December 2014

ABC-AHP-NCNPR Botanical Adulterants Program

Laboratory Guidance Documents

Explanation of Purpose

Background

As the global market for herbal medicines and dietary supplements (also known as food supplements in some countries) has increased and continues to be financially lucrative, so have confirmed reports of undisclosed ingredients being added to botanical raw materials, extracts, essential oils, and finished botanical-based consumer products. These reports include situations in which materials of inferior quality are added or substituted for the listed botanical ingredient, as well as the undeclared addition of active pharmaceutical ingredients (APIs) and drug analogues. These problems not only present a significant challenge to the global botanical medicine and herbal supplement industries but more importantly put the health and safety of the consumer at risk.

Regulatory authorities around the world now increasingly require appropriate testing for identity and authenticity of botanical materials that are to be used in herbal medicines and dietary/food supplements. Though requirements vary from country to country with some regulatory authorities being more active than others, the World Health Organization (WHO) has identified in its new global strategy, WHO Traditional Medicine Strategy: 2014-2023, the need for testing for quality and ensuring appropriate regulations as key priorities in allowing consumers to safely include these products within their health care options.¹ Examples of how certain countries and regions have approached this issue can be found below.

In the United States, under Food and Drug Administration (FDA) current Good Manufacturing Practice (cGMP) regulations for dietary supplements, it is the responsibility of any company that manufactures, packages, labels, or holds dietary supplements to “conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient.”² Specifically, the company must establish an identity specification for every dietary ingredient (and other quality specifications, i.e., purity, strength, composition, and limits on contaminants that may adulterate or lead to adulteration of the dietary supplement). The tests and examinations used to determine whether a specification is met must be appropriate, scientifically valid methods, and must include at least one of the following analyses: (1) gross organoleptic, (2) macroscopic, (3) microscopic, (4) chemical, or (5) other scientifically valid methods.²

The European Medicines Agency (EMA) has issued numerous guidelines concerning the quality and testing of herbal substances and herbal medicinal products. According to EMA guidelines for identity testing, “Identification testing optimally should be able to discriminate between related species and/or potential adulterants/substitutes, which are likely to be present. Identification tests should be specific for the herbal substance and are usually a combination of three or more of the following: macroscopical characters, microscopical characters, chromatographic procedures, [and] chemical reactions.”³

The same requirements are also described for herbal medicines (excluding extracts) in the Australian regulatory guidelines for complementary medicines (ARGCM), published by the Therapeutic Goods Administration. For herbal extracts, there are three options to authenticate the material: (1) comparison with descriptions in the current scientific literature (generally acceptable are descriptions in national pharmacopeias); (2) chromatographic comparison against an authenticated reference specimen; or (3) chromatographic comparison against a reference extract.⁴

Canada has a regulatory framework based on pre-market approval of Natural Health Products before they come to market. For medicinal ingredients in Natural Health Products, Health Canada requires appropriate testing sufficient to characterize the ingredient and distinguish the correct ingredient/plant species and parts from likely adulterants. Health Canada recommends a “combination of botanical characteristics and chemical identification tests … to eliminate misidentification of the botanical.”⁵

The specific approach and amount of testing required varies and may include organoleptic/macroscopic, microscopic, and chemical identification, depending on the type of ingredient, e.g., raw material or extract. Authentication methods for botanical materials are available in various official compendia (e.g., the United States Pharmacopeia, the European Pharmacopoeia, the Chinese Pharmacopoeia, et al.), as well as monographs from the unofficial American Herbal Pharmacopoeia® and Therapeutic Compendium. However, given the rapid evolution in the sector, particularly in phytochemical and emerging genetic (e.g., DNA barcoding) analysis, methods may be outdated or may not exist for the botanical raw material or extract of interest. Though new analytical methods have improved the ability to establish the identity of plant-based ingredients and characterize their composition to aid in the detection of adulteration, unscrupulous manufacturers and suppliers have succeeded in finding ways to deceive potential buyers. In many cases, this is done by providing botanical ingredients that appear to comply with standardization requirements for specific marker/active compounds but in fact just take advantage of the lack of specificity of tests used to measure them.

Identifying and applying test methods that are suitable for their purpose is crucial for both in-house quality control units and third-party analytical testing laboratories. However, a review of all the available published analytical methods can be a daunting task, and an assessment of each of these methods with regard to their ability to authenticate an ingredient and to detect adulteration is an expensive and time-consuming process.

The ABC-AHP-NCNPR Botanical Adulterants Program Laboratory Guidance Documents aim to address this challenge by providing expert, peer-reviewed guidance on selecting suitable methods for complying with regulatory requirements worldwide. This is specifically done by focusing on the identity, purity, strength, and composition testing requirements mandated in the United States under FDA regulations governing cGMP in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements (21 C.F.R. Part 111), as well as those requirements of other leading regulatory bodies, as noted above.

Purpose

The ABC-AHP-NCNPR Botanical Adulterants Program Laboratory Guidance Documents identify the most suitable analytical methods for detection of certain adulterants and authentication of specific botanical materials in all the available forms (whole, cut, powdered raw materials, extracts, and/or essential oils). To ensure all aspects are covered, positive assessments of analytical methods are based on a thorough review of available methods from official compendia and unofficial compendia (e.g., the American Herbal Pharmacopoeia and Therapeutic Compendium), plus those provided by industry supporters and underwriters of the Botanical Adulterants Program – including botanical ingredient suppliers, manufacturing companies, and independent third-party analytical laboratories – in addition to the relevant methods in the published peer-reviewed literature. The primary assessment of each method is based on its ability to detect a suspected adulterant; extent of validation, labor, and analysis time are used as secondary criteria for making recommendations. This Guidance is intended for quality control personnel in the herbal medicine, botanical ingredient, and dietary supplement industry sectors, and analysts in analytical testing laboratories, to help them identify the appropriate techniques and methods for their specific analytical needs.

Contents

A consistent approach is taken with all the Laboratory Guidance Documents starting with a description of the purpose and scope of the document in regard to the particular species covered. This information is followed by a short overview of the botanical nomenclature of the species and its known adulterants. The list of known adulterants is based on published data and, in some instances, input from the private sector. The section on analytical techniques generally includes macroscopic, microscopic, chemical, and genetic assays. Since most of the available methods focus on the determination of marker/active compounds, much emphasis is given to chemical analysis, including a short summary of the phytochemical composition of the species in question and the known adulterant(s). Each sub-section on analytical methods ends with an assessment of the available techniques and a short comment of the suitability to authenticate the botanical ingredient and detect adulteration. An overview of strengths and limitations of the various assays in a table format completes the analytical section. Complete references are provided with links to original source documents.

Disclaimer Notice

The Laboratory Guidance Documents produced by the ABC-AHP-NCNPR Botanical Adulterants Program are for educational and informational purposes only and are not intended to provide or to replace appropriate legal or regulatory advice. Although the documents have been produced from sources believed to be reliable, no warranty, expressed or implied, is made regarding the accuracy, completeness, legality, reliability, or usefulness of any information contained therein. The information is provided solely on an “as is” basis. Changes to information in the Laboratory Guidance Documents may periodically be made, and notice of such changes will be posted from time to time on the Botanical Adulterants Program website, and by other means, e.g., the “Botanical Adulterants Monitor” (an electronic newsletter produced by the Program) and other email communications. Anyone who believes that there are any errors or omissions to information contained in the Laboratory Guidance Documents is encouraged to report them to the ABC-AHP-NCNPR Botanical Adulterants Program.

Every company that manufactures, packages, labels, or holds dietary supplements in the United States has the duty to ensure compliance with FDA regulations at 21 C.F.R. Part 111 and related legal and regulatory requirements. These requirements include the responsibility to perform an identity test on incoming dietary ingredients. The identity testing must confirm that the dietary ingredient meets the established specifications. In some instances, and on a case-by-case basis, confirmation of identity may include the need to rule out adulteration with non-target botanical species (species that are not part of those aimed to be detected by the specific analytical method, e.g., adulterants that have not been previously reported). If a single test is not suitable or adequate to determine whether the ingredient meets the identity specifications, then more than one test will be needed. Multiple identity tests for botanical materials are already required by various regulatory agencies in other countries outside of the U.S.^3-5

The ABC-AHP-NCNPR Botanical Adulterants Program Laboratory Guidance Documents are not intended to suggest that a company must test for all the species listed in the documents as known adulterants. Some of the listed adulterant species represent incidences of historical significance but occurrence may be rare or absent in the current marketplace. Testing methods and procedures should be based on a risk assessment of the supply chain and the ingredient specifications. As noted above and as mandated in the United States in 21 C.F.R. Part 111, manufacturers are required to set their own specifications under § 111.70(b), (c), and (e) “for contaminants that may adulterate or that could lead to adulteration of the [finished] dietary supplement,” explained by FDA in the preamble to the GMP regulations.⁶ FDA noted that “under this final rule, the manufacturer has the flexibility—and the responsibility—to develop specifications that are appropriate to the circumstances.” FDA has also indicated that the agency “would not expect [a manufacturer] to set limits for every potential contaminant or for every naturally occurring constituent of a botanical.” Stated differently, manufacturers are required to set their own specifications, including those for reasonably anticipated adulterants,* to ensure the dietary supplement consistently meets the specifications for identity, purity, strength, and composition.

The inclusion of a specific test method for a material in its particular matrix in this Laboratory Guidance Document is for educational purposes only and does not reduce or remove the responsibility of laboratory and quality control personnel to demonstrate the suitability of the analytical method for its intended use, as described in the following: the US Food and Drug Administration’s Final Rule for Current Good Manufacturing Practice for Dietary Supplements (as published in 21 C.F.R. Part 111),⁶ and by AOAC International,⁷ the International Organization for Standardization (ISO),⁸ the United States Pharmacopeia,⁹ and the International Conference on Harmonisation (ICH).¹⁰ These materials are not intended to be an exhaustive list of potentially useful resources.

* The term “adulterants” (or, as it is phrased by the FDA, “contaminants that may adulterate”) is defined more broadly in the statute and as enforced by FDA in inspections of dietary supplement manufacturers conducted under the Part 111 regulations. Accordingly, potential adulterants of dietary supplements (other foods, and herbal medicines) also include the following: (1) filth, insects, or other extraneous material; (2) microorganisms; and (3) toxic substances (pesticides, fungal toxins, residual solvents, heavy metals, et al.).⁶ Products containing contaminants that are not within the specified levels established by the manufacturer are considered adulterated.

References

1. World Health Organization. WHO Traditional Medicine Strategy: 2014-2023. Geneva, Switzerland: World Health Organization; 2013. Available at: http://www.who.int/medicines/publications/traditional/trm_strategy14_23/en. Accessed December 16, 2014.

2. US Food and Drug Administration. Code of Federal Regulations Title 21, Volume 2, Part 111 (21CFR111): Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=111. Revised April 1, 2014. Accessed December 16, 2014.

3. Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP). Guideline on Specifications: Test Procedures and Acceptance Criteria for Herbal Substances, Herbal Preparations and Herbal Medicinal Products/Traditional Herbal Medicinal Products. London, UK: European Medicines Agency; March 30, 2006. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003393.pdf. Accessed December 16, 2014.

4. Australian Government Department of Health, Therapeutic Goods Administration. Identification of herbal materials and extracts. Available at: http://www.tga.gov.au/publication/identification-herbal-materials-and-extracts. Published May 25, 2004. Updated October 28, 2014. Accessed December 16, 2014.

5. Health Canada, Natural Health Products Directorate. Quality of Natural Health Products Guide. Available at: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/eq-paq-eng.php. Published May 1, 2013. Accessed December 16, 2014.

6. US Food and Drug Administration. 72 FR 34752, 34837, 34840. Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements: A Rule by the Food and Drug Administration. Available at: https://www.federalregister.gov/articles/2007/06/25/07-3039/current-good-manufacturing-practice-in-manufacturing-packaging-labeling-or-holding-operations-for. Published June 25, 2007. Accessed December 16, 2014.

7. AOAC Official Methods of Analysis. Appendix K: Guidelines for Dietary Supplements and Botanicals. Part I: AOAC Guidelines for Single-Laboratory Validation of Chemical Methods for Dietary Supplements and Botanicals. Part II: AOAC Guidelines for Validation of Botanical Identification Methods. Part III: Probability of Identification: A Statistical Model for the Validation of Qualitative Botanical Identification Methods. Rockville, MD: AOAC International; 2013. Available at: http://www.eoma.aoac.org/app_k.pdf. Accessed December 16, 2014.

8. International Organization for Standardization (ISO). Standards Catalogue 03.120.30: Application of statistical methods. ISO 5725-1:1994: Accuracy (trueness and precision) of measurement methods and results -- Part 1: General principles and definitions. ISO 5725-2:1994: Part 2: Basic method for the determination of repeatability and reproducibility of a standard measurement method. ISO 5725-3:1994: Part 3: Intermediate measures of the precision of a standard measurement method. ISO 5725-4:1994: Part 4: Basic methods for the determination of the trueness of a standard measurement method. ISO 5725-5:1998: Part 5: Alternative methods for the determination of the precision of a standard measurement method. Geneva, Switzerland: International Organization for Standardization. Available at: http://www.iso.org/iso/iso_catalogue/catalogue_ics/catalogue_ics_browse.htm?ICS1=03&ICS2=120&ICS3=30. Accessed December 16, 2014.

9. The United States Pharmacopeial Convention. USP 36-NF 31: <1225> Validation of Compendial Procedures. In: The United States Pharmacopeia 36^th Revision - National Formulary 31^st Edition. Vol. 1. Rockville, MD: The United States Pharmacopeial Convention; 2013.

10. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Validation of Analytical Procedures: Text and Methodology Q2(R1). Geneva, Switzerland: International Conference on Harmonisation (ICH). Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf. Published November 6, 1996. Updated November 2005. Accessed December 16, 2014.