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 factorIn 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.