In aseptic processing, people are the primary source of contamination. Less human contact during manufacturing means less risk of contamination. To address this issue, Patheon successfully implemented a robotic filling line that operates in a closed isolator environment with no glove ports. This case study takes a look at the technology involved and highlights the implementation team’s experience with installation and qualification.
By: Terrence Hollis, Process Engineering Manager, Patheon
Terrence Hollis has 11 years of process engineering experience in the manufacturing of sterile injectables. Having worked in site and global engineering roles, his areas of focus include; moist heat sterilization, gaseous decontamination, UV decontamination, isolator technologies, aseptic processing, terminal sterilization and parametric release.
This article originally appeared in the Parenteral Drug Association (PDA) Letter, and is republished here with PDA’s permission.
The firm installed the Vanrx SA25, a gloveless robotic aseptic filling isolator (or aseptic filling “Workcell”), which consists of two isolators separated by a passthrough-style door. Sterile, ready-to-use (RTU) components are loaded in the bio-decontamination and staging isolator (DSI); then, filling and closure operations take place downstream in the filling isolator. The SA25 WorkCell can fill nested syringes, vials and cartridges. All material handling, filling and closing activities are performed by robotics within the closed system.
Internal surfaces of the the DSI and filling isolator do not come in contact with product, and they are biodecontaminated using vapor-phase hydrogen peroxide (VPHP). A validation strategy was developed to ensure the biodecontamination process provides a spore logarithmic reduction ≥6 and reduces residual hydrogen peroxide to 1 ppm at the end of aeration.
The horizontal, unidirectional airflow within the filling isolator is environmentally monitored by viable and nonviable sampling. Nonviable sampling uses a standard particle-counter system, whereas viable sampling is customized. Viable samples are collected periodically throughout a filling batch via a rotary centrifugal air sampler (RCS). The RCS unit provides sterile docking and undocking to/from the isolator through an integrated Getinge 190mm Beta Flange and a robotic arm inside the filling isolator actuates the alpha/beta door during sampling. A separate “labscale” isolator is required to create a sterile, Grade A environment for RCS preparation (e.g. decontamination and agar strip insertion) and for subsequent agar strip removal.
The filling system consists of a single needle, gamma-irradiated, fully disposable fluid pathway and a peristaltic pump. The filling operation consists of the following sequence:
The process repeats until the desired quantity is filled.
Onsite installation involved un-crating, movement to the filling suite and tying in to utilities (instrument air, process air, electrical and exhaust). The SA25 Workcell is relatively small (13.5’x6’x8’), so moving the equipment into the filling suite was straight forward and required no major disassembly. In fact, the isolator was moved from the first to the fourth floor of the building using a standard freight elevator. The isolator was then installed in a Grade C/ISO 8 filling suite with sufficient space to accommodate staging of commodities and filled units. Even with this allowance, the Workcell only took up 560 square feet of room space.
Validation followed the standard approach of factory acceptance testing, site acceptance testing, installation qualification, operation qualification and performance qualification. Key components included automation validation, filling and machinability validation, bio-decontamination cycle validation, and environmental monitoring validation. The most time consuming activity? Development and validation of the bio-decontamination cycles.
The SA25 Workcell consists of three bio-decontamination cycles: full system, DSI and filler. The full system cycle is carried out at the beginning of a batch before loading the DSI, which serves two purposes: decontamination of the filling isolator and decontamination of the transfer door gasket that separates the DSI and filling isolators. Following the full system bio-decontamination cycle, the DSI is loaded and the DSI bio-decontamination cycle is carried out. The filler bio-decontamination cycle is only used if the filler requires decontamination (e.g., sterility of the filling isolator is breached).
In general, the bio-decontamination cycle comprises four process steps: leak test, preheating, decontamination and aeration. The process does not include a step to condition air inside the chamber. The temperature and humidity of the air within the isolator depends on room conditions at the start of the cycle and must be strictly monitored and controlled. No air flows into or out of the isolators during the bio-decontamination process; internal fans are used to help distribute the VPHP during the exposure period. External HEPA-filtered air is introduced only during aeration.
The bio-decontamination validation strategy included development activities (conducted via engineering studies) to establish critical process parameters and biological indicator placement locations. Baseline parameters were derived from vendor-executed microbiological studies. Key components of the development included:
The performance qualification occurred subsequent to confirmation runs conducted during development and included biological indicator studies, as well as aeration evaluations.
This project introduced several new technologies to the site, which pushed the implementation team to think outside the box and collaborate with others in the industry. They quickly learned that having appropriate resources and internal support is essential for successful implementation.
As with any new project, more time was allotted for factory acceptance testing activities and to ensure that all cross-functional teams participated. At a minimum, a factory acceptance testing team should include representatives from the engineering, quality, maintenance and operations departments. The vendor played a key role in other studies. Vanrx executed several microbiological studies for the biodecontamination cycles and provided summary reports which were extremely helpful in establishing test functions and monitoring locations for development studies.
Communication was crucial to the successful validation of the Vanrx SA25 filler: good communications and strong working relationships between equipment vendors and end-users. The project team and management had to understand the inherent risk of setbacks involved when working with new technologies.
Robotic automation presented new challenges to the team who were unfamiliar with the technology. Robotic movements are precise and, if unaccounted for, dimensional variability of incoming commodities can greatly impact the fill operation (e.g., dimensional tolerances). Consequently, reviewing vendor specifications was essential. And, although the SA25 Workcell is designed for full automation, some occasions required operator intervention—via robot movements. So operators must be well trained on the technology. The team found that those with a background in automation adapted most readily.
As robotics and automation improve, the human element will be removed entirely from isolator technology, greatly reducing the risk of contamination. Yet, humans will still play a vital role in the successful implementation and validation of new isolator technologies.