#259 
Stability Testing of New Veterinary 
Drug Substances and Medicinal 
Products in Climatic Zones III and IV 
VICH GL58 
Guidance for Industry 
Submit comments on this guidance at any time.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  All comments should be identified with the docket number FDA-2018-D-4662. 
For further information regarding this document, contact AskCVM@fda.hhs.gov. 
Additional copies of this guidance document may be requested from the Policy and 
Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 
7500 Standish Place, Rockville, MD 20855, and may be viewed on the Internet at either 
https://www.fda.gov/animal-veterinary or https://www.regulations.gov/. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
April 2020  Contains Nonbinding Recommendations 
 
 
VICH GL 58 (QUALITY) - STABILITY: 
CLIMATIC ZONES III AND IV 
For adoption at Step 7 
 
 
Stability Testing of New Veterinary Drug 
Substances and Medicinal Products in 
Climatic Zones III and IV 
 
 
 
 
 
Recommended for Adoption at Step 7 of the VICH Process 
in September 2019 
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 7 of the 
Process the final draft is recommended for adoption to the regulatory bodies of the European 
Union, Japan and USA. 
 
   
2  Contains Nonbinding Recommendations 
Table of Contents 
1. INTRODUCTION ..........................................................................................................4 
1.1  Objectives of the Guidance ...................................................................................4 
1.2  Background ............................................................................................................4 
1.3  Scope of the Guidance ...........................................................................................5 
2. GUIDANCES ..................................................................................................................5 
2.1  Continuity with the Parent Guidance ..................................................................5 
2.2  Storage Conditions ................................................................................................6 
2.2.1  General Case.......................................................................................................6 
2.2.2.  Medicinal products packaged in impermeable containers.............................7 
2.2.3  Medicinal products packaged in semi-permeable containers ........................7 
2.2.4  Tests at elevated temperature and/or extremes of humidity .........................7 
2.3  Additional Considerations ....................................................................................8 
3. REFERENCES ...............................................................................................................8 
Appendix ................................................................................................................................9 
3  Contains Nonbinding Recommendations 
Stability Testing of New Veterinary Drug 
Substances and Medicinal Products in 
Climatic Zones III and IV 
Guidance for Industry 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on 
FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA 
staff responsible for this guidance as listed on the title page. 
1. INTRODUCTION
In general, FDAs guidance documents 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. 
1.1  Objectives of the Guidance 
This document is an annex to the VICH parent stability guidance, CVM Guidance for 
Industry (GFI) #73 (VICH GL3(R)), Stability Testing of New Veterinary Drug Substances 
and Medicinal Products (Revision)1 and provides guidance regarding the stability data 
package for a new veterinary drug substance and medicinal product to be included in a 
registration or application submitted within the regions in climatic zones III and IV. 
The guidance seeks to exemplify the core stability data package for new veterinary drug 
substances and medicinal products, but leaves flexibility to encompass the variety of different 
practical situations that may be encountered due to specific scientific considerations and 
characteristics of the materials being evaluated.  Alternative approaches can be used when 
there are scientifically justifiable reasons. 
1.2  Background 
The world can be divided into four climatic zones, I-IV, based on the prevailing annual 
climatic conditions and the guideline published by the World Health Organization (see 
Appendix section). 
The parent guidance, GFI #73 (VICH GL3(R)), describes the stability data package for the 
three VICH regions, the European Union (EU), Japan, and the United States (US), which are 
all in Climatic Zones I and II.  To harmonize with the long-term storage condition for Zone 
IVA, the intermediate storage condition in the General Case for Zones I and II in the parent 
guidance has been revised to 30C  2C/65% RH  5% RH.  This condition of 30C  
2C/65% RH  5% RH can also be a suitable alternative to 25C  2C/60% RH  5% RH as 
1 https://www.fda.gov/media/70241/download 
4  Contains Nonbinding Recommendations 
the long-term storage condition for Zones I and II.  Therefore, the parent guidance can be 
followed to generate the stability data package for a registration or application in countries or 
regions in Climatic Zones I, II and IVA. 
This guidance provides additional guidance on the storage conditions for stability testing to 
be used for products intended to be marketed in countries located in Climatic Zones III (hot 
and dry) and IVB (hot and very humid), which are not covered by GFI #73 (VICH GL3(R)).  
For completeness, the conditions outlined in the parent guidance for Zones IVA (30C  
2C/65% RH  5% RH or intermediate storage conditions), are listed again here in this 
guidance. 
1.3  Scope of the Guidance 
This guidance addresses the information to be submitted in registrations or applications for 
new veterinary drug substances and associated medicinal products.  This guidance does not 
seek to cover information to be submitted for abbreviated or abridged applications, variations, 
or clinical trial applications. 
Further guidance on stability testing of new dosage forms, medicated premixes, and on 
biotechnological/biological products can be found in GFI #74 (VICH GL4), Stability 
Testing of New Veterinary Dosage Forms,2 GFI #91 (VICH GL8), Stability Testing for 
Medicated Premixes,3 and GFI #99 (VICH GL17), Stability Testing of New 
Biotechnological/Biological Veterinary Medicinal Products,4 respectively.  Stability testing 
following first use of the product (e.g., first broaching of a vial) is not covered within this 
guidance. 
2.  GUIDANCES
2.1  Continuity with the Parent Guidance 
This guidance should be used in conjunction with the parent guidance GFI #73 (VICH 
GL3(R)) and subsequently published quality guidances and/or annexes GFI #74 (VICH 
GL4), GFI #75 (VICH GL5), Stability Testing-Photostability Testing of New Veterinary 
Drug Substances and Medicinal Products,5 GFI #91 (VICH GL8), GFI #99 (VICH GL17), 
and GFI #198 (VICH GL45), Bracketing and Matrixing Designs for Stability Testing of 
New Veterinary Drug Substances and Medicinal Products.6  The recommendations in the 
parent guidance and the associated guidances, as referenced, should be followed unless 
specific alternatives are described within this guidance.  The following sections of the parent 
guidance can be considered common to any territory in the world and are not reproduced 
here: 
 Stress testing
2 https://www.fda.gov/media/70255/download 
3 https://www.fda.gov/media/70356/download 
4 https://www.fda.gov/media/70404/download 
5 https://www.fda.gov/media/70262/download 
6 https://www.fda.gov/media/77128/download 
5  Contains Nonbinding Recommendations 
 Selection of batches
 Container closure system
 Specification
 Testing frequency
 Storage conditions for drug substance or medicinal product in a refrigerator
 Storage conditions for drug substance or medicinal product in a freezer
 Stability commitment
 Evaluation
 Statements/labeling
2.2  Storage Conditions 
2.2.1  General Case 
For the General Case (as described in the parent guidance) for the drug substance and the 
medicinal product, the recommended long-term and accelerated storage conditions for 
Climatic Zones III and IV are shown below: 
Study  Climatic Zones  Storage condition  Minimum time 
period covered by 
data at submission 
Long-Term  Zone III (Hot and Dry)  30C  2C/35% RH   Drug substance: 
5% RH  12 months 
Medicinal product: 
6 months 
Long-Term  Zone IVA (Hot  30C  2C/65% RH   Drug substance: 
and Humid) *  5% RH  12 months 
Medicinal product: 
6 months 
Long-Term  Zone IVB (Hot and  30C  2C/75% RH   Drug substance: 
very Humid)  5% RH  12 months 
Medicinal Product: 
6 months 
Accelerated  Zone III  40C  2C/not more than  6 months 
(NMT) 25% RH 
Accelerated  Zones IVA and IVB  40C  2C/75% RH   6 months 
5% RH 
*Same conditions as for the alternative long-term storage conditions for Zones I and II as described in the parent
guidance.
No intermediate storage condition for stability studies is recommended for Climatic Zones III 
and IV. 
If the product is intended to be marketed in several climatic zones, it is up to the applicant to 
decide whether long-term studies are performed at the highest temperature and humidity 
conditions, as applicable.  Selection of the conditions for stability testing should be based on 
a risk analysis. 
6  Contains Nonbinding Recommendations 
 
2.2.2. 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 can be 
conducted under any controlled or ambient humidity condition. 
 
2.2.3  Medicinal products packaged in semi-permeable containers 
 
For drug products packaged in semi-permeable containers (as described in the parent 
guidance), the recommended long-term and accelerated storage conditions for Climatic Zones 
III and IV are shown below: 
 
Study  Storage condition  Minimum time period 
covered by data at 
submission 
Long-term  30C  2C/35% RH   6 months 
5% RH 
Accelerated  40C  2C/not more  6 months 
than (NMT) 25 % RH  
5% RH 
 
An alternative approach to studying at the low relative humidity as recommended in the table 
above (for either long-term or accelerated testing) is performing the stability studies under a 
higher relative humidity and deriving the water loss at the lower relative humidity through 
calculation.  This approach for deriving the water loss rate at the reference relative humidity 
can be followed as described in the parent guidance. 
 
If the medicinal product is an aqueous-based product packaged in a semi-permeable 
container, appropriate information should be provided to assess the extent of water loss. 
 
2.2.4  Tests at elevated temperature and/or extremes of humidity 
 
Special transportation and climatic conditions outside the storage conditions recommended in 
this guidance should be justified based on the results from studies in accelerated conditions 
(i.e., short excursions out of the long-term conditions), and, if necessary, be supported by 
additional data under more stressful conditions.  For example, these data can be obtained 
from studies on one batch of drug product conducted for up to 3 months at 50C/ambient 
humidity to cover hot and dry conditions and at 25C/75% RH to cover extremely high 
humidity conditions.  It is recommended that permeable containers should not be used for 
long-term storage of products intended to be marketed in territories with extremely high 
humidity conditions, such as in climatic Zone IVB, unless stability data is available to 
support such storage conditions. 
 
Stability testing at a high humidity condition, e.g., 40C/80% RH, is recommended for solid 
dosage forms in water-vapour permeable packaging, e.g., tablets in PVC/aluminum blisters, 
intended to be marketed in territories with extremely high humidity conditions, such as in 
climatic Zone IVB.  However, for solid dosage forms in primary containers designed to 
provide a barrier to water vapour, e.g., aluminum/aluminum blisters, stability testing at a 
storage condition of extremely high humidity is not considered critical. 
7  Contains Nonbinding Recommendations 
 
 
2.3  Additional Considerations 
 
If it cannot be demonstrated that the drug substance or drug product will remain within its 
acceptance criteria when stored at the conditions as listed in section 2.2.1 for the duration of 
the proposed retest period or shelf life, the following options should be considered: (1) a 
reduced retest period or shelf life, (2) a more protective container closure system, or (3) 
additional cautionary statements in the labeling. 
 
3.  REFERENCES 
 
1.  WHO Technical Report Series, No.953, 2009, Annex 2; Stability Testing of active 
pharmaceutical ingredients and finished pharmaceutical products 
2.  GFI #73 (VICH GL3(R)), Stability Testing of New Veterinary Drug Substances and 
Medicinal Products (Revision)7 
3.  GFI #74 (VICH GL4), Stability Testing of New Veterinary Dosage Forms 
4.  GFI #75 (VICH GL5), Stability Testing-Photostability Testing of New Veterinary Drug 
Substances and Medicinal Products 
5.  GFI #91 (VICH GL8), Stability Testing for Medicated Premixes 
6.  GFI #99 (VICH GL17), Stability Testing of New Biotechnological/Biological 
Veterinary Medicinal Products 
7.  GFI #198 (VICH GL45), Bracketing and Matrixing Designs for Stability Testing of New 
Veterinary Drug Substances and Medicinal Products 
   
                                                 
7All FDA guidances mentioned in this document are also available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
8  Contains Nonbinding Recommendations 
 
Appendix 
 
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.  At the fortieth meeting of the WHO 
Expert Committee on Specifications for Pharmaceutical Preparations held in Geneva in 
October 2005, it was recommended to split the current Climatic Zone IV (hot and humid) into 
two zones: Climatic Zone IVA  for which 30 C/65% RH will remain the standard long-
term testing condition  and Climatic Zone IVB for which, if justified, 30 C/75% RH will 
become the long-term testing condition. 
 
Based on the survey conducted in 2010, the current WHO definition of climatic zones 
coupled with long term storage conditions are listed in the table below: 
 
Climatic  Definition  Criteria  Storage condition 
zone  Mean annual temperature 
measured in the open air 
air/mean annual partial 
water vapour pressure 
I  Temperate climate  <15C/<11 hPa  21C/45% RH 
II  Subtropical and  >15 to 22C/>11 to 18 hPa  25C/60% RH 
Mediterranean climates 
III  Hot, dry climate  > 22C /<15 hPa  30C/35% RH 
IVA  Hot, humid climate  > 22C / > 15 to 27 hPa  30C/65% RH 
IVB  Hot and very humid  > 22C /> 27 hPa  30C/75% RH 
climate 
 
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