1. Present and Future Changes to the Packaging Industry
Updates from USP, ASTM, ISO

2. Agenda
Overview of changes that have been implemented within the last year and what changes are coming
Pharmaceutical packaging industry changes
USP Guidance chapter <1207> PACKAGE INTEGRITY EVALUATION—STERILE PRODUCTS
Medical device packaging industry changes
ASTM work item method developments and updates.
F1608, F88, F2638,…

3. Introduction What’s the purpose of changing the methods?
Why is it important to change the test methods?
1)Technological advances have improved test method reliability, sensitivity and capabilities not before available.
2) Undetected integrity breaches can lead to crucial drug/device shortages in the industry.

4. Introduction-How are the standards made?
USP- Scientific nonprofit organization setting standards for…drugs… that are enforceable by the FDA.
ASTM –participating members develop high quality, market relevant standards that advance technology and innovation
ISO/AAMI – opportunity to help define the standards for tomorrows healthcare technology

6. USP <1207>
<1207> Package Integrity Evaluation—Sterile Products
<1207.1> Test Method Selection And Validation
<1207.2> Package Integrity Leak Test Technologies
<1207.3> Package Seal Quality Test Technologies
Official August , formally one chapter now 4, increased from a couple pages to 40+

7. <1207> PACKAGE INTEGRITY EVALUATION—STERILE PRODUCTS
“provides guidance on the integrity assurance of nonporous packages intended for sterile pharmaceutical products”
-includes detailed recommendations on selection, validation, and use of leak test methodologies for vials, bottles, ampoules, syringes, cartridges, flexible bags/pouches, etc.

8. <1207> PACKAGE INTEGRITY EVALUATION—STERILE PRODUCTS
Key concept:
Integration of package integrity as a component of the entire product life cycle
Leaks of Concern – a function of the package protection demanded by the product to ensure quality attributes are met through product expiry and use
i.e, product sterility failure, gas exchange failure, or even dosage form escape/exchange (drug pill, powder, suspension, solution, etc)
Previously container closure integrity = microbiologically sound , Now encompasses the absence of all leaks leading to product quality risks.

9. <1207> PACKAGE INTEGRITY EVALUATION—STERILE PRODUCTS
Introduction of Maximum Allowable Leak Limit (MALL)
a leak size that is tolerable for a given product package combination that poses no risk to product safety.
Integrity is assured if the packaging allows no leakage greater than the MALL
Use of the term leakage because there is no such thing as leak free. Its determining what's an acceptable value or MALL.
Leakage is different from Permeation – leakage is the unintentional entry or escape of matter through a defect(breach); permeation is the ability of something to penetrate through a solid barrier – nonporous packaging can permit permeation but considered insignificant.

10. <1207.1> TEST METHOD SELECTION AND VALIDATION
Describes package integrity verification through 3 phases of life cycle
Package development
Product manufacturing
Product shelf-life stability assessment
Provides guidance on how to select, develop, and validate leak test methods
Shelf life – allows you to perform initial test of integrity, place on test, verify integrity at time point and then use for another test. Not appropriate to return to the chamber and continue aging.

11. <1207.1> TEST METHOD SELECTION AND VALIDATION
Test method selection criteria
Contents/Design
Closure type
MALL
Physiochemical or Microbiological
Deterministic/Probabilistic
Method outcome
Design – rigid vs flexible, fixed vs moveable, transparent/opaque
Closure type – mated closures, bonded, or multi dose
Physio – includes both deterministic and probabilistic
Micro – probabilistic
Outcome – presence of leak path, location, rate of leak, quantitative/qualitative

12. <1207.1> TEST METHOD SELECTION AND VALIDATION
Preference for deterministic methods versus probabilistic methods
Deterministic
Probabilistic
Predictable results
Simultaneous events
Physical/chemical endpoint
Random outcome using probability
Quantitative
Qualitative
Non destructive
Mostly destructive
Little to no sample prep
Sample prep required
Deterministic tests have less impact on the results, probabilistic has significant operator intervention increasing the risk for error, or interpretation.
Not to say that by taking a probabilistic method and evaluating it on an instrument giving a value makes it deterministic.

13. <1207.2> PACKAGE INTEGRITY LEAK TEST TECHNOLOGIES
Specific to the selection and use of leak testing methods
Divided into 2 categories: deterministic and probabilistic
Discusses each approach
Pairs each method to a leak size (microns)
Important to understand system suitability and usage of positive and negative controls
Leak size chart in <1207.1> ties gas rate to orifice leak size

14. <1207.2> PACKAGE INTEGRITY LEAK TEST TECHNOLOGIES
Deterministic methods
Probabilistic Methods
“ are capable of detecting leaks at clearly defined and predictable detection limits.”
“are preferred when establishing the inherent integrity of a container closure system”
“ are best chosen when the method outcome requirements demand a specific probabilistic approach”
“are more challenging to design, develop, validate and implement”

15. <1207.2> PACKAGE INTEGRITY LEAK TEST TECHNOLOGIES
Examples of Deterministic tests:
High voltage leak detection (HVLD)
Pressure decay
Mass Extraction
Vacuum decay
Laser based gas headspace analysis

16. <1207.2> PACKAGE INTEGRITY LEAK TEST TECHNOLOGIES
Examples of probabilistic tests:
Bubble emission
Bacterial immersion
Tracer gas detection (sniffer)
Liquid tracer (dye immersion)
The test methodology most appropriate for a particular product-package configuration maybe unable to detect the smallest leak of concern. It is possible the product matrix can interfere with the ability of the test to detect these leaks. Ex: microcapillary suitability sample became clogged over time

17. <1207.3> PACKAGE SEAL QUALITY TEST TECHNOLOGIES
2 page chapter specific to evaluating seal quality tests
seal quality and leak tests work together to ensure package integrity
References ASTM Methods
F1140/F2054
F88
F2063
Does not provide information on the integrity of a package

18. ASTM F1608 Microbial Ranking
Test method published June 2016
Changes included:
Updating the document to allow for other extraction methods
Correct the diagram of the chamber
Issues to be dealt with
Nebulizer

19. ASTM F2097 Design and Evaluation of Primary Flexible Packaging
Test method published June 2016
Changes included:
ISO series
F2981 nonporous material verification
3 new oxygen transmission standards
Round cup peel testing
Nonporous dye migration
2 climatic stressing

20. ASTM D4169 Performance testing of Shipping Containers and Systems
Test method published June 2016
Changes included:
Assurance level changed to Power Spectral Density Levels
More frequency options (doubled)

22. ASTM F88 Seal Peel Testing
Looking at ways of incorporating a new method using trays as they are, no coupons
Looking at the difference between the lbf/in vs. N/mm

23. ASTM F2638 Aerosol Filtration Test
Revision of 2012 document
Updating the exposure of particles from low to high. Currently states to perform high to low which could cause blinding of the sample giving artificially low Pmax values.
Incorporation of mesh screen to prevent collapse of test specimen
Work item

24. ASTM F2096 Bubble Emission Testing
Work item 51617
Looking at possibly starting a new round robin test
General clarification points
Only 1 package size (tyvek/film pouches and similar trays). Porous materials were observed to be seen easier with certain sizes and shapes, be careful of the high pressures ( pop right after reaching pressure point of seeing defect) nonporous – very difficult to find the defects ( stretched around the puncture probe creating smaller defects than intended. Used a much higher pressure to see the defects.

25. DIN 58953-6 Sterile supply part 6
Microbial barrier testing of packaging materials for medical devices which are to be sterilized
Currently in the midst of a round robin test by Germany
Europe/China are looking for a microbial test that has pass/fail criteria

26. Future documents/possible updates?
Validation of packaging test methods:
Work item
Information regarding the process of validating packaging test methods

27. ASTM F1929/3039 Dye Migration Testing
Triton X-100
Scientifically known as Octylphenol ethoxylates (OPE’s)
Submitted to European Chemical Agency (ECHA) as Substance of Very High Concern (Jan 2016)
Suspected to have endocrine disrupting properties in the environment
Possibility of identifying alternative surfactant

28. ISO 11607 May move towards additional conditioning requirements
Reiteration of using acceptance criteria to drive your microbial barrier testing (unless nonporous)
#1 “unless a rational and data can be provided demonstrating that the shorter conditioning requirements have no impact on the test results.”
#2 materials shall have microbial barrier properties which are consistent with the specified ‘acceptance criteria’ unless they meet the criterion of impermeability when evaluated per annex C
#3 Usability testing shall demonstrate that the design requirements have been met, in particular for aseptic presentation.”

29. Conclusion
Multiple changes in all arenas of the packaging industry including both pharmaceutical and medical devices.
The next few years will continue to evolve bring advances in technology and science driving these changes to make our standards better.

30. Questions
Wendy Mach Packaging Section Leader Nelson Laboratories, LLC