Single-use bioprocessing equipment has become well-accepted in a relatively short time. These disposable devices have created market niches and new segments that continue to evolve.
Since the mid-1990s, there has been a continuous rise in the number of single-use bioreactors installed in laboratories. The advantages are as obvious as they are wide ranging. They include lower cleaning and sterilization costs due to shorter downtimes and a lessened cross-contamination risk, as well as the capability for lower volumes per batch. Overall, the increased operational flexibility and shorter lead times can lower capital expenditure costs by as much as 80 percent.
The disposable-bioreactor market is quite dynamic, with new entrants and variants continually being tested as alternatives to stainless steel for commercial applications. Single-use technologies today comprise a large percentage of small- and mid-scale biopharmaceutical manufacturing, particularly in clinical testing and research and development (R&D). Upstream single-use technologies are experiencing rapid market growth and they include disposable bioreactors, mixers, containers, tubing, connectors, sampling systems, purification devices and columns, and probes/sensors.
Biotech international suppliers of integrated solutions for the biopharmaceutical industry have to deal with fermentation, cell cultivation, filtration, and purification. As early as 1990, a market was created for bag systems used in various production processes and single-use products have since been integrated in nearly every key stage in the manufacture of biopharmaceuticals.
This huge demand for single-use bioreactors led biotech companies to develop a bag that meets all the design criteria offered by conventional stainless steel reactors, giving birth to the first completely disposable and scalable solution on the bioreactor market. In essence, a chamber is optimized for cell cultivation using stirred motion mixing technology, as in reusable bioreactors. It is suitable for a large variety of cell types, such as mammalian and insect cells.
A question of scale
While such disposable bags are often found on the lab bench holding as little as 10 liters of liquid, bioreactor bags have now been scaled up to hold a total volume exceeding 2,000 liters. This naturally incurred some technical challenges.
For example, the aim was to retain the proven geometry and impeller design as well as the tip speed and power input per volume. However, on a scale-up of this size, a huge amount of torque would be applied to the stirrer inside the reactor. A new drive assembly for the mixing technology inside the bag was therefore needed.
Particular attention has to be paid to specifically targeting the assembly requirements without jeopardizing quality and compliance. Tim Miller, Technical Manager at Trelleborg Sealing Solutions, says, “As with any project on a scale of this size, the first real challenge is to define the exact requirements.”
A conventional planar coupling would not suffice but a radial magnetic coupling with an assembly incorporating a special bearing proved to provide an excellent solution. The complete assembly consisting of the radial magnetic coupling and a polyethylene port, which is welded on the bag, ensures a hermetical sealing in between the bag and the external environment, eliminating the risk of contamination.
One of the difficulties encountered is the much higher force that the assembly has to withstand in the large-scale bag compared with a smaller scale bioreactor bag.
A global collaboration
The development of this project lasted several years and involved multiple worldwide locations in different countries and continents. This entailed true global cooperation across companies to complete this solution so efficiently. Improvements can be made through the contribution of product design, technology, and ideas. Suppliers are increasingly helping manufacturers by collaborating through shoulder-to-shoulder engineering to develop advanced designs and materials.
In series production, parts are produced with injection molding tools in order to guarantee a cost effective production process. Assurance of supply and business continuity is of the utmost importance to the market served by the manufacturer. Therefore, a long-term partnership ensures stable supply of the radial magnetic coupling with defined safety stock levels.
On-site testing of several mechanical evaluation prototypes proved that the radial magnetic coupling is be very stable with no rocking or tilting, even when subjected to high forces. The final design has bioreactor bags resulting in a complete surface area greater than 13 square meters/140 square feet.
Following successful trials that confirmed the biological performance and mechanical robustness of the new product, the bioreactor bag was ready to go into mass production.
Reducing contamination, increasing cleanliness
The single use bioreactor bag fulfills a growing requirement for minimizing contamination and maximizing cleanliness in life sciences manufacturing.
Cleanliness is no longer only the responsibility of the end product manufacturer. Life sciences customers are subcontracting cleanroom manufacturing to contract manufacturers, who then subcontract components and sub-assemblies to suppliers. The responsibility for cleanliness is being pushed further and further down the supply chain and has become an essential factor for success. This has forced organizations to continuously develop cultural changes that increase the cleanliness of their manufacturing processes — thus, becoming expected and mandatory rather than something that is just nice to do.
In the case of advanced components that are manufactured for sophisticated products such as medical devices, contaminants can generate a wide range of defects. For example: in order to be accepted into the cleanroom, materials need to meet specific conditions and be delivered in suitable containers. Solid controls, staff training, testing, periodic auditing, and record keeping are a central part of the strict process required for cleanroom manufacturing. In addition, keeping machines under a precise maintenance program is vital because practically any malfunction can result in contamination of the environment.
Customers that require cleanroom manufacturing place stricter controls on the contamination of its products and choose responsible suppliers that take this matter extremely seriously — those that can exhibit adequate cleaning standards in cleanrooms and logbooks. It’s not only about suppliers with state-of-the-art operations but also those with the knowledge and experience to deliver product in compliance with customers’ quality requirements.
The amount of investment to set up and operate cleanrooms is extremely high — but for any component manufacturer that wishes to supply to industries that need super clean parts, it is becoming a specific requirement.
Quality is fundamental to the success of device manufacturers. The use of cleanrooms plays an important role in mitigating contamination during the manufacturing process. This is an ongoing evolution that will bring increased monitoring and regulatory requirements to guarantee that the overall process is always in compliance. Much progress has been achieved in this area and further improvements are yet to be unveiled due to the growing trend towards stringent and well-defined, cleaner manufacturing environments.
Luis Tissone is Director of Life Sciences at Trelleborg Sealing Solutions in Colmar, Pa. tss.trelleborg.com
This article appeared in the November/December 2015 issue of Controlled Environments.