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Parenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants. They are sterile products intended to be administrated directly into human bodies. Parenteral drug products are expected to be free from microorganisms, pyrogenic substances as well as other visible particles. Contaminated parenteral drug products can cause serious health concerns to the patient. Hence, sterility assurance and package integrity testing are of paramount importance in parenteral drug manufacturing. Read on to know more about parenteral products package testing methods offered by PTI.

Parenteral products package testing methods:

1. Vacuum Decay technology

Vacuum Decay technology is a non-destructive Container Closure Integrity test method primarily used to detect leaks in package seals. Proven to be the most practical and sensitive vacuum-based leak test method, Vacuum Decay technology is capable of identifying leaks in sealed rigid, semi-rigid and flexible packaging made of non-porous or porous materials. It provides reliable, accurate and repeatable test results that ensure deterministic package testing and leak detection. Vacuum Decay technology has established itself as a non-destructive alternative to traditional test methods like Water Bath and Dye Ingress, making it a practical solution for leak detection in the Pharmaceutical and Medical Device industry.

How does Vacuum Decay technology work?

The principle behind Vacuum Decay technology is simple and it challenges container integrity based on fundamental physical properties. The test begins by placing sample packages in a closely fitting evacuation test chamber, which is equipped with an external vacuum source. Based on the test sample and level of sensitivity required, a pre-determined vacuum level is chosen for the test. The next step involves evaluating the test chamber and test system dead space for a pre-determined period. Differential pressure transducers are used to monitor changes in vacuum levels for a specified period. A pressure increase beyond the predetermined pass/fail limit indicates container leakage.

Benefits of Vacuum Decay technology

• Non-destructive package inspection system
• Accurate and reliable results
• Definite pass/fail result based on quantitative test data 
• Accommodates multiple packaging formats
• Eliminates destructive, subjective testing methods
• Effective in detecting even minute leaks
• ASTM Test Method F2338, FDA Consensus Standard and USP 1207 compliant
 

2. MicroCurrent HVLD Technology

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 effective 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 is a leading solution of sturdy container closure integrity test 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 USP 1207 Guidance for CCIT

Parenteral product package systems are expected to provide barriers against drug contamination and ensure stability and sterility throughout the entire shelf life. Any defect in packaging can cause microbial contamination, exposure to gases and water vapor, resulting in product deterioration. Furthermore, the industry has seen a spike in demand for combination products and patient-centered drug delivery systems, that present a high level of technical risk for maintaining container closure integrity (CCI). Therefore, container closure integrity testing is an important stage in the sterile drug product lifecycle.

Automated package inspection with VeriPac LPX

As the pharmaceutical industry continues to grow, manufacturers require capable, consistent automated solutions for container closure integrity testing. Automated inspection systems improve package reliability, reduce chances of product recalls and packaging failure.

PTI's VeriPac LPX series are a line of fully automated package quality inspection systems for 100% inline testing. The LPX enables enhanced automated testing that provides a high level of confidence in packaging line performance. Veripac LPX is a practical and reliable solution for the problems associated with performing infrequent testing as well as for recognizing and correcting process-related quality issues.

Sensitivity and reliability go hand in hand with CCI testing. The VeriPac LPX 430.8S is the next generation automated inspection system for container closure integrity testing of parenteral products. Automated for 100% testing or batch release, the VeriPac PLX 430.8S is an eight-station dual chamber design, with robotic testing platform for pre-filled syringes and vials, products filled with lyophilized product, small molecule liquids and Water for Injection (WFI).

The VeriPac LPX features a dynamic robotic design, tailored to fit varied production requirements. LPX Series are scalable, modular solutions to meet production line demands. This adaptable platform provides reliable automated handling of a variety of packaging formats. Applications for LPX automation range from flexible packaging to rigid containers, and parenteral products. Additionally, VeriPac LPX allows easy changeover for testing different size packages on the same system.

Benefits of VeriPac LPX test systems

• Automated testing enables the highest level of container quality assurance
• Self-teach software
• Non-drift transducers for consistent leak detection
• Low false rejects
• Operator friendly
• Reject statistics & test result trends
• 24/7 operation
• Increased productivity
• Reduced downtime
• Low maintenance

Over the years, there has been a steady increase in the demand for pre-filled syringes for injectable drug products that can be self-administered. However, considering the complex nature of pre-filled syringes, Container Closure Integrity assurance can be quite challenging. Container Closure Integrity is understood as the ability of containers to maintain a sterile barrier against possible contamination. A leak or breach in the sterile barrier can rapidly convert a lifesaving drug into a threat for patients. Parenteral products are the highest risk of all packaging formats. Vials, ampoules, and pre-filled syringes have the highest potential for microbial growth, and the risk to the end patient amplifies the focus needed on CCI for these applications.

High Voltage Leak Detection (HVLD) has been in the market for decades. However, PTI’s MicroCurrent technology has revolutionized HVLD. MicroCurrent HVLD  aims to achieve a high level of CCI assurance across the entire range of parenteral products. High Voltage Leak Detection is a deterministic test method included in USP 1207, and is an established and reliable solution for all liquid filled parenteral products.

Pre-filled syringe testing using HVLDmc (E-Scan 655) technology

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 a non-destructive conductivity test method, exposing the package and product to lower voltage than other conductivity-based solutions.

The E-Scan 655 features a fast test cycle and simple operation. It can accommodate a wide range of applications and products, including low conductivity sterile water for injection (WFI) and proteinaceous products with suspensions. The technology uses a non-contact, non-invasive test method that requires no sample preparation. Additional benefit include ability to migrate from laboratory to 100% inline testing applications at high production speeds.

Technology Overview

The E-Scan testing process uses a set of electrode probes to scan a non-conductive container that is sealed. The container material can be glass, plastic, or poly laminate. The container or package must contain liquid (minimum fill 30%). In the presence of a pinhole, crack, or other defects, 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 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

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

Today’s healthcare industry assures treatments that were unimaginable a few years ago. As pharmaceutical industry grows in importance, the techniques of primary packaging for healthcare products, especially parenteral products has taken on new prominence. Common parenteral packaging methods include Liquid-filled containers such as vials, ampoules, syringes, blow-fill-seals and auto-injectors and containers filled with lyophilized products. Since these drugs are directly administered into human bodies, high sensitivity integrity tests are required to ensure product quality throughout its shelf life. For reasons of safety, packaging material, integrity and design are regulated by Food And Drug Administration as strictly as the product itself.

Container Closure Integrity Testing is a leak detection test conducted using a non-destructive packaging inspection system to protect the drug from any possible contamination. It is a crucial step in evaluating safety and integrity of the primary packaging so as to maintain a sterile barrier and to avoid leakage resulting in contamination of the drug. Packaging components like bottles, vials, syringes that are in direct contact with the product are called primary components while aluminum caps, cardboard boxes are secondary components as they are not in direct contact with the product. Proper packaging should be a priority for all drug products, but in case of parenteral products, these concerns amplifies several folds as they are directly injected. Hence initiating a proper container closure system is vital for product and consumer safety.

Although Container Closure Integrity Testing(CCIT) can be performed in many different ways, it can be broadly classified into Probabilistic methods and Deterministic methods. Probabilistic test methods including Microbial Challenge by Immersion, Tracer Liquid Tests (e.g. Dye Ingress), Bubble Tests etc. are traditional test methods where result accuracy may be uncertain. On the other hand, Deterministic test methods like Electrical Conductivity and Capacitance Test (HVLD), Laser-based Gas Headspace Analysis, Mass Extraction, Pressure Decay provide quantitative results with high accuracy. The United States pharmacopeia released guidance in 2016 stating that deterministic methods are preferred over probabilistic test methods.Packaging Technologies And Inspection (PTI’s) Microcurrent HVLD technology and vacuum decay technology are the latest inventions in package integrity testing of parenteral products.

1. Microcurrent HVLD Technology: Microcurrent HVLD is a unique High Voltage Leak Detection Technology, highly effective across all parenteral products. Its Applications include liquid-based products ranging from extremely low conductivity sterile water for injection (WFI) to proteinaceous products with suspensions. Its ability to detect small pinholes, micro cracks and seal defect detection down to single-digit microns makes it an ideal choice for testing parenteral products.

2. VeriPac Vacuum Decay Technology: VeriPac Vacuum Decay Technology, based on the ASTM vacuum decay leak test method (F2338-09) and accredited by the FDA for package integrity testing, is a non-destructive inspection system, capable of defect detection down to 0.002 cc/min. This system is applicable for empty and pre-filled syringes, liquid-filled and lyophilized vials and other flexible and rigid liquid-filled packaging. Depending on the package type and leak test sensitivity needed, appropriate VeriPac model can be selected.

PTI’s next generation PERMA- VAC technology addresses vacuum decay detection at the very core of physical test measurement by controlling the test system volume and maximizing the SNR between good and defective samples. This makes PERMA-VAC the most reliable vacuum-based leak test available in the market.