10 Steps to Thermal Package Qualification Kevin ODonnell

10 Steps to Thermal Package Qualification Kevin O’Donnell Director & Chief Technical Advisor Tegrant Corp. , Thermo. Safe Brands HPCL Spring Conference 31 March 09 Philadelphia, PA © 2008 Tegrant Corporation, Thermo. Safe Brands

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How do you tell which vial has been temperature abused and is no longer Potent? Efficacious? Safe? 4 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 5 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermal Container Development and Qualification CQ/DQ OQ PQ 6 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 7 © 2008 Tegrant Corporation, Thermo. Safe Brands

The 10 Step Process to a Qualified Thermal Package 8 8 © 2008 Tegrant Corporation, Thermo. Safe Brands

The 10 Step Process to a Qualified Container 1. 2. 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 9 9 © 2008 Tegrant Corporation, Thermo. Safe Brands

1. Understand the product’s stability • Acceptable temperature range, allowable excursions (e. g. 2 -8°C storage, 0 -20°C for 48 hrs 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 10 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 48 hrs 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 11 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 CO 2 ) Cryogenically Frozen, CO 2 or LN 2: (-70° or -180°C) Reference: USP & ICH 12 12 © 2008 Tegrant Corporation, Thermo. Safe Brands

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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 14 14 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 15 © 2008 Tegrant Corporation, Thermo. Safe Brands

Active Temperature Control Transport Options 16 16 © 2008 Tegrant Corporation, Thermo. Safe Brands

Active Systems Advantage 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 Haz. Mat) Physical quality variability Self-contained units have 48 hour life before refueling or re-icing Pick up / return charges 17 17 © 2008 Tegrant Corporation, Thermo. Safe Brands

Passive Temperature Control Transport Options Gel/ice packs Dry Ice Insulated Containers 18 18 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 19 1 to 3” wall rigid closed cell polyurethane (PUR) 2. 0 lb cu. ft. density © 2008 Tegrant Corporation, Thermo. Safe Brands 19

Insulated Shipping Containers Conventional pallet size containers: 3” PUR 6 PKD 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 20 © 2008 Tegrant Corporation, Thermo. Safe Brands

Passive Pallet System for Bulk Transport Stainless tank with bulk bio-pharmaceutical inside insulated pallet system; Required strict 2 -8 C shipping via 2 -day airfreight – used frozen gels for temperature maintenance (shown with door open inside test chamber for thermal test) 21 21 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 • • Voluminous Warehousing considerations Multiple components Refrigerant conditioning Longer assembly time Disposal / recycling issues Closed-loop reuse management 22 22 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamics and Their Influence on Packaging Performance 23 23 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 24 © 2008 Tegrant Corporation, Thermo. Safe Brands

Shipping Performance is Based On: ü Container Insulation (type, construction, wall thickness, size) ü Refrigerant/Temperature Stabilizers ü Ambient Exposure ü Product Mass (thermal heat capacity of load) ü Staging (temperatures of all materials prior to loading) 25 25 © 2008 Tegrant Corporation, Thermo. Safe Brands

Shipping Performance is Based On: ü Container Insulation ü Refrigerant/Temperature Stabilizers ü Ambient Exposure ü Product Mass ü Staging 26 26 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 27 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 28 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 29 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamic Principles of Packaging Performance Heat Flow Direction – to establish equilibrium 30 30 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamic Principles of Packaging Performance Heat Flow Direction – to establish equilibrium 31 31 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamic Principles of Packaging Performance Heat Flow Direction – to establish equilibrium 32 32 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamic Principles of Packaging Performance Heat Flow Direction – to establish equilibrium 33 33 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamic Principles of Packaging Performance Heat Flow Direction – to establish equilibrium 34 34 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thermodynamic Principles of Packaging Performance Heat Flow Direction – to establish equilibrium 35 35 © 2008 Tegrant Corporation, Thermo. Safe Brands

Movement to Syringes and Pens Reduces Thermal Mass of Product – Harder to Hold Tight Ranges 36 36 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 c. GDP quality control points in place or needed? 37 37 © 2008 Tegrant Corporation, Thermo. Safe Brands

“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 38 © 2008 Tegrant Corporation, Thermo. Safe Brands

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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) 40 40 © 2008 Tegrant Corporation, Thermo. Safe Brands

Example of High Performance, Prequalified, 2 to 8°C Container System for 48 hours under +45 to 20°C exposures 41 41 © 2008 Tegrant Corporation, Thermo. Safe Brands

Dedicated Summer & Winter Configurations » How & When to Implement • • • Calendar Dating Temperature at Origin Temperature at Destination Daily Forecasts / Weather Mapping Formulas Software Algorithms 42 42 © 2008 Tegrant Corporation, Thermo. Safe Brands

Dedicated Summer & Winter Configurations » Summary • • All have advantages / disadvantages Operationally dependant All should be documented Training is essential 43 43 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 -15 C, no excursions 44 44 © 2008 Tegrant Corporation, Thermo. Safe Brands

5. Know cold-chain suppliers capabilities • • Products available Capabilities (engineering and testing? ) Locations, local and global supply considerations Reputation Quality Procedures, c. GMP’s, ISO? JIT local delivery & pre-frozen gels Local packaging distributor partners? 45 45 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 46 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 47 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 48 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 49 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 50 © 2008 Tegrant Corporation, Thermo. Safe Brands

What Can Go Wrong – Things Not Discovered During Qualification: Develop and qualify a package for a 2 -8 C product under an extreme summer temperature profile – in actual shipment the package never is exposed to those extremes PRODUCT CAN FREEZE 51 51 © 2008 Tegrant Corporation, Thermo. Safe Brands

What Can Go Wrong – Things Not Discovered During Qualification: Develop and qualify a package for a 2 -8 C product under extreme winter temperature profile, as above, in actual shipment, the temperatures are above normal PRODUCT CAN GET TOO WARM 52 52 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 c. GMP’s and change control? 53 53 © 2008 Tegrant Corporation, Thermo. Safe Brands

Value and Sensitivity of Product/Product Packaging Dictate Level of Dynamic Testing • Shock and vibration – ASTM 4169, ISTA 1 A ruggedness/non simulation • Conditioning, shock, vibration – ISTA 2 A simulation performance • Atmospheric conditioning and pressure becoming critical for syringes and pens – product displaced or damaged 54 54 © 2008 Tegrant Corporation, Thermo. Safe Brands

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 55 © 2008 Tegrant Corporation, Thermo. Safe Brands

The 10 Step Process to a Qualified Container 1. 2. 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 56 56 © 2008 Tegrant Corporation, Thermo. Safe Brands

Thank You 57 57 © 2008 Tegrant Corporation, Thermo. Safe Brands