Chapter 9 Production, standardization and quality control
• pure compounds, which are often isolated from botanical drugs (and which are not considered to be herbal medicines)
• traditionally used medicinal plants, loose or in teabags to form infusions, including ‘instant teas’, and tinctures, ethanolic extracts, essential oils, fatty acids and dried extracts
• cut or powdered botanical crude drugs (generally simply called crude drug throughout the text), used as such (i.e. unprocessed)
• non-standardized extracts, with varying information about quality and, consequently, sometimes uncertain information about clinical efficacy and pharmacological effects
• standardized extracts, generally with relatively well-established clinical and pharmacological profiles.
Here a very short overview is given of the whole process, from the agricultural production of materials collected from the wild, to the processing and production of the pharmaceutical product or health-food supplement. A more detailed discussion is beyond the scope of this introduction, but can be found, for example, in Evans (2009).
In all cases, the basis for drug production is the botanical drug (see Chapter 2), which can be defined as:
dried parts of entire plants, plants organs, or parts of plant organs for use as medicines, aromatics and spices, or as excipients used in the production of pharmaceuticals. A typical example is the flower of camomile (Matricaria recutita)
Isolated products obtained directly from plants but which no longer have an organ structure, such as essential and fatty oils, balsams, etc. An example is the exudate of the leaves of aloe [Aloe vera (L.) Burm. f., or Aloe barbadensis Mill.], obtained by cutting the fleshy leaves and collecting the resulting liquid, which is called ‘aloes’ when dried.
Biological resources and conservation
• Problems in obtaining a consistent quality of product, including the risk of adulteration
• Over-exploitation of native populations of certain plant species.
More than half of all medicinally used species are still collected from the wild, including the less frequently used species. An example of an over-exploited resource collected from the wild has been discussed in detail by Lange (2000). Pheasant’s eye (false hellebore or Adonis vernalis L.) is a native of Southern and Central Europe and is used there for cases of minor cardiac arrhythmias. The plant is threatened not only by its pharmaceutical use (as a phytomedicine as well as a homoeopathic remedy), but also by its use as an ornamental plant and a dye source. Exploitation of Adonis vernalis affects many south-eastern European countries, including Hungary, Romania and the Ukraine. Importantly, detrimental (unsustainable) harvesting techniques are still used and there is a constant risk that the exploited biomass exceeds the sustainable levels and that techniques are used which harm the population severely (Lange 2000).
Agricultural and biotechnological production
• temperature and annual course of temperature
• rainfall (if it is not possible to irrigate the fields)
• soil characteristics and quality (edaphic factors)
• day length and sun characteristics
Moisture levels
All drugs are at risk of decaying if the humidity in the drug material exceeds 15%. Improperly stored botanical drugs have a musty smell and often change colour (green material turning yellow or brown). However, different levels of moisture are acceptable for each drug. For example, the moisture contents given in Table 9.1 are considered to be within the normal range and do not pose any problems for these drugs.
Table 9.1 Acceptable moisture content for storage of some botanical drugs (after Franz 1999)
Botanical drug | Moisture content (%) |
---|---|
Chamomile flower (Matricariae flos, from Matricaria recutita L.) | 8–10 |
Linseed (Lini semen from Linum usitatissimum L.) | 5–9 |
Digitalis leaf (Digitalis lanatae folium, from Digitalis lanata Ehrh.) | 8–12 |
Frangula bark (Frangulae cortex, from Rhamnus frangula L, syn. Frangula alnus Mill.) | 5–8 |
Thyme herb (Thymi herba, from Thymus vulgaris L.) | 8–11 |
Gentian rootstock (Gentianae radix, from Gentiana lutea L.) | 8–15 |
Fennel fruit (Foeniculi fructus, from Foeniculum vulgare Mill. subsp. vulgare) | 6–12 |
Pesticides
Pesticides are commonly used to prevent the infestation of the botanical material with large amounts of unwanted species of plants, insects or animals. These may cause harm or otherwise interfere with the production, storage, processing, transport and marketing of botanical drugs. Acceptable limits have been defined in the Eur. Ph. (Chapter 2.8.13). There is also a detailed description of the sampling methods and the relevant qualitative and quantitative methods. Importation of herbs from countries with less restrictive legislation on pesticides means that this material should be checked very carefully. Examples of relevant limits for some important pesticides are given in Table 9.2.
Table 9.2 Limits of some important pesticides allowed in botanical material
Pesticide | Concentration limit (mg/kg) |
---|---|
Aldrin and dieldrin (sum of) | 0.05 |
Chlordane (sum of cis-, trans– and oxychlordane) | 0.05 |
DDT (sum of various related compounds) | 1.0 |
Endrin | 0.05 |
Fonofos | 0.05 |
Malathion | 1.0 |
Parathion | 0.5 |
Permethrin | 1.0 |
Pyrethrins (sum of) | 3.0 |
Source: Eur. Ph. 2002.
In vitro cultivation
• as a starting point for investigating the biochemical basis of the biosynthesis of natural products and for breeding new varieties/strains
• as a basis for vegetative propagation of plants to be used as a phytomedicine or for isolating a pure natural product, especially if a consistent quality of the strains or a fungi- or virus-free culture is required. For example, high-yielding strains of Catharanthus and Dioscorea may be required, or the development and maintenance of pyrrolizidine-free strains of common comfrey (Symphytum officinale L.) and coltsfoot (Tussilago farfara L.), or virus-free Digitalis lanata Ehrh. cultures
• for the semi-synthetic production of some natural products (e.g. production of digoxin from digitoxin)
• for the direct synthesis of a medicinal natural product, although this is only rarely achieved by this method. Today, this process is restricted to the production of paclitaxel and its precursors (first isolated from the Pacific yew, Taxus brevifolia Nutt.) and shikonin (a dye and medicinal product used in Asian medicine from Lithospermum erythrorhizon Sieb. & Zucc.).
The Pacific yew as an example
The Pacific yew (Taxus brevifolia Nutt., Taxaceae) is a botanical drug which exemplifies all the various approaches for producing a medicinally used natural compound. In 1962 several samples of Taxus brevifolia Nutt. were collected at random for the National Cancer Institute (NCI) and the US Department of Agriculture. These samples were included in a large screening programme at the NCI. A potent cytotoxic effect was documented in one in vitro system. After a lengthy development process, clinical studies started 13 years later in 1984. It took a further 10 years before paclitaxel was approved for the treatment of anthracycline-resistant metastasizing mammary carcinomas. In the meantime the compound had been licensed for a variety of other cancers and semi-synthetic derivatives produced such as docetxel, which are also now employed (see also Chapter 8).
• Taxus brevifolia is a very slow-growing species, which produces the active ingredients only in very small amounts. Since paclitaxel was for many years isolated from the bark, trees had to be felled in order to obtain it. The requirement for paclitaxel increased dramatically with progress in the clinical development of the drug in the mid-1970s (the amount required to meet the annual therapeutic requirements of patients with ovarian cancer in the USA was estimated to be 15–20 kg). If other cancers common in the USA were to be treated with this compound, around 200–300 kg of the pure compound would have been required per year. This amount can be isolated from approximately 145,000 tons of bark. Collecting such amounts would have been completely unsustainable and would have resulted in the extinction of the species within a few years.
• In the 1990s the semi-synthetic production of paclitaxel from natural products in other Taxus spp. (10-desacetylbaccatin II isolated from the European yew, T. baccata) allowed for the production of large amounts of paclitaxel. Up to this point, a conflict of interest between conservation and medicinal use was unavoidable.
• Large-scale production using cell-culture techniques is now feasible and has been approved by the FDA. Today, most of the paclitaxel required is produced using fermentation technology (Goodman & Walsh 2001).
Drug preparation and extraction
There are many different types of drug preparations, including:
• fresh plant material, used popularly as an infusion or decoction
• dried and cut drug material, often used in industrial production
• dried and powdered drug material, commonly used as an infusion or decoction. If such material is to be used pharmaceutically it must comply with standards as defined in the monograph for the specific botanical drug. If no such monograph exists the material has to comply with the general monograph for herbal drugs (Eur. Ph. 2002, 01/2002-1433)
• extraction and subsequent bulk production of pure natural products (e.g. morphine, digoxin, digitoxin, camptothecin) or a mixture of closely related ones (e.g. sennosides from Senna, aescin from horse chestnut, quillaia saponins from soapbark) using validated, standard phytochemical techniques (chromatography, partitioning between solvents of differing polarity, precipitation, etc.)
• unstandardized tinctures are hydroalcoholic (or alcoholic) extracts of crude drug material used as a liquid botanical drug
• an extract prepared from dried drug material using defined solvent systems is processed into a variety of pharmaceutical products (e.g. tablets for crude extracts). Such extracts are often characterized by the drug:solvent ratio, which gives the relationship of the volume of solvent to the amount of drug extracted (e.g. 1:10) (see p. 154). In many high-quality products, these extracts are ‘standardized’ by mixing high- and low-yield material. By ‘spiking’ the extract with an enriched extract, a ‘modified’ extract with a defined range of active natural products is obtained (e.g. dry aloe extracts standardized to 19.0–21.0% of hydroxyanthracene derivatives calculated as barbaloin)
• a particularly interesting case is that of the so-called ‘special extracts’. A special extract is prepared by first extracting the drug with a defined solvent system and then processing the extract so that a well-defined extract with specific ranges of ingredients is obtained. These extracts have a significantly reduced percentage of unwanted compounds, and an increased percentage of compounds that contribute significantly to the pharmacological activity and clinical effectiveness. In the case of ginkgo leaves (Ginkgo folium, Ginkgo biloba L.), for example, the desired natural products include the flavone glycosides (16–26%) and the terpene lactones (5–7%); whereas the polyphenols, polysaccharides, and especially the ginkgolic acids, are less desirable constituents (for details see p. 158–159 and 249)
• there are several special methods of extraction; for example, the cold pressed extract of the rootstock of Echinacea species is developed into an immunostimulant product. The fresh rootstock is used for this and the sap is processed into a commercial botanical pharmaceutical. For material to be used pharmaceutically, the process must be validated.
Effect of preparation methods on content
Different methods of preparing botanical material and subsequent extraction result in extracts with differing composition and different concentrations of active (as well as undesired) ingredients. A wide range of factors both in relation to the production of the botanical starting material (the botanical drug) and its processing, extraction and formulation have an impact on the chemical composition and thus the pharmacological activity of a phytotherapeutic preparation (Fig. 9.1). Strictly speaking, for an assessment of the pharmacological effect and clinical effectiveness of a botanical drug, precise data on the composition of the extract are needed. Just as importantly, pharmacological or clinical data on two products can only be compared meaningfully if the composition of the extracts is known. This implies, for example, that a meta-analysis of clinical studies is only feasible if the botanical drug materials used are similar and the resulting extracts have a comparable composition, a consideration often omitted by authors of such studies.
Quality control and standardization
Quality control: general procedures
• the quality of the botanical material used, which in turn is influenced by a multitude of biogenic (e.g. infections with fungi) and climatic factors, and also includes the risk of contamination with heavy metals, pesticides, herbicides and the like (see above)
• the adequate processing of the fresh material, including drying, transportation and storage
• the use of appropriate and reproducible extraction techniques
• storage under appropriate conditions (generally dry, cool, in the dark)
• use of the material only within the generally accepted shelf-life of the botanical drug.
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