73 

Guidance for Industry 

Stability Testing of New Veterinary Drug 

Substances and Medicinal Products (Revision) 

VICH GL3(R)

REVISED FINAL GUIDANCE 

(October 28, 2010, this guidance document was revised to update contact information, correct broken 

internet links and minor formatting changes)

Comments and suggestions regarding the document should be submitted to Division of Dockets 

Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 

20852. Submit electronic comments to http://www.regulations.gov. All comments should be identified 

with the Docket No. 2006D-0139. 

For questions regarding this document, contact Norman Gregory, Center for Veterinary Medicine, (HFV143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 240-276-8253, e-mail: 

norman.gregory@fda.hhs.gov. 

Additional copies of this final guidance document may be requested from the Communications Staff 

(HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 

Rockville, MD 20855, and may be viewed on the Internet at 

http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

November 21, 2007 
Contains Non-Binding Recommendations 

VICH GL3(R) (QUALITY) 

September 2007 

Revision at Step 9 

STABILITY: STABILITY TESTING OF NEW 

VETERINARY DRUG SUBSTANCES AND MEDICINAL 

PRODUCTS (REVISION) 

Recommended for Consultation 

at Step 9 of the VICH Process 

in September 2007 

by the VICH Steering Committee 

This Guidance has been developed by the appropriate VICH Expert Working Group and is subject to 

consultation by the parties, in accordance with the VICH Process. At Step 9 of the Process the final draft 

will be recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 

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Contains Non-Binding Recommendations 

Page iii

TABLE OF CONTENTS 

1. INTRODUCTION................................................................................................................. 1 

1.1. Objectives of the Guidance ...........................................................................................................1 

1.2. Scope of the Guidance ...................................................................................................................1 

1.3. General Principles..........................................................................................................................2 

2. GUIDANCES......................................................................................................................... 2 

2.1. Drug Substance ..............................................................................................................................2 

2.1.1 General ..................................................................................................................................2 

2.1.2. Stress Testing .........................................................................................................................2 

2.1.3. Selection of Batches...............................................................................................................3 

2.1.4. Container Closure System......................................................................................................3 

2.1.5. Specification...........................................................................................................................3 

2.1.6. Testing Frequency..................................................................................................................4 

2.1.7. Storage Conditions.................................................................................................................4 

2.1.8. Stability Commitment ............................................................................................................6 

2.1.9. Evaluation ..............................................................................................................................6 

2.1.10. Statements/Labeling...............................................................................................................7 

2.2. Medicinal Product..........................................................................................................................8 

2.2.1. General ...................................................................................................................................8 

2.2.2. Photostability Testing ............................................................................................................8 

2.2.3. Selection of Batches ..............................................................................................................8 

2.2.4. Container Closure System......................................................................................................8 

2.2.5. Specification...........................................................................................................................9 

2.2.6. Testing Frequency..................................................................................................................9 

2.2.7. Storage Conditions...............................................................................................................10 

2.2.8. Stability Commitment ..........................................................................................................14 

2.2.9. Evaluation ............................................................................................................................15 

2.2.10. Statements/Labeling.............................................................................................................15 

3. GLOSSARY......................................................................................................................... 17 

4. REFERENCES .................................................................................................................... 21 
Contains Non-Binding Recommendations 

Stability Testing of New Veterinary Drug Substances and Medicinal 

Products

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on the subject 

matter. 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. 

1. INTRODUCTION 

1.1. Objectives of the Guidance 

The following document is a revised version of VICH GL3 and provides guidance regarding the 

stability data package for a new veterinary drug substance and medicinal product to be included 

in a registration application submitted within the three regions of the European Union (EU), Japan, 

and the United States. 

The guidance seeks to exemplify the core stability data package for new veterinary drug 

substances and medicinal 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 may be used when there 

are scientifically justifiable reasons. 

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. 

1.2. Scope of the Guidance 

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

veterinary drug substances and associated medicinal 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. 

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Contains Non-Binding Recommendations 

Further guidance on new dosage forms, medicated premixes, and on biotechnological/biological 

products can be found in VICH guidances GL4, GL8, and GL17, respectively. Stability testing 

following first use of the product (e.g., first broaching of a vial) is not covered within this 

guidance. 

1.3. General Principles 

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

medicinal product varies with time under the influence of a variety of environmental factors, 

such as temperature, humidity, and light, and to establish a re-test period for the drug substance 

or a shelf life for the medicinal 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. 

2. GUIDANCES 

2.1. Drug Substance 

2.1.1. General 

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

stability evaluation. 

2.1.2. Stress Testing 

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

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

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

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

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

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

testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the 

drug substance. The testing should also evaluate the susceptibility of the drug substance to 

hydrolysis across a wide range of pH values when in solution or suspension. Photostability 

testing should be an integral part of stress testing. The standard conditions for photostability 

testing are described in VICH GL5. 

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Contains Non-Binding Recommendations 

Examining degradation products under stress conditions is useful in establishing degradation 

pathways and developing and validating suitable analytical procedures. However, it may not be 

important to examine specifically for certain degradation products if it has been demonstrated 

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

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

authorities.

2.1.3. Selection of Batches 

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

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

synthetic route as, and using a method of manufacture and procedure that simulates the final 

process to be used for, production batches. The overall quality of the batches of drug substance 

placed on formal stability studies should be representative of the quality of the material to be 

made on a production scale. 

Other supporting data should be provided. 

2.1.4. Container Closure System 

 

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

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

2.1.5. Specification 

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

acceptance criteria, is addressed in VICH GL39 and GL40. In addition, specification for 

degradation products in a drug substance is discussed in GL10(R). 

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. 

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Contains Non-Binding Recommendations 

2.1.6. Testing Frequency 

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

the drug substance. For drug substances with a proposed 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 

re-test period. 

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

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

expectation (based on development experience) exists that 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. 

2.1.7. Storage Conditions 

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

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

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

subsequent use. 

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

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

the proposed re-test period. Additional data accumulated during the assessment period of the 

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

accelerated storage condition and, if appropriate, from the intermediate storage condition should 

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 

is not specifically covered by a subsequent section. Alternative storage conditions may be used, 

if justified. 

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Contains Non-Binding Recommendations 

2.1.7.1. General case 

Study Storage condition Minimum time period covered by 

data at submission 

Long term* 25°C ± 2°C/60% RH ± 5% RH 

or 

30°C ± 2°C/65% RH ± 5% RH 

12 months 

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

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

* It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/60% 

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

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

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

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

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

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

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

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

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

2.1.7.2. Drug substances intended for storage in a refrigerator

Study Storage condition Minimum time period covered by 

data at submission 

Long term 5°C ± 3°C 12 months 

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

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

guidance, except where explicitly noted below. 

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

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

storage condition. 

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

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

storage condition, e.g., during shipping or handling. This discussion can be supported, if 

appropriate, by further testing on a single batch of the drug substance for a period shorter than 3 

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

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

months. 

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Contains Non-Binding Recommendations 

2.1.7.3. Drug substances intended for storage in a freezer 

Study Storage condition Minimum time period covered by 

data at submission 

Long term -20°C ± 5°C 12 months 

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

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

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

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

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

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

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

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

2.1.8. Stability Commitment 

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

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

studies post approval to firmly establish the re-test period. 

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

proposed re-test period, a post-approval commitment is not recommended. Otherwise, one of the 

following commitments should be made: 

1. If the submission includes data from stability studies on at least three production batches, a 

commitment should be made to continue these studies through the proposed re-test period. 

2. If the submission includes data from stability studies on fewer than three production batches, 

a commitment should be made to continue these studies through the proposed re-test period 

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

studies through the proposed re-test period. 

3. If the submission does not include stability data on production batches, a commitment should 

be made to place the first three production batches on long-term stability studies through the 

proposed re-test period. 

The stability protocol used for long-term studies for the stability commitment should be the same 

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

2.1.9. Evaluation 

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Contains Non-Binding Recommendations 

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

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

the physical, chemical, biological, and microbiological tests), a re-test period applicable to all 

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

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

within specification throughout the assigned re-test period. 

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

the data that the requested re-test period will be granted. Under these circumstances, it is 

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

omission should be sufficient. 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

observed range to extend the re-test period can be undertaken at approval time, if justified. This 

justification should be based, 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, existence of supporting stability data, etc. However, this 

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

observed data. 

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

other appropriate attributes. 

2.1.10. Statements/Labeling 

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

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

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

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

temperature” should be avoided. 

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Contains Non-Binding Recommendations 

A re-test period should be derived from the stability information, and a re-test date should be 

displayed on the container label, if appropriate. 

2.2. Medicinal Product 

2.2.1. General 

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

knowledge of the behavior and properties of the drug substance and from stability studies on the 

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

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

studies should be stated. 

2.2.2. Photostability Testing 

Photostability testing should be conducted on at least one primary batch of the medicinal product, 

if appropriate. The standard conditions for photostability testing are described in VICH GL5. 

2.2.3. Selection of Batches 

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

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 medicinal 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 

medicinal product unless bracketing or matrixing is applied. 

Other supporting data can be provided. 

2.2.4. Container Closure System 

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

system proposed for marketing (including, as appropriate, any secondary packaging and 

container label). In some cases, a smaller container closure system simulating the actual 

container closure system for marketing may be acceptable. In these instances, a justification for 

using a smaller container closure system should be provided. Any available studies carried out 

on the medicinal product outside its immediate container or in other packaging materials may 

form a useful part of the stress testing of the dosage form or may be considered as supporting 

information, respectively. 

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Contains Non-Binding Recommendations 

2.2.5. Specification 

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 VICH GL39 and GL40. In addition, specification for degradation 

products in a medicinal product is addressed in GL11(R). 

Stability studies should include testing of those attributes of the medicinal 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 data demonstrating preservative effectiveness of a 

development batch of the proposed formulation artificially prepared to contain the lowest 

permitted levels of the antimicrobial preservative(s) according to the shelf-life specification. A 

single primary stability batch of the medicinal 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.

2.2.6. Testing Frequency 

 

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

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

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

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

shelf life. 

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

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

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

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

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

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

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

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

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Contains Non-Binding Recommendations 

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

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

2.2.7. Storage Conditions 

In general, a medicinal 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 medicinal 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, repeating this testing on commitment batches is not recommended. 

The long-term testing should cover a minimum of 6 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 may 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 medicinal 

products are detailed in the sections below. The general case should apply if the medicinal 

product is not specifically covered by a subsequent section. Alternative storage conditions may 

be used, if justified. 

2.2.7.1. General case 

Study Storage condition Minimum time period covered by 

data at submission 

Long-term* 25°C ± 2°C/60% RH ± 5% RH 

or 

30°C ± 2°C/65% RH ± 5% RH 

6 months 

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

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

* It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/60% 

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

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

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Contains Non-Binding Recommendations 

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

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

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

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

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

In general, “significant change” for a medicinal product is defined as: 

1. A 5% change in assay from its initial value, or failure to meet the acceptance criteria for 

potency when using biological or immunological procedures; 

2. Any degradation product’s exceeding its acceptance criterion; 

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality 

test (e.g., color, phase separation, resuspendibility, caking, hardness); however, some changes 

in physical attributes (e.g., softening of suppositories, melting of creams) may be expected 

under accelerated conditions; and, as appropriate for the dosage form; 

4. Failure to meet the acceptance criterion for pH; or 

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. 

2.2.7.2. Medicinal products packaged in impermeable containers 

Sensitivity to moisture or potential for solvent loss is not a concern for medicinal 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 may be conducted 

under any controlled or ambient humidity condition. 

2.2.7.3. Medicinal products packaged in semi-permeable containers 

Aqueous-based medicinal products packaged in semi-permeable containers should be evaluated 

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

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

Ultimately, it should be demonstrated that aqueous-based medicinal products stored in semipermeable containers can withstand low relative humidity environments. 

Other comparable approaches may be developed and reported for non-aqueous, solvent-based 

medicinal 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 

6 months 

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Contains Non-Binding Recommendations 

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 studies are performed at 25 ± 2°C/40% 

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

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

For long-term studies conducted at 25°C ± 2°C/40% RH ± 5% RH, additional testing at the 

intermediate storage condition should be performed as described under the general case to 

evaluate the temperature effect at 30°C if significant change other than water loss occurs during 

the 6 months’ testing at the accelerated storage condition. A significant change in water loss 

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

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

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

relative humidity of 40% RH. 

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

packaged in a semi-permeable container after an equivalent of 3 months’ storage at 40°C/NMT 

25% RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 5% 

or more after an equivalent of 3 months’ storage at 40°C/NMT 25% RH may be acceptable, if 

justified. 

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

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

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

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

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

water loss rates between the two humidity conditions at the same temperature. The permeation 

coefficient for a container closure system may be experimentally determined by using the worst 

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

product. 

Example of an approach for determining water loss: 

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

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

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

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

relative humidity over the storage period should be demonstrated. 

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

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

water loss rate ratio. 

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Contains Non-Binding Recommendations 

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 may also be used. 

2.2.7.4. Medicinal products intended for storage in a refrigerator 

Study Storage condition Minimum time period covered by data at 

submission 

Long-term 5°C ± 3°C 6 months 

Accelerated 25°C ± 2°C/60% RH 

± 5% RH 

6 months 

If the medicinal product is packaged in a semi-permeable container, appropriate information 

should be provided to assess the extent of water loss. 

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

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. 

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 medicinal product for a period shorter than 

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

test a product through 6 months when a significant change has occurred within the first 3 months. 

2.2.7.5. Medicinal products intended for storage in a freezer 

Study Storage condition Minimum time period covered by data at 

submission 

Long-term -20°C ± 5°C 6 months 

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For medicinal 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 medicinal products intended to be stored in a freezer, testing on a single 

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

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

storage condition. 

 

2.2.7.6. Medicinal products intended for storage below -20°C 

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

2.2.8. Stability Commitment 

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

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

post approval to firmly establish the shelf life. 

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

the proposed shelf life, a post-approval commitment is not recommended. Otherwise, one of the 

following commitments should be made: 

1. If the submission includes data from stability studies on at least three production batches, a 

commitment should be made to continue the long-term studies through the proposed shelf 

life and the accelerated studies for 6 months. 

2. If the submission includes data from stability studies on fewer than three production batches, 

a commitment should be made to continue the long-term studies through the proposed shelf 

life and the accelerated studies for 6 months, and to place additional production batches, to a 

total of at least three, on long-term stability studies through the proposed shelf life and on 

accelerated studies for 6 months. 

3. If the submission does not include stability data on production batches, a commitment should 

be made to place the first three production batches on long-term stability studies through the 

proposed shelf life and on accelerated studies for 6 months. 

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

primary batches, unless otherwise scientifically justified. 

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

condition for the primary batches, testing on the commitment batches may 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. 

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2.2.9. Evaluation 

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

the medicinal 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 unnecessary to go through the formal 

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

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

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

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

advantageous to combine the data into one overall estimate. This may 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 may 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 may be represented by a linear, quadratic, 

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

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

assumed degradation line or curve. 

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

observed range to extend the shelf life may 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, existence of supporting stability data, etc. However, this 

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

observed data. 

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

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

the mass balance and different stability and degradation performance. 

2.2.10. Statements/Labeling 

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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 

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

medicinal 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 medicinal product. An expiration date must be displayed on the container label (see 21 

CFR §§ 201.17 and 211.137). 

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3. GLOSSARY 

Accelerated testing: 

Studies designed to increase the rate of chemical degradation or physical change of a drug 

substance or medicinal product by using exaggerated storage conditions as part of the formal 

stability studies. Data from these studies, in addition to long-term stability studies, should be 

used to assess longer term chemical effects at non-accelerated conditions and to evaluate the 

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

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

Bracketing: 

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

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

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

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

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

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

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

Bracketing may 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 medicinal 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 medicinal 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. 

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 medicinal 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 should not be used. 

Formal stability studies: 

Long-term and accelerated (and intermediate) studies undertaken on primary and/or commitment 

batches according to a prescribed stability protocol to establish or confirm the re-test period of a 

drug substance or the shelf life of a medicinal 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 medicinal product intended to be stored 

long term at 25°C. 

Long-term testing: 

Stability studies under the recommended storage condition for the re-test period or shelf life 

proposed (or approved) for labeling. 

Mass balance: 

The process of adding together the assay value and levels of degradation products to see how 

closely these add up to 100% of the initial value, with due consideration of the margin of 

analytical error. 

Matrixing: 

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

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

another subset of samples for all factor combinations is tested. The design assumes that the 

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

point. The differences in the samples for the same medicinal 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 medicinal 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. 

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

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

New Veterinary Drug Substance (also referred to as "drug substance" in this guidance): 

The designated therapeutic moity that has not been previously registered in a region or member 

state for use in a veterinary medicinal product (also referred to as a new molecular entity or new 

chemical entity). It may be a complex, simple ester, or salt of a previously approved substance. 

New Veterinary Medicinal Product (also referred to as "medicinal product" in this 

guidance): A pharmaceutical product type, for example, tablet, capsule, solution, cream, etc., 

containing a new or existing drug substance which has not previously been registered in a region 

or member state, and which contains a drug ingredient generally, but not necessarily, in 

association with excipients. 

Pilot scale batch: 

A batch of a drug substance or medicinal product manufactured by a procedure fully 

representative of and simulating that to be applied to a full production scale batch. For solid oral 

dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale. 

Primary batch: 

A batch of a drug substance or medicinal product used in a formal stability study, from which 

stability data are submitted in a registration application for the purpose of establishing a re-test 

period or shelf life, respectively. A primary batch of a drug substance should be at least a pilot 

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

and the third batch may 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 medicinal product manufactured at production scale by using 

production equipment in a production facility as specified in the application. 

Re-test date: 

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

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

of a given medicinal product. 

Re-test period: 

The period of time during which the drug substance is expected to remain within its specification 

and, therefore, may be used in the manufacture of a given medicinal 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 medicinal product should be re-tested for 

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

re-tested multiple times and a different portion of the batch used after each re-test, as long as it 

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

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

may be true for certain antibiotics.

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Semi-permeable containers: 

Containers that allow the passage of solvent, usually water, while preventing solute loss. The 

mechanism for solvent transport occurs by absorption into one container surface, diffusion 

through the bulk of the container material, and desorption from the other surface. Transport is 

driven by a partial pressure gradient. Examples of 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 medicinal 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 VICH GL39 and GL40. 

Specification - Release: 

The combination of physical, chemical, biological, and microbiological tests and acceptance 

criteria that determine the suitability of a medicinal product at the time of its release. 

Specification - Shelf life: 

The combination of physical, chemical, biological, and microbiological tests and acceptance 

criteria that determine the suitability of a drug substance throughout its re-test period, or that a 

medicinal 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 (medicinal product): 

Studies undertaken to assess the effect of severe conditions on the medicinal product. Such 

studies include photostability testing (see VICH GL5) and specific testing of certain products 

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

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Supporting data: 

Data, other than those from formal stability studies, that support the analytical procedures, the 

proposed re-test period or shelf life, and the label storage statements. Such data include (1) 

stability data on early synthetic route batches of drug substance, small-scale batches of materials, 

investigational formulations not proposed for marketing, related formulations, and product 

presented in containers and closures other than those proposed for marketing; (2) information 

regarding test results on containers; and (3) other scientific rationales. 

4. REFERENCES 

VICH GL4 Stability Testing of New Veterinary Dosage Forms

VICH GL5 Photostability Testing of New Veterinary Drug Substances and Medicinal Products 

VICH GL8 Stability Testing for Medicated Premixes 

VICH GL10(R) Impurities in New Veterinary Drug Substances 

VICH GL11(R) Impurities in New Veterinary Medicinal Products 

VICH GL17 Stability Testing of Biotechnological/Biological Veterinary Medicinal Products 

VICH GL39 Specifications: Test Procedures and Acceptance Criteria for New Veterinary Drug 

Substances and New Medicinal Products: Chemical Substances 

VICH GL40 Specifications: Test Procedures and Acceptance Criteria for New 

Biotechnological/Biological Veterinary Medicinal Products