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
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. 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
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.
2.1.6. 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 12-
month 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.
2.1.7.1. General case
Study Storage condition Minimum time period covered
by data at submission
Long term 25°C ± 2°C/60% RH ± 5% RH 12 months
Intermediate 30°C ± 2°C/60% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months
When “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.
2.1.7.2. Drug 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
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 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.
If significant change occurs within the first 3 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 drug substance for a period shorter than 3 months but with
more frequent testing than usual. It is considered unnecessary to continue to test a
drug substance through 6 months when a significant change has occurred within
the first 3 months.
2.1.7.3. Drug 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 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.
2.1.7.4. Drug substances intended for storage below -20°C
Drug substances intended for storage below -20°C should be treated on a case-bycase
basis.
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
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. Underthese circumstances, it is normally unnecessary to go through the formal statistical
analysis; providing a justification for the omission should be sufficient.
An approach for analyzing 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 extend the re-test period can be undertaken at
approval time, 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 cover not only the assay, but also the levels of degradation
products and other appropriate attributes.
2.1.10. Statements/Labeling
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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