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Container Closure Integrity testing (CCIT) is vital for maintaining the sterility and efficacy of pharmaceutical products. Even a small breach in a container’s barrier can compromise safety—especially in parenteral formats like vials, ampoules, and prefilled syringes. The industry has evolved from probabilistic methods such as dye and microbial ingress to deterministic technologies that deliver precise, verifiable results. Among these, High Voltage Leak Detection (HVLD) has become a trusted solution for testing liquid-filled parenteral containers.

However, with the rise of low-conductivity biologics and protein-based formulations, conventional HVLD systems face limitations. This challenge has driven the development of PTI’s MicroCurrent HVLD, a next-generation technology designed to ensure accurate, safe, and reliable CCI testing for today’s complex pharmaceuticals.

Understanding High Voltage Leak Detection

High Voltage Leak Detection (HVLD) works on the principle of electrical conductivity. The technique relies on the difference in conductivity between the container and its liquid contents:

• The container wall acts as a non-conductive barrier that resists electrical flow.
• The liquid inside serves as a conductive medium.

HVLD offers key advantages over older probabilistic methods such as dye ingress testing:

• Non-destructive to the sample.
• Quantitative and deterministic with discrete pass/fail results.
• Calibratable and repeatable, allowing validation under regulatory frameworks such as USP <1207>.

Yet, traditional HVLD systems have constraints. They require a certain minimum conductivity of the liquid—typically greater than 5 µS—to achieve reliable detection. This makes testing low-conductivity solutions, such as Sterile Water for Injection (WFI) or some biologics, challenging. Additionally, conventional HVLD systems expose products to high voltages, raising concerns about ozone generation and potential product degradation over time.

What Makes PTI’s MicroCurrent HVLD Unique?

PTI’s MicroCurrent HVLD (HVLDmc) technology represents a major advancement in deterministic CCI testing. The system has been designed to overcome the core limitations of traditional HVLD while enhancing sensitivity, safety, and versatility.

1. Low Voltage Exposure

MicroCurrent HVLD exposes the product to less than 5 % of the voltage used in conventional HVLD systems. This dramatic voltage reduction minimizes:

• The risk of product damage or denaturation, especially in protein-based or sensitive biologic drugs.
• The generation of ozone during testing, ensuring both product safety and a healthier working environment.

Experimental data show that PTI’s MicroCurrent HVLD produces virtually no ozone, eliminating a key environmental and operational hazard found in legacy systems.

2. Broader Conductivity Range

Unlike traditional HVLD, which requires moderate to high liquid conductivity, MicroCurrent HVLD can test liquids across an expanded conductivity range—including ultra-low-conductivity products such as WFI and complex biologics. This flexibility makes it a universal solution for inspecting diverse parenteral containers like vials, cartridges, and prefilled syringes.

3. Non-Contact, Non-Invasive Testing

The system employs a non-contact and non-invasive test method that requires minimal sample preparation. This ensures that each container remains intact and can proceed to market following inspection, reducing both waste and cost.

4. Deterministic, Traceable Results

MicroCurrent HVLD delivers quantitative pass/fail data that can be stored, trended, and validated under 21 CFR Part 11 compliant software (PTI ETHOS). Each test generates hard traceable data, eliminating the subjectivity inherent in visual or dye-based testing methods.

5. Integration with PTI E-Scan 615

The E-Scan 615 system is PTI’s flagship MicroCurrent HVLD platform, engineered for high-precision, high-throughput leak detection. Key features include:

• Defect detection below 1 µm, including cracks, pinholes, and plunger defects.
• Test cycle time of a few seconds, ideal for batch release testing or at-line inspection.
• Quick changeover and recipe setup, supporting multiple product types and container sizes.
• Stainless steel enclosure with integrated touch-screen and data connectivity options for streamlined operation.

With these capabilities, the E-Scan 615 delivers unmatched flexibility for both laboratory and production-floor environments

Benefits of MicroCurrent HVLD

• Non-destructive, non-invasive, no sample preparation
• High level of repeatability and accuracy
• Effective across all parenteral products, including extremely low conductivity liquids
• Low voltage exposure to the product and environment
• Listed in USP Chapter <1207> as recommended method for parenteral liquid package integrity testing.
• Robust method and approximate 3x Signal-Noise-Ratio for a wide range of product classes and package formats
• Simplifies the inspection and validation process

Conclusion

The shift from conventional to MicroCurrent HVLD marks a defining evolution in Container Closure Integrity Testing (CCIT). As drug products become more complex and sensitive, testing methods must adapt to ensure uncompromised quality and safety.

PTI’s MicroCurrent HVLD technology delivers unparalleled sensitivity, non-destructive operation, and complete data traceability. It enables manufacturers to verify package integrity confidently, meeting both scientific and regulatory expectations for deterministic CCI testing. In a landscape where sterility assurance defines patient safety, MicroCurrent HVLD stands as the new benchmark for HVLD-based CCI Technologies—safer, smarter, and scientifically superior.

As the pharmaceutical and biotechnology industries continue to advance, the need for maintaining product integrity during ultra-low temperature storage and transport has never been more critical. Modern therapeutics, such as cell and gene therapies, vaccines, and protein-based biologics, require deep-cold environments to preserve their stability and efficacy. These sensitive products often demand storage conditions that extend far below typical refrigeration, reaching temperatures of –20°C, –80°C, or even –180°C for cryogenic applications.

While these storage conditions are essential to safeguard product quality, they introduce a significant challenge: ensuring Container Closure Integrity (CCI) under extreme cold. Traditional packaging systems, though proven effective at ambient conditions, may not guarantee seal integrity when exposed to such harsh temperatures. This is where advanced CCI technologies, particularly Helium Leak Testing, play a pivotal role.

Ultra-Low Temperature Storage and Transport Challenges

The push toward deeper cold storage has exposed a fundamental issue in pharmaceutical packaging — material behavior at low temperatures. Many primary container systems, such as glass vials with elastomeric closures (screw or crimp tops), were not originally designed to maintain tight seals in ultra-cold conditions. When packaging materials are subjected to extremely low temperatures, several physical and chemical transformations occur:

• Elastomeric closures can reach or surpass their glass transition temperature, causing them to lose elasticity and form microscopic gaps.
• Shrinkage and rigidity in materials like rubber or silicone stoppers can lead to seal failure between the vial and closure.
• Thermal contraction of dissimilar materials (e.g., glass vs. elastomer) can introduce mechanical stress at the interface, further compromising CCI.

Such issues often result in leakage at the primary seal area, which may not be detected under normal room temperature testing. Even minute leaks can allow contaminants or moisture to enter the container, threatening sterility, potency, and patient safety. Therefore, verifying CCI performance directly under low-temperature conditions is essential for risk mitigation and regulatory compliance with USP <1207> guidelines.

CCI Testing at Ultra-Low Temperatures Using Helium Leak Testing

To address these challenges, PTI has engineered advanced CCIT systems capable of evaluating packaging integrity under true ultra-cold conditions. The Helium Leak Testing method stands out as one of the most precise and sensitive approaches for this application.

Why Helium Leak Testing?

Helium Leak Testing is a deterministic and quantitative method for assessing container integrity. It works by filling or exposing the package to helium—a small, inert tracer gas—and measuring its leakage through potential defects using a mass spectrometer-based detector. This allows detection of leak rates as low as 1x10?¹¹ mbar·L/s, offering far greater sensitivity compared to traditional dye or microbial ingress tests. Helium Leak Testing offers several advantages:

• Highly sensitive and reliable quantitative measurement of leak rates.
• Compliance with USP <1207> and other global regulatory standards.
• Ability to simulate real-world cold storage conditions for accurate performance assessment.

PTI’s LT80 Low-Temperature Test System

To meet the industry’s growing need for accurate low-temperature CCI evaluation, PTI’s engineering team developed the LT80 – Low Temperature (-80°C) Test System, designed for use with the PTI SIMS range of helium leak detectors. The LT80 system offers a comprehensive solution for temperature-controlled CCI testing, integrating:

• Concurrent temperature conditioning and monitoring down to –80°C.
• Precise helium leak detection across glass and polymer-based container systems.
• Compatibility with dry ice (-78.5°C) and extended testing capabilities to even lower ranges using cryogenic modules (down to –160°C).

The PTI SIMS 1915+ LT80 represents the first off-the-shelf, Part 11-compliant helium leak testing system specifically configured for low-temperature applications. It combines the trusted performance of the SIMS 1915+ platform with integrated Cryo Chiller technology, enabling both routine and developmental testing for cold-chain drug products. This system empowers manufacturers to:

• Evaluate packaging systems for fine leaks at sub-zero conditions.
• Optimize package selection and assembly parameters based on real temperature data.
• Demonstrate scientific understanding and regulatory readiness in line with USP <1207> and FDA expectations.

As biologics and cell therapies continue to redefine modern medicine, ensuring container closure integrity throughout ultra-low temperature storage and transport is no longer optional—it’s essential. Standard room-temperature testing cannot capture the subtle yet critical leak pathways that emerge at cryogenic conditions.

By implementing Helium Leak Testing with PTI’s LT80 system, pharmaceutical manufacturers can confidently evaluate and validate their packaging performance at temperatures as low as –80°C. In an era of complex biologics and global cold-chain logistics, advanced CCI technologies like Helium Leak Testing are setting new standards for quality assurance in pharmaceutical packaging.

In the highly regulated pharmaceutical industry, the integrity of a product’s packaging is just as critical as the formulation itself. Container Closure Integrity (CCI) ensures that sterile products remain free from contamination, moisture ingress, and loss of sterility throughout their shelf life. Traditionally, destructive methods such as dye ingress or microbial challenge tests were used to verify package integrity. While effective to some extent, these methods have significant limitations, including sample loss and lack of quantitative data.

Non-destructive CCI technologies has emerged as a reliable, science-based alternative that meets stringent regulatory requirements while protecting valuable products. By offering repeatable, quantitative, and non-invasive testing, these technologies are redefining the way pharmaceutical manufacturers validate the integrity of vials, pre-filled syringes, ampoules, and other critical packaging systems.

Role of Non-Destructive CCI Testing in Ensuring Package Integrity

Non-destructive CCI testing methods allow manufacturers to test every package—or perform statistically significant sampling—without damaging the product or compromising sterility. This approach provides several key advantages:

• Regulatory Compliance: The U.S. FDA, EMA, and USP <1207> guidelines emphasize deterministic, quantitative methods over traditional probabilistic ones. Non-destructive methods align with these recommendations.
• Cost Efficiency: By preserving tested units, manufacturers reduce waste and avoid the cost of discarding valuable pharmaceutical products.
• Enhanced Data Quality: Non-destructive techniques provide numerical data for leak rates or pressure changes, allowing for precise analysis and easier process validation.
• Operational Flexibility: These methods can be implemented in-line for 100% inspection or off-line for batch verification, supporting continuous quality assurance.

By eliminating subjectivity and improving reproducibility, non-destructive CCI testing not only ensures product safety but also enhances operational efficiency across the supply chain.

Non-Destructive Deterministic CCI Test Methods Offered by PTI

PTI (Packaging Technologies & Inspection) is a global leader in deterministic, non-destructive CCIT solutions. Their portfolio includes advanced technologies that have been validated and adopted by major pharmaceutical companies worldwide. The key methods include:

1. Vacuum Decay Technology

Vacuum Decay is a practical, highly sensitive, and industry-recognized method for vacuum-based leak detection. It delivers quantitative, reproducible results and provides a clear pass/fail determination for package integrity. PTI’s VeriPac systems played a pivotal role in the development of ASTM F2338, the standard test method for vacuum decay leak detection. This method is also referenced in the United States Pharmacopeia (USP) <1207> guidelines for CCI testing and is classified under ISO 11607.

The technology operates by using an absolute or differential pressure transducer to monitor the vacuum level within a sealed test chamber. Any rise in pressure indicates the presence of a leak or hidden defect. VeriPac’s non-destructive approach ensures accurate detection of leaks without compromising the tested product, making it ideal for a wide range of pharmaceutical packaging applications.

2. MicroCurrent HVLD Technology

PTI has advanced traditional High Voltage Leak Detection (HVLD) by introducing MicroCurrent HVLD, a breakthrough solution specifically engineered for the integrity testing of parenteral and biological products—including low-conductivity liquids such as sterile water for injection (WFI).

Unlike standard HVLD systems, MicroCurrent HVLD operates at approximately 50% lower voltage, reducing exposure to less than 5% of the typical electrical levels. This makes it significantly safer for sensitive pharmaceutical products and the testing environment.

The technology can identify and precisely locate a wide range of defects, including pinholes, micro-cracks, stopper or plunger leaks, and non-visible leaks beneath crimping. By combining high sensitivity with a gentler testing process, MicroCurrent HVLD offers a more efficient and product-friendly solution for critical applications in pharmaceutical manufacturing. Non-destructive CCI testing is no longer just an emerging trend; it is becoming the industry standard for ensuring the sterility and safety of pharmaceutical products. By delivering quantitative, reproducible, and regulator-approved results, methods like Vacuum Decay and MicroCurrent HVLD provide manufacturers with the confidence that every unit shipped maintains its intended barrier properties.

As regulatory bodies and market demands continue to emphasize product quality and patient safety, investing in non-destructive CCI technologies is not just a compliance measure—it is a strategic advantage for pharmaceutical manufacturers.