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ABSTRACT

Medicines from natural products have been used throughout human history. Because of growing interest, traditional medicine-based herbal medicines and botanical dietary supplements are popular among consumers. However, due to insufficient quality of many products, safety and efficacy are challenges from the modern medicine's point of view. This is particularly important at the global level because increased international commerce without the evidence of quality at global level makes consumers more prone to being exposed to low quality products. Efforts to ensure the quality of botanical products need the support of global public standards, and their proper use for quality assessments is also highly important. Differences in regulatory status among countries prompted the need for quality standards to include appropriate test methods and specifications. Pharmacopeial monographs define the specifications which herbal products need to show proper quality. Because of the complexity of the botanical materials, building quality standards in pharmacopeias needs careful consideration to include proper methods for identity, purity and strength, as well as appropriate acceptance criteria.

Keywords: Dietary Supplements; Herbal Medicine; Quality; Standards; Pharmacopoeia

HERBAL MEDICINES AND BOTANICAL DIETARY SUPPLEMENTSNature has been a source of medicinal products for a long time. Chemical diversity and novel mechanisms of action made natural products valuable in many drug development and research programs, generating interesting and meaningful developments because of their ability to interact with numerous, varied biological targets, and some have become important drugs.1 Natural products from plant origin are important in healthcare systems and many useful drugs have been developed from plant sources.2,3

Many plant materials have been used as herbal medicines in traditional medicine systems worldwide. This includes Traditional Chinese Medicine, Korean Traditional Medicine, Kampo, Ayurveda, Unani, Siddha, and various systems from Africa and Latin America.4-7 In the United States (US), herbal medicines were brought mainly by European immigrants

Food Suppl Biomater Health. 2021 Mar;1(1):e10https://doi.org/10.52361/fsbh.2021.1.e10pISSN 2765-4362·eISSN 2765-4699

Review Article

Received: Dec 15, 2020Revised: Mar 12, 2021Accepted: Mar 16, 2021

Correspondence:Nam-Cheol Kim, PhDScience Division, Department of Dietary Supplements and Herbal Medicines, United States Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852, USA.E-mail: nck@usp.org

© 2021 Health Supplements Future ForumThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ORCID iDsNam-Cheol Kim https://orcid.org/0000-0003-1959-4278

DisclosureThe author has no potential conflicts of interest to disclose.

Nam-Cheol Kim

Science Division, Department of Dietary Supplements and Herbal Medicines, United States Pharmacopeia, Rockville, MD, USA

Need for Pharmacopeial Quality Standards for Botanical Dietary Supplements and Herbal Medicines

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and from Native Americans. The first edition of United States Pharmacopeia (USP) included 425 botanical substances.8 Herb and herbal product monographs reached their peak of 636 botanical substances in USP V in 1870, but by the time USP X was published in 1926, the total number of botanically-related monographs decreased to 203 botanical substances. This represents herbal medicines that were widely used in the US until herbals began to be replaced with non-herbal pharmaceutical drugs in the 1920s.9

Increasing interest in self-care in recent years especially during 1970s and 1980s, together with scientific and clinical developments, resulted in an increased growth in popularity of herbal-based remedies.10 Some consumers show positive attitudes towards herbal products, mostly because they are natural, and such products are more likely to be considered safe and used as part of a healthy lifestyle.11 In the US, Congress established the National Institutes of Health (NIH) Office of Alternative Medicine in 1992, then upgraded to the National Center for Complementary and Integrative Health (formerly National Center for Complementary and Alternative Medicine) in 1998.12 The NIH Office of Dietary Supplements was created in 1994 to conduct and coordinate research in herbs and supplements. The Dietary Supplement Health and Education Act (DSHEA), enacted in 1994, provided the current legal landscape for dietary supplements, including botanical dietary supplements. Regulations implemented under the authority granted under DSHEA recognized the need for quality specifications for dietary supplements marketed in the US.

While the perception of the general public is that herbal products are safe to use because they have been used traditionally for many years, there are issues to incorporate them into modern medicine's context. Traditional uses of herbal ingredients as an acute treatment, are now being utilized more for health promotion or disease prevention. Because insufficient information and different doses and concentrations in traditional uses, the efficacy and safety of many of these products has not been properly demonstrated using modern scientific investigation.11

ENSURING QUALITY OF HERBAL MEDICINES AND BOTANICAL DIETARY SUPPLEMENTSThe safety and quality of herbal materials and finished herbal products has become a concern for health authorities, pharmaceutical industries, and the public.13 Many herbal products remain untested and their use is also not properly monitored. This makes knowledge of their potential side effects very limited, and identification of the safe and effective therapies of herbal medicines as well as the promotion of their intended use more difficult.14

A report from World Health Organization (WHO) estimated that about 80% of its member countries use some form of traditional and alternative medicines.15 Large populations receive herbal medicines either from alternative and complementary medicine practitioners or from the open online global market. This allows consumers around the world to easily purchase traditional medicines from other countries. Many countries reported that the lack of appropriate mechanism for control of herbal medicines is one of the main regulatory difficulties.16 Opinions on the degree of necessary quality testing are often different among regulatory frameworks, and amongst health professionals and manufacturers.17 Countries develop frameworks that largely reflect national and regional priorities and needs, but because products are consumed internationally, it is necessary to have a consistent definition, especially for dietary supplements, and harmonized regulation for herbal

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products in international countries as well as global quality public standards. This issue on quality for herbal medicines and botanical dietary supplements is emphasized in the WHO's Strategy on Traditional Medicines 2014–2023 where quality is still seen as a challenge in different countries.18 The quality of finished herbal products is influenced by the quality of the raw materials used. In case of botanical extracts, blends, and finished products, the quality faces even more challenges in misidentification and contamination, thus requirements and methods for quality control for these products are even more complex.13,17

Traditional use of herbal ingredients coupled with significant growth and international regulatory challenges have led to a need for a more relevant and accessible set of quality standards. There are issues associated with developing botanical standards based on the traditional botanical products, including the following:

• Very few systems of traditional medicines have much documentation or regulations in place.• There is a sustainability issue in terms of knowledge and resources. In many countries,

traditional medicine practices have been inherited mostly through undocumented practices.• Natural products are often used simultaneously for foods, functional foods, dietary

supplements and herbal medicines.• The opportunity for education is often limited due to the limited availability of expertise.• Lack of standards and deficient of standards.

Regulatory approaches vary internationally. In the US, botanical products are regulated as drugs, foods, or dietary supplements, depending on how they are intended to be used, and labeled for use, as applicable, and there is no regulatory category at the US federal level specifically for traditional medicines. “Botanical Drug Development: Guidance for Industry” describes a pathway for botanical articles to be legally marketed as botanical drugs.19 Herbal medicines in the US have a long history of use before the regulations for food and drugs were in place. DSHEA established the first comprehensive definition of dietary supplements, resulting in certain botanicals being considered foods based, in part, on intended use.20 A dietary supplement product cannot be marketed or portrayed as a product with therapeutic, medicinal, or pharmacological value. If it is marketed as a dietary supplement with a claim to cure, treat, diagnose, mitigate, or prevent a disease, US Food and Drug Administration considers the product to be a drug.21 However, dietary supplements can be produced, sold, and marketed without first demonstrating safety and efficacy, which is required for pharmaceutical drugs. In many other countries, botanical materials for medical use are regulated as drugs with no prescriptions are required. The permit for these herbal medicines is premarket authorization basis but the underlying premise is a preference for making these products available if they have a history of traditional use.

For many botanical articles that have been considered traditional medicines somewhere around the world, not all of them meet all the regulatory requirements in order to be legally marketed as drugs or dietary supplements in the US. As a result, consumers may choose botanical articles of questionable quality, purity, and strength. Thus, developing public standards for these articles is important to protect the US consumers from the exposure to such products. USP publishes public quality standards (monographs) in several compendia to include botanical articles. Only approved drugs (including herbal medicines) that are legally marketed can be included in USP-NF. Certain herbal medicines that have been grandfathered before Food, Drug, and Cosmetics Act in 1938 are also included in USP. For dietary supplements, since the passage of DSHEA in 1994, USP increasingly has focused attention on developing public monographs for dietary supplements and their ingredients.

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USP included a separate section for dietary supplements in USP from 2003 and published first version of Dietary Supplements Compendium (DSC) in 2009. In order to admit newly recognized traditional medicine based botanical articles for the use of medicines, USP started to publish the Herbal Medicines Compendium (HMC) for herbal articles that (1) are approved by a national authority for use as ingredients of herbal medicines, or are included in a national pharmacopeia; and (2) are deemed appropriate for inclusion in the HMC by a USP Expert Committee.22

Public standards are valuable because they provide scientific basis for decision making, ensure a consistent approach to quality, and are useful for monitoring adulterants, substandard products, and quality generally. Therefore, they should include appropriate titles, useful definitions, validated methods and established limits.23 Quality public standards should be set by independent experts using a robust, transparent process that involves the evaluation and incorporation of public comments, and expertise drawn from diverse sectors, including academia, industry, and regulatory bodies. Public standards should also be set based on the development and submission of robust data, and intended to meet the needs of different manufacturers, regulators, suppliers, practitioners and consumers.24 A pharmacopoeia is a legally binding collection of standards and quality specifications for medicines used in a country or region.25 In 2019 survey, WHO reported that 110 countries around the world use national or other pharmacopoeia that includes herbal medicines and 65 of them stated the pharmacopoeia to be legally binding.15 The worldwide spread in the use of herbal products has produced various attempts to develop monographs to define quality standards. The German Commission E has been publishing therapeutic monographs since 1984. The European Scientific Cooperative for Phytotherapy has been developing therapeutic monographs since 1991 and the WHO has initiated a project to write monographs on widely used herbs around the world. In the United Kingdom herbal monographs have been published since 1983.26 In USP, monographs for traditional medicine based botanical articles are included in USP, HMC, and DSC.

PHARMACOPEIAL STANDARD DEVELOPMENT

Herbal pharmacopeias are intended to promote the responsible use of herbal medicines with the highest possible degree of efficacy and safety through the development of standards of identity, purity, and analysis for botanicals including the review of traditional and scientific data regarding their efficacy and safety.27 Previously, pharmacopeias for herbal medicines were focused primarily on plant source and the plant part, using macroscopic and microscopic descriptions. However, the gradual development of analytical techniques including chromatographic fingerprints and tests for impurities improved the quality of pharmacopoeial monographs.28 Herbal drugs with potent pharmacological activity made the inclusion of an assay important. The latest “Good Pharmacopoeial Practices: Draft Chapter on Monographs on Herbal Medicines” by WHO mentioned that the pharmacopoeial monographs for herbal medicines should contain information in the definition that is consistent with the monograph title followed by specifications for quality, including identity, purity and content.29 Individual monographs describe test procedures together with the corresponding specifications. The monograph may include official title, definition, identification section, tests/limits on contaminants, and an assay section determining constituents (compounds with known therapeutic activity, active markers or analytical markers). Analytical procedures can be selected from scientifically valid methods either from

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existing compendial methods or methods from scientifically peer-reviewed journal articles. The method should be validated or verified for the intended purpose. Once the procedure is chosen for compendial method, it can be modified only if the modification is acceptable to meet system suitability. If the modified method is to be acceptable, validation or verification is necessary.

Given the complexity of the matrices of herbal products, attributes of an analytical method in dietary supplement and herbal medicines monographs that are fit for the intended purpose depend on the nature of the analyte, matrices, as well as the analytical objectives (qualitative, quantitative, or others).30 Botanical macroscopic/microscopic and DNA analyses can be used for plant materials or their powder forms, not for extracts or processed forms. In latter cases, analytical methods such as chromatographic or spectroscopic techniques should be utilized. To achieve more comprehensive qualification and quantification, these techniques are often used together in identification, composition, and detection of adulterants.

Components and considerations for herbal medicines and botanical dietary supplements monographs in USP and European Pharmacopoeia are well summarized and described.30-33 Table 1 shows components and associated General Chapters in typical USP herbal medicines and botanical dietary supplement monographs. Following are general consideration for composing botanical monographs.

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Table 1. Components in USP botanical monographMonograph section Description GC/guidelineMonograph title Standard common name or, Latin binomial without authority followed

by the name of the plant part(s) or plant product (e.g., latex, exudates, resin, gum-resin, oleo gum resin)

Nomenclature guidelines for dietary supplements

Definition • Full Latin binomial• Botanical characteristics of the plant (genus, species, variety,

chemotype), parts of the plants• Harvest/collection period• Synonyms, if applicable• Acceptance limits for the content of bioactive or marker compounds• HMC monographs provide additional information on synonyms, potential

confounding materials, common names, and constituents of interestIdentification • Phytochemical characteristics • GC <563> Identification of Article of Botanical Origin

• Profile/fingerprinting of the constituents • GC <203> HPTLC Procedure for Articles of Botanical Origin• Area ratio between constituents • GC <621> Chromatography

Composition/strength • Content of marker compounds • GC <621> Chromatography• Content ratio between constituents• Limits test for toxic constituents

Contaminants • Microbial levels• Aflatoxins• Elemental impurities• Residual solvents• Pesticide residues• Other adulterants

• GC <2021> Microbial Enumeration Tests• GC <2022> Absence of Specified Microorganisms Microbial

Enumeration Tests• GC <561> Articles of Botanical Origin• GC <2251> Screening for Undeclared Drugs and Drug

Analogues

Specific tests • Macroscopic and microscopic characterization • GC <563> Identification of Article of Botanical Origin• Foreign organic matter • GC <561> Articles of Botanical Origin• Total ash• Loss on drying• Acid-insoluble ash• Alcohol-soluble extractives• Water-soluble extractives

Labeling and packaging

• GC <565> Botanical Extracts

USP = United States Pharmacopeia, HMC = Herbal Medicines Compendium, HPTLC = high-performance thin layer chromatography, GC = General Chapter.

TitleThe monograph title should indicate accurately what is covered in the monograph and needs to be consistent with the Definition section in the monograph. Clear nomenclature is the key for the correct definition and identification. Botanical articles require accurate and universally accepted names of the contained botanicals. Common names are familiar to stakeholders, traders, and consumers, but may be used for different plants in different regions. Many botanical species can be found in specific regions around the world. However, due to the increase of international commerce, many species may be available in various places. Use of scientific names provides a greater degree of accuracy than common names. This limits the number of species that are acceptable, and provides appropriate tests for the botanical article to ensure the article of trade conforms to the proscribed quality standards.34 In USP, the monograph titles follow the guidelines for dietary supplements and herbal medicines.35,36

DefinitionThe definition correctly indicates the proposed article. It includes the accepted full Latin binomial, the plant family and parts, the harvest/collection period as well as the applicable processed form (e.g., powder, extract). Synonyms are also added if they are widely known for the particular plant material. The acceptance limits for the content of bioactive or characteristic marker constituents are included. In addition, the Definition may include the chemical names and molecular formulas of the constituents that were quantified.

IdentificationThe important purpose of the identification test is to make sure the target plant article for the monograph is in agreement with what is stated in the monograph title, definition, and package labeling. Compendial identification tests for herbal ingredients include macroscopic/microscopic, chemical, chromatographic, and spectroscopic methods. Since the objective of an identification test is to be able to discriminate between related species and/or potential adulterants or substitutes, the specific tests for a botanical ingredient usually include a combination of 2 or 3 procedures.

The tests can be used to determine the plant's botanical characteristics such as macroscopic and microscopic analyses to include morphological and histological characteristics: description of diagnostic morphological and anatomical features of vascular plants and the various plant parts including roots, stems, leaves, flowers, fruits and seeds. Diagnostic features in individual monograph may include the presence of particular tissue within an organ, the arrangement and type of cells within tissues, the presence and type of secretory canal, oil, orresin duct, or laticifers within an organ, the number of epithelial cells surrounding a secretory canal, the presence and type of ergastic substances such as starch, inulin, fat globules, essential oils, calcium oxalate crystals, cystoliths, polyphenols, fluids or materials occurring in the cytoplasm, organelles, vacuoles, cavities or cell wall.37

Modern chromatographic methods including high-performance liquid chromatography, ultra-high-performance liquid chromatography, high-performance thin layer chromatography (HPTLC), and gas chromatography are utilized because of their ability to determine unique fingerprints of the desired plant article in highly selective way. The chromatographic patterns can be used to distinguish closely related species, confounding materials, or adulterated/substituted plant articles. The acceptance range for fingerprinting tests should account for reasonable variability between different botanical article suppliers

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and processors, and natural variability of the authentic article acquired under various cultivation and geographic conditions. The fingerprints must be able to distinguish these materials from other materials having potential for species substitution, particularly those with known toxic effects or existing safety concerns. The acceptance criteria for identification tests using chromatographic methods must contain a description of the critical features of the fingerprint chromatograms such as the presence of specified peaks, their order of elution, and, where possible, their relative magnitude. To the extent possible, efforts to assign these peaks to known constituents must be made. Acceptance criteria for peak ratios and elution order should be determined, taking into account the variability associated with the compendial article. For planar chromatographic tests, thin layer chromatography (TLC) and HPTLC, the description must include color and position of the characteristic bands under specified illumination modes. A color image of a typical TLC/HPTLC chromatogram for multiple samples should be provided. In addition to identification using specified markers, chromatographic identification may be achieved by describing the chromatographic profile without specific mention of markers, but with referencing of the chromatographic peaks or bands to known compounds.

With its advantage in botanical identification,38 USP recently introduced DNA-based methods for the identification of botanical articles in General Chapter <563> Identification of the Articles of Botanical Origin.37,39

Different kinds of reference standards can be used depending on the type of identification test. For botanical identification, whole plant powdered plant materials can be used. For chemical identification, powdered plant materials, powdered extracts, purified fractions or pure compounds may be used. Powdered plant materials are used for the identification using DNA. Figs. 1 and 2 show examples of chemical fingerprinting for ginseng species.40

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UV 366 nm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

White light

Fig. 1. HPTLC of ginseng species. 1: ginsenoside Ro; 2: ginsenoside Rb1; 3: ginsenoside Rb2; 4: ginsenoside Rc; 5: ginsenoside Rd; 6: Panax ginseng steamed root and rhizome dry extract; 7: Panax ginseng steamed root and rhizome; 8: Panax ginseng root and rhizome (Asian ginseng); 9: Panax quinquefolius root and rhizome (American ginseng); 10: Panax notoginseng root and rhizome (Tienchi ginseng); 11: ginsenoside Re; 12: notoginsenoside R1; 13: ginsenoside Rf; 14: ginsenoside Rg2; 15: ginsenoside Rg3; 16: ginsenoside Rg1. HPTLC = high-performance thin layer chromatography, UV = ultraviolet.

Composition/strengthQuantitative determination for marker constituents is important in quality monographs to represent the article's bioactivity. Proper marker component(s) should be carefully selected. If the content of bioactive components or marker constituents found in the desired plant article is too low, the component may not deliver the appropriate dose to achieve its intended biological effect. Quantitation is also important to track the presence and contents in the plant material in formulated products. The results of quantitative determinations are often expressed as the total amount of a class of constituents that are determined individually. Because of the complex biosystem, a single constituent cannot be responsible for specific plant bioactivity. Also, determination of single constituent may generate biased result because of the possibility of adulteration. Markers commonly found in other plants are not recommended unless they are present in distinctively high amounts in the plant of interest. In this case, additional markers need to be included to confirm the distinction from related plants or adulterants. For accurate analysis, chromatographic methods, such as liquid chromatographic and gas chromatographic method, are preferred over nonspecific methods, such as colorimetric or titration methods.

Quantitative tests use chromatographic methods that should meet the system suitability requirements. Suitable resolution is required to ensure that the peaks to be quantitated achieve baseline separation. Other requirements may include minimum number of theoretical plates to ensure sufficient retention and efficiency of the separation, maximum tailing factor to minimize integration issues caused by asymmetric peaks as well as relative standard deviation. Another important requirement for system suitability in USP botanical monograph testing is chromatogram similarity, which is needed to correctly identify

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Rg1 Rb1

Rb2Re Rf

Ro

Rc Rd

Rg1 Rb1

Rb2Re Rf

Ro

Rc Rd

Rg1 Rb1

Rb2Re

RoRc Rd

Rg1

Rb1

Rd

1

2

3

4

Fig. 2. HPLC of ginseng species. 1: Panax ginseng steamed root and rhizome; 2: Panax ginseng root and rhizome; 3: Panax quinquefolius root and rhizome; 4: Panax notoginseng root and rhizome. HPLC = high-performance liquid chromatography.

peaks of interest for the quantitation. Chromatogram similarity is determined against the authenticated reference botanical material or extract standard. To do this, a standard solution containing plant material or extract is injected, and the resulting chromatogram is then compared to a reference chromatogram provided in the USP certificate of that reference standard (RS) lot. The analyst is able to identify peaks for different components by comparison with the reference chromatogram.

To reduce the cost and simplify the analysis, a single RS of a purified isolated constituent is typically used to quantitate multiple compounds. If the analytes have response factors that are significantly different from the RS, the conversion factor for each analyte versus the RS should be used for the calculation. To obtain reliable conversion factors, fixed test conditions should be used, and test results should be statistically calculated from multiple determinations of an RS of known purity.

Quantitative analytical procedures should be validated. Typical validation parameters include accuracy, different levels of precision, specificity, detection limit, quantitation limit, linearity ranges, and robustness. USP follows the guideline in General Chapter <1225> Validation of Compendial Procedures.41

Purity (limit of contamination)Contaminants may be found in botanical materials and they can occur naturally or by human activities such as industrial waste and pollution. In addition, inappropriate post-harvesting practices could result the contamination of herbal materials, such as microbial and fungal contamination that can lead to mycotoxins such as aflatoxins. The limits for such contaminants should be appropriately set based on safety considerations according to the provisions in related General Chapters and other guidelines. Tests that are included in here are: elemental impurities, residual solvents, pesticides, microbial contamination, and aflatoxins.

Specific testsThere are quality parameters that apply to most pharmacopeial articles of botanical origin, including foreign organic matter, total ash, acid-insoluble ash, loss on drying or water determination, water-soluble extractives, and alcohol-soluble extractives. Certain tests are specific to certain herbal materials, such as the water-soluble extractives and alcohol-soluble extractives tests for bitterness, test for tannins, hemolytic tests for saponins, and some functionality testing for attributes such as swelling, foaming, and coloring intensity or coloring power. Submissions containing these tests must give the rationale and analytical test data in support of the suggested specifications.

Also, an individual botanical article may require specifications that are particular to that item, especially when safety or adulteration is an issue. Thus, limits may be set for certain constituents of the article that are considered undesirable negative markers, negative botanical characteristics, or markers of species substitution. If proposing a limit for undesirable substances that are either naturally present in the article or formed as a result of processing, the submission must be accompanied by toxicity data (if available), and specific procedures aimed at limiting or removing offending substances.

Additional requirementsPackaging and storage, labeling, and the RS used in the monograph may be included. The label statement of botanical monographs may include the Latin binomial name following

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the authority; the plant part(s), plant product, or processed form contained in the article or from which the article was derived; and content, in percentage, of active principles or marker compounds. In addition to the labeling contained in the compendium, a botanical article is subject to compliance with such labeling requirements as may be promulgated by regulatory bodies. Particularly for botanical dietary supplements, a cautionary label statement may be included in some monographs based on the available information. USP has a system to evaluate dietary supplement admission to USP.42 This component acts as safeguard against inclusion of articles in USP and DSC that may give rise to safety concerns regardless of their legal marketing status. Reference materials included as a component of a monograph are authentic specimens that have been approved as suitable for use as comparison standards in the monograph tests.22 Reference standards are highly purified compounds for quantitative and qualitative determinations, and complex plant materials such as botanical extracts or authenticated plant powders for comparative references. They are designed to meet the monograph requirements of the particular ingredient and are used when testing a material for pharmacopoeial conformity, a requirement in the drug regulations of most countries.34 Pharmacopoeial reference materials are mainly intended for the use in compendial methods.43 When a reference standard is required within compendial methods, it is used to help ensure that the products are of appropriate identity, strength, quality and purity.

CONCLUSION

Global consumers concerned about health need quality standards because of the challenges of using traditional based herbal medicines and botanical dietary supplements. To address these concerns, pharmacopeias, including USP, provide the quality standards by setting the specifications for identity, strength and purity to reflect the quality of the products. The current regulatory status for botanical products in many countries may not appropriately address quality without appropriate standards. Proper application of pharmacopeial specifications is strongly recommended to ensure the quality of botanical herbal medicines and dietary supplements.

ACKNOWLEDGEMENTS

The author thanks Dr. Kit Goldman in USP for reviewing the manuscript.

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