Making Connections: The Crucial Junctions in Single-use Systems

Single-use systems have risen in popularity for numerous reasons, one being disposability that eliminates cleaning requirements and risk of cross contamination. Disposable hose barb and sanitary flange connectors are crucial to both the assembly of individual process systems and to ensuring a controlled fluid path communication between process systems. Many features of disposable connectors, which have been long proven in critical medical equipment design, are now being integrated into a broad spectrum of biopharmaceutical applications.

Jerold Martin

Process designers in the biopharmaceutical industry are constantly being challenged to come up with user-friendly, cost-effective systems and components that comply with the industry's strict regulations (and potential concerns). A significant amount of time in this design process is put toward the selection of sanitary fittings, clamps, and tubing connectors for the transfer and management of media, buffers, intermediates, APIs, bulk drug products, and final formulations.

Choosing the right disposable components, however, can be a challenge. Plastic connectors offer more options for material selection, user interface, and customized design than metal connectors. Users often rely on system integrators to recommend connector fittings, but a basic understanding of the options available with plastic connectors will help system designers, integrators, and end-users specify the most optimized features to achieve peak performance in the equipment design.

Connectors may be considered in several categories:

• Traditional fittings, including hose barb and sanitary flange (e.g., hygenic, tri-clamp) and associated clamps

• Quick-connectors and disconnectors, which facilitate aseptic fluid path communication, or closure and separation, under strict environmentally controlled conditions

• Steamable fittings, which enable sterile communication between stainless and single-use polymeric systems

• Sterile connectors and disconnectors, which facilitate sterile or aseptic communication, or closure and separation, between single-use systems under reduced environmentally controlled conditions.

Choosing the most ideal connector first requires a careful assessment of the application and its connection and disconnection requirements. The following must be considered:

• Can connection be pre-assembled prior to system sterilization and/or use?

• What are the dimensions of intended tubing and sanitary fittings?

• What is the process system application—clean, aseptic, sterile?

• What are the process connection and disconnection requirements?

• What is the user interface? Consider the level of human handling expected with the system and connectors or disconnectors.

Once the application is defined, the following are prime factors to be considered:

• Temperature range. Staying within the minimum and maximum temperature tolerances that the connectors will need to function. Depending on connector material, temperature tolerances can range from -70 °C to 93 °C and above. For most single-use systems sterilized by gamma radiation, temperature extremes may not be a concern, but where systems are autoclave sterilized, resistance to steam autoclaving will be crucial. For systems to be frozen, shrinkage, burst pressure, and resistance to embrittlement will be crucial.

• Pressure range. Determining the minimum, maximum, and working pressures that the connectors will be expected to tolerate. With single-use systems, pressure range is typically a crucial concern.

• Flow rate. Assessing the required volume per minute and the effect of fluid pulsation and modulations from connect and disconnect forces. Where the lumen size is comparable to the tubing or pipe diameter, connectors provide little additional resistance. Even if somewhat narrower, the short length of a connector will not reduce flow significantly unless one is operating at high flow rates.

• Fluid compatibility. Analyzing the solvent property, viscosity, sensitivity, and corrosiveness of the fluid, powder, or gas to be moved through the connection.

• Exposure. Be aware of the degree of impact from external or internal conditions, such as UV, wind, dust, vibration, radiation, gases, water submersion, chemicals, or cleaning agents and mechanical stress; radiation resistance, cleanliness.

• Manufacturing environment. Molded and extruded plastics are typically low in particulates, bioburden, and free of endotoxins by the nature of their manufacturing process. Visible particles ("flash") may be generated in the mold release step, however, if not well controlled. Review manufacturing conditions with connection supplier or integrator to maintain cleanliness and minimize risk of particulate contamination.

• Extractables, animal-derived raw materials. Due to the small contact surface area of connectors relative to the total contact area of a single-use system, as well as the small surface area to process fluid volume ratio, extractables from connectors will generally not contribute significant amounts of migrants (potential leachables ) to the process. Pre-qualification per United States Pharmacopeia (USP) <87> or <88> Biological Reactivity Tests will generally be sufficient. Extractables can also be reviewed for absence of International Conference on Harmonization (ICH) Q3 Class 1 Solvents and any known genotoxicants, which should be avoided.

The requirements of the application will then determine what materials would be best suited for the connectors.

Plastic Connector Material Options

For hose barb and sanitary flange fittings, in most cases, polypropylene connectors provide sufficient physical, chemical, and functional properties suitable for single-use systems. In systems intended to be gamma irradiated, the polypropylene must be formulated as "gamma stable" using appropriate antioxidants to preclude premature degradation after irradiation. For unique applications, additional parameters to consider would include chemical compatibility with the process fluid formulation, extractables, mechanical properties such as toughness, ductility, impact strength, and physical properties such as transparency and lubricity.

Connectors should be manufactured from virgin resins, with accompanying certification of lot traceability. Resins that are either free of animal derivatives or certified to FDA and European Medicines Agency (EMA) BSA/TSK risk per US 21 CFR part 189.5 and EMA 410/01 rev 3, respectively, and meet standards such as ISO 10993 and USP <87> Biological Reactivity, in vitro (MEM Elution Cytotoxicity), and USP <88> Biological Reactivity, in vivo for Class VI plastics are particularly important in biopharmaceutical applications.

A broad spectrum of plastic resins can be selected to produce connectors, each with different characteristics to match the needs of system designers. The lack of need for sterilization in particular can make this choice easier, as steam or ionizing radiation exposure generally rules out a number of materials. These plastic resins are commonly employed in producing connectors used for biopharmaceutical applications:

• Polycarbonate—hard, transparent thermoplastic with moderate chemical resistance. It provides good impact resistance and superior dimensional stability.

• Polypropylene—soft thermoplastic polymer that is highly resistant to chemical attack from solvents and chemicals in harsh environments.

• Polyvinylidene fluoride (PVDF)—thermoplastic polymer that is mechanically strong with good ductility over a broad temperature range, as well as excellent chemical resistance.

• Polysulfone—a hard thermoplastic polymer known for its toughness, chemical resistance, transparency, and stability at high temperatures.

Connection Options

Connectors are designed to accommodate tubing of varying hardness (durometer), from soft and flexible like PVC, silicone, and thermoplastic elastomer (e.g., C-flex or Advantaflex brands), to semi-rigid types like polypropylene, polyethylene, polyurethane, and ethylene vinyl acetate (EVA).

To facilitate these varying styles of tubing and their respective application needs, different connector types are used, including sanitary fittings, bag ports, tri-clamps, check valves, and barbed luer, quick connect, and tube-to-tube fittings. These basic connector styles can cover a wide range of liquid and air applications in manufacturing:

• Sanitary fittings are used in applications such as fluid transport systems and wherever sensitive fluids must be transferred. Flanged fittings are essential in a variety of areas of biopharmaceutical manufacturing including filters, pumps, and bioprocess containers.

• Bag ports are a crucial component of the processing stage due to the effect processing has on media transfer. Therefore, careful consideration must be taken into flow design.

• Tri-clamps have traditionally been a reusable component; however, single-use systems now require users to dispose of all components after each process. A user-friendly, affordable clamp is now necessary in each system.

• Tube-to-tube connectors are a popular choice for applications that do not require the disconnection of equipment or parts at any point during production or use. Hose-barbed tubing connectors are available in many different configurations, sizes, and material options to adapt different tube sizes or styles, reroute the flow direction without kinking, act as a manifold, or similar.

• Luer connectors. Delivery systems can employ conical or taper seal connectors, called luers, to link various system components. The male and female components of luer connectors join together to create secure, yet detachable, leak-proof connections with no o-ring or gasket required. Luer connectors are typically sized for quarter-inch and smaller inside diameter (ID) tubing.

• Quick connects allow flexible tubing and/or equipment to be quickly and safely connected and disconnected. They may be preferred over hose barb or sanitary flange fittings for fluid control because they require less manipulation, can incorporate built-in shut-off valves that prevent spillage, and allow multiple disconnection and re-connections and faster servicing.

Many of the latest quick-connect designs focus on the user interface and are equipped with intuitively simple latch mechanisms to make for easy handling in pharmaceutical management applications while mitigating costly leakage.

Sterile (aseptic) connectors/disconnectors

Multiple design options offer the user or system designer a choice of options to make tubing connections outside of a hooded environment. Major benefits of these connectors are to provide sterile connection and disconnection options in uncontrolled environments. Sterile connectors are available in genderless and gendered designed. The gendered designs can provide an additional indication of intended process flow direction.

Barbs. Plastic barb-style connectors provide designers with a capability to accommodate the widest possible range of tubing properties and application conditions, including a multitude of configurations such as tees, "y"s, elbows, and manifolds. A number of barb designs are available—each with unique characteristics to tailor connection performance to specific needs—for handling assembly forces, tensile resistance, and blow-off resistance without the need for clamps.

Barbs derive their holding capability by expanding tubing above its nominal ID, creating some amount of interference for a secure seal and good mechanical retention. The tube expansion can vary dramatically, from lower profile, easier connections to much more aggressive interferences, depending on the pressure and tensile pull requirements.

The selection of the barb style is important to the connector's tube-holding capability. The cylindrical surface behind the barb should allow the tubing to relax against the fitting. In choosing a barb style, it should be ensured that the barb is designed with a sharp peak, allowing it to "bite" into the tubing for optimal retention.

Some tubing or hose connectors may use a multibarb, which can make for an inferior tube connection and seal. Multibarbs cannot create a sharp bite on the tube, inhibiting retention, and do not allow the tube a chance to relax behind the barb, also resulting in poor tensile pull strength.

Multibarbs are also relegated to a manufacturing process that leaves a parting line on the sealing surface, creating a potential leak path. This is an inherent design flaw, yet all multibarb connector designs, including metal connectors, display this liability. An optimally designed and properly injection molded connector will incorporate a singular barb with no parting line, a sharp bite, and a clean sealing surface.

Design Optimization

The latest generation of plastic connector technology affords designers and manufacturers wide latitude of flexibility to design and set-up applications that custom fit to their specific needs. Some connector manufacturers provide comprehensive design centers to help single-use system designers and assemblers to achieve the highest level of performance from their connectors. With good consultation up front on the user's application requirements, the pitfalls of inappropriate connection technologies can be avoided and optimal system designs can be executed.

ACKNOWLEDGMENT The author wishes to acknowledge Ken Davis of Value Plastics for his contribution to this column.

Jerold Martin is senior vice-president of Global Scientific Affairs at Pall Life Sciences, jerold_martin@pall.com