CVM GFI #259 (VICH GL58) Stability Testing of New Veterinary Drug Substances and Medicinal Products in Climatic Zones III and IV

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

#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

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VICH GL 58 (QUALITY) - S TABILITY:
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.

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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

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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, FDA’s guidance documents 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.
1.1 	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 30°C ± 2°C/65% RH ± 5% RH. This condition of 30°C ±
2°C/65% RH ± 5% RH can also be a suitable alternative to 25°C ± 2°C/60% RH ± 5% RH as
1 https://www.fda.gov/media/70241/download

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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 (30°C ±
2°C/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

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• 	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) 	30°C ± 2°C/35% RH ±
5% RH
Drug substance:
12 months
Medicinal product:
6 months
Long-Term 	Zone IVA (Hot
and Humid) *
30°C ± 2°C/65% RH ±
5% RH
Drug substance:
12 months
Medicinal product:
6 months
Long-Term 	Zone IVB (Hot and
very Humid)
30°C ± 2°C/75% RH ±
5% RH
Drug substance:
12 months
Medicinal Product:
6 months
Accelerated 	Zone III 	40°C ± 2°C/not more than
(NMT) 25% RH
6 months
Accelerated 	Zones IVA and IVB 	40°C ± 2°C/75% RH ±
5% RH
6 months
*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.

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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 	30°C ± 2°C/35% RH ±
5% RH
6 months
Accelerated 	40°C ± 2°C/not more
than (NMT) 25 % RH ±
5% RH
6 months
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 50°C/ambient
humidity to cover hot and dry conditions and at 25°C/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., 40°C/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.

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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.

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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
zone
Definition 	Criteria
Mean annual temperature
measured in the open air
air/mean annual partial
water vapour pressure
Storage condition
I 	Temperate climate 	<15°C/<11 hPa 	21°C/45% RH
II 	Subtropical and
Mediterranean climates
>15 to 22°
C/>11 to 18 hPa 	25°C/60% RH
III 	Hot, dry climate 	> 22°C /<15 hPa 	30°C/35% RH
IVA 	Hot, humid climate 	> 22°C / > 15 to 27 hPa 	30°C/65% RH
IVB 	Hot and very humid
climate
> 22°C /> 27 hPa 	30°C/75% RH