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As technological advancements lead to an ever-increasing world of routes of administration for new and existing drugs, packaging decisions for such options have become more challenging. There are multiple options for drug delivery container formats, and each should be continuously reviewed with reference to compliance and accuracy of delivery. Packaging is a critical point of concern whenever a new drug product is introduced into the market. When it comes to parenterals, there has been a dramatic increase in these packaging formats over the past 10 years. Apart from typical formats of vial and syringes, dual-chamber devices, cartridges and electronically enabled devices have been introduced, all which demand high levels of packaging accuracy. So how do we ensure the ability of the packages to maintain sterility of the drug? Quality assurance with the proper Container Closure Integrity Test (CCIT) method is critical.

CCI Testing using E-Scan 655 MicroCurrent HVLD

The E-Scan 655 technology utilizes the MicroCurrent conductivity test method to non-destructive evaluate container closure integrity. MicroCurrent technology exposes the package and product to lower voltage than other conductivity based solutions. This unique technology requires no sample preparation and is a non-contact and non-invasive test method. What makes E-Scan 655 technology unique is its ability to test a wide range of liquid-based products including low conductivity sterile water for injection (WFI) and proteinaceous products with suspensions. The system also features a fast test cycle and is simple to operate. Additional benefits include quick product changeover and an easy recipe set up to accommodate a wide range of products and applications. The offline E-Scan 655 method can be migrated from the laboratory to automated 100% inline testing applications at high production speeds.

Testing Procedure

Using a set of electrode probes, E-Scan system tests a non-conductive container that is sealed. The container material can vary from glass, plastic, or poly laminate. The container or package must contain liquid (minimum fill 30%). In case of any defect including pinhole or crack, there will be a resistance differential and change in current flow indicating a breach in the container. The approximate defect location can be identified.

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 <1207> as recommended method for parenteral liquid package integrity testing
• Robust method and approximate 3x Signal-Noise-Ratio for a wide range of product classes and package formats
• Simplifies the inspection and validation process

Packaging is an essential part of the pharmaceutical industry, given the sensitive nature of the contents. High-risk medications and lifesaving drugs need utmost care and protection until they reach the patient. As such, stringent industry standards apply to pharmaceutical packaging. Manufacturers give high priority to safety and quality while selecting packaging materials for a drug or healthcare product. The packaging should be able to act as a barrier against external contamination and chemical reactions. Exposure to reactive gases can alter the physical, chemical and biological attributes of the products. This makes Container Closure Integrity Testing of pharmaceutical packaging a regulatory requirement.

Role of MicroCurrent HVLD in ensuring pharmaceutical package integrity

Often referred to as the conductivity and capacitance test, High Voltage Leak Detection (HVLD) is a test method found to be highly effective in detecting the presence and location of leaks in a wide range of pharmaceutical and parenteral applications. It can be used for leak testing in nonporous, rigid or flexible packages, as well as packages containing liquid or semi-liquid products. High Voltage Leak Detection test is conducted using electrical conductivity and resistance principle. This method operates by passing high voltage micro current signals through sample packages. Under the presence of a leak, the electrical resistance of the sample declines, causing an increase in current. Compared to other leak detection methods that rely on flow of gas or liquid, HVLD technology relies on “flow” of current. This reduces challenges with defect clogging compared to flow-based analysis.

The latest evolution of HVLD, PTI’s patent pending MicroCurrent technology, aims to achieve a high level of CCI assurance across the entire range of pharmaceutical products. The MicroCurrent HVLD reduces voltage exposure to the product to less than 5% of the voltage exposure experienced when testing with comparable HVLD solutions. Reducing exposure voltage not only reduces any risk that the voltage poses to the product, but also greatly reduces the production of Ozone during operation when compared with traditional HVLD solutions. Ozone in the headspace of a container can be detrimental to the product, and in the operating environment can affect respiratory health.

Benefits:

Container closure integrity may be understood as the ability of container closure systems to maintain a sterile barrier against possible contaminants that can deteriorate the quality of the final product. Even a microscopic leak or breach of the sterile barrier can cause external contaminants to enter the product and compromise its healing properties. Parenteral products are at the highest risk of all package formats. Vials, ampoules and prefilled syringes have the highest potential for microbial growth, and the risk to the end patient amplifies the focus needed on CCI for these applications. Although dye ingress and microbial ingress are common leak testing methods, they are proven to provide subjective results that lack accuracy. Hence regulatory bodies have instructed a shift towards more deterministic test methodologies that can be controlled, calibrated and provide a definitive determination of CCI.

High Voltage Leak Detection (HVLD) is an effective Container closure integrity technique for non-destructive package inspection of non-porous pharmaceutical and parenteral products. This technology operates on the simple property of electrical current. The latest evolution of HVLD, PTI’s patented MicroCurrent HVLD technology , aims to achieve a high level of CCI assurance across the entire range of parenteral products. It can precisely detect any leak in a wide range of liquid- filled products including extremely low conductivity sterile water for injection (WFI) and proteinaceous products with suspensions. The MicroCurrent HVLD reduces voltage exposure to the product to less than 5% of the voltage exposure experienced when testing with comparable HVLD solutions. Reducing exposure voltage not only reduces any risk that the voltage poses to the product, but also greatly reduces the production of Ozone during operation when compared with traditional HVLD solutions.

How does MicroCurrent HVLD technology work?

Under this method, the container is scanned by the high voltage probes. High voltage is applied to one side of the container and a ground probe on the opposing side. If the package has 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 vial. If there is a micro-leak or crack in one of the container walls, the break-down resistance is reached and the current passes through. HVLD is the only leak detection technology that does not require mass to pass through a defect site, requiring only the passage of electricity through a crack. This characteristic makes HVLD sensitive to leaks in which most leak test solutions cannot identify. Applications of High Voltage Leak Detection Technology include testing of the following package formats:

• Pre-filled syringes
• Ampoules
• Drug product cartridges
• Liquid filled vials

Benefits of MicroCurrent HVLD:

• Deterministic, non-destructive, non-invasive
• High level of repeatability and accuracy
• Ideal package integrity solution for parenteral products
• Low voltage exposure to the product and environment
• Offline and 100% online inspection at high production speeds
• Referenced in USP 1207 guideline

Often described as the driving force of pharmaceutical industry, biologic drugs have the ability to address chronic diseases, unmet medical needs and comprise of more than half of the drugs in development. These are generally large complex molecules, derived from human, animal, or microorganisms through biotechnology. Examples include blood components, cells, vaccines, tissues, and recombinant proteins. The ability of biological drugs to treat life threatening diseases coupled with aging population has lead to tremendous growth in the global biological drugs market. However, the rapid growth of biological products has also increased packaging challenges to deliver safe and effective products.

Drug contamination is a serious concern in any medical industry; however, for biologics, it amplifies several folds because they are used to treat serious illnesses and chronic conditions. Contamination has a direct impact on product stability resulting in reduced shelf life and efficacy. Along with maintaining an acceptable shelf-life, there are other challenges too. Another important factor that can affect the quality of a drug is environmental conditions. For example, if a product is exposed to extreme temperature during transit, the product quality may be compromised. A biologic can also lose its stability if it’s unable to withstand variations in light and chemicals that it might encounter. Therefore, in order to cover packaging challenges associated with biological products, ensuring its container closure integrity is crucial.

Ensuring package integrity with PTI’s MicroCurrent HVLD technology

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

Benefits of PTI’s MicroCurrent HVLD technology

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

Ensuring pharmaceutical package integrity has always been a priority for drug product manufacturers. However, over the past few decades, innovations in health care sector have also accelerated pharmaceutical package integrity challenges. Although testing package quality of all healthcare products is important, in the case of parenteral products it is amplified significantly. Parenteral products are defined as injectible products that can be either liquid or powders. Solutions can contain suspensions, emulsions and be proteinaceous in nature. ”. Since these drugs are directly administered into human bodies, ensuring complete integrity of such packages is crucial. Common packaging formats for parenteral products include Liquid-filled containers such as vials, ampoules, syringes, BFS and auto injectors; Lypholized (powder) products are often packaged in vials. Even a minute breach in the package can cause microbial contamination leading to product deterioration. Hence ensuring container closure integrity is a critical process in the life cycle of parenteral products.

What is HVLD Methodology?

High Voltage Leak Detection (HVLD)) is a non-destructive Container Closure Integrity Test (CCIT) method used primarily to evaluate closure integrity of parenteral product packaging. HVLD technology makes use of quantitative electrical conductivity measurement principles. This method operates by passing high voltage micro current signals through sample packages. Under the presence of a leak, the electrical resistance of the sample declines, causing an increase in current. Applications of High Voltage Leak Detection Technology include testing of the following package formats:

• Pre-filled Syringes
• Ampoules
• Drug Product Cartridges
• Liquid Filled Vials
• Blow-Fill-Seal (BFS) Container

PTI’S MicroCurrent HVLD technology has revolutionized the conventional HVLD method. MicroCurrent HVLD is a non-destructive, non-invasive CCI technique that can be applied to a wide range of liquid filled products including low conductivity sterile water for injection (WFI) and highly proteinaceous drug products within suspensions. PTI’s E-scan HVLD, a highly sensitive CCI testing process uses electrode probes to scan sealed non-conductive containers. Under the presence of a leak, there will be a change in current flow indicating a defect in the container along with its approximate location. This unique technique uses about 50% less voltage and exposes the product and environment to less than 5% of the voltage. An important feature of E-scan HVLD is its ability to easily shift from the laboratory offline to 100% inline testing applications. With the capability to accommodate multiple packaging formats including glass, plastic or poly laminates, it is an ideal solution for parenteral package testing.

Benefits of MicroCurrent HVLD:

• Deterministic, non-destructive, non-invasive
• High level of repeatability and accuracy
• Ideal package integrity solution for parenteral products
• Low voltage exposure to the product and environment
• Offline and 100% online inspection at high production speeds