Issue: 91 Page: 40-55
Reproducible Efficacy and Safety Depend on Reproducible Quality: Matching the Various Quality Standards that have been Established for Botanical Ingredients with their Intended Uses in Cosmetics, Dietary Supplements, Foods, and Medicines
by Josef Brinckmann
HerbalGram. 2011; American Botanical Council
Whether using a botanical ingredient as food (for sensory experience; aroma, color, taste, mouthfeel and/or texture) or as medicine (for symptomatic relief, treatment, or prevention of disease), if the botanical is observed to be effective (or ineffective), can one draw conclusions about the effects of the botanical species broadly? Or, must conclusions be confined to the specific quality of botanical that was used? Can a specified quality of a botanical be effective for its intended use while another specified quality of the same species is observed to be ineffective? This article discusses and provides examples of quantifiable differences in the composition, purity, quality, and strength of various defined qualities of botanical ingredients that are commercially traded. Furthermore, quality standards monographs for botanical ingredients have been developed expressly for different uses and purposes by many standards setting organizations (SSOs) around the world. Product manufacturing companies may base their own specification requirements (for purchasing and quality control testing) on a specific standard as defined in a suitable monograph. Reproducible results (safety and efficacy), whether they affect sensory satisfaction or relief of symptoms, are intrinsically linked to consistent and reproducible quality. As a prerequisite of reproducible efficacy, an herbal product manufacturer can define the effective quality of an ingredient as accurately and as narrowly as possible in the form of a written specification that the company’s quality unit can implement. However, if a product manufacturer loosely allows the interchangeable use of different qualities of the botanical ingredient in its finished product, the quality will not be reproducible and, correspondingly, the results may vary.
Certain Botanicals Exist in Different Quality Grades Suitable for Different Purposes
Most everything that is commercially traded, including botanical ingredients, is available in a range of defined grades and qualities; from inexpensive inferior grades (usually with broad and general standards that are relatively easy to meet), to the most expensive superior grades (usually with narrow and specific standards that are not so easy to meet), and various grade designations in between. In the United States there are markets for all qualities. The highest grades of botanicals are available for quality-oriented buyers who need their herbal products to demonstrate reproducible efficacy and safety for specific intended health benefits. The lowest grades of botanicals are available for price-oriented buyers who need their herbal products to satisfy considerable consumer demand for low prices and discounts and/or shareholder demand for higher profits.
But it is not so black and white. Botanicals often have multiple end uses and purposes, and each could necessitate a different quality standard in order to deliver the intended effect of the product and/or to comply with regulatory requirements. For example, any active ingredient or botanical drug substance included in a US Food and Drug Administration (FDA) nonprescription (also known as over-the-counter [OTC]) drug monograph must be recognized in an official United States Pharmacopeia (USP) drug monograph that sets forth its standards of identity, strength, quality, and purity.1
In addition to the significant qualitative and quantitative differences between the specification requirements for food or spice grades and therapeutic or pharmacopeial quality standards for botanicals, there are also considerable and justifiable differences in costs (See Table 1). For many botanicals, post-harvest steps include various cleaning (aspiration [i.e., using forced air], de-stoning, metal detection, sieving), sorting, sizing, and grading steps, as well as laboratory analysis to enable grading by chemical composition. Batches may be sorted and separated into different grades using a combination of traditional methods (e.g., sorted by biological age, crop maturity, organoleptic properties such as coloration, bitterness, or pungency values, size, or purity percentage of plant part by hand or mechanical separation) with modern methods (e.g., volumetric determination of essential oil content followed by chemical composition analysis of the distilled oil by Gas Chromatographic-Mass Spectrometry [GC-MS]). A single harvested crop may be processed into several distinct quality grades, with each separated lot number marketed with a different specification and each with a different assigned monetary value.
How does the botanical product manufacturer (whether cosmetic, dietary supplement, food, or medicine) or the practitioner of herbal medicine sort out all of the various commercial grades and qualities in order to select and specify a quality that would be best suited for use in her and/or his unique product or prescription? While a food- or spice-grade botanical, if tested for use as an active medicinal ingredient, may be rejected as sub-standard, it would remain an acceptable grade for use as a food ingredient. If a food-grade botanical were used for a therapeutic purpose, the purity and strength per dose can be lower than the purity and strength of a therapeutic-quality. Thus, the customer, client, or patient may be under-dosing and not experiencing the intended effect. Conversely, if a therapeutic-quality botanical were used as a food ingredient, the customer may be disappointed with its sensory characteristics. In some cases, therapeutic quality standards specify higher minimum levels of certain constituents that, for example, may increase bitterness perception noticeably.
This article provides selected examples that aim to illustrate differences between the various commercial quality designations, including: animal feed, dietary supplement, excipient, food, spice, and pharmacopeial or therapeutic qualities. Additionally, the link between labeling standards monographs (showing the recommended use or purpose and dosage) and quality standards monographs (defining the minimum quality for the intended use or purpose) is clarified and information about the available monographs and the SSO is provided.
Who Defines Botanical Quality Standards and Why?
A range of governmental organizations (GOs), international governmental organizations (IGOs), and non-governmental organization (NGOs) act as SSOs. Within these organizations, expert committees, councils, or working groups are established with the charge of developing botanical monographs of specified quality standards for various intended uses. To give the reader an idea of the profuse number of standards that have been developed for quality testing of botanicals, the following is a brief summary of selected SSO’s in just one country: the United States of America (USA).
Botanical SSOs in the United States of America
United States Pharmacopeial Convention: The USP is a non-governmental, official public standards-setting authority for prescription (Rx) and OTC medicines and other healthcare products manufactured or sold in the United States, including excipients, food ingredients, and dietary supplements. The USP’s standards are recognized and used in more than 130 countries around the globe. The USP produces 4 types of monographs that cover a large range of botanical ingredients: (1) dietary supplement component; (2) excipient; (3) food ingredient; and (4) pharmaceutical active ingredient (OTC and Rx).
Dietary supplement standards: The Dietary Supplement Health and Education Act of 1994 (DSHEA) amendments to the Federal Food, Drug, and Cosmetic Act (FD&C Act) named the United States Pharmacopeia and National Formulary (NF) as official compendia for dietary supplement ingredient quality standards. At the same time, industry compliance with USP-NF standards was made voluntary. Nonetheless, the amendments stipulate that if an herbal dietary supplement that is covered by the specifications of an official compendium is represented as conforming to the specifications of an official compendium, and fails to conform to such specifications, it shall be deemed misbranded. Thus, compliance with a USP monograph becomes mandatory only in cases where the product label specifies that it contains components with a USP quality designation. Examples of USP herbal dietary supplement monographs include American Ginseng USP (dried roots) † (Panax quinquefolius, Araliaceae), Cranberry Liquid Preparation USP (juice from fresh fruits) (Vaccinium macrocarpon or V. oxycoccos, Ericaceae), Echinacea purpurea Aerial Parts USP (Echinacea purpurea, Asteraceae), Goldenseal USP (dried roots and rhizomes) (Hydrastis canadensis, Ranunculaceae), and Saw Palmetto USP (partially dried ripe fruits) (Serenoa repens, Arecaceae), among others.
Excipient standards: The FD&C Act recognizes the NF as an official compendium. The NF provides specifications for excipients (e.g., antioxidants, binders, bulking agents, coloring agents, flavoring agents, perfumes, pharmaceutical bases, sweetening agents). Examples of NF botanical excipient monographs include Candelilla Wax NF (purified wax from the leaves) (Euphorbia antisyphilitica, Euphorbiaceae), Cardamom Seed NF (Elettaria cardamomum, Zingiberaceae), Carnauba Wax NF (wax from the leaves) (Copernicia cerifera, Arecaceae), Cherry Juice NF (from fresh ripe fruit) (Prunus cerasus, Rosaceae), Stronger Rose Water NF (solution of odoriferous principles of the flowers) (Rosa centifolia, Rosaceae), and Vanilla NF (cured, full-grown, unripe fruits) (Vanilla planifolia or V. tahitensis, Orchidaceae), among others.
Food ingredient standards: The Food Chemicals Codex (FCC) is a compendium of internationally recognized standards for the purity and identity of food ingredients. Various FCC specifications are incorporated in the US Code of Federal Regulations (CFR) to define specific ingredients (e.g., Clove bud oil 21CFR 184.1257). The FCC monographs include food-grade coatings, coloring agents, emulsifiers, flavoring agents, masticatory substances (e.g., Chicle FCC), nutrients (e.g., Kelp FCC as a source of iodine), thickeners and stabilizers, vitamins, and functional food ingredients. Examples of FCC botanical monographs for food use include Annatto Extract FCC (from seeds) (Bixa orellana, Bixaceae), Bois de Rose Oil FCC (essential oil from chipped wood) (Aniba rosaeodora var. amazonica, Lauraceae), Copaiba Oil FCC (essential oil of exudate from tree trunk) (Copaifera spp., Fabaceae), Kelp FCC (dehydrated seaweed) (Macrocystis pyrifera, Lessoniaceae and Laminaria digitata, L. cloustoni, and L. saccharina, Laminariaceae), and Rebaudioside A FCC (from the leaves) (Stevia rebaudiana, Asteraceae), among others.
Standards for OTC & Rx Ingredients: The FD&C Act recognizes the USP as the official compendium for drug quality standards. Compliance with pharmacopeial standards is mandatory for active pharmaceutical ingredients. Botanical drug active ingredients with USP monographs include Capsicum Oleoresin USP (extract of the dried ripe fruits) (Capsicum annuum var. minimum and C. frutescens, Solanaceae), Digitalis USP (dried leaves) (Digitalis purpurea, Scrophulariaceae), Elm USP (dried inner bark) (Ulmus rubra, Ulmaceae), Ipecac USP (dried rhizomes and roots) (Cephaëlis acuminata or C. ipecacuanha, Rubiaceae), Podophyllum USP (dried rhizomes and roots) (Podophyllum peltatum, Berberidaceae), Psyllium Husk USP (Plantago ovata or P. arenaria, Plantaginaceae), Senna Leaf USP (Cassia acutifolia or C. angustifolia, Fabaceae), Rauwolfia Serpentina USP (dried roots) (Rauvolfia serpentina, Apocynaceae), and Witch Hazel USP (distillate from recently cut and partially dried dormant twigs) (Hamamelis virginiana, Hamamelidaceae), among others.
Homoeopathic Pharmacopoeia Convention of the United States (HPCUS): The Homoeopathic Pharmacopoeia of the United States (HPUS) is recognized in the FD&C Act as an official compendium for homeopathic drug component quality standards (OTC and Rx). The HPUS contains about 1,300 drug monographs, mostly botanically derived. Compliance with pharmacopeial standards of identity, strength, quality, and purity is mandatory for homeopathic drugs.
United States Department of Agriculture (USDA) Agricultural Marketing Service (AMS): The USDA AMS develops voluntary US Grade quality standards covering a range of agricultural commodities including some botanicals that may be used as foods or as starting materials for dietary supplements or other natural health products. USDA quality standards are based on measurable attributes that describe the value and utility of the product. Examples of USDA US Grade Standards published for botanicals include American Ginseng (cultivated roots), Blueberry (cultivated fruits) (Vaccinium australe, V. ashei, or V. corymbosum, Ericaceae), Cranberry (cultivated fruits), and Garlic (bulbs) (Allium sativum, Liliaceae), among others. The USDA also publishes some botanical specifications in the form of Commercial Item Descriptions (CID). USDA specifications established for botanicals include a CID for Black Tea Leaf (Camellia sinensis, Theaceae) and a Spices CID that includes specifications for Allspice (dried, nearly ripe fruits) (Pimenta dioica, Myrtaceae), Basil (dried leaves) (Ocimum basilicum, Lamiaceae), and Ginger (dried roots or rhizomes) (Zingiber officinale, Zingiberaceae), among others.
Additionally, the USDA has established certain standards for grades that become mandatory if the botanical article will be used as an active pharmaceutical ingredient of an FDA-approved OTC drug. There are cases where (1) a botanical is classified by FDA as Generally Recognized as Safe and Effective (GRASE) for a specific OTC drug use in either a final CFR monograph or in a tentative final monograph published in the Federal Register (FR); whereby (2) the specifications for the botanical drug must comply with the corresponding USP monograph; and in which (3) the USP monograph additionally requires compliance with a USDA US Standard-grade designation. For example, Bran CFR (pericarp, testa, nucellar tissue, and aleurone layer) (Triticum aestivum, T. compactum, or T. durum, Poaceae) is an OTC bulk-forming laxative active ingredient (as per Tentative Final Monograph 21CFR §334.10(a); Federal Register. 1985; Vol. 50, No. 10). The corresponding quality standards monograph (Wheat Bran USP) requires that the starting material comply with USDA’s US Standard for No. 1 Wheat (7CFR §810.2201). The OTC skin protectant and poison ivy/oak/sumac active ingredient Colloidal Oatmeal CFR (powder from whole oat grain) (consists of 50% or more of Avena sativa and/or A. byzantina [Poaceae]), and may contain not-more-than [NMT] 25% of A. fatua and/or A. sterillis) provides another good example. It is mandatory for Colloidal Oatmeal CFR to test in compliance with the standards of the Colloidal Oatmeal USP monograph, in which there is an additional requirement for compliance with USDA's US Standards for No. 1 or No. 2 Oats (7CFR §810.1001).
US Food and Drug Administration (FDA): In some cases, FDA provides a botanical quality specification in a CFR labeling standards monograph that does not correspond directly to a USP quality standards monograph. For example, in the case of the OTC cholecystokinetic‡ active ingredient Hydrogenated Soybean Oil (from seeds) (Glycine max, Fabaceae), the CFR monograph (21CFR §357.210) permits use of food-grade oil, which, in principle, should be satisfied by compliance with the NF monograph for Hydrogenated Soybean Oil. However, compliance with the CFR specification, which provides different quantitative standards from the NF monograph (e.g., different requirements for fatty acid composition, iodine value, and melting point), is mandatory if the soybean oil will be used as an OTC active ingredient. Another example is the case of psyllium husk, which, in addition to being an OTC bulk-forming laxative active ingredient (as per Tentative Final Monograph 21CFR §334.10(a); Federal Register. 1985; Vol. 50, No. 10), is also an FDA-approved soluble fiber food for reducing the risk of heart disease (as per Final Monograph 21CFR §101.81). To qualify for the soluble fiber health claim, the psyllium food must comply with the specifications outlined in the CFR which are different from the psyllium drug active ingredient specifications outlined in the USP monograph. Psyllium Husk CFR has requirements for minimum soluble fiber and maximum protein content (relevant for the heart health claim), which are not required in the USP standard. The USP standard does include a swell volume requirement that is not present in the CFR food-grade standard (swelling index is more relevant for intended use as a bulk-forming laxative drug).
Additionally, FDA’s Center for Drug Evaluation and Research (CDER) Office of New Drug Quality Assessment (ONDQA) may, in certain cases, consider acceptability of the use of standards from alternative compendia in lieu of compliance with a USP monograph, in particular in cases of new drug applications (NDAs) wherein the applicant can justify the use of an equivalent or better standard from the British Pharmacopoeia (BP), European Pharmacopoeia (PhEur), or Japanese Pharmacopoeia (JP).
American Spice Trade Association (ASTA): ASTA is a non-profit, non-governmental trade association that has developed non-official yet authoritative quality standards for spices. ASTA publishes its “Cleanliness Specifications for Spices, Seeds, & Herbs,” which contains specifications for macroscopic examination of foreign and domestic spices, which are part of ASTA’s standard contracts utilized by ASTA member companies. ASTA has also developed a series of spice monographs that include definitions, classifications, quality criteria, and flavor chemistry.
American Herbal Pharmacopoeia (AHP): AHP is a non-profit, non-governmental, non-official yet authoritative standards-setting body. AHP has produced a series of critically reviewed documents within the “American Herbal Pharmacopoeia® and Therapeutic Compendium” that outline the quality control criteria needed to ensure the identity, purity, and quality of botanical raw materials that are used as herbal dietary supplement components or as medicinal natural health products. Botanical raw materials with AHP monographs include Black Cohosh Rhizome AHP (Actaea racemosa, Ranunculaceae), Black Haw Bark AHP (Viburnum prunifolium, Caprifoliaceae), Cramp Bark AHP (Viburnum opulus, Caprifoliaceae), Cranberry Fruit AHP, Echinacea purpurea Aerial Parts AHP, and Skullcap Aerial Parts AHP (Scutellaria lateriflora, Lamiaceae), among others. AHP has published 27 monographs to date (July 2011).
The summary of SSOs in the USA is but a fragment of the global picture because some countries—the Republic of India, for example—have even more SSOs developing botanical quality standards than the USA and the European Union (EU) combined. In India, it is possible to find multiple quality standards for the same botanical (especially if the botanical is used as a food, spice, and medicine) established in several authoritative and/or official publications including the AGMARK Grading and Marking Rules, the Ayurvedic Pharmacopoeia of India (API), the Bureau of Indian Standards (BIS) Specifications, the Indian Herbal Pharmacopoeia (IHP), the Indian Pharmacopoeia (IP), the Multi Commodity Exchange of India Ltd (MCX) Contract Specifications, the National Multi-Commodity Exchange of India Ltd (NMCE) Contract Specifications, the Prevention of Food Adulteration (PFA) Act and Rules for Spices, the Siddha Pharmacopoeia of India (SPI), and the Unani Pharmacopoeia of India (UPI). And there are international SSOs developing botanical quality standards that may be used voluntarily by companies. In some cases, however, certain international standards are adopted by a national authority and therefore become official in that country (especially in countries without their own national pharmacopeia* and formulary). These may include quality standards established by the Codex Alimentarius Commission, by the International Organization for Standardization (ISO), the Joint FAO/WHO Expert Committee on Food Additives (JEFCA), and the World Health Organization (WHO). Although WHO monographs may be used by a company as a basis for its botanical quality specifications, the WHO monographs are not intended to replace any official compendia such as national pharmacopeias, formularies, or legislative documents.
Differentiating Botanical Quality Designations: Selected Examples
Psyllium husk. A useful example to illustrate differences in botanical grading standards is the Indian food supplement and medicinal plant psyllium husk. Psyllium husk, the cleaned, dried seed coat (epidermis) separated from psyllium seeds, is used in animal and human foods, veterinary and human medicines, and as a fiber supplement. It is marketed and valued mainly on the basis of percentage (%) of purity grade designations. Psyllium grade designations include certain quantitative standards that have a corresponding relationship to a specific use and minimum effective dose (e.g., the percentage of pure husk and the swelling index correspond to single-dose efficacy). In its country of origin, Indian exporters of psyllium husk typically specify at least 7 different purity grades (99%, 98%, 95%, 90%, 85%, 80%, and 70%). The 70% purity grade, a.k.a. “Industrial Grade Kha-Kha Powder” or “Psyllium Industrial Dust,” is a byproduct used mainly as horse-feed and in veterinary medicines but is also used in landscaping to prevent soil erosion. The 80%, 85%, and 90% grades, respectively, are used mainly as food additives, pharmaceutical aids (excipients), and/or dietary supplement ingredients. Purity grades of 95%, 98%, and 99% are the therapeutic quality grades that are used mainly as bulk-forming laxative active ingredients for relief of occasional constipation2 or as soluble fiber products taken to reduce the risk of heart disease.3
In addition to the percent purity grades established by the Indian trade, the Government of India established 3 food-grade designations (AGMARK Isubgol Husk Grade I, Grade II, and Grade “Special”).4 Indian exporters must reconcile their own national and trade standards against international pharmacopeial standards, particularly for exports to OTC drug manufacturing companies in the EU Member States (the material must be of Ispaghula Husk PhEur-grade)5 and in the US (must be of Psyllium Husk USP-grade).6
Psyllium percent purity grades are generally determined by a calculation of [100– (%L + %H)], i.e., 100 minus the combined percentages of light extraneous matter (L) + heavy extraneous matter (H); however, some producers consider only the light extraneous matter in their calculation [100– (%L)] as heavy extraneous matter is negligible or absent after cleaning steps. For psyllium husk, light extraneous matter includes gritty particles, broken or entire embryo, fragments of endosperm and/or capsular wall of fruits. Heavy extraneous matter includes sand or dirt.
Psyllium husk is separated from the seed traditionally by winnowing and threshing, but on a commercial scale this is accomplished by mechanical cleaning, separating, and milling processes. To obtain different purity grades of husk, the seeds are subjected to a multi-stage process comprising a pass through a magnetic separator (to remove ferrous/metal residue), several passes through an aspirator (which uses air to classify by size and density), several passes through a centrifugal sieving machine (to screen for sand and dust, and to dispose of underdeveloped seeds), a pin mil (to polish), a de-stoner (to separate out heavy impurities), and various grinding and de-husking machines. The husks are then passed through gravity separators for further purification.
Table 1 shows typical Indian purity grades of psyllium husk with corresponding swell volume values. Column 3 of the table shows typical market prices for full-container-load (FCL) quantities for most of the grades available from the 2010 harvest in India. As international pharmacopeial standards require NLT 95% purity and NLT 40 ml/g swell volume, only 3 of the listed commercial grades could comply, for example, with the Psyllium Husk USP monograph; i.e. 95% grade, 98% grade, and 99% grade.
Table 2 compares 2 AGMARK food-grades (Isubgol Husk Grade-I and Grade-II) against the PhEur and USP pharmacopeial standards. The table shows that the AGMARK food grades do not have a minimum swell volume requirement while both PhEur and USP standards require NLT 40 ml/g. The food grades also permit much higher levels of foreign matter, 12.5% organic impurities in Grade II and 7.5% in Grade I, while PhEur quality allows 2% (= 98% Grade) and USP quality allows 5% of light extraneous matter (= 95% Grade).
American Ginseng Root. American ginseng root (P. quinquefolius, Araliaceae) is used as a component of food products, herbal dietary supplement products, and herbal medicinal products. The People’s Republic of China (PRC) has established not only pharmacopeial quality standards for the use of American ginseng root in Chinese medicines but also State Standards for the grade and quality of other products of processed American ginseng root (e.g., tea-bagged products). The Codex Alimentarius Commission has published a food grade standard for American ginseng root while the USP Convention has published a dietary supplement monograph. Table 3 compares various American ginseng root quality standards including the (1) Codex Alimentarius Commission food grade (Codex Stan 295R-2009);7 (2) State Standard of the PRC tea bag grade (GB/T 17356.5-1998);8 (3) USP dietary supplement-standard (American Ginseng USP);6 and (4) Pharmacopoeia of the PRC therapeutic-standard (Radix Panacis Quinquefolii PPRC).9 In addition to the aforementioned American ginseng quality standards, the USDA’s United States Standards for Grades of Cultivated Ginseng describe 4 grades: US Premium, US Select, US Medium, and US Standard.10 The USDA grades are not included in the following table as the parameters used are quite different from the other compendia. The USDA grades are determined mainly by appearance, external color, size (diameter and length), wrinkle, and the following 3 calculations: (a) the Whole Root Score, which is measured by separating the prongs and fiber, culls, and foreign material from the whole roots, and weighing each separated category; (b) Total Root Deductions, found by weighing the internal and external defects and determining each percentage of the sample; and (c) Graded Value, which is calculated by subtracting the Total Root Deductions from 100 and multiplying the results by the Whole Root Score.
Capsicum Fruit. Capsicum fruit (Capsicum annuum and C. frutescens, Solanaceae) and/or its extracted oleoresin is used as a component of cosmetics (for humectant and/or skin conditioning),11 of dietary supplements (for digestive and circulatory system support),12 of foods (as a color additive,13 flavoring agent, spice, or seasoning),14 and of medicines (as an external analgesic active ingredient).2 Table 4 compares various capsicum fruit quality grades and standards including the AGMARK Standard Spice Grade of Chillies/Capsicums/Paprika,15 the International Organization for Standardization (ISO) Food Grade of Chillies and Capsicums,16 in addition to European Pharmacopoeia (Capsicum PhEur)5 and USP (Capsicum USP)6 standards of capsicum fruit for use as an active pharmaceutical ingredient of external use drug products. The table shows that neither ISO food grade nor AGMARK standard spice grade have a content requirement while the PhEur standard requires NLT 0.4% of total capsaicinoids, of which NMT 5.0% is nonivamide. The USP standard requires NLT 12% of nonvolatile ether-soluble extractive.
Peppermint Leaf. When peppermint leaf (Mentha × piperita, Lamiaceae) is to be used as a component of tabouleh mix, food-grade peppermint will suffice, and if used as a pharmaceutical aid (as filler, flavor, or perfume), excipient-quality peppermint would be suitable. But if peppermint leaf is to be used as an active medicinal ingredient of tinctures or teas for symptomatic relief of dyspepsia and flatulence, pharmacopeial-quality peppermint leaf is best suited for that therapeutic purpose. Table 5 compares various peppermint leaf quality grades and standards including excipient standard (Peppermint NF),6 food grades I and II (Peppermint ISO 5583:1984),17 and therapeutic quality (Peppermint leaf PhEur).5 The table shows that the excipient standard does not have an essential oil content requirement. Food grade II requires NLT 0.8% of essential oil; food grade I requires NLT 1%; and therapeutic-quality requires NLT 1.2% in the whole leaf, but NLT 0.9% in the cut leaf. However, because licensed or registered drug products must test in compliance with the monograph up until the labeled expiration date, in practice, companies may establish higher-than-pharmacopeial quantitative standards, especially in the case of essential oil drugs like peppermint leaf that may lose some quality and strength over time. A company may establish an essential oil specification that is higher than the pharmacopeial standard based on the results of their own shelf-life stability trials and a known rate of volatilization under their specific packaging and storage conditions.
Components of Quality Standards Monographs and Labeling Standards Monographs
Quality Standards Monographs
A botanical quality standards monograph provides a specification that consists of a series of tests, procedures for the tests, limits, and acceptance criteria for the composition, identity, purity, quality, and strength of a botanical ingredient or preparation. Table 6 provides examples of monograph components that would fall within the 5 aforementioned criteria. The types and numbers of tests are species-specific depending on what is most relevant to determine a specified quality. For example, a strength test for determination of bitterness value (by comparison with quinine) is relevant for dandelion herb or root (Taraxacum officinale, Asteraceae) but not for marshmallow leaf or root (Althaea officinalis, Malvaceae), for which strength is determined instead by a swelling index test (to measure the volume of mucilage after swelling in liquid).
Examples of English-language standards that may be used as the basis for specifications for purchasing and quality control testing of botanical ingredients are listed in Table 7. Such standards include color reaction tests, TLC tests, total and acid-insoluble ash, water-soluble extractive, etc.
Labeling Standards Monographs
Labeling standards monographs, sometimes referred to as therapeutic monographs, provide text that should appear on the label of the finished herbal product. In some cases, the monograph also provides essential information that must appear in the Patient Information Leaflet (PIL) or package insert. In the case of licensed, listed, or registered herbal medicinal products (OTC or Rx), the labeling standards monograph is linked by regulation to a specified quality standards monograph. In other words, the approved therapeutic uses and dosage for the medicinal product are permitted only for active ingredients of a specific defined pharmacopeial quality.
Components of a labeling standards monograph may include the standard common name with its corresponding Latin binomial, the plant part and processed form, quality specification requirement, dosage form(s) (dry extract in capsules or tablets, fluid extract, herbal tea, tincture), therapeutic indications for use, dosage and method of administration, duration of use, and risk information (cautions, contraindications, interactions, overdose, side effects, pregnancy, and lactation statements). To illustrate the types of monographs that may form the basis of finished herbal product labels, Table 8 provides links to official labeling standards monographs for witch hazel (Hamamelis virginiana, Hamamelidaceae), from Health Canada Natural Health Products Directorate (NHPD), European Medicines Agency (EMEA), and FDA.
The Link between Labeling Standards and Quality Standards
Again, using psyllium husk as an example, Table 9 illustrates the regulatory link between approved therapeutic use from labeling standards or positive therapeutic monographs and corresponding prerequisite quality standards. The table shows the approved therapeutic uses for psyllium husk by the following 4 governmental regulatory agencies: EMEA,18 FDA,19 NHPD,20 Australian Therapeutic Goods Administration (TGA),21 along with the corresponding quality specification requirements in each case.
Regulatory Requirements for Defined Qualities of Botanicals
Australia. For active ingredients of listed herbal medicines, the quality standards of the BP are the minimum standard that must be applied in its entirety. The monographs of the PhEur and USP, respectively, have also been adopted as additional default standards under the Therapeutic Goods Act.22
Canada. Licensed natural health products (NHPs) must comply with the minimum specifications outlined in the current NHPD Compendium of Monographs, or of those published in a currently valid edition of an acceptable pharmacopeia (e.g. BP, PhEur, or USP).23 For active ingredient specifications, pharmacopeial standards currently accepted by the NHPD are the BP, PhEur, and USP.24 All ingredient (medicinal and non-medicinal) and finished product specifications should meet—as a minimum—the standards described in the publications referred to in Schedule B to the Food and Drugs Act, or equivalent standards. Where no Schedule B monograph exists for the dosage form, specifications should be similar to those of a comparable compendial dosage form. In the absence of a Schedule B standard for any dosage form, testing must be adequate to demonstrate the product’s identity, potency, purity and quality.25
European Union. Herbal medicinal products must be composed of pharmacopeial quality active ingredients. Registered THMPs sas well as licensed well-established herbal medicinal products (WEHMPs) should comply with quality standards in relevant PhEur monographs. If there is no PhEur monograph, they may comply with a monograph in the pharmacopeia of an EU Member State (e.g., BP, DAB, DAC, PhFr, or ÖAB [see Table 10]).26 If no monograph for the herbal substance is given in the PhEur or in the pharmacopeia of an EU Member State, the applicant must prepare and supply a comprehensive specification for the herbal substance which should be set out in the same way where practicable, as in the herbal drug monographs in the PhEur.27 Labeling standards monographs of the MEA specify the corresponding quality standards monograph that must be applied. In some cases, more than 1 pharmacopeial monograph is permitted (especially in cases where various national pharmacopeial monographs have not yet been harmonized and entered into the PhEur). For example, the EMEA monograph for maté leaf (Ilex paraguariensis, Aquifoliaceae) permits the active ingredient specification to be defined as per the German Drug Codex monograph (Mate folium viride DAC) or the French Pharmacopoeia monograph (Maté Vert PhFr).
United States of America. FDA’s final rule for current Good Manufacturing Practices (cGMPs) for dietary supplement requires the establishment of a specification for each component used in a dietary supplement product. The component specification must establish its identity, include other requirements necessary to ensure that specifications for purity, strength, and composition of dietary supplements containing the component are met, as well as limits on contaminants that could adulterate the product.28 Compliance with official compendial standards is voluntary for dietary supplements; however, it is mandatory if the product label claims to comply with the standard. For botanical drug products, the FD&C Act designates the USP as the official compendia. Compliance with a USP monograph is mandatory for all FDA-approved drugs.
In recent years, a plethora of quality standards and specifications have been established for botanical ingredients worldwide. It can be difficult for buyers and sellers of botanicals in the global marketplace to sort out and select the most suitable specification for the intended purpose of the ingredient. Using an unsuitable quality standard may not deliver the intended effect. Reliable, reproducible safety and efficacy depends on the establishment and implementation of suitable reproducible quality specifications. In countries where herbal medicinal products are regulated mainly as OTC and/or Rx drug products there is a regulatory link that connects the labeling standards monographs to specified quality standards monographs.
Josef Brinckmann is the vice president of research and development at Traditional Medicinals Inc., in Sebastopol, California, a member of the Dietary Supplements Monographs Expert Committee of the USP, a member of the Advisory Committee of the American Herbal Pharmacopoeia (AHP), a consultant on market intelligence for medicinal plants & extracts to the International Trade Centre (ITC) of the United Nations, and a member of the Advisory Board of the American Botanical Council (ABC).
* The term pharmacopeia—Latin, literally meaning a collection of or many drugs—is also frequently used with its more previously preferred spelling pharmacopoeia (i.e., with the diphthong containing the o). In this article, when referring to pharmacopeias in general, the US spelling (without the o) is used. However, most other countries still use the older spelling, especially with respect to the actual title of their respective pharmacopeias, in which case the spelling with the o is retained.
†Note on pharmacopeial nomenclature: USP monograph titles appear to be inconsistent concerning inclusion of the plant part. Some monographs include the plant part in the monograph title and others do not. In this article, in cases where the plant part is not part of the official monograph title, it is added parenthetically. As a matter of clarification, the USP Nomenclature, Safety and Labeling Expert Committee made a conscious decision: If only one plant part is the subject of a USP monograph, then the name of the monograph does not need to include the plant part (although the plant part is noted in the body of the monograph). If more than one plant part is the subject of a USP monograph, then the name of the monograph will contain the plant part as well as the name of the plant. Saw palmetto is an example of the former, Echinacea purpurea is an example of the latter as there are monographs for both aerial parts and roots.
‡A drug product that causes contraction of the gallbladder and is used during the course of diagnostic gallbladder studies (cholecystography).
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