10 Steps to Thermal Package Qualification
Kevin O’Donnell
Director & Chief Technical Advisor
Tegrant Corp., ThermoSafe Brands
HPCL Spring Conference
31 March 09 Philadelphia, PA
© 2008 Tegrant Corporation, ThermoSafe Brands
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How do you tell which vial has been temperature
abused and is no longer Potent? Efficacious? Safe?
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Parenteral Drug Association (PDA)
Technical Report No. 39
Guidance for Temperature-Controlled Medicinal Products:
Maintaining the Quality of Temperature-Sensitive Medicinal Products
through the Transportation Environment
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Thermal Container Development and
Qualification
CQ/DQ
OQ
PQ
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CDER’s General Principles of Process
Validation
 Component Qualification/Design Qualification (CQ/DQ)
» Establishing confidence in design testing that ancillary components
are capable of consistently operating within established limits and
tolerances
 Operating Qualification (OQ)
» Establishing confidence that the process is effective and
reproducible
 Performance Qualification (PQ)
» Establishing confidence through appropriate testing that the product
produced by a specified process meets all release requirements for
functionality
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The 10 Step Process to a
Qualified Thermal Package
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The 10 Step Process to a Qualified Container
Understand the product’s temperature stability for transport
Define customers’ requirement for load size (quantity of product) per
shipper size
3. Learn the packaging options and best applications for each – CQ
4. Understand the package handling environment (temperature exposure,
shock, vibration)
5. Know cold-chain suppliers’ and pkg. test lab’s capabilities
6. Understand requirements for package performance testing by
regulatory agency
7. Perform design testing for a working system – DQ
8. Qualify the packaging system to a Protocol (e.g. min/max loads,
summer/winter ambients) - OQ
9. Let suppliers know your expectations – execute a quality agreement
10. Quality System Implementation (should-be’s) SOP’s for warehouse and
PQ
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1. Understand the product’s stability
• Acceptable temperature range, allowable
excursions (e.g. 2-8°C storage, 0-20°C for 48hrs in
transit)
• Thermal mass (e.g liquid volume, lyophilized, primary
pkg)
• Load configurations (e.g. min/max, secondary pkg.)
• Value of product
• Other considerations, humidity, fragility
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Product stability AND regulatory requirements define
transit temperatures and allowable excursions for
distribution
An example from one company for its’ US distribution of a
temperature sensitive biopharmaceutical:
Temperature range for shipment in US:
2-8°C; allowable excursions 0-20°C for 48hrs in transit
Questions:
• Are wholesalers and distributors exempt from these requirements for
the same product?
• Do mfg’s give them product distribution temperatures & excursion
limits?
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Families of Temperature Sensitive Pharmaceuticals
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Room Temperature: CRT 20-25°C
Cool: 8-15°C
Refrigerated: 2-8°C
Frozen or Refrigerated: < 8°C
Do Not Freeze: > 0°C
Frozen: < -20°C (some must protect from CO2 )
Cryogenically Frozen, CO2 or LN2: (-70° or -180°C)
Reference: USP & ICH
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2. Define customer requirements
• Image and presentation, container markings
• Quality upon receipt (e.g product condition upon receipt
and beyond in chain)
• Handling issues, weight, refrigerant, amount and type of
packaging, environmental concerns
• Delivery expectations (e.g. overnight, 2-day)
• Cost expectations
• Re-Use of Container/Refrigerant & Return Options
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3. Learn the packaging options and best
applications for each – DQ/CQ
• Various insulation materials are available, EPS, PUR,
VIP’s, Misc.
• Container form/construction (e.g. 6-panel KD, molded,
various closures, insulation thickness and densities)
• Package sizes needed (e.g. small, medium and large to
pallets)
• Alternate transport methods (e.g. refrigerated trucks,
ocean containers, thermostatically controlled containers)
• Refrigerants (temperature stabilizers)
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Active Temperature Control Transport Options
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Active Systems
Advantage Considerations
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No Warehousing of container
Secure
Leased not purchased
Quick loading / unloading
Drop off / pick up
Fits all wide body aircraft
Disadvantage Considerations
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Availability
Limited lane segments
Mechanical failure risks
Winter use risk in cold climates
Some contain dry ice (Class 9
HazMat)
Physical quality variability
Self-contained units have 48 hour
life before refueling or re-icing
Pick up / return charges
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Passive Temperature Control Transport Options
Gel/ice packs
Dry Ice
Insulated Containers
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Insulated Shipping Containers
 Conventional small to medium size containers:
1 to 2-1/2” wall EPS (expanded
polystyrene) 1.5 to 1.8 lb cu.ft.
density
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1 to 3” wall rigid closed cell
polyurethane (PUR) 2.0 lb cu.ft.
density
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Insulated Shipping Containers
 Conventional pallet size containers:
3” PUR 6PKD walls within
corrugate shell (15-60
cu.ft.)
5 day refrigerated shipper with 18 x 48
oz. frozen gel ice (6 bottom 12 top)
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Passive Pallet System for Bulk Transport
Stainless tank with bulk
bio-pharmaceutical
inside insulated pallet
system;
Required strict 2-8C
shipping via 2-day
airfreight – used frozen
gels for temperature
maintenance
(shown with door open
inside test chamber for
thermal test)
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Passive Systems
Disadvantage Considerations
Advantage Considerations
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Holds tighter temperature range
Limitless destinations
Repeatable performance
No mechanical components or
risk
Disposable or reusable
Year-round use
Designed/qualified for “x” days
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Voluminous
Warehousing considerations
Multiple components
Refrigerant conditioning
Longer assembly time
Disposal / recycling issues
Closed-loop reuse management
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Thermodynamics and Their Influence on Packaging Performance
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Cold Chain Packaging Objective:
Temperature Maintenance During Transport
Primary Issue: transit environment that is
unpredictable, uncontrollable and relatively
unreliable
Industry Practice: design and qualify commonly
available insulated containers and refrigerants
under the temperature extremes measured in the
companies’ transit routes
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Shipping Performance is Based On:
Container Insulation (type, construction, wall
thickness, size)
Refrigerant/Temperature Stabilizers
Ambient Exposure
Product Mass (thermal heat capacity of load)
Staging (temperatures of all materials prior to loading)
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Shipping Performance is Based On:
Container Insulation
Refrigerant/Temperature Stabilizers
Ambient Exposure
Product Mass
Staging
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Controlling Heat
Transfer – The Key
To Cold Chain
Maintenance
3 types of heat transfer:
Conduction is the process by which heat energy is transmitted through
contact with neighboring molecules. Some solids, such as metals, are good
conductors of heat while others, such as wood, are poor conductors.
Convection transmits heat by transporting groups of molecules from place to
place within a substance. Convection occurs in fluids such as water and air, which
move freely.
Radiation is the transfer of heat energy without the involvement of a physical
substance in the transmission. Radiation can transmit heat through a vacuum.
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Basic Heat Flow – Convection is Most Critical to Temperature Control in
Packaging
Convection: since convection goes on when
air is free to move, the benefit in container
design is to allow heat to move to cold (e.g.
heat from environment, passing through wall
absorbed by frozen gels), thus providing a
way to maintain the payload within the
required temperature range.
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Most Critical Design Criteria for Cold Chain:
» 1. have an adequate amount of temperature stabilizers
(e.g. frozen, refrigerated, room temp gels, dry ice, etc.);
» 2. Sufficient insulation in the container to limit the heat
flow from the outside environment to the inside of the
container for the duration of the transit period.
» 3. Adequate airflow within the container allowing
convection to channel the heat away from the payload to
the temperature stabilizers. Direct contact of the product
and stabilizers will result in conduction and is not a desired
design characteristic.
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Thermodynamic Principles of Packaging Performance
Heat Flow
Direction –
to establish
equilibrium
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Thermodynamic Principles of Packaging Performance
Heat Flow
Direction –
to establish
equilibrium
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© 2008 Tegrant Corporation, ThermoSafe Brands
Thermodynamic Principles of Packaging Performance
Heat Flow
Direction –
to establish
equilibrium
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© 2008 Tegrant Corporation, ThermoSafe Brands
Thermodynamic Principles of Packaging Performance
Heat Flow
Direction –
to establish
equilibrium
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© 2008 Tegrant Corporation, ThermoSafe Brands
Thermodynamic Principles of Packaging Performance
Heat Flow
Direction –
to establish
equilibrium
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© 2008 Tegrant Corporation, ThermoSafe Brands
Thermodynamic Principles of Packaging Performance
Heat Flow
Direction –
to establish
equilibrium
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Movement to Syringes and Pens Reduces Thermal Mass of Product – Harder to
Hold Tight Ranges
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4. Understand the package handling
environment
• Walk the “system” – learn times and temperatures
• Storage/packing environment, pre-storage, packing and
post packing environments
• Carrier options, differences in overnight vs. 2-3 day
express freight – segment analysis; best partners for
freight forwarding
• Dynamic environment - truck, air options with shock,
vibration & atmospheric pressure considerations
• Internal cGDP quality control points in place or needed?
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“You must thoroughly understand the nature
and extent of the hazards within the
distribution environment through which the
product must travel”
Fundamentals of Packaging Technology
- Walter Soroka
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Universal Packaging Configuration
» A qualified package that meets all limits of anticipated
or expected extremes of temperature within a
distribution environment
(both high and low)
Dedicated Packaging Configuration
» A qualified package that meets a single limit of
anticipated or expected extremes of temperature
within a distribution environment
(either high or low)
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Example of High
Performance, Prequalified, 2 to 8°C
Container System for
48 hours under +45 to
-20°C exposures
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Dedicated Summer & Winter
Configurations
» How & When to Implement
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Calendar Dating
Temperature at Origin
Temperature at Destination
Daily Forecasts / Weather Mapping
Formulas
Software Algorithms
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Dedicated Summer & Winter
Configurations
» Summary
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All have advantages / disadvantages
Operationally dependant
All should be documented
Training is essential
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Examples of Allowable Excursions for Distribution
• Example 1 (actual manufacturer’s information to wholesalers for distribution of
their product):
– Storage: Refrigerated: 2-8°C
– Distribution (shipping): 2-8°C, excursion to 25° no > 25°C
• Example 2 (actual information as above):
– Storage: Refrigerated: 2-8°C
– Distribution (shipping): 2-15C, no excursions
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5. Know cold-chain suppliers capabilities
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Products available
Capabilities (engineering and testing?)
Locations, local and global supply considerations
Reputation
Quality Procedures, cGMP’s, ISO?
JIT local delivery & pre-frozen gels
Local packaging distributor partners?
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6. Understand requirements for package
performance testing
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What are the shipping scenarios that need to be tested?
What is your level of risk to avoid over-engineering pkg.
Can you defend your test ambients?
Make sure the test lab’s quality system matches your
expectations (audit)
• Determine requirements for trip monitoring –
considerations for using monitors in qualification tests
• What level of documentation is needed? Will the lab’s test
report be adequate?
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7. Perform design testing for a working system DQ/ CQ
• Helps establish total packaging costs for each option =
container, refrigerant, weight for transport costs
• Provides the foundation for a cost/benefit analysis to
select the best package for qualification in a risk
management scenario
• Leads to the detailed packing configurations to be
qualified through the protocol development process
for compliance
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Thermal Testing Considerations
 Tests are general simulations only – do not replace actual
measurements in the distribution network (e.g. PQ);
 Test conditions are under tight control vs real world;
 Primary issue is selection of defendable test profiles that
provide as much information as possible – e.g. summer
and winter are typical, very few do a non-extreme normal
profile too
 Consider dynamic testing (e.g. atmospheric conditioning,
shock and vibration) following thermal qualification,
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8. Qualify the packaging system
• Collaborate with lab to write qualification protocol
• Carefully consider the content (acceptance criteria, allowable
excursions)
• Understand time and cost requirements for testing; min, max
loads, summer and winter testing, N=3, etc.
• Consideration of running “normal” ambients in addition to
extreme summer and winter
• Inclusion of dynamic testing (shock, vibration, pressure)
• Incorporate in Validation Master Plan process
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Cold-Chain
Shipping Container Qualification
Manufacturer’s Consensus Practice:
» Qualify containers and configurations for each
product or each family of product temperatures using
a standardized thermal testing method
» Testing based on written protocols; testing done in
triplicate (N=3) to assure reproducibility; min and max
loads, summer and winter exposure profiles; plus
normal profile for complete information;
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What Can Go Wrong –
Things Not Discovered During Qualification:
 Develop and qualify a package for a 2-8C
product under an extreme summer
temperature profile – in actual shipment the
package never is exposed to those extremes
PRODUCT CAN FREEZE
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What Can Go Wrong –
Things Not Discovered During Qualification:
 Develop and qualify a package for a 2-8C
product under extreme winter temperature
profile, as above, in actual shipment, the
temperatures are above normal
PRODUCT CAN GET TOO WARM
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9. Let suppliers know your expectations
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Will supplier sign a quality agreement?
Can they guarantee to supply what was tested?
Do they have traceability to their raw materials?
Are their manufacturing processes repeatable?
Are the quality control checks documented?
Will products be consistent from one lot/batch to the next?
Do they understand cGMP’s and change control?
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Value and Sensitivity of Product/Product Packaging Dictate Level of
Dynamic Testing
• Shock and vibration – ASTM 4169,
ISTA 1A ruggedness/non simulation
• Conditioning, shock, vibration – ISTA
2A simulation performance
• Atmospheric conditioning and
pressure becoming critical for
syringes and pens – product
displaced or damaged
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10. Implementation
 Warehouse SOP’s should be developed based on test
report/internal report
 Warehouse staff should be trained and monitored regularly
 Companies should get feedback from customers who
receive packaging
 Companies should require notification if changes are made
in products supplied or carrier’s routes/methods
 Companies should monitor transit environment for changes,
document all deviations, failures of packages
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The 10 Step Process to a Qualified Container
Understand the product’s temperature stability for transport
Define customers’ requirement for load size (quantity of product) per shipper
size
3. Learn the packaging options and best applications for each – CQ
4. Understand the package handling environment (temperature exposure,
shock, vibration)
5. Know cold-chain suppliers’ and pkg. test lab’s capabilities
6. Understand requirements for package performance testing by regulatory
agency
7. Perform design testing for a working system – DQ
8. Qualify the packaging system to a Protocol (e.g. min/max loads,
summer/winter ambients) - OQ
9. Let suppliers know your expectations – execute a quality agreement
10. Quality System Implementation (should-be’s) SOP’s for warehouse and PQ
1.
2.
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Thank You
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