Blogs

Clinical trials depend heavily on the reliability and stability of drug products—especially biologics, sterile injectables, and advanced therapies. Even microscopic leaks can compromise sterility, degrade sensitive molecules, or alter product potency. As regulatory expectations evolve and USP <1207> pushes the industry toward deterministic methods, PTI has become a trusted partner for pharmaceutical companies needing accurate, deterministic, and defensible container closure integrity anchor (CCI) data. PTI’s testing systems ensure that every batch used in clinical and stability studies maintains the highest level of integrity throughout storage, handling, and distribution. Our solutions and services support clients throughout the entire product lifecycle.

How Leak Testing Affects Product Reliability in Trials?

Leak testing directly influences the consistency and safety of products administered during clinical trials. A biologic stored in a compromised container can undergo structural degradation or sterility loss long before reaching the trial site, affecting trial outcomes and data reliability.

Traditional methods such as dye ingress or visual inspection are inadequate for detecting small but critical defects. PTI’s deterministic technologies, Vacuum Decay, High Voltage Leak Detection, and Helium Leak Detection, address these limitations by providing quantitative, and reproducible results.

Their impact is especially clear in three areas:

• Sterility assurance: PTI systems detect microchannels that allow microbial or gas ingress, preventing sterility failures.
• Consistency across batches: Deterministic measurements reduce variability in drug exposure, potency, and pharmacokinetics.
• Protection against delays: Early detection of closure issues prevents trial interruptions, recalls, or regulatory holds.

By ensuring dependable CCI performance, PTI technologies strengthen the entire clinical supply chain.

Role of PTI Technologies in Clinical Trials and Biologic Stability Studies

PTI offers the most advanced suite of deterministic CCI platforms used in clinical development. Each technology addresses specific packaging formats and sensitivity requirements, ensuring comprehensive integrity evaluation.

1. Vacuum Decay Technology (VeriPac Series)

Vacuum Decay stands as one of the most accurate and widely adopted deterministic methods in the pharmaceutical industry. PTI is the global leader in its development.

Key advantages include:

• Quantitative leak measurement
• High sensitivity to microdefects
• Ideal for vials, syringes, cartridges, and flexible formats

It is widely chosen for long-term stability studies and clinical batch release because it provides consistent, scientifically defensible results.

2. HVLD for Liquid-Filled Biologics

Biologics formulated in liquid form often require a testing method that does not stress or damage the product. PTI’s HVLD uses a low-voltage approach that prevents protein oxidation while maintaining exceptional sensitivity.

This method is particularly effective for:

• Prefilled syringes
• Liquid-filled vials
• Cartridges used in autoinjectors

Its ability to detect microcracks, stopper issues, and seal failures without harming delicate formulations makes it a preferred choice for clinical-stage biologics.

PTI’s Helium Leak Detection for High-Sensitivity Applications

For products that demand the highest level of sensitivity, such as gene therapies, viral vectors, long-acting injectables, and oxygen-sensitive biologics, PTI’s Helium Leak Detection provides unmatched precision.

It supports:

• Ultra-tight CCI requirements
• Container qualification studies
• Cold chain and cryogenic stability programs
• eak rate quantification down to 10?¹¹ mbar·L/s

This makes it invaluable for advanced therapies where the smallest leak can alter therapeutic stability.

Regulatory Alignment and Data Integrity

PTI instruments are engineered for full regulatory compliance. They support:

• USP <1207> deterministic CCI requirements
• 21 CFR Part 11 electronic data integrity
• Complete audit trails and secure data systems
• Validation-ready workflows for clinical and GMP environments

This level of compliance gives pharmaceutical companies confidence during regulatory submissions and inspections.

Conclusion

PTI Technologies plays a vital role in maintaining the safety, stability, and integrity of high-value biologics throughout the product lifecycle. With industry-leading deterministic platforms such as Vacuum Decay, HVLD, Helium Leak Detection, and Seal-Scan systems, PTI provides unmatched sensitivity, reliability, and regulatory alignment. By ensuring that every unit used in clinical research meets the highest standards of package integrity, PTI helps pharmaceutical companies protect patients, generate consistent clinical data, and accelerate the development of the next generation of biologic therapies.

Life-saving drugs—including vaccines, monoclonal antibodies, oncology drugs, and parenteral formulations—require packaging systems that maintain sterility and protect the product throughout its shelf life. Traditional destructive test methods once served as the standard approach for checking package integrity, but these methods do not offer the sensitivity, repeatability, or scientific defensibility needed for today’s high-risk drug categories.

With increasing regulatory pressure from USP <1207>, the FDA, EMA, and other global agencies, manufacturers must now adopt deterministic, non-destructive, and validated CCI testing methods. These methods not only enhance detection accuracy but also preserve valuable product, support strong quality systems, and ensure patient safety.

Non-destructive Container Closure Integrity testing (CCIT) has emerged as the most reliable and scientifically sound approach to safeguarding high-value, life-saving drug products. PTI has led this shift by developing deterministic technologies that ensure accurate, repeatable, and regulatory-compliant inspection across all packaging formats.

Limitations of Destructive Tests

Destructive methods such as dye ingress testing have long been used in the industry, but their deficiencies are widely known. They rely heavily on operator interpretation, have limited sensitivity, and cannot generate quantitative data. Dye ingress is particularly inconsistent because its results depend on factors such as dye concentration, immersion conditions, and subjective visual inspection.

Destructive CCI tests also lead to product loss. In many cases—especially with high-value biologics, limited-volume batches, or clinical supplies—sacrificing samples is costly and impractical. Additionally, destructive methods cannot be performed at the frequency or consistency needed to establish statistical confidence in batch integrity.

Ultimately, destructive tests do not align with modern regulatory standards or the safety expectations surrounding life-saving drugs.

Benefits of Non-Destructive Testing

Non-destructive CCI methods eliminate the drawbacks of destructive testing and provide significant advantages for protecting high-value drugs:

• Complete product retention: Packages remain intact, ensuring no loss of valuable or limited drug product.
• Supports higher testing frequency: Enables increased sampling or even 100% testing without affecting batch volume.
• Quantitative and deterministic results: Provides measurable, traceable data for trend analysis and quality improvement.
• Enhanced leak detection sensitivity: Identifies micro-leaks that destructive methods commonly miss.
• Ideal for biologics and advanced therapies: Particularly important for products with high manufacturing costs and strict sterility requirements.
• Regulatory compliance: Meets USP <1207> expectations for deterministic, instrument-based CCI testing.

PTI’s Approach to Life-Saving Drug Package Integrity

PTI has become a global leader in deterministic, non-destructive CCI technologies specifically developed for pharmaceutical and biologic products. With solutions implemented across major drug categories, PTI systems deliver unmatched sensitivity, repeatability, and compliance with regulatory expectations.

PTI’s vacuum decay technology, delivered through the VeriPac series, is widely adopted for vials, syringes, cartridges, flexible packaging, and combination devices. Vacuum decay offers exceptionally high sensitivity to micro-leaks, producing quantitative results unattainable through destructive methods.

PTI also emphasizes comprehensive method development, validation support, and data integrity across all inspection workflows, ensuring that life-saving drugs remain protected from packaging to patient use.

Conclusion

The integrity of pharmaceutical packaging plays a critical role in protecting life-saving drugs. Destructive and probabilistic methods like dye ingress testing no longer meet the sensitivity, reliability, or regulatory expectations required for modern therapies. Their inability to detect micro-leaks, along with significant product wastage, makes them unsuitable for high-value drug products.

Non-destructive CCI testing provides the accuracy, repeatability, and scientific foundation necessary to ensure sterility and stability. PTI’s deterministic technologies—including vacuum decay and HVLD—empower manufacturers to retain product, increase testing frequency, and maintain strong regulatory compliance.

By adopting non-destructive CCI methods, pharmaceutical companies strengthen their ability to deliver safe, effective, and uncompromised therapies to patients who depend on them.

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 today’s pharmaceutical landscape, the demand for high-quality and data-driven container closure integrity solutions has grown exponentially. From biologics and cell therapies to injectables and combination products, the need for precise leak detection and reliable integrity assurance is greater than ever.

Method development is not just a procedural step, it is the foundation that determines the accuracy, sensitivity, and robustness of the entire CCI testing process. A well-developed method ensures that every integrity test performed delivers consistent and meaningful data aligned with USP <1207> regulatory expectations.

At PTI, our approach to method development integrates advanced CCI technologies such as Vacuum Decay, Helium Leak Detection, and High Voltage Leak Detection (HVLD), supported by decades of expertise in packaging science and feasibility testing.

Importance of Method Development in CCI Technologies

Method development serves as the bridge between theoretical technology capability and real-world application. Even the most sophisticated CCIT instrument cannot guarantee reliable results without a method that is specifically optimized for the product’s characteristics, such as material, size, headspace volume, and sealing system.

Here’s why method development is essential in the context of CCI technologies:

• 1. Customization for Packaging Types: Each container type, be it glass vials, pre-filled syringes, or flexible IV bags, exhibits unique mechanical and permeability properties. A tailored method ensures the chosen CCI technology effectively detects leaks at the required sensitivity level.
• 2. Regulatory Compliance and Data Integrity: Global agencies like the FDA, EMA, and USP <1207> demand deterministic testing methods with validated, quantifiable results. A robust method ensures compliance with these standards, providing traceable data and repeatable performance across multiple test runs.
• 3. Minimizing False Results: Inadequate method development can lead to false positives or negatives, compromising product safety and increasing manufacturing costs. A well-validated method minimizes such risks by accounting for variables like temperature, sample preparation, and environmental factors.
• 4. Optimizing Instrument Performance: Technologies such as PTI’s Helium Leak Detection systems or Vacuum Decay platforms deliver their best performance only when the test parameters, pressure levels, dwell times, and sensitivity thresholds, are optimized through method development studies.
• 5. Supporting Lifecycle Management: As packaging materials or formulations evolve, established test methods can be revalidated or refined, allowing manufacturers to maintain consistent integrity standards throughout the product lifecycle.

Steps for Setting Up a Reliable Container Closure Integrity Testing Process

Developing and validating a robust method for Container Closure Integrity Testing involves a structured, science-based approach. PTI’s method development process typically includes the following stages:

1. Feasibility Study: The first step is to evaluate the suitability of various CCI technologies for the specific container system. This involves understanding the packaging design, material composition, headspace conditions, and product type (liquid, lyophilized, or gas-filled). At PTI, our feasibility studies identify the most appropriate deterministic method, whether Vacuum Decay, Helium Leak Detection, or HVLD, based on the detection limits required and regulatory expectations.

2. Baseline Testing: Once the technology is selected, baseline measurements are taken using known good and defective samples. This helps establish initial performance metrics, leak rate thresholds, and system sensitivity.

3. Method Optimization: In this phase, critical parameters such as test pressure, dwell time, vacuum levels, and data acquisition rates are fine-tuned. The objective is to ensure repeatability and reproducibility across different sample batches. PTI’s engineers leverage extensive testing data to achieve optimal test conditions that yield highly sensitive and consistent readings.

4. Validation and Robustness Studies: The developed method undergoes a rigorous validation process in accordance with USP <1207> and other relevant standards. Validation typically covers:

• Accuracy (ability to detect true leaks)
• Precision (repeatability and reproducibility)
• Specificity (distinguishing true defects from non-relevant variables)
• Detection Limit (smallest detectable leak rate)
• Robustness (method reliability under varied conditions)

5. Documentation and Training: Comprehensive documentation of all procedures, parameters, and validation outcomes is prepared for regulatory submission and internal use. Additionally, operator training ensures consistent execution of the method during routine production testing.

6. Continuous Monitoring and Revalidation: A robust method is not static. Regular performance verification ensures that the system continues to deliver accurate results as packaging materials, storage conditions, or production parameters evolve. PTI provides ongoing support for revalidation and method refinement to maintain long-term reliability.

Conclusion

A scientifically developed and validated method is the backbone of a reliable Container Closure Integrity Testing (CCIT) program. It ensures that every product reaching the market maintains its sterility, stability, and safety safeguarding both patient health and brand reputation.

At PTI, we combine deep technical expertise with advanced CCI technologies to deliver end-to-end CCI services, from feasibility studies and method development to full validation and production implementation. By prioritizing method robustness, we help pharmaceutical and biotech manufacturers build confidence in their package integrity programs and achieve global compliance.

In an era where precision and reliability define product quality, a robust method development process is not just good practice, it is an essential step toward ensuring the highest standards of pharmaceutical packaging integrity.

In the pharmaceutical and nutritional industries, packaging is more than just a container, it’s a safeguard for product safety, efficacy, and shelf life. As companies increasingly adopt flexible packaging for its convenience and sustainability, the challenge lies in ensuring that every pouch, sachet, or bag remains completely leak-free. Even a microscopic defect can compromise product integrity, leading to contamination, instability, or regulatory non-compliance. To address these challenges, manufacturers are turning to advanced Container Closure Integrity Testing (CCIT) solutions such as PTI’s VeriPac FLEX system, a trusted technology for ensuring consistent, reliable results.

Flexible Package Integrity Tpackage sting Challenges

Flexible packaging poses unique challenges for integrity testing. Unlike rigid containers, pouches and sachets are made from pliable materials that can deform under pressure, making traditional test methods inconsistent or unreliable.

Common issues include:

• Variations in headspace that affect test accuracy
• Seal irregularities caused by heat or pressure inconsistencies
• Difficulty detecting micro-leaks that are invisible to the naked eye
• Limitations of destructive testing methods such as blue dye or water bath tests, which are subjective and wasteful

To overcome these limitations, manufacturers are shifting towards deterministic, quantitative, and non-destructive test methods that ensure repeatability and precision—essential for meeting FDA and USP <1207> guidelines.

Package Integrity Testing Using VeriPac FLEX

PTI’s VeriPac FLEX system is a non-destructive vacuum decay leak testing solution designed specifically for flexible packaging applications. It delivers a clear PASS or FAIL result, along with quantitative data that correlates directly to leak rates. The system is known for its high sensitivity, reliability, and ability to test a wide variety of flexible package formats and sizes without the need for changeovers or adjustments.

What sets the VeriPac FLEX apart is its flexible membrane test chamber that adapts to the shape of each package, preventing stress or damage to delicate film materials. The technology supports multiple chamber configurations to suit different applications, from the Integrated Flexible Chamber (IFC) for small sachets and stick packs to the Drawer Style (D-Series) chambers for medium and large pouches. For bulk products or special packaging, PTI also offers customized solutions.

Recognized by the FDA and compliant with ISO 11607, the VeriPac FLEX offers manufacturers a robust, regulatory-approved package integrity testing method. It simplifies validation, supports high-throughput testing, and eliminates the waste associated with destructive methods.

Benefits of VeriPac FLEX

Implementing VeriPac FLEX technology brings measurable benefits across production, quality, and sustainability goals:

• Deterministic and quantitative testing – Provides clear, data-driven results
• Non-destructive and non-subjective – No product loss or operator bias
• Multiple packages tested simultaneously – Enhances throughput and efficiency
• Rapid return on investment – Reduces waste, labor, and rework costs
• Supports zero-waste initiatives – Aligns with sustainability objectives
• Simplifies validation and inspection – Streamlined process for quality assurance

Conclusion

Flexible packaging may be versatile, but maintaining its integrity demands uncompromising precision. PTI’s VeriPac FLEX system ensures that pharmaceutical and nutritional products reach consumers safely and without contamination. By replacing outdated, destructive methods with a proven vacuum decay technology, manufacturers can achieve true confidence in their packaging process, ensuring every delivery remains leak-free, compliant, and reliable.