The Significance of Container Closure Integrity (CCI)
Establishing a well-defined container closure system preserves the sterility of a drug over its shelf life. Container closure integrity (CCI) is important because it determines product and consumer safety. To keep patients safe, pharma manufacturers should implement container closure systems that avert contamination from microorganisms, reactive gases, and other substances.
Although scientific evidence shows that the benefits of vaccines far outweigh the risks, historically, there have been several major concerns about the safety of vaccines. One notable case of a vaccine recalled by Merck & Company, Inc. highlights the potential risk of contamination. In 2007, Merck recalled 1.2 million doses of Haemophilus influenzae type b (Hib) due to concerns about potential contamination with B. cereus, a type of bacteria that causes food poisoning or gastrointestinal infections. Fortunately, there were no reports of infection from B. cereus in the individuals that received the vaccine.
One way to ensure the sealing integrity of vials is through testing. Container Closure Integrity (CCI) testing is an assay that helps companies evaluate whether their container closure systems are sufficient for maintaining a sterile barrier against potential contaminants.
Properties that Affect Storage Container Closure Integrity
Threats to CCI include the type and design of materials used in packaging the drug, the equipment used in the sealing process, the method applied during sealing, and the environment or temperatures in which the vials are stored. Additionally, the vial dimensions, assembly, and exposure to temperature extremes can make it difficult to measure, predict, and control CCI.
Certain COVID-19 vaccine formulations in development (for example, mRNA and DNA) require cold chain storage as low as -80 °C using dry ice.3–5 Many cell and gene therapies demand cryogenic storage with liquid nitrogen that approaches -196 °C.6,7 These storage requirements further complicate CCI for vial closure systems that were never designed for such extreme conditions.
Advantages of the Cyclic Olefin Polymer Molding Process for Manufacturing SiO2 Vials
SiO2 vials have unmatched advantages because of the tight dimensional control inherent in the cyclic olefin polymer molding process. The dimensions of cyclic olefin polymer vials can be controlled to extremely tight tolerances that are ten to one hundred times lower than that of tubular or molded glass vials. Improving the dimensional precision has reduced and controlled stacking tolerances from the stopper and vial. This has resulted in a better fit and seal in all SiO2 vials.
Furthermore, the thermal coefficient of expansion of the cyclic olefin polymer is lower than elastomeric rubber stopper materials and is more closely matched to that of borosilicate glass. This means that the amount of shrinkage at cold or cryogenic temperatures will be more like the rubber stopper than glass and therefore reduce the risk of separation that could lead to CCI failure.
The coating itself does not interfere with sealing integrity nor dimensional variability. The total thickness of the barrier coating system is less than half a micron, which is at least two and a half times below the dimensional variability of the polymer vial. Additionally, the deposition of the coating conforms to the internal surface of the cyclic olefin polymer vial. This means that the texture or roughness of the vial surface is completely unaltered after the coating is deposited. The rubber stopper, therefore, seals against the coating as it would against the cyclic ole fin polymer.
The risk of the barrier coating system delaminating from the vial wall at cryogenic storage conditions was shown to be robust down to -196°C. SiO2 vials were completely immersed in liquid nitrogen for 6 hours and brought back to room temperature. The exposure to liquid nitrogen causes the polymer vial to shrink, putting the barrier coating system under compressive stress at the surface. However, the oxygen transmission rate (OTR) measured before and after liquid nitrogen immersion was essentially the same as shown in Figure 2. This experimental evidence suggested that the barrier system was well-bonded and intact on the surface of the vial.
Quality Control: CCI Cold Storage Testing at SiO2
SiO2 has developed quality control procedures in collaboration with Lighthouse Labs for cold storage CCI testing. Cold storage CCI evaluations were conducted on 10 mL SiO2 vials. The vials were sealed with West Novapure stoppers at three different residual seal force settings and stored on a bed of dry ice at -80°C. The residual seal force is the amount of force exerted on the vial opening by the rubber stopper after the crimp cap is applied.
The CCI – determined by the CO2 headspace partial pressure measurement – of unfilled SiO2 vials was low and unchanged after six months of storage compared to positive control vials with a 5-micron hole drilled through the wall by a laser (Figure 3).
The CCI cold storage testing will continue to be monitored for at least one year. Separately, a cell therapy customer developing a viral vector vaccine already reported one year of drug stability in SiO2 2 mL vials stored at -80°C filled with their proprietary formulation [unpublished communication].
Implications for COVID-19 Vaccines: The Closure Integrity of SiO2 Vials
Given that previous vial closure systems were not designed for extremely cold temperature storage, SiO2 offers an advantage for the storage and transportation of COVID-19 vaccines on a global scale.
The barrier coating system on the inside of SiO2 vials do not delaminate at cryogenic storage conditions, even when under compressive stress. Therefore, the novel hybrid barrier coating used in manufacturing SiO2 vials have very strong bonds that will hold up under tough storage and transportation conditions. SiO2 is well-positioned to supply high-quality products to regulated markets at very high volume at extreme temperatures.
Let SiO2’s Smart Vials help bring your new innovations to life and keep your patients safer.
- Hib Vaccine Recall (2007) | Vaccine Safety | CDC. Published August 20, 2020. Accessed November 12, 2020. https://www.cdc.gov/vaccinesafety/concerns/history/hib-recall.html
- Friday, September 30, Share 2016. Understanding Container Closure Integrity Testing. Accessed November 12, 2020. http://www.americanpharmaceuticalreview.com/Featured-Articles/239498-Understanding-Container-Closure-Integrity-Testing/
- Fabre A-L, Colotte M, Luis A, Tuffet S, Bonnet J. An efficient method for long-term room temperature storage of RNA. Eur J Hum Genet. 2014;22(3):379-385. doi:10.1038/ejhg.2013.145
- Seelenfreund E, Robinson WA, Amato CM, Tan A-C, Kim J, Robinson SE. Long term storage of dry versus frozen RNA for next generation molecular studies. PloS One. 2014;9(11):e111827. doi:10.1371/journal.pone.0111827
- Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA vaccines for infectious diseases. Front Immunol. 2019;10:594.
- Hunt CJ. Technical Considerations in the Freezing, Low-Temperature Storage and Thawing of Stem Cells for Cellular Therapies. Transfus Med Hemotherapy. 2019;46(3):134-150. doi:10.1159/000497289
- Weng L, Beauchesne PR. Dimethyl sulfoxide-free cryopreservation for cell therapy: A review. Cryobiology. 2020;94:9-17. doi:10.1016/j.cryobiol.2020.03.012