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Shung-Chang Jong, Ph.D. ATCC, Manassas, VA, 20110-2209, USA

Ensuring the Quality of Dietary Supplements from Medicinal Mushrooms Using U.S. FDA-prescribed Current Good Manufacturing Practices. Shung-Chang Jong, Ph.D. ATCC, Manassas, VA, 20110-2209, USA. The Life Sciences Industry Group The Singapore Manufacturing Federation.

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Shung-Chang Jong, Ph.D. ATCC, Manassas, VA, 20110-2209, USA

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  1. Ensuring the Quality of Dietary Supplements from Medicinal Mushrooms Using U.S. FDA-prescribed 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

  2. 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 acommon origin” + The tenet of Hippocrates C 400 B.C. “Let food be your medicine andmedicine be your food”

  3. 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

  4. 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

  5. Source Materials of Dietary Ingredientsfrom 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) brothharvested from submerged liquid cultures grown in bioreactors

  6. 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

  7. 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) 10% • Self-sterile species (heterothallism) 90% Bipolar (single series of incompatibility factors) 25% Tetrapolar (two series of incompatibility factors) 75 % e.g.,Coprinuscinereus12,000 mating types Schizophyllumcommune20,000 mating types Note: Each individual mushroom is the repository for an immense amount of genetic information, providing directeconomic value to humans in the form of marketable products

  8. The Interconnected Cellular Networks and Complexityof Medicinal Mushroom Cells

  9. 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 variationin 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 supplementor nutritional supplement

  10. 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 protectingintellectual 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

  11. 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 standardsfor mushrooms • ingredientsin dietary supplements – “standardwithout standardization” • Lack of methods for ensuring that dietary supplements are what they purport to be and they contain the active ingredients of interest

  12. 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 forhealthfunctions • 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

  13. Ordinance – a Three-pronged Approach to Ensure the Strict Enforcement of Food Safety Law in China • To implement food safety as thefirst 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 strengthengovernment 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

  14. 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)

  15. 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”

  16. 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 (pre-market activities) * Local Health Departments: conducts post-market vigilance of health food products

  17. 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 foodproducts from medicinal mushrooms have been approved for registration • Health foods are widely available in pharmacieschartered under theNational Health InsuranceProgram, 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 conductingrandom testing of products

  18. 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 perspectiveof 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 health-promoting 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

  19. Nutraceutical and Functional Food Regulations in the United States • Functional foods were defined by the Institute ofMedicine of the U.S. Academy of Sciencesas “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 DietarySupplement and Education Act of 1994, andfoodsare marketed under theNutrition Labeling andEducation Act of 1990.

  20. 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 InstitutesofHealth (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

  21. 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 health-related 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 cannot mention any specific disease.

  22. Overview of the Dietary Supplement Health and Education Act (DSHEA) of 1994 (2) • Defined the term “dietary supplement” (DS) as a producttaken by mouth that contains a“dietary ingredient”intended to supplement thediet. • Defined both of the terms “dietary ingredient” and “newdietary 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 distributorssubmits 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”

  23. Five Specific Information Requirementsin Notification to FDAfor 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

  24. 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 newingredients, 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).

  25. Overview of the Dietary Supplement Health and Education Act (DSHEA) of 1994 (4) • Before 1994, the original definition of a supplementwas 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 doesnot authorize or test dietary supplements before marketing. • The FDA can only step in when the supplement has been shown to be unsafe.

  26. 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 notbeen evaluated by the FDA. This product is not intended to diagnose, treat, cure, or preventany 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.

  27. 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

  28. Regulatory Definition of a Dietary Supplement in the United States (1) The Dietary Supplement Health andEducation Act (DSHEA) of 1994 defines dietary supplements as: a product “intended to supplement the diet” that containsone ormore of followingINGREDIENTS: > 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

  29. Regulatory Definition of a DietarySupplement 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 soleitem of a meal or thediet” - labeled as a “dietary supplement”

  30. Regulatory Definition of a Dietary Supplement in the United States (3) • Specifically EXCLUDES: > articles that were approved as newdrugs 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.

  31. The Office of Dietary Supplements at the National Institutes of Health (NIH) • DSHEAestablished 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

  32. 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 theresults 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.

  33. 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 constituentsand proceed to conduct both preclinical and clinical evaluations of the botanicals under consideration. • The center will also continue to serve as a primaryinformation resource for the consumer public.

  34. 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

  35. Function of the Commission on Dietary Supplement Labels • Develop recommendations for the regulations of label claims and statementsfor 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

  36. 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

  37. 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

  38. 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 SeriousAdverse Event Reporting(SAER)law; and (B) The publication of the final rule on the Current Good Manufacturing Practices(CGMPs) for dietary supplements 8/31/2014

  39. 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 Supplementand Non-Prescription ConsumerProtection Act” signed into law on December 22, 2006. The law requires manufacturers, packers, ordistributors of dietary supplement products to submit reports to FDA about all seriousadverse events involving such products based on specific information that they receive from the public. 8/31/2014

  40. Statutory Definition of Serious Adverse Events under the “Dietary Supplement andNon-prescription Drug ProtectionAct” 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 non-prescription drugs 8/31/2014

  41. The Final CGMP Rule for Dietary Supplements Issued by FDA in 2007 • 2007FDA published the final rule, effective August24th,2007. • 2008 became effective in June for companies with more than 500 employees • 2009became effective in June for companies with less than 500but more than20employees • 2010will become effective in June for companies with less than 20 employees

  42. Basic Terms of Regulatory Significance in New FDA CGMPs for Dietary Supplements (1) • Quality: The dietary supplement consistently meets the establishedspecifications for identity,purity, strength, and composition, and limits oncontaminants, and has been manufactured, packaged, labeled and held under conditions to prevent adulteration • Adulteration: If a dietary supplement is or contains a dietary ingredientthat 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

  43. 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.

  44. 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.

  45. 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 singlemanufacturing record during the same cycle of manufacture.

  46. 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, orprocessed 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.

  47. 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. 8/31/2014

  48. 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

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