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The FDA has approved over twenty (20) cell and gene therapy drugs, and with the rapid growth of the cell and gene therapy market, there is greater demand than ever to demonstrate container-closure integrity (CCI) at ultra-low temperatures. To preserve the product’s efficacy, most cell and gene therapy drugs are stored at temperatures below -60ºC. Many of these products are packaged in either vial systems or cryogenic freezing bags. While each of these container-closure systems poses a unique challenge for the evaluation of CCI at ultra-low temperatures, the discussion in this blog focuses specifically on vial systems.
The most common issue with storage of vial systems at ultra-low temperatures is the potential formation of transient leaks. While a vial system may achieve leak rates at or below the maximum allowable leakage limit (MALL) at room temperature, the same may not always be true at -80ºC or below. Most butyl rubber elastomeric stoppers reach the glass transition temperature (Tg) at approximately -65ºC. This is the temperature at which an elastomer loses its elasticity and becomes more rigid or glass-like. When the elastomer passes its glass transition temperature, it may lose its ability to form a tight seal against the neck and land seal of the vial. Transient leaks form, allowing the ingress of unwanted microorganisms or gases such as carbon dioxide or nitrogen from the storage environment. The ingress of carbon dioxide could affect product quality by causing a change in the pH of the formulation, and the ingress of objectional microorganisms can result in sterility breaches.
Once the vial is removed from the ultra-low storage temperature, any gas ingress through a transient leak during storage can result in an overpressure in the vial when it equilibrates back to room temperature. As the elastomer warms, it regains its elasticity and can once again form a tight seal against the vial. Since the transient leak is no longer present, the gas that had ingressed into the headspace of the vial during deep cold storage becomes trapped inside the vial system and begins to expand at room temperature. This phenomenon has been considered by West scientists, TSB 2020/072: Potential Over-pressurization Issues with Ultra-Low Temperature or Cryogenic Storage of Improperly Sealed Vial/Stopper Primary Package Systems. An over-pressurized vial can force a syringe needle out of the vial when the stopper is pierced and can cause the drug product to spray out of the vial through the needle piercing. Any amount of the drug product that escapes containment could not only impact the dose delivered to the patient but could also pose a safety risk to those administering the drug to the patient.
So now that we know why it is important to understand CCI at ultra-low temperatures, how can these transient leaks be detected and mitigated? West offers several solutions for evaluating vial system performance at ultra-low temperatures. These solutions provide the data to support a science-based holistic approach to ensuring the integrity of a vial system. With this approach, methods are developed to correlate attributes such as residual seal force (RSF) with CCI. As per USP <1207.3> Package Seal Quality Tests, RSF provides an indirect measure of the compressive force exerted by the stopper onto a vial finish after capping and is linearly related to closure compression: more tightly capped vials yield higher RSF values. Vial system components are chosen, and capping force ranges are optimized for the vial system through process studies using both RSF and CCI testing. Once an appropriate CCI method has been established, shipping and shelf-life studies can be conducted to monitor CCI at any storage condition, including ultra-low temperatures.
Studies have demonstrated that higher RSF values typically result in better CCI. Therefore, it is important to understand the correlation between RSF and CCI for your vial system. Optimal RSF values can vary depending on the durometer (hardness) of the elastomer, but typical RSF values for tightly sealed vial systems can range between approximately 18 – 25 lbf. Both helium leak detection and laser-based gas headspace methods can be used in conjunction with RSF testing to establish the inherent CCI of the vial system. These same technologies can also be used to monitor CCI at temperatures such as 2-8ºC, -20ºC, -80ºC, -120ºC, and -180ºC or any other desired temperature in between. The experts at West Analytical Services can design and perform RSF and CCI studies using RSF testing, helium leak detection, oxygen headspace analysis, carbon dioxide headspace analysis, and pressure headspace analysis.
Helium leak detection is a fast, accurate, and deterministic way to evaluate the inherent CCI of a vial system at any temperature. The sensitivity of helium leak detection makes it ideal for testing CCI for products that need to maintain both headspace gas as well as sterility. Helium leak detection is most often used in conjunction with RSF testing during the package development phase of the product life cycle to optimize capping parameters and to evaluate component performance at ultra-low temperatures. The only drawback to helium leak detection is that it is a destructive test.
Laser-based gas headspace analysis, however, is a non-destructive deterministic option to test package integrity of drug product-filled vial systems and is applicable during all three phases of the product life cycle (package development, manufacturing, and commercial stability). When shipping or storing vial systems in a carbon dioxide rich environment (i.e., on dry ice) carbon dioxide headspace analysis is the perfect tool to determine if the vial system experienced a transient leak at the -80ºC storage or shipping condition. Increased carbon dioxide levels can be detected in as little as seven days of storage on dry ice. Overpressure conditions in the vial due to carbon dioxide or nitrogen ingress through a transient leak can be detected using pressure headspace analysis. In addition, decreases in oxygen levels in the headspace air can be detected for a vial system stored in a carbon dioxide rich environment or in the vapor phase of liquid nitrogen using oxygen headspace analysis.
As you can see, West Analytical Services is well equipped to perform CCI studies at both ambient and a range of ultra-low temperatures using helium leak detection or a variety of laser-based gas headspace analysis technologies. We use quantitative deterministic methods to establish package integrity and to monitor CCI performance over the entire product life cycle, in accordance with the requirements of USP <1207> and the various FDA, EU, and Japanese regulations and guidance documents on package integrity. We would love to help you to develop integral vial systems and to mitigate risk using a holistic approach to package development. For more information, click here or contact our business development team.
Take an in-depth look at the science behind containment & delivery of injectable medicines in the West Knowledge Center.