The Egyptian Guidelines for Registration of Herbal Medicines

May 31

2015

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Contents Introduction ................................................................................................................. 2

Purpose and objectives of the guidelines ......................................................................... 2

Specific objectives ........................................................................................................ 2

Definition of herbal medicines ....................................................................................... 3

Herbal substances: .................................................................................................... 3

Herbal preparations: ................................................................................................. 3

Classification of herbal medicines ................................................................................... 4

Minimum requirements for assessment of safety of herbal medicines ................................ 5

Safety category ......................................................................................................... 5

Specific requirements for assessment of safety of four categories of herbal medicines ..... 5

Minimum requirements for efficacy of herbal medicinal products ...................................... 7

Claims categories ...................................................................................................... 7

Minimum requirements for assessment of the efficacy of .............................................. 8

herbal medicines ....................................................................................................... 8

Quality assurance of herbal medicinal products ............................................................. 10

Coordinating quality control ..................................................................................... 10

· Adherence to GACP, GMP and GLP guidelines: ...................................................... 10

· Setting specifications: ......................................................................................... 10

· Quality control measures. ................................................................................... 11

Vitamins and minerals in herbal medicinal products for human use .................................. 13

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Introduction

The term “herbal medicine” is medicinal products that contain active ingredients aerial or underground parts of plants, or other plant materials, or combinations thereof, whether in the crude state or as plant preparations.

Herbal medicine represents an important component part of health care system for the population that relies on natural remedies for their health care needs. Currently, herbal medicines are used to treat a wide range of illnesses, including diabetes, diarrhea, HIV/AIDS, hypertension and microbial infections.

Purpose and objectives of the guidelines

The purpose of this document is to propose a framework for the registration of herbal medicines. The proposed framework is based on the criteria of pharmaceutical quality, safety of use and therapeutic efficacy, it should accelerate the registration and circulation of standardized herbal medicines of consistent quality.

Specific objectives

The specific objectives of the guidelines are as follows:

1. To set a definition of herbal medicines;

2. To propose a classification scheme for herbal medicines;

3. To propose general minimum regulatory requirements for the registration of herbal

medicines including minimum requirement to assess safety, efficacy and quality.

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Definition of herbal medicines

Any finished, labeled medicinal product (for oral , external or inhalation uses),

exclusively containing as active substances one or more herbal substances or one or

more herbal preparations, or one or more such herbal substances in combination with

one or more such herbal preparations; Herbal medicines may contain conventional

excipients in addition to the plant-based active ingredients. In some cases, they may

also contain, by tradition, natural organic or inorganic ingredients which are not of plant

origin. However, products to which chemically-defined active substances have been

added, including for example, synthetic compounds and/or isolated constituents from

herbal materials, are not considered to be herbal medicinal products.

Herbal medicinal products may contain vitamins/minerals as supplementary substances.

WHO- EMA- MHRA

Herbal substances:

All mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an

unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not

been subjected to a specific treatment are also considered to be herbal substances.

Herbal substances are precisely defined by the plant part used and the botanical name

according to the binomial system (genus, species, variety and author);

Herbal preparations:

They are obtained by subjecting herbal substances to treatments such as extraction,

distillation, expression, fractionation, purification, concentration or fermentation. These

include comminuted or powdered herbal substances, tinctures, extracts, essential oils,

expressed juices and processed exudates.

EMA

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Classification of herbal medicines

(WHO for East Asian)

Category 1: Indigenous herbal medicines

This category of herbal medicines is historically used in a local community or region and is very well known through long usage by the local population in terms of its composition, treatment and dosage. Detailed information on this category of TM, which also includes folk medicines, may or may not be available. It can be used freely by the local community or in the local region. However, if the medicines in this category enter the market or go beyond the local community or region in the country, they have to meet the requirements of safety and efficacy laid down in the Egyptian regulations for herbal medicines. Category 2: Herbal medicines in systems

Medicines in this category have been used for a long time and are documented with their special theories and concepts, and accepted by the countries. For example, Ayurveda, Unani and Siddha would fall into this category of TM. Category 3: Modified herbal medicines

These are herbal medicines as described above in categories 1 and 2, except that they have been modified in some way–either shape, or form including dose, dosage form, mode of administration, herbal medicinal ingredients, methods of preparation and medical indications. They have to meet the Egyptian regulatory requirements of safety and efficacy of herbal medicines. Category 4: Imported Herbal medicinal products

This category covers all imported finished products herbal medicines. Imported herbal medicines must be registered and marketed in a reference country of origin. The safety and efficacy data have to be submitted to and need to meet the requirements of safety and efficacy of regulation of herbal medicines Egypt.

Only Imported Herbal medicinal products from category 2,3 are allowed to register in Egypt,

Category 1 are allowed only for local manufacturers.

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Minimum requirements for assessment of safety of herbal medicines

(WHO)

Safety category

A drug is defined as being safe if it causes no known or potential harm to users. There are three categories of safety that need to be considered, as these would dictate the nature of the safety requirements that would have to be ensured. · Category 1: safety established by use over long time. (More than 30 years in Egypt) · Category 2: safe under specific conditions of use (such herbal medicines should be covered by well-established documentation) · Category 3: herbal medicines of uncertain safety (the safety data required for this class of drugs will be identical to that of any new substance)

Data will be required on the following: · Acute toxicity · Long-term toxicity Data may also be necessary on the following: · Organ-targeted toxicity · Immunotoxicity · Embryo/fetal and prenatal toxicity · Mutagenicity/genotoxicity · Carcinogenicity

Specific requirements for assessment of safety of four categories of herbal

medicines

Before any category of herbal medicine listed above is introduced into the market, the relevant safety category needs to be reviewed and the required safety data obtained, based on that particular safety category. Category 1: Indigenous herbal medicines These can be used freely by the local community or region, and no safety data would be required. However, if the medicines in this category are introduced into the market or moved beyond the local community or region, their safety has to be reviewed by the established national drug control agency. If the medicines belong to safety category 1,2 safety data are not needed. Medicines belonging to safety category 3, i.e. ‘herbal medicines of uncertain safety’, will be identical to that of any new substance. Category 2: Herbal medicines in systems The medicines in this category have been used for a long time and have been officially documented. Review of the safety category is necessary. If the medicines are in safety categories1 or 2, safety data would not be needed. If the medicines belong to safety category 3, they have to meet the requirements for safety of ‘herbal medicines of uncertain safety’. Category 3: Modified herbal medicines The medicines in this category can be modified in any way including dose, dosage form,

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Mode of administration, herbal medicinal ingredients, methods of preparation, or medical indications based on categories 1 and 2. The medicines have to meet the requirements of safety of herbal medicines or requirements for the safety of ‘herbal medicines of uncertain safety’, depending on the modification. Category 4. Imported products require safety data, which have to meet the requirements for safety of ‘herbal medicines of uncertain safety.

Requirements for safety of “new herbal medicines”

The safety data required for registration of new herbal medicines will be identical for any new substance:

•single-dose toxicity

•repeated-dose toxicity

Acute toxicity: to determine lethal dose in 50%(LD50) in different species of small animals.

Chronic toxicity: in varying does in large animals to determine the effect on development, vital organ functions, blood chemistry and picture.

•organ-targeted toxicity, if necessary

•immunotoxicity

•embryo/ foetal and prenatal toxicity, if necessary

•mutagenicity/ genotoxicity, if necessary

•carcinogenicity, if necessary

•local tolerance.

In special circumstances, such as new combinations of well-known substances, some of these studies may not be necessary.

Requirements for safety of traditional herbal medicines (Safety categories 1,2)

A literature search must be performed. This should include general literature such as traditional handbooks specific to the individual form of therapy, modern handbooks on phytotherapy, phytochemistry and pharmacognosy, articles published in scientific journals, official monographs such as WHO monographs, EU database monographs, national monographs and other authoritative data related to herbal medicines, if available, database searches in online or offline databases, e.g. the WHO adverse drug reaction database, National Library of Medicine’s Medline, etc. Searches should focus not only on the specific herbal drug preparation, but should include different parts of the plant, related plant species and information originating from chemotaxonomy. Toxicological information on single ingredients will be assessed for its relevance to the herbal medicines.

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In assessing these bibliographic data, particular attention will be given to the characteristics and type of preparation described in the literature:

• does the literature refer to the same herbal preparation?

• can the data be extrapolated, e.g. extract prepared with ethanol 40% vs. extract prepared with ethanol 60%?

• the duration and extent of use of the herbal medicine; can the use have generate sufficient experience on safety?

•is it plausible that risks would have been recognized empirically?

The need for additional data or additional new tests would be considered in light of the information requirements for new herbal medicines. Many of the tests required for these new medicines may be replaced by documented experience. However, it would be carefully considered whether all questions on toxicology raised can be answered adequately and in a plausible way by the available knowledge. Particular attention would be given to effects that cannot be readily detected empirically, e.g.genotoxicity.

The assessment would seek to determine if there is sufficient information to guarantee safe use in vulnerable populations such as pregnant or lactating women and in small children. In assessing safety in pregnancy, information on traditional misuse, e.g. as an agent to induce abortion, should be assessed.

All documentation that will answer previous questions concerning safety should be included in the dossier.

Minimum requirements for efficacy of herbal medicinal products

Claims categories

Disease · Acute disease: Diseases that have a rapid onset and a relatively short duration. · Chronic disease: Diseases that have a slow onset and last for long periods of time. Diseases of acute onset could also progress to a chronic state. In most cases, severe diseases refer to a life-threatening illness or those diseases in which delayed treatment will lead to deterioration of the disease state or loss of capability to cure them. For example, severe cardiovascular, gastrointestinal, endocrine, haematological diseases, and immune disorders and diseases fall into this group. · Health condition: Problems related to health conditions are those which, with time, could recover spontaneously, even without any medical intervention, e.g. loss of appetite, hay fever, menopause, etc. The efficacy for this category could be supported by data in existing well-established documents such as national pharmacopoeia and monographs as well as other authoritative documents such as WHO monographs. Pre-clinical and clinical data of efficacy may not be necessary.

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Minimum requirements for assessment of the efficacy of herbal medicines

· The assessment of efficacy for herbal medicines in categories 1 and 2 are not required if they are used locally; · For medicines in category 3, pre-clinical data and clinical data may or may not be required depending on the modification(s), which are given in Table 2; · For medicines in category 4, efficacy data are required.

Biological studies

It is indicated to determine the ingredient pharmacokinetics:

Absorption by the different routes of administration.

Distribution.

Metabolism.

Excretion.

These are determined by using sensitive assay procedures e.g. chromatography, spectrophotometer, radioisotopes … etc.

The results are collected and introduced to the Authority to be evaluated on human to be used topical, oral or rectal administration only other formulations e.g. injectable, ophthalmic ….etc. are not allowed as herbal remedies.

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Quality assurance of herbal medicinal products

Quality assurance of herbal medicinal products is the shared responsibility of manufacturers and regulatory bodies. The manufacturers have to adhere to Good Agricultural and Collection Practices (GACP), GMP and Good Laboratory Practice (GLP) standards, establish appropriate specifications for their products, intermediates and starting materials and compile a well-structured, comprehensive documentation on pharmaceutical development and testing. The producers should make continued efforts to improve standards and adapt them to the present state of knowledge. A cooperative approach between different manufacturers, e.g. by establishing drug master-files for specifications and quality control are encouraged.

Coordinating quality control

A coordinating agency on GACP should be established to facilitate the availability of good quality herbal medicines to the market. Manufacturers and importers of herbal medicinal products who possess certificates of adherence to the GACP from their botanical suppliers are encouraged to submit it.

· Adherence to GACP, GMP and GLP guidelines:

All parties involved in the production of herbal medicinal products should adhere to the principles set out in the WHO GACP guidelines for medicinal plants, GMP and GLP. Manufacturers of herbal medicines should be licensed and registered in MoH. The quality assurance system should be adequate and proportionate to the type of production and the regional situation, e.g. agricultural production or industrial production. The implementation of a credible concept of quality assurance, e.g. identifying and eliminating potential sources of contamination, rather than implementing all individual technical aspects, should be the primary goal. The following areas should be considered while studying the WHO guidelines: · Control of raw materials (refer to the GACP and Quality Control Methods for Medicinal Plant Products); · Control of starting materials and intermediate substances; · In-process control (Standard Operating Procedure for Processing Methods should be mentioned); · Finished product control (It should be performed with reference to the control of raw materials, starting materials and intermediate substances).

· Setting specifications:

The basis for quality control is the establishment of appropriate specifications and standards. Information on appropriate standards can be found in official pharmacopoeias and monographs. A comprehensive specification must be developed for each herbal substance even if the starting material for the manufacture of the herbal medicinal product is a herbal preparation.

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Latin name should be given to ensure correct identification of a plant. A definition and description of the part of the plant from which the medicine is made (e.g. leaf, flower, and root) should be provided, together with an indication of whether fresh or dried processed material is used. The active and characteristic constituents and their biological & geographical variation should be specified and, if possible, content limits should be defined. A qualitative statement should be defined about the organoleptic character(s) which includes characteristic and the macroscopic and microscopic botanical characters of the herbal substance. A comprehensive specification must be developed for each herbal preparation based on recent scientific data. A statement of the botanical source, part used, extraction solvent, the type of preparation (e.g. dry or liquid extract), and the ratio of the herbal substance to the genuine herbal preparation must be stated. A qualitative description of the dosage form should be provided (e.g., size, shape, colour). The acceptance criteria should include the final acceptable appearance at the end of the shelf-life. If colour changes occur during storage, a quantitative procedure may be appropriate. The physical and chemical stability of the product in the container in which it is to be

marketed should be tested under defined storage conditions and the shelf-life should be

established.

The best approach that can be proposed for determining the quality of a herbal

medicine is the level of active components or key biological markers. This form of

standardization, i.e., stating the content of active constituents versus drug

concentration ratio, allows for dosage to be based on active constituents.

The manufacturing procedure including (temperature effects, residual solvents), and

formula including (the quality of the herbal substance and/or herbal preparation,

amount of excipients and profile and stability of the active substance/formulation in

packaging) should be described in detail. A finished product specification should be

defined. A method of identification and quantification of the plant material in the

finished product should be defined.

· Quality control measures.

In choosing analytical methods, the availability, robustness and validity of the methods must be considered, such as microscopic identification, thin layer chromatography (TLC), titration of active substance and, if possible, a full validation of more sophisticated methods, such as high-performance liquid chromatography (HPLC), gas chromatography (GC), and gas chromatography-mass spectrometry (GC-MS). If such advanced methods are used, a full validation for each test would be necessary. Tests of Foreign matter & Total ash should be applied. Water content test is important when the herbal substances are known to be hygroscopic.

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Foreign matter, impurities, toxic metals, radioactive elements, insecticide/ pesticides and microbial content (microbial levels, mycotoxins (aflatoxins) should be defined or limited. Voucher specimens, representing each lot of plant material processed, should be authenticated by a qualified botanist. A method for identification & assay of the constituents with known therapeutic activity or active or analytical markers in herbal preparation should be added. If identification of an active principle is not possible, it should be sufficient to identify a characteristic substance or mixture of substances (e.g. "chromatographic fingerprint") to ensure consistent quality of the preparation. Drying conditions, residual solvents in extracts, and stability of the constituents should be defined. Water content test is important when the herbal preparations are known to be hygroscopic. The need for inclusion of tests and acceptance criteria for Impurities including Inorganic impurities, toxic (heavy) metals, Microbial limits, Mycotoxins (aflatoxins), Pesticides, Fumigation agents, etc. should be studied during development and the manufacturing process. In finished product: In choosing analytical methods, the availability and robustness of the method must be

considered. It may be preferable to use simple methods (such as microscopic

identification, thin-layer chromatography or titration of active substance) if a full

validation of more sophisticated methods (such as high-performance liquid

chromatography, gas chromatography and gas chromatography/mass spectrometry) is

not possible. If such advanced methods are used, a full validation for each test will be

necessary.

If the identification of an active principle is not possible, it should be sufficient to identify

a characteristic substance or mixture of substances (e.g. "chromatographic fingerprint")

to ensure consistent quality of the product. The finished product should comply with

general requirements for particular dosage forms.

Identification tests should establish the specific identity of the herbal substance(s) and/or

herbal preparation(s), in the herbal medicinal product and optimally should be

discriminatory with regard to substitutes/adulterants that are likely to occur. In the case

of herbal medicinal products containing powdered or comminuted herbal substances,

microscopical and macroscopical characterization could be used for identification in

combination with other methods, if justified.

In the case of products containing herbal substances and/or herbal preparations with

constituents of known therapeutic activity, validated assays of the content of these

constituents are required along with details of the analytical procedure(s). In cases where

use of a non-specific assay is justified, other supporting analytical procedures should be

used to achieve overall specificity, i.e. a combination of the assay and a suitable test for

identification (e.g. fingerprint chromatography) can be used. A specific, stability-indicating

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procedure should be included to determine the content of the herbal substance(s) and/or

herbal preparation(s) in the herbal medicinal product.

In the case of herbal medicinal products containing herbal substance(s) and/or herbal

preparation(s) where the constituents with known therapeutic activity are not known,

validated assays of active or analytical markers or other justified determinations are

required. The choice of such markers should be justified. In cases where a specific assay

of each active substance of a herbal medicinal product is not possible other justified

determinations are required (for example, in multi-component herbal medicinal

products for human use the same markers may be present in more than one herbal

substance/preparation).

There is a need to specify the total count of aerobic micro-organisms, the total count of

yeasts and moulds, and the absence of specific objectionable bacteria. These microbial

counts should be determined using pharmacopoeial procedures or other validated

procedures.

Impurities arising from the herbal substance(s) and/or herbal preparations e.g. contaminants such as pesticide/fumigant residues, toxic metals, if controlled during the testing of the herbal substance/preparation, it is not necessary to test for these in the herbal medicinal product. Similarly, residual solvent arising from the manufacture of the herbal preparation (e.g. an extract) need not be controlled in the herbal medicinal product provided. It is appropriately controlled in the extract specification. However, solvents used for example in tablet coating will need to be controlled in the dosage form.

Vitamins and minerals in herbal medicinal products for human use

Impurities arising from degradation of the vitamin(s) or mineral(s) should be monitored

in the herbal medicinal product for human use. When it has been demonstrated

conclusively by provision of a significant body of data (generated using appropriate

analytical methods, that the vitamin(s) and/or mineral(s) do not degrade in the specific

formulation and under the specific storage conditions proposed in the application)

degradation product testing may be reduced or eliminated upon approval by the

regulatory authorities.

This should cover all important aspects of the quality assessment of herbal medicines. It should be

sufficient to make reference to a pharmacopoeial monograph if one exists.

Product information for registration This should include all necessary information on the proper use of the product. The detailed information of the herbal medicinal products should include the following requirements for registration:

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· Quantitative list of ingredients; if this is difficult, it could be replaced by including the plant names and plant parts used (i.e. Latin name); · Full product formula for imported herbal-based medicinal products (in the language of the importing and exporting countries); · A set containing labels, pamphlet, carton and specimen sales pack; · Particulars of manufacturer(s) and assembler(s); · Manufacturer’s licence or certificate from the drug regulatory authority. Pre-export notification and Certificate of Free Sale of the herbal-based medicinal product should be obtained from the concerned authority; · Brand name of product; · Dosage form; · Indications; · Dosage; · Mode of administration; · Duration of use; · Adverse effects, if any; · Contraindications, warnings, precautions and major drug interactions, if possible; · Date of manufacture; · Expiry date of product; · Lot/Batch number; · Storage condition.

Pharmacovigilance of herbal medicinal products is subjected to the guidelines issued by Egyptian Pharmaceutical Vigilance Center EPVC