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©JCTCM-Professor Kelvin Chan PhD DSc FSB FCP FRPharmS FRSM©

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Translating Pharmacognosy Knowledge into Healthcare: Research on Quality and

Standards10:55-11:15

Title: Current research on standards of medicinal plant products: Decoction pieces, granules and proprietary products as phytomedicines

Kelvin Chan, The University of Sydney & Western Sydney, Australia

11:15-11:35

Title: Notorious Aristolochic acids in traditional herbal medicines: Successful identification and validation using DNA barcodes, Real-Time PCR with TaqMan technology and UHPLC-HR-MS

Wei Sun, China Academy of Chinese Medical Sciences, China

11:35-11:55

Title: Progress of R&D of Chinese materia medica to keep up with advances in technology

De-an Guo, Chinese Academy of Sciences, China

11:55-12:15

Title: Authentication and quality control of TCM herbs and herbal preparations

Yuan-Shiun Chang, China Medical University, Taiwan


4

Current research on standards of medicinal plant products:

decoction pieces, granules and proprietary products as phyto-

medicines

Kelvin ChanJoint Chair Professor in TCMFaculty of Pharmacy, USyd

The National Institute of Complementary Medicine, UWS

©JCTCM-Professor Kelvin Chan PhD DSc FSB FCP FRPharmS FRSM© 5

Topics to be touched on

• The current public views on herbal products

• Pharmacopoeia standards of Chinese materia medica:

Role of methodology development

• The current global regulations for Chinese herbal

products as phyto-medicines

• The future actions


Frequently Asked Questions/Concerns about Herbal Medicinal Material and Proprietary Herbal Medicinal

Products

• What are the active ingredients prescribed herbal medicines?

• Do herbal products have to pass through the same strict legislative procedures as pharmaceuticals?

• What is known about the quality, safety and efficacy of the herbal products?

• What are the latest research directions towards QC/QA of herbal drugs?


7

WHO Report on Traditional Medicine


8

Differences between Orthodox Drugs and Chinese Medicinal Materials (CMM)

** refer to chemically defined established drugs. ** refer to either single herb or combination of several herbs in one prescription. From: Chan & Cheung, Interactions

between Chinese Herbal Medicinal Products and Orthodox Drugs, Taylor & Francis Group, September 11, 2000 by CRC Press

Physico-Chemical Characteristics

Properties Orthodox drugs* CMM/Products**

Active ingredients

Pure compound available

Accessible for analysis

Raw materials available

Quality of the raw materials

Standardisation

Stability

Known

Yes

Yes

Dependable

Good

Easy

Achievable

Very often unknown

Rarely

Complex/Difficult

Limited/exhaustible

Variable

Difficult/ may be achievable

Difficult/may be achievable


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Process in quality assurance of herbal medicines

Typical procedure for quality standardisation of herbal medicines


Total Quality Management of Chinese Medicines Industry

*GACP is now adopted as Good Agricultural & Collection Practice

*


Strategies for Achieving Quality Medicinal Herbal Products

Establishment of • Good Agricultural & Collection Practice for of medicinal plants

• Good Sourcing Practice for supply of materials

• Good Laboratory Practice for chemical/biological analyses

• Establishing reliable pattern recognition procedures for

fingerprinting relationship of source materials

• GMP of ready-made products with approved fingerprinting

• GCTP of ready-made products


Min County, Gansu: Transferring Danggui Young Seedlings in Green House to Open Fields

甘肃岷县：将当归幼苗转至绿色大棚以开辟土地


Danggui’s GAP Test Farms

当归良好农业规范试验田Min County, Gansu Province

甘肃省岷县


GAP production bases of TCM herbs adopted by national certification before 2010 in China

Zhang et al (2010), GAP Production of TCM herbs in China. Planta Medica, 76: 1948-1955

GAP refers to: Good Agricultural Practice


Some Current GAP Bases of Chinese Materia Medica in China

[Zhang et al (2010), GAP Production of TCM herbs in China. Planta Medica, 76: 1948-1955] Site of bases Cultivated medicinal Plants

Anhui province Paeonia suffruticosa Chongqing Pinellia ternata Gansu province Angelica sinensis Guangxi province Momordica grosvenorii GuiZhou province Dendrobium candidum; Eucommia ulmoides; Hebei province Angelica dahurica; Scutellaria baicalensis Heilongjiang province Panax ginseng Henan province Panax ginseng Hubei province Kehmannia gluiinosa Hunan province Lespedeza cyrtobotrya Inner Mongolia Eucommia umloides Jiangsu province Glycyrrhiza uralensis Jilin province Chrysanthemum morifolium Liaoning province Panax ginseng; Panax quinquefolium Ningxia province Panax ginseng Shandong province Lycium chinensis Shanghai Lonicera japonica Shanxi province Crocus sativus Sichuan province Salvia miltiorrhiza Tibet province Crocus sativus; Ligusticum chuanxiong Yunnan province Rhodiola roseaDracaena draco; Panax notoginseng


Role of European Directorate for Quality Medicines & Healthcare (EDQM)


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The EP Commission in Strasbourg 2005

* ‘Monographs on Herbal Drugs used in

Traditional Chinese Medicine should be developed

to give

a modern quality standard according to

European Pharmacopoeia principles and

to facilitate and encourage use

by practitioners for safe,

authorised products’ *Slide from Prof Franz-©2009 EDQM, Council of Europe, All rights reserved


21

Commission of European Pharmacopoeia (2008):

Set up Working Party of TCM at Strasbourg, EDQM Président/Chairman Prof. Dr. Gerhard Franz

Other Experts:

A Prof. Dr. Rudolf BAUER

A Dr. Erich Andreas STOEGER

B Dr. Pierre DUEZ

CH Dr. Albert BLARER

CH Dr. Thomas LEHMANN

CH Dr. Eike REICH

D Dr. Uwe Michael GASSER

D Dr. Bernhard Klier

E Ms. Gloria GARCIA LORENTE

F Prof. Isabelle FOURASTE

F Mr. Robert SOUSSAIN

UK Prof. Dr. Kelvin CHAN -- AU Observer (since Mar 2010)

I Prof. Francesco VINCIERI

NL Dr. Mei WANG

TR Prof. Kemal Husnü Can BASER


Multi-disciplinary methods for the quality standardisation of CMM

Pharmacognosy: GAP and sample preparation

Capillary ElectrophoresisCarbohydrate

analysis

Chemometrics

Authentication:TLC

DNA finger printing

UPLC/HPLCLC-MS

Biological ClinicalStudies


Strategic priorities1. Optimisation of manufacturing and analysis methods to

achieve herbal product standardisation and predictable

bioactivity.

2. Contribute to R&D product development methodologies in

TCM.

3. Progress TCM bioinformatics / data management.

4. Assisting the development of Chinese herb cultivation in Australia

(encompassing Good Supply Practice/Good Agriculture Practice

issues).

5. Developing the national and international profile of NSW and

Australia in TCM.

6. Further development of strategic TCM research priorities (to

articulate with NICM TCM priorities).


Salvia Miltiorrhiza Radix & Rhizoma (Danshen)

Panax Notoginseng Radix & Rhizoma (Sanqi)

Angelica Sinensis Radix (Danggui)

Pueraria Lobata Radix (Gegen)

Zingiber officinale Rhizoma (Ginger)

Granule comparison with raw materials

Standardisation


Analysis Using TLC and UPLC, quantifying several reference

compounds. Antioxidant activity Chemometrics

Granules


General results between decoction pieces & granules

• CMM decoction pieces were in their own group.

• CMM decoction pieces had consistent yields.

• Antioxidant activity favoured CMM decoction pieces .

• Quantification of more markers allowed greater comparison of products.

• Did industry follow traditional decoction?

Pharmacopoeia needs to define standards for herbal granules


27

Difference in registration of herbal products

– China: TCMs treated and registered as a medicine, health-supplement

– Europe: Traditional Herbal Medicinal Product Registration Scheme is good for European traditional remedies (NB 30/15 year rule) but is a barrier to entry for TCMs and other non-EU traditional remedies

– USA: stringent rules, need to claim efficacy for disease– Canada: ease of access via Natural Health Products route– Australia: risk strategy approach (different levels)


Dantonic® [Danshen Diwan: Radix Salviae miltiorrhizae, Radix notoginseng and Borneolum Syntheticum] developed as a formulation for treating chronic stable angina pectoris in early 1990s

Approved as a Class 4 drug by the SFDA in 1993

CMC information (formulation development, specification, manufacturing process, stability test, etc)

pre-clinical data (pharmacological studies and acute and sub-acute toxicity studies

clinical evidence (157 patients, positive control studies, Fu Fang Danshen Pian).

Used by more than 25 million people in chronic, 3-5 month administration, with substantial benefits and bioactivity superior to existing pharmaceuticals in one or more aspects in terms of safety, efficacy and cost-effectiveness

In 1996, Dantonic® entered the first foreign market – Vietnam

The currently active IND (70,359) from the FDA received in June 2006 for the treatment and management of chronic stable angina

Phase II, randomized, placebo controlled studies in the USA and Australia conducted 2008-2009

In July 2010, the EOPII meeting with the US FDA was held, and the phase III studies are under active planning in the USA, EU, Australia and Asia

Case study: Dantonic® Worldwide Markets (1)

©TCM&NP Symposium-Nanning-2011.08.13-15-Prof. K Chan PhD DSc FSB FCP FRPS FRSM-©

Country/Region Legal status Approval time

USA Dietary supplement Sep 2000

The United Arab Emirates Prescription drug Jun 2001

South Korea OTC Jan 2002

Cuba Drug* Jul 2002

Singapore TPM** Oct 2002

Mongolia Drug* Oct 2002

Nambia CAM** Aug 2003

Kazakhstan Prescription drug Jan 2004

Ivory coast Functional product*** Mar 2005

Dantonic® Worldwide Markets (2)

* Drug: there is no clear classification between prescription drugs and OTC in some developing countries ** TPM: Traditional Patent Medicine; CAM: Complementary and Alterative Medicine; TM: Traditional Medicine; TCM: Traditional Chinese Medicine; *** Functional product: Similar to dietary supplement or food supplement;


Dantonic® Worldwide Markets (3)

South Africa CAM** Sep 2005

Vietnam Prescription drug Oct 2005

Russia Prescription drug Dec 2005

Nigeria CAM** Dec 2006

India Functional product*** Mar 2007

Thailand TM** Feb 2008

Hong Kong TCM** Mar 2008

Canada OTC Jul 2008

Philippines OTC Jul 2009

Uganda Functional product*** Aug 2009


31

Di’ao Xinxuekang Capsule - the 1st authorised THM from outside the EU

Approved by Dutch Medicines Evaluation Board (MEB) on

14 March 2012

The application was evaluated very carefully on the basis of: pharmaceutical qualitysafety andthe justification of traditional use, i.e. 30/15 year rule

(Dioscorea nipponica rhizome)

The marketing authorisation holder is obliged to implement a pharmacovigilance system

The manufacturing site of Di’ao in Chengdu, China was

inspected on GMP by the Dutch Pharmaceutical Inspection.


Email Addresses for Regulatory Agencies in various regions

Australia --- http:/www.tga.gov.au/cm/cm.htm#argcm

Canada--http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/index_e.html

China---http://www.sfda.org.cn/

Hong Kong Chinese Medicine Division--http://www.cmchk.org.hk/cm/english/idx_ord.htm

The European Agency for the Evaluation of Medicinal Products— http:www.emea.eu.int/

USA-- -FDA---http://www.fda.gov/cder/guidance/index.htm


Pharmacopoeia of various countries or regions that have monographic standards for CMM

Chan K, Leung KS, Zhao SS. Harmonization of monographic standards is needed to ensure the quality of Chinese medicinal materials. BMC-Chin Med 2009; 4: 18

Pharmacopoeia and monograph Authority StatusWHO Monographs on Selected Medicinal Plants WHO unofficialChinese Pharmacopoeia SFDA China officialAU Regulatory Guidelines for Complementary Medicines TGA Australia officialEuropean Pharmacopoeia EDQM officialHong Kong Chinese Materia Medica Standards DHHKSAR, China officialJapanese Pharmacopoeia PA Japan officialThai Herbal Pharmacopoeia TFDA officialBritish Pharmacopoeia BPC, UK officialAmerican Herbal Pharmacopoeia (AHP) prívate unofficial


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Take home messages• Open mindedness collaboration/cooperation/networking• Ensure good practices in GACP, GSP, GLP, GMP & GCTP• Linking technologies, chemometrics & bioinformatics with regulatory

requirements• Evidence-based assessment of efficacy & safety • Global harmonisation of regulatory control/ pharmaco-vigilance system

• To achieve these we need:– Updating monographic standards of CMM with R & D data – Local, national and global networking on all issues is a MUST– Recognition of industrial specifications for GCTP- proven brand-

named products.– Train local human resources in coping with demand—role of

university & educational institutes– Do the utmost to establish a state of harmony between "tradition"

and "modern" in the provision of global healthcare


Thank you for your attention


Lets Meet again at Pharmacognosy-2015

3rd International Conference and Exhibition on Pharmacognosy, Phytochemistry and Natural

ProductsOctober 26-28, 2015 Hyderabad, India

Theme: Advanced trends for the future of Herbal Drugs and Products

Website: http://pharmacognosy-phytochemistry-natural-products.pharmaceuticalconferences.com/

http://pharmacognosy-phytochemistry-natural-products.pharmaceuticalconferences.com/

http://pharmacognosy-phytochemistry-natural-products.pharmaceuticalconferences.com/

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