Dietary Supplements Joint Committee Meeting

Dietary Supplements Joint Committee Meeting

Tuesday, October 13, 2011

1:00-5:00 pm (PST)

Venetian Casino Resort Toscana 3609

Las Vegas, NV

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JOINT COMMITTEE – DIETARY SUPPLEMENTS Thursday, October 13, 2011

Las Vegas, NV

Draft Agenda

Time Tab

1

Item Speaker 1:00 pm Welcome J. Hoffman / P. Brown

Antitrust Statement J. Hoffman Review of draft Meeting Summary: June 16, 2011 P. Brown

Tab 2

Old Business 1:15 pm Review of Recent Ballots J. Hoffman

173i29r3e – Methods/QC Update K. LeVanseler 173i30r4e – Aristolochic Acid K. LeVanseler 173i38r1e – Normative References and Definition K. LeVanseler 173i39r1e – Macroscopic Test Methods K. LeVanseler

Task Group Updates 1:45 pm Task Group on Membership P. Brown 2:00 pm Task Group on Heavy Metals C. McLellan 2:15 pm Task Group on Oxidation and Rancidity H. Rice 2:30 pm APH Monograph Review Task Group R. Upton

Tab 3

New Business 2:45 pm DS-2011-6-Targeted Verification E. Wyszumiala 3:30 pm DS-2011-7-Pesticide Testing Requirements K. LeVanseler 4:15 pm DS-2011-8-AOAC Dietary Supplement Task Group L. Saldanha / P. Brown 4:45 pm Next meeting P. Brown 5:00 pm Adjournment P. Brown


Joint Committee on Dietary Supplements Draft Meeting Summary

June 16, 2011

Distributed on June 28, 2011 Page 1 of 8

I OPENING REMARKS J. Hoffman welcomed Joint Committee members and observers. She recorded the attendance, read the NSF Antitrust Statement, and turned the meeting over to P. Brown, JC Chair.

II ADMINISTRATIVE

Introduction of New Members Paula welcomed and introduced the following new members: Harry Rice: Vice president of regulatory and scientific affairs for the United Natural Products Alliance (UNPA) and the Global Organization for EPA and DHA Omega-3s (GOED), Harry has worked in the ingredient, dietary supplement, functional food, and consumer packaged goods industries for more than ten years. Harry has an MS and a Ph.D in nutrition from Penn State and a BS in dietetics from Miami University. Duffy MacKay: Vice president, scientific and regulatory affairs, for the Council for Responsible Nutrition (CRN; Washington, DC), Duffy is a licensed naturopathic doctor and was a co-owner and practitioner in a family-owned New Hampshire complementary and alternative medicine private practice for seven years. Greg Cumberland: Co-founder of Bent Creek Institute, North America’s only medicinal plant and endophyte germplasm repository. Greg served on its Board of Directors until assuming the Presidency in January 2011. Prior to Bent Creek Institute, Mr. Cumberford worked for nearly 14 years at Gaia Herbs.

Review of Meeting Summary – October 19, 2010 Paula asked for revisions or changes to the October 19, 2010 Draft Meeting Summary. In the absence of a quorum, S. Eisner motioned to recommend that the Meeting Summary be approved as written, and M. McGuffin seconded. III TASK GROUP UPDATES

AHP Monographs Review Task Group For R. Upton, Paula mentioned that the American ginseng monograph is underway along with several other new monographs. Paula also indicated that Roy is the best person to discuss the status of and timeline for the various AHP monographs.

Heavy Metals Task Group For C. McLellan, K. Cox stated the Metals Task Group had met several times and most recently reviewed AHPA metal limits, NSF metal limits, and USP levels. The TG also looked into the basis for how those numbers were established, in attempt to revise the current values in NSF/ANSI 173. Kevin indicated that consensus had been reached on the following proposals:


June 16, 2011


Lead: TG recommends reducing the current lead limit in NSF/ANSI 173 from 20 to 10 micrograms per day for finished products. This change would harmonize the lead number in Standard 173 with APHA and USP. Cadmium: TG recommends reducing the current cadmium limit from 6 to 4 micrograms per day for finished products, putting it slightly below the Prop 65 number of 4.1. Mercury: TG had discussed correcting the current NSF/ANSI 173 level of 0.02 mg/day that was set based on inorganic mercury. That value was based on a mathematical error and should have been 0.002 mg (total mercury). Kevin mentioned the Task Group had also discussed changing limits for other metals as well as limits for raw materials but that consensus had not yet been reached. The TG is moving cautiously and awaiting release of new metal limits from ICH, The International Conference on Harmonisation. Kevin acknowledged the need for additional Task Group meeting discussions and invited feedback from the Joint Committee on the lead, cadmium, and mercury TG proposals for finished products. Regarding the proposed cadmium limit change from 6 to 4, M. McGuffin commented that AHPA had revised its cadmium level to 4.1 to harmonize with Prop 65, and that he likes harmonization. Regarding the proposed lead limit change to 10, Michael greatly appreciates and thinks it is appropriate to make such a reduction. He also reported there are ongoing conversations at AHPA to consider reducing their limit to 6, the FDA limit, but this is only in committee discussion. As there were no additional comments, Kevin indicated the Metals Task Group plans to move forward with ballot proposals for changing the lead level and correcting the mercury level for finished products. The TG will also take it under advisement to consider changing the cadmium limit from 4 to 4.1 to harmonize with AHPA. Additionally, the TG will continue to meet in attempt to resolve other NSF/ANSI 173 pass/fail criteria. Paula pointed out that the current Health Canada lead limit is 20 micrograms per day for finished products. Martin Charron added that Health Canada is considering reducing its lead limit to 10, which was of interest to M. McGuffin. K. LeVanseler advised that we are moving in the right direction and that it might be wise to propose a ballot to reduce the NSF/ANSI 173 lead limit from 20 to 10 until harmonization on a lower limit is reached.

Membership Task Group

Paula explained that this Task Group was established to assist her with reviewing JC membership composition and the JC applicant pool. Three new members were added recently: one-Industry, one-Public Health/Regulatory, and one-User/Consumer. There are several open applications out for Industry and User/Consumer members; suggestions for additional User/Consumer JC member candidates would be welcomed. Additionally, the TG would welcome ideas for increasing the engagement and participation of JC members.

IV REVIEW OF RECENT BALLOTS

173i18r3 – Allergen-free claims


June 16, 2011


K. LeVanseler explained that this issue dates back to 2006 and ends here with the failure of the 173i18r3 ballot. Results of this ballot show that the Joint Committee favors not incorporating specific language into NSF/ANSI 173 for the assessment and evaluation of allergen-free claims. Thus, without a detailed section on allergens, the Standard will default to the following ‘no claims’ section:

5.3.7 Other product claims Claims that a product is free of a particular contaminant or substance shall be verified in accordance with 7.4 and/or 8.

There were no comments or concerns raised.

173i29r3 – Methods/QC Update

Kerri explained that the current ballot merges several issues and includes feedback, and she thanked JC members who had provided their assistance and expertise. The purpose of the current 173i29r3 ballot is:

1. To update Section 6, Test methods used by testing laboratories for identification and quantification of ingredients – raw materials and finished products;

2. To update Section 7.4, Test methods for chemical contaminants; 3. To remove Tables 3 and 4; and 4. To update the quality assurance sections related to verification testing performed to

evaluate compliance with NSF/ANSI 173. After discussion of the proposed new language, JC members were encouraged to review the proposal and to vote on the ballot by Tuesday, June 28, 2011.

173i30r4 – Aristolochic Acid

Kerri thanked JC members who had provided assistance with this issue. The revision 4 ballot was approved by the Joint Committee on Dietary Supplements, the Technical Committee on Dietary Supplements, and the CPHC – Council of Public Health Consultants, with an official ANSI Approval Date of Final Action of March 28, 2011. Thus, the approved ballot language will be included in the next published version of NSF/ANSI 173.


June 16, 2011


V ISSUE PAPERS

DS-2011-1 – Oxidation / DS-2011-3 – Rancidity Based on his experience (Perfect Source Natural Products, Inc.) with certification to NSF/ANSI 173, A. Yurcho presented on the issue of oxidation and freshness claims of edible oils, primarily fish oil. As marine lipids can be viewed as a source of contamination, Andy stressed the importance of finished product testing. Issue Paper DS-2011-1 proposes the following changes to Standard 173:

1. Revise 5.3.7 Other Product Claims:

Claims that a finished product is free of a particular contaminant or substance shall be verified in accordance with 7.4 and/or 8.

2. Revise 5.5 Oils:

Finished products Supplements containing oils at greater than 2% by weight of the formulation shall demonstrate non-rancidity of the ingredients by having a peroxide value (PV) less than 10 milliequivalents/Kg oil, a p-anisidine value (p-AV) less than 20 and a total oxidation (Totox) number (p-AV + 2PV) less than 26.

3. Revise 7.4 Test methods for chemical contaminants:

Testing shall be performed based on USFDA’s Method for Determination of Aristolochic Acid in Traditional Chinese Medicines and Dietary Supplements.

The most appropriate method shall be used to confirm claims for the product under evaluation. The source of these methods may include AOAC International, USP, EPA, FDA, AHP, European, German, Japanese monographs, INA, industry standards, etc. The use of any new method shall require that a validation be performed which includes an evaluation of specificity, linearity, reproducibility, spike recovery, and method detection limit. More rigorous validation could follow according to the guidelines of ICH, FDA, CEN, GLP, and/or AOAC, as appropriate.

Unless a manufacturer has controls in place to assess the rancidity of oil ingredients and finished products, the following finished product testing shall be performed to confirm the finished product meets the manufacturer’s specification. The Peroxide Value of the finished product shall be tested according to AOAC Method 965.33 (which is equivalent to AOCS 8-53). The p-Anisidine Value of the finished product shall be tested by AOCS Cd 18-90.The Totox Number shall be <26 and calculated as the sum of the p-Anisidine Value and two times the Peroxide Value.

H. Rice thanked Andy for his presentation and clarified that the GOED monograph is for oils preformulation, and that the intent was for measurement prior to any kind of formulation which would include the addition of any flavor. Andy explained that Duffy MacKay (CRN) had told him otherwise. Harry, who works for GOED, confirmed that the intent of the 2006 monograph revision was preformulation.


June 16, 2011


Kerri stressed that Andy’s proposed language is just too general: “Finished products containing oils at greater than 2%...” Staci agreed with the intent of Andy’s proposal and that what matters to consumers is the finished product which should have the highest possible quality. However, Staci also thought Andy’s proposal was not be the best way to accomplish this. There was general agreement about the toxicity of oxidation by-products. The problem, according to Kerri, is that the test methodology does not differentiate toxic aldehydes from esthetically pleasing flavor components that also have aldehyde functional groups. Staci stressed that the test is just not suitable for its intended purpose of testing degradation products in flavored or formulated fish oil products. GCMS would be the suitable test method. B. Sears highlighted the need for setting a standard for consumer confidence and stated that flavors are added to fish oils to hide off-flavors which come from aldehydes and ketones. Paula pointed out that it cannot be assumed that manufacturers are adding flavors and have flavor profiles based on the intent of hiding unwanted products. There was general agreement with Barry’s view that if a NSF certified product has Totox levels greater than 26, it should be on the manufacturer to demonstrate that the levels of aldehydes and ketones derived from breakdown products of marine fatty acids are below certain specified limits. Michael drew attention to the fact that there seemed to be no disagreement about Andy’s basic position on the need for testing finished products, although we would need to make sure the right analytical method is used. He wondered if Barry’s viewpoint takes us back to the ingredient, and if so, is it fair to burden formulators who are adding citric oil for the right reasons with additional testing or not. Staci stressed the reason there would be a reason for testing finished products and not just ingredients is that with the process of doing the manufacturing or during storage of the bottle on the shelf, oxidative changes can occur. Thus, it is not enough just to control the raw material quality. Kerri indicated that it wouldn’t be a huge instrumental burden to revise the Standard and have it be demonstrated in the finished product that Totox elevation is due to non-toxic aldehydes. Paula emphasized that our intent is the safety of products. Agreeing with a suggestion made earlier by Staci, Paula also stated that there is no reason not to have a finished product specification that sets a Totox number that is reasonable for that given product and is based on an appropriate analysis which demonstrates what other ingredients are contributing to that value. While the discussion was focused on rancidity, Kerri discussed her issue paper on the topic of rancidity. She mentioned NSF has run into problems in terms of living up to the way the Standard is written. It should be core to the GMP quality lab for the manufacturer to verify that all of the ingredients are not rancid and that there is adequate information to show their formulation processes do not generate toxic oxidation by-products. Kerri went on to say that Standard 173 may be too prescriptive on test methodology and may need to be revised. After much discussion, it was agreed that a task group be formed to address Issue Papers DS-2011-1 Oxidation and DS-2011-3 Rancidity. Volunteers for this task group include Andy Yurcho, Barry Sears, Staci Eisner, Harry Rice, Duffy McKay, Kerri LeVanseler, and Kevin Cox. Harry agreed to chair this task group. Joan will send out a meeting date request for the first TG meeting.


June 16, 2011


DS-2011-2 – PCBs

Andy explained that his proposal is in contrast to how the CRN/GOED monograph is written and proposes revising testing total PCBs in NSF/ANSI 173 to include all 209 PCB congeners. Staci wondered if such a change would be practical. Kerri thought additional testing would not be required. She knows that all 209 congeners are not equally toxic but is not sure if the seven stated congeners are those with higher toxicity levels. Harry volunteered to research the history of why these seven congeners were selected. This information will be shared with the Joint Committee and should simply the determination of subsequent actions. Paula will also share information on Health Canada’s requirements.

DS-2011-4 – Organoleptic/Macroscopic Test Methods

S. Dentali shared that he had noticed an omission of organoleptic test methods in section 6.1.1, which he didn’t think was intentional. Since gross organoleptic analysis is a scientifically valid test method for botanical identification if done by an appropriate qualified individual, it should be included in NSF/ANSI 173. W. Applequist asserted that qualitative characteristics are preferred over quantitative measurements for the identification of species. Kerri explained that when this section of Standard 173 was written, it was implied that you would have the actual plant and could look at the cell and see the leaf structure, and she supports the addition of ‘organoleptic.’ Joan mentioned a comment received via email from Trish Flaster (Botanical Liaisons, LLC) suggesting the use of ‘sensory evaluation’ instead of ‘organoleptic.’ It was agreed that since ‘organoleptic’ is in the regulation, it should be included. There was general agreement that the new language could be worded as follows: 6.1.1.1 MOrganoleptic/sensory evaluation and macroscopic test methods

VI NEW BUSINESS

Pesticides

K. LeVanseler stated there are very specific requirements in NSF/ANSI 173 in terms of pesticide residues for ginseng based products, a limit of10 ppb, yet there are no such specifications for pesticide residues in other herbal ingredients. Even though FDA had historically been detaining more ginseng and using low levels, Kerri wonders if we want to continue to hold ginseng to a tighter tolerance than any other herbs. She is seeking input from JC members on the topic of pesticide residue and also mentioned the idea of perhaps broadening this section of the Standard to include testing all products with herbals for pesticides. Staci thought it might make sense to harmonize with EP/USP and mentioned that USP recently broadened their range to harmonize with the EP.

Modernization of Standard 173 / NSF Deviation

This topic will be presented at the next Joint Committee meeting.


June 16, 2011


Next Meeting

The group had previously expressed an interest in meeting face-to-face again at SupplySide West. Those in attendance were leaning towards meeting on Thursday, October 13, 2011. A date request memo will be sent to the full Joint Committee. VII ADJOURNMENT P. Brown thanked everyone for their participation. Meeting adjourned at 3:09 pm (EDT). VIII ATTENDANCE

Other Attendees Name Company Interest Category Role

Steven Dentali American Herbal Products Association (AHPA) General Interest Observer

Brad Williams FDA Public Health / Regulatory Observer

Andy Yurcho Perfect Source Natural Products Industry Guest

Barry Sears DrSears.com Industry Guest

JC Members

Name Company Interest Category Role

Wendy Applequist Missouri Botanical Garden Public Health/Regulatory Member

Heather Arnold Access Business Group LLC Industry Member

Joseph Betz National Institutes of Health (NIH) Public Health/Regulatory Member

Paula Brown British Columbia Institute of Technology (BCIT) Public Health/Regulatory Chair

Martin Charron Health Canada Public Health/Regulatory Member

Staci Eisner Cortex Scientific Botanicals Industry Vice chair

Michael McGuffin American Herbal Products Association (AHPA) Industry Member

Harry Rice United Natural Products Alliance (UNPA) Industry Member

Sidney Sudberg Alkemists Labs User Member

Cara Welch Natural Products Association Industry Member

Kerri LeVanseler NSF International User Member

Joan Hoffman NSF International General Interest Secretariat


June 16, 2011


Angela Ewing NSF International General Interest Observer

Kevin Cox NSF International General Interest Observer

Jacob Larson NSF International General Interest Observer

Lisa Thomas NSF International General Interest Observer

Ed Wyszumiala NSF International General Interest Observer

JC Members NOT in Attendance

Name Company Interest Category Role

Roger Clemens USC Public Health/Regulatory Member

Greg Cumberford Bent Creek Institute Public Health/Regulatory Member

John Fitzloff UIC Public Health/Regulatory Member

Mary Hardy UCLA Public Health / Regulatory Member

Frank Jaksch Chromadex User Member

Duffy MacKay Council for Responsible Nutrition (CRN) User Member

Vince Rocco Schiff Nutrition International Industry Member

Andrew Shao Herbalife Industry Member

Katherine Sharpless NIST Public Health/Regulatory Member

Roy Upton American Herbal Pharmacopoeia User Member

Darryl Sullivan Covance, Inc. User Member

Anthony Windust National Research Council (NRC) - Canada Public Health/ Regulatory Member

Tab 2


Review of Recent Ballots


173i29r3e – Methods/QC Update

Purpose: (1) to update Section 6, Test methods used by testing laboratories for identification and quantification of ingredients – raw materials and finished products; (2) to update Section 7.4, Test methods for chemical contaminants; (3) to remove Tables 3 and 4; (4) to update the quality assurance sections related to verification testing performed to evaluate compliance with NSF/ANSI 173. Sections affected: 6, 7, Tables 3 & 4

• JC/TC Ballot passed June 28, 2011

• CPHC Ballot passed August 5, 2010

• The new language is “in effect” and published in NSF/ANSI 173 - 2011

173i30r4 – Aristolochic Acid

Purpose: (1) to update Sections 5.3.4 Natural Toxins and 7.4 Test Methods for Chemical Contaminants; (2) to revise Table A1 - Botanicals Known or Suspected to Contain Aristolochic Acid in NSF/ANSI 173. Sections affected: 5.3.4, 7.4, & Annex A

• JC/TC Ballot passed February 22, 2011

• CPHC Ballot passed March 22, 2011


173i38r1e - Normative References & Definition

Purpose: To add additional Normative References and a definition for “qualified individual” to NSF/ANSI 173.

Sections affected: 2 & 3

• JC/TC Ballot passed June 28, 2011



173i39r1e - Macroscopic Test Methods Purpose: To update the subsection heading for 6.1.1.1, Macroscopic test methods in NSF/ANSI 173. Section affected: 6.1.1.1

• JC/TC Ballot passed August 9, 2011



New Business


Item No. DS-2011-6 (For NSF International internal use)

Issue document.doc

Joint Committee Issue Document

NOTE: An issue document may be submitted at any time – it comprises two parts: the cover sheet (this page) and a description of the issue to be submitted to the Joint Committee (following page). A separate issue form is required for each issue submitted. Issue papers include proposals for modification of a standard, information reports and (of current research, etc.). An issue paper shall be categorized as being for ACTION or for INFORMATION. Submitters should limit the Issue Paper to 1 or 2 pages – attachments detailing full recommendations or background information may be attached with supplementary information. The Chairperson of the appropriate Joint Committee will respond within 30 days of receipt of the issue document advising what steps will be taken. Any issue document intended for discussion at a Joint Committee meeting must be received at least 21 days prior to the meeting to ensure inclusion in the agenda. Submit to: NSF International Attn: Standards Department 789 Dixboro Rd. Ann Arbor, Michigan 48105 Fax: 734-827-6831 e-mail: [email protected] Submitter’s contact information: Name: Clif Mclellan Company: NSF International Mailing Address: PO Box 151 City: Ann Arbor State: Michigan Zip Code: 48105 Telephone Number: 734 913 5737 E-mail: [email protected] I hereby grant NSF International the non-exclusive, royalty free rights, including non-exclusive, royalty free rights in copyright; in this item and I understand that I acquire no rights in any publication of NSF International in which this item in this or another similar or analogous form is used. Signature of Submitter * Clif McLellan Date: 9-23-2011 *Type written name will suffice as signature


Issue document.doc

Please insert a check (X) in the appropriate place to indicate if you wish the item to be considered as an action item or as an information item. Action ______X________ Information ___________________ NSF Standard(s) Impacted: NSF/ANSI 173 Issue Statement: Provide a concise statement of the issue, which reference as appropriate any specific section(s) of the standard(s) that are related to the issue. NSF International (“NSF”) has determined that the current testing requirements of NSF/ANSI Standard 173 should be modified to account for finished product and ingredient GMP requirements set forth under 21 CFR § 111 (which are incorporated into Section 8 of the Standard). NSF is requesting to modify NSF/ANSI Standard 173 to allow NSF increased flexibility in selecting specific finished product claims for analysis based upon the number of finished product claims and ingredients present on the product label. Background: Provide a brief background statement indicating the cause and nature of concern, the impacts identified relevant to public health, public understanding, etc, and any other reason why the issue should be considered by the Committee. As stated above, NSF is requesting to modify the finished product claim testing requirements of NSF/ANSI Standard 173 to allow NSF the ability to test a limited number of finished product claims based upon the total number of finished product claims and ingredients present on the product label. It should be noted that NSF has historically taken the approach of testing ALL ingredients and/or label claims where feasible. This prior approach has led to significant difficulties and delays in obtaining test results due to the complexities of matrices of the various supplement products. The proposed approach, which is being designated as “targeted verification”, will significantly reduce the amount of finished product claim testing performed by NSF by only verifying a limited number of finished product claims. This issue arose due to the amount of testing being performed by NSF on finished products, ingredients as well as raw materials used in finished products. Upon review, it was determined that certain tests being performed by NSF were duplicative to GMP testing requirements. As an example, NSF was performing identity testing on raw materials when such identity testing could not be performed on the finished product due to testing matrix issues. If compliant with GMP requirements, manufacturers will already have identity test data for such raw materials. Due to the overlap of GMP and NSF testing, it is intended that the “targeted verification” approach will complement the GMP requirements by


Issue document.doc

testing a limited number of finished product claims as way to further verify that the product is being produced in accordance with GMP regulations. Regarding the impact of this proposal on public health, it should be noted that this deviation is only applicable to finished product claims and not contaminant testing. NSF will continue to perform the full battery contaminant testing on finished products and ingredients. NSF will also continue to test for adulterants that are associated with specific ingredients. As part of this proposal, NSF will also be modifying the pesticide testing requirements to no longer allow manufacturers who screen for pesticides to avoid pesticide testing by NSF under Section 5.3.2. By continuing to test for contaminants and adulterants, it is NSF’s position that the proposed change to a “targeted verification” approach will not have a negative impact on public health. Recommendation: If action by the Joint Committee is being requested, clearly state what action is needed: e.g., recommended changes to the standard(s) including the current text of the relevant section(s) indicating deletions by use of strike-out and additions by highlighting or underlining; e.g., reference of the issue to a Task Force for detailed consideration; etc. If recommended text changes are more than a half page, please attach a separate document. Due to the extent of the changes required, attached to this document is the approved deviation to NSF/ANSI Standard 173 that was issued in May 2011 which incorporates the changes necessary to implement the new testing approach proposed by NSF. Please see attached document. Supplementary Materials (photographs, diagrams, reports, etc.): If not provided electronically, the submitter will be responsible to have sufficient copies to distribute to committee members. Signature of Submitter * Clif McLellan Date: 9-23-2011

Dietary supplements

NSF International Standard/ American National Standard

NSF/ANSI 173 – 2010

NSF International, an independent, not-for-profit, non-governmental organization, is dedicated to being the leading global provider of public health and safety-based risk management solutions while serving the interests of all stakeholders.

This Standard is subject to revision. Contact NSF to confirm this revision is current.

Users of this Standard may request clarifications and interpretations, or propose revisions by contacting:

Chair, Joint Committee on Dietary Supplements

NSF International 789 North Dixboro Road, P.O. Box 130140

Ann Arbor, Michigan 48113-0140 USA Phone: (734) 769-8010 Telex: 753215 NSF INTL

FAX: (734) 769-0109 E-mail: [email protected]

Web: http://www.nsf.org

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NSF International Standard/ American National Standard for Dietary Supplements ―

Dietary supplements Standard Developer

NSF International American National Standards Institute Designated as an ANSI Standard November 22, 2010 American National Standards Institute

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Prepared by The NSF Joint Committee on Dietary Supplements Recommended for Adoption by The NSF Council of Public Health Consultants Adopted by NSF International January 2003 Revised July 2005 Revised August 2006 Revised July 2007 Revised April 2008 Revised September 2008 Revised April 2009 Revised November 2010 Published by NSF International PO Box 130140, Ann Arbor, Michigan 48113-0140, USA For ordering copies or for making inquiries with regard to this Standard, please reference the designation “NSF/ANSI 173 – 2010.” Copyright 2011 NSF International Previous editions © 2009, 2008, 2007, 2006, 2005, 2003 Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from NSF International. Printed in the United States of America.

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Disclaimers1 NSF, in performing its functions in accordance with its objectives, does not assume or undertake to discharge any responsibility of the manufacturer or any other party. The opinions and findings of NSF represent its professional judgment. NSF shall not be responsible to anyone for the use of or reliance upon this Standard by anyone. NSF shall not incur any obligation or liability for damages, including consequential damages, arising out of or in connection with the use, interpretation of, or reliance upon this Standard. NSF Standards provide basic criteria to promote sanitation and protection of the public health. Provisions for mechanical and electrical safety have not been included in this Standard because governmental agencies or other national standards-setting organizations provide safety requirements. Participation in NSF Standards development activities by regulatory agency representatives (federal, local, state) shall not constitute their agency's endorsement of NSF or any of its Standards. Preference is given to the use of performance criteria measurable by examination or testing in NSF Standards development when such performance criteria may reasonably be used in lieu of design, materials, or construction criteria. The illustrations, if provided, are intended to assist in understanding their adjacent standard requirements. However, the illustrations may not include all requirements for a specific product or unit, nor do they show the only method of fabricating such arrangements. Such partial drawings shall not be used to justify improper or incomplete design and construction. Unless otherwise referenced, the annexes are not considered an integral part of NSF Standards. The annexes are provided as general guidelines to the manufacturer, regulatory agency, user, or certifying organization.

1 The information contained in this Disclaimer is not part of this American National Standard (ANS) and has not been processed in accordance with ANSI’s requirements for an ANS. Therefore, this Disclaimer may contain material that has not been subjected to public review or a consensus process. In addition, it does not contain requirements necessary for conformance to the Standard.

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Contents 1 General ................................................................................................................................................... 1 1.1 Purpose ............................................................................................................................................ 1 1.2 Scope ............................................................................................................................................... 1 1.3 Formulation submission ................................................................................................................... 1 2 Normative references ........................................................................................................................... 32 3 Definitions ............................................................................................................................................. 65 4 Labeling and literature requirements .................................................................................................... 87 5 Product requirements – verified by testing laboratories ....................................................................... 87 5.1 Identity ............................................................................................................................................ 87 5.2 Quantity ........................................................................................................................................ 108 Table 1 – Quantity of dietary ingredients required for testing ...................................................... 108 5.3 Contaminants ............................................................................................................................... 118 5.4 Disintegration ............................................................................................................................. 1210 5.5 Oils ............................................................................................................................................. 1311 6 Test methods used by testing laboratories for identification and quantification

of ingredients – raw materials and finished products ....................................................................... 1311 6.1 Identification test methods ......................................................................................................... 1311 6.2 Quantification test methods ....................................................................................................... 1412 7 Test methods used by testing laboratories for detection of contaminants – raw

materials and finished products ........................................................................................................ 1614 7.1 Test methods for metals............................................................................................................. 1614 7.2 Pesticides ................................................................................................................................... 1714 Table 2 – CAS numbers for pesticides present in Panax ginseng and Panax quinquefolius .... 1714 7.3 Test methods for microbiological contaminants ......................................................................... 1715 7.4 Test methods for chemical contaminants .................................................................................. 1916 8 Good Manufacturing Practices ......................................................................................................... 2017 8.1 Written recall procedures ........................................................................................................... 2017 8. 2 Compliance with The Public Health Security and Bioterrorism Preparedness and

Response Act of 2002 ..................................................................................................................... 2017 8.3 Compliance with the Dietary Supplement and Non Prescription Drug Consumer

Protection Act ................................................................................................................................... 2017 Table 3 – Test methods for dietary ingredients ......................................................................... 2018 Table 4 – Test methods for marker constituent compounds ...................................................... 2320 Table 5A – Acceptable limits for microbiological contaminants in raw materials....................... 2421 Table 5B – Acceptable limits for pathogenic microbiological contaminants in raw materials .... 2421 Table 6A – Acceptable limits for microbiological contaminants in finished products ................. 2522 Table 6B – Acceptable limits for pathogenic microbiological contaminants in finished products2522

Annex A ....................................................................................................................................................... A1 Table A1 – Botanicals known or suspected to contain aristolochic acid ....................................... A1 Annex B ....................................................................................................................................................... B1 B.1 Metals ............................................................................................................................................. B1 B.2 Microbiological contaminants ......................................................................................................... B1

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Annex C ....................................................................................................................................................... C1 C.1 Normalization of laboratory data .................................................................................................... C1 C.2 Sampling and reporting of laboratory data ..................................................................................... C1 C.3 Normalization calculations ............................................................................................................. C1

© 2011 NSF NSF/ANSI 173 – 2010

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Foreword2 The purpose of NSF/ANSI 173 is to serve as an evaluation tool for analyzing dietary supplements. Certification to this Standard serves as a communication tool between manufacturers of ingredients and finished product, retailers, healthcare practitioners, and consumers. This Standard provides test methods and evaluation criteria to allow for the determination that a dietary supplement contains the ingredients claimed on the label, either qualitatively or quantitatively, and that it does not contain specific undeclared contaminants. In some instances, validated laboratory methods are not yet available for analyzing certain ingredients. In such cases, new methods will be added to this Standard as they become available. NSF/ANSI 173 was developed with participation from the dietary supplements industry, public health regulators, and distributors of dietary supplements. Participation and technical guidance was provided by representatives of the American Herbal Products Association, the American Pharmaceutical Association, the Consumer Healthcare Products Association, the Council for Responsible Nutrition, the National Institutes of Health, and the National Nutritional Foods Association. This edition of the Standard (NSF/ANSI 173-2010) includes the following revisions:

Issue 31 - Diethylene glycol (DEG) Sections 5.3.6.2 Contaminants in Glycerin and 7.5.2 Test methods for Glycerin have been added to the Standard. Issue 33 - Section 7 Testing methodologies have been updated in Section 7.3 Test methods for microbiological contaminants.

Issue 34 – Dioxins Acceptance levels for dioxins and dioxin-like PCBs have been updated in Section 5.3.6 Industrial Contaminants. Issue 35 - Enteric Coated Tablets Disintegration testing for delayed release/enteric coated capsules and tablets has been updated in Section 5.4 Disintegration.

NSF offers a certification program to this Standard. Products certified by NSF carry the NSF Mark, the leading mark in public health and safety certification around the world. The NSF Mark on a product gives consumers and retailers assurance that the product meets the requirements of the NSF Standard. For more information on the NSF certification program, please contact the General Manager of Dietary Supplements, P.O. Box 130140, Ann Arbor, Michigan 48113–0140 or at 734-769-8010. Suggestions for improvement of this Standard are welcome. Comments should be sent to Chair, Dietary Supplements, c/o NSF International, Standards Department, P.O. Box 130140, Ann Arbor, Michigan, 48113-0140,USA.

2 The information contained in this Foreword is not part of this American National Standard (ANS) and has not been processed in accordance with ANSI’s requirements for an ANS. Therefore, this Foreword may contain material that has not been subjected to public review or a consensus process. In addition, it does not contain requirements necessary for conformance to the Standard.

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NSF International Standard for Dietary Supplements ―

Dietary supplements 1 General 1.1 Purpose This Standard provides test methods and evaluation criteria for dietary supplement products to allow for the determination that the ingredients in the product are accurately identified, that the product contains the quantity of dietary ingredients and marker constituents declared on the product label, and that the product does not contain unacceptable quantities of contaminants. This Standard also provides criteria for determining that Good Manufacturing Practices were followed in the production of dietary supplements. 1.2 Scope This Standard contains requirements for dietary supplements that contain 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 combinations of these ingredients. This Standard does not include products represented for use as conventional foods. Products and ingredients deemed a hazard to public health or safety by a regulatory agency having jurisdiction shall be excluded from the scope of this document. Conventional foods are excluded from the scope of this Standard. Compliance to this Standard does imply the product evaluated meets all applicable regulatory requirements. This statement is intended to add clarification regarding the scope of this standard. 1.3 Formulation submission The manufacturer shall submit, at a minimum, the following information for each product:

– complete formulation information, which includes the following:

– the composition of the formulation (in percent or parts by weight for each ingredient in the formulation including excipients);

NOTE – Ranges shall be considered acceptable.

– the reaction process, if applicable;

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– the raw material ID number (if applicable), chemical/material name, trade name and supplier(s) for each chemical present in the formulation;

– a list of known or suspected impurities associated with the finished product; and

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– when available, an analytical method used to verify the claims listed on the label or certificate of analysis.

2 Normative references The following documents contain provisions that, through reference in this text, constitute provisions of this Standard. At the time this Standard was written, the editions indicated were valid. All documents are subject to revision, and parties are encouraged to investigate the possibility of applying the most recent edition of the document indicated below. 21 CFR, Chapter 9, Federal Food, Drug and Cosmetic Act (FFDCA)3 40 CFR Part 141, National Primary Drinking Water Regulations3

AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Ashwagandha Root, April 20004 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Astragalus Root, August 19994 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Bilberry fruit, 20014 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Black Cohash root, 20024 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Black Haw Bark, June 20004 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Chaste Tree Fruit, 20014 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Cramp Bark, February 20004

AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Cranberry, 20024 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Dang Gui Root, 20034 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Echinacea purpurea Root, 20044 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Ginkgo Leaf, 20034 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Goldenseal, 20014 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Hawthorn Berry, June 19994 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Hawthorn Leaf with Flower, February 19994 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Reishi Mushroom, September 20004 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, St. John’s Wort, July 19974 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Schisandra Berry, October 19994 AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Valerian Root, April 19994

3 US Government Printing Office, Washington, D. C. 20402 <www.gpo.gov>. 4 American Herbal Pharmacopoeia (AHP), P. O. Box 66809, Scotts Valley, CA 95067 <www.herbal-ahp.org>.

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AHP, American Herbal Pharmacopoeia and Therapeutic Compendium, Willow Bark, December 19994 AHPA, Herbs of Commerce, 2nd Edition, 20005 AOAC International/Food and Drug Administration, Bacteriological Analytical Manual, (BAM) 8th edition, 19986 AOAC International, Official Methods of Analysis, 18th edition (2005)7 American Oil Chemists’ Society, AOCS Official Method Cd 18-90, p-Anisidine Value, Sampling and Analysis of Commercial Fats and Oils, 19978 British Herbal Medicine Association, (BHMA), British Herbal Pharmacopoeia, 19969 Compliance Services International, Analytical Method for the Determination of Quintozene and Its Degradates and Impurities in Ground Dried Ginseng Root by Gas Chromatography Laboratory validation of analytical method number CSI-023-01, 199910 Dietary Supplement Health and Education Act of 1994 (DSHEA), Public Law 103-4176 GOED, Voluntary Monograph11

Health Canada, Fish Oil Monograph12 INA, Allicin by High-Performance Liquid Chromatography13 INA, Black Cohosh Assay by ELSD13 INA, Catechins and Gallic Acid in Green Tea by HPLC13 INA, Fatty Acid Content in Saw Palmetto by Gas Chromatography13

INA, Ginkgo Flavonol Glycoside Assay by HPLC13 INA, Ginkgoterpenoid Assay by HPLC13 INA, Kavalactone Assay by HPLC13

5 American Herbal Products Association (AHPA), 8630 Fenton St., Suite 918, Silver Spring, MD 20910 <www.ahpa.org>. 6 US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002 <www.fda.gov>. 7 AOAC International, 481 N. Frederick Avenue, Suite 500, Gaithersburg, MD 20877 <www.aoac.org>. 8 AOCS, 2710 S. Boulder, Urbana, IL 61802 <www.aocs.org>. 9 British Herbal Medicine Association, P.O. Box 583, Exeter EXI 96X UK <www.bhma.info>. 10 Compliance Services International, 7501 Bridgeport Way West, Lakewood, WA 98499 <www.complianceservices.com>. 11 Global Organization for EPA and DHA Omega-3s (GOED), 1075 Hollywood Ave., Salt Lake City, UT 84105 <www.goedomega3.com>.

12 Health Canada, Address Locator 0900C2, Ottawa, Ontario K1A 0K9 Canada <www.hc.sc.gc.ca >.

13 Institute for Nutraceutical Advancement (INA), c/o NSF International, 789 N. Dixboro Road, Ann Arbor, MI 48105 <http://www.nsf.org/business/ina/index.asp?program=INA>.

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INA, Phenolics in Echinacea by HPLC13

INA, St. John’s Wort Assay by HPLC13 INA, Sterols Content in Saw Palmetto by Gas Chromatography13 International Code for Botanical Nomenclature (St. Louis Code), 200014 NTIS/IEC 17025: 1999 General requirements for the competence of testing and calibration laboratories15 The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals (Annual)16 NSF International White Book: Listing of Proprietary Substances and Nonfood Compounds17 USEPA Methods for the Determination of Metals in Environmental Samples – Supplement, 1 – EPA/600/R-94-111 – May 199418 USEPA Microwave Assisted Acid Digestion of Sediments, Sludges, Soils and Oils, EPA Method 3510 – September 199418 USFDA, Pesticide Analytical Manual (PAM) Volume I. Multiresidue Methods, 3rd Edition, 19946

USFDA, Pesticide Analytical Manual (PAM) Volume I. Updates. 20036

USFDA, Pesticide Analytical Manual (PAM) Volume II. Methods for Residues of Individual Pesticides – 19916 USFDA, Food Code 2001 Recommendations of the United States Public Health Service Food and Drug Administration6 USFDA, A Multiresidue Pesticide Monitoring Procedure for the Determination of 112 Halogenated Pesticides Using Gas Chromatography with Mass Selective Detection and Selected ion Monitoring. Laboratory Information Bulletin, 43046

USFDA, Determination of Aristolochic Acid in Traditional Chinese Medicines and Dietary Supplements6

USFDA, Public Health Security and Bioterrorism Preparedness and Response Act of 2002, H.R.3448.ENR6 USP, Dietary Supplements Compendium (DSC)19 USP, Glycerin Monograph19

USP, United States Pharmacopeia – National Formulary (USP-NF)19

14 Koeltz Scientific Books, P.O. Box 1360, D-61453, Koenigstein, Germany <www.koeltz.com>. 15 National Technical Information Service, 5285 Port Royal Rd., Springfield, VA 22161 <www.ntis.gov>. 16 Merck & Company, One Merck Drive, Whitehouse Station, NJ 08889 <www.merck.com>. 17 NSF International, 789 N. Dixboro Road, Ann Arbor, MI 48105 <www.nsf.org>. 18 USEPA, Washington, DC 20460 <www.epa.gov>. 19 United States Pharmacopeia (USP), 12601 Twinbrook Parkway, Rockville, Maryland 20852 <www.usp.org>.

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World Health Organization, WHO Guidelines for Drinking-Water Quality20

World Health Organization, WHO Monographs on Selected Medicinal Plants, Volume 1, 2 and 320

3 Definitions Terms used in this Standard that have special technical meaning are defined here. 3.1 active ingredient: The principal ingredient identified in a product’s name or on its principal display panel. 3.2 adulteration: As defined by the Federal Food and Cosmetic Act, §402, adulterated food is defined in Title 21, USC §342. 3.3 batch or lot: A specific quantity of a finished product or other material that is intended to have uniform character and quality, within specified limits, and/or is produced according to a single manufacturing order during the same cycle of manufacture. 3.4 botanical ingredient (botanical): An ingredient consisting of, or derived from a plant or microorganism (e.g. fungi or cyanobacteria). 3.4.1 botanical ingredient - extract: The complex, multicomponent mixture obtained after using a solvent to dissolve components of the biomass. Extracts may be in dry, liquid, or semi-solid form. Excipients may be added to extracts to adjust the concentration, enhance stability, limit microbial growth, and to improve drying, flow, or other manufacturing characteristics. Extracts are not the same as expressed juices, pure chemicals isolated from an herb, or synthetically modified plant constituents. 3.4.2 botanical ingredient - non-extract: Crude botanical material (whole, cut or powdered herb). 3.5 chewable: Intended to be reduced through mastication. 3.6 dietary ingredient: An ingredient intended for use or used in a dietary supplement that is 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, or extract. 3.6.1 Class I (dietary ingredient): An added nutrient. 3.6.2 Class II (dietary ingredient): A naturally occurring (indigenous) nutrient. 3.7 dietary supplement: A product (other than tobacco) that:

– is intended to supplement the diet and 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 combinations of these ingredients; – is intended for ingestion in pill, capsule, tablet, powder, or liquid form; – is not represented for use as a conventional food or as the sole item of a meal or diet; – is labeled as a “dietary supplement” or has the word “dietary” deleted and replaced by the name of the dietary ingredient/s in the product (e.g., calcium supplement) or an appropriately

20 World Health Organization, 1211 Geneva 27, Switzerland <www.who.int>.

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descriptive term indicating the type of dietary ingredients that are in the product (e.g., herbal supplement with vitamins); and – includes an article that is approved as a new drug under section 505, certified as an antibiotic under section 507, or licensed as a biologic under section 351, of the Public Health Service Act (42 U.S.C. 262), and was, prior to such approval, certification, or license, marketed as a dietary supplement or as a food unless the Secretary (U.S. Department of Health and Human Services, USFDAP) has issued a regulation, after notice, and comment, finding that the article, when used as or in a dietary supplement under the conditions of use and dosages set forth in the labeling for such dietary supplement, is unlawful under section 402(f), and does not include an article that is approved as a new drug under section 505, certified as an antibiotic under section 507, or licensed as a biologic under section 351 of the Public Health Service Act (42 U.S.C. 262) or an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food unless the Secretary, in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful.

3.8 finished product: A product requiring no further processing prior to sale to the consumer. 3.9 Good Manufacturing Practices (GMP): A system of procedures and documentation, written or analytical, to ensure that the product has the identity, strength, composition, quality, and purity that it is represented to possess. 3.10 in-process material: A material fabricated, compounded, blended, ground, extracted, sifted, sterilized, derived by chemical reaction, or processed in any other way that is produced for, and used in, the preparation of a dietary ingredient or supplement prior to packaging as ready for sale. 3.11 lot number: A distinctive combination of letters, numbers, or symbols, or any combination thereof from which the complete history of the manufacture, processing, packaging, holding, and distribution of a batch or lot of a finished dietary ingredient, dietary supplement, or other material can be determined. 3.12 manufacture or manufacturing: All operations associated with the production of dietary supplements, including packaging, labeling, testing, and quality control of a dietary ingredient or dietary supplement. 3.13 major food allergen: In accordance with the USFDA’s Food Allergen Labeling and Consumer Protection Act of 20046 and for the purposes of this Standard, major food allergens are considered milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans. Highly purified oils are exempt by law. 3.14 marker constituent: A compound present in a botanical that is characteristic of the botanical and used for technical purposes, and that allows for the quantification of the ingredients incorporated into the product, e.g., identification of the botanical or process control. 3.15 measure of uncertainty: An estimation of the variability in an analytical result that can be reasonably expected based on the methodology employed. The estimate is based in part on parameters such as reproducibility, reference materials, and sample effects including matrix spike recoveries and scientific experience. 3.16 plant: A building or facility, or parts thereof, used for or in connection with the manufacturing, packaging, labeling, and/or holding of a dietary product. 3.17 pest: An objectionable animal or insect, e.g., bird, rodent, insect, or larva.

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3.18 quality control system: A planned systematic procedure for taking all actions necessary to produce consistent, unadulterated dietary ingredients or dietary supplements. 3.19 quality control unit: A person or organizational element designated by a firm to be responsible for duties relating to quality control operations. 3.20 raw material: An ingredient intended for use in the manufacture of a dietary ingredient or dietary supplement, including those that may not appear in such finished product. 3.21 representative sample: A sample that consists of a number of units that are drawn based on rational criteria, such as random sampling, and is intended to ensure that the sample accurately portrays the material being sampled. 3.22 rework: Clean, unadulterated material that has been removed from processing for reasons other than unsanitary conditions, or that has been successfully reconditioned by reprocessing, and that is suitable for use in the manufacture of a dietary product. 3.23 specifications: The quality parameters to which the products or materials shall conform and that serve as a basis for quality evaluation. 4 Labeling and literature requirements Product labels shall declare the identity of dietary ingredient(s) and/or marker constituent(s) included in the product. Labels of products other than proprietary blends shall declare the quantity of each dietary ingredient and/or marker constituent, which shall be labeled by common name according to the Merck Index or in accordance with the appropriate regulatory agency guidance when available. Labels of products containing botanicals shall include the part of the plant from which the ingredients are derived. Common names of botanicals shall be in accordance with Herbs of Commerce or the International Code of Botanical Nomenclature. The amount of active or desired ingredient shall be listed in addition to the total amount of the ingredient. Product literature may also include this information. Labels shall comply with appropriate regulatory requirements. [This implies that the label meets all FTC and FDA requirements which is not a realistic expectation. In addition, unforeseen liability exists for NSF if a product is certified by NSF that may not meet the interpretations of the FDA or FTC]. 5 Product requirements – verified by testing laboratories All dietary supplements shall meet all applicable regulatory requirements. [This implies that the product meets all FTC and FDA requirements which may not be a realistic expectation. In addition, unforeseen liability exists for NSF if a product is certified by NSF that may not meet the interpretations of the FDA or FTC]. The removal of “verified by testing laboratories was removed because there are aspects of the product requirements that are verified by auditing and/or the testing that is performed by the client. 5.1 Identity 5.1.1 Raw materials

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The identity of the raw material shall be verified in accordance with 6.1 and/or 8 using the test method(s) appropriate for establishing identity based on the manufacturer’s claims. 5.1.2 Finished product All Manufacturers are responsible for ensuring finished products shall contain each of the dietary ingredients and/or marker constituents declared on the label when tested in accordance with 6.1. The source of each ingredient shall be verified as listed on the label. This change is being made because of the requirements that manufacturers of Dietary Supplements meet GMP requirements. When the Standard was originally written, these requirements were not in place. This is accomplished through compliance with Good Manufacturing Practices as indicated in section 8. Identity testing is a GMP requirement for each lot of raw material prior to incorporation into a finished product. Proof that adequate identity testing is in place shall be provided upon request to ensure compliance with the requirements herein.


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5.2 Quantity 5.2.1 Raw materials The quantity of marker constituents shall be verified in accordance with 6.2 when declared on the certificate of analysis. Other declarations made in the certificate of analysis and/or the Raw Material Specification shall be verified in accordance with 6.2, 7.4, and/or 8. 5.2.2 Finished products “Finished product claims will be reviewed to determine a set of verification tests to confirm quantity of dietary ingredients, marker constituents and/or nutritional declarations as declared on the label in accordance with 6.2 and/or 8.” The product shall contain at least 100% (minus the measure of uncertainty) of the quantity of each Class I dietary ingredient and/or marker constituent that is subject to verification testing. The product shall contain at least 80% (minus the measure of uncertainty) of the quantity of each Class II dietary ingredient and/or marker constituent that is subject to verification testing. The quantity of dietary ingredients and/or marker constituents declared on the label shall be verified in accordance with 6.2 and/or 8. Nutritional declarations shall be verified in accordance with 6.2 only when the quantity claimed is greater than 2% of the daily recommended value (DRV) (based on the reference caloric intake of 2,000 calories) as detailed in the following table (ref. is 21 CFR 101.9).

Table 1 – Quantity of dietary ingredients required for testing

Component DRV (units) Level requiring testingcholesterol 300 mg > 6 g/serving Fat 65 g > 1.3 g/serving fiber 25 g > 0.5 g/serving potassium 3,500 mg > 70 mg/serving protein 50 g > 1 g/serving saturated fatty acids 20 g > 0.4 g/serving sodium 2,400 mg > 48 mg/serving total carbohydrate sugar 300 g > 6 g/serving

The product shall contain at least 100% (minus the measure of uncertainty) of the quantity of each Class I dietary ingredient and/or marker constituent declared on the label. The product shall contain at least 80% (minus the measure of uncertainty) of the quantity of each Class II dietary ingredient and/or marker constituent declared on the label. The product shall not contain quantities in excess of those permitted by GMP (manufacturer’s specifications). This change is due to the recognition that testing for the substances in this table when they are present at ONLY 2% of the DRV may not be meaningful. In addition, testing these substances at that low of level can require significant resources due to difficulties with matrix effects which exceed the value of the test. In addition, This change is also being made because of the requirements that manufacturers of Dietary Supplements meet GMP requirements. When the Standard was originally written, these requirements were not in place. This is accomplished through compliance with Good Manufacturing Practices as indicated in section 8. Identity testing is a GMP requirement for each lot of raw material prior to incorporation into a finished product. Proof that adequate identity testing is in place shall be provided upon request to ensure compliance with the requirements herein.

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5.3 Contaminants 5.3.1 Metals 5.3.1.1 Raw materials Raw materials shall not contain undeclared metals in amounts greater than the following:

– arsenic content shall not exceed 5 parts per million (ppm); – cadmium content shall not exceed 0.3 ppm; – chromium (VI) content shall not exceed 2 ppm; – lead content shall not exceed 10 ppm; and – mercury content shall not exceed 0.2 ppm.

5.3.1.2 Finished products

Finished products shall not contain undeclared metals at rates of intake greater than the following:

– inorganic arsenic content shall not exceed 0.01 milligrams per daily dose (mg/d); – cadmium content shall not exceed 0.006 mg/d; – chromium (VI) content shall not exceed 0.02 mg/d; – lead content shall not exceed 0.02 mg/d; and – mercury content shall not exceed 0.02 mg/d.

5.3.2 Pesticides Unless a manufacturer has controls in place to screen for pesticides or use certified organic ingredients as demonstrated in the GMP audit, a A broad pesticide screen shall be performed to confirm compliance with USFDA and USEPA regulated limits and the absence of banned pesticides in botanical products. The purpose of this deviation is to assure all botanical products are tested for banned pesticides. Raw materials and finished products containing Panax ginseng or Panax quinquefolius shall not contain pesticides listed in 7.2.2 (limit of detection is less than 10 parts per billion (ppb)). 5.3.3 Microbiological contaminants Raw materials shall not contain aflatoxins at levels greater than 20 ppb and shall not contain microorganisms in quantities greater than permitted in tables 5A and 5B. Finished products shall not contain aflatoxins at levels greater than 20 ppb and shall not contain microorganisms in quantities greater than permitted in tables 6A and 6B. Finished products in a liquid form with an alcohol content less than or equal to 50% shall not contain Pseudomonas aeruginosa. Finished products with an alcohol content greater than or equal to 50% are exempt from microbial testing. 5.3.4 Natural toxins Botanicals listed in Annex A shall not contain aristolochic acid (limit of detection is 0.5 g/gm).

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5.3.5 Known adulterants Products shall be evaluated to ensure that they do not contain known adulterants including, but not limited to, the following:

– Eleutherococcus senticosus shall not contain Periploca sepium root. – Plantago lanceolata shall not contain Digitalis lanata leaf. – Scutellaria lateriflora shall not contain Teucrium chamaedrys. – Stephania tetranda shall not contain Aristolochia fangchi.

5.3.6 Industrial Contaminants 5.3.6.1 Contaminants in Fish Oil

For ingredients and products containing natural fish oil, manufacturers shall have controls in place to screen for polychlorinated biphenyls (PCBs), polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like PCBs in the oil ingredient. The content of dioxins and furans expressed as the sum of PCDDs and PCDFs shall not exceed 2 pg WHO-TEQ per gram of oil and dioxin-like PCBs shall not exceed 3 pg WHO-TEQ per gram of oil.21 The dioxin-like PCBs shall include the IUPAC congeners 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169 and 189. In the event that the per gram limits for dioxins and furans or dioxin-like PCBs are exceeded, a daily dose based limit will be applied. The daily dose of the sum of the dioxins/furans and the dioxin-like PCBs shall not exceed 20 pg.12

NOTE – The acceptable daily dose of 20 pg/day is based on the Health Canada Fish Oil Monograph limit of 2 pg/kg b.w./day. Due to the targeted marketing of fish oils to children, a body weight of a child (10 kg) was used to derive the daily dose of 20 pg/day for dioxin/furan (PCDD and PCDF).

Total PCBs shall not exceed 0.09 mg/kg of oil (w/w). Total PCBs shall, at a minimum, include IUPAC congeners 28, 52, 101, 118, 138, 153, and 180. 5.3.6.2 Contaminants in Glycerin For ingredients and products containing glycerin, manufacturers shall have good manufacturing controls in place to verify that any specific lot of glycerin used in the manufacture or preparation of products is tested for diethylene glycol (DEG). Diethylene glycol in glycerin raw materials shall not exceed 0.1% as stated in the USP Glycerin monograph.19 5.3.7 Other product claims Claims that a product is free of a particular contaminant or substance shall be verified in accordance with 7.4 and/or 8. 5.4 Disintegration

21 Global Organization for EPA and DHA Omega-3s, GOED Voluntary Monograph Omega-3, July 2006 Dioxin limits include the sum of polychlorinated dibenzo-para-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) and are expressed in World Health Organization (WHO) toxic equivalents using WHO-toxic equivalent factors (TEFs). This means that analytical results relating to 17 individual dioxin congeners of toxicological concern are expressed in a single quantifiable unit: TCDD toxic equivalent concentration or TEQ.

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5.4.1. Uncoated, film-coated, plain-coated, and hard and soft gelatin capsules

Supplements shall be verified as meeting the requirements for disintegration when tested using the equipment described in the currently promulgated version of the United States Pharmacopeia (USP) and in the USP monograph applicable to the product being evaluated. For products where no USP monograph applies, testing will be performed using deionized water as the immersion fluid for a time period of 60 min. . 5.4.2. Delayed release (enteric coated tablets)

Supplements which are claimed to be “delayed release” or “enteric coated” shall be verified as meeting the disintegration requirements for delayed release (enteric coated tablets) using the method described in the currently promulgated version of the United States Pharmacopeia (USP). The method employs simulated gastric fluid for one hour, followed by simulated intestinal fluid for a time period no greater than 8 h or for the time specified in the USP monograph if applicable to the product being evaluated. The tablets shall not disintegrate within the first hour of immersion. 5.4.3 Timed or slow release

Supplements which claim “timed release” or “slow release” shall be tested for disintegration using the equipment described in the currently promulgated version of the United States Pharmacopeia (USP). Testing will be performed using 0.1 M hydrochloric acid as the immersion fluid for a time period no greater than 8 h or for the time period indicated on the product label. The tablets shall not disintegrate within the first hour of immersion. 5.4.4 Other products

Chewables, powders, and liquids are exempt from disintegration testing requirements. 5.5 Oils Supplements containing oils at greater than 2% by weight of the formulation shall demonstrate non-rancidity of the ingredients by having a peroxide value (PV) less than 10 milliequivalents/Kg oil, a p-anisidine value (p-AV) less than 20, and a total oxidation (Totox) number (p-AV + 2PV) less than 26. 6 Test methods used by testing laboratories for identification and quantification of ingredients – raw materials and finished products 6.1 Identification test methods 6.1.1 Botanicals 6.1.1.1 Macroscopic test methods The identity of products shall be evaluated by an appropriate qualified individual based on the information contained in the monographs listed in table 3. 6.1.1.2 Microscopic test methods The identity of products shall be evaluated by an appropriate qualified individual based on the information contained in the monographs listed in table 3. 6.1.1.3 Chemical test methods

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The identity of dietary ingredients shall be evaluated in accordance with the methods in table 3. If no method exists or if improved technology allows for a more accurate and precise method to be developed, one may be developed. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity and reproducibility. More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate.

6.1.2 Vitamins The identity of vitamins shall be evaluated in accordance with the methods listed in the currently promulgated version of the United States Pharmacopeia (USP). If no method exists or if improved technology allows for a more accurate and precise method to be developed, one may be developed. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity and reproducibility. More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate.

6.1.3 Minerals The identity of minerals shall be evaluated in accordance with the methods listed in the currently promulgated version of the United States Pharmacopeia (USP). If no method exists or if improved technology allows for a more accurate and precise method to be developed, one may be developed. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity and reproducibility. More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate. 6.1.4 Other dietary supplement ingredients An effort shall be made to seek out the most appropriate method to The most appropriate method available would be selected to confirm claims for the product under evaluation, t. The source of these methods may include AOAC International, USP, AHP, European, German, Japanese monographs, INA, etc. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity and reproducibility. More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate.. The purpose of this change is to add transparency regarding the limits of the available methodology regarding the testing of dietary supplements. The language that states “an effort shall be made” presents an onerous barrier to completing the analysis and testing of these products. The matrixes are variable and complex and many times completing the tests are not achievable. 6.1.5 Quality assurance for identification test methods Identification test methods shall be performed using certified reference standards or materials when available. These shall include vouchered specimens, certified reference materials, and/or single chemicals with established identity. To the extent to which it is feasible, the reference standard or material shall be prepared in the same manner as the sample being evaluated. 6.2 Quantification test methods

22 ICH Secretariat, c/o IFPMA, 15, chemin Louis-Dumant, P.O. Box 195, 1211 Geneva 20, Switzerland <www.ich.org>. 23 European Committee for Standardization (CEN), Avenue Marnix 17, B-1000, Brussels <www.cen.eu>.

Formatted





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6.2.1 Botanicals If declared on the label, the identity of marker constituents shall be evaluated in accordance with the methods in table 4.[ If no method exists or if improved technology allows for a more accurate and precise method to be developed, one may be developed. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity, linearity, reproducibility, accuracy, spike recovery, and method detection limit (if applicable). More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate.

6.2.2 Vitamins The quantity of vitamins shall be evaluated in accordance with the methods listed in the USP-NF. If no method exists or if improved technology allows for a more accurate and precise method to be developed, one may be developed. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity, linearity, reproducibility, accuracy, spike recovery, and method detection limit (if applicable). More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate. 6.2.3 Minerals The quantity of minerals shall be evaluated in accordance with the methods listed in the United States Pharmacopeia (USP). If no method exists or if improved technology allows for a more accurate and precise method to be developed, one may be developed. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity, linearity, reproducibility, accuracy, spike recovery, and method detection limit (if applicable). More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate. 6.2.4 Other dietary supplement ingredients An effort shall be made to seek out the most appropriate method The most appropriate method available would be selected to confirm claims for the product under evaluation. The source of these methods may include AOAC International, USP, AHP, European, German, Japanese monographs, INA, etc. The use of any new method shall require that a validation be performed, following the principles of the AOAC Single Lab Validation Guideline7 as a minimum, which includes an evaluation of specificity, linearity, reproducibility, accuracy, spike recovery, and method detection limit (if applicable). More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate. The purpose of this change is to add transparency regarding the limits of the available methodology regarding the testing of dietary supplements. The language that states “an effort shall be made” presents an onerous barrier to completing the analysis and testing of these products. The matrixes are variable and complex and many times completing the tests are not achievable. 6.2.5 Quality assurance for quantitative test methods 6.2.5.1 Calibration Quantification test methods shall be performed using certified reference standards as calibration standards. The standards are typically purchased as single chemicals with greater than 95% purity. If a

Formatted


Formatted

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high-purity standard is not available, a lower-purity material shall be used if there is a means by which the actual purity can be measured (e.g., UV absorbance). 6.2.5.1.1 Multi-level calibration curves Multi-level calibration curves shall be prepared with a minimum of three concentration levels such that any sample preparations under evaluation would be bracketed by a calibration standard. Curves shall give a correlation coefficient of 0.995 or higher. 6.2.5.1.2 Single-level calibration curves If a single level calibration is employed, the standard shall be run in triplicate and the relative standard deviation between these runs shall not exceed 2%. The detector response of the prepared sample shall be within 90-110% of that of the standard. 6.2.5.1.3 Blanks A method/reagent blank shall be included in each analytical run. 6.2.5.1.4 Reproducibility/accuracy All unfamiliar matrices shall be prepared in triplicate. Whenever possible, two additional preparations shall be spiked with the reference standard(s) to assess recovery/accuracy. The reproducibility between the two spiked samples as measured by percent relative difference shall be no greater than 20%.

NOTE – When spiking with the reference standard is price prohibitive, a control sample with a known result shall be tested as part of the analysis run; this shall include a certified reference material or a sample that has been analyzed in the past.

6.2.5.1.5 Continuing Calibration Verification (CCV) Continuing Calibration Verification (CCV) standards shall be run after every 10 sample preparations and/or at the end of the run. The recovery for the CCV shall be within the uncertainty of the method for the data to be acceptable. CCV standards, which are run to confirm an existing calibration, must show recovery of 90-110%. If the result falls outside this range, a new calibration shall be run. 7 Test methods used by testing laboratories for detection of contaminants – raw materials and finished products 7.1 Test methods for metals The presence of arsenic, cadmium, chromium (total) (see following note), lead, and mercury (elemental) shall be measured in accordance with the following methods:

– sample preparation method: Samples shall be prepared by microwave-assisted acid digestion using a closed cell unit equipped with temperature monitoring. The temperature program and the selection of reagents shall be modified or optimized as appropriate for the product being evaluated; and

– analytical method: USEPA 200.7 Metals: Inductively Coupled Plasma-Atomic Emission Spectrophotometric Method for Trace Element Analysis of Water and Wastes. Alternate methodologies, such as graphite furnace atomic emission spectrophotometry, ICP-MS, and flow injection analysis may be used for specific samples at the discretion of the analyst.

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NOTE – If the chromium (total) result exceeds the pass/fail criteria (5.3.1), levels of Cr (VI) will be determined using a liquid chromatography method based on EPA Method 218.6.18 Modifications to the sample preparation and extraction procedures will be employed based on the dietary supplement product or ingredient matrix.

7.2 Pesticides 7.2.1 Multi-residue method The multi-residue method contained in the USFDA’s Pesticide Analytical Manual (PAM I) shall be used to evaluate botanical products unless manufacturers have controls in place to screen for pesticides or use certified organic ingredients as demonstrated in the GMP audit. 7.2.2 Test methods for pesticides in Panax ginseng and Panax quinquefolius Products containing Panax ginseng or Panax quinquefolius shall be evaluated based on the FDA Pesticide Monitoring Procedure using Gas Chromatography with Mass Selective Detection and Selective Ion Monitoring method or the “Analytical Method for the Determination of Quintozene and Its Degradates and Impurities in Ground Dried Ginseng Root by Gas Chromatography” as validated by the Council for Responsible Nutrition/ American Herbal Products Association Joint Task Force, December 14, 2000. The testing determines the presence of the following pesticides:

Table 2 – CAS numbers for pesticides present in Panax ginseng and Panax quinquefolius

Analyte CAS #alpha-benzene hexachloride (CAS # 319-84-6) beta-benzene hexachloride (CAS # 319-85-7) delta-benzene hexachloride (CAS # 319-86-8) difenoconazole (CAS # 119446-68-3) hexachlorobenzene (CAS # 118-74-1) Lindane (gamma-benzene hexachloride) (CAS # 58-89-9) pentachloroaniline (CAS # 527-20-8) pentachlorobenzene (CAS # 608-93-5 pentachlorothioanisole (CAS # 1825-19-0) quintozene (pentachloronitrobenzene) (CAS # 82-68-8) Technazene (CAS # 117-18-0) tetrachloroaniline (CAS # 3481-20-7)

7.3 Test methods for microbiological contaminants 7.3.1 Reference methods Testing shall be performed based on the currently promulgated version of the United States Pharmacopeia (USP). With the exception of Pseudomonas, testing methods shall adhere to those described in USP <2021> Microbial Enumeration Tests – Nutritional and Dietary Supplements and USP <2022> Microbiological Procedures for Absence of Specified Microorganisms – Nutritional and Dietary Supplements. For Pseudomonas, testing methods shall adhere to those described in USP <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms.

NOTE – Methods that have been validated using established guidelines, such as those described by AOAC and USP, and have been demonstrated to yield equivalent or better results compared to the aforementioned USP methodologies may be substituted.

7.3.2 Preparatory Testing

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Preparatory testing, as specified in the currently promulgated version of the United States Pharmacopeia (USP) shall be performed on all products. Certain products may themselves inhibit the multiplication of microorganisms that might be present, thus interfering with quantitative and qualitative microbiological assays detailed in section 7.3. Products shall be inoculated with the challenge microorganisms specified in USP <2021> and USP <2022>. For the quantitative assays, at least a 70% bioburden recovery compared to a control medium must be demonstrated. For the qualitative assays, the challenge organism must be recovered on the applicable selective media. If a product fails to meet the recovery limit, a suitable neutralizer (e.g. soy lecithin, 0.5%; or polysorbate 20, 4.0%) shall be added to the culture medium to neutralize inhibitory substances.

NOTE – In lieu of performing preparatory testing, a suitable neutralizer may be automatically added to the product and testing for the individual indicator organisms and pathogens may proceed as described in the following sections.

7.3.3 Total Aerobic Microbial Counts Per the United States Pharmacopeia (USP), the Membrane Filtration Method or Plate-Count Method shall be used for products that are freely soluble. Moderately soluble and translucent products shall be processed via the Plate-Count Method. The Multiple-Tube Method shall be used for all other products. The media, diluent and incubation conditions specified by the USP shall be used. 7.3.4 Total Combined Molds and Yeasts Count Per the United States Pharmacopeia (USP), the Membrane Filtration Method or Plate-Count Method shall be used for products that are freely soluble. Moderately soluble and translucent products shall be processed via the Plate-Count Method. The Multiple-Tube Method shall be used for all other products. The media, reagents and incubation conditions specified by the USP shall be used. 7.3.5 Enterobacteriaceae Per the United States Pharmacopeia (USP), the sample shall be dissolved or suspended in Phosphate buffer or Fluid soybean casein digest medium and diluted to 100 mL with Fluid soybean casein digest medium. The suspension shall be pre-incubated and subsequently processed using the media, reagents and incubation conditions stated by USP. 7.3.6 Salmonella spp. Testing shall be performed based on the USP Test for the Absence of Salmonella spp. (USP <2022>). 7.3.7 Escherichia coli 7.3.7.1 Generic Escherichia coli For finished products, testing shall be performed based on the qualitative USP Test for the Absence of Escherichia coli (USP <2022>). 7.3.7.2 Pathogenic Escherichia coli If the presence of E. coli is confirmed, then testing shall be performed based the US FDA’s Bacteriological Analytical Manual (BAM, Chapter 4A) to determine whether the product contains pathogenic Escherichia coli, including but not limited to 0157:H7. 7.3.8 Staphylococcus aureus Testing shall be performed based on the USP Test for Absence of S. aureus (USP <2022>).

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7.3.9 Pseudomonas aeruginosa For semisolid or liquid products containing less than 25% alcohol v/v, testing shall be performed based on the USP <62> Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms. 7.3.10 Aflatoxins Testing shall be performed based on the methods described in Chapter 49, Natural Toxins, pp 49-1 to 49-49 of the AOAC Official Methods of Analysis. 7.4 Test methods for chemical contaminants Testing shall be performed based on USFDA’s Method for Determination of Aristolochic Acid in Traditional Chinese Medicines and Dietary Supplements. The most appropriate method shall be used to confirm claims for the product under evaluation. The source of these methods may include AOAC International, USP, EPA, FDA, AHP, European, German, Japanese monographs, INA, industry standards, etc. The use of any new method shall require that a validation be performed which includes an evaluation of specificity, linearity, reproducibility, spike recovery, and method detection limit. More rigorous validation could follow according to the guidelines of ICH22, USFDA6, GLP6, CEN23, and/or AOAC7, as appropriate. Unless a manufacturer has controls in place to assess the rancidity of oil ingredients, the following testing shall be performed. The Peroxide Value of the oil shall be tested according to AOAC Method 965.33 (which is equivalent to AOCS 8-53). The p-Anisidine Value of the oil shall be tested by AOCS Cd 18-90.7 The Totox Number shall be calculated as the sum of the p-Anisidine Value and two times the Peroxide Value. 7.5 Test methods for industrial contaminants 7.5.1 Test methods for Fish Oil Testing of fish oil samples for PCBs and dioxin-like PCBs shall be performed utilizing a high resolution gas chromatography-high resolution mass spectrometry (HRGC-HRMS) method, EPA Method 1668, Revision A: Chlorinated Biphenyl Congeners in Water, Soil Sediment and Tissue by HRGC-HRMS. Testing of fish oil samples for dioxins and furans shall be performed utilizing a high resolution gas chromatography-high resolution mass spectrometry (HRGC-HRMS) method, EPA Method 1613, Revision B: Tetra- through Octa-Chlorinated Dioxins and Furans by Isotope Dilution HRGC-HRMS. The preparation steps for these methods are applicable to water, soil, fish tissue and other environmental samples. For the analysis of fish oil, for both methods, the preparation of the sample involves dissolution in hexane followed by column based sample clean-up steps prior to the described instrumental analysis. Manufacturers shall meet this testing requirement by one of the following routes:

– through the use of compliant ingredients as demonstrated by third party testing; or – performing testing utilizing a laboratory accredited for PCBs, Dioxin and Furans under ISO 17025 and providing the sample results, data, and quality control results, for review to support compliance

7.5.2 Test methods for Glycerin Testing for diethylene glycol in the glycerin raw material shall be performed utilizing identity tests, including the gas chromatographic limit test for DEG, which appear in the USP Glycerin monograph or other method that is scientifically valid and demonstrated as fit for purpose.

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Manufacturers shall meet this testing requirement by providing testing documentation which can be reviewed and clearly shows the association of the test results with the lot of finished product material being certified. Manufacturers shall meet this test requirement by either providing their own data, providing data from their qualified supplier(s) or acquiring third party test data. 8 Good Manufacturing Practices The manufacture and handling of dietary supplements and dietary supplement ingredients shall meet all applicable regulatory requirements set forth by 21 CFR § 111, with the following additional requirements. 8.1 Written recall procedures Procedures shall be established and followed that define the recall of a product(s) should it become necessary. Written procedures shall be established and followed. 8.2 Compliance with the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 Manufacturers of Dietary Supplements shall submit application to USFDA for registration, receive a Registration Number, and provide the Registration Number upon request. 8.3 Compliance with the Dietary Supplement and Non Prescription Drug Consumer Protection Act Written procedures shall be established and followed for reporting serious adverse events to the USFDA in accordance with the Dietary Supplement and Non Prescription Drug Consumer Protection Act.6

Table 3 – Test methods for dietary ingredients

Dietary ingredient

Latin binomial (standardized common name)

Plant part Chemical

identificationmethod

Sourceof

methods

Validationof

Method(1) Actaea racemosa (Black Cohosh) root/rhizome TLC(2) BHP mutual recognition Aesculus hippocastanum (Horse Chestnut)

Fruit TLC(2)

BHP mutual recognition

Allium sativum (Garlic) Cloves TLC(2) USP mutual recognition Astragalus membranaceus (Astragalus Root)

Root TLC(2)

AHP mutual recognition

Capsicum annuum (Cayenne) Fruit TLC(2) BHP mutual recognition Crataegus monogyna, Crataegus laevigata (Hawthorn)

berry/leaf/flower TLC(2)


Echinacea angustifolia, Echinacea pallida Echinacea purpurea, (Echinacea)

root/aerial parts TLC(2)


Eleutherococcus senticosus root/rhizomes TLC(2) BHP mutual recognition

Formatted: Justified

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Table 3 – Test methods for dietary ingredients (Eleuthero) Ganoderma lucidum (Reishi Mushroom)

Whole TLC(2)


Ginkgo biloba (Ginkgo) Leaf TLC(2) USP mutual recognition Hydrastis Canadensis L. (Goldenseal)

Root TLC(2)


Hypericum perforatum (St. John’s Wort)

aerial parts TLC(2)


Matricaria recutita (Chamomile) aerial parts TLC(2) USP mutual recognition Panax ginseng (Asian Ginseng) (Chinese Ginseng) (Korean Ginseng)

Root TLC(2)

USP mutual recognition

Piper methysticum (Kava) Rhizome TLC(2) BHP mutual recognition Serenoa repens (Saw Palmetto) Berry TLC(2) USP mutual recognition Salix daphnoides, Salix fragilis, Salix pentandra, Salix purpurea (Willow Bark)

Bark TLC(2)


Silybum marianum (Milk Thistle) Seed TLC(2) USP mutual recognition Schisandra chinensis (Schisandra Berry)

Berry TLC(2)


Tanacetum parthenium (Feverfew)

aerial parts TLC(2)

USP mutual recognition

Uncaria tomentosa (Cat’s Claw) Bark TLC(2) BHP mutual recognition Vaccinium macrocarpoon, Vaccinium oxycoccos (Cranberry Fruit)

Fruit HPLC(3) USP mutual recognition

Valeriana officinalis (valerian) Root TLC(2) AHP mutual recognition Viburnum opulus (Cramp Bark) stem/root TLC(2) AHP mutual recognition Viburnum prunifolium (Black Haw Bark)

stem/root TLC(2)


Vitex agnus-castus (Chaste tree) Fruit HPTLC(4) AHP mutual recognition Withania somnifera (Ashwagandha Root)

Root TLC(2) AHP mutual recognition

Zingiber officinale (Ginger) root/rhizome TLC(2) USP mutual recognition

(1) Methods Validation Levels (AOAC draft document dated 12/13/00)

1. Collaborative Method Validation 8-10 laboratory validation study 2. Mutual Recognition Method Validation 3-4 laboratory validation study 3. Peer-Verified Method Validation Single independent laboratory validation study in

addition to in-house validation

4. In-House Method Validation In-house validation study with but not limited to accuracy, precision, linearity, ruggedness, robustness, specificity, sensitivity, limit of detection, and limit of quantitation.

5. Emergency Method Validation Validation study with two different positive and negative controls.

(2) TLC = thin layer chromatography

(3) HPLC = high-performance liquid chromatography

(4) HPTLC = high-performance thin layer chromatography

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– concluded –

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Table 4 – Test methods for marker constituent compounds Dietary ingredient

Latin binomial (Standardized

common name)

Marker constituent compound Test method Validation of method

Actaea racemosa (Black cohosh)

Actein, 26-deoxycimifigoside, Cimiracemoside A, 27-deoxyactein, Acetyl shengmanol xyloside, Cimicifugoside, Cimiracemoside F, Cimiracemoside C, and Cimiracemoside E.

INA, Black Cohosh Assay by ELSD

mutual recognition method

Allium sativum (Garlic)

Allicin INA, Allicin by High-Performance Liquid Chromatography

in-house method

Astragalus membranaceus (Astragalus Root)

Calycosin, Formononetin, Ononin AHP, Astragalus Flavonoids by HPLC


Camellia sinensis (Green tea)

Epigallocatechin, catechin, Epicatechin, Epigallocatechin gallate, Catechin Gallate, Gallocatechin gallate, Epicatechin Gallate and Gallic acid

INA, Catechins and Gallic Acid in Green Tea by HPLC

in-house method

Crataegus monogyna, Crataegus laevigata (Hawthorn Leaf and Flower)

Vitexin AHP, Flavonoids in Hawthorn Leaf and Flower by HPLC


Echinacea angustifolia Echinacea pallida Echinacea purpurea (Echinacea)

Caftaric acid, Cichoric acid, Chlorogenic acid, Echinacoside

INA, Phenolics in Echinacea by HPLC

in-house method

Ginkgo biloba (Ginkgo)

Ginkgolide A, Ginkgolide B, Bilobalide INA, Ginkoterpenoid Assay by HPLC

in-house method

Ginkgo biloba (Ginkgo)

Kaempferol, Quercetin, Isorhamnetin INA, Ginkgo Flavonol Glycoside Assay by HPLC

in-house method

Hypericum perforatum (St. John’s Wort)

Rutin trihydrate, Hyperoside, Hypericin, Quercitrin, Chlorogenic Acid, Hyperforin, Isoquercitrin, Quercetin, Pseudohypericin

INA, St. John’s Wort Assay by HPLC

in-house method

Piper methysticum (Kava)

Desmethoxyyangonin, Dihydromethysticin, Dihydrokavain, Methysticin, Yangonin, Kavain

INA, Kavalactone Assay by HPLC

in-house method

Salix daphnoides, Salix fragilis, Salix pentandra, Salix purpurea (Willow Bark)

Salicin, L-Picein AHP, Willow Bark Assay by HPLC

in-house method

Schisandra chinensis (Schisandra Berry)

Schisandrin A, Schisandrin B AHP, Schisandra berry Assay by HPLC


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Table 4 – Test methods for marker constituent compounds Dietary ingredient

Latin binomial (Standardized

common name)

Marker constituent compound Test method Validation of method

Serenoa repens (Saw palmetto)

Hexanoic, Hexanoic, Nonanoic Decanoic, Dodecanoic, Tetradecanoic, Hexadecanoic, Heptadecanoic, Octadecanoic, 9-Octadecenoic, 9,12- Octadecadienoic, 9,12,15- Octadecatrienoic acids

INA, Fatty Acid Content in Saw Palmetto by Gas Chromatography

in-house method

Serenoa repens (Saw palmetto)

Stigmasterol, campesterol, brassicasterol, and ß-sitosterol

INA, Sterols Content in Saw Palmetto by Gas Chromatography

in-house method

Valeriana officinalis (Valerian)

Valerenic acid, acetoxyvalerenic acid, hydroxyvalerenic acid

AHP, Valerenic Acids in Valerian by HPLC


Vitex agnus-castus (Chaste tree)

Casticin AHP, Casticin Assay in Chaste Tree Fruits by HPLC

mutual recognition method – concluded –

Table 5A – Acceptable limits for microbiological contaminants in raw materials Ingredient Aerobic Yeast/Mold EnterobacteriaceaeVitamin and/or mineral ingredient 1 x 103

CFU/g 1 x 102

CFU/g 1 x 102 CFU/g

Botanical ingredient – extract / Other dietary supplement ingredient

1 x 107

CFU/g 1 x 105

CFU/g 1 x 104 CFU/g

Botanical extract / Other dietary supplement ingredient

1 x 104

CFU/g 1 x 103

CFU/g 1 x 102 CFU/g

Table 5B – Acceptable limits for pathogenic microbiological contaminants in raw materials

Ingredient Salmonella

sp. Escherichia

Coli(1) Staphylococcus

aureus Vitamin and/or mineral ingredient ND(2) ND(2) ND(2)

Botanical ingredient – non-extract(1) ND(2) 1 x 102

CFU/g ND(2)

Botanical ingredient – extract / Other dietary supplement ingredient

ND(2) ND(2) ND(2) (1) Upon the presence of Escherichia coli, 7.3.6.2 is to be followed to determine whether the colonies are enterovirulent. There is a zero tolerance for the presence of enterovirulent Escherichia coli. (2) ND = Not Detected. Not Detected requires that no colonies shall be present in 10 g of sample when tested under the conditions of the USP method cited in 7.3. The detection level for this testing is 10 CFU/g for the period of time tested.

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Table 6A – Acceptable limits for microbiological contaminants in finished products(1) Finished Products Aerobic Yeast/Mold Enterobacteriaceae

Category 1 Finished products containing only vitamin and minerals

1 x 103

CFU/g 1 x 102

CFU/g 1 x 102 CFU/g

Category 2

Finished products containing Botanical ingredient – extract / Other dietary supplement ingredient

1 x 104

CFU/g 1 x 103

CFU/g 1 x 102 CFU/g

Category 3 Finished products containing botanical ingredients – non-extract

1 x 107

CFU/g 1 x 105

CFU/g 1 x 104 CFU/g

(1) The category designation shall be based on ingredients present at 1% or more by weight in the formula as provided in the full product formulation. For a product containing ingredients from more than one category, the finished product category will be assigned based on the ingredient with the highest category number.

Table 6B – Acceptable limits for pathogenic microbiological contaminants in finished products(1)

Finished Products Salmonella

spp. Escherichia

Coli(2) Staphylococcus

Aureus

Category 1 Finished products containing only vitamin and minerals

ND(3) ND(3) ND(3)

Category 2

Finished products containing Botanical ingredient – extract / Other dietary supplement ingredient

ND(3) ND(3) ND(3)

Category 3 Finished products containing botanical ingredients – non-extract

ND(3) 1 x 102

CFU/g ND(3)

(1) The category designation shall be based on ingredients present at 1% or more by weight in the formula as provided in the full product formulation. For a product containing ingredients from more than one category, the finished product category will be assigned based on the ingredient with the highest category number. Examples:

a) A product containing only Vitamin C and Zinc shall be in category 1. b) A product containing Vitamin C, Zinc, and Green Tea Extract shall be in category 2. c) A product containing Vitamin C, Zinc and Echinacea shall be in category 3.

(2) Upon the presence of Escherichia Coli, 7.3.7 is to be followed to determine whether the colonies are enterovirulent. There is a zero tolerance for the presence of enterovirulent Escherichia Coli. (3)ND = Not detected. Not Detected requires that no colonies shall be present in 10 g of sample when tested under the conditions of the USP method cited in 7.3. The detection level for this testing is 10 CFU/g for the period of time tested.

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Annex A (normative)

Table A1 – Botanicals known or suspected to contain aristolochic acid24

Aristolochia spp. Asarum splendens Aristolochia acuminata Asaum forbesii Aristolochia argentina Asarum heterotrpoides Aristolochia baetica Asarum sieboldii Aristolochia bracteata Akebia spp. Aristolochia chilensis Akebia quinata Aristolochia cinnabarina Akebia trifoliate Aristolochia clematitis Bragantia wallichii Aristolochia contorta Clematis spp. Aristolochia cymbifera Clematis armandii Aristolochia debilis Clematis chinensis Aristolochia elegans Clematis hexapetala Aristolochia esperanzae Clematis Montana Aristolochia fangchi Clematis uncinata Aristolochia fimbriata Cocculus spp. Aristolochia indica Cocculus carolinus Aristolochia kaempferi Cocculus diversifolius Aristolochia kwangsiensis Cocculus hirsutus Aristolochia macrophylla Cocculus indicus Aristolochia manschuriensis Cocculus laurifolius Aristolochia maurorum Cocculus leaebe Aristolochia maxima Cocculus madagascariensis Aristolochia mollissima Cocculus orbiculatus Aristolochia pistolochia Cocculus palmatus Aristolochia rigida Cocculus pendulus Aristolochia rotunda Cocculus thunbergii Aristolochia serpentaria Diploclisia affinis Aristolochia watsoni Diploclisia chinensis Aristolochia watsonii Menispernum dauricum Aristolochia westlandi Saussurea lappa Aristolochia westlandii Sinomenium acutum Aristolochia zollingeriana Stephania spp. Asarum canadense Stephania tetrandra Asarum himalacium Vladimiria souliei Asarum himalaycum

24 The source of this table is an April 19, 2001 US FDA correspondence from the Office of Nutritional Products, Labeling and Dietary Supplements <www.cfsan.fda.gov/~/~dms/ds-bot14.html>.

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Annex B (informative)

Reference information for contaminant level acceptance criteria

This annex contains reference information regarding the sources of information used to establish acceptance criteria for contaminant levels. B.1 Metals Acceptance limits for cadmium and lead were obtained from the Joint FAO/WHO Expert Committee on Food Additives, World Health Organization,20 International Programme on Chemical Safety, Safety Evaluation of Certain Food Additives and Contaminants. The acceptance limit for chromium was obtained from the US Environmental Protection Agency18 (1998), Integrated Risk Information System (IRIS): Hexavalent Chromium. The acceptance limit for mercury was obtained from the US Environmental Protection Agency18 (1989), Integrated Risk Information System (IRIS): Mercury (inorganic). The acceptance limit for arsenic was obtained from the British Herbal Pharmacopoeia.9

B.2 Microbiological contaminants The acceptance limits contained in tables 5A, 5B, 6A, and 6B for microbiological contaminants were established with consideration of limits allowed by WHO and USP and were agreed to by the Joint Committee on Dietary Supplements.

© 2011 NSF NSF/ANSI 173 – 2010

C1

Annex C (informative)

Calculating acceptance criteria

This annex contains information for calculating acceptance criteria for metal contamination levels for finished products. C.1 Normalization of laboratory data Normalization is the mathematical adjustment of laboratory results to estimate actual human exposure levels based on the manufacturer’s recommended daily dosage. C.2 Sampling and reporting of laboratory data The laboratory will test a quantity of sample sufficient to minimize sampling error and to reach the desired limit of detection that is required for each metal contaminant. The laboratory results will be reported in milligrams of contaminant per gram of tested product (mg/g) for solid materials. If the product is a liquid, it will be reported as milligram contaminant per milliliter of tested product (mg/mL). C.3 Normalization calculations

– Normalized concentration = mg contaminant / g finished product x Maximum Daily Dosage (MDD); and – MDD = maximum dose recommended on the label by the manufacturer.

The normalized concentration is compared to the acceptance criteria for finished product. Example:

– MDD = (2) 500mg tablets taken 3 times a day = 3g of product; – per laboratory results, the mg contaminant/g finished product = 0.002mg lead/g finished product; – normalized concentration = 0.006mg/d = 0.002mg lead/g finished product x 3g (MDD); and – acceptance criteria for lead is 0.02mg/d, therefore product is acceptable.


Issue document.doc

Joint Committee Issue Document

NOTE: An issue document may be submitted at any time – it comprises two parts: the cover sheet (this page) and a description of the issue to be submitted to the Joint Committee (following page). A separate issue form is required for each issue submitted. Issue papers include proposals for modification of a standard, information reports and (of current research, etc.). An issue paper shall be categorized as being for ACTION or for INFORMATION. Submitters should limit the Issue Paper to 1 or 2 pages – attachments detailing full recommendations or background information may be attached with supplementary information. The Chairperson of the appropriate Joint Committee will respond within 30 days of receipt of the issue document advising what steps will be taken. Any issue document intended for discussion at a Joint Committee meeting must be received at least 21 days prior to the meeting to ensure inclusion in the agenda. Submit to: NSF International Attn: Standards Department 789 Dixboro Rd. Ann Arbor, Michigan 48105 Fax: 734-827-6831 e-mail: [email protected] Submitter’s contact information: Name: Kevin Cox Company: NSF International Mailing Address: 789 Dixboro Rd. City: Ann Arbor State: Michigan Zip Code: 48105 Telephone Number: 734-769-8010 ext 6823 E-mail: [email protected] I hereby grant NSF International the non-exclusive, royalty free rights, including non-exclusive, royalty free rights in copyright; in this item and I understand that I acquire no rights in any publication of NSF International in which this item in this or another similar or analogous form is used. Signature of Submitter * Kevin Cox Date 9/26/2011 *Type written name will suffice as signature


Issue document.doc

Please insert a check (X) in the appropriate place to indicate if you wish the item to be considered as an action item or as an information item. Action ______X________ Information ___________________ NSF Standard(s) Impacted: NSF/ANSI Standard 173 – Dietary Supplements Issue Statement: Provide a concise statement of the issue, which reference as appropriate any specific section(s) of the standard(s) that are related to the issue. NSF International (“NSF”) is requesting two modifications to the current pesticide testing requirements under NSF/ANSI Standard 173, Section 5.3.2. Due to variations and limitations in manufacturer testing, NSF proposes removal of the option for manufacturers to either maintain controls or use certified organic ingredients as alternatives to NSF conducting pesticide testing. Additionally, NSF proposes to modify the additional requirements specific to Panax ginseng or Panax quinquefolius to only apply the zero tolerance limits to products sold and/or distributed within the United States. Background: Provide a brief background statement indicating the cause and nature of concern, the impacts identified relevant to public health, public understanding, etc, and any other reason why the issue should be considered by the Committee. NSF is proposing modifications to the pesticide testing requirements under Section 5.3.2 of NSF/ANSI Standard 173 in order to broaden the testing to be performed for pesticide residues in products containing botanicals and focus the application of Panax ginseng or Panax quinquefolius requirements to products sold and/or distributed in the United States. As indicated above, NSF is proposing to eliminate the option of the manufacturers to have either “controls in place to screen for pesticides or use certified organic ingredients” in place of testing performed by NSF for pesticide residues. A primary concern is that the typical screening performed by manufacturer may not be as comprehensive or target the appropriate pesticides. NSF testing capabilities will allow for broader pesticide testing to be performed on finished products. Regarding removal of the organic certification option, the USDA has proposed rule changes to require periodic residue testing on a percentage of organic products; therefore, by removing the certified organic ingredient option, NSF will perform pesticide screening that will serve as additional verification of the organic product. An expansion to the reference to the test procedure to be used is being proposed as the QuEChERS method is often being employed by government agencies as a multi-residue screening technique.


Issue document.doc

Under Section 5.3.2, products that contain Panax ginseng or Panax quinquefolius cannot contain any of the pesticide residues listed in Table7.2.2. This “zero tolerance” applies only to Panax ginseng or Panax quinquefolius as tolerances for these pesticide residues have been set for other crops such as beans, broccoli and potatoes (see 40 CFR § 180.319). It is the understanding of NSF that the requirement relating to Panax ginseng or Panax quinquefolius is a recommendation from the FDA and industry trade associations regarding the sale and distribution of these herbs in the United States and that the limits are not based upon a safety or risk assessment of the individual pesticides; therefore, NSF proposes to allow products sold and/or distributed outside of the United States that contain Panax ginseng or Panax quinquefolius to contain residues of the pesticides listed in Table 7.2.2 so long as the residual concentrations are compliant with FDA or EPA safety limits. Recommendation: If action by the Joint Committee is being requested, clearly state what action is needed: e.g., recommended changes to the standard(s) including the current text of the relevant section(s) indicating deletions by use of strike-out and additions by highlighting or underlining; e.g., reference of the issue to a Task Force for detailed consideration; etc. If recommended text changes are more than a half page, please attach a separate document. Currently, Standard 173 Section 5.3.2 is as follows: “Unless a manufacturer has controls in place to screen for pesticides or use certified organic ingredients as demonstrated in the GMP audit, a broad pesticide screen shall be performed to confirm compliance with USFDA and USEPA regulated limits and the absence of banned pesticides in botanical products. Raw materials and finished products containing Panax ginseng or Panax quinquefolius shall not contain pesticides listed in 7.2.2 (limit of detection is less than 10 parts per billion (ppb)).” NSF proposes to modify the above language as follows: “Unless a manufacturer has controls in place to screen for pesticides or use certified organic ingredients as demonstrated in the GMP audit, A broad pesticide screen shall be performed to confirm compliance with USFDA and USEPA safety limits and the absence of banned pesticides in botanical products. Raw materials and finished products containing Panax ginseng or Panax quinquefolius which are to be sold and/or distributed in the United States shall not contain pesticides listed in 7.2.2 (limit of detection is less than 10 parts per billion (ppb)). Product that does not meet the requirements for pesticides listed in 7.2.2 must be labeled in a manner that would preclude its sale and/or distribution in the United States. Additionally, Standard 173 Section 7.2.1 will be modified as follows: The multi-residue method(s) contained in the USFDA’s Pesticide Analytical Manual (PAM I) or a QuEChERS methodi shall be used to evaluate botanical products unless manufacturers have controls in place to screen for pesticides or use certified organic ingredients as demonstrated by GMP audit.

Formatted: Font: 10 pt, Highlight


Issue document.doc

Supplementary Materials (photographs, diagrams, reports, etc.): If not provided electronically, the submitter will be responsible to have sufficient copies to distribute to committee members. Submitter Kevin Cox Date 9/26/2011 i QuEChERS is a term used to describe a sample analysis approach used to evaluate pesticide residues in food. The term is based on the descriptions "Quick, Easy, Cheap, Effective, Rugged, and Safe".[

Item No._______ (For NSF International internal use)

Information Paper.doc

Information Paper

NOTE: Information Papers can include: Task Group updates, news of events or activities related to the field of interest of the Joint Committee. Time permitting, these papers will be reviewed at the Joint Committee meeting. They must be received at least 21 days prior to the meeting to ensure inclusion in the agenda and distribution. Submit to: NSF International Attn: Standards Department 789 North Dixboro Rd. Ann Arbor, Michigan 48105 Fax: 734-827-6831 e-mail: [email protected] Contact information: Name: Leila G. Saldanha, PhD, RD.______________________ ____

Chair AOAC’s Dietary Supplement Ingredient Ranking Subcommittee____ Company: Office of Dietary Supplements/NIH; Mailing Address: 6100 Executive Blvd, Rm 3B01, MSC 7517 City: Bethesda _____ State: MD Zip Code:20892-7517 Telephone Number: 202-460-3529__ E-mail:[email protected]________ I hereby grant NSF International the non-exclusive, royalty free rights, including non-exclusive, royalty free rights in copyright; in this item and I understand that I acquire no rights in any publication of NSF International in which this item in this or another similar or analogous form is used. Signature *___Leila G. Saldanha___ Date _09/27/2011____ *Type written name will suffice as signature

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Item No._______ (For NSF International internal use)

Information Paper.doc

Subject: (If the topic concerns a Task Group's activity or status, please identify the Task Group and the relevant NSF Standard. If the report involves an issue to be balloted or for which a decision of the Committee is need, an Issue Paper should be completed.) The purpose of this Information Paper is to seek NSF input on identifying dietary supplement ingredients or constituents in need for method validation. This request is not to create a new NSF Standard or revise an existing standard. Brief statement of information provided:

The AOAC Dietary Supplement Task Group (DSTG) was formed in 2001. The mission of this task group is “to advise AOAC INTERNAIONAL on how to meet the analytical needs of the dietary supplements community and to participate in meeting those needs.” The mission of the Ingredient Ranking Subcommittee (IRS), a subgroup of the DSTG is to “rank method needs for dietary supplement ingredients for which validated analytical methods are needed and provide the rationale for the high-prioritized ingredients resulting from the ranking process.” NSF is a voting member of the DSTG and IRS. A list of dietary supplement ingredients for which analytical methods have been developed, optimized, and/or validated is available at the Office of Dietary Supplement, NIH website: . http://ods.od.nih.gov/Research/AMRMAnalyticalMethods.aspx. (NOTE: This list will be made available as a handout at the meeting)

Since analytical methods are necessary to meet dietary supplement label claims and CGMP requirements. AOAC’s DSTG would like to obtain NSF member input into what methods the task group should consider to meet these regulatory requirements. Currently the DSTG is seeking information on the following ingredients; however, NSF can nominate ingredients not on this list for consideration by AOAC’s DSTG. Following is a list of ingredients that have been previously nominated, for which additional information is needed to justify developing a validated method: • Andrographis paniculata; Angelica/ Dong Quai; Artichoke; Ashwagandha

(Withania somnifera); Astragalus; Bacopa; Beta Glucan; Black Cohosh; Boswellia; Cinnamon; Coleous forskohlii; Devil’s claw; Dragon's blood; Echinacea; Eleuthero Root; English plantain leaf (Plantago lanceolata) (digitalis); Epimedium; Eurycoma longifolia Jack (Tongkat Ali); Fenugreek; Flaxseed; Fraxinus excelsior (European Ash); Ganoderma lucidum; Germander; Germanium; Goji (wolfberry or Lycium barbarum); Gotu kola; Grape Seed Extract; Guarana; Guggul; Gymnema sylvestre; Hawthorn (Chinese; English); Hibiscus; Holy Basil; Hoodia gordonii aerial parts; Hops; Kava; Long chain alcohols (polycosanol); Maca; Mangosteen; Noni; Olive Leaf; Oregano oil; Passionflower; Peak E in tryptophan; Phosphatidyserine/choline; Phytosterols; Pine Bark Extract; Pygeum; Pyrrolizidine alkaloids; Red Clover; Ribose (SUPPLEMENT VS BODY FLUIDS/TISSUES); Skullcap; Slippery Elm Bark (Ulmus rubra); Taxine alkaloids (Yew tea); Thyroxine; Total phenolics (Folin Ciocalteu?); Usnic acid; Vitex; and Willow Bark.

Signature *___Leila G. Saldanha___ Date _09/27/2011____

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The Office of Dietary Supplements Analytical Methods and Reference Materials (AMRM) Program

has updated its Web site!

Topics include:

http://ods.od.nih.gov/AnalyticalMethods

AMRM Program Description A brief description of the AMRM program’s goals, collaborators, program components, and achievements.

Reference Materials for Dietary Supplement Analysis A description of the ODS-NIST collaboration to develop reference materials and calibration standards relevant to dietary supplements, as well as their stage of development, public availability, and resulting publications.

Dietary Supplements Laboratory Quality Assurance Program Information on the ODS-supported laboratory quality assurance program established by the NIST and how to participate in upcoming exercises.

Analytical Methods for Dietary Supplements Listings of analytical methods by stages of development (e.g., in progress, developed, validated) and supporting articles in the Journal of AOAC International.

Training, Education, Outreach Opportunities to link to ODS-sponsored conferences, workshops, meeting exhibits, presentations, and other activities related to analytical methods and reference materials.

Related Resources Links to Web sites of Federal government agencies and nongovernmental institutions collaborating with or sponsored by ODS to develop analytical methods and reference materials for dietary supplement ingredients.

Glossary Terms and abbreviations used in this Web site are defined.

For more information from ODS:

http://ods.od.nih.gov

July 26, 2011

Consumer Use/Market

ShareEndurance

Availability of Reference Materials

Availability & Quality of Methods

Research Interest

Safety Concerns/

Risk of Economic

AdulterationConcern

Industry (Involvement &

Support)

Total Score

Interested in Measuring

Ingredient

41 Chondroitin 5 5 5 4 5 5 29 Submitted by FDA 2011

1 Chromium salts (III) methods for determination of chromium complex and species; CrVI contamination

4 5 4 5 5 3 26 Speciation

44 Sildenafil 5 5 4 1 5 5 25 Market Share scored was based on ED products. Sildenafil and analogs

5 Aloe 4 4 4 2 5 5 24 aloin A & B

39 Iodine 4 5 4 5 2 4 24 Submitted by FDA 2011

43 Sibutramine 5 5 3 1 5 5 24 Market Share score was based on weight loss products.

3 Garlic 4 4 4 4 2 5 23 Allacin precursor

2 Anthocyanins profile for berries Blueberry, Bilberry, Acai, Elderberry

5 3 4 4 2 4 22 Anthocyanins

42 Folate 5 5 4 4 1 3 22 Submitted by FDA 2011

SCORE: 5-1

GROUP 1: Active List

Ingredient Ranking Table

July 26, 2011

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Ingredient SCORE: 5-1

4 Pomegranate 3 4 5 3 2 4 21 ellagitannins liquid juice and extracts

6 Ginger 4 4 4 4 2 3 21 Gingerols

7 Mate 4 5 4 1 5 2 21 PAH's in smoked herbal materials

11 ***Black Cohosh: distinguish root/rhizome of Actaea racemosa from other Actaea and Cimicifuga species (moved for consideration to identity working group)

3 4 4 4 4 2 21 Identity Method

8 Echinacea (alkamides)

4 2 4 4 1 5 20

45 Thyroxine 3 5 2 1 5 4 20 Submitted by FDA 2011

9 Skullcap (identification) Germander (Teucrin A)

2 3 4 4 4 2 19 Differentiation for safety

July 26, 2011

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10 Black Cohosh: quantitate triterpene glycosides of Actaea racemosa

3 4 4 4 1 2 18

40 Germanium 1 5 5 1 5 1 18 Submitted by FDA 2011

12 Peak E in tryptophan 3 5 4 1 2 2 17 ethylidine-bis-tryptophan. Place on hold need justificaiton form

13 Mangosteen (Xanthone)

5 4 4 2 1 1 17 Xanthone

14 Angelica/ Dong Quai 4 4 4 2 2 1 17 Place on hold need justification form

15 Eleuthero Root 3 5 4 2 1 2 17 Eleutherosides

16 Oregano oil 4 4 4 2 1 2 17 Place on hold need justification form

17 Red Clover 3 4 4 2 2 1 16 Isoflavones

21 Ashwagandha (Withania somnifera)

2 4 4 3 1 2 16 withanolides

18 Guggul 2 5 4 1 1 2 15 guggul sterols

19 Willow Bark 2 5 4 1 2 1 15 Salacyline. Needs ID Methods. Rank today for Salacyline rank later for id method

20 English plantain leaf (Plantago lanceolata) (digitalis)

1 2 5 1 4 2 15 lanatoside & cardiac glycosides

24 Kava (Lactones) 2 4 5 2 1 1 15 Lactones

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22 Holy Basil 3 3 4 1 2 1 14 Place on hold need justification form

23 Pygeum 1 4 4 1 2 2 14 Phytosterols

25 Hawthorn (Chinese; English)

3 3 4 1 1 2 14 vitexens and hyperosides. Needs id method

26 Astragalus 3 3 3 2 1 1 13 astragalasides

27 Bacopa 2 2 3 2 1 2 12 bacosides

28 Taxine alkaloids (Yew tea)

1 4 2 1 3 1 12 in Taxus spp. Place on hold need justificaiton

29 Grape Seed Extract-Proanthocyanidines (Polyphenols)

3 1 1 4 1 2 12 proanthocyanidines (polyphenols)

31 Phosphatidyserine/choline

3 2 2 2 1 2 12 Place on hold need justification form

32 Goji (wolfberry or Lycium barbarum)

5 1 1 1 1 2 11 Place on hold need justification form

33 Boswellia 2 2 2 2 1 2 11 boswellic acids

34 Cinnamon 3 1 2 3 1 1 11 Place on hold need justification form

30 Hoodia gordonii aerial parts

1 2 3 1 2 1 10 quantitation of pregnane glycosides. Contamination issue.

35 Kava (neo kavalactone)

2 1 1 1 3 1 9 place on hold need justification form

36 Pine Bark Extract (proanthocyanidins)

3 1 1 1 1 2 9 proanthocyanidins

Ingredients Requester & E‐mail Organization Address Need/Analyte Reason Existing methods? Support Comments

Andrographis paniculataAngelica/ Dong Quai antioxidant potentialArtichokeAshwagandha (Withania somnifera) AstragalusBacopaBeta GlucansBlack Cohosh 1) triterpene lactones,

2) Identity: distinguish root/rhizome of Actaea racemosa from other Actaea and Cimicifuga species and blue cohosh

BoswelliaCinnamonCocoaColeous forskohliiDevil’s clawDragon's bloodEchinacea alkamidesEleuthero RootEnglish plantain leaf (Plantago lanceolata) (digitalis)EpimediumEurycoma longifolia Jack (Tongkat Ali)FenugreekFlaxseedFraxinus excelsior (European Ash)Ganoderma lucidumGermander teucrin AGermaniumGoji (wolfberry or Lycium barbarum)Gotu kolaGrape Seed Extract proanthocyanidinsGuarana

List of Ingredients That Have Been Previously Nominated for Which Additional Information is Needed to Justify Developing a Validated Method

Ingredients Requester & E‐mail Organization Address Need/Analyte Reason Existing methods? Support Comments

GuggulGymnema sylvestreHawthorn (Chinese; English)HibiscusHoly BasilHoodia gordonii aerial partsHopsKava 1) lactones

2) neo kavalactoneLong chain alcohols (polycosanol)MacaMangosteen xanthoneNoniOlive LeafOregano oilPassionflowerPeak E in tryptophanPhosphatidyserine/cholinePhytosterolsPine Bark Extract proanthocyanidinsPygeumPyrrolizidine alkaloids Red CloverRibose (SUPPLEMENT VS BODY FLUIDS/TISSUES)Skullcap identity: distinguish

from GermanderSlippery Elm Bark (Ulmus rubra )Taxine alkaloids (Yew tea)

ThyroxineTotal phenolics (Folin Ciocalteu?)Usnic acidVitexWillow Bark

List of Ingredients Completed and Published Ingredients JAOAC and the NIH PubMed site.

Chondroitin:

ERP Date: November 28, 2003 Single laboratory validation completed; manuscript published in JAOAC (2007) 90(3) 659‐669. Determination of Chondroitin Sulfate Content in Raw Materials and Dietary Supplements by High‐Performance Liquid Chromatography with Ultraviolet Detection After Enzymatic Hydrolysis: Single‐Laboratory Validation David Ji, Mark Roman, Joseph Zhou, & Jana Hildreth Mark Roman at Tampa Bay Analytical undertook collaborative study; study failed.

Cranberry:

ERP Date: July 21, 2009 Single laboratory validation completed; manuscript published in JAOAC (2011) 94(2) 459‐466 Determination of Anthocyanins in Cranberry Fruit and Cranberry Fruit Products by High‐Performance Liquid Chromatography with Ultraviolet Detection: Single‐Laboratory Validation Paula N. Brown and Paul R. Shipley

Cranberry Organic Acid:

ERP Date: August 26, 2005 Rick Myers at Schiff undertook method development and optimization.

Echinacea:

ERP Date: November 10, 2005 Single laboratory validation completed; manuscript scheduled for publication in JAOAC (2011) 94(5) Determination of Major Phenolic Compounds in Echinacea spp. Raw Materials and Finished Products by High‐Performance Liquid Chromatography with Ultraviolet Detection: Single‐ Laboratory Validation Matrix Extension Paula N. Brown, Michael Chan, Lori Paley, and Joseph M. Betz

Ginseng: ERP Date: November 9, 2005 Single laboratory validation completed; manuscript scheduled for publication in JAOAC (2011) 94(5) Determination of Ginsenoside Content in Asian and North American Ginseng Raw Materials and Finished Products by High‐Performance Liquid Chromatography: Single‐Laboratory Validation Paula N. Brown

Lutein:

ERP Date: September 7, 2006 Tatania Emmick at Kemin Health developed SLV protocol. Sample materials were identified.

Milk Thistle:

ERP Date: July 22, 2009 BCIT undertook method development and optimization; SLV study to begin July 2011.

MSM/DMSO ERP Date: June 23, 2006 Mark Roman of Tampa Bay Analytical undertook collaborative study, study discontinued due to inadequate number of collaborators.

Omega 3 ERP Date: May 9, 2005 Sandy Diltz at Martek submitted SLV report to JAOAC on February 28, 2008, and based on peer review, minor revisions were requested. No revision was submitted. Manuscript never published. Single Laboratory Evaluation of a Method For Determination of DHA, EPA, and ALA Omega‐3 Fatty Acids in Dietary Supplements by Gas Chromatography with Flame Ionization Detection

Turmeric: ERP Date: February 16, 2010 Not in process.

SAMe: ERP Date: April 11, 2005 USP undertook SLV study, but no manuscript was submitted to the JAOAC. Wendy Sorenson at Covance developed collaborative study protocol, protocol was approved by Official Methods Board. C/S did not move forward.

St. John’s wort:

ERP Date: April 7, 2003 (1st ERP), May 4, 2004 (2nd ERP) Steve Baugh at Industrial Labs undertook SLV study; study failed.

Simultaneous Determination of Protopseudohypericin, Pseudohypericin, Protohypericin, and Hypericin Without Light Exposure (2005) J. AOAC Int. 88(6) 1607‐1616 Steve Baugh

Vitamin B6 ERP Date: April 1, 2009 USDA undertook SLV study, and plans to submit manuscript to JAOAC this fall.

Vitamin B12:

ERP Date: April 2, 2009 Not in process.

Vitamin D: ERP Date: June 8, 2009 Sui Kay Wong of the Hong Kong Government Laboratory undertook SLV study. In process.

Vitamin E:

ERP Date: August 25, 2004 Not in process.

Yohimbe:

ERP Date: February 17, 2010 USDA plans to submit SLV report by year‐end

The following studies have been completed and the manuscripts have been published in the Journal of AOAC INT. and submitted to PubMed:

Determination of Aconitum Alkaloids in Dietary Supplements and Raw Botanical Materials by Liquid Chromatography/UV Detection with Confirmation by Liquid Chromatography/Tandem Mass Spectrometry: Collaborative Study J AOAC Int January 1, 2009

Validation of High‐Performance Thin‐Layer Chromatographic Methods for the Identification of Botanicals in a cGMP Environment J AOAC Int January 1, 2008

Determination of β‐Carotene in Supplements and Raw Materials by Reversed‐Phase High Pressure Liquid Chromatography J AOAC Int September 1, 2005

Determination of Campesterol, Stigmasterol, and Beta‐Sitosterol in Saw Palmetto Raw Materials and Dietary Supplements by Gas Chromatography: Collaborative Study J AOAC Int May 1, 2007

Determination of Aristolochic Acid I in Botanicals and Dietary Supplements Potentially Contaminated with Aristolochic Acid I Using LC‐UV with Confirmation by LC/MS: Collaborative Study J AOAC Int July 1, 2007

Determination of Chondroitin Sulfate Content in Raw Materials and Dietary Supplements by High‐Performance Liquid Chromatography with Ultraviolet Detection After Enzymatic Hydrolysis: Single‐Laboratory Validation J AOAC Int May 1, 2007

Evaluation of a Method to Determine Flavonol Aglycones in Ginkgo biloba Dietary Supplement Crude Materials and Finished Products by High‐Performance Liquid Chromatography J AOAC Int January 1, 2007

Determination of Campesterol, Stigmasterol, and beta‐Sitosterol in Saw Palmetto Raw Materials and Dietary Supplements by Gas Chromatography: Single‐Laboratory Validation J AOAC Int January 1, 2006

Method for the Determination of Aconitum Alkaloids in Dietary Supplements and Raw Materials by Reversed‐Phase Liquid Chromatography with Ultraviolet Detection and Confirmation by Tandem Mass Spectrometry: Single‐Laboratory Validation J AOAC Int November 1, 2006

Determination of Hydrastine and Berberine in Goldenseal Raw Materials, Extracts, and Dietary Supplements by High‐Performance Liquid Chromatography with UV: Collaborative Study J AOAC Int July 1, 2008

Determination of Ubidecarenone (Coenzyme Q10, Ubiquinol‐10) in Raw Materials and Dietary Supplements by High‐Performance Liquid Chromatography with Ultraviolet Detection: Single‐Laboratory Validation

J AOAC Int September 1, 2007

Determination of Aflatoxins B1, B2, G1, and G2 and Ochratoxin A in Ginseng and Ginger by Multitoxin Immunoaffinity Column Cleanup and Liquid Chromatographic Quantitation: Collaborative Study J AOAC Int May 1, 2008

Determination of ephedra alkaloids by liquid chromatography/tandem mass spectrometry. J AOAC Int May 1, 2003

Determination of aristolochic acid in botanicals and dietary supplements by liquid chromatography with ultraviolet detection and by liquid chromatography/mass spectrometry: single laboratory validation confirmation. J AOAC Int July 1, 2006

Determination of Coenzyme Q10 Content in Raw Materials and Dietary Supplements by High‐Performance Liquid Chromatography‐UV: Collaborative Study J AOAC Int July 1, 2008

Determination of flavonol aglycones in Ginkgo biloba dietary supplement crude materials and finished products by high‐performance liquid chromatography: single laboratory validation. J AOAC Int May 1, 2005

Single laboratory validation of a method for determination of glucosamine in raw materials and dietary supplements containing glucosamine sulfate and/or glucosamine hydrochloride by high‐performance liquid chromatography with FMOC‐Su derivatization. J AOAC Int September 1, 2004

Determination of Aflatoxins and Ochratoxin A in Ginseng and Other Botanical Roots by Immunoaffinity Column Cleanup and Liquid Chromatography with Fluorescence Detection J AOAC Int May 1, 2006

Determination of Glucosamine in Raw Materials and Dietary Supplements Containing Glucosamine Sulfate and/or Glucosamine Hydrochloride by High‐Performance Liquid Chromatography with FMOC‐Su Derivatization: Collaborative Study J AOAC Int July 1, 2005

Determination of Total Soy Isoflavones in Dietary Supplements, Supplement Ingredients, and Soy Foods by High‐Performance Liquid Chromatography with Ultraviolet Detection: Collaborative Study J AOAC Int May 1, 2008

Method for the Determination of β‐Carotene in Supplements and Raw Materials by Reversed‐Phase Liquid Chromatography: Single Laboratory Validation J AOAC Int September 1, 2004

Determination of Ephedra Alkaloids in Urine and Plasma by HPLC‐UV: Collaborative Study J AOAC Int January 1, 2004

Determination of Ephedrine Alkaloids in Botanicals and Dietary Supplements by HPLC‐UV J AOAC Int January 1, 2004

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Dietary Supplements Joint Committee Meeting