QUALITY OF HERBAL REMEDIES Guideline Title Quality of Herbal Remedies Legislative basis Directive 75/318/EEC as amended Date of first adoption November 1988 Date of entry into May 1989 force Status Last revised 1988 Previous titles/other None references Additional Notes This note for guidance concerns the application to herbal based remedies of Part 2 of the Annex to Directive 75/318/EEC as amended, with a view to the granting of a marketing authorisation for a medicinal product. CONTENTS A QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS B DESCRIPTION OF THE METHOD OF PREPARATION C CONTROL OF STARTING MATERIALS D CONTROL OF TESTS CARRIED OUT AT AN INTERMEDIATE STAGE OF THE MANUFACTURING PROCESS OF THE FINISHED PRODUCT E CONTROL TESTS ON FINISHED PRODUCT F STABILITY TESTS ANNEX 195
QUALITY OF HERBAL REMEDIES Note for guidance concerning the application of Part 2 of the Annex to Directive 75/318/EEC as amended. The special problems of herbal remedies and the differences between medicinal products containing chemically defined active substances are described in this note for guidance. Consistent quality for products of vegetable origin can only be assured if the starting materials are defined in a rigorous and detailed manner including especially the specific botanical identification of the plant material used. It is also important to know the geographical source and the conditions under which the vegetable substance is obtained to ensure material of consistent quality. Reference substances used in the control of all stages of the manufacturing process should be clearly defined. A QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS 1. In the case of a vegetable substance either a) the quantity of vegetable substance must be stated or b) the quantity of a vegetable substance may be given as a range corresponding to a defined quantity of constituents with known therapeutic activity. EXAMPLE a) Active substance 900 mg or b) Active substance 830-1000 mg, corresponding to 25 mg of hydroxyanthracene glycosides, calculated as Sennoside B Other substance 0-170 mg, corresponding to the quantity of Sennae folium 197
3AQ22a 2. In the case of a vegetable substance preparation either a) the equivalent quantity, or the ratio e.g. 8:1 of the vegetable substance to the vegetable substance preparation must be stated (this does not apply to fatty or essentials oils). or b) the quantity of the vegetable substance preparation may be given as a range corresponding to a defined quantity of constituents with know therapeutic activity (see example). The composition of any solvent or solvent mixture and the physical state of the extract must be indicated. If any other substance is added during the manufacture of the vegetable substance preparation to adjust the vegetable substance preparation to a certain level of constituents with known therapeutic activity, or for any other purpose, the added substance must be mentioned as an other substance and the genuine extract as the active substance. EXAMPLE a) Active substance 125 mg dry 60% ethanolic extract (8:1) or 125 mg equivalent to 1000 mg dry 60% ethanolic extract or b) Active substance dry 60% ethanolic extract (8:1) 100-130 mg, corresponding to 25 mg of hydroxyanthracene glycosides, calculated as Sennoside B Other substances Dextrin 20-50 mg 198
B DESCRIPTION OF THE METHOD OF PREPARATION The manufacturing process within the meaning of this section is the preparation of the finished product from the starting materials. The description should include details of any comminution or size reduction step, and details of any process such as fumigation etc. used to reduce the levels of microbial contamination together with the controls exercised over the process. If vegetable substance preparations are the starting material, the manufacture of the vegetable substance preparations and their controls do not belong under this section but under section C. C CONTROL OF STARTING MATERIALS 1. Control of the vegetable substance A complete monograph for each vegetable substance must be submitted, even if the starting material is a vegetable substance preparation. This also applies if the applicant is not the manufacturer of the preparation. In the case of fatty or essential oils a complete monograph for the vegetable substance is not required, only the scientific name of the parent plant and its part(s) have to be stated. If no monograph for the vegetable substance is given in a Pharmacopoeia referred to i n Directive 75/318/EEC as amended, Annex 1, a monograph on the vegetable substance must be supplied and should be set out in the same way where practicable, as the monographs on vegetable substances in the European Pharmacopoeia. This should include the botanical name and authority and the common name if used for labelling purposes. Information on the site of collection, the time of harvesting and stage of growth, treatment during growth with pesticides etc., and drying and storage conditions should be included if possible. The monograph should be established on the basis of recent scientific data. In the case of vegetable substances with constituents of known therapeutic activity, assays of their content (with test procedure) are required. The content must be included as a range, so as to ensure reproducibility of the quality of the finished product. As a general rule, vegetable substances must be tested for microbiological quality and for residues of pesticides and fumigation agents, radioactivity, toxic metals, likely contaminants and adulterants, etc., unless otherwise justified. Specifications and descriptions of the analytical procedures must be submitted, together with the limits applied. Reference samples of the vegetable substances must be available for use in comparative tests e.g. macro and microscopic examination, chromatography etc. 2. Control of vegetable substance preparations If the herbal remedy contains not the vegetable substance itself but a preparation, the monograph on the substance must be followed by a description and validation of the manufacturing process for the vegetable substance preparation. For each vegetable substance preparation, a monograph must be submitted. This must be established on the basis of recent scientific data and must give particulars of the characteristics, identification tests and purity tests. This has to be done e.g. by different appropriate chromatographic methods. If deemed necessary by the results of the analysis of the starting material, tests on microbiological quality, residues of pesticides, fumigation 199
3AQ22a agents, radioactivity, solvents and toxic metals have to be carried out. Quantitative determination (assay) of characteristic constituents is required. The content must be indicated with the lowest possible tolerance. The test methods must be described in detail. If preparations from vegetable substances with constituents with known therapeutic activity are standardised (i.e. adjusted to a certain level of constituents with known therapeutic activity) it must be stated how such standardisation is achieved. If another substance is used for this purpose, it is necessary to specify as a range the quantity that can be added. D CONTROL OF TESTS CARRIED OUT AT AN INTERMEDIATE STAGE OF THE MANUFACTURING PROCESS OF THE FINISHED PRODUCT Details of all control tests with details of test procedures and limits applied at any intermediate stages of the manufacturing processes are required, especially if these tests cannot be done in the finished product. E CONTROL TESTS ON FINISHED PRODUCT The control tests on the finished product must be such as to allow the qualitative and quantitative determination of the composition of the active substances and a specification has to be given which may be done by using markers if constituents with known therapeutic activity are unknown. In the case of vegetable substances or vegetable substance preparations with constituents of known therapeutic activity, these constituents must also be specified and quantitatively determined. If a herbal remedy contains several vegetable substances or preparations of several vegetable substances and it is not possible to perform a quantitative determination of each active substance, the determination may be carried out jointly for several active substances. The need for this procedure must be justified. F STABILITY TESTS Since the vegetable substance or vegetable substance preparation in its entirety is regarded as the active substance, a mere determination of the stability of the constituents with known therapeutic activity will not suffice. It must also be shown, as far as possible e.g. by means of appropriate fingerprint chromatograms, that other substances present in the vegetable substance or in the vegetable substance preparation are likewise stable and that their proportional content remains constant. If a herbal remedy contains several vegetable substances or preparations of several vegetable substances and if it is not possible to determine the stability of each active substance, the stability of the medicinal product should be determined by appropriate fingerprint chromatograms, appropriate overall methods of assay and physical and sensory tests or other appropriate tests. If the only evidence that can be submitted concerning the stability of the finished product consists of results of trials in which each active substance was separately tested in a 200
formulation corresponding to that of the finished product, the reasons why it is not possible to carry out stability tests on the finished product must be stated in full. It must furthermore be shown that interactions between the active substances and the excipients in the finished product are unlikely to occur. 201
3AQ22a ANNEX Glossary Herbal remedies (herbal medicines) are medicinal products containing as active substances exclusively plant material and/or vegetable substance preparations. Vegetable substances are plant material used for a medicinal purpose. A vegetable substance or a preparation thereof is regarded as one active substance in its entirety whether or not the constituents with therapeutic activity are known. Vegetable substance preparations are comminuted or powdered vegetable substances, extracts, tinctures, fatty or essential oils, expressed juices etc. prepared from vegetable substances, and preparations whose production involves a fractionation, purification or concentration process. However, chemically defined isolated constituents or their mixtures are not vegetable substance preparations. Other substances such as solvents, diluents, preservatives may form part of vegetable substance preparations. These substances must be indicated. Constituents with known therapeutic activity are chemically defined substances or groups of substances which are known to contribute to the therapeutic activity of a vegetable substance or of a preparation. Markers are chemically defined constituents of a vegetable substance which are of interest for control purposes. Markers may serve to calculate the quantity of vegetable substance or preparation in the finished product if that marker has been quantitatively determined in the vegetable substance or preparation when the starting materials were tested. 202