PHARMACEUTICAL PACKAGE INTEGRITY EVALUATION – MICROBIOLOGY, GUIDANCE AND STRATEGY Don Singer GSK

IVT Microbiology Week Philadelphia, PA August, 2014

I. AN INTEGRATED APPROACH

Product

Package

Purity

Critical quality parameter = the package

Primary packaging process is critical to product

design robustness

EVALUATE DESIGN

EVALUATE DESIGN

CONSIDERATIONS FOR EVALUATION

Components Sealing Product Headspace

EVALUATE DESIGN

EVALUATE DESIGN

EVALUATE DESIGN

PACKAGE INTEGRITY

Purity

Leakage

WHAT IS A LEAK?

A breach in a package wall, or a gap between

package components capable of permitting the passage of gas or liquid.

Common perception is a hole of a certain diameter or a channel of certain diameter and length. Leaks that occur naturally are rarely dimensionally uniform. They are complex, multi-cavity tortuous paths.

MICROBIOLOGY PERSPECTIVE

COLLABORATION

RELEVANCE

PACKAGE INTEGRITY = PRODUCT PROTECTION

Sterile Product Package Integrity keeps product

contents in their container Prevention from environmental contaminants

Microorganisms Reactive gases Other substances

HISTORICAL ORIGIN OF CONCERN

Early 1970’s IV manufactured and filled in glass bottles with

aluminum screw caps fitted with elastomeric liners (commonly used at that time).

2000-8000 cases of bloodstream infection

(septicemia) leading to thousands of deaths Traced to contaminated coolant water that entered

through the cap threads during terminal sterilization cooling cycle

MICROBIOLOGY AT THE FOREFRONT

Sterility was lost due to package design and

process mismatch

Container and closure integrity was a highly visible issue

Microbiological methods and physical test approaches were considered

MICROBIOLOGY AND CONTAINER CLOSURE INTEGRITY TESTING

Led to the development of a microbial challenge

test method

Seal force evaluation

Many other physical methods considered – dependent on package type

II. INTEREST IN CONTAINER CLOSURE INTEGRITY EVALUATION BEGINS

PDA published Technical Report 27 in 1998 FDA published guidance for Container Closure

Systems for Packaging Human Drugs and Biologics in 1999

USP published general information chapter <1207>

Sterile Product –Package Integrity Evaluation

PDA TR 27 PHARMACEUTICAL PACKAGE INTEGRITY

A more definitive and detailed presentation about

evaluating barrier qualities of a pharmaceutical package (replacing Bulletin No. 4 – Aspects of Container/Closure Integrity)

Adds discussion about any non-porous barrier system.

Emphasis on sterile products

TR 27 CONTENTS

Assurance Through Product Life Cycle Package Integrity and Leak Rate Specifications Test Method Selection (sensitivity and other criteria Methods of Establishing Microbial Package Integrity

(microbial challenge vs physical tests) Decision Tree Leak Test Methods

FDA GUIDANCE – CONTAINER CLOSURE SYSTEMS FOR PACKAGING HUMAN DRUGS AND BIOLOGICS

Table 3 Information that should be submitted in an original application for any drug product

Suitability: “Protection (by each component and/or container closure system) from solvent loss or leakage, microbial contamination (sterility/container integrity)”

E. Drug products for injection and ophthalmic drug

products “Injectable drug products require protection from

microbial contamination (loss of sterility or added bioburden)”

USP <1207> ORIGINAL

Purpose: maintenance of microbiological integrity of sterile product packaging

Product Life cycle relevance Physical and microbial testing implied in early

development of products, yet physical are preferred Recommended comparison of microbial and

physical methods Types of physical methods and selection approach

FDA GUIDANCE – CONTAINER AND CLOSURE SYSTEM INTEGRITY TESTING IN LIEU OF STERILITY TESTING AS A COMPONENT OF THE STABILITY PROTOCOL FOR STERILE PRODUCTS

2008 Sterility is considered a stability characteristic in

sterile products Sterility test has limitations when used for product

stability evaluation Alternative methods, such as container and closure

integrity testing, may be more reliable “Sterility tests are not recommended as a

component of a stability program…confirming sterility through a product’s shelf life”

NEW USP <1207> IN PF SEP-OCT 2014

<1207> Sterile Product – Package Integrity Evaluation Introduction

Package Integrity and Test Method Selection <1207.1>

Package Integrity Leak Test Methods <1207.2> Package Seal Quality Test Methods <1207.3>

WHAT IS USP <1207> ALL ABOUT?

Sterile Product Package Integrity defined Container closure systems defined

Is absolute integrity realistic?

Leakage versus permeation

What are leaks?

<1207.1> PACKAGE INTEGRITY AND TEST METHOD SELECTION

Integrity verification occurs during product life cycle phases

Fit for purpose components, measurement consistency, control of assembly

Impact of manufacturing process

Deterministic and probabilistic methods

How to determine Limit of Detection

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

DETERMINISTIC AND PROBABILISITIC

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 ---

<1207.2> PACKAGE INTEGRITY LEAK TEST TECHNOLOGIES

<1207.3> PACKAGE SEAL QUALITY TEST METHODS

Unique to seal quality only Does not ensure whole package integrity Torque test Burst test Residual seal force test

PDA TRXX A new report,“Pharmaceutical Package Integrity

Testing: Industry Challenges, Technology and Advancement”

“The content covered by USP <1207> …will serve as the primary informational reference chapter focusing on the basics of understanding package integrity and the current best practices in sterile product package integrity evaluation and integrity testing.”

“New report should build upon the package integrity basics established by USP <1207> by focusing on more advanced issues related to pharmaceutical package integrity.”

PDA TRXX – DRAFT OUTLINE

Introduction Purpose and scope Background History

Glossary Package integrity: Challenges methodology Package integrity: Challenges design Technologies: Emerging Technologies: Existing but used in new way Decision Tree Future Directions

III. STRATEGY FOR SELECTION AND USE OF INTEGRITY TEST METHODS

Guidance, education and learning about available methods

LIFE CYCLE APPROACH

Three phases of life cycle may indicate different

concerns, different criteria, leading to different methods

NO SINGLE METHOD FOR ALL PACKAGES

Practical approach Use available expertise, guidance

WHAT ARE COMMON METHODS/TECHNOLOGIES IN USE?

Deterministic

Electrical conductivity and capacitance test

Laser-based headspace analysis

Vacuum decay Pressure decay Mass flow Tracer gas (vacuum

mode)

Probabilistic

Microbial challenge Liquid tracer (e.g. dye) Bubble test Tracer gas (sniffer mode)

HIGH VOLTAGE LEAK DETECTION

VACUUM DECAY

LASER-BASED HEADSPACE ANALYSIS

MICROBIAL CHALLENGE- LIQUID IMMERSION

LIQUID TRACER – DYE INTRUSION

WHAT ARE REGULATORS ASKING FOR?

Validated method

Appropriate controls – positive and negative

Appropriate Limit of Detection

Relevant challenge of container to conditions of storage and distribution

Rationale for number of units tested

ENSURING EVALUATION IS ADEQUATE

Practical method selection

Intent to assure integrity

Relevant to Individual Package

Thank You