Container Closure Integrity Testing: Mitigating Ultracold Storage and Transport Risk

Certain sterile pharmaceutical products require deep cold storage, either near -80˚C or even at cryogenic temperatures (down to -180˚C). Messenger RNA and live viral vaccines, gene therapies or products that contain active cells often need deep cold storage to maintain stability and/or activity. Studies have shown that deep cold storage temperatures can introduce risk to pharmaceutical primary packaging systems. In particular, the cold temperatures pose risks to the container closure integrity (CCI) of vial-rubber stopper combinations traditionally used to fill sterile pharmaceutical products [1-3]. It is therefore critical that robust development and qualification work is done to demonstrate the CCI performance of any primary packaging components used for a product needing deep cold storage and transport temperatures.

There are several fundamental material phenomena that can lead to primary packaging failure at these low temperatures:

1. Commonly used rubber butyl stoppers lose their elastic properties at low temperatures because the glass transition temperatures (Tg) of the rubber formulations lie between -55°C and -70°C. This makes the rubber stopper hard and brittle.
2. As temperature decreases, the packaging components shrink at varying rates due to the different rates of thermal expansion of the materials (glass vial, rubber stopper, metal crimp). This introduces the risk of gaps appearing at the material interfaces. X-ray tomography images have shown shrinkage of a rubber stopper of roughly 8.5 percent by volume at cryogenic conditions. In contrast, the shrinkage in volume of a borosilicate glass vial will be significantly less.

In conclusion, when the rubber stopper loses its elastic properties, gaps can appear between the sealing surfaces due to material shrinkage, risking the loss of seal integrity. These risks can be mitigated by robust development and qualification activities based on quality-by-design principles applied to critical packaging and process development studies:

• Since the specific design as well as the relative dimensional fit of the vial and rubber stopper is critical for maintaining CCI at ultracold temperatures, conducting packaging development studies enable the choice of appropriate primary packaging components
• Vial sealing process must also be consistent and robust, which can be ensured by qualification of appropriate capping and crimping parameters through process studies
• Lastly, the new EU GMP Annex 1 mandates the inclusion of container closure integrity in the transport validation, especially if transport and distribution involves extreme conditions such as ultracold temperatures

In this webinar, the featured speakers will elaborate on a specific program for generating appropriate packaging data for deep cold storage products. This program ensures good CCI during ultracold storage and transport and enables meeting recent regulatory requirements. The program is based on a holistic science-based approach that has been developed and recently described [4] and enables coordinated robust packaging data generation in a number of stages following a product life cycle approach.

Register today to learn how to maintain container closure integrity of primary packaging components during ultracold storage and transport.

REFERENCES:

[1] Zuleger, B.; Werner, U.; Kort, A.; Glowienka, R.; Wehnes, E.; Duncan, D. Container/Closure Integrity Testing and the Identification of a Suitable Vial/Stopper Combination for Low-Temperature Storage at –80 °C. PDA J. Pharm. Sci. Technol. 2012, 66 (1), 453–465.

[2] Presentation ‘Ensuring container closure integrity of a gene therapy cancer vaccine needing deep cold storage’, Josine Wilmer, 2019 PDA Parenteral Packaging Conference, Venice, Italy

[3] Presentation ‘Correlating Vial Seal Tightness to Container Closure Integrity at Various Storage Temperatures’, Derek Duncan and Roger Asselta, 2015 PDA Parenteral Packaging Conference, Frankfurt, Germany

[4] 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

Speakers

Derek Duncan, PhD, Director Product Lines, Lighthouse Instruments

Dr. Derek Duncan began his career at the Dutch Institute for Atomic & Molecular Physics in Amsterdam. He moved into industry holding Product & Application Development positions. Having joined LIGHTHOUSE in 2003, Dr. Duncan is currently 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.

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Brandon Zurawlow, Chief Scientific Officer, CS Analytical

As Chief Scientific Officer at CS Analytical, Brandon Zurawlow leverages over 10 years of cGMP experience applying compendial chapters such as USP <381>, <660>, <661> and their EP counterparts; as well as the choice, development and validation of CCI methods now found in USP <1207>. Brandon is a contributor to industry documents and textbook chapters, and a speaker on the topic of compendial container testing and CCI at client sites, training seminars and conferences in the US, Europe and Asia.

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