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In the pharmaceutical industry, the integrity of packaging plays a pivotal role in ensuring the safety, efficacy, and quality of medications. Packaging serves as a barrier that protects pharmaceutical products from external factors, such as moisture, air, light, and contaminants, which could compromise their stability and effectiveness. Ensuring the integrity of pharmaceutical packaging is not only crucial for regulatory compliance but also for maintaining patient safety and confidence in the products.

Traditional methods of package testing often involve destructive techniques, where samples are opened, punctured, or otherwise altered for assessment. However, these methods come with inherent drawbacks, including product wastage, the need for additional samples, and prolonged testing times. To address these challenges, the pharmaceutical industry has increasingly turned to non-destructive methods for package integrity testing.

What are the Non-destructive Methods Used for Pharmaceutical Package Testing?

Vacuum Decay Technology

Vacuum decay is a non-destructive Container Closure Integrity Test (CCIT) that provides reliable, repeatable, reproducible, and accurate results along with clear pass/fail quantitative data. The basic idea of Vacuum decay technology is to question the integrity of containers based on their fundamental physical properties. Sample packages are initially placed within a tightly sealed evacuation test room with an external vacuum source. Based on the test sample and the needed level of sensitivity, a predetermined vacuum level is selected. The test chamber and test system dead space must be evacuated after that for a certain period of time. To monitor variations in vacuum level over time, differential pressure transducers are utilized. The container is leaking if the pressure rises over the designated pass/fail limit.

Volumetric Imaging Technology

Non-destructive leak detection of blister packages is done using OptiPac One-Touch Tool-less technology. The OptiPac uses volumetric imaging technology to monitor the movements of a blister package while it is under vacuum in order to identify leaks. The interface is practical and simple to set up with new blister package forms, necessitating no tooling changeover or significant parameter revisions as with previous non-destructive blister package inspection systems. In response to different cavity shapes, sizes, and combinations of various blister pack types, the system gathers volumetric data from each cavity.

Airborne Ultrasound Technology

Airborne ultrasound is a deterministic test technique for seal quality inspection in materials including aluminum, foil, paper, plastic, poly, film, and Tyvek. It has been proven to be one of the most effective non-destructive testing techniques for flexible package seals. According to studies, conventional seal inspection methods are ineffective because they miss undetectable defects and incorrectly reject pouches that are tightly sealed. On the other hand, Airborne ultrasound technology has been successful in both online and offline solution options. Airborne ultrasound is a typical test method for evaluating seal quality and integrity in accordance with ASTM F3004-13.

Microcurrent HVLD technology

High Voltage Leak Detection, often known as HVLD, is a deterministic, non-destructive leak detection technique used to evaluate the Container Closure Integrity of vials, cartridges, and other liquid-filled parenteral products. It is one of the most efficient approaches for online container closure testing. MicroCurrent HVLD uses around 50% less voltage and exposes the product and environment to less than 5% of the voltage when compared to standard HVLD systems. This technique doesn't require sample preparation and is non-invasive. Pre-filled syringe testing is one of the main uses of MicroCurrent HVLD, along with vial leak testing.

Non-destructive Package Integrity Testing Method Benefits

Non-destructive package integrity testing holds significant importance in the pharmaceutical industry due to the critical nature of pharmaceutical products and the strict regulatory requirements in place. Here are some key benefits of using non-destructive package integrity testing in the pharmaceutical industry:

• Product Safety: Ensuring the integrity of pharmaceutical packaging is paramount for product safety. Non-destructive testing methods can identify leaks, defects, or breaches in packaging that could lead to contamination, spoilage, or compromised efficacy of the medication.
• Regulatory Compliance: The pharmaceutical industry is heavily regulated to ensure patient safety and product quality. Non-destructive package integrity testing helps companies meet regulatory requirements outlined by agencies such as the FDA (U.S. Food and Drug Administration) and other international regulatory bodies.
• Reduced Risk of Contamination: Non-destructive testing methods can detect micro-leaks or breaches in packaging that may not be immediately visible to the naked eye. This reduces the risk of contamination from external factors like air, moisture, or pathogens.
• Preservation of Sterility: Many pharmaceutical products require a sterile environment to maintain their efficacy and safety. Non-destructive testing ensures that the packaging's sterile barrier is intact, preventing any potential breach of sterility.
• Enhanced Product Quality: Maintaining package integrity helps prevent degradation of pharmaceutical products caused by exposure to light, moisture, or air. This ensures that medications maintain their intended potency and effectiveness.
• Cost Efficiency: Non-destructive testing methods save costs by preventing the need for destructive testing, which would require additional samples for analysis. This also reduces the need for retesting, minimizing waste and resource consumption.

As the demand for stringent quality control and regulatory adherence in the pharmaceutical sector continues to grow, understanding the nuances of non-destructive package testing methods becomes essential. By adopting these innovative techniques, pharmaceutical manufacturers can uphold their commitment to patient safety, product efficacy, and overall excellence in the field.

Combination products are medical devices that combine two or more different types of medical products (e.g., a drug-device combination or a biologic-device combination) into a single entity. These products present unique challenges in terms of design, development, and regulatory approval due to the integration of different technologies and functionalities. Therefore, it is crucial to use appropriate techniques to evaluate combination product’s safety, efficacy, and overall performance.

The FDA's Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) developed the "Guidance for Industry and FDA Staff - Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology" to help manufacturers evaluate combination products containing nanomaterials. While this guidance specifically addresses nanotechnology, many of the concepts and principles apply more broadly to evaluating combination products.

What are the three main categories of combination products?

Combination products are categorized into three main types based on their primary mode of action.

1.Drug-Device Combination Products: These products combine a drug and a medical device into one single entity. The drug and device components work together to achieve the intended therapeutic effect. An example of this type of combination product is an auto-injector that contains a drug and a delivery device.

2. Biologic-Device Combination Products:These products combine a biological product (such as a vaccine, cellular therapy, or tissue product) with a medical device. The device is integral to the administration or use of the biological product. An example of this type of combination product is a pre-filled syringe containing a biological medication.

3. Drug-Biologic Combination Products: These products combine a drug and a biological product. This category is less common than the others, but it involves combining a drug with a biologically sourced material. An example of this type of combination product is a drug formulated with a growth factor derived from human tissues.

Combination Products Quality Control Techniques

Microcurrent HVLD technology

MicroCurrent High Voltage Leak Detection (HVLD mc) is a non-destructive container closure integrity testing method that has been proven to be significantly more effective in identifying leaks in various types of parenteral and pharmaceutical applications. It may be used to check for leaks in nonporous, rigid, or flexible packaging as well as packaging that contains liquids. Tests for high voltage leak detection are carried out using electrical conductivity and resistance theories. This method operates by transmitting high voltage, low current impulses through sample packages. When there is a leak, the electrical resistance of the sample falls, causing an increase in current. HVLD technology depends on the "flow" of current, compared to conventional leak detection methods that depend on the movement of gas or liquid.

MicroCurrent HVLD Applications

• Vials
• Ampoules
• Cartridges
• Pre-filled Syringes
• BFS

Helium Leak testing

Helium leak detection is a method for finding leaks in a variety of sealed or enclosed systems by utilizing helium as a "tracer" gas. It is a CCI technique used to evaluate the integrity of critical injectable or parenteral products. Since helium is non-toxic, non-flammable, and non-condensable, helium gas is a great option for tracer gas. Helium is present in the atmosphere in amounts of little more than 5 ppm, making minor leaks easy to pass through. Helium is also more readily available and less expensive than other tracer gases, available in a variety of cylinder sizes. The test is performed by attaching the test component to the leak detector, which is then filled with helium gas. Helium escapes from the test components when there is a leak, and this partial pressure is measured, with the results shown on the meter.

Benefits of Helium Leak Testing

• Practical and sensitive flow-based leak test method,
• Enables the discovery of extremely small microleaks.
• Detects leaks with sensitivity level as low as 1x10-10 mbar L/sec.
• Helium is a non-explosive, non-toxic and non-destructive tracer gas.
• Applicable across package design, failure analysis, packaging line setup and validation.
• A faster test cycle reduces cost and total processing time.

The specific techniques and requirements for evaluating combination products may vary depending on the nature of the product (e.g., drug-device vs. biologic-device) and the intended use. Manufacturers are encouraged to engage in early communication with regulatory authorities to clarify the requirements and expectations for their combination product. Additionally, seeking the expertise of professionals with experience in evaluating combination products can be beneficial throughout the development and approval processes.

The pharmaceutical industry has witnessed a remarkable surge in the use of pre-filled syringes, offering convenient and precise drug delivery for patients worldwide. As the demand for these pre-filled syringes continues to grow, the need for robust quality control and inspection processes becomes increasingly paramount. Traditional manual inspection methods have limitations in terms of efficiency, accuracy, and scalability, paving the way for innovative solutions that can meet the stringent demands of the modern pharmaceutical landscape.

Robotic inspection of pre-filled syringes is a cutting-edge technology that holds the potential to revolutionize the quality assurance process in pharmaceutical manufacturing. Robotic inspection systems offer the advantages of precision, speed, and consistent performance, addressing some of the most critical challenges associated with conventional inspection methods. This novel approach aims to enhance product safety, improve quality control, and streamline the production process, ultimately benefiting both pharmaceutical companies and, more importantly, patients.

What are the Challenges Associated with Robotic Inspection of Pre-filled Syringes?

Robotic inspection of pre-filled syringes present various challenges that are important to address to ensure the safety and quality of pharmaceutical products. Some of the key challenges associated with robotic inspection of pre-filled syringes include:

• Fragility of syringes: Pre-filled syringes are delicate and can be prone to breakage or damage during the inspection process, especially when handled by robots. Ensuring gentle and precise manipulation by the robotic systems is crucial to avoid any product loss or compromise.
• Contamination risk: Maintaining a sterile environment is crucial in the pharmaceutical industry. Robotic inspection systems need to be designed and maintained carefully to prevent any potential contamination from the robot itself or the inspection environment.
• System validation and compliance: Robotic inspection systems used in the pharmaceutical industry must adhere to strict regulatory standards and guidelines. Validating the robotic inspection system and ensuring compliance with regulatory requirements can be a complex and time-consuming process.
• Cost considerations: Implementing robotic inspection systems can involve significant upfront costs. Pharmaceutical companies must carefully evaluate the cost-effectiveness and return on investment of such systems.
• Flexibility and adaptability: The pharmaceutical industry may introduce new products or modify existing ones over time. Robotic inspection systems must be flexible and adaptable to accommodate these changes without significant reconfiguration or reprogramming.

E-Scan RTX Robotic Test System

The E-Scan RTX platform is a fully automated system that uses MicroCurrent HVLD technology to test the container closure integrity of pre-filled syringes. It is a reliable and versatile solution that can be customized to fit your production needs.

The system uses a robotic arm to pick up syringes from a conveyor belt and rotate them through two test stations. The first station checks for needle shield defects, and the second station inspects the rest of the syringe body. The test results are automatically generated and indicate whether the syringe is passed or failed. The adjustable failure reference allows you to set the LOD (limit of detection) for the test. This means that you can customize the test to be more or less sensitive, depending on your specific requirements. After the test, the syringes are automatically loaded back to the tray or a reject tray.

Here are some specific benefits of the E-Scan RTX platform:

• It is fully automated, which can help to improve efficiency and accuracy.
• It uses MicroCurrent HVLD technology, which is a sensitive and reliable method for detecting leaks.
• It is versatile and can be customized to fit your production needs.
• It is easy to use and maintain. .

Robotic inspection of pre-filled syringes presents a promising path forward for the pharmaceutical industry, offering unprecedented levels of accuracy, efficiency, and compliance with regulatory standards. By harnessing the power of robotics, pharmaceutical companies can elevate their quality control processes, uphold their commitment to patient safety, and stay ahead in an increasingly competitive market.

Leak testing is an essential process in the pharmaceutical industry to ensure the safety and quality of the products. The purpose of leak testing is to detect any leaks or defects in the packaging, that could compromise the integrity of the product.

There are different methods of leak testing available, and the choice of method depends on various factors, including the type of packaging, the product being packaged, and the desired sensitivity of the test. Some of the commonly used methods for leak testing in the pharmaceutical industry are:

Vacuum Decay Technology

Vacuum Decay is a non-destructive container closure integrity test (CCIT) method that focuses on package integrity and detecting leak paths. Compared to manual inspection and other non-deterministic test methods, Vacuum Decay measurements offer deterministic and reliable test results to ensure package integrity. Vacuum Decay technology can accommodate a wide variety of packaging formats, including filled and sealed rigid, semi-rigid, flexible, non-porous or non-porous materials. This test works by placing packages in a well-equipped evacuation test chamber with an external vacuum source. Vacuum levels are continuously monitored to detect any deviations from predetermined targeted vacuum levels. A defect in the package can cause air to escape from the package into the test chamber. On the other hand, defect-free packages hold in air by maintaining a constant chamber vacuum level. Vacuum Decay technology has proven over the years to be one of the most practical and sensitive vacuum-based leak detection solutions.

MicroCurrent HVLD Technology

High Voltage Leak Detection (HVLD) is a non-destructive container closure integrity test (CCIT) for evaluating parenteral product packaging integrity. The concepts of quantitative electrical conductivity measurement are used in HVLD technology. HVLD is based on the fundamental nature of electric current. The package barrier must be non-conductive and prevent the flow of electricity, while the package contents must generally be able to carry voltage. The container is placed horizontally on the rotating stage. As the container rotates, a high voltage is applied to one side, and a ground probe is attached to the opposite side. If the package does not leak, the two container walls (high voltage and ground) offer complete electrical resistance and will not record significant current as it travels through the bottle. Breakdown resistance is encountered if there is a micro-leak or crack in one of the container walls and the current passes through. Examples of high-voltage leak detection technology applications include pre-filled syringes, ampoules, drug product cartridges, liquid-filled vials, and blow-fill-seal (BFS) containers.

Force Decay Technology

Force Decay is a quantitative leak detection method that works particularly well with low-headspace packaging. Non-porous materials such as foils, laminates, and films can be used for packaging types. Since it is a non-destructive test procedure, the sample packets are not harmed or changed. Packages do not need to be discarded away when the test is over; they can be added back to the batch. The test system use nested tooling to place the package in the same place and to prevent unmeasured extension of the package under test. Once the test is started, a vacuum is drawn onto the test chamber, which causes the package to expand inside the chamber. The ASTM F2338 vacuum decay leak test technique monitors vacuum levels during the test cycle to evaluate the package. The expansion of the package being tested applies force to the VeriPac force measurement system.

Volumetric Imaging Technology

OptiPac Leak Detection System is one of the deterministic non-destructive package integrity test solutions made especially for blister packs. The One-Touch Technology used in the design and engineering of OptiPac allows for a quick test cycle without the need for sample preparation or changeover. Depending on the size of the blister cavity, this unique technique can quickly identify defects less than 5 microns. Although the OptiPac system employs similar concepts to those used in a vacuum-based blue dye test, it uses controlled inputs and monitored outputs without the hassle and reliability issues of the dye ingress technique. To identify leaks, OptiPac use volumetric imaging technology to measure the motion of a blister package while it being vacuumed.

It is important to note that leak testing should be done at various stages of the packaging process, including before and after filling, and during storage and transport. Proper leak testing can help ensure that the pharmaceutical product is safe and of high quality, which is crucial for patient safety.