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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

Low head space packages are a common type of packaging used for a variety of products, including pharmaceuticals, medical devices, and food. These packages are designed to have a minimal amount of space between the product and the packaging material, which can help extend the shelf life of the product and protect it from contamination. Low head space packages are typically made of a flexible material, such as film or foil. The material is then sealed to the product, creating a tight seal that helps to preserve the product's integrity.

However, low head space packages can also be more susceptible to leaks, which can lead to sterility breaches, product spoilage and contamination. Therefore, it is important to ensure that these packages are properly sealed to prevent leaks and contamination. VeriPac 410 is a non-destructive seal and leak detection system that can help ensure the integrity of low head space packages.

Applications of low head space packages

Low head space packages are used in a variety of industries, including:

• Pharmaceutical industry: Low head space packages are used to package pharmaceuticals, such as tablets, capsules, and transdermal patches.
• Medical device industry: Low head space packages are used to package medical devices, such as, suture packaging.
• Personal care industry: Low head space packages are used to package personal care products, such as serums, lotions and creams packaged in sachets and pouches.

Low Head Space Package Inspection Using Force Decay Technology

Force Decay serves as a quantitative method for detecting leaks, especially in packaging with low headspace. The applicable packaging formats encompass non-porous materials, such as films, laminates, or foils. This method, being non-destructive, leaves the sample packages undamaged and unaltered. Following the completion of the test, the packages can seamlessly return to the batch without the need for disposal.

The testing system employs nested tooling to position the package consistently and restrict the unmeasured expansion of the package under examination. Initiating the test involves creating a vacuum in the test chamber, prompting the package to expand within it. Vacuum levels are continuously monitored throughout the test cycle, evaluating the package using the ASTM F2338 vacuum decay leak test method.

Multiple packages can undergo testing in a single test cycle, with the force decay measurement system discerning any defective packages. Defective packages exhibit a decay in the expansion force or vacuum level during the test cycle. The location of the defective package or cavity is then pinpointed. Force decay proves most effective when assessing multi-cavity package formats.

PTI’s VeriPac 410 inspection technique leverages force decay technology for non-destructive seal and leak detection in blister packs, sachets, and pouches with low headspace. VeriPac 410 functions as a vacuum based Container Closure Integrity test (CCIT) method, capable of testing multiple packages in a single test cycle. The force decay measurement system identifies any defective packages. This technology accurately measures force by observing the surface deflection of a package during a typical vacuum-based test cycle. The force measurement capability enables the VeriPac 410 series to pinpoint which package is defective while also conducting leak tests on packages with minimal headspace. Force decay remains the most effective technology, particularly in the assessment of multi-cavity package formats. This technology is scalable from the laboratory to automated inline inspection platforms.

Benefits of Force Decay leak testing

• Non-destructive and non-invasive
• Non-destructive, non-subjective, no sample preparation
• The test protocol is programmed into the testing unit with high degree of repeatability.
• Multiple packages can be tested in a single test cycle
• The test is operator independent and can be performed with minimal training
• Supports sustainable packaging initiatives
• Optimal solution for in-process testing
• Cost effective with rapid return on investment

In the early days, coffee was often packaged in simple sacks or bags made from natural materials, such as burlap or hemp. These materials were not very airtight, so they could not keep coffee fresh for long periods of time. Vacuum sealed packaging was invented during the 1900s. This packaging removes all of the air from the packaging, which helps to keep coffee fresh for an extended period of time. Vacuum sealed packaging is also lightweight and relatively inexpensive, so it quickly became the most popular type of coffee packaging.

In recent years, there has been a growing trend towards more sustainable coffee packaging. This trend is driven by concerns about the environmental impact of traditional coffee packaging materials, such as plastic and tin.

Overview of Coffee Packaging

Coffee packaging refers to the process of packaging and presenting coffee beans or ground coffee for distribution, sale, and consumption. Coffee packaging serves several important purposes, including preserving the freshness and flavor of the coffee, protecting it from external elements such as light, moisture, and oxygen, and providing information to consumers.

Coffee packaging plays a crucial role in ensuring that coffee reaches consumers in optimal condition, with its flavor and aroma preserved. It also serves as a means of communication between coffee producers and consumers, conveying information about the coffee's characteristics and the values of the company that produces it.

Integrity testing of coffee packaging ensures that the packaging is free of leaks and defects that could compromise the quality of the coffee. This is important to do, as leaks can allow oxygen, moisture, and light to enter the packaging, which can all degrade the flavor of the coffee.

Here are some of the benefits of integrity testing for coffee packaging:

• It can help prevent coffee from going stale or developing off-flavors.
• It can help protect coffee from contamination.
• It can help ensure that coffee meets quality standards.
• It can help reduce product recalls.
• It can help improve customer satisfaction.

Quality Testing Using Vacuum Decay Technology

Vacuum decay technology is a non-destructive method for testing the integrity of coffee packaging. It is a Container Closure Integrity Test (CCIT) method with a proven capability of non-destructively testing packaging at the production line with unmatched reliability and sensitivity. Non-destructive testing not only allows a greater understanding of package quality, but also reduces waste as compared to destructive test methods. Waste reduction, in turn, results in a higher return on investment and brings operations closer to green initiatives.

Vacuum decay technology operates by placing sample packages in a closely fitting evacuation test chamber, which is equipped with an external vacuum source. Single or dual vacuum 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. VeriPac series is a practical alternative to destructive test methods and can precisely detect leaks as small as 5 microns, identifying process issues before they become critical, avoiding catastrophic quality deviations.

Benefits of Vacuum Decay Test System

• Non-destructive technology.
• ASTM Test Method F2338, FDA Consensus Standard and referenced in USP 1207 Guidelines.
• Accurate, repeatable results.
• Pass/fail results backed by quantitative test data.
• Completely tool-less with no changeover to test different packaging formats.
• Identifies which cavity is defective.
• Eliminates destructive, subjective testing methods.

Vacuum decay technology is a valuable tool for ensuring the quality of coffee packaging. It can help prevent coffee from going stale or developing off-flavors. It can also help protect coffee from contamination. If you are a coffee roaster or retailer, integrity testing of coffee packaging is an important quality control measure that you should implement.

Container closure integrity (CCI) testing of intravenous (IV) bags is an important quality control measure to ensure the safety and efficacy of the products. CCI testing helps verify that the container closure system, including the bag and its closure, maintains its integrity throughout the product's shelf life and prevents any leakage or contamination.

Various methods, including visual inspection, dye immersion testing, bubble emission testing, headspace gas analysis, and Vacuum decay testing can be employed to assess the integrity of the container closure system. These methods help to identify any defects or breaches that may compromise the sterility and stability of the IV bags. Manufacturers should select an appropriate method based on their specific requirements and regulatory guidelines to ensure the quality and safety of the IV bags.

Vacuum Decay Technology for CCI Testing of Intravenous Bags

Vacuum decay technology is an FDA-approved leak detection technique that can be used for CCI testing of high-risk package applications. The non-destructive nature of the process allows for greater understanding of packages, testing at a greater frequency with more accuracy and with less waste. Vacuum decay technology is capable of detecting leaks in sealed rigid, semi-rigid and flexible packaging made of non-porous or porous materials and has been proven to provide repeatable, reliable and quantitative test results.

VeriPac testing systems using Vacuum decay leak testing are highly effective for leak testing of IV bags. Using a differential pressure transducer leak test system, the test method is capable of detecting package leaks and invisible defects in the IV bag body and also in seams, welds and port areas. This method is non-invasive, non-subjective and does not require sample preparation.

The test method works by connecting the VeriPac test systems to a manually operated test chamber containing an IV bag. The next step is to draw a vacuum on the IV bag in the test chamber and observe any changes in the vacuum level. If there is any damage to the package, air or liquid will flow from the package into the chamber, causing pressure fluctuations. On the other hand, defect-free packages do not leak any pressure into the chamber, keeping the chamber vacuum level constant. Regardless of the location of the defect, the vacuum decay system can pick up both large and small defects. It takes about 30 seconds for testing IV bags, repeatable and sensitive to 15 microns for liquid and gas leaks.

Benefits of Vacuum Decay Technology

• Eliminates destructive, subjective testing methods.
• Non-destructive technology.
• Accurate, repeatable results.
• Pass/fail results backed by quantitative test data.
• Eliminates destructive, subjective testing methods.
• ASTM Test Method F2338, FDA Consensus Standard and referenced in USP 1207 Guidelines.
• Meets Annex 1 regulatory guidelines.

Recent regulatory changes have shifted requirements and strategies for container closure integrity. IV bags and flexible parenteral presentations have experienced the greatest impact from these new perspectives on quality. IV bags have always presented a significant risk. New provisions to Annex 1 have made the requirements for quality risk management (QRM) clear, and USP guidance documents outline the need for greater control. Based on the regulatory requirements and guidance, practical solutions for IV bag container closure integrity should offer non-destructive, practical and deterministic approaches to assure integrity. There are critical considerations for IV bag QRM, and strategic approaches to assuring integrity of IV bags and flexible parenteral presentations to satisfy the shifting regulatory environment.

Vacuum Decay is a non-destructive method for testing the integrity of container closures for package integrity and leak path detection. The technology provides quantitative, deterministic, and reliable test results to assure package integrity in comparison to manual inspection and other non-deterministic test techniques. The vast range of package types that may be accommodated by Vacuum Decay technology includes filled and sealed rigid, semi-rigid, and flexible packaging consisting of non-porous or porous materials.

Vacuum Decay Technology

Vacuum Decay is one of the most efficient and accurate vacuum-based leak detection methods. The method operates by placing the package within a properly outfitted evacuation test chamber that contains an external vacuum source. To detect any deviations from a predetermined targeted vacuum level, the vacuum levels are continually monitored. If there is a defect in the packaging, air or liquid will leak into the chamber from the package and cause a change in pressure. On the other hand, non-defective packages do not leak any pressure into the chamber, maintaining the chamber vacuum level constant. The test cycle is quick, non-invasive, and non-destructive to both the product and the container. The Vacuum decay system can detect both major and minor defects, regardless of where they are located. The system has various applications in the field of pharmaceuticals and medical devices.

Applications of Vacuum Decay Technology in Various Industries

• Pharmaceutical

Pharmaceutical products are a range of substances used for treating, diagnosing, or changing organic processes to help the management of public health. Pharmaceutical products are tested to make sure they adhere to strict safety and quality requirements. Previously, pharmaceutical packaging was only subjected to sterility testing. However, the United States has recognized that sterility testing alone is not sufficient to maintain the integrity of pharma products. FDA (Food and Drug Administration) has published guidance related to pharma industry on submission of documentation for sterilization process evaluation in human and veterinary drug products.

Container closure integrity (CCI) testing is a non-destructive package inspection technology for finding leaks and avoiding potential contamination. A test like this is necessary since any defect in the container might allow foreign particles to enter the product and thereby reduce its shelf life. Since it impacts both the product and the patient, a manufacturer places high priority on implementing the proper container closure system. Thus, the relevance of container closure integrity testing in the pharmaceutical industry has increased substantially over time. Vacuum Decay and MicroCurrent HVLD are the most chosen technologies for testing pharmaceuticals.

• Medical Device

Maintaining medical device package integrity is essential to make sure the product is delivered to the end user unharmed. Medical device packaging and delivery options range from rigid non-porous containers to flexible porous packaging. Every packaging format has a different set of characteristics and requirements, so choosing the right inspection technique requires a thorough approach. Package challenges have risen along with packaging format and material innovations. Among all medical equipment, Class III devices produce the greatest risk to maintaining package integrity. These implanted devices preserve or maintain life. Pacemakers, cardiovascular stents, respiratory ventilators, and breast implants are a few examples of Class III medical devices. Since these devices are inserted into human bodies directly, even a small packaging defect puts patient’s safety at risk. Therefore, it is essential to evaluate the container closure integrity of medical devices.

Vacuum Decay Technology Benefits

• Non-destructive, non-subjective and does not require sample preparation.
• Detection of defects down to 0.01 cc/min.
• Results show that they are more accurate than dye ingress.
• Quantitative, deterministic testing technique.
• Supports initiatives for waste reduction and sustainable packaging.
• ASTM test method and FDA recognized standard.

When determining the integrity of pharmaceutical and medical devices, Vacuum decay leak testing is the best non-destructive option. The test measurement generates a reliable and accurate quantitative result, as well as a pass or fail decision. The FDA recognizes the standard Vacuum Decay leak test technique (ASTM F2338) as a consensus standard for evaluating container closure integrity (CCI). The test technique is referenced in the United States Pharmacopeia Chapter on CCI (USP Chapter 1207) and listed in ISO 11607.

Testing Container Closure Integrity (CCI) is crucial for ensuring the quality of Class III medical devices. Class III medical devices are sterile components that are designed to be inserted directly into the human body. These devices often sustain or support life, are implanted or pose an unreasonably high risk of disease or damage. A compromised package can serve as a vehicle for microbial transmission and compromised sterility, leaving patient safety at risk. When bacteria or other impurities enter the container, the device ceases to be a treatment and becomes a danger to the patient. Similarly, a breach of the seal affects the sterility of the device and may present a serious quality concern at a key point of usage.

Testing Challenges in the Medical Device Industry

There are three basic approaches to package integrity testing:

• 100% in-line testing: All products in a batch are tested on a high-speed production line at an acceptable level of CCI assurance.
• Small batch testing: Testing a statistically significant batch size for certain quality parameters and extrapolating to match the quality of the manufacturing lot.
• Testing Offline: Operators test packages individually or in smaller batches.

Dye penetration is a technique for identifying defects in package body and seals that has a variable detection capacity. When carried out correctly, the approach can identify pinholes and channel defects as small as 20 microns. This method is only used to validate the packaging process and offers minimal value to in-process quality monitoring. The method is time-consuming to implement and provides limited information in the effort to ensure the quality of high-risk applications.

For CCI testing, the majority of medical device manufacturers use a 100% in-line manual visual inspection technique. Manual visual inspection has been proved to be one of the least reliable techniques for ensuring quality. The failure of manual visual inspection is caused by a number of factors. According to ASTM test method F1886, a manual visual inspection may detect 75-micron channel defects in a transparent seal 60-100% of the time. Although manual visual inspection can be applied as a 100% test method, performance on the task decreases significantly over time. This method is not applicable if the package format is not transparent or semi-transparent.

How Vacuum Decay and Airborne Ultrasound Technologies are Automated?

Vacuum Decay is a deterministic method proven to offer predictable and reliable results for CCI testing of high-risk package applications. This is an ideal solution for non-porous medical device applications. When the major focus of the inspection is the final seal of a porous package, Airborne Ultrasound is exceptionally efficient and reliable at detecting seal defects that are invisible to the manual visual inspector. Both approaches have shown to be reliable non-destructive testing methodologies, and one or the other can be used for inspection based on the unique features of the product and container.

The automation of each technology looks a little different. Vacuum Decay enables approximately 25 to 50 samples per minute, with low throughput detecting single-digit micron leak sizes. Airborne Ultrasound is a rapid-fire sensor that transmits 1000 pulses per second of sound through the seal. The final seal of Tyvek® pouches and other flexible packaging systems may be scanned at a rate of 20 inches per second (~40 cm/sec), with the capacity to detect the most frequent seal faults and seal quality concerns. Both methods enable a production line to ensure quality while reducing production throughput.

The Airborne Ultrasound technology offered by PTI can be automated in many ways. Basically, the technology can measure the quality of a quantitative seal in any way that the pouch seal can pass through the ultrasound inspection head. Ultrasound can be applied to the production flow, which captures seal quality when exiting a band-sealer or transferring pouches through a production line. Robotic handling may also be used to do a full 360-degree seal inspection on all pouch seals. Airborne Ultrasound has the flexibility to be deployed in a variety of production lines and has high reliability in detecting critical defects.

Vacuum decay is often utilized for both Tyvek® trays and non-porous container types. While a vacuum takes longer to do a test (about 5 seconds on a Tyvek tray), the sensitivity and stability of this technology make it perfect for low output applications with high sensitivity requirements. Robotic handling solutions can serve many test stations at the same time, allowing for increased product throughput without losing sensitivity.

Medical devices are packaged and delivered in a variety of ways, ranging from porous flexible packaging to non-porous rigid containers. The range of product types and packaging options create unique inspection challenges that must be overcome in order to assure seal strength, sterility, and quality. Airborne Ultrasound and Vacuum Decay offer 100% testing capabilities as well as an accurate inspection that includes quantitative test results and a pass/fail result. These new automated technologies, with more sensitive leak detection capabilities, inspect containers at a higher rate.

Pre-filled syringes are becoming more popular as a preferred container closure system for biologics. Pre-filled syringes must offer an inherent barrier that maintains drug product stability and sterility throughout its entire shelf life as a primary container closure system. The ability of the system to retain its microbial barrier integrity must be checked and demonstrated by the drug manufacturers. In 2008, the FDA endorsed CCI testing as part of the sterile product stability protocol.

The pharmaceutical industry has witnessed substantial technical developments in CCI testing in response to rising regulatory demands. MicroCurrent HVLD, Vacuum Decay Leak Testing and Helium Leak Detection are examples of new technologies that have proven enhanced detection capabilities above traditional Dye and Microbial Ingress approaches. Many of the technologies have been employed for CCI testing of drug product stability.

CCI Testing Strategy for Development

Many CCI failure modes can occur throughout the life cycle of a syringe, from component production to drug product filling and sealing, device assembly and packaging, and finally distribution and storage. It is critical to create a comprehensive plan for conducting CCI testing across the whole syringe life cycle.

The creation of the CCI testing technique begins with a detailed study of the construction, design, and manufacturing procedures used in syringes. The failure modes and impacts associated with each aspect of CCI were identified first. The next step was to evaluate whether CCI testing is required, as well as the intended uses and testing frequencies, using a risk-based approach. Knowing that the needle shield compartment seal integrity had been verified by the component supplier, apply a non-routine CCI test to validate its seal integrity during drug product loading and sealing, as well as during device assembly. To ensure CCI was achieved and successfully maintained, implement a complete set of CCI tests across the entire product development cycle for the product-containing syringe barrel compartment.

Method Development and Method Validation

Method development consists of optimizing testing parameters and determining the appropriate pass/fail threshold.

• Testing parameters optimization

Initially, several defect standards of known sizes were examined alongside undamaged samples using varied testing conditions. The relationships between key method parameters and instrument responses to intact and defect samples were comprehensively investigated, with the objective of determining a set of variables that give optimal separation between intact and defect samples. i.e. signal-to-noise ratio or SNR.

• Pass/fail threshold determination

The improved method was utilized to evaluate different lots of filled intact syringes representing relevant product variations, such as drug product batches, and packaging locations and lines, in order to define the preliminary pass/fail threshold. For intact samples, the results of the tests were statistically assessed to determine the instrument baseline and variation (σ). Typically, the pass/fail threshold should be 10 σ higher than baseline. The pass/fail threshold was then further refined and verified by testing defect standards of known sizes.

CCI testing techniques were validated for the pharmaceutical product package. Since the drug product formulation and package design may change during the early development stages, a step-by-step approach was adopted to validate the methods in line with the product development stages. Once product design and packaging design are complete, the methods are fully validated to support CCI testing for initial consistency and process evaluation. The power of the additional long-term method may be further validated before this method is implemented in QC laboratories for routine testing.

During package and pharmaceutical product development and manufacturing, properly selected and verified methodologies are critical for demonstrating container closure integrity. It should be noted that existing CCI testing methods do not provide an optimal solution for all pre-filled syringe CCI testing requirements. To maintain total container closure integrity, an integrated solution involving CCI testing as well as additional engineering and administrative controls is required.