Skip to main content

Main menu

  • Home
  • Content
    • Current Issue
    • Past Issues
    • Accepted Articles
    • Email Alerts
    • RSS
    • Terms of Use
  • About PDA JPST
    • JPST Editors and Editorial Board
    • About/Vision/Mission
    • Paper of the Year
  • Author & Reviewer Resources
    • Author Resources / Submit
    • Reviewer Resources
  • JPST Access and Subscriptions
    • PDA Members
    • Institutional Subscriptions
    • Nonmember Access
  • Support
    • Join PDA
    • Contact
    • Feedback
    • Advertising
    • CiteTrack
  • .
    • Visit PDA
    • PDA Letter
    • Technical Reports
    • news uPDATe
    • Bookstore

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
PDA Journal of Pharmaceutical Science and Technology
  • .
    • Visit PDA
    • PDA Letter
    • Technical Reports
    • news uPDATe
    • Bookstore
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
PDA Journal of Pharmaceutical Science and Technology

Advanced Search

  • Home
  • Content
    • Current Issue
    • Past Issues
    • Accepted Articles
    • Email Alerts
    • RSS
    • Terms of Use
  • About PDA JPST
    • JPST Editors and Editorial Board
    • About/Vision/Mission
    • Paper of the Year
  • Author & Reviewer Resources
    • Author Resources / Submit
    • Reviewer Resources
  • JPST Access and Subscriptions
    • PDA Members
    • Institutional Subscriptions
    • Nonmember Access
  • Support
    • Join PDA
    • Contact
    • Feedback
    • Advertising
    • CiteTrack
  • Follow pda on Twitter
  • Visit PDA on LinkedIn
  • Visit pda on Facebook
Research ArticleResearch

Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies

Sarah S. Peláez, Hanns-Christian Mahler, Christoph Herdlitschka, Toni Wertli, Matthias Kahl, Atanas Koulov, Anja Matter, Satish K. Singh, Martina Widmer, Oliver Germershaus and Roman Mathaes
PDA Journal of Pharmaceutical Science and Technology May 2019, 73 (3) 220-234; DOI: https://doi.org/10.5731/pdajpst.2018.009332
Sarah S. Peláez
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hanns-Christian Mahler
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christoph Herdlitschka
2Wilco AG, Wohlen, Switzerland; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toni Wertli
2Wilco AG, Wohlen, Switzerland; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthias Kahl
2Wilco AG, Wohlen, Switzerland; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Atanas Koulov
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anja Matter
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Satish K. Singh
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martina Widmer
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oliver Germershaus
3Institute for Pharma Technology, School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roman Mathaes
1Lonza Drug Product Services, Basel, Switzerland;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: roman.mathaes@lonza.com
  • Article
  • Figures & Data
  • References
  • Info & Metrics
  • PDF
Loading

Abstract

The sterility of drug products intended for parenteral administration is a critical quality attribute (CQA) because it serves to ensure patient safety and is thus a key requirement by health authorities. While sterility testing is a probabilistic test, the assurance of sterility is a holistic concept including adequate design of manufacturing facilities, process performance, and product design. Container closure integrity testing (CCIT) is necessary to confirm the integrity of a container closure system (CCS), until the end of a product's shelf life. The new and revised United States Pharmacopeia (USP) General Chapter <1207> is a comprehensive guidance on CCI. Nevertheless, practical considerations including the choice of CCIT methods, the acceptance criteria, or the positive control samples (artificial leaks) must be addressed by the pharmaceutical manufacturer.

This study is the first to provide a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA), and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks).

The results from these experiments provide comprehensive data to allow a direct comparison of the capabilities of the individual methods. The results confirmed that the He leak detection method, which is considered the “gold-standard” for pCCIT regarding method sensitivity, indeed demonstrates the highest detection sensitivity (lowest detection limit). In comparison to the dye ingress method, HSA and vacuum decay also demonstrated better detection sensitivity in our study.

Capillary leaks with orifice diameter (capillary leak with flow according to an ideal orifice) and micro holes yielded similar leak rates, whereas capillaries with nominal diameters yielded significantly lower leak rates. In conclusion, method sensitivity cannot be compared by means of a leak diameter, but requires the consideration of multiple impacting factors (e.g., path length, uniformity).

LAY ABSTRACT: Sterility of drug products intended for parenteral administration is a critical quality attribute to ensure patient's safety and is thus a key requirement by health authorities. The absence of microbial contamination must be demonstrated by container closure integrity (CCI) of the container closure system (CCS). Currently, the revised United States Pharmacopeia (USP) General Chapter <1207> provides the most extensive guidance on how CCI should be assessed. Nevertheless, practical considerations on the choice of an appropriate CCIT method, artificial leaks or the choice of an acceptance criteria are lacking and must be addressed by the pharmaceutical manufacturer.

This study provides a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA) and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks).

  • Container closure integrity testing
  • Artificial leaks
  • Primary packaging
  • USP <1207>
  • Mass spectrometry-based helium leak detection
  • Laser-based headspace analysis
  • Abbreviations

    atm. pressure
    Atmospheric pressure
    CCI
    Container closure integrity
    CCIT
    Container closure integrity testing
    CCS
    Container closure system
    CQA
    Critical quality attribute
    DP
    Differential pressure
    He
    Helium
    HSA
    Lased-based headspace analysis
    ID
    Inner diameter
    LOD
    Limit of detection
    LOQ
    Limit of Quantification
    mCCIT
    Microbial container closure integrity testing
    N2
    Nitrogen
    O2
    Oxygen
    OD
    Outer diameter
    pCCIT
    Physical container closure integrity testing
    SD
    Standard deviation
    SST
    system suitability test
    USP
    United States Pharmacopeia
    PFS
    prefilled syringe.
    • © PDA, Inc. 2019
    View Full Text

    PDA members receive access to all articles published in the current year and previous volume year. Institutional subscribers received access to all content. Log in below to receive access to this article if you are either of these.  

    If you are neither or you are a PDA member trying to access an article outside of your membership license, then you must purchase access to this article (below). If you do not have a username or password for JPST, you will be required to create an account prior to purchasing. 

    Full issue PDFs are for PDA members only.

    Note to pda.org users

    The PDA and PDA bookstore websites (www.pda.org and www.pda.org/bookstore) are separate websites from the PDA JPST website. When you first join PDA, your initial UserID and Password are sent to HighWirePress to create your PDA JPST account. Subsequent UserrID and Password changes required at the PDA websites will not pass on to PDA JPST and vice versa. If you forget your PDA JPST UserID and/or Password, you can request help to retrieve UserID and reset Password below.

    Log in using your username and password

    Forgot your user name or password?

    Log in through your institution

    You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.
    If your organization uses OpenAthens, you can log in using your OpenAthens username and password. To check if your institution is supported, please see this list. Contact your library for more details.

    Purchase access

    You may purchase access to this article. This will require you to create an account if you don't already have one.

    patientACCESS

    patientACCESS - Patients desiring access to articles

    Full issue PDFs are for PDA members only. You can join PDA at www.pda.org. 

    PreviousNext
    Back to top

    In This Issue

    PDA Journal of Pharmaceutical Science and Technology: 73 (3)
    PDA Journal of Pharmaceutical Science and Technology
    Vol. 73, Issue 3
    May/June 2019
    • Table of Contents
    • Index by Author
    Print
    Download PDF
    Article Alerts
    Sign In to Email Alerts with your Email Address
    Email Article

    Thank you for your interest in spreading the word on PDA Journal of Pharmaceutical Science and Technology.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies
    (Your Name) has sent you a message from PDA Journal of Pharmaceutical Science and Technology
    (Your Name) thought you would like to see the PDA Journal of Pharmaceutical Science and Technology web site.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    7 + 11 =
    Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
    Citation Tools
    Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies
    Sarah S. Peláez, Hanns-Christian Mahler, Christoph Herdlitschka, Toni Wertli, Matthias Kahl, Atanas Koulov, Anja Matter, Satish K. Singh, Martina Widmer, Oliver Germershaus, Roman Mathaes
    PDA Journal of Pharmaceutical Science and Technology May 2019, 73 (3) 220-234; DOI: 10.5731/pdajpst.2018.009332

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    Share
    Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies
    Sarah S. Peláez, Hanns-Christian Mahler, Christoph Herdlitschka, Toni Wertli, Matthias Kahl, Atanas Koulov, Anja Matter, Satish K. Singh, Martina Widmer, Oliver Germershaus, Roman Mathaes
    PDA Journal of Pharmaceutical Science and Technology May 2019, 73 (3) 220-234; DOI: 10.5731/pdajpst.2018.009332
    Reddit logo Twitter logo Facebook logo Mendeley logo
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Jump to section

    • Article
      • Abstract
      • Introduction
      • Materials and Methods
      • Results and Discussion
      • Conclusion
      • Conflict of Interest Declaration
      • Abbreviations
      • References
    • Figures & Data
    • Info & Metrics
    • References
    • PDF

    Related Articles

    • No related articles found.
    • PubMed
    • Google Scholar

    Cited By...

    • Container Closure Integrity Test Using Frequency Modulation Spectroscopy Headspace Analysis with Carbon Dioxide as a Tracer Gas
    • Google Scholar

    More in this TOC Section

    • Container Closure Integrity of Vial Primary Packaging Systems under Frozen Storage Conditions: A Case Study
    • Advances in Large Volume Subcutaneous Injections: A Pilot Tolerability Study of an Innovative Needle-Free Injection Platform
    • Quantification and Stability Impact Assessment of Drop Stresses in Biologic Drug Products
    Show more Research

    Similar Articles

    Keywords

    • Container closure integrity testing
    • Artificial leaks
    • Primary packaging
    • USP <1207>
    • Mass spectrometry-based helium leak detection
    • Laser-based headspace analysis

    Readers

    • About
    • Table of Content Alerts/Other Alerts
    • Subscriptions
    • Terms of Use
    • Contact Editors

    Author/Reviewer Information

    • Author Resources
    • Submit Manuscript
    • Reviewers
    • Contact Editors

    Parenteral Drug Association, Inc.

    • About
    • Advertising/Sponsorships
    • Events
    • PDA Bookstore
    • Press Releases

    © 2023 PDA Journal of Pharmaceutical Science and Technology ISSN: 1079-7440

    Powered by HighWire