Ensuring the Quality of Dietary Supplements prescribed Current Good Manufacturing

Ensuring the Quality of Dietary Supplements
from Medicinal Mushrooms Using U.S. FDAprescribed Current Good Manufacturing
Practices
Shung-Chang Jong, Ph.D.
ATCC, Manassas, VA, 20110-2209, USA
The Life Sciences Industry Group
The Singapore Manufacturing Federation
September 17, 2009, Singapore
History of the Food Industry

Up to 19th Century: Survival Food Age
 20th Century: Convenience Food Age
 21st Century: Functional Food Age
+ “Food as medicine”, existing at the interface
between foods and drugs
+ There is Chinese saying that “medicine & foods
have a common origin”
+ The tenet of Hippocrates C 400 B.C. “Let food be
your medicine and medicine be your food”
Infrastructure of Health Food Industry
and Regulatory Strategy
 Raw Materials Supplier:
monitoring and evaluation of raw
materials, including starter cultures
 Ingredient Supplier:
Monitoring and verification of identity and
safety of dietary ingredient
 Manufacturer:
Assuring of product quality (Current Good
Practice, CGMP)
 Distributor/Marketing:
Monitoring and evaluation of product
labeling
Genuine Nutritional Value of Edible and
Medicinal Mushrooms Served as
Sources of Dietary Ingredients
 Essential amino acids
 Non-essential amino acids and amides
 Vitamins
 Minerals
 Unsaturated fatty acids essential for the diet
 Other dietary substances (e.g., enzymes,
polysaccharides, peptides, ergosterol, terpenoids
and other metabolites) for use to supplement the
diet by increasing the total dietary intake
Source Materials of Dietary Ingredients
from Medicinal Mushrooms
 For use as specific dietary ingredients, many
medicinal mushrooms have been
+ PREPARED THROUGH separation, extraction,
and filtration
+ FROM
a) fruiting bodies cultivated or collected from the
wild
b) mycelia cultured in broth or harvested
from submerged fermentation cultures, or
growing upon grain substrates
c) broth harvested from submerged liquid
cultures grown in bioreactors
Genetic Diversity of Mushroom Species on
the Earth Potential for Use as
Dietary Supplements
 Estimated total species
300,000
 Mushroom species known
15,000
 Edible mushrooms known
5,000
 Prime edible mushrooms
2,000
 Medicinal mushrooms known
1,800
 Edible ectomycorrhizal mushrooms known 900
 Edible & medicinal mushrooms commercially
cultivated
100
 Medicinal mushrooms used as dietary
supplements
50
Genetic Complexity of Sexuality in Basidiomycetes
(Mushrooms) in Screening for and Breeding of Novel
Strains as Starters for Production of Dietary
Supplements
Self-fertile species (homothallism)
Self-sterile species (heterothallism)
Bipolar (single series of incompatibility factors)
Tetrapolar (two series of incompatibility factors)
e.g., Coprinus cinereus
Schizophyllum commune
10%
90%
25%
75 %
12,000 mating types
20,000 mating types
Note: Each individual mushroom is the repository for an
immense amount of genetic information, providing direct
economic value to humans in the form of marketable
products
Hierarchy of Living Systems in
Mushroom Biotechnology
Biol ogi cal
Hierarch y
Fu nction al
Appl icati on
The Interconnected Cellular Networks and
Complexity of Medicinal Mushroom Cells
Genetic
Aging
Disease
Food /Drug Environment
CELL
DNA
Transcription
Reverse
transcription
mRNA
Protein
Translation
Post-translational
ribosomal modifications
Metabolite
Enzymatic/Biochemical
reactions
Genomics Transcriptomics Proteomics
High
molecules
Glycomics
Low
molecules
Metabolomics
Variations in Response to Mushroom
Dietary Supplements by Individual People
(Consumers)
> Molecular biologists start to recognize
- the variation in genetic make-up of
individual consumers may cause the variation
in response to nutrient and dietary
supplement intake
> Human Genome Read-out and molecular biological
tools
- lead to “NUTRIGENEMICS” and
“NUTRIGENETICS”
Note: A dietary supplement is also known as food
supplement or nutritional supplement
Challenges in the Mushroom Dietary
Supplement Industry
Mushroom biotechnology: standards without
standardization
Mushroom industry: government regulations not strictly
enforced
Mushroom economy: market monopoly unlikely
Mushroom safety & effectiveness: products diverse &
variable
Mushroom genetic resources: difficulties in protecting
intellectual property assets
Note: Due to the growing demand for mushroom-derived products by the dietary supplement
industry, marketing of these products comes under increasing scrutiny by regulatory
agencies such as FDA, Federal Trade Commission, the media, practitioners, consumer
groups & consumers
Problems in the Global Market of the Dietary
Supplements from Medicinal Mushrooms
 Health claims
 Variation in definition, product category, product
batch
 Lack of governmental standards to control the
production and ensure the safety, effectiveness,
and quality of mushroom dietary supplement
products
 Lack of scientific substantiation
 Lack of quality standards for mushrooms
 ingredients in dietary supplements – “standard
without standardization”
 Lack of methods for ensuring that dietary
supplements are what they purport to be and they
contain the active ingredients of interest
Regulation of Health Foods in China
 On 28th February 2009, the National People’s
Congress passed the first comprehensive Food
Safety Law (FSL), which came into force on 1st
June to replace China’s Food Hygiene Law of 1995
 Following the FSL, China’s State Council
promulgated the implementing regulations for the
FSL on 20th July 2009
 Health food is defined as food processed for
health functions
 The rules broadened the government’s authority
to regulate food production and granted
consumers a right of action to sue for
compensatory and punitive damages
Ordinance – a Three-pronged Approach to
Ensure the Strict Enforcement of
Food Safety Law in China
 To implement food safety as the first
responsibility of food companies, strengthening
prevention and control of production and
management process, and enhancing traceback
and recordkeeping that includes all records
relating to manufacturing, processing, packing,
distribution, receipt, holding, or importation
 To strengthen government agencies in the duties
of supervision, and improve the regulatory
authorities in the division of labor and
coordination of a combination of institutional
coordination, convergence and cooperation
 To make the national food safety system effective
and efficient
Government Regulatory Authorities
Involved in Implementation of the Food
Safety Law in China
 Ministry of Health (MOH)
 General Administration of Quality Supervision,
Inspection and Quarantine (AQSIQ)
 State Food and Drug Administration (SFDA)
 Ministry of Agriculture (MOA)
 Ministry of Commerce (MOC)
 Ministry of Industry and Information Technology
(MIIT)
 State Administration of Industry and Commerce
(AIC)
Regulation of Health Foods in Taiwan
Health Food Control Act of 1999,
amended 2006, governs matters
relating to health food products
Health food is legally defined as “food
with specific nutrient or health
maintenance effects which are
especially labeled or advertised, and
do not aim at treating human diseases”
Government Authorities Involved in the
Regulation of Health Foods in Taiwan
* Dept of Health of the Executive Yuan
(DOH):
* implements the Health Food Control Act;
* issues permits to manufacturers and
importers, and
* prescribes standards for health food
products, e.g., complying with GMPs &
meeting labeling standards (premarket activities)
* Local Health Departments: conducts post-
Regulation of Mushroom Health Foods
in Taiwan
 Mushroom Products are evaluated by DOH for
safety and validity of health maintenance effects
(Pre-market)
 Since 1999, only fourteen (14) health food
products from medicinal mushrooms have been
approved for registration
 Health foods are widely available in pharmacies
chartered under the National Health Insurance
Program, chain pharmacies, supermarkets, and
approved direct sale companies
 Post-market activities are conducted regularly,
including inspecting the premises, facilities and
business of health food operators, and conducting
random testing of products
Powerful Market Forces in the Dietary
Supplement Industry in the United States
 Rapid advances in scientific knowledge on the critical role of
diet in health and disease prevention
 The change of consumers in perspective of food, which is
no longer viewed as merely a means of providing
sustenance
 Skyrocketing health care costs, causing an ever-rising
burden on the U.S. healthcare system
 Dramatic increase in aging population
 Technical advances and the expansion and globalization of the
food industry that allow the development of healthpromoting foods marketed to health-conscious consumers
at a reasonable price
 A wide variety of dietary supplements available 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
 A major segment of the U.S. import and export trade market
 The changing regulatory environments
Nutraceutical and Functional Food
Regulations in the United States
 Functional foods were defined by the Institute of
Medicine of the U.S. Academy of Sciences as “foods
that encompass potentially healthful products,
including any modified food or food ingredient that
may provide a health benefit beyond the nutrients
it contains.”
 There is no provision in the existing food regulations
for foods intended to be consumed to prevent disease.
 Dietary supplements are marketed under the Dietary
Supplement and Education Act of 1994, and foods
are marketed under the Nutrition Labeling and
Education Act of 1990.
Overview of the Dietary Supplement Health
and Education Act (DSHEA) of 1994 (1)
Created a new category of a regulated
product called “dietary supplement”
Set up a new framework for FDA regulations
of dietary supplements
Created an office in the National Institutes of
Health (NIH) to coordinate research on
dietary supplements
Called President Clinton to set up an
independent dietary supplement commission to
report on the use of claims in dietary
supplement labeling
Permissible Claims of Mushroom Dietary
Supplements under DSHEA of 1994
Health claim describes a relationship
between a dietary supplement ingredient,
and reducing risk of a disease of healthrelated condition.
Nutrient content claim describes the relative
amount of a nutrient or dietary substance in
a product.
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.
Overview of the Dietary Supplement Health and
Education Act (DSHEA) of 1994 (2)
 Defined the term “dietary supplement” (DS) as a product
taken by mouth that contains a “dietary ingredient” intended
to supplement the diet.
 Defined both of the terms “dietary ingredient” and “new
dietary ingredient” (NDI) as components of dietary
supplements.
 A “new dietary ingredient” (NDI) is one that meets the
definition for a “dietary ingredient” and was not sold in the
U.S. in a dietary supplement before October 15, 1994. DS is
adulterated if it contains an NDI unless, manufacturers or
distributors submits information to FDA 75 days before
marketing, including “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”
Five Specific Information Requirements in Notification to
FDA for New Dietary Ingredients before Marketing
 The name and address of the distributor or
manufacturer
 The name of the ingredient, which must include
the Latin binomial (including the author) if the
ingredient is a botanical
 A description of the supplement containing the
ingredient, including the level of use and
conditions of use
 The evidence on which a reasonable expectation
of safety is based, including copies and English
translations of references
 A signature
Overview of the Dietary Supplement Health
and Education Act (DSHEA) of 1994 (3)
 Before 1994, FDA regulated dietary supplements
as foods to ensure that they were safe and
wholesome, and that their labeling was truthful
and not misleading.
 Ensuring safety involved evaluation of all new
ingredients, including those used in dietary
supplements.
 Under DSHEA, supplements are no longer
regulated like other products such as foods,
drugs, food additives, cosmetics, medical devices,
and radiation emitting consumer products
(microwave).
Overview of the Dietary Supplement Health
and Education Act (DSHEA) of 1994 (4)
Before 1994, the original definition of a
supplement was a product that contained
one or more the essential nutrients.
After DSHEA, the definition of a supplement
was changed to any product intended for
ingestion as a supplement to the diet.
Unlike drugs and food additives, FDA does
not authorize or test dietary supplements before
marketing.
The FDA can only step in when the
supplement has been shown to be unsafe.
Overview of the Dietary Supplement Health
and Education Act (DSHEA) of 1994 (5)
Beginning in March of 1999, a new statement
on the label must read: “This statement has
not been evaluated by the FDA. This product is
not intended to diagnose, treat, cure, or prevent
any disease.”
If consumers find a dietary supplement
whose label states or implies that the
product can diagnose, treat, cure, or prevent
a disease, these claims are illegal in the
U.S., and as such should not be evaluated
as safe or effective.
The Goals of DSHEA of 1994
To promote healthful diets and thereby
possibly mitigate the need for expensive
medical procedures;
To empower consumers to make choices
about preventative health care programs
based on data from scientific studies of
health benefits related to particular dietary
supplements; and
To improve the flow of safe products to
consumers
Regulatory Definition of a Dietary
Supplement in the United States (1)
The Dietary Supplement Health and Education Act
(DSHEA) of 1994 defines dietary supplements as:
a product “intended to supplement the diet” that
contains one or more of following INGREDIENTS:
> a vitamin
> a mineral
> an amino acid
> an herb or other botanical (e.g., mushrooms)
> a dietary substance for use to supplement the
diet by increasing the total dietary intake
> a concentrate, metabolite, constituent, extract
or combination of any ingredient described above
Regulatory Definition of a Dietary
Supplement in the United States (2)
A dietary supplement must also conform to
the following CRITERIA:
- intended for “ingestion” (by mouth) in the
form of pill, capsule, tablet, softgel,
gelcap, powder or liquid
- not “represented for use as a conventional
food or as the sole item of a meal or the
diet”
- labeled as a “dietary supplement”
Regulatory Definition of a Dietary
Supplement in the United States (3)
• Specifically EXCLUDES:
> articles that were approved as new
drugs prior to being marketed as a
dietary supplement or food.
> articles authorized for investigation as a
new drug for which substantial and
public clinical investigations have been
instituted prior to being marketed as a
dietary supplement or food.
The Office of Dietary Supplements at the
National Institutes of Health (NIH)
DSHEA established the Office of Dietary
Supplements within NIH in 1995
The purpose is
(1) to explore the potential role of dietary
supplements as a significant part of the
efforts of the U.S. to improve health care,
and
(2) to promote scientific study of the
benefits of dietary supplements in
maintaining health and prevent chronic
disease
The Duties of the Office of Dietary
Supplements (ODS) at NIH
 The duties outlined by DSHEA for ODS are related
to conducting, coordinating, or compiling the
results of scientific research.
 ODS is directed by DSHEA (1) to conduct and
coordinate scientific research relating to dietary
supplements within NIH, (2) to coordinate funding
for such research, (3) to compile a database of
such research, and (4) to serve as the principal
advisor to HHS, NIH, CDC, and FDA on issues
relating to safety, benefits, and labeling of dietary
supplements.
The Strategic Plan of the Office of Dietary
Supplements at NIH
 Establishment of the “Center for Dietary
Supplements: Botanicals”
 Capacity of the NIH Dietary Supplement Research
Centers is to identify, characterize and
authenticate botanicals as well as access the
bioavailability and bioactivity of botanical
ingredients.
 The center will identify the mechanisms of action
of the active constituents and proceed to conduct
both preclinical and clinical evaluations of the
botanicals under consideration.
 The center will also continue to serve as a primary
information resource for the consumer public.
The Commission on Dietary Supplement
Labels
The DSHEA, signed into law on October 25,
1994, mandated the establishment of the
Commission (CDSL).
Appointments of the seven members of the
Commission were confirmed by the
President on November 9, 1995
From February 1996 to August 1997, the
Commission held nine meetings
The final report was delivered the Office
President, the Congress, and the Secretary of
DHHS on November 24, 1997
Function of the Commission on Dietary
Supplement Labels
Develop recommendations for the
regulations of label claims and statements
for dietary supplements.
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
Benefits of Dietary Supplement
Manufacturers under DSHEA of
1994
The law essentially gives dietary
supplement manufacturers freedom to
(1) market more products as
dietary supplements, and
(2) provide information about their
products benefits in product
labeling
Responsibility of the Dietary Supplement
Manufacturer under DSHEA of 1994
Manufacturers have an essential
responsibility to substantiate the safety of
their products and for determining that any
representations or claims made about their
products are substantiate by adequate
evidence to show that they are not false or
misleading
Two New Regulations for the Dietary
Supplement Industry in 2007
The dietary supplement industry
experienced two once-in-a-decade events in
2007:
(A) The implementation of a Serious
Adverse Event Reporting (SAER) law;
and
(B) The publication of the final rule on the
Current Good Manufacturing Practices
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(CGMPs) for dietary supplements
Serious Adverse Event Reporting Law
Mandatory reporting to FDA of serious
adverse events is now required as a result
of the enactment of the Drug “Dietary
Supplement and Non-Prescription Consumer
Protection Act” signed into law on December
22, 2006.
The law requires manufacturers, packers, or
distributors of dietary supplement products
to submit reports to FDA about all serious
adverse events involving such products
based on specific information that they
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receive from the public.
Statutory Definition of Serious Adverse
Events under the “Dietary Supplement and
Non-prescription Drug Protection Act” of
2006
Defined as death, life-threatening,
being admitted to hospital as an
inpatient, disability, birth defect, and
medical or surgical intervention due to
dietary supplements and nonprescription drugs
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The Final CGMP Rule for Dietary
Supplements Issued by FDA in 2007
2007 FDA published the final rule, effective
August 24th, 2007.
2008 became effective in June for
companies with more than 500 employees
2009 became effective in June for
companies with less than 500 but more than
20 employees
2010 will become effective in June for
companies with less than 20 employees
Basic Terms of Regulatory Significance in New
FDA CGMPs for Dietary Supplements (1)
 Quality: The dietary supplement consistently
meets the established specifications for identity,
purity, strength, and composition, and limits on
contaminants, and has been manufactured,
packaged, labeled and held under conditions to
prevent adulteration
 Adulteration: If a dietary supplement is or contains
a dietary ingredient that present a significant or
unreasonable risk of illness or injury under
conditions of use recommended or suggested in
labeling or, if no such conditions, under ordinary
conditions of use
Basic Terms of Regulatory Significance in the
New FDA CGMPs for Dietary Supplements (2)
Quality control: A planned and systematic
operation or procedure for ensuring the
quality of a dietary supplement.
Quality control personnel: Any person,
persons, or groups, within or outside of
your organization, who you designate to be
responsible for your quality control
operations.
Basic Terms of Regulatory Significance in the
New FDA CGMPs for Dietary Supplements (3)
Dietary Component: Any substance that is in
the manufacture of a dietary supplement,
including those that may not appear in the
finished batch of the dietary supplement
Dietary Ingredient: Any substance that is
used in the manufacture of a dietary
supplement and that is intended to be
present in the finished batch of the dietary
supplement.
Basic Terms of Regulatory Significance in the
New FDA CGMPs for Dietary Supplements (4)
Actual yield: The quantity that is actually
produced at any appropriate step of
manufacture or packaging of a particular
dietary supplement.
Batch: A specific quantity of a dietary
supplement that is uniform, that is intended
to meet specifications for identity, purity,
strength, and composition, and that is
produced during a specified time period
according to a single manufacturing record
during the same cycle of manufacture.
Basic Terms of Regulatory Significance in the
New FDA CGMPs for Dietary Supplements (5)
 In-process material: Any material that is fabricated,
compounded, blended, ground, extracted, sifted,
sterilized, derived by chemical reaction, or
processed in any other way for use in the
manufacture of a dietary supplement.
 Certificate of Analysis: The documentation that goes
with each product run. This certificate lists the
formula for the ingredients as well as the amount of
each raw material/ingredient. It also contains the
results of tests of contaminants.
The Public Health Security and Bioterrorism
Preparedness and Response Act
(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 supply and other food-related
emergencies.
 To carry out certain provisions of the Bioterrorism
Act, FDA has established new regulations
requiring that:
- Food facilities are registered with FDA, and
- FDA be given advance notice on shipments of
imported food.
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Summary of Mushroom DS Regulatory
Framework
 Facility registration required
 Ingredients must conform to statute
 Product forms limited to oral use
 Adulterated if a significant or unreasonable risk of
illness or injury is present
 Safety data must be submitted to FDA for “new
dietary ingredients” 75 days before marketing
 Marketer must have substantiation for claims
 Implementation of CGMP ongoing
 SAERS received must be submitted to FDA
Food Safety Modernization Act of 2009
Passed by the House
The house has passed its version of
the Food Safety Modernization Act, now
it is the Senate’s turn
.
The main purpose is to establish a new
federal agency to be known as “Food
Safety Administration” within the
Department of Health and Human
Services (DHHS)
Summary of the Provisions of the Food Safety
Modernization Act of 2009 by the House (1)
 Inspections of records
 Registration of food facilities
 Hazard analysis and risk-based preventive
controls
 Performance standards
 Standards for produce safety
 Protection against international adulteration
 National agriculture and food defense
strategy
 Facilities, and ports of entry
 Recognition of laboratory accreditation of
Summary of the Provisions of the Food Safety
Modernization Act of 2009 Passed by the
House(2)
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Integrated consortium of laboratory networks
Enhancing traceback and recordkeeping
Surveillance
Mandatory recall authority
Voluntary qualified importer program
Authority to require import certifications for food
Review of a regulatory authority of a foreign country
Inspection of foreign food facilities, and
Foreign offices of the Food and Drug
Administration
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