Steam-in-place (SIP) sterilization is an essential process in the pharmaceutical and biotechnology industries. The American Society of Mechanical Engineers Bioprocessing Equipment (ASME-BPE) standard recommends diaphragm valves for aseptic and sterile systems. Weir-type sanitary valves with polytetrafluoroethylene (PTFE) diaphragms are most commonly used in these systems, but sanitary diverter valves and valves with hermetic PTFE diaphragm stem seals are also used extensively.
Typical SIP cycle temperature parameters are 120°C to 135°C at corresponding saturated steam pressure, with exposure time dependent on system design and complexity . The ASME-BPE 2009 Standard Appendix J for simulated SIP cycle parameters calls for minimum 130°C steam and one hour exposure . Overkill SIP parameters are minimum 140°C steam for two to four hours exposure. These SIP cycles are cooled slowly with pressurized clean air.
To achieve more frequent batch changes and greater production yields, some in the pharmaceutical industry have begun to use high-temperature, short-time (HTST) sterilization systems with SIP temperatures ranging from 140°C to 160°C . These SIP cycles are cooled more quickly with air or water, often resulting in blistering of PTFE diaphragms, posing sterility problems if not detected early enough and reducing their service lives.
Recently, we did our own experimentation to investigate this phenomenon. This article will discuss the types of valves and diaphragms tested, the test equipment and procedures used, analysis of blistered PTFE diaphragms, the mechanics of blister formation, and what can be done to alleviate it.
Modern pharmaceutical and bioprocessing plants have large aseptic systems of vessels, fermentors and bioreactors interconnected by a maze of piping. Integral to these systems are diaphragm valves, which the ASME-BPE standard recommends for pharmaceutical and bioprocessing applications with product contact . The types of diaphragm valves recommended are weir-type, diverting and other two-piece stem and plug valves with diaphragm stem seals.
The most commonly used diaphragm valves are weir-type (Figure 1). These valves provide the self-draining capability required for hygienic processing. Usually made of 316L stainless steel, the valves are supplied with either manual or automated actuators.
The heart of a weir valve is the PTFE diaphragm. As shown in Figure 1, the two-piece diaphragms consist of a PTFE face layer and EPDM elastomer backing, which provides resiliency and compression during valve actuation. Having no center hole, the PTFE diaphragm isolates the product from the valve stem and actuator mechanism. PTFE diaphragms are used in critical, high-temperature SIP applications and with harsh chemicals.
|Figure 1. Weir-type Sanitary Valve with PTFE/EPDM Diaphragm|
PTFE polymers are known for their high purity, exceptional non-adhering properties, chemical resistance, and temperature capabilities up to 260°C. These polymers have ultra-low-level extractables, conforming to FDA 21 CFR 177.1550 and USP28 Class VI Part 87 and 88. Chemically, biochemically, and enzymatically inert, they have wide acceptance in pharmaceutical and biotechnology industries.
PTFE polymers are grouped into two types: conventional, which are white in appearance, and modified, which are more translucent. Containing up to one percent perfluoropropyl vinyl ether (PPVE), modified PTFE compounds represent the next generation of PTFE polymers, available in a number of different grades. Compression molded parts of modified PTFE have a lower percentage of voids and lower permeation rates for liquid and vapor chemicals and helium gas. Modified PTFE diaphragm disks typically offer a 30% reduction in permeability for different chemicals .
Pictured in Figure 2 are conventional and modified PTFE diaphragms for weir-type valves. The diaphragms are manufactured by compression-molding powder resin, followed by sintering. The threaded drive stud in the center is usually a molded-in metal bolt or machined from PTFE stock, as seen in the round conventional PTFE diaphragm. Some valve manufacturers mold their own diaphragms, while others purchase them from distributors. Pharmaceutical and bioprocessing facilities also purchase replacement diaphragms based on published dimensional specifications, service temperature ratings, and certification of conformance to applicable FDA and USP regulations. Distributors publish maximum intermittent steam temperatures or SIP sterilization capabilities up to 165°C for PTFE/EPDM diaphragms.
Differences in production processes and grades result in PTFE diaphragms with different performance properties and durability. PTFE diaphragms manufactured by some processes cannot withstand high-temperature applications or meet the demands of SIP sterilization.
|Figure 2. Conventional and Modified PTFE Diaphragms for Weir-type Valves|
Diaphragm Integrity and Performance
SIP cycles consist of three stages—heat-up, hold/exposure and cool-down. During the heat-up stage, saturated steam is injected, and the equipment with valves is heated to the required sterilization temperature. This stage is complete when the cold spot in the system—usually the condensate drain, dead leg, tank bottom, or furthest location from steam inlet—reaches the pre-set sterilization temperature. When a thermocouple probe at the slowest heating location reaches this temperature, the hold or exposure stage begins, during which both pressure and temperature must be accurately controlled. Exposure time is typically 30 to 45 minutes at 20 to 30 psi with corresponding steam temperatures of 121°C to 135°C . For systems with hard-to-access areas, exposure times will be longer.