Traditional Chinese medicine -- General requirements for manufacturing procedures and quality assurance of granules

This document specifies general requirements for manufacturing procedures and quality and safety assurance of granules and compactates made from traditional Chinese medicine extracts or powder for oral use. This document excludes granules or compactates made from pure compounds (chemically defined) even if they are isolated as naturally occurring constituents of decoction pieces or crude herbal and mineral drugs.

Médecine traditionnelle chinoise -- Exigences générales relatives aux modes opératoires de fabrication et à l'assurance de la qualité des granules

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Publication Date
06-Dec-2021
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5060 - Close of voting Proof returned by Secretariat
Start Date
02-Nov-2021
Completion Date
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INTERNATIONAL ISO
STANDARD 23419
First edition
2021-12
Traditional Chinese medicine —
General requirements for
manufacturing procedures and quality
assurance of granules
Médecine traditionnelle chinoise — Exigences générales relatives aux
modes opératoires de fabrication et à l'assurance de la qualité des
granules
Reference number
ISO 23419:2021(E)
© ISO 2021
---------------------- Page: 1 ----------------------
ISO 23419:2021(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
© ISO 2021 – All rights reserved
---------------------- Page: 2 ----------------------
ISO 23419:2021(E)
Contents Page

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

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

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

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

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

4 General requirements of manufacturing procedures ................................................................................................. 3

4.1 General ........................................................................................................................................................................................................... 3

4.2 Crushing ....................................................................................................................................................................................................... 4

4.3 Extraction ................................................................................................................................................................................................... 4

4.4 Liquid-solid separation ................................................................................................................................................................... 5

4.5 Concentration and drying ............................................................................................................................................................. 5

4.6 Granulation ................................................................................................................................................................................................ 6

4.6.1 General ........................................................................................................................................................................................ 6

4.6.2 Dry granulation ................................................................................................................................................................... 6

4.6.3 Semi-dry granulation ..................................................................................................................................................... 7

4.6.4 Wet granulation ................................................................................................................................................................... 7

4.7 Compaction ................................................................................................................................................................................................ 8

4.8 Packaging and labelling .................................................................................................................................................................. 8

5 General requirement of quality assurance .............................................................................................................................. 8

5.1 General ........................................................................................................................................................................................................... 8

5.2 Equivalency evaluation ................................................................................................................................................................... 9

5.3 Identification ............................................................................................................................................................................................ 9

5.4 Assay ................................................................................................................................................................................................................ 9

5.5 Particle size and particle size distribution ................................................................................................................... 9

5.6 Dissolution or disintegration test .......................................................................................................................................... 9

5.7 Determination of water or moisture content .............................................................................................................. 9

5.8 Uniformity of dosage units ....................................................................................................................................................... 10

6 Requirements of safety tests ...............................................................................................................................................................10

6.1 Pesticide residues ............................................................................................................................................................................. 10

6.2 Heavy metals ......................................................................................................................................................................................... 10

6.3 Aflatoxins ................................................................................................................................................................................................. 10

6.4 Microorganism .................................................................................................................................................................................... 10

Annex A (informative) Production, quality and selection of crude drugs ................................................................11

Annex B (informative) Particle size distribution ................................................................................................................................12

Annex C (informative) Equivalency evaluation .....................................................................................................................................13

Annex D (informative) Determination of the content of methanol-soluble extractives ............................15

Bibliography .............................................................................................................................................................................................................................17

iii
© ISO 2021 – All rights reserved
---------------------- Page: 3 ----------------------
ISO 23419:2021(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.

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.
© ISO 2021 – All rights reserved
---------------------- Page: 4 ----------------------
ISO 23419:2021(E)
Introduction

Herbal medicines used in traditional Chinese medicine have been used as decoctions for thousands

of years. However, from the aspect of advantage and convenience in preparation, portability and

sanitation, dry extract preparations such as granules or compactates, tablets and capsules have been

developed as alternative forms of dosage for decoctions. Decoction is still the most common form of

dosage in China, Korea, Australia and many other countries. However, exceptionally in Japan, nearly

100 % of the Kampo product market is taken up by dry extract preparations. Application of dry extract

preparations in other countries has increased in recent years and this is expected to continue.

Among the dry extract preparations mentioned above, granules and compactates are the most cost-

effective forms of dosage made by simple manufacturing procedures. Although granules are listed in

many pharmacopoeias as a major form of dosage, there is no standard specializing in granules made

from medicinal plants. In the manufacturing procedure of granules of medicinal plants, there are many

critical points to be taken into account. To obtain granules and compactates with consistent good

quality and without major processing troubles during manufacturing, these critical points must be

clarified and optimized prior to commercial production.
© ISO 2021 – All rights reserved
---------------------- Page: 5 ----------------------
INTERNATIONAL STANDARD ISO 23419:2021(E)
Traditional Chinese medicine — General requirements
for manufacturing procedures and quality assurance of
granules
1 Scope

This document specifies general requirements for manufacturing procedures and quality and safety

assurance of granules and compactates made from traditional Chinese medicine extracts or powder

for oral use. This document excludes granules or compactates made from pure compounds (chemically

defined) even if they are isolated as naturally occurring constituents of decoction pieces or crude

herbal and mineral drugs.
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 18664, Traditional Chinese Medicine — Determination of heavy metals in herbal medicines used in

Traditional Chinese Medicine

ISO 19609-1, Traditional Chinese medicine — Quality and safety of raw materials and finished products

made with raw materials — Part 1: General requirements

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 19617, Traditional Chinese medicine — General requirements for the manufacturing process of natural

products

ISO 21371, Traditional Chinese medicine — Labelling requirements of products intended for oral or topical

use

ISO 22283, Traditional Chinese medicine — Determination of aflatoxins in natural products by LC-FLD

ISO 22467, Traditional Chinese medicine — Determination of microorganism in natural products

ISO 23723, Traditional Chinese medicine — General requirements for herbal raw material and materia

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

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

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
© ISO 2021 – All rights reserved
---------------------- Page: 6 ----------------------
ISO 23419:2021(E)
3.1
crude drug

medicinal part obtained from plants or animals, cell inclusions and secretions separated from the

origins, their extracts and minerals
[SOURCE: ISO 19617:2018, 3.8, modified — Notes to entry removed.]
3.2
critical parameter

parameter whose variability has an impact on quality and productivity of each product or process

Note 1 to entry: Critical parameters depend largely on type and size of production devices as well as physical

properties of matrices. Critical parameters can be individually verified and optimized prior to commercial

production.
3.3
granules

coated or uncoated small grains which range from approximately 0,2 mm to 4 mm in diameter, made

from a uniform mixture of powdered extract and excipients

Note 1 to entry: Granules are made from extracts or powder made from single or multiple herbs or decoction

pieces. They are used instead of decoction pieces or instead of traditionally prescribed herbal recipes described

in the classic medicine books of ancient China, such as Shanghan lun (傷寒論) and Jinguiyaolue (金匱要略), or

books related to Kampo and Korean medicines.

Note 2 to entry: Granules are made from non-treated crude extracts or powder, or simple fractionated crude

extracts, as far as they can be legally categorized as traditional Chinese medicine.

Note 3 to entry: Excipients are diluents or binders to improve lubricity and binding of extract powder for

granulation.
3.4
compactate

irregular shaped agglomerate obtained directly from the dried extract by compaction

Note 1 to entry: Compactates are made from non-treated crude extracts or powder made from single or multiple

herbs or decoction pieces. They are used instead of decoction pieces or instead of traditionally prescribed herbal

recipes described in the classic medicine books of ancient China, such as Shanghan lun (傷寒論) and Jinguiyaolue

(金匱要略), or books related to Kampo and Korean Medicines, as they can be legally categorized as traditional

Chinese medicine.
3.5
dry extract

dried solid or powder (3.6) obtained from water or aqueous ethanol extracts of medicinal herbs or

decoction pieces
Note 1 to entry: Sources of dry extract include minerals and herbal drugs.
3.6
powder

fine particles made through crushing or milling of medicinal herbs or decoction pieces

Note 1 to entry: Sources of powder include minerals and herbal drugs without solvent extraction.

3.7
out-of-specification lot
lot which failed quality criteria
© ISO 2021 – All rights reserved
---------------------- Page: 7 ----------------------
ISO 23419:2021(E)
3.8
granulation

process of particle enlargement by agglomeration technique with and without small amounts of

excipients

Note 1 to entry: Granulation involves agglomeration of fine particles into larger granules, typically of between

0,1 mm and 4,0 mm, depending on their subsequent use. The resulting shapes can be balls, spheroids, small

cylinders or irregular.
3.9
dry granulation

granulation (3.8) without a mixing process of moistening with liquid to bind excipients and drug

substances
3.10
compaction

agglomeration of dry extracts (3.5) and excipients without adding liquid(s) with high pressure

Note 1 to entry: Compaction uses mechanical compression or compaction (roller technic) to facilitate the

agglomeration of dry powder into irregularly shaped particles.
3.11
semi-dry granulation

granulation (3.8) with a slight amount (1 % to 4 %) of granulating fluid before the granulation step

Note 1 to entry: Semi-dry granulation is a variation of the conventional wet granulation technique.

3.12
wet granulation

granulation (3.8) with a mixing process of moistening with liquid to bind excipients and drug substance

followed by a drying process
3.13
first pass yield

efficiency index of a process expressed by the ratio of acceptable output to whole input obtained by a

single operation

Note 1 to entry: First pass yield is a good measure of the efficiency of a process.

3.14
dosage unit
dosage amount contained in a single or daily administration

Note 1 to entry: Dosage unit of granules means minimum package unit, such as a sachet or bottle.

3.15
uniformity of dosage unit
degree of uniformity in the amount of the drug substance among dosage units
4 General requirements of manufacturing procedures
4.1 General

a) All manufacturing procedures, facilities and apparatus shall be managed under controlled

conditions to ensure quality consistency between granules and traditional decoction. This

document specifies general items of critical parameters in each procedure.

b) Critical parameters shall be individually verified and optimized prior to commercial production.

They shall be modified according to the physical nature of the raw materials.
© ISO 2021 – All rights reserved
---------------------- Page: 8 ----------------------
ISO 23419:2021(E)

c) All critical parameters shall be determined by experiments in laboratories and test plants, then

modified for commercial production scale. Thereafter, three lots of repetitive test production in

practical production scale is required for verification study.

d) The manufacturing processes of granules shall follow the general requirements given in ISO 19617.

e) Quality testing of starting raw materials shall be conducted in accordance with the requirements

given in ISO 23723. For the production and lot selection of crude drugs as starting materials, see

Annex A.

f) Powder made by crushing and milling of crude drugs without extraction shall only be used in this

manufacturing process instead of dry extracts if this pharmaceutical form is based on traditional

usage.

g) Simple fractionation, such as two-layer partition, can be applied in the manufacturing procedure.

4.2 Crushing

a) Crude drugs shall be cut or crushed into small pieces by devices suitable for the processing of crude

drugs.

b) The appropriate particle size shall be determined according to the result of equivalency evaluation

(5.2).
c) In this process, the critical parameter is particle size of herbs (mm).

d) When needed, mixing usage of multiple lots of single crude drugs should be considered to avoid

batch-to-batch variation and to obtain consistent quality in the final granules, as described in

Annex C.
4.3 Extraction

a) Crushed drugs shall be extracted using purified water or aqueous ethanol (e.g. white wine, less

than 50 % of ethanol) according to traditional methods.
b) Acidic or alkaline solvents shall not be used as extraction solvents.
c) Supercritical CO gas extraction shall not be used.
d) The amount of solvent to be added is 3 to 20 times the weight of crude drugs.

NOTE This varies depending on the density and water adsorption capacity of crushed drugs.

e) Extract repetition time is set according to the result of equivalency evaluation given in Annex C.

f) Essential oils can be separately collected during the extraction process and mixed after the

extraction with the obtained crude extract or sprayed on the granules or compactates.

g) In this process, the critical parameters are as follows:
1) weight of herbs or
...

FINAL
INTERNATIONAL ISO/FDIS
DRAFT
STANDARD 23419
ISO/TC 249
Traditional Chinese medicine —
Secretariat: SAC
General requirements for
Voting begins on:
2021­09­06 manufacturing procedures and quality
assurance of granules
Voting terminates on:
2021­11­01
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 23419:2021(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 2021
---------------------- Page: 1 ----------------------
ISO/FDIS 23419:2021(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
CH­1214 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/FDIS 23419:2021(E)
Contents Page

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

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

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

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

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

4 General requirements of manufacturing procedures .................................................................................................... 3

4.1 General ........................................................................................................................................................................................................... 3

4.2 Crushing ........................................................................................................................................................................................................ 4

4.3 Extraction .................................................................................................................................................................................................... 4

4.4 Liquid-solid separation .................................................................................................................................................................... 5

4.5 Concentration and drying .............................................................................................................................................................. 5

4.6 Granulation ................................................................................................................................................................................................ 6

4.6.1 General...................................................................................................................................................................................... 6

4.6.2 Dry granulation ................................................................................................................................................................. 6

4.6.3 Semi-dry granulation ................................................................................................................................................... 7

4.6.4 Wet granulation ................................................................................................................................................................ 7

4.7 Compaction ................................................................................................................................................................................................ 8

4.8 Packaging and labelling ................................................................................................................................................................... 8

5 General requirement of quality assurance ............................................................................................................................... 8

5.1 General ........................................................................................................................................................................................................... 8

5.2 Equivalency evaluation .................................................................................................................................................................... 9

5.3 Identification ............................................................................................................................................................................................ 9

5.4 Assay ................................................................................................................................................................................................................ 9

5.5 Particle size and particle size distribution ...................................................................................................................... 9

5.6 Dissolution or disintegration test ........................................................................................................................................... 9

5.7 Determination of water or moisture content ............................................................................................................... 9

5.8 Uniformity of dosage units ........................................................................................................................................................10

6 Requirements of safety tests .................................................................................................................................................................10

6.1 Pesticide residues ..............................................................................................................................................................................10

6.2 Heavy metals ..........................................................................................................................................................................................10

6.3 Aflatoxins ..................................................................................................................................................................................................10

6.4 Microorganism .....................................................................................................................................................................................10

Annex A (informative) Production, quality and selection of crude drugs ..................................................................11

Annex B (informative) Particle size distribution ..................................................................................................................................12

Annex C (informative) Equivalency evaluation .......................................................................................................................................13

Annex D (informative) Determination of the content of methanol-soluble extractives ..............................15

Bibliography .............................................................................................................................................................................................................................17

© ISO 2021 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/FDIS 23419:2021(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 non­governmental, 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.

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
---------------------- Page: 4 ----------------------
ISO/FDIS 23419:2021(E)
Introduction

Herbal medicines used in traditional Chinese medicine have been used as decoctions for thousands

of years. However, from the aspect of advantage and convenience in preparation, portability and

sanitation, dry extract preparations such as granules or compactates, tablets and capsules have been

developed as alternative forms of dosage for decoctions. Decoction is still the most common form of

dosage in China, Korea, Australia and many other countries. However, exceptionally in Japan, nearly

100 % of the Kampo product market is taken up by dry extract preparations. Application of dry extract

preparations in other countries has increased in recent years and this is expected to continue.

Among the dry extract preparations mentioned above, granules and compactates are the most cost-

effective forms of dosage made by simple manufacturing procedures. Although granules are listed in

many pharmacopoeias as a major form of dosage, there is no standard specializing in granules made

from medicinal plants. In the manufacturing procedure of granules of medicinal plants, there are many

critical points to be taken into account. To obtain granules and compactates with consistent good

quality and without major processing troubles during manufacturing, these critical points must be

clarified and optimized prior to commercial production.
© ISO 2021 – All rights reserved v
---------------------- Page: 5 ----------------------
FINAL DRAFT INTERNATIONAL STANDARD ISO/FDIS 23419:2021(E)
Traditional Chinese medicine — General requirements
for manufacturing procedures and quality assurance of
granules
1 Scope

This document specifies general requirements for manufacturing procedures and quality and safety

assurance of granules and compactates made from traditional Chinese medicine extracts or powder

for oral use. This document excludes granules or compactates made from pure compounds (chemically

defined) even if they are isolated as naturally occurring constituents of decoction pieces or crude

herbal and mineral drugs.
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 18664, Traditional Chinese Medicine — Determination of heavy metals in herbal medicines used in

Traditional Chinese Medicine

ISO 19609­1, Traditional Chinese medicine — Quality and safety of raw materials and finished products

made with raw materials — Part 1: General requirements

ISO 19609­2, 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 19617, Traditional Chinese medicine — General requirements for the manufacturing process of natural

products

ISO 21371, Traditional Chinese medicine — Labelling requirements of products intended for oral or topical

use

ISO 22283, Traditional Chinese medicine — Determination of aflatoxins in natural products by LC-FLD

ISO/FDIS 22467, Traditional Chinese medicine — Determination of microorganism in natural products

ISO 23723, Traditional Chinese Medicine — General requirements for herbal raw material and materia

medica
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 https:// www .electropedia .org/
1) Under preparation. Stage at the time of publication: ISO/FDIS 22467:2021.
© ISO 2021 – All rights reserved 1
---------------------- Page: 6 ----------------------
ISO/FDIS 23419:2021(E)
3.1
crude drug

medicinal part obtained from plants or animals, cell inclusions and secretions separated from the

origins, their extracts and minerals
[SOURCE: ISO 19617:2018, 3.8, modified — Notes to entry removed.]
3.2
critical parameter

parameter whose variability has an impact on quality and productivity of each product or process

Note 1 to entry: Critical parameters depend largely on type and size of production devices as well as physical

properties of matrices. Critical parameters can be individually verified and optimized prior to commercial

production.
3.3
granules

coated or uncoated small grains which range from approximately 0,2 mm to 4 mm in diameter, made

from a uniform mixture of powdered extract and excipients

Note 1 to entry: Granules are made from extracts or powder made from single or multiple herbs or decoction

pieces. They are used instead of decoction pieces or instead of traditionally prescribed herbal recipes described

in the classic medicine books of ancient China, such as Shanghan lun (傷寒論) and Jinguiyaolue (金匱要略), or

books related to Kampo and Korean medicines.

Note 2 to entry: Granules are made from non-treated crude extracts or powder, or simple fractionated crude

extracts, as far as they can be legally categorized as traditional Chinese medicine.

Note 3 to entry: Excipients are diluents or binders to improve lubricity and binding of extract powder for

granulation.
3.4
compactate

irregular shaped agglomerate obtained directly from the dried extract by compaction

Note 1 to entry: Compactates are made from non-treated crude extracts or powder made from single or multiple

herbs or decoction pieces. They are used instead of decoction pieces or instead of traditionally prescribed herbal

recipes described in the classic medicine books of ancient China, such as Shanghan lun (傷寒論) and Jinguiyaolue

(金匱要略), or books related to Kampo and Korean Medicines, as they can be legally categorized as traditional

Chinese medicine.
3.5
dry extract

dried solid or powder (3.6) obtained from water or aqueous ethanol extracts of medicinal herbs or

decoction pieces
Note 1 to entry: Sources of dry extract include minerals and herbal drugs.
3.6
powder

fine particles made through crushing or milling of medicinal herbs or decoction pieces

Note 1 to entry: Sources of powder include minerals and herbal drugs without solvent extraction.

3.7
out-of-specification lot
lot which failed quality criteria
2 © ISO 2021 – All rights reserved
---------------------- Page: 7 ----------------------
ISO/FDIS 23419:2021(E)
3.8
granulation

process of particle enlargement by agglomeration technique with and without small amounts of

excipients

Note 1 to entry: Granulation involves agglomeration of fine particles into larger granules, typically of between

0,1 mm and 4,0 mm, depending on their subsequent use. The resulting shapes can be balls, spheroids, small

cylinders or irregular.
3.9
dry granulation

granulation (3.8) without a mixing process of moistening with liquid to bind excipients and drug

substances
3.10
compaction

agglomeration of dry extracts (3.5) and excipients without adding liquid(s) with high pressure

Note 1 to entry: Compaction uses mechanical compression or compaction (roller technic) to facilitate the

agglomeration of dry powder into irregularly shaped particles.
3.11
semi-dry granulation

granulation (3.8) with a slight amount (1 % to 4 %) of granulating fluid before the granulation step

Note 1 to entry: Semi-dry granulation is a variation of the conventional wet granulation technique.

3.12
wet granulation

granulation (3.8) with a mixing process of moistening with liquid to bind excipients and drug substance

followed by a drying process
3.13
first pass yield

efficiency index of a process expressed by the ratio of acceptable output to whole input obtained by a

single operation

Note 1 to entry: First pass yield is a good measure of the efficiency of a process.

3.14
dosage unit
dosage amount contained in a single or daily administration

Note 1 to entry: Dosage unit of granules means minimum package unit, such as a sachet or bottle.

3.15
uniformity of dosage unit
degree of uniformity in the amount of the drug substance among dosage units
4 General requirements of manufacturing procedures
4.1 General

a) All manufacturing procedures, facilities and apparatus shall be managed under controlled

conditions to ensure quality consistency between granules and traditional decoction. This

document specifies general items of critical parameters in each procedure.

b) Critical parameters shall be individually verified and optimized prior to commercial production.

They shall be modified according to the physical nature of the raw materials.
© ISO 2021 – All rights reserved 3
---------------------- Page: 8 ----------------------
ISO/FDIS 23419:2021(E)

c) All critical parameters shall be determined by experiments in laboratories and test plants, then

modified for commercial production scale. Thereafter, three lots of repetitive test production in

practical production scale is required for verification study.

d) The manufacturing processes of granules shall follow the general requirements given in ISO 19617.

e) Quality testing of starting raw materials shall be conducted in accordance with the requirements

given in ISO 23723. For the production and lot selection of crude drugs as starting materials, see

Annex A.

f) Powder made by crushing and milling of crude drugs without extraction shall only be used in this

manufacturing process instead of dry extracts if this pharmaceutical form is based on traditional

usage.

g) Simple fractionation, such as two-layer partition, can be applied in the manufacturing procedure.

4.2 Crushing

a) Crude drugs shall be cut or crushed into small pieces by devices suitable for the processing of crude

drugs.

b) The appropriate particle size shall be determined according to the result of equivalency evaluation

(5.2).
c) In this process, the critical parameter is particle size of herbs (mm).

d) When needed, mixing usage of multiple lots of single crude drugs should be considered to avoid

batch-to-batch variation and to obtain consistent quality in the final granules, as described in

Annex C.
4.3 Extraction

a) Crushed drugs shall be extracted using purified water or aqueous ethanol (e.g. white wine, less

than 50 % of ethanol) according to traditional methods.
b) Acidic or alkaline solvents shall not be used as extraction solvents.
c) Supercritical CO gas extraction shall not be used.
d) The amount of solvent to be added is 3 to 20 times the weight of crude drugs.

NOTE This varies depending on the density and water adsorption capacity of crushed drugs.

e) Extract repetition time is set according to the result of equivalency evaluation given in Annex C.

f) Essential oils can be separately collected during the
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