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Ethical Sourcing Assessments for Ingredients, Supplements and Foods

by NaturPro in Uncategorized Comments: 0

NaturPro has served an essential role in helping our clients source and evaluate ethically sourced ingredients. 

Our Ethical Sourcing Assessments include elements from many recognized programs such as Fairtrade(R), and uses one of the most comprehensive set of standards guiding the evaluation of the social and environmental impact of natural products and foods.

Ethical Sourcing Assessments are Key to Understanding Social, Environmental and Product Sustainability

Ethical Sourcing of Ingredients for Supplements and Foods
Ethical Sourcing of Ingredients for Supplements and Food is used to benchmark sustainability and identify ways to improve supply chains.

The following outline covers subject matter covered in our evaluation protocol, which is derived from multiple sources, including the International Labour Organization Labour Principles of the United Nations Global Compact, the UN Forum on Sustainability Standards, Fairtrade,, WHO GAP, Global G.A.P., and NOP Organic.

General Guidelines for Ethical Sourcing: The Human Element

Product:

  1. Contact information
  2. Product name
  3. Specifications, nomenclature
  4. Sourcing origin
  5. Land use and inputs
  6. Harvest practices
  7. Plant population care
  8. Raw material processing and labeling

Relationships

  1. Type and controls
  2. Prices and wages
  3. Non-discrimination
  4. Reciprocity
  5. Communications

Employment

  1. Labor practices
  2. Fair wages and prices
  3. Child labor
  4. Harrassment
  5. Working conditions
  6. Worker safety

Environment

  1. Legal requirements
  2. Policies and communications
  3. Management responsibilities
  4. Waste management
  5. Emissions
  6. Energy usage

Management and Supply Chain

  1. Written policies
  2. Training
  3. Supplier management
  4. Dealing with non-compliances
  5. Audit program
  6. Geographic risk
  7. Community improvements

NaturPro fits our review protocol and minimum standards according to your practices currently in place, and we also evaluate according to the ‘stretch goal’ standards our clients are working to achieve, and set a clear path towards improved social and environmental impact.

Global Herb Producer Cooperative
Reviewing your ‘people practices’ helps our clients to better understand and support their supply chain.

Here are a couple examples of case studies we have performed for clients:

1. “Seed-to-Shelf Independent Audit” — A comprehensive, umbrella independent review of all quality and ethical procedures, relating to both farm-level and manufacturing practices.

We review all documentation, audit reports and other information, provide a list of opportunities to improve quality, identify gaps that minimize business, regulatory and product quality risk, help our clients meet the minimum level of regulatory compliance, and identify ‘best practices’ that are either already in place, or can be implemented. 


2. “Human Impact Audit” – A third-party independent review of the “human element” of an agricultural or wild-collected product, focusing in particular on staff training, farming practices and GAP, worker health and safety, and cultural preservation.   This includes a review of personnel SOP, safety, fair trade, farm practices, environmental impact estimates, ethical sourcing & organic practices.

The above 2 programs could be done separately or combined, and are typically performed in 2 phases: 

Phase 1: Document Audit
Phase 2: In-person/field Audits

3. Program marketing and communications – A comprehensive review paper that describes in detail all the elements of the program, references to the standards applied, and images or video footage. This comprehensive review can then be broken down into separate stories, that can become webpages, Youtube videos and social media posts that educate your audience.

Contact us for more information on NaturPro Scientific’s ingredient traceability and ethical sourcing programs. 

Product Strategy Consultants for Dietary Supplements

by NaturPro in Uncategorized Comments: 0

Product strategy for health products like supplements requires extensive knowledge of consumer trends, marketing, consumer behavior, food science, regulatory requirements and technical and scientific affairs.

NaturPro Scientific combines expertise in a wide array of product types and disciplines, offering clients a way to maximize chances for consumer product success in the market.

Product Strategy – Cores of Discipline 

A product may be determined as safe and effective, and also legal and kosher — but still not be positioned for success.  For example, it may be undifferentiated in a crowded market, or not provide a meaningful benefit that is valued by the consumer. A great product may find itself swimming in infested waters filled with competitors.

Supplement capsules prototype pilot samples
NaturPro offers seed-to-shelf strategy and execution for supplement product development

 Our in-depth analysis and advisory process helps to guide our clients in the right direction.

Some main considerations for any supplement product design consultants includes the following:

  1. Target Health Category(s) and subcategories, including potential niche markets
  2. Market Opportunity Analysis
  3. Market Size & Market Leaders
  4. Key Competitor Analysis
  5. Pricing Sensitivity
  6. Consumer Preference Analysis, including consumner surveys and focus groups
  7. Key Product Benefit
  8. Regulatory Review
  9. Customer Demographics
  10. Differentiation, Positioning and Competitive Analysis
  11. Innovation Strategy
  12. SWOT Analaysis
  13. Marketing and Distribution Channel Analysis

FSVP: FDA’s Requirements under FSMA for Imported Ingredients

by NaturPro in Quality Comments: 0

Importing any food or supplement products? Do you have training, procedures and records according to FDA’s FSVP guidance? 

Many firms in the food and dietary supplement industry are quietly putting significant investment into meeting the Food Safety Modernization Act (FSMA). FSMA was signed by President Obama in 2011 as the first major legislation to update food safety regulations in more than 50 years. FSMA and FSVP represent the best approach to ensuring a safe global food chain.

supplement food verification

For supplements and health foods, its more reliable to verify than it is to trust.

FDA Requires You To Do these Things:

  1. Your FSVP includes all written procedures and records that demonstrate compliance with FSMA, especially the requirements for Supply Chain Preventive Controls (PC). If you purchase any ingredients directly from foreign sources outside the U.S., then you must have a written FSVP. And if your U.S. based supplier imports ingredients, you are responsible for verifying their FSVP is effective.
  2. Warehouses, marketers and distributors, and supplement manufacturers are subject to “modified” FSVP requirements. Even if you don’t receive product, or open any containers, you must still verify those you designate to handle, order, process or store your product.  If your name is on the  label of any product or package, then you must be able to show (with written documentation) that your supplier, warehouse, processor, and customer ensures the safety of the product within 24 hours of the FDA visiting you or requesting this information by phone.
  3. If you import, own and/or have a financial stake in the imported goods, then you are probably responsible for the goods as the designated “FSVP Importer”. For imports involving multiple U.S. parties, there must be a written agreement specifying who is responsible for what. Foreign firms who send goods to the U.S. without a designated buyer must have a U.S.-based agent to act as importer, and take responsibility for the shipment once it arrives to the U.S.
  4. You need to have a Qualified Individual or QI to write your FSVP. No standard training is required to be a QI, but it will greatly help your QI to be trained on PCQI and/or FSVP. Because the final FSVP rule includes more than 300 mentions of the word ‘flexibility’, you still gotta know what you’re doing.
  5. With few exceptions, importers must perform a hazard analysis on all imported products. This requires you to know how your ingredients are grown and made, where they came from, and what biological, chemical or physical hazards may be present that could make them unsafe. A hazard requiring a preventive control is defined as one that is “known or reasonably foreseeable to cause significant injury or illness”. It’s up to your QI to determine these hazards.  You can agree in writing with your supplier or customer to ensure that they are responsible for a preventive control – otherwise, the responsibility probably falls on you.
  6. The most common hazards are:
    1. Undeclared allergens
    2. Salmonella
    3. Listeria
    4. These three are the source of 88% of all product recalls! 
  7. Economically Motivated Adulteration (EMA) and radiological contamination are often overlooked as hazards, and often require PC in the FSVP guidance.
  8. Much of the available information on hazards is provided by FDA for free. Some examples:
    1. FDA Import Alerts
    2. FDA Warning Letters
    3. FDA Product Recalls
    4. FDA Guidance on Potential Hazards for Foods and Processes
    5. FDA Bad Bug Book
    6. FDA Guidance on Chemical Hazards
    7. FDA Reportable Food Registry
    8. Product specifications that control for hazards like salmonella and allergens. These are often not publicly available, but many are found on industry databases like UL Prospector.
  9. The easiest and most impactful thing you can do to start evaluating your foreign supplier is to request their hazard analysis!
  10. Third party experts are the most popular way to develop FSVP programs. A couple days of staff training is not the same as experience and expertise, especially with today’s global supply. Remember that suppliers are not allowed to verify themselves – this duty is left to customers, third party auditors, or other qualified individuals sent on behalf of the customer.

If you don’t have the time or expertise on staff to handle your supplier verification according to FSMA, make sure you talk to someone trained in FSVP with experience in qualifying your type of products and suppliers.

For more information on FSVP, visit the FDA page “FSMA Final Rule on Foreign Supplier Verification Programs (FSVP) for Importers of Food for Humans and Animals

NaturPro Scientific LLC is a leading natural products consultancy specializing in evaluating and maximizing the value of foods and dietary supplements. Contact us for more information at http://naturproscientific.com/contact-us




7 Steps to Dietary Supplement Product Development


We often get asked what we think of a product concept. The thought process to develop an answer is generally similar, regardless of the type of product, and whether its a consumer packaged good (CPG) or finished product, or an ingredient or raw material.

A number of considerations go into developing and producing successful, effective, safe and compliant dietary supplements, foods, and food and dietary ingredients.  These include:

  • What does the product do?
  • What can be claimed about the product?
  • Is the evidence supporting the claims sufficient?
  • How safe is the product?
  • Who will benefit from the product?
  • How is the dosage determined?
  • Are the ingredients available at an acceptable quality, cost and volume?

 

The 7 Steps to Dietary Supplement Product Development

There are seven basic elements to developing a groundbreaking product:

  1. Begin with the finished product in mind. Determine in full detail how the product will be marketed, what the desired product claims will be, and how the product will address an unmet market need.
  2. Intimately understand the product value and market positioning compared to the competition. How will the product address an unmet need, or be different than what is already found on the market?  How will the product be priced compared to the competition? A full competitive analysis is important to determine positioning.
  3. What language will be used to describe the product? (This language, found on product labels and on webpages, is considered to be part of product claims.)
  4. In what country(s) will the product be marketed?  Regulations in different countries vary, and it is important to understand the unique requirements of each location.
  5. How will it be sold? Online, Amazon, Whole Foods, health food stores, clubs, MLM and practitioner channels have distinct customer needs, pricing and positioning requirements
  6. Evaluate the regulatory landscape. What steps need to be taken to access the market? What gaps need to be filled in order to be compliant with the regulations?
  7. Evaluate ingredients and suppliers. An ingredient that is processed in a way that makes it different than material used in studies will negate the supporting evidence. And, an ingredient that does not meet GMP and quality requirements under FDA is illegal to sell. Don’t go far down the path of product development without a rigorous evaluation of supply and ingredients.

 

Product Development Planning

Working backwards from the product claim may sound simple, but it is an analytical process that benefits greatly from industry experience and forethought.  A solid plan is what separates a rocket from a dud.


Sufficient time spent in the planning phase is the difference between success and failure.


Product development plans often coordinate the knowledge of supplement consultants and experts, review regulatory status of the product and evaluate the available scientific evidence.  A good development plan will identify not only opportunities, but also gaps and risks that may prevent success.

Contact us for more information on Natural Product Development

 

Additional Reading:

Food and Supplement Claims with Confidence

Dietary Supplement Formula Development

Dietary Supplement Ingredient Regulatory Status

Supplement Manufacturing Consulting

Creating Natural Product Intellectual Property

 

 




Dietary Supplement Facts and Label Review


There’s a lot of detail required for dietary supplement labels. Between supplement facts, structure-function health claims, content claims, and required formatting, it’s easy to overlook some of the FDA requirements for labeling.

Supplement Label Review Nutrition Facts

Supplement Label Review for Supplement Facts, Nutrition Labeling and Claims

Dietary Supplement Facts and Label Review

As part of our Label Review services, NaturPro helps clients develop, review and suggest improvements to dietary supplement labels, to ensure compliance with FDA regulatory requirements

Our clients enjoy the following benefits:

  1. Reliability: 100% accuracy and FDA compliance
  2. Experience: 15+ years of experience reviewing supplement labels
  3. Science-driven: Our reviews are based on the most current, reliable information, techniques and evidence
  4. Perspective: We have experience on the business side of the industry, so we know what the law is, whether it’s followed, and what is likely to happen if you don’t.

Updated Pricing:

Label Review (Basic): $350-550  — review only label — for “red flags” and suggested improvements

Label Review (Complete): $550-850 – review of label for red flags and suggested improvements, and matching finished product specifications

Label and Marketing Review: $800-1500 per label – web page / sales sheet

 (Volume discounts may apply for similarly labeled products — Contact for Pricing


FDA Dietary Supplement Labeling Guidelines

See our Dietary Supplement Label Review Checklist.

The following outlines some of the most frequently asked questions (FAQ) for dietary supplement labels:

  1. How are dietary supplements defined?Dietary supplements are defined, in part, as products (other than tobacco) intended to supplement the diet that bear or contain one or more of the following dietary ingredients:
    1. A vitamin;
    2. A mineral;
    3. An herb or other botanical;
    4. An amino acid;
    5. A dietary substance for use by man to supplement the diet by increasing the total dietary intake; or
    6. A concentrate, metabolite, constituent, extract, or a combination of any ingredient mentioned above.Further, dietary supplements are products intended for ingestion, are not represented for use as a conventional food or as a sole item of a meal or the diet, and are labeled as dietary supplements.
  2.  What label statements are required on the containers and packages of dietary supplements?Five statements are required: 1) the statement of identity (name of the dietary supplement), 2) the net quantity of contents statement (amount of the dietary supplement), 3) the nutrition labeling, 4) the ingredient list, and 5) the name and place of business of the manufacturer, packer, or distributor.
  3.  Where do I place the required label statements?You must place all required label statements either on the front label panel (the principal display panel) or on the information panel (usually the label panel immediately to the right of the principal display panel, as seen by the consumer when facing the product), unless otherwise specified by regulation (i.e., exemptions).
  4.  What label statements must I place on the principal display panel?You must place the statement of identity and the net quantity of contents statement on the principal display panel. Where packages bear alternate principal display panels, you must place this information on each alternate principal display panel.
  5.  How do I locate the principal display panel?The principal display panel of the label is the portion of the package that is most likely to be seen by the consumer at the time of display for retail purchase. Many containers are designed with two or more different surfaces that are suitable for use as the principal display panel. These are alternate principal display panels.
  6.  What label statements must I place on the information panel?You must place the “Supplement Facts” panel, the ingredient list, and the name and place of business of the manufacturer, packer, or distributor on the information panel if such information does not appear on the principal display panel, except that if space is insufficient, you may use the special provisions on the “Supplement Facts” panel in 21 CFR 101.36(i)(2)(iii) and (i)(5). See questions 46 and 56 in Chapter IV for more details.
  7.  Where is the information panel?The information panel is located immediately to the right of the principal display panel as the product is displayed to the consumer. If this panel is not usable, due to package design and construction (e.g. folded flaps), the panel immediately contiguous and to the right of this part may be used for the information panel. The information panel may be any adjacent panel when the top of a container is the principal display panel.
  8.  What name and address must I list on the label of my product?You must list the street address if it is not listed in a current city directory or telephone book, the city or town, the state, and zip code. You may list the address of the principal place of business in lieu of the actual address.
  9.  May I place intervening material on the information panel?No. You may not place intervening material, which is defined as label information that is not required (e.g., UPC bar code), between label information that is required on the information panel.
  10.  What type size, prominence and conspicuousness am I required to use on the principal display panel and the information panel?You are required to use a print or type size that is prominent, conspicuous and easy to read. The letters must be at least one-sixteenth (1/16) inch in height based on the lower case letter “o,” and not be more than three times as high as they are wide, unless you petition for an exemption in accordance with 21 CFR 101.2(f). The lettering must contrast sufficiently (it does not need to be black and white) with the background so as to be easy to read. See Chapter IV for the type size requirements for the nutrition label.
  11.  Do I need to specify the country of origin if my product, or the ingredients in my product, is not from the United States?Yes. Unless excepted by law, the Tariff Act requires that every article of foreign origin (or its container) imported into the United States conspicuously indicate the English name of the country of origin of the article.
  12. What is the nutrition label for a dietary supplement called?The nutrition label for a dietary supplement is called a “Supplement Facts” panel.
    1. You must list dietary ingredients without RDIs or DRVs in the “Supplement Facts” panel for dietary supplements. You are not permitted to list these ingredients in the “Nutrition Facts” panel for foods.
    2. You may list the source of a dietary ingredient in the “Supplement Facts” panel for dietary supplements. You cannot list the source of a dietary ingredient in the “Nutrition Facts” panel for foods.
    3. You are not required to list the source of a dietary ingredient in the ingredient statement for dietary supplements if it is listed in the “Supplement Facts” panel.
    4. You must include the part of the plant from which a dietary ingredient is derived in the “Supplement Facts” panel for dietary supplements. You are not permitted to list the part of a plant in the “Nutrition Facts” panel for foods.
    5. You are not permitted to list “zero” amounts of nutrients in the “Supplement Facts” panel for dietary supplements. You are required to list “zero” amounts of nutrients in the “Nutrition Facts” panel for food.How does “Supplement Facts” differ from “nutrition facts?”The major differences between “Supplement Facts” panel and “Nutrition Facts” panel are as follows:
  13. What information must I list in the “Supplement Facts” panel?You must list the names and quantities of dietary ingredients present in your product, the “Serving Size” and the “Servings Per Container.” However, the listing of “Servings Per Container” is not required when it is the same information as in the net quantity of contents statement. For example, when the net quantity of contents statement is 100 tablets and the “Serving Size” is one tablet, the “Serving Per Container” also would be 100 tablets and would not need to be listed.
  14. How must I display the “Supplement Facts” panel?The “Supplement Facts” nutrition information (referred to as a panel) must be enclosed in a box by using hairlines. The title, “Supplement Facts,” must be larger than all other print in the panel and, unless impractical, must be set full width of the panel. The title and all headings must be bolded to distinguish them from other information.
  15. How must I present the information in the “Supplement Facts” panel?You must present all information using the following:
    1. A single easy-to-read type style;
    2. All black or one color type, printed on a white or neutral contrasting background, whenever practical;
    3. Upper- and lowercase letters, except that you may use all uppercase lettering on small packages (i.e., packages having a total surface area available to bear labeling of less than 12 square inches);
    4. At least one point leading (i.e., space between lines of text); and
    5. Letters that do not touch.

  16. What are the type size requirements for the “Supplement Facts” panel?Except as provided for small and intermediate-sized packages, you must set information other than the title, headings, and footnotes in uniform type size no smaller than 8 point. You also must use a type size larger than all other print size in the nutrition label for the title “Supplement Facts.” You may set the column headings and footnotes in type no smaller than 6 point type. See the section on “Special Labeling Provisions” for the exceptions for small and intermediate-sized packages.
    For more information, visit FDA Dietary Supplement Labeling Guide

Cannabis, Hemp & CBD | SOP and Procedures


Standard operating procedures (SOP) for CBD and Cannabis operations can be challenging to create and implement.

NaturPro Scientific’s experience with all types of document requirements, including SOP and specifications, helps you meet the requirements as efficiently as possible.

Cannabis & Hemp Procedures and SOP (Standard Operating Procedures) are the central part of operations of any cultivation, extraction, processing, packaging or testing business. Startups who invest in solid standard operating procedures (SOP) find themselves several steps ahead.

Cannabis SOP are required by each state where cannabis, marijuana or hemp are regulated.

Cannabis SOP and procedures

Cannabis SOP and procedures are required each state

Any cannabis, hemp, medical or adult-use (recreational) marijuana product is subject to a number of controls, from seed to shelf. NaturPro Scientific has supported a number of clients in the aim of providing safe, effective cannabis and hemp products to support human health.

What should you follow?

Here’s some free advice: we recommend to follow the quality assurance and quality control guidelines from these organizations:

Need help meeting the requirements? Contact us anytime!


PRIMARY CATEGORIES FOR SOP

  1. Cultivation or Processing
    1. Management
    2. Applicable Regulations
    3. Operations
    4. Training & Safety
    5. Hygiene
    6. Sanitation & Cleaning
    7. Farm or Facility
    8. Equipment
    9. Seeds and Propagation Materials
    10. Agricultural Inputs
    11. Pre-harvest practices
    12. Harvesting
    13. Post-harvest practices
    14. Drying & Milling
    15. Sampling
    16. Testing (Potency, purity, cannabinoids, microbiology, heavy metals, pesticides)
    17. Waste Management
  2. Quality Management Systems
    1. Product Quality Policy/Manual
    2. Recordkeeping
      1. Document Control
      2. Formula Records
      3. Batch Records
      4. Certificates of Analysis
    3. Traceability & Recall
    4. Risk Analysis
      1. Hazard Analysis
      2. Purchasing Criteria & Specifications
      3. Supplier Qualification
      4. Intentional Adulteration
      5. Preventive Controls
    5. Product Approval & Rejection, Material Inspection
    6. Complaints & CAPA (Corrective Actions)

———————

A BASIC EXAMPLE for FARM OPERATIONS

The following information is a partial excerpt from draft from U.S. Hemp Roundtable guidance for CBD products, which NaturPro was fortunate to contribute to.

CBD SOP’s and Cannabis Procedures

U.S. Hemp Guidance Program PHASE 2

1 GROWER
1.1 GENERAL TERMS & DEFINITIONS

The following Definitions and Interpretations apply to such terms when used in this U.S. Hemp Guidance Program.

Adulteration refers to a food that may be considered adulterated if it contains “any poisonous or deleterious substance which may render it injurious to health…..or if any valuable constituent has been in whole or in part omitted or abstracted therefrom; or (2) if any substance has been substituted wholly or in part therefor; or (3) if damage or inferiority has been concealed in any manner; or (4) if any substance has been added thereto or mixed or packed therewith so as to increase its bulk or weight, or reduce its quality or strength, or make it appear better or of greater value than it is”.

Batch means a specific quantity of industrial hemp that is uniform, that is intended to meet specifications for identity, purity, strength, and composition, and that is produced during a specified period of time according to a single manufacturing record.

Batch number, or lot number means any distinctive group of letters, or numbers, or any combination of them, from which the complete history of the processing, packaging, labeling, and/or storage of a batch or lot of industrial hemp product can be determined.

Biomass means the amount of living matter in a given habitat, expressed either as the weight of organisms per unit area or as the volume of organisms per unit volume of habitat.

Component means any substance intended for use in the manufacture of industrial hemp, including those that may not appear in the finished batch of the industrial hemp.

Growth Medium means the solid, liquid or semi-solid substance used to support the growth of the plant.

Hemp refers to cannabis varieties and any part of the plant, whether growing or not, containing a delta-9 tetrahydrocannabinol (THC) concentration of no more than three-tenths of one percent (0.3%) on a dry weight basis.

Industrial Hemp is Hemp
Ingredient means any substance that is used in the manufacture of hemp and that is intended to

be present in the finished batch of the hemp product.

In-process material means any material that is compounded, blended, ground, extracted, sifted, sterilized, derived by chemical reaction, or processed in any way for use in the manufacture of the hemp product.

Lot means a batch, or a specific identified portion of a batch, or, in the case of a hemp product produced by continuous process, a specific identified amount produced in a specified unit of time or

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1

U.S. Hemp Guidance Program PHASE 2

quantity in a manner that is uniform and that is intended to meet specifications for identity, purity, strength, and composition.

Microorganisms means yeasts, molds, bacteria, viruses, toxins, and other similar microscopic organisms which may or may not have a health or sanitary concern.

Pest means any objectionable insect or other animal including but not limited to birds, rodents, flies, mites, and larvae.

Physical plant or facility means all or any part of a building or facility used for or in connection with manufacturing, processing packaging, labeling, or storage of industrial hemp products or ingredients.

Processor means making a transformative change to the hemp plant or product following harvest.

Product complaint means any communication that contains any allegation, written, electronic, or oral, expressing concern, which may or may not have be related to the quality of an industrial hemp product.

Quality means that the hemp product 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.

Quality Management Systems means a planned and systematic operation or procedure for ensuring the quality of a hemp product.

Quality Management Systems personnel means any person, persons, or group, within or outside the organization, designated to be responsible for quality control operations.

Representative sample means a sample with an adequate number of units that are intended to ensure that the sample accurately portrays the material being sampled.

Reserve sample means a representative sample of product that is held for a designated period of time.

Sanitize means to adequately treat cleaned equipment, containers, utensils, etc.by a process that is effective in destroying of microorganisms of public health concerns.

2

U.S. Hemp Guidance Program PHASE 2

1.2 REGISTRATION/APPLICATION/NOTIFICATION

Prior to the Industrial Hemp Grower planting any seed, a license or agreement with the State must be obtained. The following information is required to make the application before a license will be issued: (Each State may have different regulations – refer to application – See Kentucky Hemp Policy Guide as an example)

1.2.1 Registration/Application Guidance

  • Name of the person or corporation to whom the license or authorization is to be issued
  • Address of the farm or place including county and township or legal description
  • The number of acres
  • Global Positioning System coordinates
  • Intended purpos of industrial hemp
  • In the case of a plant breeder, the variety of industrial hemp that may be cultivated; and

o Any conditions that are necessary to minimize security, public health or safety hazards related to the licensed or authorized activities.

o Specify if the hemp is for food or non-food purposes

1.2.2 Notification of Changes to the licensor by the licensee

Every licensee shall notify the State of any changes to the information provided on the application, within 15 days after the change, including:

  • Corporate name or ownership, or officers, and the replacement of an officer, or director
  • Any change to the address of the licensee
  • The replacement of an individual referred to a licensee
  • Any change in the mailing address of the licensee
  • Any change in the ownership of the land used to cultivate industrial hemp
  • Any change to the approved cultivar being sown or, in the case of a plant breeder, to thevariety of industrial hemp being sown;
  • Any genetic modification.

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Signature: _____________________________ Date: ________________________ Printed Name: __________________________ Company/Location: ________________________

3

U.S. Hemp Guidance Program PHASE 2

1.3 PERSONNEL

Qualified employees who grow, manufacture, package, or label industrial hemp shall be qualified to do so, and those responsible for quality control or performing any quality control operations, must have the education, training, or experience to perform the assigned functions.

Supervisors shall be qualified by education, training, or experience to supervise.
Contamination Prevention and Hygienic measures shall be taken to exclude from any operations

any person who might be a source of microbial contamination.

Such measures shall include the following:

  • Exclude personnel from working in any operations that may have an illness, infection, open lesion, or any other abnormal source of contamination.
  • Instructing employees to notify their supervisor if there is a possibility that they have a health condition described above.
  • Wearing outer garments in a manner that protects against the contamination.
  • Maintaining adequate personal cleanliness.
  • Washing hands thoroughly, and sanitizing if necessary, in a hand-washing facility.
  • Removing or covering all unsecured jewelry and other objects that might fall into components, industrial hemp, equipment, or packaging.
  • Using gloves when appropriate.
  • Wearing, where appropriate, hair nets, caps, beard covers, shoes, PPE etc.Personnel and employee safety measures shall include the following:
  • Appropriate and Adequate First Aid Equipment
  • Adequate bathrooms and changing rooms
  • Appropriate OSHA warnings, labels, and training
  • Appropriate training and personal protective equipment for pesticide application

4

U.S. Hemp Guidance Program PHASE 2

1.3.1 U.S. HEMP GUIDANCE – GROWER – PERSONNEL CHECKLIST

√ ifApplicable

YES

NO

NOTES

Are the supervisors qualified for their responsibilities by training, education or experience?

Do the employees performing the growing, processing, packaging and labeling tasks, have the proper training necessary to perform the tasks?

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Are contamination and hygienic measures in place to exclude personnel who might be a source of contamination?

Are personnel excluded from operations if they have, an illness, infection, open lesion, or any other abnormal source of contamination?

Do employees notify their supervisor if there is a possible health condition as described above?

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Do personnel wear outer garments in a manner that protects against the contamination?

Do operating personnel maintain adequate personal cleanliness?

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Are hand washing facilities available and used?

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Do operating personnel remove or cover unsecured jewelry etc. to prevent them from falling into hemp products or causing harm?

Are gloves used when appropriate?

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Are caps, shoes and head covering used when appropriate?

Is the appropriate Personal Protective Equipment (PPE) used as needed?

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Are there adequate and appropriate first aid equipment available?

Is there adequate bathrooms and changing rooms?

Are the OSHA warnings and signs visible?

Has there been adequate training?

If applicable is the PPE and trains available for the pesticide applicators?

Signature: _____________________________ Date: ________________________ Printed Name: __________________________ Company/Location: ________________________

5

U.S. Hemp Guidance Program PHASE 2

1.3.2 U.S. HEMP GUIDANCE – GROWER – BEST MANAGEMENT PRACTICES CHECKLIST

NOTES

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YES

NO

Are you using the best soil available?

Have you Soil tested for macro and micro nutrients?

Have you used the appropriate Growth Medium for intended purposes?

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Has the licensee determined the concentration of THC in the hemp?

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Is seed planted listed on the license?

Is the entire hemp plant used as licensed?

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Do you properly use pre- plant weed control?

Do you have a Germination Certificate from the seed supplier

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Did you use the proper Certified Seed suitable for location?

Did you use the proper seed treatment?

Do you have a site history?

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Do you have a water quality report or history?

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Did you use fertilizer to target desired yield per acre according to soil test?

Did you use animal manure for fertilizer or biomass purposes?

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Did you plant by optimum seeding date?

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Did you plant at the optimum rate of seeds per acre?

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Have samples of the industrial hemp been collected in accordance with the Guidance Procedures?

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Has the equipment used to sow, harvest and transport the hemp been thoroughly cleaned to prevent contamination?

Are you prepared to harvest when the plant is ready?

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Have you complied with the drying procedures

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Do you have sufficient and proper storage facilities or adequate transportation equipment available?

Is the biomass sold to a licensed person or entity according the Guidance Procedures?

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Is the biomass packaged, labeled, and transported according to the Transportation Guidance Procedures?

Has any loss or theft been reported according to the license requirements?

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Are the records being kept according to the Guidance Procedures for Record Retention?

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Grower Signature___________________________ Date _________________ Printed Name___________________ Farm location or identifier__________________

6

U.S. Hemp Guidance Program PHASE 2

1.3.3 U.S. HEMP GUIDANCE – GROWER – FACILITY & BIOSECURITY AWARENESS CHECKLISTA.

√ ifApplicable

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Facility Security (physical security of buildings and grounds)

Is the facility using:

YES

NO

NOTES

Security lighting

Perimeter fencing

Controlled gate access

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Off-hours security guard

Electronic motion detectors

Door alarms

Video cameras

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Adequate indoor lighting

Alarms linked to an off-site security system

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Door hardware is of industrial design

Guards are installed on exterior ladders

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Exit doors and gate are electronically/mechanically secured

Entry and discharge points of exterior tanks are padlocked when not in use

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All vehicles parked outside are locked

Empty/loaded containers are parked inside

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Law enforcement patrol over company premises on regular but unpredictable basis

Employees reporting any suspicious behaviors

Restricted access to computer process control and data systems

Safeguard of data systems using data security program

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Backup of all data and processes at an off-site place

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B.

√ ifApplicable

Visitor Policy

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Is the facility using:

YES

NO

NOTES

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Company representative for visitor to check in with

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Signs informing visitors where to report

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Specific area for visitor parking

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Records of visitors (include name, company, arrival and departure, and purpose of visit)

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Visitor badges/identification cards

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Company representative to escort visitor all the time

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Restricted access to key manufacturing areas

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C.

√ ifApplicable

Distribution

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Is the facility implementing the following:

YES

NO

NOTES

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Bulk containers are inspected prior to loading for foreign and/or suspicious material

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7

U.S. Hemp Guidance Program PHASE 2

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Verify that all customer pick-up drivers are representatives of the customer

The product stream is inspected visually

Container access points are secured after loading

Seal numbers are documented on the shipping papers

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Shipping documents are used to identify the contents of each compartment

Shipping log is maintained

Bio-sanitation program is implemented

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Procedures exist to disinfect vehicles and drivers

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D.

√ if Applicable

E.

√ ifApplicable

Housekeeping

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Is the facility implementing the following:

YES

NO

NOTES

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Written housekeeping program for all areas of the facility

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Written pesticide and rodenticide program

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Emergency Response

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Is the facility implementing the following:

YES

NO

NOTES

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Employees are adequately trained to respond to a crisis as calmly and safely as possible

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Current inventory of all hazardous and flammable products

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A plan to provided MSDS to emergency response teams etc.

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A list of emergency contacts is posted

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An action plan to deal with suspicious devices or substances

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Evacuation plan in case of fire and explosions is published

page11image5858272page11image5858480page11image5858688page11image2974416page11image2973856page11image5859728page11image5859936page11image5860144page11image5860352page11image5860560page11image5860768page11image5860976

Establish and maintain an up-to-date employee roster and visitor log to facilitate personnel head count at any time

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Disaster Preparedness Plan

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A weapons security program

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Conduct evacuation and respond drill periodically

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Post a site plan depicting escape routes, fire-fighting and rescue equipment

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Signature: _____________________________
Printed Name: __________________________ Company: ________________________________

Date: ________________________________ Facility Location: ________________________________8

U.S. Hemp Guidance Program PHASE 2

1.4 SAMPLING AND HANDLING HEMP FOR THC & CBD1.4.1 Definitions

delta-9-THC means delta-9-tetrahydrocannabinol concentration.
Authority having jurisdiction usually means the state, but it could be FDA, USDA,

county or city.

Certified seed means seed for which a certificate or any other instrument has been issued, by an agency authorized under the laws of a state, territory, or possession to certify seed and which has standards and procedures approved by the United States Secretary of Agriculture to ensure the genetic purity and identity of the seed certified.

Plot means a contiguous area in a field, greenhouse, or indoor growing structure containing the same variety or strain of hemp throughout the area.

ppm means parts per million.ppb means parts per billion.

Post-Harvest Sample means a sample taken from the harvested hemp materialfrom a particular plot’s harvest. The entire plot’s harvest must be in the same form(e.g., intact-plant, flowers, ground materials, etc.), homogenous, and not mixed with non-hemp materials or hemp materials from another plot.

Pre-Harvest Sample means a composite, representative portion from plants in a hemp plot collected in accordance with the procedures as defined by the state providing authority.

Processing means converting an agricultural commodity into a marketable form.Prohibited Variety means a variety or strain of cannabis excluded from the state

providing authority.

Sample means a sufficient amount of material that is representative of the population from which it is taken. A sample may be a particular plant part, including inflorescence (flower), leaf, stalk or seed, or it may be a processed product (oil, extract, powder. Samples must be dried to a sufficiently low moisture content so as not to harbor growth of microorganisms.

Seed source means the origin of the seed or propagules as determined by the state providing authority.

9

U.S. Hemp Guidance Program PHASE 2

  1. 1.4.2  Sampling Timeline and Grower Responsibilities
    1. The grower shall refer to the jurisdiction having authority to determine a timeline.
    2. During the sampling, the grower or an authorized representative shall be present at the growing site.
    3. Floral materials harvested for phytocannabinoid extraction shall not be moved beyond the processor, nor commingled, nor extracted, until test results are complete
  2. 1.4.3  Pre-Harvest Sampling Procedure
    1. Adequate personal protective equipment shall be used.
    2. Proper equipment shall be used to prevent cross contamination.
    3. The material selected for Pre-Harvest Sampling will be determined by the grower. Cuttings will be collected to make one representative sample.
    4. Refer to the authority having jurisdiction to determine adequate number of samples and proper locations. In the absence of jurisdictional requirements, the following guidance is given.
      1. Clip the top 12 inches of hemp plant’s primary stem, including female floralmaterial.
      2. Take cuttings from at least five (5) hemp plants within the plot.
      3. Place the complete sample in a paper bag.
      4. Seal the bag by folding over the top once and staple the bag shut.
      5. A separate sample must be taken from each non-contiguous plot of a given variety.
      6. A separate sample must be taken for each variety.
      7. Samples shall be secured in a paper bag (to allow for air-drying during transport).
      8. Label the sample container with a sample ID.
  3. 1.4.4  Handling Procedures of Pre-Harvest Samples
    1. Samples will be taken for drying and storage.
    2. Samples should be arranged in a single layer for drying.
    3. Drying oven will be used when possible.
    4. Samples in the oven will be left in the labeled sample bag.
    5. If selected for testing, the entire sample will be sent to a testing lab for analysis.
  4. 1.4.5  Post-Harvest Sampling Procedures for Floral Material
    1. Refer to the authority having jurisdiction to determine adequate number of samples and proper locations. In the absence of jurisdictional requirements, the following guidance is given.
    2. Adequate personal protective equipment shall be used.
    3. Proper equipment shall be used to prevent cross contamination
    4. The plot selected for sampling shall be designated by the Pre-Harvest Sampleresults. The material selected for Post-Harvest Sampling from this plot will be

10

U.S. Hemp Guidance Program PHASE 2

determined by the grower. All Post-Harvest Samples of floral material shall be taken from the designated harvested plot materials in the form (intact-plant, flowers, ground materials, etc.) in which the material will be sent to the processor

e. Grower must inventory the entire harvest to determine the form in which it exists and follow the protocol as appropriate in part a), b), or c) below.

  1. If, upon inventory, the grower determines that the entire harvest is not in a homogenous form (intact-plant, flowers, ground materials, etc.), it must be determined to take additional samples or other course of action or take the pre-harvest results.
  2. For intact-plant post-harvest samples:
    1. Ensure that the entire harvest is accounted for and in the sameform (i.e., intact-plants).
    2. Clip the top 12 inches) of hemp plant, primary stem, includingfemale floral material.
    3. Take cuttings from at least five (5) non-adjacent hemp plantswithin the harvest’s storage/drying area.
    4. Place the complete sample in a paper bag.
    5. Seal the paper bag by folding over top once and stapling to keep closed.
    6. Complete sampling procedures in part (d) –(f).
  3. For ground plant or ground floral material Post-Harvest Samples:
    1. Ensure that the entire harvest is accounted for and in the sameform (i.e., all harvested material whether whole plant or floral material only must be ground with no intact plants or whole flowers remaining from that harvest).
    2. Sample material from bag or container.
    3. Sample from a minimum of four locations within the containers from a given harvest.
    4. Place the complete sample in a plastic sample container.
    5. Seal the plastic sample container.
    6. Complete sampling procedures in part (d) –(f).
  4. For Post-Harvest Samples in other forms (e.g., trimmed floral material, or floral material and stems, etc.):
    1. Ensure that the entire harvest is accounted for and in the same form (i.e., all harvested material must be uniform).
    2. Randomly collect at least one cup of material by volume.
    3. Place the complete sample in a paper bag or plastic containerand seal the container, as appropriate.
    4. Complete sampling procedures in part (d) –(f).
  5. A separate sample must be taken for each plot designated for Post-Harvest Sampling.
  6. Samples shall be labeled and prepared for transport to the lab.
  7. Label the sample container with a sample ID.

11

U.S. Hemp Guidance Program PHASE 2

1.4.6 Handling Procedures of Post-Harvest Samples

  1. The entire sample will be sent to the testing lab for analysis.
  2. Industrial hemp crops generated from Certified seed will incur pre-harvest testing of at least five percent (5%) of growing plots per variety, per seed source.
  3. Industrial hemp crops from planting materials other than Certified seed will incur pre- harvest testing of at least fifty percent (50%) of growing plots per variety, per seed source.
  4. 100% of post-harvest samples will be tested.



Historical Food and Supplement Adulterant List


Adulteration of food and agricultural materials has a long history. NaturPro has generated a list of references citing adulteration of food and dietary ingredients in recent times (publications in the past ~30 years).

Historical Food and Supplement Adulterant List

The intent of this list to promote awareness for historical adulterants in natural products. This list is for comprehensive and historical reference only.

Free Download:

 




Workshop on Product Testing at Supplyside

by NaturPro in Quality Comments: 0

2018 SUPPLYSIDE WORKSHOP — Effectively Partnering with a Contract Laboratory

Location: Lower Level, North Convention Center

Wednesday, November 7 | 1:30-4:30pm

  • NaturPro Scientific will be discussing common pain points (and reliable cures) to forging long-lasting client-lab partnerships. For example, many companies responsible for testing their product pay little attention to how the material is being tested, and whether the lab is using a scientifically valid method.
  • Miscommunication, lack of transparency, and insufficient lab QC practices can hamper the reliability and consistency of lab test results. Ultimately, product quality suffers.
  • Open communication, verification, and investment in testing of ingredients and finished products are critical factors of successful partnerships in many ways — the main being to prove the validity of test methods required by GMP, and ensure accurate and reliable results.
  • The business benefits of positive client-lab relationships are often reflected in key performance metrics such as fewer production delays and product recalls, and reduced testing expenses.

——————

About the Workshop:

The extensive range of requirements for testing—of ingredients and finished products—places a great burden on manufacturers to invest in their own laboratory facilities, or to select an appropriate contracted partner. Many companies do both, using internal resources for day-to-day operations and outsourcing higher cost tests or seeking independent validation of results. Understanding the steps involved in selecting the right laboratory partner to meet your needs, and managing that partnership over the long term, can lead to greater peace of mind and, ultimately, ensure you’re delivering the highest quality products to consumers.

  • Top considerations and questions for a contract laboratory partner
  • Ensuring your laboratory is compliant with all regulations—and that you’re covered
  • Determining the type of testing that can be accommodated in-house and what is best served by an outside partner.

Speakers:

  • Tara Couch, EAS Consulting
  • Blake Ebersole, NaturPro Scientific
  • Michael Hoard, Arizona Nutritional Supplements
  • Holly Johnson, AHPA
  • Aaron Secrist, NOW Foods

Underwritten By:

American Testing Lab

Eurofins

Micro Quality Labs




Good Manufacturing Practices (GMP) for Natural Products

by NaturPro in Quality Comments: 0

Scientific Publications on Natural Products, including Food, Medicine and Dietary Supplements: With a focus on Good Manufacturing Practices (GMP) for Natural Products, Quality Management Systems, and Good Agricultural and Collection Practices (GACP)

(Have a suggestion to add? Contact us!)

    1. A Field Guide to Herbal Dietary Supplements, AHPA-ERB Foundation, http://www.ahpafoundation.org/fieldguide.pdf
    2. A Harvester’s Handbook to Wild Medicinal Plant Collection in Kosovo (2003). Lonner J. and Thomas M. Source: http://www.gowildconsulting.com/wp-content/uploads/2011/02/harvesters_handbook.pdf
    3. AHPA-AHP Good Agricultural and Collection Practice for Herbal Raw Materials, December 2006. (Updated draft 2016)
    4. AHPA Botanical Identity References Compendium, http://www.botanicalauthentication.org/index.php/Main_Page
    5. AHPA Guidance Policies, http://www.ahpa.org/Portals/0/PDFs/Policies/AHPA_Guidance_Policies.pdf
    6. Aspects of sustainable wild plant collection (2012) Rodina K, WWF Hungary/TRAFFIC
    7. Biological Diversity Act 2002 (India)
    8. BRC’s Global Standard for Food Safety
    9. Canadian Herb, Spice and Natural Health Product Coalition (CHSNC) Good Agriculture and Collection Practices (GACP). Kehler C. Source: https://www.cotr.bc.ca/webs_media/Creston/_docManager/docs/Good%20Agricultural%20and%20Collection%20Practices(1).pdf
    10. Canadian Horticultural Council OFFS (CanadaGAP)
    11. Code of Good Agricultural Practices of Georgia (2007). Ministry of Agriculture of Georgia. Source: http://iwlearn.net/iw-projects/633/reports/aret-code-of-good-agriculture-practices-of-georgia
    12. Code of hygienic practices for spices and dried aromatic herbs. (2014) Codex Alimentarius Commission, CAC/RCP 42-1995
    13. Codex Alimentarius Commission Recommended International Code of Practice – General Principles of Food Hygiene CAC/RCP1-1969, Rev. 4 -2003
    14. Current good manufacturing practice in manufacturing, packaging, labeling or holding operations for dietary supplements (21 CFR 111)
    15. Current good manufacturing practice, hazard analysis and risk-based preventive controls for human food (21 CFR 117)
    16. Development of a Good Agricultural Practice Approach. November 5, 2003. Source: http://www.fao.org/prods/GAP/archive/GAPCONCEPT12_en.pdf.
    17. Development of Good Wildcrafting Practices and Wildcrafter Certification for Medicinal Plants. (2006) Howe A. Source:  http://www.bestlibrary.org/best_teachers/files/Wildcraftingfinalreport.pdf
    18. Dietary Supplement Ingredient Database, https://dietarysupplementdatabase.usda.nih.gov/
    19. Dietary Supplement Label Database, https://ods.od.nih.gov/factsheets/DietarySupplements-HealthProfessional/
    20. Dietary supplement laboratory quality assurance program: the first five exercises. Phillips MM, Rimmer CA, Wood LJ, Lippa KA, Sharpless KE, Duewer DL, Sander LC, Betz JM.  J AOAC Int 2011;94:803-14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173719/
    21. Dietary Supplement Online Wellness Library (OWL), Council for Responsible Nutrition (CRN), http://www.supplementowl.org/
    22. EFSIS Safe & Legal: https://www.saiglobal.com/assurance/food-safety/SafeandLegal.htm
    23. Ensuring the Compliance of Raw Herbal Materials stemmed from China with European Good Agricultural and Collection Practice. Philippe A. et al. Chinese Herbal Medicine, (2011) 3(4): 251-256
    24. FairWild Standard, Version 2.0 (2010).
    25. FairWild Standards Map. Source: http://search.standardsmap.org/assets/media/FairWild/English/AtAGlance_EN.pdf
    26. FDA Food Safety Modernization Act http://www.fda.gov/Food/GuidanceRegulation/FSMA/
    27. FDA Dietary Supplement Labeling Guide, http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm2006823.htm
    28. Field Techniques Used by Missouri Botanical Garden. Compiled by R. Liesner with suggestions from MO staff and others. Source: http://www.mobot.org/MOBOT/molib/fieldtechbook/pdf/handbook.pdf
    29. GAP Production of TCM Herbs in China (2010) Zhang B. et al. Planta Med 2010 76:1948-1955
    30. General guidelines for good agricultural practices: spices. International Organisation of Spice Trade Associations (IOSTA) (2013). Source: http://www.esa-spices.org/download/iosta-gap-final.pdf
    31. Global GAP, http://www.globalgap.org/uk_en/
    32. Good Agricultural and Collection Practices – Guidelines for the cultivation and collection of herbal medicines. (2012) Republic of Kenya.
    33. Good agricultural and collection practices for medicinal plants: Illustrated booklet for farmers and collectors. Source: http://www.dmapr.org.in/Downloads/Illustratedbooklet.pdf
    34. Good Agricultural and Wild Collection Practice (GACP) of Medicinal Plants in Europe, EUROPAM,( EHGA), c/o Veterinaerplatz, Vienna.
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Article: Dietary Supplements: Regulatory Challenges


Dietary Supplements: Regulatory Challenges and Research Resources

Johanna T. Dwyer, Paul M. Coates, and Michael J. Smith

Nutrients 2018, 10, 41; doi:10.3390/nu10010041 (Open Access)

Abstract: Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

Keywords: dietary supplements; food supplements; supplement science; scientific challenges; regulatory challenges; natural health product; complementary medicine; traditional medicines; National Institutes of Health; Office of Dietary Supplements

1. Introduction

The fundamental challenge in any discussion about the regulation of dietary supplements is that there is no global consensus on how the category of products known variously as dietary supplements, natural health products (NHPs), complementary medicines or food supplements in different countries is defined. For example, a product considered to be a dietary supplement and regulated as a food in the USA, in another jurisdiction may be considered a food supplement or a therapeutic good (complementary medicine) or a therapeutic good (prescription medicine) or potentially even a controlled substance. The situation is even more complicated when countries like China or India that have an existing regulatory framework for traditional medicine or phytomedicine that includes crude botanicals are considered. To add further to the confusion, many regulatory frameworks are changing.

Another challenge is that while all regulatory scientists want to protect consumers from harm, ensure that consumers have the ability to make informed choices about the products they use, and do the right thing, the scientific challenges and regulatory systems that have arisen to deal with them vary greatly from country to country. Even in countries with similar cultures, legal systems, and levels of economic development, regulations applying to dietary supplements vary considerably. Some of these differences are explored below, using examples from Australia, Canada and the USA, all English-speaking countries with largely similar cultures and legal systems to illustrate this point. The discussion of other countries with similar legal systems such as the United Kingdom, New Zealand and South Africa or other nations in the Americas, Europe, Africa and Asia, often with different cultures, legal systems, and levels of economic development is left for others with greater expertise and experience.

A final challenge is that “dietary supplement” health products are often very emotive and polarizing topics, evoking a diverse range of opinions and viewpoints. While some observers may contend that these products should be considered in a similar fashion to conventional drugs and foods, others believe that a more tailored approach is necessary since there is often a traditional or historical evidence base and products often contain multiple ingredients. Increasingly, this situation has become even more complex because of the lucrative nature of the global dietary supplement sector, increased involvement of a growing industry sector producing them, and the introduction of many new and innovative products onto the market. A detailed discussion of the politics of the subject is outside the scope of this paper. However, it must be recognized that politics may play both a positive and negative role in shaping both regulatory frameworks and research agendas. Irrespective of the reader’s point of view, this context is important in any discussion of dietary supplement products.

1.1. Importance of Research on Dietary Supplements

Until relatively recently, there was limited scientific research on dietary supplements and so little was known about them [1]. However, the prevalence of supplement use has increased dramatically over the past 20 years [2], and they have become a matter of consumer interest [3,4]. At the same time, the application of state-of-the art scientific methods to explore issues involving dietary supplements has advanced rapidly. The other invited articles in this special issue illustrate progress in our understanding of supplement science as it applies to several nutrients, including vitamin D, iron, omega-3 fatty acids, and iodine. Progress on botanicals and other non-nutrient ingredients (e.g., glucosamine, methylsulfonylmethane (MSM), coenzyme Q10) has been more challenging [5]. There is no global consensus in terminology for the category of products known variously as dietary supplements, NHPs, and food supplements in different countries and while we recognize this limitation, for the purpose of this article the term dietary supplement will be used to refer to such products as nutritional supplements, herbal medicines and traditional medicines. This article summarizes some of the scientific challenges in supplement research and some resources that may be useful in studying them. Most of the scientific challenges in supplement science are ubiquitous and global, so it is vital for scientists to collaborate across nations to help meet them without duplicating effort. A case study is provided by the work of the NIH Office of Dietary Supplements (ODS) which has been pursuing this goal since 2000. Some freely available resources and tools that ODS has developed for advancing health-related scientific knowledge on supplements are presented. The supplement marketplace is increasingly international, making collaboration between regulators essential since national decisions have international implications. Since products are consumed world-wide, calls for global quality standards are emerging. The remainder of the article focuses on regulatory challenges involving dietary supplements, and perspectives on how the regulatory systems in a number of different countries deal with them. Key resources for learning more about these approaches are provided.

1.2. Areas of Scientific Consensus about Supplement Science

Although there is broad consensus on the need for advances in science to make progress, opinions vary on the best paths to take and on priority areas for consideration.

1.2.1. Quality

The supply of ingredients used in supplements has outpaced the availability of methods and trained personnel to analyze them [6]. For example, in 1994, when the Dietary Supplement Health and Education Act (DSHEA) first became law in the USA, about 600 U.S. manufacturers of supplements were producing an estimated 4000 products. By 2000, more than 29,000 supplement products were on the US market but few documented analytical methods or reference materials (RM) were available for these products. This growth in the market has also been evident internationally. For example, there are anecdotal reports that over 100,000 product license applications have been approved in Canada since the Natural Health Products Regulations came into force in 2005. The need for improving quality continues today, since now there are estimated to be more than 85,000 supplement products in the US marketplace and concerns about ingredient misidentification, safety concerns, and quality assurance/control problems continue to be important for the industry and the public [7,8].

The first step in characterizing supplement products is generally identifying the ingredients [9]. Plant identification is a particular challenge. Even when easily identified whole plants or plant parts are used, unless the chain of custody is tight, and the exact manufacturing process is known and well characterized, the quality of extracts and blends such as those found in many botanical products is difficult to ascertain. Reliable analytical methods to characterize the bioactive components in supplements are helpful, but even for the nutrients in supplements, specific analytical chemistry methods must be often developed [10]. The bioactives in supplements differ from those in foods in their matrices in that the forms, combinations, and doses in which they are consumed, and the circumstances under which they are used are likely to differ. Analytical techniques for other bioactives in supplements are further complicated because the active compound(s) are often unknown, and even when they are known, validated analytical methods may not exist for determining their content. Reference materials are often unavailable to compare results between different laboratories for research purposes and to monitor data and supplement quality.

1.2.2. Safety

Manufacturers are prohibited from marketing supplement products that are unsafe or contain unsafe ingredients. This includes assuring that safe upper levels of intake for nutrients or maximum dosages for other constituents are not exceeded and ensuring that toxic contaminants are absent. Improved accuracy and precision of the nutrient measurements, bioactive marker compounds for other ingredients, natural toxins, toxic elements and/or pesticides in dietary supplement ingredients and finished products will be helpful to regulatory agencies.

1.2.3. Efficacy

Demonstration of efficacy typically depends on a number of research approaches ranging from basic in-vitro research on the mechanisms of action to animal and human studies. For example, in the past, large and expensive clinical trials using poorly characterized herbal supplement products for which the mechanisms of action were not understood were performed, leading to results that were inconclusive and irreproducible [11–13]. These experiences led publishers and funders to demand better product characterization and funders to demand more mechanistic evidence of bioactivity. Once mechanistic plausibility is established, animal and small phase 1 and phase 2 trials should precede the launch of large phase 3 studies of efficacy. More and better clinical studies of the safety and efficacy of dietary supplements on “hard” health outcomes are also sorely needed. Health outcomes such as changes in validated surrogate markers for performance, functions, morbidity, and mortality from diseases or conditions are required rather than changes in biochemical measures in blood with unvalidated surrogate markers. The question of the use of evidence from traditional forms of health and healing such as Traditional Chinese Medicine (TCM) makes the question of efficacy often more complex. This is briefly explored in the regulatory section below.

1.2.4. Translation of the Science

Widespread consensus exists on the need to translate the scientific evidence on supplements into appropriate recommendations, regulations, and policies that ensure the public health. Population-based prevalence estimates of supplement use are needed to estimate total exposures to nutrients or other bioactives that can be related to health outcomes [14]. Monitoring is especially important when supplementation is used as a public health strategy to fill nutrient gaps in deficient populations. It is also needed in other countries such as the USA where use of certain supplements is high, and where substantial proportions of total intakes of nutrients such as vitamin D and calcium come from supplements, especially among older adults [15].

2. Challenges and Resources: Regulatory Perspectives

As with other categories of regulated goods such as foods and drugs, the development of regulations is a balancing act where many different factors need to be taken into account. Notable among these are ensuring that products are of high quality and safe, that any claims made are truthful and not misleading, and that there is reasonable and appropriate access to the marketplace. All regulatory scientists want to both protect consumers from harm and support them in making informed choices about the products they include—or as importantly do not include—in their healthcare options. Appropriate regulatory oversight of this category is very challenging, and requires that scientists and regulators work together, as the former director general of the World Health Organization, Margaret Chan, MD urged [16]. This section provides a concise overview of how these regulations have been developed, and common themes as well as challenges faced in a global market.

2.1. Definition of “Dietary Supplements”

Although the definition of dietary supplement within a specific jurisdiction such as the USA is quite precise [17,18], a fundamental challenge to any discussion on regulation is that there is no global consensus on either what falls within this category or even what the category is called. Intuitively many equate a dietary supplement in the USA with a NHP in Canada or a traditional herbal medicine in the European Union or a complementary medicine in Australia, but this is not the case. For example, while melatonin is regulated in the USA as a dietary supplement and in Canada as a NHP, in Australia it is considered as a prescription medicine [19–21]. Dehydroepiandrosterone (DHEA) is readily available as a dietary supplement in the US, while in many other jurisdictions it is regulated as a controlled substance and is subject to significant regulatory oversight [22].

This situation is even more complicated when one considers that in addition to dietary supplements such as vitamins and minerals, many of these products come from traditional systems of health and healing such as TCM in China and Ayurvedic/Unani/Siddha medicine in India. For this reason, we must differentiate between the manner in which nations regulate the practice of medicine and the manner in which they regulate marketed products used in medical practice or as foods. In the U.S., the practice of medicine is regulated by the states, while marketed food and drug products in interstate commerce are regulated by the Federal government. Approaches and regulatory frameworks in many parts of the world, notably in Asia, reflect this fact with terminology and categories developed accordingly [23].

To assist in development of its Traditional Medicine Strategy 2014–2023, the World Health Organization refers to this category as Traditional and Complementary Medicines (T & CM) [16]. Although this classification does have significant limitations, it recognizes the fact that definitions for this category vary significantly globally. Descriptions of specific national/regional definitions and categories can be found through the list of resources in Table 1.

Health Canada
EU Parliament and Council
European Food Safety Authority (EFSA)
China Food and Drugs Administration (CFDA)
Health Ministry—Chinese Medicine Division
Food Safety and Standards Authority of India (FSSAI)
Ministry of Ayurveda, Yoga, Unani, Siddha and Homeopathy (AYUSH)
WHO World Health Organization
World Self Medication Industry
International Alliance of Dietary/Food Supplement Associations (IADSA)

While it would be easy just to consider that the substance itself is the defining factor in determining whether or not a product is a dietary supplement, this is not the case. Two other important factors considered are the claim that the product is making and how the product is supplied or recommended (intended use). In many jurisdictions such as the USA, Canada and Australia, dietary supplements are considered suitable for self-selection without the need for the intervention of a practitioner or prescription. Here the claims that can be made are limited to minor conditions and to the support of health and wellness depending on the jurisdiction [24,25]. In other jurisdictions, notably those where a traditional form of health and healing is recognized, traditional and complementary medicine products are often prescribed, and in some cases supply is limited only to trained practitioners.

2.2. Regulatory Models

As with the definition of the products themselves, there is no consistent global approach to regulation, with many different frameworks developed that largely reflecting national and regional priorities and needs. That being said, there are a number of common themes and approaches that have been taken internationally.

2.2.1. Where Does the Category Fall within Existing Legislation?

With a few exceptions, notably where traditional forms of health and healing exist, most countries do not regulate dietary supplements as a stand-alone category. Rather, they include them as a subset of existing legislation [17,18]. That is, they “hang from the hook” that is set in existing legislation. In the past, this was largely a question of whether these products should be considered a subset of drugs or foods; increasingly though, a third option is to capture them under existing regulations for biologics. It is important to note that overarching legislation is often one of the most important factors impacting the type of claim that can be made and what level of scrutiny and oversight will exist. For example, countries that regulate these products as a subset of drugs or therapeutic goods such as Australia, Canada and the European Union (EU) for traditional herbal medicines allow far more specific clinical claims to be made than in a jurisdiction such as the USA, where dietary supplements are captured in regulations under the existing food legislation, with their advertising regulated by trade regulations [20,25,26].

2.2.2. Should They Be Regulated as a Group?

As noted above in many jurisdictions dietary supplements are simply captured under the existing food or drug regulations and legislation with no specific consideration for these products, in some cases specific regulations have developed to reflect the category. In these cases, two different regulatory models have typically been adopted that reflect their domestic use, national priorities and public health needs. In many jurisdictions, the first model applies. Dietary supplements are simply captured under the existing food or drug regulations and legislation. In that model, a wide range of products (typically herbal medicines, traditional medicines and dietary or nutritional supplements) reside under an umbrella term such as dietary supplements in the USA, complementary medicines in Australia or NHP in Canada [20,24,25]. In the second model, specific regulations are developed to deal with these products. In this case, specific categories are developed with very structured regulatory frameworks for specific types of T&CMs. This is particularly the case in countries with a strong traditional form of health and healing such as Chinese proprietary medicines in China (TCM), Ayurvedic medicines in India and Kampo medicines in Japan [23].

Irrespective of the approach taken, it is rare that one set of regulations will encompass all products commonly considered to be dietary supplement-like. Typical examples of this are guidelines and legislation related to advertising that apply irrespective of whether or not a product is considered to be a dietary supplement.

2.2.3. Common Elements of Regulatory Frameworks

As with other forms of regulations, independent and irrespective of the approach taken, frameworks that deal with dietary supplements may contain a number of common elements, in this case often specifically developed to reflect the challenges and nature of the products. These common elements include: process for approval of a product to be sold; provisions related to manufacture and Good Manufacturing Practices (GMPs); reporting of adverse events; controls on labeling related to indications, contraindications and warnings; and, where claims are permitted, the type and quality of supporting evidence required. Again, the number and nature of these elements applied are determined by the specific regulations in place.

2.2.4. Risk-Based Approach

Operationally, the regulation of dietary supplements faces a number of issues and challenges not shared with conventional drugs or even food products. Notable amongst these are the sheer number of individual dietary supplements on the domestic markets, often numbering in the tens of thousands, and the fact that the sector contains many different types of products often posing very different risks that are grouped together often by the fact that they do not fit under any other regulatory regime. In particular, considerable challenges are posed especially by herbal and traditional medicine products that contain crude botanicals and a complex milieu of potentially active moieties, unlike conventional allopathic pharmaceuticals.

While a completely pre-market approach, where all products and manufacturing sites are ‘approved’ before the dietary supplement is marketed would be the optimal situation, given the challenges mentioned above, this is often impractical. This has led to the development of regulatory frameworks that increasingly blend elements looking at products and sites both before they come to market as well as once they are available to consumers, or post-market. This regulatory oversight is sometimes referred to as a “life-cycle” approach. Examples of post-market regulatory approaches (i.e., once the dietary supplement is on the market) include target audits where dietary supplements already on the market are analyzed for quality or manufacturers are requested to submit evidence they may hold that supports a specific claim. The determining factor on which approach is applied is largely determined by risk posed to the consumer. Since most dietary supplements when appropriately manufactured are considered to be inherently low risk, increasingly regulatory frameworks are increasingly focused more on post-market review than pre-market licensure.

Even in countries that are in many ways socially, economically and legally similar, different approaches to the definition and regulation of dietary supplement health products are evident although they contain some common elements. Illustrative examples of this are evident in the different regulatory frameworks in place in the United States, Australia and Canada.

In the United States, dietary supplements are regulated under the Dietary Supplements Health Education Act of 1994 (DSHEA) as a subset of foods and limited to those taken orally. This approach is primarily post-market in nature. However, it does contain pre-market elements. For example, manufacturers must hold evidence to support their claims and they cannot make specific disease treatment claims but only claims related to nutritional support (which includes physiological structure and function) [20]. All products must carry a disclaimer on the label stating that claims have not been reviewed by the US Food and Drug Administration (FDA). Provisions also include a post-market site audit process for manufacturing sites for Good Manufacturing Practice compliance and mandatory reporting of serious adverse effects by manufacturers. Companies must notify the Food and Drug Administration before marketing products with new dietary ingredients (NDI) [27]. There is at present no indication that DSHEA will be substantially changed or modified by Congress, in recent years the regulatory authority has given more attention to the notification and classification of NDIs as well as the importance of Good Manufacturing Practices (GMP) [20].

In Australia, although a small number of these products are captured by a food standard, most are regulated as therapeutic goods under the Australian Therapeutic Goods Act. Products are referred to as complementary medicines and are legally defined as being a listed therapeutic good or a registered therapeutic good. The legislation itself does not define these terms, but a comprehensive set of guidelines describes how they are considered. Most complementary medicines are listed medicines and are managed through an online portal called the Electronic Listing Facility (ELF). Permitted claims are limited to minor, self-limited considerations and those traditional forms of health and healing such as traditional Chinese medicine. Evidence for efficacy is assured through a random and targeted post-market audit system and new listable substances are evaluated pre-market. As with all registered therapeutic goods, registered complementary medicines are evaluated pre-market for safety, quality and efficacy. Manufacturers of either finished listed or registered complementary medicines must undergo an on-site audit to ensure GMP [28].

In 2014, complementary medicines were included within a comprehensive review of regulations for all therapeutic goods and medical devices to be conducted by an external expert panel [29]. The Commonwealth government accepted the majority of the recommendations from the panel and preliminary draft legislation was made public in September 2017. Although one of the recommendations was to keep complementary medicines as a distinct category, some significant changes are proposed, allowing mid-level claims through a new third regulatory route between the listed and registered therapeutic goods process as well as changes to how advertising is approved and compliance management [25,30].

In Canada, the majority of these dietary supplement products are referred to as natural health products (NHPs) and are considered a subset of drugs under a specific set of regulations—the Natural Health Products Regulations. Products must undergo a premarket assessment for safety, quality and efficacy. This is done in part through an online submission process with permissible claims supported by Health Canada monographs. Producers of NHPs who wish to make novel claims not supported through the monograph process must submit a full dossier of evidence for review. The products can make therapeutic claims, but their use is limited to self-care situations. While manufacturers are required to have a valid site license following approved GMP guidelines, no pre-market site audit is needed; the process being primarily paper based [24]. To address the growing number of NHPs sold in a food-like format, Health Canada has created a new category of food currently defined through regulatory policy called “supplemented foods”. The category does allow for some health claims, but they are limited reflecting the nature of the products [31].

Unlike Australia, Canada is proposing to take different approach and rather than keeping NHPs as a distinct category, will include them in a self-care health product category together with non-prescription medicines and cosmetics. The intent of this initiative is to support informed consumer choice through a more consistent regulatory approach to these product categories that is based on risk. Key questions being explored deal with topics including evidence needed to support claims, provisions ensuring safety and quality and introduction of cost recovery framework [32].

2.2.5. Competing Types of Evidence

While it is clear that high quality scientific evidence is always required to support the quality of a dietary supplement, from a regulatory perspective the same may not always be true with regard the type and nature of the evidence required to support a product claim. Given the nature of the dietary supplement sector and the fact that it often encompasses traditional medicines with a long history of use, the question faced by regulators is how to balance the need for robust scientific evidence with a respect for diverse forms of health and healing.

Globally, no consistent approach has been taken in answering this question. In some jurisdictions such as Canada and Australia, the approach has been to link the form of evidence, whether it be traditional or evidence based from scientific research, to the level and type of claim that can be made. In these cases, typically products based on traditional evidence making traditional health care claims are ‘approved’ according to pre-cleared and approved sources of information such as monographs or labeling standards. For products making higher level, clinical claims, in a way similar to that for conventional pharmaceuticals, companies must supply a full dossier with appropriate supporting evidence such as that from randomized controlled trials (RCTs) [24,28]. In many countries such as the United States with no pre-market approval framework system, claims that can be made are more limited [17,18]. In countries with long-established traditional forms of medicines such as in China, India, and Japan, specific regulatory frameworks have been developed for these types of products with the type of claim that can be made and the evidence required to reflect this approach [23].

As the dietary supplement sector matures and develops and the market for raw ingredients becomes more global, establishing a balance between evidence generated by scientific research and that coming from traditional forms of health and healing is becoming increasingly demanding. This will be discussed later.

2.3. Evolving Regulatory Landscape—Challenging Issues

International regulatory frameworks are still considered by many to be a new and novel sector, although many of them are now more than two decades old. They were developed to reflect a time when the sector and nature of the market, not to mention the needs and demands of the consumer, were very different. This has meant that some decisions made in the past around policies and regulatory decisions may need to be revisited. These include the need to evaluate evidence of the “grandfathering” of dietary supplements already on the market when new regulations were implemented, the need to ensure that approaches are sustainable through cost-recovery mechanisms and the more global nature of the market place. Table 1 provides links to some of the regulatory frameworks of different countries that provide insights into the ways issues are dealt with in them.

2.3.1. Evaluating Evidence for Product Claims

As the market for dietary supplements has increased, so has the amount and diversity of scientific evidence and research to support, or not support, their use. This market is made more complex when there are conflicting evidence bases and conflicting ways for evaluating them. For example, how, or should, traditional evidence be evaluated within the framework of traditional healing theories or those of allopathic evidence based medicine; what should be done when evidence from traditional forms of health and healing are not supported by more conventional evaluation mechanisms such as randomized clinical trials; and how can consumers, often wanting to explore both conventional and traditional medicine, be supported in making informed choices about including, or not including, these products in their health care options.

The original concept of Evidence Based Medicine is based on three basic premises—individual clinical expertise, the best external evidence and patients’ values and expectations [33]. The challenge faced by the regulator is to ensure that these are in play and to support consumers in making informed choices that are often made in a self-care setting.

2.3.2. Questions at the Regulatory Interface

It has never been easy to distinguish between a dietary supplement and other categories such as conventional foods, drugs and biologics. As all these sectors have evolved, this question of product classification has become even more complex. Two of the main questions at the regulatory interface are: what are the boundaries are between dietary supplements and conventional foods and between dietary supplements and over-the-counter drugs?.

As the popularity of dietary supplements available in a food-like format such as a pre-prepared drink or bar has increased, the line between what a consumer would understand to be a food as compared to a dietary supplement has become increasingly blurred. In essence, how does the regulator provide for appropriate regulatory oversight? This has been particularly challenging for those jurisdictions that consider these products as a sub-set of drugs with regulation and often legislation governing them that is very different from that for foods. In these cases, the regulatory frameworks are more specific to such dosage forms as capsules, tablets and tinctures. The challenge is one primarily of balance in providing a regulatory approach that is appropriate and not unnecessarily restrictive with the need to ensure that consumers are aware that these food-like dietary supplements that they are considering are not typical foods. This lack of clarity is also challenging for the private sector in determining what regulatory framework applies to a product, either food or drug, that they wish to develop and bring to market. In Canada, this concern required the government to create a new category called “supplemented foods” distinct from NHPs where products in a food like format are considered as a subset of foods and not as natural health products [31]. In other jurisdictions such as Australia, authority has been given to the respective regulators to deem something to be either a therapeutic good or a food based a specific set of criteria [34].

The challenge at the over-the-counter (OTC)/dietary supplement interface is even more pronounced. A number of herbal medicines with a long history of use within the conventional health care model, such as senna and cascara, are regulated in most countries as OTC drugs rather than dietary supplements. As described above, Health Canada is proposing to address this issue in part by considering both NHPs and OTC drugs within a single regulatory approach for self-care products [32].

2.3.3. Working on the Global Stage

Although science and research may be global, regulations are still made primarily to reflect domestic needs and pressures. This poses a challenge regarding dietary supplements and dietary supplement ingredients that are now often sourced and/or manufactured outside of the country where they are sold. In spite of calls for regulatory harmonization, examples of true harmonization are limited to regions such as countries in the Association of South East Asian Nations (ASEAN) with the lack of a coherent and consistent regulatory approach prohibiting this globally [35]. Even if regulatory harmonization is not possible, regulatory cooperation is often a viable option, taking into account inputs from stakeholder groups such as industry and not just governments. For example, to support cooperation between regulators, in 2005 in Ottawa, the World Health Organization supported the creation of the International Cooperation on Herbal Medicine (IRCH). IRCH now has over twenty members and provides a forum and mechanism for regulators to share information on safety issues and common challenges they all face [36]. Increasingly governments are working together as well as with other stakeholders such as industry and consumers to address common problems and in some cases to provide regulatory decisions in one jurisdiction that can be used as a basis for action in another.

2.3.4. Strengthening Product Quality

As the dietary supplement market has become more global and lucrative, so have the importance of ensuring product quality and the challenges in doing so. There are increasing numbers of cases of adverse reactions and some fatalities due to contaminants or adulterants in the product rather than in the dietary supplement ingredients themselves. In some cases this has been due to intentional fraud by producers of these poor quality products who have developed sophisticated methods for overcoming existing regulations and oversight. This situation is explored in greater depth elsewhere in this paper.

2.4. Need for Continued Science in Support of Regulation

Irrespective of whether the goal is to support production of high quality products or to develop, apply or modify methods for evaluation of evidence in support of claims, the need for robust and relevant science and research on dietary supplements has never been more necessary. As regulatory frameworks evolve, many of the questions posed above will need to be addressed, balancing the need for robust science with a respect for traditional forms of health and healing.

3. Challenges: Scientific Perspectives

3.1. Issues Involving Human Requirements

Scientists often disagree about definitions of human requirements for bioactives and the implications for supplements. They differ on whether some non-nutrient bioactives are required for certain population subgroups and also on the health effects associated with the use of non-nutrient bioactives. It has been known for over 100 years that inborn errors of nutrient metabolism exist that can be remediated by supplying the lacking nutrient that has become conditionally essential. However, it is not clear that such a model based on single gene defects is useful for the amelioration of multigenic complex diseases. It is unclear that there are large numbers of individuals with common diseases and conditions such as type 2 diabetes or depression whose unique genetic characteristics cause them to have special nutritional requirements requiring supplements or medical foods [37].

Discoveries of genetic polymorphisms and the advent of inexpensive genetic tests that are widely available to consumers have nutritional implications. They have led to the rise of personalized or “precision nutrition” [38] and to the proliferation of boutique “personalized” eating plans and “precision” dietary supplements supposedly tailored to an individual’s genetic profile. The extent to which such supplements are efficacious in reducing chronic degenerative disease remains to be determined.

3.2. Supplement Quality, Safety and Efficacy

Challenges remain on the appropriate means for assuring supplement quality, safety and efficacy.

3.2.1. Quality

Regulators, health professionals and manufacturers often disagree on how much quality testing is necessary for supplements. This is echoed by the World Health Organization’s Strategy on Traditional Medicines 2014–2023 [39] where quality is seen as a cornerstone of the sector. Botanical extracts and blends present particular challenges for detecting misidentification and contamination. The presence of adulterants and contaminants of both a biological and chemical nature in supplements is also challenging. Certain categories of supplements, such as athletic performance, sexual performance, and weight loss products, are particularly prone to the deliberate “spiking” with unlabeled extraneous or synthetic substances to confuse analytical techniques and even occasionally the addition of active synthetic drugs. Purity is a special problem for individuals with inborn errors of metabolism for specific nutrients such as vitamin B-6 or choline who require reliable, high quality sources of the nutrient. In countries that do not require that added nutrients be pharmaceutical grade or provide nutrients free to such patients, afflicted individuals must buy products that vary greatly in their quality on the open market.

The scientific challenges involved in all of the problems cited above depend in part on the adequacy and application of analytical methods. Analytical methods and reference standards are lacking for many of the thousands of different bioactive ingredients in dietary supplements. There is still disagreement about whether only a single officially endorsed method of analysis is acceptable. Any analytical method that is appropriately calibrated to a recognized reference standard should suffice but the onus is on the user of the method to demonstrate that affirmative requirements are met and that the method is suitable for its intended use and yields results that are accurate and precise. Methods that are suitable for foods may not be so for dietary supplements. Opinions also differ on whether government or the private sector is responsible for developing reference standards and analytical methods, and, if the private sector develops them, how they can be both kept independent and objective and made publicly available to avoid duplication of effort while preserving the marketing advantage of the developer. Tension also exists between researchers who desire ever more precise analytical methods for ingredients in dietary supplements and manufacturers who are concerned about the expertise and monetary costs required to apply some of the methods. A balance needs to be struck between the two.

3.2.2. Safety

Apart from concerns related to product quality, the safety of dietary supplements depends largely on dose. High doses of some nutrients are more likely to pose problems than others, although there is disagreement about the levels at which problems arise. For example, some dialysis patients who are receiving very large doses of calcium and the active form of vitamin D on a chronic basis may exceed the Tolerable Upper Level (UL) and incur adverse effects on health, including calcification of the soft tissues [40]. Very high doses of vitamin D may also cause adverse effects in people with normal kidney function [41]. There is little evidence that usual doses and forms of these nutrients give rise to health problems [42]. The possibilities of excessive intakes of nutrients from dietary supplements are greater in countries with programs to fortify their food supplies than in others, and therefore they must also be evaluated [43–46].

Dose-response data for establishing safe levels of intakes of non-nutrient bioactives in supplements is frequently lacking [47,48]. Some dietary supplements containing non-target herbs added intentionally (like germander as an adulterant for skullcap), or others such as black cohosh, kava extract, green tea and others have been associated with liver injures of various types even after taking into account concomitant use with acetaminophen and alcohol and consumption while fasting [49]. Extracts that are used in bodybuilding and weight loss have also been linked to liver injury. This has led to studies of the composition of different supplements [50,51]. Causes of liver toxicity from supplements appear to be due to insufficient regulatory authority, inaccurate product labeling, adulterants and inconsistent sourcing of ingredients [52]. There is controversy about whether evidence of causality is sufficient for regulators to take action against supplements that seem to pose a hepatotoxic risk [53]. Some possible actions include requirements for warning labels with usage instructions as is done for drugs, or/and removal of products from the market. Adulterated or fraudulent tainted products sold as dietary supplements are already illegal and subject to recall [54].

Interactions of some ingredients in supplements with other dietary supplements, nutrients, prescription or over-the-counter drugs are well documented. Of particular concern are adverse reactions occurring with commonly used medications, such as anti-hypertensive and cardiovascular preparations [55]. In addition, much interest focuses around concomitant use of herbal medicines such as St. John’s Wort which has been shown to alter drug metabolism of a number of drugs notably those used in the treatment of HIV/AIDS, warfarin, insulin, aspirin and digoxin [56].

3.2.3. Efficacy

Among the most hotly debated issues in supplement research is the type and amount of evidence needed to demonstrate the efficacy of dietary supplements. Many of the issues involving efficacy include those common in testing of all medications such as study designs, significance testing, appropriate outcomes, effect sizes, acceptable biomarkers of effect, and the differences between statistical and clinical significance. In order to be efficacious, dietary supplements must be bioavailable, and yet in some countries regulations do not require testing of supplements for disintegration and dissolution and some products on the market fail such tests. This is a matter of concern both to researchers and regulators since such results have a negative impact on studies of dietary supplement efficacy. In-vitro methods are available for testing disintegration and dissolution of drugs, and these are adaptable for use with dietary supplement products. Regulators in some countries insist on changes in health outcomes or in validated surrogate biochemical markers of effect on the causal pathway to a health or performance outcome. Others accept changes in intermediary biochemical markers that may or may not be surrogates of health outcomes. These considerations have come to the fore because supplements on the market in some countries apparently have little or no demonstrated efficacy. For example, one recent review of 63 randomized, placebo-controlled clinical trials of dietary supplements in Western adults found that in 45 of them no benefits were found, 10 showed a trend toward harm and 2 showed a trend toward benefit, while 4 reported actual harm, and 2 both harms and benefits; only vitamin D and omega 3 fatty acids had strong enough benefits and lack of harm to suggest possible efficacy [3]. This is an area of controversy that is highly polarized with questions being raised that depend on the type of dietary supplement being used, notably herbal medicines, the quality of the studies included in the review, and additional factors such as product quality of the supplement being evaluated that need to be taken into account [57].

3.2.4. Standards of Efficacy for Traditional Natural Products

The traditional use of Chinese medicines, Ayurvedic medicines and other remedies is embedded in larger healing systems and cultural or metaphysical beliefs that are part of users’ larger and more holistic world views. Should usual standards for efficacy should apply to them when they are used in the traditional manner? Clearly such uses are quite different than the use of a single product or ingredient at much higher traditional doses and without such a cultural context.

3.3. Policy

Although policy issues arise with all types of dietary supplements, the examples below will focus on nutrient-containing dietary supplements since these are particularly germane to discussions of nutritional status.

3.3.1. Nutrient Supplements Are Only One of Many Strategies for Improving Nutrient Intakes

There are many strategies for filling nutrient gaps in dietary intakes. They include nutrition education on appropriate food choices, fortification and enrichment that add nutrients to staple foods, genetic engineering that increases the nutrient content of a commodity itself either by genetic engineering/biotechnology, biofortification involving conventional breeding, and the use of nutrient containing dietary supplements. Dietary supplements provide concentrated sources of bioactives that are low or lacking in some individuals’ ordinary dietary intakes. The supplements can be used selectively by those whose diets have gaps in them. However, supplements have disadvantages. Their use depends upon individual motivations. Because they provide concentrated sources of bioactives at relatively high levels, they may increase the risks that some individuals will ingest excessive quantities and suffer health risks. Moreover, since dietary supplements can contain ingredients that lack a history of safe use, their long-term health effects may be unknown. The advantages and disadvantages of dietary supplements as a strategy to improve dietary intakes therefore must be carefully considered.

3.3.2. Supplementation as a Strategy to Achieve Nutritional Adequacy

The cost-effectiveness of using supplements to fill gaps in nutrient intakes as opposed to other means such as fortification or nutrition education varies from one nutrient to another and by country, and so each situation is unique and must be evaluated independently. There are also questions about what the supplement should be, if supplementation is chosen. In countries where nutrient containing dietary supplements are common, the use of multivitamin-multi-mineral (MVM) supplements is often associated with a greater proportion of the population reaching the estimated average requirement (EAR) for nutrients [58]. However, for some of these nutrients, intakes are already adequate, so that the increased intakes may do little good, and in some cases supplements may increase the risk of exceeding the upper safe level (UL) of intakes.

3.3.3. Monitoring of Supplement Use

Monitoring of supplement use is particularly important in countries where premarket approval is not required to detect potential adverse reactions. Dietary indicators are known to be imprecise and estimates of usual intake are lacking for many nutrients [59]. Biochemical indicators of deficiency are often not well linked with adverse health outcomes, underscoring the need for more attention to be paid to the development of agreed on measures of deficiency and excess [60]. Recent work on key nutrient biomarkers is now available, facilitating the monitoring of high risk groups, such as pregnant women for folate status [61,62].

3.3.4. Authoritative Recommendations for Dietary Supplements

Health and nutrition experts differ on whether it is appropriate to include recommendations for nutrient containing dietary supplements in national health promotion and disease prevention recommendations. Many countries opt to recommend that adequate nutrient intake for the general public be achieved solely from foods, and reserve recommendations of specific nutrient supplements for specific subgroups in the population. Others recommend only food alone with no recommendations for special populations.

3.3.5. Inclusion of Dietary Supplements in Food Programs to Reduce Malnutrition

There is pressure by industry to include MVM or other dietary supplements in food programs. However, there is little evidence that the target groups are deficient in the ingredients in the supplements, nor has it been demonstrated that provision of a supplement leads to better health outcomes.

3.3.6. Stimulating Innovation

The development of new and more highly bioavailable forms of the nutrients, timed release, dosage forms, novel bioactive constituents and the appropriate application of new technologies such as nanotechnology are all important, but some pose new scientific and regulatory challenges.

4. Case Study: Office of Dietary Supplements (ODS), National Institutes of Health (NIH), USA

This case study highlights some examples of dietary supplement research supported by or conducted at the ODS, and provides some research tools it has developed that may be useful resources for scientists both there and abroad.

4.1. Background

Since its establishment in 1995 as part of the implementation of the Dietary Supplement and Health Education Act [17,18] of 1994, the ODS is the lead federal agency devoted to the scientific exploration of dietary supplements. Its mission is to support, conduct and coordinate scientific research and provide intellectual leadership to strengthen the knowledge and understanding of dietary supplements in order to enhance the US population’s health and quality of life. ODS’s four goals are to: expand the scientific knowledge base on dietary supplements by stimulating and supporting a full range of biomedical research and by developing and contributing to collaborative initiatives, workshops, meetings and conferences; enhance the dietary supplement research workforce through training and career development; foster development and dissemination of research resources and tools to enhance the quality of dietary supplement research; and translate dietary supplement research findings into useful information for consumers, health professionals, researchers, and policymakers.

Several of its major initiatives that have expanded the scientific knowledge base on dietary supplements are described elsewhere in this special issue of NUTRIENTS. They include studies to clarify the implications for public health of omega-3 fatty acids [63], iodine [64], vitamin D [65], and iron [66].

4.2. Research Resources and Tools

This section provides the details on freely available research resources developed by ODS that are available for scientists to use to enhance the quality of dietary supplement research and meet public health priorities, with a focus on those that may be useful to scientists in other countries.

4.3. Analytical Methods for Dietary Supplements

The rigorous assessment of dietary supplement ingredients requires accurate, precise and reliable analytical methods and matching reference materials. The ODS Analytical Methods and Reference Materials program accelerates the creation and dissemination of validated methods and reference materials. It provides resources for characterization and verification of supplement product content that enhance the reliability and reproducibility of research using these products and supports product quality [67].

The genesis of the program was the paucity of publicly available methods for the analysis of supplement ingredients [68,69]. In 2000, the US dietary supplement community tended to use proprietary or compendial methods for quality control operations, and scientists and laboratories often kept their proprietary methods to themselves. Negative publicity about discrepancies between label claims and the results of product testing performed by third parties led to some unsuccessful efforts on the part of the industry to pay a laboratory to develop and validate methods through the Association of Official Analytical Chemists International (AOACI). The program was not successful for several reasons, including lack of expert technical guidance and conflicting sponsor priorities. However, this early effort led to a collaboration between trade associations, ODS, the AOACI, the United States Pharmacopoeia (USP), NSF International, and others in an attempt to establish standard methods for dietary supplement analysis. The ODS became involved because explicit wording in DSHEA required the Government to use “publicly available” analytical methods for enforcement actions involving dietary supplements. In response to the need for such publicly available methods and to support efforts to validate methods used in biomedical research on dietary supplement ingredients, ODS established the Analytical Methods and Reference Materials (AMRM) program in 2002.

ODS has been involved in sponsoring the creation of AOAC Official Methods of Analysis for dietary supplements and in the development and dissemination of numerous analytical methods and reference materials for 15 ingredients in dietary supplements in the USA, 32 botanical identification and documentation projects, and 45 studies determining contamination and adulterants. It has also helped to develop guidance on the validation of identity methods for botanical ingredients [70] and the conduct of single-laboratory validation studies for dietary supplements, Appendix K, AOAC Official Methods of Analysis, and provided guidance to evaluation of the literature on botanical supplements [71,72]. The portion of the ODS website includes a searchable database of analytical methods; these can be accessed at: https://ods.od.nih.gov/Research/AMRMProgramWebsite.aspx.

ODS also supports the Dietary Supplement Laboratory Quality Assurance Program in which participants measure concentrations of active and/or marker compounds and nutritional and toxic elements in practice and test materials. Exercises have included water and fat-soluble vitamins, nutritional and toxic elements, fatty acids, contaminants (e.g., aflatoxins, polyaromatic hydrocarbons (PAH’s)) and botanical markers (e.g., phytosterols and flavonoids).

4.4. Reference Materials

ODS supports the development of certified reference materials for dietary supplement ingredients with assigned values for concentrations of active and/or marker compounds, pesticides, and toxic metals to assist in the verification of product label claims and in quality control during the manufacturing process. A reference material is a material that is sufficiently homogeneous and stable with respect to one or more specified properties, which have been established to be fit for its intended use in a measurement process. A certified reference material (CRM) is a reference material characterized by a metrologically valid procedure for one or more specified properties, accompanied by a certificate that provides the value of the specified property, its associated uncertainty, and a statement of metrological traceability. Certified reference materials can be used for laboratory proficiency studies, methods development, method verification, and method validation studies. Calibration standards are the single chemical entities necessary for construction of calibration curves for quantitative analysis and for confirming analyte identity. Several processes are used to produce calibration standards. ODS provided funding to the U.S. Department of Commerce’s National Institute of Standards and Technology (NIST) for the development and distribution of calibration standard solutions and matrix standard reference materials (SRM®; a NIST-trademarked type of CRM). The materials fall into one of the following categories: (1) pure chemical entities or their mixtures, including many nutrients and other ingredients in dietary supplements for use in establishing analyte identity and for calibrating instruments; (2) natural matrix materials that represent the supply chain of a particular dietary supplement, e.g., biomass (ginkgo leaves and powder), processed botanical ingredient (ginkgo extract), finished product; (3) natural matrix materials that cover a range of analytes including nutritional compounds, botanical marker compounds, and compounds with known health concerns (heavy metals, pesticides, plant toxins); and (4) Clinical materials that can be used to assist clinical laboratories assess nutrient status or exposure, such as the measure of measure of vitamin D status commonly used around the world, serum 25-hydroxyvitamin D [73–75]. ODS is now expanding efforts to develop biomarkers of nutrient exposure and status in blood and other biological specimens in relation to chronic disease risk in individuals and populations. ODS has worked with NIST to produce and make available reference materials for calibration of various laboratory methods. Supplementary Table S1 shows NIST Standard Reference Materials (SRM®) now available. Supplementary Table S2 shows dietary supplement and nutritional assessment SRMs that are currently in progress.

4.5. Dietary Supplement Databases

Two databases have been developed by ODS that are described elsewhere in detail [76–80]. The goal of the Dietary Supplement Label Database (DSLD) is to include labels for virtually all dietary supplements sold in the USA. This provides all the information on the product label including composition, claims, and manufacturer contact information. It now contains over 72,000 dietary supplement labels, with new labels added at the rate of 1000 per month. Used together with food composition databases it is possible to estimate total daily intakes of nutrients and other bioactive ingredients from both foods and dietary supplements. A mobile version of DSLD is now available for use on smartphones to enhance consumer access to it [78,80]. It is primarily aimed at researchers and so contains information about products that are currently on the market, as well as those that have been removed from the market.

The Dietary Supplement Ingredient Database (DSID) provides analytically derived information on the amount of labeled ingredients of a representative sample of commonly used categories of supplement products sold in the USA, including adult, child and prenatal MVM supplements and omega-3 fatty acids. DSID is now being expanded to examine botanicals and other ingredients in supplements that are of public health interest, such as green tea products. Calculators included with the DSID permit a consumer to examine how closely the labeled contents of a nutrient in a product compare to chemical analyses of all products in the category [79].

4.6. Nutrition Research Methods and Review Methodology

Systematic reviews of dietary supplements require special techniques. ODS has sponsored a series of technical reports on the application of review methodology to the field of nutrition and dietary supplements [81–86]. Staff have also collaborated in performing systematic reviews with other groups [87,88].

4.7. Population-Based Monitoring of Dietary Supplement Use

In collaboration with the National Health and Nutrition Examination Survey (NHANES) of the National Center for Health Statistics, ODS investigates patterns of dietary supplement use using national and other large cohorts, and assesses supplements’ effects on total nutrient intakes. Several studies have focused on adults [89], children [90,91], and others in the population and their supplement use. Other studies have focused on the contributions to total intakes of nutrients made by dietary supplements. Investigators at ODS have been active in funding monitoring efforts on the links between intakes of folic acid and health [92]. They have devoted particular attention to blood levels of folic acid and dietary intake patterns that are associated with very low and very high intakes of the nutrient [93–95]. The survey methods used are well documented and they may be useful for those in other countries planning similar population-based surveys to consult [96].

The motivations for use of dietary supplements are also documented; they often differ from those specified in regulations. NHANES contains several items that are consumer tested and available for use in other surveys on motivations. Knowledge of motivations can improve understanding of how people use these products and may provide clues for encouraging appropriate supplement use.

4.8. Translation of Supplement Science for Health Professionals and the Public

ODS has produced and periodically updates a library of more than two dozen fact sheets on the ingredients in supplements such as vitamin D, magnesium, and special products such as MVM supplements and products marketed for weight loss. There is a detailed version for professionals that is complete with detailed references, as well as easy-to-read versions for consumers in both English and Spanish. ODS also works with the National Library of Medicine (NLM) to produce and update a Dietary Supplement Subset of NLM’s PubMed. The National Center for Complementary and Integrative Health (NCCIH) at NIH produces a series of fact sheets on many botanicals and other non-nutrient bioactives in supplements that are also useful. They can be accessed at https:

//www.nccih.nih.gov. ODS also hosts an intensive, free 3-day course on issues in dietary supplement research annually for researchers. Further information about these and other projects is accessible at:https://www.ods.od.nih.gov.

4.9. Other Resources

In order to foster the development of appropriate study methods for dietary supplement research, ODS sponsors workshops on the latest knowledge and emerging approaches to the study of dietary supplements. It also supports the development of cutting–edge approaches to elucidate the mechanisms of action of complex botanical dietary supplements. It co-funds the Centers for Advancing Research on Natural Products (CARBON) with the NCCIM, including its program to develop high content high throughput methods to rapidly generate hypotheses on active compounds and the cellular targets. These and other resources are announced as they become available on the ODS website.

4.10. Fostering Use of Systematic Evidence Reviews in Policy Making and Clinical Practice

ODS has strengthened the scientific framework for developing dietary recommendations by encouraging the incorporation of systematic reviews into the development of the DRI. It has sponsored 18 systematic reviews on topics related to dietary supplements. These include ephedra, B vitamins, MVM supplements, omega-3 fatty acids, soy, probiotics, and vitamin D. The ephedra systematic review was helpful to the US government in banning ephedra products from the US market. The systematic reviews of omega-3 fatty acids funded over a decade ago and more recent updates on their associations with cardiovascular disease and infant health outcomes have been useful for planning intervention programs as well as for regulatory purposes. Current AHRQ reviews are available on the AHRQ website (https://www.ahrq.gov).

5. Future Needs

Attitudes toward safety, efficacy, and values about what is important in food and life will be important in determining future needs involving supplement science in the countries we have discussed and perhaps elsewhere in the world. Safety is critical, and requires better chains of custody and product characterization that exists at present for these products, particularly those involving global markets. Efficacy, that is that the health promotion claims for the product are true and not misleading is also critical. Demonstrating efficacy requires clinical studies with well defined products and rigorous experimental designs, and the studies must be replicable. To that end, many publishers now require that submitted manuscripts comply with established guidelines for the reporting of clinical trial results (e.g., CONSORT guidelines), while funders require demonstration of product integrity by applicants [97,98]. Finally there are issues of personal choice and values, sometimes involving the efficacy of supplements as complementary and alternative therapies that are part of a larger philosophical or religious world views and systems. These must be accommodated without abandoning safety.

Both basic and more applied challenges will continue well into the future. Much remains to be learned about the effects of bioactive constituents such as flavonoids in foods and dietary supplements on health outcomes, as many recent papers in Nutrients and elsewhere indicate [99–101]. More and better biomarkers need to be developed and their associations with health outcomes clarified [102]. Supplements intended to enhance sports performance [103] botanicals used for disease treatment [104] and those ingredients thought to slow aging [105] all require identification of valid biomarkers of efficacy as well as of exposure. The role of supplements and the gut microbiome also must be explored for its associations with common diseases and conditions [106]. The associations between supplement ingredients and health outcomes in chronic degenerative disease must be clarified [47,105,107–109]. High risk groups need more attention Certain subgroups within the population such as athletes consume very high amounts of some supplements and it is important to monitor them to prevent adverse outcomes and study the effects, if any, on athletic performance [110]. Others use supplements in the hope that they will improve cognitive performance [103]. Those who practice polypharmacy with prescription, non-prescription drugs and dietary supplements represent another high-risk group, and interventions to limit the potential for adverse events are needed [111,112]. Collaborations among scientists in many countries are needed to drive supplement science forward.

Irrespective of the type of health product, high quality science is fundamental to the success of any regulatory framework. Assessments of the safety, quality and efficacy of nutrients and other bioactives are needed to provide the scientific information that regulators need [113]. As mentioned earlier, the nature and diversity of the sector means that regulators face a number of very specific challenges for these low risk products. These include evaluating traditional evidence, dealing with products that contain multiple bio-actives and addressing the growing challenges of ensuring product quality. It is critical that scientists and regulators work together and learn from each other in both identifying issues and developing ways in which they can be addressed. Although regulatory challenges must be met at the national level, there must be due regard paid to the fact that national regulatory decisions about supplements have global implications.

6. Conclusions

Science is vital in regulatory settings, and there is no reason that science and regulation should be incompatible [114]. The challenges in supplement science and its regulation provide new opportunities for scientists and regulators to work together both nationally and internationally, to learn from each other, and to cooperate and when appropriate harmonize approaches to improve the public health.

Supplementary Materials: The following are available online at www.mdpi.com/2072-6643/10/1/41/s1, Tables S1 and S2 Table S1 Standard Reference Materials (SRM®) available from the National Institute of Science and Technology, US Department of Commerce. Table S2 Dietary supplement and nutritional assessment Standard Reference Materials (SRM®) currently under development at the National Institute of Science and Technology, US Department of Commerce (as of December 2016).

Acknowledgments: Funded by the National Institutes of Health, Bethesda, MD, USA. We thank Joseph M. Betz, Leila Saldanha, Cara Welsh, for their thoughtful and critical reviews of the manuscript, and Joyce Merkel, for technical editing and support.

Author Contributions: J.T.D. and P.M.C. developed the concept for the manuscript. J.T.D., P.M.C. and M.J.S. wrote the manuscript.

Conflicts of Interest: Johanna T. Dwyer holds stock in several food and drug companies, and serves on the scientific advisory boards of Conagra Foods, McCormick Spices, and as a consultant for Gerber/Nestle. She accepted partial travel and per diem expenses to speak at a symposium on dietary supplements sponsored by the International Association of Dietary/Food Supplement Associations at the International Congress of Nutrition in Buenos Aires, Argentina in October 2017. Michael J. Smith holds stock in several food and drug companies as well as acting as a consultant with clients in both the private and public sector including companies in dietary supplement and natural health products sector. He sits on the scientific advisory board of ISURA and the advisory board of the American Botanical Council. Paul M. Coates reports no conflicts of interest.

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