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Disposable systems only require initial cleaning validation, and ongoing validation activities are typically limited to operator training and routine monitoring.
Single-use filter capsules and integrated systems with disposable containers, tubing, and connectors are used throughout bioprocessing operations. Disposable unit operations are employed for a variety of direct-flow filtration operations including depth filtration, prefiltration, sterilizing, and virus filtration, as well as for chromatographic separation applications, including contaminant removal (DNA, host cell proteins, viruses, endotoxins) and capture (plasmids, viruses, proteins).
These disposable systems provide both upstream and downstream benefits. Stainless steel is expensive and in limited supply. Its use can be reduced or eliminated completely with a disposable system, resulting in cost savings and faster installation. Furthermore, hard-piped systems require cleaning and cleaning validation, both of which can be greatly reduced or eliminated by employing a single-use system. Cleaning validation, in particular, can require considerable effort and is often an important driver for the selection of a single-use system over a hard-piped system. Disposable systems only require initial cleaning validation, and ongoing validation activities are typically limited to operator training and routine monitoring. Additional validation testing is required when there is a change in product, process, procedure, or equipment.
Steam-in-place (SIP) sterilization, required for many traditional systems, requires process time as well as validation efforts. Some operations require one or more shifts to assemble, steam, and cool down process equipment. Errors in processing can create even longer delays, making disposable systems — presterilized by gamma irradiation and ready to use immediately out of box — a time saver.
Bioprocess operations also involve gas stream handling. There are many applications for disposables in gas filtration.
Membranes used for sterile filtration of gas streams are typically made of hydrophobic materials, such as polytetrafluoroethylene (PTFE). Hydrophobic membranes, which do not spontaneously wet with water, are desirable in gas applications because hydrophilic filters can become wet and clogged.
While PTFE is often used for vent and gas filtration applications in hard-piped systems, it cannot be subjected to the level of gamma irradiation required for sterilization — typically a 25 kGy minimum dose. However, hydrophobic polyvinylidenefluoride (PVDF) filter capsules, which can be gamma irradiated, are available for gas applications.
Table 1: Time required for use of a vent filter in disposable capsule and stainless steel housing
Disposable systems often include flexible containers (typically, fluid contact is with polyethylene) that replace stainless steel tanks in hard-piped operations, as well as smaller, rigid containers or carboys. A 0.2 mm sterilizing-grade vent filter is typically used to fill and empty rigid containers. Since disposable containers (bags) are empty before they are filled, a vent filter is not required — a further cost savings and operation simplification.
For applications that require an SIP-sterilized stainless steel tank, a hybrid system incorporating a capsule filter with a PTFE membrane can be used. The filter capsule housing is constructed of a specially engineered plastic (polyetherimide) that can be subjected to multiple SIP cycles.
The use of a capsule can reduce capital costs associated with stainless steel filter housings, as well as the labor required for filter assembly. Table 1 illustrates the steps required to assemble a gas filter on a tank. The overall time savings when a capsule is used is 3.3 hours. Given a labor rate of $75 per hour, this is a cost reduction of approximately $250 per change-out. If there are 500 filters used per year, the cost reduction is approximately $125,000. Approximately 42 40-hour weeks of process time is also saved.
Disposable bioreactors are available for cell-culture applications. These systems incorporate single-use flexible containers as well as tubing and a means of mixing the fluid in the bioreactor. Since carbon dioxide is produced during fermentation, these containers must be vented. The bioreactors are presterilized by gamma irradiation, and they can be vented with integrity-testable 0.2 mm sterilizing-grade capsule filters with hydrophobic PVDF membranes. Filter capsules are available in a variety of sizes (surface area) to ensure proper venting. Integrity tests are typically performed after fermentation is completed. If a pre-use test is performed, the filter must be flushed with a wetting fluid and dried prior to use.
Long tubing runs are required for some disposable applications. For example, filter effluent may need to be transferred to the filling suite, requiring several feet of tubing. Depending on its length and arrangement, it may be desirable to install a vent filter in the tubing.
Barrier isolators used for bioprocessing unit operations are typically sterilized by vapor phase hydrogen peroxide (VHP). The sterilization process includes the following steps: dehumidification of the air in the isolator chamber, injection of VHP from a generator into the chamber, and aeration to remove the VHP. A sterilizing-grade filter can be used to filter the VHP, ensuring the isolator's sterility. A hydrophobic filter is necessary, as dehumidification is critical for successful VHP sterilization. The filter must be sterilized before installation to protect the isolator from contamination. Autoclave sterilization is not recommended due to potential filter wetting; presterilization by gamma irradiation is preferred. Hydrophobic PVDF capsule filters appropriate for this application have been tested to confirm compatibility with VHP after gamma irradiation.
While most disposable filtration applications involve liquid, some gas and vent applications benefit from single-use capsule filters. PTFE is typically the membrane of choice for gas applications due to its high hydrophobicity, and disposable capsules with PTFE membranes are available that can be subjected to SIP operations. Such capsules provide significant time savings for filter assembly and cleaning. Hydrophobic PVDF filter capsules that can be gamma irradiated are available for applications that require presterilization by gamma irradiation. As the bioprocessing industry continues to embrace disposable technology, further applications for gas filters, as well as other filtration and separation technologies, will emerge.