CCIT (Container Closure Integrity Testing) and HGA (Headspace Gas Analysis) methods

Methods for detecting leaks in blister packaging and analysing headspace gas in ampoules and vials have traditionally involved a destructive and non-deterministic process. However, non-destructive and deterministic methods, which do not result in wasted products, have emerged as viable alternatives. Bonfiglioli Engineering and Sepha, both part of TasiTest, are leading specialists in these packaging leak test and inspection solutions. Between them, Sepha and Bonfiglioli have developed a number of innovative deterministic and non-destructive solutions for pharmaceutical container closure integrity requirements.

Blister pack leak testing

Demonstrating the integrity of pharmaceutical blister packs is critically important, any defects can affect the shelf life and efficacy of the contents. In addition, it is also an FDA requirement as specified in current Good Manufacturing Practice (cGMP) 21 CFR 211.166 for finished pharmaceuticals.

Ensuring a robust, objective and repeatable process (deterministic) for leak testing is key to proving product stability and reducing the risk of product recalls or contamination, in addition to preventing a reduction in drug efficacy.

Blister packs typically are composed of a thermoformed polymer or cold formed aluminum tray, with a number of individual pockets to hold the product. After the tablets or capsules are placed in the pockets, the packs are heat sealed with a paper or foil laminate sheet. During these production stages, there is a risk of microbial containment or degradation of the products if any defects are present in the packaging. Such defects can take the form of rips or pinholes in the tray or lid materials, faulty seals and channel leaks between pockets.

Destructive vs non-destructive testing

The current industry standard for testing blister pack integrity is non-deterministic blue dye testing, which consists of placing a selection of packs into blue dye water, subjecting the packs to a vacuum of typically 400-600mBar for several minutes and then removing the vacuum, which allows any defective pockets to take up the dye. The packs are manually deblistered and inspected for dye ingress. This technique has two main problems; it is subjective as it relies on operator judgment and it is destructive to the blister packaging and product as all blisters need to be destroyed after testing in blue dye water.

Sepha have developed a number of technologies which are deterministic and non-destructive in the evaluation of package integrity, enabling all defect free packs to be returned to the production process. Sepha’s technology also enables companies to test integrity packaging before the start of clinical trials. This ensures that laboratories and R&D departments can rule out the variable of package integrity during a study.

Sepha VisionScan

The Sepha VisionScan is a tool-less, non-destructive leak detection device developed for testing pharmaceutical blister packs. It measures pack deflection using camera and projection technology in response to an applied vacuum. Images of the pack surface before and after the application of two vacuum levels are compared. The lidding material of a good pack will deform when a vacuum is applied due to differences in pressure between the pocket interior and the applied vacuum. Any defect will allow this pressure differential to equalize and change the way in which the pack deflects when the vacuum is applied.

The Sepha VisionScan generates accurate, reliable and repeatable results with clear pass or fail information. It can detect defects in individual blister pockets, channel leaks and weak seals equivalent to a 7µm laser drilled pin hole. It has a rapid test time down to 10 seconds for micron holes (<30µm) and as low as six seconds for gross holes (>30 µm). The system is uses qualified thresholds which allows the detection of faulty packs without operator subjectivity. The system does not require dedicated tooling for each pack type and allows multiple packs to be tested in a single test cycle.

Headspace gas analysis systems for parenteral manufacturing processes

Headspace content verification is a solution to ensure parenteral product stability and sterility maintenance. Integrity defects as well as failures in the aseptic manufacturing process, including unexpected variability in the nitrogen flushing or vacuum application, pose a risk to product quality and patient safety.

Monitoring the maintenance of container headspace conditions is needed for sterile drugs such as oxygen sensitive liquid products and lyophilised or powdered products; any modification in the headspace pressure, moisture or oxygen level may result in the degradation of the active drug, likewise in the reduction of drug potency and product shelf life.

Specific requirements for sterile drugs packaged under full or partial vacuum are covered by EU GMP Annex 1 ‘Manufacture of Sterile Medicinal Products,’ section 123: “Containers sealed under vacuum should be tested for maintenance of that vacuum after an appropriate, pre-determined period.”

In addition to that, new regulations are expected to enter into force and are to include measures to demonstrate the maintenance of sterility over time for drug products into controlled headspace gas packaging. In particular the proposed revision of USP <1207> ‘Sterile Product – Package Integrity Evaluation“ is expected to provide clearer guidance for headspace critical content verification through the entire product life cycle, from stability studies to commercial production stage.

Destructive vs non-destructive Headspace Gas Analysis

Even with a well-defined manufacturing process in places, it is still almost impossible to keep up with regulatory and quality requirements without a system ensuring a reliable and repeatable monitoring of the headspace critical gas content. Most of the headspace gas measurement methods available on the market are destructive, therefore they are generally performed on samples, at regular intervals, during the production cycle. The main disadvantage of these destructive approaches arises when out of specification conditions are detected and the entire batch is to be rejected.

Bonfiglioli Engineering has developed different innovative, non-destructive solutions in the field of HGA with significant advantages over other existing system including the Bonfig LaserCube.

Bonfig LaserCube

The Bonfig LaserCube is a benchtop system that uses a non-destructive and non-invasive laser-based inspection technology for measuring the level of gases including oxygen, moisture content and absolute pressure in the headspace of sterile pharmaceutical containers. It is mainly focussed on the inspection of the closure integrity of pharmaceutical finished containers and of the maintenance of the proper headspace conditions for products packaged under modified atmosphere or under vacuum.

The HGA inspection process is based on the Tunable Diode Laser Absorption Spectroscopy (TDLAS) method which uses a laser beam to detect the target molecules within container head space, ideal for the accurate inspection of translucent containers, head space conditions for products packaged under modified atmosphere and closure integrity in pharmaceutical finished containers.

The Bonfig LaserCube is a compact and lightweight system that is easy to use and set up via an integrated PC or any wireless touchscreen tablet. It is suitable for inspection of a wide range of different sized glass containers including vials, ampoules, bottles and pre-filled syringes.

ACE technologies is an official representative of Tasitest in India.

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