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Quality assurance of pharmaceuticals

A compendium of guidelines and related materials Volume 2: 
Good manufacturing practices and inspection

 

WHO good manufacturing practices: specific pharmaceutical products
Sterile pharmaceutical products
Biological products
Investigational pharmaceutical products for clinical trials in humans
Herbal medicinal products

 

Herbal medicinal products

1. Glossary

The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.

constituents with known therapeutic activity
Substances or groups of substances which are chemically defined and known to contribute to the therapeutic activity of a plant material or of a preparation.

herbal medicinal product
Medicinal product containing, as active ingredients, exclusively plant material and/or preparations. This term is generally applied to a finished product. If it refers to an unfinished product, this should be indicated.

markers
Constituents of a medicinal plant material which are chemically defined and of interest for control purposes. Markers are generally employed when constituents of known therapeutic activity are not found or are uncertain, and may be used to calculate the quantity of plant material or preparation in the finished product. When starting materials are tested, markers in the plant material or preparation must be determined quantitatively.

medicinal plant
A plant (wild or cultivated) used for medicinal purposes.

medicinal plant material (crude plant material, vegetable drug)
Medicinal plants or parts thereof collected for medicinal purposes.

plant preparations
Comminuted or powdered plant material, extracts, tinctures, fatty or essential oils, resins, gums, balsams, expressed juices, etc., prepared from plant material, and preparations whose production involves a fractionation, purification or concentration process, but excluding chemically defined isolated constituents. A plant preparation can be regarded as the active ingredient whether or not the constituents having therapeutic activities are known.

2. General

Unlike conventional pharmaceutical products, which are usually prepared from synthetic materials by means of reproducible manufacturing techniques and procedures, herbal medicinal products are prepared from material of plant origin which may be subject to contamination and deterioration, and may vary in composition and properties. Furthermore, in the manufacture and quality control of herbal medicinal products, procedures and techniques are often used which are substantially different from those employed for conventional pharmaceutical products.

The control of the starting materials, storage and processing assumes particular importance because of the often complex and variable nature of many herbal medicinal products and the number and the small quantity of defined active ingredients present in them.

3. Premises

Storage areas

Medicinal plant materials should be stored in separate areas. The storage area should be well ventilated and equipped in such a way as to protect against the entry of insects or other animals, especially rodents. Effective measures should be taken to limit the spread of animals and microorganisms introduced with the plant material and to prevent cross-contamination. Containers should be located in such a way as to allow free air circulation.

Special attention should be paid to the cleanliness and good maintenance of the storage areas, particularly when dust is generated.

The storage of plants, extracts, tinctures and other preparations may
require special conditions of humidity and temperature or protection from light; steps should be taken to ensure that these conditions are provided and monitored.

Production area

To facilitate cleaning and to avoid cross-contamination whenever dust is generated, special precautions should be taken during the sampling, weighing, mixing and processing of medicinal plants, e.g. by the use of dust extraction or dedicated premises.

4. Documentation

Specifications for starting materials

In addition to the data called for in sections 14 and 18 of "Good manufacturing practices for pharmaceutical products"(1), the specifications for medicinal plant materials should as far as possible include the following:

The botanical name, with reference to the authors.

Details of the source of the plant (country or region of origin, and where applicable, method of cultivation, time of harvesting, collection procedures, possible pesticides used, etc.).

Whether the whole plant or only a part is used.

When dried plant is purchased, the drying system.

A description of the plant material based on visual and/or microscopical inspection.

Suitable identification tests including, where appropriate, identification tests for known active ingredients or markers.

The assay, where appropriate, of constituents of known therapeutic activity or markers.

Suitable methods for the determination of possible pesticide contamination and the acceptable limits for such contamination.

The results of tests for toxic metals and for likely contaminants, foreign
materials, and adulterants.

The results of tests for microbial contamination and aflatoxins.

Any treatment used to reduce fungal/microbial contamination or other infestation should be documented. Instructions on the conduct of such procedures should be available and should include details of the process, tests and limits for residues.

Qualitative and quantitative requirements

These should be expressed in the following ways:

1. Medicinal plant material: (a) the quantity of plant material must be stated; or
(b) the quantity of plant material may be given as a range, corresponding to
a defined quantity of constituents of known therapeutic activity.

Example:
Name of active ingredient
Sennae folium
Quantity
(a) 900 mg or (b) 830–1000 mg, corresponding to 25 mg of hydroxyanthracene
glycosides, calculated as sennoside B

2. Plant preparation:
(a) the equivalent quantity or the ratio of plant material to plant preparation
must be stated (this does not apply to fatty or essential oils); or
(b) the quantity of the plant preparation may be given as a range, corresponding to a defined quantity of constituents with known therapeutic activity (see example).

The composition of any solvent or solvent mixture used and the physical state of the extract must be indicated.

If any other substance is added during the manufacture of the plant preparation to adjust the level of constituents of known therapeutic activity, or for any other purpose, the added substance(s) must be described as "other ingredients" and the genuine extract as the "active ingredient".

Example:
Name of active ingredient

Sennae folium
Quantity
(a) 125 mg ethanolic extract (8:1) or 125 mg ethanolic extract, equivalent to
1000 mg of Sennae folium or (b) 100–130 mg ethanolic extract (8:1), corresponding
to 25 mg of hydroxyanthracene glycosides, calculated as sennoside B

Other ingredient
Dextrin 20–50 mg

Specifications for the finished product

The control tests for the finished product must be such as to allow the qualitative and quantitative determination of the active ingredients. If the therapeutic activity of constituents is known, this must be specified and determined quantitatively. When this is not feasible, specifications must be based on the determination of markers.

If either the final product or the preparation contains several plant materials and a quantitative determination of each active ingredient is not feasible, the combined content of several active ingredients may be determined. The need for such a procedure must be justified.

Processing instructions

The processing instructions should list the different operations to be performed on the plant material, such as drying, crushing and sifting, and also include the temperatures required in the drying process, and the methods to be used to control fragments or particle size. Instructions on sieving or other methods of removing foreign materials should also be given. Details of any process, such as fumigation, used to reduce microbial contamination, together with methods of determining the extent of such contamination, should also be given.

For the production of plant preparations, the instructions should specify any vehicle or solvent that may be used, the times and temperatures to be observed during extraction, and any concentration methods that may be required.

5. Quality control

The personnel of quality control units should have particular expertise in herbal medicinal products to be able to carry out identification tests, and check for adulteration, the presence of fungal growth or infestations, lack of uniformity in a consignment of medicinal plant materials, etc.

Reference samples of plant materials must be available for use in comparative tests, e.g. visual and microscopic examination and chromatography.

Sampling

Sampling must be carried out with special care by personnel with the necessary expertise since medicinal plant materials are composed of individual plants or parts of plants and are therefore heterogeneous to some extent.

Further advice on sampling, visual inspection, analytical methods, etc., is given in Quality control methods for medicinal plant materials (2).

6. Stability tests

It will not be sufficient to determine the stability only of the constituents with known therapeutic activity, since plant materials or plant preparations in their entirety are regarded as the active ingredient. It must also be shown, as far as possible, e.g. by comparisons of chromatograms, that the other substances present are stable and that their content as a proportion of the whole remains constant.

If a herbal medicinal product contains several plant materials or preparations of several plant materials, and it is not feasible to determine the stability of each active ingredient, the stability of the product should be determined by methods such as chromatography, widely used assay methods, and physical and sensory or other appropriate tests.

References

1. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:44–52; 75–76 (WHO Technical Report Series, No. 823).

2. Quality control methods for medicinal plant materials. Geneva, World Health Organization, 1992 (unpublished document WHO/PHARM/92.559/rev. 1; available on request from Health Technology and Pharmaceuticals, World Health Organization, 1211 Geneva 27, Switzerland).

 

Footnotes

1 Good manufacturing practices for pharmaceutical products, Part Three, section 17. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:59–72 (WHO Technical Report Series, No. 823). The original numbering has been retained.

2 Parts One and Two, Part Three, section 18, and the Introductory note, General considerations and Glossary of Good manufacturing practices for pharmaceutical products are reproduced elsewhere in this volume (see pp. 6–13, 13–45, 46–53, 75–83).

3 Good manufacturing practices for biological products. In: WHO Expert Committee on Biological Standardization. Forty-second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical Report Series, No. 822) and WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1993, Annex 3 (WHO Technical Report Series, No. 834).

4 Good manufacturing practices: supplementary guidelines for the manufacture of investigational pharmaceutical products for clinical trials in humans. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 7 (WHO Technical Report Series, No. 863).

5 Guidelines for the assessment of herbal medicines are provided in Quality assurance of pharmaceuticals: a compendium of guidelines and related materials. Vol. 1. Geneva, World Health Organization, 1997:31–37.

6 Good manufacturing practices: supplementary guidelines for the manufacture of herbal medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Heath Organization, 1996, Annex 8 (WHO Technical Report Series, No. 863).  p.134-139

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