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42 BioPharm International eBook June 2018 www.biopharminternational.com Single-Use Systems Bioreactors larger-scale, stainless-steel bioreactors and as production-scale bioreactors in fully single-use facilities. Under the appropriate circum- stances, hybrid and fully single-use facilities may provide greater effi- ciency, flexibility, and economic value compared to past approaches. With the proper selection and implementation of single-use bio- reactor technology, multi-product, simultaneous, and continuous bio- manufacturing models may fully replace legacy paradigms of the past. In a conservative, regulated industry, change does not come eas- ily, nor should it. The nature of bio- pharmaceutical products demands a deliberate, methodical approach to change (2,3). To accomplish any fundamen- tal change, all relevant stakeholders must take part. As alternatives are considered, respective stakeholder requirements must be represented and communicated. The expe- r ience ga i ne d a nd k nowle dge compiled from legacy biomanufac- turing operations establish a refer- ence. This reference can benefit a thorough assessment of new meth- ods and technologies, and it can aid in the transition or adoption of new approaches. With respect to stain- less-steel and single-use bioreactors, lifecycle, design space, and product platform concepts are discussed in the following sections. Interpretation and use of this information by spe- cific stakeholders in making relevant decisions is encouraged. TALE OF TWO LIFECYCLES In an industry with origins rooted in stainless-steel processing equipment and piping, biopharmaceutical man- ufacturing has a long history in the specification, design, deployment, and use of such equipment, includ- ing production-scale bioreactors. As such, buyers and suppliers have cre- ated an extensive supply chain com- prised of the materials, components, assemblies, subsystems, and systems required to construct and operate a biomanufacturing facility. Beyond buyers and suppliers are well-estab- lished architectural, engineering, and project-execution service orga- nizations. Extending this highly evolved, mature supply chain fur- ther are inspection and qualification service companies. The scope and scale of capacity expansion projects engages these supply-chain members in a variety of ways. The legacy biomanufacturing par- adigm and associated supply chain have created a lifecycle for bioreac- tors within capital expansion proj- ects. Figure 1 is a representation of this lifecycle. The stages or events are mostly sequential, requiring the preceding event to complete prior to the start of the next one. For discussion purposes, physical bioreactor design (4), stainless-steel or single-use, may be decomposed into a set of primary subsystems: vessel and frame, input/output (I/O) cabinets, and controller. Within or mounted to these physical elements are the functional subsystems for gas flow management, liquid addi- tion/removal management, and measurement and control (i.e., auto- mation). Physical design combined with materials of constr uction, components, and associated doc- umentation define the bioreactor design space (see Figure 2). For stainless-steel bioreactors, pip- ing may be included in the vessel and frame subsystem. For single- use bioreactors, "process piping" is part of the disposable bioreac- tor bag assembly and can be con- sidering another subsystem. This single-use assembly has its own dis- tinct lifecycle (5,6). Bag assemblies are functionally equivalent to the stainless-steel bioreactor's compa- rable vessel and piping subsystems. Compared to stainless-steel biore- actors, single-use bioreactors pos- sess none of the persistent, reusable process-contacting piping, valves, ag it ator a sse mbl ies, me c ha n i- cal seals, O-rings, or gaskets. With fewer mechanical components, the single-use bioreactor is a "simpler machine" that typically consumes less space. The single-use bioreac- tor bag assembly has its own design space (see Figure 2), separate from but aligned with the hardware, made up of bag film; cartridge filters; impeller assemblies; and numerous polymeric tubing, fittings, and connectors. Although historically, some stan- dardization has been attempted in stainless-steel systems as large as 1000 L to 2500 L, scale, complexity, and unique requirements imposed on production-scale, engineered-to- order bioreactors leaves a very open design space (see Figure 2). For exam- ple, unique requirements associated with facility layout; specific, compo- nent-level, buyer-preferred suppliers; and automation integration have limited bioreactor suppliers' inclina- tion to sufficiently standardize. This variability and limitation have been hallmarks of the legacy approach. Driven by the disposable bioreac- tor bag assembly, established single- use bioreactor suppliers have spent considerable time and effort under- standing a wide range of process, regulatory, and market requirements. The critical nature of the bag assembly, from the selection of biocompatible materials to the robustness and repeatability of the manufacturing processes, motivate the suppliers to standardize. Well- known, mainstream single-use bio- reactor suppliers have established commercially available, standard- ized product platforms to 2000-L working volume (although larger volumes have been reported), based on def ined desig n spaces. T he expanse of the design space and the flexibility of the platform vary by