Articles

Herbal products: good manufacturing practice from raw material to finished product

A new system for the licensing of herbal products has been called for by the Royal Pharmaceutical Society's Science Committee working party on complementary and alternative medicine. This is one part of its presentation of evidence to the House of Lords Science and Technology Committee's inquiry into complementary and alternative medicine (see PJ, June 17, 2000, p898). The proposed system would be based on ensuring quality and safety; to meet quality requirements, products should be manufactured according to good manufacturing practice (GMP). Some herbal product manufacturers already manufacture products to GMP standards. Jo Barnes visited the ELISA partnership — a GMP facility for the extraction of St John's wort — in Ireland, and the new factory at Lichtwer Pharma AG's new production facility at its headquarters in Berlin, Germany, to follow the preparation of herbal medicines according to GMP from raw material to finished product

The ELISA partnership extraction facility is located at Ringaskiddy, County Cork, Ireland. The partnership is a joint venture between two well-established German companies, Dr Willmar Schwabe GmbH & Co (established in 1866) and Lichtwer Pharma AG (established in 1981). The facility represents a capital investment of around £20m, and employs around 40 staff. The joint venture was set up to combine the expertise of both companies in the extraction of the active ingredients from the plant Hypericum perforatum (St John's wort). Alongside this, maintenance activities, operation of utilities to support the processing operation (extraction), quality control activities, and administrative and other support activities are also carried out. Raw material St John's wort plants for use in the extraction process are grown in Europe (Germany, Bulgaria, Hungary, Poland, etc) and South America (mainly in Chile). In Europe, St John's wort flowers in June, so the raw material is sourced from a variety of different countries to ensure a year-round supply. Mr Martin Schneider (medicinal plant cultivation and purchasing manager) visits the suppliers to carry out inspections and to advise farmers on what fertilisers and pesticides, etc, are acceptable. The regimen is to use as little as possible, as all material is checked for chemical residues. Suppliers are usually visited once every year, or immediately if any special problems arise. This is to ensure that the production of material is carried out in accordance with with good agricultural practice (GAP) guidelines for medicinal plant cultivation. The raw material comprises approximately the top 25cm of H perforatum plants. The plants are harvested when in flower, and the material is then dried and packaged in bales or bulk bags. A sample of the material is sent to ELISA for testing and, if it is found acceptable, the batch is shipped to Ireland in closed shipping containers. Baled plants are stored in the warehouse. There are no specific storage requirements, for example, temperature control. The main requirement is that the plants are kept dry. Preparing the plant material for extraction involves transferring the bales on to a conveyor system leading to a unit which breaks up the compacted bales and finely chops the plant material into a form resembling tea leaves. The finely chopped material is then conveyed pneumatically via a pipe system to the extraction end ("wet" end) of the production building. Extraction A computer-controlled, counter-current, solvent extraction system is used to extract the active ingredients from the material into the methanol/water solvent. The prepared material and the solvent are input to sealed, agitated vessels where the extraction takes place. The output from the extraction, known as a miscella, is a mixture of the extract in methanol/water. Following extraction, the mixture passes on to the evaporation phase, during which the extract becomes concentrated before drying. Evaporation occurs under vacuum in a forced circulation evaporator. The evaporated methanol is condensed and the methanol distillate is fed back into the system for reuse in the extraction process. Around 99 per cent of the methanol is recovered for reuse. Furthermore, if the concentration of recovered methanol is low, it can be further concentrated and purified in the rectification system before reuse (see below).

Rectification system and solvent recovery Methanol from various stages of the extraction process, such as the methanol distillate from the evaporation process and the drying of the waste material, can be fed into the rectification system. The distillates are transferred to the tank farm methanol rectification feed tank from which they are fed into the rectification system. The system comprises a distillation column, distillation column condenser and distillate cooler. The rectification system produces a liquid distillate with a higher methanol concentration for subsequent reuse in the process. The "bottoms" from the distillation column are routed to the effluent treatment plant. As a result of the extraction and evaporation process design, and the rectification system, almost 100 per cent solvent recovery is possible. This minimises the volume of methanol used in the process, and the volume of waste methanol produced. Waste methanol is only generated if the process methanol or water becomes contaminated so that it cannot be used in the process.

Spent waste or fully extracted waste plant material from the process is discharged into a dryer which is also linked to the solvent recovery system. Methanol from the spent plant material is evaporated in the drying process and recovered for subsequent reuse in the process, again following rectification if necessary. Following extraction and evaporation, the extract is pumped to the "dry" end of the production building where it is dried in a continuous vacuum belt dryer. The dried product is then milled to a fine powder and stored in bulk containers while awaiting analysis. After analysis, the product is blended in a sealed container and packaged for shipment in plastic-lined drums. Around 100 drums of dried extract per week are generated. Quality control The manufacturing operations are regulated by the code of good manufacturing practices promulgated by the United States Food and Drug Administration. Thus, detailed analysis of all raw materials, finished products and in-process materials is carried out. Most of the analysis is conducted in the facility's quality control laboratory using a combination of wet chemical analysis and instrumentation, including gas chromatography and high-pressure liquid chromatography. Analyses include determination of the hypericin and hyperforin content of the extract at different stages of the extraction process. Environmental analysis, such as pH monitoring of effluent, is also carried out. Into quarantine Drums of dried extract are exported to Lichtwer Pharma AG's new DM70m (approximately £23m) GMP production facility in Berlin, Germany, as well as to other international health care and pharmaceutical markets, for formulation and tableting. Raw materials, which include excipients as well as hypericum extract, are received into a "goods in" area in the warehouse. All raw materials are given a computer-generated batch number and bar code specific for that batch so that they can be traced throughout the production process. Materials are held in quarantine until they have been released for use. Information regarding the quarantine status of the raw material is held on the bar code — this system ensures that raw materials still in quarantine cannot erroneously be used in production, as the bar code must be scanned at the production stage in order for equipment to operate. For active ingredients, a sample is taken from every container and analysed using near-infrared and infrared spectrophotometry. For each batch of excipients, randomised sampling of containers is undertaken. Once materials are released for use, a computer-generated system provides a warehouse location number and controls the use of materials on a "first in, first out" basis. The warehouse is temperature controlled at ground, middle and ceiling level, and is linked to a warning system to alert staff to deviations. Pest control is also carried out according to a standard operating procedure (SOP). Analyses done on raw materials include tests for heavy metals, pesticides and aflatoxins, as well as microbiological tests for aerobic bacteria, moulds, yeasts and Escherichia coli. In the grey zone: production The factory's GMP production facility comprises clean areas and a clean corridor system accessed by an air lock; clean areas in Germany are known as "grey zones". Operators are required to scrub hands before entering a clean area, and to wear protective clothing (overcoat, hat, overshoes and masks, goggles, protective ear wear and gloves, where necessary). All stages of the production process, including cleaning of equipment, are controlled by SOPs. The production process is computer controlled, and each stage involves scanning the specific bar code of the raw material (eg, St John's wort extract, excipients) before any production equipment can be operated. The bar code scanner is used to check that the correct raw material is being used, and that the material is in a room with the correct status, ie, clean. The computer system also instructs operators with regard to what weight of material to use, and each step of the production process filled in on batch documentation is also recorded on the computer. Materials for the day's work are transferred to a storage area and housed only on plastic pallets. After weighing, raw materials are conveyed pneumatically to an intermediate bulk container before mixing and blending. After the dry granulation stage, bins containing material for tableting are taken to a docking station from where the material is fed down to tablet presses. These include a Korsch Pharmapress 800 machine which is capable of producing one million tablets per hour. Samples for in-process controls are taken at the beginning of tableting and then every two hours while in operation; in-process control tests include weight, hardness, thickness, and diameter. Tablets are then transferred to a Driacoater 1600 sugar-coating machine with a capacity of 300kg of tablets. The machine injects sugar-coating suspension every three minutes, and each batch receives 60 to 70 coats over approximately an eight-hour period. Coated tablets are dried using equipment that sucks air through vessels containing the tablets. The next stage is sorting, when a machine sorts tablets by diameter and thickness; the rejection rate is usually between 1 and 3 per cent, and should not be greater than 5 per cent. Blistering of tablets and packaging into cartons is all carried out on one piece of equipment. The equipment incorporates a camera which views the tablet blisters and rejects any that are out of shape. Batch number and expiry date are stamped on to the blister foils before individual blisters and a patient information sheet are inserted into packs. The machine also assembles packs into "outers" and carries out a weight check which will reject an "outer" if the weight check detects that as little as one blister is missing. At the end of the production process, a quality control check is carried out on the batch before it can be released. In accordance with GMP, this includes checking batch number and expiry date, and results from in-process control tests for physical parameters, as well as verifying that two packs taken from the beginning of the batch correspond to two packs from the end of the batch. A check list is used to ensure that all necessary final batch documentation is present, such as the certificate of analysis and results of microbiological tests. Only when all requirements are met can the batch be signed off for release by specified personnel. Released batches are transferred to the warehouse for storage before distribution within Germany or export to countries around the world, including to the UK and the US. Phytopharmaceutical development In addition to the full-scale production facility, the Berlin site includes a small-scale production facility used for developing new formulations. The facility contains a single-punch-press tablet machine which produces the tablet core and which is used to investigate the effect of different excipients and different compression forces. There is a blending room, sugar-coating machine, film coater and physical testing room, where samples of formulations in development are subject to the same in-process controls, such as disintegration testing, as used in normal production. There is a separate area in production for the manufacture of clinical trials materials.

Jo Barnes is teaching and research fellow in the Centre for Pharmacognosy and Phytotherapy, School of Pharmacy, University of London, 29–39 Brunswick Square, London WC1N 1AX (e-mail jobarnes@cua.ulsop.ac.uk)

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