For the first time, Thermo Fisher Scientific VVS (formerly Brammer Bio) is relying on an OPTIMA VFVM isolated filling and closing machine for fill/finish of viral vector products. This provides the Thermo Fisher Scientific group's Viral Vector Contract Development and Manufacturing Organization (CDMO) with a safe turnkey solution and minimal product loss per batch, as well as other benefits.
As a CDMO, Thermo Fisher Scientific VVS has already processed over 60 different viral vector products. In this relatively new field of gene therapeutics, this particular wealth of experience has been incorporated into the project with Optima.
Viral vector products are very expensive. Hence, the new filling system with integrated product saving features ensures the highest number of filled vials per batch, explains Dena Flamm (Business Development Manager at Optima Pharma). At the project start, Thermo Fisher Scientific VVS provided her with a list of these and other technical requirements. Optima, in turn, brought its experience from other viral vector projects to influence the design.
Due to the need to freeze viral vector products for storage, Crystal Zenith® plastic vials (CZ vials) from West are a preferred vial type of Thermo Fisher Scientific VVS’s clients, which Optima took into consideration during design of the machine:
Both, CZ vials and glass vials, which can also be processed on the line, are ready-to-use components, pre-sterilized and shrink-wrapped in a vacuum. It is not easy to remove the vacuum sealed packaging material, but it is easily manageable at the ergonomically well-designed de-traying station even when using isolator gloves. If glass vials, such as from the Stevanato Group, are being processed, a Tyvek removal station is also activated. For all vial types, this is followed by an automatic de-trayer.
In a typical line design, an infeed (rotary) table would be used to align vials at the infeed lock. CZ vials have a high tendency to tip over and then block the infeed path, requiring multiple repeat interventions by operators to provide a steady incoming supply of vials. A specific linear infeed, which completely prevents vials from falling over, takes over here instead and transports even scratch-sensitive CZ vials in a very gentle manner to the infeed. At the end of the infeed system, vials are transferred into linear processing. This is accomplished with a robot that uses vacuum suction to transfer vials into the linear transportation system, a rake with grippers.
Material transfer airlock for ready-to-use vials. In addition, the OPTIMA VFVM can process vials up to a size of 100R.
Vial trays are automatically removed with a robot before being moved into a linear infeed system.
Thermo Fisher Scientific VVS decided to utilize all available product-saving functions into the system. A peristaltic dosing pump, using single-use flow path components, is able to dose with extreme precision. At the start of the batch run, the priming function fills the first vials directly on the weighing cell up to their target weight. Because the weighing cell provide instant feedback on the fill solution volume dispensed, it eliminates the generation of rejected vials due to incorrect fill volumes which typically occur during priming of the fill system. During the filling process, 100% fill weight check and re-dosing functions can be activated to minimize rejected vials due to incorrect fill weights. The re-dosing function allows the filling system to add the exact amount of product solution to meet the required fill volume.
Likewise, the closing process is designed for maximum efficiency and to minimize rejected vials. After the stopper is placed, sensors are used to check that it is actually positioned correctly. If the system detects that a stopper is missing, it can re-stopper the affected vial. Before aluminum caps move into the pickup location, they are checked for deformation. Deformed caps are dropped into a bin. This ensures that only round caps are applied to the vial. If, however, the system detected the absence of a cap, the process will be repeated. Besides minimizing or eliminating rejected vials during the fill process, another advantage of these process safeguards is that, in line with GMP, operator interventions are reduced to an absolute minimum.
The amount of valuable pharmaceutical product that is available per batch is optimally utilized using Optima technologies to achieve maximum product yield. This includes dosing on the weighing cell for priming and re-dosing.
At the end of the filling and closing process, the vials are collected in special trays.
Once the vials are closed, they leave the isolator-protected area and are automatically reloaded into trays.
Due to Biosafety Level 2 requirements Optima has integrated a differential pressure cascade concept into the isolator that is adapted to meet these requirements. Differential pressures between the processing zones are designed to direct the air flow specifically to the tray-loading area, which has the lowest differential pressure (air sink), thus avoiding operator contact with air from the product processing isolator zones. Within the isolator plenum, air returned from the processing zone is recirculated and then purified by HEPA filters. As an additional safety measure, “neutralized” return air from the isolator – about 10 percent of the total air volume – is vented outside the building and not supplied back into the cleanroom HVAC system.
The Metall+Plastic isolator works with the award-winning DECOpulse®system. As a result, Thermo Fisher Scientific VVS benefits from fast cycle times coupled with highly uniform vaporized hydrogen peroxide (VHP) concentrations inside the isolator. This specific characteristic is created by generating extremely small microdroplets that evaporate even at room temperature in a stream of compressed air. Targeted turbulence and injection nozzles that have been optimally positioned based on flow simulations ensure that the vaporized H2O2 is distributed extremely evenly. This ensures reliable decontamination, combined with short cycle times, especially since there is no need to heat up the vaporization system as required for tradition thermal vaporization processes.
Typically, viral vector products are manufactured in smaller batch sizes compared to other types of treatment. Thermo Fisher Scientific VVS anticipated a maximum batch size of 5,000 vials during the design process with Optima. Being a CDMO means that product and format changes are carried out frequently. Peristaltic pumps used with single-use components ensure fast, safe product changeovers. This is complemented by a central HMI for the filling machine and isolator, which generally simplifies operation. The configurations for upcoming product and format changes can be done on the HMI. Particularly noteworthy is the fully automatic, linear transport system, which requires no size-specific change parts. The OPTIMA VFVM can handle vial formats up to 100R.
Apart from the innovative product-saving features, the comprehensive turnkey approach – the CSPE process (Comprehensive Scientific Process Engineering) – was another reason for Thermo Fisher Scientific VVS choosing Optima. When the final installation of the OPTIMA VFVM with isolator is carried out in the new building at Thermo Fisher Scientific VVS’s site in Plainville (Massachusetts, USA), all that will remain to be done is to reconnect electrical connections and interfaces, which have already been tested, and finalize the connections to building utilities. Because the system is very compact and only few connections needed to be disconnected for shipment, the installation process is very fast. After successful installation, the fill line with isolator will undergo Qualification, followed by decontamination cycle development.
Optima filling systems are already in use at several sites of our Pharma Services Group worldwide.
We as a CDMO service provider are currently setting up a new production facility in Plainville (Massachusetts, USA) for gene therapy treatments. The extra capacity will enable us to serve more customers on a larger scale in this fast-growing market. In our existing production facilities, we use filling systems with isolators and have identified potential room for improvement. Optima Pharma's bespoke isolator filling system allows us to do this as required.
Optima filling systems are already in use at several sites of our Pharma Services Group worldwide. This means that we have gained extensive experience in a wide range of applications. The cost of producing gene therapy products also makes it important to use technologies that can fully utilize the amount of fill solution available. Optima Pharma has implemented product-saving technologies in the design. These include what is known as priming the filling system, re-dosing if necessary, re-closing if necessary, and checking the crimp caps for deformation. Optima Pharma also has one of the best isolator manufacturers in the industry through its subsidiary Metall+Plastic. By evaporating hydrogen peroxide at room temperature, the operation and installation of the isolator have been greatly simplified in comparison to other isolators.
Sourcing the filling system and the isolator from the same manufacturer makes the project much easier to manage. If there were two or more manufacturers involved in a project, then we, the client, would become responsible for all of the project coordination and signal exchange – and these issues can quickly become a pain. The Optima philosophy includes performing comprehensive internal commissioning prior to the Factory Acceptance Test (FAT) and Site Acceptance Test (SAT). This provides high levels of assurance that no major problems will be detected while running FATs and SATs. The equipment is fully tested before the handover to the customer; this significantly increases the chances of a successful, smooth start-up.
The filling system FAT was completed in November 2021, and the product-saving technologies worked faultlessly during the test runs. Over the course of a three-hour test run with 0.5 mL Crystal Zenith® vials, not a single vial tipped over, which is an impressive performance. Not a single vial was rejected due to a system error during the test runs. We look forward to installing the system in the coming months.