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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.

Leak Detection Associates’ most current model, the Seal Integrity Monitoring System (SIMS) 1915+, is the ideal choice for your helium based leak detection system. Using helium as the tracer gas, packages can be quantitatively tested to levels far exceeding the vacuum bubble and dye penetration test methods. This Quantitative approach allows direct comparison across various packaging materials and forms, production line settings and stability storage conditions. The LDA SIMS 1915+ is a proven and effective tool for package design, tooling qualification, production line setup and on-going product quality monitoring of a variety of package types including cold form blister cards, foil pouches, parenteral vials, syringes, pre-filled syringes and unique medical devices.

Each SIMS 1915+ Helium Leak Testing instrument manufactured by Leak Detection Associates is custom built to client-specific standards. Key factors that determine instrument build specifications include:

What type of package(s) will you be testing with this instrument – Vials, Blister Cards, Syringes, Cartridge System or Medical Device? Size and closure type should be included and whenever possible a schematic of the package or device can be helpful in optimizing the test system.

Projected amount of use the instrument will see?

Country where the instrument will be installed?

Leak Detection Associates Seal Integrity Monitoring System (SIMS) Model 1915+ helium-based leak testing system features an oil-free detector and integrated power system that is designed for the needs of the pharmaceutical and medical device industries, enabling the client to quantitatively analyze package system at a sensitivity level as low as 1 x 10 -10 cc/s at room temperature. The most critical component, the Helium Leak Detector Module (HLDM), is engineered into a Console Frame Assembly that features a Stainless Steel working surface and Dual Test Port Manifold. The console has a locking wheel and will be fitted with an articulating arm system for mounting of the computer, monitor, key board and direct access printer, making the freestanding unit easy to use and maneuver.

The First Helium Leak Detectors

The genesis for the use of helium as a method for leak detection can be traced back to the 1940’s and the Manhattan Project. The first atomic bomb created used uranium isotope 235, which is taken by way of separation from uranium-238. The separation was accomplished in a huge “diffusion” plant using microporous tubing as the diffusion medium and this process needed to be done in a manner that prevented any trace of moist ambient air in the process chambers. In essence, it was imperative that all the equipment be free of any leaks. Equipment of this size and magnitude had never before been tested to such and extreme leak detection specification. A number of various leak detection devices were tried, and they all proved unsuccessful as they could not meet the required standard for sensitivity. Eventually, a simplified mass spectrometer based on the Nier 60 spectrometer tube was chosen for leak detection and helium was the gas of choice used with it. It was determined that helium flow as sensitive as 10−6 std cm3 could easily be detected.

Major Improvements in Helium Leak Detection

In the 70+ years since the inception of the Manhattan Project, helium leak detectors have understandably been drastically improved. The size of an actual helium detector that in 1945 required a large scale, multi-story warehouse building, can now fit on a standard laboratory benchtop and the level of detection has been improved to levels that meet or exceed flows rates of 10−10–10−11 std cm3. With the inception of computers, operation of a helium detector has been fully automated. Based upon these developments, the use of helium as a medium for leak detection has become common and wide-spread practice and thus has a presence in almost every conceivable industry from refrigeration, semi-conductors, automotive and food and drug packaging components.

Modes of Operations using Helium Leak Detection

Conceptually, the principle of operations has not changed much in the past 50 years although, as noted, the size has been drastically reduced. The central piece of the helium leak detector is the cell in which the residual gas is ionised and the resulting ions accelerated and filtered in a mass spectrometer. Most of the current detectors use, as in the original design, a magnetic sector to separate the helium ions from the other gases. Permanent magnets are generally used to generate the magnetic field. The adjustment needed for the selection of the helium peak is made by varying the ion energy. At the highest sensitivity range, currents as low as femtoamperes have to be measured. This is achieved with the use of an electron multiplier in the most modern detectors. If the cell of a leak detector is not much different from the original design, the pumping system has considerably changed with the original diffusion pumps now being replaced by turbomolecular pumps or dry molecular-drag pumps. The sensitivity of the helium leak detector is given by the ratio between the helium flow through the leak and the partial pressure increase in the cell. In order to increase the sensitivity, the pumping speed of the tracer gas has to be reduced. This must be done without diminishing the pumping speed for the other gases (mainly water as leak detection usually takes place in unbaked systems) in order to keep the appropriate operating pressure for the filament emitting the ionising electrons. Selective pumping is therefore needed to provide a high pumping speed for water and a low pumping speed for helium

We hope that you have learned something regarding the history of helium leak detectors. In future installments, we will address various test methods and case studies that will provide more specific insight into the use of helium applied to the package leak testing needs of the pharmaceutical and life sciences industries.

The adoption of deterministic, quantitative test methods for comprehensive container closure integrity testing (CCIT) has become the norm over the past decade. Recent and future regulatory guidance directives have continued this trend. However, this trend of increasing scrutiny, and thus, increasing complexity for regulated companies, is not in vain. The benefits of such a method are plentiful, and their usage can span the entire lifecycle of a product-package system, right from development of the package, to stability, to analysis of package integrity after distribution cycles. In fact, the need for CCIT at multiple product lifecycle stages is explicitly discussed in USP <1207>.

In the current version of USP <1207>, there are a total of four subsections. USP <1207.1> discusses critical background information and rationale for the selection of an appropriate test method. Included in this subchapter is a detailed discussion of CCI evaluation during a product life cycle, which states: “Package integrity verification occurs during [at least] three product life cycle phases: 1) the development and validation of the product– package system, 2) product manufacturing, and 3) commercial product shelf-life stability assessments”. The idea behind such a statement is that CCI should be built into the design of the product-package system and the processes that yield it.

This is a notable shift from the somewhat pervasive tendency to consider CCI as a checkbox, something verified as a company is assembling documentation for a filing, perhaps after the final configuration and manufacturing has been finalized. This latter approach has inherently more risk. What if the vial-stopper configuration chosen does not have an ideal fit? What if the assembly parameters used for capping that vial do not yield consistently integral final packaging? Situations like this are not uncommon, and can lead to expensive changes, product recall, or risk to patient safety. Fortunately, modern, deterministic methods, such as helium leak detection, can help characterize and mitigate these risks.

Early on in the development process, the inherent integrity of the chosen product-package system should be evaluated, essentially answering the question: “Are these components, when mated optimally, capable of creating an integral seal?”. This concept is called inherent integrity, or whether the package components, as an inherent function of themselves, can create and maintain an integral seal. For a manufacturer considering the implementation of a stopper from a potential catalog or stock of many varieties, for example, a helium leak test study can be developed in order to assess the relative performance of each component. In the experience of LDA and its partners, there can be a significant difference between stoppers with the respect to their ability to create adequate seals, regardless of capping conditions. Future blogs in the LDA resource center will highlight these applications.

A specific, upstream and preventive CCI program that is gaining in popularity is that of a “Capping Study”; a program in which optimal sealing parameters are determined through correlation with low leakage rates. In such programs, there are typically a range of sample sets assembled at capping parameters from very low (aluminum crimp seal barely applied) to very high (possibly yielding stress cracks in the vial neck area). These samples are subsequently assessed for % compression of the stopper and residual seal force (RSF), an indirect measure of the amount of force the stopper is applying to the land-seal of the vial. The third, and most critical part of the triad, is helium leak testing. As each set of samples undergo helium leak testing, differences in leak performance between the sets can be identified. An ideal set of capping parameters that correlates to consistently low leak rates can be determined. Additionally, an ideal residual seal force range can be identified.

The correlations between capping parameters, RSF, and helium leak rate can be immensely valuable. For example, this work can be performed at lab-scale for development purposes, helping to inform final settings for a manufacturing setting. Manufacturing capping settings can be tailored to yield package RSF data in line with laboratory results. Package systems produced on that full-scale line can be further tested by helium leak detection as final confirmation and as part of a complete assembly validation for the product-package system and its assembly processes.

To further provide insight into the value of this approach, if product is being manufactured at 3 sites, the identified capping settings can be employed at each site, aiding in the transfer and validation process. More importantly, samples can be pulled from the line at each site and routinely checked by RSF. If the samples pulled off the line exhibit RSF values within a range that correlates to reduced risk of leakage and consistent with historical data, capping processes are likely under control. Although this does not guarantee package integrity, it provides an added layer of control, and can be referred to as an ongoing seal quality test. Similarly, helum leak detection can be employed on a routine basis for additional confidence, as helium would be considered a true seal integrity test.

Numerous capping optimization and assembly validation studies like these have been performed using LDA SIMS 1284+ helium leak detector and LDA’s unique range of accessories for the pharmaceutical and medical device industries. As the concept of CCI, and inherent CCI specifically, continues to be a topic regulatory agencies are more interested in, it is likely this trend of evaluating CCI in package development and validation will become an expectation. However, this change is one that should be welcomed by industry. Evaluating components prior to their use potentially prevents costly component changes down the road, and can lead to safer, less recall-prone packaging.

In a recent blog, we discussed the application of helium leak detection (HeLD) as part of a capping optimization study or assembly validation for glass and plastic vials. A defining characteristic of helium leak detection, instruments such as the SIMS 1284+ have sensitivity capable of measurement below the maximum allowable leakage limit (MALL) of many pharmaceutical and medical device products. This allows for study-based comparisons and data-informed decision making at a very fine scale. More importantly, these types of studies can be used to support regulatory documentation and in fulfillment of guidance such as USP <1207>.

While applications of this approach to vials are well established, if increasingly popular, very similar approaches can be taken for other common package systems used in the industry. Cartridges, which are frequently used as part of a device delivery system, are one such format. Similar to a traditional vial, one end of a cartridge is typically sealed with an elastomer-lined crimp. Compared to that of a 20mm or 13mm vial, cartridge crimp seals are relatively small and intricate. On the other end, a cartridge is typically sealed by an elastomeric plunger, similar to that which may be found on a syringe. Each of these unique sealing interfaces present specific challenges from a CCI perspective.

Considering the crimp interface of the cartridge, similar studies as for a vial can be performed to optimize and validate component choice as well as assembly parameters and processes. Comparative studies can be performed to choose the most robust cartridge-seal combination given machinability limits. Studies involving multiple crimp configurations, in conjunction with HeLD and RSF, can help elucidate a set of capping parameters that consistently yields an integral seal with low leakage. As with vials, it is possible that dimensional stack-ups, in conjunction with limitations in machinability, yield defects such as loose crimps, misaligned seals, stress cracking from high crimp force, etc. Characterizing these risks through quantitative, deterministic analyses can inform mitigation strategies and quality decision making about the assembly process. With final components and assembly parameters chosen, assembly validation using cartridges capped real-time can be performed, fulfilling best practices outlined through industry standard guidance such as USP <1207>.

Unlike the crimp-sealed end, the barrel end of a cartridge is less a function of an applied force. However, similar optimization and assembly validation practices apply. As with any package system requiring a high degree of leak protection, early on in the development process, the inherent integrity of the chosen product-package system should be evaluated, essentially answering the question: “Are these components, when mated optimally, capable of creating an integral seal?”. This extends to the choice of suitable barrel-plunger interfaces as well. Arguably, since the barrel-plunger interface is not a function of a controllable process such as crimping, inherent integrity evaluations become even more critical. The achieved seal will be primarily a function of the dimensional overlap between the cartridge inner diameter and the plunger outer diameter.

In a laboratory setting, consider a study designed to evaluate barrel-plunger samples paired at dimensional extremes. Within their respective dimensional tolerances, the widest barrel inner diameter paired with the smallest plunger presents the highest risk for leakage, as there may be insufficient or inconsistent compression of the plunger against the cartridge wall. On the other hand, consider the smallest barrel inner diameter paired with the widest plunger. In this case, it is critical to ensure proper function, lack of stress-related defects such as cracking or fitment-related issues risking leakage, such as mis-aligned plungers. A study exploring these dimensional extremes provides confidence that components, within their dimensional stack-up ranges, will provide integral seals. This can be further confirmed by assessing real-world cartridges assembled on the line.

This type of work can be performed at a production facility, using client-owned instrumentation or in-house contract services. Additionally, LDA’s sample filler allows for sample preparation at time of test, enabling analysis of samples previously produced and sealed, or transfer of samples between manufacturing and testing sites. With increasing regulatory scrutiny as well as risk in poor package development and validation practices, helium leak detection, as enabled by the LDA SIMS 1284+ system, is a versatile tool in generating a robust foundation of CCI data for modern package systems

Presentation Summary

At the 2019 PDA Container Closure Integrity Testing Workshop in Gothenburg, Sweden, the following presentation was given as a 20 minute introduction to the use of helium leak detection for container closure integrity testing (CCIT).

Presented on behalf of Leak Detection Associates, the world’s premier manufacturer of custom-built helium leak detection solutions for pharmaceutical, biotechnology, medical device and food packaging clients, the presentation seeks to impart reviewers with an overview understanding of helium leak detection principles of operation, realistic methods for application to pharmaceutical packaging, and case study applications.

Helium gas is a small, nonreactive molecule, making it an ideal tracer for leakage testing, as employed by LDA’s SIMS 1915+ Helium Leak Detector. However, when it comes to preparing samples and subjecting them to a test, there are a range of approaches, each with respective ideal use cases. This presentation aims to illustrate some of the more common ways in which helium leak testing is applied to pharmaceutical packaging such as blisters, vials, and syringes. Reviewed approaches include the sniffer test, filling samples with helium prior to sealing, post-seal helium fill, using LDA’s proprietary vial filler and HSAM, and continuous fill using unique fixtures. Test approaches with reference to ASTM F2391 are discussed.

Important to the message of the presentation are the two case applications presented. The first discusses the application of helium leak testing to vial capping optimization, or assembly validation. In the second case application, an approach for evaluating individual ribs of a plunger is proposed. This type of approach is beneficial to those evaluating inherent integrity or defining their sterile barrier, which has implications for plunger movement during transit. This concept is becoming increasingly relevant as the expansion of prefilled syringe and cartridge-based delivery systems continues.

Dating back to the late 1990’s, the Food and Drug Administration (FDA) began to address the use of computers and software systems in the drug/device discovery, submission and approval process. This lead to the establishment of Title 21 CFR Part 11 which is the part of the Code of Federal Regulations that establishes the FDA’s regulations on electronic records and electronic signatures. Commonly referred to as simply Part 11, it defines the criteria under which electronic records and electronic signatures are considered trustworthy, reliable, and equivalent to paper records. In laymen’s terms, FDA 21 CFR Part 11 compliance dictates that those companies who use electronic systems for document and signature control must provide assurance that the electronic documents are authentic. This concept is widely referred to as data integrity.

The following diagram outlines all the key components of 21 CFR Part 11 requirements:

A review of some simple and direct questions regarding Part 11 compliance can help you to understand its requirements and implementation.

Which systems are affected by the 21 CFR Part 11 Requirements?

Part 11 applies whenever information is to be electronically generated, amended, stored, transferred or accessed. This can involve very different types of information, such as text data, images and videos and even audio files. The requirements for IT systems must be met if the documents generated, stored, transmitted or amended are used to demonstrate compliance with regulatory requirements, such as:

• Release and test protocols
• Process and work instructions
• Design drawings, software architecture documentation
• Specifications, request documents
• Records (example: production records, test results)
• Review protocols

As a rule of thumb, you can say that systems are subject to 21 CFR Part 11 data integrity regulations if the documents “managed” within the systems are submitted to the FDA or relevant for an FDA inspection, i.e. the testing of the Quality Management system to ensure it complies with 21 CFR Part 820.

What are the “key” obligations of a 21 CFR Part 11 Compliant System?

• System validation that confirms the ability to detect invalid or altered records
• Generation of human readable records.
• Ensuring the protection of records – records/data cannot be altered
• Limiting system access to authorized individuals
• Use of computer-generated, time-stamped audit trails that show who changed what and when.
• Operational system checks to ensure that only the permitted sequencing of steps and events is enforced.
• Authority checks to ensure that only authorized users can use the system and access the operating system, computer or peripherals.
• Peripherals check to ensure that the inputs and outputs are correct.
• Training of the people who work with the system or develop it.
• Prevention of falsification so that people are liable in writing for what they sign.
• System documentation on who has access to the system, how this access is granted, whether it be for the use or maintenance of the system, and on who changed what in the system and when.

A key component of any current Part 11 Software centers on the use of Digital or Electronic Signatures. What are the necessary parameters to insure this section of the system meets the FDA requirements?

• Content: A digital signature must contain the name of the signatory, the date and time of the signature and the meaning of the signature (e.g. review, approval, author, etc.).
• Protection against falsification: It must not be possible to falsify the digital signature
• Link to document: The signature must be linked to the document in such a way that it cannot be used on other documents.
• Uniqueness: It must be possible to assign the signature to a specific individual.
• Biometric and non-biometric methods: The identification must be based on biometric methods or two distinct identification components such as an identification code and password.

While a read through of the actual CFR document specific to Part 11 compliance can understandably make anyone’s head spin, the key questions outlined can help you form a basic understanding of the FDA requirements. The requirements are truly based on a simple directive: ensure that the data generated by a system is authentic, maintains integrity and is not subjected to alteration in any form.

The Leak Detection Associates’ Management Team understands the significance of regulatory guidance and requirements to its clients and is leading the helium leak detection industry sector in the area of 21 CFR Part 11 data integrity regulations specifically. Currently under development is a new software program that will operate a Helium Leak Detector in a manner that will adhere to all 21 CFR Part 11 Compliance 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.

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