Combination products, automation, and separative technologies
The first project began in 1994, when Shibuya Kogyo designed several filling lines for Nipro Corporation (Osaka, Japan) (6).
These aseptic fill lines were for beta-lactam antibiotics and involved both automatic parts feeding and assembly. The first
filling line involved no less than 13 isolators, a blow–fill–seal bag filling process, terminal sterilization with automatic
feed and unload, and two semicontinuous vapor-phase hydrogen peroxide (VPHP) surface decontamination systems for component
in feed. The finished product consisted of a terminally sterilized bag aseptically assembled to a double-ended linkage into
which a prefilled standard glass vial was fit. The user activated the product and initiated reconstitution by simply twisting
the linkage that contained a device with double-ended needles.
A fully safe liquid pathway was then created to mitigate risk that inevitably arises from product admixture. Nipro designed
and built the main assembly system that incorporated robotic assembly stations. Shibuya was responsible for the isolators,
the VPHP tunnels, the parts feeders, and total system integration. The largest isolator was the autoclave interface, which
contained the conveying apparatus for loading specially designed bag positioning pallets into the autoclave. This isolator
had an enclosed volume of more than 1800 ft3, in fact the both the number and total enclosed isolator volume of this project still exceed that of any aseptic processing
line build anywhere in the world.
Given the size, scope, and complexity of this system, success would simply not have been possible without an extensive use
of automation. In some cases, the materials supply requirements were such that undertaking them by human intervention would
have been impossible in isolator technology.
Shibuya Kogyo and Nipro have collaborated on several other filling lines for dual-container products in which two separate
bags are assembled together and reconstitution occurs by the opening of a pealable seal between the two bags. These products
require both a highly automated liquid fill line and a powder fill line as well as an assembly station. Restricted access
barrier systems (RABS), isolators, automation, and terminal sterilization are used to achieve the most reliable outcome in
terms of sterility assurance while retaining desired production reliability and therefore consistent throughput (4)
Radiopharmaceuticals are not only aseptically filled but also have human exposure considerations. For this application, an
isolator was the most effective choice for the filling environment, while robots were used for product packaging, labeling,
and inspection. This system produces radiopharmaceuticals in both vials and syringes, which underscores another important
feature of robotics: positive container handling with easy adaptability without the change parts normally associated with
Robotics has the further advantage of avoiding the need for extensive lead shielding because the system is designed to operate
without intervention. This design saves both equipment and facility costs and makes access simpler when the facility is undergoing
periodic maintenance. The flexibility of the robots also facilitated the incorporation of visual systems for the inspection
of each syringe and vial and the verification of proper labeling information. The system has automatic alarm and rejection
should a problem be detected. This production system proved again that a variety of advanced technologies, including isolators,
automatic inspection systems, automated filling systems, and robotics could be brought together to ensure a high level of
aseptic process control with enhanced overall production reliability.
A few years ago, Shibuya Kogyo undertook the design and manufacture of a high-speed vial line for vaccines that was delivered
to Handai-Biken (Kagawa, Japan) (7). Commercial production from this facility commenced in 2005. All product filling, lyophilization,
and stoppering are performed in unidirectional airflow isolators that comply with ISO 14644 Class 5 requirements. The system
consists of five isolator sections:
- Depyrogenation tunnel and filler interface
- Filling and stoppering
- Rubber stopper supply system
- Lyophilizer conveyor
- Lyophilizer loading and unloading.
The total enclosed volume for this isolator network is 47.3 m3, with the lyophilizer loading and unloading and rubber stopper feed isolators each comprising about 17 m3 of total enclosure volume.