VICH Outreach Forum

Stability Studies to address

climatic zones III and IV
Mai Huynh
US FDA/Center for Veterinary
Medicine
October 26-27, 2015
 US FDA - Center for Veterinary Medicine
Protecting both Human and Animal Health

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 From the VICH Press Release
• Published 26 February 2015

– The Steering Committee mandated the

Quality Expert Working Group to develop
guidance on stability testing in the climatic
zones III and IV (based on concept paper
submitted by the Task Force)
 Concept Paper
• Task Force: Chair: Thérèse Nugent, IFAH - Europe
– Other members:
• JMAFF : T. Ogata
• US FDA: M. Huynh
• EU: N. Möller
• Senasa : A. Desuque
• South Africa : H. Leng
• JVPA : H. Yabe
• Thai FDA : Yaowalak Wattanapisit
• AHI : Rex Henry
• Camevet: C.Francia
 Climate zones
• Current WHO definition of climatic zones:
Climatic Definition Storage condition
zone
I Temperate climate 21°C/45% r.h.
II Subtropical and 25°C/60% r.h.
Mediterranean
climates
III Hot, dry climate 30°C/35% r.h.
IVA Hot, humid climate 30°C/65% r.h.*
IVB Hot and very 30°C/75% r.h.
humid climate
• *conditions covered in current GL3 (R )
 From VICH GL3 (R)
• From VICH GL3 (R):
– 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.
GL3(R) : Stability Testing Medicinal Product
• General case:
Study Storage condition Minimum time
period covered
by data at
submission
Long-term* 25°C ± 2°C/60% RH 6 months
± 5% RH
or
30°C ± 2°C/65% RH
± 5% RH

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

± 5% RH
Accelerated 40°C ± 2°C/75% RH 6 months
± 5% RH
GL3(R) : Stability Testing Medicinal Product

• General case:
– *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.
 Stability Testing
• If the applicant selects to test the product
at: 30°C ± 2°C/65% RH ± 5% RH.

• Zones IVA (according to WHO guideline)

is already covered in the current VICH
GL3 (R)
 Stability Testing
• What’s left to be considered:

– Zone III: 30°C /35% RH - Hot and dry

climate

– Zones IVB: 30°C /75% RH – Hot and

very humid climate
 Points to consider
• The majority of active substances are also used for
human medicinal products. Their stability is therefore
widely tested in accordance with the
temperature/humidity conditions used for human
medicinal products.
• There are some veterinary medicinal products which
were approved first as human medicinal products. The
stability studies for these products will therefore have
been carried out under the temperature/humidity
conditions used for human medicinal products.
 Points to consider
• Testing at elevated temperature and
higher humidity conditions may result in
shorter expiry
– Therefore, it may not be so desirable to
conduct testing at conditions for zones III and
IV only
– Extrapolation among the various conditions
may not be found acceptable
 Points to consider
• Potential problems with extrapolation (EU, US
FDA):
– US FDA current thinking:
• From the concept paper: Extrapolation from
storage at higher temperatures (e.g., 30°C)
and humidities (e.g., 75% RH) to existing
temperatures (e.g., 25°C) and humidities (60%
RH) or vice versa:
– Not the conditions described in VICH GL51:
Statistical Evaluation of Stability Data
 Points to consider
• Potential problem with extrapolation (cont.):
– Poolability, matrixing, as described in VICH
GL51 are based on testing conditions
described in VICH GL 3 (R) – see slide 6
• Therefore, if extrapolation is to be considered in
the new GL, as stipulated in the concept paper,
a re-evaluation of VICH GL51 may be needed
>>>not a desirable outcome
 ICH Q1F
• ICH Q1F was withdrawn:
– WHO survey: consensus – adopted and implemented in 2003 in
non ICH countries
• 300C/65% RH: long term storage conditions for climatic zone
III/IV countries
– Some countries in climatic zone IV:
• 300C/75% RH; long term storage conditions for hot and humid
conditions
– ICH Q1F was withdrawn due to the divergence in
global stability testing
– Defer to WHO for definition of storage conditions in
climatic zones III and IV
 Moving forward
• Based on survey conducted by the WHO:
– Majority of the results:
• Long term testing conditions:
– 300C /65% RH
– 300C/75% RH

• Selection of the conditions for stability

testing is based on a risk analysis.
 Moving Forward
• Testing at a more severe long term condition can
be an alternative to storage testing at 250C /60%
RH or 300C /65% RH, as long as data generated
can support the proposed expiry.
• Caution: Such selection may yield a shorter
expiry than the standard testing conditions
outlined in GL3 (R)
• Extrapolation, if considered, should be
discussed with regulators prior to
implementation
 Proposed Testing Scheme for climate zone IVA

• From ICH Q1F: General case:

Study Storage Minimum time

condition period covered
by data at
submission
Long Term 300C + 12 months
2oC/65% RH
+ 5% RH
Accelerated 400C + 6 months
2oC/75% RH
+ 5% RH
Proposed Testing Scheme for climate zone IVB

Study Storage Minimum time

condition period covered by
data at
submission
Long Term 300C + 2oC/75% 12 months
RH + 5% RH

Accelerated 400C + 2oC/75% 6 months

RH + 5% RH
 Proposed Testing Scheme
• No intermediate storage condition
for stability studies is
recommended for Climatic Zones
III and IV.
 Proposed Testing Scheme
• Sections from GL3 (R ) that can be
considered common to any country in any
of the climatic zones:
– Stress testing
– Selection of batches
– Container/closure
– Specification
– Testing frequency
 Proposed Testing Scheme
• Sections from GL3 (R ) that can be considered
common to any country in any of the climatic
zones (cont.):
• Storage conditions for drug substance or product in a
refrigerator
• Storage conditions for drug substance or product in a
freezer
• Stability commitment
• Evaluation
• Statement/labeling
 Questions
• If we concur on the common sections, they
will not be repeated in the new GL:

• Refer to VICH GL3 (R ) as the parent

guideline
 Questions
• Will there be a need to revise GL51?
– Not necessarily if we do not extrapolate data
among various temperatures
– Extrapolation may still be applied to the same
data sets generated within the same testing
scheme
 Questions
• Should 80% RH be the testing humidity
condition, instead of 75% RH?
– For example, solid dosage forms in water-
vapor permeable packaging, e.g., tablets in
PVC/aluminumm blisters, intended to be
marketed in zones IVB?
• How should studies be designed to account for
extremely hot and humid conditions (e.g. during
transport)?
 Questions
• Should there be a testing scheme
developed for climate zone III?
– Only 1 country among 203 is identified in the
WHO report with stability conditions listed for
zone III
– Or can zone III adopt the testing scheme
outlined for Zone IVA?

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 Why do we need stability studies?
• Data collected from stability testing is used:
– To support product expiry
– To support label storage conditions
• Product expiry: VICH GL3 (R) & VICH GL51
• Label storage conditions:
• In the US: US Pharmacopeia:
• Chapter <659>: Packaging and Storage
Requirements
 Recommended labeling statements
• Recommended labeling statements for finished
pharmaceutical products (FPPs) in the US

Testing conditions under Recommended labeling

which the stability of the statements
FPP has been
demonstrated
25oC/60% RH (long term) Do not store above 25oC*
40 oC /75% RH
(accelerated)
25oC/60% RH (long term) Do not store above 25oC*
30 oC /65% RH Or
(intermediate, failure of Store at 20-25ºC with
accelerated) excursions permitted
between 15-30ºC
 Recommended labeling statements
• Recommended labeling statements for finished pharmaceutical products
(FPPs) in the US
Testing conditions under which Recommended labeling
the stability of the FPP has been statements
demonstrated

30oC/65% RH (long term) Store at or below 30C

40 oC /75% RH (accelerated) Or
Do not store above 30oC*
Or
Stored at controlled room
temperature (15oC - 30 oC), with
excursions up to 40oC
25oC/60% RH (long term) Do not store above 25oC*
30 oC /65% RH (intermediate, Or
failure of accelerated) Store at 20-25ºC with excursions
between 15-30ºC
 Recommended labeling statements
• *Statements suggested on slide 28/29 are based
on the assumption that the product has been
found acceptable under freeze thaw conditions-
otherwise additional statement can also be added:
– “Do not freeze”
– “Do not refrigerate or freeze”
• Statement such as “Room temperature” or
“ambient conditions” is not acceptable (in the US)

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 Additional considerations
• If it cannot be demonstrated that the drug substance or
drug product will remain within its acceptance criteria,
when stored at the proposed testing scheme for the
duration of the proposed retest period or shelf life:
– Reduce the retest period or shelf life
– Consider a more protective container closure system
– Additional cautionary statements in the labeling
 Additional considerations
• For products marketed in the US:
– US FDA/CVM will accept any testing
conditions (i.e. temperature and humidity)
proposed by the applicant
– Selection of the conditions for stability testing
is based on a risk analysis. Testing at a more
severe long-term condition can be an
alternative to storage testing at 25oC/60% RH
or 30oC/65% RH
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 Timeline

• 6 months – 1 year for completion of draft

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 New members to Quality EWG
• According to the mandate, the new
members from South Africa and VOF
countries/regions (China, CAMEVET and
Morocco) were nominated as QEWG
experts (October 2015)
 Quality Expert Working Group
•Chair: JMAFF
ORGANISATION NAME TELEPHONE •Chair: JMAFF
FAX E-MAIL

US FDA M. HUYNH + 1 240-402-0669   mai.huynh@fda.hhs.gov

AHI (BAYER) R. HENRY     rex.henry@bayer.com

T. OGATA
JMAFF + 81 423 21 1849 + 81 423 21 1769 tomokot@nval.maff.go.jp
(Chair)
CANADA VDD J. BENOLIEL + 1 613 957 6841 + 1 613 946 4589 Joseph.Benoliel@hc-sc.gc.ca
N. MÖLLER + 49 30 18444 + 49 30 18444
EU (BVL) norbert.moeller@bvl.bund.de
(expert) 30200 30009
A. MORGAN
USDA + 1 301 734 8245 + 1 301 734 4314 albert.p.morgan@usda.gov
(advisor)
JVPA (Nippon
A. YOSHITA
Zenyaku Kogyo + 81 24 945 2361 + 81 24 945 2421 yoshita-akihiro@zenoaq.jp
(expert)
Co)
ANZ (MPI) W. HUGHES +64 4 8942560 +64 4 8942566 warren.hughes@mpi.govt.nz
 Quality Expert Working group
IFAH-EU (Merial) Th. NUGENT +1 678 638 3811 +1 678 638 3732 therese.nugent@merial.com
V. NERON
IFAH-EU DE SURGY viviane.nerondesurgy@vetoquinol.co
+33 3 84 62 55 86  
(Vetoquinol) (climatic zone m
III and IV)
SOUTH AFRICA H. LENG +27 21 855 4159   hmjleng@gmail.com
P. COGHLAN
(Advisor -
ANZ     phil.coghlan@apvma.gov.au
climatic zone
III and IV)
X. LIANG
CHINA (CIVDC) (climatic zone +8610 621 03557 +8610 621 03562 lxm990@163.com
III and IV)
M. AGUIRRE
 
CAMEVET (climatic zone   milenaaguirre@over.com.ar
 
III and IV)
A. ELGHAFKI
MOROCCO (climatic zone     amina.elghafki@gmail.com
III and IV)
 References
1. World Health Organization: Who Technical Report, Annex 2: Stability testing of active
pharmaceutical ingredients and finished pharmaceutical products

2. VICH GL 3 ( R): Stability of New Veterinary Drug Substances

3. VICH GL 4: Stability of New Veterinary Dosage Forms

4. VICH GL 51: Statistical Evaluation of Stability Data

5. ICH Q1A (R2): Stability Testing of New Drug Substances and Products

6. ICH Q1F: withdrawn

7. US Pharmacopeia
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Questions/Comments/Suggestions?
Contact: Mai.Huynh@fda.hhs.gov

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Thank You

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