ISO 8284:2024

International
Standard
ISO 8284
First edition
Traditional Chinese medicine —
2024-12
Simplified accelerated stress
simulation methods
Médecine traditionnelle chinoise — Méthodes simplifiées de
simulation accélérée des contraintes
Reference number
© ISO 2024
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Published in Switzerland
ii
Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Simplified accelerated stress simulation methods . 2
4.1 General .2
4.2 Different types of accelerated stress simulation .3
4.2.1 Types of accelerated stress .3
4.2.2 Accelerated gas stress simulation.3
4.2.3 Accelerated chemical stress simulation .3
4.2.4 Accelerated storage stress simulation .4
5 Application methods for accelerated gas stress simulations . 4
5.1 General .4
5.2 Stability-relevant reactions .4
5.2.1 General .4
5.2.2 Oxidation with gaseous reactants .4
5.2.3 Reduction with gaseous reactants .5
5.2.4 Other gaseous reactants .5
5.3 Reagents .5
5.4 Apparatus .5
5.5 General stress simulation setup.7
5.6 General implementation . .7
5.7 Analysis .8
5.8 Oxidative gas stress simulation .8
5.8.1 Oxygen as gas stress factor .8
5.8.2 Sulfur dioxide as gas stress factor .8
5.8.3 Nitrogen oxide as gas stress factor .9
5.9 Reductive gas stress simulation .9
5.9.1 Carbon monoxide as gas stress factor .9
5.9.2 Hydrogen as gas stress factor .9
5.10 Other gas stress simulation by use of carbon dioxide as gas stress factor.9
6 Application methods for accelerated chemical stress simulations .10
6.1 General .10
6.2 Types of accelerated chemical stress simulations .10
6.2.1 Catalytic stress simulation .10
6.2.2 Redox and pH stress simulation .10
6.3 Accelerated catalytic stress simulation .10
6.3.1 General .10
6.3.2 Pre-simulation with a catalytic heavy metal mixture .11
6.3.3 Identification of a specific stability-influencing catalytic reaction . 13
6.4 Accelerated redox and pH stress simulation .14
6.4.1 General .14
6.4.2 Reagents .14
6.4.3 Apparatus .14
6.4.4 Execution . . 15
6.4.5 Sample preparation and analysis . 15
6.4.6 Accuracy criterion for accelerated Redox pH stress simulation (validation) .16
7 Application methods for accelerated storage stress simulations .16
7.1 General .16
7.2 Types of accelerated storage stress simulation .16
7.2.1 Temperature stress simulation .16

iii
7.2.2 Humidity stress simulation .16
7.2.3 Combined humidity and temperature stress simulation .17
7.3 Accelerated temperature stress tests .17
7.3.1 Reagents .17
7.3.2 Apparatus .17
7.3.3 Execution . .17
7.3.4 Analysis .18
7.3.5 Accuracy criterion for accelerated temperature stress simulation (validation) .18
7.4 Accelerated humidity stress simulation .18
7.4.1 Reagents .18
7.4.2 Apparatus .19
7.4.3 Execution . .19
7.4.4 Analysis . 20
7.4.5 Accuracy criterion for accelerated humidity stress simulation (validation) . 20
7.5 Accelerated humidity and temperature stress tests . 20
Annex A (informative) Accuracy criterion for accelerated gas stress simulation (validation) .21
Bibliography .23

iv
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
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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).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent
rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a)
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Any trade name used in this document is information given for the convenience of users and does not
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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.

v
Introduction
Stability is the most important quality criterion for pharmaceutical products after production. So typically
for all pharmaceutical products an accurate expiry date is established based on scientific measurement
data. In addition to long-term storage tests, accelerated stability tests under specific stress conditions can
be carried out at the same time in order to reproduce possible degradation reactions. The aim of the stability
tests should be to obtain the most accurate possible assessment of the effects of packaging, closure, dosage,
batch, temperature, humidity, pH value and light, as well as other potential factors influencing decomposition
processes.
Phytopharmaceuticals are substances from plants, plant parts and plant components in processed or
unprocessed condition. Like all other medicinal products, they are subject to authorisation; and the quality,
efficacy and harmlessness of the respective preparations must be demonstrated. In contrast to chemically
defined drugs, the active ingredient of a phytopharmaceutical is not a single substance, but usually an
extract.
The extract as a whole is regarded as the active substance. Depending on the state of knowledge on the
active principle of medicinal plants, extracts can be classified as follows:
— extracts for which the efficacy-determining ingredients are known and for which a clear dose-response
relationship can be established (e.g. anthraquinone drugs);
— extracts for which co-efficacy-determining ingredients are known, but other (possibly unknown)
ingredients are responsible for the overall effect (e.g. St. John’s wort);
— extracts which show pharmacological effects but for which the effect cannot be assigned to specific
substances.
All pharmaceutical manufacturers must guarantee the consistent, high quality of their products in the whole
shelf life. According to international health laws, quality means the nature of a drug, which is determined by
the identity, content, purity and other chemical, physical and biological properties or by the manufacturing
process as well as the stability.
Herbal medicinal products in the sense of rational therapy are regarded as real remedies. In this respect, the
same legal requirements regarding efficacy and harmlessness apply as for chemically defined substances.
Nevertheless, there are significant differences in the composition of the two forms of medicine. While
chemically defined substances are usually considered as single substances or combinations of a few
substances, herbal medicinal products are highly complex multi-component mixtures with hundreds of
ingredients. Therefore, a much greater analytical effort is required to satisfy the qualitative demands on the
finished product.
According to the national and international requirements on the quality of herbal medicinal products, the
drug or the single herbal finished product as a whole is regarded as the active substance to be investigated.
National or international guidelines for new or existing active substances and final products are taken into
consideration in the process of stability control. However typically the guidelines already indicate that they
are not intended to apply for biologically or biotechnologically manufactured medicinal products; and the
guidelines do not take into account the specificities of herbal medicinal products.
Quantitative studies of the content of efficacy-determining ingredients ensure, that under defined storage
conditions there are no changes in content of typically more than ±5 % compared to the initial value over
the proposed shelf life. If no defined active substances are present, a deviation of ±10 % from the content of
main substances can be accepted. Other “significant changes” mentioned in the guidelines are changes in pH
value, solubility and appearance which would lead to a failure of the approval.
The stability of a few ingredients is the basis for the stability of the whole herbal preparation.
To monitor the qualitative and quantitative composition, high pressure liquid chromatography (HPLC) with
ultra violet (UV)-diode array detection is mostly used, because the highest measurement accuracy can be
expected from this method. In addition, the extracts are examined by thin layer chromatography (TLC)
with various mobile phase systems as a further fingerprint method for qualitative changes in the ingredient

vi
spectrum. In order to avoid the problem of repeatability in TLC, the samples should not be measured
immediately but should be collected as deep-frozen samples.
In addition to the monitoring of the ingredients by chromatographic methods, the physical changes of the
drugs and extracts should also be documented at the respective sampling times. Other quality features
include a change in appearance and organoleptically measurable changes.
International regulations define the framework conditions for accelerated stress simulation without making
detailed proposals for its realization in the laboratory.
This document defines simple and detailed methods for the technical implementation of the required
stability tests.
NOTE Stress testing of the active substance can help identify the likely degradation products, which can in turn
help establish the degradation pathways and the intrinsic stability and validate the stability indicating power of the
analytical procedures used.
When no data are available in the scientific literature, including official pharmacopoeias, stress testing
should be performed.
Examining degradation products under stress conditions is useful in establishing degradation pathways
and developing and validating suitable analytical procedures.
Since the herbal substance or herbal preparation in its entirety is regarded as the active substance, a mere
determination of the stability of the constituents with known therapeutic activity does not suffice. The
stability of other substances present in the herbal substance or in the herbal preparation should, as far as
possible, also be demonstrated, for example, by means of appropriate fingerprint chromatograms. It should
also be demonstrated that their proportional content remains comparable to the initial fingerprint. If a
herbal medicinal product contains combinations of several herbal substances or herbal preparations, and
if it is not possible to determine the stability of each active substance, the stability of the medicinal product
should be determined by appropriate fingerprint chromatograms, appropriate overall methods of assay and
physical and sensory tests or other appropriate tests.

vii
International Standard ISO 8284:2024(en)
Traditional Chinese medicine — Simplified accelerated stress
simulation methods
1 Scope
This document specifies the application of simplified accelerated stress simulation methods for stress tests
of finished products, used in and as Traditional Chinese medicine (TCM). Testing for stability or degradation
under the influence of daylight or sunlight is outside the scope of this document.
2 Normative references
There are no normative references in this document.
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
accelerated stress simulation
exaggerated conditions, such as gas, chemical and storage, to increase the rate of chemical degradation or
physical change of a product
3.2
centrifuge tube with plug seal screw cap
standardized plastic test tube with a screw top cap
3.3
fermenting tube
fermentation tube
glass tube with two spheres, which allows the escape of emerging gas and prevents entering of ambient air
into a closed system
3.4
marker compound
chemical constituent that can be used to verify the potency or identity of a medicinal product
3.5
out-of-specification
OOS
examination, measurement or test result that does not comply with defined acceptance criteria
[SOURCE: ISO 22716:2007, 2.21, modified — The abbreviated term "OOS" has been added.]
3.6
SPE cartridge
short column (generally an open syringe barrel) containing porous metal or plastic frits

4 Simplified accelerated stress simulation methods
4.1 General
Drug stability and the course of changes in a product from manufacture to consumption by the patient
are critical parameters in the product development. So far, only theoretical mathematical relationships or
experimental test series for the simulation of longer storage conditions exist.
Valid test procedures therefore must be critically questioned as to whether they can also be applied over the
entire stability period – usually 36 months. The test procedures shall coincide with those of the approval
or registration procedure and cannot simply be subsequently adapted to any changed external conditions.
If the products do not meet the stability criteria, i.e. out-of-specification (OOS) results occur in the testing
laboratory, the causes for this shall be identified and risk assessment processes shall be established.
It is therefore imperative to make appropriate stability predictions by means of a bundle of analytical
investigations and simulated stress conditions, without additionally extending the often long development
process by the prescribed 36 months.
It is therefore necessary to establish a cost-effective and fast simulation for finished products with a
relatively large chance of being able to make a realistic stability prediction by suitable accelerated stress
simulations. This proves to be an obstacle that is difficult to overcome, especially in the case of herbal
preparations, since the concrete active substance in the chemical sense is often not known in comparison
to the chemically defined active substance in synthetic preparations. The mechanism of action of herbal
extracts is usually known, so analytics shall be focused on one or more meaningful lead substances (marker
compounds). To ensure the reliability of the results, each test approach should be carried out with three
parallel test samples.
4.2 Different types of accelerated stress simulation
4.2.1 Types of accelerated stress
Figure 1 — Types of accelerated stress
4.2.2 Accelerated gas stress simulation
Typical gas stress can be generated by:
— oxidative gases;
— reductive gases;
— other types of reactive gases.
Accelerated gas stress simulation should be used to assess the influence of these gases on the stability of
finished products (see Figure 1 column 1).
For validation of the proposed test setup, an accuracy criterion is described in Annex A.
4.2.3 Accelerated chemical stress simulation
Typical chemical stress can be generated by:
— catalytic constituents;
— compounds with a specific redox potential;

— acidic or alkaline constituents which modify the pH.
Accelerated chemical stress simulation should be used to assess the influence of these compounds on the
stability of finished products (see Figure 1 column 2).
4.2.4 Accelerated storage stress simulation
Typical storage stress can be generated by storage under:
— defined temperature storage conditions;
— defined humidity storage conditions;
— defined combined temperature and humidity storage conditions.
Accelerated storage stress simulation should be used to assess the influence of storage conditions on the
stability of finished products (see Figure 1 column 3).
5 Application methods for accelerated gas stress simulations
5.1 General
On a critical examination, with regard to a certain long-term relevance, six candidates are identified. These,
in addition to external supply, are also subject to certain de novo conditions that can arise during storage as
a result of degradation reactions in the product.
In order to make core statements about the lability of the marker compound in the shortest possible time in
an accelerated stress procedure, novel experimental set-ups are designed from common consumables in the
laboratory, which can then be disposed simply and without risk after use as single-use approaches.
The system is designed in such a way that the relevant gaseous reactants from chemical precursors are only
produced de novo at the time of simulation. This also eliminates the problem of having to maintain and use
corresponding compressed gas cylinders with partly toxic contents to a greater extent. Due to their small
quantities, the critical gases can be discharged safely for the employees via normal exhaust ventilation.
Three basic chemical types are identified as possible stability-relevant reactions:
— oxidation reactions;
— reduction reactions;
— further reactions.
5.2 Stability-relevant reactions
5.2.1 General
Based on the different types of gas stress (see 4.2.2), the typical gaseous reactants described in 5.2.2 to
5.2.4 shall be applied for accelerated gas stress simulation.
5.2.2 Oxidation with gaseous reactants
In order to detect oxidative degradation and rearrangement processes at an early stage, a standardized
amount of test sample is exposed to a standardized amount of oxidizing agent in a standardized period of
time in the respective test arrangements and thus also the associated marker compound.
The following three gases are identified as potentially effective candidates:
— oxygen (O );
— sulfur dioxide (SO );
— nitrogen oxides (NO ).
x
By suitable chemical reactions it is possible to produce equimolar amounts in a simplified and standardized
way. In this special case 500 ml of these gases are produced at normal pressure and passed through the test
sample including the marker compound.
5.2.3 Reduction with gaseous reactants
In addition to the experiments described in 5.2.2, corresponding reactions with reducing agents can also be
simulated under identical conditions in the same experimental set-ups.
These are:
— carbon monoxide (CO);
— hydrogen (H ).
5.2.4 Other gaseous reactants
In some cases, natural carbon dioxide (CO ) in the ambient air and as a left-over group during degenerative
processes can be responsible for changes and thus loss of stability of marker compounds and products. In order
to exclude this risk, CO is also included in the test. The experimental setup described in 5.2.2 shall be used.
5.3 Reagents
— zinc (laboratory grade);
— calcium carbonate (laboratory grade);
— copper (laboratory grade);
— sodium sulfite (laboratory grade);
— manganese (IV) oxide (laboratory grade);
— sulfuric acid 96 % (laboratory grade);
— formic acid 100 % (laboratory grade);
— hydrogen peroxide 15 % (laboratory grade);
— nitric
...