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Class III medical devices in the United States are subject to stringent regulation by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. These devices, characterized by their high-risk nature, include those vital to sustaining human life or preventing health impairment, as well as those posing potential, unreasonable risks of illness or injury.

Examples of Class III devices encompass implantable pacemakers, specific prosthetic devices, and innovative technologies such as certain in vitro diagnostic devices. Classification is determined by factors like intended use, indications, and associated risks. Due to their complexity and critical roles in medical procedures, Class III devices undergo a rigorous pre-market approval (PMA) process.

Manufacturers must furnish extensive scientific and clinical evidence to demonstrate a device's safety and efficacy before it can be marketed. This robust regulatory framework ensures that Class III medical devices meet the highest standards for safety and performance, safeguarding patient health.

Packaging for these devices plays a critical role in maintaining the integrity of the product, ensuring it reaches the end user in a safe and effective condition. The packaging of Class III medical devices faces unique challenges due to the stringent regulatory requirements and the critical nature of the enclosed products. Ensuring the integrity of the packaging is essential to prevent contamination, maintain sterility, and safeguard the efficacy of the medical devices.

How to Ensure Container Closure Integrity of Class III Medical Device Packaging

Container Closure Integrity (CCI) is a vital aspect of ensuring the reliability of Class III medical device packaging . CCI testing involves assessing the seals and closures to confirm they effectively prevent the ingress of contaminants and maintain the sterility of the device. This testing is crucial to meeting regulatory standards and ensuring patient safety.

PTI’s VeriPac series are non-destructive, non-invasive inspection systems for leak detection and package integrity testing. These systems reduce waste and provide operators with a clear understanding of package quality. The VeriPac test system produces real time results from precise quantitative measurements that identify packaging defects before critical process issues get out of control. Tests can be performed in any sequence and even repeatedly on a single sample. Good packages can be returned undamaged to the packaging line. Testing is more reliable, sensitive and efficient than destructive methods. VeriPac series utilizes the ASTM approved patented Vacuum Decay leak test method F2338, recognized by the FDA as a consensus standard for package integrity testing.

Technology Overview

PTI’s VeriPac leak testers connect to a test chamber that is specially designed to contain the package to be tested. The package is placed inside the test chamber to which vacuum is applied. The absolute transducer technology is used to monitor the test chamber for both, the level of vacuum as well as the change in vacuum over a predetermined test time. The changes in absolute and differential vacuum indicate the presence of leaks and defects within the package. The test cycle takes only a few seconds, results are non-subjective, and testing is non-destructive to both product and package. The sensitivity of a test is a function of the sensitivity of the transducer, the package design, the package test fixture and critical test parameters of time and pressure. Test systems can be designed for manual or fully automated operation. This inspection method is suitable for laboratory offline testing, QA/QC statistical process control, automated batch or 100% inline testing.

Benefits of VeriPac series

• Non-destructive, non-subjective, no sample preparation
• Deterministic, quantitative test method
• Defect detection down to single digit microns.
• High level of sensitivity, repeatability and accuracy
• Short cycle time provides operator with PASS/FAIL result
• Small footprint and modular portable design
• ASTM test method and FDA standard
• Referenced in USP 1207 guidance

Blister packaging has gained widespread popularity as a versatile and efficient method for packaging various products, particularly in industries like pharmaceuticals, nutraceuticals and food. This packaging solution typically involves the creation of a plastic cavity or blister that is custom designed to securely hold and protect the product it contains. The design of the blister can vary significantly, accommodating a wide range of product shapes and sizes, making it a versatile option for manufacturers. It ensures that the product remains visible to consumers, allowing for easy identification and branding, which is especially crucial in retail settings.

To ensure the product's integrity and longevity, blister packaging is typically sealed with materials like aluminum foil or plastic film. This sealing process not only provides a protective barrier against external factors such as moisture, light, and contaminants but also enhances the product's shelf life. In the pharmaceutical industry, blister packaging is widely used to provide precise dosages of medications and to maintain their stability and sterility. In the food industry, it is often employed to preserve the freshness of perishable items and prevent tampering or contamination. Overall, blister packaging offers a combination of product visibility, protection, and convenience, making it an indispensable choice for many manufacturers looking to meet both functional and marketing requirements.

However, the significance of maintaining the integrity of blister packaging cannot be overlooked, as it plays a pivotal role in avoiding contamination, preserving product freshness, and extending shelf life. One highly effective method employed for assessing blister package integrity is helium leak detection, a process that relies on the unique properties of helium as a tracer gas.

Blister Package Integrity Testing using Helium Leak Detection.

Helium leak detection is a Container Closure Integrity Test (CCIT) that is used to identify leaks in blister packages. The test works by introducing helium gas into the blister package and then measuring the amount of helium that escapes. If there is a leak in the package, helium will escape, and the leak detector will produce a signal.

To test a blister package for leaks using (helium leak detection), the package is first placed in a test chamber. The test chamber is then evacuated, and helium gas is introduced into the package. The package is then held under vacuum for a period of time. After the holding time has elapsed, the test chamber is vented, and the leak detector is used to measure the amount of helium that has escaped from the package. If the amount of helium that has escaped from the package is above a certain threshold, the package is considered defective. Defective packages are rejected and not shipped to customers.

Why is Helium used as a Tracer Gas?

• It is the smallest and lightest gas, so it can easily escape through even the smallest leaks.
• It is inert, meaning that it does not react with other substances.
• It is non-toxic and non-flammable.
• It is abundant and relatively inexpensive.

Helium leak detection is a highly sensitive and reliable method for testing the integrity of blister packages. It is widely used in the pharmaceutical industry to ensure that blister packs are leak-proof and protect the contents from moisture, oxygen, and other contaminants.

Container Closure Integrity (CCI) is primarily intended to ensure parenteral bio-pharmaceutical sterility and product quality throughout its shelf-life and usage. Guidelines for initial qualification and standards for validation have been set out and are available in chapter 1207 of the US Pharmacopeia (USP<1207>) (1). Any common CCI testing (CCIT) approach can be used to obtain a method that is suitable for its intended application within an end-use cycle. the principles outlined in USAP<1207>. CCI is an integrative and comprehensive process.

Common challenges faced by the pharmaceutical packaging

Pharmaceutical packaging plays a very important role in ensuring protection and maintaining the quality of pharmaceutical products. As a result, a great number of challenges are faced by pharmaceutical packaging. Let us see some of the challenges.

1. Preserving the medical quality of products

The medicines may lose their therapeutic properties, which is one of the biggest challenges faced by the industry, owing to a continuous exposure to heat and moisture. Pharmaceutical materials must be carefully selected and must not be allowed to alter the product by external elements or the product may become totally waste.

2. Ensuring safe transportation of liquid medications and injections

The other big challenge faced by pharmaceutical packing involves ensuring the safe shipping of non-solid medications such as liquids medications and injections. Due to it’s fluid nature, these non-solid medications are considerably harder to handle, especially with glass packaging. There is a high chance of breaking down. In order to avoid this problem, modern technologies like foam packaging and roto molding cases are integrated into the pharmaceutical packaging industry so that the glass packaging does not break down.

3. Proper information of medicine and dosage

The specified dose consumption of medicine is very much important. Also the package must provide information on the required dose, and information about the medicine it is composed of, expiry date and the serial number in order to avoid any misunderstanding.

Role of CCI testing in reducing pharmaceutical package problems

CCI testing helps mitigate pharmaceutical package issues to a great extent. The capacity to describe elements and chemicals which are able to move through container closure system components and contaminate the therapeutic product is a crucial stage in knowing the biological safety and appropriateness of a container. The US Pharmacopeia (USP) and Food and Drug Administration (FDA) are the main forces behind the safety assessment of materials and container closure systems in the United States. These are complying with high Container Closure Integrity Testing criteria (CCIT).

Many damaging procedures were considered suitable to guarantee that container closures preserve the sterility of devices. Basically blue dye or water bath are the procedures. These procedures were actually time consuming, inaccurate and unreliable. Moreover, test operators may not be able to control some test aspects and the resultant findings may be subjective. As a result, the FDA led the industry to shift away from the probabilistic test techniques in favor of deterministic technologies that make it possible for variables to be checked better, performed in consistent circumstances and reliably detect major leakages. Until the emergence of new technologies such as Vacuum Decay and MicroCurrent HVLD, a proper balance between sensitivity and reliability was a difficult factor. These new technologies can successfully scan containers with a greater sensitive leak detection capacity at a much faster speed than ever before.

Vacuum Decay technology: A non-destructive Container Closure Integrity(CCI) testing method which measures leak by vacuum decay. This technology is usually used for sealed packages. In nonporous, stiff or flexible packaging the vacuum decay test identifies leaks. The vacuum decay leak test method is used to check the packages after they are filled to verify the integrity of the product. This method is mainly used by the food package manufacturer, beverages and pharmaceutical industries. This approach minimizes the number of precious completed medicines needed to evaluate stability because the test is not destructive of the samples. After the vacuum decay test, the same samples may be utilized for additional laboratory tests normally necessary for stability studies.

MicroCurrent HVLD technology: MicroCurrent HVLD is a non-invasive Container Closure Integrity(CCI) technology applicable for a broad variety of parenteral filled liquid goods, including exceptionally injecting low conductivity sterile water and protein-filled products. The test procedure assures CCI by scanning a container that is non-conductive and sealed with electrode samples to identify pinholes, micro cracks, leakage of stoppers/plungers, invisible leaks, etc. The resultant difference of resistance and change in current flow indicates a breakdown in the container. Thus a defect is detected with exact defect location.

In addition to offline laboratory systems for leak detection and package quality testing, CCIT offers configurations that provide the capability of fully automated inspection. These technologies do not compromise the reliability of test measurement and automatic inspections take the perfect time to manage and monitor expensive final goods. Automated inspection platform provides best in class CCI testing with no compromise within the parenteral process. PTI’s technologies provide the reliability and accuracy in test measurement, while the automation platform provides the flexibility needed to not compromise on quality.

Did you know that majority of defects in high-risk pharmaceuticals including pre-filled syringes are caused by seal defects, attributed to both process and personnel error? While micro leaks pose a risk, the primary causes of defects are larger seal related quality deviations.

As the pharmaceutical industry is constantly seeking opportunities to develop convenient drug delivery methods, pre-filled syringes have come up as practical and reliable source for unit dose medication. The demand for glass syringes faded as the industry moved towards plastic and disposable syringes. Pre-filled syringes are applied across a wide range of medical sector including vaccines, blood stimulants, and therapeutic proteins.

Convenience in use and reduced dosage errors are the primary benefits associated with pre-filled syringes. They make injections easier and safer for both doctors and patients. In addition, pharmaceutical companies are able to minimize drug waste and increase product life span- which are important factors, particularly with costly biopharmaceuticals. However, considering the fact that pre-filled syringes are complicated combination products, manufacturers face a number of challenges in terms of quality control and stability concerns. Therefore, pharmaceutical package testing demands sound knowledge of various CCI testing methods. In this blog, we will understand how Microcurrent HVLD technology offers reliable seal quality testing of pre-filled syringes.

MicroCurrent HVLD Technology for CCI testing of pre-filled syringes.

High voltage leak detection (HVLD) has been a common technology in the market for decades. The latest evolution of HVLD, MicroCurrent technology, aims to achieve a high level of CCI assurance across the entire range of parenteral products. High voltage leak detection is a method included in USP 1207 as a deterministic test methodology and is an established and reliable solution for all liquid filled parenteral products.

HVLD operates on the simple property of electrical current. The package barrier must be non-conductive and would resist voltage from passing through, while the package contents should generally be able to carry voltage. Liquid products with a conductivity of 5 microsiemens and greater meet the requirement for PTI’s MicroCurrent HVLD

The E-Scan 655 is a Microcurrent HVLD technology-based leak test instrument used to inspect vials, syringes, and other liquid filled parenteral products. It is completely non-destructive to the container and product; exposing the package and product to lower voltage than other conductivity-based solutions. The technology uses a non-contact and non-invasive test method that requires no sample preparation. E-Scan 655 can be used with a wide range of liquid-based products including low conductivity sterile water for injection (WFI) and proteinaceous products with suspensions.

Benefits of MicroCurrent HVLD technology

• Non-destructive, non-invasive, no sample preparation.
• High level of repeatability and accuracy.
• Effective across all parenteral products, including extremely low conductivity liquids (WFI).
• Lower voltage exposure produces no ozone, eliminating risk to the product and environment.
• Listed in USP Chapter as recommended method for parenteral liquid package inspection.
• Robust method and approximate 3x Signal-Noise-Ratio for a wide range of product classes and package formats.
• Simplifies the inspection and validation process.

Container Closure Integrity Testing is a leak detection test conducted using non-destructive package inspection systems, to evaluate whether container closure systems can maintain sterile barriers against potential damages. CCIT plays a vital role in ensuring that the products are free from any possible contamination. Container closure systems are made up of primary packaging components and secondary packaging components. Components like glass, vials or syringes that are in direct contact with the product are called primary packaging components. Secondary packaging components include aluminum caps, cardboard boxes etc. that are not in direct contact with the product.

While there are multiple ways to conduct a Container Closure Integrity test, these methods can be broadly classified into probabilistic and deterministic test methods. Traditional methods like bubble tests, dye ingress and microbial challenge by immersion come under probabilistic test methods. Since it was found that such test results lacked accuracy and reliability, the United States pharmacopeia released guidance in 2016 stating that deterministic methods are preferred over probabilistic test methods. Let us now understand how Microcurrent HVLD technology ensures sensitive CCI testing across different industries and applications.

MicroCurent HVLD technology is a non-destructive test method capable of achieving high levels of CCI assurance across the entire range of parenteral products. It is an FDA recognized ASTM test method capable of detecting the presence and location of pinholes, micro-cracks, stopper/plunger leaks, non-visible leaks under crimping and many other defects. Additionally, MicroCurent HVLD technology is found to be effective in detecting leaks in a wide range of liquid- filled products including extremely low conductivity sterile water for injection (WFI) and proteinaceous products with suspensions. A unique feature of Microcurrent HVLD technology is that it does not require mass to pass through a defect site, requiring only the passage of electricity through a crack.

How does MicroCurrent HVLD technology work?

MicroCurrent HVLD technology functions on the simple property of electrical current. The first step is to place container horizontally on the rotating stage. While rotating the container, high voltage is applied on one side of the container and a ground probe on the opposing side. In the presence of a micro-leak or crack in one of the container walls, break-down resistance is reached and the current passes through. On the other hand, if there is no leak, the two container walls (high voltage side and ground side) provide full electrical resistance and no significant current is measured passing through the package.

MicroCurrent HVLD reduces voltage exposure to the product to less than 5% of the voltage exposure experienced when testing with other HVLD solutions. Reduced voltage exposure has twin benefits- limits any risk that the voltage may cause to the product, and greatly reduces production of ozone during operation. In fact, experiments have shown that MicroCurrent HVLD produces essentially no Ozone

Benefits MicroCurrent HVLD technology

• Non-destructive, non-invasive, no sample preparation.
• High level of repeatability and accuracy.
• Effective across all parenteral products, including extremely low conductivity liquids (WFI).
• Lower voltage exposure produces no ozone, eliminating risk to the product and environment.
• Listed in USP Chapter as recommended method for parenteral liquid package inspection.
• Robust method and approximate 3x Signal-Noise-Ratio for a wide range of product classes and package formats.
• Simplifies the inspection and validation process.

Blister packs are popular packaging options for pharmaceuticals and consumer goods. A wide range of pharmaceutical products are packed in blister packs, ranging from capsules and tablets to high-risk hormone-based drugs and steroidal treatments. Commonly made of thermoformed plastic, these are quite useful in guarding products against external factors like heat, moisture and humidity.

However, concerns over integrity of blister packaging have increased over the years. Even a minute breach in the packaging can result in compromised package integrity. Hence, pharmaceutical manufacturers concerned about quality and shelf life of their products make Container Closure Integrity testing a crucial part of their manufacturing process. There are several methods available to test blister packs, and each has its own merits and demerits. For instance, the most common method to test blister packs remain dye ingress. However, this method is subjective, probabilistic and lacked accuracy in test results. This encouraged manufacturers to use non-destructive CCI test methods, that were accurate and produced quantitative results with measurable result data.

Blister Package Inspection with VeriPac UBV Technology

The VeriPac UBV Leak Detection System is a deterministic, non-destructive technology designed specifically for multi-cavity blister packs. The VeriPac UBV utilizes volumetric imaging under vacuum to detect the presence and location of leaks. It is a rapid test requiring no changeover or sample preparation. Operators simply input the number of blister cavities, place the blister pack on the inspection plate and press the START button. Within seconds, the operator sees a definitive pass/fail result, along with a volumetric measurement reading. The location of the defective cavity is presented to the operator with an image of the tested package. The intuitive and simple method makes it a practical solution giving rapid feedback to production line operators.

The UBV technology can provide rapid detection of defects as small as 10 microns with a fast test time, averaging 10-30 seconds depending on blister cavity volume. Test system requires no tools or test parameter changes for different blister formats. This technology is particularly advantageous for small to tiny blister cavities that are notoriously difficult to detect with a standard Vacuum Decay technology due to the very low headspace.

Technology Overview

Under this method, the sample is first placed inside the hinged test chamber. After pressing the start button, vacuum is pulled to a defined level. The blisters expand under vacuum, driving air out of the blister through any leaks present. If there is a leak in the blister, the air escapes into the chamber leaving a collapsed blister package. During the dynamic vacuum test sequence, a volumetric measurement reading is taken which determines which blister cavities are defective.

Benefits of VeriPac UBV Technology

• Non-destructive technology
• Accurate and repeatable results
• Pass/fail results backed by quantitative test data
• Completely tool-less
• No changeover to test different blister formats
• Identifies which cavity is defective
• Eliminates destructive, subjective testing methods

Pharmaceutical drugs are the backbone for the pharmaceutical industry as it brings new solutions that help patients to live longer and healthier. These pharmaceutical drugs usually biological & parenteral products like blood components, cells, vaccines, tissues and recombinant proteins. These products contain large complex molecules that are derived from human, animal or microorganisms through biotechnology. The evolution of these complex products has also increased challenges in terms of packaging and transportation.

Owing to the highly sensitive nature of these drugs to various external factors like oxygen, moisture, chemicals, and bacteria, any containment to the drugs is a concern in the health care industry. Poor package performance can cause even chemical alterations to the remedial property of these products. Therefore, parenteral product leak testing has an important role to meet the packaging challenges associated with biological products and to assure the safety of the products during the product life cycle.

Package integrity of parenteral & biologic products

PTI’s Microcurrent is patent-pending unique CCI technology that has revolutionized the conventional high voltage leak detection method. It is a non-invasive and deterministic container closure integrity testing method that is effectual across all parenteral and biologic products including low conductivity liquids such as sterile water for injection. The Microcurrent HVLD test method is highly effective in detecting the presence and location of pinholes, micro-cracks, stopper/plunger leaks, non-visible leaks under crimping and many other defects across applications like pre-filled syringes, vials, cartridges, ampoules, BFS, bottles and pouches. A unique mode of Microcurrent HVLD uses about 50% less voltage and reduces the exposure of product and environment to less than 5% of the voltage when compared to conventional HVLD solutions. The E-scan HVLD series have joined the line of sturdy packaging integrity equipment.

Benefits of MicroCurrent HVLD technology

• Non-destructive & requires no sample preparation
• Deterministic & non-invasive
• Highly effective across all parenteral products
• High levels of sensitivity, accuracy and reliability in results
• Offline and 100% online inspection at high production speeds
• Simplifies the inspection and validation process
• Referenced in Chapter Guidance for CCIT

We, being the think tank of Europe’s container closure integrity always aim to achieve a high-level of package integrity across the entire range of parenteral products