Harmonisation of quality standards by the European

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.

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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).

J. Sanz-Biset ©2017 EDQM, Council of Europe. All rights reserved. 3

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

Members and Observers

Green: Ph. Eur. member states Yellow: Observers to the convention on the elaboration of a Ph. Eur.


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


Contents of the European Pharmacopoeia: More than 2500 monographs and about 350 general

methods


Herbal drug and herbal drug preparation monographs

General monographs Individual monographs General methods/chapters


Monographs

Herbal drugs and herbal drug preparations

in European Pharmacopeia 9th Edition 2017 (9.2)

6 general monographs, e.g.:

Herbal drugs (1433)

Essential oils (2098)

294 individual monographs, e.g.:

Aloes cape (0258)

Aloes dry extract standardised (0259)

Cassia oil (1496)

Matricaria liquid extract (1544)

Rosemary leaf (1560)

Valerian tincture (1899)

General notices

General chapters

General texts

General monographs

Individual monographs


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


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)


Identification section of an individual monograph:

Macroscopic botanical

characters

Microscopic

botanical characters

Thin-layer chromatography


Test section of an individual monograph may contain:

Quality Foreign matter

Loss on drying/ Water

Pesticides

Heavy metals

Total ash

Ash soluble in HCl HPLC, GC

Swelling index

Bitterness value

Extractable matter

TLC


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


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)

In 2017 work 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)

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

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


Validation and type of analytical procedure:

Validation is an essential requirement in the elaboration of monographs, including herbals


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


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


TCM: why do we need specific monographs in Europe?

• In Europe quality problems observed: - Problems with correct identification of materials on the

European market

• - Confusion between related species

• - Contamination with, e.g. heavy metals

• - Addition of synthetic compounds to Herbal Drugs to fake pharmacological effects

links: Clematidis armandii caulis (chuanmutong) mitte: Akebiae caulis (mutong), rechts: Aristolochiae mandshuricae caulis (guanmutong)

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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)


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?


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

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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