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In the rapidly evolving field of biologics, maintaining container closure integrity is essential for product safety, regulatory compliance, and overall efficacy. By employing advanced CCI testing methods, manufacturers can ensure their packaging systems provide robust protection for sensitive biologic products, ultimately contributing to better patient outcomes and advancing the field of pharmaceutical science. As the demand for biologics continue to grow, the importance of rigorous CCI testing will only become more pronounced, underscoring the need for continued innovation and adherence to best practices in packaging integrity.

Importance of Maintaining Sterility and Efficacy in Biologic Products

Biologic products, which include vaccines, monoclonal antibodies, and therapeutic proteins, are essential in treating a wide range of diseases. Ensuring their sterility and efficacy is vital for several reasons:

• Patient Safety: Sterility is critical to prevent contamination by harmful microorganisms, which can lead to severe infections or adverse reactions. A lapse in sterility can compromise patient safety, potentially causing serious health issues.
• Product Integrity: Maintaining both sterility and efficacy is essential for the product’s overall quality and reliability. Consistent quality reassures healthcare providers and patients, reinforcing trust in the therapy and supporting its widespread adoption.
• Minimizing Risks: Ensuring that biologic products are sterile and effective minimizes the risk of treatment failures and associated complications. This contributes to better patient outcomes and enhances the overall success of therapeutic interventions.

Prioritizing these factors supports the successful application of biologic therapies and upholds the high standards required in the biotechnology industry.

Package Integrity Solutions for Biologics Packaging

Helium Leak Detection Technology

Helium leak testing detects leaks in sealed systems by using helium as a tracer gas and measuring its escape. This method provides highly accurate leak rate data, surpassing other techniques. It is particularly effective for evaluating the integrity of pharmaceutical and parenteral packaging. The process involves filling the package with helium, applying a vacuum, and using a detector to measure the escaping helium, determining the leak rate. This technology is crucial for package design, failure analysis, tooling qualification, packaging line validation, and quality monitoring.

For cold storage CCI applications, helium is a highly sensitive and reliable technology for assessing the performance of vials, syringes, and cartridges at cryogenic temperatures.

MicroCurrent HVLD Technology

MicroCurrent HVLD technology is an innovative High Voltage Leak Detection method for container closure integrity testing (CCIT), proving highly effective for a wide range of applications including pre-filled syringes, vials, cartridges, ampoules, BFS, bottles, and pouches. This non-destructive, non-invasive technology uses approximately 50% less voltage, exposing the product and environment to less than 5% of the voltage compared to conventional HVLD solutions. It stands as one of the most effective CCI technologies for all parenteral and biological products.

To ensure Container Closure Integrity, the method uses electrode probes to scan a non-conductive sealed container. Defects in the package cause a resistance differential, altering the current flow within the container. The MicroCurrent HVLD test method can accurately detect and locate defects such as pinholes, micro-cracks, stopper/plunger leaks, non-visible leaks under crimping, and more.

Advanced CCI testing methods, including Vacuum Decay and MicroCurrent HVLD, offer diverse and highly accurate solutions for detecting potential leaks and defects. By employing these techniques and adhering to best practices, manufacturers can ensure that their packaging systems effectively preserve the quality and safety of biologic products, ultimately enhancing patient outcomes and advancing the pharmaceutical industry.

In the field of pharmaceutical packaging, the quest for robust Container Closure Integrity (CCI) testing methods has evolved significantly beyond traditional approaches such as blue dye testing. As the industry continues to prioritize safety, efficacy, and regulatory compliance, innovations in CCI testing are poised to redefine standards and practices.

Recent advancements in CCI testing methods are driving a transformative shift towards more sensitive, reliable, and versatile techniques. These innovations are not only enhancing detection capabilities but also addressing the limitations that have historically challenged conventional methods like blue dye testing.

Limitations of Blue Dye Testing

Blue dye testing, a traditional method for leak detection in packaging, has several limitations that make it less favourable compared to more modern techniques. Here are some of the key drawbacks:

• Destructive testing: The biggest disadvantage is that the test destroys the packaging being tested.
• Subjectivity: Relying on visual inspection of the packaging for dye presence can be subjective.
• Limited leak detection: Blue dye tests are not very sensitive and may miss certain types of leaks, particularly those with low permeability or microscopic tears.
• Environmental concerns: The disposal of the dye solution used in the testing process can raise environmental concerns.

How Modern CCI Testing Methods Detect Issues that Blue Dye Might Miss?

Modern CCI testing methods offer significant advantages over traditional techniques like blue dye testing by providing sensitive, quantitative, non-destructive, and versatile approaches to assessing container closure integrity. These advancements enhance the reliability and effectiveness by ensuring product quality and patient safety.

MicroCurrent HVLD Technology

MicroCurrent HVLD is a non-destructive technology for Container Closure Integrity Testing (CCIT) used to assess the integrity of parenteral product packaging. This approach employs quantitative electrical conductivity measurements inherent to HVLD technology, which relies on the fundamental principle of electrical current. During testing, the container is positioned horizontally on a rotating stage. As the container rotates, one side receives a high voltage, while a ground probe is connected to the opposite side. If the package remains intact without leaks, the two container surfaces (high voltage and ground) exhibit complete electrical resistance, resulting in minimal current flow through the vial. However, if there is a micro-leak or crack in the container walls, the electrical resistance is compromised, allowing current to pass through. MicroCurrent HVLD finds application in testing various types of pharmaceutical packaging, including pre-filled syringes, ampoules, drug product cartridges, liquid-filled vials, and Blow-Fill-Seal (BFS) containers.

Vacuum Decay Technology

Vacuum Decay is a non-destructive approach to assessing container closure integrity, focusing the detection of package integrity and leak paths. The test procedure is simple, evaluating container integrity based on critical physical attributes. This technique has proven to be a non-destructive alternative to traditional water bath leak testing. In this method, packages are placed within an evacuation test chamber that utilizes an external vacuum source. The test continuously monitors vacuum levels to identify any deviations from a predefined target vacuum level. If a package is defective, it allows air to escape into the test chamber. Conversely, intact packages maintain a stable vacuum level within the chamber. Over time, Vacuum Decay technology has established itself as one of the most effective and sensitive solutions for vacuum-based leak detection.

Helium Leak Detection Technology

Helium leak detection technology has revolutionized Container Closure Integrity Testing (CCIT) by offering extremely sensitive and accurate detection of leaks. This method involves using helium gas to identify leaks in sealed or closed systems, measuring its concentration as it escapes through any leaks present. Helium leak testing finds diverse applications across various packaging formats, such as pre-filled syringes, vials, cold form blister packs, foil pouches, and others. This technology excels at precisely evaluating the integrity of specific components within primary container closure systems, making it highly suitable for ensuring the integrity of pharmaceutical products. Helium gas is uniquely suited as a tracer for leak detection due to its exceptional properties. Manufacturers leverage these properties to conduct thorough testing that can pinpoint even minute leaks, thereby enhancing quality control and product safety.

Innovations in Container Closure Integrity (CCI) testing have propelled the field beyond traditional methods like blue dye testing, ushering in a new era of enhanced precision and reliability. Technologies such as MicroCurrent HVLD, Vacuum Decay, and Helium leak detection have revolutionized how pharmaceutical packaging integrity is assessed, offering sensitive, non-destructive, and comprehensive approaches.

With ongoing developments in analytical capabilities and testing methodologies, the landscape of CCI testing is poised for further advancements, driving towards greater efficiency, accuracy, and compliance. By embracing these innovations, pharmaceutical manufacturers can confidently navigate the complexities of packaging integrity, setting new benchmarks for quality assurance in the healthcare sector.

Blister packaging has gained widespread popularity as a versatile and efficient method for packaging various products, particularly in industries like pharmaceuticals, nutraceuticals and food. This packaging solution typically involves the creation of a plastic cavity or blister that is custom designed to securely hold and protect the product it contains. The design of the blister can vary significantly, accommodating a wide range of product shapes and sizes, making it a versatile option for manufacturers. It ensures that the product remains visible to consumers, allowing for easy identification and branding, which is especially crucial in retail settings.

To ensure the product's integrity and longevity, blister packaging is typically sealed with materials like aluminum foil or plastic film. This sealing process not only provides a protective barrier against external factors such as moisture, light, and contaminants but also enhances the product's shelf life. In the pharmaceutical industry, blister packaging is widely used to provide precise dosages of medications and to maintain their stability and sterility. In the food industry, it is often employed to preserve the freshness of perishable items and prevent tampering or contamination. Overall, blister packaging offers a combination of product visibility, protection, and convenience, making it an indispensable choice for many manufacturers looking to meet both functional and marketing requirements.

However, the significance of maintaining the integrity of blister packaging cannot be overlooked, as it plays a pivotal role in avoiding contamination, preserving product freshness, and extending shelf life. One highly effective method employed for assessing blister package integrity is helium leak detection, a process that relies on the unique properties of helium as a tracer gas.

Blister Package Integrity Testing using Helium Leak Detection.

Helium leak detection is a Container Closure Integrity Test (CCIT) that is used to identify leaks in blister packages. The test works by introducing helium gas into the blister package and then measuring the amount of helium that escapes. If there is a leak in the package, helium will escape, and the leak detector will produce a signal.

To test a blister package for leaks using (helium leak detection), the package is first placed in a test chamber. The test chamber is then evacuated, and helium gas is introduced into the package. The package is then held under vacuum for a period of time. After the holding time has elapsed, the test chamber is vented, and the leak detector is used to measure the amount of helium that has escaped from the package. If the amount of helium that has escaped from the package is above a certain threshold, the package is considered defective. Defective packages are rejected and not shipped to customers.

Why is Helium used as a Tracer Gas?

• It is the smallest and lightest gas, so it can easily escape through even the smallest leaks.
• It is inert, meaning that it does not react with other substances.
• It is non-toxic and non-flammable.
• It is abundant and relatively inexpensive.

Helium leak detection is a highly sensitive and reliable method for testing the integrity of blister packages. It is widely used in the pharmaceutical industry to ensure that blister packs are leak-proof and protect the contents from moisture, oxygen, and other contaminants.

Combination products are medical devices that combine two or more different types of medical products (e.g., a drug-device combination or a biologic-device combination) into a single entity. These products present unique challenges in terms of design, development, and regulatory approval due to the integration of different technologies and functionalities. Therefore, it is crucial to use appropriate techniques to evaluate combination product’s safety, efficacy, and overall performance.

The FDA's Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) developed the "Guidance for Industry and FDA Staff - Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology" to help manufacturers evaluate combination products containing nanomaterials. While this guidance specifically addresses nanotechnology, many of the concepts and principles apply more broadly to evaluating combination products.

What are the three main categories of combination products?

Combination products are categorized into three main types based on their primary mode of action.

1.Drug-Device Combination Products: These products combine a drug and a medical device into one single entity. The drug and device components work together to achieve the intended therapeutic effect. An example of this type of combination product is an auto-injector that contains a drug and a delivery device.

2. Biologic-Device Combination Products:These products combine a biological product (such as a vaccine, cellular therapy, or tissue product) with a medical device. The device is integral to the administration or use of the biological product. An example of this type of combination product is a pre-filled syringe containing a biological medication.

3. Drug-Biologic Combination Products: These products combine a drug and a biological product. This category is less common than the others, but it involves combining a drug with a biologically sourced material. An example of this type of combination product is a drug formulated with a growth factor derived from human tissues.

Combination Products Quality Control Techniques

Microcurrent HVLD technology

MicroCurrent High Voltage Leak Detection (HVLD mc) is a non-destructive container closure integrity testing method that has been proven to be significantly more effective in identifying leaks in various types of parenteral and pharmaceutical applications. It may be used to check for leaks in nonporous, rigid, or flexible packaging as well as packaging that contains liquids. Tests for high voltage leak detection are carried out using electrical conductivity and resistance theories. This method operates by transmitting high voltage, low current impulses through sample packages. When there is a leak, the electrical resistance of the sample falls, causing an increase in current. HVLD technology depends on the "flow" of current, compared to conventional leak detection methods that depend on the movement of gas or liquid.

MicroCurrent HVLD Applications

• Vials
• Ampoules
• Cartridges
• Pre-filled Syringes
• BFS

Helium Leak testing

Helium leak detection is a method for finding leaks in a variety of sealed or enclosed systems by utilizing helium as a "tracer" gas. It is a CCI technique used to evaluate the integrity of critical injectable or parenteral products. Since helium is non-toxic, non-flammable, and non-condensable, helium gas is a great option for tracer gas. Helium is present in the atmosphere in amounts of little more than 5 ppm, making minor leaks easy to pass through. Helium is also more readily available and less expensive than other tracer gases, available in a variety of cylinder sizes. The test is performed by attaching the test component to the leak detector, which is then filled with helium gas. Helium escapes from the test components when there is a leak, and this partial pressure is measured, with the results shown on the meter.

Benefits of Helium Leak Testing

• Practical and sensitive flow-based leak test method,
• Enables the discovery of extremely small microleaks.
• Detects leaks with sensitivity level as low as 1x10-10 mbar L/sec.
• Helium is a non-explosive, non-toxic and non-destructive tracer gas.
• Applicable across package design, failure analysis, packaging line setup and validation.
• A faster test cycle reduces cost and total processing time.

The specific techniques and requirements for evaluating combination products may vary depending on the nature of the product (e.g., drug-device vs. biologic-device) and the intended use. Manufacturers are encouraged to engage in early communication with regulatory authorities to clarify the requirements and expectations for their combination product. Additionally, seeking the expertise of professionals with experience in evaluating combination products can be beneficial throughout the development and approval processes.

The quality of the product and the maintenance of the sterile barrier against outside forces are both critically dependent on the packaging. Even a tiny hole in the packaging might allow moisture, reactive gases, or other dangerous elements to enter the product, limiting its ability to heal. Additionally, a contaminated pharmaceutical product can cause serious health issues to the user, making it more of a threat than a treatment. Maintaining Container Closure Integrity is extremely important due to the sensitive nature of pharmaceutical products.

Container Closure Integrity testing is a leak detection technique for determining how well sterile barriers are maintained against external contamination. These tests may be roughly divided into probabilistic and deterministic test methods. Manufacturers choose deterministic test procedures since they provide precise, guaranteed quantitative results. One such test method is helium leak detection technology.

Helium Leak Detection Technology Overview

Helium leak testing is the method of identifying leaks in various enclosed or sealed systems by utilizing helium as a "tracer" gas and measuring the concentration of the gas as it leaves due result of a leak. A vial is a good example of package system. A pre-filled syringe, a foil pouch, and a cold form blister card are some other examples. Each of these package types is intended to keep the pharmaceutical product contained while preventing the entry of potentially dangerous environmental contaminants like dust, bacteria, or even gases. Helium leak testing method can evaluate these package types. It is a highly efficient approach for finding leaks that provide quantitative leak rate data considerably beyond the capabilities of existing leak testing techniques.

The following describes how helium leak detection works: The package is initially vacuumed and helium-filled. The amount of helium escaping the package is then measured quantitatively and expressed as a leak rate using a helium leak detector. The technique is also ideally suited for packaging line setup and validation, failure analysis, tool qualification, monitoring product quality, and package design.

Why Use Helium as a Tracer Gas?

• Deterministic seal quality inspection method that produces quantitative outcomes.
• Regardless of color, transparency, print, surface polish, or porosity, this method works for all material types and combinations.
• Non-destructive and non-subjective test technique that does not require any sample preparation.
• Technology may be used for 100% online final pouch seal defect detection.
• Seal quality inspection results are repeatable, reproducible and reliable.
• Cost-effective solution for testing seal integrity and seal analysis that characterizes the overall quality and uniformity of the seal.

Helium Leak Detection Merits

• Practical and sensitive flow-based leak test method.
• Enables the discovery of extremely small microleaks.
• Detects leaks with sensitivity levels as low as 1x10-10 mbar L/sec.
• Helium is a non-explosive, non-toxic and non-destructive tracer gas.
• Applicable across package design, failure analysis, packaging line setup and validation.
• Faster test cycle reduces cost and total processing time.

Applications of Helium Leak Detection

• Vials
• Pre-filled syringes
• Blister packs
• Combination products
• Bottles
• Foil pouches

Helium leak detection is the best option for evaluating the inherent integrity of specific primary container closure systems of pharmaceutical and parenteral products. It is a commonly used technology in early stage pharmaceutical package development and component compatibility evaluation. In comparison to other leak test techniques, helium leak testing has the highest level of sensitivity, making it the most used CCI test method. In accordance with ASTM F2391, helium leak detection is a widely used method in the pharmaceutical industry.

We all know that the primary function of any package is storing, handling & protecting the product. So, what is package integrity? Package integrity is defined as a package’s ability to protect its contents from potential hazards that include various physical, microbial & chemical factors. Its usefulness may have many nuances depending on the products & content. But industries like pharmaceutical, nutrition & medical device, deal with lifesaving & sustaining products that are shipped across the globe. Any discontinuity in the package can result in the contamination of the product making a life-saving product into a life-threatening one. Therefore, package integrity is imperative to ensure the safety of the products at the time of use.

The selection of the appropriate package inspection method is essential to maintain the quality standards that the regulatory bodies stand by today. Since 2016, the United States Pharmacopeia (USP) released guidance encouraging the use of deterministic, reliable test methods. Package leak test methods offered by CCIT s.a. are all deterministic, non-destructive, quantitative test methods with a specific on the reliability of the test result to assure integrity at the highest level.

VeriPac Vacuum Decay Technology

Vacuum decay is validated as one of the most reliable & sensitive vacuum-based leak detection methods that give quantitative & reproducible results with a pass or fail determination. PTI’s VeriPac inspection method is based on vacuum decay technology. It is one of the most ideal non-destructive container closure integrity testing solutions for different types of package formats that include parenteral packaging and other types of flexible and semi-flexible package formats. This method is non-invasive, non-subjective & requires no sample preparation. VeriPac 400 series can be used in various applications like stability studies, clinical trials, quality assurance testing and production statistical process control.

With PERMA-VAC, PTI redefined the vacuum-based leak detection method and addresses vacuum decay leak detection at the very core of physical test measurement & maximizing the SNR between good and defective samples.

Microcurrent HVLD

PTI has revolutionized the conventional HVLD method with the new HVLDmc – MicroCurrent HVLD, a highly sensitive leak detection method for all Parenteral and Biologic Products. The new E-scan 655 Microcurrent HVLD system exposes the product and environment to less than 5% of the voltage than conventional HVLD solutions. Referenced in USP <1207>, PTI’s HVLDmc has proven to be a highly sensitive leak detection method for applications like pre-filled syringes, vials, cartridges, ampoules, BFS, bottles, pouches.

Airborne Ultrasound

PTI’s proprietary Airborne Ultrasound technology is one of the most reliable seal quality inspection methods that characterize the overall quality and uniformity of the seal. This technology can be integrated for 100% online leak detection of pouch seals. Airborne ultrasound can be used for many material types such as Tyvek ®, paper, foil, film, aluminum, plastic & poly. This technology is referenced in the new USP <1207> Chapter guidance as a deterministic test method for seal quality testing. It is also an ASTM Test Method and FDA-recognized standard for seal quality testing.

Automated Inline Solutions

CCIT provides automated package inspection solutions across all PTI technology platforms – Vacuum Decay, Airborne Ultrasound and MicroCurrent HVLD. The Automated Systems are designed using PTI’s VeriPac, MicroCurrent HVLD and Airborne Ultrasound technologies for applications that include automated statistical process control (SPC) testing and 100% inline testing. The configurations are equipped with the capability of fully automated inspection with robotic pick and place. HVLDmc and Vacuum Decay overlap in capabilities, but more importantly encompass the full parenteral market range. The Airborne Ultrasound Technology for the 100% inline inspection of pouch seals has been an efficacious solution to verify final pouch seal quality.

Helium Leak Testing

Helium leak testing can be used for packaging tests quantitatively using helium as a tracer gas. Helium-based leak testing systems allow comparison between multiple packaging materials and forms production line settings and stability storage conditions, supporting the entire lifecycle. This method is also effective for various package types including cold form blister cards, foil pouches, parenteral vials, syringes, pre-filled syringes and unique medical devices.

The package systems of complex drug and biologic required to be stored at below -20°C, and needs storage and distribution environment that include dry ice (~-78.5°C), or even liquid nitrogen (~-200°C) can be quantitively and accurately tested using helium leak detection technology. This one technology has many applications for container closure integrity testing of pharmaceutical and medical device products.