A look back at the recent history of aseptic fill/finish and how AST brought new multi-format flexibility to the market with the development of the first ASEPTiCELL®
The Robotic Revolution: Looking back and moving forward after a decade of innovation
For decades now, robots have attracted the attention of drug manufacturers with the alluring promise of ergonomic and operational efficiencies. In the pharmaceutical industry, additional drivers to shift towards automation have appeared gradually and more frequently, but robots have only recently started coming into their own and proving their value in the field. This article will delve into some of the history of robotic applications in pharmaceuticals, particularly regarding early adopters in packaging and fill/finish processing. It highlights specific technological developments and includes an interview with a manufacturer who lived on the tip of the revolution as well as feedback from the one of the top robot manufacturers for the pharmaceutical space.
The use of robots can be seen across a variety of pharmaceutical applications. From end-of-line packaging and kitting to the handling of highly potent APIs, robots can be seen handling the critical operations that would otherwise put either the product, the operator, or even the patient at risk. The sterile space in particular has become an important niche market where nearly every major equipment vendor, along with various emerging parties, can be seen offering solutions that utilize the advantages robots have to offer.
In this sterile processing space, the shift towards robotics truly began with early adopters such as Vetter Pharma. These companies saw the value that robotics could offer in their contamination control strategy, and as early as 1992 Vetter adapted robots to support their sterile products. By implementing robotics in the lyo- loading and transfer process of manufacturing their dual-chamber syringes, they demonstrated early on how robots were capable of handling aseptic processing and meeting existing guidelines.1 In 1994, Nipro Corporation in Japan began successfully running. a complex robotic fill line for processing sterilized bags joined to a double-ended linkage for fitting prefilled vials. The system was massive and convoluted, with a total isolator volume of around 1,800 m3, but it did prove the remarkable capabilities of even primitive robots.2 Yet despite these early accomplishments, the market did not rapidly show much interest.
Even after the U.S. Food and Drug Administration (FDA) published its updated guidelines on aseptic processing in 2003, the fill/finish industry had remained cautious of evolving technologies to meet the new standards and felt the challenges outweighed their potential benefits. Nowadays, it is easy to walk the trade show floor and come across all sorts of isolated, robotic platforms for a variety of applications, but back in 2010 robots were not ubiquitous. This is when Revalesio, a biotech company based in Tacoma, WA focused on research into a promising potential treatment for Amyotrophic Lateral Sclerosis (ALS). Revalesio president Greg Archambeau described his own experience as follows: “Like many early stage companies, we started with an outsourcing strategy, as it seemed to make sense at the time. When our CMO partner encountered some quality issues, including a warning letter from FDA, we decided that having more control over the quality and timing of our clinical batches was something we would not compromise on moving forward. We chose to instead bring our fill/finish processing in-house.”
According to Greg, Revalesio had several specific design aspects that they were insistent on but unable to find solutions for. “We knew that our compound required flexibility and were willing to sacrifice speed for increased flexibility. So, we did our homework: we went to one of the mega packaging shows in Europe, scheduled meetings with the usual packaging suppliers, and even visited some sites. The usual players in aseptic filling did not see a potential market in the flexibility we were envisioning. This was no surprise to us, but we were not in a situation where we felt ready to compromise on our desire to have a single platform for filling IV bags, syringes, or vials,” said Greg.
What started as an impassible wall quickly became an open doorway for an innovative robotic solution. As Greg began looking to find a way to resolve this need for flexibility, he found a nearby vendor, Automated Systems of Tacoma (AST), who engineered a solution and brought to market the first ever robotic, multi-format fill/finish system.
A Need for Something New
So, how exactly did this roadblock evolve from Revalesio’s problem into AST’s solution? Greg reflects, “Rather than expanding our budget to accommodate a larger cleanroom and multiple fillers, we decided to seek out a partner. AST had pitched us their concept and proposed a collaboration. We knew that this effort would be an investment, both for the company and for the future of the industry.”
According to AST president Joe Hoff, “It was certainly a turning point in AST’s history, and we were very eager to begin working on the concept we had discussed with Revalesio. Based on our conversations, it quickly became clear that there was a real opportunity here. While other groups were exploring ways to reduce the stresses associated with routine tasks and contamination risks, no one had yet explored the flexibility that robots could bring. We had identified this gap in the market and felt that in the coming years, having a multi-format filling line would become a more attractive option. We saw a chance to pioneer something new, and with Revalesio providing a specific application we ran with it.”
For the robots themselves, the timing was perfect to bring in Staubli as a partner. Sebastien Schmitt, Staubli’s North American Division Manager, recalls: “In the past we had enjoyed success in semiconductor production and assembly, but by this time had developed a keen interest in pharmaceutical clean room applications. We had recently launched a new line of robots after successfully certifying them for vaporized H2O2 compatibility. The complete process application AST had envisioned for the Revalesio project was the perfect opportunity to showcase exactly how versatile and easily programmable these newer models could be. It felt like a good chance to prove something to the industry at large.” These robots addressed all of the industry’s commonly cited concerns: perceived difficulties in programming, worries of robots themselves posing a danger to operators, and a general lack of familiarity of what their operation would involve in terms of training and maintenance.
So, with these advanced robots providing improved programming flexibility, the new filling line was able to match the needs of multi-format aseptic processing. Breaking the mold in this manner demonstrated to both customers and other machine manufacturers that this degree of robotic automation is not only possible, but preferable. “Human operators remain the greatest risk of contamination in any aseptic environment,” remarked Joe, “so taking this step to prove that automation could solve a problem that had not yet been addressed, the need for multi-format processing, was absolutely critical. Without this flexibility, a facility would require separate fill lines for different container types, each machine carrying its own needs for training and maintenance, and the facility becomes needlessly complex to manage.” Sebastien added, “Nowadays, customers in the pharmaceutical industry are very interested in robotic automation solutions for a variety of reasons. Robots offer a high level of flexibility in clean and aseptic environments, hygienic design, lower contamination risk, and overall reduce the possibility of human error. Automation can now completely take over the delicate and repetitive tasks, giving employees a chance to focus their valuable time elsewhere.”
While forward-thinking development can lead to long-term returns, there are many hurdles to overcome along the way. Decisions must be made, and at times they can be made in error. Looking back, Greg stated: “We chose to rely upon manual sanitization versus VHP when we designed the system. It has worked out fine for us and the proof is in our 100% success rate in our verification media fills since our initial validation work in 2011. However, if I had to do it all over again, we would have invested in isolator technology leveraging VHP. We had also installed a closed RABS system, and our design to get components into the machine was innovative at the time but falls short when compared with modern fill lines.” Indeed, most equipment manufacturers on the market today are offering isolated lines with VHP capability. Modern systems with robots and integrated barriers are performing packaging operations for injectables, ampoules, capsules, and more.
For a multi-format system, customers also want to see that switching between container types is fast and easy. Though the original Revalesio line brought new flexibility to the market, the actual changeover process could be slow or clunky at times. Joe noted, “We have also done a lot of work to evolve our format change parts for operator efficiency and accessibility. The original line we had developed required much more effort.” On today’s platforms this format part changeover is much more user friendly and takes a matter of minutes on a robotic system. Companies like AST, Groninger, Steriline, and more are all boasting user-friendly format changeovers on isolated lines that use robotics to process nested containers.
Now that the market has caught up and adopted this new multi-format standard, it is exciting to imagine what the next steps might be. It seems likely that we will continue to see advances in format flexibility as manufacturers strive to keep facility costs down while staying competitive in terms of the products they offer. Asked about the future, Joe stated, “I see several core fundamentals of the fill/finish industry that will continue to define flexible aseptic fill/finish and drive technological innovations, including: small batch manufacturing, format flexibility, line configuration flexibility, high yield outputs, improved dispensing accuracies, limited or no operator interventions, and a desire for shortened lead times. Our customer driven experience is that flexible, multi-format fill lines using robotic automation, with enhanced intelligence are essential to meeting those demands.”
Greg also commented, saying “There have already been quite a few changes from our initial design to what is seen in the market today. As I look back, to not have to sacrifice productivity for flexibility would be great. I knew I was making that tradeoff a decade ago, and it worked for us during that stage of development, but it is exciting to see that this tradeoff is no longer necessary.”
Regarding upcoming developments in the field of robotics, Sebastien said, “We hope to continue developing robotic models that offer cleanroom-compatible design, higher repeatability, and overall low performance loss with increased speed. Our vision is to meet that need for flexibility and productivity with user-friendly machines that have the speed necessary to streamline critical pharmaceutical operations.
Programing, ease-of-use, and integration are also topics that we constantly work on with the goal of making our robots simpler and more user-friendly without compromising performance. We have our eye on “Industry 4.0” and the processing of big data, and we hope to continue advancing the use of computer vision in ways that we feel will push the pharmaceutical industry forward.”
The drug product trends identified over 10 years ago that led to the development of a new class of fill finish machines are only expected to continue. With high value orphan drugs expected to account for about 20 percent of all drug sales in dollars by 2024 , and an average annual cost that is 25 times that of traditional drugs, these high value orphan drugs will undoubtedly continue to drive technological innovation. The industry must continue pushing towards high flexibility, absolute precision, zero loss filling, and new container technologies that respond to the specific concerns involved with these products.
- Vetter - Company history. (2020). Retrieved June 25, 2020, from https://www.vetter-pharma.com/en/about-us/history
- Akers, J. E., & Izumi, Y. (2009, May 1). The Impact of Automation on Aseptic Processing. Retrieved June 25, 2020, from http://www.pharmtech.com/impact-automation-aseptic-processing?id=&pageID=1
- Pomeranz, Karen, and Karen Siriwardana. Orphan Drug Report, 2020, pp. 2–4. Retrieved June 25, 2020, from https://www.evaluate.com/orphan-drugs