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Current Step 4 version
dated 6 February 2003

CH. Srinivasa Reddy
Quality Assurance at JUBILANT
GENERICS LIMITED

The purpose of this note is to outline the
changes made in Q1A(R) that result from
adoption of ICH Q1F “Stability Data
Package for Registration Applications in
Climatic Zones III and IV”. These changes
are:

 The intermediate storage condition has been changed from 30°C ±
2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH in the
following sections:
 • 2.1.7.1 Drug Substance - Storage Conditions - General Case
 • 2.2.7.1 Drug Product - Storage Conditions - General Case
 • 2.2.7.3 Drug products packaged in semi-permeable containers
 • 3 Glossary - “Intermediate testing”

30°C ± 2°C/65% RH ± 5% RH can be a
suitable alternative long-term storage
condition to 25°C ± 2°C/60% RH ± 5% in
the following sections:

30°C ± 2°C/35% RH ± 5% RH has been
added as a suitable alternative long-term
storage condition to 25°C ± 2°C/40% RH ±
5% and the corresponding example for the
ratio of water-loss rates has been included
in the following section:

Mid-stream switch of the intermediate
storage condition from 30°C ± 2°C/60%
RH ± 5% RH to 30°C ± 2°C/65% RH ± 5%
RH can be appropriate provided that the
respective storage conditions and the date
of the switch are clearly documented and
stated in the registration application.

The following guideline is a revised version
of the ICH Q1A guideline and defines the
stability data package for a new drug
substance or drug product that is sufficient
for a registration application within the
three regions of the EC, Japan, and the
United States. It does not seek necessarily
to cover the testing for registration in or
export to other areas of the world.

The guideline addresses the information to
be submitted in registration applications for
new molecular entities and associated
drug products. This guideline does not
currently seek to cover the information to
be submitted for abbreviated or abridged
applications, variations, clinical trial
applications

The purpose of stability testing is to
provide evidence on how the quality of a
drug substance or drug product varies with
time under the influence of a variety of
environmental factors such as
temperature, humidity, and light, and to
establish a re-test period for the drug
substance or a shelf life for the drug
product and recommended storage
conditions.

The choice of test conditions defined in
this guideline is based on an analysis of
the effects of climatic conditions in the
three regions of the EC, Japan and the
United States. The mean kinetic
temperature in any part of the world can be
derived from climatic data, and the world
can be divided into four climatic zones, I-
IV. This guideline addresses climatic zones
I and II.

2.1.1. General
Information on the stability of the drug
substance is an integral part of the
systematic approach to stability evaluation.

Stress testing of the drug 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 drug
substance and the type of drug product
involved.

Stress testing is likely to be carried out on
a single batch of the drug 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% RH or greater) where
appropriate, oxidation, and photolysis on
the drug substance.

The testing should also evaluate the
susceptibility of the drug 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. The
standard conditions for photostability
testing are described in ICH Q1B.

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.

Data from formal stability studies should be
provided on at least three primary batches
of the drug 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 stability studies should be
conducted on the drug substance
packaged in a container closure system
that is the same as or simulates the
packaging proposed for storage and
distribution.

Specification, which is a list of tests,
reference to analytical procedures, and
proposed acceptance criteria, is addressed
in ICH Q6A and Q6B. In addition,
specification for degradation products in a
drug substance is discussed in Q3A.

Stability studies should include testing of
those attributes of the drug substance that
are susceptible to change during storage
and are likely to influence quality, safety,
and/or efficacy. The testing should cover,
as appropriate, the physical, chemical,
biological, and microbiological attributes.
Validated stability-indicating analytical
procedures should be applied.

 For long term studies, frequency of testing
should be sufficient to establish the stability
profile of the drug substance. For drug
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 3 months over the first
year, every 6 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.

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.

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

*It is up to the applicant to decide whether
long term stability studies are performed at
25 ± 2°C/60% RH ± 5% RH or 30°C ±
2°C/65% RH ± 5% RH.
**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 6 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 6 months’ data from a 12-month
study at the intermediate storage condition.
 “Significant change” for a drug substance is defined as
failure to meet its specification

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

If significant change occurs between 3 and
6 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

Study Storage condition Minimum
time period covered by data at
submission
Long term - 20°C ± 5°C 12 months

For drug 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 drug
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) 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.

Drug substances intended for storage
below -20°C should be treated on a
case-by-case basis.

 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
 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.

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 purpose of the stability study is to establish,
based on testing a minimum of three batches of
the drug 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 drug 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

A storage statement should be established for the labeling in
accordance with relevant national/regional requirements. The
statement should be based on the stability evaluation of the
drug substance. Where applicable, specific instructions
should be provided, particularly for drug substances that
cannot tolerate freezing. Terms such as “ambient conditions”
or “room temperature” should be avoided.

A re-test period should be derived from the
stability information, and a retest date
should be displayed on the container label
if appropriate.
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