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 36th Revision -
National Formulary 31st 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.