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Herbal Products Resources

Resources for your further exploration of herbal products regulations in the US. 

 

Dietary Supplement Health and Education Act of 1994

The Dietary Supplements Health and Education Act of 1994 established the first comprehensive definition of dietary supplements as, legally equivalent to foods.  The legal definition of dietary supplements was determined to be a vitamin, mineral, herb/other botanical, amino acid, dietary substance for use by people to supplement the diet by increasing the total dietary intake, a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause.  DSHEA established the regulatory framework for dietary supplements and defined FDA’s authority over these products.  FDA is required, under DSHEA, to establish if a dietary supplement ingredient presents “significant or unreasonable risk of illness or injury.”  This mandates that the burden of proof of safety is up to the FDA, not the manufacturer of the product.  This means that there is no premarket approval process for dietary supplements and no post-market surveillance requirements.  However, new dietary ingredients need to be submitted to FDA as a notification of entering the market. 

New dietary ingredients (NDI), those not marketed prior to the passage of DSHEA in 1994, require manufacturers to notify FDA within 75 days of introducing a new dietary ingredient to market.  FDA does not approve these notifications, rather the agency will follow up if there are any questions and/or concerns regarding the notification.  Notifiers may market their products once 75 days have passed without any further FDA objection.  Dietary ingredients that were marketed prior to the passage of DSHEA in 1994, do not need to submit an NDI notification prior to marketing of the product.  

It is the manufacturers responsibility to provide FDA with relevant information that outlines the manufacturers determination that the dietary supplement ingredient will be safe.  This includes the history of use or any other evidence of safety which establishes that the dietary supplement ingredient will reasonably be expected to be safe under the recommended conditions.  Please click here (hyperlink Resources: Dietary Supplements-Herbal Products: Dietary Ingredients) for more information regarding FDA notifications and dietary ingredients.  

DSHEA also established good manufacturing practices that are specific for dietary supplements (21 CFR 111).  These practices were modeled off of food production practices, but are modified to specifically address the manufacturing of dietary supplements.   Please click here (hyperlink Resources: Dietary Supplements-Herbal Products: Good Manufacturing Practices) for more information regarding good manufacturing practices for dietary supplements. 

DSHEA also outlined the labeling and health claims requirements of dietary supplements.  

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Food Modernization Act (FSMA) 2011

The food safety modernization act of 2011 was drafted in response to rising cases of food borne illness in the US.  Through this legislation, FDA finalized seven major rules.  These rules translate the legislation into specific actions for each point in the global supply chain.  All of the rules were designed to reduce contamination of food products and make it easier to implement changes.  

The seven rules are as follows:

1. Preventive Controls for Human Food

Registered human food facilities in the US, must implement written hazard control plans with preventative controls.  

 

2. Preventive Controls for Animal Food

Registered animal food facilities in the US, must implement written hazard control plans with preventative controls. 

 

3. Product Safety

Defined minimum quality standards for growing, harvesting, packing, and storing produce.  

 

4. Foreign Supplier Verification Program

Imported food additives or food products need to verify that their global supplier complies with FDA regulations.  

 

5. Third-Party Certification

Accreditation to third party consultants and regulatory auditors to conduct audits in order to help companies prepare for regulatory audits.

6. Food Defense (intentional adulteration)

Registered food facilities in the US must develop and write a plan to assess contamination vulnerabilities and document potential mitigation strategies for each vulnerability. 

 

7. Sanitary Transportation

Outlined new requirements for the transport of food.  Includes shippers, receivers, loaders, and carriers of food products.  

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Food Safety Modernization Act (FSMA)

 

Notification of Ingredients 

DSHEA 1994, established that a dietary supplement is defined as containing one or more dietary ingredients.  According to section 201(s) and 409 of the FD&C (Food, Drug, and Cosmetic Act), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA; however, DSHEA clearly outlined that dietary ingredients could not be regulated as food additives.  This means there are no premarket approval requirements for dietary supplements, instead the legislation created two categories for dietary ingredients, “grandfathered” and “new dietary ingredients.”  Grandfathered dietary ingredients were marketed before October 15, 1994, everything else is considered a New Dietary Ingredient notification (NDI) and must submit a notification to FDA at least 75 days before marketing a new ingredient.    

 

Some herbal products are classified as general and/or conventional foods.  In that classification you might have food additives (instead of dietary ingredients) that are Generally Recognized as Safe (GRAS).  This determination is based on a safe history of use in food prior to 1958 or through consensus of qualified experts that safety is scientifically substantiated.  If you have an NDI notification for a dietary ingredient and your product is subsequently used as a food additive, an additional evaluation under GRAS is necessary.  If a substance is GRAS and is used as a dietary ingredient, you may not need to submit an NDI notification.

Generally Recognized as Safe (GRAS)

Some botanical products may be classified as general foods and not dietary supplements.  These products will need to conduct a safety review of their ingredients as food additives and not dietary ingredients.

Generally Recognized as Safe (GRAS) process was established under the Food Additives Amendment of 1958.  This amendment required manufacturers to test new food additives and file an additive petition with the FDA.  Under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (FD&C), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excepted from the definition of a food additive.

  

Manufacturers of general food products must either submit a GRAS notification to FDA for approval of their food additives, or self-affirm their GRAS notification.  A self-affirming GRAS notification is not submitted to FDA, but should be prepared to defend its GRAS status should FDA challenge the notification.  GRAS notifications must include a history of safe use which begins prior to 1958, and/or employ a qualified panel of experts to evaluate current scientific data regarding the additives safety.  

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FDA: About GRAS Notifications

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FDA: How U.S. FDA's GRAS Notification Program Works

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FDA’s Approach to the GRAS Provision: A History of Processes

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FDA Draft Guidance for Industry:

  • Regulatory Framework for Substances Intended for Use in Human Food or Animal Food on the Basis of the Generally Recognized as Safe (GRAS) Provision of the Federal, Food, Drug, and Cosmetic Act

 

New Dietary Ingredients (NDI)

DSHEA 1994, established that a dietary supplement is defined as containing one or more dietary ingredients.  According to section 201(s) and 409 of the FD&C (Food, Drug, and Cosmetic Act), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA; however, DSHEA clearly outlined that dietary ingredients could not be regulated as food additives.  This means there are no premarket approval requirements for dietary supplements, instead the legislation created two categories for dietary ingredients, “grandfathered” and “new dietary ingredients.”  Grandfathered dietary ingredients were marketed before October 15, 1994, everything else is considered a New Dietary Ingredient notification (NDI) and must submit a notification to FDA at least 75 days before marketing a new ingredient.    

 

Some herbal products are classified as general and/or conventional foods.  In that classification you might have food additives (instead of dietary ingredients) that are Generally Recognized as Safe (GRAS).  This determination is based on a safe history of use in food prior to 1958 or through consensus of qualified experts that safety is scientifically substantiated.  If you have an NDI notification for a dietary ingredient and your product is subsequently used as a food additive, an additional evaluation under GRAS is necessary.  If a substance is GRAS and is used as a dietary ingredient, you may not need to submit an NDI notification.

Dietary supplements are regulated as a food product, but their ingredients are excluded from premarket review and approval by FDA.  Instead, dietary ingredients fall into two categories: grandfathered or new dietary ingredients.  Dietary supplements which contain new dietary ingredients, those with no marketing history prior to October 15, 1994, need to submit a notification to FDA before marketing the finished dietary supplement product.  This notification is called the New Dietary Ingredient Notification (NDIN), requiring manufacturers to establish their scientific basis for considering their product to be safe under the recommended conditions of use.

  

NDIN submissions generally include ingredient identity information, a history of use, and safety testing data which usually includes a 90-day animal safety study and/or a clinical trial.   It usually takes around 70 days for FDA to review the submitted notification and provide a response.  If no response is received within 75 days of the submission you are assumed clear for marketing.  

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FDA Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues

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FDA Draft Guidance for Industry: New Dietary Ingredients in Dietary Supplements- Background for Industry 

 

Testing of Dietary Supplement Ingredients

According to US Federal Code, manufacturers are responsible for selecting the appropriate standards to test for identity, purity, and potency of dietary ingredients (21 CFR 111.70).  Proper testing of dietary ingredients should be the manufacturer's responsibility, not the supplier.  

When testing for the proper identification of a dietary ingredient, it is not sufficient to rely on Certificates of Analysis (COA) provided by the supplier.  The manufacturer of the finished dietary supplement will need to conduct at least one test which confirms the identity of the dietary ingredient.  

Identity testing of botanical raw materials (dietary ingredients) need to be scientifically valid, which can include macroscopic identification, microscopic identification, chemical testing (i.e. HPLC, TLC, GC, IR, FTIR), DNA (molecular) testing, or organoleptic testing.  It is highly recommended that multiple identity tests are utilized, to ensure 100% positive identification of your botanical raw materials (dietary ingredients).  

Standards for the identity, purity, and potency testing of dietary ingredients can come from published scientific journals, established monographs, or common industry practice.  Once a standard is identified, a specification will need to be developed which outlines the manufacturers expectation of the ingredients purity, strength, and composition. 

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National Center for Natural Products Research: Botanical Raw Material Identification and Authentication

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Sustainable Herbs Program: The Supply Chain: Quality Control

 

Good Manufacturing Practices-Dietary Supplements 21 CFR 111

Dietary supplement good manufacturing practices, apply to finished dietary supplements not the individual ingredients.  Although dietary ingredients are not included in cGMP, manufacturers are still accountable for the quality control of those materials.  According to US Federal Code, manufacturers are responsible for selecting the appropriate standards to test for identity, purity, and potency of dietary ingredients (21 CFR 111.70).  Current Good Manufacturing Practices (cGMP) are a system which ensures that finished products are consistently produced and controlled according to established quality standards.  Although cGMP for dietary supplements have been in place for over a decade, companies continue to struggle with compliance issues related to these regulations.  Some of the most common infractions on cGMP warning letters are, failure to establish and meet designated specifications, deficiencies in batch product records, deficiencies in SOP’s and quality control operations, and deficiencies with master manufacturing records.  These practices must be adhered to, otherwise FDA will deem your product adulterated and issue a Warning Letter (483) to your company.  

Some of the most common infractions on cGMP warning letters are, failure to establish and meet designated specifications, deficiencies in batch product records, deficiencies in SOP’s and quality control operations, and deficiencies with master manufacturing records.  For more information regarding best practices for good manufacturing, please refer to FDA’s Draft Guidance for Industry: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, found below. 

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FDA Draft Guidance for Industry: Small Entity Compliance Guide: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements

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FDA: Current Good Manufacturing Practices (CGMPs) for Food and Dietary Supplements

 

Good Agricultural and Collection Practices (GACP)

The overall quality of herbal products is highly dependent upon the quality of botanical raw materials used in the manufacture of the product.  Good Agricultural and Collection Practices (GACP) for medicinal plants is the first step in quality assurance of your herbal product.  Written and developed by the World Health Organization (WHO), GACP outlines quality controls that can be implemented to create quality assurance of the botanical raw materials used in herbal products. 

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WHO Guidelines on Good Agricultural and Collection Practices (GACP) for Medicinal Plants

 

Labeling and Claims (21 CFR 101)

Dietary supplements are considered food products and are not intended to diagnose, cure, mitigate, treat, or prevent disease in humans.  Botanical product companies need to ensure they are staying within the permitted claims of dietary supplements on their marketing, web-presence, labeling, and public communications.  The FDA and FTC work collaboratively in the regulation of dietary supplements.  The FDA has primary responsibility for claims on the products labeling, which includes the packaging, inserts, or other promotional materials distributed at the point of sale.  The FTC has primary responsibility for claims in advertising, which includes print and broadcast ads, infomercials, catalogs, social media activity, websites, and online marketing.  

Health Claims

There are several claims that are permitted by FDA: a health claim that describes a relationship between a food, food component, or dietary supplement and/or a reduction of risk of a disease or health-related condition (21 CFR 101.14), a structure/function claim which describes the impact of a dietary supplement on a structure of the body or bodily function (21 CFR 101.93), or a nutrient content claim which describes the relative amount of a nutrient or dietary substance in a product (21 CFR 101.54).  These claims must be adhered to, otherwise FDA will consider your product misbranded and issue a Warning Letter (483) to your company.  

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FDA Guidance for Industry: Structure/Function Claims: Small Entity Compliance Guide

FDA Guidance for Industry: Substantiation for Dietary Supplement Claims Made Under Section 403(r)(6) of the Federal Food, Drug, and Cosmetic Act

FDA Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims

FDA Guidance for Industry: Notification of a Health Claim or Nutrient Content Claim Based on an Authoritative Statement of Scientific Body

Labeling

Labeling is important in the regulation of your botanical product.  The label will distinguish your botanical product as either a general food or a dietary supplement. 

 

One way the labeling distinguishes this differentiation is with the implementation of a Nutritional Facts panel for a general food, or a dietary supplement with a Supplement Facts panel on your products labeling. Dietary supplement products also need to declare that they are a dietary supplement on the labeling.  

The following statement should be included:

“This statement has not been evaluated by the Food and Drug Administration.  This product is not intended to diagnose, treat, or prevent any disease.” 

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FDA: Dietary Supplement Labeling Guide: Chapter I. General Dietary Supplement Labeling

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FDA Guidance for Industry: Statement of Identity, Nutrition Labeling, and Ingredient Labeling of Dietary Supplements Small Entity Compliance Guide

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FDA Guidance for Industry: Food Labeling: Nutrient Content Claims; Definition for “High Potency” and Definition for “Antioxidant” for Use in Nutrient Content Claims for Dietary Supplements and Conventional Foods Small Entity Compliance Guide

 

Federal Trade Commission (FTC)

The Federal Trade Commission (FTC) monitors the advertising of health claims for dietary supplements.  The role of the FTC is to enforce laws which outlaw “unfair or deceptive acts or practices.”   The primary concern of the FTC is that advertising of dietary supplements is truthful, not misleading, and scientifically substantiated.

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Federal Trade Commission (FTC)

FTC Dietary Supplement Advertising Guide for Industry

 

Clinical Trials- Dietary Supplements

Often manufacturers of dietary supplements wish to conduct clinical investigations to scientifically substantiate their existing label claims.  It is important to understand that clinical investigations of dietary supplements do not validate the use of unauthorized health claims related to the diagnosis, cure, mitigation, treatment, or prevention of disease in humans.  Clinical investigations that aim to access an unauthorized dietary supplement health claim, will need to submit an Investigational New Drug (IND) application with FDA.  Otherwise, manufacturers are free to conduct clinical investigations for approved  dietary-supplement label claims without submitting  an IND application.  All clinical investigations of interventional products need to obtain Institutional Review Board (IRB) approval prior to initiating the trial. 

Dietary supplements, under DSHEA, are not considered a drug and are not subject to premarket review by FDA (i.e. an IND); this includes the clinical investigation of dietary supplements.  However, clinical investigations of dietary supplements need to adhere to acceptable health claims for dietary supplements in order to continue without submitting an IND to FDA.  To conduct a clinical trial as a dietary supplement, the clinical investigation needs to be designed to study a dietary supplement’s effect on the normal structure or function in humans or to characterize the mechanism by which a dietary supplement acts to maintain such structure or function. Without an IND, the primary endpoint of the study cannot support the dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent disease.  

Here are some examples: 

  1. The study of Hawthrone and its effect on the heart’s inotropic effect, would not need an IND

  2. The study of Hawthorne and its efficacy as a treatment for heart disease, would need an IND

  3. The study of Marshmallow root and its effect on bowel regularity, would not need an IND

  4. The study of Marshmallow root and its efficacy in the prevention of inflammatory bowel disease (IBD), would need an IND

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FDA Guidance for Industry: Investigational New Drug Applications (INDs)- Determining Whether Human Research Studies Can be Conducted Without an IND