INTERNATIONAL
CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS
FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN
USE
ICH
HARMONISED TRIPARTITE GUIDELINE
STABILITY
TESTING OF
NEW
DRUG SUBSTANCES AND PRODUCTS
Q1A(R2)
Current
Step 4 version
dated
6 February 2003
This
Guideline has been developed by the appropriate ICH Expert Working Group and
has
been subject to consultation by the regulatory parties, in accordance with the
ICH
Process. At Step 4 of the Process the final draft is
recommended for adoption to the
regulatory
bodies of the European Union, Japan and USA.
TABLE
OF CONTENTS
1.
INTRODUCTION
1.1.
Objectives of the Guideline
1.2.
Scope of the Guideline
1.3.
General Principles
2.
GUIDELINES
2.1.
Drug Substance
2.1.1.
General
2.1.2.
Stress Testing
2.1.3.
Selection of Batches
2.1.4.
Container Closure System
2.1.5.
Specification
2.1.6.
Testing Frequency
2.1.7.
Storage Conditions
2.1.8.
Stability Commitment
2.1.9.
Evaluation
2.1.10.
Statements/Labeling
Stability Testing of New Drug Substances
and Products
2.2.
Drug Product
2.2.1.
General
2.2.2.
Photostability Testing
2.2.3.
Selection of Batches
2.2.4.
Container Closure System
2.2.5.
Specification
2.2.6.
Testing Frequency
2.2.7.
Storage Conditions
2.2.8.
Stability Commitment
2.2.9.
Evaluation
2.2.10.
Statements/Labeling
3.
GLOSSARY
4.
REFERENCES
STABILITY TESTING OF NEW DRUG SUBSTANCES
AND PRODUCTS
1. INTRODUCTION
1.1. Objectives of the Guideline
> 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 seeks to exemplify the
core stability data package for new drug substances and products, but leaves
sufficient flexibility to encompass the variety of different practical
situations that may be encountered due to specific scientific considerations
and characteristics of the materials being evaluated. >Alternative approaches
can be used when there are scientifically justifiable reasons.
1.2. Scope of the Guideline
> 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, etc.
>Specific details of the sampling and
testing for particular dosage forms in their proposed container closures are
not covered in this guideline.
>Further guidance on new dosage forms
and on biotechnological/biological products can be found in ICH guidelines Q1C
and Q5C, respectively.
1.3. General Principles
>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 retest 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.
>The principle has been established that
stability information generated in any one of the three regions of the EC,
Japan and the United States would be mutually acceptable to the other two
regions, provided the information is consistent with this guideline and the
labeling is in accord with national/regional requirements.
2. GUIDELINES
2.1. Drug Substance
2.1.1. General
>Information on the stability of the
drug substance is an integral part of the systematic
approach to stability evaluation.
2.1.2. Stress Testing
1.Stability Testing of New Drug Substances
and Products
>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.
>Results from these studies will form an
integral part of the information provided to regulatory authorities.
2.1.3. Selection of Batches
>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 overall quality of the batches of
drug 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.
2.1.4. Container Closure System
>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.
2.1.5. Specification
>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. Whether and to what extent replication should be performed will depend
on the results from validation studies.
2 .Stability Testing of New Drug Substances
and Products
2.1.6. Testing Frequency
>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 12month study
is recommended.
2.1.7. Storage Conditions
>In general, a drug 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.
>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
drug substances are detailed in the
sections below.
>The general case applies if the drug
substance is not specifically covered by a subsequent section.
>Alternative storage conditions can be
used if justified.
