The scale: a system approximately the size of a three-story detached family house for filling and sealing, with four isolators and two freeze dryers. The technology: flexible processes for sensitive biopharmaceutical medicines. The implementation: seamless, as confirmed by the world’s largest generic drug manufacturer Teva.
It may come as a surprise that sometimes, when the order is placed or even when the system SAT is carried out, the medicinal products to be processed have still not been specified at all. This is not unusual if pharmaceutical companies wish to be prepared for D-Day with regard to their product pipeline. When a new medicine is approved, the production processes are then made available as quickly as possible.
Flexible processes are essential if – as is the case here – the system needs to be suitable for processing a wide range of medicines. Due to the high product and employee safety standards required by biotechnological medicines, the use of isolator technology and freeze dryers in this project was essential. The system’s range of operating modes and processing pathways ensure flexibility. The system is equipped with four isolators, so parallel batch processing is an option too.
Three processing pathways
The preparation process for the vials begins with an ultrasonic bath. This removes any encrustations and enhances the washer’s cleaning effect afterwards. A rotary washer takes in the pre-cleaned vials, washes the inner and outer surfaces and then dries them with air. The containers then enter a depyrogenation tunnel for sterilization.
Once the vials have left the tunnel, they enter an isolator-protected area of the system. The ten-head filling and sealing machine dispenses the product using particularly gentle peristaltic pumps. The double-decker configuration saves space. In the interest of simple operation, Optima Pharma installed the entire product feed outside sterile zone A. An RTP port connects the distributor hose securely with the pumps inside the sterile zone.
A sophisticated 100%-in-process control not only regulates the high degree of filling precision of srel +/- 0.75 %, but optimizes it too. In the first step, load cells calculate the tare weight of the vials. 100% of the filling weight is then dispensed in the weighing and dispensing process.
The system exits this start-up mode automatically when the product pathway has been vented and a defined degree of filling precision is being consistently achieved. The 100%-in-process control then goes on to check that each vial is at its filling weight. This filling system also offers advantages in its empty running mode. It can dispense the medicine until it starts to run out. The second set of load cells ensures that no under-filled vials find their way into circulation. Products that are over- or underweight are always ejected.
Maximizing the amount of sellable product
The sealing process plays an equally important role in transforming the available amount of the medicine into a maximum amount of sellable product. A pick and place system is involved here that gets the stoppers from a sorting bowl. A swivel arm takes the stoppers and pushes them into the vials under a nitrogen gas supply. Light barriers detect whether there is indeed a stopper on the vial. If there is no stopper, the conveyance system stops. The swivel arm with single valve control now repeats the sealing action in the relevant position. (As is customary, freeze-drying stoppers are only pushed in halfway.)
The vials now reach an intersection which either takes them to the freeze-drying process or straight to be crimped. This intersection zone is also isolator-protected.
Two freeze-drying systems, each with a set-up surface of 23.5 m², are available for freeze-dried products. The loading system forms what is known as a hexagonal cluster from the vials, which are fed in laterally. It fully loads a set-up surface each time. It is also important at this stage to use isolator protection to ensure pharmaceutical integrity.
If there is medicine undergoing the freeze-drying process, lasting from several hours to several days, Teva can use the system’s filling and sealing process in parallel for products that do not need to be freeze-dried. Up to the intersection, the processing pathway is the same as for freeze-dried products. The filled vials are now taken straight to the capping station, where the crimp caps are placed on the vials and sealed. A camera control checks they are in the correct position. The capping station is the system’s fourth isolator-protected zone.
The third pathway: once the freeze-drying process has ended, the vials, with fully inserted stoppers, proceed from the freeze-drying zone, via the intersection zone, to the capping process. After crimping, these vials are considered sealed in pharmaceutical terms.
FMEA, interface tests and simulations
Turnkey – in this project, this also involved monitoring particles with particle counters and air samplers installed by Optima. It also involved the redundant SCADA system, which is fitted with two servers. This controls the entire system from a central computer, for example the functions for selecting formats and formulas, and delivers batch reports. The camera system used, which checks the position of the crimp caps, is also quite remarkable. After just two days of tests and fine tuning, this system delivered the requested consistent results – which, in this industry, is an extremely short time span.
During the installation stage at the Israeli site, the customer only had to deal with one contact, just as they had throughout the project. On site, Optima Pharma largely handled filling and sealing, freeze drying, and isolator technology operations at the same time.
FMEA (Failure Mode and Effects Analysis) risk analyses were performed in advance to investigate the process for potential hazards. The interface tests carried out before hand also contributed to the success of the project, which, as the turnkey supplier, Optima Pharma guarantees. Controlling the freeze-drying systems was also simulated in advance to identify any potential faults. Over the course of this project, the CIP/SIP processes for the freeze dryers were optimized using simulations and visualizations. This project used new set-up surfaces for the first time, with laterally improved guiding mechanisms.
And the customer’s verdict? “Collaborating with Optima went perfectly. Our contact always found just the right solution. The teamwork between Optima and Teva was an essential key to success.” (Yakov Harony, Teva). In Spring 2016, the system will process its first medicines.
How does Turnkey “work”?
Excellent project management, communication, and technical coordination between teams are three conditions required for the benefits of the turnkey idea to come into play. The demand to deliver “turnkey” is high.
Approaching the customer with one central contact is a key feature of turnkey project management. This then benefits the customer, as it substantially reduces the complexity of project control. Additional advantages range from comprehensive support and standardized interfaces and documentation, to the centralized SCADA system within the complete system.
Any prospective turnkey system manufacturer needs to do their homework first. It doesn’t sound very spectacular at first but it means nothing less than introducing company processes and standardizations for all teams across the project:
- Uniform standards of communication for project management
- Reliable mechanical, electric, and software interfaces
- Standardized database for all construction departments