Unit ...d EU AND ICH GUIDELINES FOR QUALITY CONTROL OF HERBAL DRUGS Objectives: Upon completion of this Chapter, the student should be able to: * Appreciate EU and ICH guidelines for quality control of herbal drugs. + Understond research guidelines for evaluating the safely and efficacy of herbal medicines 3.1 INTRODUCTION The International Council for Harmonization (ICH) of technical requirements for pharmaceuticals for human use brings together the medicines regulatory authorities and pharmaceutical industry around the world. ICH aims to achieve greater harmonization worldwide for the development and approval of safe, effective and high-quality medicines in the most resource-efficient manner. The European Medicines Agency (EMA), in collaboration with the EU Member States, supports the European Commission's membership in ICH and plays a key role in the development and implementation of ICH guidelines. The reformed ICH is intended to transform ICH into a truly global initiative supported by a robust and transparent governance structure. 3.2 EUROPEAN UNION (EU) GUIDELINES FOR QUALITY CONTROL OF HERBAL DRUGS The European Medicines Agency's (EMAs) Committee for herbal medicinal products for human and veterinary use prepares scientific guidelines in consultation with regulatory authorities in the European Union (EU) Member States, to help applicants prepare marketing authorization applications for human and veterinary medicines. Guidelines reflect a harmonized approach of the EU Member Stetes and the Agency on how to interpret end apply the requirements for the demonstration of quality, safety and efficacy set out in the Community orders. atQuality Control and Standardization of Herbals. EUand ICH Guidelines for... Fig. 3.1: Scientific Gui 3.2.4 Quality () Guidelines on the declaration of herbal substances and herbal preparations in herbal medicinal products/traditional herbal medicinal products: The declaration is proposed to describe the identity and quantity of the herbal substance/preparation, being the active substance of the herbal medicinal product and should focus on those characteristics found to be useful in ensuring the safety and efficacy of the herbal substance/preparation and herbal medicinal product. Therefore, a declaration system has been established which reflects the main characteristics of herbal substances/preparations as defined in the respective specifications. (a) Standardized herbal substances: Standardized herbal substances are adjusted within an acceptable tolerance to a given content of constituents with known therapeutic activity. Standardization is achieved by adding excipients for adjustment to the herbal substance or by blending batches of the herbal substance. For such herbal substances, the name and content of the constituent(s) with known therapeutic activity should be stated. The equivalent quantity of the genuine herbal substance should be given (as a range), (b) Quantified herbal substances: Quantified herbal substances are adjusted to a defined range of constituents. Adjustments are made by blending batches of herbal substances used in the manufacturing process. For quantified herbal substances, the name of the active markers should be stated and their content should be given in a range. The equivalent quantity of genuine herbal substance should be given. (©) Other herbal substances: For other herbal substances, neither constituents with known therapeutic activity nor active markers are generally known. Therefore, these herbal substances are essentially defined by their production process and their specifications. For other herbal substances, the name and content of the analytical marker(s) should not be stated, The quantity of genuine herbal substance should be given. (d) Declaration of herbal preparations in the Summary of Product Characteristics (SmPC): The declaration of herbal preparation should cover the name of the herbal substance and the definition of the herbal preparation including; the physical state, ratio of herbal substance to genuine herbal preparation and extraction of solvent(s). The name of the herbal substance is the scientific Latin name of the plant species according to the binomial system (genus, species, variety and author) with the Latin term of the plant part, followed by ines on Herbal Medicinal Products 32Quality Control and Standardization of Herbals. EUand ICH Guidelines for... the common name of the monograph of the European Pharmacopoeia if available, or else of the Pharmacopoeia of a Member State, if available, or else the common name of the herbal substance. In those special cases, where many different Latin plant species apply to the same herbal substance, the list of Latin names could be shortened to the genus name followed by the word "species", e.g. ‘Crataegus species”. This option is only applicable in cases where, no restrictions concerning the species used are known from the quality documentation. (i) Standardized herbal preparations: Standardized herbal substances are adjusted within an acceptable tolerance to a given content of constituents with known therapeutic activity. Standardization is achieved by adding excipients for adjustment to the herbal substance or by blending batches of the herbal substance. For such herbal substances, the name and content of the constituent(s) with known therapeutic activity should be stated. The equivalent quantity of the genuine herbal substance should be given (as a range). (ii) Quantified herbal preparations: They are adjusted to a defined range of constituents. Adjustments are made by blending batches of herbal substances used in the manufacturing process. For quantified herbal substances, the name of the active markers should be stated and their content should be given in a range. The equivalent quantity of genuine herbal substance should be given. ii) Other herbal substances: They are essentially defined by their production process and their specifications. For such preparations, the name and content of the analytical marker(s) should not be stated. The quantity of genuine herbal preparation should be stated, quoting the amount of herbal substance (given as a range). When solvent(s) are used in herbal preparation (extraction solvent), the name and composition of the solvent(s) used in the first extraction step should be included in the declaration of the herbal medicinal product. If purification procedures are used, the word “refined” should be added to the name of the herbal preparation, where applicable. If a fresh herbal substance is used as a starting material for the manufacture of the herbal preparation, this should be added to the name of the herbal preparation, as appropriste. (e) Herbal preparations consisting of comminuted or powdered herbal substances: The following characteristics have to be stated in the declaration: 1, Name of the herbal substance used. Physical state of the herbal preparation, if relevant. Quantity of genuine herbal preparation, Name and quantity of the constituent(s) with known therapeutic activity. Name and quantity (given as a range) of the active markers (quantified herbal preparations), if applicable. yan 33Quality Control and Standardization of Herbals. EUand ICH Guidelines for... (f) Herbal preparations produced by steps which exceed comminution/powdering (eg. extracts): The following characteristics have to be stated in the declaration: Name of the herbal substance used. Type/physical state of the herbal preparation, Quantity of genuine herbal preparation. Name and quantity of the constituent(s) with known therapeutic activity. Name and quantity (given as a range) of the active markers, if applicable Drug extracts ratio (DER genuine) or equivalence in the quantity of the herbal substance (as arrange), 7. Name and composition of the extraction solvent(s). (1 Guidelines on Good Agricultural and Collection Practice (GACP) for Starting Materials of Herbal Origin: To confirm appropriate and reliable quality of medicinal plant/herbal substances, it is necessary to establish good agricultural and collection practice for herbal starting materials, (GACP). Collection from wild habitats may present special problems, especially with regard to confusion with similar plants, environmental damage, lack of control and poorly qualified personnel. This guideline is intended to address the specific concerns of growing, collecting and primary processing of medicinal plants/herbal substances that are used for medicinal purposes. The main aim is to ensure consumer safety by establishing proper quality standards for medicinal plants/herbal substances. Important aspects of medicinal plants/herbal substances includes: aye wne * They are produced hygienically, to reduce microbiological contamination to a minimum. * They are handled with care so that, medicinal plants/herbal substances are not adversely affected during collection, cultivation, processing and storage. During the production process medicinal plants/herbal substances and their preparations are exposed to a large number of microbiological and other contaminants, This guideline provides recommendations for producers to reduce contamination to a minimum. Growers and collectors of medicinal plants/herbal substances must ensure that they avoid damage to existing wildlife habitats. (@) Quality assurance: Agreements between producers and buyers of medicinal plants/herbal substances with regard to quality such as; content of active principle, macroscopical and olfactory properties, limit values for microbial contamination, chemical residues and heavy metals, etc. must be based on recognized regional and/or national specifications and should be laid down in the written form. 34Quality Control and Standardization of Herbals. EUand ICH Guidelines for (b) Personnel and Education: * All primary processing procedures should follow regional and/or national guidelines on food hygiene. Personnel assigned with the handling of medicinal plants/herbal substances should be required to have a high degree of personal hygiene. + The welfare of all staff involved in growing and processing should be ensured. * Personnel must be protected from contact with toxic or allergenic medicinal plants/herbal substances using adequate protective clothes. + Persons suffering from known infectious diseases transmittable via food; including diarrhoea, or being transmitters of such diseases, must be suspended from areas where, they are in contact with medicinal plants/herbal substances, according to regional and/or national regulations. * People with open wounds, inflammations and skin-infections should be suspended from areas where, the plant processing takes place or should have to wear appropriate protective clothing/gloves until their complete recovery. * Personne! should receive adequate botanical training before performing tasks that require this knowledge. * Collectors must have sufficient knowledge of the plant they have to collect. This includes; identification, characteristics and habitat requirements. The collectors must be able to differentiate between the collected species and botanically related and/or morphologically similar species to avoid any risk to public health, Collectors should have sufficient knowledge about the best time to harvest and harvesting technique and the importance of primary processing to guarantee the best possible quality. * If collectors are without sufficient knowledge, a local supervisor should guarantee the education, supervision and documentation. * It is advisable to educate all personnel dealing with the medicinal plant/herbal substance and all those engaged in its cultivation regarding cultivation techniques including the appropriate use of herbicides and pesticides. * Collectors of medicinal plants/herbal substances should be instructed on all issues relevant to the protection of the environment and conservation of plant species. This will include information on regulations related to protected species. (©) Building and Facil * Buildings used in the processing of harvested medicinal plants/herbal substances must be clean, as well as thoroughly aerated and must never be used for housing livestock. * Buildings must provide adequate protection for the harvested medicinal plants/herbal substances against birds, insects, rodents and domestic animals. In all storage and processing areas suitable pest control measures such as; baits and electric insect killing machines must be operated and maintained by professionally qualified staff or contractors. 35Quality Control and Standardization of Herbals. EUand ICH Guidelines for © Itis recommended that the packaged medicinal plant/herbal substance to be stored: © In buildings with concrete or similar, so that it is easy to clean the floors. © With a sufficient distance from the wall © Well separated from other herbal substances to avoid cross-contamination. © Organic products must be stored separately. Buildings, where plant processing is carried out, must have changing facilities as well as toilets including; hand washing facilities, according to regional and/or national regulations. (d) Equipment: Equipment used in plant cultivation and processing should: * Be clean, regularly serviced and oiled to ensure good working order. Furthermore, machinery used in fertilizer and pesticide application must be regularly calibrated. * Those machine parts that are in direct contact with the harvested medi plant/herbal substances must be cleaned after use to ensure that the remaining residue does not result in subsequent cross-contamination. * The equipment should be made from appropriate materials so that, cross contamination of medicinal plants/herbal substances with chemicals and other non- desirable substances is prevented. (e) Documentation: * All processes and procedures that could affect the quality of the product must be documented * During the growth period, if any extraordinary circumstances occur that may influence the chemical composition of the medicinal plant/herbal substance such as; extreme weather conditions and pests, particularly in the harvest period must be documented. * For cultivated medicinal plants/herbal substances, all processing steps have to be documented including; the location of cultivation. Field records showing previous crops and plant protect products used should be maintained by all growers. + For cultivated medicinal plants/herbal substances, it is essential to document the type, quantity and date of harvest as well as the chemicals and other substances used during production such as: fertilizers, pesticides, herbicides and growth promoters. + The application of fumigation agents must be documented. © The geographic location of the collection area and the harvest period should be described as detailed as possible. * Batches of medicinal plant materials should be labeled and batch assignments should take place as early as possible. Collected and cultivated medicinal plant/herbal substance material should carry different batch numbers. * Batches from different geographical areas should be mixed only if it can be guaranteed that the mixture itself will be homogenous. Such processes should be well documented. 36Quality Control and Standardization of Herbals. EUand ICH Guidelines for... * All agreements (production guidelines, contracts, etc) between producer or collector and buyer should be in written format. It should be documented that cultivation, harvesting and production have been performed in accordance with these agreements. Minimum information included in the documentation should cover geographical location, country of origin and responsible producer. + The results of audits should be documented in an audit report (copies of all documents, audit reports, analysis reports) to be stored for a minimum of 10 years. (f) Seeds and Propagation Material + Seeds should originate from plants that have been identified in terms of the genus, species, variety/cultivar/chemotype and the origin and should be traceable, The same applies to vegetatively propagated medicinal plants. Seeds and/or vegetatively propagated medicinal plants used in organic production have to be certified as organic. * The starting material should be free from pests and diseases to guarantee healthy plant growth. Where possible, species naturally resistant or tolerant to disease should preferably be used. The presence of different species, varieties or different plant parts has to be controlled during the entire production process and such adulteration should be avoided. The use of genetically modified medicinal plants or seeds must comply with regional and/or national regulation. (g) Cultivation: Different SOPs may be acceptable depending on whether conventional or organic methods of cultivation are employed. However, care should be taken to avoid any environmental impact. The principles of good crop husbandry must be followed including appropriate rotation of crops. (h) Soil and fertilization: * Medicinal plants should not be grown in soil contaminated with sludge, heavy metals, residues, plant protection products or other chemicals, etc. Any chemicals used in the growth or protection of the crop should be kept to a minimum. + Manure applied should be thoroughly composted and should be void of human feces. + All other fertilizing agents should be applied carefully and in accordance with the needs of the particular species. * Fertilizers should be applied in such a manner as to minimize leaching. (i) Irrigation: * Inigation should be controlled and carried out according to the needs of the medicinal plant. Water used in irrigation should comply with regional/national quality standards. (@ Crop maintenance and plant protection: * Tillage should be adapted to plant growth and requirements. 37Quality Control and Standardization of Herbals. EUand ICH Guidelines for * Pesticide and herbicide applications should be avoided as far as possible. When necessary, approved plant protection products should be applied at the minimum effective level in accordance with the recommendations from the manufacturer and authorities. The application should be carried out only by qualified staff using approved equipment. Regional and/or national regulations on maximum residue limits in the European Pharmacopoeia, European Directives, Codex Alimentarius, etc. should be complied (k) Collection: * Individuals should be designated to identify and verify collected medicinal plants/herbal substances and to supervise collectors. * Collection must be carried out in compliance with existing regional and national and/or national species conservation legislation. Collection methods must not damage the growth environment ensuring optimum conditions for regeneration of the medicinal plant/herbal substance harvested. * Medicinal plants/herbal substances from species that are listed as endangered (CITES, Convention on International Trade in Endangered Species of Wild Fauna and Flora) must not be collected unless the relevant competent authority has given its authorization () Harvest: + Medicinal plants/herbal substances should be harvested when they are of the best possible quality for the proposed use. + Damaged plants or plant parts need to be excluded or limited in accordance with a specific pharmacopoeial monograph, where relevant. * Medicinal plants/herbal substances should be harvested under the best possible conditions avoiding wet soil, dew, rain or exceptionally high air humidity. If harvesting occurs in wet conditions possible adverse effects on the medicinal plant/herbal substance due to increased moisture levels should be counteracted. + Cutting devices or harvesters must be adjusted such that contamination from soil patticles is reduced to a minimum. The harvested medicinal plant/herbal substance should not come into direct contact with the soil. It must be promptly collected and transported in dry, clean conditions * During harvesting, care should be taken to ensure that no toxic weeds mix with harvested medicinal plants/herbal substances. * All containers used during harvesting must be clean and free of contamination from harvests. When containers are not in use, they must be kept in dry conditions free of pests and unreachable from mice/rodents, livestock and domestic animals. * Mechanical damage and compacting of the harvested medicinal plant/herbal substance that would result in undesirable quality changes must be avoided. In this respect, attention must be paid to-overfilling of the sacks and stacking up of sacks. 38Quality Control and Standardization of Herbals. EUand ICH Guidelines for... * Freshly harvested medicinal plants/herbal substances must be delivered as quickly as possible to the processing facility to prevent thermal degradation. + The harvested crop must be protected from pests, mice/rodents, livestock and domestic animals. Any pest control measures taken should be documented. (m)Primary Processing: * Primary processing includes; washing, cutting before drying, fumigation, freezing, distillation, drying, etc. All these processes must conform to regional and/or national regulations and should be carried out soon after harvesting. * On arrival at the processing facility, the harvested medicinal plant/herbal substance has to be promptly unloaded and unpacked. * Prior to processing the material should not be exposed directly to the sun, except in cases where, there is a specific need and must be protected from rainfall, insect infestation, etc. * Inthe case of natural open air drying, the medicinal plant/herbal substance must be spread out in a thin layer. In order to secure adequate air circulation, the drying frames must be located at a sufficient distance from the ground. Drying directly on the ground or under direct exposure to the sunlight should be avoided unless specifically required. Attempts must be made to achieve uniform drying of the medicinal plant/herbal substance and thus, avoid mould formation. + Except in the case of open-air drying, the drying conditions such as; temperature, duration, air circulation, etc, must be selected taking into consideration the medicinal plant part such as; root, leaf or flower and the nature of its active constituent such as; essential oils. All the conditions must be recorded in detail * All materials must be inspected and wherever necessary sieved to eliminate substandard product and foreign bodies. Sieves must be maintained in a clean state and should be serviced regularly. * Clearly marked waste-bins should be available, emptied daily and cleaned. (n) Packaging: + Inorder to protect the product and to reduce the risk of pest attacks, early packaging is advisable. * The product should be packaged in clean and dry, preferably new sacks, bags or cases. The label must be clear, permanently fixed and made from non-toxic material Information must conform to regional and/or national labeling regulations. * Reusable packaging material should be well cleaned and properly dried prior to use. No contamination should occur through the reusing of bags. * Packaging materials must be stored in a clean and dry place that is free of pests and unreachable to livestock and domestic animals. It must be guaranteed that no contamination of the product occurs by the use of packaging materials, particularly in the case of fiber bags. 39Quality Control and Standardization of Herbals. Vand ICH Guidelin (0) Storage and Distribution: * Packaged dried medicinal plants/herbal substances including; essential oils, should be stored in a dry, well-aerated building, in which daily temperature fluctuations are limited and good aeration is ensured. Fresh products should be stored between 1°C and 5°C while frozen products should be stored below -18°C (or below -20°C for long term storage). * Inthe case of bulk transport, it is important to secure dry conditions. To reduce the risk of mould formation or fermentation. As a substitute, the use of sufficiently aerated transport vehicles and other aerated facilities is recommended. Essential oil transport must conform to appropriate regulations. Regional and/or national regulations on transport have to be respected, * Fumigation against pest attack should be carried out only where, necessary and must be carried out exclusively by licensed personnel. Only registered chemicals must be used. Any fumigation against pest attack should be reported in the documentation * For fumigation of warehouses, only substances permitted by the regional and/or national regulations should be used. * When frozen storage or saturated steam is used for pest control, the humidity of the material must be controlled after treatment. (Il) Guideline on the quality of the com medicinal products: Herbal medicinal products can be combinations of herbal substances and/or herbal preparations. In most of cases, herbal substances are extracted separately and then mixed in the herbal medicinal product. However, in some cases, herbal substances are mixed before extraction. Herbal medicinal products contain herbal substances/preparations each consisting of a large number of chemical constituents of which only a few may be characterized. Also, herbal substances are natural in origin and consequently, their chemical composition varies. In most cases, the constituents responsible for the therapeutic activity are unknown or only partly explained and often markers are used to characterize these products. For herbal medicinal products containing combinations of herbal substances and/or herbal preparations, quality control may be more problematic because other herbal substances and/or preparations may interfere with the analysis. €.g. Extraction or detection of a marker may be affected by other herbal substances present in the herbal medicinal product. The quality of a combination of herbal medicinal product should be guaranteed and demonstrated in accordance with the existing guidance. All relevant parameters should be tested in the herbal medicinal product and identification and assay of each herbal substance/herbal preparation included in the product are required. 3:40Quality Control and Standardization of Herbals. EUand ICH Guidelines for... If individual active substance testing for identity, assay or to demonstrate stability cannot be performed in the herbal medicinal product, alternative strategies may be considered. The simple omission of test(s) is not acceptable as the quality of combination herbal medicinal products should be comparable to the quality of other (herbal) medicinal products. In this regard, reducing the number of active substances in the herbal medicinal product could increase the possibilities to perform all tests (Eg. identification, assay, etc.) in the herbal medicinal product. (a) Identification test of each active substance in combination with herbal medicinal products: * The identification test of the herbal substance/preparation should be performed as in process control at the latest point in the manufacturing process of the herbal medicinal product where, analysis is still possible. The approach taken should be Justified by the applicant. The identification test should be supported by documented evidence on the manufacture of the herbal medicinal product batch (batch records) and process validation. * If IPC testing of the herbal substance/preparation is not possible, it is identified according to its specifications immediately before the introduction of the active substance in the manufacture of the herbal medicinal product. This approach taken should be justified by the applicant. + The identification test should be supported by documented evidence on the manufacture of the herbal medicinal product batch (batch records) and process validation. This documentation should be available upon inspection by the Competent Authorities. (b) Assay of each active substance in combination with herbal medicinal products: * An individual assay of the active substance should be performed in the herbal medicinal product in accordance with the guideline. If an individual assay of the herbal substance/preparation is not possible, the quantitative determination can be carried out jointly for two or more herbal substances/preparations. * An assay of a common marker gives limited information on the relative composition of the concerned herbal substances/preparations in the herbal medicinal product. As such, markers for joint analysis should be carefully selected and justified, If a joint analysis is considered acceptable, the specifications of the concemed herbal substances/preparations should include a limit for the common marker. The approach taken should be justified by the applicant. Each approach should be supported by careful process validation and documentary evidence should be available. * An appropriate manufacturing process design, supported by strict and well- documented process validation, should ensure that the manufacture and quality of the herbal medicinal product is well controlled and the composition of the herbal medicinal product conforms to the declared composition. The manufacturing process development studies and other studies are crucial in this regard and should support 3aQuality Control and Standardization of Herbals. EUand ICH Guidelines for... the proposed approach to ensure the quality and composition of the herbal medicinal product. The approach taken should be justified by the applicant. Tests should be supported by documented evidence on the manufacture of the herbal medicinal product batch (batch records). (©) The stability of the combination herbal medicinal product: * Asper the Guidelines, if a herbal medicinal product contains combinations of several herbal substances and/or herbal preparations and if it is not possible to determine the stability of each active substance, the stability of the combination has to be demonstrated by fingerprint chromatograms, overall methods of assay and physical or other appropriate tests. The appropriateness of the tests should be justified by the applicant. jonal herbal medicinal This guideline covers the general quality aspects of herbal medicinal products (for human and veterinary use) including; traditional herbal medicinal products for human use. Products containing chemically defined isolated constituents or a mixture thereof are not herbal medicinal products. Reliable quality for products of herbal origin can only be assured if the starting materials are defined in a detailed manner, particularly the specific botanical identification of the plant material used. It is also important to know the geographical source and the conditions under which the herbal substance is obtained to ensure the material of consistent quality (a) Qualitative and quantitative particulars of the active substance(s) of a herbal medicinal product: ‘+ Standardized herbal substances/herbal preparations are adjusted to a given content of constituents with known therapeutic activity within an acceptable tolerance; standardization is achieved by adjustment of the herbal substances/herbal preparations with excipients or by blending batches of herbal substances and/or herbal preparations. ‘* Quantified herbal substances/herbal preparations are adjusted to a defined range of constituents (active markers), adjustment is exclusively achieved by blending batches of herbal substances and/or herbal preparations. © Other herbal substances/herbal preparations are active substances for which neither constituents with known therapeutic activity nor active markers are known. These herbal substances/herbal preparations are not adjusted to a defined content of analytical marker. ‘+ Incases where, excipients for the manufacture of active substances are used (E.g. for technological reasons or for adjustment of standardized herbal substances/preparations), the name and the quantity of these excipients have to be stated. 342Quality Control and Standardization of Herbals. Vand ICH Guidelin oF an (b) Herbal substances and herbal prep: © tions consisting of comminuted or powdered herbal substances: For herbal substances and herbal preparations consisting of comminuted or powdered herbal substances, the grade of comminution has to be given. Furthermore, the following has to be indicated: In the case of standardization: The quantity of the herbal substance/preparation should be given as a range corresponding to a defined quantity of constituents with known therapeutic activity. Eg: Active substance: Sennae folium Quantity: 415-500 mg, corresponding to 125 mg of hydroxyanthracene glycosides, calculated as Sennoside B. In the case of quantification: The quantity of the herbal substance/preparation should be stated as a distinct content and the content of the quantified substance(s) should be specified in a range. Eg: Active substance: Salicis cortex Quantity: 4 gm, corresponding to 40 to 48 mg of total phenolic glycosides, expressed as salicin For all other cases: The quantity of the herbal substance or the quantity of genuine herbal preparation should be stated as a distinct content. Eg: Active substance: Valerianae radix Quantity: 900 mg. Herbal preparations produced by steps, which exceed comminution: Herbal preparation which is produced by steps that exceed comminution, the nature and concentration of the solvent and the physical state of the extract have to be given. Furthermore, the following has to be indicated: (*)'a' and‘b’ or ‘x’ and 'y’ have to be justified by the applicant. Standardized extracts: The equivalent quantity of the herbal substance x-y (*), or the ratio (a-b): 1 (*) of the herbal substance to the genuine herbal preparation should be stated and the quantity of the genuine herbal preparation may be given as a range corresponding to a defined quantity of constituents. Eg. Active substance: Sennae folium dry Quantity: 50-65 mg, corresponding to extract ethanolic 60% (V/V) ((a-b): 1) _—-125 mg of hydroxyanthracene glycosides, calculated as Sennoside B. Quantified extracts: The equivalent quantity of the herbal substance x-y (*), or the ratio (a-b): 1(*) of the herbal substance to the genuine herbal preparation should be stated and the quantity of the genuine herbal preparation has to be given as a 343oF an Quality Control and Standardization of Herbals. Vand ICH Guidelin distinct content. Furthermore, content of the quantified substance(s) should be specified in a range. Eg: Active substance: Ginkgo folium dry Quantity: 60 mg, containing 13.2-162 extract acetonic 60% (V/V) (equivalent to mg of flavonoids expressed as flavone x-y mg Ginkgo folium) glycosides, 1.68-2.04 mg of ginkgolides A, B and C, and 156-192 mg of bilobalide. * Other extracts: The equivalent quantity of the herbal substance x-y (*), or the ratio (@-b): 10°) of the herbal substance to the genuine herbal preparation should be stated and the quantity of the genuine herbal preparation has to be given as a distinct, content. Es. Active substance: Valerianae radix dry Quantity: 125 mg extract ethanolic 60% (V/V) equivalent to xy mg Valerianae radix. * The composition of any extraction solvent or extraction solvent mixture and the physical state of the extract must be indicated. If any other substance is added during the manufacturing of the herbal preparation to adjust the preparation to a defined content 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’. * However, where different batches of the same extract are used to adjust constituents with known therapeutic activity to a defined content, or, for any other purpose, the final mixture should be regarded as the genuine extract and listed as the “active substance" in the unit formula. Full details of production and control must however, be provided in the dossier. (d) Description of the method of preparation of the herbal medicinal product: The description should include details of the process together with the controls exercised. If herbal preparations are the starting material, the manufacture of the herbal preparations and their controls should be located under the section entitled “Control of starting materials". (e) Control of starting materials: (Control of herbal substances: * A comprehensive specification for each herbal substance must be submitted. This also applies if the applicant is not the manufacturer of the herbal substance. If the starting material is a herbal preparation, (Eg. in the case of fatty or essential oils used as active substances of herbal medicinal products), a specification for the herbal substance is required. The binomial scientific name of the plant (genus, species, variety and author), chemotype and name of its parts, have to be stated. 314Quality Control and Standardization of Herbals. EUand ICH Guidelines for... * If no monograph for the herbal substance is given in Pharmacopoeia, a complete specification for the herbal substance must be supplied and should be set out in the same way as the monographs on the herbal substance in the European Pharmacopoeia. * Information on the site of collection, the time of harvesting and stage of growth, treatment during growth with pesticides, ete. and drying and storage conditions should be included, if possible. + The complete specification should be established based on recent scientific data. In the case of herbal substances with constituents of known therapeutic activity, assays of their content (with the test procedures) are required. The content must be included as a range, to ensure reproducibility of the quality of the herbal medicinal product. in the case of herbal substances where, constituents of known therapeutic activity are not known, assays of marker substances (with the test procedures) are required. The choice of markers should be justified. * Herbal substances must be tested, for microbiological quality, for mycotoxins (aflatoxins, ochratoxin A) and for residues of pesticides and fumigation agents, toxic metals likely; contaminants and adulterants, etc. The use of ethylene oxide is prohibited for the decontamination of herbal substances. * Radioactive contamination should be tested. = Specifications and descriptions of the analytical procedures must be submitted, together with the limits applied. Analytical procedures not given in Pharmacopoeia should be validated in accordance with the ICH guidelines. * Reference samples of the herbal substances must be available for use in comparative tests. E.g. macro and microscopic examination, chromatography, etc (i) Control of herbal preparations: * Ifthe herbal medicinal product contains a preparation, the complete specification for the herbal substance must be followed by a description and validation of the manufacturing process for the herbal preparation. This also applies if the applicant is not the manufacturer of herbal preparation. The information may be supplied either as part of the marketing authorization application or by using the European Active Substance Master File procedure. * For each herbal preparation, a comprehensive specification is required. This should be established based on recent scientific data and should give particulars of the characteristics, identification tests and purity tests. Appropriate chromatographic methods should be used. * Tests on microbiological quality, mycotoxins (aflatoxins, ochratoxin A), residues of pesticides and fumigation agents, toxic metals and solvents should be performed Radioactivity should be tested if there are reasons for concern. + A quantitative determination (assay) of substances with known therapeutic activity or ‘of markers is also required. 345Quality Control and Standardization of Herbals. Vand ICH Guidelin tor + For standardized herbal preparation, the content of constituents with known therapeutic activity must be indicated with the lowest possible tolerance (with both upper and lower limits). * Inthe case of active markers used for quantified extracts, the content of the markers has to be given as a defined range. In the case of an analytical marker of an extract for which neither constituents of known therapeutic activity, nor active markers are known, the specified minimum and maximum content is related to the validated analytical range as a base for analytical suitability within the frame of batch related to control. The test methods should be described in detail + If preparations from herbal substances with constituents of known therapeutic activity are standardized (Le. adjusted to a defined content of constituents with known therapeutic activity). It should be stated how such standardization is achieved. If another substance is used for these purposes, it is necessary to specify as a range for the quantity that can be added. (ii) Control of vitamins and minerals (if applicable): * Vitamin(s) and mineral(s), which could be ancillary substances in traditional herbal medicinal products for human use, should fulfil the requirements of the Guideline. (iv) Control of excipients: * Excipients including; those added during the manufacturing of the herbal preparations, should be described according to the Guideline (A) Control tests carried out at an intermediate stage of the manufacturing process of the herbal medicinal 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 performed on the herbal medicinal product. (g) Control tests on the herbal medicinal product: * The control tests on the finished product should allow the qualitative and quantitative determination of the active substance(s). * A specification should be provided and this may include the use of markers where, constituents with known therapeutic activity are unknown. In the case of herbal substances or herbal preparations with constituents of known therapeutic activity, these constituents should be specified and quantitatively determined. * For traditional herbal medicinal products for human use containing vitamins and/or minerals, the vitamins and/or minerals should also be specified and quantitatively determined. * Ifa herbal medicinal product contains a combination of several herbal substances or preparations of several herbal substances and if 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 should be justified. 316Quality Control and Standardization of Herbals. Vand ICH Guidelines for * The criteria given by the European Pharmacopoeia to ensure the microbiological quality should be applied. The frequency of testing for microbial contamination should be justified, according to the (V) ICH guidelines, (h) Stability tests: * Since the herbal substance or herbal preparation as @ whole is regarded as the active substance, a simple determination of the stability of the constituents with known therapeutic activity will not be sufficient. The stability of other substances present in the herbal preparation, should as far as possible, also be demonstrated, using fingerprint chromatograms. It should also be demonstrated that their proportional content remains comparable to the initial fingerprint. * Ifa herbal medicinal product contains combinations of several herbal substances or herbal preparations and if it is not possible to determine the stability of each active substance, the stability of the medicinal product should be determined by fingerprint chromatograms, overall methods of assay and physical and sensory tests or other appropriate tests. The appropriateness of the tests should be justified by the applicant. * In the case of a herbal medicinal product containing a herbal substance or herbal preparation with constituents of known therapeutic activity, the variation in content during the proposed shelf life should not exceed +5% of the declared assay value. In the case of a herbal medicinal product containing a herbal substance or herbal preparation where, constituents with known therapeutic activity are unknown, a variation in marker content during the proposed shelf life of 410% of the initial assay value can be accepted if justified by the applicant. * In the case of traditional herbal medicinal products for human use containing vitamins and/or minerals, the stability of the vitamins and/or minerals should be demonstrated. (V) Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products: The quality of herbal substances, herbal preparations and herbal medicinal products is determined by the quality of the starting plant material, development, in-process controls, GMP controls and process validation and by specifications applied to them throughout development and manufacture. This guideline addresses specifications, ie, those tests, procedures and acceptance criteria used to assure the quality of the herbal substances/preparations and herbal medicinal products at release and during the shelf life. Specifications are an important component of quality assurance. The following concepts are important in the development and set of specifications. They are not universally applicable, but each should be considered in particular circumstances. Generally, proposals to implement these concepts should be justified by the applicant and approved by the appropriate regulatory authority before being put into effect. 347Quality Control and Standardization of Herbals. Vand ICH Guidelin (a) Specifications: @ efinition and justification: A specification is defined as a list of tests, references to analytical or biological procedures and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described. It establishes the set of criteria to which a herbal substance, herbal preparation and herbal medicinal product should conform to be considered acceptable for its intended use. Specifications are legally binding quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities. Itis possible that, in addition to release tests, a specification may list in-process tests, periodic (skip) tests and other tests, which are not always conducted on a batch-by- batch basis. In such cases, the applicant should specify which tests are routinely conducted batch-by-batch and which tests are not, with an indication and justification of the actual testing frequency. In this situation, the herbal substance/preparation and/or herbal medicinal product should meet the acceptance criteria if tested. It should be noted that changes in the specification after approval of the application will need prior approval by the regulatory authority. Justification: The setting of specifications for a herbal substance/preparation and herbal medicinal product is a part of an overall control strategy which includes; control of raw materials and excipients, in-process testing, _ process evaluation/validation, stability testing and testing for consistency of batches. When combined in total, these elements assure that the appropriate quality of the product will be maintained. Since specifications are chosen to confirm the quality rather than to characterize the product, the manufacturer should provide the rationale and justification for including and/or excluding testing for specific quality attributes. The following points should be taken into consideration when establishing scientifically justified specifications: Specifications for herbal substances are linked to: Botanical characteristics of the plant (genus, species, variety, chemotype, usage of genetically modified organisms}, parts of the plants. Macroscopical and microscopical characterization, phytochemical characteristics of the plant part constituents with known therapeutic activity or markers, toxic constituents (identity, assay, limit tests). Biological/geographical variation. Cultivation/harvesting/drying conditions (microbial levels, mycotoxins (aflatoxins, ochratoxin A), toxic metals, etc.). Pre-/post-harvest chemical treatments (pesticides, fumigants). Profile and stability of the constituents. 348Quality Control and Standardization of Herbals. Vand ICH Guidelin (ii) Specifications for herbal preparations are linked to: Quality of the herbal substance. Definition of the herbal preparation (drug extract ratio, extraction soivent(s)} Method of preparation from the herbal substance. Constituents with known therapeutic activity or active or analytical markers. Other constituents (identification, assay, limit tests), Drying conditions (Eg. microbial levels, residual solvents in extracts). Profile and stability of the constituents. Microbial purity on storage. Batches used in pre-clinical/clinical testing (safety and efficacy considerations). (ii) Specifications for herbal medicinal products are linked to: © Quality of the herbal substance and/or herbal preparation. © The manufacturing process (temperature effects, residual solvents). © Profile and stability of the active substance/formulation in packaging. © Batches used in pre-clinical/clinical testing (safety and efficacy considerations). Changes in the manufacturing process and degradation produced during storage may result in a product, which differs from that used in pre-clinical and clinical development. The significance of these changes should be evaluated. (b) Universal tests/criteria: () Herbal substances: Herbal substances are a diverse range of botanical materials including; leaves, herbs, roots, flowers, seeds, bark, etc. A complete specification must be developed for each herbal substance. In the case of fatty or essential oils used as active substances of herbal medicinal products, a specification for the herbal substance is required unless justified. The specification should be established based on recent scientific data and should be set out in the same way as the European Pharmacopoeia monographs. The general monograph ‘Herbal Drugs’ of the European Pharmacopoeia should be consulted for interpretation of the following requirements: The following tests and acceptance criteria are considered generally applicable to all herbal substances. * Definition: A qualitative statement of the botanical source, plant part used and its state (Eg whole, reduced, powdered fresh, and dry). It is also important to know the geographical source(s) and the conditions under which the herbal substance is obtained * Characters: A qualitative statement about the organoleptic character(s), macroscopic and microscopic botanical characters of the herbal substance. * Identification: Identification testing optimally should be able to discriminate between related species and/or potential adulterants/substitutes, which are likely to be present. Identification tests should be specific for the herbal substance and are 000000000 349)Quality Control and Standardization of Herbals. Vand ICH Guidelin tor usually a combination of three or more like; macroscopical characters, microscopical characters, chromatographic procedures and chemical reactions. Tests: Foreign matter, total ash, ash insoluble in hydrochloric acid, water-soluble extractive and extractable matter. Particle size: For some herbal substances intended for use in herbal teas or solid herbal medicinal products, particle size can have a significant effect on dissolution rates, bioavailability, and/or stability. In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided. Particle size can also affect the disintegration time of solid dosage forms. Water content: This test is important when herbal substances are known to be hygroscopic. For non-pharmacopoeial herbal substances, acceptance criteria should be justified by data on the effects of moisture absorption. A Loss on drying procedure may be adequate, however, in some cases (essential oil containing plants), a detection procedure that is specific for water is required. (heavy) metals: The need for inclusion of tests and acceptance criteria for inorganic impurities should be studied during the development and based on knowledge of the plant species, whether it is wild or cultivated and the manufacturing process. Acceptance criteria will depend on safety considerations. Procedures and acceptance criteria for sulphated ash/residue on ignition/heavy metals should follow pharmacopoeial standards. Microbial limits: There may be 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. The source of the herbal material should be taken into account when considering the inclusion of other possible pathogens (Eg. Campylobacter and Listeria species), in addition to those specified in the European Pharmacopoeia. Microbial counts should be determined using pharmacopoeial procedures or other validated procedures. The European Pharmacopoeia gives guidance on acceptance criteria. Mycotoxins (aflatoxins, ochratoxin A): The potential for mycotoxins contamination should be fully considered. For aflatoxins and ochratoxin A, procedure and acceptance criteria should follow pharmacopoeial patterns. Pesticides, Fumigation agents, etc.: The potential for residues of pesticides, fumigation agents, etc. should be fully considered. Where necessary suitable validated methods should be used to control potential residues and the acceptance criteria should be justified. In the case of pesticide residues, the acceptance criteria of the European Pharmacopoeia should be applied unless fully justified Radioactivity: Radioactive contamination should be tested if there are any reasons for concerns. 3.20Quality Control and Standardization of Herbals. Vand ICH Guidelines for © Assay: In the case of herbal substances with constituents of the known therapeutic activity or with active markers, assays of their content are required with details of the analytical procedure. Where possible, a specific, stability-indicating procedure should be included to determine the content of the herbal substance. In the case of herbal substances where, the constituents responsible for the therapeutic activity are unknown, assays of analytical markers or other justified determinations are required. The appropriateness of the choice of markers should be justified. (ii) Herbal preparations: Herbal preparations are also diverse ranging from simple, comminuted plant material to extracts, tinctures, oils and resins. A complete specification must be developed for each herbal preparation based on recent scientific data. The general monograph ‘Herbal drug preparations’ of the European Pharmacopoeia should be consulted for the interpretation of the following requirements. The following tests and acceptance criteria are considered generally applicable to all herbal preparation: * Definition: A statement of the botanical source, and the type of preparation (E.g.: dry or liquid extract). The ratio of the herbal substance to the genuine herbal preparation must be stated. * Characters: A qualitative statement about the organoleptic characters of the herbal preparation. + Identification: identification tests should be specific for the herbal preparation concerning substitutes/adulterants that are likely to occur. Identification test by the combination of chromatographic tests (E.g: HPLC and TLC densitometry) or a combination of tests into a single procedure such as; HPLC/UV diode array, HPLC/MS, or GC/MS may be acceptable. ‘+ Tests-Water content: This test is important when the herbal preparations are known to be hygroscopic. The acceptance criteria may be justified with data on the effects of hydration or moisture absorption. A Loss on drying procedure may be adequate, however, in some cases (essential oil containing preparations), a detection procedure that is specific for water is required. + Impurities: © Residual solvents: Impurities arising from manufacturing processes should be followed as per European Pharmacopoeia. © Inorganic impurities, toxic (heavy) metals: The need for inclusion of tests and acceptance criteria for inorganic impurities should be studied during development and based on knowledge of the plant species, whether it is wild or cultivated and the manufacturing process. If the manufacturing process reduces the burden of toxic residues, the tests with the herbal substance may be sufficient. Acceptance criteria will ultimately depend on safety considerations. Where justified, procedures and acceptance criteria for sulphated ash/residue on ignition/heavy metals should follow pharmacopoeial standards. 3.21Quality Control and Standardization of Herbals. EUand ICH Guidelines for... © Microbial limits: There may be a need to specify the total count of aerobic mic organisms, the total count of yeasts and moulds and the absence of specific objectionable bacteria. Microbial counts should be determined using European pharmacopoeial procedures or other validated procedures. © Mycotoxins (aflatoxins, ochratoxin A): The potential for mycotoxins contamination should be fully considered. For aflatoxins and for ochratoxin A, procedure and acceptance criteria should follow pharmacopoeial standards. © Pesticides, Fumigation agents, etc: The potential for residues of pesticides, fumigation agents, etc. should be fully considered. Where necessary, suitable validated methods should be used to control potential residues and the acceptance criteria should be justified. In the case of pesticide residues, the acceptance criteria of the European Pharmacopoeia should be applied. © Assay: In the case of herbal preparations with constituents of the known therapeutic activity or with active markers, assays of their content are required with details of the analytical procedure. Where possible, a specific, stability-indicating procedure should be included to determine the content of the herbal substance in the herbal preparation. In cases where, the use of a non-specific assay is justified, other supporting analytical procedures may be used to achieve overall specificity if required. In the case of herbal preparations where, the constituents responsible for the therapeutic activity are unknown, assays of analytical markers or other justified determinations are required. The appropriateness of the choice of markers should be justified, Vitamins and minerals in traditional herbal medicinal products for human use: The following tests and acceptance criteria are considered generally applicable to traditional herbal medicinal products for human use containing vitamins/minerals as ancillary substances: + Identification: identification tests should establish the specific identity of the vitamin(s) and/or mineral(s). * Assays: Validated assays of vitamins and minerals are required. * Impurities: Impurities arising from degradation of the vitamin(s) or mineral(s) should be monitored in the traditional herbal medicinal product for human use. (iv) Herbal medicinal products: The following tests and acceptance criteria are considered generally applicable to all herbal medicinal products: * Description: A qualitative description of the dosage form should be provided (Eg: 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. * Identification: Identification tests should establish the specific identity of the herbal substance(s) and/or herbal preparation(s), in the herbal medicinal product. 3.22Quality Control and Standardization of Herbals. Vand ICH Guidelin tor Identification solely by chromatographic retention time is not regarded as being specific. However, a combination of chromatographic tests or a combination of tests into a single procedure such as; HPLC/UV-diode array, HPLC/MS or GC/MS may be acceptable. 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. Assay: 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). A specific, stability-indicating procedure should be included to determine the content of the herbal substance(s) and/or herbal preparation(s) in the herbal medicinal product. In cases where the use of a non-specific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. In the case of herbal medicinal products containing the herbal substance(s) and/or herbal preparation(s) where the constituents with 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. Impurities arising from the herbal substance(s) and/or herbal preparations like 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 need not be controlled in the herbal medicinal product provided it is appropriately controlled in the extract specification. However, solvents used in tablet coating should be controlled in the dosage form. In cases where, degradation products of the herbal substance/preparation are evident (Eg: aglycones from hydroxyanthracene glycosides), they should be monitored in the herbal medicinal product. Acceptance limits should be stated for such degradation products. Ithas been demonstrated by the provision of a significant body of data, generated using appropriate analytical methodologies that the herbal substance and/or herbal preparation do not degrade in the specific formulation and under the specific storage conditions proposed in the marketing authorization. Degradation product testing may be reduced or eliminated upon approval by the regulatory authorities. icrobial limits: 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 3.23Quality Control and Standardization of Herbals. Vand ICH Guidelines for pharmacopoeia procedures or other validated procedures. The European Pharmacopoeia gives guidance on acceptance criteria (©) Specific tests/criteria: In addition to the universal tests, the following tests may be considered applicable to herbal medicinal products on a case-by-case basis. Individual tests/criteria should be included in the specification when the tests have an impact on the quality of the herbal medicinal product for batch control. Tests other than those listed below may be needed in particular situations or as new information becomes available. 1. Herbal medicinal products: Additional tests and acceptance criteria generally should be included for particular herbal medicinal products. The following selection presents a representative sample of both the herbal medicinal products and the types of tests and acceptance criteria, which may be appropriate. The specific dosage forms addressed include; solid oral herbal medicinal products and liquid oral herbal medicinal products. (® Tablets (coated and uncoated) and hard capsules: One or more of these tests may also apply to soft capsules and granules. * Dissolution/disintegration: © In the case of immediate release, herbal medicinal products for which constituents with therapeutic activity are not known, the test for in vitro active substance release can be omitted. © For immediate release products containing herbal preparations, which are highly soluble throughout the physiological pH range, disintegration testing may sometimes be sufficient. Disintegration testing is most appropriate when a relationship to dissolution has been established or when the disintegration is shown to be more discriminating than dissolution. In such cases, dissolution testing may not always be necessary or maybe proposed as a periodic test. © Single-point measurements are normally considered to be suitable for immediate- release dosage forms. For modified release dosage forms, appropriate test conditions and sampling procedures should be established. © Where multiple-point acceptance criteria are necessary, in vitro/in vivo correlation may be used to establish these criteria when human or target animal species bioavailability data are available for formulations exhibiting different release rates. + Hardness/friability: It is appropriate to perform hardness and/or friability testing as an in-process control. If the characteristics of hardness and friability have a critical impact on herbal medicinal product quality (chewable tablets), acceptance criteria should be included in the specification. * Uniformity of mass: The pharmacopoeial procedure should be used. If appropriate, this test may be performed as in-process control, the acceptance criteria should be included in the specification, * Water content: A test for water content should be included. The acceptance standard may be justified with data on the effects of or water absorption on the herbal medicinal product. In some cases, a Loss on drying procedure may be 3.24Quality Control and Standardization of Herbals. Vand ICH Guidelines for adequate, however, a detection procedure, which is specific for water (Karl Fischer titration), is required. * Microbial limits: Microbial limit testing is seen as an attribute of Good Manufacturing Practice, as well as of quality assurance. It is advisable to test the herbal medicinal product unless its components are tested before manufacturing and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination. For guidance on acceptable limits, reference should be made to the European Pharmacopoeia or other validated procedures. Gi) Oral liquids: One or more of the following specific tests will normally apply to oral liquids and to powders intended for reconstitution as oral liquids. * Uniformity of mass: Generally, acceptance criteria should be set for weight variation, fill volume and/or uniformity of fill. Pharmacopoeial procedures should be used. © If appropriate, tests may be performed as in-process controls, however, the acceptance criteria should be included in the specification. This concept may be applied to both single-dose and multiple-dose packages. © The dosage unit is considered to be the typical dose taken by the patient. If the actual unit dose, as taken by the patient, is controlled, it may either be measured directly or calculated, based on the total measured weight or volume of the drug, divided by the total number of doses expected. If dispensing equipment (such as; medicine droppers or dropper tips for bottles) is an integral part of the packaging, this equipment should be used to measure the dose. Otherwise, a standard volume measure should be used. The dispensing equipment to be used is normally determined during development. © For powders for reconstitution, uniformity of mass testing is generally considered acceptable. + pH: Acceptance criteria for pH should be provided where applicable and the proposed range justified. + Microbial limits: Microbial limit testing is seen as an attribute of Good Manufacturing Practice, as well as of quality assurance. It is advisable to test the herbal medicinal product unless its components are tested before manufacture and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination. For guidance on acceptable limits, reference should be made to the European Pharmacopoeia or other validated procedures. + Antimicrobial preservative content ‘For oral liquids requiring an antimicrobial preservative, acceptance criteria for preservative content must be stated. These criteria should be based on the levels necessary to maintain microbiological product quality throughout the shelf life. © Antimicrobial preservative effectiveness. should be demonstrated during development, during scale-up and throughout the shelf life. 3.25Quality Control and Standardization of Herbals. Vand ICH Guidelin tor Antioxidant preservative content: Release testing for antioxidant content should normally be performed. When antioxidant content testing is performed as an in- process test, the acceptance criteria should remain part of the specification. If only release testing is performed, this decision should be reinvestigated whenever either the manufacturing procedure or the container/closure system changes. Extractable: When the development and stability data show no significant evidence of extractable from the container/closure system, elimination of this test may be proposed. This should be reinvestigated if the container/closure system changes. Alcohol content: Where it is declared quantitatively on the label in accordance with relevant regulations, the alcohol content should be specified. Dissolution: It may be suitable to include dissolution testing and acceptance criteria for oral suspensions and dry powder products for resuspension. Dissolution procedures using either pharmacopoeial or non-pharmacopoeial apparatus or conditions should be validated. Single-point measurements are normally considered suitable for immediate-release dosage forms. Multiple-point sampling, at appropriate intervals, should be performed for modified-release dosage forms. Acceptance criteria should be set based on the observed range of variation and should take into account the dissolution profiles of the batches that showed acceptable performance in vivo. Developmental data should be considered when determining the need for either a dissolution procedure or a particle size distribution procedure. Dissolution testing may be performed as an in-process test, or as a release test, depending on its relevance to product performance. The discussion of dissolution for solid oral dosage forms and of particle size distribution, should also be considered. Particle size distribution: Quantitative acceptance criteria and a procedure for the determination of particle size distribution may be appropriate for oral suspensions. Particle size distribution testing may be performed as an in-process test or as a release test, depending on its relevance to product performance. if these products have been demonstrated during development to have consistently rapid drug release characteristics, the exclusion of a particle size distribution test from the specification may be proposed. Particle size distribution testing may also be proposed in place of dissolution testing, justification should be provided. Acceptance criteria should be set based on the observed range of variation end should take into account the dissolution profiles of the batches that showed acceptable performance in vivo, as well as the intended use of the product. The 3.26Quality Control and Standardization of Herbals. Vand ICH Guidelin oF an potential for particle growth should be investigated during product development; the acceptance criteria should take the results of these studies into account. Redispersibility: For oral suspensions, which settle on storage (produce sediment) acceptance criteria for redispersibility may be appropriate. Shaking may be an appropriate test. The procedure (mechanical or manual) should be indicated. The time required to achieve re-suspension by the indicated procedure should be clearly defined. Data generated during product development may be sufficient to justify skip lot testing, or elimination of this attribute from the specification. Rheological properties: For relatively viscous solutions or suspensions, it may be appropriate to include theological properties (viscosity) in the specification. The test and acceptance criteria should be stated. Data generated during product development may be sufficient to justify skip lot testing, or elimination of this attribute from the specification. Specific gravity: For oral suspensions, or relatively viscous or non-aqueous solutions, acceptance criteria for specific gravity may be appropriate. Testing may be performed as an in-process control. Reconstitution time: Acceptance criteria for reconstitution time should be provided for dry powder products, which require reconstitution. The choice of diluent should be justified. Data generated during product development may be sufficient to justify skip lot testing or elimination of this attribute from the specification. Water content: For oral products requiring reconstitution, a test and acceptance criterion for water content should be proposed when appropriate. Loss on drying is generally considered sufficient if the effect of absorbed moisture vs. water of hydration has been adequately characterized during the development of the product. In certain cases (essential oil containing preparations), a more specific procedure (Karl Fischer titration) is required. 2. Herbal Medicinal Products containing exclusively herbal substances (herbal teas): One or more of these tests may apply to herbal medicinal products containing exclusively herbal substances. Loss on drying: To be specified depending on the plant parts present in the herbal medicinal product, if not performed on the herbal substance. Identification: Identification tests (chromatographic methods) must establish the specific identity of the herbal substance(s) in the herbal medicinal product and ‘optimally should be discriminatory between the different herbal substances and with regards to substitutes/adulterants that are likely to occur. Microscopical and macroscopical characterization can be used to support identification if justified. Purity: Relevant adulterants and substitutes should be determined (when toxic adulterants or substitutes are known). 327Quality Control and Standardization of Herbals. Vand ICH Guidelin * Uniformity of mass/Average mass of the sachet (herbal tea): © Generally, acceptance criteria should be set for weight variation and/or fill volume. Pharmacopoeial procedures should be used. If appropriate, tests may be performed as in-process controls, however, the acceptance criteria should be included in the specification. This concept may be applied to both single-dose and multi-dose products. © The dosage unit is considered to be the typical dose taken by the patient. If the actual unit dose, as taken by the patient, is controlled, it may either be measured directly or calculated, based on the total measured weight or volume of herbal substance, divided by the total number of doses expected. If dispensing equipment is an integral part of the packaging, this equipment should be used to measure the dose. Otherwise, a standard volume measure should be used. The dispensing equipment to be used is normally determined during development. = Assay: © Inthe 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). A specific, stability-indicating procedure should be included to determine the content of the herbal substance(s) © In the case of herbal medicinal products containing the 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. * Particle size: A suitable specification has to be given by the manufacturer. robial qui © Microbial limit testing is seen as an attribute of Good Manufacturing Practice, as well as of quality assurance. It is advisable to test the herbal medicinal product unless its components are tested before manufacture and the manufacturing process is known, through validation studies, not to carry a significant risk of microbial contamination. © Reference should be made to the European Pharmacopoeia for guidance on acceptable limits. © Periodic testing may be appropriate. Where appropriate, acceptance criteria should be set for the total count of aerobic microorganisms, the total count of yeasts and moulds, and the absence of specific objectionable bacteria (E.g, Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas). Counts should be determined using pharmacopoeial or other validated procedures, and at a sampling frequency or time point in manufacture which is justified by data and experience. 3.28Quality Control and Standardization of Herbals. Vand ICH Guidelin 3.2.2 Non-clinical Guidelines () Guideline on the assessment of genotoxicity of herbal substances/preparations: This guideline describes a general framework and practical approaches on how to test the potential genotoxicity of herbal substances/preparations and how to interpret the results. In the development of this guideline, recent experiences in the hazard and risk assessment of some specific preparations such as; genotoxicity risks associated with furocoumarins in Angelica archangelica L. containing preparations or herbal preparations containing asarone, methyleugenol and safrole have been taken into account. Herbal medicinal products (HMPs) present several characteristics that clearly differentiate them from other medicinal products. Examples of important differences may include: * _HMPs are made of natural substances that may be part of regular, dietary, and/or environmental exposure, ie. the contribution of the substance to the overall exposure needs to be considered. * HMPs contain as active substance(s) complex mixtures with a large number of constituents that are present in sometimes highly variable amounts. * The composition of a defined preparation may vary as a function of harvesting time, geographical origin, mode of preparation, etc. * The complete composition is very difficult to unravel, so it may be argued that there are always many unknown constituents and thus, there may be "hidden" dangers. HMPs are similar to other medicinal products for human use that contain synthetic active substances: * The same basic legislation determines their legal position. * Many HMPs have been used for long time by a sizable portion of the population. Clinical experience, despite its shortcomings, may point to their relative safety, at least to the most apparent adverse reactions, but as with other medicinal products, signals of adverse effects arise only occasionally. Legal Basis: * Guidelines for genotoxicity testing of pharmaceuticals have been established by OECD, ICH and EMEA committees. Testing of medicinal products involves genotoxicity tests, in which pro and eukaryotic systems in in vitro and in vivo experimental setups with and without metabolic activation are employed. * Inthe HMPC Guideline on non-clinical documentation for herbal medicinal products in applications for marketing authorization (bibliographical and mixed applications) and in applications for simplified registration, a stepwise procedure for assessing genotoxicity of HMPs should be established. + The basic requirement is to assess genotoxicity initially in a bacterial reverse mutation test using a test battery of different bacterial strains and metabolic activation If 3.29Quality Control and Standardization of Herbals. Vand ICH Guidelines for positive results cannot be attributed to specific constituents with a well-established safety-profile for quercetin, additional in vitro, (mouse lymphoma cell assay), and, if necessary, in vivo studies were proposed, Guideline includes: * Testing strategy: The stepwise testing process described below is also presented in the form of a decision tree (Fig. 3.2) which should be read in conjunction with the text. * It is recognized that a single test, ce. the Ames test, in the first step cannot cover all genotoxic endpoints and thus, a significant sphere of genotoxic potential, in relation to chromosomal damage, remains untested. * The stepwise approach described below represents a pragmatic approach to address both scientific aspects of genotoxicity testing and the special needs of HMPs within the current regulatory framework applicable for these products. Step 1: The Ames test: The Ames test should be performed and interpreted in conformity with existing OECD and EU guidelines. Briefly, a set of different Salmonella typhimurium strains with various mutations present in a certain amino acid synthesizing gene is incubated in the presence of the studied substance/preparation and metabolic activation system (usually rat liver $9 mix containing induced drug-metabolizing enzymes). Chemical induced mutations which restore the functional capability of the bacteria to synthesize an essential amino acid (‘evertants’) are counted. The purpose of this test is to reveal the mutagenic potential of a substance in a prokaryote organism and whether the reactive metabolite is 2 product of metabolic activation by mammalian enzymes. Scenario 1: Negative test result: If the tests were considered to have been performed according to the ICH guidelines and the result is negative, no further genotoxicity testing is required based on HMPC non-clinical Guidelines. A negative test result fulfills the genotoxicity testing requirements for including a herbal substance or preparation in the community list of herbal substances, preparations and combinations thereof for use in traditional herbal mecicinal products. Scenario 2: Equivocal test result: Genotoxicity result, which is very weak or not consistent regarding the usual positive response in the test, deserves special considerations. The first option is to repeat the test to reveal whether the test outcome is the same as in the original experiment. In all cases, a proper assessment involves a survey of at least the following considerations: + Is the response dose-dependent or does it exhibit unusual or irregular features with regard to concentration? ‘+ Are there indications that the preparation affects the growth of test organisms thus, preventing the detection of genotoxic constituents? 330Quality Control and Standardization of Herbals. Vand ICH Guidelines for * The final assessment should be conducted via a thorough and transparent consideration of the test outcome in the light of test material and test conditions. Step 1: The Ames Test ‘SCENARIO 1: Positive test Negative result results T ‘SCENARIO 2: No further Equivocal test result Ge est 2 T SCENARIO 3 Weight-c-evidence considerations Ts the evidence ‘supporting the negative result? Yes + No further testing Fig. 3.2: A Decision Tree on the Assessment of Genotoxicity of Herbal Preparations Scenario 3: Positive test result: If the test outcome is judged clearly positive, the next step is dependent on whether some known genotoxic compounds are present or not in the herbal substance or preparation. The need of proceeding to step 2 is dependent on the assessment of the result, taking all information about the substance or preparation into consideration. Step 1 (a): A well-characterized and assessed genotoxic substance is identified to be responsible for genotoxic activity: If a well-known genotoxicant is identified and quantified in the preparation and if there an internationally acknowledged risk assessment on this well-known genotoxicant (quercetin) is available, it may be used as a basis of the genotoxicity risk assessment of the HMPs. In this case, the most important factor is to determine the potential exposure scenario in light of the assessed toxicity risk to humans. The concentration of the identified genotoxicant in the preparation should be measured as a pre-condition for risk assessment, as outlined in step 4. 331Quality Control and Standardization of Herbals. Vand ICH Guidelin SCENARIOS: Positive test result ‘Are any known Genotoric compounds ‘present in the herhal substance / preparations? Yes Step 1a: Well characterized and ‘Step 1b: Genotoxic response assessed genotoxic substance is cannot be attributed to any present and responsible for specific constituents genotoxic activity a Step 4: Risk assessment Step 2: The mouse considerations Lymphoma Assay Negative result? No further testing No further oe ‘Negative result? ‘Step 4: Risk assessment considerations Fig. 3.3: A Decision Tree on the Assessment of Genotoxicity of Herbal Preparations ‘Step 1 (b): Genotoxic response cannot be attributed to any specific constituents: If there is no knowledge about the active principle(s), the herbal substance or preparation has to be studied in a step 2 test. 332Quality Control and Standardization of Herbals. Vand ICH Guidelin Step 2: Mouse lymphoma assay or other mammalian cell assays: The mouse lymphoma assay should be performed and interpreted in conformity with existing OECD and EU guidelines. L5178Y mouse lymphoma cells in culture are exposed to a compound or preparation under study and gene mutations in the thymidine kinase gene are detected. The purpose is primarily to confirm or disprove the positive finding in the Ames test, ie. the ability of a substance to induce gene mutations ("large colonies") in a mammalian cell line. Additionally, mouse lymphoma assay might give information on the ability of a herbal substance or preparation to cause chromosomal damage (“small colonies’). If the test result is negative, no further testing is required, But if the test result is positive for chromosomal damage ("small colonies’) the relevance of the finding should be thoroughly assessed as it is known that the mouse lymphoma assay can give biologically irrelevant findings, in relation to conditions of high cytotoxicity. If the test result is unequivocally positive and considered relevant either in gene mutation or chromosomal damage, it is advisable to proceed to step 3 Step 3: Rodent micronucleus test or other in vivo genotoxicity tests: The rodent micronucleus test should be performed and interpreted in conformity with the existing OECD and EU guidelines. Mice or rats are treated with a compound or preparation under study in a vehicle and via an appropriate route of administration and micronuclei in bone marrow or peripheral blood cells are counted. The purpose of the micronucleus assay is to identify agents that cause structural and numerical chromosome changes in in vivo conditions, ie. a living mammal. If another mammalian in vivo tests are employed for genotoxicity tests, their use and comparability have to be justified. If the test result is negative, no further testing is required. Still the positive test results of Step 1 and 2 tests have to be fully addressed in the expert report supporting the marketing authorization/registration application. Step 4: Risk assessment considerations: Toxicological background: Current regulatory practice conceming pharmaceuticals assumes that genotoxic ‘compounds have the potential to damage DNA at any level of exposure and thus, there is no visible threshold and any level of exposure carties a risk. Ithas been increasingly recognized that there may be practical thresholds and that linear extrapolation from high in vitro or animal concentrations to low human exposures is scientifically questionable. It is difficult to experimentally prove both the existence of a threshold for the genotoxicity and the linearity of genotoxic response at extremely low exposures. For these reasons, it may be practical to adopt approaches, which involve a concept of a level of exposure that carries an acceptable risk. It is not possible to recommend a single specific approach to perform risk assessment. The standard uncertainty (safety) factor approach, which is a common practice in toxicology, is probably unsuitable for genotoxicity (and carcinogenicity) in the majority of cases. The 333oF an Quality Control and Standardization of Herbals. Vand ICH Guidelin margin of exposure approach for the risk assessment of genotoxic and carcinogenic compounds (comparison on the animal experimental dose-response curve divided by the estimated intake by humans), which is recommended by the EFSA (European Food Safety Authority) Scientific Committee on Food, is probably not applicable for HMPs, because this approach is based on available carcinogenicity data, which is usually lacking in case of HMPs. If such data are available, the EFSA Committee is of the opinion that a compound with a calculated margin of exposure of 10,000 or higher would be of low health risk. A Risk Assessment by the Threshold of Toxicological Concern (TTC): Risk assessment schemes have originally been developed for identified single chemicals or well-characterized mixtures of chemicals. If an herbal preparation contains a detectable genotoxic compound, the TTC approach could be applied. ATIC value of 1.5 pig/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100000 over a lifetime) for most pharmaceuticals. From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as; short-term exposure periods. The same approach might be considered for genotoxic constituents in herbal substances/preparations, if sufficiently justified by the applicant. Also, higher limits may be applied when the applicant submits additional data and 2 toxicologically reasonable argumentation for the required justification. Genotoxic Substances with Threshold: If a genotoxic substance is a compound with a demonstrated threshold mechanism, permissible exposure levels without appreciable risk of genotoxicity can be established according to the usual procedure employing the No Observable Effects Level (NOEL) from the most relevant (animal) study applying uncertainty factors, if available The Identification and Quantification of the Genotoxic Constituent: Herbal preparations being complex mixtures with partially unidentified components, it is quite possible that the compound(s) responsible for genotoxicity is (are) still not identified at the end of the testing protocol. There are no established ways to perform a risk assessment of genotoxicity due to unidentified substances in herbal preparations. The usual procedure for toxicity testing and risk assessment of mixtures consists in isolation and identification of various principal constituents and testing of the isolated ‘compounds individually. This is a recommended option for clearly genotoxic HMPs, because this approach would provide relevant and reliable information for risk assessment. However, because isolation and identification may require long times and extended efforts, the initial risk assessment should be performed based on the above testing strategy. On the basis of these results and a careful consideration of benefits and risks a marketing authorization with the obligation to complete some additional tests may be considered. A risk from administration of an HMP might be accepted if its contribution to the overall exposure through food is considered to be small. 3.34Quality Control and Standardization of Herbals. Vand ICH Guidelin Exposure Considerations: Because many herbal substances and preparations are derived from plants which are also used as food, it is apparent that exposure to various herbal constituents can also occur via diet. It is clear that amounts and ratios of these constituents vary enormously, depending on individual and population dietary preferences. For a proper tisk assessment, dietary ‘exposures should be assessed and quantified, as far as possible and a comparative assessment of exposures via diet and herbal substances and preparations consumption should be performed. In many cases, it may be advisable to contact dietary health risk assessing bodies for information and/or discussion of risk assessment considerations. (1) Guideline on non-clinical documentation in applications for marketing authorization/registration of well-established and traditional herbal medicinal products: This guideline provides guidance on the minimum requirements for non-clinical data for well-established herbal medicinal products in bibliographical applications for marketing authorizations and on the question which non-clinical safety aspects should be addressed in the expert report for the simplified registration of traditional herbal medicinal products and which additional non-clinical safety tests might be necessary to prove safety. The guideline may also be used in the framework of assessment for the establishment of an European Union herbal monograph or an entry into the list of traditional herbal substances Non-clinical documentation includes: ® General aspects: The documentation should be based on a comprehensive scientific literature including; handbooks and monographs specific to phytotherapy and traditional herbal medicine and searches in electronic databases. The search strategy and the results of the search must be documented. + Ifassessment reports of the HMPC supporting EU herbal monographs/list entries for the herbal substances/herbal preparations in question exist, those can be seen as starting points for a comprehensive literature search starting from the given time of the literature search mentioned in the assessment report. + Many herbal preparations contained in traditional herbal medicinal products have an acceptable safety profile, which has been based on their long-term medicinal and/or food use. However, in cases where, a safety concern is recognized or suspected, non- clinical investigations may be needed. Any additional studies should be provided to support 2 marketing authorization or registration. * The documented experience gathered during the long-standing use will be the main basis of the non-clinical assessment of traditional and well-established herbal medicinal products. For this reason, attention should be paid to effects that are difficult or even impossible to detect clinically. These effects include; toxicity to reproduction, genotoxicity and carcinogenicity. 335