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, (HFV-
143), 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 
 
 
 
 
S : S T N
TABILITY   TABILITY  ESTING OF  EW 
V D S M
ETERINARY  RUG  UBSTANCES AND  EDICINAL 
P (R )  
RODUCTS  EVISION  
 
 
 
 
 
 
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. 
 
 
  Page ii Contains Non-Binding Recommendations 
 
 
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 
 
 
  Page iii Contains Non-Binding Recommendations 
 
 
Stability Testing of New Veterinary Drug Substances and Medicinal 
Products 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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. 
 
  Page 1 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 10C increments (e.g., 50C, 60C, 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. 
 
  Page 2 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.  
  Page 3 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.  
 
  Page 4 Contains Non-Binding Recommendations 
 
 
2.1.7.1.  General case 
 
Study  Storage condition  Minimum time period covered by 
data at submission 
Long term*  25C  2C/60% RH  5% RH  12 months 
or 
30C  2C/65% RH  5% RH 
Intermediate**  30C  2C/65% RH  5% RH  6 months  
Accelerated  40C  2C/75% RH  5% RH  6 months  
* It is up to the applicant to decide whether long-term stability studies are performed at 25  2C/60% 
RH  5% RH or 30C  2C/65% RH  5% RH. 
** If 30C  2C/65% RH  5% RH is the long-term condition, there is no intermediate condition. 
 
If long-term studies are conducted at 25C  2C/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  5C  3C  12 months 
Accelerated  25C  2C/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. 
  Page 5 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  -20C  5C  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., 5C  3C or 25C  2C) 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 -20C 
 
Drug substances intended for storage below -20C 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 
 
  Page 6 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.  
 
  Page 7 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. 
 
  Page 8 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. 
 
  Page 9 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 in-
use period of the constituted or diluted product.  This testing should be performed on the 
constituted or diluted product through the proposed in-use period on primary batches as part of 
the formal stability studies at initial and final time points and, if full shelf life long-term data will 
not be available before submission, at 12 months or the last time point for which data will be 
available.  In general, 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*  25C  2C/60% RH  5% RH  6 months 
or 
30C  2C/65% RH  5% RH 
Intermediate**  30C  2C/65% RH  5% RH  6 months  
Accelerated  40C  2C/75% RH  5% RH  6 months  
* It is up to the applicant to decide whether long-term stability studies are performed at 25  2C/60% 
RH  5% RH or 30C  2C/65% RH  5% RH. 
** If 30C  2C/65% RH  5% RH is the long-term condition, there is no intermediate condition. 
 
  Page 10 Contains Non-Binding Recommendations 
 
 
If long-term studies are conducted at 25C  2C/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 products 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 semi-
permeable 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 *  25C  2C/40% RH  5% RH  6 months 
or 
30C  2C/35% RH  5% RH 
  Page 11 Contains Non-Binding Recommendations 
 
 
Intermediate**  30C  2C/65% RH  5% RH  6 months 
Accelerated   40C  2C/not more than  6 months  
(NMT) 25% RH 
* It is up to the applicant to decide whether long-term stability studies are performed at 25  2C/40% 
RH  5% RH or 30C  2C/35% RH  5% RH. 
** If 30C  2C/35% RH  5% RH is the long-term condition, there is no intermediate condition. 
 
For long-term studies conducted at 25C  2C/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 30C 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 25C 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 40C/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 40C/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., 40C, 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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Alternative relative  Reference relative  Ratio of water loss rates at a given 
humidity  humidity  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  5C  3C   6 months 
Accelerated  25C  2C/60% RH  6 months  
 5% RH 
 
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  -20C  5C  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., 5C  3C or 25C  2C) 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 -20C 
 
Medicinal products intended for storage below -20C 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). 
 
 
  Page 16 Contains Non-Binding Recommendations 
 
 
 
 
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 30C/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 25C. 
 
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). 
 
  Page 20 Contains Non-Binding Recommendations 
 
 
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 
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