Quality Standards for Botanicals — Legacy of USP’s 200 Years of Contributions
by Josef Brinckmann
How botanical quality standards have evolved over the last two centuries to maintain the safety and uniformity of botanical, chemical, and biological medicines nationwide.
The Pharmacopoeia of the United States of America (USP),† first published in 1820, was intended to bring nationwide uniformity to the quality of drugs, most of which at the time was based on botanical and mineral ingredients. Over the last 200 years, the United States Pharmacopeial Convention (USP) has adapted to evolving technologies and products and has continued to provide public quality standards for botanical, chemical, and biological medicines. This article examines the history of the evolution of botanical quality standards, as well as the current status of botanical monographs for drugs, herbal medicines, dietary supplements, and excipients (i.e., antioxidants, binders, bulking agents, coloring agents, flavoring agents, pharmaceutical bases, sweetening agents). It also provides an outlook for the future, in which USP anticipates adapting to rapid changes in technologies. This article is an abbreviated version of a more detailed paper by the authors and has been revised for HerbalGram.
As the settlements of European colonists expanded through the 16th to 18th centuries, native American botanical species and their uses in the indigenous systems of medicine were observed, documented, classified in a European context, and initially monographed in pharmacopeias of the colonial powers. The American War of Independence (1775-1783) created an urgent need for pharmacopeias that could serve the needs of military hospitals. William Brown (1748-1792), Physician-General of the Middle Department of the Continental Army, while stationed at the army hospital in Lititz, Pennsylvania, compiled a work now known as the Lititz Pharmacopoeia, published in 1778. (The full title, translated from Latin, is Pharmacopoeia of simple and efficacious remedies for use of the military hospital, belonging to the army of the Federated States of America; specially adapted to our present poverty and straitened circumstances, caused by the ferocious inhumanity of the enemy, and the cruel war unexpectedly brought upon our fatherland.)1 Much of the traditional knowledge of the indigenous peoples was adopted more formally into American medical practice and, by the late 18th century, codified in the first pharmacopeias and dispensatories of the new country, the United States of America.2 Examples of plants native to North America that were of medicinal importance to indigenous peoples and were also published in Scottish physician William Cullen’s (1710-1790) 1769 handbook on medicines included capsicum (Capsicum annuum, Solanaceae), sarsaparilla (then Smilax sarsaparilla, now S. glauca, Smilacaceae), sassafras (Sassafras albidum, Lauraceae), and Seneca snakeroot (Polygala senega, Polygalaceae).3
Publishing in English, another factor in the development of a truly American pharmacopeia was championed by physicians James Jackson (1777-1867) and John Collins Warren (1778-1856), who formed the committee for the 1808 Pharmacopoeia of the Massachusetts Medical Society.4 Dr. Samuel Latham Mitchill (1764-1831; misspelled “Mitchell” in the 1820 and 1831 editions of the USP) and Dr. Valentine Seaman (1770-1817) followed a similar approach in their Pharmacopeia of the New York Hospital, published in 1816.5 They wanted their work to be written in English and mutually convenient to the physician and pharmacist. Most European pharmacopeias at that time were written in Latin.
The United States Pharmacopeial Convention was founded on January 1, 1820, by 11 forward-thinking physicians, three of whom were responsible for leading the effort. The idea to form a national pharmacopeia originated with Dr. Lyman Spalding (1775-1821), a passionate physician and masterful organizer from New York; the previously mentioned Mitchill, a charismatic statesman and former senator from New York as well as a physician who was president of the USP Convention and helped promote the creation of the first national pharmacopeia; and Dr. Jacob Bigelow (1787-1879), from Harvard University in Massachusetts, an expert in plant drugs and an experienced editor, who oversaw its publication. Physicians at the time wanted “to recognize the full range of truly American medicinal plants that patriotic medical gentlemen expected.”6
Building on the pharmacopeias of the Massachusetts Medical Society and the New York Hospital and under the direction of Mitchill, the first national Pharmacopoeia of the United States of America was published in 1820.7 It was divided into sections, beginning with the front matter, historical introduction, and preface, followed by the materia medica (a primary list of 217 drugs, including 145 botanicals); most of the entries were botanicals or botanically derived ingredients.8 This section was followed by a secondary list of 71 drugs with ingredients of “doubtful efficacy” and whose use was uncertain, including 67 botanicals; a section on weights and measures; and an untitled section of 329 preparations and compositions.9 In the section that included formulae for the preparation and compositions of medicines, all articles that were presented by the District Conventions (that held regional meetings prior to the National Convention) were included, except in cases where two preparations were considered similar, in which case only one formula was included.
Some native North American plants included in USP 1820 were substitutes for European plants of the same genus with similar qualities. The pharmacopeia reflected the therapeutics of the time, including tonics, strong laxatives, diuretics, and flavoring herbs. The preparations included cerates (waxy preparations for external use), confections, decoctions, extracts, honeys, infusions, liniments, mixtures, ointments, pills, plasters, powders, spirits, syrups, tinctures, troches (lozenges), vinegars, washes, waters, and wines. Recipes and compounding techniques were included, but no analytical methods appeared in the monographs.9 The USP also recognized that new medical discoveries would lead to many new articles that would expand the materia medica to an unmanageable size. The USP, therefore, planned for the “retrenchment of superfluities,” creating what became known as the process of “omission” of articles from the pharmacopeia in the later years.
There were two-second editions of the USP, the New York version of 183010 and the Philadelphia version of 183111; the latter was more accurate and actually became the first decennial revision of the USP, also called USP I. From these versions onward, the monographs included brief botanical descriptions, macroscopic, and organoleptic properties to be verified for identification of the articles. The complexity of this information increased with subsequent editions. However, to address the need for standards of identity, purity, and strength, additional detailed information on each USP article was included in The Dispensatory of the United States of America, which was published from 1833 to 1973.
As USP evolved into an authoritative compendium for drugs of the first choice, other efforts for “standardization of names and formulas for dosage forms of drugs not described elsewhere” were in development.12 One such publication was the National Formulary (NF), which was intended to provide formulas that could be “compounded on a small scale that physicians and the self-medicating public wanted.” The first issue of the National Formulary of Unofficinal Preparations was published in 1888 by the American Pharmaceutical Association (APhA), now called the American Pharmacists Association.13 The first editions of the USP and the US Dispensatory were authoritative but not official; the USP and the NF achieved legal recognition with the passage of the Food and Drug Act of 1906.
Botanicals have always been prone to intentional economically motivated adulteration or unintentional substitution with closely resembling species that may share the same common name. Collaboration between pharmacists and physicians improved the quality of standards in the early years. The role and importance of pharmacy and public trust in medicines grew with the increase in quality standards made available in the USP. Gregory J. Higby, Ph.D., pharmacy historian and former executive director of the American Institute of the History of Pharmacy, described the methods used by Dr. William Procter, Jr. (1817-1874) in examining the adulteration of aloe (Aloe spp., Xanthorrhoeaceae) latex.14 Procter used an intelligent combination of organoleptic sensory tests (color, appearance, odor) coupled with a comparison of observations of authentic material for solubility in different solvents and the ash values to distinguish the “original” material from the adulterated aloe.
Standardization of botanical and chemical nomenclature for pharmacopeial articles was another goal of the USP. As Pharmacopoeia of the Massachusetts Medical Society authors Jackson and Warren noted in 1808: “In this, as in former ages, men are creating confusion by creating names. The object of the reforms in scientific language is to obviate this evil and to establish nomenclature upon solid grounds.”4
Botanicals and botanically derived medicines were considered critical for the US Army Medical Department during the Civil War.15 These included South American cinchona (Cinchona spp., Rubiaceae) tree bark extract; quinine (obtained from cinchona tree bark extract); opium (Papaver somniferum, Papaveraceae) capsule exudate; camphor (a monoterpene ketone obtained by distillation of the bark and wood of the East Asian camphor tree [Cinnamomum camphora, Lauraceae]); and ginger (Zingiber officinale, Zingiberaceae) rhizome. Issues of quality and adulteration concerned the pharmacists and physicians of the mid-19th century. In addition, the need for larger-scale manufacturers to adopt and use the pharmacopeia was highlighted during the 1870-1900 revisions. USP came to be valued increasingly as a source of industry-wide standards for nomenclature, strength, and purity, while the role of the compounding guide was assumed by the US Dispensatory.15
BOTANICALS IN USP 1820 AND THEIR CONTINUED USE IN 2020
The first issue of the USP, published on December 15, 1820, contained monographs for 217 drugs in its Primary List,16 of which about 130 listed substances were herbal drugs used by Native Americans.8 For example, pharmacist John Uri Lloyd (1849-1936) wrote that the medical uses of black cohosh (Figure 1), then called “black snakeroot” (then Cimicifuga serpentaria, now Actaea racemosa, Ranunculaceae), was introduced “by the Indians” to “early domestic American medicine.” An aqueous decoction preparation of black cohosh was indicated for “diseases of women, for debility, to promote perspiration, as a gargle for sore throat, and especially for rheumatism.”17 While most of the botanicals in USP 1820 were native plant species, by 1820 many European species had become naturalized in North America and adopted for use in indigenous medicine as well.
Several botanicals described in USP 1820 have remained relevant for health care and appear in the USP–NF 2020 edition. These include many native American species such as black cohosh root, capsicum fruit, ipecac (then Callicocca ipecacuanha, now in the USP as Cephaëlis acuminata or Cephaëlis ipecacuanha, both of which are subsumed under the currently accepted name Carapichea ipecacuanha, Rubiaceae) rhizome and root, podophyllum (Podophyllum peltatum, Berberidaceae) rhizome and root, and slippery elm (Ulmus rubra, Ulmaceae) inner bark, among others.
USP also included imported botanicals that still appear in USP–NF as of 2020. Some of these are African plants such as aloe (Aloe spicata) latex; myrrh (Commiphora molmol syn. C. myrrha, Burseraceae) oleo-gum resin; and senna (then Cassia senna, now Senna alexandrina, Fabaceae) leaflet. Asian species include garlic (Allium sativum, Amaryllidaceae) bulb; ginger rhizome; opium capsule exudate; turmeric (Curcuma longa, Zingiberaceae) rhizome; and the European species include valerian (Valeriana officinalis, Caprifoliaceae syn. Valerianaceae) root. Many of the aforementioned botanicals that appeared in USP in both 1820 and 2020 are top-selling herbs in the US market today as dietary supplement ingredients, especially aloe, black cohosh, garlic, ginger, senna, and turmeric.18
BOTANICALS IN THE NATIONAL FORMULARY AND THEIR MIGRATION TO USP
The National Formulary of Unofficinal Preparations was first published by the authority of APhA in 1888. The title of this compendium changed to National Formulary from the fourth edition in 1916 onward. The immediate predecessor and basis for the NF that today accompanies the USP was the New York and Brooklyn Formulary of Unofficinal Preparations, published in 1884, edited by Dr. Charles Rice (1841-1901) (Figure 2), a pharmacist and chair of the Committee of Revision for the 1880 edition of the USP. The National Formulary of Unofficinal Preparations published in 1888 was based on those unofficial (preparations not included) articles of the USP 1880 that were in the most frequent demand, to provide formulas that would enable pharmacists to prepare them to a uniform standard.19
Rice also established the first subcommittees and pioneered the use of revision circulars (Figure 3). This gave each member of the USP’s Committee of Revision equal influence in the revision process by implementing a voting and commenting system, the framework of which is still in use today (Figures 4 and 5).
Joseph P. Remington (1847-1918) (Figure 6) was a distinguished Philadelphia pharmacist who succeeded Rice as the chair of the USP’s Committee of Revision. Rice served as chair from 1880 to 1901 and Remington from 1901 to 1918. Remington was a member of the APhA Pharmacopeial Committee that was appointed specifically to provide APhA’s input for the pharmacopeia. By the start of the 20th century, pharmacists began to dominate the revision of the pharmacopeia and make it more relevant to the times.
The admission of articles to the NF was based on the extent of use rather than therapeutic value. The NF did not include monographs of botanical raw materials until 1916. “In listing a botanical drug, for example, the NF IV (1916) provided specifications of the species and part of the plant to be utilized, permissible percentage of foreign matter, odor, taste, and color, a description of the macroscopic and microscopic appearance, in addition to other characteristics,” wrote Higby.20 There was a dramatic increase with two-thirds more articles than the previous revision of the NF, resulting from increasing recognition of uncompounded botanical and chemical ingredients for the first time. Depending on the USP’s admission criteria, a monograph developed for the NF could appear in the USP, and those dropped from the USP could be admitted into the NF if there was widespread usage, even if the therapeutic value had not been proven.
As shown in Table 1 on page 58, the two compendia borrowed from each other in terms of organization, and thus monographs in the two became similar. According to Higby:
The general thrust was to harmonize the NF with the activities and the character of the USP while preserving the traditional conceptual difference between the two books — the USP setting specifications for drugs of the first choice therapeutically, the NF for other drugs whose extent of using justified development of a monograph… Of equally durable interest was a question about which drugs should be recognized by the NF and dealt with in the monographs. The [USP] had stuck by its original concept of scope, recognizing only drugs of the first choice in each therapeutic category, as determined by representatives of organized medicine. This left a majority of the medicaments open for selection by the NF and left ample room for differences of opinion. The pharmacist’s journals reflected this interest at least until industrialization removed drug manufacture and most compounding from the local pharmacy.20
In the NF V (1926), at the end of a botanical monograph, a list of preparations that included it as an essential ingredient was published. Many botanical drugs were deleted (omitted) in the NF IX (1950).
Long before the Federal Food and Drug Act of 1906, the 1848 Drug Importation Act was enacted to control the number of spurious and adulterated articles coming into the United States. New York City was the major port of entry for drugs, and since the 1830s, inspectors were seeing imports that were not of consistent quality. In an article titled “Good Enough for America,” Professor Dennis B. Worthen wrote: “Six articles dealing with adulteration or questionable identity of calomel, rhubarb,** morphine, colocynth, and quinine were published in 1835, four by NYCCoP [New York City College of Pharmacy].”21 The NYCCoP and many others, including Dr. Montgomery J. Bailey, an examiner in the NY Customs House, had also cataloged adulterated and counterfeit drugs coming through New York City. The bill passed quickly through the House of Representatives and Senate and was signed into law by President James K. Polk. In the Act, USP was mentioned along with other pharmacopeias and it was stipulated that articles that originated from England, Scotland, France, and Germany had to adhere to their respective pharmacopeias, and any others had to comply with the USP.
USP and NF standards were recognized in the Food and Drug Act of 1906, which provided a definition for drugs and misbranding and established the importance of standards. During the same time period, the chemical industry was growing, while the use of medicines derived from natural products was declining. This changed the pharmacopeial structure, with the inclusion of many more chemical medicines than botanicals. The Federal Food, Drug, and Cosmetic Act (FD&C Act), first enacted in 1938, defined the term “official compendium” as the official USP, the official NF, the official Homeopathic Pharmacopoeia of the United States, or any supplement to these publications.
To eliminate duplication of the same standards in different publications, the USP acquired the NF in 1975, and the combined volumes then became USP–NF.16 In the United States, compliance with a USP–NF monograph, if one exists, is mandatory for botanical drugs for the drug’s nonproprietary name, identity, strength, quality, purity, packaging, and labeling. Thus, USP–NF standards play a role in the prevention of adulteration and misbranding provisions of the FD&C Act.
In 1994, the Dietary Supplement Health and Education Act (DSHEA) amendment to the FD&C Act recognized voluntary compliance with the “official compendia of United States” for dietary supplements. The amendment provided that a dietary supplement may be deemed misbranded if it is covered by a monograph in an official compendium, and is represented as conforming to this monograph, but fails to so conform. The dietary supplement must be represented as conforming to a USP–NF dietary supplement monograph for the compendial standards to apply. This contrasts with pharmaceutical products, for which conformance to the monograph is mandatory whether or not the product claims to conform.22 This means that a dietary supplement is not required to meet USP standards unless the label includes a USP quality claim. Many dietary supplement products do not claim to conform to USP standards. When public standards are not mandatory, as in the case of dietary supplements, products that may be traded under identical names may possess vastly dissimilar attributes, and thus may be dissimilar in quality, benefits, and safety for consumers.
In 1995, a resolution at the USP Convention passed by its member delegates recognized the need for standards for dietary supplements and provided the mandate to USP to contribute in this area. Consistent with the regulatory recognition, the structure of the USP–NF publication introduced a separate section for dietary supplements.
Notable Inclusions and Omissions since USP 1820
The preface to the first edition of USP stated: “It is the object of a Pharmacopoeia to select from among substances which possess medicinal power, those, the utility of which is most fully established and best understood.” Faithful to this principle, and also in association with the rise in government regulation of both drugs and new drug claims, USP has evolved over time. Starting out as a compendium of complex botanicals whose pharmacology and composition were not well established or understood, USP has evolved in favor of including more of the simple small molecules for which the pharmacological mechanisms and composition were much clearer. In the early 20th century, analytical technology was not sufficient to enable a clear understanding of the composition of the complex mixtures used in traditional medicines, much less the underlying pharmacological mechanisms that involve multiple synergies and compensating interactions among constituents. Fortunately, this situation is changing rapidly, as new knowledge and analytical technologies emerge that can appropriately characterize botanicals.
Examples of important botanicals that were published in the pharmacopeia after USP 1820 and omitted in subsequent revisions, but later reintroduced or are presently in the process of being included, are American ginseng (Panax quinquefolius, Araliaceae) root and cannabis (Cannabis sativa, Cannabaceae) female (pistillate) inflorescence.
The American ginseng trade began in Québec, New France, in the early 18th century, and the article was initially defined in the Dictionnaire de l’Académie Française. Later, it entered the 1827 edition of Pharmacopée française, ou Code des médicaments, which included the Iroquois common name “Garent-Oguen” (meaning “resembles man” or “a man’s thigh”) among others under the entry “Panax De La Chine.”23 While initially appearing only on the Secondary List of materia medica of the second revision of the USP 1840, “Panax” (described as the root of Panax quinquefolium, now P. quinquefolius) had a short pharmacopeial life. Secondary List drugs were articles deemed to be of secondary importance; they were on probation toward a dismissal or toward promotion to the Primary List but were not for use in officinal preparations.24 Panax root was dismissed 40 years later from the USP VI (1880). After a 122-year hiatus, American ginseng root reentered the USP, published in the USP 26 in 2002,23 this time as a dietary ingredient along with monographs for processed forms, such as powder and dry extract, and in dietary supplement dosage forms, namely capsules and tablets.
Cannabis, under the entry “Extractum Cannabis. Extract of Hemp. An alcoholic extract of the dried tops of Cannabis sativa—variety Indica,” first appeared in the Secondary List of USP III (1850). It was subsequently elevated to the Primary List in USP IV (1860). Interestingly, USP V (1870) included monographs for both “Cannabis Americanae” (flowering tops of C. sativa cultivated in North America) and “Cannabis Indicae” (flowering tops of female C. sativa var. indica from India), as well as monographs for their respective preparations, “Extractum Cannabis Americanae” and “Extractum Cannabis Indicae.” In 1888, both “Extract of Indian Cannabis” and “Tincture of Indian Cannabis” were included as components of several multi-ingredient preparations monographed in the first issue of NF.13,25 Cannabis extract remained in USP until the twelfth decennial revision (USP XII, 1940), published in 1942.
In recent years, there has been active and growing interest in cannabis inflorescence for medical purposes. In light of the unique regulatory status of cannabis, USP published a Stimuli Article for public comment in 2016 on the topic of the advisability and feasibility of developing new USP quality standards for medical cannabis. As a result of legalization of the medical use of cannabis in numerous US states and in other countries, and in the absence of modernized quality standards such as monographs (i.e., other than the extensive but unofficial Cannabis monograph published by the American Herbal Pharmacopoeia in 2014), USP was asked to develop such standards.26 The USP Cannabis Expert Panel was established, comprising scientific experts in areas of cannabis testing, procedure development and validation, and compendial procedures. The USP Cannabis Expert Panel has recommended specifications for fit-for-purpose analytical methods and to limit contaminants such as toxic elemental impurities, pesticides, microorganisms, and fungal toxins. Multiple complementary tests are included to provide an exhaustive quality characterization. The Expert Panel also highlighted the importance of naming, the definition of chemotypes based on the cannabinoid profile, use of reference materials, and packaging/storage conditions. In April 2020, the USP Cannabis Expert Panel published a peer-reviewed article in the Journal of Natural Products describing quality attributes for cannabis inflorescence.27 USP also submitted public comments to the US Food and Drug Administration (FDA) and US Department of Agriculture (USDA) regarding the need for quality standards for cannabis and cannabis-related compounds.
While USP 1820 listed 145 botanical drugs in its Primary List, many more were admitted in the subsequent decennial revisions throughout the remainder of the 19th century. NF provided for the continuance of official standards for drugs deleted from the USP during periodic revisions. Table 1 provides a list of selected notable articles of botanical origin admitted through USP VIII (1900), along with their year of dismissal and eventual readmission (including those that are expected to be readmitted). Additional information on the regional types and geographic origins of each botanical species is included in the table, although such data were generally not included in the USP. Inclusion in the table indicates significant current use in herbal foods, herbal dietary supplements, botanical drugs, and other natural health products in North America. In the 20th century, when an article was dismissed from the USP, it was generally admitted to the next edition of the NF. Furthermore, most botanicals were eventually dismissed from the NF as well. Thus, the Dismissed column of Table 1 shows dismissals from the USP and, in most cases, subsequent dismissal from the NF. Many of the dismissed botanicals in Table 1 that subsequently entered the NF and left the NF eventually reentered the merged USP–NF in the late 20th century, or are again prioritized for readmission in the early 21st century. In 1995, the use of Roman numerals ceased, replaced with Arabic numerals starting with USP 23–NF 18.
The introduction of bioassays in USP IX (1910) marked a notable method for testing the potency of some botanicals. Optional bioassay methods were introduced for digitalis (Digitalis purpurea, then Scrophulariaceae, since moved to Plantaginaceae) leaf, squill (then Urginea maritima, now Drimia maritima, Asparagaceae) bulb inner scales, strophanthus (Strophanthus kombe or S. hispidus, Apocynaceae) ripe seed, and aconite (Aconitum napellus, Ranunculaceae) tuberous root. A bioassay requirement was also introduced for cannabis and its preparations. The bioassay for cannabis is based on the symptoms of incoordination in dogs and then adjusting the strength by comparison with a standard preparation. This requirement was omitted by USP XI (1930), possibly due to the challenges with bioassays (large variability) and a preference for replacing bioassays with chemical assays, as evidenced by a paragraph in Anderson & Higby’s (1995) Spirit of Voluntarism stating concerns with bioassay reliability and reproducibility.28
Current Status of USP Botanical Standards
Over the last two centuries, the Pharmacopeia’s content has evolved dramatically, from simple descriptions to comprehensive monographs with specifications for identity, assays, impurities, and characterization of quality, as well as detailed requirements for storage, packaging, and labeling. An elaborate description of the current monograph specifications has been published16,29 with examples by both Schiff et al. (2006) and Ma et al. (2018) (see also the section A Walk Through a USP Monograph, available in the full-length paper). The number of monographs has increased substantially from a few hundred in 1820, which consisted mostly of botanicals and minerals, to nearly 5,000 in 2020, which are mostly chemical medicines but also include about 300 botanical ingredients, botanically-derived compounds, and their dosage forms (see Table 2 in the full-length paper).
Depending on the manufacturer’s claims and intended use(s), botanical articles described in the USP can be considered drugs, dietary ingredients, or excipients. The monographs in the USP–NF compendium are organized into different sections. When an article of botanical origin can be legally used as a drug, the monograph that describes the article’s quality attributes would appear in the main section of the USP. When the article is used to supplement the diet, not intended to diagnose, prevent, treat, or cure a disease, it would appear in the dietary supplements section of the USP. If the botanical article is intended as an excipient, it would appear in the NF. Some articles may be used legally across these categories, thus their monographs may appear in multiple sections of the compendium, at times with different names pursuant to the nomenclature guidelines of the USP30 or as cross-references.
USP botanical drugs. The current edition of the USP includes 60 botanical drugs (see Table 3 in the full-length paper), most of which are legacy articles included in early editions of the USP (e.g., belladonna [Atropa belladonna, Solanaceae], digitalis, and podophyllum) and botanical drugs of more frequent use that are available over the counter (OTC), such as senna, psyllium (Plantago ovata or P. arenaria, Plantaginaceae) husk, and capsicum oleoresin. Botanical drugs that are developed according to the recent FDA guidance for “botanical drugs,” such as sinecatechins, a partially purified extract of green tea (Camellia sinensis, Theaceae) leaf, and crofelemer, a preparation of dragon’s blood croton (Croton lechleri, Euphorbiaceae) latex, could be admitted to USP as botanical drugs, but are not yet listed.
Herbal Medicines Compendium (HMC). Recognizing the need for and the gap in standards for herbal medicines, USP published a Stimuli Article in 2012 to seek comments on the development of a specialized compendium of herbal medicines.31 The Stimuli Article reviewed regulatory approaches in the United States and other countries, as well as the rationale for USP’s development of standards for traditional medicines. After the public comments were received and considered, the HMC was developed as an online resource that provides standards for herbal ingredients used in herbal medicines.32 Articles that are approved by a national authority for use as ingredients of herbal medicines, or are included in a national pharmacopeia, and are also deemed appropriate for inclusion in the HMC by a USP Expert Committee, are admitted into the compendium.
Through the HMC, USP created a forum for advancing standards for herbal ingredients used in traditional medicines around the world. The HMC publication, which is available in electronic form, contains only articles that are recognized as ingredients of herbal medicines in other countries and jurisdictions. Given that a botanical may be used as both traditional medicine and a dietary ingredient, some of the HMC monographs overlap with the USP’s dietary supplement monographs, although their nomenclature would be different because of the different nomenclature guidelines for the two compendia. Currently, more than 45 monographs in the HMC are at the Final Authorized stage, and 25 monograph proposals are open for public comment. The expert volunteers of regional Expert Panels, for example, the South Asia Expert Panel and East Asia Expert Panel, prioritize and recommend the standards for adoption. HMC provides the avenue to set standards for botanicals such as Polygonum multiflorum (syn. Reynoutria multiflora, Polygonaceae) and Cullen corylifolium (Fabaceae) that do not qualify for admission into the USP. In these two cases, the USP Dietary Supplements Admission Evaluations Joint Standard-Setting Subcommittee decided not to proceed with monograph development due to safety concerns if used as dietary supplements. However, the HMC is an appropriate home for such botanicals when used within their traditional medicine contexts with specific indications and posology.
Botanical dietary ingredients. A major advance toward including botanicals in USP–NF came after the 1994 passage of DSHEA, which defined dietary supplements as including herbs and other botanicals and extracts thereof, among other substances. The USP adopted a resolution in 1995 that “encouraged the USP to explore the feasibility and advisability of establishing standards and developing information concerning dietary supplements.” This resolution enabled USP to develop new monographs for this category of articles, including botanicals within the NF section until 2002, after which a separate section for dietary supplements was created in the USP. Since then, USP has steadily added new monographs of plant materials used as dietary ingredients with due diligence in the prioritization and admission of the ingredients for standards development.16
Dietary Supplements Compendium (DSC). In 2009, USP published a separate compendium dedicated to dietary supplements named the Dietary Supplements Compendium (DSC). By 2019, the DSC transitioned to an online-only publication with annual updates. The DSC includes all the monographs for dietary supplements and dietary ingredients published in USP–NF, plus other monographs for dietary ingredients that are included in the Food Chemicals Codex (FCC) and monographs for other non-dietary ingredients published in the NF that can be used to formulate dietary supplements. The DSC also includes supplemental information of interest to the dietary supplements industry, such as FDA guidance documents pertaining to dietary supplements (e.g., dietary intake tables) and supporting material for the monographs, such as sample chromatograms and micrographs.
Botanical excipients. Botanicals and botanically derived excipients have always been included in the NF, but if an excipient is also used as a pharmaceutically active ingredient in an FDA-approved product sold in the United States, its monograph will appear in the USP section instead. That is because some botanicals may function as excipients at non-therapeutic dosage levels but as active ingredients when used at therapeutic dosage levels. The criterion for inclusion of botanical excipients in NF is based on whether the article is used as an ingredient in one or more FDA-approved drugs or legally marketed as an excipient in the United States. The article must be included in the FDA Inactive Ingredient Database, referenced in the FDA approved drug label, or included in a drug awaiting approval by the FDA.33,34 Thus, USP works closely with the FDA to prioritize new monographs to be developed for excipients.35
Reference Standards (RSs). USP monograph tests for identification and quantitation of active principles or marker compounds require well-characterized materials. The USP RSs for botanicals are thoroughly characterized for use in qualitative tests (such as identification by fingerprint tests, system suitability tests, or chromatographic peak markers) and quantitative tests (such as assays for ingredients and formulations, assays for the composition of major constituents, limit tests, or control tests). These RS are intended for use in specific analytical tests in monographs in which properties of the product under examination are compared with those of the relevant RS. Depending on the intended purpose, the botanical RSs may be represented by a powdered plant material (e.g., USP Powdered Ginger RS), a dry extract (e.g., USP Powdered Asian Ginseng [Panax ginseng] Extract RS), a purified fraction (e.g., USP Ginkgo [Ginkgo biloba, Ginkgoaceae] Terpene Lactones RS), or a pure compound (e.g., USP Valerenic Acid RS). USP RSs are authentic specimens that have been collaboratively tested and approved for use as comparison standards in USP–NF or HMC tests and assays. USP RSs are provided for legal metrology purposes (the practice and process of applying regulatory structure and enforcement to metrology, which is the science of measurement) and can help ensure the comparability of results and traceability to the SI or metric units. Additional information regarding USP RSs is presented in the general chapter USP Reference Standards <11> (“chapter 11”). These RSs help to determine whether an article meets the monograph acceptance criteria to be deemed a USP-grade material.36
USP guidance documents. USP has developed several guidance documents that explain aspects of the monograph development process. The Admission Evaluation guidance describes the prioritization, selection, and evaluation of information in admitting a monograph to the USP monograph development process.37 Nomenclature guidance explains how monograph titles and article names are constructed.30,38 Additional guidance documents, available on the USP website, address how to define the quality parameters for submission of monograph proposals.39
General chapters. General chapters (found in every USP revision) are documentary standards that cover general requirements for tests and assays, and general information on analytical procedures. The most relevant general chapters pertaining to herbal medicine ingredients and botanical dietary supplements are:
- Articles of Botanical Origin <561>
- Identification of Articles of Botanical Origin <563>
- Botanical Extracts <565>
- High-Performance Thin-Layer Chromatography Procedure for Identification of Articles of Botanical Origin <203>
- Residual Solvents <467>
- Chromatography <621>
- Water Determination <921>
- Identification of Articles of Botanical Origin Using High-Performance Thin-Layer Chromatography Procedure <1064>
- Microbial Enumeration Tests-Nutritional and Dietary Supplements <2021>
- Microbial Procedures for Absence of Specified Microorganisms-Nutritional and Dietary Supplements <2022>
- Elemental Contaminants in Dietary Supplements
EVOLUTION OF BOTANICAL MONOGRAPHS
“The value of the Pharmacopoeia depends upon the fidelity with which it conforms to the best state of medical knowledge of the day.”— Jacob Bigelow, MD (1820)
The monographs in USP–NF undergo periodic revision to ensure that the pharmacopeial standards remain state-of-the-art in terms of the methods and technologies they describe, so they help meet the regulatory requirements. While the publications in the early 19th century did not include quality parameters to address the purity of chemicals (i.e., chemical formula, identifications, or assays, which are hallmarks of a modern pharmacopeia), the monographs were periodically revised and modernized in the 20th century to update the standards in line with the state of the science.
The revision history of the valerian monographs is presented here to illustrate the major changes over time. The first edition of USP in 1820 included monographs for Valerian, Infusion of Valerian, Tincture of Valerian, and Ammoniated Tincture of Valerian (Figure 7). The monograph for the plant material provided a compendial name for the botanical and defined the part of the plant. The monographs for the tea infusion and tincture provided a method to compound the plant material into a standardized form. These monographs did not include methods to analyze the active principles or marker compounds or limits for contaminants.
Revisions of valerian monographs over time expanded the description of the morphological characteristics and included detailed methods for preparing the extract and tinctures. Shown in Figure 8 are the valerian monographs in USP IX, 1910.
Monographs for the valerian family were omitted from USP XII (1940) and NF IX (1950), apparently due to the decreased use of botanical remedies in the 1940s. The passage of DSHEA in 1994 provided a framework for botanical dietary supplements, and thereafter the standards for botanical dietary supplements were introduced in the NF portion of the USP–NF where they resided until 2002. Accordingly, the monographs for valerian were reintroduced in the USP 23–NF 18, 8th Suppl. (1998) as NF monographs. With the creation of a separate Dietary Supplements section within the USP portion of the USP–NF, all dietary supplement monographs and related general chapters were migrated to this new section as of USP 27–NF 22 (2004). As of January 2020, these monographs for Valeriana officinalis are official in USP 43:
- Powdered Valerian
- Valerian Tablets
- Valerian Tincture
- Valerian Root Powdered Capsules
- Powdered Valerian Extract
- Valerian Root Dry Extract Capsules
The current monographs for valerian provide detailed descriptions of quality parameters in alignment with the state of the science and regulations (see A Walk Through a USP Monograph in the full-length paper). Modern monographs in the Dietary Supplements Compendium include illustrations of macro- and microscopic features with photographic material to aid the analysts.
Identification tests are based on characteristic chromatographic fingerprints using high-performance thin-layer chromatography (HPTLC) and high-performance liquid chromatography (HPLC). The content of relevant constituents is typically determined by chromatographic methods such as HPLC. Detection of adulterants and contaminants is a major concern, and modern monographs now typically include provisions in the identification tests to rule out potential confounders, as well as modern purity tests to detect contaminants such as heavy metals by inductively coupled plasma (ICP) or pesticides by advanced chromatography.
Figures 9-15 illustrate the comprehensive requirements of current USP monographs for valerian, reflecting the current state of the science.
An Outlook for The Future
Up-to-date and modernized standards. USP is committed to keeping its monographs up to date by following the principles articulated for the valerian monographs. Another aspect of the evolution is reflected in the fact that print editions of USP–NF are being phased out. USP is moving from print media in the form of published books to digital and visual media in the form of databases of standards and knowledge accessible electronically. This new format creates opportunities for users of the pharmacopeia to access a reference repository of data linked to monographs for comparison. For example, chemometric approaches to identification of botanicals could be introduced in the modernized monographs with links to digital databases to provide an avenue to compare the phytochemical profile of a test sample with that of several samples from multiple locations and growing conditions. This approach could further refine the monograph acceptance criteria.
New technologies. USP recognizes the value of new technologies with greatly improved analytical sensitivity but also knows they are likely to pose an undue burden on users familiar with older methods. To address this dilemma, USP formed a Modern Analytical Methods Joint Subcommittee to evaluate the full breadth of available approaches for including modern technologies in both the development of monographs and the establishment of reference materials. The subcommittee is a collaborative effort led by the Botanical Dietary Supplements and Herbal Medicines Expert Committee (EC) in conjunction with the Non-Botanical Dietary Supplements EC and the Food Ingredients EC. New research and innovation projects related to botanicals include DNA analysis for the identification of herbal/botanical articles and the use of quantitative nuclear magnetic resonance (qNMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) procedures in dietary supplement monographs. As an example, it may be possible to use qNMR as a simultaneously selective and universal screening tool. The qNMR and LC-MS methods also have the potential to enhance pharmacopeial efforts in sourcing suitable reference materials. USP also recognizes new trends in pharmaceutical manufacturing such as “continuous manufacturing technologies.” It remains to be seen as to how these new trends will be adopted for herbal medicine production and the impact of these approaches on future pharmacopeial standards.
Considering the constant challenge of economically motivated adulteration, there is an unmet need for non-targeted methods that can detect such adulteration (e.g., adulteration of dietary supplements with prescription drugs and their unapproved drug analogs, as well as with other dietary supplements and natural product articles with unapproved drug admixtures). LC-MS procedures could serve as non-targeted approaches to detect adulteration with synthetic drugs or drug analogs.
Science of standards beyond monographs. USP ECs and staff engage in several activities to support the standard-setting work and move the science forward. EC members and USP staff have published several articles in peer-reviewed journals on the topics of quality, safety, and nomenclature.29,40-42 Besides the use of Pharmacopeial Forum as a primary portal for seeking stakeholder input, new avenues such as Stimuli Articles and roundtable discussions are used for seeking public input on issues such as rational limits for pesticide residues, DNA methods for botanical identification, and standards for cannabis and cranberry (Vaccinium macrocarpon, Ericaceae) fruit. Focused Expert Panels have been formed on topics such as standards for cannabis, development of multi-criteria decision-based modeling approaches to assess the safety of multi-ingredient dietary supplements, and evaluating the potential hepatotoxicity of green tea extract. USP Expert Panels are convened when additional specialized expertise beyond the EC is needed.
Novel ingredients. As the supply chain for botanicals becomes increasingly global — both in terms of adoption of traditional herbs from other cultures by American consumers and increased use of botanicals as a part of health systems around the world — USP prioritization and admission criteria are playing an important role in admitting botanicals into the compendia by focusing on the botanicals that provide maximum public health impacts of USP’s standard-setting work.
USP’s public health mission has remained steady and consistent from the organization’s inception in 1820 to the present, and it is reflected in the current mission statement: “to improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.” To remain relevant as science advances, timely adoption of the innovative ways of manufacturing and quality assurance is essential. In tune with the fast-paced technological developments and novel challenges, and to maintain its relevance and usefulness as a pharmacopeia, USP is rapidly adapting, and in some cases leading, in modernizing public standards with the introduction of new, fit-for-purpose technologies and modalities. Trust in quality standards is more important now than ever before, given that standards drive quality across the global supply chain. Based on its 200-year legacy of making contributions to botanical standards, USP is poised to continue its public health mission for the future.
Four of the seven authors are employees of USP, which is a nonprofit organization that sells documentary and physical reference standards to sustain its activities. The views presented in this article do not necessarily reflect those of the organizations for which the authors work. No official support or endorsement by these organizations is intended or should be inferred.
The authors acknowledge contributions from Guido Pauli, Ph.D., the University of Illinois at Chicago. The authors thank Kornepati Ramakrishna, Ph.D.; Anton Bzhelyansky, MS; Nam-Cheol Kim, Ph.D.; Kit Goldman, Ph.D.; and Renee Settle, all of USP, for reviewing or contributing to this manuscript, and Christina Chase and Katie Daud, both of USP, for their scientific-technical writing assistance.
* Address correspondence to N.D. Sarma, United States Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, United States. Phone: +1.301.816.8354. Email: firstname.lastname@example.org.
† The abbreviation USP (without italics) is used in this article to refer to the United States Pharmacopeial Convention, and the abbreviation USP (in italics) is used to refer to the pharmacopeial compendium.
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