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Container Closure Integrity Test Method Development on Vials Stored at -80°C Using Headspace Carbon Dioxide Analysis.

Ken Victor1, Allison Alix Caudill2, James Veale2

  • 1Lighthouse Instruments, LLC., Charlottesville, VA 22902, USA kvictor@lighthouseinstruments.com.

PDA Journal of Pharmaceutical Science and Technology
|March 17, 2022
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Summary
This summary is machine-generated.

Container closure integrity (CCI) testing for cold-stored vials is challenging. New methods detect leaks in frozen vials using carbon dioxide ingress, addressing temporary seal failures common at low temperatures.

Keywords:
Carbon dioxideContainer closure integrityDeep cold storageFrequency modulation spectroscopyFrozen productHeadspace gas analysisMethod developmentUSP 1207−80°C storage

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Area of Science:

  • Pharmaceutical Packaging
  • Material Science
  • Analytical Chemistry

Background:

  • Container closure integrity (CCI) is critical for pharmaceutical product stability, especially for vials stored at sub-zero temperatures (-80°C).
  • Low temperatures impact vial sealing due to rubber stopper glass transition and differential thermal expansion of packaging components.
  • Existing CCI tests at room temperature fail to detect transient leaks that reseal upon warming.

Purpose of the Study:

  • To develop and validate novel methods for CCI testing of frozen vials.
  • To detect leaks that occur specifically under cold storage conditions.
  • To utilize carbon dioxide ingress as a leak indicator in product-filled vials with unmodified headspace.

Main Methods:

  • Two distinct CCI testing methods were developed for frozen vials, employing carbon dioxide ingress.
  • Method 1: Effusive flow detection, suitable for specific storage conditions.
  • Method 2: Diffusive flow detection, designed for different gas flow dynamics.

Main Results:

  • The effusive method detected defects ≥2 µm (laser-drilled) and ≥0.4-0.6 µm (microwire) in glass and plastic vials.
  • The diffusive method detected defects ≥2 µm (laser-drilled) and ≥0.8-2.6 µm (microwire) in glass and plastic vials.
  • The study also investigated the influence of product-defect interactions and storage duration on CCI.

Conclusions:

  • The developed methods provide reliable CCI assessment for frozen pharmaceutical vials.
  • These techniques effectively identify leaks missed by traditional room-temperature testing.
  • The findings are crucial for ensuring the integrity of temperature-sensitive pharmaceutical products during cold chain storage and transport.