Validation of Nondestructive Systems for Monitoring Vacuum Levels in Parenteral Containers

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Validation of Nondestructive Systems for
Monitoring Vacuum Levels in Parenteral Containers
PDA International Congress February 16, 2004

• Dr. James Veale, President
• Lighthouse Instruments

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Todays Agenda

• About Lighthouse Instruments
• Motivations for Developing New Leak Detection
  Technologies
• Laser Spectroscopic Methods for Leak Detection in
  Sterile Products
• Overview of Optical Technology
• Measuring Pressure and Oxygen concentration
• Validation and Applications of Systems
• Laboratory and near-line systems
• In-line 100 inspection systems

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Company Overview

• Founded in 1995
• Product development funded by FDA
• Began developing systems 1998
• First oxygen analyzer delivered 2000
• First moisture analyzer delivered 2001
• First pressure analyzer delivered2002
• Introduced 100 leak detection system 2003

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Motivation from Regulatory Agencies Excerpts
from FDA draft guidance documents

• "Sterile Drug Products Produced by Aseptic
  Processing Current Good Manufacturing Practices
• "A container closure system that permits
  penetration of air, or microorganisms, is
  unsuitable for a sterile product. Any damaged or
  defective units should be detected, and removed,
  during inspection of the final sealed product.
• "PAT A Framework for Innovative Pharmaceutical
  Manufacturing and Quality Assurance"
• Manufacturers are encouraged to use the latest
  scientific advances in pharmaceutical
  manufacturing and technology.
• With real time quality assurance, the desired
  quality attributes are ensured through continuous
  assessment during manufacture.

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Motivations from IndustryLimitations of
Existing Methods for In-Process Leak Detection

• Lyophilized Product Package Inspection (leak
  detection)
• Spark Testing
• Evidence of product degradation in some
  biological products
• Only useful for products packaged at full vacuum
• Differential Pressure
• Difficult to detect leaks lt5 microns
• Container must be leaking at time of measurement

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Benefits of Spectroscopic Measurement Methods

• A containers ability to maintain headspace gas
  composition and/or pressure are indicative of
  container closure integrity.
• Changes in the headspace gas composition and/or
  pressure are indicative of a leak.
• Optical measurement methods can
• Monitor gas composition and pressure directly and
  nondestructively
• Rapidly test 100 of the product

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Products Developed with FDA Funding
Benchtop analyzers for Pressure
(Vacuum) Oxygen Moisture
In-line systems for Pressure (Vacuum) Oxygen
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Current US, European and Asian Customers

• Amgen
• Baxter
• Bayer
• Ben Venue
• Biogen
• BMS

• Centocor
• DSM
• Eli Lilly
• Genentech
• H. Lundbeck
• JJ

• King (Parkedale)
• Merck
• Pfizer
• Serum Institute
• Wyeth

US and European Automation Partners

• Genesis Machinery Products
• Bonfiglioli Engineering

• BOC Edwards Pharmaceutical Systems

• Diamond Machine Werks

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Publications

• Oxygen Merck
• Templeton, A., et al, Rapid Headspace Oxygen
• Analysis for Pharmaceutical Packaging
  Applications,
• Pharmaceutical Technology, July 2002 pgs 44-61.

• Pressure Genentech
• Lin, T. et al, Application of Frequency
  Modulated
• Spectroscopy in Vacuum Seal Integrity Testing of
• Lyophilized Biological Products, PDA Journal of
• Science and Technology, To Be Published Spring
  2004.

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The Technique

• Frequency Modulation Spectroscopy (FMS)
• Provides 104 increase in sensitivity over NIR
  techniques
• Non-destructive
• lt1 second measurement times
• Simple and reliable
• Versatile
• Scalable

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The Measurement Technology

• Shine laser light through the container headspace
• Tune the laser frequency to match an internal
  absorption frequency of target molecule
• Width of the absorption signal is proportional to
  the total headspace pressure
• Amplitude is proportional to concentration
• Use differential absorption and phase sensitive
  detection techniques to enhance sensitivity

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Overview of Measurement Technique
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Example of Absorption Signal
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Effect of Pressure on Peak Width
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Effect of Oxygen Concentration on Signal Amplitude
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Pressure as a Leak Indicator

• Advantage
• Direct measure of total headspace pressure
• Disadvantage
• Requires some moisture to be present
• All lyo products have some residual moisture

Oxygen as a Leak Indicator

• Advantage
• Doesnt require moisture
• Disadvantage
• Not a pressure measurement
• Assumes leak occurs in air

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Validation of Analyzers

• Method Validation
• USP 24 General Test lt1225gt
• Accuracy, Precision, Linearity, Specificity, LOD,
  LOQ, Ruggedness
• Equipment Qualification
• Use NIST traceable standards for OQ
• Performed side by side comparison with validated
  methods for PQ

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Pressure Measurement Precision
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Pressure Measurement Accuracy
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Pressure Measurement Linearity
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Validation Summary
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Case Study Evaluation of Packaging Components

• The Problem
• Gain insight into failure rate of packaging
  components used for lyophilized products
• The Experiment
• Evacuated 1,000 15cc vials to 0.5 torr
• Stoppered and removed from chamber
• Measured pressure at 1, 5 and 7 hour intervals

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Case Study Packaging Components

• The Results
• Only one vial found to be leaking (0.10)
• Leak rate 5.5x10(-4) ccs (1 micron pore
  diameter)
• Large enough for microbial ingress

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In-Line Measurements
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VISTA Top View
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Pressure Data Product
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In-line Performance Data Standards
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In-line Performance Data
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Performance Summary

• Accuracy /- 10 torr
• Precision lt 2
• Linearity
• 1.02 slope
• 0.99 linear correlation coefficient
• Range of Measurement
• 0 to 0.5 atm (380 torr)

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In Summary

• Collaborating with FDA, PDA and Pharmaceutical
  Industry to bring novel nondestructive package
  inspection technologies to market.
• Successfully developed and validated benchtop and
  in-line systems for oxygen, moisture and vacuum
  (leak) detection.
• Spectroscopic methods for leak detection will
  allow a broader range of products to be tested.