Stability
Testing of
New Drug Substances and Products
Document History
First
Codification
|
History
|
Date
|
New
Codification
November 2005 |
Q1
|
Approval by
the Steering Committee under Step 2 and release for public
consultation.
|
16 September
1992
|
Q1
|
Q1A
|
Approval by
the Steering Committee under Step 4 and recommendation for adoption to
the three ICH regulatory bodies.
Q1 was
renamed Q1A.
|
27 October
1993
|
Q1A
|
Q1A(R)
|
Approval by
the Steering Committee of the first revision under Step 2 and release
for public consultation.
|
7 October
1999
|
Q1A(R1)
|
Q1A(R)
|
Approval by
the Steering Committee of the first revision under Step 4 and
recommendation for adoption to the three ICH regulatory bodies.
|
8 November
2000
|
Q1A(R1)
|
Current Step 4 version
Q1A(R2)
|
Approval by
the Steering Committee of the second revision directly under Step 4 without
further public consultation, to include consequences of the adoption of Q1F (Stability Data Package for
Registration Applications in Climatic Zones III and IV), and recommendation for adoption to the
three ICH regulatory bodies.
|
6 February
2003
|
Q1A(R2)
|
Cover Note for Revision of Q1A(R)
Stability Testing of
New Drug Substances and Products
New Drug Substances and Products
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:
1.
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”
2.
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:
·
2.1.7.1 Drug Substance - Storage Conditions - General Case
·
2.2.7.1 Drug Product - Storage Conditions - General Case
3.
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:
·
2.2.7.3 Drug products packaged in semi-permeable containers
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.
Stability Testing of
New Drug Substances and Products
New Drug Substances and Products
ICH Harmonised Tripartite Guideline
First
Recommended for Adoption at Step 4 of the ICH Process on 27 October
1993.
Revised
under Step 2 of the ICH Process on 7 October 1999 and Recommended for
Adoption at Step 4 of the ICH Process on 8 November 2000.
This
guideline has been Revised a second time and has reached Step 4 of the ICH Process at the ICH Steering Committee meeting on
6 February 2003. It is recommended for adoption to the three regulatory parties
to ICH
TABLE OF CONTENTS
1. INTRODUCTION 1
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
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
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.
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.
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 Japan and the United States
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.
Results from these studies will form an
integral part of the information provided to regulatory authorities.
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.
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. Whether and to what extent replication should be
performed will depend on the results from validation studies.
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.
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
Storage condition
|
||
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.
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
|
|
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-by-case basis.
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.
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.
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.
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.
The design of the formal stability studies
for the drug product should be based on knowledge of the behavior and
properties of the drug substance and from stability studies on the drug
substance and on experience gained from clinical formulation studies. The
likely changes on storage and the rationale for the selection of attributes to
be tested in the formal stability studies should be stated.
Photostability testing should be conducted
on at least one primary batch of the drug product if appropriate. The standard
conditions for photostability testing are described in ICH Q1B.
Data from stability studies should be
provided on at least three primary batches of the drug 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 drug product
should be manufactured by using different batches of the drug substance.
Stability studies should be performed on
each individual strength and container size of the drug product unless
bracketing or matrixing is applied.
Other supporting data can be provided.
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 drug 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.
Specification, which is a list of tests,
reference to analytical procedures, and proposed acceptance criteria, including
the concept of different acceptance criteria for release and shelf life
specifications, is addressed in ICH Q6A and Q6B. In addition, specification for degradation
products in a drug product is addressed in Q3B.
Stability studies should include testing of
those attributes of the drug product 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, preservative content (e.g., antioxidant,
antimicrobial preservative), and functionality tests (e.g., for a dose delivery
system). Analytical 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 drug
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.
For long term studies, frequency of testing
should be sufficient to establish the stability profile of the drug 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 3 months
over the first year, every 6 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.
In general, a drug 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.
Stability testing of the drug product after
constitution or dilution, if applicable, should be conducted to provide
information for the labeling 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 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 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 products are detailed in
the sections below. The general case
applies if the drug product is not specifically covered by a subsequent
section. Alternative storage conditions
can be used, if justified.
2.2.7.1. General
case
Study
|
Storage
condition
|
|
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. The initial
application should include a minimum of 6 months’ data from a 12-month study at
the intermediate storage condition.
In general, “significant change” for a drug
product is defined as:
1. A 5% change in assay from
its initial value; or failure to meet the acceptance criteria for potency when
using biological or immunological procedures;
2. Any
degradation product’s exceeding its acceptance criterion;
3. Failure to meet the
acceptance criteria for appearance, physical attributes, and functionality test
(e.g., color, phase separation, resuspendibility, caking, hardness, dose
delivery per actuation); however, some changes in physical attributes (e.g.,
softening of suppositories, melting of creams) may be expected under
accelerated conditions;
and, as appropriate for the dosage form:
4. Failure
to meet the acceptance criterion for pH; or
5. Failure
to meet the acceptance criteria for dissolution for 12 dosage units.
2.2.7.2. Drug products packaged in impermeable
containers
Sensitivity to moisture or potential for
solvent loss is not a concern for drug products packaged in impermeable
containers that provide a permanent barrier to passage of moisture or solvent.
Thus, stability studies for products stored in impermeable containers can be
conducted under any controlled or ambient humidity condition.
2.2.7.3. Drug
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 drug
products stored in semi-permeable containers can withstand low relative
humidity environments.
Other comparable approaches can be
developed and reported for non-aqueous, solvent-based products.
Study
|
Storage
condition
|
|
Long term*
|
25°C ± 2°C/40%
RH ± 5% RH
or 30°C ± 2°C/35% RH ± 5% RH |
12 months
|
Intermediate**
|
30°C ± 2°C/65%
RH ± 5% RH
|
6 months
|
Accelerated
|
6 months
|
*It is up to the applicant to decide whether long term stability
studies are performed at 25 ± 2°C/40%
RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH.
**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 6 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 will not have significant water loss
throughout the proposed shelf life if stored at 25°C and the reference relative
humidity of 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 3 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 3
months’ storage at 40°C/NMT 25% RH may be appropriate, if justified.
An alternative approach to studying at the
reference 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 reference 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 drug 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 reference relative humidity is to multiply the water
loss rate measured at an alternative relative humidity at the same temperature
by a 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.
Alternative relative humidity
|
Reference relative humidity
|
Ratio of water loss rates at a given
temperature
|
60% RH
|
25% RH
|
1.9
|
60% RH
|
40% RH
|
1.5
|
65% RH
|
35% RH
|
1.9
|
75% RH
|
25% RH
|
3.0
|
Valid water loss rate ratios at relative
humidity conditions other than those shown in the table above can also be used.
2.2.7.4. Drug
products intended for storage in a refrigerator
Study
|
Storage
condition
|
|
Long term
|
5°C ± 3°C
|
12 months
|
Accelerated
|
25°C ± 2°C/60%
RH ± 5% RH
|
If the drug 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 this guideline, except where
explicitly noted below.
If significant change occurs between 3 and
6 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 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 shipment and handling. This discussion
can be supported, if appropriate, by further testing on a single batch of the drug
product for a period shorter than 3 months but with more frequent testing than
usual. It is considered unnecessary to continue to test a product through 6
months when a significant change has occurred within the first 3 months.
2.2.7.5. Drug
products 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 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 drug 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) for an appropriate
time period should be conducted to address the effect of short term excursions
outside the proposed label storage condition.
2.2.7.6. Drug
products intended for storage below -20°C
Drug products intended for storage below
-20°C should be treated on a case-by-case basis.
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 6 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 6 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 6 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 6 months.
The stability protocol used for studies on
commitment batches should be the same as that for the primary batches, unless
otherwise scientifically justified.
Where intermediate testing is called for by
a significant change at the accelerated storage condition for the primary
batches, testing on the commitment batches can be conducted at either the
intermediate or the accelerated storage condition. However, if significant
change occurs at the accelerated storage condition on the commitment batches,
testing at the intermediate storage condition should also be conducted.
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 three batches of the drug product, a
shelf life and label storage instructions applicable to all future batches of
the drug 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; providing a justification for the omission
should be sufficient.
An approach for analyzing data of 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.
The nature of the 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 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
shelf life can be undertaken at approval time, if justified. This justification
should be based on what is known about the mechanisms 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.
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 product.
Where applicable, specific instruction should be provided, particularly for
drug products that cannot tolerate freezing. Terms such as “ambient conditions”
or “room temperature” should be avoided.
There should be a direct link between the
label storage statement and the demonstrated stability of the drug
product. An expiration date should be displayed
on the container label.
The following definitions are provided to
facilitate interpretation of the guideline.
Accelerated testing
Studies designed to increase the rate of
chemical degradation or physical change of a drug substance or drug 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.
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.
This is based on the concept described by W. Grimm (Drugs Made in Germany,
28:196-202, 1985 and 29:39-47, 1986).
Commitment batches
Production batches of a drug substance or
drug 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 contain and protect the dosage form. This includes primary packaging
components and secondary packaging components, if the latter are intended to
provide additional protection to the drug 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 a drug substance generally, but
not necessarily, in association with excipients.
Drug product
The dosage form in the final immediate
packaging intended for marketing.
Drug substance
The unformulated drug substance that may
subsequently be formulated with excipients to produce the dosage form.
Excipient
Anything other than the drug substance in
the dosage form.
Expiration date
The date placed on the container label of a
drug 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 a drug substance or the shelf life of a drug product.
Impermeable containers
Containers that provide a permanent barrier
to the passage of gases or solvents, e.g., sealed aluminum tubes for
semi-solids, sealed glass ampoules for solutions.
Intermediate testing
Studies conducted at 30°C/65% RH and
designed to moderately increase the rate of chemical degradation or physical
changes for a drug substance or drug product intended to be stored long term at
25°C.
Long term testing
Stability studies under the recommended
storage condition for the re-test period or shelf life proposed (or approved)
for labeling.
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
drug 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
a drug substance or drug 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 J. D. Haynes (J. Pharm. Sci.,
60:927-929, 1971) can be used.
New molecular entity
An active pharmaceutical substance not
previously contained in any drug product registered with the national or
regional authority concerned. A new
salt, ester, or non-covalent-bond derivative of an approved drug substance is
considered a new molecular entity for the purpose of stability testing under
this guidance.
Pilot scale batch
A batch of a drug substance or drug 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 a drug substance or drug 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 a drug substance should be at least a pilot scale batch. For a drug 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 a drug substance or drug 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 drug
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
drug product.
Re-test period
The period of time during which the drug
substance is expected to remain within its specification and, therefore, can be
used in the manufacture of a given drug product, provided that the drug substance
has been stored under the defined conditions. After this period, a batch of
drug substance destined for use in the manufacture of a drug product should be
re-tested for compliance with the specification and then used immediately. A
batch of drug 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
absorption 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 drug 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 Q6A and Q6B.
Specification – Release
The combination of physical, chemical,
biological, and microbiological tests and acceptance criteria that determine
the suitability of a drug 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 a drug substance throughout its re-test period, or that a
drug 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 (drug substance)
Studies undertaken to elucidate the
intrinsic stability of the drug 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 (drug product)
Studies undertaken to assess the effect of
severe conditions on the drug product.
Such studies include photostability testing (see ICH Q1B) 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 drug 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.
4.
REFERENCES
ICH Q1B: “Photostability
Testing of New Drug Substances and Products”
ICH Q1C: “Stability Testing of New Dosage Forms”
ICH Q3A: “Impurities in New Drug Substances”
ICH Q3B: “Impurities in New Drug Products”
ICH Q5C: “Stability Testing of Biotechnological/Biological Products”
ICH Q6A: “Specifications:
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances”
ICH Q6B: “Specifications:
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Biotechnological/Biological Products”