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A contract development and manufacturing organization (CDMO) is a company that provides drug development and manufacturing services. Pharmaceutical companies collaborate with CDMOs to outsource drug development and manufacturing. CDMOs can handle the entire process of medication research and production, and they also deal with clients who want to outsource specific steps in their workflow and manufacturing.

Pharmaceutical businesses increasingly depend on CDMOs to handle the complicated requirements of drug research and production. Having a CDMO partner can be a great resource with many advantages for pharmaceutical companies to focus their efforts and resources on initiatives that move their company forward, whether it's navigating the highly regulated drug development framework required by the FDA or scaling production to meet deadlines and demand.

Quality assurance is a key concern for prospective clients when choosing a CDMO because strict quality control procedures are what makes the difference when it comes to protecting a product on its journey to the patient.

The packaging of a drug is a crucial element in preserving its quality since it protects both the product and the manufacturer's commitment to patient safety throughout the product's life cycle till delivery. Container closure integrity testing (CCIT), in accordance with USP 1207>, provides confirmation of a package's capacity to prevent loss and maintain product sterility. ¹ However, a lack of knowledge of CCIT could put a CDMO at a disadvantage when compared to rivals that have adopted advanced CCIT solutions that cater to the particular needs of the goods of their clients. As a result, it's critical that CDMOs have a thorough understanding of CCIT.

Container Closure Integrity Testing Methods Offered by PTI.

Pharmaceutical packaging innovation has paved the way for a diverse range of advanced technologies and materials that enable drug manufacturers to design container and closure systems based on the unique properties of their products.

Traditional leak testing methods, such as the dye ingress leak test and the water bath, have been commonly used methods, but their test results are highly subjective. Since some items, like cell and gene therapy treatments, are only produced in small amounts, manufacturers cannot take the chance of the dye ingress leak test being detrimental to the product itself.

Probabilistic methods rely on a series of sequential and/or simultaneous events, each associated with uncertainties, yielding random outcomes described by probability distributions. On the other hand, deterministic approaches produce objective quantitative data by following a predetermined course of events, and leakage is detected using physiochemical technologies that are simple to regulate and monitor. PTI offers a wide range of non-destructive container closure integrity test methods applicable across a wide range of industries.

PTI's goal is to help our clients succeed by delivering on the promise of science through exceptional CCIT solutions. Life-changing products rely on dependable, high-quality delivery systems that can withstand the rigors of the journey from the lab to the patient.

That is why our experts are committed to providing strong CCIT through exceptional engineering and an organizational drive to achieve our own purpose and mission. We recognize the importance of our role in delivering safe and effective products and are excited about the opportunity to collaborate with you to advance the future of medicine.

As pharmaceutical products leave the laboratory for distribution, they may be exposed to certain conditions that put their integrity at risk. Product quality deterioration and economic losses may be caused due to extreme temperatures or shocks during transportation. Pharmaceutical package inspection is vital to identify and control materials that may alter the protective capacities of packaging. Container Closure Integrity Testing of pharmaceuticals is performed with the purpose of guaranteeing the safety of the products during its distribution and storage lifecycle until delivery to the patient. CCIT helps in determining the integrity and stability of packaging or container until the point of delivery.

CCI testing using Vacuum decay technology

To guarantee integrity and consistency of packages, the ability to precisely detect leaks and defects is necessary. Although destructive Container Closure Integrity Testing (CCIT) methods like water bath, dye tests, peel and burst tests can detect leaks, they are time-consuming, unreliable and produce subjective test results. Additionally, they generate significant product loss and wastage. Over the years industry has seen an increasing demand for non-destructive package integrity testing methods. One such method is Vacuum Decay technology.

Vacuum Decay is a test method that has been proven over decades as the most practical and sensitive vacuum-based leak test method. It is a simple test method that challenges container integrity based on fundamental physical properties. Vacuum Decay technology creates reliable and accurate quantitative results with a pass or fail determination and has been established as a non-destructive deterministic alternative method to the blue dye test. The standard vacuum decay leak test method (ASTM F2338), developed using PTI's VeriPac instruments, is recognized by the FDA as a consensus standard for container closure integrity (CCI) testing. The test method is listed in ISO 11607 and referenced in the United States Pharmacopeia Chapter on CCI (USP Chapter 1207)

How does Vacuum Decay Technology work?

Under this method, the leak testers are first connected to a test chamber that is specifically designed to hold the package to be tested. Vacuum is applied to the package placed inside the test chamber. Using single or dual vacuum transducer technology test chamber and level of vacuum are monitored along with a 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. This inspection method is suitable for laboratory offline testing and can be designed for manual or fully automated operation. The test cycle is non-destructive to both product and package and takes only a few seconds. It provides significant savings by not wasting products for a leak test and generates a return on investment in under six months for many products.

Key Benefits of Vacuum Decay technology

• Non-destructive and non-invasive
• No sample preparation
• ASTM approved test method
• FDA Recognized Consensus Standard
• Allows for increased sampling
• Quantitative results
• Repeatable
• Rapid test time
• Eliminates cost and waste of destructive testing
• Test results can be easily validated
• SPC laboratory testing or online applications

Sterility testing of pharmaceutical products is crucial to ensure that drugs and other biopharmaceutical therapeutics are actually sterile and safe for human use. No pharmaceutical drug can be released into the market without appropriate sterility testing. Pharmaceutical drug products often contain complex active ingredients that stress the importance of sterility and CCI testing. Even a minute breach in the package can cause moisture, air, or other harmful substances to enter the product- thus compromising its healing properties. Moreover, a contaminated drug product can cause serious health issues to the user, making it more of a threat than treatment. Hence, ensuring container closure integrity holds high relevance.

Ensuring Package Sterility with Vacuum Decay Technology

Vacuum Decay is a non-destructive CCIT method that has been proven over decades and improved with new technology innovations. The test method is simple in principle and challenges container integrity based on fundamental physical properties. 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.

Being a non-destructive test method, it provides significant savings by not wasting product for a leak test and generates return on investment in under six months for many products. Vacuum Decay technology has established itself as a non-destructive alternative to the blue dye leak test. The standard vacuum decay leak test method (ASTM F2338), developed using PTI's VeriPac instruments, is recognized by the FDA as a consensus standard for container closure integrity (CCI) testing. The test method is listed in ISO 11607 and referenced in the United States Pharmacopeia Chapter on CCI (USP Chapter 1207).

Overview of PTI’s VeriPac Vacuum Decay Technology

PTI's improvements in the form of VeriPac test systems have raised a bar for excellence and performance reliability in terms of non-destructive package testing equipment. Its ability to detect leaks down to the sub- micron level and identify process issues before they become critical has made it an ideal choice for pharmaceutical package integrity. The next generation of VeriPac systems combines both technological innovation and practical adjustments to current technology to make it the most sensitive and versatile vacuum-based leak detection technology to date. Through the introduction of unique test cycles, pneumatic controls and processing algorithms, the VeriPac technology is establishing itself as the foremost vacuum-based leak detection technology.

Benefits of Vacuum Deacy Technology

• 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

What is VeriCon Technology?

VeriCon system encompasses a complete line of leak testers for empty bottles and containers. It is a powerful leak detection system that operates round-the-clock to ensure high leak test sensitivity with the capability to measure down to 200 microns. Under this process, the container is filled with pressure to a certain level. The rate of pressure decay is analyzed and measured which corresponds to pressure within the container. The operating panel displays pass/fail results and the defective container is rejected from the line . With PTI’s VeriCon technology, users can choose from a wide range of leak tester configurations, according to different container specifications. Its applications include plastic, blow molding, food, beverage and pharmaceutical industries. VeriCon technology works well for small, medium to large size containers and has inspection rates upto150 bottles/min. range. According to Heinz Wolf, general manager, Packaging Technologies and Inspection “In addition to the basic inspection economics of identifying leaking containers and minimizing false rejects, VeriCon systems offer many additional advantages that increase overall operational efficiency. The Auto-learn feature for example, automates setup of accept/reject criteria. Real time inspection data with reject statistics and test result With reject statistics & test result trends, VeriCon technology ensures on demand analyses of container quality.”

VeriCon technology can be implemented using pressure decay or vacuum decay technology. Plastic containers of almost all sizes use pressure decay technology. In situations where due to specific characteristics of the container, pressure decay technology is not capable of detecting leaks, Vacuum decay technology is applicable. Depending on the line speed/hole size requirement, VeriCon testers are available in one to four station configurations.

VeriCon Configurations

• Trimmer mount: available in single and dual station configurations, VeriCon trimmer mount systems are designed precisely for indexing systems installations.
• Linear Leak Testers: available in single or multi-station configurations for standard online linear leak detection with inspection speeds up to 70 bottles/min.
• Continuous Motion Testers : available in 1 to 4 station configurations with inspection speeds up to 150 bottles/min. Continuous motion inspection’s high speed testing ensures uninterrupted inspection of containers.

Benefits of VeriCon technology:

All VeriCon systems offer the following features and benefits:

• VeriCon technology uses high-resolution non-drifting transducers thereby ensuring consistent leak detection.
• Accurate leak testing with repeatable results
• 24/7 operation
• Capable of accommodating multiple container specifications and test sensitivity requirement

Ensuring packaging quality is pivotal in all manufacturing. For efficient packaging, it is important for manufacturers to have complete knowledge of packaging material used and test sensitivity desired, so that appropriate package integrity tests can be undertaken.

The global pharmaceutical industry has seen tremendous growth over the last few decades. The complex nature of the industry coupled with frequent breakthroughs has made it a favorite subject of scrutiny. Since any defect in the packaging of drugs can have serious consequences, assuring the quality of the packaging is of prime interest for every manufacturer. Pharmaceutical products are expected to be free from microbial contamination and safe to use right from production throughout their shelf-life. The drug’s stability can be adversely affected through contamination in the form of oxygen, humidity or microbiological ingress. In order to prevent such risks, integrity tests with high sensitivity are required.

Previously, only sterility testing was conducted on pharmaceutical packaging. However, when it was realized that sterility testing alone is not sufficient to hold the integrity of the medical products, the US FDA published Guidance for Industry for Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. This emphasised the importance of verification of microbial barrier properties of a pharmaceutical product package (i.e., CCI). FDA defines Container Closure Integrity Testing (CCIT) “as the sum of packaging components that together contain and protect the dosage form”.

Container Closure Integrity Testing is a method of leak detection using a non-destructive packaging inspection system to prevent possible contamination. Such a test is essential since any defect in the container can cause external particles to enter the product, thereby reducing its shelf life. Implementing right Container Closure System has been of prime importance for a manufacturer as it affects both the product and the patient. Hence, the relevance of CCI Testing in the pharmaceutical industry has steadily increased over the years. Contaminants that can enter a product include micro-organisms, reactive gases, and other substances. CCIT ensures product quality is maintained from the point of manufacture throughout its distribution and use. Container closure systems include primary packaging components and secondary packaging components. Components such as a glass vial or syringe, which come into direct contact with the product, are primary packaging components. On the other hand, components that are crucial to ensure correct package assembly, such as aluminum caps, over stoppers etc. are the secondary packaging components

CCI Testing Methods

Container closure integrity testing can be performed in many different ways. Each method has its own merits and demerits. A number of factors have to be considered while selecting appropriate testing methods. These factors include, but are not limited to; the reliability of the test method, material of the primary package and inline versus an offline testing requirement. CCI testing methods can also be selected depending on specific desired outcomes. Examples of desired outcome include: identifying the presence of leak paths, understanding leak path’s location, evaluating leak rate for the whole package, and measuring potential for microbial ingress. The United States pharmacopeia released guidance in 2016 stating that deterministic methods are preferred over probabilistic test method.

1. Probabilistic methods: Here, the testing methods are more traditional, and the accuracy of the result is uncertain. The probabilistic methods include the following:

• Microbial Challenge by Immersion
• Tracer Liquid Tests (e.g. Dye Ingress)
• Bubble Tests
• Tracer Gas (Sniffer Mode)

2. Deterministic methods: Such methods provide quantitative results with a higher level of accuracy. The chances of errors are also minimal. The deterministic methods include the following:

• Electrical Conductivity and Capacitance Test (HVLD)
• Laser-based Gas Headspace Analysis
• Mass Extraction
• Pressure Decay
• Tracer Gas (vacuum mode)
• Vacuum Decay