Leak detection in plastic ampuls

The formation of the primary container is an integral part of the BFS operation and container-closure defects can be a major problem. US regulatory authorities require that "as a final measure, the inspection of each unit of a batch should include a reliable, sensitive, final product examination that is capable of identifying defective units (e.g. "leakers")"(8). It is also stated in the EU guidelines that "containers closed by fusions, e.g., glass or plastic ampoules should be subject to 100% integrity testing"(5).

There are multiple leak-detection technologies available, such as the vacuum-decay method, high-voltage leak detector, or near infrared leak detection. Among these methods, the vacuum-decay method is often selected for biological manufacturing becauese it has no product quality impact (even though there is no documented product quality impact from other methods to the authors' knowledge). During vacuum decay leak detection, the test article is placed inside a chamber, which is then evacuated to a known pressure. If the product container exhibits a leak, the chamber pressure will rise at a rate greater than a predetermined baseline value.

Alternatively, the needle valves can be calibrated with a flow meter to a specific flow rate corresponding to a specific orifice size. Calibrated needle valves represent a suitable qualification approach to the system that will demonstrate the system's ability to detect an actual leaking sample with a known hole size and flow rate.

Another main challenge with in-line leak detection operation is the high false rejection rate. Due to the high temperature required for plastic extrusion, the ampuls, immediately after BFS process, are notably warmer than room temperature. When the products are immediately placed in a vacuum-detection chamber, the heat from the ampul can cause a slight increase in pressure which the instrument may interpret as a leaky sample, which will trigger a false rejection signal. Therefore, it is highly advisable to have the product equilibrated to room temperature prior to subjecting the product to vacuum leak detection.

Packaging requirements, extractables and leachables

The primary containers of ampuls manufactured using BFS process are plastic materials, such as LDPE or PP, which are gas-permeable to some degree. During long-term storage, water vapor may diffuse out of the ampul resulting in alterations in drug concentration. Conversely, oxygen permeation could cause protein oxidation. Gas permeation can be minimized by sealing the plastic ampuls inside laminated foil pouches (as a secondary packaging layer). For example, in the development of the Pulmozyme drug product, studies showed that protein concentration increased by more than 30% due to water loss when the naked product was stored at 37 °C for ~700 days (1). Such water loss was prevented by adding an aluminum foil pouch as a secondary packaging layer. In addition, the aluminum foil pouch protects the drug product from light-induced degradation. Furthermore, oxygen-sensitive products can be sealed into pouches under a nitrogen blanket (overlay) to provide additional protection against oxidation.

Secondary packaging materials are typically comprised of multiple layers of polymers (i.e., polyester, PP, or polyethylene), inks, adhesives, as well as possibly unreacted monomers and oligomers derived from adhesive materials. When in direct contact with primary containers, these materials have the potential to penetrate through plastic ampuls. In addition, the direct contact between the liquid product and the primary container (even though the primary container material is typically made of much cleaner polymers) could lead to extraction of chemicals. These chemical extracts and leachates from plastic packaging materials could act as adjuvants in stimulating an immune response in the patient (9). Leachates would especially be of concern if the product is to be injected subcutaneously, as the localized concentration of product and adjuvant is more likely to stimulate the production of neutralizing antibodies than intravenous injection or inhalation (9). Therefore, it is imperative that the extractable and leachable program for plastic ampul products be conducted with both pouched and unpouched samples to understand the respective extracts and leachates from both the primary and the secondary packaging materials (10–12).