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Pharmaceutical packaging is designed to protect drug products from environmental exposure, contamination, and mechanical damage. Any compromise in packaging can affect the performance, stability, and shelf life of the product. Even minor defects may lead to degradation or compromised sterility. As packaging materials and formats evolve to meet diverse drug delivery needs, so does the need for reliable methods to detect and address defects early. Understanding the types of packaging issues and how they influence drug quality helps manufacturers maintain consistency throughout the product lifecycle.

Types of Packaging Defects in Pharmaceutical Products

Pharmaceutical packaging defects can occur during forming, sealing, or handling processes. These defects may be visible or hidden, and their impact varies based on package type and product sensitivity.

• Seal Weakness or Incomplete Seals: Often caused by improper heat sealing or contamination at the seal area. Weak seals may not maintain a barrier against moisture or microbial ingress.
• Pinholes and Micro Cracks: Small, often invisible openings that can form due to material stress, poor handling, or equipment issues. They can lead to gas exchange, product oxidation, or moisture ingress.
• Channel Leaks: Typically occur in flexible packaging when a small path forms through the heat-sealed area, allowing leakage without visible damage.
• Component Mismatch or Misalignment: Stoppers, plungers, or caps that do not seal correctly can compromise container closure integrity.
• Defective Components: This includes flaws in rubber stoppers, flip-off caps, plungers, or cartridge closures that may cause container integrity failures.

Impact of Packaging Defects on Drug Quality and Patient Safety

Defective packaging can allow ingress of moisture, oxygen, or microbial contaminants, all of which may alter the stability or sterility of a pharmaceutical product. Exposure to air or humidity may lead to chemical degradation, especially for moisture-sensitive or oxygen-sensitive compounds. For sterile injectables, even a microscopic breach may be sufficient to allow microbial entry, affecting product safety and efficacy.

Other quality concerns include loss of vacuum in sealed containers, or compromised headspace integrity. Physical damage to packaging may also cause product leakage, incorrect dosing, or difficulty in administration.

From a patient perspective, degraded products may result in therapeutic inefficacy, side effects, or adverse events. Healthcare professionals also face increased workloads when identifying compromised packaging or managing incidents related to packaging-related issues.

Technologies Used to Detect Packaging Defects

Pharmaceutical manufacturers use a range of advanced testing methods to identify packaging issues with precision and repeatability.

Vacuum Decay: Vacuum Decay is a non-destructive Container Closure Integrity Testing (CCIT) method that detects leaks and verifies package integrity. It offers deterministic, quantitative, and repeatable results, unlike manual or probabilistic methods. Suitable for rigid, semi-rigid, and flexible containers—both porous and non-porous—it works by placing packages in a sealed chamber with a vacuum source. A pressure rise indicates a leak, while stable vacuum levels suggest an intact package. Vacuum Decay has proven to be a reliable and sensitive solution for leak detection across diverse packaging formats.

MicroCurrent HVLD: MicroCurrent HVLD is a non-destructive, non-invasive CCIT method effective for formats like pre-filled syringes, vials, cartridges, ampoules, BFS containers, bottles, and pouches. It detects leaks in various liquid-filled products, including low-conductivity solutions like sterile water for injection (WFI) and protein-based formulations. In this method, electrode probes scan the sealed container, identifying leaks through changes in current flow and providing approximate defect location. This method uses about 50% less voltage and limits exposure to under 5% compared to traditional HVLD, making it well-suited for parenteral and biologic product testing.

Helium Leak Testing: Helium leak testing is a highly sensitive method that uses helium gas as a tracer to identify microscopic leaks. During the test, the package is filled with helium, then placed in a vacuum chamber connected to a mass spectrometer. If any leaks are present, helium escapes from the container and is detected as a rise in helium concentration, which is measured and expressed as a leak rate. It is widely accepted in the pharmaceutical industry, particularly for high-risk products, and aligns with the deterministic testing principles of USP <1207>.

Conclusion:

Packaging defects in pharmaceutical products can lead to product degradation, contamination, or compromised therapeutic performance. Identifying and addressing these defects through advanced inspection methods supports consistent product quality throughout manufacturing and distribution. Technologies such as vacuum decay, helium leak testing, and MicroCurrent HVLD offer accurate, repeatable detection methods that can be integrated into production lines or used for laboratory analysis. By maintaining reliable packaging systems, manufacturers can better support product performance, patient safety, and regulatory alignment over time.

Combination products such as autoinjectors are transforming drug delivery by combining device technology with drug formulations in a single, user-friendly format. However, with innovation comes complexity—particularly in ensuring container closure integrity (CCI). Autoinjectors, which often house a pre-filled syringe within a device shell, must maintain sterility and product stability across varying conditions and stages of use. Regulatory bodies emphasize robust CCI strategies for these products to ensure patient safety and therapeutic efficacy. As a result, developing a comprehensive CCI profile tailored to autoinjectors is not just a quality control requirement—it’s an essential part of lifecycle management.

Understanding the Testing Challenges for Autoinjectors

Autoinjectors present unique CCI challenges due to their multi-component construction. Unlike standard vials or syringes, autoinjectors enclose a pre-filled syringe within a protective plastic or composite housing, often with complex geometries and multiple interfaces. This layered design introduces risks of mechanical stress, potential micro-leaks, and seal integrity failures at various points—including the plunger, needle shield, and syringe barrel.

Moreover, autoinjectors undergo extensive handling, storage, and transportation, increasing exposure to temperature fluctuations, vibration, and impact—all of which can compromise packaging integrity. Traditional leak detection methods such as dye ingress or bubble tests often fall short in detecting small breaches in these intricate assemblies.

Advanced deterministic CCI testing methods like Helium Leak Detection and High Voltage Leak Detection (HVLD) have emerged as preferred technologies for autoinjectors. Helium mass spectrometry, for example, offers ultra-sensitive detection of micro-leaks down to 10?¹° mbar L/s, making it highly suitable for dry and non-porous systems. HVLD, on the other hand, is effective for liquid-filled syringes and can detect leaks by measuring electrical conductivity across package walls—ideal for identifying seal failures without disassembly.

Building the Package Integrity Profile Across Lifecycle Stages

Creating a robust CCI strategy involves generating a package integrity profile—a lifecycle-based roadmap using multiple testing technologies to assess integrity at key stages.

1. Package Development Stage: Helium Leak Detection

At this early stage, testing focuses on evaluating the inherent integrity of components. Helium leak detection is ideal for this purpose due to its exceptional sensitivity. Components like the plunger-barrel interface, needle bonding areas, and other sealing regions in the PFS can be tested in isolation. These insights help select suppliers, define dimensional specifications, and establish quality thresholds—essential for robust component design.

2. Manufacturing and In-Process Testing: High Voltage Leak Detection (HVLD)

Once the drug is filled into the PFS, HVLD becomes the method of choice. It detects defects by measuring electrical conductivity in the presence of a leak. HVLD can detect small orifices (~3µm) and helps evaluate variables introduced during manufacturing—such as plunger insertion cracks or sealing defects. It supports both routine quality control and in-process testing, making it a vital link in the integrity profile.

3. Final Assembly and Stability Testing: Vacuum Decay Testing

Although vacuum decay has limitations in sensitivity due to device complexity and internal air pockets, it remains the best option for testing the fully assembled autoinjector. To mitigate performance concerns, water-filled surrogates can be used for validation. This approach enables testing for risks like needle-shield back-off, syringe cracking during assembly, and long-term stability after simulated distribution. These insights help optimize secondary and tertiary packaging, ensuring the combination product maintains integrity until end use.

By applying the right CCI test at the right stage, manufacturers can generate a comprehensive data set proving product robustness under real-world conditions.

Autoinjectors require a modern, multi-technology approach to container closure integrity testing. Rather than relying on a single method applied at the final stage, building a package integrity profile across development, manufacturing, and stability stages ensures robust risk management and compliance. Helium leak testing, HVLD, and vacuum decay each play a unique role, together creating a powerful strategy to safeguard product integrity. With rising regulatory scrutiny and the growing complexity of combination products, pharmaceutical companies must adopt this lifecycle-based approach to not only meet global standards but also to deliver safe and effective therapies to patients with confidence.

Pharmaceutical packaging is engineered to protect product quality and maintain sterility. One often-overlooked factor in designing effective Container Closure Integrity (CCI) tests is the material composition of the packaging. Whether it's glass, plastic, or a multilayer laminate, each material interacts differently with environmental stresses, manufacturing processes, and test conditions. These material properties influence both the likelihood of leakage and the selection of appropriate CCI testing methodologies. To ensure effective quality assurance, manufacturers must consider how materials affect CCI outcomes.

Understanding the Material Used in Pharmaceutical Packaging

The pharmaceutical industry uses a variety of packaging materials, each selected based on product compatibility, regulatory requirements, and barrier performance. Common materials include glass, cyclic olefin polymers, high-density polyethylene (HDPE), and multilayer films. Each of these materials brings distinct physical and chemical characteristics that impact Container Closure Integrity testing.

Glass containers, like vials and ampoules, offer excellent barrier properties but are rigid and brittle. Their fragility makes them more prone to cracks or micro-fractures during handling or transportation, which may not always be visible. In contrast, plastic containers such as HDPE or polypropylene are more flexible but can be permeable to gases or moisture over time. Multilayer laminates used in sachets and pouches bring a combination of barrier layers but may introduce seal complexity and heterogeneous material zones.

These material properties dictate how leaks form, how they behave under vacuum or pressure conditions, and how detectable they are using different technologies. For example, a micro-leak in a glass vial may behave differently from one in a flexible film pouch due to surface tension, container rigidity, and internal pressure dynamics. Recognizing these nuances is vital when tailoring CCI test parameters.

Optimizing Test Methodologies for Different Packaging Materials

Choosing the right test method is dependent not just on the container type, but on its material composition and structure. Deterministic methods such as vacuum decay, high-voltage leak detection (HVLD), and helium leak testing must be evaluated for compatibility with specific materials.

• Vacuum Decay

Vacuum decay is well-suited for testing both rigid containers such as glass vials and syringes as well as flexible packaging, i.e. pouches and sachets. As a deterministic and non-destructive approach to container closure integrity testing (CCIT), it offers improved sensitivity, repeatability, and compliance with regulatory standards when compared to dye-based methods. The process places the sealed container in a vacuum chamber, applies a controlled vacuum, and tracks pressure levels over time. An increase in pressure suggests the presence of a leak, with the ability to detect even micro-level defects. This method offers strong reliability and versatility for testing rigid, semi-rigid, and flexible packaging composed of porous or non-porous materials, making it a dependable choice for quality control in production environments.

• MicroCurrent HVLD

High-voltage leak detection is particularly suitable for liquid-filled containers with conductive products, such as pre-filled syringes. It works by measuring the electrical conductivity between the container surface and a high-voltage probe. This non-destructive, non-invasive technology operates with approximately 50% less voltage and exposes both the product and environment to under 5% of the voltage used in traditional HVLD systems. It stands out as one of the most effective CCI solutions for parenteral and biological products.

• Helium Leak Detection

Helium leak testing is widely regarded for its high sensitivity and is particularly effective across a range of packaging materials. This technique uses helium as a tracer gas to detect extremely small leaks, even those at the micron level. It is especially valuable for rigid containers like glass vials and ampoules, as well as complex structures such as pre-filled syringes and sealed cartridges. Helium leak testing enables quantitative and repeatable results, making it a suitable option for validating integrity in a variety of material formats, particularly when high assurance levels are required.

Material composition is a core factor in the design and success of container closure integrity testing. From the brittleness of glass to the permeability of polymers and the complexity of multilayer laminates, each material introduces specific challenges and behaviors that influence both leak potential and test method selection. A one-size-fits-all approach to CCI does not account for these variations. Aligning test methodologies with the physical characteristics of the container ensures more accurate, reliable results. By understanding how materials interact with their environment and test technologies, pharmaceutical manufacturers can create robust integrity strategies that support product safety and regulatory compliance.

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.

In pharmaceutical manufacturing, product quality relies heavily on a system-wide approach that identifies and controls potential issues before they impact safety or efficacy. Quality Risk Management (QRM) offers a structured framework to assess where challenges might arise and how they can be mitigated. Among the many factors assessed through QRM, packaging systems—and specifically container closure integrity (CCI)—receive heightened focus. As regulatory expectations shift and technology evolves, so too does the way manufacturers handle the assessment and assurance of CCI performance.

Quality Risk Management in Pharma: A Quick Overview

Quality Risk Management (QRM) in the pharmaceutical field provides a structured way to evaluate and address potential issues that may affect product quality. It combines scientific understanding with knowledge of processes to identify areas where challenges could arise and supports decisions that lead to more consistent outcomes. Using tools such as Failure Mode and Effects Analysis (FMEA) and risk ranking methods, manufacturers can prioritize actions based on the probability of occurrence and the possible consequences. This approach encourages proactive thinking and allows for adjustments before problems develop. It also supports clear documentation, which is useful for meeting regulatory expectations. QRM can be applied across all stages of a product’s lifecycle, from development and manufacturing to packaging and distribution. By helping teams focus on specific risks and their impact, QRM contributes to a more predictable and controlled manufacturing environment. It remains a widely adopted method for maintaining quality in increasingly complex production landscapes.

The Role of Container Closure Integrity in Quality Risk Management

Container Closure Integrity (CCI) is a significant aspect of Quality Risk Management (QRM) as it ensures that packaging maintains its ability to safeguard the product from contamination or degradation. In pharmaceutical manufacturing, CCI is evaluated to detect any flaws in the container that could compromise the sterility or stability of the product. Testing methods such as Vacuum Decay, Helium Mass Spectrometry, and High Voltage Leak Detection are used to identify leaks or defects in packaging that might not be visible to the naked eye. By including CCI testing in the QRM process, manufacturers can pinpoint risks associated with packaging and take steps to address them before they affect product quality. This approach supports more informed decision-making, helps meet regulatory requirements, and ensures that the product remains secure from production through distribution. Effective CCI testing contributes to maintaining product integrity and minimizing potential risks to both safety and performance.

Moving from Probabilistic to Deterministic Testing

The shift from probabilistic to deterministic testing in pharmaceutical manufacturing reflects a move toward more precise and consistent methods for evaluating packaging integrity. Probabilistic approaches, such as dye ingress or bubble emission, rely on visual interpretation and can yield variable results due to differences in test conditions or operator skills. In contrast, deterministic methods like Vacuum Decay, Helium Mass Spectrometry, and High Voltage Leak Detection provide quantitative data, offering more reliable and repeatable results. These techniques are increasingly adopted as they allow for better detection of even the smallest defects in packaging, enhancing product safety and stability. By moving to deterministic testing, manufacturers are able to reduce uncertainty in their risk assessments and make more confident decisions regarding packaging quality. This transition also aligns with evolving regulatory expectations, as deterministic testing methods are seen as more reliable for ensuring product integrity and maintaining consistent quality throughout production and distribution.

As pharmaceutical packaging becomes more complex, and product requirements more demanding, QRM provides a way to maintain control and adapt to evolving conditions. Within this framework, container closure integrity testing continues to gain attention. Moving toward deterministic test methods allows for better alignment with data-driven decision-making and supports more predictable outcomes. The transition reflects a broader industry shift toward precision, reproducibility, and ongoing improvement in product oversight. By integrating advanced CCI testing into QRM strategies, manufacturers are better positioned to uphold product quality from production through patient delivery.

Container Closure Integrity (CCI) testing ensures that pharmaceutical packaging systems maintain sterility and product quality throughout their shelf life. USP <1207> provides a detailed framework for evaluating the integrity of container closure systems, offering guidance on testing methodologies, validation, and regulatory expectations. By following these guidelines, manufacturers can verify the reliability of their packaging and address potential risks, such as contamination or leakage. USP <1207> emphasizes the use of advanced, reliable, and non-destructive testing methods to support consistent results. This approach strengthens compliance with regulatory requirements while helping ensure safe and effective pharmaceutical products reach patients.

What is USP <1207>?

USP <1207> is a chapter in the United States Pharmacopeia that outlines guidelines for Container Closure Integrity (CCI) testing of sterile pharmaceutical packaging. It ensures packaging systems maintain sterility, prevent contamination, and preserve product safety and efficacy throughout their shelf life.

The chapter categorizes CCI testing methods into deterministic and probabilistic types. Deterministic methods, such as vacuum decay, helium leak detection, and high-voltage leak detection (HVLD), are preferred for their precision and repeatability. In contrast, probabilistic methods, like dye ingress and bubble tests, rely on subjective assessments and are less reliable. USP <1207> also promotes non-destructive testing to reduce waste and improve efficiency. By addressing CCI testing throughout the product lifecycle, from development to post-market evaluation, USP <1207> provides a robust framework for pharmaceutical packaging integrity. Following these guidelines helps manufacturers meet regulatory standards and deliver safe, high-quality drugs to patients.

Why is Container Closure Integrity Testing Essential for Regulatory Compliance?

Container Closure Integrity (CCI) testing supports the sterility and quality of pharmaceutical products, meeting regulatory requirements and safeguarding public health. It demonstrates that packaging systems effectively prevent contamination and leakage, ensuring the product remains safe and stable throughout its shelf life. Regulatory bodies like the FDA place significant emphasis on CCI testing to uphold Good Manufacturing Practices (GMP) and reduce risks associated with packaging failures. By implementing robust CCI testing methods, manufacturers can confirm the reliability of their container closure systems and address potential vulnerabilities early in the process. Testing techniques, such as vacuum decay, helium leak detection, and high-voltage leak detection, provide measurable and repeatable results, supporting compliance and quality assurance.

Adhering to CCI testing standards, including those outlined in USP <1207>, fosters trust in pharmaceutical packaging and helps manufacturers avoid costly recalls, while protecting the safety of patients and the integrity of products.

Key Components of USP <1207> for CCI Testing

USP <1207> outlines a structured approach for evaluating the integrity of container closure systems to ensure the sterility of pharmaceutical products. Its key components include:

• Testing Methodologies: The chapter categorizes testing into deterministic and probabilistic methods. Deterministic methods, such as vacuum decay, helium leak detection, and high-voltage leak detection (HVLD), are precise, repeatable, and sensitive. Probabilistic methods, like dye ingress and bubble tests, are qualitative and less reliable.
• Non-Destructive Testing: USP <1207> encourages the use of non-destructive methods to preserve sample integrity and minimize waste while delivering reliable results.
• Lifecycle-Based Testing: The chapter emphasizes the importance of testing across the product lifecycle, from development to manufacturing and post-market, ensuring consistent packaging integrity.
• Validation and Sensitivity: CCI methods must be validated to demonstrate their ability to detect leaks at specified thresholds, ensuring compliance with regulatory standards. .

These components provide a comprehensive framework for verifying packaging reliability and enhancing patient safety.

Following the guidance of this USP <1207> helps avoid potential risks, safeguard product quality, and demonstrate commitment to patient safety. As regulatory expectations continue to evolve, staying up to date with testing methods and industry standards remains an ongoing priority for pharmaceutical companies to maintain compliance and trust in their products.

Maintaining container closure integrity (CCI) in radioactive pharmaceuticals safeguards safety and regulatory compliance. Even small leaks can result in contamination, radiation exposure, and decreased drug effectiveness. For these sensitive products, advanced CCI testing accurately detects any breaches that could compromise packaging integrity. The complexities of handling radioactive materials demand specialized approaches to ensure reliable assessments without affecting product quality. By applying precise and consistent testing methods, manufacturers protect the integrity of radioactive pharmaceuticals throughout their shelf life, supporting both patient safety and healthcare standards.

What are Radioactive Pharmaceuticals?

Radioactive pharmaceuticals, or radiopharmaceuticals, are specialized medications containing radioactive isotopes, used primarily in diagnostic imaging and targeted therapy. These compounds emit controlled radiation, enabling healthcare professionals to visualize internal organs, assess tissue function, and treat diseases like cancer with precision. In diagnostics, they emit radiation that is detected by imaging devices, offering detailed insights into organ function and disease. In treatment, radiopharmaceuticals deliver targeted radiation to diseased cells, particularly in cancer therapy, thereby reducing damage to surrounding healthy tissues. Their unique ability to target specific areas makes radiopharmaceuticals indispensable in modern medicine, providing accurate diagnoses and effective treatments while minimizing systemic side effects.

Challenges of CCI in Radioactive Pharmaceuticals

Container Closure Integrity (CCI) testing for radioactive pharmaceuticals presents unique challenges due to the specialized nature of these products. Here are some key challenges:

• Cost-Efficiency: Unlike more complex testing methods, this approach allows for immediate testing and precise data collection, reducing the time spent on preparation and analysis. This results in faster decision-making, quicker time-to-market, and lower overall costs, all while maintaining high levels of accuracy and reliability in detecting leaks.
• Radiation Safety: Handling radioactive materials requires strict safety protocols, complicating testing environments. Specialized containment may be necessary to reduce radiation exposure risks.
• Material Compatibility: Packaging must resist radiation-induced degradation over time. Selecting materials that maintain integrity despite exposure is crucial.
• Test Method Selection: Traditional CCI methods may not be suitable for radioactive products. Non-destructive techniques, such as vacuum decay or helium leak testing, are often preferred.
• Regulatory Compliance: Radiopharmaceuticals face stringent pharmaceutical and radiation safety standards. Meeting dual regulatory requirements can complicate CCI validation.
• Sterility Assurance: Maintaining sterility without compromising the product is essential. Traditional sterilization methods may not be suitable for radioactive pharmaceuticals.

Testing Integrity in Radioactive Pharmaceuticals Using Vacuum Decay Technology

Vacuum Decay leak testing is a non-destructive Container Closure Integrity Test (CCIT) method commonly used to detect leaks in sealed packaging. Known for its sensitivity and practicality, it can identify leaks in rigid, semi-rigid, or flexible packages, whether made from porous or non-porous materials. This method offers reliable, accurate, and consistent results, ensuring precise package integrity testing. As a non-destructive alternative to traditional water bath and dye ingress tests, vacuum decay provides an effective solution for leak detection in the pharmaceutical and medical device sectors.

Vacuum Decay operates on fundamental physical principles of container integrity. The package is placed inside a sealed vacuum chamber connected to an external vacuum source. A specific vacuum level is applied based on the packaging type and required sensitivity. The system then monitors the chamber and any dead space for a set duration. Sensitive differential pressure transducers track changes in vacuum levels over time. A pressure increase beyond the pre-defined pass/fail limit signals a leak in the container.

As the pharmaceutical industry continues to evolve, adopting specialized CCI testing enhances product quality and builds trust in the supply chain. Prioritizing precise and thorough CCI evaluations contributes to safer and more reliable radioactive pharmaceuticals in the market.

Container Closure Integrity Testing (CCIT) is an essential process in the pharmaceutical and medical device industries, ensuring that products remain safe and effective throughout their shelf life. Among the various methods available, helium leak testing stands out for its precision and reliability. PTI specializes in offering expert Helium Leak Testing services tailored specifically for pharmaceutical packaging, a critical component in ensuring product safety and efficacy. Our helium leak testing combines advanced technology with industry expertise to provide cost-efficient solutions without compromising on quality. This method not only delivers reliable data but also allows for significant flexibility in testing parameters, accommodating the unique needs of each client. With a focus on speed, our services ensure rapid turnaround times, enabling manufacturers to make timely decisions and maintain production schedules.

Helium Leak Testing for Pharmaceutical Packaging

Helium leak testing is a highly effective and precise method used in the pharmaceutical industry to ensure the integrity of packaging. This method leverages helium’s small atomic size and inert properties, making it ideal for detecting even the smallest breaches in packaging that could compromise product safety. In this process, helium is introduced into or around the pharmaceutical package—such as vials, ampoules, or blister packs. If there is any leakage, highly sensitive detection instruments can identify and trace the helium escaping from the tiniest of openings. This method offers a high level of precision, capable of detecting leaks as small as 10^-10 mbar L/s, which ensures the highest level of packaging integrity.

Unlike other leak detection methods, helium testing is both highly sensitive and safe, as helium does not react with the product or packaging materials. It ensures compliance with stringent regulatory requirements, like USP <1207>, which focus on container closure integrity. The ability to accurately detect micro-leaks helps prevent contamination, ensuring that pharmaceutical products remain sterile and effective throughout their shelf life. By employing helium leak testing, pharmaceutical companies can not only maintain product quality and safety but also optimize their quality assurance processes, reducing waste and avoiding costly recalls, all while delivering confidence to regulators and patients alike.

CCIT Helium Leak Testing Services

• Cost-Efficiency: Unlike more complex testing methods, this approach allows for immediate testing and precise data collection, reducing the time spent on preparation and analysis. This results in faster decision-making, quicker time-to-market, and lower overall costs, all while maintaining high levels of accuracy and reliability in detecting leaks.
• Reliable Data: Unlike probabilistic methods, where outcomes can vary and are influenced by factors like chance or operator judgment, helium leak testing delivers precise, objective results. Since it relies on measurable physical principles, the data is free from operator subjectivity, ensuring accuracy and repeatability. This makes helium leak testing a trusted solution for industries that require stringent quality control, as it guarantees dependable leak detection every time.
• Time Savings: Reduces the time required for leak detection compared to headspace analysis, often completing the process in less than a day. While headspace analysis can take several days due to its complex sample preparation and analysis procedures, helium leak testing streamlines the testing process with its straightforward methodology. This rapid turnaround enables companies to quickly assess the integrity of their products, leading to faster decision-making and minimizing delays in production.
• Flexibility: Our testing services provide exceptional flexibility, allowing us to customize our approach to meet your specific requirements without the additional costs associated with adhering to stringent Good Manufacturing Practice (GMP) guidelines. This adaptability means we can adjust testing parameters, methodologies, and timelines based on your requirements, ensuring that you receive the most relevant and effective solutions.

Helium leak testing services offer vital benefits for the pharmaceutical industry. They enable immediate, precise data collection, enhancing cost efficiency while ensuring product integrity and safety. The objective results from this deterministic method eliminate uncertainties, boosting confidence in quality control. Rapid testing further streamlines operations and enables quick responses to market demands. With the flexibility to tailor methodologies to specific client needs, helium leak testing services are essential for maintaining high standards and ensuring the reliability of pharmaceutical packaging throughout its shelf life

In the dynamic and highly regulated world of pharmaceuticals, biotechnology, and medical devices, ensuring the integrity of product packaging is vital for maintaining safety and compliance. Container Closure Integrity Testing (CCIT) play a crucial role in verifying that packaging systems effectively safeguard products from contamination, leakage, and environmental factors. From initial feasibility studies to the development of precise test methods, and from stability testing to specialized helium leak detection, these services provide essential insights into the effectiveness of packaging solutions. By leveraging advanced technologies and methodologies, CCIT ensure products remain protected and meet stringent regulatory standards throughout their lifecycle.

Advanced Laboratory Testing Services

CCI testing services provide a comprehensive suite of solutions designed to assess and verify the integrity of packaging systems. Our CCI testing services encompass a range of specialized offerings, including:

Feasibility Studies: These experimental studies are the first step in determining the most suitable inspection technology and test method for a specific application. Our feasibility studies are backed by detailed reporting and comprehensive test result data, providing a solid foundation for subsequent testing and validation.

Test Method Development Support: Our services include the development and documentation of test methods, including advanced initial recipe creation, container qualification, and system suitability testing. We provide thorough testing and documentation to ensure the accuracy and reliability of test methods.

Stability Testing: This service ensures that products maintain container closure integrity throughout their stability period. Stability testing is crucial for verifying that packaging continues to protect the product over time, under various storage conditions.

Recall & Batch Release Testing: Designed for recalled products, products on hold, and batch release, this service provides critical testing to ensure product integrity and compliance before market release.

Helium Testing Services: Helium testing is used for a variety of purposes, including R&D work, component/material selection, packaging equipment qualification, and ongoing quality monitoring. Our helium testing services cover:

• Cold storage testing at temperatures ranging from -0°C to -160°C.
• Helium pre-filled and 100% Helium Flow Method testing.
• Compliance with USP 1207 standards.
• Testing for parenteral formats, blister cards, pouches/sachets, and various industrial applications.
• Package validation, component selection, stability sample testing, and R&D studies.

All leak testing is conducted in a non-GMP environment, ensuring flexibility and efficiency in testing procedures. Our CCI testing services are designed to meet the unique needs of each client, providing reliable and accurate results that support product quality and safety. These services are not just a regulatory requirement but a fundamental component of a commitment to quality and safety in product development and manufacturing.

Class III medical devices in the United States are subject to stringent regulation by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. These devices, characterized by their high-risk nature, include those vital to sustaining human life or preventing health impairment, as well as those posing potential, unreasonable risks of illness or injury.

Examples of Class III devices encompass implantable pacemakers, specific prosthetic devices, and innovative technologies such as certain in vitro diagnostic devices. Classification is determined by factors like intended use, indications, and associated risks. Due to their complexity and critical roles in medical procedures, Class III devices undergo a rigorous pre-market approval (PMA) process.

Manufacturers must furnish extensive scientific and clinical evidence to demonstrate a device's safety and efficacy before it can be marketed. This robust regulatory framework ensures that Class III medical devices meet the highest standards for safety and performance, safeguarding patient health.

Packaging for these devices plays a critical role in maintaining the integrity of the product, ensuring it reaches the end user in a safe and effective condition. The packaging of Class III medical devices faces unique challenges due to the stringent regulatory requirements and the critical nature of the enclosed products. Ensuring the integrity of the packaging is essential to prevent contamination, maintain sterility, and safeguard the efficacy of the medical devices.

How to Ensure Container Closure Integrity of Class III Medical Device Packaging

Container Closure Integrity (CCI) is a vital aspect of ensuring the reliability of Class III medical device packaging . CCI testing involves assessing the seals and closures to confirm they effectively prevent the ingress of contaminants and maintain the sterility of the device. This testing is crucial to meeting regulatory standards and ensuring patient safety.

PTI’s VeriPac series are non-destructive, non-invasive inspection systems for leak detection and package integrity testing. These systems reduce waste and provide operators with a clear understanding of package quality. The VeriPac test system produces real time results from precise quantitative measurements that identify packaging defects before critical process issues get out of control. Tests can be performed in any sequence and even repeatedly on a single sample. Good packages can be returned undamaged to the packaging line. Testing is more reliable, sensitive and efficient than destructive methods. VeriPac series utilizes the ASTM approved patented Vacuum Decay leak test method F2338, recognized by the FDA as a consensus standard for package integrity testing.

Technology Overview

PTI’s VeriPac leak testers connect to a test chamber that is specially designed to contain the package to be tested. The package is placed inside the test chamber to which vacuum is applied. The absolute transducer technology is used to monitor the test chamber for both, the level of vacuum as well as the change in vacuum over a predetermined test time. The changes in absolute and differential vacuum indicate the presence of leaks and defects within the package. The test cycle takes only a few seconds, results are non-subjective, and testing is non-destructive to both product and package. The sensitivity of a test is a function of the sensitivity of the transducer, the package design, the package test fixture and critical test parameters of time and pressure. Test systems can be designed for manual or fully automated operation. This inspection method is suitable for laboratory offline testing, QA/QC statistical process control, automated batch or 100% inline testing.

Benefits of VeriPac series

• Non-destructive, non-subjective, no sample preparation
• Deterministic, quantitative test method
• Defect detection down to single digit microns.
• High level of sensitivity, repeatability and accuracy
• Short cycle time provides operator with PASS/FAIL result
• Small footprint and modular portable design
• ASTM test method and FDA standard
• Referenced in USP 1207 guidance

Low head space packages are a common type of packaging used for a variety of products, including pharmaceuticals, medical devices, and food. These packages are designed to have a minimal amount of space between the product and the packaging material, which can help extend the shelf life of the product and protect it from contamination. Low head space packages are typically made of a flexible material, such as film or foil. The material is then sealed to the product, creating a tight seal that helps to preserve the product's integrity.

However, low head space packages can also be more susceptible to leaks, which can lead to sterility breaches, product spoilage and contamination. Therefore, it is important to ensure that these packages are properly sealed to prevent leaks and contamination. VeriPac 410 is a non-destructive seal and leak detection system that can help ensure the integrity of low head space packages.

Applications of low head space packages

Low head space packages are used in a variety of industries, including:

• Pharmaceutical industry: Low head space packages are used to package pharmaceuticals, such as tablets, capsules, and transdermal patches.
• Medical device industry: Low head space packages are used to package medical devices, such as, suture packaging.
• Personal care industry: Low head space packages are used to package personal care products, such as serums, lotions and creams packaged in sachets and pouches.

Low Head Space Package Inspection Using Force Decay Technology

Force Decay serves as a quantitative method for detecting leaks, especially in packaging with low headspace. The applicable packaging formats encompass non-porous materials, such as films, laminates, or foils. This method, being non-destructive, leaves the sample packages undamaged and unaltered. Following the completion of the test, the packages can seamlessly return to the batch without the need for disposal.

The testing system employs nested tooling to position the package consistently and restrict the unmeasured expansion of the package under examination. Initiating the test involves creating a vacuum in the test chamber, prompting the package to expand within it. Vacuum levels are continuously monitored throughout the test cycle, evaluating the package using the ASTM F2338 vacuum decay leak test method.

Multiple packages can undergo testing in a single test cycle, with the force decay measurement system discerning any defective packages. Defective packages exhibit a decay in the expansion force or vacuum level during the test cycle. The location of the defective package or cavity is then pinpointed. Force decay proves most effective when assessing multi-cavity package formats.

PTI’s VeriPac 410 inspection technique leverages force decay technology for non-destructive seal and leak detection in blister packs, sachets, and pouches with low headspace. VeriPac 410 functions as a vacuum based Container Closure Integrity test (CCIT) method, capable of testing multiple packages in a single test cycle. The force decay measurement system identifies any defective packages. This technology accurately measures force by observing the surface deflection of a package during a typical vacuum-based test cycle. The force measurement capability enables the VeriPac 410 series to pinpoint which package is defective while also conducting leak tests on packages with minimal headspace. Force decay remains the most effective technology, particularly in the assessment of multi-cavity package formats. This technology is scalable from the laboratory to automated inline inspection platforms.

Benefits of Force Decay leak testing

• Non-destructive and non-invasive
• Non-destructive, non-subjective, no sample preparation
• The test protocol is programmed into the testing unit with high degree of repeatability.
• Multiple packages can be tested in a single test cycle
• The test is operator independent and can be performed with minimal training
• Supports sustainable packaging initiatives
• Optimal solution for in-process testing
• Cost effective with rapid return on investment

In the early days, coffee was often packaged in simple sacks or bags made from natural materials, such as burlap or hemp. These materials were not very airtight, so they could not keep coffee fresh for long periods of time. Vacuum sealed packaging was invented during the 1900s. This packaging removes all of the air from the packaging, which helps to keep coffee fresh for an extended period of time. Vacuum sealed packaging is also lightweight and relatively inexpensive, so it quickly became the most popular type of coffee packaging.

In recent years, there has been a growing trend towards more sustainable coffee packaging. This trend is driven by concerns about the environmental impact of traditional coffee packaging materials, such as plastic and tin.

Overview of Coffee Packaging

Coffee packaging refers to the process of packaging and presenting coffee beans or ground coffee for distribution, sale, and consumption. Coffee packaging serves several important purposes, including preserving the freshness and flavor of the coffee, protecting it from external elements such as light, moisture, and oxygen, and providing information to consumers.

Coffee packaging plays a crucial role in ensuring that coffee reaches consumers in optimal condition, with its flavor and aroma preserved. It also serves as a means of communication between coffee producers and consumers, conveying information about the coffee's characteristics and the values of the company that produces it.

Integrity testing of coffee packaging ensures that the packaging is free of leaks and defects that could compromise the quality of the coffee. This is important to do, as leaks can allow oxygen, moisture, and light to enter the packaging, which can all degrade the flavor of the coffee.

Here are some of the benefits of integrity testing for coffee packaging:

• It can help prevent coffee from going stale or developing off-flavors.
• It can help protect coffee from contamination.
• It can help ensure that coffee meets quality standards.
• It can help reduce product recalls.
• It can help improve customer satisfaction.

Quality Testing Using Vacuum Decay Technology

Vacuum decay technology is a non-destructive method for testing the integrity of coffee packaging. It is a Container Closure Integrity Test (CCIT) method with a proven capability of non-destructively testing packaging at the production line with unmatched reliability and sensitivity. Non-destructive testing not only allows a greater understanding of package quality, but also reduces waste as compared to destructive test methods. Waste reduction, in turn, results in a higher return on investment and brings operations closer to green initiatives.

Vacuum decay technology operates by placing sample packages in a closely fitting evacuation test chamber, which is equipped with an external vacuum source. Single or dual vacuum transducer technology is used to monitor the test chamber for both the level of vacuum as well as the change in vacuum over a predetermined test time. The changes in absolute and differential vacuum indicate the presence of leaks and defects within the package. VeriPac series is a practical alternative to destructive test methods and can precisely detect leaks as small as 5 microns, identifying process issues before they become critical, avoiding catastrophic quality deviations.

Benefits of Vacuum Decay Test System

• Non-destructive technology.
• ASTM Test Method F2338, FDA Consensus Standard and referenced in USP 1207 Guidelines.
• Accurate, repeatable results.
• Pass/fail results backed by quantitative test data.
• Completely tool-less with no changeover to test different packaging formats.
• Identifies which cavity is defective.
• Eliminates destructive, subjective testing methods.

Vacuum decay technology is a valuable tool for ensuring the quality of coffee packaging. It can help prevent coffee from going stale or developing off-flavors. It can also help protect coffee from contamination. If you are a coffee roaster or retailer, integrity testing of coffee packaging is an important quality control measure that you should implement.

Container closure integrity (CCI) testing of intravenous (IV) bags is an important quality control measure to ensure the safety and efficacy of the products. CCI testing helps verify that the container closure system, including the bag and its closure, maintains its integrity throughout the product's shelf life and prevents any leakage or contamination.

Various methods, including visual inspection, dye immersion testing, bubble emission testing, headspace gas analysis, and Vacuum decay testing can be employed to assess the integrity of the container closure system. These methods help to identify any defects or breaches that may compromise the sterility and stability of the IV bags. Manufacturers should select an appropriate method based on their specific requirements and regulatory guidelines to ensure the quality and safety of the IV bags.

Vacuum Decay Technology for CCI Testing of Intravenous Bags

Vacuum decay technology is an FDA-approved leak detection technique that can be used for CCI testing of high-risk package applications. The non-destructive nature of the process allows for greater understanding of packages, testing at a greater frequency with more accuracy and with less waste. Vacuum decay technology is capable of detecting leaks in sealed rigid, semi-rigid and flexible packaging made of non-porous or porous materials and has been proven to provide repeatable, reliable and quantitative test results.

VeriPac testing systems using Vacuum decay leak testing are highly effective for leak testing of IV bags. Using a differential pressure transducer leak test system, the test method is capable of detecting package leaks and invisible defects in the IV bag body and also in seams, welds and port areas. This method is non-invasive, non-subjective and does not require sample preparation.

The test method works by connecting the VeriPac test systems to a manually operated test chamber containing an IV bag. The next step is to draw a vacuum on the IV bag in the test chamber and observe any changes in the vacuum level. If there is any damage to the package, air or liquid will flow from the package into the chamber, causing pressure fluctuations. On the other hand, defect-free packages do not leak any pressure into the chamber, keeping the chamber vacuum level constant. Regardless of the location of the defect, the vacuum decay system can pick up both large and small defects. It takes about 30 seconds for testing IV bags, repeatable and sensitive to 15 microns for liquid and gas leaks.

Benefits of Vacuum Decay Technology

• Eliminates destructive, subjective testing methods.
• Non-destructive technology.
• Accurate, repeatable results.
• Pass/fail results backed by quantitative test data.
• Eliminates destructive, subjective testing methods.
• ASTM Test Method F2338, FDA Consensus Standard and referenced in USP 1207 Guidelines.
• Meets Annex 1 regulatory guidelines.

Recent regulatory changes have shifted requirements and strategies for container closure integrity. IV bags and flexible parenteral presentations have experienced the greatest impact from these new perspectives on quality. IV bags have always presented a significant risk. New provisions to Annex 1 have made the requirements for quality risk management (QRM) clear, and USP guidance documents outline the need for greater control. Based on the regulatory requirements and guidance, practical solutions for IV bag container closure integrity should offer non-destructive, practical and deterministic approaches to assure integrity. There are critical considerations for IV bag QRM, and strategic approaches to assuring integrity of IV bags and flexible parenteral presentations to satisfy the shifting regulatory environment.

Vacuum Decay is a non-destructive method for testing the integrity of container closures for package integrity and leak path detection. The technology provides quantitative, deterministic, and reliable test results to assure package integrity in comparison to manual inspection and other non-deterministic test techniques. The vast range of package types that may be accommodated by Vacuum Decay technology includes filled and sealed rigid, semi-rigid, and flexible packaging consisting of non-porous or porous materials.

Vacuum Decay Technology

Vacuum Decay is one of the most efficient and accurate vacuum-based leak detection methods. The method operates by placing the package within a properly outfitted evacuation test chamber that contains an external vacuum source. To detect any deviations from a predetermined targeted vacuum level, the vacuum levels are continually monitored. If there is a defect in the packaging, air or liquid will leak into the chamber from the package and cause a change in pressure. On the other hand, non-defective packages do not leak any pressure into the chamber, maintaining the chamber vacuum level constant. The test cycle is quick, non-invasive, and non-destructive to both the product and the container. The Vacuum decay system can detect both major and minor defects, regardless of where they are located. The system has various applications in the field of pharmaceuticals and medical devices.

Applications of Vacuum Decay Technology in Various Industries

• Pharmaceutical

Pharmaceutical products are a range of substances used for treating, diagnosing, or changing organic processes to help the management of public health. Pharmaceutical products are tested to make sure they adhere to strict safety and quality requirements. Previously, pharmaceutical packaging was only subjected to sterility testing. However, the United States has recognized that sterility testing alone is not sufficient to maintain the integrity of pharma products. FDA (Food and Drug Administration) has published guidance related to pharma industry on submission of documentation for sterilization process evaluation in human and veterinary drug products.

Container closure integrity (CCI) testing is a non-destructive package inspection technology for finding leaks and avoiding potential contamination. A test like this is necessary since any defect in the container might allow foreign particles to enter the product and thereby reduce its shelf life. Since it impacts both the product and the patient, a manufacturer places high priority on implementing the proper container closure system. Thus, the relevance of container closure integrity testing in the pharmaceutical industry has increased substantially over time. Vacuum Decay and MicroCurrent HVLD are the most chosen technologies for testing pharmaceuticals.

• Medical Device

Maintaining medical device package integrity is essential to make sure the product is delivered to the end user unharmed. Medical device packaging and delivery options range from rigid non-porous containers to flexible porous packaging. Every packaging format has a different set of characteristics and requirements, so choosing the right inspection technique requires a thorough approach. Package challenges have risen along with packaging format and material innovations. Among all medical equipment, Class III devices produce the greatest risk to maintaining package integrity. These implanted devices preserve or maintain life. Pacemakers, cardiovascular stents, respiratory ventilators, and breast implants are a few examples of Class III medical devices. Since these devices are inserted into human bodies directly, even a small packaging defect puts patient’s safety at risk. Therefore, it is essential to evaluate the container closure integrity of medical devices.

Vacuum Decay Technology Benefits

• Non-destructive, non-subjective and does not require sample preparation.
• Detection of defects down to 0.01 cc/min.
• Results show that they are more accurate than dye ingress.
• Quantitative, deterministic testing technique.
• Supports initiatives for waste reduction and sustainable packaging.
• ASTM test method and FDA recognized standard.

When determining the integrity of pharmaceutical and medical devices, Vacuum decay leak testing is the best non-destructive option. The test measurement generates a reliable and accurate quantitative result, as well as a pass or fail decision. The FDA recognizes the standard Vacuum Decay leak test technique (ASTM F2338) as a consensus standard for evaluating container closure integrity (CCI). The test technique is referenced in the United States Pharmacopeia Chapter on CCI (USP Chapter 1207) and listed in ISO 11607.

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.