Guidance for Industry

Q1A(R2) Stability Testing

of New Drug Substances 

and Products

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

November 2003

ICH

Revision 2
Guidance for Industry

Q1A(R2) Stability Testing

of New Drug Substances 

and Products

Additional copies are available from:

Office of Training and Communication

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

 http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research

 Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448 

 http://www.fda.gov/cber/guidelines.htm. 

 (Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

November 2003

ICH

Revision 2
Contains Nonbinding Recommendations

i

TABLE OF CONTENTS

I. INTRODUCTION (1) ................................................................................................1

A. Objectives of the Guidance (1.1).............................................................................................................1

B. Scope of the Guidance (1.2).....................................................................................................................2

C. General Principles (1.3)............................................................................................................................2

II. GUIDANCE (2)..........................................................................................................2

A. Drug Substance (2.1).................................................................................................................................2

1. General (2.1.1)..............................................................................................................................................2

2. Stress Testing (2.1.2)...................................................................................................................................3

3. Selection of Batches (2.1.3)........................................................................................................................3

4. Container Closure System (2.1.4)..............................................................................................................3

5. Specification (2.1.5).....................................................................................................................................3

6. Testing Frequency (2.1.6)...........................................................................................................................4

7. Storage Conditions (2.1.7)..........................................................................................................................4

8. Stability Commitment (2.1.8)......................................................................................................................6

9. Evaluation (2.1.9).........................................................................................................................................7

B. Drug Product (2.2).....................................................................................................................................8

1. General (2.2.1)..............................................................................................................................................8

2. Photostability Testing (2.2.2).....................................................................................................................8

3. Selection of Batches (2.2.3).......................................................................................................................8

4. Container Closure System (2.2.4)..............................................................................................................8

5. Specification (2.2.5).....................................................................................................................................9

6. Testing Frequency (2.2.6)...........................................................................................................................9

7. Storage Conditions (2.2.7)........................................................................................................................10

8. Stability Commitment (2.2.8)....................................................................................................................14

9. Evaluation (2.2.9).......................................................................................................................................15

10. Statements/Labeling (2.2.10).................................................................................................................16

GLOSSARY (3) .............................................................................................................. 17

REFERENCES (4).......................................................................................................... 21

ATTACHMENT List Of Revision 2 Changes.................................................................. 22
Contains Nonbinding Recommendations

1

Guidance for Industry1

Q1A(R2) Stability Testing of New Drug 

Substances and Products

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION (1) 2

This guidance is the second revision of Q1A Stability Testing of New Drug Substances and 

Products, which was first published in September 1994 and revised in August 2001. The 

purpose of this revision is to harmonize the intermediate storage condition for zones I and II with 

the long-term condition for zones III and IV recommended in the ICH guidance Q1F Stability 

Data Package for Registration Applications in Climatic Zones III and IV. The changes made in 

this second revision are listed in the attachment to this guidance. 

A. Objectives of the Guidance (1.1)

This guidance is intended to define what stability data package for a new drug substance or drug 

product is sufficient for a registration application within the three regions of the European Union 

(EU), Japan, and the United States. It does not seek to address the testing for registration in or 

export to other areas of the world. The guidance exemplifies the core stability data package for 

new drug substances and products, but leaves sufficient flexibility to encompass the variety of 

different practical situations that may be encountered due to specific scientific considerations and 

characteristics of the materials being evaluated. Alternative approaches can be used when there 

are scientifically justifiable reasons.

 

1

This guidance was developed within the Expert Working Group (Quality) of the International Conference on 

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 

subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed 

by the ICH Steering Committee at Step 4 of the ICH process, February 2003. At Step 4 of the process, the final draft 

is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.

2

 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee 

at Step 4 of the ICH process. 
Contains Nonbinding Recommendations

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B. Scope of the Guidance (1.2)

The guidance addresses the information to be submitted in registration applications for new 

molecular entities and associated drug products. This guidance does not currently seek to cover 

the information to be submitted for abbreviated or abridged applications, variations, or clinical 

trial applications.

Specific details of the sampling and testing for particular dosage forms in their proposed 

container closures are not covered in this guidance.

Further guidance on new dosage forms and on biotechnological/biological products can be found 

in ICH guidances Q1C Stability Testing for New Dosage Forms and Q5C Quality of 

Biotechnological Products: Stability Testing of Biotechnological/Biological Products, 

respectively.

C. General Principles (1.3)

The purpose of stability testing is to provide evidence on how the quality of a drug substance or 

drug product varies with time under the influence of a variety of environmental factors, such as 

temperature, humidity, and light, and to establish a retest period for the drug substance or a shelf 

life for the drug product and recommended storage conditions.

The choice of test conditions defined in this guidance is based on an analysis of the effects of 

climatic conditions in the three regions of the EU, Japan, and the United States. The mean 

kinetic temperature in any part of the world can be derived from climatic data, and the world can 

be divided into four climatic zones, I-IV. This guidance addresses climatic zones I and II. The 

principle has been established that stability information generated in any one of the three regions 

of the EU, Japan, and the United States would be mutually acceptable to the other two regions, 

provided the information is consistent with this guidance and the labeling is in accord with 

national/regional requirements.

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required.

II. GUIDANCE (2)

A. Drug Substance (2.1)

1. General (2.1.1)

Information on the stability of the drug substance is an integral part of the systematic approach to 

stability evaluation. 
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2. Stress Testing (2.1.2)

Stress testing of the drug substance can help identify the likely degradation products, which can 

in turn help establish the degradation pathways and the intrinsic stability of the molecule and 

validate the stability indicating power of the analytical procedures used. The nature of the stress 

testing will depend on the individual drug substance and the type of drug product involved.

Stress testing is likely to be carried out on a single batch of the drug substance. The testing 

should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C) above that for 

accelerated testing), humidity (e.g., 75 percent relative humidity or greater) where appropriate, 

oxidation, and photolysis on the drug substance. The testing should also evaluate the 

susceptibility of the drug substance to hydrolysis across a wide range of pH values when in 

solution or suspension. Photostability testing should be an integral part of stress testing. The 

standard conditions for photostability testing are described in ICH Q1B Photostability Testing of 

New Drug Substances and Products.

Examining degradation products under stress conditions is useful in establishing degradation 

pathways and developing and validating suitable analytical procedures. However, such 

examination may not be necessary for certain degradation products if it has been demonstrated 

that they are not formed under accelerated or long-term storage conditions.

Results from these studies will form an integral part of the information provided to regulatory 

authorities.

3. Selection of Batches (2.1.3)

Data from formal stability studies should be provided on at least three primary batches of the 

drug substance. The batches should be manufactured to a minimum of pilot scale by the same 

synthetic route as production batches and using a method of manufacture and procedure that 

simulates the final process to be used for production batches. The overall quality of the batches 

of drug substance placed on formal stability studies should be representative of the quality of the 

material to be made on a production scale.

Other supporting data can be provided.

4. Container Closure System (2.1.4)

The stability studies should be conducted on the drug substance packaged in a container closure 

system that is the same as or simulates the packaging proposed for storage and distribution.

5. Specification (2.1.5)

Specification, which is a list of tests, references to analytical procedures, and proposed 

acceptance criteria, is addressed in ICH Q6A Specifications: Test Procedures and Acceptance 

Criteria for New Drug Substances and New Drug Products: Chemical Substances and Q6B 
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Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New 

Drug Products: Biotechnological/Biological Products. In addition, specification for degradation 

products in a drug substance is discussed in ICH Q3A Impurities in New Drug Substances.

Stability studies should include testing of those attributes of the drug substance that are 

susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. 

The testing should cover, as appropriate, the physical, chemical, biological, and microbiological 

attributes. Validated stability-indicating analytical procedures should be applied. Whether and 

to what extent replication should be performed should depend on the results from validation 

studies. 

6. Testing Frequency (2.1.6)

For long-term studies, frequency of testing should be sufficient to establish the stability profile of 

the drug substance. For drug substances with a proposed retest period of at least 12 months, the 

frequency of testing at the long-term storage condition should normally be every 3 months over 

the first year, every 6 months over the second year, and annually thereafter through the proposed 

retest period.

At the accelerated storage condition, a minimum of three time points, including the initial and 

final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an 

expectation (based on development experience) exists that the results from accelerated studies 

are likely to approach significant change criteria, increased testing should be conducted either by 

adding samples at the final time point or including a fourth time point in the study design.

When testing at the intermediate storage condition is called for as a result of significant change at 

the accelerated storage condition, a minimum of four time points, including the initial and final 

time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.

7. Storage Conditions (2.1.7)

In general, a drug substance should be evaluated under storage conditions (with appropriate 

tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture. The storage 

conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and 

subsequent use.

The long-term testing should cover a minimum of 12 months’ duration on at least three primary 

batches at the time of submission and should be continued for a period of time sufficient to cover 

the proposed retest period. Additional data accumulated during the assessment period of the 

registration application should be submitted to the authorities if requested. Data from the 

accelerated storage condition and, if appropriate, from the intermediate storage condition can be 

used to evaluate the effect of short-term excursions outside the label storage conditions (such as 

might occur during shipping).

Long-term, accelerated, and, where appropriate, intermediate storage conditions for drug 

substances are detailed in the sections below. The general case should apply if the drug substance 
Contains Nonbinding Recommendations

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is not specifically covered by a subsequent section. Alternative storage conditions can be used if 

justified. 

a. General case (2.1.7.1)

Study Storage condition Minimum time period covered 

by data at submission

Long-term* 25°C ± 2°C/60% RH ± 5% RH

or

30°C ± 2°C/65% RH ± 5% RH

12 months

Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months 

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months 

* It is up to the applicant to decide whether long-term stability sturdies are performed at 

25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

** If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and significant change

occurs at any time during 6 months’ testing at the accelerated storage condition, additional 

testing at the intermediate storage condition should be conducted and evaluated against 

significant change criteria. Testing at the intermediate storage condition should include all tests, 

unless otherwise justified. The initial application should include a minimum of 6 months’ data 

from a 12-month study at the intermediate storage condition.

Significant change for a drug substance is defined as failure to meet its specification.

b. Drug substances intended for storage in a refrigerator (2.1.7.2)

Study Storage condition Minimum time period covered 

by data at submission

Long-term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months 

Data from refrigerated storage should be assessed according to the evaluation section of this 

guidance, except where explicitly noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, 

the proposed retest period should be based on the real time data available at the long-term 

storage condition.

If significant change occurs within the first 3 months’ testing at the accelerated storage 

condition, a discussion should be provided to address the effect of short-term excursions outside 

the label storage condition (e.g., during shipping or handling). This discussion can be supported, 

if appropriate, by further testing on a single batch of the drug substance for a period shorter than 
Contains Nonbinding Recommendations

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3 months but with more frequent testing than usual. It is considered unnecessary to continue to 

test a drug substance through 6 months when a significant change has occurred within the first 3 

months.

c. Drug substances intended for storage in a freezer (2.1.7.3)

Study Storage condition Minimum time period covered 

by data at submission

Long-term -20°C ± 5°C 12 months

For drug substances intended for storage in a freezer, the retest period should be based on the 

real time data obtained at the long-term storage condition. In the absence of an accelerated 

storage condition for drug substances intended to be stored in a freezer, testing on a single batch 

at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should 

be conducted to address the effect of short-term excursions outside the proposed label storage 

condition (e.g., during shipping or handling). 

d. Drug substances intended for storage below -20°C (2.1.7.4)

Drug substances intended for storage below -20°C should be treated on a case-by-case basis.

8. Stability Commitment (2.1.8)

When available long-term stability data on primary batches do not cover the proposed retest 

period granted at the time of approval, a commitment should be made to continue the stability 

studies postapproval to firmly establish the retest period.

Where the submission includes long-term stability data on three production batches covering the 

proposed retest period, a postapproval commitment is considered unnecessary. Otherwise, one 

of the following commitments should be made:

• If the submission includes data from stability studies on at least three production 

batches, a commitment should be made to continue these studies through the 

proposed retest period.

• If the submission includes data from stability studies on fewer than three 

production batches, a commitment should be made to continue these studies 

through the proposed retest period and to place additional production batches, to a 

total of at least three, on long-term stability studies through the proposed retest 

period.

• If the submission does not include stability data on production batches, a 

commitment should be made to place the first three production batches on longterm stability studies through the proposed retest period.
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The stability protocol used for long-term studies for the stability commitment should be the same 

as that for the primary batches, unless otherwise scientifically justified.

9. Evaluation (2.1.9)

The purpose of the stability study is to establish, based on testing a minimum of three batches of 

the drug substance and evaluating the stability information (including, as appropriate, results of 

the physical, chemical, biological, and microbiological tests), a retest period applicable to all 

future batches of the drug substance manufactured under similar circumstances. The degree of 

variability of individual batches affects the confidence that a future production batch will remain 

within specification throughout the assigned retest period.

The data may show so little degradation and so little variability that it is apparent from looking at 

the data that the requested retest period will be granted. Under these circumstances, it is 

normally unnecessary to go through the formal statistical analysis; providing a justification for 

the omission should be sufficient.

An approach for analyzing the data on a quantitative attribute that is expected to change with 

time is to determine the time at which the 95 percent, one-sided confidence limit for the mean 

curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is 

small, it is advantageous to combine the data into one overall estimate. This can be done by first 

applying appropriate statistical tests (e.g., p values for level of significance of rejection of more 

than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. 

If it is inappropriate to combine data from several batches, the overall retest period should be 

based on the minimum time a batch can be expected to remain within acceptance criteria.

The nature of any degradation relationship will determine whether the data should be 

transformed for linear regression analysis. Usually the relationship can be represented by a 

linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical methods 

should be employed to test the goodness of fit of the data on all batches and combined batches 

(where appropriate) to the assumed degradation line or curve.

Limited extrapolation of the real time data from the long-term storage condition beyond the 

observed range to extend the retest period can be undertaken at approval time if justified. This 

justification should be based, for example, on what is known about the mechanism of 

degradation, the results of testing under accelerated conditions, the goodness of fit of any 

mathematical model, batch size, and/or existence of supporting stability data. However, this 

extrapolation assumes that the same degradation relationship will continue to apply beyond the 

observed data.

Any evaluation should cover not only the assay, but also the levels of degradation products and 

other appropriate attributes.
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10. Statements/Labeling (2.1.10)

A storage statement should be established for the labeling in accordance with relevant 

national/regional requirements. The statement should be based on the stability evaluation of the 

drug substance. Where applicable, specific instructions should be provided, particularly for drug 

substances that cannot tolerate freezing. Terms such as ambient conditions or room temperature

should be avoided. 

A retest period should be derived from the stability information, and a retest date should be 

displayed on the container label if appropriate.

B. Drug Product (2.2)

1. General (2.2.1)

The design of the formal stability studies for the drug product should be based on knowledge of 

the behavior and properties of the drug substance, results from stability studies on the drug 

substance, and experience gained from clinical formulation studies. The likely changes on 

storage and the rationale for the selection of attributes to be tested in the formal stability studies 

should be stated.

2. Photostability Testing (2.2.2)

Photostability testing should be conducted on at least one primary batch of the drug product if 

appropriate. The standard conditions for photostability testing are described in ICH Q1B.

3. Selection of Batches (2.2.3)

Data from stability studies should be provided on at least three primary batches of the drug 

product. The primary batches should be of the same formulation and packaged in the same 

container closure system as proposed for marketing. The manufacturing process used for 

primary batches should simulate that to be applied to production batches and should provide 

product of the same quality and meeting the same specification as that intended for marketing. 

Two of the three batches should be at least pilot scale batches, and the third one can be smaller if

justified. Where possible, batches of the drug product should be manufactured by using different 

batches of the drug substance.

Stability studies should be performed on each individual strength and container size of the drug 

product unless bracketing or matrixing is applied.

Other supporting data can be provided.

4. Container Closure System (2.2.4)

Stability testing should be conducted on the dosage form packaged in the container closure 

system proposed for marketing (including, as appropriate, any secondary packaging and 
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container label). Any available studies carried out on the drug product outside its immediate 

container or in other packaging materials can form a useful part of the stress testing of the dosage 

form or can be considered as supporting information, respectively.

5. Specification (2.2.5)

Specification, which is a list of tests, references to analytical procedures, and proposed 

acceptance criteria, including the concept of different acceptance criteria for release and shelf life 

specifications, is addressed in ICH Q6A and Q6B. In addition, specification for degradation 

products in a drug product is addressed in ICH Q3B Impurities in New Drug Products.

Stability studies should include testing of those attributes of the drug product that are susceptible 

to change during storage and are likely to influence quality, safety, and/or efficacy. The testing 

should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, 

preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., 

for a dose delivery system). Analytical procedures should be fully validated and stability 

indicating. Whether and to what extent replication should be performed will depend on the 

results of validation studies. 

Shelf life acceptance criteria should be derived from consideration of all available stability 

information. It may be appropriate to have justifiable differences between the shelf life and 

release acceptance criteria based on the stability evaluation and the changes observed on storage. 

Any differences between the release and shelf life acceptance criteria for antimicrobial 

preservative content should be supported by a validated correlation of chemical content and 

preservative effectiveness demonstrated during drug development on the product in its final 

formulation (except for preservative concentration) intended for marketing. A single primary 

stability batch of the drug product should be tested for antimicrobial preservative effectiveness 

(in addition to preservative content) at the proposed shelf life for verification purposes, 

regardless of whether there is a difference between the release and shelf life acceptance criteria 

for preservative content.

6. Testing Frequency (2.2.6)

For long-term studies, frequency of testing should be sufficient to establish the stability profile of 

the drug product. For products with a proposed shelf life of at least 12 months, the frequency of 

testing at the long-term storage condition should normally be every 3 months over the first year, 

every 6 months over the second year, and annually thereafter through the proposed shelf life.

At the accelerated storage condition, a minimum of three time points, including the initial and 

final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an 

expectation (based on development experience) exists that results from accelerated testing are 

likely to approach significant change criteria, increased testing should be conducted either by 

adding samples at the final time point or by including a fourth time point in the study design.
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When testing at the intermediate storage condition is called for as a result of significant change at 

the accelerated storage condition, a minimum of four time points, including the initial and final 

time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.

Reduced designs (i.e., matrixing or bracketing), where the testing frequency is reduced or certain 

factor combinations are not tested at all, can be applied if justified. 

7. Storage Conditions (2.2.7)

In general, a drug product should be evaluated under storage conditions (with appropriate 

tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential 

for solvent loss. The storage conditions and the lengths of studies chosen should be sufficient to 

cover storage, shipment, and subsequent use. 

Stability testing of the drug product after constitution or dilution, if applicable, should be 

conducted to provide information for the labeling on the preparation, storage condition, and inuse period of the constituted or diluted product. This testing should be performed on the 

constituted or diluted product through the proposed in-use period on primary batches as part of 

the formal stability studies at initial and final time points, and if full shelf life, long-term data 

will not be available before submission, at 12 months or the last time point for which data will be 

available. In general, this testing need not be repeated on commitment batches.

The long-term testing should cover a minimum of 12 months’ duration on at least three primary 

batches at the time of submission and should be continued for a period of time sufficient to cover 

the proposed shelf life. Additional data accumulated during the assessment period of the 

registration application should be submitted to the authorities if requested. Data from the 

accelerated storage condition and, if appropriate, from the intermediate storage condition can be 

used to evaluate the effect of short-term excursions outside the label storage conditions (such as 

might occur during shipping). 

Long-term, accelerated, and, where appropriate, intermediate storage conditions for drug 

products are detailed in the sections below. The general case should apply if the drug product is 

not specifically covered by a subsequent section. Alternative storage conditions can be used if 

justified.
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a. General case (2.2.7.1)

Study Storage condition Minimum time period covered 

by data at submission

Long-term* 25°C ± 2°C/60% RH ± 5% RH

or

30°C ± 2°C/65% RH ± 5% RH

12 months

Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months 

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months 

* It is up to the applicant to decide whether long-term stability sturdies are performed at 

25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

** If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

If long-term studies are condcuted at 25°C ± 2°C/60% RH ± 5% RH and significant change

occurs at any time during 6 months’ testing at the accelerated storage condition, additional 

testing at the intermediate storage condition should be conducted and evaluated against 

significant change criteria. The initial application should include a minimum of 6 months’ data 

from a 12-month study at the intermediate storage condition.

In general, significant change for a drug product is defined as one or more of the following (as 

appropriate for the dosage form):

• A 5 percent change in assay from its initial value, or failure to meet the 

acceptance criteria for potency when using biological or immunological 

procedures

• Any degradation product’s exceeding its acceptance criterion

• Failure to meet the acceptance criteria for appearance, physical attributes, and 

functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, 

dose delivery per actuation). However, some changes in physical attributes (e.g., 

softening of suppositories, melting of creams) may be expected under accelerated 

conditions.

• Failure to meet the acceptance criterion for pH

• Failure to meet the acceptance criteria for dissolution for 12 dosage units

b. Drug products packaged in impermeable containers (2.2.7.2)

Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged 

in impermeable containers that provide a permanent barrier to passage of moisture or solvent. 

Thus, stability studies for products stored in impermeable containers can be conducted under any 

controlled or ambient humidity condition. 
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c. Drug products packaged in semipermeable containers (2.2.7.3)

Aqueous-based products packaged in semipermeable containers should be evaluated for potential 

water loss in addition to physical, chemical, biological, and microbiological stability. This 

evaluation can be carried out under conditions of low relative humidity, as discussed below. 

Ultimately, it should be demonstrated that aqueous-based drug products stored in semipermeable 

containers can withstand low relative humidity environments. Other comparable approaches can 

be developed and reported for nonaqueous, solvent-based products.

Study Storage condition Minimum time period covered 

by data at submission

Long-term * 25°C ± 2°C/40% RH ± 5% RH

or

30°C ± 2°C/35% RH ± 5% RH

12 months

Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months

Accelerated 40°C ± 2°C/not more than 

(NMT) 25% RH

 6 months 

* It is up to the applicant to decide whether long-term stability sturdies are performed at 

25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH.

** If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition, there is no intermediate 

condition.

When long-term studies are conducted at 25°C ± 2°C/40% RH ± 5% RH and significant change 

other than water loss occurs during the 6 months’ testing at the accelerated storage condition, 

additional testing at the intermediate storage condition should be performed, as described under 

the general case, to evaluate the temperature effect at 30°C. A significant change in water loss 

alone at the accelerated storage condition does not necessitate testing at the intermediate storage 

condition. However, data should be provided to demonstrate that the drug product will not have 

significant water loss throughout the proposed shelf life if stored at 25°C and the reference 

relative humidity of 40 percent RH. 

A 5 percent loss in water from its initial value is considered a significant change for a product 

packaged in a semipermeable container after an equivalent of 3 months’ storage at 40°C/NMT 25 

percent RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 

5 percent or more after an equivalent of 3 months’ storage at 40°C/NMT 25 percent RH may be 

appropriate if justified.

An alternative approach to studying at the reference relative humidity as recommended in the 

table above (for either long-term or accelerated testing) is performing the stability studies under 

higher relative humidity and deriving the water loss at the reference relative humidity through 

calculation. This can be achieved by experimentally determining the permeation coefficient for 

the container closure system or, as shown in the example below, using the calculated ratio of 

water loss rates between the two humidity conditions at the same temperature. The permeation 
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coefficient for a container closure system can be experimentally determined by using the worst 

case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product.

Example of an approach for determining water loss:

For a product in a given container closure system, container size, and fill, an appropriate 

approach for deriving the water loss rate at the reference relative humidity is to multiply the 

water loss rate measured at an alternative relative humidity at the same temperature by a water 

loss rate ratio shown in the table below. A linear water loss rate at the alternative relative 

humidity over the storage period should be demonstrated. 

For example, at a given temperature (e.g., 40°C), the calculated water loss rate during storage at 

NMT 25 percent RH is the water loss rate measured at 75 percent RH multiplied by 3.0, the 

corresponding water loss rate ratio.

Alternative 

relative humidity

Reference 

relative humidity

Ratio of water loss rates at a 

given temperature

60% RH 25% RH 1.9 

60% RH 40% RH 1.5

65% RH 35% RH 1.9

75% RH 25% RH 3.0

Valid water loss rate ratios at relative humidity conditions other than those shown in the table 

above can also be used. 

d. Drug products intended for storage in a refrigerator (2.2.7.4)

Study Storage condition Minimum time period covered by data 

at submission

Long-term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% RH 

± 5% RH

 6 months 

If the drug product is packaged in a semipermeable container, appropriate information should be 

provided to assess the extent of water loss.

Data from refrigerated storage should be assessed according to the evaluation section of this 

guidance, except where explicitly noted below.

If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, 

the proposed shelf life should be based on the real time data available from the long-term storage 

condition.
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If significant change occurs within the first 3 months’ testing at the accelerated storage 

condition, a discussion should be provided to address the effect of short-term excursions outside 

the label storage condition (e.g., during shipment and handling). This discussion can be 

supported, if appropriate, by further testing on a single batch of the drug product for a period 

shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to 

continue to test a product through 6 months when a significant change has occurred within the 

first 3 months.

e. Drug products intended for storage in a freezer (2.2.7.5)

Study Storage 

condition

Minimum time period covered by data 

at submission

Long-term -20°C ± 5°C 12 months

For drug products intended for storage in a freezer, the shelf life should be based on the real time 

data obtained at the long-term storage condition. In the absence of an accelerated storage 

condition for drug products intended to be stored in a freezer, testing on a single batch at an 

elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be 

conducted to address the effect of short-term excursions outside the proposed label storage 

condition.

f. Drug products intended for storage below -20°C (2.2.7.6)

Drug products intended for storage below -20°C should be treated on a case-by-case basis.

8. Stability Commitment (2.2.8)

When available long-term stability data on primary batches do not cover the proposed shelf life 

granted at the time of approval, a commitment should be made to continue the stability studies 

postapproval to firmly establish the shelf life.

Where the submission includes long-term stability data from three production batches covering 

the proposed shelf life, a postapproval commitment is considered unnecessary. Otherwise, one 

of the following commitments should be made:

• If the submission includes data from stability studies on at least three production 

batches, a commitment should be made to continue the long-term studies through 

the proposed shelf life and the accelerated studies for 6 months.

• If the submission includes data from stability studies on fewer than three 

production batches, a commitment should be made to continue the long-term 

studies through the proposed shelf life and the accelerated studies for 6 months, 

and to place additional production batches, to a total of at least three, on long-term 

stability studies through the proposed shelf life and on accelerated studies for 6 

months.
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• If the submission does not include stability data on production batches, a 

commitment should be made to place the first three production batches on longterm stability studies through the proposed shelf life and on accelerated studies for 

6 months.

The stability protocol used for studies on commitment batches should be the same as that for the 

primary batches, unless otherwise scientifically justified.

Where intermediate testing is called for by a significant change at the accelerated storage 

condition for the primary batches, testing on the commitment batches can be conducted at either 

the intermediate or the accelerated storage condition. However, if significant change occurs at 

the accelerated storage condition on the commitment batches, testing at the intermediate storage 

condition should also be conducted.

9. Evaluation (2.2.9)

A systematic approach should be adopted in the presentation and evaluation of the stability 

information, which should include, as appropriate, results from the physical, chemical, 

biological, and microbiological tests, including particular attributes of the dosage form (e.g., 

dissolution rate for solid oral dosage forms). 

The purpose of the stability study is to establish, based on testing a minimum of three batches of 

the drug product, a shelf life and label storage instructions applicable to all future batches of the 

drug product manufactured and packaged under similar circumstances. The degree of variability 

of individual batches affects the confidence that a future production batch will remain within 

specification throughout its shelf life.

Where the data show so little degradation and so little variability that it is apparent from looking 

at the data that the requested shelf life will be granted, it is normally unnecessary to go through 

the formal statistical analysis; providing a justification for the omission should be sufficient.

An approach for analyzing data of a quantitative attribute that is expected to change with time is 

to determine the time at which the 95 percent one-sided confidence limit for the mean curve 

intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, 

it is advantageous to combine the data into one overall estimate. This can be done by first 

applying appropriate statistical tests (e.g., p values for level of significance of rejection of more 

than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. 

If it is inappropriate to combine data from several batches, the overall shelf life should be based 

on the minimum time a batch can be expected to remain within acceptance criteria.

The nature of the degradation relationship will determine whether the data should be transformed 

for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, 

or cubic function on an arithmetic or logarithmic scale. Statistical methods should be employed 

to test the goodness of fit on all batches and combined batches (where appropriate) to the 

assumed degradation line or curve.
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Limited extrapolation of the real time data from the long-term storage condition beyond the 

observed range to extend the shelf life can be undertaken at approval time if justified. This 

justification should be based, for example, on what is known about the mechanisms of 

degradation, the results of testing under accelerated conditions, the goodness of fit of any 

mathematical model, batch size, and/or existence of supporting stability data. However, this 

extrapolation assumes that the same degradation relationship will continue to apply beyond the 

observed data.

Any evaluation should consider not only the assay but also the degradation products and other 

appropriate attributes. Where appropriate, attention should be paid to reviewing the adequacy of 

the mass balance and different stability and degradation performance.

10. Statements/Labeling (2.2.10)

A storage statement should be established for the labeling in accordance with relevant 

national/regional requirements. The statement should be based on the stability evaluation of the 

drug product. Where applicable, specific instruction should be provided, particularly for drug 

products that cannot tolerate freezing. Terms such as ambient conditions or room temperature

should be avoided.

There should be a direct link between the label storage statement and the demonstrated stability 

of the drug product. An expiration date should be displayed on the container label.
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GLOSSARY (3)

The following definitions are provided to facilitate interpretation of the guidance. 

Accelerated testing: Studies designed to increase the rate of chemical degradation or physical 

change of a drug substance or drug product by using exaggerated storage conditions as part of 

the formal stability studies. Data from these studies, in addition to long-term stability studies, 

can be used to assess longer term chemical effects at nonaccelerated conditions and to evaluate 

the effect of short-term excursions outside the label storage conditions such as might occur 

during shipping. Results from accelerated testing studies are not always predictive of physical 

changes.

Bracketing: The design of a stability schedule such that only samples on the extremes of certain 

design factors (e.g., strength, package size) are tested at all time points as in a full design. The 

design assumes that the stability of any intermediate levels is represented by the stability of the 

extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the 

strengths are identical or very closely related in composition (e.g., for a tablet range made with 

different compression weights of a similar basic granulation, or a capsule range made by filling 

different plug fill weights of the same basic composition into different size capsule shells). 

Bracketing can be applied to different container sizes or different fills in the same container 

closure system.

Climatic zones: The four zones in the world that are distinguished by their characteristic, 

prevalent annual climatic conditions. This is based on the concept described by W. Grimm 

(Drugs Made in Germany, 28:196-202, 1985 and 29:39-47, 1986). 

Commitment batches: Production batches of a drug substance or drug product for which the 

stability studies are initiated or completed postapproval through a commitment made in the 

registration application.

Container closure system: The sum of packaging components that together contain and protect 

the dosage form. This includes primary packaging components and secondary packaging 

components if the latter are intended to provide additional protection to the drug product. A 

packaging system is equivalent to a container closure system.

Dosage form: A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that 

contains a drug substance generally, but not necessarily, in association with excipients.

Drug product: The dosage form in the final immediate packaging intended for marketing.

Drug substance: The unformulated drug substance that may subsequently be formulated with 

excipients to produce the dosage form.

Excipient: Anything other than the drug substance in the dosage form.
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Expiration date: The date placed on the container label of a drug product designating the time 

prior to which a batch of the product is expected to remain within the approved shelf life 

specification, if stored under defined conditions, and after which it must not be used.

Formal stability studies: Long-term and accelerated (and intermediate) studies undertaken on 

primary and/or commitment batches according to a prescribed stability protocol to establish or 

confirm the retest period of a drug substance or the shelf life of a drug product. 

Impermeable containers: Containers that provide a permanent barrier to the passage of gases 

or solvents (e.g., sealed aluminum tubes for semi-solids, sealed glass ampoules for solutions). 

Intermediate testing: Studies conducted at 30°C/65% RH and designed to moderately increase 

the rate of chemical degradation or physical changes for a drug substance or drug product 

intended to be stored long-term at 25°C.

Long-term testing: Stability studies under the recommended storage condition for the retest 

period or shelf life proposed (or approved) for labeling.

Mass balance: The process of adding together the assay value and levels of degradation

products to see how closely these add up to 100 percent of the initial value, with due 

consideration of the margin of analytical error.

Matrixing: The design of a stability schedule such that a selected subset of the total number of 

possible samples for all factor combinations is tested at a specified time point. At a subsequent 

time point, another subset of samples for all factor combinations is tested. The design assumes 

that the stability of each subset of samples tested represents the stability of all samples at a given 

time point. The differences in the samples for the same drug product should be identified as, for 

example, covering different batches, different strengths, different sizes of the same container 

closure system, and, possibly in some cases, different container closure systems.

Mean kinetic temperature: A single derived temperature that, if maintained over a defined 

period of time, affords the same thermal challenge to a drug substance or drug product as would 

be experienced over a range of both higher and lower temperatures for an equivalent defined 

period. The mean kinetic temperature is higher than the arithmetic mean temperature and takes 

into account the Arrhenius equation. 

When establishing the mean kinetic temperature for a defined period, the formula of J. D. 

Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used.

New molecular entity: An active pharmaceutical substance not previously contained in any 

drug product registered with the national or regional authority concerned. A new salt, ester, or 

noncovalent bond derivative of an approved drug substance is considered a new molecular entity 

for the purpose of stability testing under this guidance.

Pilot scale batch: A batch of a drug substance or drug product manufactured by a procedure 

fully representative of and simulating that to be applied to a full production scale batch. For 
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solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full 

production scale or 100,000 tablets or capsules, whichever is larger.

Primary batch: A batch of a drug substance or drug product used in a formal stability study, 

from which stability data are submitted in a registration application for the purpose of 

establishing a retest period or shelf life, respectively. A primary batch of a drug substance 

should be at least a pilot scale batch. For a drug product, two of the three batches should be at 

least pilot scale batch, and the third batch can be smaller if it is representative with regard to the 

critical manufacturing steps. However, a primary batch may be a production batch.

Production batch: A batch of a drug substance or drug product manufactured at production 

scale by using production equipment in a production facility as specified in the application.

Retest date: The date after which samples of the drug substance should be examined to ensure 

that the material is still in compliance with the specification and thus suitable for use in the 

manufacture of a given drug product.

Retest period: The period of time during which the drug substance is expected to remain within 

its specification and, therefore, can be used in the manufacture of a given drug product, provided 

that the drug substance has been stored under the defined conditions. After this period, a batch 

of drug substance destined for use in the manufacture of a drug product should be retested for 

compliance with the specification and then used immediately. A batch of drug substance can be 

retested multiple times and a different portion of the batch used after each retest, as long as it 

continues to comply with the specification. For most biotechnological/biological substances 

known to be labile, it is more appropriate to establish a shelf life than a retest period. The same 

may be true for certain antibiotics.

Semipermeable containers: Containers that allow the passage of solvent, usually water, while 

preventing solute loss. The mechanism for solvent transport occurs by absorption into one 

container surface, diffusion through the bulk of the container material, and desorption from the 

other surface. Transport is driven by a partial pressure gradient. Examples of semipermeable 

containers include plastic bags and semirigid, low-density polyethylene (LDPE) pouches for 

large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.

Shelf life (also referred to as expiration dating period): The time period during which a drug 

product is expected to remain within the approved shelf life specification, provided that it is 

stored under the conditions defined on the container label.

Specification: See ICH Q6A and Q6B. 

Specification, Release: The combination of physical, chemical, biological, and microbiological 

tests and acceptance criteria that determine the suitability of a drug product at the time of its 

release.
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Specification, Shelf life: The combination of physical, chemical, biological, and 

microbiological tests and acceptance criteria that determine the suitability of a drug substance 

throughout its retest period, or that a drug product should meet throughout its shelf life.

Storage condition tolerances: The acceptable variations in temperature and relative humidity 

of storage facilities for formal stability studies. The equipment should be capable of controlling 

the storage condition within the ranges defined in this guidance. The actual temperature and 

humidity (when controlled) should be monitored during stability storage. Short-term spikes due 

to opening of doors of the storage facility are accepted as unavoidable. The effect of excursions 

due to equipment failure should be addressed and reported if judged to affect stability results. 

Excursions that exceed the defined tolerances for more than 24 hours should be described in the 

study report and their effect assessed.

Stress testing (drug substance): Studies undertaken to elucidate the intrinsic stability of the 

drug substance. Such testing is part of the development strategy and is normally carried out 

under more severe conditions than those used for accelerated testing.

Stress testing (drug product): Studies undertaken to assess the effect of severe conditions on 

the drug product. Such studies include photostability testing (see ICH Q1B) and specific testing 

of certain products (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid 

products).

Supporting data: Data, other than those from formal stability studies, that support the 

analytical procedures, the proposed retest period or shelf life, and the label storage statements. 

Such data include (1) stability data on early synthetic route batches of drug substance, smallscale batches of materials, investigational formulations not proposed for marketing, related 

formulations, and product presented in containers and closures other than those proposed for 

marketing; (2) information regarding test results on containers; and (3) other scientific rationales.
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REFERENCES (4)3

ICH Q1B Photostability Testing of New Drug Substances and Products 

ICH Q1C Stability Testing for New Dosage Forms 

ICH Q3A Impurities in New Drug Substances 

ICH Q3B Impurities in New Drug Products 

ICH Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological 

Products 

ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances 

and New Drug Products: Chemical Substances 

ICH Q6B Specifications: Test Procedures and Acceptance Criteria for New Drug Substances 

and New Drug Products: Biotechnological/Biological Products 

 

3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 

guidance page at http://www.fda.gov/cder/guidance/index.htm
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ATTACHMENT

List of Revision 2 Changes

The revisions to this Q1A guidance result from adoption of the ICH guidance Q1F Stability Data 

Package for Registration Applications in Climatic Zones III and IV. The following changes 

were made.

1. The intermediate storage condition has been changed from 30°C ± 2°C/60% RH ± 5% 

RH to 30°C ± 2°C/65% RH ± 5% RH in the following sections:

• II.A.7.a (2.1.7.1) Drug Substance - Storage Conditions - General case

• II.B.7.a (2.2.7.1) Drug Product - Storage Conditions - General case

• II.B.7.c (2.2.7.3) Drug products packaged in semipermeable containers

• Glossary (3) Intermediate testing

2. 30°C ± 2°C/65% RH ± 5% RH has been added as a suitable alternative long-term storage 

condition to 25°C ± 2°C/60% RH ± 5% in the following sections:

• II.A.7.a (2.1.7.1) Drug Substance - Storage Conditions - General case

• II.B.7.a (2.2.7.1) Drug Product - Storage Conditions - General case

3. 30°C ± 2°C/35% RH ± 5% RH has been added as a suitable alternative long-term storage 

condition to 25°C ± 2°C/40% RH ± 5% and the corresponding example for the ratio of 

water-loss rates has been included in the following section:

• II.B.7.c (2.2.7.3) Drug products packaged in semipermeable containers

Midstream switch of the intermediate storage condition from 30°C ± 2°C/60% RH ± 5% RH to 

30°C ± 2°C/65% RH ± 5% RH can be appropriate provided that the respective storage conditions 

and the date of the switch are clearly documented and stated in the registration application.

It is recommended that registration applications contain data from complete studies at the 

intermediate storage condition 30°C ± 2°C/65% RH ± 5% RH, if applicable, by three years after 

the date of publication of this revised guideline in the respective ICH tripartite region.