AOAC 2022 Midyear Meeting: BDSIP Session

AOAC INTERNATIONAL BOTANICAL AND DIETARY SUPPLEMENT INTEGRITY PROGRAM

AOAC Midyear Meeting Gaithersburg Marriott Washingtonian Center Gaithersburg, Maryland March 14 – 18, 2022

Wednesday, March 16, 2022 3 :30am ET – 5:30pm ET

Draft Agenda

Moderator: Dr. Darryl Sullivan (Eurofins)

I.

WELCOME & INTRODUCTIONS Dr. Darryl Sullivan (Eurofins) will welcome attendees, lead introductions, and review the session agenda.

II.

THOUGHT LEADER DISCUSSION (90 minutes) a. Overview (10 minutes)

i. GRMA Overview (Allyn Shultis) ii. AOAC Overview (Palmer Orlandi)

b. Discussion Topics

i. Consensus standards and compendial methods to support authenticity, label claims, and contaminant concerns, ii. validation and verification criteria to meet laboratory accreditation requirements, iii. Greater awareness of quality testing practices through training and education activities.

III. Community Consensus on the draft standard: Determination of Folic Acid in Chewable Gels, Soft Gels and Tablets (Dr. Sneh Bhandari and Deborah McKenzie)

IV.

NEXT STEPS & LOOKING AHEAD (Sullivan, Orlandi, McKenzie)

V.

ADJOURNMENT

ACCESS TO AOAC BYLAWS, POLICIES & PROCEDURES, AND STRATEGIC PLAN

AOAC INTERNATIONAL Bylaws

AOAC INTERNATIONAL Policies and Procedures • AOAC INTERNATIONAL Policy on Antitrust • AOAC INTERNATIONAL Policy on Use of Association Name, Initials, Identifying Insignia, Letterhead and Business Cards • AOAC INTERNATIONAL Policy on Volunteer Conflict of Interest

AOAC INTERNATIONAL Strategic Plan

AOAC DUE PROCESS FOR DEVELOPMENT OF NON ‐ METHOD CONSENSUS STANDARDS AND DOCUMENTS Policy for Due Process in the Development of AOAC Standards and Consensus Documents

AOAC INTERNATIONAL (AOAC) develops and publishes voluntary consensus standards and documents in support of method development, method modification, and method use or implementation. AOAC establishes voluntary consensus standards and documents in accordance to national and international principles for ensuring due process. AOAC’s consensus and standards development activities include participation from diverse perspectives across a given analytical industry or community area, discipline or issue. Standards are developed upon consensus of stakeholders. Approval of standards is based upon confirmation that the standard has been developed in accordance with AOAC’s processes 1 and principles, and as outline in Figure 1. Examples of AOAC consensus documents and standards include voluntary consensus standards; performance standards; methods of analysis; guidance documents; concepts of operation; best practice recommendation documents, and sampling approaches. POLICY STATEMENT AOAC develops national and international analytical non ‐ method consensus and standards documents according to the national and international principles for ensuring due process in the development of consensus documents and standards: openness, transparency, lack of dominance, balance, due consideration, coordination, consensus, and appeals. The AOAC Official Methods Board oversees the implementation of scientific and technical policies and procedures established by the AOAC Board of Directors including those for ensuring due process in establishing standards and consensus documents as outlined in Figure 1. The rules of engagement and parliamentary procedures for AOAC standards developing bodies follow Robert’s Rules of Order (latest edition) in accordance with AOAC bylaws and policies.

Figure 1 ‐ Overview Flow for Consensus & Standard Development

1 AOAC has documentation on the details of the processes used to develop its standards and consensus documents. These supporting documentation include terminology, process details in text with an accompanying flowchart, and a document stage handout.

Approved by AOAC Board of Directors on June 10, 2020.

Dietary Supplement Product Integrity

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Why? Dietary Supplement Product Integrity Testing

Industry & Consumer Misconceptions

Analytical Methods Vary

Limited Regulatory Action

Audits Alone Aren’t Enough

Common Measuring Stick

Potential Limits on Innovation

Quality Concerns

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Activity Since 12/16

Initial Dietary Supplement Product Integrity Committee Meeting

Post TLD Survey & Gathering of Feedback

Key Themes During Committee Meeting

Standard Guidance (Validation, Verification, Sampling)

Members & Active Observer Organizations

One, Harmonized Approach

OMA/Proficiency

Manufacturers, Suppliers, (B&M & Omni-Channel) Retailers, DTC, Certifiers, Labs, and more

Transparency – Consistent Compliance & Method Clarity

“Fit for purpose”/Suitability criteria

Creditability – Reliable & Shareable Data

Finalizing Goals/Objectives

Qualification pathway for method developers & analysts

Mobilizing

Defining Role of Labs

Increase Transparency

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Technical Building Blocks & Key Committee Specification Questions

21 CFR 111 / NSF/ANSI 455-2 NSF/ANSI 173

ISO 17011

ISO 17025

ISO 17043

ACIL – Dietary Supplement 3 rd Party Lab Best Practices

Samples • Reference • Submission

Certificate of Attestation vs. Accreditation

Published Compendial Methods

Lab Training / Qualification

Test Method Selection & Definition

Internal Labs & Independent Labs

Product Innovation

Other

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AOAC Standards & Conformity Assessment

Standards Development

R. Deborah McKenzie Sr. Director, Standards & Official Method SM AOAC International

What Are Standards? • Common and repeated use of rules, conditions, guidelines or characteristics for products or related processes . • The definition of terms; classification of components; delineation of procedures; processes, products, systems, services, or practices; test methods and sampling procedures. • A Performance standard is a standard that states requirements in terms of required results with criteria for verifying compliance but without stating the methods for achieving required results. • Voluntary Consensus standards are standards developed or adopted by voluntary consensus standards bodies , both domestic and international.

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Basic Types of Standards • Voluntary o Drafted with openness and transparency by experts/professionals of both private and public sectors • De facto o Rules or principles that has become a standard due to wide use although it did not go through an official standards development process • Consortia o Broad category of standards that may be developed by a specific group or sectors of which membership may be required and participation may require financial commitment.

• Regulatory o Specifications or rules that are written and/or adopted by government agencies • Other o Company or corporate standards

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Why do we need standards? • Participation in global standard development o Provides access to technologies and helps to reduce trade barriers o Reduces redundancy as harmonized efforts can allow for international standards to be adopted or used as the basis for national and regional standards o Provides access on current emerging technologies and trends

o Helps to level the playing field on the global expectations are.

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Countries Endorse the Following Global Principles

Transparency Openness Impartiality Effectiveness & Relevance Consensus Performance-Based

WTO-Technical Barriers to Trade Standards Principles Coherence Due Process Technical Assistance Flexible Timely Balance

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In the US - OMB A-119 and NTTAA

US OMB Circular A-119 • Standards developed by voluntary consensus standards bodies are often appropriate for use in achieving federal policy objectives and in conducting federal activities, including procurement and regulation • Encourages federal agencies to benefit from the expertise of the private sector • Promotes federal agency participation in such bodies to ensure creation of usable standards • Reduces reliance on government-unique standards

• National Technology Transfer and Advancement Act of 1995 o Directs federal agencies with respect to their use of private sector standards and conformity assessment practices. o Directs federal agencies to adopt private sector standards, wherever possible, in lieu of creating proprietary non-consensus standards. o Codified existing policies in A-119, established reporting requirements, and authorized the National Institute of Standards and Technology (NIST) to coordinate conformity assessment activities of federal agencies.

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How Does AOAC Develop Standards?

A concerted standards development process

Adherence to Standards Principles

Leverage global membership, partnerships and body of science to form collaboration consensus volunteer bodies

Scientific and Performance Based

Integrated Science Programs Individual ASF affiliated Working Groups

Forms Working Groups as needed

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The “Idea Incubator” Outreach and Collaborative Horizon Scanning

Program Development Propose Evaluate Prioritize Implement Program & WG Project Activities

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Very Basic AOAC Process

Program/Project Scope Defined for Period of Time

• ASF Emerging Challenge/Technology • Individual/Sole Source

•Working Group draft standands • Draft standards receive input from all interests until consensus is achieved

• Advisory Panel formed by program/project sponsors •Working Group Chairs and Science Advisor(s) assigned as needed

New Program/Project Formed

Standards Developed

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• Stakeholder Panels (2007 – 2018) o AOAC formed these community-based volunteer bodies for the specific purpose of creating and approving consensus standards o SP = Stakeholder Panel – on Agent Detection Assays (SPADA) – on Infant Formula and Adult Nutritionals (SPIFAN) – on Strategic Food Analytical Methods (SPSFAM) – on Dietary Supplements (SPDS) • Onset of Analytical Solutions Forum (2019 – present) o Funded panels with active working groups and ERPs transitioned into integrated science programs o Repurposed term “stakeholder panels” o Funded active WGs were transitioned under the ASF

Stakeholder Panels, Integrated Science Programs & ASF Working Groups

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Integrated Science Programs

•Ongoing deliverables; Incorporate >2 AOAC Core Programs & Services •Programs with AOAC brand identity as panels - replaces “Program” “Panel” •Stakeholder Program on Agent Detection Assays (SPADA) •Stakeholder Program on Infant Formula & Adult Nutritionals (SPIFAN)

Integrated Science Programs & ASF Working Groups

Cannabis Analytical Science Program (CASP) •Food Authenticity and Fraud Program (FAM)

•Single project or limited deliverable(s); Incorporation 1-2 AOAC Core Programs & Services •ASF WGs may transition into integrated science programs •WG on Food Allergen Assays, WG on Quantitative Microbiology, WG on Rosins •WG on Glyphosates ASF Science Working Groups (WG)

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Standards and Consensus Products

• Transparency • Openness • Balance of Interests • Due Process • Consensus • Appeals Basic Principles

Integrating AOAC Consensus Products

• Performance Requirements • Guidelines • Sampling Standards • Methods of Analysis • Best Practices • Operational Documents • Reference Materials • Training

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Program or Project Stakeholders

• All stakeholders are entitled to due process. o All stakeholders can share their perspectives o Anyone with a material interest may participate o Standards are established by a group that lacks dominance by any one interest - BALANCE

Stakeholder Panel Composition

Perspective 1

Perspective 2

Perspective 3

• Draft standard must contain input of stakeholders of varying perspectives.

Perspective 6

Perspective 4

Perspective 5

• AOAC will confirm consensus regardless of mechanism used to demonstrates consensus of the stakeholders.

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Program/Project Participants - Broad Perspectives

ngo 2%

academia 4%

government 14%

industry 80%

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vet drugs 2% Program/Project Participants - Specific Perspectives

cro 14%

tech providers 14%

dietary supp 5%

state regulators 7%

research 5%

food/beverage 14%

regulators 12%

food/formula 9%

ref materials 5%

iso 2%

food/ingred 5%

indep 2%

food/cro 2%

formula 2%

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Program/Project Participants - Regional Perspectives

Argentina 3%

Australia 3%

Italy 2%

Netherlands

Canada 5%

2% New Zealand 2% Singapore 2%

Sweden 2%

Switzerland UK 2% 2%

USA 75%

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Stakeholders/Participants - Regional and Specific Perspectives

CANADA cro 2%

AUSTRALIA cro 2%

ITALY research 2%

ARGENTINA research 2%

USA vet drugs 2%

CANADA regulator 2%

NEW ZEALAND iso 2%

CHINA regulator 2%

NETHERLANDS food/formula 2%

USA tech provider 11%

SINGAPORE food/formula 2%

USA state regulator 7%

SWEDEN regulator 2% SWITZERLAND food/formula 2% UK tech provider 2%

USA regulator 4%

USA reference materials 4%

USA cro 11%

USA food/ingred 4%

USA independent 2%

USA food/formula 7%

USA food/beverage 13%

USA dietary supplements 4%

USA food/cro 2%

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Representative Stakeholders Input on Standards

Industry - Food

Government

Academia/Research

STANDARD

NGO

Industry - CRO

Industry – Technology Provider

Industry – Dietary Supplement

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Example SMPR: Selected Food Allergens

Specified intended method use

Performance parameters and targets that method must meet

How the method is to be applied

Definitions used for this SMPR as it relates to the method

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Example SMPR: Selected Food Allergens (con’t)

Commodities from which the method should

be able to determine allergenic targets

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Basic AOAC Standards Development Activity Framework

Advisory Panel Meeting

WG Meetings

Community Consensus

Works with AOAC to define scope of work to be launched, including development of new programs and/or new working groups (WGs)

WG begin work and draft consensus documents via web conference and reach general consensus on draft standard between AOAC meetings

WG chair(s) present final draft standard along with reconciled comments for deliberation and consensus.

At AOAC meetings, launch WG effort by refining a preset scope of work into a basic applicability statement from which the WG to began drafting the standard (e.g., SMPR, guidelines, etc) Launching New WG Activities

Draft standard is posted for public comments. Comment period is ≥ 30 days Virtual public comment session via webconference Draft Standard Public Comment Period

Approval of Standard follows consideration of all input and with oversight by Official Methods Board (OMB). Publication of Standard is in the OMA Approval/Publication of Standard

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8 Stages of AOAC Standards Development

Initiate and launch the working group meeting virtually to develop and agree on draft standard. Stage 3: Working Group (WG) Draft Standard

Reach agreement on scope of work for the type of standard to be developed. Stage 1: Project Initiation: Work Scope

Comments on the draft standard are reconciled and the working group revises and agrees on a revised draft standard. The document is now ready for presentation to broader stakeholders for their consensus. Stage 5: Working Group Draft Revision

Stage 7: Audit Review

Consensus draft standard undergoes an audit by the AOAC Official Methods Board (OMB). Once all parameters are satisfactorily met, the Consensus draft standard is approved by the OMB and is now an AOAC consensus standard.

The working group presents the draft revised standard to the stakeholder assembly for their deliberation and consensus. Stakeholders reach consensus on the acceptability of the final draft thereby recommending the consensus draft standard for approval.

AOAC invites subject matter experts Publicize standards activity & open call for working group members. Assign Scientific Advisor (if needed) and working group chair. Vet applicants and establish working group.

AOAC standards are published online on the AOAC website & in the Official Methods of Analysis SM of AOAC INTERNATIONAL. Summaries of deliberations and stage changes are published in the Inside Laboratory Management magazine. Stage 8: Publication of Standard and Outcomes

Once working group has reached consensus on the standard, it will be posted for public comments with input from a broader group of stakeholders.

Stage 4: Public Comments

Stage 2: Outreach

Stage 6: Stakeholder Consensus

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Conformity Assessment • “Conformity assessment” is a demonstration, whether directly or indirectly, that specified requirements relating to a product, process, system, person, or body are fulfilled. Conformity assessment includes sampling and testing, inspection, supplier’s declaration of conformity, certification, and management system assessment and registration. Conformity assessment also includes accreditation of the competence of those activities.” OMB Circular A-119

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Conformity Assessment

o Performance Tested Methods SM (PTM) – Test kits o Reviewed and Recognized SM (R 2 ) – Application notes o Official Methods of Analysis SM (OMA) – Regulatory use

• Programs - Tailored to your method • Processes - Tailored to your situation • Traditional, Harmonized, ERV, TME, On- site • Services – Making it all happen

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Basic AOAC Official Methods SM Program Activity Framework

Call for Methods or Experts

ERPs are vetted, approved, and appointed. Methods are reviewed and ERPs meet to review and reach consensus on methods ERP Assembly & Review of Methods

Approved methods are tracked by ERP in partnership with the method author. Methods that satisfy ERP requirements and demonstrate reproducibility are recommended for Final Action Method Tracking of First Action Methods

AOAC issues call for methods and call for experts

Final versions of methods along with supporting documentation are submitted to OMB for their decision on the recommendation Final Action Review Status

Approved methods are published in the Official Methods of Analysis of AOAC INTERNATIONAL and in the Journal of AOAC INTERNATIONAL

Method authors may submit methods that may meet the approved standard in AOAC Format

First Action Method Publication

Submission of Methods

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Documentation and Communication

AOAC carefully documents the actions of Integrated Science Programs, Working Groups, and ERP

Communicate summaries to participants/stakeholders, etc…. Publish summaries in the Referee section of AOAC’s Inside Laboratory Management

AOAC will prepare summaries of the meetings

AOAC publishes its consensus standards and Official Methods Official Methods of Analysis of AOAC INTERNATIONAL Journal of AOAC INTERNATIONAL AOAC publishes the status of standards and methods in the Referee section of AOAC’s Inside Laboratory Management

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AOAC Official Methods Board • AOAC’s Technical Oversight Volunteer Body • Recommends and Implements Technical Policy • Approval of Method Related Volunteers • Oversee development and approval of content in the Official Methods of Analysis of AOAC INTERNATIONAL • 10 infrastructure working groups • Monthly meetings

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OMB INFRASTRUCTURE WORKING GROUPS

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Auxiliary Information and Services

AOAC Policy for Due Process and Consensus Building

Method can be submitted into Performance Tested Methods SM program Certification program for commercial proprietary methods only

AOAC Consulting Service

Education & Training

for Standards Development Approved in 2020

Develop validation testing study designs Draft manuscripts and methods into AOAC format Special science projects

Training Courses Orientations

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Contact: Deborah McKenzie dmckenzie@aoac.org

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Potential Panel Questions  What do labs perceive to be the needs of the DS industry?  What are labs pain points with Quantification/Identification/Contamination Testing?  What is so technical challenging about Dietary Supplements that makes them uniquely different then Foods and Drugs?  What are you prepared to offer?  Every profession is changing. How is the lab profession changing and how are these changes affecting customers?  What are best practices/points of reflection that we could learn from this sort of initiative on the food side?  What do you think are the biggest challenges this new committee will face?  What do you see as the purpose and major goals of the Botanical and Dietary Supplement Integrity Program?

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Working Group for Folates in dietary supplements – Submits SMPR for approval Sneh D. Bhandari Independent Consultant

16 th March, 2022 – AOAC Midyear Meeting

Outline

• Work group members • Work group meetings • Background • Mission of working group of folic acid • Details about developed SMPR • Performance requirements • Comments submitted and responses • Acknowledgements • Motion for the SMPR approval

Folate (DS) Working Group Members

• Sneh Bhandari, Independent Consultant • Andres Belalcazar, Nutrianalisis • Tammy Blakemore, SORA Labs • Carolyn Burdette, NIST • Esther Campos-Giminez, Nestle • France Cho, Bureau Veritas • Carol Donnelly, R-Biopharm Rhone Ltd • Nour Eddine ES-SAFI, Mohammed V University in Rabat • Adam R. Gabriel, Eurofins • Eric Gordon, Certified Laboratories • Ajai Prakash Gupta, CSIR-Indian Institute of Integrative Medicine • Greg Jaudzems, Nestle

• George Joseph, Assure Quality, NZ • Mohamed Koroma, Pharmavite

Folate (DS) Working Group Members

• Siheng Li , doTERRA • Rodney Major, Bureau Veritas

• Salvatore Parisi, Al Balqa Applied University • Tom Phillips, Maryland Dept. of Agriculture • Sanjay Poman, Merck Life Science P Ltd • Amr Fuad Saeed, National Dairy and Food –HAS • Leila Saidanha, ODS/NIH • Jeffrey Shipar, Eurofins Food Integrity and Innovations • Sookwang Lee, FDA • Darryl Sullivan, Covance • John Szpylka, Food Safety Net Services, Ltd. • Tomasz Tuzimski, Medical University of Lublin, POLAND • Hong You, Eurofins • Hui Zhao, Agilent Technologies, Inc • Garrett Zielinski, Eurofins

Folate (DS) Working Group: Work to Date • Work group launch meeting, November 11, 2021 (Remote) • 4 Work group meetings (Remote) • WG Meeting #1: Friday, November 19, 2021 • WG Meeting #2: Tuesday, November 30, 2021 • WG Meeting #3: Monday, December 13, 2021 • WG Meeting #4: Monday, December 20, 2021 1 SMPR Drafted • Posted for Public Comments period (31 st January, 2022 to 14 th March, 2022 ) • SMPRs made ready for SPDS review and approval

Background - Needs to upgrade the current methods • USP methods are often used for this purpose. The methods are specific to dosage forms. The methods applicable to various dosage forms are required • The methods which can analyzed not only folic acid but also 5-CH3-THF are required • The methods which can not only analyze folic acid but also other B vitamins will be helpful • The methods which can analyze FA but also related products are of use for stability evaluation. • LC-MS/MS methods analyzing folates can provide a better specificity

Mission undertook by folate (dietary supplements) working group • The objective of the work group for folate in DS was to develop voluntary consensus standard (or standards) for quantitation of folates in a variety of dosage forms, including tablets, capsules, soft gels, chewable gels, and other types of dietary supplements.

Intended Use of the SMPR developed

• Reference Method for compliance with FDA Dietary Supplement cGMPs, or other relevant regulatory agencies.

Applicability

• Determination of folate in the forms of supplemental folic acid (CAS 59-30-3) and/or 5-methyl-tetrahydrofolate (CAS 134-35-0), in all forms of dietary supplements (such as tablets, capsules, softgels, gelcaps, liquids, powders, chewable gels, or other forms) intended to be taken by mouth.

Matrices for folate Supplements

• Tablets • Capsules • Liquids • Powders • Softgels • Gelcaps • Chewables • Others

Specific Performance Claims

Parameters

Analyte Folic Acid 5-methyl-THF

Analytical Range (ug/g)

50-1500

LOD (ug/g) LOQ (ug/g)

15

50 5-methyl-THF = 5-methyl-tetrahydrofolic acid

Specific Performance Claims for folic acid Parameters Performance at conc range Conc (ug/g) <100 100-1000 >1000 Repeatability (RSDr, %) <10 (<12) <7 (<9) <5 (<7) Recovery, % 90-110 (85- 115) 95-105 (90- 110) 97-103 (92- 108) Reproducibility (RSDR, %) <15 (<18) <10 (<12) <7 (<10) Parentheses indicate requirements for difficult matrices (i.e., gummies, chewables)

Specific Performance Claims for 5-methyl tetrahydrofolic acid Parameters Performance at conc range Conc (ug/g) <100 100-1000 >1000 Repeatability (RSDr, %) <10 (<12) <7 (<9) <5 (<7) Recovery, % 80-110 (75- 120) 85-115 (80- 115) 90-110 (85- 115) Reproducibility (RSDR, %) <15 (<18) <10 (<12) <7 (<10) Parentheses indicate requirements for difficult matrices (i.e., gummies, chewables)

System Suitability Tests and/or Analytical Quality Control

• Suitable methods will include blank check samples and check standards at the lowest point and midrange point of the analytical range.

Reference Material(s)

• National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) SRM 3280 and 3289 - Multivitamin/Multielement Tablets. The SRM 3252, a protein drink mix, with an assigned folic acid value is also one of the choice in the lack of the SRM 3280 and 3289 .

Validation Guidance

• Appendix K: Guidelines for Dietary Supplements and Botanicals, Official Methods of Analysis (current edition), AOAC INTERNATIONAL, Rockville, MD, USAhttp://www.eoma.aoac.org/app_k.pdf). Also at: J. AOAC Int . 95, 268(2012); DOI: 10.5740/jaoacint.11-447

Comments Submitted 1. Comments about definition of Dietary Ingredients : • In place of Man -Human or Animal • Suggest changing "man" to "human" for consistency with regulatory language and politically correctness RESPONSE: Replace man by humans in the definition 3. Comment about definition of Dietary Supplements : • Definition does not state if it covers human and/or animal supplements RESPONSE: Add humans to the definition 4. Comment about definition of LOQ • Only concentration is given in the matrix RESPONSE: Definition is kept flexible to fit different scenarios

Comments Submitted 5. Comment about Reference Material(s) :

• NIST SRM 3280 is discontinued and will be replaced with SRM 3289. Recommend removing the reference to SRM 3280 as this is no longer an available product • SRM 3252 is a protein drink mix with a value assigned for folic acid and may be useful for method validation. • RESPONSE: Reference Material section has been updated to indicate the availability of the SRM 3252 in the lack of the SRMs 3280 and 3289 which is a protein drink mix with an assigned value for folic acid

Comments Submitted

7. Comment about Validation Guidance : • Appendix K includes validation guidance and should at least be repeated in the section on Validation (6), if not completely moved there. Otherwise, the validation guidance is unclear. OMA contains numerous appendices containing validation guidance and the guidance most applicable to this SMPR (Appendix K) should be referenced here . • RESPONSE: Information about Appendix K has been moved to Section 6, Validation Guidance

Comments Submitted 8. Comments about Table 1a (Method performance requirements (folic acid) : • Title and table number missing • 1a is not labeled as such nor what analyte is covered. I assume it's folic acid. RESPONSE: A title to the Table, "Method performance requirements (folic acid)" has been added. • Limit of quantification will not fit these two ranges 100- 1000ug/g and >1000ug/g; - Analytical range and LOD are missing. RESPONSE: A Row Indicating Analytical Rage of 50-1500 ug/100 has been added and another row providing LOD of 15 /100 h l b dd d

Comments Submitted 12. Comment about Table 1b (Method performance requirements (5-methyl-THF) : • Recovery % maybe 75-115. • Recovery % maybe 80-120 . RESPONSE: The work group wanted to provide more flexibility about recovery at different concentration .

Acknowledgement

The workgroup members came prepared for the meetings and were very focused on the the SMPR items under discussion. I and the AOAC greatly appreciate their efforts in completing the SMPR draft in very short time.

Motion

• All comments have been addressed. I on behalf of the working group move to approve the SMPR for folate in Dietary Supplements as presented.

Discussion

Table 1a. Method performance requirements (folic acid) Analytical Range 50 – 1500ug/g Limit of detection (LOD) 15ug/g Limit of quantitation (LOQ) 50ug/g Range < 100ug/g 100 – 1000ug/g

AOAC SMPR® Working Template

Standard Method Performance Requirements (SMPRs) for Folate in Dietary Supplements Intended Use : Reference Method for compliance with FDADietary Supplement cGMPs, or other relevant regulatory agencies. supplemental folic acid (CAS 59-30-3) and/or 5-methyl-tetrahydrofolic acid (CAS 134-35-0 ), in all forms of dietary supplements (such as tablets, capsules, softgels, gelcaps, liquids, powders, chewable gels, or other forms) intended to be taken by mouth. 1 Analytical Technique Any analytical technique that meets the Applicability Determination of folate in the forms of following method performance requirements is acceptable. 2 Definitions Dietary Ingredients. —Vitamin, mineral, herb, or other botanical; an amino acid; a dietary substance for use by humans to supplement the diet by increasing total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any of the above dietary ingredients. {United States Federal Food Drug and Cosmetic Act §201(ff) [U.S.C. 321 (ff)]} Dietary Supplements. — A dietary supplement is a product for humans to be taken by mouth that contains a "dietary ingredient" intended to

> 1000ug/g

Repeatability (RSDr, %) *

≤ 10 (≤12)

≤ 7 (≤9)

≤ 5 (≤7)

95 – 105 (90 – 110) 97 – 103 (92 – 108)

Recovery, % *

90 –110 (85- 115)

Reproducibility (RSDR, %) * ≤ 7 (≤10) * Parentheses indicate requirements for difficult matrices (i.e., gummies, chewables) ≤ 15 (≤18) ≤ 10 (≤12)

Table 1b. Method performance requirements (5-methyl-THF) Analytical Range 50 – 1500ug/g Limit of detection (LOD) 15ug/g Limit of quantitation (LOQ) 50ug/g Range < 100ug/g 100 – 1000ug/g

> 1000ug/g

Repeatability (RSDr, %) *

≤ 10 (≤12)

≤ 7 (≤9)

≤ 5 (≤7)

Recovery, % *

80 –110 (75- 120)

90 – 110 (85 – 115)

85 – 115 (80 – 115)

Reproducibility (RSDR, %) * ≤ 7 (≤10) * Parentheses indicate requirements for difficult matrices (i.e., gummies, chewables) ≤ 15 (≤18) ≤ 10 (≤12)

supplement the diet. Dietary supplements may be found in many forms such as tablets, capsules, gels, softgels, gelcaps, liquids, or powders. Limit of detection (LOD ).—The minimum concentration or mass of analyte that can be detected in a given matrix with no greater than 5% false- positive risk and 5% false-negative risk. Limit of quantitation (LOQ) .—The minimum concentration or mass of analyte in a given matrix that can be reported as a quantitative result. Repeatability .—Variation arising when all efforts are made to keep conditions constant by using the same instrument

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and operator, and repeating during a short time period. Expressed as the repeatability standard deviation (SDr); or % repeatability relative standard deviation (%RSDr). Reproducibility .—The SD or RSD calculated from among laboratory data;

5 Reference Material(s) National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) SRM 3280 and 3289 - Multivitamin/Multielement Tablets. 6 Validation Guidance Appendix K: Guidelines for Dietary Supplements and Botanicals, Official Methods of Analysis (current edition), AOAC INTERNATIONAL, Rockville, MD, USA (http://www.eoma.aoac.org/app_k.pdf). Also at: J. AOAC Int . 95, 268(2012); DOI: 10.5740/jaoacint.11-447

expressed as the reproducibility standard deviation(SDR), or % reproducibility relative standard deviation (%RSDR).

Recovery .—The fraction or percentage of spiked analyte that is recovered when the test sample is analyzed using the entire method. 3 Method Performance Requirements See Table 1a and 1b. 4 System Suitability Tests and/or Analytical Quality Control Suitable methods will include blank check samples and check standards at the lowest point and midrange point of the analytical range.

7 Maximum Time-to-Signal No maximum time.

8 Reference Refer to USP <1151> Pharmaceutical Dosage Forms for definitions (1151 PHARMACEUTICAL DOSAGE FORMS (usp.org)

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Working Group for Folic Acid Ballot Access – SMPR for Folate in Dietary Supplements

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