Container Integrity

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Container Integrity

Steve Richter, Ph.D.
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Definitions

• Closure
• Leak (all packages leak to some extent)
• Leakage (ex unit sccs)
• leakage rate SOP
• Package Seal
• Seal
• Tortuous Path

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Regulations/Standards

• CFR (Code of Federal Regulation)
• PDA (Parenteral Drug Assoc.)
• AOAC (Assoc. of Official Analytical Chemists)
• BAM (Bacterial Analytical Manual)
• ASTM (Am. Soc. for Testing Matls)
• USP (United States Pharmacopoeia)
• EP (European Pharmacopoeia) Self Sealing Test

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Standards/Regulations Summary

• CFR - Section 211.94 - Container closure systems
  shall provide adequate protection against
  foreseeable external factors in storage and use
  that can cause deterioration or contamination of
  the drug product.

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Standards/Regulations Summary

• PDA - Report that reviews issues of
  pharmaceutical product package integrity and
  provides guidance for evaluating the barrier
  qualities of a pharmaceutical package. (Technical
  Report 27, 1998 Supplement Supersedes PDA
  Monograph 4)

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Standards/Regulations Summary

• AOAC - Helium Leak Test, Official Method 984.36
  (See also PDA)
• BAM - Examination of Containers for Integrity
  (Ch. 22)
• Dye, Leak, Microbial
• ASTM E165-94 Liquid Penetrant Examination

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Nomograph for Use With Seam Projector
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Standards/Regulations Summary

• USP - Section lt661gt - Outlines the physical test
  methods of packaging dry oral dosage forms not
  meant for constitution into solution.
• (High/low density
• polyethylene and
• glass containers)

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Standards/Regulations Summary

• USP - Section lt671gt Containers -Permeation
• Proposed USP General Chapter Section lt1207gt (In
  Progress) Sterile Product Packaging Integrity
  Evaluation

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Validation of Package Integrity

• Design (Selection)
• In-Process Control (Sealing Operation)
• Product Testing
• Release Testing
• Stability Testing

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Validation of Package Integrity

• Leak Rate Specifications
• Selection of Testing
• Method Validation
• Sensitivity is Key

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Challenge Methods Overview

• Microbial (Small Bacteria)
• Direct Incubation or
• Pressure/Vacuum or
• Aerosol
• Sterility Testing on Final Product

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Challenge Methods Overview

• Physical
• Dye (Pressure/Vacuum)
• Bubble Test
• Do Microbial and Physical Correlate?

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Microbial Challenge

• Direct Incubation - Challenge Containers are
  Immersed in a Microbial Suspension (Pressure
  Differential) and Incubated (Container Contents
  Must Support Microbial Growth).

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Microbial Challenge

• Aerosol - Containers are Subjected to a
  Microbial Aerosol (B. subtilis spores). The
  Containers are Incubated and Observed for
  Microbial Growth (Container contents must support
  microbial growth) ASTM F1585-95, F1608-95.

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Dye Challenge

• Pressure Differential - Containers are Immersed
  in a Dye Solution and Subjected to Pressure and
  Vacuum Variances. Dye Ingress is Determined
  Spectrophotometrically.

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Physical Challenges

• Bubble Test - The package is submerged in water
  or other suitable clear, colorless solvent. A
  vacuum is exerted on the test system, and the
  package is examined visually for evidence of
  gaseous leakage.

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Physical Challenges

• Package Headspace Analysis The headspace content
  is analyzed and monitored for change over time.

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Physical Challenges

• Particulate Transmission - The packages are
  placed in a chamber and subjected to a charged
  aerosolized dust. The units are removed from the
  chamber and examined for dust ingress.

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Physical Challenges

• Helium Mass Spectrometry
• High Voltage Leak Detection
• Lid Deflection
• Liquid Tracer
• Tracer Gas Leak Detection
• Weight Loss/Gain

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Physical Challenges

• Ultrasonic Detection of Gas Flow
• Ultrasonic Imaging
• Vacuum/Pressure Decay
• Vacuum/Pressure Retention
• Residual Gas Ionization
• Visual Inspection
• Volumetric Gas Flow

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Stress Parameters

• Pressure Differentials
• Temperature Variations
• Moisture Variations
• Environmental
• Shock
• Vibration
• Sterilization - USP lt1211gt

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Summary

• FDA Regulations
• USP Requirements
• PDA Guidance
• Test Method Development
• Microbial vs. Physical