The Regulatory System of Herbal Mushroom Antrodia cinnamomea
Products Used as Dietary Supplements and NDIs in the United States
美國對牛樟芝產品作為膳食補充劑及新膳食成分的法規系統
Shung-Chang Jong, Ph.D.鍾順昌
Consultant for Global Affairs, Director Emeritus of Microbiology
ATCC, Manassas, VA 20110-2209, USA. sjong@atcc.org; www.atcc.org
Abstract
Antrodia cinnamomea, commonly called “Niu-Chang-Chih” by indigenous
communities, is a rare herbal mushroom known only from Taiwan. The mushroom is
popular in folk medicine, as it is used in treatments of numerous ailments due to the
presence of diverse biologically active compounds. Its presence in nature is restricted to
the tree Cinnamomum hanehirae, a species of cinnamon that grows at the altitude
between 450-2,000 meters in mountain ranges. Because of its host specificity and
scarcity in nature, this mushroom has become very expensive as medicinal material
with prices up to US$44,000 per kilogram of good quality fruiting bodies collected
from nature. The United States is the world’s largest healthcare market with annual
sales of dietary supplement (DS) products approximately $23.7 billion in 2007 and the
U.S. Government Accountability Office (GAO) estimated 75,000 DS products in the
marketplace. It is critical for Niu-Chang-Chih DS manufacturers and exporters in
Taiwan to understand the relevant U.S. federal laws and regulations if they are to
establish long-term positions in the healthcare marketplace in the U.S. The regulation
of foods and food ingredients is governed by various statutes enacted by the U.S.
Congress. Pursuant to the Federal Food, Drug and Cosmetics Act (FDCA) and
accompanying legislations, the Food and Drug Administration (FDA) has authority to
oversee the safety and quality of substances sold as foods in the U.S. and to monitor
claims made in labeling both the composition and the health benefits of foods. The
1994 Dietary Supplement Health Education Act (DSHEA) created a regulatory
framework for dietary supplements (DSs) that included provisions establishing current
good manufacturing procedures (DS CGMP), mechanisms for pre-market safety
notifications for new dietary ingredients (NDIs), and a mechanism for establishing
claims used in product labeling. All herbal mushroom Niu-Chang-Chih products used
as DSs and NDIs are carefully regulated by U.S. federal authorities to ensure that they
are safe to eat and are accurately labeled in the marketplace. Although Taiwan has
created a regulatory framework specifically designed for health foods since 1999 (under
the Health Food Control Act of 1999), Niu-Chang-Chih DS manufacturers in Taiwan
that intend on exporting their products to the U.S. should carefully review their
operating procedures to ensure that they comply with the regulatory requirements
established by the FDA to meet standards as well as the expectation of U.S. consumers.
Keywords: Antrodia cinnamomea, Niu-Chang-Chih, dietary supplement, new dietary
ingredient, U.S. federal law, FDA regulation, herbal mushroom, quality standard, safety
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I. Introduction
The herbal mushroom Antrodia cinnamomea Chang et Chou (1994), commonly called
“Niu-Chang-Chih” by local communities, is hailed as a national treasure in Taiwan. In
the wild, the rare and unique herbal mushroom grows solely on the tree Cinnamomum
hanehirae Hayata, a species of cinnamon that grows at the altitude 450-2,000 meters
above sea level in the mountainous terrain. It has long been used in folk medicine as an
antidote for alcohol, food and drug intoxication, as an anticancer agent in liver cancer,
and in the treatment of numerous ailments, such as diarrhea, abdominal pain,
hypertension and skin itching. Like other medicinal mushrooms, the mushroom
contains many biologically active ingredients that are believed to exhibit effects of
purifying the blood, removing toxic substances, toning kidneys, protecting the liver,
regulating intestines, strengthening the heart, adjusting blood pressure, anti-bacteria,
resisting cold, suppressing cough, eliminating sputum, alleviating pain, tranquilizing,
anti-cancer, relieving tumor, expelling toxin, and anti-fatigue. For use as specific
dietary ingredients (DIs), many Niu-Chang-Chih products have been prepared through
separation, extraction, and filtration from fruiting bodies cultivated or collected from
the wild. Large scale extraction can be obtained from in submerged liquid bioreactors
or from solid state fermentation on grain substances. They are sold in the form of dried
fruiting bodies and biomass, pill, softgel, gelcap, capsule, tablet, powder and liquid.
Today a wide variety of Niu-Chang-Chih products are widely available in Taiwan as
dietary supplements (DSs) in health food stores, supermarkets, drug and national
discount chain stores, as well as through the Internet, TV programs, mail-order catalogs,
and direct sales. However, rapid technological advances and the expansion and
globalization of the health food industry present significant challenges, not the least of
which, are regulatory variances between countries active in the marketplace. The
United States is the world’s largest healthcare market, with annul sales of DS products
approximately $23.7 billion in 2007 and the U.S. Government Accountability Office
(GAO) estimated 75,000 DS products are available on the market. About half of adults
in the U.S. report regularly using DSs, and the DS industry and market is growing
every year. It is critical for Niu-Chang-Chih DS manufacturers and exporters in Taiwan
to understand the relevant U.S. federal laws and regulations if they are to establish
long-term positions in the healthcare marketplace in the United States.
II. U.S. Federal legislations regulating food and dietary supplement
products in marketplace
The U.S. currently leads all other countries in the extent and details of its food safety
legislation. Compliance with the following specific laws and regulations is an important
factor in the availability of safe, wholesome, and properly labeled food/dietary
supplement products in marketplace in the United States.
(1) Federal Food, Drug and Cosmetics Act (FDCA), 1938
(2) Food Additive Amendments Act (FAAA), 1958
(3) Fair Packaging and Labeling Act (FPLA), 1966
(4) Nutrition Labeling and Education Act (NLEA), 1990
(5) Dietary Supplement Act (DSA), 1992
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(6) Dietary Supplement Health and Education Act (DSHEA), 1994
(7) Public Health Security and Bio-terrorism Preparedness and Response Act
(the Bioterrorism Act), 2002
(8) Dietary Supplement and Nonprescription Drug Consumer Protection Act
(DSNDCPA), 2006
(9) Food and Drug Administration Modernization Act (FDAMA), 2007
(10) Dietary Supplement Current Good Manufacturing Practices (DS CGMP),
2007
(11) Food Safety Modernization Act (FSMA), 2010
The Federal Food, Drug, and Cosmetic Act (FDCA) of 1938, which replaced the 1906
Pure Food and Drugs Act, is the basis of U.S. food and DS supply. It broadened
prohibition against economic “adulteration” and authorized the establishment of
“standards.” The FDCA requires the label of every processed packaged food/DS to
contain the name of the food, its net weight, the name and address of the manufacturer
or distributor, and for certain products, a list of ingredients. It prohibits labeling
statements that are false or misleading. Although the FDCA has been amended a
number of times since its passage, its basic principles to prevent the “adulteration” and
“misbranding” of food/dietary supplement (DS) remain essentially unchanged.
A “food additive” as defined by the FDCA is a substance that may become component
of a food or affect the characteristic of a food but is not a GRAS substance (Generally
Regarded as Safe), a prior sanctioned material, a pesticide chemical residue, or a color
additive. The Food Additive Amendment Act of 1958 was a milestone in that it
required “safety testing” for additives used in processed foods prior to their use and
shifted the burden for conducting that testing from the government to the industry, and
gave the FDA the authority for “premarket review and approval” of additives. Thus,
premarket approval is not required if the proposed use of the substance is GRAS that is
distinguished from a food additive based on the common knowledge about the safety of
the substance for its “intended use.” GRAS status for a food ingredient can be
achieved either through its extensive history of common use in food before 1958 or
through published scientific evidence. Any food additive that is intended to have a
technical effect in the food is deemed unsafe; and any food that contains an unsafe food
additive is adulterated. Similarly, any substance that is added to food and imparts color
to the food is a color additive. Unlike the definition for food additive, there is no GRAS
exemption for color additives. Any food that contains an unsafe color additive is
adulterated.
The Fair Packaging and Labeling Act (FPLA) of 1976 was a step forward in regulating
information on labels, particularly concerning the quantity of contents, in order to
facilitate value comparisons. It applies to all consumer products in interstate commerce
intended for retail.
The Nutrition Labeling and Education Act (NLEA) of 1990 amended the FDCA,
reaffirming the FDA’s labeling initiative and establishing an explicit timetable for
implementation. The NLEA required mandatory nutritional labeling for virtually all
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food, including conventional foods and dietary supplements (DSs), standardized
serving sizes, and the uniform use of health claims. According to the NLEA, the FDA
was to determine what diet-disease relationships are adequately supported by scientific
evidence and then promulgate regulations under which claims may be made for specific
food products. The FDA proposed rules as required by the NLEA in 1991, and was
about to publish final rules a year later when Congress published the Dietary
Supplement Act (DSA) of 1992. The DS Act provided a one-year moratorium on
application of the NLEA to dietary supplements and required the FDA to propose new
rules on nutrition labeling of and nutrient content claims for DSs. Before the DS Act
could be implemented, Congress intervened by passing the Dietary Supplement Health
and Education Act (DSHEA) of 1994.
The DSHEA created a new framework for the regulation of DSs, which signals a major
departure from the well-established “food” versus “drug” dichotomy that guided the
FDA policy with respect to such products for over fifty years. The DSHEA defined
dietary supplements (DSs), set criteria for regulating labeling and claims, and
established government agencies to serve as a watchdog over regulations of DS. DSs
were no longer regulated like other products such as foods, drugs, food additives,
GRAS ingredients, cosmetics, and medical devices, but rather they became a new
category of food substances or “dietary supplements (DS).” The goals of DSHEA are
to promote healthful diets and thereby possibly mitigate the need for expensive medical
procedures; to empower consumers to make choices about preventive health care
programs based on data from scientific studies of health benefits related to particular
DSs, and to improve the flow of safe products to consumers.
The Public Health Security and Bio-terrorism Preparedness and Response Act (the Bioterrorism Act) of 2002 requires registration of facilities with the FDA and recordkeeping regulations extend to those that transport, distribute, receive, or import
foods/dietary supplements. The Dietary Supplement and Nonprescription Drug
Consumer Protection Act (DSNDCPA) of 2006 requires a manufacturer, packer, or
distributor whose name appears on the label of a DS, known as “responsible person”,
to report a serious event to FDA within 15 days of receipt of the information. The Food
and Drug Administration Modernization Act (FDAMA) of 2007 prohibits the addition
of drugs or biologics to food and to authorize the creation of a “reportable food
registry” collect information about any food/DS that may pose serious health risks.
The Dietary Supplement Current Good Manufacturing Practices ( DS CGMP) of 2007
requires that proper controls are in place for DSs so that they are processed in a
consistent manner, and meet “quality standards” through manufacturing, packaging,
labeling, and storing of DS products.
The Food Safety Modernization Act (FSMA) of 2010 was signed into law by President
Obama on January 4, 2011. The law is the most sweeping reform of food safety laws in
more than 70 years. It shifted the focus of FDA away from responding to problems and
toward prevention. One of the law’s priorities is creating a new system of import
oversight. Increasing globalization of food/DS supply is one reason given for why
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FSMA was needed. However, the FDA currently inspects less than one pound in a
million of imported foods/DSs (New York Times).
III. Statutory definition of dietary supplements and dietary
ingredients set by U.S. Congress through DSHEA of 1994
The Institute of Medicine of the U.S. Academy of Sciences has defined “functional
foods” as those that “encompass potentially healthful products, including any modified
food or food ingredient that may provide a health benefit beyond the nutrients it
contains.” The term “functional food” comes in a plethora of name forms such as
“dietary supplement”, “food supplement”, “nutritional supplement”, “nutraceutical,
health food”, “medical food”, “vita food”, “designer food”,” natural health product”,
and “pharmafood” in the U.S. marketplace. “Functional foods” essentially are
“conventional foods” that have ingredients put in them for which health-related claims
are made. Under U.S. laws, there are no recognized “functional foods” or “traditional
medicines.” There are, however, “dietary supplements.” Thus, the term “dietary
supplement” (DS) is now being more widely accepted and recognized by consumers.
Through DSHEA, DSs are regulated as a special category of food for almost all
purposes under FDCA. But, there are “safety” and “claims” provisions relating DSs
that are different than those that apply to other food categories.
The DSHEA expands the definition of DSs to include herbs and other botanicals in
addition to vitamins, minerals, amino acids, concentrates, metabolites, constituents,
extracts or combinations of any of these ingredients. In addition, a DS is limited to
products that are intended for “ingestion” in tablet, capsule, powder, softgel, gelcap, or
liquid, or other form, that are not represented as a “conventional food” or as a sole item
of a meal or of the diet, and are labeled as “dietary supplements.”
The DSHEA also defined both the term “dietary ingredient” (DI) and “new dietary
ingredient (NDI) as components of DSs. An NDI is one that meets the definition for a
DI and was not marketed in the U.S. prior to October 15, 1994 and does not include any
old DI which was marketed in the U.S. prior to October 15, 1994. Understanding the
legal distinction between “old” and “new” dietary ingredients/supplements is
imperative for any company marketing a Niu-Chang-Chih DS product in the U.S.
marketplace.
DSHEA classifies a DS as adulterated if it “presents a significant or unreasonable risk
of illness or injury.” In DSHEA, an “unreasonable risk” has a meaning independent
from a “significant risk.” Thus, “unreasonable risk” is a distinct term and requires
more than evaluation of the significance of risk. In other words, an “unreasonable risk”
is relative to the circumstances; the potential risk is more “unreasonable” if the
potential benefit is smaller.
In January of 2014, the FDA released a “Guidance for Industry: Distinguishing
Liquid Dietary Supplements from Beverages.” The purpose of the guidance is to,
“to help dietary supplement and beverage manufacture and distributors determine
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whether a product in liquid form is properly classified as a dietary supplement or as a
beverage. The guidance discusses a combination of factors for consideration, which
includes
(1) Product or brand name,
(2) product packaging,
(3) serving size and total recommended daily intake,
(4) composition,
(5) recommendations and directions for use,
(6) statements or graphic representations in labeling or adverting,
(7) other marketing practices.
The guidance also pays special attention to powers, concentrated liquids and
effervescents that are added to water or other liquids.
IV. Premarket notification for a new dietary ingredient (NDI)
required by FDA
Any DS that contains an NDI is deemed adulterated unless the manufacturers,
marketers or distributors submit information to FDA at least 75 days prior to the
introduction of an NDI into the market with sufficient information qualifying the safety
of the NDI. Generally, the “pre-market safety notification” must include the history
of use or other evidence of safety establishing that the NDI will reasonably be expected
to be safe under the conditions of use recommended or suggested in the labeling. The
scientific name of the NDI must include the “Latin binomial” (including the author) if
the ingredient is a botanical or microbe when filing an NDI submission. FDA uses the
NDI notification process as its safety gatekeeper to monitor and evaluate the safety of
the NDI contained in DSs. Any DS containing ingredients that fail to meet the NDI
review process is deemed unlawfully marketed and prohibited from sale until the NDI
requirements have been met. The Division of Dietary Supplement NDI Review Team in
the Office of Nutrition, Labeling and Dietary Supplements at the Center for Food
Safety and Applied Nutrition (CFSAN) reviews NDI notifications.
Any DS that contains an NDI is deemed adulterated unless it meets one of the
following requirements:
(1) It is a DS that contains only DIs that have been present in the food supply as an
article used for food in a form in which the food has not been chemically altered.
Food is not chemically altered if in processing there is minor loss of volatile
components, dehydration, lyophilization, milling, tincture or solution in a water
slurry, powder, or solid in suspension.
(2) There is a history of use or other evidence of safety establishing that the DI when
used under the conditions recommended or suggested in the labeling of the DS
will reasonably be expected to be safe.
The overall regulatory status of a DS is affected by the regulatory status of each
individual DI. It is the responsibility of the manufacturer of any DS products to ensure
that all ingredients used are of food-grade purity and comply with specifications and
limitations in all applicable authorizations. To determine compliance, each
authorization must be composed of three parts:
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(1) identity of the substance (e.g., chemical, herbal/botanical, and microbiological)
used as a DI in a DS,
(2) specifications including purity and physical properties, and
(3) limitations on the conditions of use.
FDA instituted this proceeding to help the DS industry comply with the DSHEA.
V. Regulations for permissible claims and labeling of dietary
supplements required by FDA
FDA is tasked with overseeing claims on product labeling, including all labels and
other written, printed, or graphic matter upon any article or any of its containers or
wrappers, or accompanying such article. The label of a DS may contain one of the
following three types of claims:
(1) Health claim describes a relationship between a DS ingredient, and reducing
risk of a disease of health-related condition.
(2) Nutrient content claim describes the relative amount of a nutrient or DS
substance in a product.
(3) Structure/function claim is a statement describing how a product may affect
the organs or systems of the body and it can not mention any specific disease.
Different requirements apply to each type of claim. According to DSHEA, DS labels
can carry these claims without obtaining “pre-marketing authorization” from the FDA.
The manufactures are responsible for ensuring the accuracy and truthfulness of such
label claims that are not approved by FDA. But for structure/function claims,
manufacturer must provide FDA with the text of the claim within 30 days of putting the
product on the market. Product labels containing such claims must also include a
disclaimer “prominently displayed and in boldface type” that states:
“The statement has not been evaluated by FDA. This product is not intended to
diagnose, treat, cure, or present any disease”
DSHEA essentially gives the DS manufacturer freedom to
(1) market more products as DSs, and
(2) provide information about the benefits of their products in product labeling.
FDA regulations require that the term “dietary supplement” appears as part of the
statement of identity on the Principal Display Panel (PDP) of a DS product. DS labels
must also display a fact panel that identifies each DI and the amount of its DIs used to
manufacturing their products. They are further responsible for determining that any
representations or claims they make about their products are supported by adequate
evidence to show that they are not false or misleading.
VI. Regulations for advertisements of dietary supplements required by
FTC and UPS
The U.S. Federal Trade Commission (FTC) is tasked with overseeing the claims in the
advertising of DSs, including print, broadcast ads on radio and TV, informercials,
catalogs, and similar direct marketing materials. The function of the FTC is to develop
recommendations for the regulations of label claims and statement for DSs and to
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evaluate how best to provide truthful, scientifically valid, and not misleading
information to consumers so that such consumers may make appropriate health care
choices for themselves and their families The authority of the FTC is (1) to challenge
and stop advertising that is not sufficiently substantiated; (2) to negotiate a consent
order for a company to change or fix its promotional marketing or advertising practices;
and (3) to seek substantial civil penalties for violations of trade regulation rules or
violations of cease and desist from orders. FDA works closely with the FTC in this area,
but FTC’s work is directed by different laws. Marketing on the Internet is subject to
regulation in the same manner as promotions through any other media. Advertising
through promotional printouts delivered by the U.S. Postal Service (UPS) are regulated
under different laws and are subject to regulation by the U.S. Postal Inspection Service.
VII. Registration of food facilities and prior notice of imported food
shipments required by FDA through the Bioterrorism Act of 2002
The Bioterrorism Act of 2002 directs FDA to take additional steps to protect the public
from a threatened or actual terrorist attack on the U.S. food/DS supply and other foodrelated emergencies. To carry out certain provisions of the Bioterrorism Act, FDA has
established new regulations requiring that:
(1) food facilities are registered with FDA, and
(2) FDA be given advance notice on shipments of imported food.
The Act requires that domestic and foreign facilities and manufacture, process, pack, or
hold food (including DSs and DIs) for human or animal consumption in the U.S. to
register with FDA by December 12, 2003. Under FDA’s current registration regulations,
food facilities that are required to register include manufacturers, processors,
warehouses, storage tanks and grain elevators. The Act also requires every food
company to be able to trace its products both one step forward and one step back, from
company to company, through the supply chain.
VIII. Serious adverse event reporting law (SAER) effective December
2007
Mandatory reporting to FDA of serious adverse events (SAER) is now required as a
result of the enactment of the “Dietary Supplement and Non-prescription Drug
Consumer Production Act” (DSNDCPA), signed into law on December 22, 2006,
effective December 2007). The law requires manufacturers, packers, or distributors of
DS products to submit reports to FDA about all serious adverse events involving such
products based on specific information that they receive from the public. The term
“serious adverse event” is an adverse event that
(1) results in death, life-threatening, inpatient hospitalization; a persistent or
significant disability or incapacity; or a congenital abnormally or birth defects;
and
(2) requires, based on reasonable medical judgment, a medical or surgical
intervention to prevent an outcome described under subparagraph.
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The manufacturer, packer, or distributor of a DS whose name appears on the label of a
DS marketed in the U.S. must submit to the FDA an SAER no later than 15 business
days after the report is received through the address or phone number described on the
label. The responsible person shall submit to the FDA any new medical information
related to a submitted SAER that is received by the responsible person within one year
of the initial report.
FDA is now accepting online submission of voluntary and mandatory DS adverse event
reports. The new submission capability is available through the DHHS Safety
Reporting Portal (http://www.safetyreporting.hhs.gov). Reporting of DS adverse
events is critically important in protecting consumers’ health and safety. The FDA
routinely monitors the marketplace. However, with more than 75,000 DSs now on the
market and no product specific registration requirement, SEAR reporting is invaluable
in identifying harmful products in the marketplace.
IX. Current good manufacturing practice requirements for quality
control of the safety and purity of dietary supplements (DS CGMP)
established by FDA in 2007
It is difficult to determine the quality of a DS product from its label. The degree of
quality control depends on the manufacturer, the supplier, and others in the production
process. As part of DSHEA, Congress gives FDA the express authority to issue
regulations establishing “Current Good Manufacturing Practices” (CGMP) for DS
manufacturers. On June 25, 2007, the FDA issued the DS CGMP rule establishing
requirements for the production of DSs, and an identity testing Interim Final Rule (IFR)
that set forth a procedure for requesting an exemption from the requirement in the DS
CGMP rule for the manufacturer to conduct at least one appropriate test or examination
to verify any dietary ingredient that is a component of a dietary supplement. The DS
CGMP and the identity testing interim final rule were effective as of August 24, 2007,
establish industry-wide standards for both domestic and foreign companies. The
principal goals of the DS CGMP regulations are to ensure the quality, safety and purity
of DS products. The DS CGMPs have been seriously implemented only since 2010.
Based on audits completed by FDA’s compliance division in 2011 and 2012, however,
it was estimated that nearly 70% of DS manufacturers have run afoul of the FDA’s
manufacturing regulations over the last five years.
X. Requirements for dietary supplement manufacturers under the DS
CGMP rule
The CGMP rule provides standards that affect the products, processes, and people
involved in DS manufacturing. These standards support overall quality of the finished
products under the premise that “quality” is built into the manufacturing process. The
focus of CGMP regulations is on process controls to ensure that the desired outcome is
consistently achieved, and not on the inherent safety of the ingredients used, which is
matter of other statutes. The rule requires that each manufacturer focus on “Hazard
Analysis and Critical Control Point” (HACCP) to establish adequate controls over
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the production process and specifications for their products to ensure that they
consistently and reliable manufacture what is intended. However, there are no common
or minimum requirements for quality. The rule gives DS manufacturers freedom to
decide:
(1) their own specifications for identity, quality, strength, composition and absence
of contaminants for components (dietary ingredients and others); in process
materials, and finished DS products;
(2) how to qualify their suppliers in order to avoid 100% testing of components
(condition to accept “certificate of analysis”); and
(3) on the quality of “reference materials” to calibrate analytical equipment and the
use of analytical methods.
A requirement of the Food Safety and Modernization Act of 2010 (FSMA) is amending
CGMPs for food products to include “Hazard Analysis and Risk-Based Preventive
Controls for Human Food” (HARPC) that focuses on preventing problems that can
cause food borne illness. According to an FDA Fact-sheet, the HARPC rule would
apply to many domestic and foreign firms that manufacture, process, pack or hold
human food/DSs. These firms would be required to have written plans that identify
hazards, specify the steps that will be put in place to minimize those hazards, identify
monitoring procedures and record monitoring results and specify what actions will be
taken to correct problems that arise.
XI. Standards without standardization under the DS CGMP rule
No legal or regulatory definition exists in the U.S. for standardization as it applies to
DSs. Under the DS CGMP, FDA regulates only “quality and good manufacturing”
but does not ensure standardization of the active ingredients. Also, FDA does not
require manufacturers of DSs to assure that DS ingredients are safe and effective, only
that they do not contain dangerous contaminants or impurities and a label to accurately
reflect the ingredients in the finished product. Therefore, specifications for similar DS
products can vary widely from manufacturer to manufacturer; and consumers would not
know if two products containing similar ingredients and similar labels are subjected to a
different set of “quality parameters.” Some manufacturers use the term
“standardization” incorrectly to refer to uniform manufacturing practices; following a
recipe is not sufficient for a product to be called standardized. Therefore, the presence
of the word “standardized” on a DS label does not necessarily indicate product quality.
XII. Use of “certificate of analysis” and standard “reference
materials” under the DS CGMP rule
Since the active components of the botanical/herbal DSs are often not well defined,
precise, accurate and rugged “analytical methods” and standard “reference materials”
are essential for “verification of ingredient identity”, identifying and measuring
contaminants, and measuring the amount of declared “ingredients in raw materials”
and “finished products.” However, the CGMP rule does not apply to DI manufacturers
or suppliers, but only to manufacturers who produce, package, or hold DSs. The
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“certificate of analysis” (CoA) can be used as a bridge between suppliers of DIs and
manufacturers of DSs. The CoA from suppliers is acceptable as proof of compliance
with specifications established for DS components for
(1) every test except identity for DIs, and
(2) every test including identity for non-dietary ingredient components.
“Component” is defined as “any substance intended for use in the manufacture of a DS,
including those that may not appear in the finished batch of the DS.” The manufacturer
must “qualify” its supplier, periodically reconfirm the findings in the CoA, and have
knowledge of the tests upon which the certificate relied. The CGMP rule requires
calibration of analytical equipment, for which “reference materials” (RS) are needed.
The rule also gives freedom to DS manufacturers to set their own RSs and testing
protocols. The rule, however, supports (but not requires) the use of compendia
reference standards where they are available, e.g. ATCC (American Type Culture
Collection), USP (U.S. Pharmacopoeia), NIST (National Institute of Standards and
Technology, the NIH Dietary Supplement Methods and Reference Materials Program
created in 2002. An overview of the NIH program is available in the May 2007 issue of
“Analysis and Bioanalytical Chemistry” 389: 19-25.
XIII. Exemption of 100% identity testing for a dietary ingredient
under the identity testing Final Interim Rule (FIR) established by
FDA in 2007
Because of the critical importance of ensuring the proper identity of DIs, the DS CGMP
rule requires that each manufacturer conducts at least one appropriate test, or
examination to verify the identity of any component that is a DI prior to use in the
manufacturing process. This requirement for 100% identity testing of DIs applies to a
manufacturer who purchases a DI from a DI supplier and who manufacturers its own
DI for use in the manufacture of its DS. It is required for every DI, unless an FDA
exemption is obtained pursuant to the petition procedure in the accompanying identity
testing Interim Final Rule (IFR).
Under this identity testing IFR, a manufacturer is granted an exemption from the
requirement of the 100% identity testing only when a manufacturer petitions the FDA
and the FDA grants such an exemption. The petition needs to provide data and
information that are specific to each DI and each supplier. If a manufacturer is granted
an exemption, the manufacturer would still responsible for ensuring the quality of the
final DS products, and have to provide appropriate data and information in its petition
declaring that using a proposed sampling plan would not result in ingredient variation
provided by 100% identity testing. The approval of an exemption petition is only for
the DI(s) and supplier(s), requested in the petition. Manufacturers may use one petition
to request an exemption from the 100% identity testing for one or more DIs and one or
more supplies. If the manufacturer changes DI(s) or supplier(s), or any other
combination thereof, FDA’s approval would not apply to the particular changed DI.
Manufacturer would return to 100% identity testing until it files a re-petition to FDA,
and the re-petition is approved.
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XIV. Regulatory requirements for Niu-Chang-Chih products used as
dietary supplements and NDIs set by FDA govern by various laws
enacted by the U.S. Congress
DSs and their DIs derived from the herbal mushroom Niu-Chang-Chih present unique
challenges for “safety evaluation” as they are a complex mixture of numerous
chemical substances that exhibit compositional complexity and variation depending on
many factors. In addition, the ingredients of these DS products are seldom completely
chemically pure. The DS CGMP rule addresses the quality of manufacturing processes
for DSs and the accurate listing of DIs. It does not limit consumer’s access to DSs; nor
does it address the safety of their ingredients or their effects on health when proper
manufacturing techniques are used. Therefore, DS CGMP regulations do not stop DS
manufacturers from selling Niu-Chang-Chih DSs that are falsely labeled. U.S. Congress
under DSHEA gives the FDA permission to stop a company from making a DS only
when the FDA proves that the product poses a “significant risk” to the health of
Americans.
Although the FDA has created a regulation framework for DSs, similarities can be
found between the regulatory framework for DSs and that for food as DSs are deemed
as food. The following is a summary of the regulatory requirements set by the FDA
pertaining to DSs from the herbal mushroom Niu-Chang-Chih.
(1) Facility registration required
(2) Ingredients conform to legal statute
(3) 100% identity testing of every DI in the product required at each stage of the
manufacturing process
(4) Product forms limited to oral use intended for “ingestion” that is, to take into the
stomach and gastrointestinal tract by means of enteral administration through the
mouth
(5) Labeled as such using the term “dietary supplement” and displaying a “fact
panel” that identifies each DI and the amount of it contained in each serving of
the product
(6) The correct scientific name of the Niu-Chang-Chih used as a source of dietary
ingredients must include “latin bionomial” (including author)
(7) Adulterated if a significant or unreasonable risk of illness or injury is present
(8) Safety data and information be submitted to FDA for “new dietary ingredients”
(NDIs) at least 75 days before marketing
(9) Health claims be substantiated by adequate evidence to show that the claims are
not false or misleading
(10) All production must comply with DS CGMP regulations to ensure quality
throughout the manufacturing, packaging, labeling, and storing of DS products
(11) Serious adverse events received be submitted to FDA no later than 15 business
days
(12) Advance notice on shipments of imported products required
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Under the FDCA, the legal status of a DS product is dependent on whether it is offered
for use in a “conventional food” or its use is as a “dietary supplement” or as a
“dietary ingredient in a DS.” Because DSs are under the “umbrella” of foods, FDA’s
Center for Food Safety and Applied Nutrition (CFSAN) is responsible for regulating
DS ingredients and ensuring that those ingredients derived from the herbal mushroom
Niu-Chang-Chih are as safe and lawful. How CFSAN regulates the use of a substance
derived from Niu-Chang-Chih is determined by its “intended conditions of use.”
CFSAN has an essential responsibility to take action against any unsafe Niu-ChangChih DS product after it reaches the market. Generally, manufacturers do not need to
get CFAN’s approval before producing or selling DS products. The authority of the
CFSAN to regulate the DS industry includes:
(1) stop a company from selling any DS that is unsanitary or unsafe,
(2) stop the sale of any DS that makes false or non-substantiated claims on its
labeling,
(3) stop the sale of any DS that poses “significant” or unreasonable risk of illness or
injury, and
(4) oversee mandatory adverse event reporting by DS manufacturers.
Niu-Chang-Chih Products intended to diagnosis, mitigate, treat, cure, or prevent disease
in man or animals are regulated as drugs that must be proven safe and effective in
FDA-approved and reviewed clinical trial. Drugs are regulated by the FDA’s Center for
Drug Evaluation and Research (CDER).
XV. Additional U.S. federal agencies involved in advancing scientific
base of knowledge making it possible to better evaluate the safety and
effectiveness of dietary supplements
The NIH Office of Dietary Supplements (ODS) was created by DSHEA (1994) in the
Office of Disease Prevention at NIH, which began operations in November 1995. ODS
is directed by DSHEA to conduct and coordinate scientific research relating to DSs
within NIH, to coordinate funding for such research, to compile a database of such
research, and to serve as the principal advisor to HHS, NIH, CDC, and FDA on issues
relating to safety, benefits, and labeling of DS. The duties of the ODS are to strengthen
knowledge and understanding of DSs by
(1) evaluating scientific information,
(2) stimulating and supporting research,
(3) disseminating research results, and
(4) educating the public to foster an enhanced quality of life and health for the U.S.
population.
“Traditional medicine” is used as a comprehensive term to refer both to traditional
medicine systems such as Traditional Chinese Medicine (TCM) and to various forms of
the indigenous medicine being practiced traditionally by indigenous populations in the
world. Traditional medicine that has been adopted by other populations outside its
indigenous culture is often termed “complementary and alternative medicine (CAM).
The NIH National Center for Complementary and Alternative Medicine (NCCAM) is
to explore CAM healing practices in the content of rigorous science, to trains CAM
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researchers, to provide accurate information about CAM, and to help the public and
health professionals understand which CAM therapies have been proven to be safe and
effective.
In response to a Congressional mandate, in 1999 the ODS initiated the Botanical
Research Centers Program (BRC) in partnership with other NIH institutes/offices
including NCCAM, National Institute of Environmental Sciences (NIES), National
Institute of General Medical Sciences (NIGMS), NIH Office of Research on Women’s
Health (ORWH) and National Cancer Institute (NCI). The BRC program for 2010-2015
includes the following grantee institutions:
•Pennington Biomedical Research Center, Louisiana State University
•University of Illinois at Chicago
•University of Illinois at Urbana-Champaign
•University of Missouri
•Wake Forest University
The issue of safety is particularly critical given how little information is available on
the toxicity of the herbal/botanical products in the healthcare marketplace in the U.S.
The National Toxicology Program (NTP) is a federal interagency program established
in 1978, as a cooperative effort to coordinate toxicology testing programs within the
federal government, strengthen the science base in toxicology, develop and validate
improved testing chemicals to health, provide information about potentially toxic
chemicals to communities, and the public. The three agencies that form the core of the
NTP are the National Institute of Environmental Sciences of the NIH (NIEHS/NIH),
the National Institute of Occupational Safety and Health of the Centers for Disease
Control and Prevention (NIOSH/CDC), the National Center for Toxicological Research
of the FDA (NCRT/FDA). Currently, both NIEHS and NCTP are actively working with
ODS/NIH and CFSN/FDA to conduct research that addresses deficiencies in our
knowledge about DSs/Dis and their potential toxicities.
Reliable sources of information on DSs/DIs are important to evaluate the claims that
are made about them, which are based on the results of rigorous scientific testing. To
look for scientific research findings on the DSs/DIs, NCCAM/NIH, ODS/NIH and
other federal agencies have free publications, clearinghouses, and information on their
Websites. As a service of the National Library of Medicine (NLM), PubMed contains
publication information and brief summaries of articles from scientific and medical
journals (http://www.ncbi.nlm.nih.gov/pubmed). The PubMed Dietary Supplement
Subset (PMDSS) is designed to help people search for academic journal articles related
to DS literature. It succeeds the International Bibliographic Information on Dietary
Supplements (IBIDS) database to continue the ODS mission to disseminate dietary
supplement-related research results. The NLM’s MedlinePlus brings together
authoritative information from NIH as well as other Government agencies and healthrelated organizations (http://www.medlineplus.gov). In addition, the NDL’s Dietary
Supplement Ingredient Database (DSIS) has been developed by the Nutrient Data
Laboratory (NDL) within the Agricultural Research Service (ARS) of the U.S.
Department of Agriculture (USDA) in collaboration with ODS at NIH and other federal
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agencies. It provides estimated levels of ingredients in DS products sold in the U.S. The
NLM’s Dietary Supplements Label Database (DSLD) is a joint project of the ODS
and NLM. It contains the full label contents from a sample of DS products marketed in
the U.S. DSLD enables users to compare label ingredients in different brands. Its
information also provides the “structure/function” claims made by manufacturers
(http://dietarysupplements.nlm.nih.gov/dietary). The Computer Access to Research
on Dietary Supplements (CARDS) database lists current and past grant projects
focused on health effects of DSs funded by the USDA, the Department of Defense
(DOD) and the Institutes and Centers of the NIH (http://libproxy.usc.edu/login?url).
Patents contain the most complete and detailed information that is particularly
important in relation to the commercial exploitation of invention in promoting technical
innovation and the development of the Niu-Chang-Chih DS industry. The United Sates
Patents and Trademark Office (USPTO) of the Department of Commerce (DOC)
houses the Full Text and Image Database (PatFT) for all patents issued from 1976 to
present (http://www.uspto.gov/patents/process/search). USPTO also maintains the
Global Patent Search Network (GPSN) that enables users to search full texts of
Chinese patent information from the State Intellectual Property Office (SIPO) of the
People’s Republic of China (PRC). Documents available include published applications,
granted patents and utility models from 1985-2012.
XVI. Concluding remarks
Today, dietary supplements (DSs) and dietary ingredients (DIs) in DSs are more strictly
studied, regulated and monitored than at any other time in history in the U.S. The
federal government regulates DS products through FDA govern by the DS provisions
of the FDCA and accompanying legislations enacted by the U.S. Congress. The FDA’s
primary mission is to ensure that the food/DS supply is safe for 300 million American
consumers, and the American public fully expects its food/DS to be safe. The FDA
characterizes Niu-Chang-Chih products according to their use, not according to their
composition. When the intended use is to “promote” health, the agent is viewed as a
dietary supplement; when the intended use is to “treat or prevent” a disease, the agent
is considered to be a drug. Thus, FDA regulates DSs under a different set of regulations
than those covering DS and drug products. DS and DI manufacturers and distributors
are prohibited from marketing products that are “adulterated” or “misbranded.” FDA
takes action against any adulterated or misbranded DS product after it reaches the
market.
The DS CGMP for quality controls of the safety and purity of DSs, detailed in the
processing aspect of production, bear a stronger resemblance to drug CGMPs than
they do to the rather general food CGMP. A key difference is that the DS CGMP does
not require “process validation”, which is mandated by the drug CGMP. Instead, the
emphasis in the DS CGMP is on documentation that relates back to the master batch
record in terms of production, composition and processing steps.
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Therefore, the enforcement of quality controls for the safety and efficacy of NiuChang-Chih DS products depends on the manufacturer, the supplier, and others in the
production process. Under the rule of DS CGMP, Niu-Chang-Chih DS manufacturers
must establish and implement, through written procedures, a production and process
control system that covers every point, step, or stage in the manufacturing, packaging,
labeling and holding operation and specifications for the identity, quality, strength, and
compositions of their products and the absence of contaminants from the finished DSs.
Niu-Chang-Chih DS manufacturers must enforce the quality requirements for their
suppliers, periodically reconfirm the compositions in the CoA, and have knowledge of
the tests, which makes it possible to avoid the 100% testing of components. Niu-ChangChih DS manufacturers also have the flexibility and responsibility to set their own
standard RMs to validate specific measurement techniques and equipment. However,
the DS CGMP rule does not apply to Niu-Chang-Chih DI manufacturers or suppliers,
but only to DS manufacturers who produce, package, or hold DSs.
Niu-Chang-Chiih DSs are not approved by the U.S. government for safety and
effectiveness before they are marketed. If the DS contains a NEW ingredient, that
ingredient will be reviewed by FDA (not approved) prior to marketing – but only for
safety, not effectiveness. Thus, the amount of scientific evidence available for various
Niu-Chang-Chih DS ingredients will vary widely. Scientists may use several
approaches to assess the health “benefits” and “risks” of a Niu-Chang-Chih NDI or DS
product. For example, scientists may investigate the history of use of people eating the
DS product, conduct laboratory studies using cell or tissue cultures, experiment with
animals, and determine the value of Niu-Chang-Chih DS products in maintaining good
health based on the data from individual case reports, observational studies, and clinical
trials in humans.
The popular use of DSs from the unique herbal mushroom Niu-Chang-Chih as an
adjunct to an improved quality of life or for their alleged medical benefits is increasing
rapidly and is far ahead of the available scientific data on the efficacy and safety of
these products. Its marketplace has grown categorically with new products finding their
way into all retail channels. Researchers are studying many of these products in an
effort to identify what ingredients may be active and understand their effects on health
and patterns of use. With the multitude of products and brands available in the
marketplace, there have been increasing concerns over the quality, safety and efficacy
of these products. For those companies interested in long term success, careful and
diligent research into the legal status of every dietary ingredient (DI) included in a
dietary supplement (DS) should be an essential part of any new product development
effort.
XVII. Web resources
• National Center for Complementary and Alternative Medicine (NCCAM), NIH:
http://nccam.nih.gov/
• Office of Dietary Supplements (ODS), NIH: http://www.ods.od.nih.gov/
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• National Institute of Environmental Sciences (NIEHS), NIH:
http://www.niohs.nih.gov/
• Center for Disease Control & Prevention (CDC), HSS: http://www.cdc.gov/
• National Institute of Occupational Safety & Health (NIOSH), CDC:
http://www.niosh.cdc.gov/
• International Bibliographic Information on Dietary Supplements (IBDS) database:
http://www.ods.od.nih.gov/Health_information/IBIDS.aspx/
• U.S. Department of Health and Human Services (HHS): http://www.hhs.gov/ (click
on “Drug & Food” Information)
•National Library of Medicine (NLM), NIH:
http://www.dietarysupplements.nlm.nih.gov/
• U.S. Food and Drug Administration (FDA), HHS: http://www.fda.gov/
• FDA. Ingredients, Packaging & Labeling:
http://www.fda.gov/Food/IngredientsPackagingLabeling/default.htm/
•FDA. Guidance for Industry: Considerations Regarding Substances Added to Foods,
Including Beverages and Dietary Supplements (2014):
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInforma
tion/default/
• FDA. Dietary Supplements:
http://www.fda.gov/Food/DietarySupplements/default.htm/
• FDA. New Dietary Ingredients in Dietary Supplements – Background for Industry:
http://www.fda.gov/Food/DeitarySupplements/ucm109764.htm/
• FDA. New Dietary Ingredients Notification Process:
http://www.fda.gov/Food/DieatrySupplements/NewDietaryIngredientsNBotificationPro
cess/default/
• FDA. Label Claims. General Information:
http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm200687
3.htm/
• Center for Food Safety and Applied Nutrition (CFSAN), FDA:
http://www.cfsan.fda.gov/~dms/hclaims.html; http://www.cfsanfda.gov/~dms/dssavvy.html/
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• U.S. Federal Trade Commission (FTC): http://www.ftc.gov/bcp/menu-health.htm/
• National Data Laboratory (NDL), National Nutrient Database for Standard Reference,
ARS, UDSA: http://www.ars.usda.gov/ba/bhnrc/ndl/
• U.S. Department of Commerce: http://www.dod.gov/
• MedWatch, FDA: http://www.fda.gov/medwatch/
• Nutritional and Dietary Guidance, NAL, USDA: http://nutrition.gov/
• Food and Nutrition Information Center (FNIC), NAL, USDA:
http://www.nal.usda.gov/finc/
• MedlinePlus:Supplement and Herbal Information, NLM, NIH:
http://www.nlm.nih.gov/medlineplus/
• U.S. Pharmacopoeia (USP): http://usp.org/
• The Johns Hopkins Center for Complementary and Alternative Medicine:
http://www.hopkinsmedine.org/CAM/
• Complementary and Alternative Medical (CAM) Resource on the World Wide Web
(WWW) at the Rosenthal Center at Columbia University:
http://cpmenet.columbia.edu/dept/rosenthal/Guide6.html/
• National Herbal, Herbal Remedies and Medicine Guide:
http://www.naturalherbsguide.com/
• Herb Research Foundation: http://herbs.org/
• HerbMed: http://www.herbmed.org/
•U.S. Patents and Trademark Office (USPTO), Department of Commerce (DOC):
http://www.uspto.gov/
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