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Reaping the Benefits

Tue, 08/07/2007 - 12:15pm
Single-Use Transfer Lines in Biopharmaceutical Applications

By John Boehm, Bioprocess Business Unit Manager
& Brent Bushnell, Bioprocess Sales Manager
Colder Products Company


Biopharmaceutical manufacturers face increased pressure to commercialize new drugs faster and at a lower cost. As a result, production demand is outpacing available manufacturing capacity. To meet existing and future demand and maintain a competitive advantage, many manufacturers are striving to develop increased efficiencies within their manufacturing processes. This is where single-use systems - particularly single-use transfer lines - can deliver significant value, including added flexibility, improved production yields and increased cost savings.

Single-use systems, consisting of bags, tubing, connectors and filters, first gained acceptance in bioprocessing facilities for sterile cell culture media and process buffer storage applications. Following this, single-use bioreactors were developed and have quickly moved from research and development labs into pilot plants and production facilities as integral systems for production and seed-train scale-up. More recently, many downstream process engineers have overcome their initial reluctance to incorporate single-use systems and have added single-use as integral components of downstream purification and formulation steps.

The trend today is toward transfer lines or tube sets that use single-use connectors and filters to achieve sterile media transfer between process equipment or between production suites. A key benefit of single-use transfer lines is their ability to 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. Additional cost savings stem from reduced validation efforts, greater speed to market, and more flexible manufacturing facilities.

Fixed tubing and re-usable valves require cleaning and cleaning process validation between production batches to maintain desired sterility. Single-use components on the other hand, are provided pre-cleaned and pre-sterilized, effectively "outsourcing" the cleaning and sterilization activities required in a traditional operation. This not only reduces labor time and expense, it also improves the speed and safety of drug development and delivery. Pre-sterilized, single-use assemblies reduce cross-contamination risks that may lead to product loss or reduced production yields.

This benefit is further magnified for companies that conduct multi-product manufacturing within single facilities. Unlike hard piping, the flexible tubing incorporated in single-use transfer lines allows manufacturers to quickly change process steps or convert over to a new product. This is a key advantage for multiple-product facilities in which process requirements change depending on the drug being produced.
Real-World Results

Diagram 1 (Click image for larger version.)
Single-use transfer components began playing an important role in biopharmaceutical processing when the first sterile media bag was used in a manufacturing suite. As a critical link between stainless bioreactors and single-use bags, "tubing lines" made up of plastic connectors and silicone or thermoplastic tubing are used as either an inlet or outlet for bag systems. The component configurations within transfer lines are as varied as the options for tubing, connectors and filters. Basic transfer lines incorporate quick disconnects or plastic sanitary fittings that attach to the processing equipment. More sophisticated transfer lines incorporate sterile filters, single-use SIP connectors or aseptic connections to ease integration, save time and minimize the risk of media contamination.

One application for single-use transfer lines is in the aseptic transfer of inoculum through a seed train of stainless steel bioreactors (see Diagram 1). A traditional facility will feature one or more series of bioreactors that increase sequentially in capacity and are connected by CIP/SIP piping. Replacing the fixed piping with single-use transfer lines eliminates the need for CIP validation and reduces maintenance and capital expense by eliminating expensive valve and sanitary piping assemblies. Transfer lines can also increase process flexibility. Using an SIP connector like the Steam-Thru® Connection allows operators to independently steam-on both ends of the transfer lines when sterilizing each bioreactor. Transitioning the SIP valve into the flow/open position allows aseptic transfer of inoculum using either head-space pressure from the seed bioreactor or a peristaltic pump. Additionally, since the connections between seed bioreactors can be easily changed, maintenance of one bioreactor in a train series would not prevent use of the other bioreactors.


Diagram 2 (Click image for larger version.)
The flexible benefits of single-use transfer lines also apply to suite-to-suite transfers. In most bioprocessing facilities manufacturers have separate suites dedicated for distinct processes e.g. fermentation, harvest clarification, chromatography or formulation. Traditionally, the processes have been linked together via stainless steel pipes that run through a wall or ceiling to connect one suite to another. Now manufacturers can simply run a single-use transfer line through a transport door to quickly and easily link one suite to another. In facilities originally designed for a single process but retrofitted for another, single-use transfer lines offer bioprocess engineers the flexibility to reroute process flow and bypass steps unnecessary in the new process. Single-use transfer lines also allow bioprocessors to maintain process safety by creating closed loops, even with discontinuous process steps. For instance, formulation facilities often blend several sterile solutions to create the final drug product. Each solution may be stored for days or months in mobile stainless steel vessels that can be rolled into the formulation suite for mixing in a fixed blending tank. Single-use transfer lines may be designed to maintain a closed-loop, aseptic system when connecting mobile tanks to a blending tank. There are many options for connecting formulation transfer lines including configurations using a combination of SIP connectors, aseptic connections and weldable tubing (see Diagram 2).


Diagram 3 (Click image for larger version.)
Another application for single-use systems is in the final fill process in which a single-use transfer line delivers sterile drug liquid from a stainless steel holding tank to a filling machine. In these installations, the transfer line incorporates a single-use SIP connector attached to the sterile holding tank, a "through-the-wall" fluid transfer system to bring a portion of the transfer line into an isolator where filling occurs, and a quick disconnect or aseptic connector to attach to the filling machine (see Diagram 3). If the drug in question is hazardous, such as an oncolytic agent, some single-use connectors are compatible with post-transfer chemical or thermal deactivation cycles that ensure operator safety.
Lasting Implications
As more manufacturers take advantage of single-use systems, their integration with traditional stainless equipment will continue to increase. All biopharmaceutical manufacturers can benefit, but biotech start-ups gain both the operational advantages of incorporating single-use systems while also saving time and expense in the design, build and validation of new facilities. Existing production facilities are being retrofitted with single-use transfer lines to increase capacity and improve production yields with minimal expenses.

Bottom line: the benefits of single-use transfer lines aren't limited to upstream or downstream processes, large or small operations, or new or retrofit facilities. Whether it's connecting within a process or across different processes, this is a technology with bottom line advantages throughout the manufacturing operation.

About the authors: John Boehm is the bioprocess business unit manager at Colder Products Company Brent Bushnell is the bioprocess sales manager at Colder Products Company (www.colder.com), headquartered in St. Paul, MN.

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