Companies manufacturing sterile drug products using conventional filling and packaging methods continue to face challenges. Prominent among these challenges are component related defects, microbiological contamination control, and aseptic process validation. Blow–fill–seal (B/F/S) is a method for aseptically filling sterile healthcare products, which, if used properly, can help address these challenges.
B/F/S technology is an automated method for forming and filling plastic containers with liquid product in an uninterrupted, continuous process. In the container blowing step, plastic beads are melted at high temperature and formed into a hollow tube or parison, which is cut to the desired length. Two halves of the container mold close around the parison, and air is blown into the parison to expand it into the shape of the container. The partially-cooled container is immediately filled and sealed.
Advantages of B/F/S technology
B/F/S technology offers several advantages for sterile packaging. Product contact surfaces are cleaned and sterilized in place and sterile contact surfaces are protected from environmental contamination with HEPA-filtered or equivalent air. In addition, machine designs create a physical barrier, restricting personnel intervention during the container formation and filling process.
Microbiological contamination control. Operations personnel are the main source of microbiological contamination in the cleanroom and, therefore, represent a potential product contaminant. Automated, well-designed B/F/S operations minimize the need and opportunity for human intervention, thus reducing the risk of microbial contamination. In addition, B/F/S typically involves small container openings and short product exposure times, further lessening the likelihood of microbial ingress.
Reduced container defects. Product seal failures can result from defects in glass and other types of packaging components (e.g., closures). Damage or defects can occur to packaging components during transport and handling, before product filling, or due to variations in the component manufacturing process. Because B/F/S technology does not use supplier-made containers or (in most cases) closures, using B/F/S eliminates shipping and handling damage. In addition, container formation is controlled by the B/F/S product manufacturer as the container is formed immediately before the sterile product is filled and is not affected by flaws in vendor process control.
Easier process validation. B/F/S is a fully automated process that requires little operator involvement, if any. Therefore, its operations are more predictable than manual operations, less variable, and less prone to error. More of the process is controlled by the product manufacturer rather than by component suppliers. This can further reduce process variability, thus resulting in a process which is easier to validate.
Concerns with B/F/S technology
Despite these sound advantages, wider use of B/F/S has been limited by concerns such as:
Particulate control. Relatively high levels of nonviable particulates are generated by the plastic extrusion and cutting process. B/F/S machine manufacturers have taken steps to address the plastic particulate issues by designing better machine enclosures to isolate and protect the product contact surfaces from environmental conditions. Some B/F/S line designs place particle-generating equipment away from the filling zones and isolate with walls and barriers. For some products, closed-parison systems, in which the inside of the parison is continually bathed with sterile air and is not cut, can be used to further protect product contact surfaces.
Temperature effects. B/F/S containers remain at an elevated temperature of up to 60 ºC for several seconds after filling (1). It is speculated that other types of plastic with a lower processing temperature can be used to reduce this temperature. To reduce the effect of exposure to elevated temperature container surfaces, filled product can be cooled soon after filling and sealing.
Oxygen and moisture effects. Plastics typically used for B/F/S containers provide a relatively low barrier to oxygen or moisture, especially as compared to traditional glass containers (i.e., vials and syringes). For oxygen sensitive products, filled units can be placed in foil pouches or other secondary packaging. Inert gases can be used in these secondary packages to lessen risk for oxygen permeation. Process development and product stability studies using products filled using the B/F/S process, container, and packaging can provide evidence of product compatibility. Companies considering the use of B/F/S should take steps to assure that the heat and permeation issues do not have an adverse effect on product quality.
The Blow-Fill-Seal International Operators Association (BFSIOA) and the Parenteral Drug Association (PDA) have been working together to create a comprehensive technical report containing practical and scientific information regarding the use of B/F/S for aseptic manufacturing of sterile products. The report will be based on BFSIOA’s “Points to Consider” document, dialogue with industry, and input from the newly-created PDA B/F/S Industry Group. This guidance on best practices, as well as scientific rationale and data to support those practices, will help the B/F/S industry continue to improve its technology for advanced aseptic processing.
1. W. Lin, P. Lam, S. Faulhaber, and S. Sane, BioPharm Int’l. 4 (7), 22-29 (2011).
2. Blow Fill Seal International Operators Association, Points to Consider, (Alslev, Denmark, Draft).
Ken Muhvich is principal consultant of Micro-Reliance LLC, Rock Hill, South Carolina, tel: 803.324.7734, mobile tel: 803.322.2262, [email protected]. Harold Baseman is COO at Valsource LLC,918 Horseshoe Pike, Downingtown, Pennsylvania, tel: 610.269.2808, [email protected].