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High-risk pharmaceutical products refer to medications and substances that, due to their nature or intended use, pose a higher level of risk to patients and the public. These products often include injectable drugs, biologics, vaccines, and other sensitive formulations that require stringent quality control measures to ensure patient safety and regulatory compliance.

The packaging of high-risk pharmaceutical products presents unique challenges due to the need for exceptional product protection, stability, and, most importantly, containment of the product to prevent contamination. As these products are often administered directly into the body, maintaining the integrity of the container closure system is critical to prevent microbial ingress, oxygen exposure, and other factors that could compromise the drug's efficacy and safety.

Container Closure Integrity (CCI) testing is a vital process within the pharmaceutical industry to verify that the packaging of a product effectively prevents any leakage or contamination. This testing is crucial in ensuring that the pharmaceutical product maintains its integrity throughout its shelf life, safeguarding patient safety and therapeutic efficacy.

MicroCurrent HVLD Technolgy for Testing Integrity of High-Risk Pharma

PTI's MicroCurrent HVLD technology represents a non-destructive and non-invasive approach to testing the container closure integrity (CCI) of various liquid-filled products, including pre-filled syringes, vials, cartridges, ampoules, blow-fill-seal (BFS) containers, bottles, and pouches. This method has proven to be highly effective in ensuring the integrity of container closures in diverse applications.

The technology employs electrode probes to scan sealed containers, aiming to detect any potential leaks. By analyzing changes in the current flow, both the existence of defects in the container and their approximate locations can be identified with precision. This makes the MicroCurrent HVLD technology particularly versatile, capable of detecting leaks in a wide range of liquid-filled products, even those with extremely low conductivity, such as sterile water for injection (WFI) and proteinaceous products with suspensions.

One notable advantage of MicroCurrent HVLD is its efficiency in terms of voltage usage. It utilizes approximately 50% less voltage compared to conventional HVLD solutions, contributing to a more energy-efficient and environmentally friendly testing process. Moreover, the reduced voltage exposure (less than 5% compared to traditional methods) minimizes potential risks to both the product and the testing environment.

Benefits of MicroCurrent HVLD:

• Deterministic, non-destructive, non-invasive, non-subjective
• High level of repeatability and accuracy
• Ideal package integrity solution for liquid filled parenteral products
• Low voltage exposure to the product and environment
• Offline and automated online inspection
• Referenced in USP 1207 guideline

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.

High Voltage Leak Detection (HVLD) of pre-filled syringes, vials, cartridges, ampoules, BFS, bottles and liquid filled pouches detects pinholes, micro-cracks, stopper/plunger leaks, non-visible leaks under crimping and many other defects. The HVLD testing procedure also guarantees the security of the product seal by finding tiny pinholes, micro fractures and screen defects that are not visible. Eventual packing defects lead to resistance differential and changes of current flow in the container and the approximate position of the fault. It is also one of the most affordable methods for testing container closure that requires little adjustments to the infrastructure. This technology is not invasive and does not require preparation of the sample. It is one of the most powerful CCI technologies for all biological and parenteral goods

E-Scan HVLD has a high-speed test cycle, produces highly reproducible results and is easy to handle. Fast changeover and easy adjustments of test parameters for various goods and applications are further advantages. Another advantage of the HVLD technique is that it can readily be moved from the laboratory offline to 100% online testing applications at high production speeds. That is an enormous benefit and makes the inspection and validation procedure globally simpler. E-Scan employs a number of electrode probes to scan a sealed container which is not conductive. Glass, plastic or poly laminate might be the container material.

Working principle of MicroCurrent HVLD technology

In non conductive or semi-conductive packing materials, HVLD works by implementing high voltage potential for electrically conductive goods. When electrical discharges between goods and device electrodes are observed, the pinholes are determined. The two container walls (high voltage side and ground side) offer complete electric resistance when the package is not leaked, and no significant current is detected by flash. If one of the container walls has a microleak or fracture, the barrier to breakup is met and the current passes. HVLD is the only technique for leak detection that requires a crack site without mass, needing just the flow of electricity via a crack. This feature sensitises HVLD to leaks that are not identified by typical leak test systems.

Applications of MicroCurrent HVLD

• Pre-filled syringes
• Vials
• Cartridges
• Ampoules
• BFS
• Bottles
• Pouches

Advantages of MicroCurrent HVLD

• High level of repeatability and precision
• Deterministic, non-destructive, non-invasive
• Product and environmental low voltage exposure
• Offline and 100% online testing at high production speeds
• Simpler inspection and validation procedure
• Most powerful CCI technology for all parenteral and biologic products
• Robust method and approximate 3x Signal-Noise-Ratio for a wide range of product classes and package formats