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The pharmaceutical biologics are the newest class of drugs requiring complex and sensitive handling. Obtained from living organisms, biologics like vaccines and antibodies have a high susceptibility to degradation if exposed to contaminants or environmental changes. Packaging of the drug must, therefore, be air-tight to meet safety and efficacy requirements; thus, there is a need for Container Closure Integrity testing (CCIT). Traditional testing methods are mainly destructive. In that case, biologics safety cannot be ensured. However, the industry is shifting towards non-destructive, deterministic, highly accurate and reliable techniques of testing.

Overview of Biologics Packaging

Biologics are sensitive to temperature, light, and contaminants, hence requiring specialty packaging to ensure shelf-life stability. Glass vials, prefilled syringes, and ampoules are some common formats with individual specifications to produce a sterile barrier. Because biologics are easily affected, the packaging needs to maintain a completely sealed environment.

Why CCI Testing Is Important for Biologics

Biologics have even the slightest impurities reduce the product's effectiveness and make it potentially unsafe. Here's why CCI testing is so important for biologics:

• Ensures Safety and Effectiveness: Biologics degrade very fast when exposed to air or moisture or any contaminants. Appropriate CCI testing ensures that the packaging is sealed.
• Regulatory Compliance: Regulatory agencies like FDA require accurate, numerical CCI testing of biologics' packaging. Noncompliance with these requirements may even lead to recalls and, therefore, harm the reputation of a manufacturer.
• Extended Shelf Life: Biologics are expensive to produce, so obtaining the CCI results in an extended shelf life with less waste and financial losses.
• Minimal Risk to Patient: Strong packaging ensures a patient does not receive a compromised product, therefore ensuring safety for the patient.

Techniques for Ensuring Container Closure Integrity

For biologics, non-destructive and reliable methods of testing are preferred over traditional techniques. Here’s an introduction to two advanced CCI methods widely used in the industry:

1. Helium Leak Detection

Helium Leak Detection (HLD) is a precise method for identifying tiny leaks in sealed systems, using helium as a tracer gas. Helium’s small atomic size and inert, non-flammable nature make it ideal for penetrating leaks, allowing accurate leakage rate measurements. Its benefits include lower weight, cost-effectiveness, and availability in various forms, setting it apart from alternatives like hydrogen.

The technique operates on mass spectrometry principles, where ionized helium ions are accelerated and directed through a magnetic field, ensuring only helium ions reach the detector. This ion current, converted to an electric current, is then displayed as a leak rate. Compared to traditional methods like vacuum bubble and dye tests, helium testing offers highly accurate, quantitative assessments across diverse packaging conditions and lifecycle stages.

With sensitivity levels as low as 1×10-12 l/s, helium leak testing enables unmatched detection of minute leaks, supporting comprehensive package integrity evaluations.

2. MicroCurrent HVLD Technology

It is one of the most advanced non-destructive, non-invasive Container Closure Integrity Testing (CCIT) methods-PTI's MicroCurrent HVLD technology-that produces very effective CCIT in any range of application, whether it be pre-filled syringes, vials, cartridges, ampoules, Blow-Fill-Seal containers, bottles, and pouches. This technology proves to be effective for leak detection of liquid-filled parenteral products. Applications include low-conductivity products, such as sterile WFI and large molecule protein-based products.

In this process, electrode probes scan the sealed container to detect any potential leaks. A variation in current flow helps identify container defects and pinpoint their location. Notably, MicroCurrent HVLD technology operates with approximately 50% lower voltage, exposing both the product and its environment to less than 5% of the voltage used in conventional HVLD methods. This makes it one of the most effective CCI solutions for parenteral and biologic products.

The complexity and sensitivity of biologics have driven the industry toward advanced, non-destructive CCI testing methods. MicroCurrent HVLD and Helium Leak Detection provide the precision, reliability, and non-invasive testing needed to ensure that biologics remain safe, effective, and compliant with regulatory standards. These techniques not only help biologics manufacturers meet regulatory requirements but also support the safe delivery of biologics to patients, ensuring the highest product integrity.

Maintaining the sterility and efficacy of pharmaceutical products is paramount. Even the smallest breach in packaging can compromise a drug's integrity, leading to contamination or degradation. Helium leak testing offers a highly sensitive and reliable method for ensuring the integrity of pharmaceutical packaging.

Helium leak testing is a non-destructive Container Closure Integrity Test (CCIT) used to detect leaks in sealed systems. Helium, being the smallest and lightest gas molecule, readily permeates even minute leaks. The basic principle involves introducing helium into the package or placing it in a helium-rich environment. A highly sensitive detector then measures the helium escaping from any leaks present. Leak detection is achieved through mass spectrometry, where the detector isolates and measures the specific signal of helium ions.

Why is Helium Leak Testing Important for Pharmaceutical Packaging?

Pharmaceutical packaging plays a vital role in protecting the sterility and efficacy of drugs. Even microscopic leaks can allow for the ingress of contaminants like moisture, oxygen, or microorganisms. This can lead to:

• Product degradation: Exposure to air or moisture can alter the chemical composition of a drug, rendering it ineffective or even harmful.
• Microbial growth: Leaks can allow for the introduction of bacteria, fungi, or other microorganisms, posing a serious health risk.
• Reduced shelf life: Compromised packaging can shorten the shelf life of a drug, leading to product waste.

Helium leak testing offers several advantages over other leak detection methods:

• High sensitivity: Helium leak testing can detect leaks significantly smaller than those identified by other methods.
• Non-destructive: This technique does not damage the packaging, allowing for post-testing evaluation and analysis.
• Broad applicability: Helium leak testing is suitable for a wide range of pharmaceutical packaging materials and formats.

Helium Leak Services: Benefits of Partnering with PTI

PTI offers a comprehensive suite of helium leak testing services specifically tailored to the pharmaceutical industry. Our benefits include:

• Advanced instrumentation: We utilize state-of-the-art leak detectors with exceptional sensitivity and accuracy.
• Expert technicians: Our highly trained technicians possess in-depth knowledge of helium leak testing principles and pharmaceutical packaging applications.
• Customizable testing protocols: We work collaboratively with clients to develop testing protocols that meet their specific needs and product requirements.
• Rigorous quality control procedures: PTI adheres to the strictest quality control standards to ensure the reliability and consistency of our testing results.

By partnering with PTI for your helium leak testing needs, you gain access to a reliable and efficient solution that safeguards the integrity of your pharmaceutical products. This, in turn, protects patient safety, ensures product efficacy, and promotes brand reputation.

In the high-stakes world of pharmaceuticals and medical devices, ensuring the integrity of packages isn't a mere formality; it's a fundamental pillar of safety and efficacy. For decades, meticulous package integrity testing methods have served as the gatekeepers, diligently sniffing out potential breaches that could compromise lives and livelihoods. Yet, traditional approaches often fell short – lacking the sensitivity to detect microscopic flaws, the versatility to handle diverse package formats, and the quantitative data to provide actionable insights. In order to overcome the shortcomings of traditional methods, manufacturers now rely on non-destructive, deterministic package testing alternatives.

Helium Leak Detection - An Overview

Helium leak testing refers to the process of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. It is an effective container closure integrity test method, aimed at evaluating the integrity of pharmaceutical and parenteral products. The process involves filling the package with helium and subjecting it to vacuum. A helium leak detector is then utilized to quantitatively measure the amount of helium escaping from the package, which is expressed as a leak rate. Beyond evaluating container closure integrity, helium leak testing finds applications in product design, quality analysis, failure analysis, and validation. It offers flexibility as it can be conducted with or without a test chamber, enabling testing for "in-leakage" or "out-leakage," as well as locating leaks.

Helium is considered an ideal choice of tracer gas because of multiple reasons. Helium 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 relatively safe to use. Additionally, compared to other tracer gases helium is less expensive and is available in multiple cylinder sizes.

Helium Leak Testing Using SIMS 1915

The Seal Integrity Monitoring System (SIMS) 1915+ stands out as the ideal solution for helium-based leak detection across a range of pharmaceutical and medical device packaging systems, including vials, syringes, cartridges, and blister cards. It's particularly effective for parenteral products, such as ensuring the integrity of rubber stoppers on vials or plungers on syringe assemblies.

Utilizing helium as the tracer gas, this system allows for quantitative testing that surpasses traditional methods like vacuum bubble and dye penetration tests by a significant margin. This quantitative approach facilitates direct comparisons among different packaging materials, formats, production line settings, and storage conditions, supporting the entire product lifecycle. The SIMS 1915+ offers the capability for quantitative analysis with a sensitivity level as low as 1 x 10-10 mbar/L/sec. It provides comprehensive data sets instead of simplistic pass/fail criteria and can conduct testing at room temperature.

Each SIMS 1915+ Helium Leak Testing instrument is meticulously crafted to meet client-specific standards and package configurations. We specialize in engineering custom test fixtures tailored to the components being tested, ensuring precision and accuracy to fulfill your study objectives, accommodate various package configurations, and meet quality monitoring requirements.

SIMS 1915+ Options:

• LT 80 and LT 150 Cryo-Chiller Low Temperature Add-on Modules for ultra-cold Container Closure Integrity 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.

In the pharmaceutical industry, ensuring the safety and integrity of drug products is of paramount importance. Contamination or compromise in the packaging of vials can lead to significant risks for both patients and manufacturers. Hence, meticulous quality assurance measures are implemented to guarantee that every vial meets the highest standards of quality.

One crucial aspect of quality control in vial production is Container Closure Integrity testing (CCIT). CCI inspection is a vital step to verify the hermetic sealing of vials, ensuring that no leaks or defects compromise the product's sterility or stability. Over the years, various technologies have emerged to improve CCI inspection processes, and one of the most advanced and sensitive methods available today is helium leak detection.

Testing Integrity of Vials using Helium Leak Detection Technology

Helium leak detection technology has revolutionized container closure integrity testing by providing highly sensitive and precise detection of leaks in vials. Helium leak detection can be understood as the process of identifying leaks in any closed or sealed system with the help of helium gas and measuring its concentration as it escapes due to leakage. Common applications of helium leak testing include pre-filled syringes, cold form blister packs, foil pouches and many other package formats. This technology can precisely determine integrity between specific primary container closure system components, making it an ideal choice for testing the integrity of pharmaceutical products.

This method utilizes helium gas, which has exceptional properties that make it an ideal tracer for leak detection purposes. By harnessing the unique characteristics of helium, manufacturers can perform comprehensive testing to identify even the smallest leaks, enhancing the overall integrity of vial packaging.

Why is Helium used as a Tracer Gas?

• Helium is used as a tracer gas because of certain unique qualities that make it ideal for leak testing.
• Non-toxic, non-condensable, non-flammable.
• Helium gas is inert, which means it does not interact with the components being tested.
• Since the atomic size of helium is very small, it can easily breach through pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.
• Its presence in the atmosphere is not more than ppm.

Technology Overview

The test process starts by introducing helium into the package, which is then subjected to a vacuum. The quantity of helium that escapes from the package is then measured using a helium leak detector, providing a quantitative measure known as the leak rate. In addition to leak testing, helium leak detection technology has proven to be effective for tasks such as package design, failure analysis, tooling qualification, packaging line setup and validation, and monitoring product quality. The use of helium leak detection in accordance with ASTM F2391 is a widely accepted and extensively utilized method in the pharmaceutical industry.

Overall, the adoption of helium leak detection revolutionizes CCI quality assurance, upholding high standards, and supports production quality monitoring at a higher more reliable level.

A combination product may be defined as 'a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product.' In simple words, a combination product is a combination of at least two product categories such as drug, device and/or biological products. Best-known examples of combination products include prefilled syringes, pen injectors, auto-injectors, inhalers, transdermal pumps and patches, and kits containing drug administration devices or components. Often termed as high-risk medical devices, combination products host various challenges for manufacturers, demanding in-depth testing and evaluation. Read on to know how manufacturers can test the integrity of combination product packages using helium leak detection.

Package Integrity Testing using Helium Leak Testing

Helium leak detection is a highly effective technique for evaluating the integrity of a wide range of complex pharmaceutical and parenteral products. Helium leak detection can be understood as the process of identifying leaks in any closed or sealed system with the help of helium gas and measuring its concentration as it escapes due to leakage. Common applications of helium leak testing include pre-filled syringes, cold form blister packs, foil pouches and many other package formats. This technology can precisely determine integrity between specific primary container closure system components, making it an ideal choice for testing the integrity of pharmaceutical products.

Why is Helium used as a Tracer Gas?

• Helium is used as a tracer gas because of certain unique qualities that make it ideal for leak testing.
• Non-toxic, non-condensable, non-flammable.
• Helium gas is inert, which means it does not interact with the components being tested.
• Since the atomic size of helium is really small, it can easily breach through pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.
• Its presence in the atmosphere is not more than ppm.

How Does Helium Leak Detection Technology Work?

The test procedure begins by filling the package with helium, which is then subject to vacuum. Then, the amount of helium escaping from the package is quantitatively measured using a helium leak detector. This is then stated as the leak rate. Apart from leak testing, helium leak detection technology is also suitable for package design, failure analysis, tooling qualification, packaging line setup and validation, and product quality monitoring. Helium leak detection per ASTM F2391, is a well-established method recognized and widely used in the pharma industry.

Applications of Helium Leak Testing

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

The rapidly increasing preference towards combination pharmaceutical products continues to fuel innovation, while presenting unique challenges in implementing a container closure integrity (CCI) testing strategy. Common examples of combination products include prefilled syringes, pen injectors, inhalers, and drug-eluting stents, orthopedic products, infusion pumps and more. The packaging for combination products can be just as complex as the products themselves. Hence, container closure integrity testing in line with current USP <1207> guidance and regulation is critical to ensure package integrity.

Techniques to ensure CCI: Helium leak testing & Microcurrent HVLD technology

Helium leak testing refers to the process of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. Apart from being an ideal solution for ensuring Container Closure Integrity, the technology is also applicable in package design, monitoring product quality, failure analysis and line set up and validation.

Under this method, a helium leak detector otherwise known as Mass Spectrometer Leak Detector (MSLD) is used to identify and calculate size of the leak. The test part is first connected to a leak detector and then the tracer gas, helium is introduced. In the presence of a leak, helium escapes from the test parts and this partial pressure is measured and results are displayed on the meter. Helium Leak Detection per ASTM F2391, has long been recognized by the FDA as a consensus standard for package integrity evaluation. The test method is also referenced in the United States Pharmacopeia (USP) Chapter on Container Closure Integrity (CCI) – USP <1207>.

PTI’s MicroCurrent HVLD technology is a non-destructive, non-invasive container closure integrity test method that is found to be highly effective across applications such as pre-filled syringes, vials, cartridges, ampoules, BFS, bottles and pouches. This technique can precisely detect any leak in a wide range of liquid-filled products including extremely low conductivity sterile water for injection (WFI) and proteinaceous products with suspensions. Under this method, the sealed container is scanned using electrode probes to detect the presence of any leak. Defects in the container as well as its approximate location can be identified by analyzing a change in the current flow. MicroCurrent HVLD technology utilizes about 50% less voltage and exposes the product and environment to less than 5% of the voltage when compared to conventional HVLD solutions. It is one of the most effective CCI technologies for all parenteral and biologic products.

Benefits of PTI’s MicroCurrent HVLD technology

• Non-destructive, non-invasive, no sample preparation
• Highly effective across all parenteral products, including extremely low conductivity liquids (WFI)
• Ensure higher levels of accuracy and reliability in results
• Offline and 100% online inspection at high production speeds
• Simplifies the inspection and validation process
• Referenced in USP 1207 Guideline

Over the last two decades, pharmaceutical industry has seen tremendous growth in the form of technological advancements and drug delivery system innovations. However, such innovations have increased quality assurance challenges for drug manufacturers. For this reason, drug product manufacturers give at most importance to their quality control procedure as well as package integrity tests.

Packaging plays a vital role in preserving product quality and maintaining a sterile barrier against external damaging force. Even a minute breach in the package can cause moisture, reactive gases, or other harmful substances to enter the product- thus compromising its healing properties. Moreover, a contaminated drug product can cause serious health issues to the user, making it more of a threat than treatment. Given the sensitive nature of pharmaceutical products, ensuring Container Closure Integrity holds high relevance.

Container Closure Integrity testing (CCIT) is a leak detection technique for evaluating the ability of container closure systems in maintaining sterile barrier against external contaminations. Such tests can be broadly classified into Probabilistic and Deterministic test methods. Although Probabilistic test methods like Bubble Tests and Dye Ingress were initially popular, with more technical advances, better, non-destructive methods are now the go-to solutions to insure container integrity. Manufacturers are encouraged to switch to more reliable Deterministic test methods that provide guaranteed quantitative results with precision. In this blog we will be discussing in detail Helium Leak Detection Technology.

What is Helium Leak Detection Technology?

Helium Leak Detection Technology is a Container Closure Integrity test method that is used to find leaks in different types of enclosed or sealed systems. The technique uses helium as a tracer gas and its concentration is measured as it escapes through the leaks. Under this method, the package is helium filled and subjected to vacuum. The amount of helium escaping the package is quantitatively measured and stated as a leak rate. Helium is an ideal choice for package leak testing and container closure integrity testing in particular during container closure development for pharmaceutical products, due its key qualities:

• It is inert, non-toxic, non-condensable and non-flammable.
• Being inert, it is safe to use as it will not react with other materials being tested.
• The atom size of helium is really small therefore it can easily pass through leaks.
• The instrument noise due to environmental helium is inherently low because of its limited presence in the atmosphere at less than 5ppm and thus gives incredibly accurate reports.
• Helium is relatively inexpensive and is available in multiple cylinder sizes.

Seal Integrity Monitoring System

The Seal Integrity Monitoring System (SIMS) 1915+, is the ideal choice for your helium-based leak detection system for testing rigid containers including vials, syringes, and cartridges and blister cards. 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, supporting the entire lifecycle.

THE SIMS 1915+. features an oil-free detector and power system that is designed for the needs of the pharmaceutical and medical device industries. In addition, this system will enable you to quantitatively analyze package system at a sensitivity level as low as 1 x 10 -11 mbar-L/s and provides relevant data sets in place of a simple pass/fail criteria while enabling testing to be performed at room temperature.

Each SIMS 1915+ Helium Leak Testing instrument manufactured by Leak Detection Associates is custom built to client specific standards and package configurations.

Custom Built to Client Specification SIMS 1915+ Leak Detection System with Add -On Components

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