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www.biopharminternational.com Partnerships for Outsourcing eBook May 2023 BioPharm International ® 21 Manufacturing ters that must be considered when scaling suspension cell cultures, some of these are detailed in Table I. When aiming to create a seamless scale-up and scale-down, selection of a bioreactor system that is intrinsically designed to enable transfer of process between all available scales is critical. Vendors will of ten develop their SU bioreactor scales to be cylindrical in shape (although there are exceptions, such as PALL with a cubical shape) with constant ratios for height and diameter (bag height/ diameter) and d/D (impeller diameter/bag diameter). Having a constant geometrical design is beneficial for scaling-up parameters, like specific power input, kLa, and mixing time. Scaling adherent cell line upstream processes. The scaling-up of adherent cell cultures was previously not easily possible and relied on both scale-out and de- velopment of scalable microcarrier-based processes. Scale-out involves increasing the number of cultiva- tion units (e.g., T-f lasks, roller bottles, CellSTACKs [Corning]). Scale-out operations are very operator-in- tensive and harbor an inherently high risk of con- tamination as compared with scale-up technologies. Operational challenges also often arise as certain— mainly cell-related—processing parameters must be carefully considered and controlled. Scaling-up mi- crocarrier-based processes is also not an easy task and not suitable for all cell lines and product combinations (e.g., difficult for some viruses). Fortunately, SU, closed-operation, and linearly scal- able, fixed-bed bioreactor systems have now entered the market space, with the vendors including PALL (iCELLis [5]), UnivercellsTechnologies (scale-X [6]) and Corning (ASCENT [7]). These systems are generally en- gineered and designed to enable a seamless scale-up while considering factors such as shear stress, pow- er-input, medium volumes per growth surface area, and oxygen supply capacities. All three bioreactors offer scale-down development/ modeling systems for proof-of-concept, establishment, and characterization purposes, and the largest good manufacturing practice production scales comprise 500 m2 (PALL), 600 m2 (UnivercellsTechnologies) and 1000 m2 (Corning). Scalability of DSP steps Most typical downstream processes allow for linear scale-up/-down. Many processes in DSP rely on SU components, including filters and chromatography resins. Manufacturers must be aware of the chal- lenges during scaling of DSP steps when using these SU technologies, including identifying vendors offer- ing technologies across a range of scales (particularly for scale-down models). Consideration must also be made to determining whether some SUTs may be bet- ter suited to scale-out as opposed to scale-up. Normal flow filtration. Normal flow filtration (NFF) operation is normally implemented in a DSP process at the point of harvest for clarification or at the very end of the process for bioburden reduction and ter- minal sterile filtration purposes. Such filters supply either a single pore size cut-off membrane, or a range of cut-offs with a large-to-small funneling function to improve filter capacity. FIGURE 1. Input considerations and potential outputs when determining process scalability. FIGURE COURTESY OF THE AUTHOR.