Proposed revisions to USP STERILE PRODUCT - · PDF fileProposed revisions to USP STERILE PRODUCT - PACKAGE INTEGRITY EVALUATION Presented at the PDA Europe Parenteral Packaging Conference

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

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



Time frame

Current events Physical leak tests Microbial leak tests

1950s 1960s

Ampoule tip crack concern

Methods published: • Dye ingress • Radionuclide liquid

tracer • Helium spark

---

1971 Glass LVP global recall – microbial

contamination due to CCI failure

--- Microbial ingress risk described in several publications.

• 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.



Time frame

Publications, Guidances

Physical leak tests Microbial leak tests

1983 PDA Bulletin No. 4, Aspects of CCI

Bulletin names: • Vacuum retention • Vacuum chamber • Internal pressure • Dye immersion • Seal force

Bulletin names: • Static challenge • Aerosol challenge • Immersion

challenge

1998 USP <1207> Sterile product packaging –

Integrity evaluation

Physical tests are named. No details are given.

Microbial challenge tests are named. No details are given.

1998 PDA Technical Report 27

Pharmaceutical package integrity

Numerous physical test options are described.

Microbial challenge tests are described.


Time frame

Publications, Guidances

Physical leak tests Microbial leak tests

2008 FDA guidance: Container and

Closure System Integrity Testing in

Lieu of Sterility Testing as a

Component of the Stability Protocol for

Sterile Products

Encouraged using properly validated physical or chemical integrity tests …

…or microbiological container and closure system integrity tests

…instead of sterility tests to demonstrate the potential for product contamination.

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

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.


• 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


• TECHNOLOGICAL ADVANCES

– Product-packages are more complex. – Better leak testing instrumentation is now

commonly available. – New methods are being developed.



• 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




► 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



► 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


► 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


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.



► 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


► Product life cycle testing 3 Phases

1. Product package development and validation

2. Routine manufacturing

3. Marketed product stability


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.



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



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



► 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


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


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



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.”



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)



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



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



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)



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)



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?



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?



► 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

► 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


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




validation

Leak test methods Seal quality test methods

► 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


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


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


► 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


► 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




validation Leak test methods

Seal quality test methods

► 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


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


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

manipulation

Considerable test sample

preparation and/or manipulation

Risk of error - LOW Risk of error - HIGH

Proposed Changes SUMMARY

NEW: Methods are categorized as either deterministic or probabilistic

Deterministic methods Probabilistic methods Electrical conductivity and capacitance test (HVLD)

Microbial challenge

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 ---


NEW: Each method is fully described, along with appropriate testing applications, with references.

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 tolerate, and still meet specs?

Gas headspace preservation 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


NEW: Test selection factors are fully described.

Current <1207> NEW USP chapter

Method validation requirement is stated, no guidance offered

Details added: • Instrument qualification requirements • Method validation requirements

Only one type of complex package described (dual chamber)

More fully explores CCI as a function of: • Package designs • Package materials • Product contents

Product life cycle CCI testing is discussed

More fully explores: • Life cycle application • Regulatory demands


NEW: Concepts previously introduced are fully explored.

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>


MOST IMPORTANT The relationship between microbial challenge testing and

physical testing is explained, and when/how each are used.

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


NEW: Seal quality tests added

► 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.


► 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


Thank you!


Documents

Proposed revisions to USP STERILE PRODUCT - · PDF fileProposed revisions to USP STERILE PRODUCT - PACKAGE INTEGRITY EVALUATION Presented at the PDA Europe Parenteral Packaging Conference