2 Sanz Biset

Harmonisation of quality
standards by the European

Pharmacopoeia
TradReg 2017
Dr. Jaume SANZ-BISET
European Pharmacopoeia Department
EDQM
Content
 The European Pharmacopoeia

 General monographs, individual monographs,
general texts on herbals
 Technical guides
 Special topics:
- TCM (Traditional chinese medicine)
- PA (Pyrrolizidine alkaloids)
J. Sanz-Bisetl ©2017 EDQM, Council of Europe. All rights reserved.

2
The European Pharmacopoeia (Ph. Eur.)
 Lays down common, compulsory quality
standards for all medicinal products in
Europe.
 The Ph. Eur. is legally binding -> but
monographs are regularly revised to reflect
the state-of-the-art.
 Mandatory on the same date in 38 states
(CoE) and the EU (European Union
Directives 2001/82/EC, 2001/83/EC, and
2003/63/EC, as amended, on medicines for
human and veterinary use).
3
J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved.
Ph. Eur. Commission
 One delegation per signatory party or
observer
 38 Member States plus a delegation
from the EU (a representative from
DG Health & Food Safety and the
EMA)
 29 Observers: 27 Observer
countries, Taiwan Food and Drug
Administration (TFDA) and
World Health Organization (WHO)
 Three sessions a year: draft texts
are published for public consultation and
adopted by unanimous vote
 EDQM/EPD provides the secretariat
4
Members and Observers
Green: Ph. Eur. member states

Yellow: Observers to the convention on the elaboration of a Ph. Eur.
5
The Ph. Eur. network
57 active Groups of experts and working parties (+ 14 “dormant”)
elaborating and revising texts, meeting up to 3 times a year,
formed by more than 720 experts (mainly from Competent
Authorities, Industry, University)
Concerning herbal
drugs and
preparations:
 Group 13A
 Group 13B
 TCM WP
New: PA WP
6
Contents of the European Pharmacopoeia:
More than 2500 monographs and about 350 general
methods
7
Herbal drug and herbal drug
preparation monographs
 General monographs
 Individual monographs
 General methods/chapters
8
Monographs
Herbal drugs and herbal drug preparations
in European Pharmacopeia 9th Edition 2017 (9.2)
6 general monographs, e.g.:

General
 Herbal drugs (1433) notices
 Essential oils (2098)
General
chapters
294 individual monographs, e.g.: General texts
 Aloes cape (0258)
General
 Aloes dry extract standardised (0259) monographs
 Cassia oil (1496)

 Matricaria liquid extract (1544)
Individual
 Rosemary leaf (1560)
monographs
 Valerian tincture (1899)
9
Example of a general monograph:
Herbal Drugs (1433)
 Definition: state of the drug: broke, cut, fragmented

etc., scientific name, content specifications
 Production: information on origin, harvesting, drying,
etc.
 Identification
 Tests: foreign matter, LOD, pesticides, heavy metals (not
subjected to Q3D), total ash and others
 Assay: Unless otherwise prescribed or justified and
authorised, herbal drugs are assayed by an appropriate
method
10
Individual monographs on herbal drugs and
herbal drug preparations
 General monographs and individual monographs

are complementary
 The drug/preparation described in the individual
monograph has to comply with its specific
requirements and with the requirements of the
general monograph
 Requirements which are described in the general
monograph and not repeated in the individual
monograph are, for example, the test for
pesticides (2.8.13) or for heavy metals (2.4.27)
11
Identification section of an individual
monograph:
Macroscopic
botanical
characters
Microscopic
Thin-layer
chromatography botanical
characters
12
Test section of an individual monograph
may contain:
Ash
Total soluble
in HCl HPLC, GC
ash
Heavy Swelling
metals index
Bitterness
Pesticides value
Loss on Extractable
drying/
Water matter
Foreign
matter Quality TLC
13
Assay section of an individual
monograph
Specific assays are normally performed to determine

the content of:
 Constituents with known therapeutic activity or

 Active markers or
 Analytical markers
14
General methods
concerning herbal drug and herbal drug preparation
monographs
23 general methods are published in chapter 2.8 (Methods in
pharmacognosy), e.g.:
 Ash insoluble in hydrochloric acid (2.8.1)
 Pesticide residues (2.8.13)
 Test for aristolochic acids in herbal drugs (2.8.21)
 Determination of ochratoxin A in herbal drugs (2.8.22)
 HPTLC of herbal drugs and herbal drug preparations (2.8.25)
I n 2017 w ork w ill start for the elaboration of a new chapter:
 Pyrrolizidine alkaloids in herbal drugs (2.8.26)
Other general chapters published in other sections, e.g.:

 Microbiological examination of herbal medicinal products for oral use and
extracts used in their preparation (2.6.31)
15
Technical requirements for the elaboration
of Ph.Eur. texts on herbal drugs and herbal
drug preparations
[…] all tests and assay methods described in
a text must be validated according to the
procedures stated in the Technical guide
Freely available guides

from the EDQM website
… together with many
other, specific guides
16
Validation and type of analytical procedure:
Validation is an essential requirement in the elaboration of monographs,
including herbals
17
Purposes of the Technical Guides
 Represent guides for authors of pharmacopoeia texts
 May serve as guidelines in the elaboration of specifications
intended for inclusion in licensing applications
 Serve also to inform users of monographs about the
principles for the elaboration and their understanding of
monographs
 Also, internally they are good tools to have a harmonised
understanding and approach
 For all these reasons, it is important that the guides are
up-to-date and in line with current policy
18
Reference Standards
Reference standards are

an integral part of Ph.
Eur. monographs
Ph. Eur. Monographs on herbal drugs and preparations describe:

 CRS (chemical reference substance) or
 HRS (herbal reference standard)
For qualitative or quantitative use
19
TCM: why do we need specific
monographs in Europe?
• In Europe quality problems observed:
- Problems with correct identification of materials on the
European market
links: Clematidis armandii caulis (chuanmutong) mitte: Akebiae caulis (mutong), rechts:
Aristolochiae mandshuricae caulis (guanmutong)
• - Confusion between related species

• - Contamination with, e.g. heavy metals
• - Addition of synthetic compounds to Herbal Drugs to fake
pharmacological effects
20
TCM: why do we need specific
monographs in Europe?
• - Severe consequences due to name similarity: plants with
different pharmacological or toxicological properties; example:
Stephania tetandra (left) and Aristolochia fangji (right)
(Hanfang ji, Guangfang ji)
J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 21

Current topics/particular
challenges in the TCM field
 Availability of samples
 Processed via unprocessed forms
 Assay

Availability of Samples
•Required for the elaboration of a monograph:
Commercial samples (at least 5 to 8, should

reflect the quality on the market)
Reference Samples
• Authentic reference samples: used to confirm
that commercial samples are both genuine and of
an acceptable quality
• Reference samples of substitute/adulterant herbal

drugs for exclusion tests

Processed versus unprocessed forms
• Processing may reduce the toxicity and improve the stability
of TCM drugs. Enhancement of activity?
• No uniform processing methods:
 Differences in processing methods (regional differences within
China)
 No objective criteria (example fleeceflower root processed with
soya-bean juice) :
•“Processing : slices or pieces of the herbal drug Fleeceflower root (2433) are mixed with a
decoction prepared from Glycine max (L.) Merr. (soya-bean). The mixture is stewed or steamed
in a suitable non-ferrous container until the juice is absorbed. The slices or pieces are then
dried”
 No quality criteria for “excipients” (honey, vinegar…)

TCM-Assay
Current policy:
 Inclusion of an assay wherever possible
 Preferably selective chromatographic

methods, like HPLC or GC
 Choice of suitable markers:

• - active or analytical marker
• - constituent with known therapeutic activity

TCM-Assay
Current discussion:
 Is the choice of markers always
meaningful?
 Is the selective marker quantification
indicative of quality, stability or activity?
 Economic aspects: equipment, reference
standards?

26
TCM-Assay
Possible alternative:
• Semi-quantitative HPTLC:
- allows for determination of one or more markers
- provides characteristic fingerprint, already used for
identification
- may use reagents instead of reference standards
Ph. Eur. Commission decided to start a pilot phase:
Corydalis rhizome (Yanhusuo)
Leonuri herba (Yimucao)
Fritillaria thunbergii bulbus (Beimu)

Pyrrolizidine alkaloids (PA)
In May 2016 the HMPC requested the Ph Eur:

 to produce a method for quantitative analysis of pyrrolizidine
alkaloids in herbal drugs and herbal drug preparations
This request, which was considered as urgent, had been made due to
findings of contamination with PA-containing plants in several herbal
medicinal products and also foods in EU member states; this signaled a
more widespread problem of weed contamination of herbal drugs
According to investigations made by HMPC the problem cannot be solved
by simply focusing on good agriculture and collection practice

157th session of The European Pharmacopoeia
Commission (March 2017):
Approval of the Terms of Reference for the new

Pyrrolizidine alkaloids Working Party:
 Drafting of a general chapter allocated to the

group by the Commission in the field of
pyrrolizidine alkaloids
 Maintenance of the list of PA alkaloids which

may be covered by the general chapter on PA
alkaloids.

158th session of The European Pharmacopoeia
Commission (June 2017):
Approval of the proposed experts and the chair for the Pyrrolizidine
alkaloids Working Party:
 14 Experts from 8 different Member States

-----
1st meeting of the PA Working Party took place on the 5th of

September 2017

Thank you for your attention !
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Harmonisation of quality

standards by the European

 The European Pharmacopoeia

J. Sanz-Bisetl ©2017 EDQM, Council of Europe. All rights reserved.

Green: Ph. Eur. member states

6 general monographs, e.g.:

 Cassia oil (1496)

 Definition: state of the drug: broke, cut, fragmented

 General monographs and individual monographs

Specific assays are normally performed to determine

 Constituents with known therapeutic activity or

Other general chapters published in other sections, e.g.:

Freely available guides

Reference standards are

Ph. Eur. Monographs on herbal drugs and preparations describe:

• - Confusion between related species

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 21

 Processed via unprocessed forms

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 22

•Required for the elaboration of a monograph:

Commercial samples (at least 5 to 8, should

• Reference samples of substitute/adulterant herbal

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 23

 No quality criteria for “excipients” (honey, vinegar…)

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved.

 Inclusion of an assay wherever possible

 Preferably selective chromatographic

 Choice of suitable markers:

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 25

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved.

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 27

In May 2016 the HMPC requested the Ph Eur:

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 28

Approval of the Terms of Reference for the new

 Drafting of a general chapter allocated to the

 Maintenance of the list of PA alkaloids which

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 29

 14 Experts from 8 different Member States

1st meeting of the PA Working Party took place on the 5th of

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 30

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