| Public Health Service Food and Drug Administration |
New England District |
Department of Health and Human ServicesWARNING LETTER
CMS # 199792
VIA OVERNIGHT UPS
November 18, 2011
Ms. Lorene Jere-Biiezikian,
General Manager/Co-owner
Global Sweet Polyols, LLC
125 Tremont Street
Rehoboth, MA 02769
Dear Ms. Jere-Bliezikian:
The United States Food and Drug Administration (FDA) conducted an inspection of your dietary supplement facility, which packages and labels your Manno Max® D-Mannose and GlycoBiotics D-Ribose products. The inspection took place at the above-referenced address from May 27, 2011 through June 10, 2011. The inspection revealed that you failed to comply with the requirements in 21 CFR Part 111, the Current Good Manufacturing Practice (CGMP) regulations for dietary supplements. Accordingly, your products are adulterated within the meaning of Section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(g)(1)], in that they have been prepared, packed, or held under conditions that do not meet the CGMP regulations for dietary supplements. Further, our review of the labeling and promotional claims for your Manno Max® D-Mannose and GlycoBiotics D-Ribose products shows that they are promoted for conditions that cause the products to be drugs under section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)]. The claims establish that these products are drugs because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans. The marketing of your products with these claims violates the Act. You can find the Act and the referenced regulations through links in FDA's homepage at www.fda.gov.
Dietary Supplement CGMP Violations
Your products Manno Max D-Mannose and GlycoBiotics D-Ribose are adulterated within the meaning of section 402(g)(1) of the Act in that these products have been prepared, packed, or held under conditions that do not meet CGMP requirements for dietary supplements. Specifically:
1. You failed to package and label in a way that ensures that the dietary supplement is packaged and labeled as specified in the master manufacturing record, as required by 21 CFR 111.415. Specifically, you verbally confirmed to our investigator that your firm does not have written master manufacturing records for the MannoMax D-Mannose (50 grams, 250 grams, 1 kilogram, 60 tablets (1,000 mg)) and GlycoBiotics D-Ribose dietary supplement products that you package and label at your facility.
We have reviewed your response, dated June 30, 2011, and determined it to be inadequate. You indicated that you do not perform any manufacturing operations. However, 21 CFR 111.415 applies to packaging and labeling operations, and our investigator found that you receive dietary supplements in bulk powder and tablet form and conduct packaging and labeling operations on these products. Your response further stated that you will discontinue all packaging and labeling operations. Your response does not, however, indicate, by date, when you will stop packaging and labeling dietary supplements. Your response also did not provide documentation of your plans to discontinue packaging and labeling operations.
2. Your firm failed to establish specifications to provide sufficient assurance that products your firm receives from a supplier for packaging or labeling and distribution as dietary supplements are adequately identified and are consistent with your purchase order, as required by 21 CFR 111.70(f). Specifically, your firm receives from (b)(4) suppliers (b)(4) and (b)(4) that your firm repackages and labels into finished products for distribution. However, your firm did not establish specifications to provide assurance that the (b)(4) 
were adequately identified and consistent with your purchase order, as required by 21 CFR 111.70(f).
We have reviewed your response dated June 30, 2011 and determined it to be inadequate. You included in your response an SOP for Dietary Supplement Specification Development and Approval. However, your response did not provide documentation of the specifications for these products.
3. You firm failed to make and keep records of the written procedures for packaging and labeling operations, as required by 21 CFR 111.430(b). Specifically, you verbally confirmed to our investigator that your firm does not make or keep written procedures for packaging and labeling operations.
We have reviewed your response dated June 30, 2011 and determined it to be inadequate. You indicated that you will be discontinuing all packaging and labeling operations and that those operations will instead be performed by a third party packager/labeler. As stated above, however, your response did not indicate when you will cease these operations and did not identify who your third party packager/labeler is and when they will commence these operations on your behalf. You also failed to provide documentation of your plans to cease those operations.
4. You failed to establish and follow written procedures for the responsibilities of the quality control operations, as required by 21 CFR 111.103. Specifically, you confirmed that you do not have written procedures for the quality control operations.
We have reviewed your response dated June 30, 2011 and determined it to be inadequate. Your response states that you are moving all packaging and labeling operations to a third party, and that you have developed a "Quality Agreement" to which you will require all third parties stipulate. As stated above, however, you have failed to provide documentation of your plans to discontinue your packaging and labeling. Furthermore, the written procedures you submitted did not address important requirements for quality control operations. Specifically, your procedures did not address your quality control operations' responsibilities to approve or reject any reprocessed dietary supplements, as required by 21 CFR 111.103, or to approve for release or reject any packaged and labeled dietary supplement (including a repackaged or relabeled dietary supplement) for distribution, as required by 21 CFR 111.127(h).
5. Your firm did not establish written procedures for holding and distributing operations, as required by 21 CFR 111.453. Specifically, you verbally confirmed to our investigator that the firm does not have such written procedures.
We have reviewed your response dated June 30, 2011 and determined it to be inadequate. In your response, you provided a copy of a written procedure entitled "Product Receipt, Warehousing and Distribution." However, that document did not address the following:
• Holding the packaging and labels under appropriate conditions so that the packaging and labels are not adversely affected;
• Holding the packaging and labels under conditions that do not lead to contamination or deterioration of packaging or labels;
• Holding the reserve samples under conditions consistent with product labels or, if no storage conditions are recommended on the label, under ordinary storage conditions;
• Using the same container-closure system in which the packaged and labeled dietary supplement is distributed;
• Retaining reserve samples for 1 year past the shelf life date (if shelf life dating is used), or for 2 years from the date of distribution of the last batch of dietary supplement associated with the reserve sample.
7. Your firm failed to hold components, dietary supplements, packaging, and labels under conditions that do not lead to the mix-up, contamination, or deterioration of components, dietary supplements, packaging, and labels, as required by 21 CFR 111.455(c). Specifically, an unlabeled, white powdered substance was observed in your firm's packaging and labeling room without any label or other identifying information which would prevent a mix-up of the substance.
8. Your firm did not collect and hold reserve samples of each lot of packaged and labeled dietary supplements that you distribute, as required by 21 CFR 111.83(a).
For each lot of packaged and labeled dietary supplements that you distribute, your firm must collect reserve samples and hold the samples using the same container closure system in which the packaged and labeled dietary supplements were distributed [21 CFR 111.83(b)(1)]. Further, the reserve samples must be identified with the appropriate batch or lot number for at least one (1) year past the shelf life date (if shelf lift dating is used), or for two (2) years from the date of distribution of the last batch of dietary supplements associated with a reserve sample [21 CFR 111.83((b)(2)-(3)]. However, you verbally confirmed to our investigator that you do not collect or hold any reserve samples of the dietary supplements that you distribute.
We have reviewed your response dated June 30, 2011, including your Quality Agreement. You state that you will require suppliers to abide by this agreement. This response is inadequate. The Quality Agreement indicates that such suppliers be required to agree to maintain reserve samples of products, but provides no documentation of this practice or information about when you intend to begin the practice, in order to assist us in evaluating your corrections.
9. You did not establish specifications for the packaging and labeling of the finished packaged and labeled dietary supplements, as required by 21 CFR 111.70(g). Specifically, you verbally confirmed to our investigator that you do not have established specifications for the packaging and labeling of the finished packaged and labeled dietary supplements.
We have reviewed your response dated June 30, 2011 and determined it to be inadequate. You indicated that you will be discontinuing all packaging and labeling operations and that it will be performed by a third patty packager/labeler. However, as stated above, you failed to provide documentation or a time line of your plans to do so. Your response also fails to include specifications for packaging and labeling.
10. You failed to control the issuance and use of packaging and labels, as required by 21 CFR 111.410(b). Specifically, you indicated to our investigator that you do not have a control process for the issuance and use of the product labels.
We have reviewed your response dated June 30, 2011, and found it to be inadequate. Your response stated that you will cease packaging and labeling operations, but you failed to provide documentation of your plans or further specify the relevant date. Your response also stated that you will require third party packagers and labelers to implement a Quality Agreement. However, this agreement fails to provide any details on how packaging and labeling will be controlled or labels will be reconciled that would assist us in evaluating your corrections.
11. You must not allow animals or pests in any area of your physical plant, as required by 21 CFR 111.15(d)(1). However, our investigator observed you walking into the warehouse and packaging and labeling room with a dog in your arms. While 21 CFR 111.15(d)(1) allows guard or guide dogs in some areas of a physical plant if the presence of the dogs will not result in contamination of components, dietary supplements, or contact surfaces, you did not indicate that this dog was either a guard or guide dog.
12. Your firm failed to maintain, clean, and sanitize equipment and utensils used to manufacture, package, label, or hold components or dietary supplements, as required by 21 CFR 111.27(d). Specifically, your shipping manager indicated to our investigator that your firm uses a liquid dish washing detergent with triclosan for sanitizing utensils. Under 21 CFR 111.27(d)(6), cleaning compounds and sanitizing agents must be adequate for their intended use. A liquid dish washing detergent such as the one you use is not adequate for use with utensils.
Unapproved New Drugs
In addition, FDA reviewed your firm's labeling and marketing information and your web sites at the Internet addresses www.d-mannose.com and www.globalsweet.com in October 2011 and determined that the products, "Manno Max D-Mannose," and "GiycoBiotics D-Ribose" are promoted for conditions that cause the products to be drugs under section 201(g)(1) of the Act [21 U.S.C. § 321(g)(l)]. The therapeutic claims in your labeling establish that the products are drugs because they are intended for use in the cure, mitigation, treatment, or prevention of disease. The marketing of these products with these claims violates the Act.
Examples of some of the claims observed on your products' labeling include:
Manno Max® D-Mannose (catalog):
• "All natural alternative treatment/prevention for urinary tract infections."
• "Manno-Max® adheres to misplaced bacteria (3 of the most common- E coli,
Streptococcus zooepidemicus and Pseudomonas aeruginosa) preventing their attachment to the bladder lining and allowing them to be flushed harmlessly out of the body during normal urination."
D-Ribose (catalog):
• "People suffering from Ischemia or poor cardiovascular health rely on ribose because ATP keeps your heart beating, muscles contracting, rebuild energy and cell functioning. After a heart attack, taking ribose helps ATP levels and heart function return to normal within 48 hours. Reports have shown Ribose can even lower blood sugar levels. Ribose has also proven effective for people suffering with Fibromyalgia."
• "Ribose is also known to alleviate altitude sickness ... "
Manno Max D-Mannose (Tri-fold Brochure):
• "Alternative Treatment/Prevention for URINARY TRACT INFECTIONS"
• "D-mannose is 10 times more active than the fructose in cranberries when it comes to the dislodging of E. coli bacteria in the urinary tract."
• "During an infection it is recommended to take Yz tsp. or 2 capsules every 2-3 hours."
GlycoBiotics d-Ribose (pamphlet):
• "Ribose fuels ATP synthesis which reduces muscle pain and enhances the quality of life for those suffering with fibromyalgia and/or chronic fatigue."
Examples of some of the claims observed on your web sites include:
Manno Max D-Mannose (www.d-mannose.com)
• "Interstitial Cystitis And The Case For D-Mannose"
• "How do you take D-Mannose? Normal therapeutic dosage is Yz tsp. daily for chronic suffers of UTIs or weekly for preventative measures."
Your website also includes claims in the form of personal testimonials. For example:
• "Manno Max (D-Mannose) is a great product. It has cured 2 UTIs for me and 2 UTIs for my wife. It is so much better than taking antibiotics for us."
• "I suffered with UTIs for years until I tried Manno-Max D-Mannose. It's amazing!"
D-Ribose (www.globalsweet.com)
• "People suffering from Ischemia or poor cardiovascular health rely on ribose because ATP keeps your heart beating, muscles contracting, rebuild energy and cells functioning. After a heart attack, taking ribose helps ATP levels and heart function return to normal within 48 hours. Reports have shown Ribose can even lower blood sugar levels. Ribose has also proven effect for people suffering from Fibromyalgia. People suffering from this condition show signs of low ATP levels and reduced capacity to produce ATP in their muscles soreness and cramping. Ribose fuels ATP synthesis which reduces muscle. Ribose is also known to alleviate altitude sickness ...."
• "D-Ribose in Congestive Heart Failure and Ischemic Disease"
• "D-ribose in Fibromyalgia and Neuromuscular Disease"
Your products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are "new drugs" under section 201(p) of the Act [21 U.S.C. § 321(p)]. A new drug may not be legally marketed in the United States without prior approval from FDA as described in section 505 (a) of the Act [21 U.S.C. § 355(a)]. FDA approves a new drug on the basis of scientific data submitted by a drug sponsor to demonstrate that the drug is safe and effective.
Further, your Manno Max D-Mannose and GlycoBiotics D-Ribose products are offered for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layperson can use these drugs safely for their intended purposes. Thus, your products are misbranded under section 502(f)(1) of the Act [21 U.S.C. 352(f)(1)], in that the labeling for these drugs fails to bear adequate directions for use.
The above violations are not meant to be an all-inclusive list of violations at your facility or deficiencies in your products or their labeling. It is your responsibility to ensure that all of your products are in compliance with the laws and regulations enforced by FDA. You should take prompt action to correct these violations. Failure to promptly correct these violations may result in regulatory actions without further notice, such as seizure and/or injunction.
In addition to the violations discussed above, we have the following comment. Your www.globalsweet.com website includes a "References" link that lists scientific publications that support your marketing of your GlycoBiotics D-Ribose product. When scientific publications are used commercially by the seller of a product to promote the product to consumers, such publications may become evidence of the product's intended use. For example, under 21 CFR 101.93(g)(2)(iv)(C), a citation of a publication or reference in the labeling of a dietary supplement is considered to be a claim about disease treatment or prevention if the citation refers to a disease use and if, in the context of the labeling as a whole, the citation implies treatment or prevention of a disease.
Please respond to this letter within fifteen (15) working days from your receipt of this letter as to the specific steps that you have taken to correct the current violations noted above and to prevent similar violations in the future. Your response should include any documentation necessary that would assist us in evaluating your corrections. If you cannot complete all corrections within fifteen (15) working days, state the reason for the delay and the time within which you will correct any remaining violations.
Your response should be sent to the U.S. Food and Drug Administration, One Montvale Avenue, Stoneham, MA 02180, Attention: Todd Maushatt, Compliance Officer. If you have any questions about the content of this letter please contact: Todd Maushatt at (781) 587-7486.
Sincerely,
/s/
Mutahar S. Shamsi
District Director
New England District
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