Aseptic Blow-Fill-Seal Technology vs. Traditional Aseptic Processing

 
Ordinary walking by a person emits roughly 10,000 skin particles per minute. Such particles can and do hold microbial contamination. A rip in a worker’s uniform, a momentary exposed wrist, a mask placed too low on the nose or physical contact with an open fill port will increase microbial contamination within a critical area.
 
According to the FDA’s guide, airborne contamination is directly related to the number of people working in a cleanroom and the level of congregation by personnel in areas where critical aseptic manipulations are performed.  Isolation of personnel from these critical areas would eliminate the major source of contamination in traditional aseptic processing.
 
In traditional aseptic processing, changing or adjusting filling nozzles and heads necessitates the shutdown of the filling operation and requires re-sterilization of the entire equipment. This increases manual intervention in this critical area. Cleaning and sterilization which is carried out by personnel, opens the door to breaching of established procedures for microbial decontamination and potential introduction of other particulates like dirt, oil and chemicals.
 
Mold is common flora found on floors, walls and ceilings of buildings. Contamination occurs due to the retention of water in cracks, edges and joints that are susceptible because of inadequate sealing. Brooms, mops and anything used for cleaning can become contaminated and increase atmospheric contamination because of raised dust or splashing water. In traditional aseptic processing, significant manual intervention is required in critical areas to maintain compliance with established sterile mandates.

Advanced Blow-Fill-Seal Aseptic Technology

In advanced aseptic BFS processing, containers are formed from a thermoplastic granulate, filled with a liquid pharmaceutical product and then sealed within a continuous, integrated and automatic operation without human intervention.
 
Bulk solution prepared under low bioburden or sterile conditions is delivered to the machine through a product delivery system that has been previously sterilized using an automated steam-in-place process.
 
Modern BFS machines are fully automated, designed to require minimum human access and operate in a classified environment using the following steps: (a) granules of a polymer resin, conforming to a predetermined set of specifications, such as polyethylene, polypropylene, co-polymers or other blow-moldable resins, are pneumatically conveyed from a non-classified area into the hopper of the BFS machine, from which the plastic is fed into a multi-zone rotating screw extruder which produces a sterile homogenous polymer melt (160–250 degrees C); (b) then to a parison head which produces hollow tubular forms of the hot resin (called parisons). The parisons are prevented from collapsing by a stream of sterile filtered support air.  Some high-speed BFS machines have up to sixteen parisons being formed simultaneously; (c) container mold(s) close around the parisons, and the bottom of the parison is pinched closed, while the top is held open in a molten state; (d) the container is formed in the mold by blowing sterile air or creating a vacuum; (e) filling needles deposit the stipulated volume of product into the container; (f) the filling needles are withdrawn, and the upper part of the mold closes to form and seal the upper part of the BFS container; (g) the mold is opened and the completed, filled containers are conveyed out of the BFS machine to a remote station where excess plastic is removed and the finished product is then conveyed to final packaging.
 
Various in-process control parameters, such as container weight, fill weight, wall thickness and visual defects provide information that is monitored and facilitates ongoing process control.  
 
The forming, filling and sealing steps are achieved in one unit operation – the cycle being completed within seconds. Automation of BFS process steps eliminates manual intervention and reduces risk to the product.  No production personnel are present in the filling room during normal operation.

Microbial and Particulate Integrity in the Aseptic Blow-Fill-Seal System

Sterility of BFS polymeric containers, materials and processes is validated by verifying that time and temperature conditions of the extrusion, filling and sealing processes are effective against endotoxins and spores.
 
Challenge studies have been conducted on the sterility levels of advanced BFS technology, which demonstrate a uniform capability of achieving contamination rates not exceeding 0.001 percent throughout the entire process.  Even higher sterility assurance levels, approaching 0.000001 percent, have been achieved using high levels of airborne microbiological challenge particles.          
 
Endotoxins are a potential pyrogenic contaminant, essentially dead bacterial cellular matter. They can lead to serious reactions in patients, particularly with those receiving injections, ranging from fever to death.  A critical aspect of BFS technology is its pyrogen-free molding of containers and ampoules. Extensive experiments confirming the efficacy of the BFS extrusion process have been performed using high levels of spores and endotoxin-contaminated polymer granules. The typical BFS extruders have demonstrated spore contamination rates of 0.000001 percent, and 0.00001 percent for endotoxins.
 
Control of air quality is critical for sterile drug product manufacture. BFS equipment design typically employs the use of specialized measures to reduce microbial contamination and particle levels that can contaminate the exposed product. The BFS process inherently produces a very low level of particulate matter and much of potential BFS microbial contamination (viable) in the air is mitigated by the absence of manual intervention in its critical areas.  Non-viable particles generated during the plastic extrusion, cutting, and sealing processes are controlled.  Provisions for carefully controlled airflow protect the product by forcing created particles outward while preventing any inflow from the adjacent environment. These “zones of protection” can also incorporate designs that separate them from the surrounding environment, providing additional product protection.