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Testing Container Closure Integrity (CCI) is crucial for ensuring the quality of Class III medical devices. Class III medical devices are sterile components that are designed to be inserted directly into the human body. These devices often sustain or support life, are implanted or pose an unreasonably high risk of disease or damage. A compromised package can serve as a vehicle for microbial transmission and compromised sterility, leaving patient safety at risk. When bacteria or other impurities enter the container, the device ceases to be a treatment and becomes a danger to the patient. Similarly, a breach of the seal affects the sterility of the device and may present a serious quality concern at a key point of usage.

Testing Challenges in the Medical Device Industry

There are three basic approaches to package integrity testing:

• 100% in-line testing: All products in a batch are tested on a high-speed production line at an acceptable level of CCI assurance.
• Small batch testing: Testing a statistically significant batch size for certain quality parameters and extrapolating to match the quality of the manufacturing lot.
• Testing Offline: Operators test packages individually or in smaller batches.

Dye penetration is a technique for identifying defects in package body and seals that has a variable detection capacity. When carried out correctly, the approach can identify pinholes and channel defects as small as 20 microns. This method is only used to validate the packaging process and offers minimal value to in-process quality monitoring. The method is time-consuming to implement and provides limited information in the effort to ensure the quality of high-risk applications.

For CCI testing, the majority of medical device manufacturers use a 100% in-line manual visual inspection technique. Manual visual inspection has been proved to be one of the least reliable techniques for ensuring quality. The failure of manual visual inspection is caused by a number of factors. According to ASTM test method F1886, a manual visual inspection may detect 75-micron channel defects in a transparent seal 60-100% of the time. Although manual visual inspection can be applied as a 100% test method, performance on the task decreases significantly over time. This method is not applicable if the package format is not transparent or semi-transparent.

How Vacuum Decay and Airborne Ultrasound Technologies are Automated?

Vacuum Decay is a deterministic method proven to offer predictable and reliable results for CCI testing of high-risk package applications. This is an ideal solution for non-porous medical device applications. When the major focus of the inspection is the final seal of a porous package, Airborne Ultrasound is exceptionally efficient and reliable at detecting seal defects that are invisible to the manual visual inspector. Both approaches have shown to be reliable non-destructive testing methodologies, and one or the other can be used for inspection based on the unique features of the product and container.

The automation of each technology looks a little different. Vacuum Decay enables approximately 25 to 50 samples per minute, with low throughput detecting single-digit micron leak sizes. Airborne Ultrasound is a rapid-fire sensor that transmits 1000 pulses per second of sound through the seal. The final seal of Tyvek® pouches and other flexible packaging systems may be scanned at a rate of 20 inches per second (~40 cm/sec), with the capacity to detect the most frequent seal faults and seal quality concerns. Both methods enable a production line to ensure quality while reducing production throughput.

The Airborne Ultrasound technology offered by PTI can be automated in many ways. Basically, the technology can measure the quality of a quantitative seal in any way that the pouch seal can pass through the ultrasound inspection head. Ultrasound can be applied to the production flow, which captures seal quality when exiting a band-sealer or transferring pouches through a production line. Robotic handling may also be used to do a full 360-degree seal inspection on all pouch seals. Airborne Ultrasound has the flexibility to be deployed in a variety of production lines and has high reliability in detecting critical defects.

Vacuum decay is often utilized for both Tyvek® trays and non-porous container types. While a vacuum takes longer to do a test (about 5 seconds on a Tyvek tray), the sensitivity and stability of this technology make it perfect for low output applications with high sensitivity requirements. Robotic handling solutions can serve many test stations at the same time, allowing for increased product throughput without losing sensitivity.

Medical devices are packaged and delivered in a variety of ways, ranging from porous flexible packaging to non-porous rigid containers. The range of product types and packaging options create unique inspection challenges that must be overcome in order to assure seal strength, sterility, and quality. Airborne Ultrasound and Vacuum Decay offer 100% testing capabilities as well as an accurate inspection that includes quantitative test results and a pass/fail result. These new automated technologies, with more sensitive leak detection capabilities, inspect containers at a higher rate.

Pre-filled syringes are becoming more popular as a preferred container closure system for biologics. Pre-filled syringes must offer an inherent barrier that maintains drug product stability and sterility throughout its entire shelf life as a primary container closure system. The ability of the system to retain its microbial barrier integrity must be checked and demonstrated by the drug manufacturers. In 2008, the FDA endorsed CCI testing as part of the sterile product stability protocol.

The pharmaceutical industry has witnessed substantial technical developments in CCI testing in response to rising regulatory demands. MicroCurrent HVLD, Vacuum Decay Leak Testing and Helium Leak Detection are examples of new technologies that have proven enhanced detection capabilities above traditional Dye and Microbial Ingress approaches. Many of the technologies have been employed for CCI testing of drug product stability.

CCI Testing Strategy for Development

Many CCI failure modes can occur throughout the life cycle of a syringe, from component production to drug product filling and sealing, device assembly and packaging, and finally distribution and storage. It is critical to create a comprehensive plan for conducting CCI testing across the whole syringe life cycle.

The creation of the CCI testing technique begins with a detailed study of the construction, design, and manufacturing procedures used in syringes. The failure modes and impacts associated with each aspect of CCI were identified first. The next step was to evaluate whether CCI testing is required, as well as the intended uses and testing frequencies, using a risk-based approach. Knowing that the needle shield compartment seal integrity had been verified by the component supplier, apply a non-routine CCI test to validate its seal integrity during drug product loading and sealing, as well as during device assembly. To ensure CCI was achieved and successfully maintained, implement a complete set of CCI tests across the entire product development cycle for the product-containing syringe barrel compartment.

Method Development and Method Validation

Method development consists of optimizing testing parameters and determining the appropriate pass/fail threshold.

• Testing parameters optimization

Initially, several defect standards of known sizes were examined alongside undamaged samples using varied testing conditions. The relationships between key method parameters and instrument responses to intact and defect samples were comprehensively investigated, with the objective of determining a set of variables that give optimal separation between intact and defect samples. i.e. signal-to-noise ratio or SNR.

• Pass/fail threshold determination

The improved method was utilized to evaluate different lots of filled intact syringes representing relevant product variations, such as drug product batches, and packaging locations and lines, in order to define the preliminary pass/fail threshold. For intact samples, the results of the tests were statistically assessed to determine the instrument baseline and variation (σ). Typically, the pass/fail threshold should be 10 σ higher than baseline. The pass/fail threshold was then further refined and verified by testing defect standards of known sizes.

CCI testing techniques were validated for the pharmaceutical product package. Since the drug product formulation and package design may change during the early development stages, a step-by-step approach was adopted to validate the methods in line with the product development stages. Once product design and packaging design are complete, the methods are fully validated to support CCI testing for initial consistency and process evaluation. The power of the additional long-term method may be further validated before this method is implemented in QC laboratories for routine testing.

During package and pharmaceutical product development and manufacturing, properly selected and verified methodologies are critical for demonstrating container closure integrity. It should be noted that existing CCI testing methods do not provide an optimal solution for all pre-filled syringe CCI testing requirements. To maintain total container closure integrity, an integrated solution involving CCI testing as well as additional engineering and administrative controls is required.