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Food and Cosmetics Compliance Programs |
| FOOD AND DRUG ADMINISTRATION COMPLIANCE PROGRAM GUIDANCE MANUAL |
PROGRAM 7321.008 |
| SUBJECT:
DIETARY SUPPLEMENTS--IMPORT AND DOMESTIC (FY 02/03/04) |
IMPLEMENTATION DATE
UPON RECEIPT |
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| COMPLETION DATE
9/30/04
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| DATA REPORTING | |||||
| PRODUCT CODES | PRODUCT/ ASSIGNMENT CODES | ||||
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INDUSTRY CODE 54 USE APPROPRIATE PRODUCT CODES |
REPORT SAMPLE ANALYSIS UNDER THE FOLLOWING PACS:
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Note: Material that is not releasable under the Freedom of Information Act (FOIA) has been redacted/deleted from this electronic version of the program. Deletions are marked as follows: (#) denotes one or more words were deleted; (&) denotes one or more paragraphs were deleted; and (%) denotes an entire attachment was deleted.
FIELD REPORTING REQUIREMENTS
The following items must be forwarded, within the timeframes noted, to CFSAN/Dietary Supplement Monitor at the address listed below.
Within 30 days after completion of each inspection, forward:
Send the above information to:
Brenda K. Aloi
CFSAN/Food and Drug Administration (HFS-636)
*5100 Paint Branch Parkway
College Park, MD 20740-3835
Phone (301) 436-2065
FAX (301) 436-2657*
The term "dietary supplement" is defined in section 201(ff) of the Federal Food, Drug, and Cosmetic Act (the Act) as a product (other than tobacco), intended to supplement the diet, that bears or contains one or more of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract or combination of any ingredient described above. A dietary supplement is intended for ingestion in tablet, capsule, powder, softgel, gelcap, or liquid form, or if not intended for ingestion in such a form, is not represented for use as a conventional food or as a sole item of a meal or the diet and is labeled as a dietary supplement. *A dietary supplement also may not contain an article that is an approved drug or that is authorized for investigation as a new drug, and for which substantial clinical investigations have been initiated and have been made public, unless that article was marketed as a food or a dietary supplement prior to its approval as a new drug or authorization as an investigational new drug.*
The Food and Drug Administration (FDA) has the authority under section 402(g)(2) of the Act to promulgate current good manufacturing practice (CGMP) regulations for the dietary supplement industry. However, no CGMP regulations for dietary supplements have been promulgated to date.
The Dietary Supplement Health and Education Act (DSHEA) of 1994 established a framework for regulating the safety of dietary supplements. Dietary ingredients in, or intended for use in, dietary supplements are excluded from the definition of a "food additive." Therefore, deeming a substance *that is a dietary ingredient* to be an unapproved food additive is not an appropriate reason for recommending enforcement action against a dietary supplement. However, other ingredients in dietary supplements, that are not dietary ingredients within the meaning of section 201(ff)(1) of the Act (e.g., colors, flavors, technical additives, etc.), are still subject to the food additive provisions of the Act.
Section 402(f)(1) of the Act places the burden on FDA to prove that a dietary supplement presents a significant or unreasonable risk of illness or injury under the labeled conditions of use or that it contains a substance that may render it injurious to health (under section 402(a)(1) of the Act.
*
Section 413(c) of the Act defines a new dietary ingredient as a dietary ingredient that was not marketed in the United States before October 15, 1994. The manufacturer or distributor of a new dietary ingredient (or a dietary supplement containing a new dietary ingredient) must submit a premarket notification to FDA if the ingredient:
has not been present in the food supply as an article used for food; or
has been present in the food supply as an article used for food but has been chemically altered.
The notification must be sent to FDA at least 75 days prior to marketing the product. Failure of the manufacturer or distributor to file the notification may make the dietary supplement containing the new dietary ingredient adulterated within the meaning of section 402(f)(1) of the Act. The notification only applies to the manufacturer/distributor who submits the notice. For example, a different manufacturer who wants to use the same new dietary ingredient in its products must file its own notification. In addition, if a manufacturer/distributor wants to use the new dietary ingredient in a product different from the product filed previously, they must file an additional notification.
The Agency is concerned that some domestic and foreign manufactured dietary supplements may contain new dietary ingredients for which FDA should have received a premarket notification. Therefore, during each inspection, field exam, or import label exam conducted under this program, investigators must utilize the guidance provided in Part III concerning new dietary ingredients.
*
All dietary supplement products (with the exception of exempt products) labeled after March 23, 1999, are subject to the labeling *requirements of Title 21 Code of Federal Regulations Part 101.36 (21 CFR 101.36)*. Exemptions from the requirement for nutrition labeling include dietary supplement products manufactured by firms that meet the small business exemptions (21 CFR 101.36 (h)(1)(2), e.g., low volume products, and also products shipped in bulk (21 CFR 101.36(h)(3)(see ATTACHMENT E)).
Firms that believe they are entitled to an exemption from nutritional labeling for low-volume dietary supplement products for small businesses must file a notice claiming the exemption and provide the information necessary to verify their exempt status to the Center for Food Safety and Applied Nutrition/Office of Nutritional Products, Labeling, and Dietary Supplements (CFSAN/ONPLDS). The home district for the firm receives a copy of the firm's notice and ONPLDS' acknowledgement.
*Dietary supplements products in solid oral dosage form, e.g., tablets or capsules that contain added iron or iron salts for use as an iron source must bear a label warning statement (21 CFR 101.17(e)(1)). Adding iron and iron salts as iron sources to a solid oral dosage form product in an amount of 30 milligrams (mg) or more of iron per dosage unit triggers the requirement for unit-dose packaging (see 21 CFR 111.50 (a)).*
Compliance with the nutrition labeling requirements and other mandatory labeling requirements for dietary supplements will be determined through field exams and sample collections that will be limited to the following areas:
Non-exempt products that fail to bear a "Supplement Facts" panel on the label.
Products that fail to bear an appropriate statement of identity on the principal display panel.
*
Products that bear (a) a health claim or a nutrient content claim that has not been authorized by FDA; (b) a health claim that is not the subject of a letter granting enforcement discretion in response to the court decision in Pearson vs. Shalala (see ATTACHMENT J); (c) a nutrient content claim that is not appropriately based on an authoritative statement as provided for in section 403(r)(2)(6) of the Act; (d) or any health claim that appears to be based on an authoritative statement under the Food and Drug Administration Modernization Act (FDAMA). At this time, the Act does not provide for the use of health claims based on authoritative statements in the labeling of dietary supplements. See http://www.cfsan.fda.gov/~dms/hclmguid.html.
*
Products that bear authorized health claims or nutrient content claims, but fail to qualify for making the claims.
Products that bear nutrition labeling ("Supplement Facts" panel) with significant format deviations.
Products in solid oral dosage form containing 30 mg. or more of iron that are not packaged in unit-dose packaging.
Products in solid oral dosage form that contain iron or iron salts for use as an iron source that fail to bear the mandatory warning statement.
Products that fail to bear other mandatory label information.
*
Under section 403(r)(6) of the Act, a dietary supplement may bear certain claims, generally called structure/function claims, on its label or in its labeling provided that the firm has substantiation that: the claim is truthful and not misleading; the firm has notified FDA within 30 days of marketing the product bearing the claim; and the claim includes a mandatory disclaimer. At the present time, we are not asking that label claims be examined to determine if they contain the disclaimer because there are unresolved policy issues regarding the use of the disclaimer and, therefore, it is premature to examine whether the required disclaimer is properly used in accordance with 21 CFR 101.93. If a structure/function claim is an unauthorized health claim under either FDA regulations or 403(r)(3)(C), then it would fall under Area of Emphasis No. 3 above.
The Agency will, on a case-by-case basis, consider enforcement actions against products that bear egregious disease claims or structure/function claims that may be unsubstantiated. Investigators should review claims made for dietary supplements on labels or in labeling. Products that bear inappropriate disease claims or that appear to bear egregiously false or misleading structure/function claims should be referred to CFSAN for evaluation.
On April 30, 2001, an intercenter agreement was implemented between CFSAN and the Center for Drug Evaluation and Research (CDER) that outlines a working agreement between the two Centers that assigns lead Center status for the regulation of certain products that bear structure/function and/or disease claims. Districts should review this agreement at http://www.cfsan.fda.gov/~dms/ds-inter.html and be prepared to submit cases against products that bear inappropriate disease or structure/function claims to the appropriate Center based on the guidance contained in the agreement.
The preamble to the final rule that published on January 6, 2000
(65 FR 1000)--Regulations on Statements Made for Dietary Supplements Concerning the Effect of the Product on the Structure or Function of the Body, provides important background and rational for the Agency's policies related to structure/function and disease claims issue. Districts may want to refer to CFSAN's website at http://www.cfsan.fda.gov/~dms/sclmguid.html for industry guidance prepared in accordance with section 212 of the Small Business Regulatory Enforcement Fairness Act. This guidance restates in plain language the legal requirements set forth in the January 6, 2000 regulation concerning labeling claims for dietary supplements.
By letter dated November 14, 2000 (ATTACHMENT A), FDA recommended that firms that manufacture or import dietary supplements and their ingredients containing bovine tissues, including extracts or substances derived from such tissues, take whatever steps are necessary to assure that such ingredients do not come from cattle born, raised, or slaughtered in countries where bovine spongiform encephalopathy (BSE) exists or from countries that do not have controls adequate to detect or control its occurrence. BSE is a fatal transmissible spongiform encephalopathy similar to Creutzfeldt-Jakob disease in humans. BSE continues to be prevalent in Europe and several other areas.
NOTE: Although ATTACHMENTS A and B contain a list of tissues to assist investigators in identifying potential ruminant-derived ingredients, the lists are not intended to identify all ruminant-derived ingredients about which the Agency has concerns. Unless explicitly stated, any ruminant-derived tissue or ingredient from a BSE country should be considered a possible risk.
On February 9, 2001, The United States Department of Agriculture's (USDA's) Animal and Plant Health Inspection Service (APHIS) further prohibited the importation into the United States of certain edible ruminant products from BSE affected or at risk countries. FDA supported the APHIS prohibition by issuing Import Bulletin (I.B.) #99B-14 to require that FDA entry review be done to determine whether products offered for entry contain ingredients subject to APHIS prohibition. The Agency believes that immediate and concrete steps should be taken by manufacturers to reduce the potential risk of human exposure to, or transmission of, the agent that causes BSE.
The Agency believes that manufacturers and importers of dietary supplements and their ingredients should have planned, systematic procedures in place to provide assurances to themselves and to consumers that ruminant-derived tissues do not come from animals in countries where BSE occurs. An example of one such procedure would be the receipt of a certificate from the supplier that certifies that the ruminant-derived tissue came from a herd that is BSE-free.
Inspections under this compliance program will include completion of the questionnaire (ATTACHMENT C) to determine whether the firm being inspected is aware of the Agency's concerns about the transmission of BSE as outlined in the November 14, 2000 letter, and whether the firm has procedures in place to provide assurance that ruminant-derived tissues do not come from countries where BSE exists.
*
Note: Numerous import alerts and bulletins pertaining to dietary supplement ingredients have been withdrawn since the inception of DSHEA. Districts must refer to the FDA Import Alert Retrieval System (FIARS) for an up-to-date index of applicable import alerts and bulletins. Districts should contact the Division of Import Operations and Policy (DIOP), HFC-170, to determine the current status of an applicable import alert or bulletin.
The objectives of the program are as follows:
To conduct inspections under 21 CFR 110--Current Good Manufacturing Practices (CGMPs) in Manufacturing, Packing, or Holding Human Food at domestic manufacturers of dietary supplements.
To gather information during these inspections on dietary supplements containing selected dietary ingredients (as identified in Part III).
To collect and analyze a limited number of domestic and domestic-import samples of dietary supplements of vitamins, minerals, and proteins to compare label declarations to the nutritional composition of the product.
To conduct field exams to determine compliance with the nutrition labeling ("Supplement Facts" panel) and other labeling requirements that are now in effect for all non-exempt dietary supplement products.
INTERACTION WITH OTHER PROGRAMS
Include coverage of this program during inspections conducted under CDER's Drug Process Inspection Compliance Program when it is determined that the firm manufactures both drugs and dietary supplements. Use the appropriate CFSAN and CDER Program Assignment Codes (PACS) when reporting time for these inspections.
PROGRAM MANAGEMENT INSTRUCTIONS
To use the planned resources effectively, CFSAN has established priorities for selecting firms to be inspected and dietary supplements to be collected for analysis.
CFSAN's ONPLDS and Division of Enforcement and Programs (DEP) may be contacting selected districts during the year to arrange for ONPLDS personnel to accompany field investigators during routine inspections conducted under this program. A first hand knowledge of the firms comprising this industry and the manufacturing practices employed by these firms will be invaluable to ONPLDS headquarters personnel for rulemaking regarding dietary supplements.
A. Planning Instructions
As a guide to the districts in selecting firms to be inspected, DEP can provide each district with a print-out listing the known dietary supplement manufacturers in each district. Contact Brenda K. Aloi, CFSAN/DEP at *(301) 436-2065* if you would like the print-out for your district.
B. Select firms for inspection in the following order of priority:
Firms producing both dietary supplements such as botanicals (e.g., ginseng, yohimbe), animal and plant extracts (e.g., garlic extracts and inert glandulars), fats and lipid substances (e.g., oil of evening primrose, fish oils, essential fatty acids) and also producing dietary supplements such as vitamins, minerals, and proteins;
Firms producing dietary supplements such as botanicals (e.g., ginseng, yohimbe), animal and plant extracts (e.g., garlic extracts and inert glandulars), fats and lipid substances (e.g., oil of evening primrose, fish oils, essential fatty acids) but not producing any dietary supplements of vitamins, minerals, or proteins; and
Firms producing only dietary supplements of vitamins, minerals, or proteins.
The above prioritization scheme, because of its focus on firms manufacturing "non-traditional" products, may not result in sufficient products that meet the threshold for sample collection and analyses under the program, i.e., products which contain # of the Reference Daily Intake (RDI) or Daily Reference Value (DRV) of a vitamin, mineral, or protein. Districts should attempt to meet their workplan obligation for sample collections by collecting appropriate samples from other establishment types visited for purposes of conducting field exams (see C below).
C. Field Exams
In order to meet Workplan obligations, field exams may be conducted:
During the inspections planned and conducted at manufacturers, provided the firm applies the finished product label;
At firms that pack products into different containers, provided they are not bulk containers; or
At warehouses or distributors of finished products.
Note: No inspections at the above establishment types, other than at manufacturers, are planned or necessary to perform the field exams and sample collections that are planned separately in the Office of Regulatory Affairs' (ORA's) Workplan.
D. Label Exams for Import Products
*Districts should refer to CFSAN's internet cite at http://www.cfsan.fda.gov/~ear/sbellist.html for a list of exempt firms before conducting label examinations*. All products manufactured by those firms meeting the requirements for an exemption are exempt from nutrition labeling required by 21 CFR 101.36.
Products subject to detention without physical examination due to "Supplement Facts" panel labeling violations will be listed in Import Alert 99-20, *"Automatic Detention of Imported Food Products Due to NLEA Violations,"* which is accessible in FIARS.
*
E. New Dietary Ingredients
Section 413(c) of the Act defines a new dietary ingredient as a dietary ingredient that was not marketed in the United States before October 15, 1994. A manufacturer or distributor of a new dietary ingredient must submit a premarket notification to FDA (21 CFR 190.6(a)) if the ingredient:
has not been present in the food supply as an article used for food; or
has been present in the food supply as an article used for food but has been chemically altered.
The notification must be sent to FDA 75 days prior to marketing of the product. If a dietary supplement containing a new dietary ingredient is marketed without this required notification, it may be deemed adulterated within the meaning of section 402(f)(1) of the Act.
The Agency is concerned that some domestic and foreign manufactured dietary supplements may contain new dietary ingredients for which FDA should have received a premarket notification. Therefore, during each inspection, field exam, or import label exam conducted under this program, investigators will follow the guidance provided in Part III to identify and follow-up on new dietary ingredients.
*
a) If the firm appears to be following drug CGMPs in the manufacturing of their dietary supplement products, note in the EIR, and still conduct a CGMP inspections under 21 CFR 110 at each firm scheduled for inspection.
b) If inspectional evidence discloses insanitary conditions, issue a FDA 483 to the firm. In addition to samples collected to document the insanitary conditions, if the investigator observes any of the conditions outlined below, collect an official physical sample, and all available evidence documenting the suspected deficiencies and submit as exhibits with the EIR. Include documentation of interstate commerce.
Review several records of analyses, when available, for any product having nutrients declared as being present # of the RDI or DRV. Compare the results with label declarations. If the firm has not had nutrient analyses performed on its own products, determine the firm's method for assuring the accuracy of the nutrient declarations on the product label.
Determine if vitamins used for enrichment are stored in a cool place and protected from light. Improper storage as well as age of the vitamin enrichment material may result in a loss of potency.
Determine if the firm's quality assurance (QA) procedures ensure that the balances used for weighing enrichment materials are calibrated and are of a sensitivity that is adequate for the amounts being weighed.
Review quality control procedures, especially any relating to control of mechanisms regulating continuous addition of nutrients to a processing line.
If elemental iron (such as reduced iron, carbonyl iron, or electrolytic iron) is added for enrichment (rather than a compounded form of iron, such as ferrous sulfate), determine if the firm's processing lines contain magnets for removal of foreign objects. If the elemental iron is added before the product reaches the magnets, the magnets may remove the iron from the product.
*
Coverage of Ruminant Tissue and Tissue-Derived Ingredients
The questionnaire (Attachment C) was developed to determine the following at each firm inspected:
a) Whether the firm manufactures or imports products containing ruminant tissue or tissue-derived materials;
b) Whether the firm has procedures in place to ensure that it does not receive ruminant tissues from BSE-countries; and
c) The origin of all ruminant tissue or tissue-derived ingredients used by the firm and the products containing them.
Upon completion, a copy of the questionnaire (Attachment C) must be mailed or faxed to the CFSAN contact listed at the beginning of this compliance program.
Additional documentation for possible regulatory follow-up is required only when a firm is manufacturing or importing dietary supplement products or their ingredients containing any ruminant tissues or tissue-derived ingredients from a BSE affected or at risk country (See ATTACHMENT A).
Investigators must refer to I.B. #99B-14 and USDA's regulation 9 CFR 94.18--Restrictions on importation of meat and edible products from ruminants due to bovine spongiform encephalopathy--prior to conducting inspections to obtain the most recent list of BSE affected or at risk countries.
Document the following for possible regulatory consideration by CFSAN. Forward the requested information along with the Establishment Inspection Report (EIR) to CFSAN/Case Processing Branch (HFS-607):
the tissue or tissue-derived ingredients being used;
the finished products containing them;
the specific country of origin of the tissue; and
the name and address of the importer or other responsible party.
*
Collection of Product Labels and Completion of *Attachment D*
CFSAN has concerns about the ingredients listed below. The labels and/or information requested on *ATTACHMENT D* is necessary for the Center to determine the conditions of use of the products containing the ingredients and the levels of the ingredients. The information will allow CFSAN to adequately evaluate the possible health risks, if any, presented by the products and formulate appropriate policies for addressing the risks.
a) For each separate product manufactured by the firm that contains one or more of the following added ingredients, collect an original (or quality copy) of the label.
*
|
Common Name |
Latin Binomial Name |
|
aconitum (aconite root, monkshood, friar's cap, helmet flower, soldier's cap, wolfsbane) |
Aconitum spp. |
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Androstenedione nor-androstenedione androstenediol nor-androstenediol |
|
|
chaparral (creosote bush, greasewood hediondilla, tarweed, sonora gum) |
Larrea spp. |
|
Chinese cucumber, Chinese snake gourd, compound Q, gua-lou, tian-hya-fea |
Tricosanthes spp |
|
dehydroepiandosterone (DHEA) |
|
|
dogbane (indian hemp) figwort |
Apocynum spp. Scrophularia spp. |
|
germander (Woodsage) |
Teucrium spp. |
|
indian snakeroot |
Rauwolfia spp. |
|
kombe |
Strophanthus spp. |
|
penny royal |
Mentha pulegium, L. and Hedeoma pulegioides L. |
|
puncture vine |
Tribulus terrestris |
|
synthetic ephedrine alkaloids Ephedrine HCl, pseudoephedrine HCl, phenylpropanolamine and related substances |
|
|
vitamin A > 25,000 IU/day |
|
|
vitamin D > 2,400 IU/day (60 micrograms/day) for adults; > 1800 IU/day (45 micrograms/day) for infants under 1 yr.) |
|
|
vitamin B6 >200 mg/day |
|
|
yohimbe (only if it contains yohimbine HCl as an ingredient) * |
Pausinytalia yohimba |
Note: For purposes of collecting the labels, any product that represents a different product form (tablet, capsule, extract); strength (500 mg, 400 mg); formulation (different ingredients or different levels of ingredients); or a different brand name for the product, constitutes a different product.
For firms that are packaging the same product under multiple brand names, select a representative label and provide an estimate of the different brand names under which the product is sold.
b) In addition to the product label, for any product containing one or more of the above added ingredients, if the label does not list the ingredient/levels complete *ATTACHMENT D* attach to the EIR, and submit to CFSAN.
In determining whether to collect a product label or include a product containing one of the nutrients listed above with a level, e.g., vitamin B6 > 200 mg/per day, on *ATTACHMENT D*, calculate the recommended per day consumption as strength *(or level of the specific nutrient) x recommended amount consumed per day. If the calculated amount is greater than or equal to the listed level, include the product on ATTACHMENT D.*
Since the above ingredients and their levels may not be listed on product labels, whenever possible document their presence through review of product formulation or through discussions with firm management in order to complete *ATTACHMENT D*.
*
Although the Act does not specifically require management to furnish formula information for dietary supplements, this information should be requested. If quantitative formula information is refused, try to obtain the qualitative formula. If all formula information is refused, attempt to reconstruct formula by observing: a) product in production, 2) batch cards or formula sheets, and 3) raw materials and their location. Record refusals should be noted on the FDA 481(a) and discussed in the narrative of the EIR.
*
Investigators must use their judgment, based on the firm's level of cooperation, in determining whether to pursue the levels of other ingredients present in the product. These other ingredients are important as they may be involved in synergistic reactions, however, priority should be given to obtaining information on the selected ingredients noted above.
*
New Dietary Ingredients
There is no authoritative list of dietary ingredients that were marketed in dietary supplements before October 15, 1994. Therefore, manufacturers and distributors are responsible for determining if an ingredient is a "new dietary ingredient" and, if not, for documenting that a dietary supplement that contained the dietary ingredient was marketed before October 15, 1994. Once the manufacturer or distributor determines that the ingredient is a new dietary ingredient, and that it is reasonably expected to be safe under the labeled conditions of use, they must file the appropriate notification with CFSAN/ONPLDS. The specific information that must be included in this notification as well as general industry guidance can be found at http://www.cfsan.fda.gov/~dms/ds-ingrd.html. CFSAN/ONPLDS will acknowledge its receipt in writing and may contact the firm again if the notification is lacking in information or if they have questions or concerns.
The home district for the firm filing the notification will be provided with a copy of these CFSAN/ONPLDS communications and a list of the filings will also be included at the above website. Prior to conducting an inspection or field exam under this program, the investigator must review the firm jacket as well as the information contained at the above website. However, do not rely solely on the information in the firm jacket or the website.
While at the firm, the investigator should ask the firm if they have filed any new dietary ingredient notifications with the Agency and if so, the investigator should review a copy of the firm's notification against the actual finished product label to verify the following:
If while conducting the field exams (label examinations) directed below, the investigator finds any product that contains the above new dietary ingredient but was not included in the above notification(s) or any product(s) containing what they believe to be new dietary ingredients for which the firm has not filed proper notice, these products are subject to documentary sample collection and further follow-up as discussed under Part V of this program.
*
Products shipped in bulk form, not distributed to consumers in such form, and used in the manufacture of other dietary supplements are exempt from the requirements for nutrition labeling ("Supplement Facts" panel) *(21 CFR 101.36(h)(3))*.
*Firms that have filed a small business exemption notice with CFSAN will be issued an acknowledgement letter. A copy of each acknowledgement letter will be sent to the home district for the firm. Investigators must review the firm jacket prior to conducting inspections to determine whether the firm has been issued an acknowledgement letter from CFSAN. Investigators must verify the firm's status with firm management after issuing the FDA 482, but prior to conducting any field exams. Do not conduct field exams in firms that are exempt from compliance.*
*Investigators conducting import entry reviews should refer to http://www.cfsan.fda.gov/~ear/sbellist.html for a list of exempt importers and brokers before conducting label examinations.*
NOTE: A nutrient content claim, a health claim, *a claim pursuant to section 403(r)(6) of the Act, or any other statement about the nutrient content or benefits of the product (other than ingredient statements)* on a dietary supplement label negates the exempt status of the product and triggers the requirement for nutrition labeling ("Supplement Facts" panel).
Specific questions about the exempt status of a domestic firm, importer, or broker should be directed to *Wanda Kelker, CFSAN/ONPLDS/Division of Compliance and Enforcement (DCE)(HFS-820), (301) 436-2371*.
NOTE BEFORE CONDUCTING FIELD EXAMS AND LABEL EXAMS:
Areas of Emphasis Nos. 6 and 7 below concern labeling and packaging requirements for iron-containing dietary supplements. Enforcement actions will be based on the failure of products to be properly packaged or labeled as outlined below. However, the Agency must have a means to determine the level of industry compliance with the requirements, i.e., how many total products are subject to the requirements. At this time, we are requesting that investigators assist us in accumulating this baseline data by identifying and tabulating all products that are subject to the requirements as outlined under Areas of Emphasis 6 and 7. Specifically, how many products are in solid oral dosage form and contain 30 mg. or more of iron and how many products contain any amount of added iron.
This information must be reported separately in the EIR as a percentage statement, for example: "Firm manufactures or distributes XXX total products containing 30 mg. or more of iron, of which XX products (or XX%) are packed in unit-dose packaging." or "Firm manufactures or distributes XXX total products containing added iron, of which XX products (or XX%) bear the required warning statement."
Review the label of 2-3 non-exempt products labeled on or after March 23, 1999.
The following label violations will be the focus of the field exams and label reviews (Refer to Attachment F for additional guidance and examples of these violations).
Areas of Emphasis
Products that fail to bear nutrition labeling, i.e., the absence of "Supplement Facts" on the label, and the product is not covered by an exemption.
Products that fail to bear an appropriate statement of identity on the principal display panel, i.e., use of the term "dietary supplement" or *"________supplement", with the blank filled in with the name of the dietary ingredient or a term appropriately descriptive of dietary ingredients in the product (21 CFR 101.3(g))*.
*
Products that bear (a) a health claim or a nutrient content claim that has not been authorized by FDA; (b) a health claim that is not the subject of a letter granting enforcement discretion in response to the court decision in Pearson vs. Shalala (see ATTACHMENT J); (c) a nutrient content claim that is not appropriately based on an authoritative statement as provided for in section 403(r)(2)(6) of the Act; (d) or any health claim that appears to be based on an authoritative statement under the Food and Drug Administration Modernization Act (FDAMA). At this time, the Act does not provide for the use of health claims based on authoritative statements in the labeling of dietary supplements.
See http://www.cfsan.fda.gov/~dms/hclmguid.html. for guidance. in recognizing such claims.
*
Products that bear authorized health claims or nutrient content claims that do not qualify for making the claims.
Products that bear nutrition ("Supplement Facts" panel) labeling with significant format deviations (21 CFR 101.36).
Products distributed in solid oral dosage form containing 30 mg. or more of iron but fail to be packaged in unit-dose packaging (21 CFR 111.50).
Products in solid dosage form with added iron that fail to bear the required warning statement (21 CFR 101.17(e)(1)).
Products that fail to bear other mandatory label information.
*
Under section 403(r)(6) of the Act, a dietary supplement may bear certain claims, generally called structure/function claims, on its label or in its labeling provided that the firm has substantiation that: the claim is truthful and not misleading; the firm has notified FDA within 30 days of marketing the product bearing the claim; and the claim includes a mandatory disclaimer. At the present time, we are not asking that label claims be examined to determine if they contain the disclaimer because there are unresolved policy issues regarding the use of the disclaimer and, therefore, it is premature to examine whether the required disclaimer is properly used in accordance with 21 CFR 101.93. If a structure/function claim is an unauthorized health claim under either FDA regulations or 403(r)(3)(C), then it would fall under Area of Emphasis No. 3 above.
The Agency will, on a case-by-case basis, consider enforcement actions against products that bear egregious disease claims or structure/function claims that may be unsubstantiated. Investigators should review claims made for dietary supplements on labels or in labeling. Products that bear inappropriate disease claims or that appear to bear egregiously false or misleading structure/function claims should be referred to CFSAN for evaluation.
On April 30, 2001, an intercenter agreement was implemented between CFSAN and the Center for Drug Evaluation and Research (CDER) that outlines a working agreement between the two Centers that assigns lead Center status for the regulation of certain products that bear structure/function and/or disease claims. Districts should review this agreement at http://www.cfsan.fda.gov/~dms/ds-inter.html and be prepared to submit cases against products that bear inappropriate disease or structure/function claims to the appropriate Center based on the guidance contained in the agreement.
The preamble to the final rule that published on January 6, 2000 (65 FR 1000)--Regulations on Statements Made for Dietary Supplements Concerning the Effect of the Product on the Structure or Function of the Body, provides important background and rational for the Agency's policies related to structure/function and disease claims issue. Districts may want to refer to CFSAN's website at http://www.cfsan.fda.gov/~dms/sclmguid.html for industry guidance prepared in accordance with section 212 of the Small Business Regulatory Enforcement Fairness Act. This guidance restates in plain language the legal requirements set forth in the January 6, 2000 regulation concerning labeling claims for dietary supplements.
Edible Ruminant Products from BSE Affected or At Risk Countries
Refer to the guidance contained in I.B. #99B-14. Be alert for shipments subject to the APHIS prohibitions covered by this import bulletin. Refer such entries to USDA/APHIS Plant Protection Quarantine (PPQ) Headquarters via the fax back form to 301-734-8538.
New Dietary Ingredients
Refer to the guidance contained at http://www.cfsan.fda.gov/~dms/ds-ingrd.html to identify entries containing possible "new dietary ingredients." Contact Felicia Satchell, CFSAN/OPNLDS, Division of Standards and Labeling Regulation at (301) 436-2371 if in doubt as to the status of an ingredient.
Entries of new dietary ingredients or dietary supplements containing new dietary ingredients should be recommended for detention by the import district.
*
Collect a compliance sample with interstate documentation if warranted based on inspectional observations as outlined above in III A.1.
Documentary samples collected under Area of Emphasis Nos. 1, 2, 3, 5, 6, 7 and 8 will generally consist of the label only; no physical sample is required.
NOTE: When the configuration of the container makes it difficult to determine the total amount of label space available to bear labeling it will be necessary to collect the actual container along with the label. Collect one (1) product container along with the four (4) original product labels.
Compliance Samples
a) Areas of Emphasis Nos. 1, 2, 3, 5, 6, 7 and 8
(i) Collect a sample of any product that appears, on the basis of the field exam or label exam to be violative under one or more of the above Areas of Emphasis.
Import lots sampled for a violation under one of the above areas must be held pending compliance review.
(ii) The sample will consist of four (4) original labels (and one product container, if warranted) for the product being sampled. This is a documentary sample only; no physical sample is required. Prepare a Collection Report (C/R) for each potentially violative product label collected and mark as "Documentary" in the Sample Type field.
(iii) Indicate "Compliance" in the Basis field of the C/R. Under Reason for Collection indicate "Label Review Only."
(iv) Send the sample to your compliance branch for label review, sample classification, and regulatory consideration.
b) Area of Emphasis No. 4
In order to make authorized health claims or nutrient content claims, products must meet certain nutritional requirements. For example, to make a claim "High", "Rich in", or "Excellent Source of", the product must contain # or more of the Daily Value (DV) of the described vitamin, mineral, dietary fiber or potassium per reference amount (21 CFR 101.54(b)).
*Investigators should refer to the charts on CFSAN's website for nutrient content claims (relative or comparative claims) at http://www.cfsan.fda.gov/~dms/flg-6b.html and health claims at http://www.cfsan.fda.gov/~dms/flg-6c.html to determine if the amount of the nutrient listed on the nutrition label qualifies the product to make the claim. Analysis may be necessary to verify the level of the nutrient and a physical sample must be collected.*
(i) Collect a compliance sample of any product that appears to be violative under Area of Emphasis No. 4.
(ii) Because of the analytical time required to document a violation in this area, sample imported lots as follows:
After reviewing the entry documents for a shipment, DO NOT issue a May Proceed Notice or Sampling Notice immediately. Leave the entry in OASIS and conduct a field exam to determine whether the product meets the criteria for sampling. If the product appears to be violative under Area of Emphasis No. 4, collect the sample. After returning to the district office, issue the May Proceed Notice. Enter the sample into FACTS as a DI sample.
The sample will consist of 24 consumer size retail packages, 2 packages from each of 12 randomly selected shipping cases or 10 percent of the number of packages in the same inspection lot (collected in duplicate), whichever is smaller.
(iii) This sample size includes the 702(b) portion. Number the subsamples as 1a, 1b, 2a, 2b, etc., to separate the units for analysis from units that comprise the 702(b) portion.
(iv) Prepare a Collection Report (C/R) for each sample collected and mark as "Official" in the Sample Type field.
(v) Indicate "Compliance" in the Basis field of the C/R. Under Reason for Collection indicate "For insert Nutrient(s) forming the basis for the claim analysis."
2. Surveillance Samples
a) Collect for routine nutrient analysis only those vitamin, mineral, and protein supplements or combination vitamin/mineral supplements that have at least one nutrient declared on the label # of the Reference Daily Intake (RDI) or Daily Reference Value (DRV).
b) If inspections do not generate sufficient samples to meet district workplan obligations domestic and domestic-import surveillance samples may be collected at the retail level. Limit sampling to products that have been manufactured within the collecting district so that follow-up compliance sampling with interstate documentation may be conducted, if necessary.
c) In selecting samples for collection, consider factors which might result in lower nutrient quality, such as age of product (sample oldest lot) and effect of light on some nutrients (sample product in transparent packages when appropriate).
d) Do not sample products that are expired or are within six months of their expiration dates. This will allow sufficient time for analysis and regulatory consideration if the sample is found violative.
e) Do not collect dietary supplements of herbals, botanicals, animal extracts, etc. for nutrient analysis unless the product also contains a protein, vitamin, or mineral with a label declaration of # of the RDI or DRV. Refer to *ATTACHMENT G* for a list of nutrients and their established RDI or DRV levels.
f) Each sample must represent a single manufacturing lot code. Do not commingle lots within a sample.
g) Except in cases involving a serious adverse event or an imminent health hazard, do not routinely collect samples in follow-up to consumer complaints without first calling *Clinical Review Team Leader, Division of Standards and Labeling Regulations, Office of Nutritional Products, Labeling and Dietary Supplements, CFSAN at (301) 436-2371*.
Surveillance Samples: Collect 3 units (each unit must contain a minimum of 12 servings) of the product. For example, 3-2 lb tins; 3-100 tablet bottles; 3-30 capsule packets; 3-12 bar packages. The sample must represent a single lot code. Contact Atlanta Center for Nutrient Analysis (ACNA) at (404) 253-1181 if necessary for additional guidance on sample size.
Compliance Samples: Collect in duplicate--twelve (12) or 10% of the number of packages available in the same inspection lot whichever is smaller. Do not commingle codes.
Ship all samples to:
Southeast Regional Laboratory (HFR-SE680)
Atlanta Center for Nutrient Analysis (ACNA)
60 Eighth Street, N.E.
Atlanta, GA 30309
(404) 253-1181
NOTE: Notify ACNA by phone when compliance samples are collected and provide all shipping information so that arrangements can be made to expedite sample analysis.
Fully explain the reason(s) for collection on the Collection Report (C/R). For compliance samples, this would include a brief description of the inspectional observation(s)which resulted in collection, e.g., improper enrichment procedures, improper storage of raw material. For samples collected for health claim or nutrient content claim analysis, i.e., area of emphasis 4, indicate the suspect nutrient forming the basis for the health claim or nutrient content claim. Send a copy of the C/R to ACNA along with the sample.
NOTE: For compliance samples, make certain that the C/Rs are flagged "COMPLIANCE SAMPLE - ANALYZE UPON RECEIPT."
Compliance samples should be shipped to ACNA using overnight delivery service.
All documentary samples collected in support of violations under Areas of Emphasis 1, 2, 3, 5, 6, 7, or 8, *and those containing suspected new dietary ingredients* should be forwarded to the district's compliance branch for a label review and sample classification. Label reviews must be reported into FACTS and each sample that undergoes a label review must be classified.
The following items must be forwarded, within the timeframes noted, to CFSAN contact listed below.
Within 30 days after completion of each inspection, forward:
*a copy of the "Summary of Findings" for each inspection*;
all labels collected according to instructions in Part III;
a completed *Attachment D*; and
the questionnaire on BSE (Attachment C).
Send the above information to:
Brenda K. Aloi
CFSAN/Food and Drug Administration (HFS-636)
*5100 Paint Branch Parkway
College Park, MD 20740-3835
Phone (301) 436-2065
FAX (301) 436-2657*
Atlanta Center for Nutrient Analysis (ACNA), HFR-SE680.
A. Analysis
Label Review
The label of each sample will be reviewed for compliance with 21 CFR 101.9, 101.36 and other applicable labeling requirements.
For the reviewer's convenience, a model review format is provided as *Attachment H*. Use *Attachment H* for recording observations only DO NOT submit to the Center.
Nutrient Analyses
a) Do not perform nutrient analyses on samples containing more than one manufacturing lot code. Notify the collecting district to re-sample if this occurs.
b) For compliance samples collected for nutrient analysis in support of an unqualified health claim or nutrient content claim, analyze only for the suspect nutrient. Otherwise:
Select for analysis ONLY those nutrients that are declared as being present # of the RDI or DRV.
With the above criteria in mind, select a maximum of four (4) nutrients per product, giving first priority to the following nutrients: Vitamin A/Beta Carotene, Selenium, Folic Acid, Pantothenic Acid, or Vitamin C.
For any remaining analysis, select those nutrients declared at the highest percentages of the RDI or DRV at or #. In the case of "ties", randomly select from among the "ties" nutrients for the last selection.
c) Perform analyses for the selected ingredients as follows:
Compliance Samples--Prepare a composite by taking equal portions from each subsample. Use either the "a" or the "b" subsamples. For tablets, capsules, or caplets take a minimum of 2 units per subsample. For other dosage forms, use equal measured amounts from each subsample. The composite should contain an amount of analyte sufficient to perform several determinations. A separate composite shall be prepared by the check analyst for all check analyses. Retain the remaining sub-samples as the 702(b) portion.
Surveillance Samples--Sample portion for original analysis should be taken from a single subsample. For tablets, capsules, or bars, composite a minimum of 12 servings, e.g, 12 tablets, capsules, bars, etc. provided that the serving size is 1 tablet, capsule, bar, etc.. For liquids or powders, take an appropriately sized (equal to 12 servings) analytical portion from a well-mixed subsample. Another subsample unit will be used for the check analysis if necessary. Additional subsample units will remain intact.
Analyze the composite by methods contained in the AOAC, USP or National Formulary, as applicable and appropriate. Use of methods contained in one of these compendials must take precedence over use of other methods. If AOAC, USP, or National Formulary methods are not available, then use of an appropriate validated method from the scientific literature or from in-house work is appropriate. Agency policy mandates that compendial methods must be considered before non-compendial methods are considered.
d) All methods used whether compendial or non-compendial, must be validated through the use of recovery and reproducibility studies, use of positive and negative controls, use of Standard Reference Material, when available or in-house quality assurance/quality control materials, etc.
Use of in-house quality assurance/quality control samples is suitable for QA/QC purposes only when adequate documentation of the origin, age, handling (storage procedures), composition, frequency of analysis and results of analysis, etc. is readily available.
e) For nutrients labeled as USP, the appropriate USP analytical method shall be used for analysis.
f) Randomly select vitamin or mineral supplements, labeled as meeting USP requirements, for dissolution/disintegration testing using current USP methodology. Priority should be given to calcium supplements then folate/folic acid supplements, and then other appropriate supplements. This testing is not mandatory and the laboratory should use its discretion in determining when and how many samples to select for dissolution/disintegration testing within the constraints of the available resources.
g) Perform a check analysis on any apparently violative sample (Refer to Part V). The check analysis should be performed by a second analyst using an official AOAC method, a USP method where designated, or one approved by the Center.
CAUTION: Do not allow the sample to "age" as many nutrients deteriorate and some minerals precipitate with time. Vitamins A and C break down when improperly handled. Begin original analysis and check analysis (if necessary) as soon after compositing as possible.
h) When requested by the Center to support compliance actions, analyze samples labeled with a dietary fiber content using the *current edition of the AOAC, Ch. 45, Method 985.29, 991.42, 991.43, or 993.19* whichever is appropriate.
i) Contacts for questions on methodology, levels, significance of findings, are as follows:
Dr. Jeanne Rader CFSAN/ONPLDS/Division of Science and Applied Technology at (301) 436-1786 for all questions except those related to metals/minerals.
Metals/Minerals--William Mindak at *(301) 436-2005* or Steven Capar at *(301) 436-2003, CFSAN/OPDFB
Analytical Reporting
ACNA will report all samples classified as violative based on nutrient analyses to the compliance branch of the collecting district for appropriate regulatory follow-up.
Report all analytical results into FACTS using Problem Area Flag "NIF" (Infant Formula). The use of PAF "NIF" is necessary so that the following additional analytical information, not captured in PAF "NIS" will be entered:
a) the complete product name, including brand name, in the product description field;
b) the use by date; and
c) the lot or other batch identification number.
Upon notification by ACNA of potentially actionable samples, the following guidance should be used in assessing the significance of the analytical results and in recommending an appropriate regulatory action to CFSAN/DEP.
*The Agency established supplemental "Procedures for Clearing FDA Warning Letters and Untitled Letters," dated March 5, 2002. This document is available on FDA's Office of Regulatory Affairs' website at http://web.ora.fda.gov/oe/warningletters/TRKLET116R.doc.*
Note: Warning Letters and seizure recommendations should not include labeling deviations that are not of regulatory significance *(see Attachment F for guidance on the types of labeling deviations that would be considered not of regulatory significance)*.
District compliance branches must refer to *Attachment F* for additional guidance and examples of each of the violations listed below. Refer to *Attachment I* for standard language to be included in Warning Letters.
Areas of Emphasis Nos. 1, 6, and 7
Districts may issue Warning Letters directly to firms whose product(s):
fail to bear nutrition labeling and are not exempt; or
are in solid oral dosage form containing 30 mg or more of iron but are not packaged in unit-dose packaging; or
*are in solid oral dosage form and* contain added iron or iron salts but do not bear a warning statement.
This direct reference authority applies only to product labels which are violative in one or more of the above areas, but are not violative in any other area of emphasis or in other mandatory labeling information. Regulatory recommendations against product labels that are also found violative in one of the other areas of emphasis noted below must be handled as indicated below.
The Office Nutritional Products, Labeling, and Dietary Supplements (HFS-810) must be included on the distribution list for these letters. A copy of these direct reference Warning Letters must be immediately faxed to CFSAN/OC/DOE/Domestic at *(301) 436-2716*.
Areas of Emphasis 2, 3, 5, 8
fail to bear an appropriate statement of identity on the principal display panel, i.e., use of the term "dietary supplement" or *"____ supplement" with the blank filled in with the name of the dietary ingredient or a term appropriately descriptive of dietary ingredients in the product*; or
*
bear (a) a health claim or a nutrient content claim that has not been authorized by FDA; (b) a health claim that is not the subject of a letter granting enforcement discretion in response to the court decision in Pearson vs. Shalala (see ATTACHMENT J); (c) a nutrient content claim that is not appropriately based on an authoritative statement as provided for in section 403(r)(2)(6) of the Act; (d) or any health claim that appears to be based on an authoritative statement under the Food and Drug Administration Modernization Act (FDAMA. At this time, the Act does not provide for the use of health claims based on authoritative statements in the labeling of dietary supplements. See http://www.cfsan.fda.gov/~dms/hclmguid.html. *
bear nutrition labeling ("Supplement Facts" panel) with significant format deviations; or
fail to bear other mandatory labeling information.
*
The Agency will, on a case-by-case basis, consider enforcement actions against products that bear egregious disease claims or structure/function claims that may be unsubstantiated. Products that bear inappropriate disease claims or that appear to bear egregiously false or misleading structure/function claims should be referred to CFSAN for evaluation.
*
Regulatory recommendations for Areas of Emphasis 2, 3, 5 and 8 must be submitted to CFSAN/OC/DOE/Domestic Branch (HFS-607) for review and concurrence prior to issuance. Include three (3) original product labels and, if appropriate, the product container with each recommendations.
*
When an import sample is determined to be violative in Areas of Emphasis 1, 2, 3, 5, 6, 7, or 8, districts should detain the entry. In addition, the district must submit a Recommendation For Detention Without Physical Examination (DWPE) to ORA/DIOP (HFC-170). Follow the criteria stated in the Regulatory Procedures Manual (RPM) Chapter 9, Subchapter--Automatic Detentions-to place a firm/product on Import Alert 99-20 - "Automatic Detention of Imported Food Products Due to NLEA Violations".
An ORIGINAL of the label MUST be included in the package submitted to the ORA/DIOP for review.
*
Conditions of Regulatory Concern
The analysis supports the fact that the product does not qualify to make the health claim or nutrient content claim contained on the product label (Area of Emphasis No. 4), or
The sample contains less than # of the declared amount of any class 1 added vitamin, mineral, or protein.
This same threshold applies when recommending regulatory action against products labeled as meeting a USP monograph.
&
Regulatory actions will normally not be considered for products with deficiencies of declared nutrients if such nutrients are present in insignificant amounts. For purposes of this program, these nutrients include protein, vitamins, minerals and fiber. In general, we consider # of the DV per reference amount to not be of regulatory significance.
Applicable Charges for Regulatory Actions
The appropriate charge(s) for the above types of violation would be:
403(a)(1) (false and misleading labeling) for products that do not qualify for a health claim or nutrient content claim on the product label; and
403(a)(1) (false and misleading labeling) and also 402(b)(1) (adulteration; valuable constituent has been in whole or in part omitted...) for products that contain less than # of declared of any class 1 added vitamin, mineral, or protein. These are the charges to be included in all regulatory actions involving nutrient deficiencies recommended under this program.
Recommendations for Regulatory Follow-up
Follow the guidance below in recommending regulatory follow-up:
a) Compliance Samples
If the domestic sample was collected exactly as required in 21 CFR 101.36(f)(1) and a seizable size lot is available, recommend a seizure.
If the domestic sample does not fully comply with the requirements of 21 CFR 101.36(f)(1) or if a seizable size lot is not available, recommend issuance of a Warning Letter.
For actionable import samples, submit a recommendation for a new import alert for Detention without Physical Examination (DWPE) to ORA/DIOP (HFC-170). Subsequent shipments of the same product offered for entry into any FDA district port should be handled in accordance with the guidance provided in this import alert.
Each recommendation must include a copy of the collection report, an original product label (or quality copy), all analyst worksheets, and other pertinent information, such as documentation of method performance for all "Non-Official" methods utilized.
b) Surveillance Samples
Warning Letter recommendations should be prepared and forwarded for actionable surveillance samples.
Submit Warning Letter recommendations for domestic samples to CFSAN/OC/DOE/ Domestic Branch (HFS-607) for review and clearance prior to issuance. Each recommendation must include a copy of the collection report, an original product label, all analyst worksheets, and other pertinent information, such as documentation of method performance for all "Non-Official" methods utilized.
The "ingredients of concern" listed in Part III that are subject to collection of the product label or completion of *Attachment D* are of particular interest to the Center because of possible safety issues. The information from the labels and *Attachment D* will assist the Center in defining our concerns.
If safety concerns for these ingredients become evident, the Center will provide guidance as appropriate through the issuance of special assignments.
Districts should not submit recommendations for enforcement actions based on follow-up to consumer complaints without first contacting CFSAN/DEP/Case Processing Branch at 301-436-2361 for guidance.
*A copy of all consumer complaints involving dietary supplements must be sent to CFSAN, Office of Scientific Analysis and Support (HFS-700)* in accordance with Chapter 9--Investigations Operations Manual (IOM).
With the exception of serious adverse events or imminent health hazard complaints, for which the district would normally be expected to conduct immediate follow-up, the *Office of Nutritional Products, Labeling and Dietary Supplements and the Office of Scientific Analysis and Support* will use the information reported in consumer complaints to determine whether follow-up either with the consumer or with the responsible firm is appropriate.
*
If it is determined that a domestic firm is obtaining and using ruminant tissue or tissue-derived ingredients from BSE affected or at risk countries, contact CFSAN/OC/DOE/Domestic Branch (HFS-607) to discuss the facts involved and the appropriate follow-up.
Updated information on BSE affected or at risk countries must be obtained from USDA regulations contained at 9 CFR 94.18 or I.B. #99B-14.
The absence of adequate procedures to preclude use of ruminant tissue from BSE affected or at risk countries, is not by itself a sufficient basis for a regulatory recommendation.
Per instructions contained in I.B. #99B-14 shipments of ruminant tissues or tissue-derived ingredients from BSE affected or at risk countries offered for entry into the U.S. should be brought to the attention of USDA/APHIS Plant Protection Quarantine Headquarters via the fax back form to 301-734-8538.
District compliance branches must contact Felicia Satchell, CFSAN/ONPLDS at (301) 436-2371 for guidance prior to preparing a recommendation for a warning letter or a detention without physical examination for imported products. ONPLDS will be responsible for doing the required research, i.e., scientific review, database searches, etc., necessary to determine conclusively that an ingredient contained in a dietary supplement product is a "new dietary ingredient" for which prior notification should have been received.
The appropriate charge for these recommendations would be adulteration under section 402(f)(1) of the Act.
*
ATTACHMENT A - November 14, 2000 Letter to Manufacturers and Importers of Dietary Supplements and Dietary Supplement Ingredients
ATTACHMENT B - Ruminant Tissues and Tissue -Derived Ingredients
ATTACHMENT C - Questionnaire on Ruminant Tissue and Tissue-Derived Ingredients
ATTACHMENT D - Reporting Form for Products Containing Selected Ingredients
ATTACHMENT E - Exemptions from Nutrition Labeling ("Supplement Facts" Panel)
ATTACHMENT F - Guidance and Examples on Areas of Emphasis for Dietary Supplements
ATTACHMENT G - Table of Essential Nutrients and their Established RDI or DRV Levels
ATTACHMENT H - Model Nutrition Labeling ("Supplement Facts" Panel) Review Format
ATTACHMENT I - Standard Language for Warning Letters in Areas of Emphasis Nos. 1, 2, 3, 6, and 7
ATTACHMENT J - Dietary Supplement Health Claims and Disclaimers Permitted by Enforcement Discretion under the Pearson vs. Shalala Court Decision
http://www.cfsan.fda.gov/~dms/ds-inter.html; Intercenter Agreement Between the Center for Drug Evaluation and Research and the Center for Food Safety and Applied Nutrition to Assist FDA in Implementing DSHEA Regarding Products that Bear Structure/Function and/or Disease Claims
http://www.cfsan.fda.gov/~ear/sbellist.html; Small Business Labeling Exemption Requests
http://www.cfsan.fda.gov/~dms/ds-ingrd.html; New Dietary Ingredients in Dietary Supplements
http://www.cfsan.fda.gov/~dms/flg-6b.html; A Food Labeling Guide—Appendix B; Relative or Comparative Claims
http://www.cfsan.fda.gov/~dms/flg-6c.html; A Food Labeling Guide-Appendix C; Health Claims
http://www.cfsan.fda.gov/~dms/sclmguid.html; Guidance for Industry; Structure/Function Claims; Small Entity Compliance Guide
http://web.ora.fda.gov/oe/warningletters/TRKLET116R.doc; Procedures for Clearing
FDA Warning Letters and Untitled Letters
Method Inquiries
Dr. Jeanne Rader CFSAN/ONPLDS/Division of Science and Applied Technology, *(301) 436-1786* for all questions except those related to metals/minerals.
Metals/Minerals--William Mindak, *(301) 436-2005 or Steven Capar, (301) 436-2003*, CFSAN/OPDFB.
George Salem, ORA/Division of Field Science,(301) 827-1031.
Inspectional Inquiries
Barbara Marcelletti, ORA/Division of Emergency and Investigational Operations,(301) 827-5635.
Domestic-Import and Import Sampling--Linda Wisniowski, *(301) 594-3855*.
Program Contact
Brenda K. Aloi, CFSAN/OC/DFP/Compliance Programs Branch, *(301) 436-2065, Fax (301) 436-2657*.
Regulatory Contact
Regulatory/Compliance Domestic Contacts-CFSAN/OC/DOE/Domestic Branch/Nutritional Products, Labeling and Dietary Supplements Team; Team Leader Jennifer Thomas (301) 436-2094; Quyen Tien (301) 436-2086; and Lynn Szybist (301) 436-2040
Domestic-Import and Import Products - Brian Landesberg, CFSAN/OC/DOE/Import Branch, *(301) 436-1622*.
Low Volume/Small Business Exemption Questions
*John Foret*, CFSAN/ONPLDS, *(301) 436-1761*.
Compliance and BSE Policy Questions
Robert J. Moore, CFSAN/ONPLDS,(301) 436-1441 or (301) 436-2375*.
*New Dietary Ingredient Questions
Felicia Satchell, CFSAN/ONPLDS, 301-436-2371.*
During the course of this program the Director, Office of Nutritional Products, Labeling and Dietary Supplements, will identify deficiencies that may limit regulatory action. The Director, Office of Nutritional Products, Labeling, and Dietary Supplements, will review ACNA's analytical results and evaluate the accomplishments under this Compliance Program, and will prepare an annual written evaluation of this program and submit it to the Director, Division of Field Programs, HFS-615, by April 1 of the following fiscal year.
U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
November 14, 2000
Letter to Reiterate Certain Public Health and Safety Concerns to Firms Manufacturing or Importing Dietary Supplements that Contain Specific Bovine Tissues
To: Manufacturers and Importers of Dietary Supplements and Dietary Supplement Ingredients:
The Food and Drug Administration (FDA) is taking this opportunity to reiterate certain public health and safety concerns to firms manufacturing or importing dietary supplements that contain specific bovine tissues. The safety concerns about bovine-derived dietary supplement ingredients, including extracts or substances derived from such tissues, are a result of the fact that bovine-derived ingredients from cattle born, raised, or slaughtered in certain countries present a risk of transmitting the infectious agent that causes bovine spongiform encephalopathy (BSE) to humans consuming such products. FDA strongly recommends that firms should consider the public health consequences of this disease in taking whatever steps are necessary to assure themselves and the public that such ingredients do not come from cattle born, raised, or slaughtered in countries where BSE exists.
Background
BSE is a transmissible neurologic disorder of cattle and is prevalent in certain parts of the world. This neurological disease is one of a number of transmissible spongiform encephalopathies (TSE) known and is similar to other TSEs such as scrapie in sheep and Creutzfeldt-Jakob disease (CJD) in humans. It is believed that the spread of BSE in cattle in some countries, particularly Great Britain, was caused by the feeding of infected cattle and sheep tissues to cattle. While transmission of the causative agent of BSE to humans has not been definitively documented to date, inter-species transfer has been demonstrated (e.g., mice can be infected by exposure to infected bovine tissues). BSE has never been diagnosed in cattle in the United States. However, although steps have been taken to control the spread of BSE in cattle, new cases of BSE continue to be identified in certain European countries. This fact illustrates that serious public health risks associated with the consumption of animal-derived ingredients from animals sourced from BSE-positive countries remain because such tissues may contain the causative agent of BSE.
Recommendations
Although there is still no definitive evidence that the consumption of bovine tissues that contain the transmissible agent for BSE cause CJD in humans, FDA is concerned that appropriate measures to eliminate the use of bovine tissues from BSE-countries be instituted by firms that use bovine-derived ingredients in their products. The list of countries where BSE is known to exist is maintained by the U.S. Department of Agriculture (USDA) and codified in Title 9, Code of Federal Regulations, Part 94.18. Currently, the list of countries in which BSE is know to exist includes Great Britain, France, The Netherlands, Portugal, Luxembourg, Ireland, Switzerland, Oman, and Belgium.
Page 2
We strongly recommend that firms manufacturing or importing dietary supplements which contain specific bovine tissues (see enclosure), including extracts or substances derived from such tissues, take all steps necessary to assure themselves and the public that such ingredients do not come from cattle born, raised, or slaughtered in countries where BSE exists. FDA believes that any firm using BSE-derived ingredients should take immediate and continued actions to minimize the potential risk of human exposure to the infectious agent that causes BSE in cattle.
We appreciate your attention to and cooperation in this matter. If you need more information or have questions, please contact the Director, Division of Compliance and Enforcement (HFS-810), Office of Nutritional Products, Labeling, and Dietary Supplements, 200 C St., SW, Washington, DC 20204, (301) 436-1761 or your local FDA District Office.
Sincerely,
/s/
Christine J. Lewis, Ph.D.
Director
Office of Nutritional Products, Labeling, and Dietary Supplements
Center for Food Safety and Applied Nutrition
Enclosure
NOTE: The Office of Nutritional Products, Labeling, and Dietary Supplements has moved. The new mailing address is 5100 Paint Branch Parkway, College Park, Maryland 20740.
List of Tissues with Suspected Infectivity(1)
Category I (High infectivity)
Category II (Medium infectivity)
Category III (Low infectivity)
List taken from Report of a WHO Consultation on Public Health Issues Related to Animal and Human Spongiform Encephalopathies, World Health Organization, Office of Interantional Epizootics, Geneva, Switzerland, November 12-14, 1991.
1The absence of a specific tissue, organ, or gland from this list does not mean that such tissue, organ, or gland cannot contain the infectious agent responsible for BSE. It only means that there was not adequate information available at the time to assign the tissue, organ, or gland to a specific category.
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Adrenal gland Basal ganglia/basal ganglion Bone marrow Brain Brain extract Ceramide B-lactoside Ceramide dihexoside Cerebellum Cerebroside (sulfate) Cerebrospinal fluid Cranial nerves Collagen (soluble) Colon (proximal and distal) Digalactosylceramide Diglycosylceramides (cytosides) Disialoganglioside Dura mater Elastin (source: neck ligaments) Eye Galactocerebroside Galactosylcerebroside (sulfate ester) Ganglioside Glucosylcerebroside Glycerophospholipid Glycosaminoglycan Glycosphingolipid Glycosylceramide Hypothalamus Ileum Intercellular Lipids (ICL's) Lactocerebroside Lactosylceramide Liposomes Liver (including liver powder) Lung Lymph nodes |
Mammary tissues Monoglycosylceramide (cerebroside) Monosialoganglioside N-Nervonoyl cerebroside N-Oleoyl cerebroside N-Palmitoyl cerebroside Nasal mucosa Olfactory bulb or gland "Orchic" extracts Ovaries Pancreas (including pancreatin) Phospholipids Pineal gland Pituitary gland Placenta Rowamyelin Sciatic nerve Sphingosine phosphatide Sphinogomyelin Sphingolipid Spinal cord Spleen Suprarenal gland Tetraglycosylceramide Thyroid Thymus gland (sweet-bread) Tonsil Triglycosylceramide Trinitrophenylaminolauroylglucocerebroside Trinitrophenylaminolauroylgalactocerebroside Trisialoganglioside |
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NOTE: Although the November 14, 2000 letter (ATTACHMENT A) and this attachment contain a list of tissues to assist investigators in identifying potential ruminant-derived ingredients, the lists are not intended to identify all ruminant-derived ingredients about which the Agency has concerns. If any ruminant tissues or tissue derived ingredients are obtained from a BSE affected or at risk country, refer to Part III of the compliance program for additional information guidance. |
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PART A--To be Completed in Each Firm Inspected |
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Inspecting District: |
Date of Inspection: |
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Firm Name |
Central File Number: |
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Does the firm manufacture or import products containing ruminant tissue or tissue-derived materials? Yes ___ No ___ If the answer is no, do not complete the remainder of questionnaire. Give firm management a copy of the Agency's 11/14/00 letter (ATTACHMENT A) for future reference and include the questionnaire along with the EIR to be submitted to CFSAN as instructed below. |
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PART B--To be Completed in Firms Using Ruminant-Derived Material |
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YES |
NO |
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1. Is the firm aware of the Agency's 11/14/00 letter to dietary supplement firms? If the answer is no provide firm management with a copy of the Agency's 11/14/00 letter (ATTACHMENT A). |
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2. Has the firm put in place procedures to ensure that it does not receive tissues from ruminants born, raised or slaughtered in any of the countries listed in I.B. #99-14 or USDA 9 CFR 94.18? |
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3. Do the procedures include a mechanism to identify all countries where the animals used were born, raised or slaughtered? |
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4. Does the firm have a means of identifying the origin of each lot of ruminant-derived material and further identifying products made with these materials? |
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5. Does the firm have a means of tracing the disposition of imported products which contain ruminant-derived material? |
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Indicate the origin(s) of the ruminant tissue or tissue-derived ingredients used by the firm. Domestic ___ Import ___ If import origin, list below the country(ies) of origin. ____________________________________________ __________________________________________ ____________________________________________ __________________________________________ Note: Investigators must refer to IB #99B-14 or USDA 9 CFR 94.18 for an up-to-date list of BSE-countries. If one of these countries is the country of origin, refer to Part III of the compliance program (7321.008) for guidance. |
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PART C--To be Completed in Firms Using Ruminant-Derived Material |
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List in the space below all products manufactured or imported by the firm that contain a ruminant-derived ingredient (see Attachment B). If the ruminant-derived ingredient is listed on the finished product, the label may be submitted to CFSAN as instructed below along with Parts A and B of this questionnaire in lieu of completing Part C |
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To the extent possible, determine the name of any products (including brand name(s)) in which the firm uses any of the ruminant-derived material listed on Attachment B of this program. Provide the brand name of the product and the specific ruminant-derived material it contains. |
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Product Name (Including Any Brand Name(s) Used) |
Specific Ruminant-Derived Material in Product |
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Include this questionnaire along with the labels as appropriate and submit along with the completed EIR to: *CFSAN/Dietary Supplement Monitor, HFS-636, Rm. 3C007, 5100 Paint Branch Parkway, College Park, MD 20740 |
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NOTE: USE ADDITIONAL COPIES AS NECESSARY, COMPLETE FEI ON CONTINUATION SHEETS
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DISTRICT: FEI: |
FIRM NAME: |
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PRODUCT BRAND NAME: |
FORM: |
DOSAGE: |
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LIST ALL INGREDIENTS PRESENT IN THE ABOVE PRODUCT, INCLUDING THE ONES LISTED AT THE BOTTOM OF THIS FORM. |
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| INGREDIENT | LEVEL | INGREDIENT | LEVEL | INGREDIENT | LEVEL | ||||||
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| PRODUCT BRAND NAME: | FORM: | DOSAGE: | |||||||||
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LIST ALL INGREDIENTS PRESENT IN THE ABOVE PRODUCT, INCLUDING THE ONES LISTED AT THE BOTTOM OF THIS FORM. |
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| INGREDIENT | LEVEL | INGREDIENT | LEVEL | INGREDIENT | LEVEL | ||||||
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Complete the above information for any product containing one or more of the ingredients of concern listed in Part III, Section A.3 of this compliance program when information on ingredients and levels is not listed on the product label |
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A dietary supplement is not required to have a "Supplement Facts" panel if it is:
Offered for sale by a small business that has not more than $50,000 gross sales per year from food sales or no more than $500,000 from total sales in accordance with 21 CFR 101.36(h)(1);
A low-volume product (i.e., less than 100,000 units sold annually) sold by a firm with less than 100 full-time equivalent employees in accordance with 21 CFR 101.36(h)(2) *and for which a claim for exemption has been filed annually with ONPLDS*; or
Shipped in bulk form, not distributed to consumers in such form, and used in the manufacture of other dietary supplements in accordance with 21 CFR 101.36(h)(3).
NOTE: The exemptions for small businesses and low-volume products are available only to products whose labels bear no claims or other nutrition information.
Products that fail to bear nutrition labeling, i.e., the absence of a "Supplement Facts" panel on the label, and are not covered by an exemption (21 CFR 101.36).
Exempt products include those meeting the small business provisions; or bulk dietary supplements for further manufacturing.
NOTE: A nutrient declaration, nutrient content claim or health claim on a dietary supplement label generally negates the small business exemption status of the product and triggers the requirement for nutrition labeling.
Products that fail to bear an appropriate statement of identity on the principal display panel, i.e., use of the term "dietary supplement" or some variation of "_______ supplement" (21 CFR 101.3(g)).
Appropriate Statements of Identity
Inappropriate Statements of Identity
Products that bear health claims or nutrient content claims that have not been authorized by FDA by regulation *or are not authorized on the basis of an authoritative statement provided in section 403(r)(2)(G) or section 403(r)(3)(C) of the Act or have not been the subject of a letter granting enforcement discretion in response to the Pearson vs. Shalala court decision*.
Unauthorized Health Claims
Products that bear authorized health claims or nutrient content claims but fail to qualify for making the claims.
Examples of Products Not Qualifying for Nutrient Content Claims *are
available on CFSAN's website
http://www.cfsan.fda.gov/~dms/flg-6b.html
Examples of Products Not Qualifying for Health Claims are available
On CFSAN's website
http://www.cfsan.fda.gov/~dms/flg-6c.html
Products that bear nutrition labeling "Supplement Facts" panel with significant format deviations (21 CFR 101.36).
Products that bear nutrition labeling in the old pre-DSHEA format (e.g., "Nutrition Facts" panel).
Failure to declare a required nutrient if present at a level above zero.
Failure to bear the heading "Supplement Facts".
Failure to enclose the "Supplement Facts" panel in a box.
Products in solid oral dosage form containing 30 mg or more of iron that fail to be packaged in unit-dose packaging (21 CFR 111.50(a)).
Products with added iron that fail to bear a warning statement (21 CFR 101.17(e)).
Applies to products containing iron or iron salts
Does not apply to products with incidental iron contributed as a constituent of an ingredient (e.g., small amounts of declared iron contained in botanicals)
Text of warning statement:
WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.
Products that fail to bear other mandatory label information.
NOTE: Under section 403(r)(6) of the Act, a dietary supplement may bear certain claims, generally called structure/function claims, on its label or in its labeling provided that the firm has substantiation that the claim is truthful and not misleading, the firm has notified FDA within 30 days of marketing the product bearing the claim, and the claim includes a mandatory disclaimer. At the present time, we are not asking that label claims be examined to determine if they contain the disclaimer because there remain unresolved policy issues regarding the use of the disclaimer and, therefore, it is premature to examine whether the required disclaimer is properly used in accordance with 21 CFR 101.93. If a structure/function claim is an unauthorized health claim under either FDA regulations or 403(r)(3)(C), then it would fall under Area of Emphasis No. 3 above.
&
| Nutrient | RDI or DRV |
|---|---|
| Protein | 50 grams |
| Fiber | 25 grams |
| Vitamin A | 5,000 international units |
| Vitamin C | 60 milligrams |
| Calcium | 1 gram |
| Iron | 18 milligrams |
| Vitamin D | 400 international units |
| Vitamin E | 30 international units |
| Vitamin K | 80 micrograms |
| Thiamin | 1.5 milligrams |
| Riboflavin | 1.7 milligrams |
| Niacin | 20 milligrams |
| Vitamin B6 | 2.0 milligrams |
| Folate | 400 micrograms |
| Vitamin B12 | 6.0 micrograms |
| Biotin | 300 micrograms |
| Pantothenic acid | 10 milligrams |
| Phosphorus | 1000 milligrams |
| Magnesium | 400 milligrams |
| Zinc | 15 milligrams |
| Iodine | 150 micrograms |
| Copper | 2.0 milligrams |
| Potassium | 3,500 milligrams |
| Chromium | 120 micrograms |
| Molybdenum | 75 micrograms |
| Chloride | 3,400 milligrams |
RDI and DRV for Adults and Children over 4 Years of Age
Food_____________________________ Sample #____________________
Mark with:
| + | = | Information present and correct on label |
| - | = | Information present and incorrect on label |
| O | = | Information missing from label |
Label Format
Label Content
Use this form for recording observations only, do not submit to CFSAN
Follow the format in Chapter 4, page 89 of the August 1997 Regulatory Procedures Manual. Incorporate one or more of the following paragraphs as appropriate:
The product is misbranded within the meaning of section 403(q)(5)(F) of the Act in that the label fails to bear nutrition labeling ("Supplement Facts" panel), which is required under 21 CFR 101.36, and is not exempt from this requirement.
The product is misbranded within the meaning of section 403(r)(1)(A)/(B) of the Act in that the label bears the nutrient content claim/health claim "___," which has not been authorized by FDA regulation or on the basis of an authoritative statement under section 403(r)(2)(G) or 403(r)(3)(C) of the Act, *or has not been the subject of a letter granting enforcement discretion in response to the Pearson vs. Shalala court decision*.
The product is misbranded within the meaning of sections 403(i)(1) and 403(s)(2)(B) of the Act in that the label fails to identify the product using the term dietary supplement (21 CFR 101.3(g)).
The product is adulterated within the meaning of sections 402(a)(4) and 402(g) of the Act in that it is in solid oral dosage form containing 30 mg or more of iron, but fails to be packaged in unit-dose packaging (21 CFR 111.50).
The product is misbranded within the meaning of sections 403(a)(1) and 201(n) of the Act in that the label, labeling, or display of the product with added iron, fails to bear the required warning statement (21 CFR 101.17(e)).
Incorporate the following paragraph in each Warning Letter:
The above violations are not meant to be an all-inclusive list of deficiencies *for your products*. *Other violations can subject the dietary supplement to legal action*. It is your responsibility to assure that all of your products are labeled in compliance with *the Act and regulations* enforced by FDA. FDA regulations can be found in Title 21, Code of Federal Regulations and are available on FDA's website at www.fda.gov.
NOTE: Under section 403(r)(6) of the Act, a dietary supplement may bear certain claims, generally called "structure/function claims," on its label or in its labeling provided that the firm has substantiation that the claim is truthful and not misleading; the firm has notified FDA within 30 days of marketing the product bearing the claim; and the claim includes a mandatory disclaimer.
The Agency will consider, on a case-by-case basis, enforcement actions against products that bear egregious disease claims or that may be unsubstantiated and false and misleading. Investigators should review claims made for dietary supplements in labels and labeling. Products that bear inappropriate disease claims or that appear to bear egregiously false and misleading claims should be referred to CFSAN, Case Processing Branch (HFS-607) for evaluation.
*The preamble to the final rule that published on January 6, 2000 (65 FR 1000)--Regulations on Statements Made for Dietary Supplements Concerning the Effect of the Product on the Structure or Function of the Body, provides important background and rational for the Agency's policies related to structure/function and disease claims issue.* In addition to the preamble discussion, the Agency issued a guidance document on January 9, 2002, which provides additional information regarding structure/function and disease claims entitled "Guidance for Industry, Structure/Function Claims, Small Entity Compliance Guide." The guidance document complements, rather than substitutes for, the final rule and is available on CFSAN's website at http://www.cfsan.fda.gov/~dms/sclmguid.html. Districts may want to refer to this document for industry guidance prepared in accordance with section 212 of the Small Business Regulatory Enforcement Fairness Act. This guidance restates in plan language the legal requirements set forth in the January 6, 2000 regulation concerning labeling claims for dietary supplements.*
Dietary supplements which are high, i.e., at least # of the Daily Value (DV) per serving, for folic acid, vitamin B6, and vitamin B12 may bear the qualified claim below. The second sentence of the claim, i.e., the disclaimer, must be immediately adjacent to and directly beneath the first sentence, i.e., the claim itself, with no intervening material that separates the claim from the disclaimer, and the second sentence must be in the same size, type face and contrast as the first sentence.
"As part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6 and vitamin B12 may reduce the risk of vascular disease."
"FDA evaluated the above claim and found that, while it is known that diets low in saturated fat and cholesterol reduce the risk of heart disease and other vascular diseases, the evidence in support of the above claim is inconclusive."
The Agency intends to exercise its enforcement discretion with respect to qualified claims only when the claims meet the general requirements for health claims in 21 CFR 101.14. FDA finds that the provision in 21 CFR 101.14(d)(2)(vii) that "If the claim about the effects of consuming the substance at other than decreased dietary levels, ... the claim must specify the daily dietary intake necessary to achieve the claimed effect..." does not apply to this claim. Available scientific information does not support identification of specific amounts of folic acid, vitamin B6, and vitamin B12 that might be useful for reduction in risk of vascular disease. FDA therefore concludes that a claim that implied that specific amounts or combinations of folic acid, vitamin B6, or vitamin B12, are necessary to reduce the risk of vascular disease would be misleading. However, the provision in 21 CFR 101.14(d)(2)(vii) that "If the claim is about the effects of consuming the substance at other than decreased dietary levels," and a definition for the use of the term high for that substance has been established, the substance must be present at a level that meets the requirements for use of that term.
http://www.cfsan.fda.gov/~dms/ds-hclbv.html
http://www.cfsan.fda.gov/~dms/ds-ltr12.html
Dietary supplements which contain at least 0.8 milligrams (mg) per serving of folic acid may bear the qualified statement:
"0.8 mg folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form."
"FDA does not endorse this claim. Public health authorities recommend that women consume 0.4 mg folic acid daily from fortified foods or dietary supplements or both to reduce the risk of neural tube defects."
The disclaimer statement must be placed immediately adjacent to and directly beneath the claim, with no intervening material, in the same size, typeface, and contrast as the claim. Dietary supplements that recommend or suggest in their labeling, or under ordinary conditions of use, daily intakes of more than 100 percent of the Daily Value (DV) (400 micrograms (ug), when labeled for use by adults and children 4 or more years of age; and 800 micrograms, when labeled for use by pregnant and lactating women) shall identify the safe upper limit of daily folic acid intake with respect to the DV. The safe upper limit of daily intake, 1000 microgram (1 mg) may be included in parentheses. Enforcement discretion will not be applied to dietary supplements bearing the qualified claim and containing more than 100 percent of the Reference Daily Intake (RDI) for vitamin A as retinol or preformed vitamin A (5,000 International Units (IU)), or vitamin D (400 IU) per serving or per unit.
http://www.cfsan.fda.gov/~dms/ds-ltr22.html
http://www.cfsan.fda.gov/~dms/ds-ltr7.html
The Agency will consider exercising enforcement discretion for appropriately qualified eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) omega-3 fatty acid/CHD health claims when the claim statement includes the following elements:
It is known that diets low in saturated fat and cholesterol may reduce the risk of heart disease;
scientific evidence is suggestive but not conclusive for a relationship between omega-3 fatty acids and reduced risk of CHD in the general population;
studies in the general population have looked at diets containing fish and not omega-3 fatty acids and have not shown whether the diets or the omega-3 fatty acid component of fish may have a possible effect on a reduced risk of CHD; and
it is not known what effect omega-3 fatty acids may or may not have on risk of CHD in the general population.
The Agency intends to exercise enforcement discretion with respect to the use of the qualified claim on omega-3 fatty acid dietary supplements that do not recommend or suggest in their labeling, or under ordinary conditions of use, daily intakes of more than 2 grams of EPA and DHA. Dietary supplements that bear the qualified claim and that encourage intakes (in labeling or under ordinary conditions of use) above 2 grams per day would be considered misbranded. FDA encourages manufacturers to limit their dietary supplement products bearing the qualified health claim to products recommending or suggesting daily intakes of 1 gram or less of EPA and DHA omega-3 fatty acids. The evidence in support of this claim is merely suggestive and does not support the establishment of a possible effective intake level. Therefore, the Agency would consider any labeling suggesting a level of omega-3 fatty acids to be useful in achieving a claimed effect to be false and misleading.
The Agency considers the following statement about EPA and DHA omega-3 fatty acids and CHD risk to be appropriately qualified: "It is known that diets low in saturated fat and cholesterol may reduce the risk of heart disease. The scientific evidence about whether omega-3 fatty acids may reduce the risk of CHD is suggestive, but not conclusive. Studies in the general population have looked at diets containing fish and it is not known whether diets or omega-3 fatty acids in fish may have a possible effect on reduced risk of CHD. It is not known what effect omega-3 fatty acids may or may not have on risk of CHD in the general population."
http://www.cfsan.fda.gov/~dms/ds-ltr20.html
http://www.cfsan.fda.gov/~dms/ds-ltr11.html
