Valves and fittings account for the largest number of seals used in any bioprocessing system. In an individual processing suite, the seals that make up sanitary connections to tanks and vessels, valve ends and upper works, and tubular fittings may number in the hundreds.
Throughout an entire facility, the number may be in the thousands. Reliability of the seals is a function of design, quality, material selection, and installation—all considerations made before the valve or fitting is subjected to the actual service.
However, once the components are in service, they are vulnerable to thermal cycling, a major factor that affects the reliability of the seals. This article examines the effect of thermal cycling on stem seal and seats in the ball valves that are used extensively in utility systems, as well as its impacts on the seal in sanitary clamp-type fittings used throughout both the process and the utility systems.
Its goal is to highlight valve and fitting design improvements in seal containment as well as ways to improve the control of loads applied to the seals both during initial make-up and thermal cycling. Fermentation is the basis of a bioprocess and includes both microbial and mammalian cell culturing.
Although similar, each has its own unique requirements. Microbial fermentation usually refers to large-scale cultivation of living microorganisms or single-cell creatures. Mammalian cell culturing involves growing complex cells that come from the organs and tissues of animals, which are much more fragile and more difficult to grow.
A complete system for manufacturing an active ingredient for a biopharmaceutical product is made up of tanks and vessels, pumps, centrifuges, and other rotating equipment, as well as various kinds of operation-specific equipment. Fluids are transferred from device to device by means of tubing, pipe, and hose.
Fittings connect all parts of the system together, and valves control the fluid within 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.
The system consists of upstream preparation, fermentation, harvest and recovery, and purification and refining. Upstream preparation includes the preparation of media, the substrate and nutrient mixture that will be the environment in which the organisms will live and grow; buffering solutions, used to control the allimportant pH; and inoculum generation, preparation of the cultures that will be placed in the fermenter to begin the process.
The fermenter/bioreactor provides a contained and protected, controlled and homogeneous environment in which the microorganisms and mammalian cells reproduce and grow. When the fermentation process is complete, the broth is harvested and sent through a recovery process. If the product is extracellular, the cells are removed from the broth. If intracellular, the cells are disrupted and the debris removed.
Purification is the final downstream processing after recovery. During purification, the desired product is separated from the broth—using a combination of methods, including precipitation, filtration, and chromatography—refined, and concentrated. After use, each piece of equipment and each run of conduit 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:
- completely drainable, leaving no entrapment areas or puddles where contaminants can accumulate;
- cleanable using current clean-in-place (CIP) methods;
- sterilizable, allowing all internal surfaces to be in contact with steam; and
- able to withstand the thermal cycling of repeated sterilization processes.
Seals must be leak-tight throughout the entire process. Leaks cannot be tolerated, since they could result, either in the release of potentially hazardous materials out of the system, or destroy sterile condition inside the system. Internal leaks can compromise the process, cleanliness, the sterile environment, and instrumentation and control procedures.
All bioprocessing system operations must be supported by clean utility services, including pure water, clean steam, and sterile air. These services are supplied to the various pieces of equipment via extensive piping systems, which are connected by welding or sanitary fittings.
Diaphragm valves are used; however, the diaphragm may have limited life in steam service, especially where the valves are actuated frequently. Ball valves are an accepted industry standard for isolation purposes on continuous pure/clean steam service (The American Society of Mechanical Engineers standard, ASME BPE Bioprocessing Equipment, is an American National Standard).
Generally, the service parameters—pressure, temperature, and flow—are not severe in these systems. The most difficult condition valves and fittings must withstand is thermal cycling. Thermal cycling impacts the durability of the plastic and elastomer seal materials and is a common cause of leaks.
Ball valves have seals at the stem, seats, body, and at the connection into the system. The body seals are static seals, which are made up when the valve is assembled, and do not have to be cycled mechanically during service. Adequately contained, body seals normally can withstand thermal cycling without leakage, as long as the seal material is not degraded during the process.
If the manufacturers’ instructions are followed during maintenance, body seals should not pose a leakage problem. Construction personnel or technicians install the ball valves into systems when they are built or maintained. The end connections on the valves use the same kinds of fittings used to assemble the complete system and connect all the parts together.