Blow-fill-seal (BFS) technology is an automated process by which containers are formed, filled, and sealed in a continuous operation. This manufacturing technology includes economies in container-closure processing and reduced human intervention, and is often used for filling and packaging of ophthalmics and, less frequently, for injectables. This section discusses some of the critical control points of this technology. Except where otherwise noted below, the aseptic processing standards discussed elsewhere in this document should be applied to Blow Fill Seal technology.
A) Equipment Design and Air Quality
A BFS machine operates by 1) heating a plastic polymer resin; 2) extruding it to form a parison (a tubular form of the hot resin); 3) cutting the parison with a high-temperature knife; 4) moving the parison under the blow-fill needle (mandrel); 5) inflating it to the shape of the mold walls; 5) filling the formed container with the liquid product; 6) removing the mandrel; 7) sealing. Throughout this operation sterile air is used, for example, to form the parison and inflate it prior to filling. In most operations, the three steps that pose the greatest potential for exposure to particle contamination and/or surrounding air are those in which: the parison is cut; the parison is moved under the blow-fill mandrel; and the mandrel is removed (just prior to sealing).
BFS machinery and its surrounding barriers should be designed to prevent the potential for extraneous contamination. As with any aseptic processing operation, it is critical that contact surfaces be sterile. A validated steam-in-place cycle should be used to sterilize the equipment path through which the product is conveyed. In addition, any other surface (e.g., above or nearby) that has potential to contaminate the sterile product needs to be sterile.
The classified environment surrounding BFS machinery should generally meet Class 10,000 standards, but special design provisions (e.g., isolation technology) can justify an alternate classification. HEPA-filtered or sterile air provided by membrane filters is necessary in the critical zone in which sterile products or materials are exposed (e.g., parison formation, container molding/filling steps). Air in the critical zone should meet Class 100 microbiological standards. A well-designed BFS system should also normally achieve Class 100 particulate levels.
Equipment design should incorporate specialized measures to reduce particulate levels. In contrast to non-pharmaceutical applications using BFS machinery, control of air quality (i.e., particulates) is critical for sterile drug product manufacture. Particles generated during the plastic extrusion, cutting, and sealing processes provide a potential means of transport for microorganisms into open containers prior to sealing. Provisions for carefully controlled airflow could protect the product by forcing generated particles outward while preventing any ingress from the adjacent environment. Furthermore, designs separating the filling zone from the surrounding environment are important in ensuring product protection. Barriers, pressure vacuums, microenvironments, and appropriately directed high velocities of sterile air have been found useful in preventing contamination (Ref. 13).
Smoke studies and multi-location particulate data are vital when performing qualification studies to assess whether proper particulate control dynamics have been achieved throughout the critical area.
In addition to suitable design, an adequate preventative maintenance program should be established. For example, because of its potential to contaminate the sterile drug product, the integrity of the boiling system (e.g., mold plates, gaskets) should be carefully monitored and maintained.
B) Validation/Qualification
The advantages of BFS processing are known to include rapid container/closure processing and minimized interventions. However, a properly functioning process is necessary to realize these advantages. Equipment qualification/requalification and personnel practices should be given special attention. Equipment sterilization, media fills, polymer sterilization, endotoxin removal, product-plastic compatibility, forming/sealing integrity, and unit weight variation are among the key issues that should be covered by validation/qualification studies.
Appropriate data should ensure that BFS containers are sterile and non-pyrogenic. This can generally be achieved by validating that time-temperature conditions of the extrusion process destroy the worst-case endotoxin load on the polymeric material.
The plastic polymer material chosen should be pharmaceutical grade, safe, pure, and pass USP criteria for plastics. Polymer suppliers should be qualified and monitored for raw material quality.
C) Batch Monitoring and Control
In-process monitoring should include various control parameters (e.g., container weight variation, fill weight, leakers, air pressure, etc.) to ensure ongoing process control. Environmental monitoring is particularly important. Samples should be taken during each shift at specified locations under dynamic conditions. Due to the generation of high levels of particles near the exposed drug product, continuous monitoring of particles can provide valuable data relative to the control of a blow-fill-seal operation.
Container-closure defects can be a major problem in the control of a BFS operation. It is necessary for the operation to be designed and set-up to uniformly manufacture leak-proof units. As a final measure, inspection of each unit of a batch should employ a reliable, sensitive final product examination capable of detecting a defective unit. Significant defects due to heat or mechanical problems, such as mold thickness, container/closure interface deficiencies, poorly formed closure, or other deviations should be investigated in accordance with CFR Sections 211.100 and 211.192.
The author is an experienced pharmaceutical blogger.