1. 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

2. 2 Need new pictures to show supply chain 2
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3. 3 Need new pictures to show supply chain 3
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4. How do you tell which vial has been temperature abused and is no longer Potent? Efficacious? Safe?
Whatever approach you take to your qualification, the trend in the industry has been leaning ever closer to CDER’s General Principles of Process Validation, often referred to as CQ/OQ/PQ or IQ/OQ/PQ, as more and more companies are implementing it for their cold-chain packaging and distribution validation it is increasingly recognized and comprehensive approach to validation and the framework for the PDA Technical Report #39.
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5. Parenteral Drug Association (PDA) Technical Report No
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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6. Thermal Container Development and Qualification CQ/DQ OQ PQ
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7. 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
Whatever approach you take to your qualification, the trend in the industry has been leaning ever closer to CDER’s General Principles of Process Validation, often referred to as CQ/OQ/PQ or IQ/OQ/PQ, as more and more companies are implementing it for their cold-chain packaging and distribution validation it is increasingly recognized and comprehensive approach to validation and the framework for the PDA Technical Report #39.
© 2008 Tegrant Corporation, ThermoSafe Brands 7

8. The 10 Step Process to a Qualified Thermal Package8
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9. 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
Learn the packaging options and best applications for each – CQ
Understand the package handling environment (temperature exposure, shock, vibration)
Know cold-chain suppliers’ and pkg. test lab’s capabilities
Understand requirements for package performance testing by regulatory agency
Perform design testing for a working system – DQ
Qualify the packaging system to a Protocol (e.g. min/max loads, summer/winter ambients) - OQ
Let suppliers know your expectations – execute a quality agreement
Quality System Implementation (should-be’s) SOP’s for warehouse and PQ 9
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10. 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 10
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11. 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? 11
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12. Families of Temperature Sensitive Pharmaceuticals
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 12
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14. 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 14
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15. 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) 15
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16. Active Temperature Control Transport Options16
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17. Active Systems Advantage Considerations Disadvantage Considerations
No Warehousing of container
Secure
Leased not purchased
Quick loading / unloading
Drop off / pick up
Fits all wide body aircraft
Disadvantage Considerations
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 17
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18. Passive Temperature Control Transport Options
Gel/ice packs
Dry Ice
Insulated Containers 18
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19. 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
1 to 3” wall rigid closed cell polyurethane (PUR) 2.0 lb cu.ft. density 19
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20. 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) 20
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21. 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) 21
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22. Passive Systems Disadvantage Considerations Advantage Considerations
Holds tighter temperature range
Limitless destinations
Repeatable performance
No mechanical components or risk
Disposable or reusable
Year-round use
Designed/qualified for “x” days
Disadvantage Considerations
Voluminous
Warehousing considerations
Multiple components
Refrigerant conditioning
Longer assembly time
Disposal / recycling issues
Closed-loop reuse management 22
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23. Thermodynamics and Their Influence on Packaging Performance23
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24. 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 24
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25. 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) 25
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26. Shipping Performance is Based On:
Container Insulation
Refrigerant/Temperature Stabilizers
Ambient Exposure
Product Mass
Staging 26
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27. 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. 27
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28. 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. 28
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29. 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. 29
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30. Thermodynamic Principles of Packaging Performance
Heat Flow Direction – to establish equilibrium 30
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31. Thermodynamic Principles of Packaging Performance
Heat Flow Direction – to establish equilibrium 31
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32. Thermodynamic Principles of Packaging Performance
Heat Flow Direction – to establish equilibrium 32
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33. Thermodynamic Principles of Packaging Performance
Heat Flow Direction – to establish equilibrium 33
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34. Thermodynamic Principles of Packaging Performance
Heat Flow Direction – to establish equilibrium 34
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35. Thermodynamic Principles of Packaging Performance
Heat Flow Direction – to establish equilibrium 35
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36. Movement to Syringes and Pens Reduces Thermal Mass of Product – Harder to Hold Tight Ranges36
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37. 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? 37
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38. “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 38
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39. 39
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40. 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) 40
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41. Example of High Performance, Pre-qualified, 2 to 8°C Container System for 48 hours under +45 to -20°C exposures 41
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42. Dedicated Summer & Winter Configurations
How & When to Implement
Calendar Dating
Temperature at Origin
Temperature at Destination
Daily Forecasts / Weather Mapping
Formulas
Software Algorithms 42
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43. Dedicated Summer & Winter Configurations
Summary
All have advantages / disadvantages
Operationally dependant
All should be documented
Training is essential 43
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44. 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):
Distribution (shipping): 2-15C, no excursions 44
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45. 5. Know cold-chain suppliers capabilities
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? 45
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46. 6. Understand requirements for package performance testing
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? 46
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47. 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 47
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48. 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, 48
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49. 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 49
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50. 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; 50
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51. 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 51
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52. 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 52
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53. 9. Let suppliers know your expectations
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? 53
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54. Shock and vibration – ASTM 4169, ISTA 1A ruggedness/non simulation
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 54
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55. 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 55
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56. 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
Learn the packaging options and best applications for each – CQ
Understand the package handling environment (temperature exposure, shock, vibration)
Know cold-chain suppliers’ and pkg. test lab’s capabilities
Understand requirements for package performance testing by regulatory agency
Perform design testing for a working system – DQ
Qualify the packaging system to a Protocol (e.g. min/max loads, summer/winter ambients) - OQ
Let suppliers know your expectations – execute a quality agreement
Quality System Implementation (should-be’s) SOP’s for warehouse and PQ 56
© 2008 Tegrant Corporation, ThermoSafe Brands 56

57. Thank You 57
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