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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.