Aseptic filling remains a risky process with multiple contaminations occurring each year that have serious consequences. Analysis of an outbreak database shows that, among 1537 patients contaminated by parenteral product from 1990–2005, the mortality rate was 15%. While the majority was due to product preparation at the hospital pharmacy or the practices of the hospital staff, 20% of these contaminations were due to the pharmaceutical manufacturing process (1).
This high contamination risk leads authorities to regularly reevaluate their requirements, thus making aseptic filling one of the most complex processes in the pharmaceutical industry. A continuous improvement approach, however, has led to major innovations, and the rate of contamination has been significantly reduced during the past 50 years. The innovations listed below involve both the container and filling technologies:
The vial emerged as the standard primary packaging and replaced the old-fashioned ampoule, which had higher risk of breakage, contamination through small cracks, and glass particle generation when the ampoule was opened.
- Better practices have been developed for aseptic filling, such as personnel gowning, equipment/process design, and environment monitoring.
- Physical barriers have been created between the operator and the filling area. Initially the barrier was made from simple walls but now includes the isolator concept. Isolators prevent direct contact between the operator and the filling process, including the bulk products, containers, and product contact parts (2).
- Process analytical technology (PAT) was developed to perform on-line checks on product quality. Checks include the classical weight check as well as newer checks such as particle inspection and leak detection.
These innovations improve product quality but also add complexity to the aseptic-filling process. As a result, aseptic filling is expensive, demands complex quality control, and has many potential opportunities for mistakes. Closed-vial technology, however, can improve product quality and simplify the aseptic-filling process (3, 4).
Closed-vial process summary
Figure 1 shows an overview of the production and filling of closed vials, which occurs at three separate facilities. The vial is molded and assembled in an ISO5 cleanroom and rings are added. At a separate facility, the vial is sterilized by gamma irradiation, which leads to a clean, sterile, ready-to-fill vial. The vial is delivered to the pharmaceutical filling site for filling. In this process, a needle punctures the stopper and dispenses the liquid. The puncture trace is then resealed with a laser to restore the closure integrity. Finally, the vial is capped with a snap-fit, polyethylene cap.
Figure 1: Production cycle of a closed vial from molding the container to filling and capping.