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Combination products, which provide effective and novel treatment options and approaches across various disease states, have made a significant influence on the healthcare landscape in recent years. The acceleration of growth in this field of science and medicine is expected to continue propelling at an increased rate. The packaging and device industry has focused its innovation specifically on combination therapeutics to fulfill the demands of both drug developers and patients. To ensure that the best results may be obtained, these therapeutic products need to be tested for integrity and quality using a very sophisticated approach.

Challenges Faced by Combination Products

Patient safety can be improved by addressing these three challenges.

• Device Robustness and Reliability

If a pharmaceutical or biologic is not administered safely, properly, and consistently, it cannot benefit the patient. The delivery method for this is a sturdy, dependable device, and the technique to make sure that the device performs as intended is through the design control process. Verification testing is an important stage that ensures the device has been developed appropriately and operates dependably in accordance with established patient needs and drug specifications. Additionally, it assesses how well the product will withstand in the most adverse circumstances, which may include drops, climatic extremes, and moisture exposure.

• Drug - device integration

When developing combination products, it's crucial to take the interaction between the device and the drug into consideration. The FDA categorizes combination products into nine separate categories, which include pre-filled drug devices or delivery systems as well as devices that have been coated, impregnated, or mixed with drugs or biologics. The development process can be considerably influenced by the precise combination of components as well as the crucial interfaces.

• Accommodating various volumes

Large drug volumes have been difficult for patients to self-administer using devices like autoinjectors, pens, or pre-filled syringes. But the development of wearable devices is changing the game by enabling greater volumes to be administered subcutaneously over a longer period. This increases the potential for patient-centered healthcare but poses a number of manufacturing and packaging challenges.

Here, we will discuss how helium leak testing helps in testing the combination products.

Testing Integrity of Combination Products Using Helium Leak Testing

Helium leak detection is a highly sensitive technology for identifying leaks in any closed or sealed system using helium gas and monitoring the concentration of the gas as it escapes due to a leak. The integrity of a variety of complicated pharmaceutical and parenteral products may be evaluated using helium leak detection. Combination products, cold form blister packs, foil pouches, pre-filled syringes, and many more drug packages can be tested using helium leak testing. This technique is the best option for verifying the integrity of pharmaceutical products since it can accurately determine integrity between certain major container closure system components.

Helium leak detection works as follows: The package is initially vacuumed and helium filled. The quantity of helium leaving the package is then measured quantitatively and expressed as a leak rate using a helium leak detector. Helium leak testing is used in product design, product quality evaluations, failure analyses, and validation in addition to examining the integrity of container closures. It is possible to test "in-leakage" or "out-leakage" as well as the location of leaks using helium leak testing, which may be employed with or without a test chamber.

Helium Leak Testing Applications

• Seal integrity monitoring during stability studies.
• Useful in the early stages of developing a drug product packaging system.
• Selecting closure formulation and configuration.
• Ensuring container closure integrity.
• Verify and predict shelf-life seal integrity.

The need for complex drug delivery systems and combination products continues to fuel the development of new products and innovation within the medical device industry. At LDA (a PTI Company), we understand that the combination of medical devices and pharmaceuticals opens a world of promising new opportunities. LDA has the experience and expertise necessary to seize these opportunities and assist clients in testing combination products.

Container closure integrity is essential for patient safety as well as pharmaceutical product efficacy, and container closure integrity testing (CCIT) is a critical step in the manufacturing process. A paradigm change is currently taking place in the pharmaceutical industry, moving it away from conventional probabilistic procedures and toward deterministic alternatives. LDA (a PTI Company) dives into the area of CCIT, giving the industry a thorough understanding of its practices and introducing innovative helium leak detection technology.

For non-porous packaging including vials, syringes, and cartridges, helium mass spectrometry has become the new leak detection standard. The approach is favored by producers and authorities because of its greater sensitivity, quicker test times, traceability, and determinism in contrast to the probabilistic conventional methods.

Role of Helium Mass Spectrometry in Leak Testing Vials

Helium mass spectrometry is a leak detection standard for various pharmaceutical packaging formats, including vials. Mass spectrometer leak detector is an equipment often used for discovering and identifying leaks within or outside the product. Typically, it works with a vacuum chamber and a closed container filled with helium. Helium leakage from the container is measured by the mass spectrometer. In this technique, the product connected to the detector is filled with helium tracer gas. Helium from the tested product escapes into the detector, where it is measured and indicated as partial pressure.

The sector field mass spectrometer works as the fundamental component of leak detection. Helium gases are ionized as they enter the vacuum. Next, voltage is added to accelerate the helium ions, which are subsequently separated in a magnetic field. A specific detector is used to change the ion current into an electric current. Utilizing leak detecting units, this current is accelerated and displayed on the screen. The leak will be determined by the current since it is directly proportional to the helium concentration.

Why is Helium Used in Leak Detection?

• It is an inert gas molecule that is among the smallest.
• It may consistently and readily breach pathways due to its small atomic size.
• Helium is non-toxic, non-condensable, and non-flammable.
• Relatively safe to use as it will not interact with the components being tested.
• Helium is less expensive and readily available when compared to other tracer gases.
• There is no more than 5 ppm of helium in the atmosphere.

For Maximum Allowable Leakage Limit (MALL) testing in the pharmaceutical industry, LDA helium leak detection technologies are ideal. It is crucial that you control the tracer gas concentration while doing the measurement to guarantee accuracy. This is particularly challenging when working with vials or other sealed containers. Therefore, LDA (a PTI company) provides solutions to test the integrity of pharmaceutical vials.

Do you rely only on the traditional blue dye leak test method to ensure the integrity of blister packaging? While background knowledge of preventing blister pack leaks is recommended, package integrity testing is necessary.

Pharmaceutical package leak detection ensures that the product remains safe and effective in the packaging while maintaining sterility. A proper sterile container prevents air penetration and maintains product safety and effectiveness. Ingress of air from blister pack leaks, such as micro leaks and pinholes, may have a severe negative impact on pharmaceuticals, therefore you must be completely confident in your pharmaceutical package integrity, ensuring it passes the required integrity test. The best way to ensure that the pharmaceutical packaging has no significant blister pack leaks is with the helium leak detection method.

SIMS 1915+ for Blister Pack Leak Testing

Seal Integrity Monitoring System (SIMS) 1915+ helium leak detection is an ideal solution for testing the integrity of cold form blister packs. The packages may be quantitatively evaluated using helium as the tracer gas, which provides more precision than typical vacuum bubble and dye penetration test processes. This approach allows for the lifetime comparison of various packing materials and forms, as well as production line settings and stable storage conditions. LDA SIMS 1915+ is a tried-and-true method for a wide range of package types, including foil pouches, parenteral vials, syringes, bottles, pre-filled syringes, and unique medical devices. It can be used for package design, tooling qualification, production line setup, and ongoing product quality monitoring.

Each SIMS 1915+ helium leak testing equipment is built to the customer's specifications. It is composed of an oil-free pump, detector, and integrated power system that enables quantitative analysis of package systems at sensitivity levels as low as 1 x 10 -10 mbar L/s at room temperature. The most basic component is the Helium Leak Detector Module (HLDM), which is built within a Console Frame Assembly that includes a Stainless Steel working surface and an optional Dual Test Port Manifold. The freestanding consoles are easy to use and relocate since they include a locking wheel and an articulating arm mechanism for attaching the computer and accessories.

Helium Leak Detection SIMS 1915+ Configurations for CCI

• Helium Leak Detector Module (HLDM): Oil-Free, Production version in Console Frame Assembly, with Stainless Steel working surface and Nitrogen Vent Supply System for the Helium Leak Detector Module.
• Vacuum Test Fixture Model (VTFM): a custom-made fixture for testing vial container samples.
• Model VM-2 Head Space Analyzer Module (HSAM): includes three (3) Puncture Probes (two spares) for determining Helium Concentration in the headspace of vial containers.
• Dual Test Port Manifold that allows concurrent use of VTFM & HSAM on HLDM unit.
• An integral Calibration Chamber (with Calibrant Gas Flow Meter/Controller) for HSAM Calibration and a Universal Holder for various vial sizes are offered.
• Helium Leak Standard Calibrated Externally for System Calibration/Validation.

Blister Packs are intended to protect the contents from both internal leakage and contamination from outside sources. Helium leak testing is a CCI test method used to locate and measure leaks in medical and pharmaceutical packaging to ensure package and seal integrity. The package can be tested alone or with the contents inside. With over 25 years of expertise in the pharmaceutical packaging industry, LDA (a PTI Company) is continually looking ahead to enhance blister pack leak detection.

USP <1207> Package Integrity Evaluation of Sterile Products provides an overview of relevant and authorized test procedures that may be utilized to achieve certification criteria. Developing a basic knowledge of these methodologies will allow you to make an informed decision on the most effective test methodology for a specific container and package system. Various CCI test methods are available today. Among them, helium leak testing has proven to be the most chosen method due to its extreme test sensitivity.

Why Use SIMS 1915+ for Leak Detection?

Seal Integrity Monitoring System (SIMS) 1915+ is the perfect choice for a helium-based leak detection system. Using helium as the tracer gas, packages may be quantitatively analyzed to levels much above the vacuum bubble and dye penetration test processes. This quantitative technique supports the entire lifetime by providing direct comparison across numerous packing materials and types, production line settings, and stable storage conditions. SIMS 1915+ can be used for package design, tooling qualification, manufacturing line setup, and continuous product quality monitoring. Each SIMS 1915+ helium leak testing equipment is built to the customer's specifications. SIMS 1915+ can do quantitative CCI analyses on packages with sensitivity as low as 1 x 10 -10 mbar L/s.

What are the Applications of SIMS 1915+?

• Vials

Vials composed of glass and polymer are the most widely used package systems tested using helium leak detection. Vials are provided with a variety of capping to fulfill specific storage or handling needs. Vials are commonly used to store drugs or laboratory samples. Micro leaks in vials that carry sensitive drugs cannot be detected with a visual inspection. Helium leak testing is an ideal method for component qualification for empty components as well as a product-filled vial.

• Pre-filled syringes

The use of pre-filled syringes has increased significantly in the pharmaceutical industry. CCI analyses of pre-filled syringes are more complicated, but they are much more important in ensuring entire system integrity. Helium leak testing for leak detection of pre-filled syringes has proven to be an effective method for evaluating the CCI of pre-filled syringes.

• Bottles

Bottles made of glass or plastic are cost-effective traditional dosage forms ideal for the oral administration of syrups, solutions, and suspensions. Helium leak testing offered by LDA, a PTI company, quickly and effectively tests bottles for leaks and thereby defective bottles can be removed from the production line easily.

• Blister packs

Due to the extreme sensitivity offered, the helium-based test method for evaluating the integrity of a blister card containing solid dose pharmaceutical drugs has been proven to be the most effective approach. Helium remains an ideal test method for qualifying the material components of CFF blister cards.

• Foil pouches

Pharma manufacturers typically use foil pouches when a drug product requires multi-layered packaging. Helium leak testing of foil pouches is a viable and highly sensitive approach to meet strict regulatory requirements.

• Combination products

These are multi-chamber systems that require unique test requirements. Helium Leak Detection as per ASTM F2391 is a well-established and widely used method for testing combination products. Testing combination products using helium leak testing ensure all components meet the strict leak rate requirements.

LDA’s (a PTI company) Seal Integrity Monitoring System (SIMS) 1915+ is an efficient method for a wide range of package types such as pre-filled syringes, cold form blister cards, foil pouches, parenteral vials, and unique medical devices. Seal Integrity Monitoring System (SIMS) Model 1915+ Helium Based Leak Testing System is designed specifically for the needs of the pharmaceutical and medical device industries.

With the rapid growth of the cell and gene therapy sector, there is a higher demand than ever to prove Container Closure Integrity (CCI) at low temperatures. Most cell and gene therapy drugs are maintained at temperatures below -60°C to preserve the effectiveness of the product. Many of these items are packed in vials or cryogenic freezing bags. Vials made of glass or plastic are the most commonly used containers for packing. They are used to preserve pharmaceuticals or laboratory samples. Each of these container closure systems presents a unique challenge for determining CCI at low temperatures. In this blog, we will discuss how the integrity of vials can be tested using low-temperature package test systems.

Low-Temperature Test Systems for Vial Integrity Testing

The most common challenge in storing vial systems at ultra-low temperatures is the occurrence of transient leaks. While a vial system may achieve leak rates at or below the maximum permissible leakage limit (MALL) at room temperature, the same may not necessarily be true at -80°C or lower. However, many of the materials used in these package systems and those responsible for maintaining the integrity of the package are not normally evaluated at these temperatures. Physical changes can occur, especially in elastomeric elements, when in contact with deep-cold or ultra-cold temperatures, causing the material to reach its glass transition state or higher. This results in leakage at low temperatures, which is not observed at room temperature. This type of leakage is most commonly found in primary sealing areas between elastomeric closures and glass vial, such as below -60°C. Having a reliable method to test container closure integrity while at these low temperatures enables manufacturers to minimize leakage.

LDA has developed the LT80, low temperature -80°C add-on test system for use with LDA SIMS helium leak detector to meet market demand for cold temperature leak analysis. Concurrent temperature conditioning, temperature monitoring and helium leak testing of packages approaching -80°C are all possible on the LT80 system. Helium leak detection is an effective way to ensure container closure integrity, even at temperatures below -80°C. Although there are alternative methods for measuring CCI, many of them are ineffective at temperatures below -80°C. LT150 low-temperature add-on unit allows sample testing at temperatures as low as -150°C.

Applications of Helium Leak Detection

• Ensuring container closure integrity.
• Seal integrity monitoring during stability studies.
• Verify and predict shelf-life seal integrity.
• Useful in the early stages of developing a drug product packaging system.
• Selecting closure formulation and configuration.

Helium leak detection is a rapid, efficient, and deterministic method of determining the inherent CCI of a vial system at any temperature. Due to the sensitivity of helium leak detection, it is excellent for testing CCI for products that must retain both headspace gas and sterility. During the package development phase of the product life cycle, helium leak detection is most commonly utilized in evaluating component performance at ultra-low temperatures.

Pharmaceutical bottle integrity testing is an important step in assuring that the product is safe and unadulterated. It analyzes the strength and integrity of the closure mechanism as well as its capacity to maintain a sterile barrier. Container closure integrity testing analyzes the materials and chemicals for the possibility of migration or leaching into the drug product, resulting in contamination. Microorganisms, gases, and other chemicals are examples of contaminants. Container system integrity testing involves evaluating primary packaging, or everything that comes into direct touch with the product, as well as secondary packaging components required for package assembly. Helium leak detection, airborne ultrasound, vacuum decay, and high voltage leak detection are all methods for verifying the safety of container closures.

Helium Leak Detection to Ensure the Integrity of Bottles

Helium leak detection is referred to as a method of finding leaks in a sealed or enclosed system using the helium tracer gas method. The amount of helium that leaks through a breach is measured and is stated as a leak rate. It is an effective container closure integrity test technique for determining the integrity of pharmaceutical and parenteral products. Helium leak testing guarantees the sterility of drug substances and drug products packaged and, therefore, enhances patient safety.

In this method, the package is filled with helium and subjected to vacuum. The quantity of helium that exits the package is measured using a helium leak detector. The result is expressed as the leak rate. Helium leak testing, in addition to being a highly sensitive container closure integrity test technique, is also useful in product design, product quality analyses, failure analysis, and validation.

What are the Applications of Helium Leak Testing?

Some of the most important applications of helium leak testing include:

• Ensuring container closure integrity.
• Selecting closure formulation and configuration.
• Seal integrity monitoring during stability studies.
• Verification and prediction of shelf-life seal integrity.
• Useful in the early stages of developing a pharmaceutical product packaging system.

Helium leak detection offered by LDA (a PTI company) is one of the commonly used leak testing methods that can be used for pharmaceutical package leak detection. Bottles can be tested very effectively using this method. The applications of helium leak detection are also found in vials, prefilled syringes, foil pouches, and cold form blister cards. LDA has long-time expertise in designing leak testing equipment for pharmaceuticals and medical devices.

Foil pouches are a simple solution for sterile barrier packaging. These are ideal for medical equipment and pharmaceuticals as well. Aluminum foil, which is impermeable to moisture, oxygen, and other gases, as well as microorganisms and light, helps to preserve pharmaceuticals in perfect condition for a longer period of time. These materials are used to create films that are free of contaminants and toxins. As a result, one advantage of foil pouches is that they may be used to package both food and non-food products. Another benefit of utilizing foil pouches is their low cost. Foil pouches are less expensive than many packaging materials.

Leak testing foil pouches is a challenging process. Leaking pouches may destroy the quality of the product by destroying the outside package. More significantly, leaking pouches provide a point of entry for contamination into the product, which can result in product degradation and potential health risks for patients. This creates the necessity of testing foil pouches and helps assure package quality.

How Helium Mass Spectrometer Detect Leaks in Foil Pouches?

Helium leak testing is a CCI testing method for leak testing foil pouches. It is the process of finding leaks in an enclosed system using helium as the tracer gas. Helium leak testing is one of the most accurate and rapid leak detection methods which employ a mass spectrometer for analyzing/measuring leaks. For a variety of reasons, helium gas is used to locate leaks. These include the fact that it is present only 5 ppm in air, resulting in very low background levels. Helium has a low mass and is completely inert/non-reactive. Helium is also non-flammable, abundantly available, and inexpensive.

Helium mass spectrometer is a device that helps in detecting and locating leaks. The device being tested is either pressurized from the inside or pressurized with helium from the outside. The gas from any possible leaks is collected and pumped into the mass spectrometer for analysis, and any value over the helium background trace indicates a leak. The mass spectrometer works as follows-any helium molecules vacuumed into the spectrometer are ionized, and these helium ions then fly into the ion trap, where the ion current is measured and recorded. The leak rate is then calculated using the ionization current.

Benefits of Helium Leak Testing

• Identification and measurement of leaks with high sensitivity.
• The majority of the testing is done in a dry, temperature-independent environment.
• Reduced cost and processing time with shorter cycle time.
• Due to the inert properties of helium, no effect on the substances under test.

Helium mass spectrometry is ideally suited for determining the intrinsic integrity of a packaging system. Helium mass spectrometer leak detection system for foil pouches offered by LDA (a PTI company) can be used to identify both large and small leaks. These are often employed in a vacuum chamber containing a sealed container filled with helium. Because of its non-toxic nature, helium is one of the important gases that may be used to identify leaks.