FDA药品稳定指导大纲

Guidance for Industry
Q1A(R2) Stability Testing
of New Drug Substances
and Products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2003
ICH
Revision 2
Guidance for Industry
Q1A(R2) Stability Testing
of New Drug Substances
and Products
Additional copies are available from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
http://www.fda.gov/cber/guidelines.htm.
(Tel) Voice Information System at 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2003
ICH
Revision 2
Contains Nonbinding Recommendations
i
TABLE OF CONTENTS
I. INTRODUCTION (1)........................................................................................................... 1
A. Objectives of the Guidance (1.1)............................................................................................1
B. Scope of the Guidance (1.2)...................................................................................................2
C. General Principles (1.3).........................................................................................................2
II. GUIDANCE (2) ..................................................................................................................... 2
A. Drug Substance (2.1).............................................................................................................2
1. General (2.1.1) .......................................................................................................................2
2. Stress Testing (2.1.2) ..............................................................................................................3
3. Selection of Batches (2.1.3) .....................................................................................................3
4. Container Closure System (2.1.4).............................................................................................3
5. Specification (2.1.5)................................................................................................................3
6. Testing Frequency (2.1.6)........................................................................................................4
7. Storage Conditions (2.1.7) ......................................................................................................4
8. Stability Commitment (2.1.8) ...................................................................................................6
9. Evaluation (2.1.9)...................................................................................................................7
B. Drug Product (2.2) ................................................................................................................8
1. General (2.2.1) .......................................................................................................................8
2. Photostability Testing (2.2.2) ..................................................................................................8
3. Selection of Batches (2.2.3) ....................................................................................................8
4. Container Closure System (2.2.4).............................................................................................8
5. Specification (2.2.5)................................................................................................................9
6. Testing Frequency (2.2.6)........................................................................................................9
7. Storage Conditions (2.2.7) ....................................................................................................10
8. Stability Commitment (2.2.8) .................................................................................................14
9. Evaluation (2.2.9).................................................................................................................15
10. Statements/Labeling (2.2.10) ...............................................................................................16
GLOSSARY (3)........................................................................................................................... 17
REFERENCES (4) ...................................................................................................................... 21
ATTACHMENT List Of Revision 2 Changes......................................................................... 22
Contains Nonbinding Recommendations
1
Guidance for Industry1
Q1A(R2) Stability Testing of New Drug
Substances and Products
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I. INTRODUCTION (1) 2
This guidance is the second revision of Q1A Stability Testing of New Drug Substances and
Products, which was first published in September 1994 and revised in August 2001. The
purpose of this revision is to harmonize the intermediate storage condition for zones I and II with
the long-term condition for zones III and IV recommended in the ICH guidance Q1F Stability
Data Package for Registration Applications in Climatic Zones III and IV. The changes made in
this second revision are listed in the attachment to this guidance.
A. Objectives of the Guidance (1.1)
This guidance is intended to define what stability data package for a new drug substance or drug
product is sufficient for a registration application within the three regions of the European Union
(EU), Japan, and the United States. It does not seek to address the testing for registration in or
export to other areas of the world. The guidance exemplifies 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 This guidance was developed within the Expert Working Group (Quality) of the International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed
by the ICH Steering Committee at Step 4 of the ICH process, February 2003. At Step 4 of the process, the final draft
is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.
2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee
at Step 4 of the ICH process.
Contains Nonbinding Recommendations
2
B. Scope of the Guidance (1.2)
The guidance addresses the information to be submitted in registration applications for new
molecular entities and associated drug products. This guidance does not currently seek to cover
the information to be submitted for abbreviated or abridged applications, variations, or clinical
trial applications.
Specific details of the sampling and testing for particular dosage forms in their proposed
container closures are not covered in this guidance.
Further guidance on new dosage forms and on biotechnological/biological products can be found
in ICH guidances Q1C Stability Testing for New Dosage Forms and Q5C Quality of
Biotechnological Products: Stability Testing of Biotechnological/Biological Products,
respectively.
C. General Principles (1.3)
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 guidance is based on an analysis of the effects of
climatic conditions in the three regions of the EU, 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 guidance addresses climatic zones I and II. The
principle has been established that stability information generated in any one of the three regions
of the EU, Japan, and the United States would be mutually acceptable to the other two regions,
provided the information is consistent with this guidance and the labeling is in accord with
national/regional requirements.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. GUIDANCE (2)
A. Drug Substance (2.1)
1. General (2.1.1)
Information on the stability of the drug substance is an integral part of the systematic approach to
stability evaluation.
Contains Nonbinding Recommendations
3
2. Stress Testing (2.1.2)
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. The testing
should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C) above that for
accelerated testing), humidity (e.g., 75 percent relative humidity 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 Photostability Testing of
New Drug Substances and Products.
Examining degradation products under stress conditions is useful in establishing degradation
pathways and developing and validating suitable analytical procedures. However, such
examination may not be necessary 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.
3. Selection of Batches (2.1.3)
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 production batches 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.
4. Container Closure System (2.1.4)
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.
5. Specification (2.1.5)
Specification, which is a list of tests, references to analytical procedures, and proposed
acceptance criteria, is addressed in ICH Q6A Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug Products: Chemical Substances and Q6B
Contains Nonbinding Recommendations
4
Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New
Drug Products: Biotechnological/Biological Products. In addition, specification for degradation
products in a drug substance is discussed in ICH Q3A Impurities in New Drug Substances.
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 should depend on the results from validation
studies.
6. Testing Frequency (2.1.6)
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 retest 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
retest 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 the 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 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.
7. Storage Conditions (2.1.7)
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 retest 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 should apply if the drug substance
Contains Nonbinding Recommendations
5
is not specifically covered by a subsequent section. Alternative storage conditions can be used if
justified.
a. General case (2.1.7.1)
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 sturdies are performed at
25°C ± 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.
b. Drug substances intended for storage in a refrigerator (2.1.7.2)
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
guidance, except where explicitly noted below.
If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition,
the proposed retest 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
Contains Nonbinding Recommendations
6
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.
c. Drug substances intended for storage in a freezer (2.1.7.3)
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 retest 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).
d. Drug substances intended for storage below -20°C (2.1.7.4)
Drug substances intended for storage below -20°C should be treated on a case-by-case basis.
8. Stability Commitment (2.1.8)
When available long-term stability data on primary batches do not cover the proposed retest
period granted at the time of approval, a commitment should be made to continue the stability
studies postapproval to firmly establish the retest period.
Where the submission includes long-term stability data on three production batches covering the
proposed retest period, a postapproval commitment is considered unnecessary. Otherwise, one
of the following commitments should be made:
· 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 retest 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 retest period and to place additional production batches, to a
total of at least three, on long-term stability studies through the proposed retest
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 longterm
stability studies through the proposed retest period.
Contains Nonbinding Recommendations
7
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.
9. Evaluation (2.1.9)
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 retest 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 retest period.
The data may show so little degradation and so little variability that it is apparent from looking at
the data that the requested retest 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 percent, 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 retest 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 retest period can be undertaken at approval time if justified. This
justification should be based, for example, 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, and/or existence of supporting stability data. 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.
Contains Nonbinding Recommendations
8
10. Statements/Labeling (2.1.10)
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 retest period should be derived from the stability information, and a retest date should be
displayed on the container label if appropriate.
B. Drug Product (2.2)
1. General (2.2.1)
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, results from stability studies on the drug
substance, and 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.
2. Photostability Testing (2.2.2)
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.
3. Selection of Batches (2.2.3)
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.
4. Container Closure System (2.2.4)
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
Contains Nonbinding Recommendations
9
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.
5. Specification (2.2.5)
Specification, which is a list of tests, references 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 ICH Q3B Impurities in New Drug Products.
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.
6. Testing Frequency (2.2.6)
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.
Contains Nonbinding Recommendations
10
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.
7. Storage Conditions (2.2.7)
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 inuse
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 should apply if the drug product is
not specifically covered by a subsequent section. Alternative storage conditions can be used if
justified.
Contains Nonbinding Recommendations
11
a. General case (2.2.7.1)
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 sturdies are performed at
25°C ± 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 condcuted 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 one or more of the following (as
appropriate for the dosage form):
· A 5 percent change in assay from its initial value, or failure to meet the
acceptance criteria for potency when using biological or immunological
procedures
· Any degradation product’s exceeding its acceptance criterion
· 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.
· Failure to meet the acceptance criterion for pH
· Failure to meet the acceptance criteria for dissolution for 12 dosage units
b. Drug products packaged in impermeable containers (2.2.7.2)
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.
Contains Nonbinding Recommendations
12
c. Drug products packaged in semipermeable containers (2.2.7.3)
Aqueous-based products packaged in semipermeable 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 semipermeable
containers can withstand low relative humidity environments. Other comparable approaches can
be developed and reported for nonaqueous, solvent-based products.
Study Storage condition Minimum time period covered
by data at submission
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 40°C ± 2°C/not more than
(NMT) 25% RH
6 months
* It is up to the applicant to decide whether long-term stability sturdies are performed at
25°C ± 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.
When long-term studies are conducted at 25°C ± 2°C/40% RH ± 5% RH and significant change
other than water loss occurs during the 6 months’ testing at the accelerated storage condition,
additional testing at the intermediate storage condition should be performed, as described under
the general case, to evaluate the temperature effect at 30°C. 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 percent RH.
A 5 percent loss in water from its initial value is considered a significant change for a product
packaged in a semipermeable container after an equivalent of 3 months’ storage at 40°C/NMT 25
percent RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of
5 percent or more after an equivalent of 3 months’ storage at 40°C/NMT 25 percent 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
Contains Nonbinding Recommendations
13
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 percent RH is the water loss rate measured at 75 percent 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.
d. Drug products intended for storage in a refrigerator (2.2.7.4)
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 the drug product is packaged in a semipermeable 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
guidance, 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.
Contains Nonbinding Recommendations
14
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.
e. Drug products intended for storage in a freezer (2.2.7.5)
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.
f. Drug products intended for storage below -20°C (2.2.7.6)
Drug products intended for storage below -20°C should be treated on a case-by-case basis.
8. Stability Commitment (2.2.8)
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
postapproval to firmly establish the shelf life.
Where the submission includes long-term stability data from three production batches covering
the proposed shelf life, a postapproval commitment is considered unnecessary. Otherwise, one
of the following commitments should be made:
· 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.
· 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.
Contains Nonbinding Recommendations
15
· If the submission does not include stability data on production batches, a
commitment should be made to place the first three production batches on longterm
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.
9. Evaluation (2.2.9)
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 (e.g.,
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 percent 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.
Contains Nonbinding Recommendations
16
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, for example, 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, and/or existence of supporting stability data. 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.
10. Statements/Labeling (2.2.10)
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.
Contains Nonbinding Recommendations
17
GLOSSARY (3)
The following definitions are provided to facilitate interpretation of the guidance.
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 nonaccelerated 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 postapproval 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.
Contains Nonbinding Recommendations
18
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 retest 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 retest
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 percent 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
noncovalent 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
Contains Nonbinding Recommendations
19
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 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 retest 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.
Retest 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.
Retest 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 retested for
compliance with the specification and then used immediately. A batch of drug substance can be
retested multiple times and a different portion of the batch used after each retest, 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 retest period. The same
may be true for certain antibiotics.
Semipermeable 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 semipermeable
containers include plastic bags and semirigid, 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 ICH 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.
Contains Nonbinding Recommendations
20
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 retest 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 guidance. 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
of 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 retest period or shelf life, and the label storage statements.
Such data include (1) stability data on early synthetic route batches of drug substance, smallscale
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.
Contains Nonbinding Recommendations
21
REFERENCES (4)3
ICH Q1B Photostability Testing of New Drug Substances and Products
ICH Q1C Stability Testing for New Dosage Forms
ICH Q3A Impurities in New Drug Substances
ICH Q3B Impurities in New Drug Products
ICH Q5C Quality of Biotechnological Products: 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
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER
guidance page at http://www.fda.gov/cder/guidance/index.htm
Contains Nonbinding Recommendations
22
ATTACHMENT
List of Revision 2 Changes
The revisions to this Q1A guidance result from adoption of the ICH guidance Q1F Stability Data
Package for Registration Applications in Climatic Zones III and IV. The following changes
were made.
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:
· II.A.7.a (2.1.7.1) Drug Substance - Storage Conditions - General case
· II.B.7.a (2.2.7.1) Drug Product - Storage Conditions - General case
· II.B.7.c (2.2.7.3) Drug products packaged in semipermeable containers
· Glossary (3) Intermediate testing
2. 30°C ± 2°C/65% RH ± 5% RH has been added as a suitable alternative long-term storage
condition to 25°C ± 2°C/60% RH ± 5% in the following sections:
· II.A.7.a (2.1.7.1) Drug Substance - Storage Conditions - General case
· II.B.7.a (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:
· II.B.7.c (2.2.7.3) Drug products packaged in semipermeable containers
Midstream 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.
It is recommended that registration applications contain data from complete studies at the
intermediate storage condition 30°C ± 2°C/65% RH ± 5% RH, if applicable, by three years after
the date of publication of this revised guideline in the respective ICH tripartite region.