Romel A. Altamirano

PRUEBAS DE ESTABILIDAD. NUEVAS DROGAS

Stability Testing of Drug Substances
and Drug Products

I. INTRODUCTION
There are specific regulatory recommendations regarding
the design, conduct, and use of stability studies that should
be performed to support

• Investigational new drug applications (INDs)
(21 CFR 312.23(a)(7))

• New drug applications (NDAs) for both new
molecular entities and non–new molecular entities,
new dosage forms (21 CFR 314.50(d)(1))

• Abbreviated new drug applications (ANDAs)
(21 CFR 314.92–314.99)

• Supplements and annual reports (21 CFR
314.70, and 601.12)

• Biologics license application (BLAs) and product
license applications (PLAs) (21 CFR 601.2)
Given below is a comprehensive description of the
principle established in International Conference on Harmonisation
(ICH) Q1A—that information on stability
generated in any one of the three areas of the European
Union, Japan, and the U.S. would be mutually acceptable
in both of the other two areas. Also included here is a
discussion of biological products and products submitted
to the Center for Biologics Evaluation and Research
(CBER). (Note that effective July 2003, the U.S. Food and
Drug Administration has transferred several therapeutic
proteins to the Center for Drug Evaluation and Research
[CDER] from CBER.)
Given below are recommendations for the design of
stability studies for drug substances and drug products that
should result in a statistically acceptable level of confidence
for the established retest or expiration dating period
for each type of application. The applicant is responsible
for confirming the originally established retest and expiration
dating periods by continual assessment of stability
properties (21 CFR 211.166). Continuing confirmation of
these dating periods should be an important consideration
in the applicant’s stability program. The choice of test
conditions defined in this guidance is based on an analysis
of the effects of climatic conditions in the European
Union, Japan, and the U.S. The mean kinetic temperature
in any region of the world can be derived from climatic
data (Grimm, W.,Drugs Made in Germany
, 28:196–202,1985, and 29:39–47, 1986). [ICH Q1A]

II. STABILITY TESTING FOR NEW DRUG
APPLICATIONS
A. DRUG SUBSTANCE

Information on the stability of a drug substance under
defined storage conditions is an integral part of the systematic
approach to stability evaluation. Stress testing
helps to determine the intrinsic stability characteristics of
a molecule by establishing degradation pathways to identify
the likely degradation products and to validate the
stability, indicating the power of the analytical procedures
used.
Stress testing is conducted to provide data on forced
decomposition products and decomposition mechanisms
for the drug substance. The severe conditions that may be
encountered during distribution can be covered by stress
testing of definitive batches of the drug substance. These
studies should establish the inherent stability characteristics
of the molecule, such as the degradation pathways,
and lead to identification of degradation products and
hence support the suitability of the proposed analytical
procedures. The detailed nature of the studies will depend
on the individual drug substance and type of drug product.
This testing is likely to be carried out on a single batch
of a drug substance. Testing should include the effects of
temperatures in 10°C increments above the accelerated
temperature test condition (e.g., 50°, 60°C) and humidity,
where appropriate (e.g., 75% or greater). In addition, oxidation
and photolysis on the drug substance plus its susceptibility
to hydrolysis across a wide range of pH values
when in solution or suspension should be evaluated.
Results from these studies will form an integral part of
the information provided to regulatory authorities. Light
testing should be an integral part of stress testing. The
standard test conditions for photostability are discussed in
the ICH Q1B guidance. It is recognized that some degradation pathways can
be complex and that under forced conditions, decomposition
products may be observed that are unlikely to be
formed under accelerated or long-term testing. This information
may be useful in developing and validating suitable
analytical methods, but it may not always be necessary to
examine specifically for all degradation products if it has
been demonstrated that, in practice, these decomposition
products are not formed.
Primary stability studies are intended to show that a
drug substance will remain within specifications during
the retest period if stored under recommended storage
conditions. [ICH Q1A]

1. Selection of Batches
Stability information from accelerated and long-term testing
should be provided on at least three batches. Longterm
testing should cover a minimum of 12 months’ duration
on at least three batches at the time of submission.
The batches manufactured to a minimum of pilot-plant
scale should be formed by the same synthetic route and
use a method of manufacture and procedure that simulates
the final process to be used on a manufacturing scale. The
overall quality of the batches of drug substance placed on
stability should be representative of both the quality of
the material used in preclinical and clinical studies and
the quality of material to be made on a manufacturing
scale. Supporting information may be provided using stability
data on batches of drug substance made on a laboratory
scale. [ICH Q1A]
The first three production batches of drug substance
manufactured postapproval, if not submitted in the original
drug application, should be placed on long-term stability
studies postapproval, using the same stability protocol
as in the approved drug application. [ICH Q1A]

2. Test Procedures and Test Criteria
The testing should cover those features that are susceptible
to change during storage and that are likely to influence
quality, safety, or efficacy. Stability information should
cover, as necessary, the physical, chemical, biological, and
microbiological test characteristics. Validated stabilityindicating
test methods should be applied. The extent of
replication will depend on the results of validation studies.
[ICH Q1A]

3. Specifications
Limits of acceptability should be derived from the quality
profile of the material as used in the preclinical and clinical
batches. Specifications will need to include individual and
total upper limits for impurities and degradation products,
the justification for which should be influenced by the
levels observed in material used in preclinical studies and
clinical trials. [ICH Q1A]

4. Storage Conditions
The length of the studies and the storage conditions should
be sufficient to cover storage, shipment, and subsequent use.
Application of the same storage conditions applied to the
drug product will facilitate comparative review and assessment.
Other storage conditions are allowable if justified.
In particular, temperature-sensitive drug substances should be
stored under an alternative lower-temperature condition,
which will then become the designated long-term testing
storage temperature. The 6-month accelerated testing should
then be carried out at a temperature at least 15°C above this
designated long-term storage temperature (together with the
appropriate relative humidity conditions for that temperature).
The designated long-term testing conditions will be
reflected in the labeling and retest date. [ICH Q1A]
Where significant change occurs during 6 months of
storage under conditions of accelerated testing at 40°±
2°C/75% RH±5%, additional testing at an intermediate
condition (such as 30°±2°C/60% RH±5%) should be
conducted for a drug substance to be used in the manufacture
of a dosage form tested for long-term at 25°±2°C/60%RH±
5%, and this information should be included in the
drug application. The initial drug application should include
at the intermediate storage condition a minimum of 6
months of data from a 12-month study. [ICH Q1A]
Significant change at 40°C/75% RH or 30° C/60% RH
is defined as failure to meet the specifications. [ICH Q1A]
If any parameter fails significant change criteria during the
accelerated stability study, testing of all parameters during
the intermediate stability study should be performed.
If stability samples have been put into the intermediate
condition but have not been tested, these samples may be
tested as soon as the accelerated study shows significant
change in the drug substance. Alternatively, studies in the
intermediate condition would be started from the initial
time point.
Where a significant change occurs during 12 months
of storage at 30°C/60% RH, it may not be appropriate to
label the drug substance for controlled room temperature
(CRT) storage with the proposed retest period even if the
stability data from the full long-term studies at 25°C/60%
RH appear satisfactory. In such cases, alternate approaches,
such as qualifying higher acceptance criteria for a degradant,
shorter retest period, refrigerator temperature storage, or
more protective container and closure, should be considered
during drug development.
The long-term testing should be continued for a sufficient
period of time beyond 12 months to cover all appropriate
retest periods, and the further accumulated data can
be submitted to the FDA during the assessment period of
the drug application. [ICH Q1A]
The data (from accelerated testing or from testing at an
intermediate storage condition) may be used to evaluate the
effect of short-term excursions outside the label storage
conditions such as might occur during shipping. [ICH Q1A]
5. Testing Frequency
Frequency of testing should be sufficient to establish the
stability characteristics of the drug substance. Testing
under the defined long-term conditions will normally be
every 3 months over the first year, every 6 months over
the second year, and then annually. [ICH Q1A]

6. Packaging and Containers
The containers to be used in the long-term, real-time stability
evaluation should be the same as or simulate the actual
packaging used for storage and distribution. [ICH Q1A]

7. Evaluation
The design of the stability study is to establish a retest
period applicable to all future batches of the bulk drug
substance manufactured under similar circumstances,
based on testing a minimum of three batches of the drug
substance and evaluating the stability information (covering
as necessary the physical, chemical, and microbiological
test characteristics). The degree of variability of individual
batches affects the confidence that a future
production batch will remain within specifications until
the retest date. [ICH Q1A]
An acceptable approach for quantitative characteristics
that are expected to decrease with time is to determine
the time at which the 95% one-sided confidence limit for
the mean degradation curve intersects the acceptable lower
specification limit. If analysis shows that the batch-tobatch
variability is small, it is advantageous to combine
the data into one overall estimate, which can be done by
first applying appropriate statistical tests (for example,
P values for level of significance of rejection of more than
.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 may depend on the minimum time a batch may be
expected to remain within acceptable and justified limits.
[ICH Q1A]
The nature of any degradation relationship will determine
the need for transformation of the data 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. [ICH Q1A]
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 the
circumstances, it is normally unnecessary to go through
the formal statistical analysis; providing a full justification
for the omission is usually sufficient. [ICH Q1A]
Limited extrapolation may be undertaken of the realtime
data beyond the observed range to extend the retest
period at approval time, particularly where the accelerated
data support this. However, this assumes that the same
degradation relationship will continue to apply beyond the
observed data, and hence the use of extrapolation must be
justified in each application in terms of what is known
about such factors as the mechanism of degradation, the
goodness of fit of any mathematical model, the batch size,
and the existence of supportive data. Any evaluation should
cover not only the assay but also the levels of degradation
products and other appropriate attributes. [ICH Q1A]

8. Statements and Labeling
A storage temperature range may be used in accordance
with relevant national and regional requirements. The range
should be based on the stability evaluation of the drug
substance. Where applicable, specific requirements should
be stated, particularly for drug substances that cannot tolerate
freezing. The use of terms such as “ambient conditions”
or “room temperature” is unacceptable. [ICH Q1A]
A retest period should be derived from the stability
information. [ICH Q1A]

B. DRUG PRODUCT

1. General
The design of the stability protocol for the drug product
should be based on the knowledge obtained on the behavior,
properties, and stability of the drug substance and the
experience gained from clinical formulation studies. The
changes are likely to occur on storage, and the rationale
for the selection of drug product parameters to be monitored
should be stated. [ICH Q1A]

2. Selection of Batches
Stability information from accelerated and long-term testing
is to be provided on three batches of the same formulation
of the dosage form in the container and closure
proposed for marketing. Two of the three batches should
be at least pilot scale. The third batch may be smaller (e.g.,
25,000 to 50,000 tablets or capsules for solid oral dosage
forms). The long-term testing should cover at least
12 months’ duration at the time of submission. The manufacturing
process to be used should meaningfully simulate
that to be applied to large-scale production batches
for marketing. The process should provide product of the
same quality intended for marketing and should meet the
same quality specification to be applied for release of
material. Where possible, batches of the finished product
should be manufactured using identifiably different
batches of the drug substance. [ICH Q1A]
Data on laboratory-scale batches are not acceptable as
primary stability information. Data on associated formulations
or packaging may be submitted as supportive information.
The first three production batches manufactured
postapproval, if not submitted in the original application,
should be placed on accelerated and long-term stability
studies using the same stability protocols as in the
approved drug application. [ICH Q1A]
3. Test Procedures and Test Criteria
The test parameters should cover those features that are
susceptible to change during storage and that are likely to
influence quality, safety, or efficacy. Analytical test procedures
should be fully validated, and the assays should be
stability-indicating. The need for replication will depend
on the results of validation studies. [ICH Q1A]
The range of testing should cover not only chemical
and biological stability, but also loss of preservative efficacy,
physical properties and characteristics, organoleptic
properties, and, where required, microbiological attributes.
Preservative efficacy testing and assays on stored samples
should be carried out to determine the content and efficacy
of antimicrobial preservatives. [ICH Q1A]

4. Specifications
Where applicable, limits of acceptance should relate to
the release limits to be derived from consideration of all
the available stability information. The shelf-life specifications
could allow acceptable and justifiable deviations
from the release specifications based on the stability evaluation
and the changes observed on storage. They need to
include specific upper limits for degradation products, the
justification for which should be influenced by the levels
observed in material used in preclinical studies and clinical
trials. The justification for the limits proposed for certain
other tests, such as particle size or dissolution rate, will
require reference to the results observed for the batch or
batches used in bioavailability or clinical studies. Any
differences between the release and the shelf-life specifications
for antimicrobial preservatives content should be
supported by preservative efficacy testing. [ICH Q1A]

5. Storage Test Conditions
The length of the studies and the storage conditions should
be sufficient to cover storage, shipment, and subsequent
use (e.g., reconstitution or dilution as recommended in the
labeling). The recommended accelerated and long-term
storage conditions and minimum times are
Long-term testing 25°C±2° C/60%
RH±5% 12 Months; Accelerated Testing 40°C±2°
C/75% RH± 5% 6 Months.
Assurance that long-term testing will continue to cover
the expected shelf life should be provided. [ICH Q1A]
Other storage conditions are allowable if justified. Heatsensitive
drug products should be stored under an alternative
lower temperature condition, which will eventually
become the designated long-term storage temperature.
Special consideration may need to be given to products
that change physically or even chemically at lower storage
temperatures (e.g., suspensions or emulsions that may sediment,
or cream, oils, and semisolid preparations, which
may show an increased viscosity). Where a lower temperature
condition is used, the 6-month accelerated testing
should be carried out at a temperature at least 15°C above
its designated long-term storage temperature (together
with appropriate relative humidity conditions for that temperature).
For example, for a product to be stored longterm
under refrigerated conditions, accelerated testing
should be conducted at 25°±2° C/60% RH
±5%. Thedesignated long-term testing conditions will be reflected
in the labeling and expiration date. [ICH Q1A]
Storage under conditions of high relative humidity
applies particularly to solid dosage forms. For drug products
such as solutions and suspensions contained in packs
designed to provide a permanent barrier to water loss, specific
storage under conditions of high relative humidity is
not necessary, but the same range of temperatures should
be applied. Low relative humidity (e.g., 10%–20% RH) can
adversely affect products packed in semipermeable containers
(e.g., solutions in plastic bags, nose drops in small
plastic containers), and consideration should be given to
appropriate testing under such conditions. [ICH Q1A]

Where significant change occurs because of accelerated
testing, additional testing at an intermediate condition
(e.g., 30°±2°C/60% RH± 5%) should be conducted. Significant
change at the accelerated conditions is defined as

• A 5% potency loss from the initial assay value
of a batch

• Any specified degradant exceeding its specification
limit

• The product exceeding its pH limits

• Dissolution exceeding the specification limits
for 12 capsules or tablets (USP [U.S. Pharmacopeia]
Stage 2)

• Failure to meet specifications for appearance
and physical properties (e.g., color, phase separation,
ability to be resuspended, delivery per
actuation, caking, hardness) [ICH Q1A]

Should significant change occur at 40°C/75% RH, the
initial application should include a minimum of 6 months’
data from an ongoing 1-year study at 30° C/60% RH; the
same significant change criteria shall then apply. [ICH Q1A]
If any parameter fails significant change criteria during
the accelerated stability study, testing of all parameters during
the intermediate stability study should be performed.
If stability samples have been put into the intermediate
condition but have not been tested, testing these samples
may begin as soon as the accelerated study shows significant
change in the drug product. Alternatively, the study at the
intermediate condition would be started from the initial
time point.
Where a significant change occurs during 12 months
of storage at 30° C/60% RH, it may not be appropriate to
label the drug product for CRT storage with the proposed
expiration dating period even if the stability data from the
full long-term studies at 25 ° C/60%RH appear satisfactory.
In such cases, alternate approaches, such as qualifying
higher acceptance criteria for a degradant, shorter expiration
dating period, refrigerator temperature storage, more
protective container and closure, and modification to the
formulation or manufacturing process, should be considered
during drug development. If CRT storage is ultimately
justified, it may be necessary to add to the product
labeling a cautionary statement against prolonged exposure
at or above 30°C.
The long-term testing will be continued for a sufficient
period of time beyond 12 months to cover shelf life at
appropriate test periods. The further accumulated data
should be submitted to the FDA during the assessment
period of the drug application. [ICH Q1A]
The first three production batches manufactured postapproval,
if not submitted in the original application,
should be placed on accelerated and long-term stability
studies using the same stability protocol as in the approved
drug application. [ICH Q1A] A minimum of four test
stations (e.g., at 0, 2, 4, and 6 months) are recommended
for the 6-month accelerated stability study.

6. Stability Storage Conditions not Defined
in ICH Q1A
The stability sample storage conditions for most dosage
forms (e.g., solid oral dosage forms, solids for reconstitution,
dry and lyophilized powders in glass vials) are
defined in Section V.E of the ICH Q1A Guidance and in
Section II.B.5 of this guidance. However, the stability
storage conditions are not indicated in ICH Q1A for certain
other drug products including those packaged in semipermeable
containers (except for accelerated studies),
products intended to be stored under refrigerator or freezer
temperatures, or certain studies on metered dose inhalations
(MDIs) and dry powder inhalers (DPIs). Further
information about these products and containers is provided
in this section.

a. Stability Storage Conditions for Drug Products
in Semipermeable and Permeable Containers
For large-volume parenterals (LVPs), small-volume
parenterals (SVPs), ophthalmics, otics, and nasal sprays
packaged in semipermeable containers, such as plastic bags,
semirigid plastic containers, ampoules, vials and bottles
with or without droppers or applicators, which may be
susceptible to water loss, the recommended stability storage
conditions are

• Accelerated condition: 40°±2°C/15% RH±5% (hereafter referred to
as 40°C/15% 326 RH)[ICH Q1A]

• Intermediate condition: 30°±2°C/40% RH±5% (hereafter referred to
as 30°C/40% RH)

• Long-term condition: 25C±2C/40% RH
±
5%
For liquids in glass bottles, vials, or sealed glass
ampoules, which provide an impermeable barrier to water
loss,

• Accelerated condition: 40°C/ambient humidityis an acceptable alternative
to 40°C/75% RH

• Intermediate condition: 30°C/ambient humidity
is an acceptable alternative to 30°C/60% RH

• Long-term condition: 25° C/ambient humidity
is an acceptable alternative to 25°C/60% RH

b. Stability Storage Conditions for Drug
Products Intended to be Storedat Refrigerator Temperature

• Accelerated conditions: 25° C/60% RH, with
ambient humidity an acceptable alternative for
aqueous products that would not be affected by
humidity conditions

• Long-term conditions: 5°±3°C, with monitoring,
but not control of, humidity

c. Stability Storage Conditions for Drug Products
Intended to be Stored at Freezer Temperature

• Accelerated conditions: 5°±3°C/ambienthumidity

• Long-term conditions:−15°±5°C

d. Stability Storage Conditions for Some
Inhalation Products

Additional storage conditions may apply to inhalation
powders and suspension inhalation aerosols when significant
change in aerodynamic particle size distribution or
in dose content uniformity occurs at accelerated conditions
(40°C/75% RH). (At present, the agency is developing
a draft guidance to address chemistry, manufacturing,
and controls documentation for MDIs and DPIs.)

7. Testing Frequency

Frequency of testing should be sufficient to establish the
stability characteristics of the drug product. Testing will
normally be every 3 months over the first year, every
6 months over the second year, and then annually. Matrixing
or bracketing can be used if justified. [ICH Q1A]
A minimum of four test stations (e.g., at 0, 2, 4, and 6 months)
If stability samples have been put into the intermediate
condition but have not been tested, testing these samples
may begin as soon as the accelerated study shows significant
change in the drug product. Alternatively, the study at the
are recommended for the 6-month accelerated stability
study.

8. Application of ICH Stability Study Storage
Conditions to Approved Applications

Although the ICH Guidance for
Stability Testing of New Drug Substances and Products
applies only to new molecular entities and associated
drug products, applicants may
wish to voluntarily switch to the ICH-recommended storage
conditions as defined in ICH Q1A or other FDArecommended
conditions as described in Section II.B.6,
as appropriate, for previously approved drug or biologic
products. Applicants are not required to make such a switch
for either annual stability batches or batches intended to
support supplemental changes. Although the following
discussions refer only to the ICH conditions, the same
recommendations can be applied when a switch to other
FDA-recommended conditions is contemplated.
Two plans are presented to assist applicants who desire
to switch their approved drug products to the ICH-recommended
storage conditions. Under each plan, recommendations
will be made on how to initiate a switch to the ICH
storage testing conditions, select batches, collect data, report
results, and proceed if products fail the approved specifications
under the ICH conditions.
a. Plan A: Using the ICH Storage Testing
Conditions for an Approved Stability
This plan may be most suitable for drug products that have
been confirmed to be stable when exposed to the controlled
level of humidity on a long-term basis. Only one set of
conditions (i.e., the ICH conditions) and one set of testing
for each of the three verification batches, as defined below,
are necessary under this plan.

i. Drug Products with an Approved Stability Protocol
Applicants who have previously performed drug product
stability studies under an approved protocol at 25°, 30°,
or 25°–30°C without humidity controls may switch over
to the ICH long-term conditions, as defined in V.E. of the
ICH Q1A guidance and incorporated in Section II.B of this
guidance, for all of their annual stability studies. A revised
stability protocol may be submitted in the annual report,
reflecting changes in temperature and humidity to conform
to those recommended by the ICH. Any other changes to
the stability protocol should be submitted as a Prior Approval
Supplement. Once adopted through an annual report, the
ICH conditions should be used to generate stability data
for subsequent supplemental changes. Alternatively, the
applicant may report the ICH switch in a supplement, which
requires stability data, if the supplement occurs before the
next scheduled annual report. Data from the first three
consecutive annual batches after the switch can be used
to verify the previously approved expiration dating period.
However, if the applicant wishes to verify product stability
under the ICH conditions over a shorter time span, three
production batches within 1 year, instead of three consecutive
annual batches, may be studied.

ii. Products without an Approved Stability Protocol
Applicants who have previously performed stability studies
on a drug product without an approved protocol are
required to submit an appropriate protocol under a Prior
Approval Supplement under 21 CFR 314.70(b) or (g) or
601.12(b) (see Section V regarding an Approved Stability
Protocol). On approval of the protocol, applicants may
initiate stability studies on all annual batches under the
ICH long-term conditions. Data from the first three consecutive
annual batches after the switch can be used to
verify the current—or establish a new—expiration dating
period. However, if the applicant wishes to verify product
stability under the ICH conditions over a shorter time span,
three production batches within 1 year, instead of three
consecutive annual batches, may be studied

iii. Stability Data for Supplemental Changes
Stability data submitted in support of supplemental changes
for an existing drug product may be generated with samples
stored at the ICH-recommended accelerated testing
conditions, long-term testing conditions, and, if applicable,
intermediate conditions, as described in V.E of the
ICH Q1A guidance (Section II.B or Section III.B).

iv. Other Considerations
For a moisture-sensitive product, the applicant may wish to
explore the possibility of improving the container and closure
before embarking on the switch to the ICH condition.
Although 30°C/60% RH is an acceptable alternative
to 25°C/60% RH for long-term studies, these conditions
should not be used as the basis for a labeling statement
such as “store at 30°C” or “store at 15°–30°C” to gain
marketing advantage.
With respect to ongoing stability studies, applicants
may carry them to completion under the previously approved
conditions or may, for practical or economic reasons,
choose to make an immediate switch to ICH conditions
and report the change in the next annual report.

v. Data Submission to the FDA
Satisfactory Data
If the stability data generated on the first
three annual batches after the switch to the ICH-recommended
long-term testing conditions using an approved
protocol, as defined above, support the previously
approved expiration dating period under the non-ICH conditions,
the data can be submitted in the next annual report,
and the current expiration dating period can be retained.
Unsatisfactory Data If the stability data under the ICH
conditions fall outside the specifications established for
the previously approved expiration dating period, the
applicant should perform an investigation to determine
the probable cause of the failure in accordance with
current good manufacturing practices (CGMPs) regulations
under 21 CFR 211.192. In addition, the applicant
should submit an NDA Field-Alert Report in accordance
with 21 CFR 314.81(b)(1)(ii) or an error and accident
report for a biological product under 21 CFR 600.14. A
recall of the corresponding product in the marketplace
may also be necessary. If it is determined that the ICH
storage conditions, particularly the added humidity, are
the cause for the stability failure, the applicant may
shorten the expiration dating period in a Changes Being
Effected Supplement while retaining the ICH storage
condition. Subsequently, if justified, the applicant may
request an approval for a revision of the product specifications
and for reinstating the previously approved
expiration dating period under the non-ICH conditions
through a Prior Approval Supplement. Other measures
(e.g., more protective container and closure, or product
reformulation) may be considered through a Prior
Approval Supplement.
Alternatively, the applicant may, after careful consideration
of all aspects, request for a return to the previous
storage conditions in a Changes Being Effected Supplement
if justification, including all related data and investigational
results, is provided.

b. Plan B: Using the ICH Conditions under
an Alternate Protocol
An alternative to Plan A is to conduct two side-by-side
studies by simultaneously placing samples from the same
batch of drug product under the ICH conditions as well
as the previously approved storage condition. The protocol
containing the ICH storage conditions is considered an
alternative to the approved protocol. This plan may prove
to be particularly useful if the drug product is believed to
be sensitive to moisture.

i. Products with an Approved Stability Protocol
Applicants may initiate stability studies under the ICHrecommended
long-term testing conditions, in addition to
the previously approved conditions at 25°, 30°, or25°–30°C
without humidity controls, for three consecutive
annual batches. Data from these annual batches under the
ICH conditions should be used to verify the current expiration
dating period. However, if the applicant wishes to
verify the ICH conditions over a shorter time span, three
production batches within 1 year or less may be selected,
instead of three consecutive annual batches.

ii. Products without an Approved Stability Protocol
Applicants who have previously performed stability studies
on a drug product without an approved protocol should
submit an appropriate protocol as a Prior Approval Supplement.
This protocol should contain 25°C/ambient humidity
as the primary long-term storage testing conditions, and
the ICH long-term conditions as the alternative, as well
as the ICH-recommended accelerated testing conditions.
On approval of the protocol, applicants may initiate stability
studies on three consecutive annual batches at both
25°C/ambient humidity and 25°C/60% RH or 25°C/40%
RH. Data from these annual batches under the ICH conditions
can be used to verify the current—or establish a
new—expiration dating period.

iii. Other Considerations
Same as in Plan A.

iv. Protocol Revisions
Products with an Approved Stability Protocol Applicants
who have an approved stability protocol may submit the
alternate stability protocol in the annual report, reflecting
the temperature and humidity as recommended by the ICH.
Other changes to the stability protocol generally should
be submitted in a Prior Approval Supplement, unless the
changes are to comply with the current compendium.
Once adopted as an alternate protocol through an annual
report, the ICH conditions can be used, in parallel with
the previously approved conditions, to generate stability
data for subsequent supplemental changes. Alternatively,
the applicant may report the alternative ICH conditions in
a supplement, which requires stability data, if the supplement
occurs before the next scheduled annual report.
If the complete stability data generated on the first
three annual batches under the ICH long-term conditions
using an approved alternate protocol (as defined above)
support the previously approved expiration dating period
under the non-ICH conditions, the alternate stability protocol
can be adopted as the primary stability protocol
through an annual report.
Products without an Approved Stability Protocol For applications
that do not contain an approved stability protocol
as defined above, a new or revised stability protocol may
be submitted in a Prior Approval Supplement marked
“expedited review requested.” This protocol should encompass
25°C/ambient humidity as the primary long-term
storage conditions, and the ICH long-term conditions as
the alternate, as well as accelerated stability storage conditions
as defined by the ICH Guidance and above, in
addition to other recommendations described in this guidance.
On approval of the protocol, stability studies may
be initiated on annual batches and on batches intended to
support supplemental changes.

v. Stability Data for Supplemental Changes
Applicants may provide stability data in support of postapproval
supplemental changes with samples stored at the
ICH-recommended accelerated testing conditions and longterm
testing conditions, both previously approved and
ICH, as well as, if applicable, intermediate conditions. See
Change in Stability Protocol (Section IX.J) for the recommended
filing mechanism.

vi. Data Submission
Satisfactory Data If the complete stability data generated
on the first three annual batches under the ICH long-term
conditions using an approved alternate protocol support
the previously approved expiration dating period under
the non-ICH conditions, the data can be submitted in the
annual report and the current expiration dating period can
be retained.

Unsatisfactory Data If the stability data under the ICH
conditions fall outside the acceptance criteria while data
from the parallel study under the previously approved
conditions or 25°C/ambient humidity, whichever applies,
are satisfactory during the previously approved expiration
dating period, and the added humidity is determined to be
the cause for the stability failure, the product will still be
considered to be in compliance with the regulatory specifications
approved in the application. If the applicant
decides to adopt the ICH conditions, a Changes Being
Effected Supplement with a shortened expiration dating
period or a Prior Approval Supplement with revised product
specifications may be submitted where justified. Other
measures (e.g., more protective container and closure or
product reformulation) may be considered through a Prior
Approval Supplement.
Alternatively, after careful consideration of all aspects,
the applicant may decide not to pursue the switch to the
ICH conditions for the product. The applicant may eliminate
the alternate stability protocol in the next annual report
if a full explanation, including all related data and investigational
results, is provided.
In the case where the product fails to meet the specifications
under the non-ICH conditions, irrespective of
whether it also fails under the ICH conditions, a thorough
investigation in accordance with CGMP should be performed
and appropriate corrective actions should be taken,
including a Field-Alert Report and recall of the affected
product from the marketplace if warranted.

9. Packaging Materials [ICH Q1A]

The testing should be carried out in the final packaging
proposed for marketing. Additional testing of the unprotected
drug product can form a useful part of the stress
testing and package evaluation, as can studies carried out
in other related packaging materials in supporting the
definitive pack or packs.

10. Evaluation [ICH Q1A]

A systematic approach should be adopted in the presentation
of the evaluation of the stability information, which
should cover, as necessary, physical, chemical, biological,
and microbiological quality characteristics, including particular
properties of the dosage form (e.g., dissolution rate
for oral solid dose forms).
The design of the stability study is to establish a shelf
life and to label storage instructions applicable to all future
batches of the dosage form manufactured and packed
under similar circumstances based on testing a minimum
of three batches of the drug product. The degree of variability
of individual batches affects the confidence that a
future production batch will remain within specifications
until the expiration date.
An acceptable approach for quantitative characteristics
that are expected to decrease with time is to determine
the time at which the 95% one-sided confidence limit for
the mean degradation curve intersects the acceptable lower
specification limit. If analysis shows that the batch-to-batch
variability is small, it may be advantageous to combine
the data into one overall estimate by first applying appropriate
statistical tests (e.g., P values for level of significance
of rejection of more than .25) to the slopes of the regression
lines and zero time intercepts for the individual batches.
If combining data from several batches is inappropriate,
the overall retest period may depend on the minimum time
a batch may be expected to remain within acceptable and
justified limits.
The nature of the degradation relationship will determine
the need for transformation of the data for linear
regression analysis. Usually the relationship can be represented
by a linear, quadratic, or cubic function of 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.
Where the data show so little degradation and so little
variability that it is apparent from looking at the them that
the requested shelf life will be granted, it is normally
unnecessary to go through the formal statistical analysis,
but a justification for the omission should be provided.
Limited extrapolation may be taken of the real-time
data beyond the observed range to extend expiration dating
at approval time, particularly where the accelerated data
support this. However, this assumes that the same degradation
relationship will continue to apply beyond the observed
data, and, hence, the use of extrapolation must be justified
in each application in terms of what is known about such
factors as the mechanism of degradation, goodness of fit
of any mathematical model, batch size, and existence of
supportive data.
Any evaluation should cover not only the assay but also
the levels of degradation products and appropriate
attributes. Where appropriate, attention should be paid to
reviewing the adequacy of the mass balance, different stability,
and degradation performance.
The stability of the drug product after reconstituting or
diluting according to labeling should be addressed to provide
appropriate and supportive information. See Section
VIII.N for additional information on drug products that
are reconstituted or diluted.

11. Statements and Labeling

A storage temperature range may be used in accordance
with FDA regulations. The range should be based on the
stability evaluation of the drug product. Where applicable,
specific requirements should be stated, particularly for
drug products that cannot tolerate freezing.
The use of terms such as “ambient conditions” or “room
temperature” is unacceptable. There should be a direct
linkage between the label statement and the demonstrated
stability characteristics of the drug product. A single set
of uniform storage statements for NDAs, ANDAs, PLAs,
and BLAs is recommended to avoid different labeling
storage statements for products stored under controlled
room-temperature conditions. The storage statements and
storage conditions listed in this section are intended to be
standardized and harmonized with the CRT definition in
the USP and the recommendations in the ICH guidance.

a. Room Temperature Storage Statements
i. Liquid Dosage Forms in Semipermeable Containers

The recommended storage statement for LVPs, SVPs,
ophthalmics, otics, and nasal sprays packaged in semipermeable
containers, such as plastic bags, semirigid plastic
containers, ampoules, vials, and bottles with or without
droppers or applicators, that may be susceptible to water
loss but that have been demonstrated to be stable at 25°
± 2°C/40% or 60% RH ± 5% (or 30° ± 2°C/40% or 60%
RH ± 5%); at 25°C/NMT 40% or 30°C/NMT 40% RH;
or at 30°, 25°–30°, or 25°C without humidity controls, is:
Store at 25°C (77°F); excursions permitted to 15°–30°C
(59°–86°F) [see USP Controlled Room Temperature].
For sterile water for injection and LVP solutions of inorganic
salts packaged in semipermeable containers (e.g.,
plastic bags), the following statement may be used on the
immediate container labels:
Store at 25°C (77°F); excursions permitted to 15°–30°C
(59°–86°F) [see USP Controlled Room Temperature] (see
insert for further information),
and the following statement may be used in the “How
Supplied” section of the package insert:
Store at 25°C (77°F); excursions permitted to 15°–30°C
(59°–86°F) [see USP Controlled Room Temperature].
Brief exposure to temperatures up to 40°C/104°F may be
tolerated provided the mean kinetic temperature does not
exceed 25°C (77°F). However, such exposure should be
minimized.
LVP solutions packaged in a semipermeable container
(e.g., a plastic bag) and containing simple organic salts (e.g.,
acetate, citrate, gluconate, and lactate, and dextrose 10%
or less) may be labeled as above, provided there are adequate
stability data (at least 3 months at 40° ± 2°C/15%
RH ± 5% or 40°C/NMT 20% RH) to support such labeling.

ii. All Other Dosage Forms

For all other dosage forms (e.g., solid oral dosage forms,
dry powders, aqueous liquid, semisolid, and suspension
dosage forms) that have been demonstrated to be stable
at the ICH-recommended conditions (25° ± 2°C/60% RH ±
5%, or 30°C/60% RH ± 5%) or at non-ICH conditions,
such as 30°, 25°–30°, or 25°C without humidity controls
and intended to be stored at room temperature, the recommended
labeling statement is
Store at 25°C (77°EF); excursions permitted to 15°–30°C
(59°–86°F) [see USP Controlled Room Temperature].
iii. Where Space on the Immediate Container is Limited
Where an abbreviated labeling statement is necessary
because space on the immediate container is limited, either
of the following statements is acceptable provided the full
labeling statement, as shown above, appears on the outer
carton and in the package insert:
Store at 25°C (77°F); excursions 15°–30°C (59°–86°F);
Store at 25°C (77°F) (see insert).

b. Refrigerator Storage Statement

For a drug product demonstrated to be stable at 5° ± 3°,
2°–5°, or 2°–8°C with or without humidity control and
that is intended to be stored at refrigerator temperature,
the recommended storage statement for labeling may be
one of the following:
Store in a refrigerator, 2°–8°C (36°–46°F);
Store refrigerated, 2°–8°C (36°–46°F).
Where an abbreviated labeling statement is necessary
because space on the immediate container is limited, the
following statement is acceptable, provided one of the full
labeling statements, as shown above, appears on the outer
container and in the package insert:
Refrigerate (see insert).

c. Room Temperature or Refrigerator
Storage Statement

For a drug product demonstrated to be stable both at 25° ±
2°C/60% RH ± 5% and at refrigerator temperature, both
of the room temperature and refrigerator labeling statements,
as described above, are acceptable, depending on
the storage conditions intended for the product. A statement
such as “store at 2°–25°C” is not recommended.

d. Additional Cautionary Statements

If warranted, additional cautionary statements to protect a
drug product from excessive heat, light, humidity, freezing,
and other damaging conditions should be included on the
container label and the package insert. If the space on the
container label is too limited to display all the recommended
statements in detail, a reference to the package insert for
further information (e.g., “see insert”) is recommended.

e. Other Considerations

The applicant may wish to include the definition of USP
CRT in its entirety in the package insert to provide easy
reference.

f. Implementation of the Uniform Storage
Statements in Labeling for New Product
Applications

The recommended storage statements in labeling should
be adopted for new or pending NDA, ANDA, BLA, or PLA
products. For applications approved before the publication
of the guidance, the recommended storage statements
should be adopted through the annual report mechanism
at the next printing opportunity if desired, but within 3 years
of the date of the final guidance. With respect to room
temperature storage statements for already approved products,
new stability studies under the ICH conditions are
not required to adopt the recommended room temperature
labeling statements, provided the products have been demonstrated
to be stable through expiry under one of the
following controlled temperatures: 30°, 25°–30°, and 25°C,
and at ambient humidity.

C. NEW DOSAGE FORMS [ICH Q1C]

A new dosage form is defined as a drug product that is a
different pharmaceutical product type but that contains the
same active substance as included in an existing drug
product approved by the FDA.
New dosage forms include products of different administration
route (e.g., oral, when the original new drug product
was a parenteral), new specific functionality and delivery
system (e.g., modified release tablet, when the original new
drug product was an immediate release tablet), and different
dosage forms of the same administration route (e.g., capsule
to tablet, solution to suspension).
Stability protocols for new dosage forms should follow
the guidance in the ICH Q1A in principle. However,
a reduced stability database at submission time (e.g.,
6 months’ accelerated and 6 months’ long-term data from
ongoing studies) may be acceptable in certain justified cases.

D. OTHER NDAS

Stability protocols for new combination products or new
formulations (which require clinical data for approval)
should follow the guidance in the ICH Q1A in principle.
However, a reduced stability database at submission time
(e.g., 6 months’ accelerated and 6 months’ data from ongoing
studies at the long-term condition) may be acceptable
in certain justified cases, such as when there is a significant
body of information on the stability of the drug product
and the dosage form.

III. STABILITY TESTING FOR ABBREVIATED NDAS

Much of the general information provided in this guidance
is applicable to ANDAs. However, depending on the availability
of significant information on, and the complexity
of, these drug products and dosage forms, the amount of
information necessary to support these applications may
vary from that proposed for NDAs. This section is
intended to provide specific recommendations on abbreviated
applications.

A. DRUG SUBSTANCE STABILITY DATA SUBMISSION

For drug products submitted under an ANDA, including
antibiotics, supporting information may be provided directly
to the drug product ANDA or by reference to an appropriately
referenced drug master file. Publications may be
provided or referenced as supportive information. For
ANDA bulk drug substances, stability data should be generated
on a minimum of one pilot-scale batch. All batches
should be made using equipment of the same design and
operating principle as the manufacturing-scale production
equipment, with the exception of capacity. For ANDA bulk
drug substances produced by fermentation, stability data
should be provided on three production batches, at least
two of which should be generated from different starter
cultures.

B. DRUG SUBSTANCE TESTING

A program for stability assessment may include storage at
accelerated, long-term, and, if applicable, intermediate
stability study storage conditions (refer to IV.G of the ICH
Q1A Guidance and Section II.A). Stability samples should
be stored in the bulk storage container equivalent (e.g.,
same composition and type of container, closure, and liner,
but smaller in size).
If not previously generated or available by reference,
stress-testing studies should be conducted to establish
the inherent stability characteristics of the drug substance
and support the suitability of the proposed analytical
procedures. The detailed nature of the studies
will depend on the individual drug substance, type of
drug product, and available supporting information. Any
necessary testing may be carried out as described in
Section II.A.

C. DRUG PRODUCT

Original ANDAs should contain stability data generated
under the long-term and accelerated stability storage conditions
delineated in V.E of the ICH Q1A guidance (Section
II.B of this chapter). The data package for ANDAs
(e.g., the number of batches; the length of studies needed
at submission and at approval; and the accelerated, intermediate,
and long-term stability data) should be based on
several factors, including the complexity of the dosage
form, the existence of a significant body of information
for the dosage form, and the existence of an approved
application for a particular dosage form.

D. ANDA DATA PACKAGE RECOMMENDATIONS

For simple dosage forms, the following stability data package
is recommended:

• Accelerated stability data at 0, 1, 2, and 3 months:
A tentative expiration dating period of up to 24
months will be granted based on satisfactory
accelerated stability data unless not supported
by the available long-term stability data

• Long-term stability data (available data at the
time of original filing and subsequent amendments)

• A minimum of one batch; pilot scale

• Additional stability studies (12 months at the
intermediate conditions or long-term data
through the proposed expiration date) if significant
change is seen after 3 months during the
accelerated stability study; the tentative expiration
dating period will be determined on the
basis of the available data from the additional
study

E. EXCEPTIONS TO THE ANDA DATA PACKAGE
RECOMMENDATIONS
The following may be considered exceptions to the general
ANDA recommendations:

• Complex dosage forms, such as modified-release
products, transdermal patches, and metered-dose
inhalers

• Drug products without a significant body of
information

• New dosage forms submitted through the ANDA
suitability petition process (Q1C applications)

• Other exceptions may exist and should be discussed
with the Office of Generic Drugs
An ANDA that is determined to be one of the above categories
should contain a modified ICH Q1A stability data
package, including

• 3-month accelerated stability studies

• Long-term stability studies (available data at
the time of original filing and subsequent
amendments): The expiration dating period for
complex dosage forms will be determined on
the basis of available long-term stability data
submitted in the application

• A minimum of three batches manufactured in
accordance with the ICH Q1A batch size recommendations
(refer to V.B of the ICH Q1A
guidance and Section II.B of this chapter)

• Additional stability studies (12 months at the
intermediate conditions or long-term stability
testing through the proposed expiration date) if
significant change is seen after 3 months during
the accelerated stability studies (the tentative
expiration dating period will be determined
based on the available data from the additional
studies)

F. DATA PACKAGE FOR APPROVAL

Full-term stability testing of the primary stability batch or
batches is suggested. However, in the absence of full-term
stability data for the drug product, adequate accelerated
stability data combined with available long-term data can
be used as the basis for granting a tentative expiration
dating period. The batch or batches used for stability testing
should comply fully with the proposed specifications
for the product and be packaged in the market package,
and the release assay should be within reasonable variation
(taking into account inherent assay variability) from the
labeled strength or theoretical strength of the referencelisted
drug. If formulated with an overage, the overage
should be justified as necessary to match that of the reference-
listed drug.
Other supportive stability data may be submitted on
drug product batches that may or may not meet the above
criteria. Data on relevant research batches, investigational
formulations, or alternate container and closure systems,
or from other related studies, may also be submitted to
support the stability of the drug product. The supportive
stability data should be clearly identified.

G. STABILITY STUDY ACCEPTANCE

If the results are satisfactory, a tentative expiration dating
period of up to 24 months at the labeled storage conditions
may be granted. Where data from accelerated studies are
used to project a tentative expiration dating period that is
beyond a date supported by actual long-term studies on
production batches, the application should include a commitment
to conduct long-term stability studies on the first
three production batches and annual batches until the tentative
expiration dating period is verified or the appropriate
expiration dating period is determined. Extension of the
tentative expiration dating period should be based on data
generated on at least three production batches tested
according to the approved protocol outlined in the stability
commitment. Reporting of the data should follow Section
VI of this guidance.
ANDAs withdrawn before publication of this guidance
should not normally have to include stability data in
conformance with the guidance on resubmission if the
original application was withdrawn because of non–stabilityrelated
issues. However, if new stability studies are conducted
to support the submission, such studies should be
conducted as recommended in the guidance.

IV. STABILITY TESTING FOR
INVESTIGATIONAL NDAs

The regulation at 312.23(a)(7) emphasizes the graded
nature of manufacturing and controls information.
Although in each phase of the investigation, sufficient information
should be submitted to ensure the proper identification,
quality, purity, and strength of the investigational
drug, the amount of information needed to achieve that
assurance will vary with the phase of the investigation, the
proposed duration of the investigation, the dosage form,
and the amount of information otherwise available. Therefore,
although stability data are required in all phases of
the IND to demonstrate that the new drug substance and
drug product are within acceptable chemical and physical
limits for the planned duration of the proposed clinical
investigation, if very short-term tests are proposed, the supporting
stability data can be correspondingly very limited.
It is recognized that modifications to the method of
preparation of the new drug substance and dosage form,
and even changes in the dosage form itself, are likely as
the investigation progresses. In an initial phase 1 Chemistry,
Manufacturing and Control section (CMC) submission,
the emphasis should generally be placed on providing
information that will allow evaluation of the safety of
subjects in the proposed study. The identification of a
safety concern or insufficient data to make an evaluation
of safety are the only reasons for placing a trial on clinical
hold based on the CMC section.

A. PHASE 1
Information to support the stability of the drug substance
during the toxicologic studies and the proposed clinical
study or studies should include a brief description of the
stability study and the test methods used to monitor the
stability of the drug substance, and preliminary tabular data
based on representative material. Neither detailed stability
data nor the stability protocol need to be submitted.
Information to support the stability of the drug product
during the toxicologic studies and the proposed clinical
study or studies should include a brief description of the
stability study and the test methods used to monitor the
stability of the drug product packaged in the proposed
container and closure system, and storage conditions and
preliminary tabular data based on representative material.
Neither detailed stability data nor the stability protocol
need to be submitted.
When significant decomposition during storage cannot
be prevented, the clinical trial batch of drug product
should be retested before the initiation of the trial, and
information should be submitted to show that it will
remain stable during the course of the trial. This information
should be based on the limited stability data available
when the trial starts. Impurities that increase during storage
may be qualified by reference to prior human or animal
data.

B. PHASE 2
Development of drug product formulations during phase
2 should be based in part on the accumulating stability
information gained from studies of the drug substance and
its formulations.
The objectives of stability testing during phases 1 and
2 are to evaluate the stability of the investigational formulations
used in the initial clinical trials, to obtain the additional
information needed to develop a final formulation,
and to select the most appropriate container and closure
(e.g., compatibility studies of potential interactive effects
between the drug substance or substances and other components
of the system). This information should be summarized
and submitted to the IND during phase 2. Stability
studies on these formulations should be well underway by
the end of phase 2. At this point the stability protocol for
study of both the drug substance and drug product should
be defined, so that stability data generated during phase 3
studies will be appropriate for submission in the drug
application.

C. PHASE 3
In stability testing during phase 3 IND studies, the emphasis
should be on testing final formulations in their proposed
market packaging and manufacturing site based on
the recommendations and objectives of this guidance. It
is recommended that the final stability protocol be well
defined before the initiation of phase 3 IND studies. In
this regard, consideration should be given to establishing
appropriate linkage between the preclinical and clinical
batches of the drug substance and drug product and those
of the primary stability batches in support of the proposed
expiration dating period. Factors to be considered may
include, for example, source, quality and purity of various
components of the drug product, manufacturing process
of and facility for the drug substance and the drug product,
and use of same containers and closures.

STABILITY TESTING FOR POSTAPPROVAL CHANGES

A. GENERAL
Because of the great variety of changes that may be
encountered after a drug application is approved, it is
impossible to address stability requirements for all
changes in an exhaustive manner in this guidance. Some
more common examples of changes to an approved drug
application for which supportive stability data should be
submitted are listed below. All changes should be accompanied
by the standard stability commitment to conduct
or complete long-term stability studies on the first one or
three batches of the drug substance or drug product and
annual batches thereafter, in accordance with the approved
stability protocol. The accumulated stability data should
be submitted in the subsequent annual reports. Unless
otherwise noted, if the data give no reason to believe that
the proposed change will alter the stability of the drug
product, the previously approved expiration dating period
can be used.

B. CHANGE IN MANUFACTURING PROCESS
OF THE DRUG SUBSTANCE
A change in the manufacturing process of the drug substance
at the approved manufacturing site should be supported
by the submission of sufficient data to show that
such a change does not compromise the quality, purity, or
stability of the drug substance and the resulting drug product.
Because chemical stability of a substance is an intrinsic
property, changes made in the preparation of that substance
should not affect its stability, provided the isolated substance
remains of comparable quality for attributes such
as particle size distribution, polymorphic form, impurity
profile, and other physiochemical properties. Special concerns
for biological products may exist if changes are made
in the manufacturing process of a drug substance that may
not exist in a chemically synthesized drug substance.
Specific submission and stability issues will be
addressed in detail in a separate forthcoming guidance
dealing with postapproval changes for drug substances.

C. CHANGE IN MANUFACTURING SITE
Site changes consist of changes in the location of the site
of manufacture, packaging operations, or analytical testing
laboratory both of company-owned as well as contract
manufacturing facilities. The stability data package and
filing mechanisms indicated below apply to site changes
only. If other changes occur concurrently, the most extensive
data package associated with the individual changes
should be submitted.
When a change to a new manufacturer or manufacturing
site for any portion of the manufacturing process of a
drug substance or drug product is made, sufficient data to
show that such a change does not alter the characteristics
or compromise the quality, purity, or stability of the drug
substance or drug product may be necessary. The data
should include a side-by-side comparison of all attributes
to demonstrate comparability and equivalency of the drug
substance or drug product manufactured at the two facilities.
New manufacturing locations should have a satisfactory
CGMP inspection.

1. Site Change for the Drug Substance

For a change limited to an alternate manufacturing site for
the drug substance using similar equipment and manufacturing
process, stability data on the drug substance may
not always be necessary because, for essentially pure drug
substances, stability is an intrinsic property of the material.
Biotechnology and biologic products may be an exception
(see 21 CFR 601.12 and 314.70 (g)). In general, such a
change can be made in a Changes Being Effected Supplement
as allowed under 21 CFR 314.70(c)(3). The standard
stability commitment should be made to conduct long-term
stability studies in accordance with the approved stability
protocol on the first production batch of drug product produced
from a production batch of drug substance manufactured
at the new site. Ordinarily, the approved expiration
dating period for the drug product may be retained if the
drug substance is shown to be of comparable quality (e.g.,
particle size distribution, polymorphic form, impurity profile,
and other physiochemical properties). If the drug substance
is not of comparable quality, then more extensive
stability data on the drug product manufactured from the
drug substance will be needed.
Specific submission and stability issues pertaining to
manufacturing site changes for a drug substance or its
intermediates in the drug substance manufacturing process
will be addressed in a separate forthcoming guidance on
postapproval changes for the drug substance.

2. Site Change for the Drug Product
For a move of the manufacturing site within an existing
facility or a move to a new facility on the same campus
using similar equipment and manufacturing processes,
submission of stability data on the drug product in the new
facility before implementation is generally not necessary.
For a move to a different campus using similar equipment
and manufacturing processes, stability data on the
drug product in the new facility should be submitted in
a supplemental application. Three months of accelerated
and available long-term stability data on one to three
batches of drug product manufactured in the new site is
recommended, depending on the complexity of the dosage
form and the existence of a significant body of information.
A commitment should be made to conduct longterm
stability studies on the first or first three production
batch or batches of the drug product, depending on the
dosage form and the existence of a significant body of
information, manufactured at the new site in accordance
with the approved stability protocol. If the stability data
are satisfactory, the existing expiration dating period may
be used.

3. Change in Packaging Site for Solid Oral
Dosage–Form Drug Products
A stand-alone packaging operation site change for solid
oral dosage–form drug products using containers and closures
in the approved application should be submitted as
a Changes Being Effected Supplement. No up-front stability
data are necessary. The facility should have a current
and satisfactory CGMP compliance profile for the type of
packaging operation under consideration before submitting
the supplement. The supplement should also contain
a commitment to place the first production batch and
annual batches thereafter on long-term stability studies
using the approved protocol in the application and to submit
the resulting data in annual reports.
dosage–form drug products is considered a manufacturing site
change, and the data package that should be submitted for
approval is indicated in Section IX.C.2.

4. Change in Testing Laboratory
An analytical testing laboratory site change may be submitted
as a Changes Being Effected Supplement under
certain circumstances. No stability data are required.

D. CHANGE IN MANUFACTURING PROCESS OR EQUIPMENT
FOR THE DRUG PRODUCT
A change limited to the manufacturing process of the drug
product, such as a change in the type of equipment used,
can be supported by the submission of sufficient data to
show that such a change does not alter the characteristics
or compromise the stability of the drug product.

E. CHANGE IN BATCH SIZE OF THE DRUG PRODUCT
A key question in considering an increase in batch size
beyond the production batch size approved in the application
is whether the change involves a change in equipment
or its mode of operation, or other manufacturing
parameters described for the approved batch size. If no
equipment change is planned, then the next concern is the
size of the change relative to the approved batch size, with
larger changes expected to present a greater risk of stability
problems in the drug product. If an equipment change
is part of the batch size change, please refer to Change in
Manufacturing Process or Equipment of the Drug Product
(Section IX.F)
.
F. REPROCESSING OF A DRUG PRODUCT
Stability data submitted in support of reprocessing a specific
batch of a drug product should take into account the
nature of the reprocessing procedure and any specific
effect it might have on the existing stability profile of the
drug. The expiration dating period for a reprocessed batch
should not exceed that of the parent batch, and the expiration
date should be calculated from the original date of
manufacture of the oldest batch.
The acceptability of reprocessing of a specific batch of
a drug product will depend on the nature of the reprocessing
procedure, which can range from repackaging a batch when
packing equipment malfunctions to regrinding and recompressing
tablets. The appropriate chemistry review team
should be contacted to determine whether the reprocessing
procedure is acceptable. Any batch of the drug product that
is reprocessed should be placed on accelerated and longterm
stability studies using the approved protocol to generate
a Type 2 stability data package.

G. CHANGE IN CONTAINER AND CLOSURE
OF THE DRUG PRODUCT
The stability data packages for changes in container and
closure of a drug product vary. The first factor used in
determining the stability data package recommendation is
whether the protective properties of the container and closure
system are affected by the proposed change. Protective
properties of the container and closure system include, but
are not limited to, moisture permeability, oxygen permeability,
and light transmission. Changes that may affect
these properties should be supported by a greater amount
of data to support the change. The second factor is the
nature of the dosage form itself. A solid dosage form will
generally be less affected by a container change than a
liquid dosage form. Because considerably more information
will be needed to document a container and closure
change than just stability data, applicants are encouraged
to consult with the appropriate chemistry review team to
determine the appropriate filing mechanisms.

H. CHANGES IN THE STABILITY PROTOCOL
In general, modification of the approved stability protocol
is discouraged until the expiration dating period granted
at the time of approval has been confirmed by long-term
data from production batches. However, changes in analytical
methods providing increased assurance in product
identity, strength, quality, and purity, or to comply with
USP monographs, may be appropriate before the confirmation
of the expiration dating period.
Certain parameters may be reduced in test frequency
or omitted from the stability protocol for annual batches
on a case-by-case basis through a Prior Approval Supplement.
A justification for such a reduction or omission
should be adequately provided.
If justified, test frequency for all parameters may be
reduced for annual batches based on accumulated stability
data. Such a modification to the approved stability protocol
should be submitted as a Prior Approval Supplement. The
justification may include a demonstrated history of satisfactory
product stability, which may in turn include, but
not be limited to, full long-term stability data from at least
three production batches. The reduced testing protocol
should include a minimum of four data points, including
the initial time point and the expiry, and two points inbetween.
For example, drug products with an expiration
dating period of less than 18 months should be tested at
quarterly intervals, products with an expiration dating
period of 18 but not more than 30 months should be tested
semiannually, and products with an expiration dating
period of 36 months or longer should be tested annually.
It should be noted, however, that the reduced testing protocol
applies only to annual batches and does not apply to
batches used to support a postapproval change that requires
long-term stability data at submission or as a commitment.
Furthermore, whenever product stability failures occur, the
original full protocol should be reinstated for annual
batches until problems are corrected.
A bracketing or matrixing design, if proposed for
annual batches or to support a supplemental change,
should be submitted as a Prior Approval Supplement (see
Sections VII.G and H). It is acceptable to submit these
modifications to the protocol, along with data generated
there to support a supplemental change, in one combined
Prior Approval Supplement. However, the applicant is
encouraged to consult with the appropriate FDA chemistry
review team before initiating such studies.

REFERENCES
Bancroft, T.A., Analysis and inference for incompletely specified
models involving the use of preliminary test(s) of significance,
Biometrics, 20(3), 427–442, 1964.

Easterling, R.G., Discrimination intervals for percentiles in
regression, J. Am. Stat. Assoc., 64, 1031–1041, 1969.
Fairweather, W.R., Lin, T.-Y.D., and Kelly, R., Regulatory,
design, and analysis aspects of complex stability studies,
J. Pharm. Sci., 84, 1322–1326, 1995.

Food and Drug Administration (FDA) Guideline, PAC-ATLS:
Post Approval Changes: Analytical Testing Laboratory
Sites, Center for Drug Evaluation and Research (CDER),
April 1998.
FDA Guideline, SUPAC-MR, Modified Release Solid Oral Dosage
Forms, Scale-Up and Post-Approval Changes:
Chemistry, Manufacturing and Controls, in vitro Dissolution
Testing, in vivo Bioequivalence Documentation,
CDER, September 1997.

FDA Guideline, Submission of Documentation in Drug Applications
for Container Closure Systems used for the
Packaging of Human Drugs and Biologics, CDER/
CBER (Center for Biologics Evaluation and Research),
draft guidance, July 1997.

FDA Guideline, SUPAC-SS, Non-Sterile SemiSolid Dosage Forms.
Scale-Up and Post-Approval Changes: Chemistry, Manufacturing
and Controls, in vitro Release Testing, in vivo
Bioequivalence Documentation, CDER, May 1997.

FDA Guideline, SUPAC-IR/MR: Immediate and Modified Release
Solid Oral Dosage Forms, Manufacturing Equipment
Addendum, draft guidance, April 1998.

FDA Guideline, SUPAC-IR, Immediate Release Solid Oral Dosage
Form: Scale-Up and Post-Approval Changes:
Chemistry, Manufacturing and Controls, in vitro Dissolution
Testing, in vivo Bioequivalence Documentation,
CDER, November 1995

Haynes, J.D., Worldwide virtual temperatures for product stability
testing, J. Pharm. Sci., 60(6), 927, 1971.
International Conference on Harmonisation (ICH), Q1A Stability
Testing for New Drug Substances and Products, September
1994.

ICH, Q5C Quality of Biotechnological Products: Stability Testing
of Biotechnological/Biological Products, July 1996.
ICH Guideline, Q1C Stability Testing for New Dosage Forms,
November 1996.
ICH Guideline, Q1B Photostability Testing of New Drug Substances
and Products, May 1997.

Lin, K.K., Lin, T.-Y.D., and Kelley, R.E., Stability of drugs: room
temperature tests, in Buncher C.R. and Tsay J.-Y., Eds.,
Statistics in the Pharmaceutical Industry, Marcel Dekker,
New York, 1994, p. 419–444.

U.S. Department of Health and Human Services, Public Health
Service, FDA Guideline, Guideline on Validation of the
Limulus Amebocyte Lysate Test as an End-Product Endotoxin
Test for Human and Animal Parenteral Drugs, Biological
Products and Medical Devices, December 1987.

Yoshioka, S. et al. Quinine actinometry as a method for calibrating
ultraviolet radiation intensity in light-stability testing
of pharmaceuticals, Drug Dev. Industrial Pharm.,
20(13), 2049–2062, 1994.

Note: All references citing FDA or ICH or U.S. Department of
Health and Human Services are available at http://
www.fda.gov.

GLOSSARY
Accelerated Testing [ICH Q1A] — Studies designed to
increase the rate of chemical degradation or physical
change of an active drug substance and drug product by
using exaggerated storage conditions as part of the formal,
definitive stability protocol. These data, in addition to
long-term stability data, may also 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.

Acceptance Criteria [21 CFR 210.3] — Product specifications
and acceptance or rejection criteria, such as
acceptable quality level and unacceptable quality level,
with an associated sampling plan, that are necessary for
making a decision to accept or reject a lot or batch (or
any other convenient subgroups of manufactured units).

Active Substance; Active Ingredient; Drug Substance;
Medicinal Substance [ICH Q1A] — Unformulated drug
substance that may be subsequently formulated with
excipients to produce the drug product.

Approved Stability Protocol — Detailed study plan
described in an approved application to evaluate the physical,
chemical, biological, and microbiological characteristics
of a drug substance and a drug product as a function
of time. The approved protocol is applied to generate and
analyze acceptable stability data in support of the expiration
dating period. It may also be used in developing similar
data to support an extension of that expiration dating period
and other changes to the application. It should be designed
in accordance with the objectives of this guidance.

Batch [21 CFR 210.3(b)(2)] — Specific quantity of a drug
material that is intended to have uniform character and
quality, within specified limits, and is produced according
to a single manufacturing order during the same cycle of
manufacture.
Bracketing [ICH Q1A] — Design of a stability schedule
so that at any time point only the samples on the extremes,
for example, of container size or dosage strengths, are
tested. The design assumes that the stability of the intermediate
condition samples is represented by those at the
extremes.
Climatic Zones [ICH Q1A] — Concept of dividing the
world into four zones based on defining the prevalent
annual climatic conditions.

Complex Dosage Form — A form in which quality or
stability is more likely to be affected by changes because
the release mechanism, delivery system, and manufacturing
process are more complicated and thus more susceptible
to variability. Examples of complex dosage forms
include modified-release dosage forms, metered-dose
inhalers, transdermal patches, and liposome preparations.
Because of the diversity of currently marketed dosage
forms and the ever-increasing complexity of new delivery
systems, it is impossible to clearly identify simple vs.
complex dosage forms in an exhaustive manner. Applicants
are advised to consult with the appropriate FDA
chemistry review team when questions arise.

Confirmatory Studies [ICH Q1B] — Studies undertaken
to establish photostability characteristics under standardized
conditions. These studies are used to identify precautionary
measures needed in manufacturing or formulation
and whether light-resistant packaging or special labeling
is needed to mitigate exposure to light. For the confirmatory
studies, the batch or batches should be selected
according to batch selection for long-term and accelerated
testing, described in the parent guidance.

Conjugated Product [ICH Q5C] — Made upof an active
ingredient (e.g., peptide, carbohydrate) bound covalently
or noncovalently to a carrier (e.g., protein, peptide, inorganic
mineral) with the objective of improving the efficacy
or stability of the product.

Controlled Room Temperature [USP] — Temperature
maintained thermostatically that encompasses the usual
and customary working environment of 20°–25°C
(68°–77°F) and that results in a mean kinetic temperature
calculated to be not more than 25°C and allows for excursions
between 15° and 30°C (59°–86°F) that are experienced
in pharmacies, hospitals, and warehouses.

Date of Production — Date that the first step of manufacture
is performed that involves the combining of an
active ingredient, antioxidant, or preservative with other
ingredients in the production of a dosage form. For drug
products consisting of a single ingredient filled into a
container, the date of the production is the initial date of
the filling operation. For a biological product subject to
licensure, see the definition of date of manufacture in
21 CFR 610.50.

Degradation Product [ICH Q5C] — Molecule resulting
from a change in the drug substance bulk material brought
about over time. For the purpose of stability testing of the
products described in this guidance, such changes could
occur as a result of processing or storage (e.g., by deamidation,
oxidation, aggregation, and proteolysis). For biotechnological
and biological products, some degradation
products may be active.

Dosage Form; Preparation [ICH Q1A] — Pharmaceutical
product type, for example, tablet, capsule, solution,
ocream, that contains a drug substance, generally, but not
necessarily, in association with excipients.

Drug Product; Finished Product [ICH Q1A] — Dosage
form in the final immediate packaging intended for
marketing.

Drug Substance; Active Substance [21 CFR 312.3(b)] —
Active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or to affect
the structure or any function of the human body.

Excipient [ICH Q1A] — Anything other than the drug
substance in the dosage form.

Expiry or Expiration Date [ICH Q1A] — Date placed
on the container or labels of a drug product designating
the time during 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.

Extractables and Leachables — Materials or components
derived from the container and closure that have been transferred
into the contained drug substance or drug product.

Forced Degradation Testing Studies [ICH Q1B] —
Studies undertaken to degrade the sample deliberately.
These studies, which may be undertaken in the development
phase normally on the drug substances, are used to
evaluate the overall photosensitivity of the material for
method development purposes or degradation pathway
elucidation.

Formal (Systematic) Studies [ICH Q1A] — Studies
undertaken to a preapproval stability protocol that
embraces the principles of these guidances.

Immediate (Primary) Pack [ICH Q1B] — Constituent
of the packaging that is in direct contact with the drug
substance or drug product and that includes any appropriate
label.

Impurity — Any entity of the drug substance (bulk material)
or drug product (final container product) that is not
the chemical entity defined as the drug substance, an
excipient, or other additives to the drug product.

Intermediate [ICH Q5C] — For biotechnological or biological
products, a material produced during a manufacturing
process that is not the drug substance or the drug product
but for which manufacture is critical to the successful production
of the drug substance or the drug product. Generally,
an intermediate will be quantifiable and specifications
will be established to determine the successful completion
of the manufacturing step before continuation of the manufacturing
process. This includes material that may
undergo further molecular modification or be held for an
extended period before further processing.

Long-Term (Real-Time) Testing [ICH Q1A] — Stability
evaluation of the physical, chemical, biological, and
microbiological characteristics of a drug product and a
drug substance, covering the expected duration of the shelf
life and retest period, which are claimed in the submission
and will appear on the labeling.

Lot [21 CFR 210.3(b)(10)] — Batch, or a specific identified
portion of a batch, having uniform character and
quality within specified limits; or, in the case of a drug
product produced by continuous process, specific identified
amount produced in a unit of time or quantity in a
manner that ensures its having uniform character and quality
within specific limits.
Manufacturing-Scale Production [ICH Q5C] — Manufacture
at the scale typically encountered in a facility
intended for product production for marketing.

Marketing Pack [ICH Q1B] — Combination of immediate
pack and other secondary packaging such as a carton.

Mass Balance (Material Balance) [ICH Q1A] — 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 precision. This concept is a useful scientific
guide for evaluating data but is not achievable in all circumstances.
The focus may instead be on ensuring the
specificity of the assay, the completeness of the investigation
of routes of degradation, and the use, if necessary, of
identified degradants as indicators of the extent of degradation
via particular mechanisms.

Matrixing [ICH Q1A] — Statistical design of a stability
schedule so that only a fraction of the total number of
samples are tested at any specified sampling point. At a
subsequent sampling point, different sets of samples of
the total number would be tested. The design assumes that
the stability of the samples tested represents the stability
of all samples. 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 and closure, and possibly, in some
cases, different containers and closure systems. Matrixing
can cover reduced testing when more than one variable is
being evaluated. Thus, the design of the matrix will be
dictated by the factors needing to be covered and evaluated.
This potential complexity precludes inclusion of specific
details and examples, and it may be desirable to
discuss design in advance with the FDA chemistry review
team where this is possible. In every case, it is essential
that all batches are tested both initially and at the end of
the long-term testing period.

Mean Kinetic Temperature [ICH Q1A] — Isothermal
temperature that corresponds to the kinetic effects of a
time–temperature distribution.
Modified-Release Dosage Forms [SUPAC-MR] — Dosage
forms whose drug-release characteristics of time
course or location are chosen to accomplish therapeutic
or convenience objectives not offered by conventional dosage
forms such as a solution or an immediate release
dosage form. Modified release solid oral dosage forms
include both delayed and extended release drug products.

New Dosage Form [ICH Q1C] — Drug product that is a
different pharmaceutical product type but contains the
same active substance as included in the existing drug
product approved by the pertinent regulatory authority.

New Molecular Entity; New Active Substance [ICH
Q1A] — Substance that has not previously been registered
as a new drug substance with the national or regional
authority concerned.

Pilot-Plant Scale — Manufacture of either drug substance
or drug product by a procedure fully representative of and
simulating that to be applied on a full manufacturing scale.
For oral solid dosage forms this is generally taken to be
at a minimum scale of one tenth that of full production or
100,000 tablets or capsules, whichever is the larger. [Q1A]
For biotechnology products, the methods of cell expansion,
harvest, and product purification should be identical
except for the scale of production.
[ICH Q5C

]Primary Stability Data [ICH Q1A] — Data on the drug
substance stored in the proposed packaging under storage
conditions that support the proposed retest date. Data on
the drug product stored in the proposed container and
closure for marketing under storage conditions that support
the proposed shelf life.

Production Batch — Batch of a drug substance or drug
product manufactured at the scale typically encountered
in a facility intended for marketing production.

Random Sample — Selection of units chosen from a larger
population of such units so that the probability of inclusion
of any given unit in the sample is defined. In a simple random
sample, each unit has an equal chance of being included.
Random samples are usually chosen with the aid of tables
of random numbers found in many statistical texts.

Reference-Listed Drug [21 CFR 314.3] — Listed drug
identified by the FDA as the drug product on which an
applicant relies in seeking approval of its abbreviated
application.

Retest Date [ICH Q1A] — Date when samples of the
drug substance should be reexamined to ensure that the
material is still suitable for use.

Retest Period [ICH Q1A] — Time interval during which
the drug substance can be considered to remain within the
specifications and therefore be acceptable for use in the
manufacture of a given drug product, provided that it has
been stored under the defined conditions; after this period
the batch should be retested for compliance with specifications
and then used immediately.

Semipermeable Container — Container that permits the
passage of a solvent, such as water contained therein, but
prevents the passage of the dissolved substance or solute,
thus resulting in an increased concentration of the latter
over time. It may also permit the ingress of foreign volatile
materials. The transport of the solvent, its vapor, or other
volatile material occurs through the container by dissolution
into one surface, diffusion through the bulk of the
material, and desorption from the other surface, all caused
by a partial-pressure gradient. Examples of semipermeable
containers include plastic bags or semirigid LDPE
for LVPs, and LDPE ampoules, vials, or bottles for inhalation
or ophthalmic solutions.

Semisolid Dosage Forms [SUPAC-SS] — Semisolid dosage
forms include nonsterile and semisolid preparations,
for example, creams, gels, and ointments, intended for all
topical routes of administration.

Shelf Life; Expiration Dating Period [ICH Q1A] —
Time interval that a drug product is expected to remain
within the approved shelf-life specification provided that
it is stored under the conditions defined on the label in
the proposed containers and closure.

Significant Body of Information [SUPAC-IR/MR] —
Immediate Release Solid Oral Dosage Forms: A significant
body of information on the stability of the drug product
is likely to exist after 5 years of commercial experience
for new molecular entities or 3 years of commercial experience
for new dosage forms. Modified-Release Solid Oral
Dosage Forms: A significant body of information should
include, for modified-release solid oral dosage forms, a
product-specific body of information. This product-specific
body of information is likely to exist after 5 years of
commercial experience for the original complex dosage
form drug product or 3 years of commercial experience
for any subsequent complex dosage form drug product.

Significant Change [ICH Q1A] — Significant change for
a drug product at the accelerated stability condition and
the intermediate stability condition is defined as

1. A 5% potency loss from the initial assay value
of a batch

2. Any specified degradant exceeding its specification
limit

3. The product exceeding its pH limits

4. Dissolution exceeding the specification limits
for 12 capsules or tablets

5. Failure to meet specifications for appearance
and physical properties; for example, color,
phase separation, resuspendibility, delivery per
actuation, caking, hardness

Simple Dosage Form — Dosage form whose quality or
stability is less likely to be affected by the manufacturing
site because the release mechanism, delivery system, and
manufacturing process are less complicated and less susceptible
to variability. Examples of simple dosage forms
include immediate-release solid oral dosage forms; for
example, tablets, capsules, semisolid dosage forms, and oral
and parenteral solutions. Because of the diversity of currently
marketed dosage forms and the ever-increasing complexity
of new delivery systems, it is impossible to clearly
identify simple vs. complex dosage forms in an exhaustive
manner. Applicants are advised to consult with the appropriate
FDA chemistry review team when questions arise.

Site-Specific Batches — Batches of drug substance or
drug product made at the intended manufacturing-scale
production site from which stability data are generated to
support the approval of that site, as well as to support the
proposed retest period or expiration dating period, respectively,
in an application. The site-specific batch or batches
of the drug product should be made from identifiable sitespecific
batch or batches of the drug substance whenever
possible.

Specification-Check/Shelf Life [ICH Q1A] — Combination
of physical, chemical, biological, and microbiological
test requirements if a drug substance must meet up to its
retest date or that a drug product must meet throughout
its shelf life.

Specification-Release [ICH Q1A] — Combination of
physical, chemical, biological, and microbiological test
requirements that determine if a drug product is suitable
for release at the time of its manufacture.

Stability — Capacity of a drug substance or a drug product
to remain within specifications established to ensure
its identity, strength, quality, and purity throughout the
retest period or expiration dating period, as appropriate.

Stability Commitment — Statement by an applicant to
conduct or complete prescribed studies on production
batches of a drug product after approval of an application.

Stability-Indicating Methodology — Validated quantitative
analytical methods that can detect the changes with
time in the chemical, physical, or microbiological properties
of the drug substance and drug product and that are
specific so that the contents of active ingredient, degradation
products, and other components of interest can be
accurately measured without interference.

Stability Profile — Physical, chemical, biological, and
microbiological behavior of a drug substance or drug
product as a function of time when stored under the conditions
of the Approved Stability Protocol.

Storage Conditions Tolerances [ICH Q1A] — Acceptable
variation in temperature and relative humidity of stability
storage.

Strength [21 CFR 210.3(b)(16)] — Concentration of the
drug substance (e.g., weight/weight, weight/volume, or
unit dose/volume basis) or the potency, that is, the therapeutic
activity of the drug product as indicated by an
appropriate laboratory test or by adequately developed and
controlled clinical data (e.g., expressed in terms of units
by reference to a standard).

Stress Testing—Drug Product [ICH Q1A] — Light testing
should be an integral part of stress testing. Special test
conditions for specific products (e.g., metered dose inhalations
and creams and emulsions) may require additional
stress studies.

Stress Testing—Drug Substance [ICH Q1A] — Studies
undertaken to elucidate intrinsic stability characteristics.
Such testing is part of the development strategy and is
normally carried out under more severe conditions than
those used for accelerated tests.

Supporting Stability Data [ICH Q1A] — Data other
than the primary stability data, such as stability data on
early synthetic route batches of drug substance, smallscale
batches of materials, investigational formulations
not proposed for marketing, related formulations, product
presented in containers or closures other than those
proposed for marketing, information regarding test
results on containers, and other scientific rationale that
support the analytical procedures, the proposed retest
period, or shelf life and storage conditions.

Tentative Expiration Dating Period — Provisional expiration
dating period that is based on acceptable accelerated
data, statistical analysis of available long-term data, and
other supportive data for an NDA product, or on acceptable
accelerated data for an ANDA product but not on full longterm
stability data from at least three production batches.
© 2004
Romel A. Altamirano