In This Issue of the AHPA Report

The Official Publication of the American Herbal Products Association July 2013 www.ahpa.org Volume 28, Number 7

In this issue of the AHPA Report

Inside AHPA 2 ••CSPI asks FDA to ban ginkgo based on study of one unique extract ••AHPA’s Botanical Safety Handbook, Second Edition now available online ••AHPA’s two-day workshop offers practical AFCC training ••Florida ABT rescinds retailer warnings on herbal tinctures ••AHPA welcomes Haley Chitty as director of communications ••New members ••Savings opportunities for AHPA members ••AHPA in the news ••AHPA Updates for June 2013

Special Topics 9 ••Marketing teas as supplements vs. foods by Michael McGuffin, AHPA President ••Meeting 100 percent ingredient testing requirements: analytical solutions for botanical identity by James Neal-Kababick, Director of Flora Research Laboratories, and Kathryn Lawrence, Grace

Legal and Regulatory 19 ••FDA wants cGMP compliance, not companies to discuss it by Anthony L. Young, Kleinfeld, Kaplan & Becker LLP and AHPA General Counsel

Calendar of Botanical Events 21 Inside AHPA

CSPI asks FDA to ban ginkgo based on ¾¾ “The actual determination of risk to humans from chemicals study of one unique extract found to be carcinogenic in laboratory animals requires a wider analysis that extends beyond the purview of these studies.” Consumer advocate misrepresents NTP rodent study, This limitation is also noted in TR 578 by FDA’s representative to reflects on “industry full of snake oil salesmen” NTP, Dr. Paul Howard, who observes that NTP reports “are not meant to evaluate risk for humans.” In a June 3, 2013, letter, the Center for Science in the Public Interest (CSPI) urged the Food and Drug Administration (FDA) to prohibit In addition and as AHPA has previously noted, the specific ginkgo sales of foods and dietary supplements that contain ginkgo (Ginkgo extract used by NTP is dissimilar to the most prominently marketed biloba) leaf. ginkgo extract. The Chinese supplier of this extract, Shanghai Xing Ling, holds four U.S. patents for a proprietary ginkgo leaf extract, a fact CSPI’s request would apply to products that contain any amount of that was not disclosed in the NTP study. This supplier’s patents include any extract of ginkgo leaf. Its letter cites a recent study (TR 578) by declarations that indicate its product’s differences from other ginkgo the National Toxicology Program (NTP) in which lab rodents were extracts, stating, for example, “Until now it has not been possible to administered, via corn oil gavage, a specific ginkgo extract at doses prepare such highly concentrated extracts from Ginkgo biloba leaves.” up to 2,000 mg/kg body weight every day for nearly the entire lifes- pan of the test animals. The study concludes that there is “clear evi- “A thorough reading of the NTP ginkgo study indicates that the dence of carcinogenic activity” in mice that had been given this results are associated with force-feeding excessively high quantities ginkgo extract. In its letter to FDA, CSPI characterized this finding of Shanghai Xing Ling brand ginkgo extract to mice over their entire as establishing that “this herbal ingredient ... causes cancer in animals lifetimes,” added McGuffin. “But extrapolation of this risk to other and presumably in people.” ginkgo extracts or to humans is scientifically invalid.” “CSPI’s representation of the conclusions of the NTP study, con- CSPI’s letter to FDA has been the subject of widespread reporting. ducted on one brand of ginkgo extract, is completely inaccurate,” Of particular interest is an article published on June 3 in the New said Michael McGuffin, AHPA president. “In ‘presuming’ any rele- York Daily News, in which an FDA spokeswoman stated, “It is not vance of this research to humans, CSPI either misunderstands or scientifically valid to conclude with certainty that dietary supple- completely ignores the limited applicability of this and all such NTP ment products containing Gingko biloba are unsafe based solely on rodent studies.” data from the new NTP study ... [and] there may be differences in the extract used in these studies in contrast to what is available on NTP was founded in 1978 as an interagency program to coordinate the market for gingko biloba dietary supplements.” toxicology research and testing across the U.S. Department of Health and Human Services. All of its technical reports, including its recent The article also quotes CSPI’s executive director, Michael Jacobson, report on one specific ginkgo extract, clearly state that study results do as follows: “The dietary supplement industry is full of snake oil not establish evidence of harm to humans. For example: salesmen.” ¾¾ “Extrapolation of these results to other species, including char- “It appears that Dr. Jacobson’s view of the supplement trade has acterization of hazards and risks to humans, requires analyses disrupted his ability to separate the facts from his organization’s beyond the intent of these reports.” speculations,” McGuffin said.

The AHPA Report, the official voice of the AHPA Staff Send inquiries, comments or American Herbal Products Association Michael McGuffin, President requests to: (AHPA), is published monthly as a service Devon Powell, Chief Operations Officer to AHPA members and friends of the American Herbal herbal products industry. The material Haley Chitty, Director of Communications Products Association contained in this publication is for the Jane Wilson, Director of Program Development 8630 Fenton Street, Suite 918 information of AHPA members. Although Merle Zimmermann, Ph.D., Information Analyst Silver Spring, MD 20910 the information is believed to be correct, Phone: 301.588.1171 LaWanda Johnson, Communications Manager & Editor, AHPA AHPA disclaims all responsibility for any Fax: 301.588.1174 Report damage or liability that may result from Email: [email protected] any reliance on the information contained Rosie Ysasi, Certification Program Coordinator Website: www.ahpa.org in this publication. Anthony Young, General Counsel, Kleinfeld, Kaplan & Becker Articles may not be reproduced or reprinted Peter Evich, National Legislative Consultant, Van Scoyoc Associates © Copyright 2013, American without written permission from AHPA. Kellie Greene Design, Layout & Production, AHPA Report Herbal Products Association

July 2013 • Page 2 July 2013 • Page 3 AHPA’s Botanical Safety Handbook, ¾¾ Classification of each herb with safety and drug interaction Second Edition now available online ratings ¾¾ More references vetted for accuracy The American Herbal Products Association (AHPA) has launched ¾ the online version of its Botanical Safety Handbook, Second Edition. ¾ Information on adverse events reported in clinical trials or case reports AHPA’s Botanical Safety Handbook, Second Edition is an essential tool ¾¾ Safety-related pharmacology and pharmacokinetics of each for anyone who manufactures, recommends, or uses herbal products. herb, including drug interactions It provides safety information on nearly 600 species of herbs and data ¾ compiled from clinical trials, pharmacological and toxicological ¾ Additional information on the use of herbs by pregnant or lac- tating women studies, medical case reports, and historical texts. Easily understood classification systems are used to indicate the safety of each listed ¾¾ Toxicological studies and data on toxic compounds species and the potential for the species to interact with drugs. The handbook is co-edited by Zoë Gardner, research and develop- The online version is offered as a renewable, annual subscription and ment manager at Traditional Medicinals, and AHPA President is accessible online from desktops, smartphones, and tablets. A dis- Michael McGuffin. In addition, cited references were reviewed count subscription is provided to AHPA members. and vetted by an expert advisory council that includes some of the most renowned herbal and integrative medicine experts in the The online version allows subscribers to search for keywords and United States. botanical names and easily access the information they use most by saving personalized lists of entries. Each botanical entry has a quick “The online version of AHPA’s Botanical Safety Handbook, Second reference summary that provides information at a glance. The online Edition, will make it easy for dietary supplement manufacturers, version will be updated regularly with new research, and subscribers medical practitioners, pharmacists, and other industries to quickly will be notified of updates to provide immediate access to the most and easily access this one-of-a-kind information anywhere, anytime,” current information. McGuffin said. Enhancements to AHPA’s Botanical Safety Handbook, Second A free preview of several entries are available online: Edition include: ¾¾ Mentha pulegium

July 2013 • Page 4 ¾¾ Magnolia officinalis could result in criminal or civil charges being filed against retailers, ¾¾ Ocimum tenuiflorum leading retailers to remove these products from their store shelves. ¾¾ Foeniculum spp. The relevant Florida law, however, defines alcoholic beverages to exclude proprietary and other products that are “unfit for beverage ¾¾ Hypericum perforatum purposes.” Most herbal tinctures have long been considered under Subscribe to the online version or purchase a hardcover copy today. federal alcohol tax rules to be nonbeverage products that are unfit for beverage use. AHPA’s two-day workshop offers In response to these enforcement actions, AHPA issued a communi- practical AFCC training cation to its members to express its view that the warnings represented a misunderstanding of the relevant Florida law. In addition, The American Herbal Products Association (AHPA) will present an AHPA counsel contacted Florida ABT to seek clarification that intensive, hands-on workshop, “The Role of Automated Flash herbal tinctures generally are not suitable for beverage use and Chromatography in Botanical Identity and cGMP Compliance,” in should therefore be recognized as exempt from ABT jurisdiction. Deerfield, Ill., July 18 to 19. “ABT’s charge that retailers violated Florida law by selling herbal The workshop offers practical training on automated flash column tinctures without a current valid alcohol beverage license was obvi- chromatography (AFCC) as a tool to isolate botanical components, ously a misinterpretation of Florida’s ABT laws,” noted AHPA’s uncover adulterants, reduce sample preparation time, and create sec- counsel, Tony Young of Kleinfeld, Kaplan & Becker LLP. “AHPA’s ondary reference standards for critical components. prompt response and Florida ABT’s willingness to recognize this Participants will experience using AFCC to identify botanical mate- misunderstanding and correct it led to rapid resolution of this issue.” rials, isolate and collect material for additional testing, remove compounds from interfering matrices, generate reference standards, AHPA welcomes Haley isolate adulterants, and see how flash can be used as a complemen- Chitty as director of tary technique to other characterization methods. Isolation methods for common botanicals are included in the course materials. communications The agenda, which includes a classroom-style setting, will focus on The American Herbal Products simplifying complex botanical extracts and mixtures into manage- Association (AHPA) is pleased to able fractions so that more routine analytical methods can be used announce that Haley Chitty has to identify key ingredients and meet Food and Drug Administration joined the organization as its new good manufacturing practice compliance. director of communications. In this position, Chitty will manage AHPA’s The course will be taught by James Neal-Kababick, founder and communications, public relations, director of Flora Research Laboratories, which specializes in the and marketing initiatives. research and analysis of botanicals, dietary supplements, and related Haley Chitty compounds “We are excited to welcome Haley to AHPA, as he will help us con- To foster an ideal learning environment, the maximum capacity for tinue our communications and public relations efforts to increase the workshop is 10 attendees, so interested parties are encouraged to and strengthen the reputation of the herbal products industry,” said secure a seat promptly. For more information and to register, please AHPA President Michael McGuffin. “I am confident that Haley’s visit the AHPA website. extensive experience will have an immediate, positive impact by helping AHPA serve all of its diverse members and ensuring that Florida ABT rescinds retailer warnings on AHPA remains the voice of the herbal products industry.” herbal tinctures Chitty brings more than 10 years of nonprofit communications and The American Herbal Products Association (AHPA) has been public relations experience to AHPA. Most recently, Chitty served informed that Florida retailers have received letters from the Florida as director of communications at the National Association of Division of Alcoholic Beverages and Tobacco (ABT) that rescind Student Financial Aid Administrators (NASFAA), where he used notices of noncompliance with the state’s alcoholic beverage laws online and traditional media to keep members informed about the that the agency had issued last month. latest student aid news, legislation, and regulations. He also imple- The notices of noncompliance alleged that herbal tinctures are alco- mented innovative communications strategies to inform and influ- holic beverages and therefore subject to the state’s alcoholic beverage ence policymakers and the media to further NASFAA’s advocacy controls. The notices stated that the continued sale of tinctures goals. Before joining NASFAA in 2005, Chitty produced two online publications and managed a website that focused on higher educa-

July 2013 • Page 5 tion and the federal student loan program. rinth, gardens and walking paths to enjoy, as well as a grotto with a hot tub, a waterfall, and a gentle stream that flows into the pond. “I’m eager to work at the oldest and most influential organization Harmony Farm is a place of “being,” a place to step outside the serving the herbal and botanical products industry,” Chitty said. “doing” of life and connect to your own inner wisdom and the “The growing interest in a more holistic approach to health care and divine within. wellness among consumers and health care professionals makes the work of AHPA on behalf of its members more important than ever. Mama Jo’s Sunshine Herbals is a retail community herbal market I look forward to working with AHPA members, staff, and the with more than 200 products manufactured for the public and board of directors to improve the tone of the public dialogue on 200-300 products for private clients. herbs, which will lead to more accurate information for consumers Associate Members who use herbs to maintain a healthy lifestyle.” Amazon Health is a consultant for Amazon Herb Company. Chitty replaces Frank Lampe, who served as AHPA’s director of communications since January 2011. Lampe is now serving the United Natural Products Alliance in a similar capacity. Savings opportunities for AHPA members Within the pages of this edition of AHPA Report, we are pleased to New Members provide our members with several valuable, money-saving opportunities. The following goods and services are offered at a discount Active Members for—or are uniquely available to—AHPA members this month: Harmony Farm, located in central Ohio, is 120 acres of rolling »»AHPA’s Botanical Safety Handbook, 25% off page( 8) fields, woods, and a pond, with two facilities, Discover and The Heart Center, which both provide space for the healing arts, retreats, »»American Herbal Pharmacopoeia, 10% off (page 12) and educational workshops. The farm includes an 11 circuit laby- »»CPG Jobs, 15% off for employers (page 19)

July 2013 • Page 6 AHPA in the news AHPA Updates for June 2013 A monthly review of media mentions related to the American A list of the AHPA Updates issued to AHPA members during Herbal Products Association (AHPA) and/or AHPA staff. the month of June. ¾¾ Industry Calls for Aloe Study Clarification, Natural ¾¾ AHPA’s McGuffin participates in discussion and book Products INSIDER signing at MUIH

¾¾ A Non-DMAA World: The Status of DMAA in ¾¾ AHPA’s Botanical Safety Handbook, Second Edition Today’s Dietary Supplements Market, Nutritional now available online OUTLOOK ¾¾ AHPA’s Automated Flash Chromatography Workshop ¾¾ Ginkgo Ban Call Uncalled For, Natural Products ¾¾ AHPA welcomes Haley Chitty as it new director of INSIDER communications ¾¾ Consumer group asks FDA to ban gingko biloba after ¾¾ Florida ABT rescinds retailers’ warnings on herbal study links supplement to cancer in mice and rats, tinctures New York Daily News ¾¾ AHPA’s McGuffin presents at Health Beverage Expo ¾¾ Northeast Support for GMO Labeling Grows, Maine ¾¾ CSPI asks FDA to ban ginkgo based on study of one House Gives Thumbs Up, Food Product Design unique extract ¾ ¾ Federal GMO Law a Better Solution, Natural ¾¾ AHPA responds to inadequate description of aloe vera Products INSIDER used in NTP study ¾¾ Florida Alcohol Division Probing Sale of Herbal Tinctures, Natural Products INSIDER

¾¾ Proposition 65 Update, Natural Products INSIDER

¾¾ AHPA Welcomes New Communications Director, Natural Products INSIDER The Alliance of ¾¾ Advocates Invite Former U.S. Rep. Patrick Kennedy to Better Understand Medical Marijuana, The Daily International Aromatherapists Chronic presents the..

¾¾ AHPA Seminar Provides cGMP Compliance Tools, Natural Products INSIDER

¾¾ Florida Alcohol Agency Withdraws Herbal Tinctures Notices, Natural Products INSIDER

¾¾ AHPA hires director of communications, Engredea News & Analysis

¾¾ Florida ABT backs off herbal tinctures, Engredea News & Analysis

¾¾ UNPA hires Frank Lampe as VP of communications Attend this Conference and You will & industry relations, Engredea News & Analysis • Walk out the door at the end of four days with awesome ways to apply the art and science of aromatherapy. ¾¾ NPA experts talk regs at FDA-OCRA conference, • Learn how to analyze and use essential oils in a clinical setting. Engredea News & Analysis • Be able to employ powerful methodologies in your practice to enhance client care. • Understand the energetics and science of essential oils. ¾¾ Florida ABT targets herbal tinctures as alcoholic • Earn contact hours from 16 remarkable presenters. drinks, Engredea News & Analysis

¾¾ NTP skewers aloe description, say AHPA, IASC, Register Today! www.aromatherapyconference.com Engredea News & Analysis Phone: 1-877-531-6377 Fax: 303-979-7135 Email: [email protected]

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July 2013 • Page 8 Special Topics

Marketing teas as supplements vs. foods Foods can only include ingredients and additives that are generally recognized as safe (GRAS). Food ingredients include the tea itself, common By Michael McGuffin, AHPA President tea ingredients (like chamomile and peppermint) and tea flavor ingredi- Editor’s Note: This article is based on McGuffin’s presentation, titled ents (like peach or apple). GRAS additives include natural flavoring “Marketing Teas as Dietary Supplements vs. Foods,” that was delivered substances, natural substances used in conjunction with flavors, spices at the premier Healthy Beverage Expo held June 7-9 in Las Vegas, Nev. and other natural seasonings. In addition to these ingredients, supplements can include a wider range of herbs and botanicals, but not Most black and green teas and many herbal teas are marketed as tobacco or herbs containing ephedrine, aristolochic acid (comfrey, colts- conventional foods, but some tea products—mainly those with a foot, etc.) or pyrrolizidine alkaloid like wild ginger. wider range of herbal ingredients—are marketed as dietary supplements. In 1977, FDA adopted regulations which include specific lists of several hundred GRAS ingredients, but these lists rarely include inno- U.S. retail sales of ready to drink (RTD) and leaf teas sold as con- vative ingredients. Food and liquor industries worked to ensure that ventional foods were between $6.5 billion and $9 billion in 2011. common spices and herbal ingredients that they use were included, The size of the dietary supplement tea market isn’t as well docu- but it does not appear that tea companies in the mid-70s were involved mented, but there is reason to believe it is smaller. The U.S. herbal in this regulatory process because common tea ingredients like nettle dietary supplement market was roughly $5 billion in 2011, but it is leaf and dandelion root are absent from these lists. However, these unknown what percentage of that market was comprised of tea sales. ingredients could be used in teas marketed as food if they are “foods.” This article explores the regulatory differences between marketing It should be noted that a few GRAS ingredients have restrictions, for tea products – including leaf teas and RTD products – as conven- example wormwood must be safrole-free and elecampane root is tional foods or as dietary supplements. only GRAS in alcoholic beverages. Current good manufacturing practices Labeling Both conventional foods and dietary supplements are regulated The labeling requirements for foods and dietary supplements are under the federal Food, Drug, and Cosmetic Act (FDCA). Teas sold similar, but there are differences. The most obvious being that teas as food are manufactured under the Food and Drug Administration’s marketed as food are identified as “tea” on the label, but teas marketed (FDA) long-standing current good manufacturing practice (cGMP) as supplements must be identified as “supplements” on the label. for food. Tea products marketed as dietary supplements must be manufactured in compliance with FDA’s more stringent cGMP for Food labels must identify the manufacturer or distributor, disclose dietary supplements and must comply with a federal law that ingredients (with possible exceptions for some ingredients like requires any serious adverse effects associated with the product to be “natural flavors”) and may include a nutrition facts panel. Dietary reported to FDA. supplement labels include additional details including all dietary ingredients, without any exceptions, and generally must include a Any company considering marketing tea products as dietary supple- supplement facts panel. In addition, supplement labels must iden- ments should review relative cGMP requirements for foods versus tify the part of the plant used, which is not required for foods. supplements. Regulations associated with foods have been in place for decades and generally focus on cleanliness and hygiene. However, requirements are vastly greater for dietary supplements, more like Product representation for drugs, so expect more stringent cGMP requirements. Marketing teas as dietary supplements creates several potential chal- Food cGMP requirements are about to change due to the Food lenges for companies. First, supplements can’t be represented as a Safety Modernization Act (FSMA). Signed into law on Jan. 4, 2011, conventional food or the sole item of a meal. You can describe tea as this is the most sweeping reform of U.S. food safety laws in more delicious and/or great tasting if it is marketed as a food, but you than 70 years. It is not expected that these requirements become must be much more careful in doing so if it’s a supplement. This can effective through regulations for at least another year, if not longer. have regulatory repercussions when marketing tea as supplements. In 2007, FDA issued a warning letter to a company that was Ingredients marketing a tea with stevia, an ingredient that isn’t included in the Teas marketed as supplements may contain a wider range of ingredi- lists of GRAS ingredients. The package included instructions for ents than those marketed as foods. This is one of the primary reasons making iced tea. FDA said the iced tea instructions represented the companies market teas as dietary supplements. tea as a conventional food even though it was labeled as a supplement.

July 2013 • Page 9 The company resolved the issue by removing the instructions. vision that excluded products that simulate conventional foods from the list of dietary supplements. At that time, FDA noted that a Similarly, FDA warned another company for marketing a dietary sup- dietary supplement may be a product with physical attributes (e.g., plement with language that stated, “Enjoy this fully refreshing beverage product size, shape, taste, packaging) similar to that of conventional super chilled.” Beverages are foods, not supplements. However, it food, so long as it is not represented for use as a conventional food. should be noted that many teas sold and labeled as supplements In 1995 and 1997 the agency also issued rules while noting that describe flavor attributes (e.g., “pleasantly smoky aroma and flavor”). dietary supplements “may be similar to conventional foods in com- Another letter issued by the FDA in 2012, warned a company for position and form.” marketing “Roasted Coffee and Energy” products with the non- As more liquid form products were introduced as dietary supple- GRAS ingredient Ginkgo biloba as a dietary supplement. FDA said ments, FDA in 2009 issued an industry draft guidance that seemed the products were “represented as a conventional food” because to reverse its existing position. “coffee is a beverage and a conventional food.” Additionally, FDA “Liquid products that suggest through their serving size, packaging, or said, “This product is similar to a typical canned beverage in packag- recommended daily intake that they are intended to be consumed in ing and appearance.” Similarly, FDA warned a company in 2011 for amounts that provide all or a significant part of the entire daily drink- a supplement that was labeled as a “drink” and packaged in a “single ing fluid intake of an average person in the U.S., are represented as serving can similar in size, shape, and appearance to those in which beverages,” FDA said. “In addition, the name of a product can repre- single servings of beverages like soda, fruit juice, and iced tea are sold.” sent the product as a conventional food. Product or brand names that Does this mean any RTD product packaging that is similar to bever- use conventional food terms such as ‘beverage,’ ‘drink,’ ‘water,’ ‘juice,’ ages must be a conventional food and limit its ingredients to only or similar terms represent the product as a conventional food.” food and GRAS ingredients? FDA guidance on this issue has evolved The second part of this guidance didn’t spark much debate because over time. the majority of the supplement industry seemed to agree that sup- Fifteen to 18 years ago FDA seemed to envision a marketplace where plements shouldn’t be labeled as a drink. However, the American products could simulate and look just like conventional foods, as Herbal Products Association (AHPA) took issue with the first part long as they were not represented as foods. The Dietary Supplement of this guidance. In response, AHPA submitted comments stating Health and Education Act (DSHEA) of 1994 struck an existing pro- that “neither packaging nor serving size ‘represents’ the form of a

July 2013 • Page 10 food. The first is required to carry and preserve the food for the Antioxidant claims consumer, and the second [recommended daily intake] is required There are many references to antioxidants in tea labeling, either by law to be stated as part of the nutrition information for both separately or in combination with statements about flavonoid dietary supplements and conventional foods.” content. However, FDA regulations specifically limit antioxidant claims to those associated with select nutrients identified by FDA as What does this mean to those marketing RTD teas as supple- antioxidants. FDA has established recommended daily intake (RDI) ments? First, don’t label the product as a ‘beverage,’ ‘drink,’ ‘water,’ for these select nutrients. Flavonoids are not acknowledged by FDA ‘juice,’ or similar term. Second, be aware that FDA probably as one of these antioxidant nutrients and FDA has taken enforce- doesn’t want you to market this product as a supplement, but the ment action against these claims. only enforcement actions to date have incorporated at least one other factor, and haven’t been based solely on the package or In a 2010 warning letter to a company marketing green tea prod- serving size. ucts, FDA identified a claim that the “Tea is made from tea leaves rich in naturally protective antioxidants.” FDA said the term “rich Product claims in” is defined in the regulations as may be used to characterize the level of antioxidant nutrients. “However, this claim does not comply Claims about teas marketed as food are generally limited to the with [regulations] because it does not include the nutrients that are few nutrients that are required in nutrition labeling. For example, the subject of the claim or use a symbol to link the term ‘antioxi- you could say “high in Vitamin C,” but you couldn’t say “high in dant’ to those nutrients,” FDA wrote. “Thus, this claim misbrands EGCG” because Vitamin C is a nutrient required in nutrition your product.” labeling while epicgallocatechin gallate (EGCG) is not. Further, FDA noted that the product was also misbranded because Tea labeling could say “low in cholesterol,” but would also need to the label’s back panel included the statement “packed with protec- disclose that all teas are low in cholesterol. For this reason, this tive FLAVONOID ANTIOXIDANTS,” but no RDI has been labeling isn’t used much. established for flavonoids.

Health claims are generally not relevant to tea products because Similarly, a 1999 letter was issued to a company with a product they must be qualified which reduces their market benefit. For that claimed to have “just as many flavonoids as purple grape example, a company could say, “Green tea may reduce the risk of juice” and “two glasses equal the [flavonoid] strength in two glasses breast or prostate cancer although the FDA has concluded that of red wine.” there is very little scientific evidence for this claim.” “Such claims imply that both foods are good sources of flavo- Supplements can make the same claims as foods, but supplements noids,” FDA wrote. “Since there is no daily value established for can also make “statements of nutritional support,” commonly flavonoids these claims cannot be authorized. Because the claims known as “structure/function (S/F) claims.” This includes state- on this product are not authorized as nutrient content claims by ments like, “Traditionally used for soothing digestive support,” or regulation or by the act, the claims misbrand the product.” “Promotes healthy liver function; immune system-supporting; This product also contained grape seed extract, and was labeled, helps cleanse your system; supports your body’s natural defenses.” “with Essential Antioxidants … GRAPE SEED EXTRACT ...” FDA noted that this “suggests that grape seed extract is an essential The most stringent reading of the regulations allows S/F claims for nutrient. Because grape seed extract is not an essential nutrient, nutrient ingredients – such as vitamins and minerals – for either the claim misbrands the juice.” food or supplement products. But if you want to make a S/F claim for a botanical ingredient, such as echinacea, or arguably even tea, FDA has also sent warning letters to companies that have included the product needs to be marketed as a dietary supplement. FDA label statements such as “contains Echinacea” and “highest potency does not require notification from conventional food manufac- ginseng.” tures about their S/F claims and disclaimers are not required for conventional foods. Conclusion

The DSHEA established some special regulatory procedures for This article does not discuss everything you need to know in order such claims for dietary supplement labels. “If a dietary supplement to decide if your tea product is best marketed as a conventional food label includes such a claim, it must state in a ‘disclaimer’ that FDA or as a dietary supplement. It also does not cover all you need to has not evaluated the claim,” according to the FDA. “The dis- know to comply with these regulatory categories. But it does provide claimer must also state that the dietary supplement product is not a better understanding of the differences between marketing teas as intended to ‘diagnose, treat, cure or prevent any disease,’ because a food or dietary supplement. It should help you ask the right ques- only a drug can legally make such a claim.” tions when you talk to consultants and attorneys.

July 2013 • Page 11 Meeting 100 percent ingredient testing the dietary supplement industry with regard to botanicals include requirements: analytical solutions for traditional organoleptic analysis (sight, taste, smell, etc.), micros- botanical identity copy, and chemical means such as high performance liquid chromatography (HPLC), high performance thin layer chromatography By James Neal-Kababick, Director of Flora Research Laboratories, (HPTLC), flash chromatography, gas chromatography (GC), mass and Kathryn Lawrence, Grace spectrometry (MS), infra-red (MIR, NIR, FTIR), Ultraviolet and visible spectroscopy (UV-VIS), and many others. Appropriate iden- Editor’s Note: This article was originally published in the June 4, 2013 tity methods and technologies are critical to ensuring that dietary issue of the Natural Products INSIDER which is a product of Virgo ingredients are properly identified, and they increase the likelihood Publishing LLC. that adulterated raw materials will be detected before they are incorporated into finished products. Under 21 CFR111, it is stated that manufacturers “must establish an identity specification” and “test and examination method(s) used are fit for purpose.” Testing raw materials to fulfill 100 percent iden- Advanced flash column chromatography tity, especially botanical extracts or premixes sourced from around One technique that can assist in meeting the requirements of good the world, is challenging and often controversial, since many manu- manufacturing practice (cGMP), and in particular the analysis of facturers would like to see the accountability lie with suppliers botanical extracts and complex mixtures, is advanced flash column instead of themselves. chromatography (AFCC). AFCC is a complementary separation technology that, when coordinated with other technologies, such as Applicable methods HPTLC, can provide manufacturers with a significant set of tools for cGMP compliance—often at a more reasonable cost. True characterization of a material can take a lot of work and may require multiple techniques, experiments, resources, and time. More and more, companies are seeking higher-powered solutions to Although there are many scientifically valid techniques, manufac- fully characterize the sample reference set they will use for analysis of turers must factor in the cost of compliance when choosing a given the routine samples and develop truly validated methods. In partic- route for meeting the regulations. Technologies often employed in ular, implementing advanced next-generation flash chromatography

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July 2013 • Page 12 equipped with integrated multidetection by UV and ELSD to rapidly isolate, purify, and characterize new compounds has been key to addressing the majority of identity testing challenges—particularly botanical extracts and premixes. The One Pass Flash technique, developed by Flora Research Laboratories (FRL), is routinely used to Figure 1. simplify highly complex premixes and resolve them compounds was a novel ingredient not previously reported. into distinct sample fractions for immediate qualitative and quantitative evaluations of identity. That equates to higher throughput, Currently, there is no physical or chemical quality specification for less downtime, and more reliable data. commercial manufacture of kava products, and it is essential that Also, samples can be purified to prepare standards for measuring new suitable quality specifications are developed. A key objective of the compounds when no standard is available, the standard is too costly, study was to establish purity of the compounds by quantitative or it is too delayed. nuclear magnetic resonance (q-NMR) for use as a chemical reference material and for further studies. A prime example comes from excellent work on kava roots by Paula Brown, et. al., who demonstrated the use of AFCC to isolate An AFCC method for purifying targeted phytochemicals from P. novel compounds from kava, which resulted in the purification of methysticum leaves, stem peelings, and roots was developed. known cutting-edge flavokavains and the discovery that one of the Fractionation, guided by gas chromatography with mass spectro-

July 2013 • Page 13 Fig 2. GC/MS spectra for flavokavains A, B, C* and pipermethystine. [*This compound reassigned by NMR] scopic detection (GC/MS) monitoring of expected masses, was performed (Figure 1 and 2). Flavokavain A and B, as well as pipermethystine, were successfully isolated and purified using AFCC with a high degree of purity in under an hour. These isolated compounds can be used in future studies and as reference materials for phytochemical comparisons of P. methysticum traditional prep- arations and commercial products.

Mid infra-red and near infra-red

Simple screening of incoming premixes by mid infra-red (MIR) and near infra-red (NIR) or other fast-scan techniques may not ensure reasonably anticipated contaminants (RACs) are absent in the ingredients, and these techniques often fall short of Figure 3. this requirement due to lack of method validation or inadequate sampling. MIR and NIR can give a tion, contaminants) and, more importantly, met. If a product speci- picture of the whole sample but require much up-front work to vali- fication is goldenseal root extract standardized to 5 percent alkaloids, date for botanical identity methods. the product must be proven by the manufacturer (not the raw material supplier) that it meets this specification. To accomplish this NIR, perhaps the most misunderstood technique in the industry, is using MIR, it would not be unusual for a proper MIR method to problematic for identity testing if not fully validated by a chemomet- require a few hundred materials upfront to take the place of multiple ric model. In many instances, these techniques are not being properly testing methods such as HPLC and HPTLC if one wishes to confirm utilized for botanical identity testing, which can result in failures in botanical source identity as well as a quantitative assay and any con- identity. The example below (Figure 3) demonstrates how easy it is to taminants (for example, in this case, the RAC synthetic berberine). pass carrageenan as chondroitin in routine NIR analyses. As a complementary technique and to keep standard sourcing costs In addition, the cGMP requires that manufacturers ensure product low, AFCC can be used to isolate standards for use in validating specifications are established (identity, purity, strength, composi- these spectroscopic methods.

July 2013 • Page 14 AHPA Workshop:

High Performance Thin Layer Chromatography for Popular Botanical Materials Workshop

September 7-8, 2013 Costa Mesa, California

The American Herbal Products Association (AHPA) will host a two-day workshop on high performance thin layer chromatography (HPTLC) at the Alkemists Laboratories corporate headquarters. Gain the practical experience necessary to conduct HPTLC analysis on a variety of popular botanical ingredients.

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July 2013 • Page 16 High performance thin layer chromatography characterized by LCMS and NMR to identify the structure and mass. Further routine testing can be done using this standard on a HPTLC is an excellent fundamental means to examine botanical triple quad or other MS system to rapidly test subsequent shipments materials and several other dietary ingredients, but it can be more to confirm identity or to identify the marker species in a premix. labor intensive. HPTLC allows for comparison of a test sample against various reference materials (desired and adulterant), as well as grades of material. AFCC has been effective for quickly identifying markers in standardized extracts, especially when HPTLC pro- files are inconclusive compared to monograph methods, since they are based on whole botanical extract, not standardized extract. Highly concentrated extracts often require removal or reduction of other compound classes that are used in routine HPTLC methods for profiling the species. In order to properly identify these highly processed materials, AFCC is used to isolate and concentrate select markers, which allow species assignment. However, an HPTLC analysis of an extract sample of schizandra berry powder (left lane) and the standardized extract (right lane) shown in Figure 4 demonstrates the challenge to complex mixes. Note the difference in band intensity. In addition, the diagnostic band of interest does not appear in the standardized extract. This method uses bands in the profiling that are not the same as the extract markers, leaving routine identity by HPTLC lacking. However, simplifying the standardized extract by Figure 4 and 5: Flash concentrates band previously undetected using routine ID protocol. flash chromatographic separation first would essen- tially concentrate the marker band and allow for identification of new negative markers in other cases. Practical solutions Figure 5 is the result following successful isolation of a pure fraction CRO outsourcing containing the marker band for Schizandra chinensis from the sample viewed at VU 366 nm. In the left lane is starting material, while the The industry has the option either to invest in various technologies right lane is the fraction from starting material with concentrated that can be used internally by skilled staff to quickly assess ingredi- diagnostic compound. This result confirms Schizandra chinesis is ent identity or to outsource the testing work to a contract labora- present in this complex sample and demonstrates the usefulness of tory. The latter would require a laboratory proficiency demonstration the advance fractionation of the mixture before HPTLC analysis. by check samples or audit, as well as the characteristic delay time for shipping a sample, putting it into a queue and awaiting results. Liquid chromatography/mass spectrometry and nuclear However, caution is advised for firms proceeding with outsourcing; magnetic resonance qualifying questions to determine the level of expertise in identity Liquid chromatography with mass spectroscopy (LC/MS) and are often necessary. The firm will need to determine if the contract nuclear magnetic resonance (NMR) techniques employed for iden- research organization possesses the proper equipment, whether ana- tity require significant upfront capital investments, operator know- lysts have adequate training and qualifications, learn how instru- how, and cost of operation. Implementation challenges for ments are calibrated and determine whether the incoming standard developing truly validated testing protocols could include: botanical is characterized properly. Remember, even though materials may be identity methods for complex premixed blends, sourcing costly and sent out for testing by a third-party lab, the manufacturer is still obscure phytochemical standards, controlling high-level labor hours responsible for the work being done. required for advanced spectroscopy technologies, reconciling the An article, developed in cooperation with the American Herbal fact that processing standardized extracts may diminish target com- Products Association’s (AHPA) Analytical Laboratories Committee, pounds used for species identification. The AFCC isolated fraction is an excellent resource for businesses considering contract labora- in the previous Schizandra extract HPTLC example can also be tory services.

July 2013 • Page 17 In-house lab ¾¾ Lower consumable costs (savings depends on sample throughput, but could be thousands per year). AFCC systems use Consideration for return on investment (ROI), including hiring, small, inexpensive disposable cartridges preventing the early training, equipment, space, safety, and other factors, should be con- demise of LC columns which are very expensive and critical to sidered when choosing to create an in-house lab. Other factors such throughput. as intellectual property protection could also be a consideration. ¾¾ Easy to learn and use. Lab personnel quickly come up to speed on the operations and develop simple methods to address a Business benefits of implementing AFCC variety of complex botanicals and product formulations. This Independent of whether evaluations are performed by an in-house replaces other methods such as preparative TLC, open column or third-party lab or via FTIR, HPTLC, or mass spectroscopy, the chromatography and preparative HPLC. The embedded One Pass Flash technique eliminates other time-intensive sample wizards included in next-generation AFCC literally walk you through each step and help assure you have the right amount of prep work and reduces costly column replacements for a LC/MS solvent and proper cartridge and that other parameters are satis- system. By applying AFCC to the FRL arsenal of technologies to fied before you start the experiment. This can help you get the perform automated sample prep, businesses can recognize many job done right the first time every time. benefits impacting operations, including: ¾¾ Reduced sample prep time by up to 90 percent. Samples are Conclusion typically simplified and ready for qualitative examination or Under the new cGMP regulations, all companies must assure that quantitative analysis in minutes instead of hours. This is like having an extra full-time technician in the laboratory. their products are compliant. Further, the Food and Drug Administration is actively inspecting facilities at an ever-increasing ¾¾ Faster sample analysis times. Samples can now be properly rate, meaning the question isn’t “if” but “when” the agency will analyzed in one to two days versus 10 to 15 business days, inspect your facility. By properly implementing the correct modern which is more typical for exotic or complex mixtures. For companies bringing in multiple premixed products to encapsulate technologies and utilizing trained staff, with consideration given to (ready-to-encapsulate), this could mean tens of thousands of cost and ROI, companies can comply with the cGMP regulations dollars per year saved on each product SKU. and greatly mitigate the risk of an FDA warning letter and potential financial liability and loss of client trust. Choosing the right partners ¾¾ Detecting/isolating sample components quickly. Isolating is an essential step in developing or evolving your company’s labora- authentic reference standards by AFCC saves thousands of dollars yearly, and in some cases it is the only means to obtain tory operations. When you have the right equipment, right staffing, the compound unless one is willing to contract a standard strong partners, and a commitment to excellence, your company company to purify it, which will usually cost as much as buying moves from being a high-risk entity to an entity anchored in a solid an AFCC unit—and that is just one standard. Therefore, one is foundation of quality. ahead of the game after an initial compound is isolated and characterized when working on novel products. Plus, by per- Additional resources forming the work in-house, businesses’ IP can be better protected. In addition, instead of attempting a complex sample For more information on appropriate techniques for the verification separation with a long 60- to 90-minute compromised HPLC of the identity of and meeting specifications for popular botanicals, gradient, a series of simple HPTLC separations or simple and in particular how AFCC can help with botanicals/botanical HPLC marker specific compendia methods can be used to save extracts/complex mixtures, attend a workshop presented by AHPA a great deal of R&D time and avoid extra validation work. on July 18-19, in Chicago, Ill. Click here to register.

July 2013 • Page 18 Legal and Regulatory

FDA wants cGMP compliance, not anyone to use “in labeling, advertising, or other sales promotion … companies to discuss it any reference to any report or analysis furnished in compliance with section 374 of this title.” It is under section 374 that FDA provides By Anthony L. Young, Kleinfeld, Kaplan & Becker LLP and AHPA a company with an FDA Form 483-Notice of Inspectional General Counsel Observations (483) after a cGMP or other inspection. Nothing gets by the Food and Drug Administration’s (FDA) dietary supplement group. At a regulatory affairs symposium in California The prohibition on “promoting” inspection results was enacted in earlier this month, the Center for Food Safety and Applied 1953, at the same time Congress created section 374. This was back Nutrition’s Daniel Fabricant, Ph.D., detailed FDA’s statistics regard- in the day when it was also unlawful to truthfully state your drug ing dietary supplement current good manufacturing practice product was FDA approved through a new drug application. Indeed, (cGMP) inspections for fiscal year 2010 through February of fiscal at that time, some at FDA jokingly took the position that the version year 2013. Those numbers indicate that, after reviewing firms’ of the Bill of Rights in FDA’s offices began with the Second responses to inspectional observations, FDA finds “official action Amendment. indicated” (e.g., warning letters, untitled letters, or regulatory meet- Section 331(n) was obviously crafted to curtail the use of FDA ings) at a rather high rate. inspection findings or non-findings in a commercial context, lest And why not? Opportunities abound for FDA to find “low-hang- anyone read more into them than FDA believes should be read into ing fruit” with respect to cGMP inspections. Think about it: A them. But FDA undermines this aim by posting 483s on its website company’s website contains claims that are either outright disease very shortly after issuing them to compounding pharmacies and in claims or implied disease claims. Even a brief look at the product other situations where there is strong public or media interest and information panels published on the site reveals that the labels do FDA wants to deliver a strong enforcement message. not contain required information or that they are simply not com- Further, at a time when 483s are available to the press and to compliant. If you were FDA, wouldn’t you suspect that a company petitors under the Freedom of Information Act, enforcing 331(n) with two highly visible regulatory deficiencies would have cGMP against a company might be viewed as muzzling companies from compliance issues as well? defending themselves. It cannot be that section 331(n) means that Fabricant went on to advise that cGMPs are the “minimal quality everyone can talk about a 483 except the company that received it. standard,” reminding attendees that 21 USC 331(n) makes it a pro- That does not make sense, and experience tells us that laws that do hibited act under the Federal Food, Drug, and Cosmetic Act for not make sense are not—and should not be—enforced.

July 2013 • Page 19 July 2013 • Page 20 Calendar of Events

� Economic Botany 2013 � Breitenbush Herbal Conference June 28 – July 2 • Plymouth, England Sept. 5 – 8 • Detroit, Ore.

� XIII International Congress of Toxicology � Heartstone Herbal School 2013 Herbal Apprenticeship June 30 – July 4 • Seoul, South Korea Program Sept. 6 – 8 • Van Etten, N.Y. � 15th Anniversary of International Society of Antioxidants World Congress � Nutrihort July 4 – 5 • Paris, France Sept. 16 – 18 • Ghent, Belgium

� International Congress on Naturopathic Medicine � Herbal Resurgence Rendezvous July 7 – 9 Paris, France Sept. 19 – 22 • Mormon Lake, Ariz.

� � Colorado Integrative Medicine Conference 10th World Congress of Chinese Medicine Sept. 21 – 22 • Santa Clara, Calif. July 12 – 14 • Estes Park, Colo. � Plant Medicine Wilderness Retreat � Annual Meeting to the American Society of Pharmacognosy Sept. 25 – 28 • Alpine, Ariz. July 13 – 17 • St. Louis, Mo. � 11th Annual International AARM Restorative Medicine � Trends in Natural Products Research Conference July 21 – 25 • Tyrol, Austria Oct. 3 – 6 • San Diego, Calif. � NBJ Summit � Ayurveda and Cancer Care July 23 – 26 • Dana Point, Calif. Oct. 3 – 6 • Las Vegas, Nev. � Alberta Herb Gathering � 2013 Lifestyle Medicine Summit: Women’s Health July 26 – 29 • Thorsby, Alberta, Canada Oct. 5 – 6 • Chicago, Ill. � 61st International Congress and Annual Meeting of the Society � Integrative Advances in Disease Prevention and Treatment for Medicinal Plant and Natural Product Research Conference Sept. 1 – 5 • Munster, Germany Oct. 11 – 13 • San Diego, Calif.

� Rocky Mountain Dietary Supplement Forum � Southeast Wise Women 9th Annual Herbal Conference Sept. 12 – 13 • Boulder, Colo. Oct. 11 – 13 • Black Mountain, NC

July 2013 • Page 21

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July 2013 • Page 22