school of natural product studies jadavpur university, kolkata
TRANSCRIPT
Regulatory aspects of Phyto-Pharmaceuticals
Pulok K. Mukherjee, PhD, FRSCDirectorSchool of Natural Product StudiesJadavpur UniversityKolkata 700032; India [email protected] +91 33 24146046Associate Editor, J. Ethnopharmacology, Elsevier Science
“Emerging Needs and Regulations on Phytopharmaceuticals”
India International Centre, New Delhi June18, 2014
Fellow of the Royal Society of Chemistry [FRSC], U.K
Common Wealth Fellowship, UK BOYSCAST Fellowship, DST Biotechnology Overseas Award,
DBT AICTE Career Award For Young
Teachers DIA Out Standing Service Award,
USA DST-JSPS Visiting Fellow Japan The Fujii Otsuka Award Japan DIA Research Grant Award, USA APTI Young Pharmacy Teacher Award, IPA Fellowship Award Visiting Scientist at the :
King’s College LondonTokushima UniversityLeiden University , The NetherlandsSchool of Pharmacy, LondonMedical Research Council, CapeTown
Phytomedicines in Different Countries
A new and growing consumer interest innatural medicine but not recognized bythe governments including drugauthorities
Variable Situations
Strong foundation of traditional medicines havingnationally recognized parallel traditional systemsalong with western medicine
India and China
Move to give legitimacy to the traditionalhealers even after western medicine madeits appearance and took firm roots
Europe and USA
Africa
Regulation and promotion of botanicals varies –which has a global impact throughout
International co-ordination is the need of the day for proper regulation and promotion of botanicals in alternative medicine
Development of alternative medicine
Role of botanicals [herbals] in these systems
Understanding the current regulations on phytomedicines and international co-ordination on its different aspects
Highlights of the discussion
Mukherjee & Wahile, 2006, J. Ethnopharmacology 103, 25–35
Indian System of Medicine (ISM)
Traditional health care system of India
It covers all the systems which originated in India and out side butgot adopted and adapted in course of time:
ISM
Ayurveda (900-800
BC)Homeopathy (1850 AD)
Yoga and Naturopathy
Siddha(800-700
BC)
Unani(460-377
BC)
Indian Materia Medica includes about 2000 drugs of natural origin
1250 Indian medicinal plants are used in therapeutic formulations in ISM
About 85% of ISM preparations are poly -herbal
Botanicals constitute a major part in ISM
- Therapeutic Validation of herbal medicine
- Phytochemical validation
- Metabolomic studies, chemo profiling, quality control and standardization
Food as Medicine:A Systemic Approach for
Validation of Therapeutic efficacy
Mukherjee et al., 2011. Food Chem Toxicol, 49, 3142-3153.
Murraya koenigii (Rutaceae)
Trigonella foenum graecum (Fabaceae)
Clitoria ternatea (Fabaceae)
Mahanibine
Taraxerol
Trigonelline
β-Asarone
Acorus calamus Linn. (Acoraceae)
Screening of drugs as AChE inhibitors (drug development for Alzheimer’s disease)
Fitoterapia, Elsevier, 2011, 82: 342-346
Mini Review in Medicinal Chemistry, Bentham, 2011, 11: 247-262
Natural Product Research, 2012, 26: 1519–1522
Phytother. Res. Wiley, 2010, 17:292–295
Phytomedicine, Elsevier, 2010, 17: 202-205
Orient Pharm Exp Med, 2013, DOI 10.1007/s13596-013-0141-3
Illicium Verum (Illiciaceae)
H3CO
CH3
Anethole
OH
HO
O
O
HO
OH
OH
QuercetinMarsilea quadrifolia
(Marsileaceae)
Piper betel(Piperaceae) Chlorogenic acid Hydroxychavicol
India drug gives Alzheimer's hope
Scientists in the UK and India are examining the ancient Indian ayurvedic medicine for possible use in drugs to treat Alzheimer's disease.
Researchers say ayurveda works in the same way as conventional drugs for boosting mental agility in the disease. They found that the plants used in ayurveda acted to improve memory and concentration in Alzheimer's sufferers.
Alzheimer's disease is a progressive, degenerative and irreversible brain disorder. There is no known cure.
The disease causes intellectual impairment, disorientation and eventually death.
Researchers from King's College, London and Jadavpur University in the eastern Indian city of Calcutta, studied five plants commonly used in ayurvedic medicine.
They found that the plants acted to prevent the breakdown of neurotransmitters, improving memory and concentration in people with Alzheimer's disease - the most common form of dementia.
The scientists are now trying to identify the chemical compounds responsible so they can be used to develop more effective drugs.
There is no known cure for Alzheimer's disease
India drug gives Alzheimer's hope
HERBAL DRUGS NOT AS SAFE AS THEY ARE PROMOTED
Assuming that everything that isNATURAL is SAFE is not correct !
Herbal drugs are not uniformly regulated, many claims can be made
that are poorly documented !
Problems with regulated herbal
products
Authentication &Reproducibility of herbal ingredients
Adulteration/Substitution
Microbial contamination
PesticidesFumigants
Toxic metals
Other contaminants
Mukherjee et al., 2011, Botanicals as medicinal food and their effects on drug metabolizingenzymes. Food Chem Toxicol.,, 49, 3142-53.
Mukherjee et al, 2011, Drug Information Journal, Vol. 45, pp. 1–14.
Marker analysis
Bioactive compound Quantification
Spurious drug determination
Comparative fingerprint analysis
Standardization of herbs
Stability of formulations
Quality consistency
Chemo-profiling – Quality control and standardization
Pandit et al., 2011. Biomed .chromatogr., 25: 959-962
Gantait et al; 2010, JOURNAL OF AOAC INTERNATIONAL: 93
Mukherjee et al; 2009, Phytochem. Anal. 19: 244–250.Mukherjee et al; 2010, Phytochem. Anal, 21, 556–560
Quantitative estimation
Supersomes assay CYP P450 - CO complex method
Fluorometricmicrotiter plate
assay
HPLC assay
Quantitative Estimation of CYP by Microplate Reader
CYP P450 + CO CYP P450--CO Yellow complex
450 nm
Quality related safety issuesSafety evaluation of medicinal plants
CYP 450 enzyme inhibition
Enzyme : CYP3A4/CYP2D6Substrate :BFC (7-Benzyloxy- trifluromethylcoumarin)Positive control : KTZ (Ketoconazole)Cofactors:1.3 mM NADP+, 66 mM MgCl2 & 66 mM Glucose 6-PhosphateGlucose 6-Phosphate Dehydrogenase:40Unit/mL in 5 mM Sodium Citrate Buffer (pH 7.5)Stop reagent : 0.5 M Tris BaseTest extract : Plant extract (0.5 mg/ml) provided by CCRASMetabolite standard: HFC (7-Hydroxy- trifluorocoumarin)
Estimated based on metabolites formation
Mukherjee et al., 2011. Food Chem Toxicol, 49, 3142-3153.
Pandit et al., 2012. Food Res. Int.. Res. 45: 69-74
Pandit et al., 2011. Phytother. Res. 25: 1429-1434
Pandit et al., 2011. Fitoterpia., 82: 369-374Ponnusankar et al. 2011, Phytother. Res.,133:120–125
Validation of traditional FormulationsEvidence based approach
Ponnusankar et al., 2011. J. Ethnopharmacology 133 , 120-125
Ellagic acid
Triphala Tri – ThreePhala- Fruits
Quality control
Safety of the herbal preparations
Development of effective marker
Clinical efficacy of marker
Documentation
Regulatory harmonization
Global issues for promotion of natural products
AYUSH
Three subordinate offices
One public sector undertaking
Two statutory organizations
Eight educational institutions
Board
Four Research councils
Pharmacopoeial Laboratory for Indian Medicine (PLIM)
Homoeopathic Pharmacopoeial Laboratory (HPL) Ayurved Hospital, Lodhi Road, New Delhi
Indian Medicine Pharmaceutical Corporation (IMPCL)
The Central Council ofIndian Medicine(CCIM)
The Central Councilfor Homoeopathy(CCH)
Central Council for Research in Ayurveda and Siddha (CCRAS)
Central Council for Research in Unani Medicines (CCRUM)
Central Council for Research in Homoeopathy (CCRH)
Central Council for Research in Yoga & Naturopathy (CCRYN)
National Institute of Ayurveda (NIA) , Jaipur National Institute of Siddha (NIS), Chennai National Institute of ayurveda research, Kolkata National Institute of Naturopathy (NIN), Pune National Institute of Unani Medicine, Bangalore Institute of Post Graduate Teaching &
Research in Ayurveda, Jamnagar (Gujarat) Rashtriya Ayurveda Vidyapeeth, New Delhi Morarji Desai National Institute of Yoga, New Delhi
National MedicinalPlant Board
Acts Administered in the ISM Sector
• Central Council of Indian Medicine Act – 1973• Central Council of Homoeopathy Act – 1973• Drugs & Cosmetics Act -1940 and Rules there
under.• Drugs & Magic Remedies [Objectionable
Advertisement] Act -1954, 1955 and Rules there under.
• Medicinal and Toiletries Preparation acts and Rules -1995-96
Regulation of ASU Drugs
Regulation of herbal medicines deals with regulatory status of herbalmedicines, regulation requirements, products and quality controlrequirements such as GMP, monographs, etc.
Sections Subject 33C. Ayurvedic, Siddha and Unani Drugs Technical Advisory Board.
33D. The Ayurvedic, Siddha and Unani Drugs Consultative Committee. 33E. Misbranded drugs
33EE. Adulterated drugs. 33EEA. Spurious drugs. 33EEB. Regulation of manufacture for sale of ASU drugs33EEC. Prohibition of manufacture and sale of certain ASU drugs. 33EED. Power of Central Government to prohibit manufacture, etc., of ASU drugs. in
public interest. 33F. Duties of Government Analysts. 33G. Powers of Inspectors. 33H. Application of provisions of sections 22, 23, 24 and 25.
33EEB. Regulation of manufacture for sale of ASU drugs. 33EEC. Prohibition of manufacture and sale of certain ASU drugs. 33EED. Power of Central Government to prohibit manufacture, etc., of ASU drugs.
33F. Government Analysts. 33-I. Penalty for manufacture, sale, etc., of ASU drugs. 33J. Penalty for subsequent offences. 33K. Confiscation. 33L. Application of provisions to Government departments. 33M. Cognizance of offences. 33N. Power of Central Government to make rules. 33O. Power to amend First Schedule
Provisions Relating To ASU Drugs: D&C Act
To lay down standards of single drug or compound formulations included in ASU
To establish a drug depot of genuine crude drug samples after collecting them from different agro climatic zone of the country
To ensure an appropriate infrastructure or ‘quality system’ encompassing the organizational structure, procedures, process and resources.
To ensure adequate confidence that the botanicals satisfy the prescribed requirement for quality.
Procurement and documentation of Traditional methods of quality control.
Interpretation of the traditional information about identification and quality assessment in terms of modern technology.
Development of concrete methods of identification and quality assurance in terms of modern methodologies.
The regulations on ISM drugs in India mainly deals with…..
Introduction of Rule 160 A-J dtd. 31.01.2003 for approval of laboratories from private sector for testing of ASU drugs and
raw materials (http://indianmedicine.nic.in )
The Good Manufacturing Practices for ASU Drugs as described in Rule 157 of Drugs & CosmeticsRules 1945 with conditions as specified in Schedule T / GMP are to ensure that:(I) Raw materials used in the manufacture of drugs are
authentic, of prescribed quality and are free from contamination
(II) The manufacturing process is as has been prescribed to maintain the standards
(III) Adequate quality control measures are adopted(IV) The manufactured drug which is released for sale is
of acceptable quality(V) To achieve the objectives listed above, each licensee
shall evolve methodology andprocedures for following the prescribed process of manufacture of drugs which should be documented as a manual and kept for reference and inspection. However, underIMCC Act, 1970 registered Vaidyas, Siddhas and Hakeems who prepare medicines: on their own to dispense to their patients and not
selling such drugs in the market are exempted from the purview of Good manufacturing
Practice (GMP)
Rules & Regulation of ISM
Regulation on Safety study incorporatedRule 168 B dt. 10.08.2010.
Ayurvedic pharmacopoeia of India Part I:Volume Year of publishing No of monographs
I 1990 80II 1999 78III 2001 100IV 2004 68V 2006 92VI 2008 101VII 2008 21 (Minerals And
Metals)Ayurvedic pharmacopoeia of India Part II:
Volume Year of publishing No of monographsI 2007 50II 2008 51III 2010 51
Ayurvedic formulary of India:Part Year of publishing No of monographsI 1978 444II 2000 191
Official Compendium
WHO guidelines for herbal medicinal products
Assessment of safety and efficacy
28 monographs in 1999
30 monographs in 2002
31 monographs in 2007
28 monographsIn 2009
WHO Monographs on Selected Medicinal Plants - Volume 1-4
National Policy on Traditional Medicine and Regulation of Herbal
Medicine
National Policy on ISM
Strategies:
Policy support, Financing ISM & H and Medical Education
Drug Standards, Regulation & Enforcement
Medicinal Plants and The ISM Industry
Intellectual Property Rights (IPR) of ISM
Revitalization of Local Health Traditions
Medical Tourism and Export of ISM Practitioners
Ancient Medical Manuscripts and Research in ISM
Access to information and Veterinary Medicine
Integration of ISM & H and National Health Care Programmes and
Delivery System, Drug Standardization and Quality Control
Exposing the Foreign and Indian Modern Graduates to Indian
Systems of Medicine (ISM) and Building Awareness
To promote good health and expand the outreach of health care throughISM
To improve the quality of teachers, clinicians and researchers
To improve the infrastructural facilities
To ensure safe and efficacious use of drugs in ISM
To facilitate pharmacopoeialstandards of raw material
Integrate ISM in health care delivery system and clinical practice
To aware public globally for use of herbal products
To provide full opportunity for the growth and development of ISM
Objective:
(http://indianmedicine.nic.in )
• 356 monographs are included in 4 volumes of Ayurvedic Pharmacopoeia of India, so what are the standards of remaining about 1644 herbs used in Ayurvedic system of medicines?
• What are the standards of numerous Ayurvedic multi-ingredient formulations?
• Chemical characterization is not stringent enough in Ayurvedic Pharmacopoeia.
• Involvement of Modern Instrumentation techniques are required.
• More in-depth validation is required
Grey areas – Promotion and development of herbs
• Framing of Legislation on Nutritional Supplement.• Amendment of Schedule T (GMP for Ayurvedic Drug Manufacturing
Units)and its implementation.• Inclusion of 88 Monographs of Herbal Drugs in the latest edition of
Indian Pharmacopoeia-2010.• Permitted Excipients (11.05.2005): As mentioned in the Indian
Pharmacopoeia, Prevention of Food Adulteration Act, 1954.• Proposal for displaying of the ingredients on Labels of Ayurveda,
Siddha & Unani Drugs.• Heavy metal testing made mandatory (2006): Arsenic, Lead,
Mercury and Cadmium (not more than 20 ppm)• Maintaining of records of raw materials used by licensed
manufacturing units of Ayurveda, Siddha and Unani (ASU)drugs(Rule-157A, dt. 9.7.2008)
• Stipulation of Expiry date for Ayurvedic Medicines (Rule-162 B dtd.01.04.2010)
• Regulation on Safety study incorporated (Rule 168 B dt.10.08.2010)
Developments …………
Challenges - Globalisation
From … world wide applicationof traditional medicines
and … differentregulatory systems towards … global
harmonised standards
A Systematic Approach for Validation of Traditional medicine
Mukherjee et al., 2012. J. Ethnopharmacology ,143 :424–434.
International coordination
Strategies to mainstream the indigenoussystem of medicine
To promote medical pluralism
Medical Pluralisms: -Building bridges
to increase communication &to support ethical collaborations & co-operations
on use of natural products with out interfering with their individual autonomy
Globalization of Traditional Medicine12th International Congress of Ethno-pharmacology
ISE 2012, Kolkata, IndiaFebruary 17-19, 2012; www.ise-snpsju.org
Over 1000 delegates from 52 countries Over 600 scientific presentations
Inaugurated by Honourable Dr. A. P. J. Abdul Kalam, former President of India
Keynote speaker was Prof. Luc Montagnier, Nobel laureate in Medicine
Mission and Providing an environment for knowledge
sharing among researchers, healthcare-practitioners, and decision-makersinterested in Ethnopharmacology
Globalization of local knowledge andlocalizing global technologies
Organizing conference, seminars,symposiums, workshops etc in differentparts of India for dissemination ofknowledge
Inculcating scientific temperaments forvalidation of medicinal plants and naturalproducts
Encouraging the scientists through awards,honors etc.
SOCIETY FOR ETHNOPHARMACOLOGY23/3, Saktigarh, Jadavpur, Kolkata: 700032, India
Registered under the West Bengal Society Registration Act 1961
Society For Ethnopharmacology India Welcome You
for India Chapter
Mission: Promotion of Ethnopharmacology and validation of medicinal plants and other natural products
Globalizing local knowledge and localizing global technologies
“Globalizing Traditional Medicine: Present and Future prospects”
Over 700 delegates from 20 countries Over 300 scientific presentations
Inaugurated by His Excellency Sri Shekhar Dutt, Governor of ChhattisgarhKeynote speaker was also Sri Shekhar Dutt, Governor of Chhattisgarh
School of Natural Product Studies
Jadavpur University, Kolkata
Herbal Pharmacovigilance
Scientific validation of medicinal plants
Quality control & standardization
Formulation & evaluation of herbal
medicine
Bioassay guided isolation & lead finding
in natural products
Lead finding from natural products
High-throughput screening methodology
for medicinal plant
Phytochemical & pharmacological
screening
Evidence based approaches for development of tradition
medicines
Herbal therapeutics & pharmacokinetics
Safety evaluation of herbal drugs
Development & evaluation of nutraceuticals and dietary
supplements
Globalization of traditional medicine
Chemo-profiling of natural products
Dissemination of knowledge for promotion of natural products
Books & Proceedings published from SNPS, JU, India
Involvement with Peer-reviewed Publications –worldwide
Editor and Editorial Board member
Acknowledgement
CCRAS
CSIR
Faculdade de Farmácia daUFMG Brazil
Healing plants are Nature’s Gift for
EveryonePulok K. Mukherjee, PhD, FRSCAssociate Editor, J. Ethnopharmacology, Elsevier Science