Traditional Chinese medicine -- Quality and safety of raw materials and finished products made with raw materials

This document specifies general requirements within a quality control framework for raw materials and finished products used in and as traditional Chinese medicine (TCM) and derivative forms, and the comparison between the starting materials and the finished products, if necessary.

Médecine traditionnelle chinoise -- Qualité et sécurité des matières premières et des produits finis fabriqués à partir de matières premières

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Publication Date
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INTERNATIONAL ISO
STANDARD 19609-1
First edition
2021-01
Traditional Chinese medicine —
Quality and safety of raw materials
and finished products made with raw
materials —
Part 1:
General requirements
Médecine traditionnelle chinoise — Qualité et sécurité des matières
premières et des produits finis fabriqués à partir de matières
premières —
Partie 1: Exigences générales
Reference number
ISO 19609-1:2021(E)
ISO 2021
---------------------- Page: 1 ----------------------
ISO 19609-1:2021(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2021

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting

on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address

below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 19609-1:2021(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Overview of herbal medicinal products ....................................................................................................................................... 3

4.1 Raw materials .......................................................................................................................................................................................... 3

4.2 Products of raw materials ............................................................................................................................................................. 3

4.2.1 General...................................................................................................................................................................................... 3

4.2.2 Decoction pieces, medicinal decoctions prepared from decoction pieces

and wine preparations or powders ................................................................................................................. 4

4.2.3 Finished products for modernized traditional therapy ................................................................. 4

4.2.4 Non-traditionally produced finished products for phytotherapy.......................................... 5

5 Quality testing ......................................................................................................................................................................................................... 5

5.1 General ........................................................................................................................................................................................................... 5

5.2 Testing procedure ................................................................................................................................................................................. 6

6 Testing of physical parameters .............................................................................................................................................................. 6

6.1 General ........................................................................................................................................................................................................... 6

6.2 Sampling ....................................................................................................................................................................................................... 7

6.2.1 General...................................................................................................................................................................................... 7

6.2.2 Bulk sampling method ................................................................................................................................................ 7

6.2.3 Test sampling method ................................................................................................................................................. 7

6.3 Estimation of the water content of herbals and resulting products ......................................................... 8

6.3.1 General...................................................................................................................................................................................... 8

6.3.2 Testing methods ............................................................................................................................................................... 8

6.4 Requirements and testing methods for finished products for modernized

traditional therapy and non-traditionally produced finished products for phytotherapy .11

6.4.1 General...................................................................................................................................................................................11

6.4.2 Estimation of the uniformity of dosage units .......................................................................................11

6.4.3 Disintegration test for solid dosage forms like tablets and capsules ..............................12

6.4.4 Estimation of particle size for powders and other small dosage forms ........................14

6.4.5 Estimation of the pH-value of liquids, solutions or suspensions by

potentiometric determination ..........................................................................................................................15

6.4.6 Dissolution test for solid dosage forms .....................................................................................................15

6.5 Estimation of the content of residual solvents .........................................................................................................17

6.5.1 General...................................................................................................................................................................................17

6.5.2 Types of typically used solvents ......................................................................................................................17

6.5.3 Reagents ...............................................................................................................................................................................19

6.5.4 Sample preparation ....................................................................................................................................................19

6.5.5 Apparatus ............................................................................................................................................................................19

6.5.6 Procedure ............................................................................................................................................................................19

6.5.7 System suitability .........................................................................................................................................................21

6.5.8 Calculation ..........................................................................................................................................................................21

6.6 Stability of TCM products ...........................................................................................................................................................21

6.6.1 General...................................................................................................................................................................................21

6.6.2 Estimation of the stability of TCM products .........................................................................................21

Bibliography .............................................................................................................................................................................................................................22

© ISO 2021 – All rights reserved iii
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ISO 19609-1:2021(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso .org/ patents).

Any trade name used in this document is information given for the convenience of users and does not

constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to

the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see

www .iso .org/ iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 249, Traditional Chinese medicine.

A list of all parts in the ISO 19609 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www .iso .org/ members .html.
iv © ISO 2021 – All rights reserved
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ISO 19609-1:2021(E)
Introduction

The ISO 19609 series consists of four parts with different content as shown in Figure 1.

Figure 1 — Overview of the ISO 19609 series
© ISO 2021 – All rights reserved v
---------------------- Page: 5 ----------------------
INTERNATIONAL STANDARD ISO 19609-1:2021(E)
Traditional Chinese medicine — Quality and safety of
raw materials and finished products made with raw
materials —
Part 1:
General requirements
1 Scope

This document specifies general requirements within a quality control framework for raw materials

and finished products used in and as traditional Chinese medicine (TCM) and derivative forms, and the

comparison between the starting materials and the finished products, if necessary.

2 Normative references

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 760, Determination of water — Karl Fischer method (General method)

ISO 3310-1, Test sieves — Technical requirements and testing — Part 1: Test sieves of metal wire cloth

ISO 10523, Water quality — Determination of pH

ISO 12937, Petroleum products — Determination of water — Coulometric Karl Fischer titration method

ISO 19609-2, Traditional Chinese medicine — Quality and safety of raw materials and finished products

made with raw materials — Part 2: Identity testing of constituents of herbal origin

ISO 22217, Traditional Chinese medicine — Storage requirements for Chinese materia medica and

decoction pieces
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
active substance
substance of physiological or pharmacological action
3.2
finished product for modernized traditional therapy

concentrated product from hot aqueous decoctions of decoction pieces (3.3) or other starting materials

(3.11) as well as powder made from starting materials described in pharmacopoeias, applied in the

dosage forms of capsules, granules or tablets
© ISO 2021 – All rights reserved 1
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ISO 19609-1:2021(E)
3.3
decoction piece

prescription medicinal processed from Chinese Materia Medica under the direction of TCM and

processing methods for Chinese medicines and derivative forms, which can be directly used in clinical

practice or the production of prepared medicines

[SOURCE: ISO 18668-1:2016, 3.3, modified — Note 1 to entry amalgamated with definition.]

3.4
disintegration

physical breakdown of a material into very small fragments in a pharmaceutical context except

insoluble coating materials or broken capsule shell
[SOURCE: ISO 17088:2012, 3.6, definition modified.]
3.5
dissolution

process of obtaining a solution containing the analyte of interest in a pharmaceutical context

[SOURCE: ISO/TR 19057:2017, 3.6, definition modified.]
3.6
finished product
commercial product intended for sale and use, including decoction pieces (3.3)
3.7
foreign matter

material consisting of any or all foreign tissues (matter coming from the source plant but not defined

as the right herbal material) and foreign elements (other matter of vegetable, animal or mineral origin)

3.8
non-traditionally produced finished product for phytotherapy

product made from TCM raw materials (3.9) which are not decoction pieces (3.3) or finished products for

modernized traditional therapy (3.2)
EXAMPLE Organic extracts and products made from these extracts.
3.9
raw material
substance going into or involved in the manufacturing of a bulk product
[SOURCE: ISO 22716:2007, 2.28]
3.10
residual solvent

organic volatile chemical used or produced in the manufacturing of extracts or excipients or in the

preparation of medicinal products, and not completely removed by practical manufacturing techniques

3.11
starting material

material received by a manufacturer to be commercially processed, manufactured or packaged

Note 1 to entry: This includes raw materials (3.9) and other materials, for example solvents, excipients and

capsule shells.
2 © ISO 2021 – All rights reserved
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ISO 19609-1:2021(E)
4 Overview of herbal medicinal products
4.1 Raw materials
Raw materials of TCM are:

a) herbal material (e.g. flowers, herbs, seeds, fruits, roots and other parts of medicinal plants, fresh

juices, gums, natural essential oils, resins);
b) parts of animals (e.g. mussels, bombyx);
c) minerals.
NOTE Herbal and animal material can be subject to CITES rules.
4.2 Products of raw materials
4.2.1 General

Products of raw materials are divided into three groups depending on the form of therapy:

a) decoction pieces, medicinal decoction prepared from decoction pieces and wine preparations or

powders for traditional therapy;

b) finished products for modernized traditional therapy (e.g. capsules, coated and uncoated tablets,

powders and granules);

c) non-traditionally produced finished products for phytotherapy (e.g. regulated formulas as

remedies, made from extracts with other solvents instead of water).

Figure 2 shows the different types of products applied in the field of TCM. The categorization is

necessary based on the different requirements of pharmaceutical products.
© ISO 2021 – All rights reserved 3
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ISO 19609-1:2021(E)
Figure 2 — Classification of products of raw materials

4.2.2 Decoction pieces, medicinal decoctions prepared from decoction pieces and wine

preparations or powders

The typical raw materials used in and as TCM are decoction pieces in the form of cut raw materials.

These are intended to produce a preparation using hot or boiling water.

NOTE 1 In the classical TCM therapy, herbal and animal material as well as minerals were cut into smaller

pieces and used during or after a processing step (e.g. steaming, cooking, calcinating) as a source for the

individual mixture after a practitioner's or doctor's prescription.
NOTE 2 A special cutting is used for KAMPO herbals in Japan.
[10] [11]

NOTE 3 In some cases, wine can be used as a solvent instead of water according to the Chinese , Japanese

[9]
and Korean pharmacopoeias.
4.2.3 Finished products for modernized traditional therapy
Finished products for modernized traditional therapy are:
a) concentrates from hot aqueous preparations;

NOTE 1 Only hot water decoctions can be seen as typically traditional, without toxicity risks.

NOTE 2 Traditionally produced wine preparation can also be used.
[10] [11] [9]

b) powders made from raw materials which are described in the Chinese , Japanese and Korean

pharmacopoeias;

NOTE 3 In the case of powdered materials, there are risks for the patients because of the potential toxicity

of the raw materials.
4 © ISO 2021 – All rights reserved
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ISO 19609-1:2021(E)

c) capsules, coated and uncoated tablets, powders and granules as dosage forms based on a) or b).

NOTE 4 The toxic risks cannot be extrapolated from traditional use of the decoctions. A lot of lipophilic

compounds can be seen as toxic (e.g. aristolochic acid, which was not a problem in decoctions in TCM). The

toxic risks of lipophilic compounds do not appear in water decoctions, but in powders, alcoholic extracts and

lipophilic concentrates.
4.2.4 Non-traditionally produced finished products for phytotherapy

Non-traditionally produced finished products for phytotherapy are raw materials and products not

listed in 4.2.2 and 4.2.3.

The pharmacology and toxicology of these products shall be tested by the producer before marketing.

NOTE 1 TCM products can be seen in parallel to the “European Phytomedicine”.

NOTE 2 KAMPO products extracted with up to 30 % ethanol do not need to be declared in Japan.

NOTE 3 For the markets in Europe and associated countries a registration is required for each product

independent of specific dosage forms.

NOTE 4 Products made with supercritical carbon dioxide are not allowed in countries which apply the

[14]
European Pharmacopoeia .
5 Quality testing
5.1 General

The quality of therapeutics is internationally defined with three general criteria: potency, safety and

accuracy. These criteria are also relevant for TCM therapeutics (see Figure 3).
Figure 3 — General criteria for TCM therapeutics

Quality criteria of raw materials and products of raw materials are defined in the ISO 19609 series as

follows:
— correct physical parameters;
— correct identity of herbal ingredients;
© ISO 2021 – All rights reserved 5
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ISO 19609-1:2021(E)
— absence of contaminants;
— absence of preservatives and unwanted compounds.
5.2 Testing procedure

Products of raw materials shall be tested for physical parameters, if applicable, in accordance with

Clause 6.

Products of raw materials shall be tested for the identity of the herbal ingredients in accordance with

ISO 19609-2.
Products of raw materials shall be tested for the absence of contaminants.

Products of raw materials shall be tested for the absence of preservatives and unwanted compounds

for individual materials.
6 Testing of physical parameters
6.1 General
The physical tests detailed in Figure 4 should be used, if applicable.
Figure 4 — Physical parameters for TCM products (if applicable)
6 © ISO 2021 – All rights reserved
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ISO 19609-1:2021(E)

The requirements and methods are typically unique for a specific dosage form and listed also in the

different pharmacopoeias.
6.2 Sampling
6.2.1 General

In order to reduce the effect of inhomogeneity of the sample in qualitative and quantitative analysis, the

composition of the sample used shall be representative of the batch of material being examined.

6.2.2 Bulk sampling method

The bulk sample shall be collected by combining and thoroughly mixing the part samples taken from

containers, bales and bags.

One part sample from each container shall be sampled. Samples shall be taken from the upper, middle

and lower section of the container and shall be combined so that the samples are representative of

different parts of the containers.

In the case of large bales or bags, samples shall be taken from a depth of at least 10 cm.

6.2.3 Test sampling method
6.2.3.1 General

The reduction of the size of the bulk sample shall be done by the method of quartering.

Other appropriate methods that produce a homogeneous sample may be used, making sure that each

retained portion remains representative of the whole.

The minimum retained quantity of the test samples shall conform to the conditions in Table 1.

Table 1 — Minimum weight of test samples
Type of herbal material Minimum weight of test sample

Roots, rhizomes, bark, herbs 250 g or mass of whole sample if bulk sample is less

than 250 g

Leaves, flowers, seeds, fruits 125 g or mass of whole sample if bulk sample is less

than 125 g
Broken or fragmented crude materials (where the 75 g
average mass of the pieces is less than 0,5 g)
After reduction of sample size a test for foreign matter shall be done.

For the preparation of the test samples for chemical and chromatographic analysis, as well as for

determination of microscopic characteristics, a milling and sieving process is necessary.

6.2.3.2 Apparatus
Use the usual laboratory equipment and, in particular, the following.
6.2.3.2.1 Analytical balance, weighing to an accuracy of 1 mg.
6.2.3.2.2 Milling apparatus.
6.2.3.2.3 Sieves, with 1 mm and 0,355 mm screen in accordance with ISO 3310-1.
© ISO 2021 – All rights reserved 7
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ISO 19609-1:2021(E)
6.2.3.3 Procedure for producing specific test samples
6.2.3.3.1 Quartering

The bulk sample shall be placed after thoroughly mixing as a level and square-shaped heap. The

material shall be divided diagonally into four equal parts. Two opposite quarters shall be retained and

carefully remixed. The process shall be repeated as necessary until the required minimum mass (see

Table 1) is obtained for the test sample.
6.2.3.3.2 Test for foreign matter

Herbal materials should be free of mould, insects and other animal contaminants. Accepted levels of

foreign matter are documented in the relevant monographs.

Materials identified visually as foreign matter shall be separated manually and weighed with an

analytical balance.

The content of foreign matter shall be calculated as a percentage of the whole test sample. The result

shall be documented.
6.2.3.3.3 Preparing test samples for chemical and chromatographic analysis

The test sample shall be milled and sieved through a 1 mm screen or the screen size specified in a

specific monograph. The use of a milling machine is recommended.

The residue retained on the sieve shall not be more than 10 % of the total mass of the milled sample.

In those cases where this requirement cannot be met because of physical specifities of the raw material,

the test sample for analysis shall be composed of the two parts measured separately. Therefore, the

quantity required for each analysis shall be derived by weighing proportional quantities of the powder

and the residue.
6.2.3.3.4 Preparing test samples for determination of microscopic characters

A portion of the milled test sample (see 6.2.3.3.3) shall be re-milled and sieved through a 0,355 mm

screen or a finer screen.

NOTE The details of microscopic characterization are also described in ISO 19609-2 and ISO/TS 21310.

6.3 Estimation of the water content of herbals and resulting products
6.3.1 General

The water content should be not higher than 10 %, because this reduces the stability of dried raw

materials and resulting products made from herbal materials. Different water contents are specified in

the individual monographs.

NOTE On one hand chemical reactions need, in a high number of reaction types, water as solvent or as

reagent. On the other hand, higher amounts of residual water in raw materials as well as in ready products are,

together with organic substances and temperature, the best growing conditions for microorganisms and their

degradation of substrate.
6.3.2 Testing methods
6.3.2.1 General

For the estimation of the water content one of the following methods shall be used:

— loss on drying (see 6.3.2.2);
8 © ISO 2021 – All rights reserved
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ISO 19609-1:2021(E)
— quantitative analysis of water content (see 6.3.2.3).
6.3.2.2 Loss on drying
6.3.2.2.1 General

The estimation of the loss on drying is a method to estimate the total content of water and other volatile

constituents, for example essential oils. In accordance with the expected content of these volatile

constituents, one the following methods shall be used:

— method for raw materials and products with no or low content of essential oils;

— method for raw materials and products with higher content of essential oils;
— method for raw materials and products with unstable constituents.
6.3.2.2.2 Sample preparation

In a flat-bottomed weighing bottle about 50 mm in diameter and 30 mm in height quickly weigh about

0,50 g of the material or product to be examined in powdered form.
6.3.2.2.3 Reagents
6.3.2.2.3.1 Diphosphorus pentoxide.
6.3.2.2.3.2 Anhydrous silica gel.
6.3.2.2.4 Apparatus
Use the usual laboratory equipment and, in particular, the following.
6.3.2.2.4.1 Analytical balance, weighing to an accuracy of 0,1 mg.
6.3.2.2.4.2 Desiccator.
6.3.2.2.4.3 Laboratory oven (100 °C to 105 °C), if applicable.
6.3.2.2.4.4 Vacuum unit (1,5 kPa to 2,5 kPa), if applicable.

6.3.2.2.5 Method for raw materials and products with no or low content of essential oils

Drying shall be done in an oven at 100 °C to 105 °C for 3 h. After cooling in a desiccator over diphosphorus

pentoxide or anhydrous silica gel, the material shall be weighed. The calculation of the result shall be

expressed as a mass percentage.

6.3.2.2.6 Method for raw materials and products with higher content of essential oils

Drying of the material shall be done to constant mass in a desiccator. The drying shall be carried out

over diphosphorus pentoxide at atmospheric pressure and at room temperature. After weighing, the

result shall be calculated and expressed as a mass percentage.
6.3.2.2.7 Method for raw materials and products with unstable constituents

Drying of the material shall be done to constant mass in vacuo in a desiccator. The drying is carried out

over diphosphorus pentoxide at a pressure of 1,5 kPa to 2,5 kPa at room temperature. After weighing,

the result shall be calculated as a mass percentage.
© ISO 2021 – All rights reserved 9
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ISO 19609-1:2021(E)
6.3.2.3 Quantitative analysis of water content
6.3.2.3.1 General

The estimation of the quantitative analysis of water content is a method to estimate the total content of

water. One of the following methods shall be used:
— titration according to Karl Fischer in accordance with ISO 760;
— coulometric determination of water in accordance with ISO 12937;
— determination of water with distillation;

— determination of water with gas chromatography with thermal conductivity detector (TCD)

(see 6.3.2.3.2).

6.3.2.3.2 Determination of water with gas chromatography with thermal conductivity

detector (TCD)
6.3.2.3.2.1 Sample preparation

50 mg of powdered test sample shall be correctly weighed. The resulting powder shall be dissolved in

200 µl of dried dimethyl sulfoxide (DMSO) in a disposable special dried vial.
6.3.2.3.2.2 Reagents
Dried DMSO.
6.3.2.3.2.3 Apparatus
Use the usual
...

FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 19609-1
ISO/TC 249
Traditional Chinese medicine —
Secretariat: SAC
Quality and safety of raw materials
Voting begins on:
2020-10-01 and manufacturing products made
with raw materials —
Voting terminates on:
2020-11-26
Part 1:
General requirements
Partie 1: Généralités
RECIPIENTS OF THIS DRAFT ARE INVITED TO
SUBMIT, WITH THEIR COMMENTS, NOTIFICATION
OF ANY RELEVANT PATENT RIGHTS OF WHICH
THEY ARE AWARE AND TO PROVIDE SUPPOR TING
DOCUMENTATION.
IN ADDITION TO THEIR EVALUATION AS
Reference number
BEING ACCEPTABLE FOR INDUSTRIAL, TECHNO-
ISO/FDIS 19609-1:2020(E)
LOGICAL, COMMERCIAL AND USER PURPOSES,
DRAFT INTERNATIONAL STANDARDS MAY ON
OCCASION HAVE TO BE CONSIDERED IN THE
LIGHT OF THEIR POTENTIAL TO BECOME STAN-
DARDS TO WHICH REFERENCE MAY BE MADE IN
NATIONAL REGULATIONS. ISO 2020
---------------------- Page: 1 ----------------------
ISO/FDIS 19609-1:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting

on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address

below or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/FDIS 19609-1:2020(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Overview of herbal medicinal products ....................................................................................................................................... 3

4.1 Raw materials .......................................................................................................................................................................................... 3

4.2 Products of raw materials ............................................................................................................................................................. 3

4.2.1 General...................................................................................................................................................................................... 3

4.2.2 Decoction pieces, medicinal decoctions prepared from decoction pieces

and wine preparations or powders ................................................................................................................. 4

4.2.3 Finished products for modernized traditional therapy ................................................................. 4

4.2.4 Non-traditionally produced finished products for phytotherapy.......................................... 5

5 Quality testing ......................................................................................................................................................................................................... 5

5.1 General ........................................................................................................................................................................................................... 5

5.2 Testing procedure ................................................................................................................................................................................. 6

6 Testing of physical parameters .............................................................................................................................................................. 6

6.1 General ........................................................................................................................................................................................................... 6

6.2 Sampling ....................................................................................................................................................................................................... 7

6.2.1 General...................................................................................................................................................................................... 7

6.2.2 Bulk sampling method ................................................................................................................................................ 7

6.2.3 Test sampling method ................................................................................................................................................. 7

6.3 Estimation of the water content of herbals and resulting products ......................................................... 8

6.3.1 General...................................................................................................................................................................................... 8

6.3.2 Testing methods ............................................................................................................................................................... 8

6.4 Requirements and testing methods for finished products for modernized

traditional therapy and non-traditionally produced finished products for phytotherapy .11

6.4.1 General...................................................................................................................................................................................11

6.4.2 Estimation of the uniformity of dosage units .......................................................................................11

6.4.3 Disintegration test for solid dosage forms like tablets and capsules ..............................12

6.4.4 Estimation of particle size for powders and other small dosage forms ........................14

6.4.5 Estimation of the pH-value of liquids, solutions or suspensions by

potentiometric determination ..........................................................................................................................15

6.4.6 Dissolution test for solid dosage forms .....................................................................................................15

6.5 Additional requirements for non-traditionally produced finished products for

phytotherapy .........................................................................................................................................................................................17

6.5.1 Estimation of the content of residual solvents ....................................................................................17

6.6 Stability of TCM products ...........................................................................................................................................................22

6.6.1 General...................................................................................................................................................................................22

6.6.2 Estimation of the stability of TCM products .........................................................................................22

Bibliography .............................................................................................................................................................................................................................23

© ISO 2020 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/FDIS 19609-1:2020(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso .org/ patents).

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www .iso .org/ iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 249, Traditional Chinese medicine.

A list of all parts in the ISO 19609 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www .iso .org/ members .html.
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ISO/FDIS 19609-1:2020(E)
Introduction

The ISO 19609 series consists of four parts with different content as shown in Figure 1.

Figure 1 — Overview of the ISO 19609 series
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FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 19609-1:2020(E)
Traditional Chinese medicine — Quality and safety of raw
materials and manufacturing products made with raw
materials —
Part 1:
General requirements
1 Scope

This document specifies general requirements within a quality control framework for raw materials

and finished products used in and as traditional Chinese medicine (TCM) and derivative forms, and the

comparison between the starting materials and the finished products, if necessary.

2 Normative references

The following documents are referred to in the text in such a way that some or all of their content

constitutes requirements of this document. For dated references, only the edition cited applies. For

undated references, the latest edition of the referenced document (including any amendments) applies.

ISO 760, Determination of water — Karl Fischer method (General method)

ISO 3310-1, Test sieves — Technical requirements and testing — Part 1: Test sieves of metal wire cloth

ISO 10523, Water quality — Determination of pH

ISO 12937, Petroleum products — Determination of water — Coulometric Karl Fischer titration method

ISO 19609-2, Traditional Chinese medicine — Quality and safety of raw materials and manufacturing

products made with raw materials — Part 2: Identity testing of constituents of herbal origin

ISO 22217, Traditional Chinese medicine — Storage requirements for Chinese materia medica and

decoction pieces
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
active substance
substance of physiological or pharmacological action
3.2
finished product for modernized traditional therapy

concentrated product from hot aqueous decoctions of decoction pieces (3.3) or other starting materials

(3.11) as well as powder made from starting materials described in pharmacopoeias, applied in the

dosage forms of capsules, granules or tablets
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3.3
decoction piece

prescription medicinal processed from Chinese Materia Medica under the direction of TCM and

processing methods for Chinese medicines and derivative forms, which can be directly used in clinical

practice or the production of prepared medicines

[SOURCE: ISO 18668-1:2016, 3.3, modified — Note 1 to entry amalgamated with definition.]

3.4
disintegration

physical breakdown of a material into very small fragments in a pharmaceutical context except

insoluble coating materials or broken capsule shell
[SOURCE: ISO 17088:2012, 3.6, definition modified.]
3.5
dissolution

process of obtaining a solution containing the analyte of interest in a pharmaceutical context

[SOURCE: ISO/TR 19057:2017, 3.6, definition modified.]
3.6
finished product
commercial product intended for sale and use, including decoction pieces (3.3)
3.7
foreign matter

material consisting of any or all foreign organs (matter coming from the source plant but not defined

as the right herbal material) and foreign elements (other matter of vegetable, animal or mineral origin)

3.8
non-traditionally produced finished product for phytotherapy

product made from TCM raw materials (3.9) which are not decoction pieces (3.3) or finished products for

modernized traditional therapy (3.2)
EXAMPLE Organic extracts and products made from these extracts.
3.9
raw material
substance going into or involved in the manufacturing of a bulk product
[SOURCE: ISO 22716:2007, 2.28]
3.10
residual solvent

organic volatile chemical used or produced in the manufacturing of extracts or excipients or in the

preparation of medicinal products, and not completely removed by practical manufacturing techniques

3.11
starting material

material received by a manufacturer to be commercially processed, manufactured or packaged

Note 1 to entry: This includes raw materials (3.9) and other materials, for example solvents, excipients and

capsule shells.
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4 Overview of herbal medicinal products
4.1 Raw materials
Raw materials of TCM are:

a) herbal material (e.g. flowers, herbs, seeds, fruits, roots and other parts of medicinal plants, fresh

juices, gums, natural essential oils, resins);
b) parts of animals (e.g. mussels, bombyx);
c) minerals.
NOTE Herbal and animal material can be subject to CITES rules.
4.2 Products of raw materials
4.2.1 General

Products of raw materials are divided into three groups depending on the form of therapy:

a) decoction pieces, medical decoction prepared from decoction pieces and wine preparations or

powders for traditional therapy;

b) finished products for modernized traditional therapy (e.g. capsules, coated and uncoated tablets,

powders and granules);

c) non-traditionally produced finished products for phytotherapy (e.g. regulated formulas as

remedies, made from extracts with other solvents instead of water).

Figure 2 shows the different types of products applied in the field of TCM. The categorization is

necessary based on the different requirements of pharmaceutical products.
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ISO/FDIS 19609-1:2020(E)
Figure 2 — Classification of products of raw materials

4.2.2 Decoction pieces, medicinal decoctions prepared from decoction pieces and wine

preparations or powders

The typical raw materials used in and as TCM are decoction pieces in the form of cut raw materials.

These are intended to produce a preparation using hot or boiling water.

NOTE 1 In the classical TCM therapy, herbal and animal material as well as minerals were cut into smaller

pieces and used during or after a processing step (e.g. steaming, cooking, calcinating, paozhi) as a source for the

individual mixture after a practitioner's and doctor's prescription.
NOTE 2 A special cutting is used for KAMPO herbals in Japan.
[10] [11]

NOTE 3 In some cases, wine can be used as a solvent instead of water according to the Chinese , Japanese

[9]
and Korean pharmacopoeias.
4.2.3 Finished products for modernized traditional therapy
Finished products for modernized traditional therapy are:
a) concentrates from hot aqueous preparations;

NOTE 1 Only hot water decoctions can be seen as typically traditional, without toxicity risks.

NOTE 2 Traditionally produced wine preparation can also be used.
[10] [11] [9]

b) powders made from raw materials which are described in the Chinese , Japanese and Korean

pharmacopoeias;

NOTE 3 In the case of powdered materials, there are risks for the patients because of the potential toxicity

of the raw materials.
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ISO/FDIS 19609-1:2020(E)

c) capsules, coated and uncoated tablets, powders and granules as dosage forms based on a) or b).

NOTE 4 The toxic risks cannot be extrapolated from traditional use of the decoctions. A lot of lipophilic

compounds can be seen as toxic (e.g. aristolochic acid, which was not a problem in decoctions in TCM). The

toxical risks of lipophilic compounds do not appear in water decoctions, but in powders, alcoholic extracts

and lipophilic concentrates.
4.2.4 Non-traditionally produced finished products for phytotherapy

Non-traditionally produced finished products for phytotherapy are raw materials and products not

listed in 4.2.2 and 4.2.3.

The pharmacology and toxicology of these products shall be tested by the producer before marketing.

NOTE 1 TCM products can be seen in parallel to the “European Phytomedicine”.

NOTE 2 KAMPO products extracted with up to 30 % ethanol do not need to be declared in Japan.

NOTE 3 For the markets in Europe and associated countries a registration is required for each product

independent of specific dosage forms.

NOTE 4 Products made with supercritical carbon dioxide are not allowed in countries which apply the

[14]
European Pharmacopoeia .
5 Quality testing
5.1 General

The quality of therapeutics is internationally defined with three general criteria: potency, safety and

accuracy. These criteria are also relevant for TCM therapeutics (see Figure 3).
Figure 3 — General criteria for TCM therapeutics

Quality criteria of raw materials and products of raw materials are defined in the ISO 19609 series as

follows:
— correct physical parameters;
— correct identity of herbal ingredients;
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ISO/FDIS 19609-1:2020(E)
— absence of contaminants;
— absence of preservatives and unwanted compounds.
5.2 Testing procedure

Products of raw materials shall be tested for physical parameters, if applicable, in accordance with

Clause 6.

Products of raw materials shall be tested on the identity of the herbal ingredients in accordance with

ISO 19609-2.
Products of raw materials shall be tested on the absence of contaminants.

Products of raw materials shall be tested on the absence of preservatives and unwanted compounds for

individual materials.
6 Testing of physical parameters
6.1 General
The physical tests detailed in Figure 4 should be used, if applicable.
Figure 4 — Physical parameters for TCM products (if applicable)
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The requirements and methods are typically unique for a specific dosage form and listed also in the

different pharmacopoeias.
6.2 Sampling
6.2.1 General

In order to reduce the effect of inhomogeneity of the sample in qualitative and quantitative analysis, the

composition of the sample used shall be representative of the batch of material being examined.

6.2.2 Bulk sampling method

The bulk sample shall be collected by combining and thoroughly mixing the part samples taken from

containers, bales and bags.

One part sample from each container shall be sampled. Samples shall be taken from the upper, middle or

lower section of the container and shall be combined so that the samples are representative of different

parts of the containers.

In the case of large bales or bags, samples shall be taken from a depth of at least 10 cm.

6.2.3 Test sampling method
6.2.3.1 General

The reduction of the size of the bulk sample shall be done by the method of quartering.

Other appropriate methods that produce a homogeneous sample may be used, making sure that each

retained portion remains representative of the whole.

The minimum retained quantity of the test samples shall conform with the conditions in Table 1.

Table 1 — Minimum weight of test samples
Type of herbal material Minimum weight of test sample

Roots, rhizomes, bark, herbs 250 g or mass of whole sample if bulk sample is less

than 250 g

Leaves, flowers, seeds, fruits 125 g or mass of whole sample if bulk sample is less

than 125 g
Broken or fragmented crude materials (where the 75 g
average mass of the pieces is less than 0,5 g)
After reduction of sample size a test for foreign matter shall be done.

For the preparation of the test samples for chemical and chromatographic analysis, as well as for

determination of microscopic characters, a milling and sieving process is necessary.

6.2.3.2 Apparatus
Use the usual laboratory equipment and, in particular, the following.
6.2.3.2.1 Analytical balance, weighing to an accuracy of 1 mg.
6.2.3.2.2 Milling apparatus.
6.2.3.2.3 Sieves, with 1 mm and 0,355 mm screen in accordance with ISO 3310-1.
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6.2.3.3 Procedure for producing specific test samples
6.2.3.3.1 Quartering

The bulk sample shall be placed after thoroughly mixing as a level and square-shaped heap. The

material shall be divided diagonally into four equal parts. Two opposite quarters shall be retained and

carefully remixed. The process shall be repeated as necessary until the required minimum mass (see

Table 1) is obtained for the test sample.
6.2.3.3.2 Test for foreign matter

Herbal materials should be free from moulds, insects and other animal contaminants. Accepted levels

of foreign matter are documented in the relevant monographs.

Materials identified visually as foreign matter shall be separated manually and weighed with an

analytical balance.

The content of foreign matter shall be calculated as a percentage of the whole test sample. The result

shall be documented.
6.2.3.3.3 Preparing test samples for chemical and chromatographic analysis

The test sample shall be milled and sieved through a 1 mm screen or the screen size specified in a

specific monograph. The use of a milling machine is recommended.

The residue retained on the sieve shall not be more than 10 % of the total mass of the milled sample.

In those cases where this requirement cannot be met because of physical specifities of the raw material,

the test sample for analysis shall be composed of the two parts measured separately. Therefore, the

quantity required for each analysis shall be derived by weighing proportional quantities of the powder

and the residue.
6.2.3.3.4 Preparing test samples for determination of microscopic characters

A portion of the milled test sample (see 6.2.3.3.3) shall be re-milled and sieved through a 0,355 mm

screen or a finer screen.

NOTE The details of microscopic characterization are also described in ISO 19609-2 and ISO/TS 21310.

6.3 Estimation of the water content of herbals and resulting products
6.3.1 General

The water content should be not higher than 10 %, because this reduces the stability of dried raw

materials and resulting products made from herbal materials. Different water contents are specified in

the individual monographs.

NOTE On one hand chemical reactions need, in a high number of reaction types, water as solvent or as

reagent. On the other hand, higher amounts of residual water in raw materials as well as in ready products are,

together with organic substances and temperature, the best growing conditions for microorganisms and their

degradation of substrate.
6.3.2 Testing methods
6.3.2.1 General

For the estimation of the water content one of the following methods shall be used:

— loss on drying (see 6.3.2.2);
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ISO/FDIS 19609-1:2020(E)
— quantitative analysis of water content (see 6.3.2.3).
6.3.2.2 Loss on drying
6.3.2.2.1 General

The estimation of the loss on drying is a method to estimate the total content of water and other volatile

constituents, for example essential oils. In accordance with the expected content of these volatile

constituents, one the following methods shall be used:

— method for raw materials and products with no or low content of essential oils;

— method for raw materials and products with higher content of essential oils;
— method for raw materials and products with unstable constituents.
6.3.2.2.2 Sample preparation

In a flat-bottomed weighing bottle about 50 mm in diameter and about 30 mm in height the material or

product to be examined shall be weighed rapidly at about 0,50 g in powdered form.

6.3.2.2.3 Reagents
6.3.2.2.3.1 Diphosphorus pentoxide.
6.3.2.2.3.2 Anhydrous silica gel.
6.3.2.2.4 Apparatus
Use the usual laboratory equipment and, in particular, the following.
6.3.2.2.4.1 Analytical balance, weighing to an accuracy of 0,1 mg.
6.3.2.2.4.2 Desiccator.
6.3.2.2.4.3 Laboratory oven (100 °C to 105 °C), if applicable.
6.3.2.2.4.4 Vacuum unit (1,5 kPa to 2,5 kPa), if applicable.

6.3.2.2.5 Method for raw materials and products with no or low content of essential oils

Drying shall be done in an oven at 100 °C to 105 °C for 3 h. After cooling in a desiccator over diphosphorus

pentoxide or anhydrous silica gel, the material shall be weighted. The calculation of the result shall be

expressed as a mass percentage.

6.3.2.2.6 Method for raw materials and products with higher content of essential oils

Drying of the material shall be done to constant mass in a desiccator. The drying shall be carried out

over diphosphorus pentoxide at atmospheric pressure and at room temperature. After weighing, the

result shall be calculated and expressed as a mass percentage.
6.3.2.2.7 Method for raw materials and products with unstable constituents

Drying of the material shall be done to constant mass in vacuo in a desiccator. The drying is carried out

over diphosphorus pentoxide at a pressure of 1,5 kPa to 2,5 kPa at room temperature. After weighing,

the result shall be calculated as a mass percentage.
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6.3.2.3 Quantitative analysis of water content
6.3.2.3.1 General

The estimation of the quantitative analysis of water content is a method to estimate the total content of

water. One of the following methods shall be used:
— titration according to Karl Fischer in accordance with ISO 760;
— coulometric determination of water in accordance with ISO 12937;
— determination of water with distillation;

— determination of water with gas chromatography with thermal conductivity detector (TCD)

(see 6.3.2.3.2).

6.3.2.3.2 Determination of water with gas chromatography with thermal conductivity

detector (TCD)
6.3.2.3.2.1 Sample preparation

50 mg of powdered test sample shall be correctly weighted. The resulting powder shall be dissolved

within 200 µl of dried dimethyl sulfoxide (DMSO) in a disposable special dried vial.

6.3.2.3.2.2 Reagents
Dried DMSO.
6.3.2.3.2.3 Apparatus
Use the usual laboratory equipment and, in particular, the following:
Gas chromatograph, with TCD.
6.3.2.3.2.4 Procedure and analytical conditions

The gas chromatography with TCD shall be done following the conditions in Table 2.

Table 2 — Conditions for gas chromatography analysis
Solvent DMSO
Column Gas chromatography (GC) column packed with 6 % cyanopropylphenyl/94 % di-
methylpolysiloxan or another appropriate stationary phase material
Gradient Time Temperature Slope
0 min 40 °C
2 min 40 °C
18 min 200 °C 10 °C/min
Detection TCD
Conditions Carrier Helium 45 kPa
Injector temperature 250 °C
Detector temperature TCD 260 °C
Sensitivity 0 - 1 000 mV
Record interval 18 mi
...

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