Quality, Safety and Efficacy of Herbal Medicines

Quality

Over the past decade the quality of herbal products has continued to be a major concern. The importance of quality in ensuring the safety and efficacy of herbal products has been reviewed extensively.^(44–48)

Problems with unregulated herbal products

The vast majority of quality–related problems are associated with unregulated herbal products. There is substantial evidence that many ethnic medicines, in particular, those used in traditional Chinese medicine (TCM) and traditional Asian medicines (Ayurvedic and Unani), lack effective quality controls and may give rise to serious public health concerns. The problems include deliberate or accidental inclusion of prohibited or restricted ingredients, substitution of ingredients, contamination with toxic substances and differences between the labelled and actual contents. These problems are further compounded by demand outstripping supply of good–quality ingredients, confusing nomenclature over plant species, cultural differences of view over toxicity and traditional practices such as substituting one ingredient for another having a reportedly similar action.

The MCA has established an ethnic medicines forum to encourage and assist the UK ethnic medicines sector to achieve improvements to safety and quality standards in relation to unlicensed ethnic medicines in advance of any improvements to the regulatory regime which might emerge from current policy initiatives within the EU on the traditional use directive.⁽⁴⁹⁾ Although individual herbs present in traditional Chinese medicines and traditional Asian medicines are not the subject of monographs in this book, they do illustrate the problems that may be associated with the quality and safety of herbal medicines.

Substitution and adulteration

Aristolochia

Inadvertent exposure to Aristolochia species in unlicensed herbal medicines has resulted in cases of nephrotoxicity and carcinogenicity in Europe, China, Japan and the USA. Concerns were first raised about the effects of products containing aristolochic acids in Belgium where, since 1993, over 100 cases of irreversible nephropathy have been reported in young women using a preparation claimed to aid weight loss. The nephrotoxicity was traced to the inadvertent use of the toxic Aristolochia fangchi root in the formulation as a substitute for Stephania tetrandra. Aristolochic acids, the toxic components of Aristolochia species, are known to be nephrotoxic, carcinogenic and mutagenic. A number of the Belgian patients have subsequently developed urothelial cancer as a result of exposure to the toxic aristolochic acids.^(50–53)

Seven cases of nephropathy involving substitution of Aristolochia fangchi and Stephania tetrandra have been reported in France.⁽¹⁰⁾ Toxicity has also resulted from the substitution of Aristolochia manshuriensis stem for the stem of Clematis and Akebia species.⁽¹⁰⁾ In the UK, two such cases of end–stage renal failure were reported in 1999.⁽⁵⁴⁾ Other cases have been reported in China (17 cases with 12 fatalities) and Japan (ten cases of renal failure).⁽¹⁰⁾ Also, the FDA has reported two cases of serious renal disease due to Aristolochia being substituted for Clematis species in a dietary supplement.⁽⁵⁵⁾

Substitution of one plant species for another, often of a completely different genus, is an established practice in TCM. Furthermore, herbal ingredients are traded using their common Chinese Pin Yin names, and this can lead to confusion. For example, the name Fang ji can be used to describe the roots of Aristolochia fangchi, Stephania tetrandra or Cocculus species, and the name Mu Tong can be used to describe the stem of Aristolochia manshuriensis, Clematis or Akebia species.

The widespread substitution with Aristolochia species in TCM products available in the UK has been confirmed in a recent MCA study which reported the presence of aristolochic acids in at least 40% of TCM products containing Fang ji and Mu Tong.⁽⁵⁶⁾

The problems associated with Aristolochia have prompted regulatory action world–wide and new legislation has been introduced in the UK to prohibit the use of Aristolochia species in unlicensed medicines in the UK (see above).

Digitalis

Cases of serious cardiac arrhythmias were reported in the USA in 1997 following the accidental substitution of plantain with Digitalis lanata.⁽⁵⁷⁾ Subsequent investigation revealed that large quantities of the contaminated plantain had been shipped to more than 150 manufacturers, distributors and retailers over a two–year period.

Podophyllum

Fourteen cases of podophyllum poisoning have been reported from Hong Kong following the inadvertent use of the roots Podophyllum hexandrum instead of Gentiana and Clematis species.⁽⁵⁸⁾ It is reported that this accidental substitution arose because of the apparent similarity in morphology of the roots.

Aconitum

Cases of cardiotoxicity resulting from the ingestion of Aconitum species used in TCM have been reported from Hong Kong.⁽⁵⁹⁾ In TCM, Aconitum rootstocks are processed by soaking or boiling them in water in order to hydrolyse the aconite alkaloids into their less toxic aconine derivatives. Toxicity can, however, result when such processes are uncontrolled and unvalidated. In the UK, the internal use of aconite is restricted to prescription only.

Adulteration with heavy metals/toxic elements and synthetic drugs

The adulteration of ethnic medicines with heavy metals/toxic elements and synthetic drugs continues to be a major international problem. A comprehensive review has summarised test results on products and case histories of patients who had experienced toxic effects.⁽⁴⁴⁾ Similar findings continue to be reported. In most cases involving synthetic drugs, the drugs are undeclared in the product and only come to light when the user experiences adverse effects which are sufficiently serious to warrant medical intervention. Exposure to the undeclared drug is revealed in the subsequent investigation of the clinical case.

The situation with the heavy metals/toxic elements differs in that whilst these ingredients may arise from the plant ingredients themselves or be introduced as trace contaminants during processing, they are also frequently added intentionally and declared as ingredients within some TCM and Asian medicine formulations. The Chinese Pharmacopoeia, for example, includes monographs for realgar (arsenic disulfide), calomel (mercurous chloride), cinnabaris (mercuric sulfide) and hydrargyri oxydum rubrum (red mercuric oxide), and includes formulations for nearly 50 products that include one or more of these substances.⁽⁶⁰⁾

A US survey reported widespread inconsistencies and adulterations in imported Asian medicines.⁽⁶¹⁾ Of 260 imported products tested, at least 83 (32%) contained undeclared pharmaceuticals (most commonly ephedrine, chlorpheniramine, methyltestosterone and phenacetin) or heavy metals (lead, arsenic or mercury). Another survey found evidence of a continuing problem, with 10% of 500 OTC products testing positive for undeclared drugs and/or toxic amounts of lead, mercury or arsenic.⁽⁶²⁾

Elsewhere, health departments have reported similar conclusions based on their findings. A survey conducted in Singapore between 1990 and 1997 on TCM products reported that 42 different products were found to contain excessive amounts of heavy metals (mercury, lead, arsenic) and that 32 different TCM products were found to contain a total of 19 drugs.⁽⁶³⁾ In total, 93 cases of excessive content of toxic heavy metals and undeclared drugs were detected. The drugs detected included berberine, antihistamines (chlorpheniramine, promethazine, cyproheptadine), non–steroidal anti–inflammatory drugs (diclofenac, indomethacin, ibuprofen), analgesic antipyretics (paracetamol, dipyrone), corticosteroids (prednisolone, dexamethasone, fluocinonide), sympathomimetics agents (ephedrine), bronchodilators (theophylline), diuretics (hydrochlorthiazide) and the antidiabetic phenformin. A study in Taiwan found that more than 20% of 2609 products were found to be adulterated with synthetic drugs, most commonly caffeine, paracetamol, indomethacin and hydrochlorthiazide.⁽⁶⁴⁾

Other examples of adultered products come from a report from the Singapore Ministry of Health which identified sildenafil in two Chinese proprietary medicines,⁽⁶⁵⁾ and a report from the USA FDA which described the recall of a herbal product after traces of chlordiazepoxide were found in the capsules.⁽⁶⁶⁾ In 2001, the UK MCA reported presence of mercury (due to the inclusion of cinnabaris) in samples of the product Shugan Wan on the UK market.⁽⁴⁹⁾

Cases of toxicity associated with synthetic drugs present in ethnic medicines include a case of poisoning in Hong Kong resulting from the use of a TCM product containing anticonvulsant agents (phenytoin, carbamazepine and valproate).⁽⁶⁷⁾ In 2000, the USA FDA issued a public health warning on five herbal products following adverse effects in patients.⁽⁶⁸⁾ The products were found to contain the antihyperglycaemic prescription drugs glibenclamide and phenformin. In March 2001, the UK MCA reported a serious case of hypoglycaemic coma in a patient who had taken a TCM product, Xiaoke Wan, which contained glibenclamide.⁽⁶⁹⁾

Cases of toxicity associated with heavy metals in ethnic medicines include a patient from Taiwan who developed a unique syndrome of multiple renal tubular dysfunction after taking a Chinese herbal medicine contaminated with cadmium.⁽⁷⁰⁾ In the USA, two cases of alopecia and sensory polyneuropathy resulting from thallium in a TCM product have been reported.⁽⁷¹⁾ In the UK, cases have been reported of two patients with heavy metal intoxication following ingestion of an Indian remedy containing inorganic arsenic and mercury,⁽⁷²⁾ and of a patient with lead poisoning after exposure to an Indian medicine containing toxic amounts of lead, arsenic and mercury.⁽⁷³⁾ In a case reported from Macau, death of a 13–year–old girl from arsenic poisoning has been linked with a Chinese herbal product Niu Huang Chieh Tu Pien.⁽⁷⁴⁾

Quality of regulated herbal products

Compared with conventional preparations, herbal medicinal products present a number of unique problems when quality aspects are considered. These arise because of the nature of the herbal ingredients, which are complex mixtures of constituents, and it is well documented that concentrations of plant constituents can vary considerably depending on environmental and genetic factors. Furthermore, the constituents responsible for the claimed therapeutic effects are frequently unknown or only partly explained and this precludes the level of control which can routinely be achieved with synthetic drug substances in conventional pharmaceuticals. The position is further complicated by the traditional practice of using combinations of herbal ingredients, and it is not uncommon to have as many as five herbal ingredients in one product.

In recognition of the special problems associated with herbal medicinal products, the CPMP has issued specific guidelines dealing with quality aspects and manufacture.^(26,28) These guidelines have recently been updated by the CPMP Quality Working Party (QWP) and the EMEA HMPWP. In addition, a new guideline has been developed on specifications ‘Note for guidance on specifications: test procedures and acceptance criteria for herbal drugs, herbal drug preparations and herbal medicinal products (CPMP/QWP/2820/00)’.⁽²⁷⁾ The EMEA HMPWP has also developed the guidance document ‘Points to consider on Good Agricultural and Collection Practice for starting materials of herbal origin’.⁽⁷⁵⁾

The CPMP Guidelines highlight the need for good control of both the starting materials and the finished product, and emphasise the importance of good manufacturing practice in the manufacture of herbal medicinal products.

The WHO has also published guidelines dealing with the quality control of medicinal plant materials.⁽⁷⁶⁾

European Pharmacopoeia

Since its creation in 1964, the European Pharmacopoeia (Ph Eur) has devoted part of its work to the establishment of monographs on herbal drugs which are used either in their natural state after drying or extraction, or for the isolation of natural active ingredients. The Ph Eur includes over 120 monographs on herbal drugs, and a similar number of monographs are under development. Many general methods of analysis are also described in the Ph Eur, including tests for pesticides and for microbial contamination.⁽⁷⁷⁾

Herbal ingredients

Control of the starting materials is essential in order to ensure reproducible quality of herbal medicinal products.^(78–81) The following points are to be considered in the control of starting materials.

Authentication and reproducibility of herbal ingredients

The problems associated with unregulated herbal products, as illustrated above, highlight the major public health issues that can arise when their herbal ingredients have not been authenticated correctly. Herbal ingredients must be accurately identified by macroscopical and microscopical comparison with authentic material or accurate descriptions of authentic herbs.⁽⁷⁹⁾ It is essential that herbal ingredients are referred to by their binomial Latin names of genus and species; only permitted synonyms should be used. Even when correctly authenticated, it is important to realise that different batches of the same herbal ingredient may differ in quality due to a number of factors.

Inter- or intraspecies variation For many plants, there is considerable inter- and intraspecies variation in constituents, which is genetically controlled and may be related to the country of origin.
Environmental factors The quality of a herbal ingredient can be affected by environmental factors, such as climate, altitude and growing conditions.
Time of harvesting For some herbs the optimum time of harvesting should be specified as it is known that the concentrations of constituents in a plant can vary during the growing cycle or even during the course of a day.
Plant part used Active constituents usually vary between plant parts and it is not uncommon for a herbal ingredient to be adulterated with parts of the plant not normally utilised. In addition, plant material that has been previously subjected to extraction and is therefore ‘exhausted’ is sometimes used to increase the weight of a batch of herbal ingredient.
Post–harvesting factors Storage conditions and processing treatments can greatly affect the quality of a herbal ingredient. Inappropriate storage after harvesting can result in microbial contamination, and processes such as drying may result in a loss of thermolabile active constituents.
Adulteration/substitution Instances of herbal remedies adulterated with other plant material and conventional medicines, and the consequences of this, have been discussed above. In particular, the serious public health consequences that may arise from the substitution of herbal ingredients by toxic Aristolochia species have been highlighted. Reports of herbal products devoid of known active constituents have reinforced the need for adequate quality control of herbal remedies.
Identity tests In order to try to ensure the quality of licensed herbal medicines, it is essential therefore not only to establish the botanical identity of a herbal ingredient but also to ensure batch–to–batch reproducibility. Thus, in addition to macroscopical and microscopical evaluation, identity tests are necessary. Such tests include simple chemical tests, e.g. colour or precipitation and chromatographic tests. Thin–layer chromatography is commonly used for identification purposes but for herbal ingredients containing volatile oils a gas–liquid chromatographic test may be used. Although the aim of such tests is to confirm the presence of active principle(s), it is frequently the case that the nature of the active principle has not been established. In such instances chemical and chromatographic tests help to provide batch–to–batch comparability and the chromatogram may be used as a ‘fingerprint’ for the herbal ingredient by demonstrating the profile of some common plant constituents such as flavonoids.
Assay For those herbal ingredients with known active principles, an assay should be established in order to set the criterion for the minimum accepted percentage of active substance(s). Such assays should, wherever possible, be specific for individual chemical substances and high–pressure liquid chromatography or gas–liquid chromatography are the methods of choice. Where such assays have not been established then non–specific methods such as titration or colorimetric assays may be used to determine the total content of a group of closely related compounds.

Contaminants of herbal ingredients

Herbal ingredients should be of high quality and free from insect, other animal matter and excreta. It is not possible to remove completely all contaminants and hence specifications should be set in order to limit them:

Ash values Incineration of a herbal ingredient produces ash which constitutes inorganic matter. Treatment of the ash with hydrochloric acid results in acid–insoluble ash which consists mainly of silica and may be used to act as a measure of soil present. Limits may be set for ash and acid–insoluble ash of herbal ingredients.
Foreign organic matter It is not possible to collect a herbal ingredient without small amounts of related parts of plant or other plants. Standards should be set in order to limit the percentage of such unwanted plant contaminants.
Microbial contamination Aerobic bacteria and fungi are normally present in plant material and may increase due to faulty growing, harvesting, storage or processing. Herbal ingredients, particularly those with high starch content, may be prone to increased microbial growth. It is not uncommon for herbal ingredients to have aerobic bacteria present at 10²–10⁸ colony forming units per gram. Pathogenic organisms including Enterobacter, Enterococcus, Clostridium, Pseudomonas, Shigella and Streptococcus have been shown to contaminate herbal ingredients. It is essential that limits be set for microbial contamination and the Ph Eur now gives non–mandatory guidance on acceptable limits.⁽⁷⁷⁾
Pesticides Herbal ingredients, particularly those grown as cultivated crops, may be contaminated by DDT (dichlorodiphenyltrichloroethane) or other chlorinated hydrocarbons, organophos phates, carbamates or polychlorinated biphenyls. Limit tests are necessary for acceptable levels of pesticide contamination of herbal ingredients. The Ph Eur includes details of test methods together with mandatory limits for 34 potential pesticide residues.⁽⁷⁷⁾
Fumigants Ethylene oxide, methyl bromide and phosphine have been used to control pests which contaminate herbal ingredients. The use of ethylene oxide as a fumigant with herbal drugs is no longer permitted in Europe.
Toxic metals Lead, cadmium, mercury, thallium and arsenic have been shown to be contaminants of some herbal ingredients. Limit tests for such toxic metals are essential for herbal ingredients.
Other contaminants As standards increase for the quality of herbal ingredients it is possible that tests to limit other contaminants such as endotoxins, mycotoxins and radionuclides will be utilised to ensure high quality for medicinal purposes.

Herbal products

Quality assurance of herbal products may be ensured by control of the herbal ingredients and by adherence to good manufacturing practice standards. Some herbal products have many herbal ingredients with only small amounts of individual herbs being present. Chemical and chromatographic tests are useful for developing finished product specifications. Stability and shelf life of herbal products should be established by manufacturers. There should be no differences in standards set for the quality of dosage forms, such as tablets or capsules, of herbal medicines from those of other pharmaceutical preparations.

The quality of an unlicensed herbal remedy will not have been assessed by a Regulatory Authority and may thus potentially affect the safety and efficacy of the product. In view of this, it may be concluded that a pharmacist should only sell or recommend herbal medicinal products that hold a product licence. However, the majority of herbal medicinal products are only available as unlicensed products. When deciding upon the suitability of such products, a pharmacist should consider the intended use and the manufacturer. It is highly likely that unlicensed herbal remedies manufactured by an established pharmaceutical company will have been subjected to suitable in–house quality control procedures.