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The Global Challenge
The Role of the
European Pharmacopoeia for
TCM Globalisation
Gerhard FRANZ,
Chairman of the Pharmacognosy group DAB
University of Regensburg, Regensburg/Germany
Content
- TCM Herbal Medicinal Products in Europe
- Quality standards set by the
European Pharmacopoeia
- Elaboration of TCM herbal drug monographs
- Problems with processing of herbal drugs
- Outlook for the future
Acceptance of TCM in Europe
• High acceptance of Complementary Medicine
• Phytomedicine well established in the EU
• Good educational background in most
countries of the EU
• Historical good connections with the Far East
• Present in many specialised Pharmacies as
prescription medicines for TCM practitioners
Actual Problems with TCM in
Europe
• No specific regulation existing for TCM Products
• European new legislation on Traditional Herbal
Medicines difficult for CMM registration
• No animal or mineral products allowed
• Officially no Pinyin names and Sinograms allowed
TCM product classification as:
-
Medicinal Products
Nutraceuticals
Dietary -Supplements
Cosmetics
TCM in the European Union
Products not to be licensed:
- Tradidional crude (processed) herbal drugs
- Decoction pieces
- Granules for prescription
Products to be licensed:
- Chinese patent medicines
- Granules for prescriptions complex formulas
- New TCM Phytomedicines
Categories of Herbal Products
Medicinal
products
Dietary
supplements
Food Concept
- No clear guidance relating to quality for
most of the dietary supplements :
GMP?, Safety?, Efficacy?
- No claims for Therapeutic Indication
- Easy access to market as:
Botanicals – Dietary Supplements
Functional Foods, Nutraceuticals
Not relevant for Traditional Chinese Medicine
in most European countries
Content
- Herbal Medicinal Products in Europe
-Quality Standards set by the European
Pharmacopoeia
- Elaboration of Ph Eur TCM herbal drug
monographs
- Problems with Processing of herbal drugs
- Outlook for the future
European Network
National Authorities
Licensing
European Authorities
European Union (EU)
Inspection
Council
National
Pharmacopoeias
European Medicines
Agency
Parliament
Commission
DG Enterprise
Brussels
European Directorate
for the Quality
of Medicines
European
Pharmacopoeia
HMPC
(EMA)
London
Herbal Medicinal Products in Europe
All HMP‘s can only be markted in the EU demonstrating :
HMPC Monographs
Safety
Efficacy
Quality
Ph Eur Monographs
Purpose of the European Pharmacopoeia
To promote public health by the provision
of recognised common standards for use
by health-care professionals and others
concerned with the Quality of Medicines:
Safeguard Users of
Traditional Chinese Medicines !
Criteria
Impact of the Ph Eur
The standards apply to all medicines
regardless of their origin:
- chemical
- biological
- herbal, included TCM
- method of production
- mode of application (homeopathic medicines).
- Actual situation: more than 2400 Monographs
out of which :
~ 280 Herbal Monographs
~ 300 General Methods
In future editions: more than 100 TCM Monographs
Herbal – Monographs
in the Ph Eur
General Monographs:
– Herbal drugs
– Herbal drug preparations
– Herbal teas
– Extracts
– Essential oils
– Methods in Pharmacognosy (22)
Technical Requirements apply to the entire
class!
Scope of Ph Eur
Herbal Drug Monographs
QUALITY
SAFETY
minimize the risk potential by clear
Defintions, Identifications,
Tests and Assay
EFFICACY: HMPC/ LONDON, EMA
9th : 2017 60 TCM Monographs published
Content
- Herbal Medicinal Products in Europe
- Quality standards set by the European Pharmacopoeia
- Elaboration of Ph Eur TCM herbal drug monographs
- Problems with processing of herbal drugs
- Outlook for the future
TCM herbal drugs in the World
•Growing interest worldwide
•Exportation from China has increased
•Few legally binding quality standards
•Knowledge on TCM herbal drugs is limited
outside China
•Quality problems have been observed
• Future: Granules instead of Herbals?
©2009 EDQM, Council of Europe, All rights reserved
20
TCM Standards/Monographs
in various countries of the World
Pharmacopoeia/Monographs
Authority
legal status
Chinese Pharmacopoeia
European Pharmacopoeia
SFDA
EU ,EDQM
official
official
Hong Kong Chinese Materia
Medica Standards
DHKK China
official
Japanese Pharmacopoeia
PA Japan
official
British Pharmacopoeia
BPC, UK
official
German Pharmacopoeia
BfArM
official
American Herbal Pharmacopoeia
Australian Guidelines for
Complementary Medicines
private
non official
TGA Australia
official
What is actually needed for a
good TCM practice?
• better knowledge about the impact of TCM on
pharmaceutical practices and public health
• balanced information for the public about
TCM potential health risks
• more information about safety issues due to
the absence of qualified reporting systems for
undesirable effects caused by TCM
Why specific Ph Eur Monographs
on TCM?
• Imported TCM herbal drugs: often quality
problems observed
- Problems with correct Identification
- Confusion between related species
- Contamination with heavy metals, microbes
pesticides
• Addition of synthetic compounds to fake
pharmacological effects
History of the Activities:
Quality Monographs on CMM for the
EU Member States
• About 20 years ago TCM became known and more
and more popular in some European Countries with
the consequence that CMM with often doubtful
Definition/Identity and Quality were imported and
sold to the patient. Intoxications occured and several
National Authorities became alert.
• Consequence by the EU in 2005:
Decision in the EU:
Ph Eur Commission 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 products’
25
Inclusion Criteria of CMM in the
TCM Herbal Drug Working Program EP
- existance of a monograph in the Ch Ph
- volume of use in the EU member states
- documented problems of quality
- documented problems of toxicity
- risk of substitution with toxic herbal drugs
- risk of documented contaminations
Number of items on the
TCM Work Programme ?
- the average European TCM practitioner is
prescribing about 300 TCM Herbal Drugs
in daily practice
- commercial importers provide up to
400 TCM Herbal Drugs to the EU market
- the average number of CMM used in
Chinese TCM Clinics is around 500
- how many Quality Monographs are
needed in the future for the EU?
Transfer of Monographs
•
• adapt/adopt???
•who does the work ?
• where is it done ?
• how is it done ?
ANSWERS
• Adapt/adopt not possible due to different
technical requirements Ch P/ Ph Eur
• Who does the work: TCM Working Party
• Close collaboration with China
• Where is it done? By the respective Experts in
EU Member States and China
• How is it done? Examination/Modification,
Validation of all methods published in Ch P
TCM Working Party
Ph Eur Commission 2016
Chairman
Prof. Dr. G. Franz
Country:
AT:
AT:
AT.
B:
CH:
CH:
CH:
CH:
D:
D:
FR:
FR:
GB:
IT:
NL:
PL:
TR:
Prof. Dr. R.Bauer
Dr. R. Laenger
Mag. E. Stoeger
Prof.Dr. P. Duez
Dr. I.M. Bruentrup
Dr.Th. Lehmann
Dr.E.Reich
Dr.Sh. Wang-Tschen
Dr. M.Gasser
Dr.K.Wuthold
Prof.Dr.I.Fouraste
M. R.Soussain
Mr M.Whaley
rof.Dr.A.R.Bilia
Dr. M. Wang
Prof. Dr. K. Glowniak
Prof.Dr. S. Harput
University
EMA
Industry
University
Industry
OMCL
Industry
Industry
Industry
Industry
University
OMCL
NPA
University
University
University
University
Observers:
AU:
CN:
Prof.Dr.K.Chan
SATCM/NKL
University
Analytics
Microscopy
Analytics
Analytics
TLC/HPTLC
Analytics
Analytics
Microscopy
Analytics
Analytics
Analytics
Members of the TCM Working Party
and Observers
Mainland
China
Australia
Elaboration procedure of Monographs
The Ph Eur Commission decides to elaborate/revise a new Monograph
Start
Working Party: Rapporteur prepares a draft Monograph which is evaluated by the Group
1. Publication draft Monograph:
PHARMEUROPA
National Authorities comment on the published draft Monograph
Working Party examines the comments and revises the draft Monograph
The draft monograph is proposed for adoption :Commission
Commission adopts the Monograph
The Monograph is published
The monograph will be implemented
Time frame: average two years
Structure of Ph Eur
Herbal Drug Monographs
• Definition
• Identification ( Morphology, Histology,
HPTLC/TLC – fingerprinting )
• Tests ( foreign matter, water content,
pesticides, heavy metals, aflatoxins, mineral
ash, ariostolochic acid …..)
• Assay ( quantification of defined marker
compounds)
• Storage
Structure of Ch P Monographs
•
•
•
•
•
•
•
Description
Identification
Tests
Assay
Action and use: legal requirement for TCM
Dosage and Usage: legal requirement for TCM
Storage: legal requirement for all monographs
Ch P 2010
Latin
Differences:
- root tuber
versus
-tuberous root
Chinese
Ph Eur 2016
Differences:
- no family
- no collection
period
-minimum
content given
English
English
Latin
Chinese title
missing
Guide for the Elaboration of
Monographs on Herbal Drugs (Ph Eur)
A monograph on a Herbal Drug is drafted
with the same overall structure as a
Monograph on a chemical substance
The latest versions of the Technical Guide for
the Elaboration of Mongraphs and of the Style
Guide apply to monographs on Herbal Drugs
All Tests and Assay methods described in
a monograph must be validated according
to the procedures stated in the Technical
Guide.
Consequence: Apply for all TCM Herbal Drugs!
Assay
Chemically defined Substance
1% impurities
99 % chemical substance
Herbal Drug
~ 2 % active principle
98 % inert matrix
Constituents to be determined in
an Assay of a TCM Monograph
• constituents with documented therapeutic
actvity
• constituents with a toxicological risk which
have to be limited
• distinguish closely related species if not
possible by identification A,B and C
• constituents as technical markers (proper
harvesting, drying, storage, adulterations…)
Constituents with therapeutic Activity
Definition:
‘Chemically defined substances or groups of
substances which are generally accepted to
contribute substantially to the therapeutic
activity of a herbal drug or herbal drug
preparation‘
Assay essential for the Safety
of the Patient
•
•
•
•
•
•
•
TCM herbal drugs containing:
Aconite alkaloids
Pyrrolizidine alkaloids
ß- Asarone
Furano cumarines
Aristolochic acid
In these cases acceptable limits for
toxic compounds must be set
Content
- Herbal Medicinal Products in Europe
- Quality standards set by the European Pharmacopoeia
- Elaboration of Ph Eur TCM herbal drug monographs
- Problems with Processing of TCM herbal drugs
- Outlook for the future
Reasons of Processing
• Main purpose:
• Detoxification or Reducing Side Effects
• Modifying/ Reinforcing therapeutic
Effects
• Others such as dissipating odours and
taste, facilitating storage …….
Processed versus Unprocessed
• Processing reduces the toxicty of many
drugs
• Processing enhances the activty of drugs
• No uniform Processing Methods in China
(regional differences)
• No objective criteria (SOP) for the use of
excipients
• No standardised criteria for excipients in
the actual Ch P
Methods of Processing (Pao Zhi)
according to Ch P 2010
- cleaning: O.K. with Ph Eur
- cutting : O.K. with Ph Eur
-special processing
methods not in
line with Herbal Drug
Preparations
all unknown for Ph Eur,
need to be standardised
and acknowledged by the
Ph Eur Technical Guide
stir frying
stir frying with solid or liquid
materials
ca lcining
steaming/ boiling
torrefication
grinding with water
Processing of Crude Drugs:
Excipients used for different Processing Techniques
ChPh 2010
For all PhEur Monographs, the quality of excipients must
be specified: - Wine: use yellow rice wine (% alcohol?)
-Vinegar: use rice vinegar (acidity?)
-Salt water: salt dissoved in an appropriate quantity of water ?
-Ginger
juice: squeezed juice of fresh Ginger (content of ingredients ?)
-Honey: refined
honey (quality according to PhEur?)
-Fat: sebum
fat (quality parameters?)
What we need to do
- Clarifying the Processing Mechanisms
to guide the establishment of
Standard Processing Techniques
-Applying modern analysis techniques
combining with chemical/analytical ,
pharmaco-dynamics, molecular biology
and toxicology studies
Content
- Herbal Medicinal Products in Europe
- Quality standards set by the European Pharmacopoeia
- Elaboration of Ph Eur TCM herbal drug monographs
- Problems with Processing of herbal drugs
- Outlook for the future
Outlook
• Interest in TCM is permanently growing in many EU countries
• This should be reflected by the National Authorities to propose
additional CMM to the Commission of the European
Pharmacopoeia
• Consequently, the Work Programme of the TCM Working Party
• must accept additional items to be worked on in the future
• The efficiency and quality of this Work Programme must be
optimised by a close collaboration of EDQM/ Ph Eur/ Ch P/
SATCM NKI
• The Working Programme of the Ph Eur TCM WP should be
considered for the further planning of the Ch P 2020
• Consequently, Ph Eur Commission should be informed about
the future plans of Ch P
ROUNDTABLE 3: REGULATORY AND LEGISLATION
Marketing of Herbal Products
•
Products
Legislation
• Herbal Medicinal Product Medicinal Product
• Full marketing authorization
CD 2001/83 EC as amended by
•
•
Well established use
Traditional use
CD 2004/24 EC & CD 2004/27/EC
• Herbal Food Supplement Food Supplements
•
• Herbal Novel Food
CD 2002/46 EC & DC 2006/C80E
Novel Foods
Regulation 258/97
• Herbal Cosmetic
•
Cosmetics
Regulation CD76/768
Pharmacovigilance
Consumer information; labeling;advertising
Efficacy
new trials
bibliographic
Safety
new tests
bibliographic
Traditional use
expert report
bibliographic
new tests
Quality Control
Good Manufacturing Practices
Good Agricultural and
Collection Practices ( GACP)
new
52
well-established
traditional
HMPC-Scheme: Access to the market
http://www.ema.europa.eu
European quality guidelines for
approval of herbal medicinal products
• Public Statement on Good Agricultural and Collection Practice for starting
materials of herbal origin (GACP)
•
Guideline on Quality of Herbal Medicinal Products / Traditional Herbal
Medicinal Products
•
Specifications: Test procedures and Acceptance Criteria for Herbal Drugs,
Herbal Drug Preparations
• Traditional Herbal Medicinal Products
•
Guideline on Quality of Combination Herbal Medicinal Products /
Traditional Herbal Medicinal Products
• Guideline on Stability Testing
Criteria for Traditional Herbal Medicinal Products
(Directive 2004/24/EC)
- limited therapeutic indications
- specified strength and posology
- oral, external or inhalation preparations
- period of traditional use has elapsed at least 30 years, out of which
at least 15 years in the EU
- sufficient data on traditional use
Consequences:
- legal use for OTC
- no treatment of severe diseases
- high quality documentation required
- no innovative products possible
EU Directive 2004/24/EC on
Traditional Herbal Medicinal Products
 it does not cover the treatment of severe diseases
 efforts on quality are still high
 does not allow innovative products (IPR difficult)
 the legal use for OTC
For modernized TCM products for „well
established“ use or „new“ products
should be developed
Summary and Conclusions
• Depending whether used for health or desease treatment, herbal
products can be marketed in Europe as food supplements or as
medicines.
• In both cases corresponding regulations need to be considered.
• Medicinal products can be approved as new, well established, or
traditional products.
• In order to guarantee safety and efficacy, herbal medicinal products
must undergo serious quality control, which should be based on
Pharmacopoeia Monographs.
• For well established and traditional herbal medicinal products proof of
efficacy and safety can be based on bibliographic data, and
corresponding monographs should be established.
• More research is necessary to improve clinical evidence and our
knowledge on relevant constituents and mechanism of action.
Many thanks
for your kind
attention!