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Sterile manufacturing of small batches, in facilities including hospital compounding pharmacies and 503b outsourcing facilities, benefits from automation.
Traditionally, compounding facilities—also called 503B outsourcing facilities in the United States in reference to the section of the US regulation under which they are registered (1)—have conducted drug manufacturing operations manually; “on demand” production of a wide range of drugs needed by hospitals and pharmacies as well as drugs on FDA’s drug shortages list did not lend itself to automation in the way that longer-run, scheduled production did. Robotic automation technologies available today, however, offer benefits of greater efficiency and higher quality even for small volumes.
“Robotics offer several significant advantages for aseptic compounding. Most notable is that the greatest source of contamination, the person, is removed from the process,” says Chris Smalley, an independent compounding pharmacist advisor. “There is a robust traceability to what is performed, including volume, drug barcode scan and more, and it does not matter what hour or day of the week the robot operates,” explains Smalley. He notes that, in some cases, a robot is set up to operate on its own overnight (i.e., “lights-out” manufacturing), and the completed products are unloaded and checked the next day.
“Minimizing risks associated with aseptic processing is crucial when working with compounding systems,” agrees Randy Fraatz, vice-president of North American Operations at Steriline, which produces aseptic manufacturing equipment. “The primary benefit of robotics and automation in general is safety, coming from the reduction of human-related mistakes in the entire process.” Other benefits, says Fraatz, include the accuracy, efficiency, and reliability that result from automation. “If errors are reduced, process reliability and quality improve,” he explains.
Despite these advantages, uptake of robotics is slow, and many 503B outsourcing facilities continue to have technicians working in laminar flow hoods or biological safety cabinets to handle beakers and flasks for solution compounding and fill vials manually using syringes, notes Smalley. He points out that some large teaching hospitals have adopted robotics for large-volume parenterals and for oncologic compounding and filling. “Smaller hospitals that focus on a specialty, such as orthopedics or oncology, appear to be the second wave,” Smalley adds.
An early example of a hospital compounding facility that adopted automation was the overall winner of the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards in 2019 (2). The Kantonsapotheke Zurich (KAZ) supplies oral, dermal, and parenteral formulations to the Canton of Zurich hospital system under current good manufacturing practice (CGMP) conditions. Exyte, the engineering firm for the project, said in the award announcement: “This facility raised the bar for quality performance to CGMP levels, which had never been done before in a hospital compounding facility” (2).
Although robotic systems have many advantages, one of the challenges is designing and programming for flexible operations. Since it takes time to set up the systems to manage different material combinations, speed can be limited. “For a compounding combination that requires a lot of flexibility, such as handling a wide range of materials to prepare one compound, the system will need more time to process materials,” says Fraatz. “In many cases, humans are typically able to handle different types of materials and combinations faster than robotics, but contamination risks are higher.” He explains that planning ahead is important for using robotics, so that the right tools, equipment, and programming instructions are ready for a specific process.
“The user requirements need to be clearly and completely defined,” agrees Smalley. “Robotics can only work with the tools that they are constructed with, for instance vacuum-assisted suction cups, pincers, barcode scanners, syringe operators, and the like. Additionally, they can only perform tasks that were included in their programming. Refitting and reprogramming can be problematic.”
Another challenge is the need to have barcodes that can be identified by the automated system. “Not all vials have barcodes, and new products or new brands of generic drugs result in barcodes not in the robot’s database. Software updates are constantly needed,” notes Smalley.
New developments are focusing on improving software and improving material handling. “Changes are being made to software to enable the robot to operate more smoothly and efficiently, as well as to make the user interface more intuitive. For material handling, some robotics manufacturers are focusing on loading cells, while others are looking at the ‘hands,’ as it were, trying to make the way the robot grasps items more securely without the danger of breaking the item,” reports Smalley.
A best practice for robotics users is periodic service by the equipment manufacturer that includes maintenance and adjustment, as well as software updates to address operational and security needs, notes Smalley.
“Routine maintenance and attention are absolutely required for robotic automation in the compounding space,” agrees Fraatz. In his experience, various hospitals tend to be familiar with using high-tech equipment such as robotics (as in some surgical settings), but the overall compounding industry is not yet as aware of how process automation can be used in compounding environments.
In particular, integrating robotics inside isolators is a relatively new technology for the compounding environment, says Fraatz. “True isolators have become very common in the pharmaceutical processing industry, and are the safest containment solution available for the compounding market as well,” he says. “From a best practice perspective, compounding organizations need to evaluate and adjust their quality risk management philosophy, including process and validation protocols for this type of automation. Evaluating [the use of isolators and robotics] is a multi-department effort, as there are also facility considerations in terms of what they may need, concerning cleanroom design or availability of utilities, for example.” Fraatz notes that it is also important to evaluate the process flow, including how materials are introduced to the compounding environment and handled after compounding. He points out that robotic equipment can be designed to be compatible with cleanroom conditions. “Cleanroom conditions require easy to clean tools, low particulate generation, and equipment designed to respect the clean airflow required,” notes Fraatz.
A pharmaceutical manufacturing company adopting cutting-edge robotic technology for its CGMP 503B operations is Nephron Pharmaceuticals in South Carolina. The company, which specializes in producing generic respiratory medications using a fully automated process with blow-fill-seal (BFS) technology, launched its division for sterile compounded drugs in 2017 and began with manual operations, in which pharmacy technicians worked inside laminar-flow hoods to fill parenteral solutions coming from sterile filtration into intravenous (IV) bags or syringes. Now, Nephron is moving to robotic systems inside of the laminar-flow hood to perform these fill/finish operations. The company worked with the University of South Carolina (UofSC) and Clemson University in two separate projects to custom design robots for this application. In April 2021, Nephron validated the UofSC system and began commercial production, says Lou Kennedy, CEO of Nephron. A second robot is already being built, and more are planned. “We’re producing drugs on FDA’s drug shortages list, and this 503B space is growing,” she says. Robotic systems will improve productivity, reduce the burden of repetitive physical work for operators, and provide better accuracy and precision. Future projects will seek to increase speed of the robots to obtain higher throughput.
In addition to being used in commercial production at Nephron, Kennedy would like to see the robotic systems licensed to hospital compounding facilities. “What I love about both the Clemson and UofSC projects is that as we collaborate with both undergraduate and graduate students, we’re helping develop future industry employees,” says Kennedy.
Although a common fear is that robots will eliminate people’s jobs, Kennedy says this concern is unfounded. “Robotics is not eliminating people; it’s teaching people to have new skills to operate automation,” she notes. “Operators need to learn how to service the robot and work with it, to solve a jam or replenish components, for example. Operators are also needed for quality functions.”
Kennedy notes that Nephron sees a need for more pharmacy technicians, and the company works closely with local schools to help develop the future workforce. For example, Nephron built a sterile compounding lab on the nearby UofSC campus that is used to train pharmacy students at the university as well as two-year students from the local technical college in using robotics in sterile compounding.
Both developing an understanding of how robotics works and specific training with the equipment and its functions are key, adds Fraatz. “It is a new approach, which means trust needs to be gained, starting from education and understanding, so people can appreciate the purpose of robotic automation. Once they believe in the purpose, they can grow their familiarity and comfort with it.”
1. FDA, “Information for Outsourcing Facilities,” fda.gov (Sept. 10, 2020).
2. Exyte, “ISPE’s 2019 Facility of the Year Award for Operational Excellence & Facility of the Year Overall Award won by partners Exyte and Kantonsapotheke Zurich,” Press Release, Oct. 30, 2019.