100% Container Closure Inspection of Freeze-Dried Product in Quarantine

100% container closure inspection means checking the integrity of every vial in a batch. For lyophilized product, it can be done non-destructively by measuring the gas composition in each vial’s headspace. This case study shows how 100% automated headspace inspection was used to release a quarantined freeze-dried batch while rejecting only the vials that had leaked.

Container closure integrity plays an important role in maintaining the sterility and stability of lyophilized products. Concerns over patient safety, customer complaints and the cost of investigations and recalls have led to revised regulatory guidance, including the revised EU GMP Annex 1. Read more about container closure integrity testing and the methods available.

A leading contract manufacturer approached LIGHTHOUSE with a concern about the container closure integrity of several commercial batches of lyophilized product. Each batch consisted of approximately 30,000 vials, stoppered at ≥ 500 mbar of nitrogen. A suspected raised stopper issue led the manufacturer to place the batches into quarantine.

Freeze-dried vials can be prone to temporary defects when a stopper pops up before final crimping. The stopper may reseat, leaving no visible sign that the container was ever open. For a quarantined batch, that is the core dilemma: you cannot release product you are unsure of, and you do not want to destroy tens of thousands of vials that may be intact. The manufacturer decided to perform 100% container closure inspection using headspace analysis.

LIGHTHOUSE configured a headspace inspection system for automated 100% container closure inspection, fitted with a headspace oxygen sensor to measure the oxygen level in every vial. Because the vials were stoppered under nitrogen at reduced pressure, a leaking vial is identified by elevated headspace oxygen resulting from oxygen ingress through the leak.

The timeline was critical, so a standalone lease system was configured for fast delivery:

• Factory Acceptance Testing in week 4 after project start
• IQ/OQ in week 5
• PQ in week 6
• Inspection of product from week 7

Automated 100% inspection systems such as the Pulsar and Illuminator platforms apply the same headspace principle to inspect every container in a batch.

In one of the inspected batches, a raised stopper issue was indeed confirmed. Approximately 3% of the 30,000 vials showed headspace oxygen levels above the reject level.

The inspection identified gross leakers as well as vials that had leaked only temporarily, something only laser-based headspace analysis is able to detect. Oxygen that entered while a stopper was raised stays in the headspace after the stopper reseats, so the measurement reveals these vials even when the leak path has since closed. The manufacturer could reject the defective vials and confirm the container closure quality of the remaining product.

For containers not closed by fusion, Annex 1 accepts integrity testing on a scientifically justified sampling plan. Sampling is well suited to confirming that a controlled process performs as expected. It can estimate how many vials in a batch are defective, but it cannot tell you which ones.

A quarantined batch with a suspected defect is a different situation. When about 3% of vials are affected and some of them show no visible defect, the only way to separate good vials from bad is to measure each one. Non-destructive headspace inspection makes that possible without opening or destroying a single unit.

Raised stoppers are one part of the picture. Seal quality and component choice also determine whether CCI holds, as shown in our case studies on correlating residual seal force to CCI in deep cold storage and selecting a vial-stopper combination for cryogenic storage. Headspace analysis can also support optimization of lyophilization cycles through non-destructive moisture determination.

Download the case study for the full inspection results, or talk to one of our application scientists about 100% container closure inspection of your freeze-dried product.