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Yoshi Izumi is executive vice-president at Shibuya Hoppmann Co., a subsidiary of Shibuya Kogyo, Co. Ltd.
James E. Akers is the president of Akers Kennedy & Associates, PO Box 22562, Kansas City, MO 64113, firstname.lastname@example.org.
The authors review the role of automation in aseptic processing and describe their experience in implementing advanced technologies, including the use of isolators and robotics.
A visit to a pharmaceutical aseptic processing operation in the 1970s would have some automation on display, but certainly nothing like what is possible today. Just three decades ago, automation consisted primarily of filling, stoppering, and capping of vial products, or filling and heat-sealing of ampules. Filling of syringes, to the extent it was done at all, involved extensive manual intervention. Lyophilization required completely manual transport of filled and partially stoppered vials from the end of the filling line to the lyophilizer. Once the containers arrived at the lyophilizer, the unit had to be completely loaded by hand, starting generally from the top shelf and working to the bottom, with the operators often ascending and descending ladders to reach the top shelves of the large-production lyophilizers. Of course even this task was a major advance over what one would have seen in the 1940s, when aseptic processing was predominantly a manual operation using rudimentary clean booths or glove boxes.
By the late 1970s, there was a greater awareness emerging regarding the impact of gowned operators in aseptic processing, and some industry scientists began to state this fact clearly and publicly. A 1988 article entitled, "A Review of Current Technology in Parenteral Manufacturing," written by members of the PDA research committee, stated forcefully that the principal contamination concern in aseptic processing was personnel-related contamination. This article noted that emerging technologies were already mitigating contamination risk. It was in that same decade that the authors became fully aware of the impact of personnel-borne contamination and took part in projects in which the processing equipment was specifically designed to mitigate that risk through the application of automation (1).
Early experiences in automation as a risk-mitigating factor
In 1981, one of us (Akers) took a position in which he was responsible for environmental monitoring and media fill. The aseptic processing operation in this facility was quite diverse and consisted of vials, ampuls, drop-dose products (both otics and ophtalmics), powders, and ointments. The basic mode of production was generally the same in all cases. Glass or plastic containers as well as caps, stoppers, dropper tips, and ointment tubes were sterilized by dry heat, ethylene oxide gas, or moist heat. After sterilization in bags or trays, these components were manually transferred to the filling rooms and then loaded by operator interventions onto accumulators or into parts hoppers. Process filters were also autoclaved and connected to the wetted path aseptically by operators; in fact, all setup activities were manual. In addition, all on-line sampling, weight checking, and equipment adjustment during processing were fully manual and required near-constant intervention.
It is both important and interesting to note that the practice of process simulation was at that time in its infancy as an absolute requirement and in fact had not yet become a standard practice for ointments. Typical media fill acceptance criteria were no more than one contaminant per each 1000 units filled. In our facility, successful media fills (i.e., those that met the acceptance criteria) were in the majority, but perfect media fills were a rarity. It should be noted as well that no media fill required more than a 3000 unit sample size. Typical line speeds were in the 40–60 unit/min range.
It was obvious as we studied media-fill outcomes that ampul processes provided the best results. Interestingly, ampul lines consisted of only one component and generally required fewer people and fewer interventions. Plastics, tubes and–to a lesser extent–vials were more challenging and required more personnel and a higher level of intervention intensity. However, the media fills that caused the most concern were those that involved lyophilization, which not surprisingly required more personnel and more interventions because the lyophilizer chambers had to be loaded manually. Thus, we knew empirically in the early 1980s what subsequent risk analysis studies have confirmed; namely, that manual lyophilizer loading was (and in some cases still is) a significant aseptic risk factor.
After a few years, a new vial line was installed that for the first time introduced automatic vial washing, continuous dry-heat tunnel for sterilization, and depyrogenation of glass vials. This far more advanced processing line operated at up to 300 vials/min and required only two operators, while the older vial lines it replaced required as many as six people working constantly. This processing line also featured far better stopper feeding and needed far fewer line interventions. The results were dramatic. As a result of the higher speed, media-fill tests expanded in sample size to 5000 units or more, and zero contamination results became far more common (2). In addition, although the cleanroom design and gowning conditions remained unchanged, environmental monitoring results were quite obviously improved in every facet. This fact was attributed to the lower personnel population in the filling room and the less vigorous work required because vial supply, previously a laborious task, had been fully automated.
Not long after the introduction of this improved and more automated vial line, a continuous ampul line was introduced and the improved performance was even more striking. Because of the very high speed operation and changing regulatory requirements, management made the decision to conduct media fills that lasted one full hour. As a result, media-fill sample size increased to approximately 25,000 units. Only one operator was required to run the line, and by and large they were only required to observe the line and to correct infrequent jams. An important lesson was learned and a lasting impression was made: Automation and the elimination of interventions reduced risk, not just theoretically but in practice as the results emphatically demonstrated (3, 4).
During the late 1980s, Shibuya Kogyo (Kanazawa, Japan) was selected to design, build, and install a state-of-the-art vial processing line at E.R. Squibb (New Brunswick, NJ). This vial production line embodied what were a number of automated features that are now rather common but were quite unusual two decades ago. One of us (Izumi) was directly involved in this project and the other (Akers) was fortunate enough to visit the facility not long after validation was completed and eventually became a technical consultant to Shibuya Kogyo. This facility not only had a fully automated vial-washing and depyrogenation system but also included automated weight checking, vial-handling advancements designed to prevent misfeeds, automated clean-in-place and steam-in-place systems to eliminate aseptic connections in set-up, and automated lyophilizer loading of three large production lyophilizers. Although the data processing and acquisition systems available at that time were far less sophisticated than what is available today, this filling line was arguably the most sophisticated aseptic production line in use in the pharmaceutical industry at the time of its installation. Automation had eliminated even the highly risk intensive aseptic set-up and lyophilization loading activities.
The ability of this system to run with minimal line stoppages and infrequent interventions pointed the way to the future in another way. It seemed that a marriage of automation and isolator technology, which was also an emerging and exciting new concept in pharmaceutical aseptic processing, would be a logical way forward. This has proved to be the case and the remainder of this article will be devoted to an overview of a few projects undertaken over the past decade and a half and will explain the role played by automation in solving sometimes difficult production challenges.
Webster's Unabridged Dictionary defines automation as "The technique, method, or system of operating or controlling a process by highly automatic means, as by electronic devices, reducing human intervention to a minimum." This is obviously and appropriately a very broad definition that includes what might be called machine automation as well as the field of robotics. Over the years, we have been involved in several projects that use automation and robotics, usually within the same process with the objective of as Webster's says, "reducing human intervention to a minimum." However, the objectives in these pharmaceutical manufacturing projects are not merely to relieve human operators of repetitive and often boring tasks undertaken in difficult or uncomfortable environments but also to reduce end user or patient risk from contamination. Experience has shown that automation and robotics can achieve both of these goals. In cases of high pharmacological activity and allergenic, cytotoxic, and radiological products, the benefit of increased operator safety also can be added (5).
Combination products, automation, and separative technologies
The first project began in 1994, when Shibuya Kogyo designed several filling lines for Nipro Corporation (Osaka, Japan) (6). These aseptic fill lines were for beta-lactam antibiotics and involved both automatic parts feeding and assembly. The first filling line involved no less than 13 isolators, a blow–fill–seal bag filling process, terminal sterilization with automatic feed and unload, and two semicontinuous vapor-phase hydrogen peroxide (VPHP) surface decontamination systems for component in feed. The finished product consisted of a terminally sterilized bag aseptically assembled to a double-ended linkage into which a prefilled standard glass vial was fit. The user activated the product and initiated reconstitution by simply twisting the linkage that contained a device with double-ended needles.
A fully safe liquid pathway was then created to mitigate risk that inevitably arises from product admixture. Nipro designed and built the main assembly system that incorporated robotic assembly stations. Shibuya was responsible for the isolators, the VPHP tunnels, the parts feeders, and total system integration. The largest isolator was the autoclave interface, which contained the conveying apparatus for loading specially designed bag positioning pallets into the autoclave. This isolator had an enclosed volume of more than 1800 ft3, in fact the both the number and total enclosed isolator volume of this project still exceed that of any aseptic processing line build anywhere in the world.
Given the size, scope, and complexity of this system, success would simply not have been possible without an extensive use of automation. In some cases, the materials supply requirements were such that undertaking them by human intervention would have been impossible in isolator technology.
Shibuya Kogyo and Nipro have collaborated on several other filling lines for dual-container products in which two separate bags are assembled together and reconstitution occurs by the opening of a pealable seal between the two bags. These products require both a highly automated liquid fill line and a powder fill line as well as an assembly station. Restricted access barrier systems (RABS), isolators, automation, and terminal sterilization are used to achieve the most reliable outcome in terms of sterility assurance while retaining desired production reliability and therefore consistent throughput (4)
Radiopharmaceuticals are not only aseptically filled but also have human exposure considerations. For this application, an isolator was the most effective choice for the filling environment, while robots were used for product packaging, labeling, and inspection. This system produces radiopharmaceuticals in both vials and syringes, which underscores another important feature of robotics: positive container handling with easy adaptability without the change parts normally associated with format changes.
Robotics has the further advantage of avoiding the need for extensive lead shielding because the system is designed to operate without intervention. This design saves both equipment and facility costs and makes access simpler when the facility is undergoing periodic maintenance. The flexibility of the robots also facilitated the incorporation of visual systems for the inspection of each syringe and vial and the verification of proper labeling information. The system has automatic alarm and rejection should a problem be detected. This production system proved again that a variety of advanced technologies, including isolators, automatic inspection systems, automated filling systems, and robotics could be brought together to ensure a high level of aseptic process control with enhanced overall production reliability.
A few years ago, Shibuya Kogyo undertook the design and manufacture of a high-speed vial line for vaccines that was delivered to Handai-Biken (Kagawa, Japan) (7). Commercial production from this facility commenced in 2005. All product filling, lyophilization, and stoppering are performed in unidirectional airflow isolators that comply with ISO 14644 Class 5 requirements. The system consists of five isolator sections:
The total enclosed volume for this isolator network is 47.3 m3, with the lyophilizer loading and unloading and rubber stopper feed isolators each comprising about 17 m3 of total enclosure volume.
Both machine automation and robotics play central roles in the operation of this production line. The depyrogenation tunnel has push-button setup and fully automatic sterilization of the cooling zone. It also has an automatic vial-counting system to ensure that each row of glass entering the tunnel is carefully arranged and introduced without crashing the vials into the previously loaded row. This automated feature reduces the likelihood of vial breakage.
The filling system has two weight-control features. The first is an automated mass flowmeter filling system in which all fill data are digitized and electronically stored. The second system is a gravimetric weight-check system that uses load cells to take empty and filled vial weights. The gravimetric weight-check data are also digitized and stored electronically. Both systems automatically alarm and reject out-of-specification containers. Actual fill-weight accuracies attained with the mass flow system are measured within ± 0.5% of the target.
The rubber-stopper supply system is fully automatic and uses the first VPHP-compatible robots installed and validated in the world. One such robot unloads sterilized containers of rubber stoppers from the autoclave, while a second robot lifts these cans and replenishes the load of stoppers in the feed hopper when signaled to do so by a level sensor. Thus, human operators are not involved in transporting containers of stoppers nor do they play any role in the feeding of stoppers into the feed hoppers.
Like the previously described vial line installed in the United States, the Handai-Biken system has fully automated lyophilizer loading and unloading. In this case however, the loading system is not only fully automatic, it is also VPHP decontaminated and operates within an isolator enclosure. This filling line is an excellent example of the marriage of machine automation and robotics with modern isolator technology. The use of isolators and VPHP decontamination requires that all components be resistant to long-term exposure to H2O2.
This article provides only a glimpse into the history of automation in aseptic processing and its development during the past three decades (8). Although our experience is extensive, we realize that there are many other examples of the use of automation in aseptic processing and the marriage of automation with modern separative environments such as isolators. We do not see the evolution in aseptic technology described in this article coming to an end; rather we believe it will follow an accelerating trajectory onward and upward. The future of aseptic technology lies in the continued implementation of automation with the ultimate goal being the complete elimination of interventions altogether. We have glimpsed this future with the design and installation of high speed "interventionless" aseptic processing systems operating at throughputs as high as 1200 containers/min.
Robotics continue to evolve as well, and VPHP-compatible six-axis robots are being designed for cytotherapy products among other potential production, research, and testing applications. These robots can be operated either under full electronic programmed control, or by humans controlling them by remote control devices called "Manipens." Current software allows the operator to quite literally train the robot to perform a specific task. These robots can interface well with single-use technologies (disposables) and are well-suited for aseptic compounding operations as well.
The future of automation and robotics in aseptic processing is an exciting one. Thousands of industrial robots are undertaking a wide range of manufacturing tasks in facilities throughout the world. Our industry has actually been relatively slow to adopt robots, but we believe change is underway and that the future of aseptic processing is one in which human contamination is no longer a risk (9).
Yoshi Izumi is executive vice-president at Shibuya Hoppmann Co., a subsidiary of Shibuya Kogyo, Co. Ltd. James E. Akers* is president of Akers Kennedy Associates and technical consultant to Shibuya Kogyo, Co. Ltd., email@example.com
*To whom all correspondence should be addressed.
1. J. Akers et al., "A Review of Current Technology in Parenteral Manufacturing," J. Paren. Sci. Technol. 42 (4), 53–56 (1988).
2. FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing (Rockville, MD, 2004).
3. J. Akers and J. Agalloco, "Aseptic Processing: A Current Perspective," in Sterilization Technology, R. Morrisey and G.B. Phillips, Ed. (Van Nostrand Reinhold, New York, NY, 1993).
4. J. Agalloco, J. Akers, and R. Madsen, "Current Practices in the Validation of Aseptic Processing–2001," PDA Technical Report #36, PDA J. Pharm. Sci. Technol. 56 (3), (2002).
5. J. Agalloco and J. Akers, "Risk Analysis for Aseptic Processing: The Akers-Agalloco Method," Pharm. Technol. 29 (11), 24–32 (2005).
6. J. Akers et al., "Manufacture of a Dual Chamber 'Kit' Product Utilizing a Combination of Aseptic Fill in Isolators and Terminal Sterilization," Proceedings of the ISPE Barrier Isolator Technology Conference, Arlington, VA, June 2007.
7. J.E. Akers, M. Kokubo, and Y. Oshima, "The Next Generation of Aseptic Processing Equipment," Aseptic Processing Supplement to Pharmaceutical Technology, 14–18 (2006).
8. J. Akers, K. Tanimoto, and M. Kawata, "Aseptic Processing the Japanese Way," Pharma.Manufacturing 5 (6), 34–39 (2006).
9. W. Morris and E. Hough, "Risky Business-Aseptic Processing," PDA Letter XLIV (7), 1 (July-Aug., 2008).