Container Closure Integrity Testing

Pharmaceutical products are formulated in various forms: from liquid to solid, frozen forms and also lyophilized. Formulated drugs are filled and stored in a variety of container closure systems, made from glass, plastic, metal, including blisters, bottles, vials, ampules, syringes and cartridges.

The United States Pharmacopeia (USP) and Food and Drug Administration (FDA) are the main driving forces to assess and to regulate the safety of materials and container closure systems¹. The container closure systems should provide an integral barrier that protects stability and sterility of the drug product during the shelf-life against microorganisms, reactive gases and moisture². Container Closure Integrity Testing (CCIT) is a test which evaluates the appropriateness of the container closure systems for product safety.

Eurofins BioPharma Product Testing network of companies provides a state of the art method for CCIT, verifying the safety of your container closure system to meet the regulatory guidelines. Since we are part of an international network of laboratories and testing units with global reach, we can assist you to determine the best CCIT method in order to meet the needs of your project.

Techniques for Container Closure Integrity Testing (CCIT)

Based on the drug formulation (e.g. liquid or lyophilized) and the type of the container (e.g. bottle, vial, ampule and syringe etc.) various methods can be employed to perform the container closure integrity testing. In general methods can be divided in two groups: Probabilistic – Destructive and Deterministic – Non-destructive methods.

Non-destructive and deterministic tests:

Headspace (both Qualitative and Quantitative)
Vacuum/Pressure Decay (Qualitative, Quantitative feasible)
Mass Extraction (Quantitative)
High Voltage Leak Detection (HVLD) (Qualitative, Quantitative feasible) offered by Eurofins PROXY Laboratories
Helium Leak Detection (both Qualitative and Quantitative)
Optical Emission Spectroscopy (Quantitative)

Destructive and probabilistic tests:

Dye ingress (Qualitative only) offered by Eurofins PROXY Laboratories BV & Eurofins MicroSafe Laboratories
Microbial Ingress (Qualitative only) offered by Eurofins Bactimm BV

High Voltage Leak Detection (using E-Scan 655 MicroCurrent High Voltage Leak Detector) is currently available at Eurofins PROXY Laboratories. With this technique, leakage due to the package defects are detected employing high electrical voltage to the intact test article. Therefore, the HVLD technology is applicable to perform CCIT analysis on liquid-filled parenteral drug product containers, prefilled syringes, vials and ampules where the packaging is less conductive than the liquid inside. The advantages of this system are as follows:

Listed in USP Chapter <1207> for parenteral liquid package testing
Non-destructive, non-invasive and deterministic method
High level of repeatability and accuracy
2-5 mm size leak detection
Applicable to high-concentration proteinaceous products
Also effective for low conductive liquid containing samples (e.g. WFI)
Low voltage exposure to the product and environment (with negligible ozone formation)
Fast and simple for 100% visual inspection and validation process
100% testing with HVLD replaces destructive methods, which necessitate scrapping whole batches if a leak is detected. As a result, return-on-investment often is achieved with the first quality deviation identified.

In addition to the HVLD technology we also offer Dye Immersion and Microbial Challenge by Immersion (both Probabilistic tests) which have been used as leading methods for CCIT until recently. These tests are destructive to the samples under test, and typically require a significant number of units for method development and validation. The overview of other Deterministic, non-destructive technologies are presented in below table. These technologies are available within our Eurofins BioPharma Product Testing network of companies.

Technology	Instrumentation	Description	Best Applications
Helium Leak Detection	Helium Mass Spectrometer -Tracer Gas Detection, Vacuum Mode	The flow rate of helium from leaks in packaging is quantitatively determined after having been flooded with helium as a tracer gas. In the presence of a defect, the helium is drawn out of the packaging through the defect by vacuum and detected using a mass spectrometer. This method is the most sensitive offering to detect 0.2 mm defects.	This technology is suitable for package development to verify whether the package type is convenient for the type of drug, as well as routine testing and stability of various packaging types.
Vacuum Decay	VeriPac 455-M5 Vacuum Decay	Leaks are measured via vacuum decay based upon ASTM F2338. Very sensitive to determine the leaks down to approximately 5-10 microns. It is non-destructive thus the stability testing can be performed on the same sample.	This technology is non-destructive and suitable for leak testing on syringes, vials, and pouches both before and during stability studies.
Pressure Decay	TM Electronics BT Integra Burst, Creep and Leak Tester	Measures leaks by pressure decay based upon ASTM F2095.	This technology offers both seal strength and package integrity testing for flexible packaging (e.g. bags and pouches)
Oxygen Headspace	FMS-760 Oxygen Headspace Analyzer	Frequency Modulation Spectroscopy (FMS) is employed to detect oxygen in the headspace of transparent rigid containers. The decrease or increase in the oxygen levels in the container’s headspace is measured to detect a potential leak. The rate of oxygen permeation into a sealed container can be determined.	This method is non-destructive to the sample and convenient to perform leak testing of parenteral containers both before and during stability studies.