Regional Committee for the EM/RC53/12

Eastern Mediterranean August 2006

Fifty-third Session Original: Arabic

Agenda item 17

Draft regional guidelines on stability testing of

active substances and pharmaceutical products

These guidelines were developed during the WHO Consultation on Regional Guidelines on Stability Studies
of Medicines and Biologicals, held in Jeddah in February 2006. The final draft is recommended for adoption
by the Regional Committee for the Eastern Mediterranean
 Contents
Introductory note...................................................................................................... 1
1. Introduction..................................................................................................... 2
1.1 Objectives of the guideline .................................................................... 2
1.2 Scope of the guideline........................................................................... 2
1.3 General principles ................................................................................. 2
2. Guidelines ...................................................................................................... 2
2.1 Active substances ................................................................................. 2
2.2. Pharmaceutical products....................................................................... 7
3. Glossary ....................................................................................................... 16
Annexes
1. Assignment of climatic zones and recommended storage conditions .......... 20
2. Testing parameters ....................................................................................... 22
References ............................................................................................................ 25
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Introductory note
Quality and safety of medicines are one of the main components of WHO Medicine
Strategy. Development of norms and standards is one of the core functions of WHO.
According to Article 2 of the WHO Constitution, WHO is required to “develop, establish
and promote international standards with respect to food, biological, pharmaceutical and
similar products.”
WHO has been active in that field through the WHO Expert Committees which publish
guidelines, standards and recommendations that provide national authorities with the tools
to develop the national medicine quality assurance system. International harmonization is
one of the recent challenges of globalization.
Currently, WHO attends meetings of the Steering Committee and the Global Cooperation
Group of the International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) with observer status; these roles are
important and should be maintained. However, appropriate strategies for consultation and
communication with Member States need to be developed to ensure that WHO is not seen
as de facto automatically endorsing ICH products, but as providing advice on the potential
impact of those products on non-ICH Member States.
The WHO Regional Office for the Eastern Mediterranean, in its efforts to contribute to
regional harmonization, organized a Consultation on Regional Guidelines on Stability
Studies of Medicines on 25–28 February 2006 in Jeddah, Saudi Arabia. The consultation
was attended by experts from Bahrain, Egypt, Jordan, Islamic Republic of Iran, Kuwait,
Lebanon, Morocco, Oman, Pakistan, Saudi Arabia, Sudan and United Arab Emirates, as
well as international experts from Italy and Sweden. The consultation reviewed and
discussed relevant national, regional and international guidelines. The consultation also
discussed climatic conditions in the Region, with particular emphasis on determining the
mean kinetic temperature and the appropriate climate zone for each country of the Region.
The Draft Regional Guidelines on Stability Testing of Active Substances and
Pharmaceutical Products are the product of the consultation. These guidelines are based in
part on existing guidelines of the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use, European Agency for
the Evaluation of Medicinal Products, and Gulf Cooperation Council. The Regional Office
acknowledges the work of these bodies, as well as the contributions of the experts involved
in developing the draft regional guidelines.
The Regional Committee is invited to advise on the adoption of the attached draft
guidelines on Stability Testing of Active Substances and Pharmaceutical Products in
countries of the Eastern Mediterranean Region.
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1. Introduction
1.1 Objective of the guidelines
These guidelines are intended to define the stability data package for active substances and
pharmaceutical products that is sufficient for a registration application within countries of
the World Health Organization’s Eastern Mediterranean Region [1]. Countries of the
Region have agreed to accept stability information that is consistent with these guidelines
[2].
The guidelines seek to exemplify the core stability data package required for registration.
Alternative approaches can also be used when they are scientifically justified. Further
guidance can be found in guidelines published by the International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) [3].
1.2 Scope
The guidelines address the information to be submitted in applications for registration of
New Chemical Entities as well as existing active substances and their related
pharmaceutical products for human use.
1.3 General principles
The purpose of stability testing is to provide evidence on how the quality of an active
substance or pharmaceutical product varies with time under the influence of a variety of
environmental factors such as temperature, humidity and light. In addition, product-related
factors influence the stability, e.g. the chemical and physical properties of the active
substance and the pharmaceutical excipients, the dosage form and its composition, the
manufacturing process, the nature of the container-closure system, and the properties of the
packaging materials. As well, the stability of excipients that may contain or form reactive
degradation products have to be considered. The interaction of all these features affect the
eventual stability of the product.
As a result of stability testing, a re-test period for the active substance or a shelf life for the
pharmaceutical product can be established, and storage conditions can be recommended.
In order to identify adequate testing conditions, the climate in countries of the Eastern
Mediterranean Region has been analysed using the climatic data extracted from the ERA-
40 reanalysis conducted by the European Centre for Medium-Range Weather Forecasts [4].
The mean kinetic temperature, which includes the reaction rate constants in the evaluation
of heat effects on pharmaceutical products, and the mean partial water vapour pressure in
any part of the region were calculated, and accordingly climatic zones were assigned for
each country of the Region (see Annex 1).

2. Guidelines
2.1 Active substances
2.1.1 General

Information on the stability of the active substance is an integral part of the systematic
approach to stability evaluation. For active substances not described in an official
pharmacopoeial monograph, stability studies are required. For active substances described
in an official pharmacopoeial monograph, which covers the degradation products and for
which suitable limits have been set but a re-test period is not defined, two options are
acceptable:
• The manufacturer of the pharmaceutical product confirms that the active substance
complies with the pharmacopoeial monograph immediately prior to the manufacture

2
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of the pharmaceutical product. In this case no stability studies on the active

substance are required. The suitability of the pharmacopoeial monograph for the
active substance used from a named source of supply has to be demonstrated.
• The manufacturer establishes a re-test period based on the results of long-term
testing stability studies conducted on the active substance.
2.1.2 Stress testing

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 of the
molecule and validate the stability indicating power of the analytical procedures used. The
nature of the stress testing will depend on the individual active substance and the type of
pharmaceutical product involved.
For an active substance the following approaches may be used.
a) When an active substance is described in an official pharmacopoeial monograph, and
fully meets its requirements, no data are required on the degradation products if they
are named under the headings “purity tests” and/or “section on impurities”.
b) For active substances not described in an official pharmacopoeial monograph, there
are two options:
– When available, it is acceptable to provide the relevant data published in the
literature to support the proposed degradation pathways;
– When no data are available in the scientific literature, including official
pharmacopoeias, stress testing should be performed.
Stress testing is likely to be carried out on a single batch of the active substance. It should
include the effect of temperatures (in 10 °C increments (e.g. 50 °C, 60 °C, etc.) above that
for accelerated testing), humidity (e.g. 75% relative humidity (RH) or greater) where
appropriate, oxidation and photolysis on the active substance. The testing should also
evaluate the susceptibility of the active substance to hydrolysis across a wide range of pH
values when in solution or suspension.
Photostability testing should be an integral part of stress testing.
Examining degradation products under stress conditions is useful in establishing
degradation pathways and developing and validating suitable analytical procedures.
However, it may not be necessary to examine specifically for certain degradation products
if it has been demonstrated that they are not formed under accelerated or long-term storage
conditions.
Results from these studies will form an integral part of the information provided to
regulatory authorities.
2.1.3 Selection of batches

For new active substances, data from formal stability studies should be provided on at least
three primary batches of the active substance. The batches should be manufactured to a
minimum of pilot scale by the same synthetic route as, and using a method of manufacture
and procedure that simulates the final process to be used for, production batches. The
overall quality of the batches of active substance placed on formal stability studies should
be representative of the quality of the material to be made on a production scale. Other
supporting data can be provided.
For known active substances, in case the applicant is not the manufacturer of the active
substance, stability data from the manufacturer should be submitted, e.g. Drug Master File,
or a European Certificate of Suitability.
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2.1.4 Container closure system

The stability studies should be conducted on the active substance packaged in a container
closure system that is the same as or simulates the packaging proposed for storage and
distribution.
2.1.5 Specification

Stability studies should include testing of those attributes of the active substance that are
susceptible to change during storage and are likely to influence quality, safety or efficacy.
The testing should cover, as appropriate, the physical, chemical, biological and
microbiological attributes. Validated stability-indicating analytical procedures should be
applied. Whether and to what extent replication should be performed will depend on the
results from validation studies.
2.1.6 Testing frequency

For long-term studies, frequency of testing should be sufficient to establish the stability
profile of the active substance. For active substances with a proposed re-test period of at
least 12 months, the frequency of testing at the long-term storage condition should
normally be every three months over the first year, every six months over the second year,
and annually thereafter through the proposed re-test period.
At the accelerated storage condition, a minimum of three time points, including the initial
and final time points (e.g. 0, 3 and 6 months), from a 6-month study is recommended.
Where an expectation (based on development experience) exists that results from
accelerated studies are likely to approach significant change criteria, increased testing
should be conducted either by adding samples at the final time point or by including a
fourth time point in the study design.
2.1.7 Storage conditions

General case
Minimum time period covered by
Study Storage condition
data at submission
25°C ± 2°C/60% RH ± 5% RH or 12 months
Long-term*
30°C ± 2°C/65% RH ± 5% RH
Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months

* Whether long-term stability studies are performed at 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65%
RH ± 5% RH is determined by the climatic condition in which the active substance is intended to be
stored. Testing at higher humidities like 30°C ± 2°C/75% RH ± 5% RH is also acceptable.
** If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

In general, an active substance should be evaluated under storage conditions (with

appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to
moisture. The storage conditions and the lengths of studies chosen should be sufficient to
cover storage, shipment and subsequent use with due regard to the climatic zone(s) in
which the active substance is intended to be stored (see Annex 1).
The long-term testing should cover a minimum of 12 months’ duration on at least three
primary batches at the time of submission and should be continued for a period of time
sufficient to cover the proposed re-test period. Additional data accumulated during the
assessment period of the registration application should be submitted to the authorities if
requested. Data from the accelerated storage condition and, if appropriate, from the
intermediate storage condition can be used to evaluate the effect of short-term excursions
outside the label storage conditions (such as might occur during shipping).
Long-term, accelerated and, where appropriate, intermediate storage conditions for active
substances are detailed in the sections below. The general case applies if the active
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substance is not specifically covered by a subsequent section. Alternative storage

conditions can be used if justified.
If long-term-studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant
change” occurs at any time during six months’ testing at the accelerated storage condition,
additional testing at the intermediate storage condition should be conducted and evaluated
against significant change criteria. Testing at the intermediate storage condition should
include all tests, unless otherwise justified. The initial application should include a
minimum of six months’ data from a 12-month study at the intermediate storage condition.
“Significant change” for an active substance is defined as failure to meet its specification.

Active substances intended for storage in a refrigerator

Study Storage condition Minimum time period covered by data
at submission
Long-term 5 °C ± 3°C 12 months
Accelerated* 25 °C ± 2 °C/60% RH ± 5% RH 6 months
or
30 °C ± 2 °C/65% RH ± 5% RH

* Whether accelerated stability studies are performed at 25 ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ±

5% RH is determined by the climatic zone in which the active substance is intended to be stored (see Annex 1).
Testing at higher humidities like 30 °C ± 2 °C/75% RH ± 5% RH is also acceptable.

Data from refrigerated storage should be assessed according to the evaluation section of
this guideline, except where explicitly noted below.
If significant change occurs between three and six months’ testing at the accelerated storage
condition, the proposed re-test period should be based on the real-time data available at the
long-term storage condition.
If significant change occurs within the first three months’ testing at the accelerated storage
condition, a discussion should be provided to address the effect of short-term excursions
outside the label storage condition, e.g. during shipping or handling. This discussion can be
supported, if appropriate, by further testing on a single batch of the active substance for a
period shorter than three months but with more frequent testing than usual. It is considered
unnecessary to continue to test an active substance through six months when a significant
change has occurred within the first three months.
Active substances intended for storage in a freezer
Study Storage condition Minimum time period covered by data at
submission
Long-term − 20 °C ± 5°C 12 months

For active substances intended for storage in a freezer, the re-test period should be based on
the real-time data obtained at the long-term storage condition. In the absence of an
accelerated storage condition for active substances intended to be stored in a freezer, testing
on a single batch at an elevated temperature (e.g. 5 °C ± 3 °C or 25 °C ± 2 °C or 30 °C ±
2 °C) for an appropriate time period should be conducted to address the effect of short term
excursions outside the proposed label storage condition, e.g. during shipping or handling.
Active substances intended for storage below −20°C
Active substances intended for storage below −20°C should be treated on a case-by-case
basis.
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2.1.8 Stability commitment

When available long-term stability data on primary batches do not cover the proposed re-
test period granted at the time of approval, a commitment should be made to continue the
stability studies post approval in order to firmly establish the re-test period.
Where the submission includes long-term stability data on three production batches
covering the proposed re-test period, a post-approval commitment is considered
unnecessary. Otherwise, one of the following commitments should be made.
1. If the submission includes data from stability studies on at least three production
batches, a commitment should be made to continue these studies through the proposed
re-test period.
2. If the submission includes data from stability studies on fewer than three production
batches, a commitment should be made to continue these studies through the proposed
re-test period and to place additional production batches, to a total of at least three, on
long-term stability studies through the proposed re-test period.
3. If the submission does not include stability data on production batches, a commitment
should be made to place the first three production batches on long-term stability studies
through the proposed re-test period.
The stability protocol used for long-term studies for the stability commitment should be the
same as that for the primary batches, unless otherwise scientifically justified.
2.1.9 Evaluation

The purpose of the stability study is to establish, based on testing a minimum of two or
three batches of the active substance and evaluating the stability information (including, as
appropriate, results of the physical, chemical, biological and microbiological tests), a re-
test period applicable to all future batches of the active substance manufactured under
similar circumstances. The degree of variability of individual batches affects the confidence
that a future production batch will remain within specification throughout the assigned re-
test period.
The data may show so little degradation and so little variability that it is apparent from
looking at the data that the requested re-test period will be granted. Under these
circumstances, it is normally unnecessary to go through the formal statistical analysis;
providing a justification for the omission should be sufficient.
An approach for analysing the data on a quantitative attribute that is expected to change
with time is to determine the time at which the 95% one-sided confidence limit for the
mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch
variability is small, it is advantageous to combine the data into one overall estimate. This
can be done by first applying appropriate statistical tests (e.g. P values for level of
significance of rejection of more than 0.25) to the slopes of the regression lines and zero
time intercepts for the individual batches. If it is inappropriate to combine data from
several batches, the overall re-test period should be based on the minimum time a batch can
be expected to remain within acceptance criteria.
The nature of any degradation relationship will determine whether the data should be
transformed for linear regression analysis. Usually the relationship can be represented by a
linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical
methods should be employed to test the goodness of fit of the data on all batches and
combined batches (where appropriate) to the assumed degradation line or curve.
Limited extrapolation of the real-time data from the long-term storage condition beyond the
observed range to extent the re-test period can be undertaken, if justified. This justification
should be based on what is known about the mechanism of degradation, the results of
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testing under accelerated conditions, the goodness of fit of any mathematical model, batch
size, existence of supporting stability data, etc. However, this extrapolation assumes that
the same degradation relationship will continue to apply beyond the observed data.
Any evaluation should cover not only the assay, but also the levels of degradation products
and other appropriate attributes.
2.1.10 Statements/labelling

A storage statement should be established for the labelling based on the stability evaluation
of the active substance. Where applicable, specific instructions should be provided,
particularly for active substances that cannot tolerate freezing. Terms such as “ambient
conditions” or “room temperature” must be avoided.
A re-test period should be derived from the stability information, and a re-test date should
be displayed on the container label if appropriate.
The temperature and humidity conditions during transport from the place of synthesis of
the active substance to the manufacturer of the pharmaceutical product need to be taken
into account, if applicable.
2.2. Pharmaceutical products

2.2.1 General

The design of the formal stability studies for the pharmaceutical product should be based
on knowledge of the behaviour and properties of the active substance, and from stability
studies on the active substance and on experience gained from pre-formulation studies and
investigational pharmaceutical products. Attributes to be tested in the formal stability
studies are listed in Annex 2.
2.2.2 Selection of batches

Data from stability studies should be provided on at least three primary batches of the
pharmaceutical product. The primary batches should be of the same formulation and
packaged in the same container closure system as proposed for marketing. The
manufacturing process used for primary batches should simulate that to be applied to
production batches and should provide product of the same quality and meeting the same
specification as that intended for marketing. Two of the three batches should be at least
pilot scale batches and the third one can be smaller, if justified. Where possible, batches of
the pharmaceutical product should be manufactured by using different batches of the active
substance.
Stability studies should be performed on each individual strength and container size of the
pharmaceutical product unless bracketing or matrixing is applied.
Other supporting data can be provided.
2.2.3 Container closure system

Stability testing should be conducted on the dosage form packaged in the container closure
system proposed for marketing (including, as appropriate, any secondary packaging and
container label). Any available studies carried out on the pharmaceutical product outside its
immediate container or in other packaging materials can form a useful part of the stress
testing of the dosage form or can be considered as supporting information, respectively.
2.2.4 Specification

Stability studies should include testing of those attributes of the pharmaceutical product
that are susceptible to change during storage and are likely to influence quality, safety or
efficacy. The testing should cover, as appropriate, the physical, chemical, biological and
microbiological attributes, preservative content (e.g. antioxidant, antimicrobial
preservative), and functionality tests (e.g. for a dose delivery system). Analytical
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procedures should be fully validated, and stability indicating. Whether and to what extent
replication should be performed will depend on the results of validation studies.
Shelf life acceptance criteria should be derived from consideration of all available stability
information. It may be appropriate to have justifiable differences between the shelf life and
release acceptance criteria based on the stability evaluation and the changes observed on
storage. Any differences between the release and shelf life acceptance criteria for
antimicrobial preservative content should be supported by a validated correlation of
chemical content and preservative effectiveness demonstrated during drug development on
the product in its final formulation (except for preservative concentration) intended for
marketing. A single primary stability batch of the pharmaceutical product should be tested
for antimicrobial preservative effectiveness (in addition to preservative content) at the
proposed shelf life for verification purposes, regardless of whether there is a difference
between the release and shelf life acceptance criteria for preservative content.
2.2.5 Testing frequency

For long-term studies, frequency of testing should be sufficient to establish the stability
profile of the pharmaceutical product. For products with a proposed shelf life of at least 12
months, the frequency of testing at the long-term storage condition should normally be
every three months over the first year, every six months over the second year, and annually
thereafter through the proposed shelf life.
At the accelerated storage condition, a minimum of three time points, including the initial
and final time points (e.g. 0, 3 and 6 months), from a 6-month study is recommended.
Where an expectation (based on development experience) exists that results from
accelerated testing are likely to approach significant change criteria, increased testing
should be conducted either by adding samples at the final time point or by including a
fourth time point in the study design.
When testing at the intermediate storage condition is called for as a result of significant
change at the accelerated storage condition, a minimum of four time points, including the
initial and final time points (e.g. 0, 6, 9, 12 months), from a 12-month study is
recommended.
Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or
certain factor combinations are not tested at all, can be applied, if justified.
2.2.6 Storage conditions

In general, a pharmaceutical product should be evaluated under storage conditions (with

appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to
moisture or potential for solvent loss. The storage conditions and the lengths of studies
chosen should be sufficient to cover storage, shipment, and subsequent use with due regard
to the climatic zone(s) in which the product is intended to be marketed (see Annex 1).
In addition as part of the development phase, stability studies conducted on one batch of
the pharmaceutical product for up to three months at 50 °C/ambient humidity may be
useful to identify the formulation and packaging material adequate for extremely hot and
dry conditions.
Photostability testing should be conducted on at least one primary batch of the
pharmaceutical product if appropriate.
Stability testing of the pharmaceutical product after constitution or dilution, if applicable,
should be conducted to provide information for the labelling on the preparation, storage
condition, and in-use period of the constituted or diluted product. This testing should be
performed on the constituted or diluted product through the proposed in-use period on
primary batches as part of the formal stability studies at initial and final time points and, if
full shelf life long-term data will not be available before submission, at 12 months or the
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last time point for which data will be available. In general, this testing need not be repeated
on commitment batches.
The long-term testing should cover a minimum of 12 months’ duration on at least three
primary batches at the time of submission and should be continued for a period of time
sufficient to cover the proposed shelf life. Additional data accumulated during the
assessment period of the registration application should be submitted to the authorities if
requested. Data from the accelerated storage condition can be used to evaluate the effect of
short-term excursions outside the label storage conditions (such as might occur during
shipping).
Long-term, accelerated and, where appropriate, intermediate storage conditions for
pharmaceutical products are detailed in the sections below. The general case applies if the
pharmaceutical product is not specifically covered by a subsequent section. Alternative
storage conditions can be used, if justified.
General case
Study Storage condition Minimum time period covered by
data at submission

25 °C ± 2 °C/60% RH ± 5% RH
Long-term* or 12 months
30 °C ± 2 °C/65% RH ± 5% RH
Intermediate** 30 °C ± 2 °C/65% RH ± 5% RH 6 months
Accelerated 40 °C ± 2 °C/75% RH ± 5% RH 6 months
* Whether long-term stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65%
RH ± 5% RH is determined by the climatic zone in which the pharmaceutical product is intended to be
marketed (see Annex 1). Testing at higher humidities like 30 °C ± 2 °C/75% RH ± 5% RH is also
acceptable.
** If 30 °C ± 2 °C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH and “significant

change” occurs at any time during six months’ testing at the accelerated storage condition,
additional testing at the intermediate storage condition should be conducted and evaluated
against significant change criteria. The initial application should include a minimum of six
months’ data from a 12-month study at the intermediate storage condition.
In general, “significant change” for a pharmaceutical product is defined as:
4. A 5% change in assay from its initial value; or failure to meet the acceptance criteria
for potency when using biological or immunological procedures;
5. Any degradation product exceeding its acceptance criterion;
6. Failure to meet the acceptance criteria for appearance, physical attributes, and
functionality test (e.g. colour, phase separation, resuspendibility, caking, hardness, dose
delivery per actuation); however, some changes in physical attributes (e.g. softening of
suppositories, melting of creams, partial loss of adhesion for transdermal products)
may be expected under accelerated conditions;
and, as appropriate for the dosage form:
7. Failure to meet the acceptance criterion for pH; or
8. Failure to meet the acceptance criteria for dissolution for 12 dosage units.
Pharmaceutical products packaged in impermeable containers
Sensitivity to moisture or potential for solvent loss is not a concern for pharmaceutical
products packaged in impermeable containers that provide a permanent barrier to passage
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of moisture or solvent. Thus, stability studies for products stored in impermeable containers
can be conducted under any controlled or ambient humidity condition.
Pharmaceutical products packaged in semi-permeable containers
Aqueous-based products packaged in semi-permeable containers should be evaluated for
potential water loss in addition to physical, chemical, biological and microbiological
stability. This evaluation can be carried out under conditions of low relative humidity, as
discussed below. Ultimately, it should be demonstrated that aqueous-based pharmaceutical
products stored in semi-permeable containers could withstand low relative humidity
environments.
Other comparable approaches can be developed and reported for non-aqueous, solvent-
based products.
Study Storage condition Minimum time period covered by data
at submission

Long-term* 25 °C ± 2 °C/40% RH ± 5% RH 12 months

or
30 °C ± 2 °C/35% RH ± 5% RH
Intermediate** 30 °C ± 2 °C/35% RH ± 5% RH 6 months
Accelerated 40 °C ± 2 °C/not more than (NMT) 25% 6 months
RH
* Whether long-term stability studies are performed at 25 °C ± 2 °C/40% RH ± 5% RH or 30 °C ± 2 °C/35% RH ±
5% RH is determined by the climatic zone in which the pharmaceutical product is intended to be marketed (see
Annex 1).
** If 30 °C ± 2 °C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition.

For long-term studies conducted at 25 °C ± 2 °C/40% RH ± 5% RH, additional testing at

the intermediate storage condition should be performed as described under the general case
to evaluate the temperature effect at 30 °C if significant change other than water loss
occurs during the six months’ testing at the accelerated storage condition. A significant
change in water loss alone at the accelerated storage condition does not necessitate testing
at the intermediate storage condition. However, data should be provided to demonstrate that
the drug product would not have significant water loss throughout the proposed shelf life if
stored at 25 °C/40% RH.
A 5% loss in water from its initial value is considered a significant change for a product
packaged in a semi-permeable container after an equivalent of three months’ storage at
40 °C/NMT 25% RH. However, for small containers (1 ml or less) or unit-dose products, a
water loss of 5% or more after an equivalent of three months’ storage at 40 °C/NMT 25%
RH may be appropriate, if justified.
An alternative approach to studying at the low relative humidity as recommended in the
table above (for either long-term or accelerated testing) is performing the stability studies
under higher relative humidity and deriving the water loss at the low relative humidity
through calculation. This can be achieved by experimentally determining the permeation
coefficient for the container closure system or, as shown in the example below, using the
calculated ratio of water loss rates between the two humidity conditions at the same
temperature. The permeation coefficient for a container closure system can be
experimentally determined by using the worst-case scenario (e.g. the most diluted of a
series of concentrations) for the proposed pharmaceutical product.
Example of an approach for determining water loss:
For a product in a given container closure system, container size and fill, an appropriate
approach for deriving the water loss rate at the low relative humidity is to multiply the
water loss rate measured at an alternative relative humidity at the same temperature by a
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water loss rate ratio shown in the table below. A linear water loss rate at the alternative
relative humidity over the storage period should be demonstrated.
For example, at a given temperature, e.g. 40°C, the calculated water loss rate during
storage at NMT 25% RH is the water loss rate measured at 75% RH multiplied by 3.0, the
corresponding water loss rate ratio.
Low-humidity Alternative Ratio of water loss rates Calculation
testing conditions testing condition
25 °C/40% RH 25 °C/60% RH 1.5 (100-40)/(100-60)
30 °C/35% RH 30 °C/65% RH 1.9 (100-35)/(100-65)
30 °C/35% RH 30 °C/75% RH 2.6 (100-35)/(100-75)
40 °C/NMT 25% RH 40 °C/75% RH 3.0 (100-25)/(100-75)

Valid water loss rate ratios at relative humidity conditions other than those shown in the
table above can also be used.

Pharmaceutical products intended for storage in a refrigerator

Study Storage condition Minimum time period covered by data
at submission
Long-term 5 °C ± 3 °C 12 months
Accelerated* 25 °C ± 2 °C/60% RH ± 5% RH
or 6 months
30 °C ± 2 °C/65% RH ± 5% RH
* Whether accelerated stability studies are performed at 25 ± 2 °C/60% RH ± 5% RH or 30 °C ±
2 °C/65% RH ± 5% RH is determined by the climatic zone in which the pharmaceutical product is
intended to be marketed (see Annex 1). Testing at higher humidities like 30 °C ± 2 °C/75% RH ± 5%
RH is also acceptable.

If the pharmaceutical product is packaged in a semi-permeable container, appropriate

information should be provided to assess the extent of water loss.
Data from refrigerated storage should be assessed according to the evaluation section of the
guidelines, except where explicitly noted below.
If significant change occurs between three and six months’ testing at the accelerated storage
condition, the proposed shelf life should be based on the real-time data available from the
long-term storage condition.
If significant change occurs within the first three months’ testing at the accelerated storage
condition, a discussion should be provided to address the effect of short term excursions
outside the label storage condition, e.g. during shipment and handling. This discussion can
be supported, if appropriate, by further testing on a single batch of the pharmaceutical
product for a period shorter than three months but with more frequent testing than usual. It
is considered unnecessary to continue to test a product through six months when a
significant change has occurred within the first three months.
Pharmaceutical products intended for storage in a freezer
Minimum time period covered by data
Study Storage condition
at submission
Long-term − 20 °C ± 5 °C 12 months

For pharmaceutical products intended for storage in a freezer, the shelf life should be based
on the real-time data obtained at the long-term storage condition. In the absence of an
accelerated storage condition for pharmaceutical products intended to be stored in a freezer,
testing on a single batch at an elevated temperature (e.g. 5 °C ± 3 °C or 25 °C ± 2 °C or
30 °C ± 2 °C) for an appropriate time period should be conducted to address the effect of
short term excursions outside the proposed label storage condition.
 EM/RC53/12

Pharmaceutical products intended for storage below −20 °C

Pharmaceutical products intended for storage below −20°C should be treated on a case-by-
case basis.
2.2.7 Stability commitment

When available long-term stability data on primary batches do not cover the proposed shelf
life granted at the time of approval, a commitment should be made to continue the stability
studies post approval in order to firmly establish the shelf life.
Where the submission includes long-term stability data from three production batches
covering the proposed shelf life, a post approval commitment is considered unnecessary.
Otherwise, one of the following commitments should be made:
1. If the submission includes data from stability studies on at least three production
batches, a commitment should be made to continue the long-term studies through the
proposed shelf life and the accelerated studies for six months.
2. If the submission includes data from stability studies on fewer than three production
batches, a commitment should be made to continue the long-term studies through the
proposed shelf life and the accelerated studies for six months, and to place additional
production batches, to a total of at least three, on long-term stability studies through the
proposed shelf life and on accelerated studies for six months.
3. If the submission does not include stability data on production batches, a commitment
should be made to place the first three production batches on long-term stability studies
through the proposed shelf life and on accelerated studies for six months.
The stability protocol used for studies on commitment batches should be the same as that
for the primary batches, unless otherwise scientifically justified.
2.2.8 Evaluation

A systematic approach should be adopted in the presentation and evaluation of the stability
information, which should include, as appropriate, results from the physical, chemical,
biological and microbiological tests, including particular attributes of the dosage form (for
example, dissolution rate for solid oral dosage forms).
The purpose of the stability study is to establish, based on testing a minimum of two or
three batches of the pharmaceutical product, a shelf life and label storage instructions
applicable to all future batches of the pharmaceutical product manufactured and packaged
under similar circumstances. The degree of variability of individual batches affects the
confidence that a future production batch will remain within specification throughout its
shelf life.
Where the data show so little degradation and so little variability that it is apparent from
looking at the data that the requested shelf life will be granted, it is normally unnecessary
to go through the formal statistical analysis.
An approach for analysing the data on a quantitative attribute that is expected to change
with time is to determine the time at which the 95% one-sided confidence limit for the
mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch
variability is small, it is advantageous to combine the data into one overall estimate. This
can be done by first applying appropriate statistical tests (e.g. P values for level of
significance of rejection of more than 0.25) to the slopes of the regression lines and zero
time intercepts for the individual batches. If it is inappropriate to combine data from
several batches, the overall shelf life should be based on the minimum time a batch can be
expected to remain within acceptance criteria.
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The nature of any degradation relationship will determine whether the data should be
transformed for linear regression analysis. Usually the relationship can be represented by a
linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical
methods should be employed to test the goodness of fit of the data on all batches and
combined batches (where appropriate) to the assumed degradation line or curve.
Limited extrapolation of the real-time data from the long-term storage condition beyond the
observed range to extent the shelf life can be undertaken, if justified. This justification
should be based on what is known about the mechanism of degradation, the results of
testing under accelerated conditions, the goodness of fit of any mathematical model, batch
size, existence of supporting stability data, etc. However, this extrapolation assumes that
the same degradation relationship will continue to apply beyond the observed data.
Any evaluation should consider not only the assay but also the degradation products and
other appropriate attributes. Where appropriate, attention should be paid to reviewing the
adequacy of the mass balance and different stability and degradation performance.
2.2.9 Statements/labelling

A storage statement should be established for the labelling based on the stability evaluation
of the pharmaceutical product. Where applicable, specific instruction should be provided,
particularly for pharmaceutical products that cannot tolerate freezing. Terms such as
“ambient conditions” or “room temperature” must be avoided.
There should be a direct link between the label storage statement and the demonstrated
stability of the pharmaceutical product. An expiration date should be displayed on the
container label. The following statements should be used if applicable:
Testing condition where the stability of the pharmaceutical Recommended labelling statement
product has been shown

For countries in Climatic Zones I and II: “Store below 30 °C” *

25 °C/60% RH (long-term)
40 °C/75% RH (accelerated)
For countries in Climatic Zones III and IVA: “Store below 30 °C”
30 °C/65% RH (long-term)
40 °C/75% RH (accelerated)
For countries in Climatic Zones I and II: “Store below 30 °C”
25 °C/60% RH (long-term)
30 °C/65% RH (intermediate)
For countries in Climatic Zone III and IVA: “Store and transport below 30 °C”
30 °C/65% RH (long-term)
For countries in Climatic Zones I and II: “Store below 25 °C”
25 °C/60% RH (long-term)
5 °C ± 3 °C ”Store and transport in a refrigerator (2 °C
to 8 °C)” **
−20°C ± 5°C ”Store in a freezer and transport frozen (-
5 °C to -20 °C)” ***
* In the European Union, in this case the pharmaceutical product does not require any special storage condition
on the label.
** In case stability data generated at 25 °C/60% RH, 30 °C/65% or 30 °C/75% RH (accelerated) support transport
outside the refrigerator, a labelling statement “Store in a refrigerator” is acceptable.
*** In case stability data generated at 5 °C ± 3 °C (accelerated) support transport outside the freezer, a labelling
statement “Store in a freezer” is acceptable.
In principle, pharmaceutical products should be packed in containers that ensure stability
and protect the pharmaceutical product from deterioration. A storage statement should not
be used to compensate for inadequate or inferior packaging. The following additional
labelling statements could be used in cases where the result of the stability testing
demonstrate limiting factors.
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Limiting factors Additional labelling statement, where relevant

Pharmaceutical products that cannot tolerate refrigerating “Do not refrigerate or freeze”*
Pharmaceutical products that cannot tolerate freezing “Do not freeze”*
Light sensitive pharmaceutical products “Protect from light”
Pharmaceutical products that cannot tolerate excessive “Store and transport always below 30 °C”
heat, e.g. suppositories
* Depending on the pharmaceutical form and the properties of the product, there may be a risk of deterioration
due to physical changes if subjected to low temperatures, e.g. emulsions. Low temperatures may also have an
effect on the packaging in certain cases. An additional statement may be necessary to take account of this
possibility.

General precautionary statements, such as “store in a dry place”, may be included, but
should not be used to conceal stability problems.
If applicable, recommendations should also be made as to the utilization period and storage
conditions after opening and dilution or reconstitution of a solution, e.g. an antibiotic
injection supplied as a powder for reconstitution.
In-use stability
The purpose of in-use stability testing is to establish–where applicable–the period of time
during which a multi-dose product can be used while retaining acceptable quality once the
container is opened and the first dose is removed.
A minimum of two batches, at least pilot scale batches, should be subjected to the test. At
least one of the batches should be chosen towards the end of its shelf life. If such results are
not available, one batch should be tested at the final point of the submitted stability studies.
As far as possible the test should be designed to simulate the use of the product in practice
taking into consideration the filling volume of the container and any dilution or
reconstitution before use. At intervals comparable to those which occur in practice,
appropriate quantities should be removed by the withdrawal methods normally used and
described in the product literature. Sampling should take place under normal environmental
conditions of use.
The appropriate physical, chemical and microbial properties of the product susceptible to
change during storage should be determined over the period of the proposed in-use shelf
life. If possible, testing should be performed at intermediate time points and at the end of
the proposed in-use shelf life on the final remaining amount of the product in the container.
Specific parameters, e.g. preservatives, need to be studied.
Where relevant, studies on diluted or reconstituted material must be performed.
To accommodate certain specific pharmacy dosing regimes, up to three months open
storage may be required.
Variations
Once the pharmaceutical product has been registered, additional stability studies are
required whenever major variations are made like the following:
1. Change in the manufacturing process;
2. Change in the composition of the pharmaceutical product;
3. Change of the immediate packaging.
In all cases of variations, the applicant has to investigate whether the intended change will
have an impact on the quality characteristics of active substances or pharmaceutical
products and consequently on their stability.
 EM/RC53/12

The scope and design of the stability studies for variations and changes are based on the
knowledge and experience acquired on active substances and pharmaceutical products.
The results of these stability studies should be communicated to the regulatory authorities
concerned.
Ongoing stability studies
After approval, the stability of the pharmaceutical product should be monitored according
to a continuous appropriate programme that will permit the detection of any stability issue
(e.g. changes in levels of impurities or dissolution profile) associated with the formulation
in its marketed container closure system. The purpose of the ongoing stability programme
is to monitor the product over its shelf life and to determine that the product remains, and
can be expected to remain, within specifications under the labelled storage conditions.
This mainly applies to the pharmaceutical product in the container closure system in which
it is sold, but consideration should also be given to the inclusion of bulk products in the
programme. For example, when the bulk product is stored for a long period before being
packaged and/or shipped from a manufacturing site to a packaging site, the impact on the
stability of the packaged product should be evaluated and studied. In addition,
consideration should be given to intermediates that are stored and used over prolonged
periods.
The ongoing stability programme should be described in a written protocol, and results
formalized as a report.
The protocol for an on-going stability programme should extend to the end of the shelf life
period and should include, but not be limited to, the following parameters:
• Number of batch(es) per strength and different batch sizes, if applicable;
• Relevant physical, chemical, microbiological and biological test methods;
• Acceptance criteria;
• Reference to test methods;
• Description of the container closure system(s);
• Testing intervals (time points);
• Description of the conditions of storage (standardized conditions for long-term
testing as described in this guideline, and consistent with the product labelling,
should be used);
• Other applicable parameters specific to the pharmaceutical product.
The protocol for the ongoing stability programme can be different from that of the initial
long-term stability study as submitted in the marketing authorization dossier provided that
this is justified and documented in the protocol (for example the frequency of testing, or
when updating to revised recommendations).
The number of batches and frequency of testing should provide a sufficient amount of data
to allow for trend analysis. Unless otherwise justified, at least one batch per year of product
manufactured in every strength and every primary packaging type, if relevant, should be
included in the stability programme (unless none are produced during that year). The
principle of bracketing and matrixing designs may be applied if scientifically justified in
the protocol.
In certain situations, additional batches should be included in the ongoing stability
programme. For example, an ongoing stability study should be conducted after any
significant change or significant deviation to the process or container closure system. Any
reworking, reprocessing or recovery operation should also be considered for inclusion.
Out-of-specification results or significant atypical trends should be investigated. Any
confirmed out-of-specification result, or significant negative trend should be reported to the
 EM/RC53/12

relevant competent authorities. The possible impact on batches on the market should be
considered in consultation with the relevant competent authorities.
A summary of all the data generated, including any interim conclusions on the programme,
should be written and maintained. This summary should be subjected to periodic review.

3. Glossary
The following definitions are provided to facilitate interpretation of the guidelines.
Accelerated testing
Studies designed to increase the rate of chemical degradation or physical change of an
active substance or pharmaceutical product by using exaggerated storage conditions as part
of the formal stability studies. Data from these studies, in addition to long-term stability
studies, can be used to assess longer term chemical effects at non-accelerated conditions
and to evaluate the effect of short-term excursions outside the label storage conditions such
as might occur during shipping. Results from accelerated testing studies are not always
predictive of physical changes.
Active substance
The unformulated active substance that may subsequently be formulated with excipients to
produce the dosage form.
Bracketing
The design of a stability schedule such that only samples on the extremes of certain design
factors, e.g. strength, package size, are tested at all time points as in a full design. The
design assumes that the stability of any intermediate levels is represented by the stability of
the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if
the strengths are identical or very closely related in composition (e.g. for a tablet range
made with different compression weights of a similar basic granulation, or a capsule range
made by filling different plug fill weights of the same basic composition into different size
capsule shells). Bracketing can be applied to different container sizes or different fills in the
same container closure system.
Climatic zones
The four zones in the world that are distinguished by their characteristic prevalent annual
climatic conditions (see Annex 1).
Commitment batches
Production batches of an active substance or pharmaceutical product for which the stability
studies are initiated or completed post approval through a commitment made in the
registration application.
Container closure system
The sum of packaging components that together contains and protects the dosage form.
This includes primary packaging components and secondary packaging components, if the
latter are intended to provide additional protection to the pharmaceutical product. A
packaging system is equivalent to a container closure system.
Dosage form
A pharmaceutical product type (e.g. tablet, capsule, solution, cream) that contains an active
substance generally, but not necessarily, in association with excipients.
Excipient
Anything other than the active substance in the dosage form.
 EM/RC53/12

Expiration date / Expiry date

The date placed on the container label of a pharmaceutical product designating the time
prior to which a batch of the product is expected to remain within the approved shelf life
specification if stored under defined conditions, and after which it must not be used.
Formal stability studies
Long-term and accelerated (and intermediate) studies undertaken on primary and/or
commitment batches according to a prescribed stability protocol to establish or confirm the
re-test period of an active substance or the shelf life of a pharmaceutical product.
Impermeable containers
Containers that provide a permanent barrier to the passage of gases or solvents, e.g. sealed
aluminium tubes for semi-solids, sealed glass ampoules for solutions.
Long-term testing
Stability studies under the recommended storage condition for the re-test period or shelf
life proposed (or approved) for labelling.
Mass balance
The process of adding together the assay value and levels of degradation products to see
how closely these add up to 100% of the initial value, with due consideration of the margin
of analytical error.
Matrixing
The design of a stability schedule such that a selected subset of the total number of possible
samples for all factor combinations is tested at a specified time point. At a subsequent time
point, another subset of samples for all factor combinations is tested. The design assumes
that the stability of each subset of samples tested represents the stability of all samples at a
given time point. The differences in the samples for the same pharmaceutical product
should be identified as, for example, covering different batches, different strengths,
different sizes of the same container closure system, and, possibly in some cases, different
container closure systems.
Mean kinetic temperature
A single derived temperature that, if maintained over a defined period of time, affords the
same thermal challenge to an active substance or pharmaceutical product as would be
experienced over a range of both higher and lower temperatures for an equivalent defined
period. The mean kinetic temperature is higher than the arithmetic mean temperature and
takes into account the Arrhenius equation.
When establishing the mean kinetic temperature for a defined period, the formula of
Haynes [5] can be used.
New Chemical Entity (NCE)
An active pharmaceutical substance not previously contained in any pharmaceutical
product registered with the national or regional authority concerned. A new salt, ester, or
non-covalent-bond derivative of an approved active substance is considered a new
molecular entity for the purpose of stability testing under this guidance.
Pharmaceutical product
The dosage form in the final immediate packaging intended for marketing.
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Pilot scale batch

A batch of an active substance or pharmaceutical product manufactured by a procedure
fully representative of and simulating that to be applied to a full production scale batch. For
solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full
production scale or 100 000 tablets or capsules, whichever is the larger.
Primary batch
A batch of an active substance or pharmaceutical product used in a formal stability study,
from which stability data are submitted in a registration application for the purpose of
establishing a re-test period or shelf life, respectively. A primary batch of an active
substance should be at least a pilot scale batch. For a pharmaceutical product, two of the
three batches should be at least pilot scale batch, and the third batch can be smaller if it is
representative with regard to the critical manufacturing steps. However, a primary batch
may be a production batch.
Production batch
A batch of an active substance or pharmaceutical product manufactured at production scale
by using production equipment in a production facility as specified in the application.
Re-test date
The date after which samples of the active substance should be examined to ensure that the
material is still in compliance with the specification and thus suitable for use in the
manufacture of a given pharmaceutical product.
Re-test period
The period of time during which the active substance is expected to remain within its
specification and, therefore, can be used in the manufacture of a given pharmaceutical
product, provided that the active substance has been stored under the defined conditions.
After this period, a batch of active substance destined for use in the manufacture of a
pharmaceutical product should be re-tested for compliance with the specification and then
used immediately. A batch of active substance can be re-tested multiple times and a
different portion of the batch used after each re-test, as long as it continues to comply with
the specification. For most biotechnological/biological substances known to be labile, it is
more appropriate to establish a shelf life than a re-test period. The same may be true for
certain antibiotics.
Semi-permeable containers
Containers that allow the passage of solvent, usually water, while preventing solute loss.
The mechanism for solvent transport occurs by adsorption into one container surface,
diffusion through the bulk of the container material, and desorption from the other surface.
Transport is driven by a partial-pressure gradient. Examples of semi-permeable containers
include plastic bags and semi-rigid, low-density polyethylene (LDPE) pouches for large
volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.
Shelf life (also referred to as expiration dating period)
The time period during which a pharmaceutical product is expected to remain within the
approved shelf life specification, provided that it is stored under the conditions defined on
the container label.
Specification
See ICH Q6A and Q6B.
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Specification – Release
The combination of physical, chemical, biological and microbiological tests and acceptance
criteria that determine the suitability of a pharmaceutical product at the time of its release.
Specification - Shelf life
The combination of physical, chemical, biological and microbiological tests and acceptance
criteria that determine the suitability of an active substance throughout its re-test period, or
that a pharmaceutical product should meet throughout its shelf life.
Storage condition tolerances
The acceptable variations in temperature and relative humidity of storage facilities for
formal stability studies. The equipment should be capable of controlling the storage
condition within the ranges defined in this guideline. The actual temperature and humidity
(when controlled) should be monitored during stability storage. Short-term spikes due to
opening of doors of the storage facility are accepted as unavoidable. The effect of
excursions due to equipment failure should be addressed, and reported if judged to affect
stability results. Excursions that exceed the defined tolerances for more than 24 hours
should be described in the study report and their effect assessed.
Stress testing (active substance)
Studies undertaken to elucidate the intrinsic stability of the active substance. Such testing is
part of the development strategy and is normally carried out under more severe conditions
than those used for accelerated testing.
Stress testing (pharmaceutical product)
Studies undertaken to assess the effect of severe conditions on the pharmaceutical product.
Such studies include photostability testing and specific testing on certain products, (e.g.
metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).
Supporting data
Data, other than those from formal stability studies, that support the analytical procedures,
the proposed re-test period or shelf life, and the label storage statements. Such data include:
1) stability data on early synthetic route batches of active substance, small scale batches of
materials, investigational formulations not proposed for marketing, related formulations,
and product presented in containers and closures other than those proposed for marketing;
2) information regarding test results on containers; and 3) other scientific rationales.
 EM/RC53/12

Annex 1

Assignment of climatic zones and recommended storage conditions

In order to be able to reduce the amount of stability testing, the number of different long-
term testing conditions must be reduced to a sufficient extent. This was proposed by
Schumacher in 1972 [6] and Grimm in 1986 [7] and in 1998 [8] when they defined four
different long-term test conditions which match with the climatic conditions of the target
markets categorized in just four different climatic zones (CZ). This concept is described in
regulatory guidelines and pharmacopoeias and became an established standard in
developing pharmaceutical products.
At the 40th meeting of the WHO Expert Committee on Specifications for Pharmaceutical
Preparations, Geneva, October 2005 [9], it was recommended to split the current climatic
zone IV (hot and humid) into CZ IVA – for which 30 °C/65% RH will remain the standard
long-term testing condition – and CZ IVB, for which, if justified, 30 °C/75% RH will
become the long-term testing condition. The following criteria [10] and long-term testing
conditions are therefore proposed.
Criteria
Mean annual temperature measured in Long-term testing
CZ Definition
the open air/Mean annual partial water conditions
vapour pressure
Temperate
I ≤ 15 °C / ≤ 11 hPa 21 °C / 45% RH
climate
Subtropical and
II > 15 to 22 °C / > 11 to 18 hPa 25 °C / 60% RH
Mediterranean climate
Hot and dry
III > 22 °C / ≤ 15 hPa 30 °C / 35% RH
climate
IVA Hot and humid climate > 22 °C / > 15 to 27 hPa 30 °C / 65% RH
IVB Hot and very humid climate > 22 °C / > 27 hPa 30 °C / 75% RH

Additional testing conditions, i.e. accelerated and – if applicable – intermediate conditions

have to be used as described in this guideline.
The detailed analysis of meteorological measurements as described above, and the
evaluation of the climatic conditions in each country of the Region resulted in the
following classification and recommended testing condition for long-term stability studies.
 EM/RC53/12

Recommended
Country CZ II CZ III CZ IVA long-term testing
condition*
Afghanistan + + 30 °C/65% RH
Bahrain + 30 °C/65% RH
Djibouti + 30 °C/65% RH
Egypt + + 30 °C/65% RH**
Iran, Islamic
+ + + 30 °C/65% RH**
Republic of
Iraq + 30 °C/35% RH
Jordan + (+) 30 °C/65% RH**
Kuwait + 30 °C/65% RH
Lebanon + (+) 25 °C/60% RH
Libyan Arab
+ (+) 25 °C/60% RH
Jamahiriya
Morocco + 25 °C/60% RH
Oman (+) + 30 °C/65% RH
Pakistan + + + 30 °C/65% RH
Palestine + 25 °C/60% RH
Qatar + 30 °C/65% RH
Saudi Arabia + + 30 °C/65% RH**
Somalia + 30 °C/65% RH
Sudan + + 30 °C/65% RH**
Syrian Arab
+ (+) 25 °C/60% RH
Republic
Tunisia + (+) 25 °C/60% RH
United Arab
+ + 30 °C/65% RH
Emirates
Yemen + + 30 °C/65% RH
+ Climatic zone assigned
(+) Deserted part of the country
* The hottest and most humid climatic zone has been selected to establish the adequate stability testing condition
for a particular country.
** Aqueous-based solutions in semi-permeable packaging, and dosage forms sensitive to low humidity, e.g. hard-
gelatin capsules, may require testing at low humidity according to the procedure described in this guideline.

Test results conducted at higher temperatures and humidities, e.g. at 30 °C/75% RH, should
be acceptable for all countries.
 EM/RC53/12

Annex 2
Testing parameters
The following list of parameters for each dosage form is presented as a guide for the types
of tests to be included in a stability study. In general, appearance, assay and degradation
products should be evaluated for all dosage forms, as well as preservative and antioxidant
content if applicable.
The microbial quality of multiple dose sterile and non-sterile dosage forms should be
controlled. Challenge tests should be carried out at least at the beginning and at the end of
the shelf life.
It is not expected that every listed test be performed at each time point. This applies in
particular to sterility testing, which may be conducted for most parenteral products at the
beginning and at the end of the stability test period. Tests for pyrogens and bacterial
endotoxins may be limited to the time of release and at appropriate intervals during the
stability period. Sterile dosage forms containing dry materials (powder filled or lyophilized
products) and solutions packaged in sealed glass ampoules may need no additional
microbiological testing beyond the initial time point. The level of microbiological
contamination in liquids packed in glass containers with flexible seals or in plastic
containers should be tested no less than at the beginning and at the end of the stability test
period.
The list of tests presented for each dosage form is not intended to be exhaustive, nor is
expected that every listed test be included in the design of a stability protocol for a
particular pharmaceutical product (for example, a test for odour should be performed only
when necessary and with consideration for analyst safety).
The storage orientation of the product, i.e. upright versus inverted, may need to be included
in a protocol where there has been a change in the container/closure system.
1. Tablets
Dissolution (or disintegration, if justified), water content and hardness/friability.

2. Capsules
Hard gelatin capsules: brittleness, dissolution (or disintegration, if justified), water content,
and level of microbial contamination.
Soft gelatin capsules: Dissolution (or disintegration, if justified), level of microbial
contamination, pH, leakage, and pellicle formation.
3. Emulsions
Phase separation, pH, viscosity, level of microbial contamination, and mean size and
distribution of dispersed globules.
4. Oral Solutions and Suspensions
Formation of precipitate, clarity for solutions, pH, viscosity, extractables, level of microbial
contamination. Also, polymorphic conversion may be examined, if applicable.
Additionally for suspensions, redispersibility, rheological properties and mean size and
distribution of particles should be considered.
5. Powders for oral solution or suspension
Water content, and reconstitution time.
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Reconstituted products (solutions and suspensions) should be evaluated as described in

“Oral Solutions and Suspensions” above, after preparation according to the recommended
labelling, through the maximum intended use period.
6. Metered-dose Inhalers and Nasal Aerosols
Dose content uniformity, labelled number of medication actuations per container meeting
dose content uniformity, aerodynamic particle size distribution, microscopic evaluation,
water content, leak rate, level of microbial contamination, valve delivery (shot weight) and
extractables/leachables from plastic and elastomeric components. Samples should be stored
in upright and inverted/on-the-side orientations.
For suspension-type aerosols, the appearance of the valve components and container’s
contents should be evaluated microscopically for large particles and changes in
morphology of the drug surface particles, extent of agglomerates, crystal growth, as well as
foreign particulate matter. These particles lead to clogged valves or non-reproducible
delivery of a dose. Corrosion of the inside of the container or deterioration of the gaskets
may adversely affect the performance of the drug product.
7. Nasal Sprays: Solutions and Suspensions
Clarity (for solution), level of microbial contamination, pH, particulate matter, unit spray
medication content uniformity, number of actuations meeting unit spray content uniformity
per container, droplet and/or particle size distribution, weight loss, pump delivery,
microscopic evaluation (for suspensions), foreign particulate matter and
extractable/bleachable from plastic and elastomeric components of the container, closure
and pump.
8. Topical, Ophthalmic and Otic Preparations
Included in this broad category are ointments, creams, lotions, paste, gel, solutions, eye
drops, and cutaneous sprays.
Topical preparations should be evaluated for clarity, homogeneity, pH, resuspendability (for
lotions), consistency, viscosity, particle size distribution (for suspensions, when feasible),
level of microbial contamination/sterility and weight loss (when appropriate).
Evaluation of ophthalmic or otic products (e.g. creams, ointments, solutions, and
suspensions) should include the following additional attributes: sterility, particulate matter,
and extractable.
Evaluation of cutaneous sprays should include: Pressure, weight loss, net weight dispensed,
delivery rate, level of microbial contamination, spray pattern, water content, and particle
size distribution (for suspensions).
9. Suppositories
Softening range, dissolution (at 37 °C).
10. Small Volume Parenterals (SVPs)
Colour, clarity (for solutions), particulate matter, pH, sterility, endotoxins.
Stability studies for powders for injection solution should include monitoring for colour,
reconstitution time and water content. Specific parameters to be examined at appropriate
intervals throughout the maximum intended use period of the reconstituted drug product,
stored under condition(s) recommended in labelling, should include clarity, colour, pH,
sterility, pyrogen/endotoxin and particulate matter.
The stability studies for Suspension for Injection should include in addition particle size
distribution, redispersibility and rheological properties.
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The stability studies for Emulsion for Injection should include in addition phase separation,
viscosity, and mean size and distribution of dispersed phase globules.
11. Large Volume Parenterals (LVPs)
Colour, clarity, particulate matter, pH, sterility, pyrogen/endotoxin, and volume.
12. Transdermal Patches
In-vitro release rates, leakage, level of microbial contamination/sterility, peel and adhesive
forces.
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References
1. WHO. 1996. Guidelines for stability testing of pharmaceutical products containing
well established drug substances in conventional dosage forms. WHO Technical
Report Series 863, Annex 5. These guidelines were revised at the 37th meeting of the
WHO Expert Committee on Specifications for Pharmaceutical Preparations, Geneva,
22–26 October 2001.
2. The development of a regional stability guideline initiated in 1993, when the World
Health Organization (WHO) Regional Office for the Eastern Mediterranean (EMRO)
organised a workshop in Amman, Jordan. A follow-up meeting in Damascus, Syrian
Arab Republic, was held in 1994. In 1995, the Arab Union of the Manufacturers of
Pharmaceutical and Medical Appliances (AUPAM) published the “Arab Guidelines on
Stability Testing of Pharmaceutical Products”, which were updated in 2002. In
November 2003, the Executive Board of the Health Minister’s Council for GCC States
released “The GCC Guidelines on Stability Testing of Pharmaceutical Products”.
3. The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a
joint regulatory/industry project to improve, through harmonization, the efficiency of
the process for developing and registering new pharmaceutical products in Europe,
Japan and the United States, in order to make these products available to patients with
a minimum of delay. The World Health Organization (WHO) participated as observer
at ICH Steering Committee meetings, and contributed to the development of ICH
guidelines at ICH Expert Working Group (EWG) meetings.
Further information can be found at the ICH homepage
http://www.ich.org/cache/compo/276-254-1.html
The following ICH Guidelines may be consulted in the context of stability testing:
ICH Q1A: “Stability Testing of New Drug Substances and
Products”http://www.ich.org/LOB/media/MEDIA419.pdf
ICH Q1B: “Photostability Testing of New Drug Substances and
Products”http://www.ich.org/LOB/media/MEDIA412.pdf
ICH Q1C: “Stability Testing of New Dosage
Forms”http://www.ich.org/LOB/media/MEDIA413.pdf
ICH Q1D: “Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products” http://www.ich.org/LOB/media/MEDIA414.pdf
ICH Q1E: “Evaluation for Stability Data”
http://www.ich.org/LOB/media/MEDIA415.pdf
ICH Q2A: “Text on Validation of Analytical
Procedures”http://www.ich.org/LOB/media/MEDIA417.pdf
ICH Q2B: “Validation of Analytical Procedures:
Methodology”http://www.ich.org/LOB/media/MEDIA418.pdf
ICH Q3A: “Impurities in New Drug
Substances”http://www.ich.org/LOB/media/MEDIA422.pdf
ICH Q3B: “Impurities in New Drug
Products”http://www.ich.org/LOB/media/MEDIA421.pdf
ICH Q5C: “Stability Testing of Biotechnological/Biological Products”
http://www.ich.org/LOB/media/MEDIA427.pdf
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ICH Q6A: “Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical
Substances”http://www.ich.org/LOB/media/MEDIA430.pdf
ICH Q6B: “Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products”http://www.ich.org/LOB/media/MEDIA432.pdf
4. The ERA-40 Reanalysis conducted by the European Centre for Medium-Range
Weather Forecasts (ECMWF) is a process in which global weather observations are
assembled to form a regular mesh covering the earth with a resolution of about 125 km.
Measurements take place every 6th hour. Reanalysed temperatures and dewpoints from
1979 to 2002 were averaged into monthly means at 00:00 UTC, 06:00 UTC, 12:00
UTC and 18:00 UTC (Coordinated Universal Time). Vapour pressures – applying an
updated version of Wexler’s equation – and relative humidities were then determined
using basic thermodynamic relationships. For further details see Uppala SM et al. The
ERA-40 Reanalysis. Quarterly journal of the Royal Meteorological Society, 131:2961–
3012.
5. Haynes JD. Worldwide virtual temperatures for product stability testing. Journal of
pharmaceutical sciences, 1971, 60:927–9.
6. Schumacher P. Über eine für die Haltbarkeit von Arzneimitteln maßgebliche
Klimaeinteilung [The impact of climate classification on the stability of medicines].
Die Pharmazeutische Industrie, 1972, 34:481–83.
7. Grimm W. Storage conditions for stability testing (Part 2). Drugs made in Germany,
1986, 29:39–47.
8. Grimm W. Extension of the International Conference on Harmonization Tripartite
Guideline for stability testing of new drug substances and products to countries of
Climatic Zones III and IV. Drug development and industrial pharmacy, 1998, 24:313–
25.
9. 40th meeting of the WHO Expert Committee on Specifications for Pharmaceutical
Preparations, Geneva, 24–28 October 2005.
10. Zahn M et al. A risk-based approach to establish stability testing conditions for tropical
countries. Journal of pharmaceutical sciences, 2006, 95:946–65.