The authors compare four well-established aseptic filling technologies, open vial, ampul, blow-fill-seal (BFS) and prefilled syringes, to the recently developed closed-vial technology with regards to the exposure risk from viable particles from the air supply. Containers (e.g., vial, syringe barrel, or ampul), container closures (e.g., stoppers, or plungers), and filling needles have all been taken into account and weighted by exposed surface and exposure time. The study assumes that all of these technologies are normally operated under controlled environmental conditions in accordance with worldwide GMP standards and with appropriate attention to generally accepted sterility assurance guidelines, including use of an ISO 5 environment during the filling operation. The analysis showed that two technologies, BFS and closed vial technology, significantly reduce the risk of contamination due to exposure to the environment. The reduction factor for this risk can exceed 100 compared with open containers.
A recently published article in Pharmaceutical Technology Europe by Haag pointed out the risk of contamination due to exposure of the internal surfaces of the container during the filling process (1). The article described the concept of an environmental risk approach based on exposure to laminar airflow, which is susceptible to carrying viable particles. High efficiency particulate air (HEPA) filters are very effective at eliminating viable particles from ISO5 environment but the absence of particles can never be guaranteed. Haag's preliminary analysis was conducted with only three types of containers (e.g., large vial, small vial, and ampuls) and considered entry of the bacteria only through the container neck (1).The scope of this analysis has been extended to include more packaging types used for aseptic filling of liquid products. In addition to vials and ampuls, prefilled syringes, blow-fill-seal (BFS) containers, and closed vial technology have been added. The sources of contamination have been systematically screened so other parts (e.g., stoppers, plungers, and filling needles) have been taken into account.
Closed vial technology has been used to fill stability batches of Synflorix (pneumococcal vaccine, GSK Biologicals) and granted approval by the European Medicines Agency (EMA). To illustrate the effects of minimizing exposure on the risk of contamination, media fill data in normal and challenging situations using closed vial technology have been generated and are presented in this article.
To avoid confusion between different techniques, lyophilized products have been kept outside of the scope of this article. Nevertheless, a similar approach is easily applicable.
This article focuses on risk due to environmental contamination during filling operations. Many other risks for the patient are present, such as contamination generated by human intervention (e.g., machine breakdown or component transfer), contamination due to cracks in glass containers, contamination due to inadequate sanitization of contact parts, or presence of glass particles when ampuls are opened. These sources of risk are not taken into account in this article.