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

Challenges Faced by Combination Products

Patient safety can be improved by addressing these three challenges.

• Device Robustness and Reliability

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

• Drug - device integration

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

• Accommodating various volumes

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

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

Testing Integrity of Combination Products Using Helium Leak Testing

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

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

Helium Leak Testing Applications

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

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

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

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

Role of Helium Mass Spectrometry in Leak Testing Vials

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

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

Why is Helium Used in Leak Detection?

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

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

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.

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.

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.

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.

Maintaining the integrity of products from the time it is manufactured to the time it is distributed to the patient is a great challenge. Liquid pharmaceuticals, capsules, and formed tablets are typically packaged in bottles. To assure the quality of these items, leak testing is carried out on each bottle to ensure that it does not leak. Testing pharmaceutical bottles or pharmaceutical package leak detection before filling is a critical step in ensuring the integrity of the container.

Helium leak testing is one of the most sensitive Container Closure Integrity (CCI) testing techniques that can be applied to pharmaceutical bottles for testing quality. Helium is used as a tracer gas, and the quantity of helium leaving through the package is measured and stated as leak rate. Since it is non-toxic, non-flammable, and non-condensable, helium is an ideal tracer gas for finding leaks. Its atmospheric presence is restricted to 5ppm. Due to its tiny atomic size, helium can easily pass-through leaks. Helium is also safe to use since it does not react with the materials of the components under test.

Significance of Helium Mass Spectrometry in Leak Testing Pharmaceutical Bottles

Helium mass spectrometry is a leak detection standard for pharmaceutical containers including bottles. Helium mass spectrometer, a commonly used instrument detects and locates tiny leaks. It usually works with a vacuum chamber and a sealed container filled with helium. A mass spectrometer detects the rate at which helium is leaking out of the container. This method uses tracer gas - helium to fill the product attached to the detector. The tested product leaks helium into the detector, where its partial pressure is measured and displayed.

The leak detector's principle is based on a sector field mass spectrometer. In vacuum, entering helium gases are ionized. The helium ions are then accelerated by adding voltage and then separated in a magnetic field. The ion current is converted to an electric current by using a particular detector. This current is accelerated using leak detection units and displayed on the screen. The current measured will be directly proportional to the concentration of helium and therefore equal to the leak measured.

Applications of Helium Leak Detection

• Ensure container closure integrity.
• Seal integrity monitoring during stability studies.
• Verify and predict shelf-life seal integrity.
• Useful in the early stages of the development of a pharmaceutical product packaging system.
• Closure formulation and configuration selection.

Bottles are useful in the healthcare industry, hence evaluating them is a challenging task nowadays. These containers are extremely difficult to test, however, helium leak detection can be used to qualify them prior to use or as a proof of concept. LDA provides professional engineering solutions for the Active Pharmaceutical Ingredient (API) sterile container testing.

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.

In World War II, helium mass spectrometry was used in Uranium enrichment plants for leak detection. This approach is still in use today, with some adjustments, as it is regarded to be one of the most accurate ways for locating leaks. Helium gas is utilized in this approach as a tracer gas. This occurs when helium leaks in/out of the tested product and enters the detector, where its partial pressure is recorded and shown on a screen. Leakage is detected using an instrument called a Helium Mass Spectrometer, which also measures the rate of leakage.

Principle of helium leak detector

Leak Detector works on the concept of a sector field mass spectrometer. Containers that need to be tested for leakage are usually filled with Helium and put in a vacuum chamber. The tracer gas helium is ionized in a vacuum after analysis. With the addition of voltage, helium ions are accelerated and then separated in a magnetic field. Using a particular detector, the ion current is converted to an electric current. Leak detecting units accelerate the current and display it on the screen. Helium concentration determines the measured current, which is equivalent to the measured leak.

What makes helium suitable for leak detection?

Due to its numerous advantages, helium is the ideal choice for leak detection purposes.

• Non-toxic and non-flammable
• Inert and non-condensed
• Low cost
• Due to its low atomic mass, it can easily pass through even very small leaks
• Present in the atmosphere, only in trace amount

Leak detection methods using helium mass spectrometer

There are two primary methods of testing: vacuum testing and pressure testing. The goal is to find the leak and determine how much or how fast it is leaking. When using either technique, it's vital to maintain circumstances that are comparable to what the system would encounter in real life.

As part of the vacuum testing, the leak detector is inserted into the system or product that has to be tested for leaks. In order to remove air from a system and create a vacuum, a pump is utilized. Helium is then sprayed on locations where the leakage is likely to occur. Spraying should be done with proper care to ensure that no portion of the body is skipped. As soon as the detector detects a leak of Helium, it alerts the user. This approach is also known as the spray probe method, or the spray probe technique.

Under pressure testing, the product must be placed within a vacuum chamber that has been properly constructed. Helium is pumped into the chamber, and the detector is used to check for leaks. This method is also known as the sniffer probe method. Helium filled system put in a chamber with a detector attached to a vacuum pump is another mode of this approach for determining leakage rate. If there is a leak, Helium will leak out of the pump and the detector will calculate the rate of leaking once the pump is running.

Helium mass spectrometry can be used in a variety of ways to discover extremely small leaks.

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.

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