ISO 23419:2021

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 2021
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ii
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
Foreword
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iv
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.
v
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/
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
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.
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
...