BOTANICAL AND DIETARY SUPPLEMENTS INTEGRITY PROGRAM ANNUAL M

AOAC INTERNATIONAL AOAC Annual Meeting & Exposition Westin Kierland Hotel Spa & Resort Scottsdale, Arizona Sunday, August 28, 2022 11:00am – 2:00pm MST Agenda Moderator: Darryl Sullivan (Eurofins)

I. WELCOME & INTRODUCTIONS (Sullivan) (11:00am – 11:15am)

Darryl Sullivan (Eurofins) will welcome attendees and invited speakers. He will also set the stage for session by providing an overview of the analytical challenges faced by independent third-party laboratories and the “ American Council of Independent Laboratories (ACIL) Best Practices for Third Party Testing of Dietary Supplements .” II. PERSPECTIVES ON TOPICS IN BOTANICALS AND DIETARY SUPPLEMENTS ( Q&A to follow each speaker ) a. USP and Botanical Dietary Supplement Quality (Sarma) (11:15am – 11:35am) Nandakumara Sarma, PhD (Director, Dietary Supplements and Herbal Medicines, US Pharnacopeia) will share USP’s perspectives on scientifically valid methods and reference materials to address analytical challenges. He will also share the updates from the USP Dietary Supplement Sector on challenges and educational needs of healthcare professionals about botanical dietary supplements. b. Challenges in Ensuring Quality in Botanical Dietary Supplements (Johnson) (11:40am – 12:00pm) Holly Johnson, PhD (Chief Science Officer, American Herbal Product Association (AHPA)) will provide an overview of the work of the AHPA Analytical Laboratories and Botanical Raw Materials committees as they assess the analytical challenges of AHPA members. c. Stretching Our Wings (Shultis) (12:10pm – 12:30pm) Allyn Shultis (Executive Director, Global Retailers and Manufacturers Alliance) will share an organizational update related to both their certification program and the Dietary Supplement Product Integrity Committee. The heart of this session is intended to build on previous though leader discussions held collaboratively with AOAC International and identify key learnings from the committee as it relates to the first phase of the committees work – Program Review. d. Botanical Reference material (BRM) and Botanical Identification-Industry perspective (Zhang) (12:45pm – 1:05pm) Yanjun Zhang, PhD (Principal Scientist, Herbalife) will share the challenges of insufficient reference materials for botanicals and dietary supplement method development and testing as she shares highlights from the AOAC scientific session she is chairing entitled, “Development of (In -House) Botanical Reference Materials to Ensure the Quality of Herbal Dietary Supplement Products.” e. Industry/Retailer Think Tank on Adopting Harmonized Supplement Testing Requirements (Koroma) (1:10pm – 1:30pm) Mohamed Koroma (Director, R&D, Pharmavite) will provide an overview of some of the industry ’s analytical challenges and how independent third-party consensus standards development and validated methods can lead addressing analytical challenges in support quality and integrity across the supply chain.

f. Best Practices for Third Party Testing of Dietary Supplements (Sullivan) (1:35pm – 1:55pm)

Darryl Sullivan will provide an overview of the AOAC Botanical and Dietary Supplement Integrity Program with recommendations for the programs starting points, such as pyrrolizidine alkaloids, method development, method validation guidance, method end user guidance, contaminant testing, training and education, reference materials development, etc… .

III. ADJOURNMENT

Agenda Subject to Change without Notice Lunch Break will be at 12:30pm – 12:45pm MST

A multi-year, integrated science program to support the analytical needs of the Botanical and Dietary Supplement Community

OVERVIEW AOAC INTERNATIONAL (AOAC) is proposing a new multi-year program funded by stakeholders to collaboratively re-invigorate efforts to address current and newly emerging analytical needs within the botanical and dietary supplement community. The AOAC Botanical and Dietary Supplement Integrity Program (BDSIP) is designed to provide raw agricultural producers, manufacturers, testing laboratories, and retail establishments with the analytical resources necessary to ensure product integrity, including reliable Certificates of Analysis ( i.e., quality and accurate labeling for identity, purity, strength, and composition). To build upon AOAC’s compilation of previously published analyte-specific Standard Method Performance Requirements ( SMPRs® ) and fit-for-purpose Official Methods of Analysis SM , BDSIP offers a multi-faceted approach that encompasses the following workstreams: • Development of method performance standards for submission of methods for new components, dosages, environmental contaminants, and novel matrices, • Species identification (botanicals and probiotics) employing next generation sequencing applications, molecular technologies, • Updates for validation and verification criteria (AOAC Appendix K) • Training and education programs

As part of this effort, AOAC is also committing to re- evaluating and updating those “orphaned” SMPRs for which no methods were submitted through our previous program.

BACKGROUND Dietary supplements are a class of products intended to augment nutritional intake and/or ensure that an individual gets enough of the vital substances the body needs to function. They are not intended to treat, prevent, or cure diseases, used as a conventional food or as a sole item of a meal. Many ingredients in dietary supplements are regarded as nutritionals. Examples include water- and fat-soluble vitamins, co-factors, minerals, herbs, botanicals, and enzymes alone or in combination. By most international standards, they are intended to be taken orally and are marketed in multiple dose forms ( e.g., as tablets, capsules, soft gels, gel caps, powders, and liquids) and dosages. In the United States, botanical and dietary supplement safety and integrity are regulated under The Dietary Supplement Health and Education Act of 1994 (DSHEA) with authority granted to the U.S. Food and Drug Administration under 21 CFR, Part 111 (2007), “ Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. ” 21 CFR, Part 111 (2007) defines the responsibilities industry must take to ensure quality through Good Manufacturing Practices. Key points regarding analytical test methods and validity of results include: • Establish component specifications that are necessary to ensure that specifications for the purity, strength and composition of dietary supplements manufactured using the components are met, • Supplier Certificates of Analysis (COAs) of components; description of the test used and actual results of the tests or examinations. In the European Union, the manufacturing and trade of herbs and dietary supplements are regulated by pharmaceutical and food laws. While dietary supplements are subject to food laws, regulatory provisions dealing with herbs are found in pharmaceutical regulations. Regulatory oversight in Asia-Pacific Countries (APAC) e.g., China, India, Australia, Korea, and Southeast Asia (ASEAN) is similarly compartmentalized to varying degrees between food and pharmaceutical regulations. The 2021 market for botanicals and dietary supplements according to consumer sales was $48.5B in the US and $151.9B globally. The expansion of product offerings has rapidly exploded worldwide. The COVID-19 pandemic, the exponential growth of on-line sales, and trends in CBD-containing product development and market availability are recent contributing factors. The result has been a renewed call for increased regulatory scrutiny, awareness of product integrity and safety, and a greater collaborative environment among stakeholder communities that include growers, manufacturers, retailers, and regulators. Notable industry-led initiatives includ e the “Tested to be Trusted” Program (CVS, 2019), COA from an ISO/IEC 17025 accredited

laboratory (Amazon, 2020), and the formation of the Global Retailer and Manufacturer Alliance (GRMA) Dietary Supplement Integrity Committee (2022).

AOAC AND DIETARY SUPPLEMENTS AOAC has been a leader within the dietary supplement analytical community since 2001. Between 2001 and 2013, in collaboration with the National Institutes of Health Office of Dietary Supplements, AOAC adopted 11 official methods of analysis along with training materials, validation guidelines, a section in the AOAC Laboratory Accreditation Criteria Committee guidelines, a dedicated chapter in the AOAC Official Methods of Analysis SM and a dedicated section of the Journal of AOAC INTERNATIONAL to the measurement of dietary supplement components. From 2013 to 2018, AOAC INTERNATIONAL, in a continued collaboration with the National Institutes of Health Office of Dietary Supplements, embarked on a large-scale stakeholder program to develop much needed consensus-driven performance standards and analytical methods for ingredients used in dietary supplements. As a result of this five-year effort, 34 Standard Method Performance Requirements ( SMPRs) were adopted, and 16 methods were approved for First Action Status as Official Methods of Analysis SM for 25 high priority ingredients. In the intervening years since the program’s completion, new regulations, new product offerings and expanding consumer markets, have brought greater attention to recognized analytical gaps needed to support dietary supplement quality and safety for producers, retailers, and consumers alike. In addition, large retailers of dietary supplements are moving towards requiring that all such products bear a certificate of analysis ( i.e., tested by an accredited laboratory using validated compendial methods). Botanicals and dietary supplements are specific types of matrices with different types of delivery systems and dosages. As such, performance standards and current Official Methods of Analysis SM for such analytes in food matrices may not be suitable ( i.e., fit-for-purpose,) to quantify the same analytes in dietary supplement dose forms such as chewable gels, soft gels, and tablets. MOVING FORWARD WITH AOAC’ s BDSIP AOAC INTERNATIONAL is seeking financial support to launch the Botanical and Dietary Supplement Integrity Program . Based on our 20 years of analytical support and accomplishments in this product sector and as a continuing partner with the above-mentioned stakeholder communities, this program will: • Develop performance standards applicable to the analyte (including dosages), component, contaminant, and matrix of highest priority, • Instill confidence in test data reliability, for manufacturers, retailers, and regulators,

• Foster development and adoption of Official Methods of Analysis that are fit-for- purpose and apply appropriate, consensus-driven method performance standards to meet industry GMP requirements and regulatory review. Based on input received, we have already seeded this new program with two projects designed to address dosage claims and contaminant analysis. These include: Voluntary Consensus Standard for the Determination of Folic Acid in Chewable Gels, Soft Gels and Tablets (Folic-Acid- in-Dietary-Supplements-Proposal-9.16.21.pdf (aoac.org) for which a standard has recently been adopted; and, Voluntary Consensus Standard for the Determination of Pyrrolizidine Alkaloids in Teas, Herbal Infusions, and other Foods Containing Herbal Ingredients ( AOAC-Pyrrolizidine- Alkaloids-Proposal-6.11.21.pdf) that is about to get underway. It is important to note that this program is designed to support parallel workstreams to address multiple but distinct interests. These can be undertaken simultaneously with adequate Advisory Panel support for each workstream. Advisory Panel members will help to steer the overall work of the BDSIP while focusing on workstreams that will address their specific n ext- generation technology interests/needs.

Advisory Panel Workstream priority setting, Horizon-scanning

Ingredient & Product Authenticity and Integrity

Method Development and Implementation Criteria

Standards Development

Education & Training

Manufacturers & Retailers

Component Analysis, Multi-component analysis, dosages, matrices

Sampling

AOAC Consulting Service

Method Developer

Reference Materials

Performance Tested Methods Certification

Laboratory Analysts

Next Generation technologies and Applications

Agricultural Contaminants

Official Methods of Analysis

ERP Orientations

Validation and Verification Criteria

Instructional Webinars & Seminars

Supply chain tracibility

Proficiency

Seeking Support BDSIP will be guided by an Advisory Panel comprised of funding organizations from government, industry and academia to confirm priorities and working group objectives. This panel will meet quarterly to review progress and consider additional objectives. To launch this multi-year effort, AOAC INTERNATIONAL is asking organizations to join this important program with an annual contribution of $10,000. Other levels of contributions will be considered as well 1 . Each individual workstream will require $80,000 to begin working group activities 2 .

Funding will support the following for each workstream 3 :

o Identification of and recruitment for working groups and members, o Facilitating AP meetings, working group and subgroup meetings (when needed)

for drafting of consensus documentation, o Coordination of all program meetings ▪

Two (2) annual in-person program meetings, ▪ Working group meetings and subgroup meetings (both in-person, web conference, and online collaboration)

• Processes for drafting documents and consensus building, • Publication of approved consensus documents, • Travel for no more than three (3) invited key experts needed to complete the work.

Benefits as an Advisory Panel Member • Multiple workstreams for prospective AP members to select based on your priority analytical needs, • Leadership in establishing consumer confidence by driving the development of internationally recognized performance standards that will foster the development of Official Methods of Analysis, • Engagement with a select group that will set benchmarks for quality and product integrity, • Opportunity to drive the development of criteria for novel applications for botanical testing that incorporate cutting edge technologies to ensure botanical authenticity, • Steer the revision and updating of globally accepted method validation criteria and method verification criteria to ensure proper method implementation, • Lead the development of needed laboratory end-user guidance and quality testing program components for the botanical and dietary supplement community. • Earn financial discounts on select AOAC INTERNATIONAL Science Programs • Ensure that all testing data provided in a COA is accurate and reliable which will translate into consumer safety and trust.

Contact Information Palmer A. Orlandi, Jr., Ph. D.

Alica Meiklejohn

Chief Science Officer/Deputy Executive Director

Director, Business Development

AOAC INTERNATIONAL

AOAC INTERNATIONAL

2275 Research Blvd., Suite 300

2275 Research Blvd., Suite 300

Rockville, MD 20850

Rockville, MD 20850

Tel: 301-924-7077; ext. 163

Tel: 301-924-7077; ext. 101

porlandi@aoac.org www.aoac.org

ameiklejohn@aoac.org

www.aoac.org

------------------------------------------------- 1 AOAC INTERNATIONAL will continue to explore a multi-tiered funding schedule to avoid any unintended barrier to the ultimate success of this project and to encourage as many stakeholders to get involved as possible. 2 Each workstream at $80,000 supports a maximum of two (2) working groups depending on the scope of work.

3 Costs associated with method submission and review are separate and in addition to the fees for launching any workstream.

Voluntary Consensus Standard for the Determination of Pyrrolizidine Alkaloids in Teas, Herbal Infusions, and other Foods Containing Herbal Ingredients

AOAC 2021 Initiative AOAC INTERNATIONAL is proposing the establishment of a working group to develop a voluntary consensus standard (or standards) for the determination (quantification) of 35 pyrrolizidine alkaloids (PAs) (comprising 21 PAs of regulatory importance and 14 others known to co-elute with one or more of the identified 21 PAs) in teas, herbal infusions, herbs, seed spices and botanical dietary supplement ingredients to meet new maximum levels (MLs) recently adopted through the European Commission Regulation (EU) 2020/2040 1 . The Working Group will develop one or more Standard Method Performance Requirements ® , or SMPRs ® (as deemed necessary by WG experts), based on priorities established by the project’s Advisory Panel (see below). The standards adopted through this working group will provide the analytical basis for the development of new testing methods that will: • Substantiate the effectiveness of good agricultural collection practices, • Support regulatory compliance and surveillance programs, i.e. monitor prevalence of PAs in raw agricultural commodities and finished botanical products, and • Support prevention measures and minimize the risk for importers, exporters and finished product producers. Background Pyrrolizidine alkaloids (PAs) are secondary plant metabolites consisting of a necine base and 1 or 2 necic acids (esterifying acid). PAs can be open-chain mono- or diesters or macrocyclic diesters. They can be present in plants as free base or as N-oxides. PAs and their associated N- oxides are produced by an estimated 6000 plant species (about 3% of the world’s flowering plants) and are thought to act as a defense mechanism against insect herbivores. PAs with certain structural features are hepatotoxic and genotoxic carcinogens. The presence of detectable (measurable) levels of PAs throughout the food chain, e.g. in agricultural and minimally processed foods and food supplements, is of particular concern. In addition to their inherent presence in certain plants, accidental co-harvesting of PA-producing weeds is another significant contributing factor. PAs can be found in grain crops contaminated with PA containing weeds herbal products such as teas, liquid infusions, and other selected

PAs Proposal JUNE 2021

botanicals and spices. They have also been detected in foods of animal origin (milk, honey, egg, offal) though in very low amounts (ppb). This is attributed to animal grazing on PA-producing plants or feeds. In the United States, the U.S. Food and Drug Administration (US-FDA) since the early 2000s has taken the unofficial position for a zero-tolerance policy for PAs 2,3 . This position arose principally through concerns with the marketing of supplements that contain the herbal ingredient comfrey, as these plants are known sources of PA; and a recognition that these compounds present a considerable threat to human health. Regarding the establishment of maximum tolerance levels, the US-FDA took the position that no level of PA is acceptable and did not believe that there is adequate scientific evidence to establish an exposure level that would present no harm to consumers. In contrast, the EU took a more measured and actionable approach over those years to keep levels of PAs in the food chain as low as reasonably achievable through guidance on good agricultural practices, periodically updated risk assessments on exposure estimates and consumption data in products susceptible to PA contamination. In December 2020, however, Commission Regulation (EU) 2020/2040 1 finally established maximum levels (MLs) for the sum of 35 PAs in teas, herbal infusions (including those for infants and young children), pollen and pollen products, and other food and dietary commodities. Of those PAs characterized and of toxicological relevance, 21 occur in quantifiable amounts. These are the focus for the newly established EU MLs and present a new challenge analytically. To date, two laboratory testing approaches (sum parameter analysis and targeted analysis) are employed for the quantification of these PAs in commodities of importance. Each consists of a complex multi-step protocol for sampling, sample preparation and LC-MS/MS analysis; and are based on the quantified sum of these 21 analytes. However, accurate quantification for regulatory purposes using current testing paradigms may not always be possible. Fourteen (14) additional, naturally occurring isomers display chromatographic patterns (by LC retention times and MS fragmentation) that are indistinguishable by currently available methodologies. Similarly, the ratio of PA forms (PA- N -oxide and its free tertiary base) create uncertainty in accurate ML quantification. Seeking Support The Pyrrolizidine Alkaloids Advisory Panel will be comprised of funding organizations to determine initial priorities and working group strategies. This panel will meet quarterly to review progress and consider additional objectives based on working group accomplishments and any new challenges that may arise. The projected funding level needed to complete this initiative as described is $80,000 (see Appendix 1 for services provided). We are asking organizations to join this important project for a contribution of $10,000. Other levels of contributions will be considered as well * .

PAs Proposal JUNE 2021

Benefits for You Method developers

• Influence the development of consensus standards, which will be used by AOAC Expert Review Panels to evaluate your candidate methods for possible adoption as AOAC Official Methods of Analysis. • AOAC Official Methods of Analysis will be the benchmark for trade resolutions, instill consumer confidence, and contribute to consumer safety. Food manufacturers or food distributors: • Ensure that project priorities meet your needs through AOAC INTERNATIONAL’s unique standard development process, • Encourage the development of Official Methods which provide the highest level of analytical confidence for authenticity claims and detect fraudulent adulteration in priority commodities, • Provide a validated analytical means needed to meet regional and internationally adopted regulatory requirements, • Protect producers and consumers alike, maintain the reputation of products and ultimately improve the quality and safety of the food supply, i.e. substantiate the effectiveness of good agricultural collection practices, and support prevention measures and minimize the risk for importers, exporters and finished product producers. For all: • Create much-needed reference methods for PAs of regulatory importance in commodities that do not currently exist, • Generate reliable data for effective compliance-driven quality control of food materials and products, i.e. through regulatory compliance and surveillance programs designed to monitor prevalence of PAs in raw agricultural commodities and finished botanical products. * AOAC will continue to explore a multi -tiered fundi ngschedule to avoid any unintended barri er to the ultimate successof this project and to encourage as many stakehol dertso get involved aspossible.

CONTACT INFORMATION Palmer A. Orlandi, Jr., Ph. D. Chief Science Officer/Deputy Executive Director AOAC INTERNATIONAL 2275 Research Blvd., Suite 300 Rockville, MD 20850 Tel: 301-924-7077; ext. 163 porlandi@aoac.org www.aoac.org

Alic i a Meiklejohn Director, Business Development AOAC INTERNATIONAL 2275 Research Blvd., Suite 300 Rockville, MD 20850 Tel: 301-924-7077; ext. 101 ameiklejohn@aoac.org www.aoac.org

References 1 Commission Regulation (EU) 2020/2040 of 11 December 2020 amending Regulation (EC) No 1881/2006 as regards maximum levels of pyrrolizidine alkaloids in certain foodstuffs https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32020R2040&from=EN 2 https://wayback.archive- it.org/7993/20170722025637/https://www.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/uc m111219.htm

PAs Proposal JUNE 2021

APPENDIX 1 The base fee per Working Group is $80,000 USD and includes:

• Advisory Panel Meetings . AOAC will hold an Advisory Panel Meeting to identify renowned subject matter experts and to identify additional key authorities and experts to participate on AOAC working groups. • AOAC Stakeholder Meeting . Working Group Chairs will present the Working Group launch presentation and the stakeholders will refine fitness for purpose. • AOAC Working Group Meetings . The Working Groups will hold a series of teleconferences, as needed, to complete the draft SMPR(s). • AOAC Stakeholder Meeting . Working Group Chairs will present draft SMPRs for approval by the stakeholders. Stakeholders will deliberate and reach consensus on and thereby approve a final version of the SMPR(s). • Publication Costs. SMPR(s) approved by the stakeholder community will be published in A OAC venues (i.e., Official Methods of Analysis of AOAC INTERNATIONAL and AOAC w ebsite). • Training and education materials/webinar(s) for method developers. Additional Fees (as applicable): 1. Application Fees for Official Methods SM Review - $35,000 USD per method 1 : • Includes recruitment of Expert Review Panel (ERP) Members (Volunteer Experts), • Includes Preparation and Review of Methods for Review, • Includes ERP Orientation and Facilitating ERP Meetings, o Initial in-person meeting and, if methods are adopted, maintenance of ERP over the two (2) year method tracking period, • Includes ERP review of Method Modifications during the 2-year tracking period, • Includes Publications of methods and method manuscripts. 2. Application Fees for Modifying or Extending an Official Method of Analysis - $10,000 per method: • Includes Preparation and Review of Methods for Review, • Includes ERP Orientation and Facilitating ERP Meetings, o Initial in-person meeting and if methods are adopted, maintenance of ERP over the two (2) year method tracking period, • Includes ERP review of method during the 2-year tracking period, if required • Includes Publications of methods and method manuscripts.

Optional Enhancements (per method):

1 Base application fee. AOAC Organizational Member discounts may apply.

PAs Proposal JUNE 2021

• Consultation on validation test protocols: • Drafting Protocols & Review of Protocol: • Drafting of Method in AOAC Format: • Drafting of Method Manuscript in AOAC Format:

$3,000 USD $3,000 USD $2,000 USD $5,000 USD

NOTE: Travel costs of ERP members and coordination of laboratory work if needed are not covered. New application fees for resubmission will be required if an ERP does not approve the initial method submission.

PAs Proposal JUNE 2021