The Impact of Automation on Aseptic Processing - Pharmaceutical Technology

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The Impact of Automation on Aseptic Processing
The authors review the role of automation in aseptic processing and describe their experience in implementing advanced technologies, including the use of isolators and robotics.


Pharmaceutical Technology


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

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 format changes.

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.

Vaccine filling

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.


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