2018 March 16 SPDS

Stakeholder Panel on Dietary Supplements

STAKEHOLDER PANEL MEETING FRIDAY, MARCH 16, 2018

GAITHERSBURG MARRIOTT WASHINGTONIAN CENTER 9571 Washingtonian Blvd, Gaithersburg, MD, 20878 CONFERENCE ROOM: Salon C/D/E

8:30am – 12:00pm Eastern Time Registration Opens at 7:30am

CONTACT: SPDS@AOAC.ORG

Stakeholder Panel on Dietary Supplements

STAKEHOLDER PANEL MEETING FRIDAY, MARCH 16, 2018

GAITHERSBURG MARRIOTT WASHINGTONIAN CENTER 9571 Washingtonian Blvd, Gaithersburg, MD, 20878 CONFERENCE ROOM: Salon C/D/E

8:30am – 12:00pm Eastern Time Registration Opens at 7:30am

CONTACT: SPDS@AOAC.ORG

SPDS Meeting, September 22-23 – Chair and Presenter Bios

STAKEHOLDER PANEL CHAIRS

DARRYL SULLIVAN, COVANCE LABORATORIES Chair, AOAC Stakeholder Panel on Dietary Supplements

Darryl Sullivan is a Fellow of AOAC and has been an active member since 1980. He has served terms as secretary, president-elect, president, past president, and director of the Board of Directors, and previously served a three-year term as chair of the Official Methods Board, and is currently serving as Chair of the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals. In 2012 Darryl lead a very successful AOAC engagement with government and industry thought leaders in India and China on behalf of SPIFAN. He is also active with the Stakeholder Panel for Strategic Food Analytical Methods and the Stakeholder Panel for Agent Detection Assays. Sullivan also served a three-year term as a director on the AOAC Research Institute Board of Directors. He was a founding member and chair of the Presidential Task Force on Dietary Supplements and a member of the Task Force on Bacillus anthracis, as well as the AOAC Task Force on Nutrition Labeling and the AOAC Task Force on Sulfites. Prior to chairing the OMB, he served as a member and chair of the Methods Committee on Commodity Foods and Commodity Products. Sullivan was a founding member of the AOAC Technical Division on Reference Materials and served three terms on the Division's Executive Board. A staunch supporter of the Association, Sullivan was active in the e-CAM and Scholar I projects at AOAC, has exhibited at the annual meetings for many years, has presented hundreds of papers and posters at AOAC meetings and regularly publishes his research in the journal of the AOAC. He has also presented a significant number of papers on behalf of AOAC at other scientific meetings in many different parts of the world.

BRIAN SCHANEBERG, STARBUCKS CORPORATION Vice Chair, AOAC Stakeholder Panel on Dietary Supplements

Brian Schaneberg, Ph.D., is the Global Scientific & Regulatory Affairs Director for Starbucks Corporation. Brian participates in the execution of company strategies while ensuring compliance and regulatory guidelines are met and followed by the company across all products: Starbucks, Teavana, Tazo, Evolution Fresh, La Boulange, and Ethos. Brian has over 15 years of natural products experience in the area of dietary supplements and herbals. Brian was also the Quality & Food Saftey and Scientific & Regulatory Affairs Director for Mars Botanical, a division of Mars, Inc. focusing on cocoa flavanol science and products. Before Mars Botanical, he was the Director of Technical Services at ChromaDex, Inc. in Irvine, California and was an Associate Research Scientist at the National Center for Natural Products Research at the University of Mississippi under the guidance of Dr. Ikhlas Khan, in a position funded by the US FDA for the development of methods to ensure the quality and safety of botanicals and dietary supplements. Over the years, Brian has worked closely with trade groups, industry, academia and government leaders. He has been a member of various review committees including NIH grants, analytical validation ERPs at AOAC and the Registry of Carcinogens. Brian also had the pleasure of holding an adjunct faculty position at the University of Colorado, Denver, advising a student that received his MS in Analytical Chemistry isolating phytochemicals and developing analytical testing procedures for Horse Chestnut. Brian has a Ph.D. in Organic Chemistry from Virginia Commonwealth University and a B.A. in Chemistry with a minor in Biology from Central College in Iowa. He has authored or co-authored more than 50 publications and presentations.

SPDS Meeting, September 22-23 – Chair and Presenter Bios

PRESENTER BIOS

RICHARD B. VAN BREEMEN, PHD, UNIVERSITY OF ILLINOIS COLLEGE OF PHARMACY

Chair, SPDS Resveratrol Working Group

Richard B. van Breemen is the Matthias C Lu Collegiate Professor of Pharmacy

and Professor of Medicinal Chemistry and Pharmacognosy at the University of

Illinois College of Pharmacy. He serves as Director of the UIC/NIH Center for Botanical Dietary

Supplements Research and leads the Mass Spectrometry, Metabolomics and Proteomics Facility for the

University of Illinois Cancer Center. Prof. van Breemen received his B.A. in chemistry from Oberlin

College in 1980 and Ph.D. in Pharmacology and Experimental Therapeutics from the Johns Hopkins

University in 1985. He carried out post-doctoral research in laser desorption mass spectrometry at Johns

Hopkins before joining North Carolina State University in 1994 and then the University of Illinois College

of Pharmacy. He is a Regional Editor of Biomedical Chromatography and on the editorial board of Assay

and Drug Development Technologies. Prof. van Breemen has received an Expert Methods Panel award

from the AOAC International for his work on analytical methods for dietary supplements, the Harvey W.

Wiley Award from the AOAC International, and the 2015 Researcher of the Year Award from the

University of Illinois at Chicago. His research concerns the discovery and development of natural

products as chemoprevention agents and the investigation of botanical dietary supplements as

alternatives to hormone therapy for menopausal women.

STEVEN DENTALI

Chair, SPDS Kavalactones Working Group

Steven Dentali, Ph.D., consulting as Dentali Botanical Sciences and widely

considered an international authority on botanical ingredients, previously served as VP and Research

Fellow, Botanical Sciences at Herbalife after eleven years as VP and Chief Science Officer for the

American Herbal Products Association. Dr. Dentali holds a Ph.D. in Pharmaceutical Sciences, with a

Natural Products Chemistry specialization, from the University of Arizona, where he was the American

SPDS Meeting, September 22-23 – Chair and Presenter Bios Foundation for Pharmaceutical Education Edwin Leigh Newcomb Memorial Fellow.

As a key opinion leader, Dr. Dentali helps guide the establishment of shared botanical standards via

engagement in governmental and educational standard-setting organizations including AOAC

INTERNATIONAL, the American Botanical Council, the American Herbal Pharmacopoeia, the National

Institutes of Health, and the U.S. Pharmacopeial Convention. He maintains a particular fondness for

communicating basic botanical concepts and the importance of using a shared nomenclature in order to

help drive industry to higher sustainable herbal standards.

HOLLY JOHNSON, ALKEMIST LABS

Chair, SPDS Scullcap Working Group

Holly E. Johnson Ph.D., is the Chief Science Officer for the American Herbal

Products Association (AHPA). She previously served for three years as

Laboratory Director for Alkemist Labs, an ISO 17025 accredited natural

products testing lab specializing in botanical dietary supplements. Dr.

Johnson took her Ph.D. in Pharmacognosy at the College of Pharmacy,

University of Illinois – Chicago (UIC), under renowned Pharmacognosist and researcher Dr. Norman

Farnsworth. Holly was awarded a National Institutes for Health (NIH) Fellowship and trained at the

UIC/NIH Center for Botanical Dietary Supplements. She was a Postdoctoral Research Fellow at the

Institute for EthnoMedicine studying the etiology of neurodegenerative disease, and also worked for

Waters Corporation conducting technical training and regulatory consulting for pharmaceutical and

supplements companies. She is currently a Research Associate with the National Tropical Botanical

Garden and serves on AOAC working groups, stakeholders panels, and expert review panels for Foods

and Dietary Supplements. She is a member of the United States Pharmacoepia’s (USP) Medical

Cannabis Expert Panel, the Editorial Board of the Journal of AOAC International, and she serves on the

Advisory Boards of the American Botanical Council and the American Herbal Pharmacoepia. Holly has

over 20 years experience working with natural products & botanicals and spent many happy years

conducting research on medicinal plants and giving courses at the University of Hawaii.

SPDS Roster as of March 16, 2018 

SPDS Roster, March 16, 2018 

This roster is also the SPDS Mailing List! Don’t see your name on the list? Please let us know by emailing  SPDS@AOAC.ORG and we will add you right away to make sure you don’t miss any important  announcements!  Full Name  Position  Organization  Mr. Darryl M. Sullivan  Chair  Covance Laboratories  Brian T. Schaneberg  Vice Chair  Starbucks Coffee Company  Douglas O. Abbott  Member  Ms. Karen W. Andrews  Member  USDA  Dr Wendy L. Applequist  Member  Missouri Botanical Garden  Ali Asim  Member  BioCell Technology, LLC  Gisele Atkinson  Member  Council for Responsible Nutrition  Inger Reidun Aukrust  Member  Kappa Biosciences  Lei Bao  Member  Nestle Food Safety Institute  Charles A. Barber  Member  NIST  DeAnn L. Benesh  Member  3M Food Safety  Matt Bernart  Member  Neways Inc.  Joseph M. Betz  Member  NIH ‐ ODS  Sneh D. Bhandari  Member  Mérieux NutriSciences  Joe Boison  Member   University of Saskatchewan  Maria Bøjstrup  Member  Pfizer  Thomas Brendler  Member  Plantaphile  Jim Brown  Member  Sigma‐Aldrich  LaVerne L. Brown  Member  National Institutes of Health 

British Columbia Institute of  Technology  Eurofins Scientific, Inc.  Nestle Research Center 

Paula N. Brown 

Member  Member 

Paul Burns 

Esther Campos‐Gimenez Member 

Louis Carlacci  Spencer Carter  Danielle Citrolo  Neal E. Craft  Hans Cruijsen 

Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member 

FDA 

Genysis Labs 

Kyowa Hakko U.S.A., Inc.  Craft Technologies, Inc. 

FrieslandCampina 

David Cunningham  Jean‐Luc Deborde  Jeff DelFavero  Steven J. Dentali  Gregory Diachenko 

Cunningham Consulting 

SCL 

Bodybuilding.com 

Dentali Botanical Sciences 

FDA ‐ CFSAN 

Huy Dinh, MS 

U. S. Pharmacopeial

SPDS Roster as of March 16, 2018 

Full Name 

Position 

Organization 

Linda M. Dodd 

Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member 

PB Gelatins/PB Leiner 

Jennifer Donelson  John C. Edwards  Milda E. Embuscado 

VUV Analytics 

Process NMR Associates 

McCormick 

Andy Erickson 

NSF International 

Nour Eddine Es‐Safi 

Mohammed V University in Rabat 

Lisa Evans 

Pfizer 

Daniel S. Fabricant  Christine Farthing 

Natural Products Association 

Pfizer 

Heather Figore 

Healthy Directions 

John Finley 

Louisiana State University  The Natures Bounty Company  American Botanical Council 

Brian John Fischer  Stefan Gafner  Eric F. Gordon  Brad Goskowicz  Ms. Qian F. Graves 

Covance Laboratories  Microbiologics, Inc. 

FDA ‐ CFSAN 

Council Responsible Nutrition  (CRN) 

James Griffiths  April Hall, PhD  Alec Heersink 

Nutra Manufacturing  Bodybuilding.com 

American Herbal Products  Association  Natural Products Association  Schwabe North America  Consumer Healthcare Products  Association 

Jason Hendrickson  Corey Hilmas  Adam Horkey  Marcia Howard  Chung M. Hyun  Greg Jaudzems  Martha Jennens  Holly E. Johnson  Ronald L. Johnson  George Joseph  Suvash Kafley  David C. Kennedy  Philip J. Koerner  Suhail Ishaq 

Amway 

BioCell Technology LLC 

Nestle USA, Inc 

Covance Laboratories  American Herbal Products  Association 

BioMérieux, Inc. 

AsureQuality, New Zealand 

Milk Specialties  Phenomenex  Phenomenex 

Joseph David Konschnik 

Restek Corporation  Bodybuilding.com 

Rachel Kreider  Scott Krepich 

Phenomenex 

Mary Kathryn Krogull 

Eurofins

SPDS Roster as of March 16, 2018 

Full Name 

Position 

Organization 

Complete Phytochemical  Solutions 

Christian C. Krueger 

Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member 

Dana A. Krueger 

Krueger Food Laboratories, Inc.  National Institutes of Health 

Adam Kuszak  Jasen Lavoie  John Lawry 

Lily of the Desert 

Covance 

John Paul Lee, BSc 

Agilent Technologies, Inc. 

Jungmin Lee 

USDA‐ARS‐HCRL 

Wenjie Li 

Herbalife 

Stephen John Lock 

SCIEX 

Mr. Douglas MacKay, ND Member  Elaine Catherine Marley  Member 

Council For Responsible Nutrition 

R‐Biopharm Rhone Ltd  University of Guelph  Covance Laboratories  Agilent Technologies, Inc. 

Perry Anthony Martos  Katerina Mastovska 

Mary T. McBride  Barry V. McCleary  Wendy McMahon 

Megazyme 

Mérieux NutriSciences 

Linda Messick 

Covance 

Charles Metcalfe 

Custom Analytics 

Allen Misa 

Phenomenex 

Deepali Mohindra  Elizabeth Mudge 

Thermo Fisher Scientific 

BCIT 

B. Murali 

Natural Remedies Private Limited 

Brian Musselman  Maria Ofitserova 

IonSense, Inc. 

Pickering Laboratories, Inc.  SABINSA CORPORATION 

Anurag Pande  Punam Patel 

Pharmavite 

Melissa Meaney Phillips  Member 

NIST 

Tom Phillips 

MD Department Of Agriculture 

Curtis S. Phinney 

Curtis S. Phinney, CNS  Thermo Fisher Scientific 

Dan Quinn  Sanni Raju 

Natreon, Inc.  MilliporeSigma 

Kunal Rehani 

Klaus Reif 

PhytoLab GmbH & Co., KG 

Kelly Lynn Reins, B.S. 

QBD Scientific Consulting Co. Inc. 

Mitzi Rettinger 

MilliporeSigma 

Catherine A. Rimmer 

NIST 

Joe Romano  Steve Royce 

Waters Corporation 

Agilent Technologies, Inc. 

Mr. Seyed Sadjadi  Leila G. Saldanha 

NIH ‐ ODS

SPDS Roster as of March 16, 2018 

Full Name 

Position 

Organization 

Myron Sasser 

Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member  Member 

MIDI, Inc 

Mr. Daniel Schmitz 

Abbott Nutrition 

American Herbal Products  Association 

Maged Sharaf 

Anand Sheshadri 

Agilent India 

Eurofins Central Analytical  Laboratories 

Victoria S. Siegel  William Sommer 

NattoPharma  MilliporeSigma  Sigma Aldrich 

Katherine Stenerson  Linda Stephenson 

Nathan Stern  Sidney Sudberg  James L. Sullivan 

Amway 

Alkemist Labs  Nutranext, LLC 

John Szpylka  John Travis 

Mérieux NutriSciences 

NSF International 

Barry Tulk 

DuPont Nutrition and Health 

Lukas Vaclavik 

Covance 

Richard Van Breemen  Denise Lowe Walters 

Oregon State University  Pfizer Consumer Healthcare 

Cara Welch 

FDA 

Tampa Bay Analytical Research,  Inc.  Post Active Nutrition Brands  Galbraith Laboratories, Inc. 

Tyler White 

Robert Wildman  Jason Williams  John Williams 

Mérieux NutriSciences 

Walter Brent Wilson  Bryan Wirthwine  John P Woods, B.S. 

NIST 

Q Laboratories, Inc.  Thorne Research, Inc. 

Jincai Yang 

NBTY Inc. 

Jinchuan Yang  Seong‐Jae Yoo 

Waters Corporation 

Pharmavite LLC 

Hong You  Kurt Young 

Eurofins Scientific, Inc.  GNC/Nutra Manufacturing 

Weiguo Zhang  Joseph Zhou  Garrett Zielinski  Shauna F. Roman  Christopher Dent  Dawn L. Frazier  Jonathan Goodwin  Deborah McKenzie 

Synutra Pure, Ltd. 

Sunshineville Health Products, Inc 

Covance Laboratories 

OMB Advisor Capstone Nutrition 

AOAC Staff  AOAC Staff  AOAC Staff  AOAC Staff 

AOAC INTERNATIONAL  AOAC INTERNATIONAL  AOAC INTERNATIONAL  AOAC INTERNATIONAL

DRAFT, DO NOT DISTRIBUTE

MARCH 16, 2018 GAITHERSBURG MARRIOTT WASHINGTONIAN CENTER 9571 Washingtonian Blvd, Gaithersburg, MD, 20878  CONFERENCE ROOM: Salon C/D/E

8:30am – 12:00pm Eastern Standard Time Registration Opens at 7:30am

STAKEHOLDER PANEL ON DIETARY SUPPLEMENTS (SPDS) Chair: Darryl Sullivan, Covance Vice Chair: Brian Schaneberg, Starbucks A G E N D A

Welcome and Introductions (8:30‐8:35am) a. Introductions

I.

SPDS Chair:  Darryl Sullivan, Covance  (Chair, SPDS) b. Policies and Procedures

Sullivan will review AOAC’s policies and request that participants comply with the AOAC International Antitrust Policy Statement and Guidelines as well as all AOAC Policies and Procedures, found at www.aoac.org , under “About AOAC”.

Ingredient Updates (8:35am – 8:45am) Darryl Sullivan a. Status of Ingredients to Date b. Open Calls for Methods and Calls for Experts SMPR Presentations and Consensus* (8:45am – 12:00pm) a. Kavalactones (9:00am – 9:45am) Chair:  Steven Dentali, Dentali Botanical Sciences b. Resveratrol (9:45am – 10:30am) Chair:  Richard van Breemen, Oregon State University c. Skullcap  (10:45am – 11:45pm)

II.

III.

Chair: Holly Johnson, American Herbal Products Association

Next Steps & Adjourn (11:45am – 12:00pm) Darryl Sullivan a. Next Steps for the Stakeholder Panel on Dietary Supplements 

IV.

Morning Break: 10:30am – 10:45am

            Version 1  01/30/2018

*Item(s) requires a vote by SPDS

AOAC Stakeholder Panel on Dietary Supplements (SPDS): Background and Updates

Darryl Sullivan , Chair Stakeholder Panel on Dietary Supplements Covance Laboratories

March 16, 2018

AOAC SPDS History

• AOAC INTERNATIONAL signed a 5‐year contract with the  National Institutes of Health‐Office of Dietary Supplements  (NIH/ODS) to establish voluntary consensus standards for  high‐priority ingredients.  • Develop standard method performance requirements  (SMPRs) for 25 priority dietary supplement ingredients. • Deliver First Action Official Methods SM for the prioritized  dietary supplement ingredients  • Encourage participation with the dietary supplements  industry to develop voluntary consensus standards.

Status of SPDS First Action Official Methods of Analysis SM Expert Review Panels (ERPs)

•

Aloe Vera (AOAC SMPR 2017.009 , 2017.010 ) • Five methods submitted, ERP TBD • Call for new methods remains open.   Two methods submitted, one method approved. • Resubmissions from last ERP will be accepted. • Call for new methods is closed. Aloin in Aloe ( AOAC SMPR 2015.015 ) •

•

Chondroitin ERP ( AOAC SMPR 2014.008 ) •

Four methods submitted, one approved. Resubmissions from last ERP will be accepted.

• •

Call for new methods is closed.

•

•

Collagen ( AOAC SMPR 2016.005 ) • No methods submitted, no methods approved. • Call for new methods remains open.   Folin‐C ( AOAC SMPR 2015.009 ) • Four methods submitted, one method approved. • Accepting resubmissions from last ERP. • Call for new methods is closed. Free Amino Acids ( AOAC SMPR 2017.011 ) • One method submitted, no methods approved. • Cal for new methods is  closed.  Ginger ( AOAC SMPR 2017.012 ) • One method submitted, no methods approved. • Accepting resubmissions from last ERP. • Call for new methods remains open .

•

Anthocyanins ( AOAC SMPR 2014.007 ) •

•

Three methods submitted, none approved. Resubmissions form last ERP will be accepted.

• •

Call for new methods remains open.  

•

Ashwagandha ( AOAC SMPR.007 ) • One method submitted, one method approved. • Resubmissions from last ERP will be accepted. • Call for new methods is closed. One method submitted, no methods approved. • Resubmissions from last ERP will be accepted. • Call for new methods remains open.   Cinnamon ( AOAC SMPR 2015.010 ) •

•

•

•

Status of SPDS First Action Official Methods of Analysis SM Expert Review Panels (ERPs)

• Kratom ( AOAC SMPR 2015.008 )

• Turmeric ( AOAC SMPR 2016.003 )

• Four methods submitted, one method approved. • Accepting resubmissions from last ERP. • Call for new methods is  closed.  

• Two methods submitted, one method  approved. • Resubmissions from last ERP will be  accepted. • Call for new methods is closed. ( AOAC SMPR 2016.017 ) • No methods submitted, no methods  approved. • Call for new methods remains open.   ( AOAC SMPR 2017.013 ) • No methods submitted, no methods  approved. • Call for new methods remains open.   and K 2  

• Lutein ( AOAC SMPR 2016.004 )

• Two methods submitted, two methods approved. • Call for new methods is  closed .

• Vitamin B 12 

• PDE5 Inhibitors (AOAC SMPRs 2014.010 , 2014.011 , and 2014.012 ) • Five submitted, one method approved. • Resubmissions from last ERP will be accepted. • Call for Methods  closed .   • Protein (AOAC SMPRs 2016.013 , 2016.014 , 2016.015 , 2016.016 ) • Two methods submitted, two methods approved. • Call for methods  closed.

• Vitamins K 1

• Vitamin D ( AOAC SMPR 2015.016 )

• Tea ( AOAC SMPR 2015.014 )

• No methods submitted, no methods  approved. • Call for new methods remains open.

• Two methods submitted, one method approved. • Resubmissions from last ERP will be accepted. • Call for new methods is closed.

Status of SPDS First Action Official Methods of Analysis SM Expert Review Panels (ERPs)

NEW AND UPCOMING CALLS FOR METHODS (and Experts!) :

• Echinacea ( SMPR 2017.015 ) • Ginseng ( SMPR 2017.014 ) • Kavalactones* • Resveratrol* • SAMe ( AOAC SMPR 2017.016 )  • Skullcap*

*Pending SMPR Approval

Stakeholder Panel on Dietary Supplements (SPDS) Advisory Panel

• SPDS Advisory Panel met in December, 2017  and confirmed the last set of ingredients for 

the current contract and to suggest  appropriate working group Chairs.

• The Advisory Panel includes representatives  from AHPA, CRN, CHPA, NSF, NPA, NIH, USP,  and Herbalife

How do you get involved?

• Submit methods on the Call for Methods tab at  www.aoac.org

• Volunteer for Expert Review Panels on the Call for  Experts tab at www.aoac.org

• SPDS site at www.aoac.org , click “Standards”, then  Stakeholder Panel on Dietary Supplements (SPDS)  for complete information about the program

Contact Information

Darryl Sullivan, Chair SPDS Covance Laboratories Tel:  608.242.2711 Email: darryl.sullivan@covance.com Brian Schaneberg, Vice Chair, SPDS Starbucks Corporation Email:   bschaneb@starbucks.com

Contact AOAC Staff: Tel: 301.924.7077 Web: www.aoac.org • Deborah McKenzie , Sr. Director, Standards Development and AOAC Research Institute,  dmckenzie@aoac.org , ext. 157 • Dawn Frazier , Sr. Executive for Scientific Business Development, dfrazier@aoac.org , ext.  117 • Christopher Dent , Standards Development Coordinator,  cdent@aoac.org ext. 119

AOAC STAKEHOLDER PANEL ON  DIETARY SUPPLEMENTS

Kavalactones Working Group – SMPR Presentation March 16, 2018 Working Group Chair: Steven Dentali, Dentali Botanical Sciences

Marriott Washingtonian Center, Gaithersburg, Maryland, USA

SPDS Kava Working Group Members

Steven Dentali (Chair)

Salvatore Parisi

Cristina Amarillas

Klaus Reif

Tyler Blythe

Catherine A. Rimmer

Paula N. Brown

Myron Sasser

Anton Bzhelyansky Christine Fields Holly E. Johnson

Aniko M. Solyom Jeremy Stewart

John Szpylka

Scott Krepich Adam Kuszak

Michael C. Tims

Richard Van Breemen

Charles Metcalfe Maria Monagas Elizabeth Mudge

Hong You Hui Zhao

Garrett Zielinski

SPDS Kava Working Group Work To Date • One in‐person meeting  (September 23, 2017) • One teleconference  (October 26, 2017) • One SMPR Draft Completed • Determination of Kavalactones and/or Flavokavains   from Kava  (Piper methysticum) • Public comment period  (Jan 16 – Feb 26, 2018) • SMPR made ready for SPDS review & approval

Kavalactones Begin with Kava Kava is… a lot of things. A Polynesian name for the plant known as Piper methysticum G. Forst. (Piperaceae), intoxicating pepper. A domesticated plant cultivated in the South Pacific Islands with scores of cultivars.

1.

2.

3. 4. 5. 6. 7.

The beverage prepared from the plant.

The associated ceremony.

Root and rhizome raw material for ingredient manufacture. An ingredient for dietary supplement finished products. A variety of finished dietary supplement product forms.

Background: Kava

Kava History

▪ Distribution of the plant is limited to the Pacific Islands ▪ Its use predates local written languages (2,000-3,000 yrs est.) ▪ Its ritual use, central to many local cultures, was recorded by Dutch explorers in 1616 and Cook’s first voyage in 1769. ▪ Its cultivation, use, and traditional ceremony are interwoven. ▪ All cultivars are sterile and related to the wild P. wichmannii . ▪ Wide variety of cultivar phenotype (color and shape appearance). ▪ ~ 120-150 known and named cultivars that are propagated based on subjective evaluation of pharmacological effects.

Background: Kava

Kava Uses

▪ A natural alternative to anti-anxiety drugs ▪ Does not impair mental function (unlike anti-anxiety drugs) ▪ Sleep aid – mild sedative effects ▪ Relief of muscle tension or spasm due to stress ▪ Production of mild euphoria

▪ Affords mild pain relief ▪ May increase sociability

Kava Chemistry

Kava Chemistry

Bioactive constituents are known - Contains six major “kavalactones” (pyrones) - arylethylene-α-pyrenes (also chalcones and other flavones, and conjugated diene ketones) - At least a dozen other kavalactones identified - Constituent composition varies among cultivars - Relationship exists between “chemotype” and traditional status - Kava lipid soluble resin forms an emulsion (milk) in water

Kava Rituals

Kava Pharmacology

‐ Pharmacology depends on kavalactone make up, not plant’s visual appearance ‐ Only known anxiolytic substance w/o  causing impairment of mental function ‐ Possibly also direct muscle relaxant action ‐ High percentage kavain and low percentage  dihydrokavain & dihydromethysticin traditionally preferred

Kava and Kavalactones

1992

1997

SMPR Key Points: Kava

• Intended Use:  For quality assurance and compliance  to current good manufacturing practices.  • Purpose: To describe the minimum recommended  performance characteristics to be used during the  evaluation of a method.  – To be used by AOAC Expert Review Panels in their  evaluation of validation study data for methods being  considered for Performance Tested Methods or AOAC  Official Methods of Analysis , and can be used as  acceptance criteria for verification at user laboratories.

SMPR Key Points: Kava

From: Chua et al. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One . 2016 Jun 22;11(6):e0157700. doi: 10.1371/journal.pone.0157700.

SMPR Key Points: Kava

▪ Need to know strength of raw materials, ingredients, and finished products ▪ Quantitate individual kavalactones, list in order of predominance ▪ Perceived need to determine cultivar type of starting material (noble cultivar vs. two-day/tudei) ▪ Quantitate amounts of individual six major kavalactones ▪ Different cultivars are regulated differently in Vanuatu ▪ Concern for controlling/limiting amount of suspected hazard ▪ Limits for flavokavain B (< 2 mg/g) have been proposed.*

* Planta Med. 2015 Dec;81(18):1647-53. doi: 10.1055/s-0035-1558295.

Kava Chemotype

Fitness for Purpose As Agreed September 22, 2017

The method identifies and quantifies the six primary kavalactones  derived from the underground portions of kava ( Piper methysticum ),  namely desmethoxyangonin, dihydrokavain, yangonin, kavain,  dihydromethysticin, and methysticin in plant material, dietary  ingredients and dietary supplements. The method identifies and  quantifies flavokavains A, B, and C in kava plant material, dietary  supplements and dietary ingredients. Test results can be used in chemotype identification but this specific  determination is outside the method scope. Individual kavalactones  should be quantifiable within the range of 0.1 to 50 percent by weight in  forms that include liquid, soft, and dry extracts as well as in softgels,  capsules, and tablets in the presence of common excipients. The ability  to address kavalactones in beverages is an advantage but not a  requirement. No limit on analysis time is imposed.”

Kava Materials

• Whole or powdered rootstock (root, rhizome, stump, laterals) – 3%–20% dry weight kavalactones in underground plant material • Traditional non‐fermented drink (more than 1,000 yrs of use) – ~ 250‐300 mg kavalactones per serving • Liquid, soft, and dry extracts: 30%–90% kavalactones • Capsules or tablets: 50‐250 mg kavalactones per serving 

• Tea bags, Instant powdered drink mix • In combination with other ingredients

• DSLD: 42 named products with 83 w/kava somewhere on label • 2016 ABC Market Report, Natural Channel, #29, $3.2 mil,  10.3% increase over 2015 sales

Kava Industry-Interest Group Testing • American Kava Association  http://americankavaassociation.org/ – Kava growers, manufacturers, distributors, retailers and  consumers who advocate for the safe and responsible  distribution of kava in the United States. – Sets minimum quality control standards for the  distribution of Kava in North America through lab  testing and responsible marketing bylaws. HPLC and  HPTLC mentioned. • True Kava http://www.truekava.com/ – A non‐profit corporation dedicated to the traditional  use of kava • HPLC: Identification, purity, strength, chemotype. Method: USP Piper methysticum Root and Rhizome Powder • Qualitative: Indicator of noble/two day, adulteration of noble kava with two day. Method: Colorimetric assessment of kava quality, Lebot 2017 • Individual companies and contract labs also test!

SMPR Key Points: Kava

• Need to cost effectively addressing stakeholder needs • Focus methods solely on kavalactone quantitation or include other considerations for kava quality control? – Deciding to accept methods that may help differentiate cultivars (noble vs. two day/tudei) based on chemotype or presence of flavokavains A, B, and C – Include qualitative methods? • Obtain sufficient stakeholder engagement to best understand needs of the whole kava industry supply chain • Inform WHO Proposal to develop a Regional Codex Standard for Kava Products for Use as a Beverage? • Australian government funding literature safety review to determine support for Vanuatu ban on non-noble cultivars. – Chemical analysis important to consider when attempting to differentiate tudei from noble chemotypes.

Method Performance Requirements: Kava

Applicability: Identification and quantitation of the six major kavalactones and flavokavains A, B, and C derived from the underground portions of kava ( Piper methysticum ) in plant material, dietary ingredients and dietary supplements (dried plant material, liquid extracts including tinctures, soft extracts, dry extracts, tablets, and capsules including softgels).

Kavalactones* Flavokavains*

Analytical Range (mg/g)** Limit of Quantitation (mg/g) 

5 – 750

0.1 – 25

≤ 5

≤ 0.1

*Reported as individual constituents. **Range may be narrower depending on the analytical matrix.

Method Performance Requirements: Kava

Method Performance Requirements as a Function of Range

Acceptance  Criteria Lower Range  Flavokavains* 

Acceptance  Criteria  Upper Range  Flavokavains * 

Acceptance  Criteria  Kavalactones* 

Parameter

% Recovery

90 – 110 

90 – 110

% RSD r (repeatability)

≤ 7.5

≤ 15

≤ 7.5

≤ 10

% RSD R (Reproducibility)

≤ 10

≤ 20

*Reported as individual constituents.

SMPR Comments & Responses

• The purities of the standards specified should be evaluated  by both HPLC and UV Absorption (related  Ԫ ). The related  UV  Ԫ could be confirmed or validated for all the standards  and could also be used to determine the purities or  concentrations. This will ensure that the standards pushed  out will be equivalent and reduce variation between labs. – Consider adding standard purity validation step to process.

• Generally applicable to use of reference materials. • Outside the scope of individual SMPRs.

SMPR Comments & Responses • The definition of analytical range ( Includes all steps of the  analytical procedure including sample preparation and  further dilutions ) is a description, not a definition. – Issue is not limited to this SMPR. An appropriate definition is  requested. Proposed: The range range of concentration of analyte  that the method must adequately determine.  • Lower and upper range for flavokavins is not specified.  Recommended to have defined range for components,   maybe lower range of 0.1‐5 and higher range of 5‐25  (mg/g) to align with kavalactone column. – Comments on method performance req. Function‐of‐Range table.  Flavokavain range specified as 0.1 – 25 mg/g in previous table. – The working group agreed on different analytical ranges for  kavalactones and flavokavains.

Motion to Approve Kava SMPR

Move to approve the Standard  Method Performance Requirements  (SMPRs) for Determination of  Kavalactones and/or Flavokavains   from Kava  (Piper methysticum) .

More Discussion?

Thank you for your attention!

DRAFT AOAC SMPR 2017.XXX; Version 4, 11.17.2017 1 2 Method Name: Determination of Kavalactones and/or Flavokavains from Kava ( Piper 3 methysticum ) 4 5 Approved by: Stakeholder Panel on Dietary Supplements (SPDS) 6 7 Intended Use : For quality assurance and compliance to current good manufacturing practices. AOAC SMPRs describe the minimum recommended performance characteristics to be used during the evaluation of a method. The evaluation may be an on-site verification, a single- laboratory validation, or a multi-site collaborative study. SMPRs are written and adopted by AOAC Stakeholder Panels composed of representatives from the industry, regulatory organizations, contract laboratories, test kit manufacturers, and academic institutions. AOAC SMPRs are used by AOAC Expert Review Panels in their evaluation of validation study data for method being considered for Performance Tested Methods or AOAC Official Methods of Analysis , and can be used as acceptance criteria for verification at user laboratories. [Refer to Appendix F: Guidelines for Standard Method Performance Requirements , Official Methods of Analysis of AOAC INTERNATIONAL (2012) 20th Ed., AOAC 8 9 1. Purpose:

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

INTERNATIONAL, Gaithersburg, MD, USA.]

2. Applicability :

Identification and quantitation of the six major kavalactones (desmethoxyyangonin, dihydrokavain, yangonin, kavain, dihydromethysticin, and methysticin) and flavokavains A, B, and C (see table 1 for more detailed information on analytes and figure 1 for molecular structures) derived from the underground portions of kava ( Piper methysticum ) in plant

material, dietary ingredients and dietary supplements as listed table 2.

3. Analytical Technique :

Any analytical technique that meets the following method performance requirements is

acceptable.

4. Definitions :

Analytical range – Includes all steps of the analytical procedure including sample

preparation and further dilutions.

Dietary ingredient .— 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 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 supplement .— A product intended for ingestion that contains a “dietary ingredient” intended to add further nutritional value to (supplement) the diet. Dietary supplements may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders.

Limit of Quantitation (LOQ) .— The minimum concentration or mass of analyte in a given

matrix that can be reported as a quantitative result.

51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67

Repeatability .— Variation arising when all efforts are made to keep conditions constant by using the same instrument and operator and repeating during a short time period.

Expressed as the repeatability standard deviation (SD r

); or % repeatability relative standard

deviation (%RSD r ).

Reproducibility .— The standard deviation or relative standard deviation calculated from among-laboratory data. Expressed as the reproducibility relative standard deviation (SD R );

or % reproducibility relative standard deviation (% RSD R ).

Recovery .— The fraction or percentage of spiked analyte that is recovered when the test

sample is analyzed using the entire method.

5. Method Performance Requirements :

Table 3: Analytical Range & LOQ Based on Matrix

Parameter

kavalactones*

flavokavains*

Analytical Range (mg/g)**

5 – 750

0.1 – 25

Limit of Quantitation (mg/g)

≤ 5

≤ 0.1

68 69 70 71

*Reported as individual constituents.

**Range may be narrower depending on the analytical matrix.

Table 4: Method Performance Requirements as a Function of Range

Acceptance Criteria Lower Range Flavokavains*

Acceptance Criteria Upper Range Flavokavains *

Acceptance Criteria Kavalactones*

Parameter

% Recovery

90 – 110

90-110

% RSD r

≤ 7.5

≤ 15

≤ 7.5

% RSD R

≤ 10

≤ 20

≤ 10

72 73 74 75 76 77 78 79 80 81 82 83 84

*Reported as individual constituents.

6. 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. A control sample must be included.

7. Reference Material(s):

See table 5 for sources of kavalactone and flavokavains materials, and table 6 for sources of

plant materials.

Refer to Annex F: Development and Use of In-House Reference Materials in Appendix F: Guidelines for Standard Method Performance Requirements , 19 th Edition of the AOAC

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99

INTERNATIONAL Official Methods of Analysis (2012). Available at:

http://www.eoma.aoac.org/app_f.pdf .

8. Validation Guidance :

All target analytes and all matrices listed in Table 1 claimed by the method submitter shall be evaluated. Data from different matrixes may be pooled together to determine: the overall analytical range; LOQ; recovery; RSDr; and RSDR. However, all target analytes and

claimed matrices must be represented in the complete evaluation.

Appendix D: Guidelines for Collaborative Study Procedures to Validate Characteristics of a Method of Analysis; 19 th Edition of the AOAC INTERNATIONAL Official Methods of Analysis

(2012). Available at: http://www.eoma.aoac.org/app_d.pdf .

Appendix K: Guidelines for Dietary Supplements and Botanicals 19 th Edition of the AOAC INTERNATIONAL Official Methods of Analysis (2012). Also at: AOAC Int. 95, 268(2012); DOI: 10.5740/jaoacint.11-447 and available at: http://www.eoma.aoac.org/app_k.pdf .

100 101 102

9. Maximum Time-To-Determination: No maximum time.

Table 1: Information on kavalactones and flavokavaines of interest.

CAS # (alternative)

#

Common Name

IUPAC Name

UNII Code

InChI Key

PubChem

(6 R )-5,6-Dihydro-4-methoxy-6-[(1 E )-2- phenylethenyl]-2 H -pyran-2-one

1

Kavain ((R)-(+)-Kavain)

500-64-1

W1ES06373M

XEAQIWGXBXCYFX-GUOLPTJISA-N

5281565

5,6-Dihydro-4-methoxy-6-[(1 E )-2-phenylethenyl]- 2 H -pyran-2-one (6 S )-5,6-dihydro-4-methoxy-6-(2-phenylethyl)-2 H - Pyran-2-one (6 R )-6-[(1 E )-2-(1,3-Benzodioxol-5-yl)ethenyl]-5,6- dihydro-4-methoxy-2 H -pyran-2-one (6 S )-6-[2-(1,3-Benzodioxol-5-yl)ethyl]-5,6-dihydro- 4-methoxy-2 H -pyran-2-one 4-Methoxy-6-[(1 E )-2-(4-methoxyphenyl)ethenyl]- 2 H -pyran-2-one 4-Methoxy-6-[(1 E )-2-phenylethenyl]-2 H -pyran-2- one (2 E )-1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(4- methoxyphenyl)-2-propen-1-one (2 E )-1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-phenyl- 2-propen-1-one (2 E )-1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(4- hydroxyphenyl)-2-propen-1-one

3155-48-4 (1635-33-2)

2

d,l-Kavain

5L1NI60TGB

XEAQIWGXBXCYFX-BQYQJAHWSA-N

5369129

Dihydrokavain ((+)-( S )- Dihydrokavain, Marindinin) Methysticin ((+)-Methysticin, Kavahin) Dihydromethysticin (( S )-(+)- Dihydromethysticin) Desmethoxyyangonin (5,6- Dehydrokawain) Flavokavain A (Flavokawain A, 4- Methoxyflavokawain B) Flavokavain B (Flavokawain B, Persicochalcone) Flavokavain C (Flavokawain C, 4- Hydroxyflavokawain B) Yangonin

3

587-63-3

NW8ZGW9XRZ

VOOYTQRREPYRIW-LBPRGKRZSA-N

10220256

4

495-85-2

M832AIJ6HX

GTEXBOVBADJOQH-FWEMWIAWSA-N

5281567

5

19902-91-1

FZ66MQ73GS

RSIWXFIBHXYNFM-NSHDSACASA-N

88308

6

500-62-9

R970U49V3C

XLHIYUYCSMZCCC-VMPITWQZSA-N

5281575

15345-89-8 (1952-41-6) 37951-13-6 (3420-72-2) 1775-97-9 37308-75-1 (56798-34-6)

7

F2MBQ8QRUN

DKKJNZYHGRUXBS-BQYQJAHWSA-N

5273621

8

CGIBCVBDFUTMPT-RMKNXTFCSA-N

5355469

9

QKQLSQLKXBHUSO-CMDGGOBGSA-N

5356121

10

UXUFMIJZNYXWDX-VMPITWQZSA-N

6293081

Table 2: Examples of Plant Material, Dietary Supplements and Dietary Ingredients 105 106 Dried plant material 107 Liquid extracts (including tinctures) 108 Soft extracts 109 Dry extracts 110 Tablets 111 Capsules (including softgels)

112 113 114

115

Table 5: Sources of kavalactone and flavokavain materials

AK Scientific Inc. 8163AH

AvaChem Scientific

Extrasynthese (Alkemist)

Sigma

#

Compound

PhytoLab

ACC Corp.

Cerilliant

1 Kavain ((R)-(+)-Kavain)

1801

API0003191

2 d,l-Kavain

89239 89185 89250 89186 89293 89184 83762

6550

5790585

PHY89239

3 Dihydrokavain ((+)-( S )-Dihydrokavain, Marindinin) 4 Methysticin ((+)-Methysticin, Kavahin)

41866 80488 52007 75575 51773

PHY89185

PHY89186

5 Dihydromethysticin (( S )-(+)-Dihydromethysticin)

PHY89186 PHY89293

6 Yangonin

4989

7 Desmethoxyyangonin (5,6-Dehydrokawain)

8 Flavokavain A (Flavokawain A, 4- Methoxyflavokawain B)

1043

9 Flavokavain B (Flavokawain B, Persicochalcone)

83763

1045

10 Flavokavain C (Flavokawain C, 4- Hydroxyflavokawain B)

83854

1042

116 117 118

119 120

Table 6: Sources of Reference Plant Materials

Extrasy nthese (Alkemi st)

Botanical Reference Material

UNII Code

AHP

Botanical Liaisons

USP

#

Rhizome and Root

B0061

1

http://www.herbal- ahp.org/documents/ BRM- CRS%20List/AHP- BRM%20List%20Orde r%208.4.17.pdf

Piper methysticum root

BOW48 C81XP

2

3P306S 300W

http://www.botanicalliaison s.com/materials.html

Plant

3

Powdered Kava Extract

1355 709

4

121 122 123 124 125 126 127 128

129 130 131 132

Figure 1: Molecular structure of kavalactones and flavokavains of interest.

OCH 3

O

H

H

H

H 3 CO

H 3 CO

H 3 CO

O

E

E

E

O H

O H

O H

O

O

O

Kavain

Methysticin

Yangonin

O

H

H 3 CO

H 3 CO

H 3 CO

O

E

O

O

O H

O

O

O

Desmethoxyyangonin

Dihydrokavain

Dihydromethysticin

OH

OCH 3

H 3 CO

OH

H 3 CO

H 3 CO

OCH 3

OCH 3

E

E

E

OCH 3 O

OH O

OH O

133

Flavokawain C

Flavokawain B

Flavokawain A

AOAC STAKEHOLDER PANEL ON  DIETARY SUPPLEMENTS

Resveratrol Working Group – SMPR Presentation March 16, 2018 Working Group Chair: Richard B. van Breemen, Oregon State University

Marriott Washingtonian Center, Gaithersburg, Maryland, USA

Fitness for Purpose As Agreed September 22, 2017

The method must separate the cis and trans forms of resveratrol and quantitate the trans isomer in dietary supplements and dietary ingredients.

SPDS Resveratrol Working Group Members

Richard van Breemen, Oregon State University Klaus Reif, PhytoLab GmbH & Co. Anton Bzhelyansky, US Pharmacopeia Catherine A. Rimmer, NIST Nour Eddine Es‐Safi, Mohammad V University Aniko M. Solyom, GAAS Analytical Martha Jennens, Covance Jeremy Stewart, Gaia Herbs Holly E. Johnson, AHPA John Szpylka, Mérieux NutriSciences Scott Krepich, Phenomenex Hong You, Eurofins Adam Kuszak, NIH ODS Kurt Young, GNC/Nutra Manufacturing Maria Monagas, US Pharmacopeia Hui Zhao, Covance Garrett Zielinski, Covance

SPDS Resveratrol Working Group Work To Date

• 1 in-person meeting (September 23, 2017) • 1 teleconference (November 3, 2017) • 1 SMPR Draft Completed • Determination of trans -Resveratrol in Dietary Supplements and Dietary Ingredients • Public comment period (January - February, 2018) • SMPR made ready for SPDS review and approval

Background: Resveratrol

Trans- Resveratrol (C 14 ) 3,5,4′-trihydroxy- trans -stilbene CAS number: 501-36-0 IUPAC name: 5-[( E )-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol H 12 O 3

First isolated in 1939 from Veratrum album by Michio Takaoka ( J. Chem. Soc. Japan 1939; 60: 1090–1100)

Background: Resveratrol

Resveratrol cis/trans Chemistry

3

Although trans -resveratrol is the biosynthetic product, UV exposure can isomerize it to the cis isomer.

Background: Resveratrol

Resveratrol Bioactivities In 1997, Pezzuto ( Science , 1987; 275: 218) discovered that resveratrol from grapes, berries and other sources had cancer chemoprevention activity through multiple mechanisms of action • anti-inflammation (inhibits COX, iNOS, and NF-κB) • anti-oxidation (upregulates quinone reductase, glutathione, superoxide dismutase, and catalase) • induction of apoptosis Subsequently, >20,000 papers have reported multiple other activities including • prevention of cardiovascular disease • anti-aging • neuroprotection

SMPR Key Points: Resveratrol

• The method must be specific for trans -resveratrol in the presence of the cis isomer in dietary supplements and dietary ingredients • Examples of dietary supplements and dietary ingredients containing resveratrol include • Powders • Tablets • Capsules • Liquids • Softgels • Extracts • Reference materials are available from multiple sources for trans- resveratrol, [d 4 ]- trans- resveratrol, and cis -resveratrol