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Research ArticleResearch

Quantifying the Vial Capping Process: Residual Seal Force and Container Closure Integrity

Robert Ovadia, Alexander Streubel, Yenny Webb-Vargas, Lea Ulland, Joerg Luemkemann, Kamila Rauch, Juergen Eder, Philippe Lam, Vassia Tegoulia and Yuh-Fun Maa
PDA Journal of Pharmaceutical Science and Technology January 2019, 73 (1) 2-15; DOI: https://doi.org/10.5731/pdajpst.2018.008797
Robert Ovadia
1Pharmaceutical Processing and Technology Development, Genentech, CA, USA;
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Alexander Streubel
2Pharmaceutical Development & Supplies, Technical Development Biologics Europe, Basel, Switzerland;
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Yenny Webb-Vargas
3Nonclinical Biostatistics, Genentech, CA, USA; and
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Lea Ulland
2Pharmaceutical Development & Supplies, Technical Development Biologics Europe, Basel, Switzerland;
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Joerg Luemkemann
2Pharmaceutical Development & Supplies, Technical Development Biologics Europe, Basel, Switzerland;
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Kamila Rauch
4Manufacturing Science and Technology, Parenterals Manufacturing Kaiseraugst, Kaiseraugst, Switzerland.
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Juergen Eder
4Manufacturing Science and Technology, Parenterals Manufacturing Kaiseraugst, Kaiseraugst, Switzerland.
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Philippe Lam
1Pharmaceutical Processing and Technology Development, Genentech, CA, USA;
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Vassia Tegoulia
1Pharmaceutical Processing and Technology Development, Genentech, CA, USA;
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Yuh-Fun Maa
1Pharmaceutical Processing and Technology Development, Genentech, CA, USA;
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  • For correspondence: maay@gene.com
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Abstract

Capping completes the closure of parenteral drug products in the final packaging container and is critical in maintaining an integral seal to ensure product quality. Residual seal force (RSF) is considered the sole quantifiable attribute for measuring seal “goodness” and potentially enables nonsubjective, consistent setting of cappers across manufacturing sites. However, the consistency and reliability of RSF measurement and data have been scarcely reported, and the relationship between RSF and container closure integrity (CCI) remains poorly understood.

Here, we present a large data set generated from a commercial capper and the results from a laboratory capper of glass vials and rubber stoppers with aluminum caps. All RSF values exhibited significant variability. We evaluated four potential sources of variability: the capper, the RSF tester, the time-dependent nature of RSF, and the components. We determined that the capper, the tester, and the time-dependent nature are not main sources. Dimensional tolerances of the packaging components were the root cause for the container closure system (CCS) configurations tested in this study.

This study correlated RSF with CCI (via helium leakage), although CCI is not sensitive to RSF; CCI was maintained even for loosely capped vials with no measurable RSF. This was attributed to the stopper's two sealing surfaces: the valve seal and the land seal. A methodology capable of differentiating the two seals' functions demonstrated that vials with only the valve seal always passed leakage testing for a selected CCS configuration in this study, while vials with only the land seal failed CCI at low RSF values. This observation allows proposal of a low RSF limit that is safe even when the valve seal is defective. Simplified statistical analysis of commercial capping data, with the input of sample size, allowed the relationship between RSF's low limit and an allowable failing rate to be established. Overall, despite the inherent variability of RSF, this study shows that it is a feasible parameter for capping process quantification and demonstrates the potential of RSF measurement in capper setup.

LAY ABSTRACT: Pharmaceutical vials are typically closed off with an elastomeric stopper that is secured onto the vial with an aluminum crimp cap (or seal) such that the entire assembly is meant to protect the vial's contents from external contamination. Therefore, the capping process is critical for ensuring container closure integrity. Characterizing the effectiveness of a seal in a nonsubjective and quantifiable manner is challenging. In this communication, we report the evaluation of residual seal force measurements (the compression force that the crimp cap exerts on the stopper) to evaluate capping for a large set of samples generated on both an at-scale commercial capper and a benchtop laboratory capper. We propose a test methodology, based on a statistical approach, for establishing permissible lower residual force limits that would provide a high degree of confidence to the capping process. This is a useful tool for consistent capper setup and capping process quantification.

  • Residual seal force
  • RSF
  • Vial capping
  • Container closure integrity
  • CCI
  • Primary packaging components
  • Helium leakage
  • Vial
  • Stopper
  • Crimp cap
  • © PDA, Inc. 2019
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PDA Journal of Pharmaceutical Science and Technology: 73 (1)
PDA Journal of Pharmaceutical Science and Technology
Vol. 73, Issue 1
January/February 2019
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Quantifying the Vial Capping Process: Residual Seal Force and Container Closure Integrity
Robert Ovadia, Alexander Streubel, Yenny Webb-Vargas, Lea Ulland, Joerg Luemkemann, Kamila Rauch, Juergen Eder, Philippe Lam, Vassia Tegoulia, Yuh-Fun Maa
PDA Journal of Pharmaceutical Science and Technology Jan 2019, 73 (1) 2-15; DOI: 10.5731/pdajpst.2018.008797

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Quantifying the Vial Capping Process: Residual Seal Force and Container Closure Integrity
Robert Ovadia, Alexander Streubel, Yenny Webb-Vargas, Lea Ulland, Joerg Luemkemann, Kamila Rauch, Juergen Eder, Philippe Lam, Vassia Tegoulia, Yuh-Fun Maa
PDA Journal of Pharmaceutical Science and Technology Jan 2019, 73 (1) 2-15; DOI: 10.5731/pdajpst.2018.008797
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  • A New Integrated Modeling Approach with Case Studies for Gas Transmission of Container Closure Headspace
  • Quantifying the Vial-Capping Process: Reexamination Using Micro-Computed Tomography
  • Long-Term Study of Container Closure Integrity of Rubber-Glass Vial Systems by Multiple Methods
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Keywords

  • Residual seal force
  • RSF
  • Vial capping
  • Container closure integrity
  • CCI
  • Primary packaging components
  • Helium leakage
  • Vial
  • Stopper
  • Crimp cap

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