The Manufacture of Sterile Pharmaceuticals and Liquid Medical Devices Using Blow-Fill-Seal Technology. K. Downey
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This document provides information to supplement and to assist with interpretation of international standards and regulatory guidance from the perspective of BFS operations, and considers specific aspects of BFS operation which are not covered by existing published information.
The PTC is intended as a guide for industry and is not meant to supplant or duplicate any existing regulatory guidance. A list of current regulatory guidance references is provided in the Appendix.
3. BFS PROCESS OUTLINE
Blow-Fill-Seal technology is a pharmaceutical filling process in which containers are formed from a thermoplastic granulate, filled with product and then sealed in a continuous, integrated, automatic operation. Originally developed for use in other industries, BFS technology has been adapted for use in the manufacture of sterile pharmaceutical, medical device, biological, and veterinary products. The two most common types of BFS machines are the shuttling machine (with parison cut) and the rotary machine (closed parison) types. Both are considered in this document.
In the process, bulk solution/suspension is delivered to the filling machine, through the filling system to the filling needles (“mandrels”).
Polymer granules are extruded under pressure (up to 350 bar) as a hot (approx. 180°C) mouldable plastic tube (“parison”) or set of parisons.
3.1 Shuttle Type Machines
A downward flow of sterile filtered air is passed through the parison (parison support air) to prevent collapse of the molten tube. The 2 halves of a mould close around the parison(s) to form the body of the container(s). Simultaneously, the newly formed container in the mould is cut free from the parison by a “knife”.
The mould is transferred to the filling position.
The filling mandrel is lowered into the plastic tube and the container is shaped either by vacuum or with sterile blowing air or other inert gas supplied by the mandrel. Subsequently, the container is filled with the required volume of the product. During the liquid fill, headspace gas is displaced from within the container, either through the mandrel or direct to room atmosphere, depending on the container configuration.
The filling mandrel is then raised and the containers are sealed automatically by forming the still hot plastic above the main mould, by closing the upper section of the mould, (head/seal mould). The entire mould assembly then opens, releasing the filled container(s) that have been formed, filled and sealed.
This complete cycle generally takes between 10–20 seconds depending on container design and volume of fill. Parison extrusion continues, as the mould returns to the first station, and the cycle repeats (Fig. 1).
Fig. 1 Schematic representation of the open parison Blow-Fill-Seal process.
3.2 Rotary Filling Machines
There are a number of significant differences between shuttling zone machines and rotary filling machines:
● Rather than 1 or 2 sets of moulds, there are typically 15 sets located on 2 rotating chains.
● The units are produced in 1 continuous ribbon. This means that there is no ‘shuttling zone’ or knife cut required for machines of this type. As a result, particle generation is generally reduced and the units are not open to the environment at any point during the process (Fig. 2a and 2b).
Fig. 2a Schematic representation of the closed parison Blow-Fill-Seal process.
Fig. 2b Schematic representation of the closed parison Blow-Fill-Seal process.
● There is no traditional air shower as seen on ‘open parison’ machines. When not filling, the filling tips are retracted and reside completely within the extruder head and are flushed with sterile air. During filling, the filling tips are completely enclosed by the continuously extruding parison, which is sealed at the bottom by the continuous formation of the units. Throughout the whole time, the tips are surrounded by sterile air. Any loss of pressure inside the parison or not enough air entering into the parison will lead to a too small parison width. This will lead to filling being suspended and the needles will retract into the parison head. The sterility of the tips can therefore be maintained.
● Due to there being no traditional air shower, and the filling tips being completely enclosed within the parison, it is not possible to perform continuous viable and non-viable particle monitoring throughout the batch. Therefore, it is not possible to classify this area as Grade A in the same manner as for shuttling machines. Any particle monitoring device placed within the closed parison may interfere with the velocity and direction of the sterile air. This may cause the parison to collapse onto the filling tips. Once extrusion is stopped at the end of batch, the filling environment ceases to exist. Therefore, any air samples taken of the air leaving the parison head will not provide meaningful data.
Note
It can be argued that the sterile environment in which the filling tips are present during filling is actually the same as within the sealed, filled unit. Demonstrating that the filling environment is of the appropriate quality therefore requires consideration of the entire sterility assurance ‘package’ for the batch/process, i.e. monitoring of critical parameters/alarms during each batch, parison support filter integrity tests at the end of each batch, media fills, extruder validation, bioburden of incoming polymer etc.
● No operator intervention is possible within the sterile environment once the parison is formed.
3.3 Additional Applications
The majority of BFS machines operate as described above, although there are variations on the principle. Certain machines can insert devices before container closure, e.g. syringes, rubber stoppers, and eye droppers. It is important to consider that any device to be inserted during the blow-fill-seal process must be appropriately sterilised and handled to ensure its sterility is maintained.
In addition, some machines also have co-extrusion capabilities, which can provide an additional barrier to oxygen and/or volatiles migration into the final container. It can also provide an additional barrier to reduce water loss out of the final container. A typical co-extrusion machine has 5 extruders (Fig. 3).
Fig. 3 Schematic representation of the co-extrusion process.
4. ADVANTAGES & CHALLENGES OF BLOW-FILL-SEAL TECHNOLOGY
4.1 Advantages
Blow-Fill-Seal technology offers 2 highly significant advantages over “traditional” aseptic filling operations.
1. In BFS operations, personnel should not normally be present in the filling area during the filling process, thereby removing the greatest potential source of microbial contamination from the operation.
2a. For shuttling machines, the containers are formed immediately before filling, are filled under controlled conditions, and are sealed immediately after filling. Therefore, the СКАЧАТЬ