Today's market demand for new drugs — combined with the difficult economic environment — is challenging bioprocessors to review their manufacturing systems and seek ways to make them more flexible, reliable, and cost effective. Increasingly, biomanufacturers are turning to single-use aseptic processing systems to meet or beat aggressive product-introduction timeframes while controlling costs.

Innovative new single-use technologies continue to be introduced, giving pharmaceutical companies greater flexibility for replacing traditional stainless tubing, equipment, and even entire process suites with plastics-based solutions. The benefits of converting to presterilized, single-use systems have been documented in many articles and case studies, but many of those benefits would be lost if manufacturers could not safely and securely connect systems and components to create a complete aseptic process.

Connecting devices and methods may appear to be a small part of these overall systems. But connection and disconnection of tubing for process fluid transfer is a critical aspect of single-use bioprocessing. Because a connector can be the deciding factor in keeping a process truly aseptic, manufacturers need to carefully consider all available options.

Sterile Connection Options

Biomanufacturers can create an aseptic connection within or between their unit operations in many different ways. The right choice depends highly on the needs and preferences of a given facility.

Quick-disconnect couplings or fittings (sanitary and Luer-lock designs) are commonly used with a range of tubing types and sizes. These connectors provide fast, easy, and secure connections when used in conjunction with laminar-flow hoods. Tube welders, for example, provide an alternative for creating aseptic connections with thermoplastic elastomeric tubing of half-inch diameters and smaller. Such systems use heated, replaceable blades to maintain sterility while welding two separate tubes together.

Single-use steam-in-place (SIP) connectors are increasing in popularity. They create sterile connections between a range of single-use systems and stainless steel processing equipment. These solutions require a steam supply at the point of connection.

A number of available single-use sterile connectors allow a sterile tubing-to-tubing connection without needing a laminar-flow hood or tube welder. These components enable sterile fluid transfer between separate single-use systems even in gray space. For disconnecting single-use tubing, aseptic disconnect couplings with shut-off valves do not require a controlled environment to maintain fluid sterility during or after their disconnection.

Determining the best solution for a given application depends on a number of factors such as the fluid being processed, tubing selected, flow requirements, and space availability (for a laminar-flow hood, SIP system, or tube welding equipment). Additional factors to consider include material compatibility, product availability, supplier technical support, and validation — whether the connection method is already validated for use within a particular facility.

Application Examples

Fermentation Seed Trains with Stainless Reactors: Modern bioprocess facilities often feature production bioreactors with 5,000-L, 10,000-L, and even 25,000-L capacities. Scaling up inoculum from a few million cells in several milliliters of culture to such large production volumes is a challenge that requires aseptic transfer at each point along the seed train.

Traditional facilities accomplish that scale-up using a dedicated series of stainless steel bioreactors linked together with valves and rigid piping. To prevent contamination between production runs, a clean-in-place (CIP) system is designed into each bioreactor, vessel, and piping line to remove residual materials. Sterility assurance at the start of each culture is provided by an SIP system comprising steam pipes, temperature sensors, and condensate collection piping. Both CIP and SIP systems require extensive validation testing, and their valves and piping can create additional validation challenges. These systems also must be revalidated following significant maintenance or changes to the connected network of piping and valves.

Advances in single-use system technology allow bioprocess engineers to replace most storage vessels and fixed piping networks with single-use storage systems and transfer lines. Disposables eliminate the need for CIP validation of many components and reduce maintenance and capital expenses by eliminating expensive vessels, valves, and sanitary piping assemblies. Figure 1 depicts a production suite with stainless steel bioreactors, with integrated single-use technology for cell culture media storage and key transfer lines. Media storage systems arrive at the facility presterilized by gamma irradiation and may be fitted with integrated filters, sampling systems, and/or connectors. Using SIP connectors allows operators to make sterile connections between these presterilized single-use systems and stainless steel bioreactors for aseptic transfer of media.