Blogs

Pharmaceutical packaging is a critical component of product quality, regulatory compliance, and patient safety. Its role extends far beyond containment, acting as a protective barrier that maintains sterility, stability, and efficacy throughout the product’s lifecycle. From early development and clinical trials to commercial manufacturing, distribution, and final patient use, packaging systems are exposed to multiple risks that can compromise integrity if not properly controlled.

Regulatory bodies such as the FDA and guidance frameworks like USP <1207> increasingly emphasise the need for deterministic container closure integrity testing (CCIT) across the entire lifecycle. At PTI, packaging integrity is treated as a continuous, science-driven quality process rather than a final-stage inspection activity.

Why Packaging Integrity Testing Is Essential During Different Stages of the Product Lifecycle

Pharmaceutical products encounter different stress conditions as they move from development to patient delivery. A container closure system that performs well in one stage may fail in another if integrity is not consistently verified.

Packaging integrity testing is essential because it helps identify and control risks such as:

• Seal defects introduced during scale-up or high-speed manufacturing.
• Microleaks caused by material incompatibility or closure misalignment.
• Integrity degradation due to transportation, pressure changes, or long-term storage

By applying CCIT at defined lifecycle stages, manufacturers can proactively detect integrity issues, reduce product loss, and maintain compliance with global regulatory expectations.

1. Packaging Development and Design

The packaging lifecycle begins with development and design, where container materials, closure components, and sealing mechanisms are selected and evaluated. Decisions made at this stage directly influence long-term package performance. Integrity risks during development typically relate to material compatibility, seal geometry, and dimensional variability. These risks may not be visible using traditional visual or probabilistic testing methods.

PTI supports early-stage development by applying deterministic CCIT technologies, such as Vacuum Decay, to evaluate package integrity in a non-destructive and quantitative manner. This allows development teams to:

• Compare container closure systems using measurable integrity data.
• Identify potential failure modes early in the design process.
• Establish baseline integrity performance before advancing to clinical studies.

This data-driven approach reduces late-stage redesigns and supports more robust packaging selection.

2. Clinical Trials and Validation

During clinical trials, pharmaceutical packaging is exposed to real-world handling, transportation, and storage conditions. Even small integrity failures at this stage can compromise clinical data, delay regulatory submissions, or increase development costs.

Regulators increasingly expect integrity testing methods used during clinical phases to be deterministic, validated, and scientifically justified. USP <1207> highlights the limitations of probabilistic methods and supports technologies that provide consistent detection limits and repeatable results.

PTI assists with feasibility studies, test method development, and validation activities to ensure that CCIT methods are appropriate for the product and packaging system. High Voltage Leak Detection (HVLD) is commonly used for liquid-filled parenteral products during clinical trials due to its high sensitivity and non-destructive nature.

3. Scale-Up and Commercial Manufacturing

As products transition to commercial manufacturing, packaging systems face new challenges associated with higher production volumes and increased process complexity. Seal variability, equipment differences, and higher line speeds can introduce defects that may not be detected through limited sampling.

PTI’s deterministic CCIT solutions are designed for both at-line and inline inspection, supporting integrity assurance in production environments. In commercial manufacturing, CCIT helps manufacturers:

• Detect process drift before it leads to batch failure.
• Reduce reliance on destructive, subjective test methods.
• Generate robust data for regulatory inspections and audits.

4. Distribution, Storage, and Transportation

Once released, pharmaceutical products must maintain package integrity throughout distribution and storage. Environmental factors such as temperature changes, pressure fluctuations during air transport, and mechanical stress can compromise seals over time.

Integrity risks during this stage often include:

• Gradual loss of sterility due to microleaks.
• Oxygen ingress affecting product stability.
• Seal degradation during long-term storage.

PTI supports integrity testing as part of stability studies and transportation simulation programmes. Vacuum Decay technology allows manufacturers to assess package robustness under simulated distribution conditions without damaging the package, ensuring continued protection throughout the supply chain.

5. Patient Delivery and Use

The final stage of the packaging lifecycle is patient delivery, where package integrity has a direct impact on patient safety and treatment effectiveness. Any breach in integrity at this stage can lead to contamination, reduced efficacy, or adverse patient outcomes.

PTI’s lifecycle-based integrity strategy ensures that packaging performance is continuously verified rather than assumed. By applying deterministic CCIT methods at multiple lifecycle stages, manufacturers gain confidence that the product remains protected until the point of use.

Conclusion

Pharmaceutical packaging integrity must be managed across the entire product lifecycle, not verified at a single endpoint. Each stage, from development and clinical validation to manufacturing, distribution, and patient use, introduces unique risks that require scientifically validated solutions.

PTI’s expertise in container closure integrity testing (CCIT) and its deterministic technologies, including HVLD and Vacuum Decay, enable pharmaceutical manufacturers to implement a proactive, data-driven approach to packaging quality. By embedding integrity testing throughout the lifecycle, companies can strengthen regulatory compliance, reduce risk, and protect patient safety.

Container Closure Integrity (CCI) testing is a critical quality requirement for parenteral products, where even microscopic leaks can compromise sterility and patient safety. Regulatory agencies such as the FDA and guidance documents like USP <1207> emphasise the need for deterministic, validated CCI methods that provide consistent and measurable results throughout the product lifecycle.

Parenteral drug products, including injectables, biologics, and vaccines, present unique integrity testing challenges due to their complex container systems and stringent leak rate requirements. PTI addresses these challenges through its High Voltage Leak Detection (HVLD) technology, a non-destructive, deterministic CCI solution specifically designed for liquid-filled parenteral packaging.

Parenteral Products: Key CCI Testing Challenges

• Extremely Tight Leak Detection Requirements: Parenteral products require detection of leaks at the micron and sub-micron level. Conventional probabilistic methods, such as dye ingress or microbial ingress testing, often struggle to consistently detect defects of this size. These methods also lack quantitative outputs, making it difficult to establish clear detection limits.
• Complex Container Closure Systems: Parenteral packaging formats, including glass vials, pre-filled syringes, cartridges, and BFS containers, introduce multiple potential leak paths. Defects may occur at the stopper interface, crimp seal, plunger interface, or within the container itself. Accurately identifying these defects requires a technology capable of evaluating the entire container closure system.
• Destructive Testing Limitations: Many traditional CCI methods require destructive testing, which increases product waste and restricts sample sizes. Destructive approaches also prevent manufacturers from implementing 100% inspection and limit the ability to perform in-line testing during routine production.
• Regulatory Expectations for Deterministic Methods: Regulatory authorities increasingly favour deterministic CCI technologies that offer known sensitivity, reproducibility, and validated performance. Meeting these expectations using legacy methods often requires extensive justification and supplemental testing.

Non-Destructive CCI Testing Using PTI’s HVLD Technology

HVLD technology is a non-destructive and non-invasive Container Closure Integrity Test (CCIT) method that utilises controlled voltage characteristics to inspect a wide range of parenteral products, including complex combination products. The technology is suitable for pre-filled syringes, vials, cartridges, ampoules, BFS containers, bottles, and pouches.

The HVLD test method accurately detects and localises defects such as pinholes, micro-cracks, stopper or plunger leaks, non-visible leaks beneath crimp seals, and other integrity failures that may compromise sterility. To verify container closure integrity, the system scans a sealed, non-conductive container using precision electrode probes. When a defect is present, a change in electrical resistance occurs, altering the current flow and allowing the system to identify the breach.

Unlike conventional high-voltage leak detection approaches, PTI’s HVLD technology operates at significantly lower voltage levels, using approximately 50% less voltage and exposing the product and surrounding environment to less than 5% of that applied voltage. This reduced exposure minimises potential product risk while also significantly lowering ozone generation during testing. As one of the most sensitive deterministic CCI technologies available, PTI’s HVLD solution is particularly well suited for high-risk parenteral and combination product applications.

Benefits of PTI’s HVLD Technology for Parenteral CCI Testing

• Non-Destructive, Automated Inspection Capability: PTI’s HVLD technology enables full-unit inspection without damaging the product, allowing manufacturers to implement 100% testing while reducing waste and improving batch-level confidence.
• Deterministic, High-Sensitivity Detection: The technology delivers quantitative, repeatable results with sensitivity at the micron level. Clearly defined detection limits, supported by validated positive controls, strengthen method validation and regulatory submissions.
• Production-Ready and Regulatory Aligned: HVLD supports automated testing in manufacturing environments and aligns with USP <1207> expectations. Its deterministic performance simplifies validation, system suitability testing, and ongoing integrity verification while reducing operator dependence.

Conclusion

CCI testing for parenteral products demands technologies that deliver high sensitivity, repeatability, and regulatory compliance without compromising product integrity. Traditional destructive and probabilistic methods often fall short of meeting modern industry and regulatory expectations.

PTI’s High Voltage Leak Detection (HVLD) technology provides a proven, non-destructive, deterministic solution for liquid-filled parenteral packaging. By enabling high-sensitivity leak detection, scalable to be fully automated, and strong regulatory alignment, PTI’s HVLD systems help pharmaceutical manufacturers strengthen sterility assurance, reduce risk, and maintain product quality throughout the product lifecycle.

Ensuring that pharmaceutical products remain safe, sterile, and stable throughout their lifecycle is one of the most critical responsibilities in the life sciences industry. As therapies become more sensitive—ranging from biologics and vaccines to advanced injectables and cell & gene therapies—the role of Container Closure Integrity (CCI) has grown significantly. A failure in CCI can lead to contamination, loss of sterility, compromised efficacy, and potentially life-threatening consequences for patients.

This is why regulatory bodies such as the FDA, EMA, and USP continuously reinforce the need for robust, reliable, and science-based CCI testing methods. With the industry moving toward deterministic, non-destructive solutions, companies like PTI are advancing the field by providing high-precision technologies suitable for both lab and production environments.

Why CCI Testing Matters in Life Sciences

1. Protecting Product Sterility

Sterile products—including parenterals, vaccines, and biologics—must remain free from microbial contamination. Even the slightest breach in a container’s sealing interface can allow microorganisms or particulates to enter. CCI testing ensures that the container closure system maintains its protective barrier throughout manufacturing, storage, and distribution.

2. Safeguarding Drug Efficacy

Many modern drug formulations are highly sensitive to environmental factors such as oxygen, moisture, and CO2. A compromised closure system can alter the product’s chemical composition, degrade active ingredients, or destabilize formulations. CCI testing verifies that the packaging system prevents gas or vapor ingress, preserving potency from production to administration.

3. Meeting Global Regulatory Requirements

Regulatory agencies require manufacturers to demonstrate that their container closure systems ensure safety and sterility. Guidance documents such as USP <1207> mandate the use of deterministic technologies—methods with quantifiable outputs, validated accuracy, and scientific reliability. CCI testing supports compliance with:

• cGMP guidelines
• FDA requirements for parenteral products
• EU Annex 1 for sterile manufacturing

4. Reducing Patient Safety Risks

Failed CCI can lead to serious patient harm—severe infections, reduced therapeutic effect, or adverse immune responses. By implementing robust CCI testing, manufacturers reduce risks and enhance overall product quality and safety.

5. Avoiding Costly Recalls and Liability

Loss of sterility is among the top causes of pharmaceutical recalls. CCI failures discovered late in the lifecycle—especially after commercial distribution—result in extensive financial losses, legal exposure, and damage to a brand’s reputation. Deterministic CCI testing helps detect issues early, preventing such outcomes.

Life Sciences Package Integrity Testing Solutions Offered by PTI

PTI is a global leader in non-destructive, deterministic CCI technologies. Their solutions are designed to support R&D, stability studies, routine QC testing, and high-throughput production applications across the life sciences sector. Below are PTI’s key CCI testing technologies widely adopted for inspecting vials, syringes, cartridges, IV bags, BFS containers, and other sterile products.

1. Vacuum Decay Technology

Vacuum Decay is one of PTI’s most widely used deterministic methods for Container Closure Integrity testing (CCIT). It is a non-destructive technique that measures pressure changes inside a sealed test chamber to identify leaks in pharmaceutical containers. During the test, the container is placed inside the chamber, and a controlled vacuum is applied. If there is any defect—such as a crack, pinhole, or channel leak—air will escape from the container, causing a detectable rise in pressure. Because the system uses highly sensitive pressure transducers, it can identify extremely small leaks with high accuracy and repeatability. Vacuum Decay is suitable for a wide range of life sciences packaging formats, including vials, syringes, cartridges, ampoules, and blister packs. It is fully aligned with USP <1207> recommendations and is widely used for stability studies, lab testing, and automated in-line inspection.

2. High Voltage Leak Detection (HVLD)

High Voltage Leak Detection is a non-destructive electrical conductivity-based method specifically designed for liquid-filled pharmaceutical products. In this technique, a high-voltage potential is applied across the container. If the container has any micro-channel or defect, the liquid inside forms a conductive path and creates a measurable electrical response. This allows the system to detect even very small leaks that may not be visible through other inspection methods. HVLD is ideal for prefilled syringes, glass vials, cartridges, IV bags, and blow-fill-seal containers. It is fast, sensitive, and capable of handling products with complex shapes or high-value formulations. Because HVLD can be integrated into both lab environments and 100% in-line production systems, it is widely used for ensuring product sterility and regulatory compliance across the life sciences industry.

Conclusion

Container Closure Integrity is a foundational element of safe and reliable pharmaceutical packaging. In an industry where even the smallest leak can compromise sterility, efficacy, and patient trust, CCI testing serves as a critical safeguard for product quality. As regulatory expectations shift toward deterministic, science-driven methods, manufacturers must adopt advanced technologies capable of delivering quantitative, repeatable results.

PTI’s portfolio—including Vacuum Decay and High Voltage Leak Detection (HVLD)—provides life sciences companies with world-class solutions that support robust CCI programs across the product lifecycle. Whether in R&D, quality control, or commercial production, these technologies ensure that every package meets the highest standards of safety, performance, and regulatory compliance.

In regulated industries such as pharmaceuticals, biologics, and medical devices, packaging integrity is inseparable from product quality and patient safety. Regulatory authorities expect manufacturers to verify container closure integrity (CCI) using scientifically validated, deterministic, and globally accepted test methods. PTI has built its entire technology portfolio around these expectations, ensuring full alignment with ASTM standards, USP <1207>, and international regulatory frameworks. PTI’s commitment to deterministic and data-driven testing makes its platforms the preferred choice for manufacturers looking to strengthen compliance and quality assurance.

Overview of ASTM Methods Relevant to Packaging Integrity

ASTM International provides a set of rigorous methods that define how packaging integrity should be evaluated. PTI’s technologies are engineered to operate precisely within the parameters established by these standards, ensuring that results are meaningful, and repeatable.

1. ASTM F2338 – Vacuum Decay Testing

ASTM F2338 is one of the most widely recognized deterministic standards for non-destructive leak detection, especially for rigid and semi-rigid containers. This test method originally established in 2003 was developed using PTI VeriPac instruments. The method uses pressure differentials to quantify even very small leak pathways, making it suitable for sterile products, stability studies, and routine quality control. Vacuum Decay is valued in the industry because it provides objective, numerical data and eliminates the subjectivity of traditional probabilistic tests.

2. ASTM F2391 – Helium Leak Detection

ASTM F2391provides guidance for using helium mass spectrometry as an ultra-sensitive CCI technique. This method is typically used during development, validation, and feasibility studies when extremely tight sensitivity—down to 10?¹° mbar·L/s—is required. Helium-based methods are especially relevant for complex drug–device platforms, high-value biologics, and packaging systems that require the highest level of integrity assurance.

3. ASTM F3004 – Airborne Ultrasound Seal Integrity Evaluation

ASTM F3004 defines a non-destructive approach for evaluating the seal integrity of flexible packages. Ultrasonic inspection technology, which this standard is based on, generates high-resolution images of the seal area and can detect defects such as channels, inclusions, wrinkles, or weak seals. These are issues that often remain undetected through visual inspection or conventional destructive tests, making ASTM F3004 important for flexible packaging used across pharmaceutical and medical device applications.

Role of PTI Technologies in Supporting Compliance

PTI’s CCI solutions are designed to fit within the compliance expectations set by global regulatory authorities. By offering deterministic methods aligned with ASTM and USP standards, PTI helps manufacturers establish a robust, defensible quality framework.

PTI technologies integrate seamlessly into compliance structures defined by:

• USP <1207>, which prioritizes deterministic test methods over probabilistic approaches
• FDA guidance on CCI testing and sterility assurance
• EU Annex 1, particularly the 2023 revision emphasizing improved control over container integrity
• ISO 11607 for medical device packaging integrity
• ICH Q9 and Q10, which frame risk-based quality management

Beyond method alignment, PTI systems incorporate advanced data integrity controls—secure audit trails, encrypted electronic records, and role-based access—supporting 21 CFR Part 11 requirements. These capabilities ensure that packaging integrity results are reliable, traceable, and fully compliant during regulatory inspections.

PTI also plays a crucial role in method lifecycle support. Its application engineers assist manufacturers in method development, feasibility studies, and validation activities (IQ/OQ/PQ), ensuring that each method meets the sensitivity and repeatability expectations laid out in global guidelines. This partnership-oriented approach is particularly valuable for companies dealing with new and complex container systems, or high-value biologics.

The Importance of Standardization in CCI Testing

Standardization forms the backbone of modern quality systems. Without standardized, deterministic methods, manufacturers risk variability, inconsistent results, and regulatory observations. ASTM standards provide a common scientific foundation, enabling manufacturers around the world to evaluate packaging using uniform criteria.

Standardization strengthens:

• Test reproducibility across sites
• Regulatory acceptance of data
• Risk mitigation for sterility failures
• Packaging development and optimization
• Overall product safety and lifecycle quality

PTI contributes to this ecosystem by designing technologies that comply with the most trusted global standards while actively participating in the evolution of CCI science. PTI’s research, industry collaborations, and continuous technological innovation help shape best practices that are now widely adopted across the pharmaceutical packaging industry.

Conclusion

PTI’s technologies are engineered to meet the highest expectations of global regulatory authorities by aligning directly with ASTM methods, USP <1207> principles, and the requirements outlined in FDA and EU guidelines. By offering deterministic and quantitative solutions—including Vacuum Decay, Helium Leak Detection, HVLD, and Ultrasonic Seal Testing—PTI empowers manufacturers to ensure that their packaging systems maintain integrity throughout the product lifecycle. The combination of scientific rigor, regulatory alignment, and robust method development support makes PTI a trusted leader in the global package integrity testing space.

Flexible packaging has unique characteristics that make leak detection more complex than with rigid containers. The materials are elastic, sensitive to pressure variations, and can deform during handling and testing. Although dye ingress testing has been used for decades as a basic integrity check, it is not suited for today’s high-performance flexible packages or for regulatory expectations under USP <1207>.

The main issue lies in how the test fundamentally works. It relies on visual confirmation of dye penetration, which is influenced not only by the presence of a defect but also by material behavior, surface wetting, operator technique and interpretation. As a result, the test cannot provide deterministic assurance of true package integrity.

As regulatory bodies move toward deterministic CCI Technologies and away from subjective, probabilistic methods, understanding why blue dye tests fail, and what alternatives exist, is critical. PTI’s VeriPac Flex systems, based on vacuum decay technology, offer a scientifically valid and repeatable solution for these challenges.

Challenges of Applying the Dye Ingress Test to Flexible Materials

Flexible materials react to pressure changes differently than rigid containers. During testing, they tend to stretch, collapse, or crease, creating artificial leak paths or temporarily sealing existing ones. This deformation makes the behaviour of the package unpredictable when subjected to vacuum or dye immersion conditions. A real micro-leak can remain undetected simply because the film seals itself under stress, while a defect-free sample may falsely appear to fail because the material has distorted and trapped dye.

Additionally, the complexity of multilayer structures affects how dye interacts with the surface. Many flexible films have hydrophobic sealant layers or laminated barriers that resist dye penetration even when a leak path exists. This makes the ingress dependent on material wetting characteristics rather than on the actual presence of defects.

Another challenge is the inability of the dye test to simulate real-world leak conditions. The method relies on forcing liquid into a package under extreme conditions—conditions that do not reflect how leaks occur during storage, transportation, or normal handling. Flexible packages experience movement, vibration, and stress relaxation over time. A dye immersion test, conducted at a single moment, cannot reliably represent the dynamic behaviour of these materials.

Limitations of the Dye Ingress Test

• Probabilistic and subjective: Results depend on operator skill, immersion time, sample preparation, and visual interpretation.
• Poor sensitivity to micro-leaks: It cannot reliably detect micron-level leak channels that can compromise sterility or stability.
• Destructive testing method: Samples are permanently damaged, increasing product wastage and preventing additional evaluation.
• Non-quantitative: The method cannot provide measurable data, making trending and root-cause analysis difficult.
• Slow workflow: Dye preparation, immersion, drying, and inspection add considerable time to QC processes.
• Not aligned with USP <1207> guidance: It is classified as a probabilistic method and is not recommended as a primary CCIT technique

Flexible Package Inspection Using VeriPac Flex Systems

PTI’s VeriPac Flex series offers a reliable, deterministic alternative based on vacuum decay technology. Instead of relying on visual detection of dye, the system measures small variations in pressure within a test chamber and correlates them to the presence of leaks. This technique is highly sensitive, providing quantitative data capable of identifying micro-leaks at levels far below the detection capability of dye testing.

Because the method is non-destructive, manufacturers can test a higher volume of samples or even perform 100% inspection when required. Packages remain intact and can be used for further testing, stability studies, or batch release. The technology is also independent of material properties, which eliminates the complications seen with dye wetting behaviour or surface interactions.

Vacuum decay technology aligns with USP <1207> requirements for deterministic testing, making it fully suitable for pharmaceutical and medical device applications. VeriPac Flex systems offer higher sensitivity, repeatability and reliability than any probabilistic dye-based method. They allow teams to transition from subjective pass/fail assessments to quantitative measurements backed by scientific principles.

Conclusion

Blue dye leak testing has long been used in the industry, but it is increasingly recognized as an unreliable and outdated method—especially when applied to flexible packaging. The elastic nature of flexible materials, their multilayer structures, and the test’s dependence on harsh conditions and visual interpretation make dye ingress results inconsistent and non-representative of true package integrity.

With rising regulatory expectations and the need for greater accuracy, deterministic technologies like PTI’s VeriPac Flex systems have become the preferred solution. Vacuum decay testing provides precise, non-destructive, quantifiable data that ensures genuine confidence in container closure integrity.

Transitioning from dye ingress testing to VeriPac Flex not only improves detection capability but also supports compliance, enhances quality assurance workflows, and offers a modern, scientifically robust approach to flexible package inspection.

In the pharmaceutical and life sciences industry, ensuring the integrity of sterile product packaging is a non-negotiable requirement. Container Closure Integrity testing (CCIT) is central to confirming that packaging systems, vials, syringes, or flexible bags, effectively prevent microbial ingress and maintain sterility over the product’s lifecycle. Yet, achieving truly reliable CCI results requires more than just running a test; it demands a scientifically sound method development process grounded in the use of positive controls.

This blog explores how PTI’s CCI technologies and services integrate positive control strategies into method development to ensure accuracy, repeatability, and confidence in package integrity testing results.

Importance of Positive Control Setup in CCI Technologies

In CCI method development, a positive control is a reference sample that intentionally contains a known defect, such as a micro-hole or a simulated leak path. These controls are essential to verify whether a given test method or technology can consistently detect defects at or below a specified leak rate.

Without proper positive controls, a test method might appear valid but fail to detect critical leaks under real-world conditions. For this reason, regulatory bodies, including the FDA and USP <1207>, emphasize the inclusion of positive controls when developing and validating deterministic CCI test methods.

PTI’s CCI technologies, such as Helium Leak Detection, Vacuum Decay, and High Voltage Leak Detection (HVLD), each require tailored positive control setups:

• Helium Leak Detection: Uses micro-drilled defects calibrated to a specific leak rate (measured in std cc/sec). Positive controls ensure that the system’s sensitivity and calibration curve are accurate for detecting leaks at critical thresholds.
• Vacuum Decay Testing: Relies on precision-engineered packages with laser-drilled micro-holes or channels to simulate realistic defects. Positive controls help define baseline decay rates and acceptable variability limits.
• High Voltage Leak Detection (HVLD): Involves creating controlled conductive pathways within the package to confirm electrical sensitivity and detection limits.

Detecting and Quantifying Leaks for Package Integrity Testing

The accuracy of package integrity testing depends on the ability to detect and quantify leaks within a controlled, measurable range. Positive controls provide a quantifiable reference point that allows analysts to benchmark the detection sensitivity and establish the lower limit of detection (LLOD) for the test method.

Quantifying the Leak Rate

Leak rate quantification bridges the gap between a qualitative “pass/fail” result and a scientifically measurable integrity profile. For example:

• A Helium Leak Test can quantify leaks as small as 1x10?¹¹ mbar·L/s, offering a high degree of precision for parenteral and lyophilized drug products.
• Vacuum Decay Testing, a non-destructive deterministic method, quantifies pressure decay correlated to micro-leaks typically between 1x10?³ and 1x10?6 mbar·L/s.
• HVLD detects minute pinholes or seal defects in liquid-filled containers by measuring the electrical current passing through a compromised closure system.

The use of positive controls helps establish a calibration curve, linking a measured signal (like pressure decay or helium flow) with a known leak rate. This quantitative relationship ensures that the method is sensitive enough to detect leaks that could compromise sterility or product quality.

In PTI’s method development labs, engineers employ calibrated leak standards, and data correlation models to validate sensitivity and ensure reproducibility across multiple package formats.

How Positive Controls Improve Container Closure Integrity Testing Reliability

The inclusion of positive controls in CCI testing doesn’t merely confirm instrument sensitivity, it strengthens method reliability across three critical dimensions:

1. Method Robustness: Positive controls allow analysts to evaluate how the test method performs under variable environmental and operational conditions (e.g., temperature, pressure, and humidity). This helps ensure that the CCI method remains stable and reliable across different production sites and test environments.

2. System Suitability Verification: Before every batch or series of tests, positive controls are used to confirm that the CCI system is performing within its validated detection limits. This “system check” acts as a safeguard against instrument drift or calibration errors, ensuring continued confidence in test outcomes.

3. Regulatory Confidence: From a compliance standpoint, regulators increasingly favor deterministic methods supported by robust positive control validation. Demonstrating that your CCI test can consistently detect leaks of defined sizes using calibrated controls builds scientific justification for the method’s reliability, critical during inspections or product submissions.

PTI’s CCI services integrate all these best practices through a structured framework:

• Feasibility Studies – Assessing package type and determining the most suitable test method.
• Method Development & Validation – Establishing detection limits, control design, and reproducibility.
• Training & Knowledge Transfer – Ensuring that end-users understand positive control applications and data interpretation.

This holistic approach ensures that every CCI method developed by PTI is not only compliant but scientifically defensible.

Conclusion

Reliable CCI method development is not just about detecting leaks,it’s about ensuring scientific traceability and reproducibility at every stage. Positive controls serve as the foundation of this reliability, validating both the method’s sensitivity and the instrument’s performance over time.

Through its advanced CCI technologies and expert-driven services, PTI continues to lead the industry in developing robust, deterministic, and regulatory-compliant testing methods. From baseline setup to positive control verification, PTI’s science-first approach ensures that every test result truly reflects the package’s integrity—protecting product safety, efficacy, and patient trust.

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.

Evaluating the ability of the container closure system to provide a sterile barrier and prevent leaks resulting from contamination is a crucial step towards maintaining the safety and suitability of primary packaging. United States Pharmacopeia (USP) and Food and Drug Administration (FDA), the driving forces behind container closure systems in the US, enforce strict regulations for Container Closure Integrity Testing (CCIT).

Traditionally, Dye Ingress and Microbial immersion were two popular methods to evaluate container closure integrity. However, they were probabilistic methods that lacked accuracy and provided subjective test results. In 2016, USP issued guidelines that they preferred deterministic test methods over probabilistic test methods. Examples of deterministic test methods include Vacuum Decay technology, Airborne Ultrasound technology, Helium Leak Detection etc. In this blog, we will discuss the role of VeriPac 355, which is a Vacuum Decay technology in testing container closure integrity.

CCI Testing Using VeriPac 355 Technology

The VeriPac 355 is a non-destructive technology based on the ASTM vacuum decay leak test method (F2338-09) and is recognized by the FDA as a consensus standard for package integrity testing. This micro leak detection system is applicable across a wide range of packaging formats and is specially designed to test containers for gas leaks for dry products (lyophilized vials, powder-filled) as well test for liquid leaks (non-protein based liquid-filled vials, prefilled syringes). The non-destructive nature of the technology allows it to be incorporated into protocols at any point in the handling process. VeriPac 355 technology's capability of detecting leak rates as low as 0.2 cc/min makes it an optimal quantitative test method for many pharmaceutical and food applications.

VeriPac 355 Working Principle

The VeriPac 355 leak tester is connected to a test chamber designed specially to hold the package being tested. Vacuum is then applied to the package inside the test chamber. Using a high-resolution absolute transducer technology, the test chamber is monitored for the level of vacuum as well as the change in vacuum over a predetermined test time. Although the test cycle takes only a few seconds, it produces accurate and non-subjective test results. 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 semi-automatic operation. This inspection method is suitable for laboratory offline testing and QA/QC statistical process control.

Inspection Criteria

• Measures seal integrity of entire container or package
• Tests for gas leaks for dry products (lyophilized vials, powder filled)
• Tests for liquid leaks (liquid filled vials, prefilled syringes)

Benefits of VeriPac 355 Series

• Non-destructive, non-subjective, no sample preparation
• Deterministic, quantitative test method
• Measures seal integrity of entire container or package
• Tests for gas leaks for dry products (lyophilized vials, powder filled)
• Tests for liquid leaks (liquid filled vials, prefilled syringes)
• Measures and verifies container closure system integrity
• Defect detection down to 0.2 ccm
• 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

Medical device industry is crucial to health care system as they play a vital role in the delivery of many health care services. Over the past few decades, tremendous developments in medical technologies have challenged the medical device packaging industry to ensure quality and reliability in packaging. Although testing package quality of all medical devices is critical, in case of Class III medical devices it amplifies several folds. Class III medical devices are understood as devices that sustain or support life, are implanted, or present potential unreasonable risk of illness or injury. Examples include pacemakers, breast implants, and respiratory ventilators. Since these devices are directly placed into human bodies, proper packaging is required to ensure the quality of the product until it reaches the patient. Any breach in the packaging can cause contaminants to enter the device, thereby making it more of a threat to the patient than a treatment. Hence appropriate CCI technologies are needed to ensure standardized packaging quality.

Container Closure Integrity Testing(CCIT) is a leak detection test conducted using a non-destructive package inspection system to ensure sterility and product quality throughout its shelf life. Earlier, probabilistic test methods such as bubble test, dye ingress and manual visual inspection were used to test package quality of medical devices. However, these traditional methods lacked accuracy and provided uncertain and subjective results. In order to overcome the shortcomings of probabilistic methods, industries are now moving towards deterministic methods that assures a higher level of accuracy with quantitative results. According to Oliver Stauffer, Chief Executive Officer at PTI - Packaging Technologies & Inspection “ There is a huge shift in the industry toward deterministic and quantitative test method. This includes Vacuum Decay and Airborne Ultrasound for medical device applications. The industry is currently moving away from dye ingress and manual visual inspection because there are so many blind spots in applying them and there’s a huge false sense of assurance.”

Packaging Technologies & Inspection-PTI’s VeriPac Vacuum Decay Technology and Airborne Ultrasound Technology have revolutionized automated CCI Technologies.

Vacuum Decay Technology is a CCI testing method that detects leaks in nonporous, rigid or flexible packages. Such tests are conducted by placing a sample in an evacuation test chamber, drawing vacuum and monitoring vacuum level for any decay, indicating a leak. Such tests are known to provide reliable and quick results. PTI’s VeriPac Vacuum Decay Technology is a non-destructive package inspection system based on the ASTM vacuum decay leak test method (F2338-09) and accredited by the FDA for package integrity testing. Its applications include empty and pre-filled syringes, liquid-filled and lyophilized vials and other flexible and rigid liquid-filled packaging. PTI’s PERMA- VAC technology, known to provide consistent and reliable results is the latest development in the VeriPac line of test systems. The VeriPac Universal Blister Verification (UBV) system designed for non-destructive blister package leak detection uses a volumetric imaging technology to measure the motion of a blister package under vacuum to detect leaks.

PTI’s Airborne Ultrasound Technology is a non-destructive Seal Integrity Test used to examine seal quality for defects. “Ultrasound is one of the only technologies that are telling us what the quality of that physical bonded nature of the seal materials are,” says Oliver Stauffer, CEO of PTI. Under this method, high-frequency sound waves are passed through the pouch seal area, causing the reflection of sound waves. Variations of the reflected signal strength are used to reflect defects if any. PTI’s Airborne Ultrasound Technology for 100% Inline inspection of pouch seals has been extremely helpful in verifying final pouch seal quality. Any defect in the pouch seal including voids and delamination, foreign materials and inclusions, incomplete seals and misaligned seals can be detected using a Seal-Sensor scan and are automatically rejected from the production line.

Vacuum Decay Method (VDM) is used by manufacturers of packages for the food, beverage, industrial and pharmaceutical industries in order to detect leaks in rigid or flexible packages.

Both methods are established ASTM test methods: Vacuum Decay ASTM F2338 and Airborne Ultrasound ASTM F3004.These technologies are non-destructive methods and can be chosen depending on the characteristics of the product to be tested.