Today’s bioprocessing and pharmaceutical manufacturers are facing some of the most challenging market conditions ever. They are under constant pressure to shorten development cycles, reduce time to market, improve production yields, and deliver high-quality products at competitive prices. At the same time, the FDA and other regulatory agencies expect manufacturers to develop robust processes and incorporate strong risk-management programs.
In response, the industry has seen a substantial growth in the use of single-use systems. Many types of expensive, stainless-steel bioprocessing equipment, such as hold tanks and transfer lines, are being replaced with bioprocessing bags and tubing sets.
The increased volume and diversity of pharmaceutical products are causing manufacturers to design their facilities based on shorter production runs with more changeovers. Meeting these demands requires operational flexibility. Plants must be able to easily add new products to the mix, rapidly convert processes, and quickly make operational adjustments as needed. In addition, they must execute these changeovers while meeting required safety, time-to-market, and efficiency goals. Single-use systems can deliver many benefits including rapid implementation and cost-savings.
In bioprocessing applications, single-use systems can help minimize the risk of cross-contamination, which is especially critical as companies continue to increase multiproduct manufacturing. And, unlike fixed-piping systems, disposable systems enable quick modification of the media transfer between existing processing equipment.
Another important benefit is that single-use systems can help boost productivity and accelerate time to market by reducing the downtime associated with cleaning and validation. This, in turn, helps reduce operational expenses by minimizing labor, chemical, water, and energy demands.
Moreover, by incorporating a single-use strategy, manufacturers can reduce their equipment and floor-space requirements, lowering their capital-investment costs and improving profitability. The implementation of single-use technologies can increase production capacity at an existing facility where traditional fixed systems would require costly facility expansion.
Integration with Stainless Steel
Considering the industry’s large installed base of stainless systems, an important question is how to integrate single-use technologies with traditional stainless-steel equipment. To solve this problem, Colder Products (www.colder.com) developed Steam-Thru® Connection technology, which creates a sterile link between pre-sterilized bag systems or tube sets and stainless process equipment. The product features an innovative three-port design that eliminates dead legs and allows steam to pass directly through the connection to steam on to stainless equipment (Figure 1).
Functionality is further expanded with Steam-Thru II, which offers steam-on and steam-off capability, allowing both a sterile connection and sterile disconnection without the need for a laminar flow hood. This reduces the potential of microbial contamination of media, as well as environmental contamination within facilities.
Viable connection technology requires reliability, flexibility, and compatibility. The Steam-Thru product line includes several valve and termination options that provide the flexibility needed to meet today’s mounting and flow requirements. The connection is attached to single-use bag systems or tubing, then presterilized by gamma irradiation up to 50 kiloGrays or autoclaved up to 128°C for 30 minutes, depending on the product configuration.
For mounting to the processing equipment, manufacturers can specify the connection with either a 3/4-inch or 1 1/2-inch sanitary termination on the middle port. Tri-clover clamps are used to secure the middle sanitary to the equipment and the lower sanitary to the steam trap.
Once attached, these two lower ports allow a true steam-through SIP process that eliminates potential dead legs where contaminants could grow. With Steam-Thru II, an SIP cycle of up to 135°C or 35 PSI can be performed for up to 60 minutes to steam on the connector to the equipment.
Effectiveness of the steam-on cycle was confirmed through bacterial challenge testing using Bacillus stearotheromphilus performed at the University of Minnesota’s Biotechnology Research Center.
Once the SIP cycle is complete, the operator depresses the thumb latch to allow valve transition from the steam position to the flow position (Figure 2). This creates a sterile flow path between the stainless equipment and the single-use system, allowing aseptic fluid transfer to occur. A benefit of the Steam-Thru II valve design is a maximum Cv value of 8.2, which translates to a flow rate of 43.9 L/min at 2 PSI, making it appropriate for high-volume applications.
Once fluid transfer is complete, depressing the thumb latch again allows repositioning of the valve back to the steam position for a second SIP or steam-off cycle. This eliminates any biologic residual remaining between the process equipment and the single-use system, minimizing the potential of environmental contamination at disconnection.
In addition to the bacterial challenge testing completed on the steam-on cycle, bacterial challenge tests were performed following media transfer on the steam-off cycle. Bacterial ingress tests using Brevendimonas diminuta were conducted by SGS Northview Labs (www.northviewlabs.com) to verify post-sterilization seal performance.
Additional performance tests, including helium/steam leak, tensile, and maximum burst, were completed to assure design and process integrity. The Steam-Thru II is composed of nonanimal origin USP Class VI polysulfone and platinum-cured silicone seals, which were tested for biocompatibility.
As a link between stainless and single-use systems, Steam-Thru technology may be used as either an inlet or outlet point for bag systems. For holding either cell culture media or purification buffers, bag systems may be designed with a single-use filter inlet connected to a manifold consisting of tubing, a primary storage bag, several sample bags, and a Steam-Thru II connector as the outlet.
The system can be safely connected to either a bioreactor or process skid. For sterile harvest collection and process fluid-hold applications, SIP connections are ideal as the inlet for bag systems.
An emerging application for SIP connections is a part of presterilized, single-use tubing sets to replace stainless tubing and reusable hoses for sterile fluid transfer. These tubing sets may be as simple as two Steam-Thru Connections with a section of silicone tubing for transferring inoculum through a seed-train of bioreactors.
For increased process flexibility, SIP connectors have been integrated into tubing sets with presterilized filters and aseptic connecting devices. Sterile connections are especially valuable in aseptic transfer applications where filtration is undesired yet the need to avoid process-environment contamination is critical.
For example, aseptic transfer of viral vaccines would take advantage of Steam-Thru II’s functionalities to avoid filtration of bulk vaccine, while allowing for vaccine decontamination by using a second SIP cycle prior to disconnection.
SIP connections are a key component in a comprehensive package to increase facility capacity without increasing cleanroom space. Through-the-wall fluid transfer systems like Stedim Biosystems’ (www.stedim.com) RAFT allow process technicians to utilize bag systems without bringing them directly into the process environment. By integrating a Steam-Thru II with one of these systems, operators can create a sterile link to stainless equipment inside a cleanroom with a single-use system in an exterior corridor, cold room, or warehouse.
Reaping the Rewards
As more manufacturers take advantage of single-use systems, their integration with traditional stainless equipment will continue to increase. Small and large companies alike are incorporating single-use systems in order to reduce the time required to design, build, and commission new production facilities. At the same time, existing facilities are being retrofitted with single-use systems to increase capacity and improve production yields with minimum expense.
New single-use technologies like Steam-Thru II allow manufacturers to improve production flexibility and reduce costs. Companies that capitalize on this technology will forge a sustainable, competitive advantage in the years to come.