A. Equipment Design and Air Quality
Most BFS machines operate using the following steps.
•Heat a plastic polymer resin
•Extrude it to form a parison (a tubular form of the hot resin)
•Cut the parison with a high-temperature knife
•Move the parison under the blow-fill needle (mandrel)
•Inflate it to the shape of the mold walls
•Fill the formed container with the liquid product
•Remove the mandrel
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 with the greatest potential for exposure to particle contamination and/or surrounding air are those in which (1) the parison is cut, (2) the parison is moved under the blow-fill mandrel, and (3) 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 product contact surfaces be sterile. A validated steam-in-place cycle, or equivalent process, should be used to sterilize the equipment path through which the product is conveyed. In addition, any other surface that represents a potential contamination risk to the sterile product should be sterile.
The classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room. HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e.g., parison formation, container molding or filling steps). Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery. Refer to Section V of this document for guidance on personnel training, qualification, and monitoring.
BFS equipment design typically calls for use of specialized measures to reduce particle levels that can contaminate the exposed product. In contrast to non pharmaceutical applications using BFS machinery, control of air quality (i.e., particles) is critical for sterile drug product manufacture. Particles generated during the plastic extrusion, cutting, and sealing processes should be controlled. Provisions for carefully controlled airflow can protect the product by forcing generated particles outward while preventing any ingress from the adjacent environment. Furthermore, equipment designs that separate the filling zone from the surrounding environment provide additional product protection. Barriers, pressure vacuums, microenvironments, and appropriately directed high velocities of sterile air have been found useful in preventing contamination (Ref. 15). Smoke studies and multi-location particle data can provide valuable information when performing qualification studies to assess whether proper particle control dynamics have been achieved throughout the critical area.
In addition to suitable design, it is important to establish an adequate preventative maintenance program. For example, because of its potential to contaminate the sterile drug product, the integrity of the cooling, heating and other utility systems associated with the BFS machine should be maintained and routinely monitored.
B. Validation Qualification
Advantages of BFS processing are known to include rapid container closure processing and minimized aseptic interventions. However, only a properly functioning process can realize these advantages. US FDA recommend affording special attention to setup, troubleshooting of equipment, and related aseptic personnel procedures. Equipment sterilization, media fills, polymer extrusion sterilization, product-plastic compatibility, forming and sealing integrity, and unit weight variation are among the key issues to address in validation and qualification studies.
Data gathered during such studies should ensure that BFS containers are sterile and, if used for parenteral drugs, nonpyrogenic. This can generally be achieved by validating that time temperature conditions of the extrusion process are effective against endotoxin or spore challenges in the polymeric material.
The choice of appropriate polymer material for a BFS operation includes assessing if a material is pharmaceutical grade, safe, pure, and passes appropriate criteria for plastics. Polymer suppliers should be qualified and monitored for raw material quality.
C. Batch Monitoring and Control
Various in-process control parameters (e.g., container weight variation, fill weight, leakers, air pressure) provide information to monitor and facilitate ongoing process control. It is essential to monitor the microbial air quality. Samples should be taken according to a comprehensive sampling plan that provides data representative of the entire filling operation. 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 control of a BFS operation. It is critical that the operation be designed and set-up to uniformly manufacture integral units. As a final measure, the inspection of each unit of a batch should include a reliable, sensitive, final product examination that is capable of identifying defective units (e.g., leakers). Significant defects due to heat or mechanical problems, such as wall thickness, container or closure interface deficiencies, poorly formed closures, or other deviations should be investigated in accordance with §§ 211.100 and 211.192
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This Guidance is published by US FDA on September 2004
We also recommend our readers to visit US FDA’S website for undated guidances on sterile drug products