Robot System Safety in Aseptic Drug Manufacturing
The key to Advanced Aseptic Processing (AAP) is absolute control of all sources of contamination, most importantly human-generated contamination. Robotics and isolator-barrier systems will increasingly be the core technologies furthering this effort. A properly integrated robot system that is compliant with ANSI/RIA safety requirements, combined with a properly designed and implemented isolator-barrier system, offers a flexible robotic cell that is compatible with the strictest regulatory standards. Ultimately, the many layers of operator and product protection provided by isolated robotics offer superior control over the ingress of contaminants compared to traditional cleanroom manufacturing processes, and thereby protect product quality and minimize risks to patients and personnel.
Industrial manufacturing of injectable drug products presents distinct challenges centering on minimizing contamination to ensure patient and personnel safety as well as product quality. In order to meet these challenges, pharmaceutical companies are increasingly implementing Advanced Aseptic Processing (AAP) systems. These utilize advanced automation, Restricted Access Barrier Systems (RABS), isolator-barrier systems and robotics, with the goal of restricting operator access to the product and to critical areas of manufacturing machinery. An isolator-based robot system, properly implemented according to ANSI/RIA R15.06 safety requirements for industrial robots and robot systems and current Good Manufacturing Practices (GMPs), results in a robot cell that meets Advanced Aseptic Processing requirements, restricting operator access and measurably lowering the risk of product contamination.
Advanced Aseptic Processing (AAP)
The Parenteral Drug Association (PDA) describes an aseptic process as “The process for manufacturing sterile products by which microbiological contamination is eliminated from the product and product contact surfaces protecting the product from sources of contamination” (PDA Technical Report No. 44, 2008). The challenge for pharmaceutical drug manufacturers is to ensure that the products they manufacture are made in a manner that precludes microbiological contamination. This is especially critical for injectable or parenteral drugs, which carry the highest risk, since injection bypasses all of the patient’s natural barriers.
Traditionally an operator in an open, ISO 5 cleanroom environment performs sterile drug manufacturing using automated or semi-automated machinery, or even manually. Although operators within cleanroom environments wear sterile garments, they remain the greatest contributor to cleanroom and product contamination. A study by Whyte (Whyte, 1998) showed how the activities of operators wearing cleanroom gowning for particles 0.5 μm in size affects particle generation rates:
• Sitting motionless: 500,000 particles per minute
• Sitting with head, arms and body moving: 1,000,000 particles per minute
• Walking at 2 mph: 5,000,000 particles per minute
The study clearly illustrates that, due to their significant contribution to particle generation, removing human operators from the manufacturing process is essential to minimizing the risk to product sterility.
Advanced Aseptic Processing (AAP) uses automated technologies, such as robotics and physical barriers, to eliminate operator intervention with the process, open product containers, and exposed product contact surfaces. The key to AAP operation is maintaining absolute control of contamination sources, through physical and aerodynamic means, against contaminant migration into the sterile environment.
The Advantages of Using Robotics in Aseptic Processing
Aseptic manufacturing is a repetitive activity that requires a high degree of reproducibility in order to consistently produce a quality sterile product. Robots are well suited to providing the accurate and repeatable operation this process demands; further, they can operate in environments where humans cannot. This becomes particularly important in applications that require containment of highly active and potent compounds. Unlike human operators, robots can be safely integrated into critical aseptic areas, as they generate extremely low, non-viable and viable particulate levels compatible with ISO 5 environments. The TX series Stericlean and HE 6-axis robot arm from Stäubli Robotics, for example, are designed to advance the compatibility of robotics with isolators and Advanced Aseptic Processing, and have shown to be effective in applications such as sanitizing with IPA (Isopropyl Alcohol) and bio-decontamination with sporicidal agents and vapor phase hydrogen peroxide (VPHP).
Flexibility is another advantage to using isolated robotics rather than traditional aseptic machinery. Robots are completely adaptable and can change with the product or process. If the application or container format changes, the robot system can be reconfigured with relatively minimal investment. The turnaround time and resources involved, generally consisting of reprogramming, adding new or modified end-of-arm tooling, processing fixtures and utilities such as vacuum and sterile air, are considerably less than investment in a new, dedicated machine or filling line.
Robot tool changer technology, largely untapped in pharmaceutical applications, is widely used in other industrial manufacturing sectors to maximize the flexibility of robot systems. Tool changers allow the robot to quickly couple and decouple the end-of-arm tooling to perform manufacturing operations that cannot be performed on a single tool. It is conceivable that a single aseptic filling line could be designed for multiple container types i.e., syringes, IV bags, vials, etc., so that the operator would only need to provide the robot with the proper tool for each container type, thus giving the same manufacturing line more flexibility with rapid changeover.
The Role of Robot Safety in Product Safety
In typical industrial applications, a robot cell is enclosed with a safety fence having a combination of light curtains, laser area scanners, electronically interlocked doors, and awareness signaling to safeguard the operator from the robot’s “restricted operating space.” ANSI/RIA R15.06 safety requirements for industrial robots and robot systems provide robot system designers with standard methods for assessing risk to operator safety, define requirements for protecting personnel interacting with or near the robot system, and assist in devising strategies to mitigate the level of assessed risk.
The combination of isolator-barrier technology with robot safety requirements ensures that protection of the critical zone is maintained during aseptic production. With isolator-integrated robots, the isolator walls serve as the safety fence encircling the robot. Light curtains detect operator presence at the glove port(s) and access door(s) are electrically interlocked, mechanically preventing them from being opened. The electrical outputs from these safety devices can be recorded and attached to the product batch record. Additionally, quality control personnel can verify that the recorded interventions were validated per media fills and followed Standard Operating Procedures (SOPs) for the process.
In a Restricted Access Barrier System (RABS) application, the designer of the control system can utilize these same safety mechanisms, developing a systematic approach via the machine control architecture to mitigate contamination risk during open-door interventions. This strategy would prevent interventions from taking place, or manufacturing from resuming, unless certain conditions are met. Contamination risks would be reduced by having the control system walk the operator through a defined and validated process when intervention is necessary. For example, the robot could be programmed to move the tool to the farthest point away and above the intervention location (near the supply HEPA filter, for example) prior to the door being unlocked, thus minimizing contamination risk to the product where it makes contact with the robot tool.