialization, and
marketing approval for traditional or
herbal drugs in India and abroad.
Responses were collected from companies
by email, telephone, and in-person
interviews and were analyzed to draw
appropriate conclusions
Introduction: The use of plants, parts of
plants and isolated phytochemicals for the
prevention and treatment of various health
ailments has been in practice from time
immemorial. It is estimated that about 25%
of the drugs prescribed worldwide 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 andAsian
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 Fitoterapia 81 (2010) 100
metric tonnes a year [4]. Indian herbal
market is registering a significant growth
and is likely to reach Rs145,000 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
modification 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. Preclinical data and clinical
data may or may not be required
depending on the modification(s).
Imported herbal medicines (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. 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
1993, the American Herbal Products
Association (AHPA) issued an alert to
restrict the use of comfrey, a
herbalmedicine 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 (Guanmutong)
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,
angiodema, 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 Commission. This list included
some plants such as Aconitum (allspecies),
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 methysticin),
garlic (allicin), evening primrose oil (cis-
linoleic acid)
and St. John's wort (hyperforin and
quercetin) could potentially inhibit the
metabolism of co-administered
medications whose primary route of
elimination is via cytochrome 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 Health
Science Authority (HSA) Singapore,
between 1990 and 2001were found to
contain nineteen synthetic drugs. Intwelve
out of nineteen CPM manufactured in
China claimedto be tonics for the
treatment of sexual dysfunction in
maleshad 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 fromSingapore 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
foundto contain six undeclared drugs.
“Wonder Pills” used forreducing fats from
body was found to contain phenformin,
adrug banned in Singapore since 1977
[16].Substitution involves intentional
replacement with anotherplant species or
intentional addition of a foreignsubstance
to increase the weight or potency of the
productor to decrease its cost. The use of
fake or wrong herbs hasgenerated serious

questions about the safety and efficacy
ofherbal products. Many popular and
expensive Chinese herbsare 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 similarsounding. Shankhapushpi
is equated with Canscora
decussata,Evolvulus alsinoides and
Clitoria ternate in specific regions ofIndia.
Lack of knowledge about the authentic
plant can alsolead to unintentional
adulteration. Mesua ferrea is
availablethroughout 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 similarityin
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
misidentification of ginsengs based on
traditional methods of authentication 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 stepsbeginning 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
subcontinent, North America, the Middle
East, Western Europe and Australasia [22].
Lead, mercury, copper and arsenic are the
predominant contaminants. Thirty-one
ayurvedic formulations 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 concentration
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 absorption
spectrophotometry, 22% of the products
showed 10.15– 13.20 ppm of lead (10 ppm

being the maximum permissible limit)
[27]. The presence of pesticide residues in
herbal materials has seriously affected the
development and process of
internationalization of traditional herbal
medicine. Contamination of crude
medicinal plants as well as their
products/preparation (infusion, decoctions,
tinctures and essential oils). 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
electrophoresis (CE), and enzyme linked
immunosorbent assay (ELISA) are the
basic analytical methods used for
determination 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 recovered (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
have been taken by some of the companies

to cultivate Pygeum and harvest it
sustainably. Sandalwood (Santalumspp.)
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.
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.
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.
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.
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.
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.
Minimum requirements for assessment
of safety of herbal medicines
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.
· 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)
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
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 herbal medicines and, if

available, database searches Guidelines for
the Regulation of Herbal Medicines 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.
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.
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
category 3, i.e. ‘herbal medicines of
uncertain safety, will be identical to that of
any new substance.
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’.
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.
Guidelines for the Regulation of Herbal
Medicines.
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.
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?
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
pregnancy, information on misuse, e.g. as
an agent to induce abortion, should be
assessed. Guidelines for the Regulation of
Herbal Medicines.
Minimum requirements for assessment
of the efficacy of herbal medicines
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. 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 documents such as
WHO monographs. Pre-clinical and
clinical data of efficacy may not be
necessary.
Table 1. Summary of the efficacy data requirements for the
three types of disease and conditions
Type of
disease
Pre-clinical data
of efficacy
Clinical data
of efficacy
Other data or
information required
Acute Needed Control trial need
Supported by well
established documents
such as national
pharmacopoeia and
monographs
Chronic May be needed Clinical data may
or
may not be needed
Health
condition
May not be needed May not be needed
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
are needed. 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;

 New combination: Two or
more traditionally used
formulas are put together.
Table 2. Requirements data for the evaluation of efficacy of traditionally
used herbal medicines with limited modifications
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).
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, e.g. by
establishing drug master-files for
specifications and quality control, should
be encouraged.
Coordinating quality control
A coordinating agency on GACP should
be established to facilitate the availability
of goodquality 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.
Quality assurance
Elements of quality assurance are:
 adherence to GACP, GMP
and GLP guidelines;
 setting specifications; and
 quality control measures.
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 should be taken
into consideration.
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.
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.
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 obtained from the
concerned authority.
Based on the above-mentioned minimum
requirements, each national drug
regulatory
authority could develop its own
requirements for quality control of
imported herbal medicinal
products.
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.
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).
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.
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);
 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;
 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.
Pharmacovigilance of herbal medicinal
products
Of the 11 Member Countries in the South-
East Asia Region, there are only four with
national systems for monitoring the safety
of traditional medicinal products. There is
an urgent need, therefore, to set up
national systems for monitoring the safety
of medicinal products in the Region. The
national system for monitoring safety of
medicinal products should include herbal
medicinal products in the scope of its
activities. 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.
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. 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 herbal medicines and herbal medicines
should include all the necessary
information on registered herbal medicinal
products and an ADR reporting form.
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
withdrawn?
 Was the ADR
reversible?

 Did the ADR
reappear after re-
exposure?
(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?
 Can other causes be
eliminated, such as viral
markers or ethanol misuse
in hepatitis?
(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
pharmacognosy, toxicology and other
health professionals including providers of
herbal medicines. A clear conclusion on
the causality should be made using the
terms proposed by WHO Guidelines
Related to Safety Drug Monitoring.
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
sections and systems for
ADR of herbal medicines
and any other possible
medicine-related problem;
 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.
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. It is necessary
that information on the advertisement of
herbal medicinal products is shared among
countries and overall cooperation with
different, relevant national authorities is
encouraged.
Status of regulation on herbal medicines
IN the centuries preceding India’s
independence (1947), the Mughals and the
British culturally and socially influenced
the Indian subcontinent. This had also
affected the medical systems existing
during that period. The Mughals brought
in the Unani system of medicine to India,

which got indigenized, whereas the
British, by the 18th CE, systematically
relegated the Indian traditional medicine
(TM), namely Ayurveda, Siddha and
Unani to the background and promoted
their reductionist biomedicine (allopathy)
for healthcare deliverance1. Politically, in
the post-independence era, attempts were
made to restore TM to its rightful place,
but executed at a slow pace. The
announcement by the present Government
about the creation of a separate Ministry
for AYUSH (Ayurveda, Yoga and
Naturopathy, Unani, Siddha and
Homeopathy) on 9 November 2014, with
an Act separate from Drugs and Cosmetics
Act, 1940 bodes a brighter future for these
systems. Registration of practitioners,
setting up of statutory bodies controlling
education, including prescription of
standard texts and syllabus,
pharmacopoeia, research and related
guidelines and Acts would serve as
standards for evaluating the status of these
systems in modern times. As biomedicine
(BM) is unable to offer desirable relief in
certain diseases, there is a growing interest
in finding a solution through an integrative
approach by tapping the strength of TM
and BM. The concept of integrated
approach is gaining importance due to
growing focus on the necessity to provide
patient-oriented treatment which may
involve more than one medical system.
This thinking is reflected in changing of
the name of the National Centre for
Complementary and Alternate Medicine
(NCCAM), under the National Institutes of
Health (NIH), USA to (NCCIM) in
December 2014. In India too, for certain
diseases of public health importance, there
is a need to adopt an integrated approach
using TM and BM. TM is used as
household remedy in many parts of India
and therefore considered safe for self-care
due to its ‘natural’ status2. But limited
quality control and uncontrolled over the
counter (OTC) usage have led to its
misuse. For global acceptance, evidence is
required for claiming safety and
effectiveness of TM formulations.
Therefore, capacity building is necessary
to maintain international quality assurance
and quality control standards in terms of
good laboratory practices (GLP) and good
manufacturing practices (GMP).
Appropriate amendment of legislation and
regulatory framework for TM should also
include Indian position on patent and
intellectual property rights. The World
Customs Organization, which is
technically connected to the World Trade
Organization, has assisted the erstwhile
Department of AYUSH in reviewing its
guidelines and protocols. It is also
important to provide appropriate training
to the practitioners of TM to modernize or
modify their system by applying recent

advances according to contextual need. In
the following sections, development of the
abovementioned standards in TM
compared to BM will be historically traced
mainly from the British India period.
Following a Public Interest Litigation filed
in Supreme Court, it gave directions to the
Ministry of Health for rectifying or
creating systems to enable protection of
human research participants. As a result,
from 2013 onwards, the Government
through the Ministry of Health and Family
Welfare has made several amendments to
the Drugs and Cosmetics Act, 1940 and
Rules 1945 namely compensation in case
of injury or death during clinical trial (vide
GSR 53 (E) dated 30 January 2013)
(wherein Rule 122 DAB and a new
Appendix-XII in Schedule-Y has been
inserted); permission to conduct a clinical
trial (vide GSR 63 (E) dated 1 February
2013) (wherein Rule 122 DAC in part X-A
of the DCA Rules has been inserted);
registration of ethics committee (vide GSR
72 (E) dated 8 February 2013) (wherein
Rule 122 DD in the Drugs and Cosmetics
Rules has been inserted), and audio-visual
recording of the informed consent process
(vide GSR 364 (E) dated 7 June 2013)25.
Under these amendments, the definition of
new drug covers new chemical entities,
devices and vaccines but not natural
products/herbal formulations.
Herbal Products and Warfarin
Herbal products, just like many foods and
drugs, may interact with warfarin. Many
herbals contain substances that are similar
to warfarin and may put you at a higher
risk for bleeding complications. There are
also herbal products that work against the
actions of warfarin and can make you
more prone to developing clots.
Herbs That Can Increase Risk of
Bleeding
· agrimony · dandelion · onion
· alfalfa · danshen · papain
· aniseed · dihydroepiandrosterone ·
parsley
· arnica flower · dong quai · passionflower
· artemesia · fenugreek · prickly ash
· asa foetica · feverfew · poplar
· bochu · fish oil · quassia
· bogbean · garlic · red clover
· bromelains · ginger · sweet clover
· capsicum · ginkgo · sweet woodruff
· cassio · horse chestnut · tonka beans
· celery seed · horseradish · turmeric
· chamomile · licorice · wild carrot
· Chinese wolfberry · meadowsweet · wild
lettuce
· clove · melilot · willow
Herbs That Can Increase Risk of Blood
Clots
· coenzyme Q10 · goldenseal · St. John’s
wort
· ginseng · green tea · yarrow
Conclusion

Although strengthening the regulatory
mechanism with a view to ensuring quality
of herbal medicines has become the prime
concern for Indian drug regulators, drug
manufacturers are grappling with
increasing standards for herbal medicinal
products. Fragmentation of the industry,
lack of standardization of raw materials
and finished products, inadequate research
and development, slow pace of
modernization,absence of focused
marketing and branding, and inadequate
emphasis on human resource development
and education are the major reasons for
slow growth of the Indian herbal industry.
Proper implementation of DCA,
development of more elaborate guidelines
on quality control and quality assurance
aspects, and development of markerbased
standards are needed to produce safe and
effective herbal medicines in India.
Initiatives have been taken to address these
issues by the Department of AYUSH.
Schemes have been implemented to
promote development of standardized
herbal formulations. One such example is
the New Millennium Indian Technology
Leadership Initiative by the Council for
Scientific and Industrial Research. Under
this scheme, for the first time in India an
Investigational New Drug application has
been filed for an oral herbal formulation
developed by extensive studies comprising
finger printing, activity-guided
fractionation, efficacy studies, toxicology,
safety pharmacology, pharmacokinetics,
and toxicokinetics for the treatment of
psoriasis. As evidence-based submissions
are becoming increasingly essential for
establishing the safety and efficacy of
herbal products both in the domestic and
the export market, more focus should be
given on scientific and technological
advancement in the field of herbal
medicine. India must develop scientific
cultivation, postharvest technology,
processing, manufacturing, research and
extension, patenting, and marketing
strategy for medicinal plants and products.
Regulatory harmonization becomes
essential to mitigate the delays in
commercialization across countries.
Growing public demand for safe, high-
quality, and efficacious integrative and
complementary healthcare makes it
imperative for AYUSH to urgently take
steps in the fields of education, research,
clinical medicine, pharmacopeial
standards, health products, and services
and improve regulatory mechanisms.
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Address correspondence to: Niharika
Sahoo, PhD National Institute of Science,
Technology and Development Studies
(NISTADS) Dr. K.S. Krishnan Marg, Pusa
Road New Delhi 110012
India.

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