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Over the past few decades, the pharmaceutical industry has experienced tremendous growth on a global scale. Assuring the quality of the packaging is of utmost importance to every manufacturer since any defect in the packaging of pharmaceuticals can have major consequences. Pharmaceutical products must be free from microbiological contamination and safe to use from the time of manufacturing until the end of their shelf life. Through contamination in the form of oxygen, humidity, or microbial entry, the stability of the drug may be negatively impacted. Container closure integrity tests with great sensitivity are needed to reduce these risks. Hence, manufacturers choose helium leak detection technology.

Overview of SIMS 1915+

Helium Leak Detection using Seal Integrity Monitoring System (SIMS) 1915+ is a highly sensitive test method for inspecting the integrity of pharmaceuticals to identify leaks. Helium as a tracer gas may be used to quantitatively evaluate packages, providing higher degrees of accuracy than conventional vacuum bubble and dye penetration test methods. This approach makes it possible to compare various package types, sizes, and configurations, as well as manufacturing line settings and storage conditions, throughout the lifespan. LDA SIMS 1915+ is a tried-and-true technique that can be used for a range of package types, including cold form blister cards, foil pouches, parenteral vials, syringes, bottles, pre-filled syringes, and other unique medical devices. It can also be used for package design, tooling qualification, production line setup, and ongoing product quality monitoring.

SIMS 1915+ Low Temperature Add-on Test Systems

In an effort to maintain product quality aspects, complex pharmaceutical and biologic compositions have led to a constant drive towards deeper cold storage. These products, which are frequently protein-based or cell or gene treatments, must be stored in conditions that may include dry ice (-78.5°C) or even liquid nitrogen (-200°C) for storage and delivery.

The packaging system such as screw or crimp cap vials in which the products are enclosed is frequently quite conventional in nature, even if the products necessitating such deep cold storage may be complex. At these temperatures, many of the materials employed in these package systems and responsible for preserving package integrity are not normally evaluated. When subjected to deep-cold or ultra-cold temperatures, elastomeric components in particular may undergo physical changes when materials reach or exceed their glass transition state, resulting in leaks at low temperatures that would not normally be visible at room temperature. This type of leakage is frequently seen in primary seal regions, such as the interface between an elastomeric closure and a glass vial, when the temperature is below -60°C. In order to minimize leakage and demonstrate a deep understanding of a package system's performance in accordance with USP 1207, manufacturers need a method for evaluating container closure integrity while at these low temperatures. This significantly led them to decide on the best package choice and design as well as assembly parameters.

PTI and LDA’s engineering team developed the LT80, or Low Temperature -80°C, Test System, for use with the SIMS range of helium leak detectors to satisfy the market need for analyzing fine leakage at low temperatures. The LT80 system, which incorporates an SP Corporation Chiller, enables simultaneous temperature conditioning, temperature monitoring, and helium leak testing of packages down to -80°C. LT80 combines the recently announced features of the market-leading, Agilent Technologies-based SIMS 1915+ with 21 CFR Part 11 compliant SIMS Software. This is available as an upgrade for current SIMS units in the field or as a complete system. The SIMS 1915+ LT80 package is the first helium leak testing equipment particularly designed for low temperature testing down to -80°C. Sample testing close to -150°C is possible with the LT150 add-on low temperature unit.

LDA (a PTI Company) is the leading global producer of specially designed leak detection systems for pharmaceuticals and medical equipment. LDA’s low temperature add-on systems are ideal for evaluating fine leakage at cold temperatures using Helium Leak Detection Technology.

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.

Food and Drug Administration (FDA) requirements for drug testing of combination products are strict. Companies seeking FDA clearance for such products must fully understand the requirements for FDA approval in order to prevent costly and time-consuming errors. Combination products are made up of two or more regulated components, such as pharmaceuticals, devices, or biologicals, that have been physically, chemically, or otherwise combined and formed as a single entity to achieve a therapeutic effect. A combination product can combine at least two of these product categories, and sometimes all three. Traditional drug-device combination products, such as a syringe pre-filled with a drug, auto-injectors containing a filled cartridge and needle, and co-packaged or kitted products, are some of the most common types of combination products.

The constantly increasing demand for combination pharmaceutical products continues to fuel innovation and creates numerous interesting opportunities that will provide the medical community with promising new alternatives for improving patient care and results. However, bringing bio/pharmaceuticals and medical devices together to form a combination product necessitates extensive testing of all product ingredients.

Why Use SIM 1915+ for Leak Testing Combination Products?

A Helium-based leak detection system-Seal Integrity Monitoring System (SIMS) 1915+ is an excellent solution for detecting leaks in combination products. Packages may be quantitatively evaluated using helium as the tracer gas, which assures better levels of accuracy when compared to traditional vacuum bubble and dye penetration test procedures. SIMS 1915+, which has been proven to be an effective leak detection approach, may also be utilized for package design, tooling certification, manufacturing line setup, and ongoing product quality monitoring. LDA custom builds each SIMS 1915+ Helium Leak Testing device to customer specifications. Cold form blister cards, foil pouches, parenteral vials, syringes, pre-filled syringes, and unique medical devices can also be tested using SIMS 1915+.

Technology Overview

SIMS Model 1915+ helium-based leak testing system offered by LDA ( a PTI company ) is specifically designed for medical and pharmaceutical package leak detection. The SIMS 1915+ enables quantitative analysis of package systems at sensitivity levels as low as 1 x 10 -10 cc/s at room temperature. The Helium Leak Detector Module (HLDM), the most crucial component, is built within a Console Frame Assembly with a Stainless Steel working surface and an optional Dual Test Port Manifold. The consoles have a locking wheel and an articulating arm system for attaching the computer and peripherals, making the independent device simple to operate and maneuver.

The SIMS 1915+ Leak Detection System specs and add-on components are shown below.

• Helium Leak Detector Module (HLDM): Oil-Free, Production Version in Console Frame Assembly with Stainless Steel Working Surface and Dual Test Port Manifold.
• Vacuum Test Fixture Model (VTFM): a custom-made fixture for testing vial container samples.
• Head Space Analyzer Module (HSAM): Model VM-2 that includes three (3) Puncture Probes (two spares) for determining the concentration of helium in the headspace of vial containers.
• Integral Calibration Chamber (with Calibrant Gas Flow Meter/Controller) for HSAM Calibration and a Universal Holder for various vial diameters are offered.
• Helium Filling Device designed specifically for vial testing sample prep that allows vials to be filled with helium.
• Low Temperature (LT) Add-on devices created particularly for evaluating products in ultra-cold storage temperatures as low as –140 °C.

SIMS 1915+ Applications

Common applications of SIMS 1915+ include:

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

Combination products provide a safe, effective, and convenient method of administering the drug or biologic therapies. The purpose of testing combination products is to obtain information to support the claim that all use-related hazards connected with the product have been reduced to the greatest extent possible. LDA is well-versed in the extensive testing requirements and regulatory criteria for bio/pharmaceutical products and medical devices, and provides complete testing services for these components, both individually and in combination.

Helium leak testing is a non-destructive method to verify the presence of a leak in a component or device by using helium as a tracer gas. Being a highly sensitive method, it measures the amount of helium escaping through the package and is stated as a leak rate. Helium leak detection using Seal Integrity Monitoring System (SIMS) 1915+ is widely used in pharmaceutical and medical device product package systems for quality checking. SIMS 1915+ enable quantitative CCI analyses of packages at a sensitivity level as low as 1 x 10-10 mbar/L/sec. This quantitative method enables direct comparison across multiple packaging materials and formats, production line settings, and stability storage conditions. Each SIMS 1915+ Helium Leak Testing device is custom-built to meet the specifications and packaging configurations of the client. The following are the SIMS 1915+ configurations for CCI.

• Headspace Analyzer Module (HSAM)
• Helium Leak Detector Module
• External Calibrated Helium Leak Standard
• Dual Test Port Manifold
• Vacuum Test Fixture Model (VTFM)

Quality Control Leak Testing using LDA's Head Space Analyzer Module

The Head Space Analyzer Module (HSAM) is a critical component of a Leak Detection Associates (LDA) custom helium leak testing system. The Model VM-2, created by Leak Detection Associates, is the most recent version of this unique device. The HSAM includes a probe, which is essential for determining the helium concentration in the headspace of the container system. This system is simple to use and operate since it has an Integral Calibration Chamber with a Calibrant Gas Flow Control Valve and a Universal Holder that allows multiple diameter systems to be evaluated. Leak Detection Associates will provide three (3) Puncture Probes (two spares) with each unit.

The optional vial filling component enables the test preparation of already-sealed vials by replacing the headspace gas with 100% helium. This module can be used to prepare samples at the moment of testing, after capping, or to prepare samples that have been stored for a period of time prior to testing. When combined with the VM-2, these unique attachments enable accurate and sample-specific readings that may be integrated into flexible study designs.

Uses 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-stage drug product package system development.
• Selecting closure formulation and configuration.

LDA's Head Space Analyzer Module (HSAM) - SIMS 1915+ configuration ensures highly sensitive leak detection of pharmaceutical pouches. Cold form blister cards, parenteral vials, cartridges, pre-filled syringes, bottles, combination product systems, and medical device products are other applications.

Pharmaceutical containers can be tested for Container Closure Integrity (CCI) in a variety of ways. Blue dye test and bacterial or microbial immersion test come under traditional, probabilistic methods. Whereas Vacuum Decay, Airborne Ultrasound, MicroCurrent HVLD, and Helium Leak Detection belong to the deterministic group of test methods. Each approach has advantages and disadvantages that should be considered while selecting a test method for a certain container type. All the methods are not appropriate for all sample configurations. Some succeed in certain applications while failing in others. Nowadays, the pharmaceutical industry is moving away from the traditional blue dye and bacterial immersion test methods and approaching deterministic methods for CCI testing.

The helium leak rate method is proven to be a strong contender for many applications. Helium leak testing is described as the process of detecting leaks in various enclosed or sealed systems by utilizing helium as a "tracer" gas and measuring its concentration as it leaves due to leakage. Like most CCI methods, Helium Leak Detection is deterministic. This method is more sensitive and not prone to contamination as compared to traditional dye or bacterial immersion methods. Due to its highly sensitive nature, it is possible to detect extremely small leaks, which are not possible with other leak testing methods.

Validating Helium Leak Rate Method for Pharmaceutical Containers

Validation of a Helium leak rate method for pharmaceutical container closure integrity assurance required proof that this physical testing method was as excellent as, if not better than, microbial immersion challenge testing in detecting potential integrity problems. Helium leak rate and microbial challenge tests were performed on one lot of rubber-stopper, broth-filled glass vials, which include faulty vials with known leaks. Glass micropipettes (0.1 to 10 microns) were fitted into the sidewalls of the vials to prepare defective vials. A 10% seeded defect rate was present in the validation lot, with nearly 50% of the leaks having a predicted probability of failing a microbial challenge (> 10%). The test units were charged for 4 hours under 40 psi helium pressure to implant the helium tracer in them. After charging, the crucial leak rate was found to be 10(-7) standard cc/second, and test units with measured leak rates exceeding this value were considered helium leak rate failures.

Microbial immersion challenge was performed by immersing the test units for 24 hours in a bath containing 10(9-10) viable E. coli and B. diminuta organisms, followed by a 13-day incubation period at 35°C. Visually, microbial failures were identified. The mean failure rates of the helium and microbial leak test techniques were compared statistically. The average helium failure rate was 6.9%, whereas the average microbial failure rate was 2.8%. There was a considerable difference between helium and microbial failure rates. As a result, helium leak rate testing has been shown to be an acceptable pharmaceutical container/closure integrity method for container quality assurance.

The helium leak detection method is chosen to be one of the best techniques for ensuring the integrity of pharmaceutical containers. This technique may be used to test the inherent package integrity and the Maximum Allowable Leakage Limit (MALL) during package development. It is applicable to a wide range of package types, can locate leaks, and can measure leak flow rates directly.

Testing a pre-filled syringe is critical when it comes to developing and releasing safe injectables to the market. Pre-Filled syringes are becoming increasingly popular due to their efficiency and simplicity. In addition, they provide a more dependable and safe option for patients as they contain the exact dose. Container closure integrity test techniques can be utilized to satisfy the regulatory, quality, and safety demands of sterile drug products. During development, qualification, and stability testing, the FDA encourages sterile pharmaceutical manufacturers to employ established and deterministic methodologies to confirm CCI.

Ensuring Pre-Filled Syringes Integrity using SIMS 1915+

Seal Integrity Monitoring System (SIMS) Model 1915+ is a helium-based leak testing system specially designed for a variety of pharmaceutical and medical device product package systems. A pre-filled syringe is one of its applications. Vials, cartridges, and blister cards are other applications. Packages may be quantitatively evaluated to levels much above the vacuum bubble and dye penetration test procedures using helium as the tracer gas. This quantitative method supports the full lifespan by allowing direct comparison across multiple packing materials and formats, production line settings, and stability storage conditions. SIMS 1915+ allows for quantitative analysis of packages with a sensitivity as low as 1 x 10-10 mbar/L/sec and will offer meaningful data sets instead of simple pass/fail criteria.

Seal Integrity Monitoring System (SIMS) model 1915+ helium-based leak testing system from LDA includes an oil-free pump, detector, and integrated power system built for the pharmaceutical and medical device industries. The most important component is the Helium Leak Detector Module (HLDM), built into a console frame assembly with a stainless steel working surface and an optional dual test port manifold. The freestanding units are equipped with a locking wheel and an articulating arm system for attaching the computer and peripherals, making them easy to operate and move. Each SIMS 1915+ helium leak testing device is manufactured to the specifications and package configurations of the individual customer.

SIMS 1915+ Options

• Low-Temperature Add-on Systems LT 80 and LT 150 for ultra-cold CCI testing utilizing helium leak detection methods.
• Vacuum test fixtures come in a variety of sizes to meet all package types and sizes.
• Helium leak testing for non-vacuum chamber applications with custom test fixtures.
• External helium leak standards in a variety of leak rate ranges.
• Helium Sniffer Probe - for determining leak sites on a site-by-site basis.
• Vacuum clamps, O-ring seals, chamber gaskets, and other components.

Pre-filled syringes benefit the manufacturer as well as the patient. They help in reducing medication mistakes since they have fewer steps and are easier to use than empty syringes. SIMS 1915+, developed by Leak Detection Associates, is an effective technique for testing leaks in pre-filled syringes. End-users may utilize the technology to ensure that manufacturing and packaging processes are efficient and productive while still satisfying safety requirements, international regulations, and market quality standards.

Container Closure Integrity Testing (CCIT) is essential for maintaining the sterility and stability of sterile injectable products. The optimal test method varies depending on the product. CCI testing is used to determine if there is a leak between the contents of a container and its external environment. This can be done by identifying whether communication can be established between the contents of the container and its surroundings.

Pharmaceutical containers such as vials, syringes, cartridges, and blister packs are frequently tested as part of a stability study to ensure that the closure of the container can maintain a sterile barrier. As part of a stability testing methodology, the Food and Drug Administration (FDA) suggests performing a container closure integrity test instead of a sterility test. Primary packaging methods based on vials for sterile pharmaceutical products must provide protection over the shelf life. This necessitates the demonstration of Container Closure Integrity (CCI), which should be done early in the pharma product development process. Helium leak testing is the most chosen CCI test method due to its high sensitivity when compared to other leak test methods.

What is Helium Leak Testing and How it Evaluates Vial Integrity?

Helium leak testing is one of the Container Closure Integrity (CCI) test methods for testing the leakage of pharmaceuticals and medical devices. This method uses helium and the change in concentration is detected when it exits owing to leakage. The applications of helium leak testing include vials, pre-filled syringes, foil pouches, or cold form blister cards. Each of these packaging types is meant to keep out harmful environmental pollutants such as dirt, microorganisms, or even gases while maintaining the sterility of the medicinal product enclosed. The package is filled with helium and subjected to vacuum in this method. A helium leak detector is used to quantify the amount of helium that escapes the package. The result is expressed as a leak rate.

Why Use Helium as a Tracer Gas?

Due to the following reasons, helium is considered an ideal choice for this type of testing:

• Helium is inert, and it is one of the smallest gas molecules.
• Small atomic size allows it to breach pathways reliably and easily.
• Helium is non-toxic, non-condensable, non-flammable.
• 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.
• The presence of helium in the atmosphere is not more than 5ppm.

As a highly sensitive quantitative test technique, helium leak testing evaluates Container Closure System (CCS) components for parenteral applications. It offers quantitative leak rate data that significantly exceeds the detection limitations of conventional approaches. The method has proven to analyze the impact of processing factors on container closure systems, such as parenteral vial capping applications, elastomeric closure selection, or changing sealing parameters.

The use of pre-filled syringes (PFS) as a container solution for pharmaceutical products has increased significantly in recent years. It is expected that this trend will accelerate in the future decades. Pre-filled syringes have the benefit of reducing pharmaceutical waste and extending the life of the product for the pharmaceutical industry. In general, pre-filled syringes are recognized as an effective, reliable, and convenient way to dispense drugs. In addition, many injections can be self-administered without worrying about being completely transferred from a vial. It provides a safe and effective option for patients in need of long-term pharmaceutical therapies.

When compared to the conventional vial, pre-filled syringes provide extra complexity in the field of container closure integrity (CCI) inspection. The advantages of pre-filled syringes include ease of use compared to conventional vial packaging. Pre-filled syringes eliminate the necessary procedures before you use the drug in a vial. In addition, since pre-filled syringes contain the correct dose, it helps to avoid dosing errors.

Leak Testing Pre-Filled Syringes Using Helium Mass Spectrometry

The device that detects and monitors leaks within and outside a product is called Mass Spectrometer Leak Detector. This approach makes use of helium as a tracer gas, which is utilized to fill a product coupled to a detector. Helium mass spectrometry is widely known for its suitability for non-porous packaging like vials and pre-filled syringes.

The leak detector works on the basis of a sector field mass spectrometer. In a vacuum, analyzed entering gases (Helium) are ionized. Helium ions are accelerated and separated in a magnetic field using increased voltage. Using a specific detector, the ion current is converted to an electric current. The current is accelerated and displayed on the screen by leak detection units. The current measured is proportional to both, the helium concentration and the measured leakage.

Benefits of Helium Leak Testing

• Leaks may be detected and quantified with a high degree of sensitivity.
• Due to the inert properties of helium, it does not affect the substances under test.
• The testing is mostly conducted in a dry, temperature-independent environment.
• Helium leak testing has a shorter cycle time, which lowers the cost and overall processing time.

For non-porous packaging including vials, pre-filled syringes, and cartridges, helium mass spectrometry has emerged as the new leak detection standard. Unlike probabilistic traditional methods, helium leak detection methods are preferred by manufacturers and regulators for their high sensitivity, fast test time, and detection capability. Pharmaceutical industries usually choose this process during the evaluation and eligibility stages of a new packaging process, where MALL plays an important role.

Foil pouches are commonly used when a product requires multi-layered packaging. They are utilized as the innermost layers of packaging. Since the foil pouches come into direct contact with the packaged product, they must be of the highest quality and extremely hygienic. They are typically composed of aluminum and are used to protect products from high temperatures. Furthermore, foil pouches have a low moisture vapor transfer rate. Foil pouches usually contain three to four layers. The higher the number of layers, the higher the pouch quality. Each extra layer increases the strength of the pouch.

Foil pouch integrity testing offers a unique set of challenges. The occurrence of foil punctures is an issue in most packaging techniques that use foil as the product barrier. These imperfections can occur when the foil is rolled into thin sheets and microscopic particles are rolled into the foil by mistake. Handling of the packages during the assembly of the foil and insertion of the drug product is the most typical source of the defect. Although the human eye can only reliably spot punctures bigger than 100 µm, these faults are difficult to identify. Punctures smaller than this can cause substantial ingress and, as a result, affect the effectiveness of the product.

How to Inspect Foil Pouches for Quality Control Using Helium Leak Test?

A highly sensitive method of detecting leaks in enclosed systems by using helium as a "tracer gas" is known as helium leak testing. Pre-filled syringes, foil pouches, and cold form blister cards are the most common applications of helium leak testing. Each of these package types is meant to keep out harmful environmental pollutants including debris, germs, and even gases while maintaining the sterility of the drug product inside. The leak rate is calculated from the amount of helium that escapes from the package.

The sensitivity of the helium leak detection methods makes it an ideal platform for quality control testing foil-based packaging systems. The test technique is designed to identify helium that has been trapped in the packaging system and has leaked via micro-voids in the pouch. Placing the foil pouch in the custom-designed test fixture and drawing a vacuum is the first step in a test sequence. Helium thus escapes through possible defects in the package as a result of the resultant pressure difference. The flow is directed to the analyzer cell at vacuum pressure, where the escaping helium gas is measured in the cell.

The average test cycle time is between 20 and 60 seconds. The test chamber is evacuated to the environment when the test cycle is completed and the measurement is recorded, and a new sample can be tested. The LDA HSAM helium concentration device is used to detect the helium concentration value of each pouch once all samples in the designated set have been tested. This approach normalizes the helium leak rate to 100%, allowing direct comparison of all test samples as well as the manufacturing line configuration.

Helium leak testing, one of the most commonly used CCI testing methods, is used to accurately determine the tiniest of the leaky opening in the foil pouches. Using this method, leaks can be quantified and detected with a high level of sensitivity and quality control testing. The Food and Drug Administration- FDA has long recognized helium leak detection as a consensus standard for package integrity evaluation.

The integrity of the seal between the container and the closure is a major concern when choosing packaging components for a parenteral drug product. The packaging must protect the pharmaceutical product from a number of possible sources of contamination, such as microbial ingress. Container closure integrity (CCI) is defined as the capacity of a container closure system to preserve a drug product and hence retain its efficiency and sterility throughout its shelf life. The purpose of container closure integrity testing is to determine the effectiveness of packaging closure.

To ensure CCI of pharmaceutical drugs, a number of methods are used. Helium Leak Detection is one of them. In this method, helium is used as a tracer gas, to detect leaks. This testing produces quantitative data that are more repeatable and reliable than qualitative pass/fail results. Despite the fact that it is a destructive test, helium leak testing is widely used because of its sensitivity and ability to run samples at temperatures below ambient. After the sample is prepared, it may be kept and analyzed at the proper temperature.

CCI Testing of Pharmaceuticals at Low Temperature

The CCI of pharmaceuticals may be determined using a variety of approaches. Under sub-ambient temperature circumstances, several methods of container closure integrity testing, such as blue dye ingress, microbial ingress, and vacuum decay, are insufficiently sensitive or simply unsuitable. Helium leak testing is a reliable method for testing closures and ensuring product effectiveness and sterility. This method is more sensitive than other CCI testing methods.

LDA has created the LT80, Low Temperature -80°C, Add-On test system for use with the LDA SIMS helium leak detectors to meet the market demand for analyzing leaks at cold temperatures. Concurrent temperature conditioning, temperature monitoring, and helium leak testing of packages approaching -80°C are all possible with the LT80 system. Even at temperatures as low as –80°C, helium leak detection is an effective method to ensure container closure integrity. While there are alternative methods for measuring CCI, many of them are ineffective at temperatures below –80°C. The LT150 low-temperature add-on unit allows for sample testing at temperatures as low as -150° C. The highly sensitive nature of the instrument allows for leaks as low as a 2µm hole can be recognized as a failure. The quantitative results provide the analyst with a numerical value, which allows for better data trends and greater confidence in the packaging system's performance than qualitative techniques can provide.

Container closure integrity or CCI, on packaging for parenteral drug products, is crucial for drug product preservation. The packaging closing components must be carefully chosen in order to eliminate sources of contamination that could harm the pharmaceutical product. The need to extend container closure integrity testing into the cryogenic temperature range is already becoming apparent. Container closure integrity must be achieved at cryogenic temperatures if pharmaceuticals are to be kept at cryogenic temperatures. For these types of drug items, newer packaging solutions like prefilled syringes and complex self-dosing devices are increasingly being used, and CCI will need to be proved for them as well.

Helium Leak Testing is used to locate and identify extremely tiny leaks in any component that can produce a differential pressure. Helium Leak Rate can be expressed quantitatively (the quantity of leak rate). The helium leak testing method is also used to examine the performance of a component or system, as well as to study or evaluate the lifetime of a product. Helium gas is primarily utilized as a leak testing medium due to its ability to detect and quantify leak rates at very low levels.

LDA offers various helium leak testing services for pharmaceuticals and medical devices. The services are as follows:

Leak Testing Services

• Installation & Quality Assurance of Helium Leak Detector

Leak Detection Associates guarantees that each custom instrument comes with comprehensive service delivery, installation, and validation program that is appropriate for the regulated environments in which the instruments will be used. Prior to delivery, the LDA Engineering Technician will collaborate with delivery site personnel to confirm that the location has the appropriate gas and electrical supplies for instrument functioning. Once the instrument is on-site and in the position specified by the customer, the Engineering Technician will perform a formal Installation Qualification (IQ), Operation Qualification (OQ), and Performance Qualification (PQ). Prior to execution, these can be pre-approved by local Quality Assurance.

• Helium Leak Detector Service Agreement

Leak Detection Associates recognizes that maintaining instrument performance is an important part of the business’s success. While the instruments offered by LDA are simple to use and maintain, it helps to improve productivity by proactively guaranteeing performance with an LDA Annual Service Agreement. Leak Detection Associates provides service contract plans that are customized to the unique needs and specifications. The following are examples of key components of any service program:

1. Repair and replacement parts are available on-site at no additional charge

2. Annual On-Site Preventative Maintenance

3. Detailed Annual Requalification & Calibration

•  Helium Leak Detector Calibration Services

Annual calibration services for all components of the test system, including internal and exterior leak standards and HSAM probes, are also available as an alternative to a full-service contract. Failure to calibrate the leakage criteria may result in a decrease in the accuracy and validity of the results over time, as well as concerns of individuals working in a CGMP or other controlled environment. A complete calibration program at regular intervals is designed to ensure proper instrument readings for the life of the device with minimal instrument downtime. LDA can set reminders when service is required once in our calibration database, ensuring that SIMS 1915+ does not skip a beat.

• Training for Helium Leak Testing

Leak Detection Associates offers on-site training relevant to how the SIMS 1915+ Helium Leak Testing device will be utilized, with the objective of being a comprehensive solutions provider to the clients. More sophisticated parts of leak testing, as well as system care and maintenance, can be covered in training programs. The Leak Detection team has over 20 years of hands-on expertise and can help the organization with anything from basic knowledge and understanding of leak testing basics to specialized leak test method development and validation.

• Helium Leak Detection Feasibility Studies

LDA offers dependable feasibility and method development services. Prior to procuring an instrument or moving on with outsourcing solutions, feasibility services can provide proof of concept for its intended usage, or they can assist to expand existing capabilities by designing solutions for new package systems. LDA also provides full method development utilizing industry-standard positive control techniques in the cases where clients do not have internal resources experience in the development of helium leak detection tests, or where current resources need to be expanded. Methods created at LDA can be transferred and verified at the client site, or they can be utilized frequently at LDA for lab-scale, non-cGMP research.

• Onsite or In-House CCI for Package Systems

LDA offers testing capabilities at both the client's site and our location. A SIMS 1915+ purchased and installed in a controlled context can be used for client onsite testing. With hands-on expertise in cGMP and regulated laboratory and production environments, documentation procedures are quite often in line with internal and external quality standards. LDA also provides the option of bringing one of our test units to a client's site for particular investigations. In-house testing is an alternative for clients looking to analyze package systems or designs on a contract basis.

LDA provides its customers with the highest quality of services. We are the world's leading manufacturer of high sensitivity helium-based leak detection systems for the pharmaceutical and biologic industries. Our engineers and support staff are highly trained and certified, allowing us to provide professional services across a wide range of testing domains.

Blister packages are a convenient format for users and a practical way to keep tablet and capsule quality preserved. The majority of blister package applications are considered low-risk, and they do an excellent job of protecting pharmaceutical products from moisture intrusion, which can cause product degradation. Tablets with a hydrophilic nature, or a natural tendency for absorbing moisture, require extra protection.

Due to an increase in the number of hormone-based and steroidal therapies in recent years, worries concerning the integrity of blister packing have emerged. Given their propensity to degrade and impair treatment outcomes, packaging these and other groups of pharmaceutical products is considered a high-risk application. To combat this, most manufacturers choose a totally aluminum, cold-formed package, which offers the best protection against oxygen penetration, while some industries have packaged very sensitive steroidal therapies in thermoformed blister packaging. As these products are more susceptible to environmental conditions than most other tablets and capsules, it is critical to inspect for tiny leaks, regardless of the packaging utilized in this high-risk application.

Limitations of Blue Dye Test

One or more blister packs are submerged in a chamber holding blue liquid and a vacuum is drawn to conduct the blue dye test. The chamber is then restored to atmospheric pressure, and the packages are retrieved and examined to determine if any dye has entered them. No defect is detected if there is no dye in the blister packaging. The blue dye only enters the package after the vacuum phase, which is the major defect of this method. As a result, when the chamber is returned to atmospheric pressure, nothing prevents the operators from removing the packages from the dye during this final stage.

Package headspace and dye surfactant concentration are the other difficult factors to control in the blue dye test. In reality, the test just determines how easily or quickly the dye may enter the blister cavity. It does not tell you about oxygen or vapor intrusion. This is a significant disadvantage since gaseous pollutants may penetrate foil and film more readily through a tiny leak, which is subject to surface tension. This requires a relatively large single passage to enter the package. Another major disadvantage and difficulty to control is the subjective nature of the operator's inspection.

Leak Testing Blister Packages Using Deterministic Test Method

Helium leak testing is a deterministic method for identifying package leaks in blister packs using helium as a tracer gas. The change in its concentration is measured as it escapes due to leakage. The quantity of helium that escapes from the package is expressed as a leak rate. Helium leak detection is a very sensitive technique for testing pharmaceutical package integrity.

Seal Integrity Monitoring System (SIMS) 1915+ is the optimum leak detection system using helium. When compared to traditional methods such as vacuum bubble and dye penetration test, packages may be quantitatively examined with high accuracy. This method enables a comparison of different packaging materials and forms, as well as production line settings and storage conditions, thus supporting the entire life cycle. Package design, tooling qualification, production line setup and ongoing product quality monitoring are the applications that come under SIMS 1915+. It is specially designed for the pharmaceutical and medical device industries.

Blister packaging is a type of pre-formed plastic packaging that includes a base card with artwork and a clear plastic pocket called the blister. The cavity, which is composed of either plastic or aluminum foil, and the lid, which is made of paperboard, paper, plastic, or aluminum, are the two main components of blister packaging. The product is enclosed in the cavity, and the lid seals the package. Blister packing is used in the pharmaceutical industry to pack tablets, pills, capsules, granules, and lozenges. Blister packaging gets its name from the fact that each item is kept within its own small plastic bubble or blister. Blister packs can provide tamper resistance as well as barrier protection for shelf-life requirements.

Due to its extreme sensitivity, a helium-based test method is used for verifying the integrity of the blister pack. The test method operates by detecting helium that has been enclosed in the package system and is escaping through micro-channels in the package. This test sequence begins with the package being placed in the test fixture and immediately drawing a vacuum. The helium thus escapes through potential holes or cracks in the packaging as a result of the pressure differential.

Blister Pack Leak Testing Using Helium Mass Spectrometry

The Mass Spectrometer Leak Detector is a comprehensive system for locating and detecting leaks within or outside of product. This approach employs the use of helium as a tracer gas, which is utilized to fill the product attached to the detector. Helium leaks into and out of the tested product, causing its partial pressure to be measured and shown on a screen.

The leak detector works on the principle of a sector field mass spectrometer. Helium gas is ionized in a vacuum. Helium ions are accelerated and separated in a magnetic field using additional voltage. The ion current is converted to an electric current using a specific detector. The current is accelerated by leak detection units and displayed on the screen. The measured current is proportional to the helium concentration and equal to the observed leak. Helium leak detection using helium mass spectrometry is widely known for its suitability for packaging such as blister packs.

Helium Leak Detection Benefits

• With a high degree of sensitivity, leaks can be identified and measured
• No effect on the materials under test, due to the inert properties of the helium
• The testing procedure is mostly dry and temperature-independent
• Helium leak testing has a faster cycle time, which reduces the cost and overall processing time

Helium leak detection offered by Leak Detection Associates (LDA) can greatly improve the safety and health of blister package users. Blister packaging ensures that tablets and capsules are properly sealed. It is simple to do a leak test after packaging. Blister packaging is popular because of its convenience of packing, easy dosing for the patient, with its popularity increasing for many new drug solid dose/oral dose products.

LDA, the global leader in helium-based leak detection systems for the pharmaceutical and medical devices industries. Helium leak testing is a technique for locating and identifying leaks in a closed vessel using a tracer gas, helium. The method of helium leak testing is often used to evaluate system performance. Helium gas is commonly employed as a leak testing medium because of its ability to detect and quantify leak rates at extremely low levels.

SIMS Version 1.11.19 21 CFR Part 11 compliant software program

SIMS Version 1.11.19 21 CFR Part 11 is a compliance software application particularly created and manufactured for custom-built helium leak testing equipment. The application was created to support SIMS 1915+ units and makes LDA the only helium-based leak testing system provider on the market that meets all the FDA's (Food & Drug Administration’s) 21 CFR Part 11 data integrity software criteria.

With the growing usage of computer systems and electronic records over the last two decades, the FDA has published a number of guidance documents and directives outlining particular requirements for electronic data management. Users must be able to log in at different levels, utilize electronic signatures and approvals, have secure data management that prohibits changes to current results, and have an electronic audit trail that captures all relevant activities in a time and date stamped pattern.

LDA was able to build a robust and thorough helium leak testing procedure on our custom-designed and built systems. This improves functionality and usability compared to existing software options, by contracting with a development team that specializes in the development of instrument operation software programs and has extensive experience in the Part 11 area. LDA is offering a system software update program for current SIMS devices in the market for quick onsite installation for a client's existing installation base. The 21 CFR Part 11 program consists of all the instruments, including SIMS 1915+ and SIMS 1915+ LT low temperature add-on units.

Leak Detection Associates has been the major provider of custom helium leak detection equipment to the pharmaceutical, and medical device industry for over 20 years. Based on intended usage and target package system configuration, each test system is developed to meet regulated quality system requirements as well as the particular client's specifications. The LDA team creates custom add-on components for clients that need a flexible leak detection system that can be used with a variety of package types and configurations. This ensures flexibility in reaching particular research goals.

Using helium as a tracer gas is the most sensitive and commonly used tracer gas leak detection technique for CCI. When moisture-sensitive pharmaceutical products are lyophilized, their shelf life is extended, and they are better prepared for storage and transportation. A lyophilized medicinal product's quality is ensured by maintaining consistent moisture content. Proper container closure system (vial, stopper, seal) selection and sealing conditions are equally important factors. Demonstrating Container Closure Integrity (CCI) is one way of achieving this goal.

Why use helium?

Helium gas is one of the smallest molecules. In addition to being non-flammable, non-destructive, non-toxic, and inert, helium only has a trace presence in the atmosphere. Helium is generally safe to employ (compared to hydrogen) since it will not react with any of the components in the test part. Mass spectrometers detect helium in the vast majority of leak testing applications. A residual gas analyzer, on the other hand, is also an option. In general, helium leak testing ensures higher levels of sensitivity than conventional pressure decay methods.

Tracer gas method to test seal integrity

Tracer gas leak testing is a simple and very effective way of detecting leaks that offer great sensitivity, accuracy, and repeatable results. Being one of the most effective method of leak detection, tracer gas leak testing offers great sensitivity and accuracy. Micro-leaks between 1x10-4 to 10-9 scc/s can be detected using the tracer gas leak test, which utilizes the tracer gas - helium. Tracer gas leak testing can be done with either pure helium or by mixing it with another gas such as nitrogen or dry air to reduce the overall cost. A mass spectrometer is used in the standard test method for measuring package and seal integrity. Due to its low concentration in the atmosphere, and its detection using a mass spectrometer, helium is employed. It is done by injecting helium into sealed packages or adding it to sealed package’s headspace after sealing. In the following step, a mass spectrometer is used to identify and measure the presence of helium in the surrounding enclosed space.

Vacuum test method is the commonly employed tracer gas method for testing the seal integrity of pharmaceuticals products. In this method, seals are put under stress by a vacuum, which measures tiny leaks. Helium transfer rate captures the real transmission rate through the material as well as via the seals. Transmission of helium through the material as well as seals is captured by helium transmission rate. As a result, the vacuum technique is more effective in detecting leaks since it monitors helium gain in the external environment within the enclosed sample.

When packaging seals are tested for integrity, it helps guarantee that the packaging offers necessary product protection for patient safety. To ensure product quality, package seals must be reliable. Seal integrity tests are commonly used to evaluate sustainable packaging options, lower-cost packaging, and changes in manufacturing line sealing parameters, among others. Evaluating the seal strength of packing materials with reduced costs and alternative sealing procedures confirms that the seals do not leak over time.

Leak Detection Associates (LDA) designs and manufactures high-performance tracer gas (helium) leak detection systems to ensure the integrity of seals for the pharmaceutical and biological industries. Helium leak detection is the one of the most effective leak detection method to identify and locate leaks in a closed system.

Helium leak detection is referred to as the process of detecting leaks in various packaged or sealed systems by utilizing helium as tracer gas and measuring its concentration as it escapes due to leakage. A package system such as a vial that consists of a container and an elastomeric closure, is a good example. The vial is filled with helium and vacuum is applied. The quantity of helium that escapes from the package is quantified and expressed as a leak rate. A pre-filled syringe, a foil pouch, or a cold form blister card are some more examples of package systems. Each of these package types is designed to keep the pharmaceutical product enclosed while keeping out potentially harmful environmental pollutants like dust, bacteria, or even gases. The helium leak testing method can evaluate each of them.

Helium leak testing is widely utilized in the pharmaceutical and medical device industries because of its relevance in guaranteeing package integrity and quality. Now, let us see how these sectors benefit by using this technique.

1. Pharmaceutical Industry: The pharmaceutical industry has experienced enormous progress in terms of technological developments and drug delivery system innovations over the last two decades. However, such developments have created new quality assurance challenges for drug manufacturers. As a result, pharmaceutical manufacturers give major priority to both quality control procedures and pharmaceutical package leak detection.

CCI Testing is a leak detection technique that evaluates the capacity of container closure systems to maintain a sterile barrier against external contamination. These tests may be divided into two types: probabilistic test and deterministic test. Although probabilistic test methods like Bubble Tests and Dye Ingress were initially common, due to technological advancements, non-destructive approaches are now the preferred way for ensuring container integrity. Hence, pharmaceutical manufacturers are encouraged to switch to more dependable deterministic test methods, such as helium leak detection, which offer quantitative findings that are assured and precise. By using helium leak detection early in the development process, companies can improve the quality of their drug delivery system. This not only saves money and time, but also improves safety.

2. Medical Devices Industry: In the medical device industry, package integrity testing is important since product failure presents considerable risks to patients and healthcare professionals, as well as liability for manufacturers. Barriers between fluids or gases are frequently used in medical equipment. These barriers must be functional in order to safeguard the patient and, in many cases, the medical equipment. Some devices operate as channels for delivering or extracting fluids to or from specific parts of the body. If a leak develops along the channel, fluids might be supplied to the incorrect place by mistake or wrong fluids could be extracted, resulting in hazardous effects. As a result, medical device industries use various CCI test methods including helium leak testing to ensure package integrity.

Helium leak testing is the most common tracer gas method in the medical device industry. Helium or a helium-air combination is used to pressurize the test component within a vacuum chamber. The chamber enclosing the part is next evacuated, generating a vacuum that allows the helium to enter the chamber through any leaks. A mass spectrometer designed to detect helium takes a sample of the vacuum chamber and ionizes any helium detected. Even a small amount of helium is easily detected in this method.

The major reason for choosing the tracer gas technique by manufacturers is the necessity for high leak-detection sensitivity in particular medical device equipment applications. Product testing is a crucial part of the device production process in the medical industry. As quality requirements have gotten increasingly strict, leak testing has become increasingly important for medical equipment as well as pharmaceutical manufacturers.

Leak testing may be understood as a form of non-destructive quality control procedure used to determine if an object, product, or system functions within a specified leak limit. When a gas or liquid escapes through a manufacturing defect such as a hole, crack or weak seal, it is considered a leak. Since such a leak can compromise quality of the product, appropriate leak testing is an important quality control criteria for manufacturers.

Overview of helium leak testing?

Helium leak testing is considered as one of the most sensitive Container Closure Integrity test methods. In simple terms, it can be understood as the process of using helium mass spectrometry for finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. This technique is widely used for evaluating integrity of critical parenteral or injectable products. Helium is used as a tracer gas because it is non-toxic, non- flammable, non-condensable and its presence in the atmosphere is not more than 5ppm. The small atomic size of helium makes it easier to pass through leaks. Since helium does not react with other materials, it is safe to use. Additionally, compared to other tracer gases helium is less expensive and is available in multiple cylinder sizes.

Helium leak detection using SIMS 1915+

LDA's Seal Integrity Monitoring System (SIMS) 1915+ is a helium-based leak detection technique proven to be effective for a variety of pharmaceutical and medical device product package systems. Using helium as the tracer gas, packages can be quantitatively tested to levels far exceeding the vacuum bubble and dye penetration test methods. This technique is applicable across a wide range of pharmaceutical and parenteral products including vials, syringes, cartridges and blister cards.

SIMS 1915+ enable quantitative analysis of packages at a sensitivity level as low as 1 x 10-10 mbar/L/sec. and provides relevant data sets in place of a simple pass/fail criteria while enabling testing to be performed at ambient temperature as well as cryo storage conditions. Each SIMS 1915+ Helium Leak Testing instrument is custom built to client specific standards and package configurations. We specialize in the engineering and development of custom test fixtures tailored to the component to be tested, which ensures precision and accuracy to meet your study goals, package configurations and quality monitoring needs.

SIMS 1915+ Options:

• LT 80 and LT 150 Low Temperature Add-on Systems for ultra-cold CCI testing using helium leak methodology.
• Various sizes of Vacuum Test Fixtures to accommodate all package types and sizes.
• Custom Test Fixtures to allow Helium leak testing for non-vacuum chamber applications.
• Additional External Helium Leak standards in various leak rate ranges.
• Helium Sniffer probe – for site specific determination of leak sites.

Like vials package systems, bottles whether composed of plastic materials or glass, continue to be one of the most widely used package systems and Helium remains the gold standard for quality testing purposes.

Evaluating seal integrity of bottles or containers used for liquid contents is what ensures the quality of the bottles surpass the quality parameters. Seal integrity testing of bottles is done to ensure that the contents of the container do not leak out in any condition. As weak seals, partial seals or no seals can occur in the final sealing stage, manufacturers often conduct high-quality seal integrity tests that guarantee reliability and quality of bottle seals.

Thread shape, mating surface shape, and composition of the material used for making the container and the closure are common factors that can affect the seal integrity of bottles. An ideal seal can be generated if the container and closure materials are made up of distinct composition. Seal quality can also be affected by time-dependent factors. This is especially possible if containers, closures, or both are constructed using plastic resins. Similarly, exposing the bottle and its contents to freezing temperatures can affect the seal via expansion and contraction of the materials in threads and mating surface area.

Before dispatching, leak detection of sealed containers is a crucial vital step to ensure container’s seal integrity, food and nutrition, medical device and pharmaceutical industries require highly sensitive leak testing techniques to measure seal strength of the containers. One such method is helium leak detection.

Overview of helium leak testing?

Helium leak testing refers to the process of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. It is an effective container closure integrity test method, aimed at evaluating the integrity of pharmaceutical and parenteral products. Helium leak detection works in the following way: Initially, the package is helium filled and subjected to vacuum. Then using a helium leak detector, the amount of helium escaping the package is quantitatively measured and stated as a leak rate. Apart from analyzing container closure integrity, helium leak testing is also applicable in product design, product quality analyses, failure analyses and validation. Helium leak testing is a flexible method that can be used with or without a test chamber in order to test "in-leakage" or "out-leakage", as well as leak location.

Why use helium as a tracer gas?

Helium is considered as an ideal choice of tracer gas because of the following reasons:?

• Helium is non-toxic, non-condensable, non-flammable.
• It is inert, making it safe for use as it will not interact with the components being tested.
• The atom size of helium is really small, allowing it to breach pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.
• Its presence in the atmosphere is not more than?ppm.

Over the past decades, there has been steady stream of advances over combination products and a deepening trend towards self-care. This is because combination products offer a safe and convenient method of operating drug or biologic therapies. Medical devices that can be self-administered are increasingly being used to shorten procedure time and reduce the chance for practitioner errors.A combination product is a mixture of a drug and device that includes pre-filled syringes, insulin injector pens, transdermal patches, and catheters with antimicrobial coatings. These are often termed as high-risk devices in the life science industry. As such, devices they require in-depth testing and evaluation.

The risk associated with combination products depend on the likelihood of interaction between the package and the drug, as well as the level of risk associated with the administration route. For many drug-device combination products, inhalations and injections are specified as high-risk routes of administration. Hence, evaluating seal integrity of combination products is extremely critical. Due to inadequate sealing, there is a chance for water vapor or oxygen to enter the package through a permeable surface. In such cases, surfaces and seals may need to be tested depending on the nature of the products. Also, there is a need to evaluate the packaging components and dosage, ignoring which, could cause serious health risk to the patient.

Importance of Helium Mass Spectrometer Leak Detector in Combination Products

The Mass Spectrometer Leak Detector is a system used for localization and measuring leaks inside or outside a product. This method uses tracer gas – helium, which is used to fill up the product connected to a detector. It is well documented that helium mass spectrometry is most suited for non-porous packaging such as vials and syringes. The same methodology can also be applied to cartridge-based delivery systems. In most cases, the key to success is developing a text fixture device, designed and manufactured to cater to the needs of specific cartridge system being tested.

Applications of helium leak testing.

Following are the applications of helium leak testing:

• Ensuring Container Closure Integrity
• Closure formulation and configuration
• Seal integrity monitoring during stability studies
• Extremely valuable in early-stage pharmaceutical product package system development

The global pharmaceutical industry has seen tremendous growth over the past few decades. However, complex nature of the industry coupled with frequent breakthroughs has made it a favorite subject of scrutiny. Adding to that, the COVID-19 pandemic has accelerated pharmaceutical industry challenges. Along with COVID-19 vaccine, the industry has seen a spike in the production of cell and gene therapy treatments, biologics, and other large-molecule products that demand unique storage conditions to maintain sterility of the drug throughout its shelf life or until it is administered.

Since most high-risk pharmaceutical products are filled and sealed in combination devices, it’s critical for manufacturers to ensure that the components function well together. Hence, design and distribution considerations are critical to the early design of both the drug and the container. Manufacturing inconsistencies and tolerance differences in packages containing multiple components are primary contributors to distribution issues. Often, such inconsistencies result in container closure failure, causing serious implications down the supply chain. For instance, glass vials and pre-filled syringes may not seal properly at critical fill-finish closure points. Such a failure can cause oxygen or other environmental contaminants to enter the product and compromise the efficacy of the drug in the barrel. At this point, it is critical to use the most precise leak testing method possible.

In such situations, helium leak detection is the most effective sensitive test for ensuring container closure integrity. By utilizing helium leak detection early in development, companies can make considerable improvements in the quality of their drug delivery system. This not only saves cost and time, but will also raise standards of safety.

Understanding helium leak detection technology

Helium is used as a tracer gas because it is non-toxic, non-flammable, non-condensable and its presence in the atmosphere is not more than 5ppm.Being the second smallest molecule on the periodic table, helium can expose virtually any opening. Further, helium does not react with other materials, so it is relatively safe to use. Under this method, a helium leak detector otherwise known as Mass Spectrometer Leak Detector (MSLD) is used to identify and calculate size of the leak. The test part is first connected to a leak detector and then the tracer gas, helium is introduced. In the presence of a leak, helium escapes from the test parts and this partial pressure is measured and results are displayed on the meter.

Applications of Helium Leak testing

• Ensuring Container Closure Integrity
• Selecting closure formulation and configuration
• Seal integrity monitoring during stability studies
• Extremely valuable in early stage pharmaceutical product package system development

What is helium leak detection?

The pharmaceutical industry has seen a significant rise in the use of pre-filled syringes in recent years. This demand is expected to accelerate over the coming decades. Pre-filled syringes offer benefits to the pharmaceutical industry in the form of reduced drug waste and increased product life span. Health care workers consider pre-filled syringes as an efficient, convenient and reliable drug administration method. However, they pose several challenges in manufacturing and require extensive testing.

Just like any other drug product, pre-filled syringes should be free from pyrogens and should be sterile. Not just that, they are expected to be biologically, chemically and physically stable throughout its shelf life. Considering the complex nature of these products, it isn’t surprising that there are many opportunities for it to fail to meet quality requirements. Defects in pre-filled syringes mainly depend on drug product design and syringe process design. Additionally, patient related issues are also an area of concern. Therefore, it is important for manufacturers to have knowledge and understanding of various tests involved to ensure patient safety.

Container Closure Integrity testing of pre-filled syringes

Sterility is the most important quality attribute associated with any pharmaceutical/ parenteral drug product. Container Closure Integrity (CCI) testing is one of the key tests performed by manufacturers so that the product is guaranteeing sterility and microbiological quality until point of use. Container closure integrity testing evaluates the ability of container closure systems to maintain a sterile barrier against possible contaminants that can deteriorate the quality of final pharmaceutical and biological products. There are multiple methods to conduct container closure integrity tests, each with its own set of benefits and limitations. For instance, techniques like dye ingress and microbiological ingress are destructive to the samples being tested. Such tests rely on statistically representative number of samples from the batch and assume that defects are uniformly present throughout the batch. On the other hand, deterministic methods are non-destructive in nature and can be used to test every unit from the batch.

Helium Leak Testing for Pre-Filled Syringes

Helium leak testing refers to the act of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. Under this technique, the package is helium filled and subjected to vacuum. The amount of helium escaping the package is quantitatively measured with the help of a helium leak detector. The result is stated as a leak rate. Apart from being an effective container closure integrity test method, helium leak testing is also applicable in product design, product quality analyses, failure analyses and validation.

Why use helium as a tracer gas?

Helium is considered as an ideal choice of tracer gas because of the following reasons:

• Helium is non-toxic, non-condensable, non-flammable.
• It is inert, making it safe for use as it will not interact with the components being tested.
• The atom size of helium is really small, allowing it to breach pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.

What is helium leak detection?

Helium leak detection refers to the process of identifying leaks in an enclosed or sealed system using helium as a tracer gas. Helium is an ideal choice of tracer gas to find leaks because it is non-toxic, non-flammable, non-condensable, and its presence in the atmosphere is limited to 5ppm. Helium can pass easily through leaks because of its small atomic size. Additionally, helium is safe to use because it does not react with materials of parts being tested.

Overview of sniffer probe leak detection

Sniffer leak testing is a common tracer gas leak detection method that uses a sniffer probe to detect the presence of tracer gas and identify an area that is leaking. Under sniffer probe helium leak detection, helium is used as a tracer gas in combination with instrumentation to detect the presence of helium and more precisely an increase in helium due to the leaking part.

The prime objective behind conducting a sniffer probe leak detection test is to locate leaks in parts or systems so that they can be identified and repaired. The part or system is first pressurized with the tracer gas and then systematically scanned with a sniffer probe so as to detect possible leaks. Sniffer probe leak detection cannot be considered as a quantitative leak detection technique because the test results may vary depending on skill of the operator and the technique used. However, with the use of calibrated instruments, calibrated leak standards, and well-trained operators, quantitative results may be achieved. Sniffer leak testing is considered as an economical leak detection method that involves relatively low tool cost investment depending on the tracer gas used. Although sniffer probe leak testing is very effective in locating micro leaks, it may not be an ideal choice in high volume production environment.

How does sniffer probe leak detection work?

Sniffer probe leak testing begins by first filling the test object with tracer gas. The pressure inside the test object is increased to a pre-determined rate in order to create a differential in pressure. The outside of the test object is scanned using a sniffer probe that is connected to a leak detector. Because of the innate properties of helium, it readily penetrates through leaks and is sucked into the sniffer probe. The leak rate meter shows a display of the signal. On reaching maximum leak rate display, leak is located. Although the sniffer probe leak detection technique is very sensitive, its accuracy can be affected due to the amount of helium present in the atmosphere.

Advantages of Sniffer Probe leak detection

• Sniffer probe is very effective in locating minute leaks.
• Does not require expensive fixtures or test chambers and can be employed at low cost.
• Useful in testing small parts as well as complex systems.
• Higher test sensitivity can be achieved by increasing tracer gas pressure.
• Capable of detecting leaks in the range of 1.6x10-1 to 1x10-5 scc/s.

Container closure integrity plays an integral role in maintaining the stability of sterile pharmaceutical products. Most often, defects that cause vials to leak cannot be detected by a visual inspection process. Examples of such defects include microscopic cracks & scratches in the glass or temporary defects such as stopper pop-up that result in temporary container leakage. In such situations, helium leak testing ensures high sensitivity leak detection, which cannot be attained by many other leak test methods.

Overview of helium leak testing

Helium leak testing refers to the process of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. It is an effective container closure integrity test method, aimed at evaluating the integrity of pharmaceutical and parenteral products. Helium leak detection works in the following way: Initially, the package is helium filled and subjected to vacuum. Then using a helium leak detector, the amount of helium escaping the package is quantitatively measured and stated as a leak rate. Apart from analyzing container closure integrity, helium leak testing is also applicable in product design, product quality analyses, failure analyses and validation. Helium leak testing is a flexible method that can be used with or without a test chamber in order to test "in-leakage" or "out-leakage", as well as leak location.

Why use helium as a tracer gas?

Helium is considered as an ideal choice of tracer gas because of the following reasons:

• Helium is non-toxic, non-condensable, non-flammable.
• It is inert, making it safe for use as it will not interact with the components being tested.
• The atom size of helium is really small, allowing it to breach pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.
• Its presence in the atmosphere is not more than ppm.

Glass vial leak testing using SIMS 1915+

Seal Integrity Monitoring System (SIMS) 1915+ is an ideal choice for helium-based leak detection of vials, blister cards, syringes, and cartridge systems. Compared to conventional vacuum bubble and dye penetration test methods, packages can be quantitatively tested using helium as the tracer gas that ensures higher levels of accuracy. Proven to be an affective leak detection method, SIMS1915+ can also be used for package design, tooling qualification, production line setup and on-going product quality monitoring. Designed specifically for the needs of pharmaceutical and medical device industries, SIMS1915+features an oil-free pump, detector and integrated power system that ensures quantitative analysis of package systems at sensitivity levels as low as 1 x 10 -10 cc/s at room temperature. Based on the client’s specific requirement, each SIMS 1915+ Helium Leak Testing instrument manufactured by Leak Detection Associates can be customized. Given below is a list of SIMS 1915+ Leak Detection System specifications along with add-on components.

• Helium Leak Detector Module (HLDM): Oil Free, Production version in Console Frame Assembly, with Stainless Steel working surface and Dual Test Port Manifold (allows concurrent use of VTFM & HSAM on HLDM unit).
• Vacuum Test Fixture Model (VTFM) – custom designed for use in testing of vial container samples
• Head Space Analyzer Module (HSAM) – Model VM-2 that includes three (3) Puncture Probes (two spares) for determination of Helium Concentration in the headspace of vial containers.
• Integral Calibration Chamber (w/ Calibrant Gas Flow Meter/Controller) provided for HSAM Calibration and a Universal Holder to be used for various vial diameters.
• Helium Filling Device specific for vial testing sample prep to enable vials to be filled with helium
• LT Low Temperature Add on units specifically designed for testing products under ultra-cold storage testing down to –140 °C.

In two recent blogs, we’ve discussed the practical applications of helium leak detection to vial and cartridge package systems. A vial, with its single compression-based seal, can be readily tested by helium leak detection in cases to optimize sealing parameters, validate assembly, routinely test production samples, etc. On a cartridge, the compression-based crimp seal can be similarly tested and optimized. On the opposing end, an elastomeric plunger relies on a compression fit against the syringe barrel based on the dimensional overlap of the two components. This seal can be similarly assessed by helium at dimensional extremes to further demonstrate inherent integrity and robust understanding of the package assembly process.

While cartridge-based and specifically vial-based systems represent the majority of pharmaceutical and biotech industry package formats, the rate of one group’s growth far exceeds its peers: prefilled syringes (PFS). From a human factors and dose-delivery perspective, the benefits of a prefilled syringe format over a traditional vial-based injection can be myriad. Not the least is their ability to be incorporated into single-use autoinjection and safety systems. However, the PFS, and autoinjection systems in particular, present unique challenges from a CCI testing standpoint.

In a combination product autoinjection system, most frequently the syringe is fully housed inside of a device. This limits direct access to the product-containing portion of the package, preventing some technologies from being feasible from an analytical standpoint. Further, the product inside is liquid, contributing to increased challenges when testing using a vacuum-based technology. Frequently, this means that testing a fully-assembled injection system for CCI is infeasible or not sensitive enough to provide meaningful assurance. It is in these cases especially that fully characterizing the inherent integrity of the primary package, the syringe, is critical for reducing risk downstream with respect to package integrity.

Much like its application to vial and cartridge systems, helium leak detection is well suited for inherent integrity evaluations of prefilled syringes, regardless of whether their final destination is housed inside of a device body. Similar to cartridge systems, the plunger seal of a PFS system relies on a compression fit between an elastomeric plunger and the syringe barrel. Studies evaluating the inherent integrity of this fit provides insight into the quality of the seal that is likely to be present in final production units. Similarly, helium leak testing at the extreme ranges of the dimensional tolerance stack-up between the barrel inner diameter and plunger outer diameter can ensure integrity at the full range of possible dimensional combinations. This type of study can yield significant insight into seal robustness.

The opposing end of a PFS is unique in that it includes a staked needle or luer-type connection for a needle to attach. From a helium leak testing perspective, however, there is nothing unique about it. The product-holding volume of the syringe is filled with helium while the needle region of the PFS is exposed to vacuum. If a leak is present, helium will migrate through the leak path and result in an increase in helium leak rate measured by the system. Complete syringe units can even be tested by sealing the opposing end with a plunger and subjecting the entire package to vacuum in a chamber, though proper fixturing is required.

In addition to the unique configuration on a PFS, the staked needle or luer lock seal of a PFS also has another unique property. Since prefilled syringes are supplied as assembled units to drug manufacturers and CMOs, they are one seal not subject to optimization or validation during the manufacturing process. Whereas the plunger seal can be characterized by helium as a function of the compression fit between the two components, the dimensions of which can be monitored, the needle end of a PFS is subject to supplier practices. For this reason, some manufacturers also choose to implement helium leak detection of PFS units on an incoming lot inspection basis, as would be done for component dimensions. This provides some level of ongoing integrity assurance of these unique package systems in the production process. The SIMS 1284+ helium leak detector routinely and successfully supports these types of studies and ongoing analysis to fulfill modern CCI guidance and requirements.

EGG HARBOR TOWNSHIP, N.J. (PRWEB)

Leak Detection Associates (LDA), the world’s premier manufacturer of custom built, helium-based leak testing instruments for the Pharmaceutical, Biotechnology, Medical Device and Food Packaging Industries is excited to announce the launch of its newest and most advanced helium leak detection system, the SIMS Model 1915. The SIMS 1915+ unit is engineered incorporating industry-leading Agilent Technologies components and is custom designed to meet the stringent requirements of clients in FDA-regulated industries. The new unit will replace the SIMS 1284+, marketed by LDA for the past 12+ years, and represents the most advanced and sensitive system available worldwide. With a revised interface and corresponding pump configuration specifically intended for pharma/biotech package testing, clients will see an improvement in instrument performance with more intuitive operation. Notably, the launch of the system coincides with the release of the all-new 21 CFR Part 11 compliant software package developed by the Leak Detection Associates software development team.

“While the SIMS 1284+ has proven to be a workhorse with a global client installation base for over 12 years, advancements in vacuum and helium-based technology have enabled our engineering team to improve component configuration and system performance, yielding the most advanced helium leak testing system for pharmaceutical and biotechnology applications. I am confident our clients will appreciate the new features, capabilities, and usability the SIMS 1915+ will offer”, commented Jeff Morrow Lucas Director of Engineering for Leak Detection Associates.

Key features and benefits of the new SIMS 1915+ model include:
• Base Helium Leak Detector powered by Agilent Technologies, globally recognized as a leader in the regulated market industries for laboratory equipment
• An IDP-15 Dry vacuum pump (oil free) rated for 15m3/hour (9 cfm) and a Patented dual pump design for fast clean up and background suppression
• Improved power-off process keeps spectrometer under vacuum and protects the turbomolecular pump, reducing operator dependency and increasing filament longevity
• Maximum Test Port Pressure of 13 mbar (10 Torr, 1333 Pa) and 200 mbar (150 Torr, 2000 Pa) in Gross Leak Mode

The new SIMS Model 1915+ model is available for immediate order and based upon an improved supplier relationship with Agilent Technologies, lead times for custom-built orders will decrease from the previous 12-14 weeks to as short as 4 weeks. As clients have come to expect, each new SIMS Model 1915+ will be customized to client’s specific testing needs whether testing vials, blister cards, cartridges, or pre-filled syringes. Each SIMS 1915+ can be complimented with Leak Detection Associates’ robust service and contract offerings to provide end-to-end leak testing solutions.

READ ENTIRE PRESS RELEASE ON PRWEB

The use of helium gas as a medium for leak testing during the gas diffusion process dates back to the 1940’s. The mechanism that enables leak testing using helium is the helium mass spectrometer which, at its core, is simply an air sampling tool that takes accurate measurements, using a series of pumps, to quantitatively measure the amount of helium in, around or leaking from a closed vessel or system is completed. Using helium as the “tracer” gas enables the user to discover and measure extremely small leaks. With so many available gases in our ecosystem, what is it about helium that makes it the ideal tracer gas for leak testing?

In the case of leak testing, size really does matter. Helium is one of the smaller molecules known to man and boasts of an atomic mass of 4 making it “light and smalll”. In comparison, only hydrogen is lighter than helium but as the passengers of the Hindenburg can attest, hydrogen displays some other explosive properties that may make the average laboratory technician shy away from its use. Because of its size, helium has the ability to flow through much smaller openings and at a much faster rate than other gas compounds. In technical parlance, you will often see this referenced as helium displays a high sensitivity rate as low as 1 X 10-10 cc/s. In laymen’s terms, this simply means that the small molecule size of helium makes it easy to “quantitatively detect and measure”.

While we note above the major disadvantage of using hydrogen as a tracer gas due to its explosive nature, helium is on the other extreme. Helium has three key characteristics that make its use easy and ideal. It is non-explosive, non-toxic and non-destructive. These characteristics insure that helium will not interfere with, or in any way impact, the type of material or vessel that you are testing. In most instances, the system being leak testing is constructed of plastic, glass or some type of metal. The inert and odorless nature of helium makes it chemically inactive when it comes in contact with any of these material types.

The presence of helium in the atmosphere tends to hold in the 5 ppm (parts per million) range. This feature helps to insure that false readings and general atmospheric interference in a non-factor when using helium gas as a testing agent.

Collectively, the characteristics of helium gas outlined above make it a very user friendly tool for leak testing. Couple these features with the easy availability and relatively inexpensive acquisition cost, helium has become the “first choice” method for leak detection in a wide variety of settings. Advances in the development of better mass spectrometers have led to more superior and more robust techniques and methods.