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Lyophilized products, or freeze-dried formulations, are widely used in the pharmaceutical industry due to their extended shelf life and stability. These products are highly sensitive to moisture, which makes container closure integrity (CCI) testing a necessary aspect of packaging validation. Detecting micro-leaks that could allow moisture ingress is a significant focus in lyophilized drug packaging. Standard CCI methods may not always align with the characteristics of freeze-dried products, which require tailored testing strategies. By using approaches that align with the packaging system and the physical properties of lyophilized content, manufacturers can better manage packaging performance over the product's shelf life.

Addressing the Unique Challenges of Lyophilized Products

Lyophilized products present several challenges for packaging evaluation. Their sensitivity to moisture means that even very small breaches in the container system can compromise product quality. Since these products are typically packaged in glass vials with rubber stoppers and aluminum seals, attention must be given to sealing conditions, material compatibility, and stopper positioning.

Unlike liquid-filled containers, lyophilized vials may not respond the same way to traditional test conditions. For example, the absence of liquid can reduce the effectiveness of certain probabilistic methods, such as dye ingress or microbial challenge. In addition, the fragile nature of the lyophilized cake requires non-invasive, non-destructive testing methods that preserve the sample’s structural integrity.

Environmental conditions also influence testing results. Factors such as pressure differential, vacuum stability, and residual gas presence need to be considered when designing a test for a lyophilized vial. Because of these variables, deterministic methods that provide measurable and reproducible outcomes are preferred when tailoring a CCI strategy for freeze-dried products.

Customizing Deterministic CCI Testing Approaches

Vacuum Decay Technology

Vacuum Decay is a non-destructive testing method widely applied in evaluating container integrity. For lyophilized products, it offers a clean and reliable approach without damaging the vial or product. By applying a vacuum to a sealed test chamber and monitoring pressure changes, this technology detects micro-leaks across rigid, semi-rigid, and flexible formats. Its high sensitivity makes it suitable for identifying even the smallest defects, supporting both quality assurance and sustainability by minimizing waste from destructive testing. It is well-suited for laboratory use and can be adapted for manual or automated operation.

Helium Leak Detection

Helium Leak Detection offers high sensitivity and precision, making it well-suited for lyophilized vials that require tight moisture control. In this method, helium is introduced into the container system either during or after sealing, and any escaping gas is measured using a mass spectrometer. This allows detection of even the smallest micro-leaks that could allow moisture ingress. Although it requires specialized equipment and setup, the method provides quantifiable leak rates and supports package development, validation, and quality control. Helium Leak Detection is commonly used during packaging qualification or when the barrier properties of a container need close examination.

Vacuum and Pressure Decay - VeriPac Delta

VeriPac Delta systems use advanced vacuum decay technology supported by dual transducer technology to enhance sensitivity and repeatability. It detects leak rates as small as 5 microns, making it suitable for dry product containers like lyophilized vials and powder-filled packages, as well as liquid-filled vials and prefilled syringes. The system uses high-resolution transducers to monitor vacuum or pressure levels in a test chamber. By measuring changes during a short test cycle, it accurately identifies both gross and micro leaks. VeriPac Delta supports manual or semi-automatic operation, making it ideal for offline lab testing and QA/QC process control without damaging the product or packaging.

Lyophilized drug products require tailored CCI testing approaches due to their sensitivity to moisture and unique container characteristics. Deterministic methods such as Vacuum Decay, Helium Leak Detection, and VeriPac Delta provide non-destructive, data-driven solutions that align well with these requirements. These technologies offer the flexibility to detect a range of leak sizes while maintaining sample stability. By customizing test parameters and aligning methods with specific container formats, manufacturers can improve packaging evaluation and support long-term product stability.

The pharmaceutical and life science industries rely on package integrity to maintain product efficacy throughout the shelf life of a drug or biologic. Container Closure Integrity (CCI) testing forms a foundation for sterile product delivery, helping companies maintain consistency and meet stringent regulatory requirements. PTI offers a complete suite of CCI services tailored to every phase of product development and commercialization. From test method development and validation to analytical testing and ongoing system support, these services provide a pathway for organizations to implement robust CCI programs.

Comprehensive Life Science Services Offered by PTI

1. CCI Development Services

CCI development services support method creation, refinement, and validation aligned with industry standards. The process begins with Initial Recipe Creation (IRC), where measurements are performed on both defective and intact samples using various test parameters. These values are analysed to develop a starting method, which includes proposed reject limits and a comprehensive data summary.

The next step is Test Method Development, focusing on building a reliable and sensitive method through system suitability testing and statistical analysis. Proprietary equipment and dedicated facilities are used for this stage, with optional on-site testing available.

Once the method is defined, PTI offers Method Validation Support, providing execution templates based on USP <1207>, hands-on engineering support, and documented validation of method performance. Each stage concludes with a final report and client consultation to maintain transparency and alignment throughout the process.

2. CCI Analytical Testing

PTI delivers contract-based CCI analytical services that support manufacturers. Batch testing is conducted using deterministic technologies like Vacuum Decay and MicroCurrent HVLD, delivering high-sensitivity results that meet industry and regulatory expectations. For new packaging formats or inspection approaches, experimental feasibility studies help determine the most effective testing solution. These studies generate data on test viability and guide further method development. In addition, Limit of Detection (LOD) Studies define the smallest defect size a method can consistently identify. LOD studies often include laser-drilled samples and statistical analysis, offering valuable data for regulatory submissions.

Helium Leak Testing services are also available and widely used across pharmaceutical and industrial sectors. These services support R&D, process control, and large-scale testing programs with precision and speed. For products requiring ultra-low temperature storage, Cold Storage Testing is offered using helium-based methods down to –160°C, allowing accurate testing of frozen or cryogenic samples using both glass and plastic packaging formats.

3. CCI Campus – CCI Consulting & Training

The CCI Campus initiative provides extended support through consulting and training services for those seeking to implement or enhance package integrity programs. CCI consulting spans early-phase development to commercial scale-up, offering strategic guidance on test method selection, protocol implementation, and packaging challenges.

Consulting engagements also cover sample plan design, interpretation of CCI data, and compliance alignment with USP <1207>, USP <382>, and EU Annex 1 standards. For hands-on knowledge transfer, training programs are available for professionals at all levels. These sessions cover everything from regulatory overviews and MALL concepts to method comparison and system-specific training.

4. CCI Care+

The Care+ program is a comprehensive service support offering designed to sustain equipment performance and testing reliability over time. The Platinum Annual Service Contract includes calibration, documentation support, system optimization, and discounted software upgrades. Clients benefit from direct access to expert technical support for prompt issue resolution and ongoing system enhancement.

PTI also offers our Care+ GMP Turnkey Solutions – providing comprehensive, end-to-end support for Container Closure Integrity (CCI) compliance.

As part of this service suite, the Seal Quality Assurance Program focuses on flexible packaging applications. Leveraging proprietary Seal-Scan® airborne ultrasound technology (ASTM F3004), it delivers precise, non-destructive seal quality inspection for pouches and related materials. This method enhances seal validation by identifying potential defects with a high degree of sensitivity. Through Care+, clients receive a proactive maintenance strategy paired with advanced inspection capabilities to keep systems operating at peak performance.

CCI Life Science Services offer a unified approach to addressing the multifaceted requirements of container closure integrity. From initial test method creation to long-term equipment performance support, these services are structured to provide clarity, compliance, and consistency. By combining science-based methods, regulatory alignment, and dedicated service, Life Science CCI Services serve as a dependable resource for ensuring packaging integrity across diverse product lines.

Auto-injectors are compact drug delivery systems designed to simplify administration while maintaining product sterility and user safety. These devices typically contain a prefilled syringe or cartridge within a mechanical or electronic housing, making them more complex than standard pharmaceutical packaging. Ensuring integrity in such systems helps prevent contamination, supports accurate dosing, and aligns with regulatory standards. However, due to their unique design and functionality, auto-injectors require tailored approaches to container closure integrity testing (CCIT). Selecting the right testing method involves understanding the device structure, assessing potential leak paths, and aligning with applicable technologies that can evaluate integrity reliably and non-destructively.

Why Auto-Injectors Require Specialized CCIT Approaches?

Auto-injectors, as combination drug-device products, present unique challenges that demand specialized Container Closure Integrity Testing (CCIT) approaches. Unlike standard vials or syringes, auto-injectors enclose a prefilled syringe or cartridge within a complex mechanical housing, limiting direct access to the primary drug container. This integrated design makes it difficult to apply conventional CCIT methods without modifying the device or using customized testing setups. Additionally, auto-injectors often feature multiple sealing interfaces—such as needle shields, plungers, and syringe barrels—which increase potential leak paths and require highly sensitive, deterministic testing solutions to evaluate integrity effectively.

Moreover, auto-injectors are frequently used for life-saving medications, where sterility and dosage accuracy are critical. Any breach in container closure could compromise patient safety or treatment efficacy. Regulatory bodies like the FDA emphasize the use of deterministic CCIT technologies, which must be tailored and validated for the specific design and materials of the auto-injector system. Methods such as high-voltage leak detection, laser-based headspace analysis, or vacuum decay may be suitable, but only when adapted to overcome physical and mechanical constraints. As such, ensuring container closure integrity in auto-injectors involves a strategic combination of technical customization, risk-based testing, and regulatory compliance.

Technical Comparison of Common CCIT Methods: Vacuum Decay, MicroCurrent HVLD, Helium Leak Detection

Vacuum Decay

Vacuum decay leak testing is a vacuum-based method valued for its accuracy, dependability, and straightforward operation. It relies on fundamental physical principles to evaluate container integrity and provides clear quantitative pass/fail results. Recognized under USP <1207>, it acts as a non-destructive alternative to traditional blue dye tests. During testing, the package is placed inside a chamber where vacuum is applied, and pressure changes detected by sensors reveal any leaks. This technique is fast, non-destructive, and adaptable to both manual and automated workflows. It supports offline laboratory testing, reduces product waste, and delivers an economical approach to seal integrity evaluation.

MicroCurrent HVLD

MicroCurrent HVLD is a non-destructive and non-invasive container closure integrity testing (CCIT) technique that provides reliable results across a wide range of applications, including prefilled syringes, vials, cartridges, ampoules, blow-fill-seal (BFS) containers, bottles, and pouches. This method effectively detects leaks in various liquid-filled products, from low-conductivity sterile water for injection (WFI) to protein-based formulations with suspensions. During testing, electrode probes scan the sealed container to identify leaks by measuring changes in current flow, enabling both leak detection and approximate location analysis. Operating at about 50% lower voltage than traditional HVLD methods, it minimizes product and environmental exposure to less than 5% of the voltage used by conventional techniques. It stands as one of the most advanced and efficient integrity testing technologies for parenteral and biologic products.

Helium Leak Detection

Helium leak testing is an advanced and highly sensitive method designed to detect extremely small leaks and complex leak paths that other testing techniques cannot identify. By employing high vacuum technology, this method can detect leaks with thresholds as low as 1 x 10-10 mbar L/sec, enabling precise comparisons between different packaging components, material choices, and manufacturing processes. The technique uses a mass spectrometer detector with high sensitivity to assess the integrity of sealed packages or systems. For example, a vial—comprising a glass or plastic container sealed with an elastomeric closure—can be filled with helium and exposed to a vacuum. Any helium that escapes is measured quantitatively and reported as a leak rate (flow rate), expressed in mbar L/sec.

Selecting a CCIT method for auto-injectors requires a balance between technical requirements and practical limitations. Helium Leak Detection is often used for its high sensitivity in development settings. MicroCurrent HVLD provides a non-invasive option for liquid-filled containers when accessibility is not a constraint. Vacuum Decay supports routine batch testing and inline use when leak sizes fall within its detection range. Each method brings specific strengths to the table. When working with auto-injectors, test engineers and quality teams often evaluate multiple approaches to determine the most effective setup. Method selection often depends on package design, test sensitivity goals, and production workflow.

Medical devices often require packaging solutions that allow for sterilization while maintaining a protective barrier until the product is used. Porous flexible pouches, typically made from materials like Tyvek®, meet these conditions by permitting sterilizing gases to pass through while helping shield the contents from potential contaminants. These pouches are used for a wide range of products, from surgical tools to implantable devices. However, ensuring that these pouches remain consistently sealed throughout their lifecycle is an ongoing challenge. Transport, handling, and storage can all place stress on packaging materials and seals. This is where Container Closure Integrity (CCI) testing becomes a valuable tool. CCI testing evaluates whether the package has maintained a reliable seal without the need for destructive analysis. For porous flexible pouches, standard testing methods may not provide dependable results, so more specialized technologies are employed to confirm packaging performance and support consistent product delivery.

Why Integrity Testing Matters for Porous Pouches?

Porous pouches are commonly used to package medical devices that require sterilization. These pouches are designed to allow sterilizing agents to pass through while keeping contaminants out. Their structure, while functional, can be sensitive to minor imperfections such as incomplete seals, pinholes, or material inconsistencies. These small defects are often not visible and may go undetected without specific inspection methods. If undetected, such defects can impact the sterile barrier, particularly during storage, shipping, or handling.

Integrity testing offers a way to examine these pouches for potential defects before they are distributed. This type of testing can detect leaks or weaknesses that visual checks might miss. Methods used for porous materials are designed to work with breathable structures without compromising the packaging during the process. Regular testing also allows manufacturers to track consistency across production batches and observe any changes in performance over time. For products that rely on a sterile environment, ensuring pouch reliability throughout its lifecycle contributes to a more controlled packaging process. By identifying defects early, integrity testing reduces the chance of compromised packaging reaching end users and supports overall quality assurance efforts within production and distribution environments.

Challenges in Testing Porous Flexible Packaging

Unlike non-porous materials or rigid containers, porous flexible pouches bring unique testing challenges. First, the breathable nature of materials like Tyvek® allows controlled air transmission, which can make it harder to differentiate between normal permeation and an actual leak. This complicates the use of traditional vacuum decay methods, which rely on detecting pressure changes to indicate a breach. Additionally, the flexibility of these pouches makes them more susceptible to shape changes during testing. When a vacuum is applied, the package may deform, affecting the accuracy and repeatability of results. The variability in product shape, air content inside the package, and material thickness adds further complexity.

Common traditional methods such as dye ingress or bubble leak testing are destructive and often depend on visual interpretation. This approach is subjective, less reliable for small defects, and unsuitable for production environments that require rapid, non-invasive evaluations. As a result, specialized equipment and test procedures have been developed to address these challenges.

Testing the Integrity of Porous Medical Packaging Using VeriPac Technology

Testing the integrity of porous medical packaging using VeriPac technology provides a way to identify defects that may not be visible through standard inspection methods. Porous materials such as Tyvek® and medical-grade paper are commonly used in sterile barrier systems due to their ability to allow gas sterilization while offering microbial resistance. However, these materials can be affected by issues such as weak seals, microscopic holes, or material variations. VeriPac technology applies vacuum decay leak testing to detect such flaws without damaging the package. During the test, a vacuum is drawn in a chamber containing the package, and the system monitors for any changes in pressure that would indicate air leakage.

This method relies on non-destructive, quantitative measurement, which can reduce variability in results across different operators or production shifts. Packages that pass the test remain undisturbed and can proceed through the supply chain, which can lower scrap rates and reduce product loss. VeriPac systems can be used in laboratory settings for validation or installed in production environments for routine quality checks. The data produced during testing can be stored and analyzed to track patterns, identify process drift, and make timely adjustments. For porous packaging formats, which can vary in performance due to material structure or sealing methods, VeriPac provides a consistent approach to monitoring package integrity. Early detection of defects can reduce the chances of product recalls or field complaints, contributing to a more controlled and traceable packaging process.

Maintaining the integrity of porous flexible packaging is a focus area for medical device manufacturers aiming to uphold product quality throughout distribution and use. As packaging materials and formats continue to evolve, so does the demand for precise and reliable inspection technologies. Technologies like VeriPac vacuum decay support this goal with non-invasive methods that adapt to a range of pouch configurations while offering measurable performance data. By addressing challenges unique to porous materials, these systems help streamline inspection processes, reduce resource waste, and promote consistency across production. Ultimately, adopting modern CCI testing technologies enhances confidence in packaging reliability and overall process control.

Pharmaceutical products stored under cryogenic conditions face distinct packaging challenges. Products like cell therapies, biologics, and other temperature-sensitive materials require packaging that can maintain seal integrity at temperatures as low as -80°C or even in the vapor phase of liquid nitrogen. Any breach in the container closure system at these temperatures can compromise product stability and safety. Therefore, it is vital to adopt package testing methods that can effectively evaluate seal performance under extreme conditions. Container Closure Integrity (CCI) testing tailored for cryogenic storage helps manufacturers confirm whether packaging systems can withstand ultra-low temperatures without compromising performance.

Why Conventional CCI Testing May Fall Short?

Traditional CCI methods such as vacuum decay, dye ingress, and bubble emission are widely used for evaluating package integrity under standard conditions. However, these techniques are often performed at room temperature, which may not reflect how packaging behaves at cryogenic levels. Materials like plastic films and elastomeric seals can become less flexible or even contract under cold stress. These physical changes may create or enlarge leak paths that remain undetected in ambient testing.

Additionally, many traditional tests have limitations when it comes to detecting very small defects. For instance, dye ingress relies on visual inspection and may miss micro-channels or intermittent breaches. Vacuum decay testing, while more precise, can struggle to detect low-level leakage when packaging materials stiffen at low temperatures. This leaves a gap between test conditions and real-world performance.

Time is another factor. Some standard methods require extended soak or preparation periods, which may not suit fast-paced environments or small-batch production. When dealing with high-value biologics or limited-release therapies, test methods that offer timely, precise, and repeatable measurements without altering the product are often preferred.

Helium Leak Detection for Cryogenic Applications

Helium leak detection provides a method for identifying leaks that is highly sensitive and adaptable to cold-chain environments. It works by introducing helium—a small, inert gas—into the package or test system, and then measuring any escaping gas with a mass spectrometer. Because helium molecules are much smaller than water or oxygen, this technique can detect breaches that other tests might overlook.

This approach aligns well with cryogenic applications because it can be used on packages that have been pre-conditioned to low temperatures. By testing after cold exposure, helium leak detection helps confirm whether packaging maintains integrity throughout storage and handling. The test can be tailored to simulate actual use conditions, providing insights into how seal materials and container components behave when subject to temperature extremes. Another advantage is that helium leak detection is non-invasive and highly quantitative. It delivers leak rate values that can be compared against defined limits, making it easier to track performance across production lots or packaging formats. Whether testing vials, syringes, or specialty containers used for cell therapies, helium leak detection offers a consistent method for examining seal performance.

As cryogenic storage becomes more common in advanced therapies and biologics, packaging validation must keep pace with changing requirements. Conventional CCI methods may not fully address the conditions encountered during deep freezing or subsequent handling. Helium leak detection brings higher sensitivity and adaptability, especially for identifying small or temperature-induced breaches. With the ability to test under simulated storage conditions and deliver clear, measurable outcomes, this method offers a streamlined way to evaluate container performance. For manufacturers navigating the challenges of ultra-low temperature packaging, helium-based CCI testing supports both consistency and product safety from production through to end use.