Quality Control of Herbal Drugs
Quality control for efficacy and safety of herbal products is of paramount impor-
tance [14–16, 19, 20, 41–45]. Quality can be defined as the status of a drug that is
determined by identity, purity, content, and other chemical, physical, or biological
properties, or by the manufacturing processes. Quality control is a term that refers
to processes involved in maintaining the quality and validity of a manufactured
product. For the quality control of a traditional medicine, the traditional methods
are procured and studied, and documents and the traditional information about
the identity and quality assessment are interpreted in terms of modern assess-
ment. In general, all medicines, whether they are of synthetic or of plant origin,
should fulfill the basic requirements of being efficacious and safe, and this can be
achieved by suitable clinical trials. This applies both to the multinational pharma-
ceutical company conducting a multi-center, double-blind placebo-controlled study
with a herbal extract, and to the health practitioner in a rural village who applies a
locally produced herbal mixture.
Natural products in medicine constitute a vast array of “raw materials,” making
clear definitions important. Quality criteria are based on clear scientific definitions
of the raw material. The term “herbal drugs” denotes plants or plant parts that have
been converted into phytopharmaceuticals by means of simple processes involving
harvesting, drying, and storage [46]. Hence they are capable of variation. This vari-
ability is also caused by differences in growth, geographical location, and time of
harvesting. A practical addition to the definition is also to include other crude prod-
ucts derived from plants, which no longer show any organic structure, such as es-
sential oils, fatty oils, resins, and gums. Derived or isolated compounds in the pro-
cessed state such as extracts or even isolated purified compounds (e.g. strychnine
from Strychnos nux-vomica) or mixtures of compounds (e.g. abrin from Abrus precatorius)
are, as a rule, not included in the definition. Combinations with chemical-
30 2 Quality Control, Screening, Toxicity, and Regulation of Herbal Drugs
ly defined active substances or isolated constituents, and homeopathic prepara-
tions which frequently contain plants, are not regarded as herbal medicines. Their
production is already based on adequate quality control of the respective starting
materials. The following paragraphs will focus on quality control of herbal drugs in
compliance with the above definition.
In general, quality control is based on three important pharmacopeial defini-
tions:
Identity: Is the herb the one it should be?
Purity: Are there contaminants, e.g., in the form of other herbs which should not
be there?
Content or assay: Is the content of active constituents within the defined limits?
It is obvious that the content is the most difficult one to assess, since in most her-
bal drugs the active constituents are unknown. Sometimes markers can be used
which are, by definition, chemically defined constituents that are of interest for
control purposes, independent of whether they have any therapeutic activity or not
[46, 47]. To prove identity and purity, criteria such as type of preparation sensory
properties, physical constants, adulteration, contaminants, moisture, ash content
and solvent residues have to be checked. The correct identity of the crude herbal
material, or the botanical quality, is of prime importance in establishing the qual-
ity control of herbal drugs.
Identity can be achieved by macro- and microscopical examinations. Voucher
specimens are reliable reference sources. Outbreaks of diseases among plants may
result in changes to the physical appearance of the plant and lead to incorrect iden-
tification [40, 48]. At times an incorrect botanical quality with respect to the label-
ing can be a problem. For example, in the 1990s, a South American product labeled
as “Paraguay Tea” was associated with an outbreak of anticholinergic poisoning in
New York. Subsequent chemical analysis revealed the presence of a class of con-
stituents that was different from the metabolites normally found in the plant from
which Paraguay tea is made [49].
Purity is closely linked with the safe use of drugs and deals with factors such ash
values, contaminants (e.g. foreign matter in the form of other herbs), and heavy
metals. However, due to the application of improved analytical methods, modern
purity evaluation also includes microbial contamination, aflatoxins, radioactivity,
and pesticide residues. Analytical methods such as photometric analysis, thin layer
chromatography (TLC), high performance liquid chromatography (HPLC), and gas
chromatography (GC) can be employed in order to establish the constant composi-
tion of herbal preparations. Depending upon whether the active principles of the
preparation are known or unknown, different concepts such as “normalization ver-
sus standardization” have to be applied in order to establish relevant criteria for
uniformity.
Content or assay is the most difficult area of quality control to perform, since in
most herbal drugs the active constituents are not known. Sometimes markers can
be used. In all other cases, where no active constituent or marker can be defined
for the herbal drug, the percentage extractable matter with a solvent may be used
2.3 Quality Control of Herbal Drugs 31
as a form of assay, an approach often seen in pharmacopeias. The choice of the ex-
tracting solvent depends on the nature of the compounds involved, and might be
deduced from the traditional uses. For example, when a herbal drug is used to
make a tea, the hot water extractable matter, expressed as milligrams per gram of
air-dried material, may serve this purpose [18, 50].
A special form of assay is the determination of essential oils by steam distilla-
tion. When the active constituents (e.g. sennosides in Senna) or markers (e.g. alky-
damides in Echinacea) are known, a vast array of modern chemical analytical meth-
ods such as ultraviolet/visible spectroscopy (UV/VIS), TLC, HPLC, GC, mass spec-
trometry (MS), or a combination of GC and MS (GC/MS), can be employed [51].
Several problems not applicable to synthetic drugs influence the quality of her-
bal drugs:
Herbal drugs are usually mixtures of many constituents.
The active principle(s) is (are), in most cases unknown.
Selective analytical methods or reference compounds may not be available com-
mercially.
Plant materials are chemically and naturally variable.
Chemo-varieties and chemo cultivars exist.
The source and quality of the raw material are variable.
The methods of harvesting, drying, storage, transportation, and processing (for
example, mode of extraction and polarity of the extracting solvent, instability of
constituents, etc.) have an effect.
Strict guidelines have to be followed for the successful production of a quality her-
bal drug. Among them are proper botanical identification, phytochemical screen-
ing, and standardization. Quality control and the standardization of herbal medi-
cines involves several steps. The source and quality of raw materials, good agricul-
tural practices and manufacturing processes are certainly essential steps for the
quality control of herbal medicines and play a pivotal role in guaranteeing the qual-
ity and stability of herbal preparations [32, 35, 36, 47, 52–56].
The quality of a plant product is determined by the prevailing conditions during
growth, and accepted Good Agricultural Practices (GAP) can control this. These in-
clude seed selection, growth conditions, use of fertilizers, harvesting, drying and
storage. In fact, GAP procedures are, and will be, an integral part of quality control.
Factors such as the use of fresh plants, age and part of plant collected, period, time
and method of collection, temperature of processing, exposure to light, availability
of water, nutrients, drying, packing, transportation of raw material and storage,
can greatly affect the quality, and hence the therapeutic value of herbal medicines.
Apart from these criteria, factors such as the method of extraction, contamination
with microorganisms, heavy metals, and pesticides can alter the quality, safety, and
efficacy of herbal drugs. Using cultivated plants under controlled conditions in-
stead of those collected from the wild can minimize most of these factors [36, 38,
57–59].
Sometimes the active principles are destroyed by enzymic processes that contin-
ue for long periods from collection to marketing, resulting in a variation of compo-
32 2 Quality Control, Screening, Toxicity, and Regulation of Herbal Drugs
sition. Thus proper standardization and quality control of both the raw material
and the herbal preparations should be conducted.
Standardization involves adjusting the herbal drug preparation to a defined con-
tent of a constituent or a group of substances with known therapeutic activity by
adding excipients or by mixing herbal drugs or herbal drug preparations. Botanical
extracts made directly from crude plant material show substantial variation in com-
position, quality, and therapeutic effects. Standardized extracts are high-quality ex-
tracts containing consistent levels of specified compounds, and they are subjected
to rigorous quality controls during all phases of the growing, harvesting, and man-
ufacturing processes. No regulatory definition exists for standardization of dietary
supplements. As a result, the term “standardization” may mean many different
things. Some manufacturers use the term standardization incorrectly to refer to
uniform manufacturing practices; following a recipe is not sufficient for a product
to be called standardized. Therefore, the presence of the word “standardized” on a
supplement label does not necessarily indicate product quality. When the active
principles are unknown, marker substance(s) should be established for analytical
purposes and standardization. Marker substances are chemically defined constitu-
ents of a herbal drug that are important for the quality of the finished product.
Ideally, the chemical markers chosen would also be the compounds that are re-
sponsible for the botanical’s effects in the body.
There are two types of standardization. In the first category, “true” standardiza-
tion, a definite phytochemical or group of constituents is known to have activity.
Ginkgo with its 26% ginkgo flavones and 6% terpenes is a classic example. These
products are highly concentrated and no longer represent the whole herb, and are
now considered as phytopharmaceuticals. In many cases they are vastly more ef-
fective than the whole herb. However the process may result in the loss of efficacy
and the potential for adverse effects and herb–drug interactions may increase. The
other type of standardization is based on manufacturers guaranteeing the presence
of a certain percentage of marker compounds; these are not indicators of therapeu-
tic activity or quality of the herb.
In the case of herbal drug preparations, the production and primary processing
of the medicinal plant or herbal drug has a direct influence on the quality of the ac-
tive pharmaceutical ingredients (APIs). Due to the inherent complexity of natural-
ly growing medicinal plants and the limited availability of simple analytical tech-
niques to identify and characterize the active constituents solely by chemical or bi-
ological means, there is a need for an adequate quality assurance system. This as-
surance is also required during cultivation, harvesting, primary processing, han-
dling, storage, packaging, and distribution. Deterioration and contamination
through adulteration, especially microbial contamination, can occur at any one of
these stages. It is extremely important to establish good agricultural, harvesting,
and manufacturing practices for herbal starting materials in order to minimize
these undesirable factors.
In this regard producers, processors, and traders of medicinal plants or herbal
drugs have an obligation and a role to play. The manufacturers and suppliers of
herbal products should adhere to quality control standards and good manufactur-
2.3 Quality Control of Herbal Drugs 33
ing practices. Currently, only a few manufacturers adhere to complete quality con-
trol and good manufacturing procedures including microscopic, physical, chemi-
cal, and biological analysis. Organizations such as Health Canada help safeguard
Canadians’ health by carrying out premarket reviews of all drugs before they are
authorized for sale. The products available in the market are analyzed regularly to
ensure that they are free of unsafe ingredients and that the products actually con-
tain the ingredients indicated on the labels.
The potency and quality of an individual herbal product may be unclear because
of lack of regulation. It is obvious that for a given plant product its quality will also
be determined by the prevailing conditions during the growth cycle of the plant.
Therefore, for cultivated plants the GAP system has been introduced, under which
each step, including seed selection, growing conditions, use of fertilizers, and op-
timization of harvest time, harvesting, and drying, has to adhere to a set of criteria.
It is likely that GAP procedures will become an integral part of quality control in
the near future.
Quality control for efficacy and safety of herbal products is of paramount impor-
tance [14–16, 19, 20, 41–45]. Quality can be defined as the status of a drug that is
determined by identity, purity, content, and other chemical, physical, or biological
properties, or by the manufacturing processes. Quality control is a term that refers
to processes involved in maintaining the quality and validity of a manufactured
product. For the quality control of a traditional medicine, the traditional methods
are procured and studied, and documents and the traditional information about
the identity and quality assessment are interpreted in terms of modern assess-
ment. In general, all medicines, whether they are of synthetic or of plant origin,
should fulfill the basic requirements of being efficacious and safe, and this can be
achieved by suitable clinical trials. This applies both to the multinational pharma-
ceutical company conducting a multi-center, double-blind placebo-controlled study
with a herbal extract, and to the health practitioner in a rural village who applies a
locally produced herbal mixture.
Natural products in medicine constitute a vast array of “raw materials,” making
clear definitions important. Quality criteria are based on clear scientific definitions
of the raw material. The term “herbal drugs” denotes plants or plant parts that have
been converted into phytopharmaceuticals by means of simple processes involving
harvesting, drying, and storage [46]. Hence they are capable of variation. This vari-
ability is also caused by differences in growth, geographical location, and time of
harvesting. A practical addition to the definition is also to include other crude prod-
ucts derived from plants, which no longer show any organic structure, such as es-
sential oils, fatty oils, resins, and gums. Derived or isolated compounds in the pro-
cessed state such as extracts or even isolated purified compounds (e.g. strychnine
from Strychnos nux-vomica) or mixtures of compounds (e.g. abrin from Abrus precatorius)
are, as a rule, not included in the definition. Combinations with chemical-
30 2 Quality Control, Screening, Toxicity, and Regulation of Herbal Drugs
ly defined active substances or isolated constituents, and homeopathic prepara-
tions which frequently contain plants, are not regarded as herbal medicines. Their
production is already based on adequate quality control of the respective starting
materials. The following paragraphs will focus on quality control of herbal drugs in
compliance with the above definition.
In general, quality control is based on three important pharmacopeial defini-
tions:
Identity: Is the herb the one it should be?
Purity: Are there contaminants, e.g., in the form of other herbs which should not
be there?
Content or assay: Is the content of active constituents within the defined limits?
It is obvious that the content is the most difficult one to assess, since in most her-
bal drugs the active constituents are unknown. Sometimes markers can be used
which are, by definition, chemically defined constituents that are of interest for
control purposes, independent of whether they have any therapeutic activity or not
[46, 47]. To prove identity and purity, criteria such as type of preparation sensory
properties, physical constants, adulteration, contaminants, moisture, ash content
and solvent residues have to be checked. The correct identity of the crude herbal
material, or the botanical quality, is of prime importance in establishing the qual-
ity control of herbal drugs.
Identity can be achieved by macro- and microscopical examinations. Voucher
specimens are reliable reference sources. Outbreaks of diseases among plants may
result in changes to the physical appearance of the plant and lead to incorrect iden-
tification [40, 48]. At times an incorrect botanical quality with respect to the label-
ing can be a problem. For example, in the 1990s, a South American product labeled
as “Paraguay Tea” was associated with an outbreak of anticholinergic poisoning in
New York. Subsequent chemical analysis revealed the presence of a class of con-
stituents that was different from the metabolites normally found in the plant from
which Paraguay tea is made [49].
Purity is closely linked with the safe use of drugs and deals with factors such ash
values, contaminants (e.g. foreign matter in the form of other herbs), and heavy
metals. However, due to the application of improved analytical methods, modern
purity evaluation also includes microbial contamination, aflatoxins, radioactivity,
and pesticide residues. Analytical methods such as photometric analysis, thin layer
chromatography (TLC), high performance liquid chromatography (HPLC), and gas
chromatography (GC) can be employed in order to establish the constant composi-
tion of herbal preparations. Depending upon whether the active principles of the
preparation are known or unknown, different concepts such as “normalization ver-
sus standardization” have to be applied in order to establish relevant criteria for
uniformity.
Content or assay is the most difficult area of quality control to perform, since in
most herbal drugs the active constituents are not known. Sometimes markers can
be used. In all other cases, where no active constituent or marker can be defined
for the herbal drug, the percentage extractable matter with a solvent may be used
2.3 Quality Control of Herbal Drugs 31
as a form of assay, an approach often seen in pharmacopeias. The choice of the ex-
tracting solvent depends on the nature of the compounds involved, and might be
deduced from the traditional uses. For example, when a herbal drug is used to
make a tea, the hot water extractable matter, expressed as milligrams per gram of
air-dried material, may serve this purpose [18, 50].
A special form of assay is the determination of essential oils by steam distilla-
tion. When the active constituents (e.g. sennosides in Senna) or markers (e.g. alky-
damides in Echinacea) are known, a vast array of modern chemical analytical meth-
ods such as ultraviolet/visible spectroscopy (UV/VIS), TLC, HPLC, GC, mass spec-
trometry (MS), or a combination of GC and MS (GC/MS), can be employed [51].
Several problems not applicable to synthetic drugs influence the quality of her-
bal drugs:
Herbal drugs are usually mixtures of many constituents.
The active principle(s) is (are), in most cases unknown.
Selective analytical methods or reference compounds may not be available com-
mercially.
Plant materials are chemically and naturally variable.
Chemo-varieties and chemo cultivars exist.
The source and quality of the raw material are variable.
The methods of harvesting, drying, storage, transportation, and processing (for
example, mode of extraction and polarity of the extracting solvent, instability of
constituents, etc.) have an effect.
Strict guidelines have to be followed for the successful production of a quality her-
bal drug. Among them are proper botanical identification, phytochemical screen-
ing, and standardization. Quality control and the standardization of herbal medi-
cines involves several steps. The source and quality of raw materials, good agricul-
tural practices and manufacturing processes are certainly essential steps for the
quality control of herbal medicines and play a pivotal role in guaranteeing the qual-
ity and stability of herbal preparations [32, 35, 36, 47, 52–56].
The quality of a plant product is determined by the prevailing conditions during
growth, and accepted Good Agricultural Practices (GAP) can control this. These in-
clude seed selection, growth conditions, use of fertilizers, harvesting, drying and
storage. In fact, GAP procedures are, and will be, an integral part of quality control.
Factors such as the use of fresh plants, age and part of plant collected, period, time
and method of collection, temperature of processing, exposure to light, availability
of water, nutrients, drying, packing, transportation of raw material and storage,
can greatly affect the quality, and hence the therapeutic value of herbal medicines.
Apart from these criteria, factors such as the method of extraction, contamination
with microorganisms, heavy metals, and pesticides can alter the quality, safety, and
efficacy of herbal drugs. Using cultivated plants under controlled conditions in-
stead of those collected from the wild can minimize most of these factors [36, 38,
57–59].
Sometimes the active principles are destroyed by enzymic processes that contin-
ue for long periods from collection to marketing, resulting in a variation of compo-
32 2 Quality Control, Screening, Toxicity, and Regulation of Herbal Drugs
sition. Thus proper standardization and quality control of both the raw material
and the herbal preparations should be conducted.
Standardization involves adjusting the herbal drug preparation to a defined con-
tent of a constituent or a group of substances with known therapeutic activity by
adding excipients or by mixing herbal drugs or herbal drug preparations. Botanical
extracts made directly from crude plant material show substantial variation in com-
position, quality, and therapeutic effects. Standardized extracts are high-quality ex-
tracts containing consistent levels of specified compounds, and they are subjected
to rigorous quality controls during all phases of the growing, harvesting, and man-
ufacturing processes. No regulatory definition exists for standardization of dietary
supplements. As a result, the term “standardization” may mean many different
things. Some manufacturers use the term standardization incorrectly to refer to
uniform manufacturing practices; following a recipe is not sufficient for a product
to be called standardized. Therefore, the presence of the word “standardized” on a
supplement label does not necessarily indicate product quality. When the active
principles are unknown, marker substance(s) should be established for analytical
purposes and standardization. Marker substances are chemically defined constitu-
ents of a herbal drug that are important for the quality of the finished product.
Ideally, the chemical markers chosen would also be the compounds that are re-
sponsible for the botanical’s effects in the body.
There are two types of standardization. In the first category, “true” standardiza-
tion, a definite phytochemical or group of constituents is known to have activity.
Ginkgo with its 26% ginkgo flavones and 6% terpenes is a classic example. These
products are highly concentrated and no longer represent the whole herb, and are
now considered as phytopharmaceuticals. In many cases they are vastly more ef-
fective than the whole herb. However the process may result in the loss of efficacy
and the potential for adverse effects and herb–drug interactions may increase. The
other type of standardization is based on manufacturers guaranteeing the presence
of a certain percentage of marker compounds; these are not indicators of therapeu-
tic activity or quality of the herb.
In the case of herbal drug preparations, the production and primary processing
of the medicinal plant or herbal drug has a direct influence on the quality of the ac-
tive pharmaceutical ingredients (APIs). Due to the inherent complexity of natural-
ly growing medicinal plants and the limited availability of simple analytical tech-
niques to identify and characterize the active constituents solely by chemical or bi-
ological means, there is a need for an adequate quality assurance system. This as-
surance is also required during cultivation, harvesting, primary processing, han-
dling, storage, packaging, and distribution. Deterioration and contamination
through adulteration, especially microbial contamination, can occur at any one of
these stages. It is extremely important to establish good agricultural, harvesting,
and manufacturing practices for herbal starting materials in order to minimize
these undesirable factors.
In this regard producers, processors, and traders of medicinal plants or herbal
drugs have an obligation and a role to play. The manufacturers and suppliers of
herbal products should adhere to quality control standards and good manufactur-
2.3 Quality Control of Herbal Drugs 33
ing practices. Currently, only a few manufacturers adhere to complete quality con-
trol and good manufacturing procedures including microscopic, physical, chemi-
cal, and biological analysis. Organizations such as Health Canada help safeguard
Canadians’ health by carrying out premarket reviews of all drugs before they are
authorized for sale. The products available in the market are analyzed regularly to
ensure that they are free of unsafe ingredients and that the products actually con-
tain the ingredients indicated on the labels.
The potency and quality of an individual herbal product may be unclear because
of lack of regulation. It is obvious that for a given plant product its quality will also
be determined by the prevailing conditions during the growth cycle of the plant.
Therefore, for cultivated plants the GAP system has been introduced, under which
each step, including seed selection, growing conditions, use of fertilizers, and op-
timization of harvest time, harvesting, and drying, has to adhere to a set of criteria.
It is likely that GAP procedures will become an integral part of quality control in
the near future.
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