Quality and safety of herbal medicines: changing attitudes
towards control
As part of the Laboratories and Medicines Control
Section programme at the FIP Congress, on 6 September six papers reviewed
discrete aspects of the quality and safety of herbal medicinal products.
Introducing the topic, Professor Tony Moffat (chief scientist, Royal Pharmaceutical
Society) discerned a changing attitude to the regulation of herbal products
in Europe. He was satisfied that those items currently licensed as “medicines”
would be assured of quality, safety and efficacy but there were many unlicensed
products that could be freely sold provided that no medicinal claim was
made. Professor Moffat expected changes in legislation that would introduce
a third category, based on traditional use, and with current GMP (cGMP)
standards for their quality and efficacy and here he anticipated a key
role for pharmacopoeial standards.
Assuring the quality of herbs and herbal medicines
A lack of legislation for control of herbal products
was also of concern in Portugal, said Dr Ascensao Farinha (Laboratory
of Pharmaceutical Studies, Portugal). She distinguished pharmaceutical
quality, ie, reproducible production and concomitant standardised composition,
from therapeutic quality, which invoked approved efficacy and known constituents
of low toxicity. She noted the inherent variability in herbal raw materials,
and in their processing and manufacture.
In her laboratory, they had compared three species
of hypericum, by identification and in vitro comparative studies
and tabulated the correlation of therapeutic effect with biologically
active compounds. Dr Farinha described validation (accuracy, precision
and linearity) of a high performance liquid chromatographic (LC) method
that was selective for 13, mostly flavanoid, substances which were characterised
by their LC retention volume and diode array display (DAD). However, she
recognised “the big problem” of lack of authentic reference materials.
Dr Farinha reported two studies, one on marketed
ginseng products (constituents examined by LC/DAD and LC/double mass spectrometry
(MS) techniques, and compared with published mass spectra); and another
with 19 herbal medicines registered for human use (mostly freely available),
which had been checked for their alleged content of senna, hypericum,
ginseng, Ginkgo biloba and valerian. She had found that one-fifth
of “ginseng” products failed an identity test and half did not comply
with their assay claim. She reported particular problems with labelling:
39 per cent had no identification of the botanical part of the plant,
while 67 per cent bore no indication of active constituents. The accompanying
leaflets were no better, she said: 44 per cent had no indication of therapeutic
use.
Dr Farinha concluded that presentation could be
improved by labelling with the type, ratio and characterisation of botanical
extract, and some indication of analytical methodology. She recommended
more clinical studies on the efficacy of herbal medicines and hoped for
specific proposals for improved quality and transparency of composition.
Contamination of medicinal plants with pesticides
and heavy metals
A variety of European, and especially German, monographs
for herbal preparations were listed by Dr Syed Ali (Central Pharmaceutical
Laboratory, Germany), including 275 for traditional Chinese medicines
(TCMs). He noted that herbal products were increasingly popular in Germany
and that the Green Party, in particular, wanted better quality control.
He explained that residue limits for more than 400 pesticides were based
on the WHO guide for “acceptable daily intake”. He distinguished German
limits set for organo-chlorine compounds (with limits for residues in
fats and oils usually being slightly lower than those in medicinal plants)
and organophosphorus pesticides.
Dr Ali described simultaneous sample clean-up techniques
by solvent fractions, and end-analysis by capillary gas chromatography
(GC) and confirmation by a GC column of different polarity. He specified
a series of acceptable “reproducibility” and “repeatability” ranges according
to progressively smaller residue limits (1, 0.1 and 0.01mg/kg) and he
was pleased to find that no TCMs, in a recent study, had exceeded the
German limits for organochlorine compounds. From this, he inferred careful
use of common pesticides in the cultivating countries.
However, it appeared that “heavy metals were a problem”
when measured against the German guideline limits for lead, cadmium and
mercury (respectively, 0.5, 0.2 and 0.1mg/kg for most plant-derived medicines)
and somewhat lower levels permitted in medicines of animal origin. Dr
Ali emphasised the critical importance of obtaining a representative sample
of a herbal medicine before attempting the chemical digestion stage. He
discussed matching the end-analysis to the metal analyte and then supplied
an extensive tabulation of his 10-year experience of ranges of lead, mercury
and cadmium in 25 plant-derived medicines. He also reported typical levels
of these metals recently found in 17 TCMs, wherein most exceeded the mercury
limit and about half exceeded that for lead.
In subsequent discussion of his paper, Dr Ali said
he expected that the source of lead was probably motor fuel exhaust gases
but cadmium and mercury were more likely to be soil-borne contaminants.
He confirmed that radionuclide contamination had been detected in 100
plants in Germany in the season following the Chernobyl reactor incident
in 1986 but today, fortunately, significant activity was only found in
Iceland moss.
The reality of New Zealand
Experience from the southern hemisphere was reported
by Dr Ralph Richardson (Institute of Environmental Science and Research,
New Zealand). He explained that herbal remedies were not currently regulated
as medicines in New Zealand and they tended to be imported in an uncontrolled
way. Products originating, especially, from China, could be sold as food
supplements even if a therapeutic claim was made. As part of the NZ Ministry
of Health medicines testing programme, his pharmaceutical group had been
assessing the safety of alternative medicines over the past six years.
In the initial project, carried out over a four-year
period, the evaluation was limited to microbiological purity (using BP
microbial limits test), heavy metals, pesticide content and any presence
of “western” medicines. In the next two years, herbal products were assessed
from a selection made by the medicines control officers, from literature
or other warnings, from public complaints or from the night club scene.
His results indicated that a large number of the herbal products tested
exhibited a heavy metals content exceeding the recommended WHO limits
or were microbiologically contaminated or both. When the BP bio-criteria
were applied in terms of count rates, a total of 15 products contained
pathogens. However, he had found no products with pesticide residues exceeding
one-hundredth of the maximum levels recommended by WHO and only three
products had been shown to be adulterated with western medicines.
The results of tests on alternative herbal sports
supplements were well within the recommended limits proposed by the WHO
for foodstuffs. Herbal based products obtained from the night club scene
had indicated the presence of ephedrine and kava extracts, and one product
was shown to contain methylephedrine. Miscellaneous other products had
also been tested and had revealed the presence of sildenafil and chlorphenamine.
One product was implicated in the deaths of two people because of its
liver toxicity.
He reported that the NZ Ministry of Health was currently
working towards a joint agency with the Australian Therapeutic Goods Administration
and it seemed likely that herbal products would, in future, be regulated
in a similar way to the Australian “list” process. This requires a minimal
application for registration, which includes a review of potential toxicity
as well as confirmation of the product’s quality.
Methods of characterising herbal products
Eng Shi Ong (Health Sciences Authority, Singapore)
distinguished the examination of a single herb (such as ginseng), from
a possibly complex mixture of herbs, and from a medicinal presentations
such as pills or powders. For each category of product, there was a need
to fulfil regulatory guidelines, whereas following any accident they needed
a rapid universal extraction and suitable end-analysis. Having achieved
a homogeneous sample by sieving and blending, his procedure favoured a
Soxhlet solvent extraction followed by microwave assisted pressurised
liquid extraction (PLE) step, and then a modern “hyphenated” end analysis,
with a choice of GC-MS, LC-DAD or LC-MS. He was less enthusiastic about
capillary electrophoresis, which often showed plant matrix interference.
He reported that good precision had been achieved and he always used a
second, preferably different method, for confirmation. Dr Ong illustrated
use of his procedure by reference to separation of the highly polar and
renal toxic aristolochic acids I and II. In quantitative analyses, he
considered “unreliable” the practice of spiking herbal extracts with standard
additions of known components and he preferred to calibrate by use of
matrix standards of predetermined composition.
A pharmacopoeial role
The main purpose of establishing pharmacopoeias
for medicinal products for human and animal use had been to “set up standards
for listed products” asserted Professor Kelvin Chan (Hong Kong Baptist
University, China). However, his series of tabulations demonstrated the
properties of established orthodox drugs and medicines were quite different
from those of medicinal herbs and their products. Moreover, he showed,
different countries had differing pharmacopoeial approaches to regulatory
controls over the use of medicinal products.
Professor Chan said that recent WHO surveys and
reviews had confirmed that herbs and herbal products played an important
role in the health care of nearly 80 per cent of the world population,
particularly in developing countries. These preparations formed part of
treatment with traditional medicine, which had had a long history in many
developing ethnic communities. The use of herbs and herbal products presented
the sum total of the knowledge, skills and practices based on the theories,
beliefs and experiences indigenous to different cultures, whether their
mechanism of action was explicable or not. Many products were used generally
in the maintenance of health, as well as in the prevention, diagnosis,
improvement or treatment of physical and mental illnesses. He commented
that the practice of traditional herbal medicine varied greatly from region
to region, being influenced by factors such as culture, history, personal
attitudes and philosophy. In many cases, he said, the theory and application
were quite different from those of conventional medicine. Long historical
use of many practices of traditional medicine, including experience passed
on from generation to generation, had demonstrated the safety and efficacy
of traditional medicine.
Professor Chan reminded that medicinal herbs and
their ready made products had been used in China for thousands of years
for prevention and treatment of diseases, well before recently introduced
synthetic pharmaceuticals in orthodox medical practice. Historically,
there had been several stages of establishing and updating records of
human experience and various forms of pharmacopoeias had evolved in historical
Chinese medicine.
He deemed it important to establish that all medicinal
products used in humans and animals had proven quality, safety and efficacy.
Problems and difficulties had arisen with herbal products because the
actual bioactive components were seldom known. However, recent advances
in analytical chemistry, bioactivity screening and related disciplines,
had all helped elucidation of the complex compositions of medicinal herbs.
Now he saw it timely to review and update pharmacopoeias so as to include
the latest procedures, such as pattern recognition (“fingerprinting”)
for standardising listed products. Professor Chan compared pharmacopoeial
monographs from countries where medicinal herbs and herbal products were
widely used in the treatment and prevention of disease. For the way forward,
he suggested that future pharmacopoeias should take account of the recent
popularity of herbal medicines world-wide, thereby helping to set up guidelines
for controlling the quality, safety and efficacy aspects of herbs and
herbal products available to the public. He specifically called for inclusion
of modern analytical bioactivity profiles or finger prints, harmonised
criteria necessary in herbal pharmacopoeias and industrially relevant
pharmacopoeias for ready-made herbal products.
— Contributed by Professor Geoffrey Phillips, a former secretary of
the LMCS Section.
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