S3 Guo Sherry Temperature Excursion

Temperature Excursion &
Transportation Studies for

Stability Program
RELEASED - EFFECTIVE: 04-NOV-2013
Sherry Guo, Ph.D

Manager, Global Stability
Abbott Vascular
Dec 4, 2013
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Temperature Excursion and Stability Studies, IVTs Lab Compliance Week, Dec 3-5,
2013, 2013 Abbott. All rights reserved. SE2939051, Rev A
Agenda
1. Background, Scope and Purpose

2. Strategic Consideration for Temperature
Excursion & Transportation Studies
3. Design and Conduct Transportation Study
4. Apply Transportation Study Results to Quality
System
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Temperature Excursion and Stability Studies, IVTs Lab Compliance Week, Dec 3-5, 2013,
2013 Abbott. All rights reserved. SE2939051, Rev A
Terminology
Excursion:
Temperature and other environmental conditions

experienced by products outside of the registered specified
ranges.
Transportation study:
Study conducted to assess the effects of transportation on
the drug product, drug substance and excipient based on
the knowledge of the condition of transport (e.g., duration of
transport, expected temperatures during transport and
distribution, humidity, vibration, etc.). Conditions tested
include but are not limited to thermal cycling or stress at
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elevated temperature.
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Terminology
Stable Products:
Products not sensitive to environmental changes (e.g., metallic stents)
Sensitive Products:
Products with certain sensitivity to environmental conditions and that have
to be protected during transportation (e.g., most of the pharmaceutical,
biological and combinational products)
Highly Sensitive Products:

Products having a limited range of storage and transportation
conditions. Excursion outside of these ranges is an actual
cause of product deterioration (e.g., vaccines)
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Types of Stability Studies
Studies on
In Process
Material
Studies on
Product
Storage
Studies on
Product
Shipping
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Background
Why is transportation study important?

If temperature sensitive products are not adequately
protected during the transport, drug product may
degrade and lose therapeutic value, other
detrimental consequence might also occur.
Regulatory Guidance:
There are no specific guidelines like ICH Q1A-D for
testing to determine the suitability of the
transportation conditions for temperature sensitive
products.
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Scope
The presentation will focus on the transportation

studies and distribution of
Sensitive products
Highly sensitive products
Stable products are outside of scope of this talk.
Temperature excursion during transportation is

the main focus of the presentation.
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Temperature Excursion and Stability Studies, IVTs Lab Compliance Week, Dec 3-5, 2013, 2013
Abbott. All rights reserved. SE2939051, Rev A
Purpose
To share the strategy and stability program for

Designing transportation study to determine
optimal transport conditions that ensure product
quality, as well as cost effective and practical
distribution.
Use technical data and scientific rationale to
support the product transportation policy and quality
system
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Get Global Picture Before

Designing Transportation Studies
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Temperature Excursion and Stability Studies, IVTs Lab Compliance Week,

Dec 3-5, 2013, 2013 Abbott. All rights reserved. SE2939051, Rev A

Strategic Consideration
in Designing
Transportation Studies
Transportation Study Design
Product
Ware
House
Distribution
Chain
Compliance
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Temperature Excursion and Stability Studies, IVTs Lab Compliance Week, Dec 3-5, 2013, 2013 Abbott. All
rights reserved. SE2939051, Rev A
10
Cost
Product Consideration
Inputs for
Transportation Study
Product Knowledge
Stress study
Acid
Base
Oxidation
Thermal
Photo
Previous R&D stability
Long term &
Accelerated
Temperate
Temperature range
Duration
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Warehouse Environment
Are the warehouse
temperature and humidity
controlled and monitored?
How tight is the temperature
and humidity controlled?
How is temperature and
humidity monitored? How
does the alarm system work?
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Mapping Distribution Chain

Manufacturing site
Distribution Center
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Distribution Center
13
Distribution Center
Mapping Distribution Chain, continued

Distribution Center
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Distribution Chain Consideration

How is the product under consideration shipped from
manufacturing site to distribution center?
How is the product shipped from DC to the user?
Is the product allowed to be returned to the DC?
Can the product be moved from account to account?
What kind of control is needed for distribution?
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Compliance
USP <1079> GOOD STORAGE AND DISTRIBUTION

PRACTICES FOR DRUG PRODUCTS:
The good storage and distribution should facilitate the movement of drug
products throughout a supply chain that is controlled, measured, and
analyzed for continuous improvements and should maintain the integrity
of the drug product in its packaging during storage and distribution.
FDA 21 CFR part 205:

Each outgoing shipment shall be carefully inspected for identity of the
prescription drug products and to ensure that there is no delivery of

prescription drugs that have been damaged in storage or held under
improper conditions.
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The Cost Factor
$of temp control

In shipment
$ of temp
monitoring
Product
scrap
$ of out of
compliance
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Cost Saving Recommendations

Temperature control during shipment is usually
very costly. If possible, conduct studies to support
the broadest possible allowed temperature range
during product shipment.
If it is feasible, limiting the transit time is usually
more economic than requiring temperature control
shipment.
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Weighing Temperature Control &

Monitoring Options
Temperature Control
Temperature Monitoring
Active Systems
Passive Systems
Temperature indicator
Electronic data loggers
Ref: Model requirements for the

storage and transport of time
and temperature sensitive
pharmaceutical products. WHO
publication
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Gaining Global View

Take product, logistics
(warehouse storage
and distribution),
compliance, cost and
other factors into
consideration when
designing
transportation studies.
Explore the extreme of
product thermal
tolerance to lower the
cost of temp control
and monitoring during
storage and shipping.
Product.
Compliance
Logistics
Cost
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Design and Conduct

Transportation Studies
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Temperature Excursion and Stability Studies, IVTs Lab
Compliance Week, Dec 3-5, 2013, 2013 Abbott. All rights
reserved. SE2939051, Rev A
21
Interactive Exercise 1
1. If you establish long term stability condition at
25C/60% RH, would you place some control over
distribution of product in zone I and zone II countries?
1a). If yes, what kind of control would you implement?
1b). If no, why?
2. If you establish long term stability condition at
25C/60% RH, would you place some control over
distribution of product world wide?
2a). If yes, what kind of control would you implement?
2b). If no, why?
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Storage vs. Transportation Condition

FDA has presented their view that
transportation conditions may differ from
storage conditions, provided the manufacturer
presents satisfactory supporting data.*
The Key is to present satisfactory supporting
data
2006 & 2007

*FDA presentation in IBC Informa life sciences,
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Know the Temperature Range

Temperature Range During
Storage and Transportation
Mean Kinetic Temperature

(MKT)
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Approaches to Map Distribution

Environment
Study with packaged

loaded
with data logger
UPS/Fedex Data
Other publications
Historical
climatic data
World wide*
ED
EAS data and actual shipping vehicle temperature

* Note there is difference between climatic temperature
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Mapping the Distribution Chain

Environment
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An Example of Temperature Range During

Transportation
50
45
AR
Temperature, 0C
40
AZ
35
CA-LA
30
CA-OC
25
FL
IN
20
MN
15
NV
10
NJ
TX
WA
0
0
20
40
60
80
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EAS Hour
L
Time in Transportation,
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100
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Mean Kinetic Temperature

Recommended by USP to assess the effect of variable
environmental condition on product quality and shelf life
Convert variable temperature into an equivalent steady
temperature. The steady temperature is used to determine the
effect of excursion.
MKT is not an arithmetic average, but a calculation derived
from Arrhenius Equation.
MKT =
e H RT 1 + e H RT 2 + ... + e H RT n
ln
ED
EAS
Where H is the heat of activation energy,

and R is the gas constant.
R=8.3144x10-3 kJ/mole/K
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Temperature Excursion and Stability Studies, IVTs Lab Compliance Week, Dec 35, 2013, 2013 Abbott. All rights reserved. SE2939051, Rev A
28
Definitions
Temperature Cycling Study:

Studies in which the drug product, drug substance or
novel excipient is repetitiously subjected to high and low
temperatures.
Thermal Stress Study:
Testing conducted on the drug product, drug substance or
novel excipient to generate decomposition products after
exposure to specific stress condition (e.g., heat, light,
humidity, acid, base and oxidative reagents or their
combination).
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Transportation Study Design

To assess the effect of temperature fluctuation on
Thermal cycling
study
product stability and shelf life

The temperature range product experience during
transportation is usually much high than at long term
storage
If MKT long term storage temperature, this study is

Thermal stress
study at MKT
Thermal stress
study at temp
higher than MKT
not needed, use ICH stability study results

If MKT long term storage temperature, use
intermediate and accelerated study results if they are
supportive.
Usually conducted at temperature greater than

accelerated study temperature, with shorter duration
May test multiple temperature points, the higher the
temperature, the shorter the duration.
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Thermal Cycling Study

Temperature Condition
Freeze-thaw cycles, with the low and high ends temp. being the coldest
&warmest temp. from the distribution chain (DC) environment temp. mapping
Alternatively, the high end can be room temp.
# of Cycles
Typically 3
Depends on the actual situation of transportation and DC logistics
Duration of thermal cycles

Residing time at each extreme temperature depends on actual shipping
Situation, evaluate the worst case scenario.
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Allow enough time to reach temperature
equilibrium.
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Thermal Cycling Study

# of Lot Evaluated
One lot
May need to evaluate one lot per design per dose strength if these factors
Affect the study outcome
When to Conduct the Study
Pre-market approval, after product design and manufacturing process finalized

Can start during clinical phase
Attributes tested
Same as stability study, should include physical, chemical, biological
attributes if applicable
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Should include container closure
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Thermal Stress Study

Temperature Condition
Usually conducted at temperature greater than accelerated
study temperature.
May test multiple temperature point.
Study Length
Depends on the stability of the product and temperature point tested
Usually, the higher the temp., the shorter the study length
# of Time Points
Test at least 2 or 3 time points per temperature
condition
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Thermal Stress Study

# of Lot Evaluated
One lot
May need to evaluate one lot per design per dose strength if these factors
Affect the study outcome
When to Conduct the Study
Pre-market approval, after product design and manufacturing process finalized

Can start during clinical phase
Attributes tested
Same as stability study, should include physical, chemical, biological
attributes if applicable
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RE system evaluation too.
Should include container closure
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Other Transportation Studies

humidity
Light or
X-ray
Reference:
pressure
1. Guidelines for selecting

and using ISTA test
procedures and projects,
ISTA
2. ASTM standards
product
oxygen
Shock &
vibration
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35
Through temperature mapping of the distribution chain
environment, you find that your product will experience
temperature outside of your registered long term storage
temperature range during transit, you then conduct
thermal cycling and thermal stress study to support
distribution of product at temperature outside of long term
storage temperature range, do you test the product at long
term storage temperature till the end of shelf life after
exposing to thermal cycling condition or thermal stress
condition? Why?
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ICH Q1A 2.1.7 (1)
The storage conditions and the lengths of

studies chosen should be sufficient to cover
storage, shipment and the subsequent use.
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37
Apply the Transportation

Study Results to
Quality System
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Temperature Excursion and Stability Studies, IVTs Lab
Compliance Week, Dec 3-5, 2013, 2013 Abbott. All
rights reserved. SE2939051, Rev A
38
Your thermal cycling study and thermal stress study results indicate
that your temperature sensitive product can tolerate cycling between
extreme temperature during transit and is stable for short period of
time (e.g. 2 weeks) at temperature 20C higher than your long term
storage temperature, which of the following option will you prefer for
distribution of product?
a) Control transportation environment temperature to protect the
temperature sensitive product
b) Ship without temperature control but limit the transit time to
minimize the thermal degradation
c) Use protective packaging and limit transit time to ensure quality of
the product
d) Other
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Distribution Quality System
Establish Product
Distribution Policy
SOP
DOPs
Establish Tracking
System to ensure
compliance to the
company
distribution
requirements.
Conduct real time

transportation
validation study.
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40
Establish Transportation and Distribution

Process
Product Distribution
Transportation
study results
Packaging
study
Results
Distribution
Requirements
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Cost of
Transport
Options
Establish Transportation and Distribution

Process
Product Package
Requirements
Determine:
If thermostatic pack will be
used
Is it on individual product
unit or a bulk container?
Is temperature monitoring
device needed on individual
unit or bulk container?
What kind of temp
monitoring device will be
used
Product Transit
Requirement
Transit Time
Requirement
Determine:
Routes of transit
If temp control transit is
needed? If so, what kind of
temp control and how to
monitor the temp.
Commercial carriers to be
used, and specific quality
agreement
Can product be returned?
How to handle product
return?
Can product be moved
from one account center
D
to another,Ehow?
ASE
Determine:
Should transportation time
be limited
If so, how long product can
be in transit
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42
Apply Safety Margin
A hypothetical product stability and transportation study result summary
Temperature Range
Product Stability
<-20C
Unknown
-20C to 5C
At least 3 months
5C to 25C
36 months
25C to 30C
6 months
30C to 40C
1 month
40C to 50C
3 days
50C to 60C
8 hrs
Each of the temperature range is assessed separated

Consider the cumulative effect of exposure to various temperature range
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during product transportation
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2013 Abbott. All rights reserved. SE2939051 Rev A
43
Apply Safety Margin
Besides considering the cumulative effect of exposure

to multiple temperature range during transit, take the
following into consideration when establishing product
distribution process:
Seasonal climate change
Regional climate difference
Green house effect in the delivery truck without temperature
control
The transportation process should take into account of

the worst case scenario
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Transportation Validation Study

Study conducted after establishing product distribution
process.
It is a real time study mimicking the entire product transit
route from manufacturing site, to distribution center to
end users.
Include transit during hottest time of the year to the
regions with highest temperature.
Include longest route and max. transit time
Preferably include temperature monitoring device for the
study
Test all the stability attributes as in storage and
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transportation stability studies
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Tracking System
If temperature control is
required, establish appropriate
temperature monitoring
system.
If there is limit on transit time,
monitor product movement to
ensure the time limit is not
exceeded.
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Conclusions
It is acceptable to distribute product at conditions outside

of long term storage condition, as long as the
transportation condition is fully tested and that product
quality is not compromised.
Consider product intrinsic properties, distribution
logistics/needs, transportation/packaging options, cost and
compliance when conducting transportation studies.
The product distribution process should be supported by
the transportation study results.
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Conclusions
Transportation conditions have to be determined

considering
risk of product degradation
combined effect of various temperature range exposure or other
hazardous environmental conditions
seasonal climate changes
regional climate difference.
The controls implemented for product distribution should

be adequately monitored and validated.
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Questions
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SE2939051
Temperature Excursions and Transportatio
A
Effective Date: 11/4/2013
Document# Rev
SE2939051A
*SE2939051 A*
Document #: SE2939051
Current Revision:
A
Doc Owner:
Guo, Sherry
Last Review:
11/4/2013
Classification:
Title:
Temperature Excursions and Transportatio
Future Revision:
Change Type:
New Release
CO Number:
348253
Next Review:
11/3/2016
Retention:
Superceded By Doc. # (Supercede only):
Supporting Documentation Attached?
Yes
Site(s) where doc used:
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Material Disposition:
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On Order:
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Originator
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Name
Robinson,DelfaL
Guo,Sherry
Devore,RonD
Shpolyansky,Natalya
Liu,Jian
Crudup,DanaC
Site
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Signature
Robinson,DelfaL
Guo,Sherry
Devore,RonD
Shpolyansky,Natalya
Liu,Jian
Crudup,DanaC
Date
11/1/201311:02:36AM
11/4/20132:28:23PM
11/1/201311:05:14AM
11/1/201311:09:24AM
11/1/201311:29:15AM
11/1/201311:09:21AM
Comments
Revision History
Revision
A
Date
11/4/20132:31:47PM
Description of Change
Purpose: Invited speaker for IVT Conference of Compliance week 2013 on " Temperature
Excursion and Transportation Studies for Stability Program" on December 4, 2013, in
Philadelphia,PA.
Page 1 of 1
CO Number
348253
Originator
Liu,Jian
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Temperature Excursion &

Transportation Studies for

Sherry Guo, Ph.D

RELEASED - EFFECTIVE: 04-NOV-2013

1. Background, Scope and Purpose

RELEASED - EFFECTIVE: 04-NOV-2013

Temperature and other environmental conditions

RELEASED - EFFECTIVE: 04-NOV-2013

Products not sensitive to environmental changes (e.g., metallic stents)

Highly Sensitive Products:

RELEASED - EFFECTIVE: 04-NOV-2013

Types of Stability Studies

RELEASED - EFFECTIVE: 04-NOV-2013

Why is transportation study important?

RELEASED - EFFECTIVE: 04-NOV-2013

The presentation will focus on the transportation

Temperature excursion during transportation is

RELEASED - EFFECTIVE: 04-NOV-2013

To share the strategy and stability program for

RELEASED - EFFECTIVE: 04-NOV-2013

Get Global Picture Before

Temperature Excursion and Stability Studies, IVTs Lab Compliance Week,

RELEASED - EFFECTIVE: 04-NOV-2013

Transportation Study Design

RELEASED - EFFECTIVE: 04-NOV-2013

RELEASED - EFFECTIVE: 04-NOV-2013

RELEASED - EFFECTIVE: 04-NOV-2013

Mapping Distribution Chain

RELEASED - EFFECTIVE: 04-NOV-2013

Mapping Distribution Chain, continued

RELEASED - EFFECTIVE: 04-NOV-2013

Distribution Chain Consideration

RELEASED - EFFECTIVE: 04-NOV-2013

USP <1079> GOOD STORAGE AND DISTRIBUTION

FDA 21 CFR part 205:

prescription drug products and to ensure that there is no delivery of

RELEASED - EFFECTIVE: 04-NOV-2013

The Cost Factor

$of temp control

RELEASED - EFFECTIVE: 04-NOV-2013

Cost Saving Recommendations

Weighing Temperature Control &

Ref: Model requirements for the

RELEASED - EFFECTIVE: 04-NOV-2013

Gaining Global View

RELEASED - EFFECTIVE: 04-NOV-2013

Design and Conduct

RELEASED - EFFECTIVE: 04-NOV-2013

RELEASED - EFFECTIVE: 04-NOV-2013

Storage vs. Transportation Condition

2006 & 2007

RELEASED - EFFECTIVE: 04-NOV-2013

Know the Temperature Range

Mean Kinetic Temperature

Approaches to Map Distribution

Study with packaged

EAS data and actual shipping vehicle temperature

Mapping the Distribution Chain

An Example of Temperature Range During

RELEASED - EFFECTIVE: 04-NOV-2013

Mean Kinetic Temperature

Where H is the heat of activation energy,

RELEASED - EFFECTIVE: 04-NOV-2013

Temperature Cycling Study:

* NONE * (N)