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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Closed systems for aseptic fill and finish were featured at INTERPHEX 2019.
Aseptic processing is as important as ever, and new aseptic product areas, such as personalized medicine and combination products, are growing, noted James Agalloco, president of Agalloco & Associates and member of the editorial advisory board of Pharmaceutical Technology, in a presentation at INTERPHEX 2019 (1). Technology is changing rapidly, and equipment manufacturers have introduced new technologies for closed systems, including isolators and single-use disposable systems for product transfer and fill/finish.
Despite the advantages of systems that remove operator intervention, such as gloveless isolators with robotic handling of ready-to-fill components, not all users are ready to adopt these new technologies, said Agalloco. Concerns about costs, regulatory response, and potential project delays are reasons for hesitation. “Like it or not, however, closed systems are the future of aseptic processing,” concluded Agalloco.
One option for closed processing is restricted access barrier systems (RABS). RABS are a relatively easy upgrade to implement in existing cleanroom facilities and may have a lower capital expense than isolators, but are more expensive to operate. “RABS are most useful as an upgrade of an existing facility, because the investment can be staged over a period of years, and a portion of the existing infrastructure and utility systems can be reused without modification. Long term, however, I don’t think RABS have much of a future,” says Agalloco.
Isolators are an increasingly popular solution, agreed equipment vendors at INTERPHEX, where several new systems were on display. According to Randy Fraatz, vice-president of North American Operations at Steriline North America, the increase in use of isolators is driven by the need to reduce contamination risk and increase worker safety, and by encouragement from regulatory bodies to use technology such as isolators. While 25 years ago there may have been only a few isolator installations, today 80% or more of Steriline’s projects are isolator based, with only a few RABS or traditional cleanroom installations, says Fraatz.
Another trend is the increasing use of robotics, rather than traditional automation, especially for material handling within a closed system but also for handling components at the front-end and at the discharge, adds Fraatz. Robotics are more efficient and flexible, and they reduce the number of parts needed inside a closed system, which increases cleanliness. While traditional automation is still best for high-speed applications (e.g., greater than 300 vials/minute), robotics are beneficial for the flexibility in handling multiple container sizes and for reducing reject rates, which is more crucial in high-cost goods such as personalized medicines, comments Fraatz.
Olivier Cremoux, business development manager for North America, Robotics at Stäubli, agrees that there is growing demand from machine makers for robotics because robots allow a reduced footprint and lower particle generation with increased flexibility. Stäubli's Stericlean robots, including the TX2 collaborative six-axis robots and the four-axis TS2 SCARA robots, are designed to be compatible with hydrogen peroxide sterilization so that they can be used inside a closed system, explains Cremoux.
Steriline’s Robotic Vial Filling Machine (RVFM), designed for filling inside an isolator using bulk primary packaging, uses one or two robotic arms made by Stäubli to move the vials within the machine. The machine is designed to detect missing stoppers or caps and to allow repeated operations to correct the missing piece within the process so that the problem container can be fixed rather than rejected (2). While the RVFM handles bulk containers, the company’s robotic nest filling machine is designed for filling ready-to-use nested containers inside a RABS or isolator.
Fraatz sees interest in the industry in continuing to go further in removing possible contamination sources, such as designing isolators with fewer glove ports, and eventually gloveless isolators.
Vanrx Pharmasystems’ SA25 Aseptic Filling Workcell is a gloveless isolator technology in use today. In 2018, for example, Fujifilm Diosynth Biotechnologies reported that it had invested in the workcell to expand its gene therapy and viral vaccine fill/finish capabilities in support of late-phase candidates and commercial supply at Fujifilm’s Flexible Biomanufacturing Facility in College Station, Texas (3). The systems from Vanrx use robotic arms for repeatable filling that is also flexible for producing smaller batches and using different container formats (4).
Fedegari displayed a prototype of its multi-process system that contains sterilization, washing, and fill/finish, all within an isolator. The system uses a seven-axis robot, constructed completely from stainless steel, for handling containers inside the isolator. Fedegari’s proprietary Thema4 software, used for the robotic control system, provides complete audit trails and data integrity.
Other closed fill/finish systems at INTERPHEX included AST’s GENiSYS R robotic filling and closing machine; NJM’s Dara NFL/2-RDL aseptic filling and closing machine for ready-to-use, nested vials; and groninger’s Integra aseptic filling machine with an integrated isolator using SKANFOG decontamination (5). SKAN’s SKANFOG Spectra Modular Aseptic Processing and Sterility Testing Isolator System was awarded “Best in Show” at INTERPHEX 2019 (6). The system allows faster transfer into an isolator and faster isolator decontamination cycles, said the company.
Watson-Marlow Fluid Technology Group displayed its new Flexicon FPC60 peristaltic fill/finish modules that are built to fit a small footprint. The modules-which include vial infeed, filling, stoppering, capping, auto-reject, gas purging, and product outfeed-are designed for users to create their own filling system for small-batch applications. Machine guarding is standard, and integration of laminar airflow, restricted-access barrier systems, or isolators are also available. According to the company, the entire FPC60 fluid path has been developed for single-use, which simplifies cleaning validation and facilitates changeover between liquid types (7).
Several systems for decontamination of closed aseptic systems or cleanrooms were on display at INTERPHEX. The DECOpulse Biodecontamination System from Optima Pharma/Metall+Plasticreceived an INTERPHEX Exhibitor Award for its system that uses atomization to produce vapor-phase hydrogen peroxide. The approach provides faster decontamination, improved safety because of reduced outgassing, and shorter decontamination cycles, says Dena Flamm, business development manager at Optima Pharma. The patented system’s atomization-driven evaporation creates droplets of a defined size that evaporate quickly, which results in a more homogeneous and faster distribution of hydrogen peroxide, says Flamm. Another benefit is that the technique, which doesn’t require additional heating to evaporate the liquid, prevents unintended decomposition of hydrogen peroxide. Optima offers the DECOpulse system for all its isolators as a turnkey filling solution.
TOMI Environmental Solutions displayed its SteraMist binary ionization technology (BIT), a patented two-step process that creates ionized hydrogen peroxide (iHP). The process, originally developed in a program with the US Defense Advanced Research Projects Agency, uses a lower percentage hydrogen peroxide compared to other systems. The company installed SteraMist systems in four cleanroom cGMP suites in a new Pfizer facility in Chesterfield, MO, TOMI announced in an April 10, 2019 press release. The Chesterfield facility, at approximately 295,000 ft2, houses Pfizer’s BioTherapeutics Pharmaceutical Sciences R&D group. This SteraMist iHP Custom Build-In System uses 20 ceiling-mounted SteraMist applicators connected to dual-generator control cabinets, programmed to run one or all applicators simultaneously, which will be used on a daily basis to ensure total disinfection and decontamination, reported TOMI (8).
1. J. Agalloco, “Aseptic Processing 2019: Trends and Challenges,” Presentation at INTERPHEX (NYC, 2019).
2. Steriline, “New Technologies and Customization, Steriline is Following the Innovation Path to Meet Pharma Customers’ Needs,” Press Release, April 2, 2019.
3. Fujifilm, “Fujifilm Announces the Expansion of Its Fill Finish Services to Include Late Phase And Commercial Production Of Gene Therapies And Viral Vaccines to Become an End-to-End Solutions Provider,” Press Release, May 23, 2018.
4. J. Markarian, “Robotics Solve Aseptic Filling Challenges,” PharmTech.com, June 20, 2018.
5. H. Forcinio, “Packaging Innovations at INTERPHEX 2019,” PharmTech.com, March 20, 2019.
6. SKAN, “Award Winner at INTERPHEX New York,” Press Release, April 5, 2019.
7. Watson Marlow Fluid Technology Group, “Uniquely Configurable Flexicon FPC60 Fill/Finish System Offers Production Flexibility,” Press Release, Jan. 10, 2019.
8. Tomi Environmental Systems, “TOMI Environmental Solutions, Inc. Implements SteraMist Into Pfizer, Chesterfield, MO,” Press Release, April 10, 2019.