Historically, good container closure integrity (CCI) has been linked to the maintenance of sterility. A container that loses, or does not have, good closure integrity is at risk for microbial contamination.
However, the context of container closure integrity has become broader over the years. An increasing number of formulations have significant sensitivity to oxygen and need to be packaged under an inert atmosphere. A freeze-dried product requires protection against water vapor and is often packaged in a partial vacuum to help with reconstitution and/or sealing of the stopper.
In these cases, good container closure integrity is necessary not only for the maintenance of sterility but also to maintain critical headspace gas conditions. Note that, quite generally, a container that is gas-tight will also be tight against microbial ingress. Therefore, the requirement to maintain headspace gas conditions imposes higher standards on CCI than the requirement to maintain sterility.
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Regulatory requirements for container closure
With the advancement of more and more complex therapies, regulators have paid increasing attention to the performance of the container closure systems used to package these drug products. New guidance, including the USP chapter as well as the more recent EU GMP Annex 1, has triggered changes in container closure integrity testing (CCIT) best practices. The new guidelines stress the need for generating science-based data coupled with a risk-based approach, throughout the product life cycle, that ensure scientifically justified container closure. Robust development and qualification work are therefore crucial to demonstrate the CCI performance of any primary packaging system being used to fill sterile pharmaceutical products.
Headspace methods for packaging and process development studies
Traditional CCIT methods, such as microbial challenge tests or blue dye ingress tests, while described in the USP chapter on package integrity testing, come with probabilistic outcomes and uncertainties, making them hard to validate for critical leak detection. The USP recommends deterministic CCIT methods which are non-destructive analytical measurements and are recommended for use in container closure integrity testing throughout the product life cycle. Coupled with a risk-based approach, this approach enables informed CCIT strategies in commercial manufacturing. A prominent deterministic method described in USP is laser-based headspace analysis, now regularly being implemented as the ‘golden tool’ for generating robust science-based CCIT data for all types of sterile pharmaceutical products [1-4]. The use of headspace methods for recent mRNA therapies as part of a holistic science-based [1] approach to container closure integrity assurance [5] has further demonstrated headspace as the most flexible and reliable deterministic CCIT method.
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Join this webinar to discover the importance of container closure integrity and the role of headspace gas ingress methods. Learn how maintaining critical headspace gas conditions ensures product stability and safety.
REFERENCES:
- K. G. Victor, L. Levac, M. Timmins, and J. Veale, “Method Development for Container Closure Integrity Evaluation via Headspace Gas Ingress by Using Frequency Modulation Spectroscopy,” PDA J Pharm Sci Tech, vol. 71, no. 6, pp. 429–453, 2017.
- A. Caudill, K. G. Victor, M. Timmins, and J. Veale, “Container Closure Integrity Test using Frequency Modulation Spectroscopy Headspace Analysis with Carbon Dioxide as a Tracer Gas.,” PDA J Pharm Sci Technol, vol. 75, no. 2, pp. 157–172, 2021.
- K. G. Victor, A. A. Caudill, and J. Veale, “Container Closure Integrity Test Method Development on Vials Stored at -80°C Using Headspace Carbon Dioxide Analysis.,” PDA J Pharm Sci Tech, vol. 76, no. 5, 2022
- A. Caudill, K. G. Victor, and J. Veale, “A Container Closure Integrity Test Method for Vials Stored at Cryogenic Conditions using Headspace Oxygen Analysis.,” submitted for publication
- Presentation ‘Mitigating Risk to Container Closure Integrity of a COVID 19 Vaccine Product During Ultra Cold Chain Storage and Distribution’, Derek Duncan, Michael Edey, Anna Rozentsvayg, 2021 PDA/FDA Joint Regulatory Conference
Speaker
Dr. Derek Duncan, PhD, Director, Lighthouse Instruments
Dr. Derek Duncan began his career at the Dutch Institute for Atomic & Molecular Physics in Amsterdam. He moved into the industry holding product & application development positions. Currently at LIGHTHOUSE since 2003, Dr. Duncan is responsible for developing applications for process monitoring and finished product inspection. These include using headspace analysis for 100 percent container closure integrity testing, lyo chamber moisture mapping and automated media fill inspection.
Message PresenterWho Should Attend?
- Manufacturing representatives responsible for compliance to the EU GMP Annex 1
- QC representatives responsible for container closure integrity testing
- Packaging and process development representatives
What You Will Learn
Attendees will learn how to:
- Apply headspace container closure integrity testing (CCIT) methods for all types of sterile pharmaceutical products and replace the traditional probabilistic microbial ingress and blue dye ingress methods
- Design packaging development studies that enable CCI assurance
- Design and execute qualification studies including production line qualification studies with respect to container closure integrity (CCI) in a holistic science-based approach
- Design and execute product CCIT including clinical batch CCIT and package system CCI stability testing
Xtalks Partner
LIGHTHOUSE
LIGHTHOUSE is the leading global provider of laser-based headspace analysis systems and measurement services. Headspace applications include container closure integrity testing, monitoring of headspace oxygen during filling and for stability studies, water activity determination, lyo cycle optimization and chamber moisture mapping, and automated media fill inspection. LIGHTHOUSE offers a range of benchtop and in-line platforms with patented laser sensor technology commercialized with the help of funding from the Food and Drug Administration. In addition, analytical services are delivered from laboratory facilities in Amsterdam and Charlottesville, Virginia and include method development and analytical process and product studies.
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