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Michael Bridge is a marketing manager, biopharm, at Swagelok Company
How to control compressive loads on seal materials.
Thermal cycling is a major factor that affects the reliability of valves and fittings used in a bioprocessing system. This article examines gasket-sealed, clamp-type sanitary fittings and provides test results showing the impact a gasket extrusion dam may have on the cleanliness, drainability, and sterilization capabilities of a bioprocessing system. The article also presents a comparison of ISO 2852 and alternative fittings using computational fluid dynamics (CFD), flow tests, and thermal cycling tests.
Valves and fittings account for the largest number of seals used in a bioprocessing system, potentially numbering in the thousands throughout an entire facility. The reliability of these seals is a function of design, quality, material selection, and installation. After the components are in service, a major factor that affects the reliability of the seals is thermal cycling.
Seals must be leak-tight throughout an entire bioprocessing system to avoid the release of potentially hazardous materials and to maintain sterile conditions inside the system. Thermal cycling is the most difficult condition valves and fittings must withstand. It affects the durability of the plastic and elastomer seal materials and is a common cause of leaks.
Gasket-sealed, clamp-type sanitary fittings usually are used when connections in process (hygienic) and clean utility systems are to be repeatedly made and broken. The most often selected type is the ISO 2852. The gasket seal in ISO 2852 fittings, however, may extrude radially outward into the tubing or pipe as a result of over-tightening clamps or thermal cycling. The extrusion creates a dam that compromises drainability in a bioprocessing system and increases flow velocity. In addition, this extrusion compromises the ASME BPE standard that requires gaskets in a made-up sanitary fitting to be flush with the bore of the tubing or pipe.1
This article examines gasket-sealed, clamp-type sanitary fittings and provides test results showing the impact a gasket extrusion dam may have on the cleanliness, drainability, and sterilization capabilities of a bioprocessing system. The article also presents a comparison of ISO 2852 and alternative fittings using computational fluid dynamics (CFD), flow tests, and thermal cycling tests.
A complete system for manufacturing the drug substance for a biopharmaceutical product is made up of tanks and vessels, pumps, centrifuges, and various operation-specific equipment.
Fluids are transferred from device to device by means of tubing, pipes, and hoses. Fittings connect all parts of the system together, and valves control the fluid in the system. The process system is supported by certain clean utility services, such as pure water, sterile air, and steam for sterilization. The seals in all of the equipment and subsystems and the clean utilities are critical to the reliable operation of the complete system.
After use, each piece of equipment through which fluid had been transferred must be drained, cleaned, and sterilized in preparation for the next production run. Valves and fittings can have a direct effect on how effective the cleaning and sterilization process will be. These components must be:
Seals must be leak-tight throughout the entire process. Leaks out of the system can result in the release of potentially hazardous materials, and leaks into the system can destroy the sterile condition inside the system. Internal leaks can compromise the process, cleanliness, sterile environment, and instrumentation and control procedures.
Both process (hygienic) and clean utility systems are connected by welding or sanitary connections. If the connections are intended to be permanent and not meant to be made and broken during the intended service life of the system or equipment, automatic orbital welding may be used to make consistent, high-quality welds.
The ISO 2852 gasket-sealed, clamp-type sanitary fitting—used most often for connections that must be made and broken—consists of four components: two flanged ferrules, which are to be welded to the required lengths of thin-walled tubing, thin-walled tubular shapes, or other components; an elastomeric or plastic gasket located between the flanged faces of the two ferrules; and a clamp to hold the connection together (Figure 1A).
The containment of the seal and the control of the loads on that seal, both during make-up and in operation, are very important considerations. The ideal condition after make-up of the fitting is a bore-line seal. This type of seal does not extend into the inside diameter of the tubing or pipe at the seal point.
The standard, ASME BPE, requires that the gasket in a made-up sanitary fitting must be flush with the bore of the tubing or pipe. However, for a gasket seal used in an ISO 2852 fitting, this often is not the case. As the clamp is tightened during make-up, the gasket is free to extrude radially outward and inward. Installation methods and techniques vary from installer to installer and company to company. The amount of extrusion will vary with how tight an installer tightens the clamp. Because the compression on the gasket is not controlled, overtightening is possible.
Outward extrusion doesn't create much of a problem, but inward extrusion can. As the gasket material extrudes into the bore of the tubing or pipe, it creates a dam in the flow path of the lines, which are pitched to facilitate draining. The dam can create problems in pure water, clean in place (CIP), and steam sterilization systems, making cleaning, draining, and sterilization more difficult. Also, it can result in product holdup in the processing system during harvest, recovery, and downstream purification and refining.
Tests were conducted to determine the amount of extrusion that is possible at installation and to determine the impact of thermal cycling on the completed fitting assembly. Manifolds consisting of five 1.5-inch sanitary fittings, each separated with a short length of 1.5-inch x 0.065-inch tubing were built. Ethylene-propylene diene monomer (EPDM), silicone, fluorocarbon FKM, and polytetrafluoroethylene (PTFE) gaskets were used, each in a separate manifold. Clamps were tightened to the maximum possible by hand.
Before thermal testing, all pertinent dimensions were recorded, including the gasket intrusion into the bore of the tubing. The assemblies were vacuum helium leak-tested to confirm that a proper seal was made. The thermal test, intended to simulate a sterilization process, consisted of heating the assemblies to 121 °C in 30 min, stabilizing, holding at temperature for 30 min, and water quenching back to room temperature. The test was conducted for 250 cycles for an extensive view of the assemblies' performance; most companies run only 25 to 100 steam cycle tests. Ideally, gaskets should be replaced after every sterilization cycle, but many companies reuse gaskets between batches. The assemblies were removed from the test rig 17 times during the test, dimensionally checked, and helium leak tested. The results are shown in Figure 2.
Based on this information, the typical pitch of the lines in a system, and the size of the lines, a model of the puddle that could be formed behind the extruded dam was constructed on a 3D CAD system and hold-up volumes were calculated (Figure 3). Flow tests conducted with water confirmed that the model was valid.
The dam can create several problems in actual systems. In processing systems, after CIP and a final rinse, some of the rinse water can be trapped behind the gasket in each fitting in a horizontal pitched line, if excessive extrusion has occurred. The dam and the resulting puddles will not allow the system or equipment to be completely drained. During the sterilization process, steam should be in contact with all surfaces, and a puddle of water behind the extruded gasket will not allow this to happen.
After sterilization, the puddles of rinse water—plus any steam that has condensed during cool-down and added to the puddles—are locations where contamination could occur. The dams also are locations where expensive product can be trapped, resulting in waste and making subsequent cleaning more difficult.
The dams can create problems during the operation of the systems as well. Using the information generated in the thermal tests, flow was modeled using computational fluid dynamics (CFD). The model shows that, after the fluid passes over the dam, there is no flow at the surface of the tube for a certain distance downstream of the extruded gasket. An eddy is created downstream, immediately after the extruded gasket, where contaminants can become trapped and build up. The extrusion creates a dam, which acts as an orifice placed in the line.
In the CFD model, flow was introduced at 5.5 ft/sec to simulate a CIP cycle. As the fluid passes through the constriction of the extruded gasket or orifice, the fluid velocity is increased substantially (in one scenario modeled) to more than 15 ft/sec (Figure 4). Such an increase in velocity in applications where fluid shear is an important consideration, such as in harvesting mammalian cell cultures, could present an additional potential problem.
The dam also can create potential problems in ambient pure water systems. Contamination and bioburden can become trapped and build up in the dead spot that is created downstream of the dam. Under steady-state flow conditions, the probability that the trapped material will be released into the fluid stream is minimized. However, when the flow is disturbed, as would occur when a number of use points are actuated simultaneously, the resulting surges and disruption increase the chance that trapped material will be released.
After release, the material travels through the pure water system as a "plug" of contaminants. It will be discovered only if it passes a sample point at the precise time a sample is being taken. As it continues its travel through the system, it will disperse, mixing with the pure water, until it contaminates the system, at which point expensive corrective action will likely be required.
In the sterilization system and the processing equipment and systems being sterilized, thermal cycling presents a further problem. When the test manifold was disassembled after thermal cycle testing, a certain amount of wear on the face of the gasket seal was observed. The surface was roughened and some of the gasket material was gone. It was concluded that the wear and fretting of the gasket material was probably caused by the radial expansion and contraction of the gasket during heat-up and cool-down.
When the gasket expands radially into the bore of the tubing, it is no longer constrained between the faces of the two ferrules. The unconstrained portion of the gasket is free to expand back to its original thickness. The gasket material was characterized and the shape of the unconstrained portion of the gasket was modeled using finite element analysis (FEA) techniques.
The shape is bulbous. During expansion, the gasket extrudes radially, and the unconstrained portion expands axially. During contraction, as the gasket moves back into the constrained space between the ferrules, the surface of the unconstrained portion of the gasket is dragged over the relatively sharp metal corner formed by the bore of the ferrules and their flat faces. This explains the wear that was observed. The gasket material that is worn or scraped off can end up inside the system, eventually in the fluid stream.
When gaskets are subjected to high temperature and high compressive loads, some gasket materials can take a compression set and become loose. Compression set is the tendency of an elastomer to lose its memory under stress and not return to its original shape when the stress is removed. A common industry practice to address this challenge is to retighten all of the fittings after thermal cycling or sterilization. During thermal testing, regular leak tests indicated that the ISO 2852 fittings needed to be retightened after every fifth thermal cycle through the first 15 cycles, because the gasket had taken a set.
These results can explain why containment is lost immediately following a sterilization cycle. In such situations, a usual maintenance procedure would be to retighten the clamp even tighter, which would cause further extrusion and a larger dam, magnifying the other kinds of problems discussed.
Another fitting design that provides solutions to the issues discussed also was tested. In this fitting (Figure 1B), the configuration and cross-section of the gasket and the face of the ferrule are different from the ISO 2852 fitting.
The gasket consists of two parts—the rib and the crown—each having a specific function. The rib portion is a rectangular shape with flat faces. When clamped between two ferrules, the seal is made at the rib. The function of the large mass of material in the crown of the gasket is to control the amount of gasket extrusion toward the bore of the fitting. The faces of the ferrules are machined to accept the crown of the gasket and align the two ferrules for assembly of the connection. A metal-to-metal stop is provided at the maximum outside diameter of the ferrules to limit the amount of load that can be applied to the gasket during initial make-up and prevent overtightening.
The gasket was configured to maintain proper "squeeze" over its complete cross section. At initial make-up of the connection, compressive force is applied to the gasket with the same type of clamps used with an ISO 2852 fitting. Controlled extrusion permits a small amount of extrusion into the bore of the fitting, creating a stable bore-line seal, and avoids undesirable concavity at the seal point. The majority of the extrusion is taken up in the crown contained in the chamber formed between the faces of two ferrules. The chamber is not completely filled, to accommodate expansion of the gasket material during thermal cycling.
These fittings were assembled into a manifold identical to the ISO 2852 manifold discussed earlier and tested in exactly the same way. The results were quite different and are shown in Figure 2. None of these fittings required retightening during the thermal testing. Flow in this fitting also was modeled with the CFD technique, based on a velocity of 5.5 ft/sec.
The small amount of controlled intrusion at the gasket seal looked no different than the inside of a full penetration buttweld. There was no constriction of the flow through the connection and no increase of velocity through the connection (Figure 5). The CFD model showed no entrapment zone downstream of the gasket seal.
Thermal cycling during the sterilization process affects the sanitary fittings used in both utility and bioprocessing equipment and systems. The problems with the seal in sanitary fittings discussed here are a result of a lack of containment of the gasket and of control of the amount of compressive load that can be applied to the gasket during initial make-up and subsequent retightening, combined with thermal cycling.
Thermal cycling is necessary for steam sterilization and cannot be eliminated. The tests conducted showed that uncontrolled extrusion of the seal material increases with thermal cycling. The results of comparing the two styles of sealing methods confirm that proper containment of the seal material and limiting and controlling the compressive loads on the gaskets can help improve the cleaning, draining, and sterilizing of bioprocessing systems, as well as reduce the amount of fluid holdup in such systems.
In sanitary fittings, better containment of the seal material and better control of the loads placed on the seal material to make a leak-tight seal can result in improved ability to withstand the rigors of thermal cycling.
Michael Bridge is a marketing manager, biopharm, at Swagelok Company, Solon, OH, 440.349.5934, email@example.com
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