Proposed revisions to

USP <1207> STERILE PRODUCT - PACKAGE

INTEGRITY EVALUATION
Presented at the
PDA Europe Parenteral Packaging Conference
Brussels, Belgium 11Mar2014

By: Dana M. Guazzo Ph.D., RxPax, LLC

USP Packaging Storage and Distribution Expert Committee
Excepts from
Sterile Product Packaging -
Integrity Evaluation
Current Status and Future Direction
USP Packaging, Storage and Distribution EC
Oct 4-5, 2012 Meeting, Chicago, IL*

*text color denotes recent modifications

Excepts from
Proposed Revisions to USP <1207>
Sterile Product Package – Integrity Evaluation

Diane Paskiet
USP Packaging, Storage and Distribution Expert Committee

PDA Innovation and Best Practices on Sterile Technology

June 18 -19, 2012
Chicago, IL*
*text color denotes recent modifications
The Evolution of Leak Testing

 Evolution of sterile product package leak

testing
 USP <1207> revision
– Reasons for revision
– Proposed revisions
– Issues raised
 Future direction
The Evolution of Leak Testing

• A key function of packaging is to protect the

product from loss and contamination – i.e., the
package must not leak.

• In earlier days, leak testing was performed in

response to large scale package failure crises.
– 1950s, ‘60s Glass ampoule tip crack concerns

– 1971 Glass bottle LVP contamination caused by

closure integrity failure lead to thousands of
deaths and nation-wide product recall
 The Evolution of Leak Testing

Time Current events Physical leak tests Microbial leak tests

frame
1950s Ampoule tip crack Methods published: ---
1960s concern • Dye ingress
• Radionuclide liquid
tracer
• Helium spark

1971 Glass LVP global --- Microbial ingress risk

recall – microbial described in several
contamination due publications.
to CCI failure
 The Evolution of Leak Testing

• Over time, leak tests (especially physical methods)

began to be better understood and more widely
employed.
– 1980s
• Microbial challenge tests became a mainstay for leak
testing, generally used by microbiologists.
• Physical test methods were explored and published.

– 1980s to present
• Various guidance documents were created
– To explain the importance of package protection
– To list and describe leak test options
– To propose how and when such tests are to be performed.
 The Evolution of Leak Testing

Time Publications, Physical leak tests Microbial leak tests

frame Guidances
1983 PDA Bulletin No. 4, Bulletin names: Bulletin names:
Aspects of CCI • Vacuum retention • Static challenge
• Vacuum chamber • Aerosol challenge
• Internal pressure • Immersion
• Dye immersion challenge
• Seal force
1998 USP <1207> Physical tests are Microbial challenge
Sterile product named. tests are named.
packaging –
Integrity evaluation No details are given. No details are given.

1998 PDA Technical Numerous physical test Microbial challenge

Report 27 options are described. tests are described.
Pharmaceutical
package integrity
 The Evolution of Leak Testing

Time Publications, Physical leak tests Microbial leak tests

frame Guidances

2008 FDA guidance: Encouraged using …or microbiological

Container and properly validated container and closure
Closure System physical or chemical system integrity tests
Integrity Testing in integrity tests …
Lieu of Sterility
Testing as a
…instead of sterility tests to demonstrate the
Component of the
potential for product contamination.
Stability Protocol for
Sterile Products Validated tests should
• Use analytical detection techniques
appropriate to the method
• Be compatible with the specific product being
tested.
• Be proven capable of finding leaks
 The Evolution of Leak Testing

1998: USP <1207> and PDA TR 27

• State physical tests are OK to use…
…as long as the physical method is shown to be
“comparable” to microbial ingress.

2008: FDA Guidance

• Does not require a comparison of physical methods to
microbial ingress risk.
Instead, validation data are required demonstrating test
method container closure defect detection capability.
 Revision of USP Packaging Integrity Tests

• WHY?
The world of packaging and leak testing has rapidly evolved, and
greater guidance is needed

• RESEARCH DATA AND EXPERIENCE SHOW

– All leak test methods have pros/cons.
– No one method works for all applications.
– Probabilistic methods (e.g., microbial ingress and dye
tests) are no longer preferred by leak testing experts.
 Revision of USP Packaging Integrity Tests

• WHY?
The world of packaging and leak testing has rapidly evolved, and
greater guidance is needed

• TECHNOLOGICAL ADVANCES
– Product-packages are more complex.
– Better leak testing instrumentation is now
commonly available.
– New methods are being developed.
 Revision of USP Packaging Integrity Tests

• WHY?
The world of packaging and leak testing has rapidly evolved, and
greater guidance is needed

• REGULATORY DEMANDS
– More testing throughout the product life cycle is
expected.
– Well-validated, adequately sensitive physical
leak test methods (without microbial ingress
comparison) are permitted and preferred.
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Scope and application

► Sterile pharmaceutical dosage form packages
► Primary container closure systems
► Packages of nonporous, rigid or flexible, materials
► OTHER applications include, but are not limited to:
 Porous flexible packages
 Critical secondary packages
 Sterile API, Intermediates, final bulk volume packages
 Drug/device combination packages
► OUTSIDE the scope, but chapter concepts still apply:
 Sterile medical device packages
 Sterile diagnostic product packages
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Introduction
 “Package integrity” = “container closure integrity” (CCI)
“… the absence of package leakage greater than the product
package maximum allowable leakage limit.”
 “Integral package”
• Prevents microbial ingress (ensures sterility)
• Maintains product CQA within P-C label claim specs
o Limits loss of product contents
o Prevents entry by debris or detrimental gases
 Leak Tests (CCIT) and Seal Quality Tests (SQT) included
• SQT characterize and monitor seal quality and consistency
 Permeation tests are not included
 USP <1207> Proposed Revision

Introduction

 Regarding current published standard tests (e.g., ISO/ASTM)

• Reader is directed to “existing methods and technologies
supported by peer-reviewed publications and internationally
recognized standards, based on sound scientific package
testing principles.”

• The USP “encourages the development and implementation of

novel, innovative test methods.”

• Any chosen CCIT or SQT (even standard methods) require

optimization and validation.
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Product life cycle testing

3 Phases
1. Product package development and validation

2. Routine manufacturing

3. Marketed product stability

 USP <1207> Proposed Revision

Product life cycle testing

Phase 1. Product package development and validation

 Product package profile
• End use
• Stability requirements
• Method of manufacture
• Anticipated storage, shipment, distribution environment
 Package mat’ls, sources, dimensional tolerances chosen
 Package processing steps and max. limits defined
 Package filling, assembly, terminal sterilization defined
 Package robustness for storage, shipping, distribution est.
 USP <1207> Proposed Revision

Product life cycle testing

Phase 2. Routine manufacturing testing

 Procedures & controls can MINIMIZE, but not eliminate, CCI
failure risk
 “The goal…is to prevent, or identify and remove those failures of
greatest concern, precluding shipment of non-integral CC that risk
product contamination or loss.”
 CCI to be verified post major changes
• Package design, materials or manufacturing
 Nondestructive leak tests preferred in some cases
• Fusion-sealed packages: 100% CCIT
• Vacuum sealed packages: check post time for vacuum
• Critical gas headspace: check for gas content
 USP <1207> Proposed Revision

Product life cycle testing

Phase 3. Marketed product stability testing

 CCIT (not sterility tests) recommended to ensure package integrity
over long-term storage

 CCIT cannot replace initial sterility test

 Tests should be able to verify absence of package damage or

deformation that could result in loss of product or sterility

 Tests that indirectly test for leakage may be acceptable

e.g., headspace content verification
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

10 Leak test selection criteria

1. Package contents
 Gaseous vs. vacuum v. no headspace
 Liquid vs. dry product
 Proteinaceous vs. small molecule active and
excipients
 Electrically conductive vs. nonconductive product
 USP <1207> Proposed Revision

10 Leak test selection criteria

2. Package design and materials of construction

 Flexible vs. rigid
 Nonporous vs. porous
 Electrically conductive vs. nonconductive
 Contiguous containers vs. multiple seal types and
locations
 USP <1207> Proposed Revision

10 Leak test selection criteria

3. Product package maximum allowable leakage

 “Most package types demonstrate at least miniscule
gaseous leakage plus permeation even when optimally
designed and assembled. …with the exception of [well-
sealed] glass ampoules…”

 “…the maximum allowable leakage into and out of

intact packages should be so minimal that there is no
impact on product safety, and no consequential impact
on the product’s physicochemical stability.”
 USP <1207> Proposed Revision

10 Leak test selection criteria

3. Product package maximum allowable leakage

3 categories of max allowable leakage
1. Liquid leakage must be blocked
• preserving product contents and product sterility
2. Headspace gas or pressure must be preserved
• ensuring product stability and sterility
3. Microbial ingress must be prevented, while still
permitting gas/liquid flow
• ensuring product sterility (e.g, Tyvek® barrier material)
 USP <1207> Proposed Revision

10 Leak test selection criteria

4. Deterministic vs. Probabilistic methods

 Deterministic
• Leakage is based on predictable fluid flow
mechanics (gas/liquids)
• Leak detection relies on P-C technologies
• NON-probabilistic
• Validatable
• Preferred if desired outcome permits
 Examples:
Tracer gas, Vacuum decay, Electrical conductivity
 USP <1207> Proposed Revision

10 Leak test selection criteria

4. Deterministic vs. Probabilistic methods cont’d

 Probabilistic
• Leakage is based on unpredictable, random
events
• Leak detection often relies on human
interpretation
• Error prone
• NOT preferred unless desired outcome
demands
 Examples
Microbial ingress, Tracer liquid (dye), Bubble
 USP <1207> Proposed Revision

10 Leak test selection criteria

5. Method limit of detection

 LOD : The smallest leak rate/size reliably detected given
the product-package system
• Determined experimentally using positive controls
(with-leak packages) and negative controls (no-leak
package)
• LOD data allow method categorization via a LEAK
SIZE CLASSIFICATION INDEX
o Class 1 (Lowest LOD)
o Class 6 (highest LOD)
 USP <1207> Proposed Revision

10 Leak test selection criteria

6. Method largest leak detection capability

 Can the method find larger leaks of concern?
• A method with low LOD may not find largest leaks

 Method development efforts to include detection of

larger defect sizes and types (package failure modes)
 USP <1207> Proposed Revision

10 Leak test selection criteria

7. Method Outcome
 What information does the method provide?
Leak location? Leak size?
Gas flow rate? Headspace content?

8. Quantitative vs. Qualitative

 Does the method allow for leak size/rate
measurement, or simply leak detection?
 USP <1207> Proposed Revision

10 Leak test selection criteria

9. Nondestructive vs. destructive

 Does the test prevent product-package
commercialization or distribution into the clinic?
 Does the test allow the product-package to be used for
other lab tests?

10. On-line vs. off-line

 Does testing speed/handling permit on-line
implementation?
 Is the test primarily for laboratory testing?
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method
development and validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Leak Test Instrument Qualification, Method

Development and Validation
 NOT best-practices for P-C methods
1. Side-by-side comparison to microbial ingress
2. Misapplication of standard methods
Ø Using a standard method without full method development
and validation specific to product-package

3. Reliance solely on instrument qualification tests

Ø e.g., Relying on the lowest concentration of dye detected
by UV/Vis for method LOD verification
 USP <1207> Proposed Revision

Leak Test Instrument Qualification, Method Development and Validation

 Best-practice for P-C methods

1. Qualify equipment performance
2. Develop and validate method
• Requires negative and positive controls (no-leak, with-leak
packages)
o Various leak sizes/types
o Leaks in various package locations
o Leaks at product- and headspace-level
• Validation performed using randomly ordered tests
 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Leak test methods

 2 groups: 1) Deterministic 2) Probabilistic
 USP <1207> inclusion based on supportive, relevant
DATA in:
• Peer-reviewed journal publications
• P&B studies in international test standards (e.g., ASTM)

 The reader is NOT restricted to these methods

 USP is continually revised, therefore, readers are

encouraged to publish package test research
 USP <1207> Proposed Revision

Leak test methods

 Each leak test method is fully documented

1. Description
• Destructive or nondestructive
• Mode of leak detection
• Qualitative or quantitative
• Product-package testing application (broad scope)

2. Method highlights
3. Application
• Details product- package, and product life cycle testing uses

4. Leak size class detection limit

• Refers to the Leak Size Classification Index
 USP <1207> Proposed Revision

Leak test methods

 Each leak test method is fully documented – cont’d

5. Test equipment requirements

6. Test parameters to be monitored, controlled

7. Qualification considerations
• Test equipment functionality and method performance verification

8. Additional considerations
• Risks of incorrect package test results inherent in the method

9. References
 USP <1207> Proposed Revision

► Leak test methods – Deterministic

 Electrical conductivity leak test (aka HVLD)

 Laser-based gas headspace analysis

 Mass extraction

 Pressure decay leak test

 Tracer gas detection leak test (vacuum mode)

 Vacuum decay leak test

 USP <1207> Proposed Revision

► Leak test methods – Probabilistic

 Bubble leak test

 Tracer gas leak test (sniffer mode)

 Tracer liquid leak test

 Microbial challenge, aerosol exposure

 Microbial challenge, immersion exposure

 USP <1207> Proposed Revision

► Proposed USP <1207> Outline

 Scope and application
 Introduction
 Product life cycle package testing
 Leak test method selection criteria
 Leak test instrument qualification, method development and
validation
 Leak test methods
 Seal quality test methods
 USP <1207> Proposed Revision

► Seal quality test methods

 USP <1207> inclusion based on supportive, relevant
DATA in:
• Peer-reviewed journal publications
• P&B studies in international test standards (e.g., ASTM)

 The reader is NOT restricted to these methods

 USP is continually revised, therefore, readers are

encouraged to publish package test research
 USP <1207> Proposed Revision

Seal quality test methods

 Purpose
• To properly characterize and monitor pkg seal quality
• To ensure consistency of pkg assembly

 Methods cited
• Airborne ultrasound ASTM F3004
• Cap application/removal torque ASTM D2063, D3198, etc.
• Package burst test ASTM F1140, F2054
• Package seal strength (peel) test ASTM F88
• Residual seal force Stoppered, capped vials
Proposed Changes SUMMARY

NEW: Methods are categorized as either

deterministic or probabilistic
Deterministic methods Probabilistic methods
Reproducible Not reproducible

Sensitive Insensitive

Highly instrumental Little or no instrumentation used

Quantitative test result outcome Qualitative, interpretive results

Minimal test sample preparation or Considerable test sample

manipulation preparation and/or manipulation

Risk of error - LOW Risk of error - HIGH

Proposed Changes SUMMARY

NEW: Each method is fully described, along with

appropriate testing applications, with references.

Deterministic methods Probabilistic methods

Electrical conductivity and Microbial challenge
capacitance test (HVLD)

Laser-based headspace analysis Liquid tracer tests (e.g., dye)

Pressure decay Bubble tests

Tracer gas (vacuum mode) Tracer gas (sniffer mode)
Vacuum decay ---
Mass extraction ---
 Proposed Changes SUMMARY

NEW: Test selection factors are fully described.

Leak test selection factors Options
Package contents Liquid, solid, gas, vacuum
Package materials of construction Metal, glass, plastic, composite
Package design Flexible/rigid
Closure mechanism
How much leakage can the product Gas headspace preservation
tolerate, and still meet specs? Liquid content preservation
Microbial ingress prevention
What does the leak test measure? Gas leak rate
Liquid migration/presence
Microbial growth
Sensitivity (leak size detection range) <0.1 microns to several mm
Test sample preservation Destructive vs. nondestructive
Test method application On-line vs. off-line
Product life cycle phase
 Proposed Changes SUMMARY

NEW: Concepts previously introduced are fully explored.

Current <1207> NEW USP chapter

Method validation requirement is Details added:

stated, no guidance offered • Instrument qualification requirements
• Method validation requirements

Only one type of complex package More fully explores CCI as a function of:
described (dual chamber) • Package designs
• Package materials
• Product contents

Product life cycle CCI testing is More fully explores:

discussed • Life cycle application
• Regulatory demands
 Proposed Changes SUMMARY

MOST IMPORTANT
The relationship between microbial challenge testing and
physical testing is explained, and when/how each are used.
NEW USP chapter

• ELIMINATES the microbial vs. physical method comparison

requirement.
• Recommends using ONLY physical methods, unless:
• no physical method exists
• method outcome demands microbial approach (examples given).
• History text* to explain chapter direction, validating the importance both
physical and microbial testing approaches have played.

*To be part of PF stimuli article, not <1207>

 Proposed Changes SUMMARY

NEW: Seal quality tests added

NEW USP chapter

“Seal quality tests”: Test methods useful for characterizing and monitoring
package seal quality. Not leak tests, but provide additional data regarding
package seal characteristics that may impact package integrity and leakage.
• Test method description, selection, and use included.
o Closure application and removal torque
o Package burst test
o Package seal strength
o Residual seal force
o Airborne ultrasound
 USP <1207> Proposed Revision

► USP Gen. Chapters Packaging, Storage and Distribution EC

► USP <1207> Expert Panel
 Peter Buus Novo Nordisk
 Shu-chen Chen, PhD Amgen
 Ronald Forster, PhD Amgen
 Dana M. Guazzo, PhD RxPax, LLC and USP Panel leader
 Desmond Hunt, PhD USP Liaison
 Lee E. Kirsch, PhD University of Iowa
 Ron Mueller, PhD West Pharmaceutical Services
 Donald Singer, PhD GlaxoSmithKline Bio
 Marla Stevens-Riley, PhD FDA CDER
 David Walker Merck & Co.
 USP <1207> Proposed Revision

► Chapter <1207> Revision Timeline

 Expert Panel Selection 2010 COMPLETE
 Proposed Chapter Prep 2011 ONGOING
 1ST public review in USP PF 2014
 Chapter Revision 2015
 (based on public comment)
 USP Expert Committee approval 2015
 USP Official Chapter 2016
USP <1207> Proposed Revision

Thankyou!