Wash, Fill and Set
High-capacity vial processing line
An American pharmaceutical company requiring a new processing line for vials was looking for highest degrees of reliability, safety, flexibility and accuracy. From the planning stage to machine completion, over two years went into the complex production line for expensive cancer therapy drugs.
Standing in line waiting for a precious drop in quick and untiring succession - no, don't think of last week's Carnival revelers at the bar, we're speaking of filling small bottles, not draining them! The processing line built by Bausch + Ströbel at their factory in Ilshofen for a pharmaceutical company in the US, cleans, sterilizes, fills, closes and inspects 36 000 vials in just one hour. The 10.5 million Euro line will fill drugs that are often produced in complex biotechnological processes such as hormone preparations and medicines for cancer therapy. The customer requirements were correspondingly high, as Werner Wieland, head of the design department at Bausch + Ströbel, explained: "Apart from the high capacity, the CIP/SIP capability and an integrated crimping station, important aspects for the customer were high dosing accuracy and minimum residual product at the end of the batch as the medicines are so expensive to produce." The retail price of a vial will be somewhere in the region of 2000 US dollars. "Moreover the company wants to be able to fill various different kinds of liquid - without major changeover work. As water-based solutions require a different dosing system from, for example, proteins produced by genetic engineering the filling machine has two independent filling systems", said Wieland to elucidate a special feature of the line.
Seven main work modules mean a lot of testing
Due to the complexity of the production line, several mock-ups were required, starting in December 2007. Full-scale wooden models were built to simulate the situation as authentically as possible in order to ensure that all the manual interventions inside the closed isolator can really be carried out using the glove ports.
"After the Factory Acceptance Test (FAT) in December 2009 the production line is really ready for delivery", Wieland continued, explaining a further special aspect of this order, "but it is staying here for a few months longer. In the meantime we have taken the line into service together with the Swiss company Skan, who built the isolator. Now the so-called cycle development will be carried out, i.e. the program for the decontamination of the isolator will be developed here on our premises to maintain flexibility. To keep the costs down, this work is normally carried out at the customer's site as the installation of the isolator is very complicated. Moreover, it was a customer wish to have a very long training and trial phase on our premises." The whole production line occupies more than 400 m2. It can fill vials in the sizes 3, 5, 10 and 20 ml. Two employees unwrap the vials and load them onto a supply belt which provides a long buffer area independent of the machine cycles. On this belt the vials are fed to the cleaning area where they are cleaned by spraying and rinsing at six work stations. The next working step is sterilization in a tunnel. The equipment monitoring the supply of containers at the infeed to the tunnel ensures that the containers are fed smoothly into the tunnel and controls the synchronization with the machines located upstream and downstream. In the three zones of the tunnel the vials are pre-heated, then sterilized and depyrogenized and finally cooled again.
At the tunnel exit the vials are buffered and unscrambled on a rotary table optimized for the laminar air flow. From there they enter the infeed to the filling and closing machine where they are conveyed individually. This individual transport system is maintained throughout the line up to the individual marking of each vial so that the individual working positions of each and every vial can be traced (Track and Trace). The filling machine has a 12-position dosing station. Two dosing methods are available: valveless rotary piston pumps and a time/pressure dosing system which is provided in duplicate. The latter is particularly gentle for biotechnological products with long molecular chains. When changing from one batch or product to the next, all the product carrying components can be cleaned and sterilized using the integrated CIP/SIP system so that the removal and reinstallation of the parts is superfluous.
Immediate control
The amounts dispensed are permanently monitored by an In-Process Control system (IPC). Two electronically controlled precision scales determine the exact quantity dispensed by determining the tare weight prior to dosing and the gross weight after the dosing process. The system works with a check rate of 4% without reducing the production output.
The closing system provides each vial with a rubber stopper. Immediately before and during the stopper insertion process, the interior of the vial is flushed with nitrogen so that the residual oxygen inside the vial is below 2%, thereby protecting the vial contents from ageing. The suction wheels continue the individual transport to the crimp-cap machine. As the vials pass beneath the cap transfer track each pulls a cap out of the track. This cap is then crimped firmly to the vial neck in a continuous motion as the vials are conveyed through the machine. Still conveyed individually, the vials reach the coding and inspection machine where each vial receives a unique code which is subsequently checked. The last working step is loading the vials into trays.
Quick airlock for auxiliaries
The working area of the filling and closing machine is contained in an isolator which provides aseptic production conditions of the clean room class "A" (ISO class 5). The required consumables, such as rubber stoppers, are introduced into the isolator interior via special Alpha-Beta ports that maintain sterility. For other indirect material such as tools, Petri dishes, etc. a separate mobile material airlock is available in which the material is sterilized within 30 minutes. The sterilization inside the airlock is carried out with H2O2 just as the isolator interior itself. As the drug to be filled reacts to H2O2, the residual exposure level must not exceed 0.03ppm. This meant a lot of development for the Skan engineers to achieve a good decontamination cycle time.
Deciding facts
for manufacturers
- The high-capacity line processes 36000 vials per hour. It requires over 400 m2 floor space in three rooms
- Special features of the line include two independent filling systems, the in-process control of the tare and gross weights of the vials, the integrated CIP/SIP system, and the low-abrasion, individual transport system.
- The twelve position dosing station works either with valveless rotary piston pumps or with a time/pressure system that is installed in duplicate.
- The isolator has special Alpha-Beta ports so that the consumables can be brought inside without impairing sterility. An additional sterilizable material airlock is provided for tools, Petri dishes, etc.
