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Two complex technical systems that together form a functional unit. “Marrying” an isolator with a filling and closing line is vital to a fill-and-finish project – especially in systems that process highly potent active ingredients (HPAPIs). Another highlight of this customer project was the introduction of the first exterior washing machine that not only cleans vials, but also pre-filled syringes and cartridges.
Highly potent active ingredients require fill/finish systems to meet the highest requirements to protect both system operators, as well as the sterile product. The Comprehensive Scientific Process Engineering (CSPE) approach offers several key advantages to accomplish these goals.
“With CSPE we always look at the entire fill and finish process, which is a special turnkey core competency. For example, as an isolator manufacturer, we have direct access to all data from the filling and closing line and our colleagues have direct access to ours,” explains Matthias Aster (Director Sales at Optima Pharma Containment). Another common thread of this project: “A ‘team approach’ with the customer that I have never experienced before,” notes Lucas Meyer (Project Manager at Optima Pharma).
For highly potent active ingredients: The pressure zone concept of the fill-and-finish system was tailored to specific ambient pressures.
The new Optima system will process next-generation biologics that belong to the OEB 5 class. The “Occupational Exposure Band” describes the toxicology of the pure substance. OEB 5 corresponds to a load of less than 1µg/m³ – one cubic meter can only contain less than 1µg of the potent ingredient.
In addition to protection, these product types also require special safety features for employees. The pressure zone concept is a vital component of the safety equipment and the technology requirements. The system’s isolator barrier and excess pressure in the filling and closing area, compared to the atmosphere of the installation room, initially prevent potential contamination of the drug. The filling and closing lines contain pressure cascades between the different zones. These zones are only connected to each other via “mouseholes” through which the containers are transported – using pressure cascades to contain potential particles.
The filling zone has negative pressure compared to the adjacent areas. This means that HPAPI aerosols, which can never be completely avoided during filling, remain within the filling zone. The pressure decreases from the closing station to the exterior washing machine. Ultimately, there is defined negative pressure on the exterior washing machine compared to the system’s upstream zones and the surrounding atmosphere of the installation room. Potentially present particles are directed into this non-critical system zone – protecting the operator. Since the containers are already closed, they are cleaned with an exterior washing machine to remove potentially adhering particles – yet another step to improve operator safety.
This pressure zone principle, which is often utilized for highly potent active ingredients, was specifically adapted according to the customer’s requirements. The installation room (class C) and an adjoining surrounding room (class D) have positive pressures differentials compared to the atmosphere in other rooms. If an accident should occur, these “air bubbles” create a locking effect and the potent active ingredients remain within the installation room (cleanroom class C).
Another core element in HPAPI systems are specific filter concepts. Different filter variants ensure protection of the product, the operator, and the environment, depending on the customer’s requirements and philosophy. The chosen ‘bag-in-bag-out’ principle uses standard filters, which are widely available and relatively inexpensive. These filters can be tested as a group or individually and replaced if necessary. Another safety advantage when changing filters, is that they can be sealed easily during the filter change. Most Optima customers opt for this version.
The system’s cleaning functions are also fundamental to HPAPI processing. The still closed system is cleaned with water after each batch, which is partially automated here. The isolator’s return air ducts, and for the first time, the transport system are cleaned automatically. Operators use glove ports and hand showers to manually clean other components according to SOPs. In general, simulations play a major role in CSPE. “For the washdown, we can use simulations to digitally run through the entire process steps at a very early stage. If we don't like something, we change it. Simulations even allow us to determine and document qualification activities,” explains Aster.
Meyer says that HAZOP (Hazard and Operability) studies also examine how external or internal system errors could affect safety and how the filling and closing line must react. Different scenarios were analyzed together with the customer: What happens if an operator drops a tub? How does the system react after an emergency stop? A controlled machine downtime requires precise regulations for personnel, as well as system components. For example, defined valve positions that need to be programmed.
The MultiUse system was set up in Optima’s CSPE Center with an isolator, including AHU (Air Handling Unit), and test runs performed. During an intensive iFAT phase, tests were conducted from cable labeling to the “handshakes” of the signal transmission between system components. The tests also included the mechanical and software interfaces between the isolator and the filling and closing unit, as well as the safety technology. In addition, leak tests ensured the isolator had the high-level of system tightness required for HPAPIs.
Parameter developments for the “wash-down” and a preliminary cycle development for the decontamination process were performed, including “worst-case positions” in the isolator. And finally, in cooperation with the customer’s team, every single function of the isolator, including filling and closing line, was tested according to the specific functional description – leading to a successful iFAT.
The aforementioned team approach was evident in many ways: For ergonomic reasons the customer wanted to move the first filter stage during the mock-up to the clean room. Today only the redundant “police filter” is located on the technical floor. The iFAT phase also reflects the close collaboration when the customer wanted to change a glove port. Both sides agreed that this change would be beneficial. With the now offset glove intervention, the system operates even while refilling stoppers.
The “one-team idea” was also evident when the customer in Schwäbisch Hall chose to work the late shift to enable Optima to work on the system during the day. And finally, from the moment the system arrived at the customer’s site in Northern Europe: Throughout the entire installation of the system, it was exemplary how Optima was supported by the customer and how well coordinated the entire project handling was, reports Meyer.
The system was installed in the company building shortly before Christmas 2023, and all SAT tests were passed as planned in the second half of 2024. This reduced timeline is feasible because the customer measured the system completely in 3D in Schwäbisch Hall. The system was then projected in the filling room at the customer’s site and peripheral equipment was ordered accordingly. The complete installation only took approximately six weeks.
A new exterior washing machine, which is part of the installed system, cleans the three container types: vials, pre-filled syringes, and cartridges for the first time. This requires a new, flexible transport system. In addition, details like sealing the container closure areas during washing are crucial, reports Project Engineer Benjamin Hofmann. Due to the capillary effect, water can hardly be removed afterwards. The new exterior washing machine and the OPTIMA MultiUse, which was selected by the customer, complement each other perfectly. The MultiUse is also designed for all three container types and can process up to 9,000 RTU containers per hour.
As mentioned, for the first time a partially automated wet cleaning system was implemented for the filling machine’s transport area. This system operates with spray balls. The return air ducts of the isolator are washed fully automatically with spray lances and spray balls. Optima is convinced that this, in combination with hand showers and SOPs, results in the currently optimal partial automation. Full automation would result in many additional nozzles and greatly increased water consumption. Another new system function utilizes a valve to separate contaminated and non-contaminated water into different drainages. This reduces the effort required to treat and dispose of the contaminated water.
Additional functions of the Optima MultiUse system have an impact when processing highly active potent ingredients. For example, a container-friendly transport system that grabs and passes on every container, avoiding glass-to-glass contact from start to finish of the fill-and-finish process, was installed instead of a conveyor belt, which would also “transport” potentially existing active ingredients.
Product-saving features such as re-dosing and re-capping, which the customer has opted for, have the welcome side effect of reducing potential waste and thus its costly disposal. The reject station was also adapted to customer specific requirements. Instead of vacuum wheels that could suck-in highly active ingredients, grippers are used for transport.
One valve, two drainages: Contaminated and noncontaminated wastewater are separated. The cost of disposal is reduced.
The transport system prevents potential carryover of active ingredients and assures gentle handling. Semi-automatic cleaning is introduced.
Looking back on the initial investment decision, the customer says that safety and design, technology, cost-effectiveness, and partnership were key considerations. The responsible project manager recalls: “We knew that Optima’s ability to deliver a turnkey project would provide an additional advantage that would address all these factors.”
