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Pharma and Biotech
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Pharma and Biotech
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Pharma and Biotech
Pharma and Biotech
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The growing biopharma market is an attractive sector for contract manufacturers including Biovian from Finland. The One-Stop-Shop Bio-CDMO has recently expanded its equipment portfolio with a fully automated vial filling line. There were two essential requirements the filling line needed to meet – the system had to minimize losses of valuable therapeutic drugs during filling and fit into the specific physical location in Turku Bioscience Centre.
CDMO: Contract Development and Manufacturing Organization, contract manufacturers and developers that provide support in research and development and the manufacturing of pharmaceutical products, especially in the pharmaceutical industry.
CDMOs support pharmaceutical manufacturers in many ways. They help with capacity problems, respond to needs through flexible process development, and they manage up-scaling to GMP production. Partnering with a CDMO can provide a head start to many biopharmaceutical drug developers. Therefore, there has been a rapid growth in the need for contract manufacturers. Especially for those who provide comprehensive services and can produce small to mid-sized batches for clinical studies and beyond. One of the companies that can respond to the growing demand with comprehensive services is Biovian. The Finnish company was founded 18 years ago, and it has 1300 m² of GMP-compliant production space in Turku, located around 170 km west of Helsinki. Over the past few years, the plant has been further equipped with cutting-edge equipment such as single-use bioreactors. Growing demand for gene therapy drugs has driven the need for capacity expansion. The company describes itself as a One-Stop-Shop CDMO. This means it covers the entire service chain of biopharmaceutical manufacturing from early development to filling and labeling.
Biovian's customers are supported with commercial GMP batch manufacturing all the way to the fill and finish. For Pirkko Kortteinen, the Director of Development and Manufacturing, it became clear in early 2019 that there was a need for a fully automated filling system covering batch sizes of up to 10,000 vials that would also be ready for the revision of Annex 1 of the EU GMP Guide "Manufacture of Sterile Medicinal Products”. Project manager, Ulla Myllymaa, was given a task to find a supplier, who could, in addition to above mentioned, meet the specific physical requirements of the facility. This challenge was also presented to Optima, the future supplier.
The quest to find the right machine turned out to be anything but easy. Ulla Myllymaa had to realize that the options available on the market were rather limited. So, she considered focusing on the manufacturers of individual components. Initially, she wanted to learn more about Optima Pharma's filling machines. Technical Sales Manager Thorsten Meiser recalls: "In discussions, we quickly concluded that Optima could provide the complete machine for vial filling with stoppering and capping, a Restricted Access Barrier System, RABS, and an integrated system for air sampling. This was exactly what Biovian was looking for. I was able to offer Ulla Myllymaa a newly relaunched concept, where certain improvements had been made compared to previous vial filling and stoppering and capping lines.”
Luckily enough, a corresponding machine happened to be in Schwaebisch Hall waiting for delivery and Ulla Myllymaa was able to inspect all aspects of the system and test how each of its parts could be reached through the glove ports. Meiser says: "She was thrilled and would have loved to take the machine right away, just as it was.” But the machine was reserved for a German customer to whom it was delivered shortly after a successful Factory Acceptance Test. Later on, Meiser and Sabine Wildenhain, the Project Manager for this project, also learned more about Biovian’s specific requirements that would turn the seemingly standard filling machine into something unique.
Biovian was planning to place the filling machine in its manufacturing facility on the seventh floor of the Bioscience Centre. There, the ceiling height was 2.40 m which is considerably lower than in standard production facilities. This had to be considered when designing the RABS containment. Meiser explains: "By conducting a trial, we were able to reduce the height of the laminar flow unit accordingly. Obviously, we needed to assess whether there was still enough airflow to ensure that the required particle-free performance was still there." That was the biggest hurdle. Once it was cleared and Optima was able to present the solution, everything progressed fast.
The specifications were created very quickly. Meiser thinks this was because of a strong mutual trust: "The Biovian management team perceived Optima as experts who know what they are doing." Consequently, the final meeting before placing the order also went smoothly. In summer of 2019, Ulla Myllymaa and Kaisa Paasimaa, an engineering expert from Biovian, discussed the final details with Optima's team. Two days were reserved for this, but everything was finalized in one day. One of the topics was how the new vial filling machine could be moved up to the seventh floor via narrow passageways and bends. Eventually, it was decided that the machine would be designed in two parts – from both mechanical and electrical standpoints – to allow easy transport and quick assembly on-site. The filling machine was to be equipped with compensation cells that damp any vibration that could affect the accuracy and stability of weighing when dosing.
As requested by Biovian, the compact, customized VFVM231 vial system can support the use of various vial sizes from 2R to 100H and can handle fill volumes between 0.2 ml and 100 ml. The vials are supplied "ready for use" in trays and packed in sachets. Given the small batch sizes, the bags are manually removed within the containment environment, turned by a manual turning station, and pushed onto a turntable. The next stage is fully automated. The objects to be filled are fed into a rake system where they are weighed and filled with a peristaltic pump. Its hose is single-use and can be easily replaced for every batch. Flexibility is required for filling, as the products can vary in viscosity and may, in some cases, tend to foam. Most biopharmaceutical products filled by Biovian are expensive.
Optima's experts implemented special functions in the filling process, such as a so-called Redosing on Request (RoR) as part of the inprocess control. In practice, the filling needle tracks an underfilled vial on the control load cell where it is refilled. This function also removes air from the filling tube at the beginning of the process and helps to recover all bulk material at the end of each batch. Product saving features are also built into the closing machine. For example, if a stopper is missing, a new stopper is fed from the sorting pot. Because these small batches are highly valuable, the aim is to minimize the number of partially filled or improperly closed vials that would need to be rejected. The final step of the process is sealing the vials with a final cap and crimping.
In the CDMO sector, batch and product changeovers are frequent. Therefore, both the machine and its control system have been designed so that the Biovian staff, trained by Optima experts, can adapt the machine to new product characteristics or vial sizes. It has been made easy to handle the format parts and to replace them when necessary. The machine's highly compact design created some additional benefits. It allows even the shorter operators to reach all parts of the machine using gloves.
The shipping and assembly of the machine went like clockwork. Optima delivered it before Christmas, "right on schedule," says a delighted Sabine Wildenhain, the Optima Project Manager. Seemingly satisfied, she talks about the perfect interaction of everyone involved and the fact that this project was characterized by female power from both Biovian’s and Optima’s sides. She says: "We had a female project engineer in sales, a female designer for the machine, one for the filling unit, a female qualifier, and we also had a woman in charge of air preparation and particle measurement." The assembly team also showed its best, working hand in hand with the design engineer. The team's extensive experience and understanding of customer requirements greatly contributed to the smooth-running of procedures and to the building of a top quality machine. Project partners at the customer's site were understandably satisfied. Ulla Myllymaa confirms that "the cooperation with Optima was really good from start to finish. All the components were specified in the quotation. We received regular updates on all stages of the process in the form of images and teleconferences. Also, I appreciate the fact that we had a single point of contact at Optima, a deeply knowledgeable project manager. In the future, when customers visit Biovian we will be able to present high-quality filling equipment.” The customized RABS filling machine unit may one day be moved to another factory building. Its modular design will mean that this can be done easily. If needed, the machine guard (containment) could then be raised from the current 1.70 m, benefitting taller machine operators. With the new, flexible Optima machine, Biovian has future-proofed its One-Stop-Shop offering.
During stoppering, there is another product saving feature that prevents inadequately sealed vials. They are then closed with a cap and crimped.
Automation is not yet used for unpacking the vials delivered "ready to use". The bags are removed manually within the containment environment.
Biopharma companies that we work with as CDMO partners are developing the innovative medicines of the future. This means that the products we are entrusted with are extremely valuable. Many of the candidate drugs that we manufacture and aseptically fill in compliance with GMP are "first-in-human" products intended for unmet medical needs. This is why minimal product loss with the small batch sizes is a necessity. The filling system needs to be robust and reliable. The important features include full automation and automatic control of volumes.
How satisfied were you with the way the project was taken care of?The way of working was highly professional from start to finish. Optima responded quickly to change requests that we made throughout the project. Moreover, Optima kept to the exact date for the delivery of the system.
Fill and Finish is one of Biovian's core competencies and an essential part of our One-Stop-Shop CDMO concept. For us, it was important to invest in the state-of-the-art automated system with RABS that meets current and future regulatory requirements (Annex 1 of the EU GMP Guide "Manufacture of Sterile Medicinal Products”). The Optima system will enhance our ability to provide high-quality, comprehensive services to our global customer base.
