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Article CommentaryCommentary

Container Closure Integrity Testing—Practical Aspects and Approaches in the Pharmaceutical Industry

Helen Brown, Hanns-Christian Mahler, James Mellman, Alejandra Nieto, Daniel Wagner, Matthias Schaar, Roman Mathaes, Juergen Kossinna, Franz Schmitting, Sascha Dreher, Holger Roehl, Markus Hemminger and Klaus Wuchner
PDA Journal of Pharmaceutical Science and Technology March 2017, 71 (2) 147-162; DOI: https://doi.org/10.5731/pdajpst.2016.006999
Helen Brown
1Late-Stage Pharmaceutical and Processing Development, Roche;
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Hanns-Christian Mahler
2Drug Product Services, Lonza;
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James Mellman
3Biologics Technical Development and Manufacturing, Novartis;
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Alejandra Nieto
1Late-Stage Pharmaceutical and Processing Development, Roche;
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Daniel Wagner
4Pharmaceutical Sciences Operations, Sanofi;
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Matthias Schaar
5Biological and Microbiological Services, Novartis;
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Roman Mathaes
2Drug Product Services, Lonza;
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Juergen Kossinna
3Biologics Technical Development and Manufacturing, Novartis;
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Franz Schmitting
6Development Sciences, Abbvie;
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Sascha Dreher
7Device Development, Roche; and
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Holger Roehl
1Late-Stage Pharmaceutical and Processing Development, Roche;
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Markus Hemminger
7Device Development, Roche; and
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Klaus Wuchner
8Drug Product and Device Methods, Janssen R&D
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  • For correspondence: kwuchne1@its.jnj.com
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Abstract

The assurance of sterility of a parenteral drug product, prior to any human use, is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of product shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry. These may include: (1) choice of method, for example whether a deterministic CCI method (e.g., helium leak) is preferable over the probabilistic CCI method (e.g., microbial ingress), (2) the type of primary packaging (e.g., vial, syringe, device), (3) dosage form (e.g., liquid versus lyophilisate), (4) suitable acceptance criteria, (5) appropriate sample size, (6) the most appropriate way to introduce artificial leaks into the CCS, (7) ensuring suitable assurance of CCI during drug product manufacturing, and (8) evaluating CCI under intended shipment and storage conditions (e.g., in the frozen state).

A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).

LAY ABSTRACT: The assurance of sterility of a parenteral drug product prior to any human use is a regulatory requirement. Hence, all strategies related to container closure integrity (CCI) must demonstrate absence of microbial contamination through leaks as part of the container closure system (CCS) qualification, during manufacturing, for quality control purposes and to ensure microbiological integrity (sterility) during storage and shipment up to the end of shelf life. Current regulatory guidances, which differ between countries and regions, provide limited detail on how to assess CCI. The new revision of USP <1207> aims to provide extensive and detailed guidance for CCI assessments for sterile products. However, practical questions and considerations are yet to be addressed by the pharmaceutical industry.

A group of European industry peers have met to discuss these and other related questions in order to provide their viewpoint and best practice on practical approaches to CCI. Their perspective is provided in this white paper. Through these discussions, it became clear that there is currently no gold standard for CCI test methods or for the generation of artificial leaks; therefore flexibility toward CCI approaches is required. Although there should be flexibility, any CCI approach must consider the intended use (e.g., CCS qualification, routine manufacturing, or quality control) and product design (e.g., primary packaging, liquid versus dried product).

  • Container closure integrity testing
  • Methods for container closure integrity testing
  • Artificial leaks
  • Industry perspective
  • Container closure system
  • Primary packaging
  • USP <1207>
  • © PDA, Inc. 2017
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PDA Journal of Pharmaceutical Science and Technology: 71 (2)
PDA Journal of Pharmaceutical Science and Technology
Vol. 71, Issue 2
March/April 2017
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Container Closure Integrity Testing—Practical Aspects and Approaches in the Pharmaceutical Industry
Helen Brown, Hanns-Christian Mahler, James Mellman, Alejandra Nieto, Daniel Wagner, Matthias Schaar, Roman Mathaes, Juergen Kossinna, Franz Schmitting, Sascha Dreher, Holger Roehl, Markus Hemminger, Klaus Wuchner
PDA Journal of Pharmaceutical Science and Technology Mar 2017, 71 (2) 147-162; DOI: 10.5731/pdajpst.2016.006999

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Container Closure Integrity Testing—Practical Aspects and Approaches in the Pharmaceutical Industry
Helen Brown, Hanns-Christian Mahler, James Mellman, Alejandra Nieto, Daniel Wagner, Matthias Schaar, Roman Mathaes, Juergen Kossinna, Franz Schmitting, Sascha Dreher, Holger Roehl, Markus Hemminger, Klaus Wuchner
PDA Journal of Pharmaceutical Science and Technology Mar 2017, 71 (2) 147-162; DOI: 10.5731/pdajpst.2016.006999
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  • Article
    • Abstract
    • Introduction
    • Methods for CCIT
    • Introduction of Artificial Leaks
    • Considerations of Microbial Challenge Container Closure Integrity Testing (mCCIT) To Establish Acceptance Criteria for Physical Container Closure Integrity Testing (pCCIT)
    • General Considerations for the Applicability of CCIT
    • CCIT in the Product Life Cycle
    • Conclusion
    • Conflict of Interest Declaration
    • Acknowledgments
    • References
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  • References
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Cited By...

  • Container Closure Integrity Test Using Frequency Modulation Spectroscopy Headspace Analysis with Carbon Dioxide as a Tracer Gas
  • Determining Maximum Allowable Rubber Stopper Displacement for Container Closure Integrity (CCI)
  • Quantifying the Vial-Capping Process: Reexamination Using Micro-Computed Tomography
  • Single-Use System Integrity I: Using a Microbial Ingress Test Method to Determine the Maximum Allowable Leakage Limit (MALL)
  • Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies
  • Container Closure Integrity Testing--Method Development for Freeze-Dried Products Using Laser-Based Headspace Oxygen Analysis
  • Evaluation of Container Closure System Integrity for Storage of Frozen Drug Products: Impact of Capping Force and Transportation
  • Sealing Behaviour of Container Closure Systems under Frozen Storage Conditions: Nonlinear Finite Element Simulation of Serum Rubber Stoppers
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More in this TOC Section

  • Chemical and Process Parameters Influencing Gelling during Pharmaceutical Wet Media Milling
  • Challenges Encountered in the Implementation of Bio-Fluorescent Particle Counting Systems as a Routine Microbial Monitoring Tool
  • Parametric Release of Moist Heat Sterilized Products: History and Current State
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Keywords

  • Container closure integrity testing
  • Methods for container closure integrity testing
  • Artificial leaks
  • Industry perspective
  • Container closure system
  • Primary packaging
  • USP <1207>

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