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1. Packaging Validation - 101
An introduction to Packaging Validations per ISO 11607 Part 1

2. Agenda
• Introduction/overview of ISO 11607
• Determining an appropriate sample size for testing
• Writing the validation protocol
• Developing the test plan
• Test method options
• Family grouping and worst-case considerations
• Creating the appropriate samples

3. ISO 11607
• Introduced in 2006
• Divided into 2 parts
• Part 1 – Requirements for materials, sterile barrier systems
and packaging systems
• How to make and validate packaging for sterile barrier systems
• Part 2 – Validation requirements for forming, sealing and
assembly processes
• How to perform process validations
• Packaging validations and packaging process validations are
required.
• Guidance on ISO 11607 is included in ISO 16775.

4. Sample Size
ISO 11607 Part 1
ISO 16775
“The sampling plans used for selection and testing of
packaging systems shall be applicable to the package systems
being evaluated. Sampling plans shall be based upon
statistically valid rationale.”
“sample size taking into consideration that the number of units
to be tested should be based upon a statistically valid rationale
(see Annex L) ”

5. Sample Size
The right sample size depends on many factors
The reasons why the number was chosen may be more
important than the actual number selected.
 Cost considerations (e.g., maximum budget, desire to minimize cost)
 Established process variability
 Process controls
 Minimum acceptable level of deviation (confidence level)
 Variability within the population
 Sampling method
 Sampling frequency
 Number of samples available (lot size or limited batch)
 Test chosen (variable or attribute)
 Historical data showing trends or defect frequency
 Test method sensitivity
 Expected % defective in the lot
 Detectability of the expected defect

6. Different approaches to sample size
Risk Priority Number (RPN)
• Use a risk scale to assign risk priority number
• Convert RPN to desired confidence and reliability intervals
• Use Non-parametric Binomial Reliability Demonstration Test to convert CI/RI to
sample size
Acceptable Quality Level (AQL) ISO 2859-1
• Determine lot size
• Define non-conformity
• Determine desired AQL
• Select sampling plan (single/double, normal/inspection)
• Select inspection level (based on risk)
• Select sample size code letter (based on lot size & inspection level)
• Look up sample size in table based on AQL
Custom Statistical Formulas

7. Attribute vs. Variable Data
The type of data can affect your sample size considerations

8. It all starts with a plan
You need a plan in place before you can start any validation.
A validation protocol is the written plan that tells the story:
• What you are doing
• Why you are doing it
• How you will do it
• When you will do what
• Where you expect the outcome to lead you
• Tossing in a bunch of test data in a submission file is a
guarantee to get a letter from the FDA.
• Tell the story in a clear and concise manner – then do what
you said you were going to do.

9. Validation protocol
Method
Selection
Justification
What are you doing?
• Device Description
• Packaging description
• Tests performed
• Time points for testing
• Sample Size
• Aging conditions
Test Plan
Sample
Size
How will you do it?
• Condition of samples
• How to run tests
• How to interpret the results
Time
points
Aging
Conditions
Why are you doing it?
• Why choose those tests?
• Why choose that
acceptance criteria?
Acceptance
Criteria

10. Packaging Tests
 Sterilization
 Handling
 Distribution
 Storage
 Include all materials – IFU,
labeling
Evaluated
through all
intended
processes

11. Test Plan
• You must demonstrate
• Overall effectiveness of the
packaging system
• The sterile barrier system (SBS)
effectiveness using 3 properties
• Through the expected use by date

12. Strength Integrity Microbial Barrier
Seal Peel Visual Inspection F1608
Burst Test Dye Migration Microbial challenge
Creep Test Bubble Emission Gurley Nonporous
Mass Extraction F2638
Dye Immersion
Packaging Test Summary

13. Basic Validation Plan

14. Test Method Key Points
• Any test method used needs to be validated for use in your
facility and/or with your equipment:
Repeatability – variation within a lab
Reproducibility – variation from lab to lab
Sensitivity – measure of the limits of the test method
• Precision and bias statements that can be found in the
standards can help assess any variability found in validation
results.
• Some test methods are actually a process that prepares
materials for evaluation by other test methods.

15. Distribution
Distribution Testing simulates physical hazards a package
encounters throughout the shipping and distribution
environment.
These hazards include:
• Temperature
• Humidity
• Altitude
• Shock
• Vibration
• Compression

16. Distribution
Climatic
stressing
Cold
Tropical
Desert
Mimic changes
in temp during
shipping
Drop / Shock
Manual
handling and
moving through
the warehouse
Impacts from
flat objects
(floor)
Compression
Under load
during
transportation
and storage
Vibration
Long haul
trucks on
highway
Intercity
delivery
through town
Impact
Impacts from
non-flat objects
Altitude
Changes in
pressure as
altitude
changes during
transportation
over high
mountain pass
or
unpressurized
cargo in aircraft

17. Distribution Simulation – ASTM D4169 DC13

18. Test Method Options - Strength
• 1 inch or 15 mm coupon cut from seal and separated
• Acceptance criteria is material dependent only
• Results include force to separate and failure mode
Peel
Strength
• Whole package inflated to failure
• Acceptance criteria depends on material, shape and size
• Results include pressure at burst and failure location
Burst
Strength

19. Test Method Options – Peel Strength Video

20. Test Method Options – Burst Strength Video

21. Test Method Options – Integrity
• Whole package
• 250 micron defect size
• Inflate to pressure and examine for bubbles
• Result is pass or fail
Bubble
Emission
• Seal only
• 50 micron defect size
• Dye on seal, will migrate through channels
• Result is pass or fail
Dye
Migration

22. Test Method Options – Bubble Video

23. Test Method Options – Dye Migration Video

24. Test Method Options – Microbial Barrier
• Material test for porous
• 2 x 2 inch – no seals or labels
F1608
• Material test for non-porous
• 2 x 2 inch – no seals or labels
Gurley
Non-
porous
• Whole package test
• Option for smaller packages and special cases
Aerosol
Challenge

25. Test Method Options – F1608 Video

26. Test Method Options – Gurley Video

27. Test Method Options – Aerosol Video

28. Selecting appropriate tests
Strength
• Peel or burst are used, depends on historical data
• AC for burst need to be package specific as burst pressures will vary based on size
• Peel tests use a common sized coupon so the same AC can be used for multiple sized
packages of the same materials
Integrity
• Bubble is preferred as it is a whole package test and the most common failure mode in a
packaging validation is a hole in the package which would not be picked up in a dye test
• For containers may want to explore Container Closure Integrity Test methods
Microbial Barrier
• If porous – ASTM F1608 is recommended
• If non-porous – ASTM F2981 Gurley Non-porous verification
• If container – may need to consider aerosol challenge

29. Family grouping
When multiple products are similar, they can be grouped together into a family.
Word of caution – the family sticks together for both the good and the bad

30. Worst-case Considerations
Stress to seals during sterilization
Device weight
Unprotected vs. protected sharps
Shape of device (complex vs. simple)
Method of boxing
Size ratio to packaging
Storage conditions

31. Creating the validation samples
• Final configuration – final packaging
• Include all accessories
• IFU
• All protective packaging
• Worst-case conditions
• Low parameters for sealing
• 2X sterilization
• Send to the lab

32. Shipping the validation samples
Distribution boxes should be overpacked to protect the
shippers when sent individually. (Pallet shipping may have
sufficient protection). Carefully label any overpack and test
boxes so the receiving group and lab know which box to test
and don’t accidently open a shipper that needs to be tested
or test an overpack box.

33. That’s a wrap
Jennifer Gygi, B.S., RM(NRCM), SM(NRCM)
Nelson Laboratories
Expert Technical Consultant
801-290-7847
jgygi@nelsonlabs.com

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