The global market for injectable drugs is projected to experience substantial growth, with an anticipated increase from $431.8 billion in 2022 to $937 billion in 2032. As the demand for these drugs continues to rise, its imperative that the pharma industry proactively complies with evolving regulations. For drugs injected into the body, sterility is paramount. For years, drugmakers have relied on container closure integrity testing (CCIT) as a method of assuring the safety and effectiveness of sterile injectables — and now, updated regulations have further raised the container closure integrity (CCI) bar.
To better understand the issue, Pharma Manufacturing recently sat down with Derek Duncan, product line director at Lighthouse Instruments to discuss the significance of CCI and the evolving landscape of CCI testing, regulatory guidance, and the unique considerations posed by innovative therapies with extreme storage and transport requirements.
Q: What is container closure integrity and why is it critical for sterile injectable products?
A: Historically, good container closure integrity 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. Freeze-dried product requires protection against water vapor and is often packaged at a partial vacuum to help with reconstitution and/or seating 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.
Q: What are the main considerations for the CCI of a sterile product?
A: As mentioned, CCI plays an important role in maintaining the sterility and stability of sterile injectable products. The defects which cause a sterile vial to leak are not necessarily defects that will be detected by a visual inspection process. Examples of such defects are microscopic cracks and scratches in the glass, defects that are hidden by the crimp, or temporary defects such as stopper pop-up that result in temporary container leakage. It is therefore important that appropriate container closure integrity testing methods are available that enable container closure studies during packaging development to understand the performance of the primary packaging system and enable the appropriate quality testing in manufacturing and QC.
It is important to distinguish between CCI technologies and CCI test methods. Once a leak testing technology has been chosen as the basis for a test method, the next step is to perform method development studies generating data that demonstrates detection of a critical leak for a specific product container configuration using defined test method parameters. Test method parameters are optimized during method development and confirmed during validation and then the test equipment operation and performance are qualified. A final leak test method is therefore specific to a particular container-closure or product-package system.
Q: How have companies traditionally handled container closure integrity testing?
A: Traditional CCIT methods, such as microbial challenge tests or blue dye ingress tests, are described in the USP chapter on package integrity testing as methods associated with “probabilistic outcomes” having some uncertainty in the results which, in turn, makes such methods difficult to quantitatively validate for the detection of critical leaks. The chapter recommends using what are defined to be “deterministic CCIT methods” instead of the traditional probabilistic methods.
Deterministic methods are based on non-destructive analytical measurements and are recommended for use in container closure integrity testing throughout the product life cycle to generate science-based CCI data that, coupled with a risk-based approach, enables informed decisions about a CCIT strategy in commercial manufacturing. Package integrity data generated over the product life cycle serves as input for an ongoing database of CCI data (the package integrity profile) which then serves as a risk management tool to ensure that CCI of finished product meets the product quality requirements. The framework described in the USP chapter is currently driving changes in industry best practices for CCI testing.
Q: How has new regulatory guidance inspired the pharma industry to make changes in CCI testing best practices?
A: Regulators have paid close attention to CCI as a quality parameter for sterile product, and recent developments show that this will continue to be the case. New regulatory guidance, which includes the USP chapter as well as the more recent EU GMP Annex 1, has triggered changes in industry best practices in the area of CCI testing. As mentioned, the traditional CCIT methods such as microbial challenge tests or blue dye ingress tests are described as methods associated with probabilistic outcomes that result in some uncertainty in findings as well as in difficulties to quantitatively validate the method for the detection of critical leaks. The new regulatory guidance has put increased emphasis on generating science-based data throughout the product life cycle so that the best practices used, coupled with a risk-based approach, lead to an assurance of scientifically justified container closure.
Q: Have innovative therapies that require extreme storage and transport temperatures added extra considerations for container closure?
A: Certain sterile pharmaceutical products require deep cold storage, either at -80°C or even cryogenic temperatures (down to -196°C). Live viral and mRNA vaccines, gene therapies, or products that contain active cells (cell therapies) often need deep cold storage to maintain stability and/or activity. Studies have shown that ultra-cold storage temperatures can introduce risk to the CCI of vial-rubber stopper combinations traditionally used to fill sterile pharmaceutical products. Observations of overpressure have been reported in stoppered vials after storage at -80°C. When syringes were inserted into these vials, the plungers moved upwards and once the syringe was removed, product sprayed from the punctured hole indicating a substantial overpressure inside the vial. The studies showed that the overpressure was the result of a temporary loss of CCI allowing cold dense gas to ingress into the vial.
This situation raises concerns not only about the stability and efficacy of the formulation, but also about the safety of the administering health care professional and the patient, especially if the product vial contains a live viral vaccine. There are several material phenomena that lead to this temporary loss of CCI. Commonly used rubber butyl stoppers lose their elastic properties at these low temperatures because the glass transition temperatures (Tg) of the rubber formulations lie between -55°C and -70°C. In a range of temperatures around the Tg, the rubber stopper becomes brittle. In addition, the packaging components shrink at varying rates due to the different rates of thermal expansion of the materials (glass vial, rubber stopper, metal crimp) leading to possible gaps at the material interfaces.
Q: Given all these changes, what type of approach should pharma manufacturers take towards assuring good container closure?
A: New regulatory guidance recognizes CCI as a quality parameter that is critical for the maintenance of both the sterility and the stability of finished sterile products. New concepts introduced in the regulatory guidance are emphasizing industry best practices that include the following:
- Generate science-based CCI data throughout the product life cycle to build up a package integrity profile database that can be used as input for risk management
- Use deterministic CCI test methods that have been validated to detect a critical leak instead of the traditional probabilistic methods
- Implement a holistic approach to container closure assurance instead of just relying on container closure integrity testing for verification of good CCI
The new regulatory guidance leaves room for interpretation, but a general approach that includes both the implementation of validated deterministic CCIT methods and the increased generation of science-based CCI data to enable informed risk assessments, will help prepare the industry for the future.