For the past decade, the development and approval of biological drugs has increased rapidly. This increase highlights the
significance of aseptic processing because biologics commonly cannot be heat sterilized. Because aseptic processing receives
greater regulatory scrutiny than heat sterilization does, the industry developed, in addition to risk-management and risk-analysis
activities, new processing equipment and technologies to overcome potential weaknesses (1). These technologies' main purpose
was the avoidance of human intervention, which is one of the most substantial risks in aseptic processing. The technologies
included environmental-containment solutions such as isolators and restricted-access barrier systems, and new filling strategies
such as blow–fill–seal. Disposable solutions have changed, and their applications have broadened, during the past several
years.
The most far-reaching changes in the technology's early days affected processing equipment, which gradually was converted
into single-use equipment (2). The benefits of single-use equipment not only enable a potentially higher sterility-assurance
level within process steps than was possible before, but also enable production-utilization enhancements, cost savings, and
end-user protection. Single-use equipment does not require setup times of 8–10 h or copious amounts of water for cleaning
purposes (3). Furthermore, it protects end users from contact with potentially hazardous fluids. This article will focus on
recent advances in single-use technologies.
The development of single-use equipment
Figure 1 (IMAGES ARE COURTESY OF THE AUTHORS)
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The first disposable process parts to be used were tubing sets. They were followed by filtration devices called capsule filters.
Capsule filters were only available in small effective-filtration-area units, commonly between 0.5 and 2 ft2. The introduction of single-use components for mixing and fluid containment required larger filter capsules, and end users
requested small-scale pleated devices for scaling studies. These two factors led the filter-capsule range to be expanded to
an area of 0.1 to 30 ft2 (4–6). Current filter capsules are gamma-sterilizable and commonly connected to tubing sets or bag assemblies (see Figure
1).
Figure 2
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Single-use technology for mixing and holding tanks also emerged (e.g., single-use bag devices). Single-use bags are available
in volumes of 20 to 3000 L and can replace glass vessels, carboys, and stainless-steel tanks. Before single-use bags could
be introduced into the production process, they needed to demonstrate mechanical stability, chemical resistance, a barrier
to oxygen transfer, and low leachable levels, even when the bags were gamma sterilized at 50 kGy. New polymeric films laminated
onto each other made these characteristics possible and have become common (see Figure 2).
Single-use bags are used most often in an assembly format, either with or without a filter, as part of a multibag system.
The entire assembly is gamma irradiated in the packaging and is ready to use.
Single-use systems, though, are not restricted to bags and filters. Various equipment components are available that can be
combined into a single-use system or process step. Such equipment components include the following:
- Mixing systems of various designs and volumes
- Sensors (e.g., for dissolved oxygen, pH, and conductivity)
- Sterile fluid-transfer connectors and tubing
- Fluid-sampling devices
- Bioreactors of different designs, volumes, and agitation technologies)
- Aseptic-transfer systems for fluids and solids
- Freeze–thaw bags
- Ultra- and diafiltration
- Membrane-chromatography (e.g., ion exchange) columns (7, 8)
- Viral-clearance and ultraviolet-inactivation filters.
