A masterpiece of sophistication
A new isolator for sterile filling combines cleaning, sterilizing, filling and closing, monitoring and precision-counting magazining functions in one.
What has to happen to achieve a topclass sterile filling process? Two things need to coincide: a discerning customer and engineers who know how to turn the customer's vision into reality. And it happened four years ago at Bausch + Ströbel in Ilshofen/Germany, when an American pharmaceuticals company decided to place an order for a high capacity sterile filling line.
Now the line stands ready for delivery in the assembly area of the machine hall at Ilshofen and the engineers at Bausch + Ströbel and Skan, who built the isolator, are clearly very proud of their achievement. And with good reason, as not only does the machine contain a particularly high proportion of specially fabricated features but the pharmaceuticals customer is also particularly demanding when it comes to safety.
"In 20 years, we haven't come across a customer who has subjected a line to such rigorous pre-testing," comments Harald Reber, the Technical Sales Project Manager at Bausch + Ströbel. Even before the start of production, scheduled for the end of 2012, the tests alone consumed primary packing material to the value of EUR 2 million. And the next step is for engineers to travel from the USA to Ilshofen for some six months' training on the line. This will involve conducting test runs on the line under authentic operational conditions and production runs with the actual product - an option which the customer believes to be very important, emphasizes Head of Construction, Werner Wieland.
It starts and ends with safety
The star feature of the machine is the customized conveyor system which was only incorporated into the planning in early December 2009, i.e. when the design had already been signed off and the isolator was already at the planning stage as well. Even after the event, it is a situation that still brings the project manager out in a cold sweat. The clever part is that each vial is individually drawn into the filling and closing machine by pneumatic means and read by a sensor. From this point onward, the vial can be identified and traced across the entire process. At the end, a 2D data matrix code ensures that the vial is assigned to the correct batch.
"The customer expects a reduction in rejection rates from the Track and Trace System," says Wieland, based on the capacity of the system to attribute reject products to specific process steps and therefore allow the respective process steps to be optimized. The spoke wheels of the conveyor system may look like classic car parts but the design is deliberate with their minimal aerodynamic drag and the need for a particulate-free environment. In addition to this, the delicate design of the vial holders is best suited for transport by air conveyor in the filling section.
As the filling process involves extremely costly medicines, in-process monitoring has also been optimized. Two electronically controlled precision scales calculate the effective filling quantity by determining the tare weight prior to dosing and the gross weight after the dosing process. The net weight forms the basis for electronic monitoring of the amounts dispensed, which corrects automatically to the target value when required. A record with statistical evaluation is created of all the objects checked by the in-process monitoring system. The system works with a four percent check rate for this line, which Wieland believes is currently unbeatable: "I am not aware of any higher IPC rates currently on offer."
Working to the millimeter
The high capacity machine fills 36,000 vials per hour and covers a correspondingly large area; precision clad in glass and stainless steel, it extends across 400 square meters, occupying an area as large as four houses. Later on at the customer's premises, the line will be accommodated in three rooms. The line incorporates seven modules: an upwrapping and loading station, cleaning machine, sterilization tunnel, filling and closing machine, crimp-cap machine, coding and inspection machine and two magazining devices. All the individual components, from the stainless steel filling needle through to the stainless steel washing machine guard, began life as metal parts in the productions halls at the Ilshofen plant.
"We work with an extremely high degree of vertical integration," emphasizes Reber. So that all the components come together like ballet dancers in a perfectly choreographed performance later on, precision work is called for throughout the entire line - but nowhere is this more evident than in the customization of the isolator, which in this case comes from Skan. The moment of truth is when the engineers marry up the isolator with the filling machine - when they find out whether the tailor-made suit fits or not. Another feat of precision tailoring are the glove ports. In order to ensure that the ports are correctly positioned and access to the filling space is possible, a mock-up was constructed and tested thoroughly over several days. The cycle for hydrogen peroxide decontamination developed by Skan for the customer is likewise finely tuned. That is another special aspect of this project, says Wieland: "Normally, the customer does it themselves."
A further challenge was the sensitivity of the product dispensed, which reacts to hydrogen peroxide and therefore requires a residual concentration of 0.003 ppm of hydrogen peroxide. To permit as much flexibility as possible, the isolator is fitted with a quick airlock which allows non-autoclavable materials to be introduced and taken out without impairing sterility during the filling process as well.
The twelve-position filling and closing machine has two dosing stations. Therefore, the customer has the choice of applying the best dosing process for different substances in each case. The time/pressure dosing process is particularly gentle on therapeutic proteins with long molecular chains. If, on the other hand, high metering accuracy is preferred, valveless rotary piston pumps are used. The time/pressure dosing system is installed in duplicate, saving time on product changeovers. While production operations are running with time/pressure dosing system no. 1, the no. 2 system can be cleaned, sterilized and prepared for subsequent productions runs, which means that the production line is efficiently utilized even when processing small and varied batches. What is more, while operators have the option of filling four different vial sizes - 3, 5, 10 and 20 ml - there is just one object holder which saves considerable time on format changes.
