MediHerb: Our History, Philosophy and Approach to Quality Kerry Bone

1. MediHerb: Our History, Philosophy and Approach to Quality Kerry Bone Co-Founder and Director Research & Development, MediHerb Associate Professor, University of New England, Australia

2. MediHerb: 20 Years Where did we start from? • A converted goat shed on a farm • Three workers • No sales or reputation • A vision to serve and educate herbal clinicians

3. MediHerb: Some Major Milestones • An Australian company based in Queensland • Founded in 1986 by Kerry Bone and hiswife Patricia with other investors • Developed a unique cold (no heat) percolation technique for extracting herbsto make superior quality liquids • 1990 - became the leading company supplying health professionals in Australia • 1992 - awarded a pharmaceutical manufacturing licence by the Australian Therapeutic Goods Administration (TGA)

4. MediHerb: Some Major Milestones • 1996 – began production of a tablet and capsule range • 1996 – became the leading company supplying to health professionals in New Zealand • 2001 – launched into the USA • 2005 – launched into the United Kingdom and South Africa • 2007 - launched into Canada

5. MediHerb Today • Factory in Warwick, Queensland - about 8000m2 and laboratories in Brisbane • About 100 employees • Australia’s largest processing plant of raw herbs • Continuous innovation and product development to suit our practitioner customer’s needs

6. MediHerb: Intellectual Property • Knowledge of quality herbal raw material suppliers worldwide • Unique cold percolation method • Unique tableting technology that retains the actives • In-house analytical capability includes more than 70 methods for quantifying different phytochemicals in plants • Completed successful trials on Echinacea and acknowledged as leading researchers in the field • Involved in clinical trials on various subjects

7. Research & Development • Corporate philosophy committed to scientific research as the future of herbal therapy • Own R&D Department in-house • A senior team of expert scientists with an innovative approach to research: 2 PhD’s specialising in phytochemistry, 1 PhD specialising in pharmacology and 2 Associate Professors: Lehmann and Bone • Well equipped laboratories: HPLC with Diode Array, Mass Spec and ELSD detection, GC and access to NMR

8. MediHerb’s Research Credentials • Four RIRDC Grants • Two ARC-Linkage Grants • Two AusIndustry Grants • Biotechnology Innovation Fund • Commercial Ready • Two NCCAM-NIH Grants (USA) • Five PhD’s earned by University students working on MediHerb projects • One international patent (4 countries) • More than 20 scientific papers in peer reviewed journals

9. MediHerb: Our Promise of Quality • A practitioner’s company passionate about achieving clinical results (20 naturopaths on staff) • A recognition that clinical results can only be achieved through high quality products • A strong culture of quality assurance/ quality control underpinned by pharmaceutical standard good manufacturing practices (GMP)

10. Does Quality Matter? • Every healthcare practice is built on its ability to meet or exceed the expectations for treatment results from its patients • It’s a fact that 95% of patients whose expectations are not met don’t tell the practitioner - they tell their friends, and don’t come back! • This means that the best chance a healthcare business has in retaining patients and attracting more referrals is to use the best possible products in the hands of highly competent professionals

11. Australian Therapeutic Goods Act In Australia, all herbal and nutritional medicines must, by law, be made according to the code of pharmaceutical GMP. This defines a number of procedures and observances including: • Documented standard operating procedures • Control of the manufacturing environment, air and water • Quarantining and testing of raw materials, labels and packing

12. Australian Therapeutic Goods Act • Reconciliation of product, packaging and labels • Comprehensive batch record documentation • Quarantining and testing of finished products • Testing of stability of finished product • Regular audits by TGA inspectors • Enables a customer complaint or issue to be traced back through manufacturing sequence to the initial raw material

13. Quality Considerations in Herbal Medicine • In practice, herbal manufacturing under GMP is essential because the issues are more complex than those for conventional drugs • This is because a herb is biologically defined and: • May be incorrectly identified • May vary in phytochemical content and hence safety and efficacy • Carries with it a history, ie it may be contaminated with unwanted substances

14. Quality Considerations in Herbal Medicine • Harvesting, drying and storage conditions can impact on phytochemical content and hence quality • Extraction and subsequent processing of herbs may enhance or impair their safety and efficacy • Stability of products may be difficult to define and measure

15. Herbal Raw Material Testing at MediHerb • Fingerprint of identity and quality with TLC and HPLC • Macroscopic Analysis • Microscopic Analysis • Pesticide Residues • Microbial Levels • Aflatoxins • Heavy Metals • Foreign Material • Infestation • Radiation • Active or marker compounds

16. Chromatography: The Core QC Technology • Chromatography involves the separation and subsequent visualisation of chemicals in a mixture • This is the core technology used in the quality assessment of herbs becausethey are complex chemical mixtures • Chromatography is performed in two steps: • separation of the individualchemicals in a mixture by passing them through a medium • detection of the separated chemicals

17. Chromatography: The Core QC Technology • A fluid carrier flowing through the medium transports the chemicals in the mixture (the carrier can be liquid or gas) • Depending on its relative affinity for the carrier each chemical will travel at a different speed through the medium • Detection techniques can vary from the simple (naked eye) to the highly sophisticated (nuclear magnetic resonance)

18. Thin Layer Chromatography • An extract of a herb is spotted at the bottom of a thin layer of silica gel on a glass plate • The plate is dipped in a solvent mixture • The solvent draws up the layer and carries the components in the herb different distances • Sprays and/or ultraviolet light are used to view the components, giving a characteristic pattern of spots • Each spot corresponds to a component inthe herb • Different solvent systems draw out different classes of components in the herb

19. Gas Chromatography • The carrier is an inert gas • The medium is a glass column • The detector is a flame • The phytochemical must be volatile • As each phytochemical passes into the flame it causes ionisation which is detected as an electronic signal

20. High Performance Liquid Chromatography • The carrier is a liquid under high pressure • Various synthetic columns can beused as the medium • The detector is usually an ultraviolet/ visible detector which measures the spectrum ofeach phytochemical as it passes the detector (diode array) • Disadvantage is that a chromophore is necessary • Hence more sophisticated detection techniques may be necessary (MS, NMR, ELSD)

21. Silica gel plates Spray Reagents TLC X Z X Y X Z Y X Y Z Burnt in a Flame Gas Flow Heated Oven GC HPLC Liquid Flow UV-VIS ELSD MS Chromatography

22. Defining Quality: Definitions Marker Phytochemicals • Characteristic phytochemicals found in a plant which are chosen to represent a quality standard for that plant Active Phytochemicals • Phytochemicals which are important for a given therapeutic effect of a herb. May or may not include marker compounds

23. What To Test For? • What is the active ingredient? • St John’s Wort (Hypericin, Hyperforin, Flavonoids, OPC’s) • What is the importance (for Ginkgo extract) • 24% Flavonoids (3 marker compounds) • 6% Ginkgolides and Bilobalide(5 actives) • <5ppm Ginkgolic Acid (3 irritants) • Echinacea: our research has shown that the alkylamides are the most important quality markers

24. Herb Quality Issues Which Influence Clinical Results • Substitution • Marker compound absent from herb • Inappropriate measurement of marker compound • Product not complying with label claim of marker compound • Adulterated extracts masquerading as standardised extracts • Other issues eg wide variations in marker compounds among products

25. Substitution: Categories Substitution can occur at several different levels: • The wrong plant part within a species • A less active chemotype or subspecies • A related plant of the same genus • An unrelated plant (which can also have profound safety implications)

26. Substitution: The Wrong Species Skullcap • Since 1910 Skullcap (Scutellaria lateriflora) has been reported to contain scutellarin as the major flavonoid • Research by MediHerb and Southern Cross University has shown that the major flavonoid is actually baicalin • This work has been reported at conferences in Europe by MediHerb

27. Skullcap • MediHerb was the only practitioner company in Australia supplying genuine skullcap to the Australian market when this issue was investigated by the TGA in the 1990’s • Substituted herbs were: Other species of skullcap - mainly S. incana and Germander (Teucrium spp.) • Understanding the phytochemistry of skullcap and using HPLC allows MediHerb to assure that the product it supplies is the correct species and of high quality and efficacy

28. Golden Seal Substitution • Hydrastis canadensis is expensive and endangered • Often substituted by other species: • Golden Thread (Coptis chinensis) • Indian Barberry (Berberis aristata) • Oregon Grape (Berberis aquifolium) • These species do not contain hydrastine, only berberine and berberine related compounds

29. Golden Seal Substitution

30. Golden Seal Analysis Notes: - means no peak visible. GS1 was authenticated as Hydrastis by TLC Govindan M, Govindan G. Fitoterapia 2000; 71: 232-235

31. Tribulus: Different Methods and Plant Part Variation Tribulusterrestris- Bulgarian clinical trials utilised 45% furanosterolic saponins by UV-Vis, with the plant part being the above ground portion • Chinese and Indian sources typically specify the fruit analysed at 40% by gravimetric methods • Gravimetric 40% • UV 3% by Bulgarian method • Raw Herb results • Fruit 0.5% • Aerial parts 3.5%

32. 0.75 0.75 0.50 0.50 0.25 0.25 Protodioscin Volts Volts Slovakian Tribulus Herb 0.00 0.00 Clinical trial extract Australian Tribulus Herb -0.25 -0.25 Indian Tribulus Herb -0.50 -0.50 0 2 4 6 8 10 12 14 16 18 20 22 24 Minutes Tribulus by HPLC • Herb of different geographic origin has different profiles • Different plant parts have different profiles • Only aerial parts from Slovakia and Bulgaria contained protodioscin

33. Concentrate Diosgenin Dioscorea villosa herb Concentrate 5 10 15 20 25 30 35 40 45 Minutes Wild Yam -Dioscorea villosa? Products sold as Wild Yam are often not even herbal products

34. Why 1:2? • There was a need for a liquid preparation which was: • sufficiently potent and concentrated (like a 1:1) to be able to confer therapeutic doses • made without damaging the delicate phytochemical balance of the whole plant: no heat used in manufacturing (like a 1:5 tincture) • Hence MediHerb arrived at the use of the 1:2. To our surprise we later found 1:2’s mentioned in 19th century texts and the German Pharmacopeia

35. Cold Percolation: The Key To An Effective 1:2 • While efficiently extracting 1 Kg of herb into 2 litres of liquid is substantially easier than for 1 litre, it is still a difficult task • Using his background in chemistry Kerry Bone adapted the existing knowledge of percolation to produce the MediHerb 1:2 Cold Percolation Process • In this context “cold” means that damaging heat is not applied duringthe extraction process

36. Quantified Activity Extracts • Full spectrum extract • Carefully chosen active or marker phytochemicals • Minimum level of specified active or marker every time • Consistent quality • Consistent activity

37. The Solid Dose Challenge There are two main ways to put herbs into a solid dosage form: • Powdered dried herbs into tablets or capsules • Extracts into tablets or capsules The problem with the former is many dosage units often need to be consumed to achieve physiological doses

38. Solid Doses Which Do Not Compromise Quality • Most companies buy in extracts to make tablets or capsules • This is often fine for well-defined, commonly available herbal extracts such as St John’s Wort and Ginkgo • However for herbs where quality markers are less defined (eg Echinacea) or for those which are based on traditional use (eg Eyebright) the quality of extracts on the market is extremely variable and often poor

39. Solid Doses Which Do Not Compromise Quality • MediHerb makes its own extracts for tablets in these cases • This substantially broadens the therapeutic options for the herbal clinician who prefers solid doses

41. Using MediHerb Products • Can provide dramatic positive treatment results when used by well-trained health care professionals • Quality and clinical experience are built into the products • The clinical support that MediHerb provides is the best in the industry • Our website contains hundreds of referenced articles to support the health care professional • MediHerb is unsurpassed in the world of complementary medicine

42. The MediHerb Philosophy The philosopher and teacher Rudolf Steiner once said that, for every human illness, somewhere in the world there exists a plant which is the cure. We believe that there is a healing potential locked inside plants which is integral with their evolution, just as it is part of human evolution to learn to tap this wonderful gift of Nature

43. The MediHerb Philosophy This is our passion at MediHerb: to unlock the healing power of plants by combining the time-honoured wisdom of traditional knowledge with sound clinical experience and the rigour of scientific research. This quest can only be attained by the total commitment to quality and continuous improvement which permeates every aspect of our endeavours