© 2008 Tegrant Corporation, ThermoSafe Brands 10 Steps to Thermal Package Qualification Kevin...

© 2008 Tegrant Corporation, ThermoSafe Brands

10 Steps to Thermal Package Qualification

Kevin O’DonnellDirector & Chief Technical AdvisorTegrant Corp., ThermoSafe Brands

HPCL Spring Conference 31 March 09 Philadelphia, PA

© 2008 Tegrant Corporation, ThermoSafe Brands2

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Historical Perspective of Ensuring Compliance

Manufacturing plantRaw materialsHealthcare facilityWholesalerDistribution centerFilling & packagingManufacturing plantManufacturing plantRaw materialsRaw materialsHealthcare facilityHealthcare facilityWholesalerWholesalerDistribution centerDistribution centerFilling & packagingFilling & packaging

Events

Traditional In-Transit Monitoring Market

Events

Events

Within the Virtual Four Walls of the ManufacturerWithin the Virtual Four Walls of the Manufacturer


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Expanding In-Transit Monitoring Market

Regulatory Guidance Pushing Cold Chain Visibility Across the Entire Supply Chain

Manufacturing plantRaw materialsHealthcare facilityWholesalerDistribution centerFilling & packagingManufacturing plantManufacturing plantRaw materialsRaw materialsHealthcare facilityHealthcare facilityWholesalerWholesalerDistribution centerDistribution centerFilling & packagingFilling & packaging

Events

Last Mile DistributionRaw Material / Manufacturing

Events

Traditional In-Transit Monitoring Market

Events

Events E

vents

USP General Chapter <1079> Published August 1, 2005“Manufacturers and Distributors should work together to establish proper distribution and

product-handling requirements for the purpose of ensuring appropriate product maintenance in transit”.


How do you tell which vial has been temperature abused and is no longer Potent? Efficacious? Safe?


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


Thermal Container Development and Qualification

CQ/DQOQPQ


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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1. Understand the product’s temperature stability for transport

2. 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

The 10 Step Process to a Qualified Container


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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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• 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

Families of Temperature Sensitive Pharmaceuticals


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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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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 HazMat)

• Physical quality variability

• Self-contained units have 48 hour life before refueling or re-icing

• Pick up / return charges

Active Systems


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Passive Temperature Control Transport Options

Insulated Containers

Gel/ice packs

Dry Ice


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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

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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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

Passive Systems


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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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Conduction is the process by which heat energy is transmitted throughcontact 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.

Controlling Heat Transfer – The Key To Cold Chain Maintenance

3 types of heat transfer:


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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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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, Pre-qualified, 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• Calendar Dating• Temperature at Origin• Temperature at Destination• Daily Forecasts / Weather Mapping• Formulas• Software Algorithms


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Dedicated Summer & Winter Configurations» Summary

• 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

• 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

• 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

• 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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1. Understand the product’s temperature stability for transport

2. 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

The 10 Step Process to a Qualified Container


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Thank You

© 2008 Tegrant Corporation, ThermoSafe Brands 10 Steps to Thermal Package Qualification Kevin...

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