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In the pharmaceutical industry, the integrity of every vial, syringe, or cartridge is essential. A breach in a container closure system can compromise sterility, jeopardize patient safety, and trigger costly recalls or regulatory actions. For these reasons, Container Closure Integrity Testing (CCIT) has become a cornerstone of product development and quality assurance.

But not all CCIT methods are created equal. The industry is steadily moving away from archaic, probabilistic methods, like dye ingress, that provide limited data, prone to human error, and inherently subjective; factors which lead to lower levels of quality assurance. Instead, regulators and manufacturers are embracing deterministic methods, which deliver science-based, quantifiable results.

That’s where PTI’s Life Science Services program comes in. Built around the principles of USP <1207>, Life Science Services provides a complete, end-to-end framework for implementing deterministic CCIT solutions across the entire product lifecycle.

A Lifecycle Approach to CCIT through Life Science Services

1. Feasibility Studies: Every product-package system has unique challenges, from fill volume to material properties. Life Science Services begins with feasibility testing and test method selection to determine which deterministic CCIT method, such as vacuum decay, is best suited to reliably detect leaks of regulatory and clinical concern. This early stage work helps de-risk development by confirming the method’s applicability and alignment with USP <1207> before resources are heavily invested.

2. Equipment Installation and PQ (Aligned with USP <1058>): When clients deploy CCIT equipment, proper implementation is critical. Our team manages installation and qualification in full compliance with USP <1058> Analytical Instrument Qualification, covering IQ, OQ, and PQ. This ensures that instruments are installed, operated, and performing as intended, bridging the gap between laboratory feasibility and routine GMP use.

To further support compliance, the systems we implement operate on 21 CFR Part 11 compliant software, providing secure user access, audit trails, and data integrity. This makes results generated not only scientifically rigorous, but also fully defensible in global regulatory submissions.

3. Initial Recipe Creation: No two packaging configurations are the same. Recipe creation is where instrument parameters are defined that allow clear separation between conforming and leaking samples. By using both positive controls (with engineered microdefects) and negative controls (representative of finished product), we create a robust method foundation tailored to each client’s product- package.

4. Method Development: Development is where science meets rigor. Our experts stress-test the method against multiple defect sizes and package variables, using statistically appropriate control schemes, to ensure all needed method validation parameters can be met. This provides the data-driven assurance that the method is not just functional, but also resilient under real-world conditions.

5. Method Validation: Finally, PTI’s Life Science Services validates the method in alignment with USP <1207> and ICH Q2(R2), confirming that it meets critical performance attributes:

• Accuracy and Precision – Consistency in detecting and differentiating leaks
• Specificity – Clear separation between leaking and intact packages
• Detection Limit – Sensitivity down to defect sizes as small as a few microns
• Ruggedness and Robustness – Reliability across analysts, days, and deliberate parameter shifts

Validation establishes the scientific and regulatory credibility needed for routine QC and long-term lifecycle use.

Why Deterministic CCIT Matters

Adopting deterministic CCIT isn’t just about checking a regulatory box. It’s about aligning quality strategy with modern science:

• Regulatory Confidence: USP <1207>, USP <1058>, and 21 CFR Part 11 compliance provide a complete framework for global acceptance.
• Patient Safety: Reliable leak detection safeguards sterility and product efficacy.
• Operational Efficiency: Non-destructive methods reduce waste, allowing tested samples to remain in circulation.
• Lifecycle Assurance: From development through commercial stability, validated CCIT methods provide ongoing protection against integrity risks.

PTI’s Commitment

Through PTI’s Life Science Services, our mission is simple: to help safeguard sterile medicines by building CCIT programs that are scientifically sound, regulatory-ready, and operationally practical. By guiding our clients from feasibility to PQ to validation, we close the loop, ensuring that container closure integrity is not just tested, but proven.

In the highly regulated pharmaceutical and medical device industries, maintaining the sterility and integrity of product packaging is a non-negotiable requirement. Any breach in a container’s seal can compromise product quality, potentially exposing patients to harmful contaminants and forcing companies to initiate and react to costly product recalls. Such recalls not only result in financial losses but also damage brand reputation and erode consumer trust.

Container Closure Integrity Testing (CCIT) plays a critical role in preventing these risks. By ensuring that packaging systems maintain a consistent and leak-free seal throughout the product’s shelf life, CCI testing provides scientific evidence of package integrity and regulatory compliance.

How CCI Testing Mitigates the Risk of Product Recall

Product recalls often stem from contamination, loss of sterility, or degradation caused by compromised packaging. CCI testing directly addresses these risks by verifying the ability of the container closure system to protect the product from microbial ingress, oxygen, moisture, or other environmental factors.

Here’s how CCI testing reduces recall risks:

• Early Detection of Leaks: Non-destructive CCI methods can identify microleaks and seal defects during development and routine production, preventing defective units from reaching the market.
• Regulatory Compliance: Agencies like the U.S. FDA, EMA, and USP mandate robust CCI testing to ensure drug product sterility and patient safety. Meeting these standards minimizes the likelihood of regulatory enforcement actions or market withdrawals.
• Process Validation and Quality Assurance: Continuous monitoring of container closure integrity helps manufacturers validate packaging processes and maintain consistent quality across production batches.
• Shelf-Life Protection: CCI testing ensures that packaging maintains its protective barrier over the product’s entire shelf life, thereby avoiding stability-related failures that could trigger recalls.

By integrating CCI technologies into every stage, from development and scale-up to commercial manufacturing, companies create a robust defense against costly and reputation-damaging recalls.

CCI Test Methods Offered by PTI

PTI provides a comprehensive portfolio of deterministic, non-destructive CCI testing technologies that comply with global regulatory guidelines and offer high sensitivity and repeatability.

1. Helium Leak Detection: Helium Leak Detection is a highly precise method for identifying leaks in sealed systems, widely used in Container Closure Integrity (CCI) testing for parenteral and injectable products. Helium is the ideal tracer gas because it is non-toxic, non-flammable, and present in the atmosphere at only about 5 ppm, allowing it to escape even through extremely small leaks. It is also more cost-effective than many other tracer gases and is available in a variety of cylinder sizes.

During testing, the component is connected to a leak detector and helium is introduced. If a leak exists, the helium escapes and is detected by the instrument, which measures and displays the leak rate for accurate evaluation.

2. Vacuum Decay Technology: Vacuum Decay is one of the most practical and sensitive vacuum-based leak detection methods, delivering quantitative, reliable, and reproducible results along with a clear pass/fail judgment. PTI’s VeriPac equipment played a key role in developing the ASTM F2338 standard for vacuum decay testing. This method is also recognized in the United States Pharmacopeia (USP) chapter on CCI and classified under ISO 11607. Using an absolute or differential pressure transducer, VeriPac’s non-destructive technology detects leaks and hidden defects in packages with a high degree of accuracy.

3. MicroCurrent HVLD Technology: PTI has advanced the traditional High Voltage Leak Detection (HVLD) method by introducing MicroCurrent HVLD, a breakthrough technology designed for testing the integrity of all parenteral and biological products—including low-conductivity liquids such as sterile water for injection (WFI).Compared to standard HVLD solutions, MicroCurrent HVLD operates at about 50% lower voltage, exposing both the product and environment to less than 5% of the typical voltage.

This method can detect and pinpoint a wide range of defects, including pinholes, micro-cracks, stopper or plunger leaks, and non-visible leaks under crimping—making it a safer and more efficient solution for sensitive pharmaceutical applications.

Product recalls in the pharmaceutical and medical device sectors can be financially devastating and pose serious risks to patient safety. By implementing robust and deterministic Container Closure Integrity testing strategies, manufacturers can ensure that packaging systems maintain sterility and product stability throughout their lifecycle.

PTI’s advanced suite of CCI testing solutions—including Vacuum Decay, MicroCurrent HVLD, and Helium Leak Testing—enables companies to meet global regulatory expectations while protecting both brand reputation and patient health. Investing in CCI testing is not merely a compliance measure; it is a proactive step toward quality assurance and risk mitigation in an increasingly competitive and regulated market.

In the pharmaceutical and life sciences industry, sterility is not just a quality benchmark—it is a regulatory requirement and a patient safety mandate. Vials, widely used for liquid, lyophilized, and powder-based drug products, must demonstrate reliable container closure integrity (CCI) to prevent microbial ingress, leakage, and loss of product stability. Ensuring this level of integrity requires robust and scientifically validated testing methods. Among the various approaches, Vacuum Decay Testing has emerged as the gold standard for CCI testing of vials due to its high sensitivity, non-destructive nature, and regulatory acceptance.

Overview of Vial Packaging Integrity

Vials are one of the most used pharmaceutical containers because of their versatility and compatibility with different drug formulations. However, vial integrity can be compromised by defects such as micro-cracks, stopper sealing issues, or closure misalignments. Even microscopic leaks pose a significant risk, as they allow microbial ingress or compromise product sterility.

Container Closure Integrity Testing (CCIT)ensures that vials remain sterile and maintain the intended shelf life of the drug product. Over the years, several CCI test methods have been evaluated, but vacuum-based approaches, specifically Vacuum Decay Technology, have consistently proven to be the most reliable and practical solution.

CCI Testing of Vials Using Vacuum Decay Technology

Vacuum Decay Testing works on the fundamental principle of detecting changes in vacuum levels within a controlled test chamber. When a vial is placed inside the chamber, vacuum is applied. Highly sensitive vacuum transducers then measure absolute and differential pressure changes over a specified test period. Any loss in vacuum stability indicates the presence of a leak in the container system.

PTI’s VeriPac series of leak testers have been at the forefront of advancing vacuum decay technology for decades. These systems are capable of detecting leaks as small as single-digit microns, and even sub-micron levels, ensuring accurate, repeatable, and quantitative results. Testing is non-destructive, allowing the same vial to remain available for further processing or distribution—a major advantage over destructive dye ingress or microbial challenge methods.

Vacuum Decay is recognized in the ASTM F2338-09 standard and accepted by the U.S. FDA as a consensus method for package integrity testing. Its regulatory acceptance and proven performance make it a preferred choice for both laboratory and production-level CCI testing of vials.

Benefits of Vacuum Decay Technology for Vials

Vacuum Decay Testing offers significant advantages over traditional and probabilistic methods such as dye ingress or bubble emission. Key benefits include:

• Non-destructive & Non-invasive: Vials remain intact, preserving product for use and eliminating waste.
• High Sensitivity: Capable of detecting leaks in the single-digit micron range, ensuring the highest sterility assurance.
• Quantitative & Objective Results: Provides clear pass/fail outcomes without operator subjectivity.
• Regulatory Compliance: Recognized by FDA and other global regulatory bodies as a consensus standard.
• Versatility: Suitable for various vial formats—liquid-filled, lyophilized, or powder-based.
• Efficiency in Testing: Test cycles take only a few seconds, making the method practical for both R&D labs and in-process QA/QC applications.
• Scalability: Systems can be configured for manual, semi-automated, or fully automated workflows to support small-scale studies as well as commercial production.

When it comes to safeguarding the sterility of pharmaceutical vials, Vacuum Decay Testing has established itself as the gold standard in container closure integrity testing (CCIT). With proven sensitivity, regulatory backing, and non-destructive operation, it offers an unmatched balance of accuracy and practicality. As the pharmaceutical industry continues to prioritize patient safety and regulatory compliance, adopting Vacuum Decay Technology ensures that vial-packaged products meet the highest standards of quality and reliability.

By leveraging advanced platforms such as PTI’s VeriPac series, manufacturers can achieve robust CCI testing, streamline quality control, and reinforce confidence in every vial that reaches patients.

Container Closure Integrity Testing (CCIT) plays a critical role in ensuring the sterility and safety of pharmaceutical products. As many biologics, cell therapies, and other advanced formulations require storage and handling at ultra-low temperatures (ULT) often ranging from –20°C to –80°C, verifying package integrity under such extreme conditions has become increasingly important. Traditional CCIT methods often fall short in reproducing and maintaining these ultra-low conditions during testing. This is where Cryo Chiller Technology, combined with highly sensitive methods like Helium Leak Detection, brings a breakthrough solution for reliable and reproducible results in package integrity testing.

Ultra-Low Temperature CCI Testing Challenges

Testing package integrity at ultra-low temperatures presents unique difficulties:

• Material Behavior at Low Temperatures: Plastics, elastomers, and glass used in primary packaging materials can shrink, stiffen, or undergo stress fractures at ULT conditions. This affects sealing performance and may introduce micro-leaks that would not be present at room temperature.
• Reproducibility of Test Conditions: Simulating and maintaining ultra-low storage conditions during the CCIT process is technically challenging. A deviation of even a few degrees can affect material performance and compromise the validity of results.
• Moisture and Frost Interference: Exposure to ambient conditions during testing may lead to frost formation on the container, interfering with accurate detection and increasing the risk of false positives.
• Limitations of Conventional Methods: Dye ingress or microbial ingress methods are not only destructive but also unreliable at ultra-low conditions, failing to detect the extremely small leaks that are most concerning for long-term drug stability.

These challenges emphasize the need for Cryo Chiller-enabled Helium Leak Detection as a robust and precise testing solution

Role of Helium Leak Detection in Ultra-low Temperatures Testing

Helium Leak Detection has emerged as one of the most accurate and sensitive methods for Container Closure Integrity Testing. It relies on detecting the escape of helium, an inert tracer gas, from a sealed system. Its application in ultra-low temperature CCIT is enhanced when paired with Cryo Chiller Technology.

• Stable Conditioning: Cryo chillers allow packages to be conditioned and maintained consistently at their required storage temperatures during the leak test. This ensures that the stress conditions experienced by packaging materials during real storage are faithfully replicated in the test environment.
• High Sensitivity: Helium leak detection can identify leaks as small as 10?¹° mbar·L/sec, far beyond the detection limits of other methods, making it ideal for biologics and high-value products.
• Adaptability: Cryo Chiller technology ensures that even diverse packaging formats such as vials, syringes, and cartridges can be tested under ULT conditions without compromising accuracy.

Benefits of Helium Leak Detection with Cryo Chillers

Integrating cryo chillers with helium leak detection systems provides several key advantages for pharmaceutical manufacturers and researchers:

• True-to-Storage Testing: Packages are tested under the same conditions in which they will be stored, ensuring that real-world challenges like seal contraction and material stress are captured.
• Enhanced Reliability: Precise temperature control eliminates variability and increases reproducibility of results across batches and product lines.
• Regulatory Compliance: Helium leak detection is aligned with regulatory guidelines such as USP <1207>, which emphasize deterministic, quantitative test methods for CCIT. This positions pharmaceutical companies for smooth audits and compliance.
• Protection of High-Value Therapies: Biologics, vaccines, and gene therapies are often extremely sensitive to temperature and contamination. Ensuring closure integrity under ULT conditions safeguards both product quality and patient safety.
• Operational Efficiency: The ability to perform effective testing at ultra-low temperatures reduces wastage of expensive products, making it cost-effective in the long run.