Catalog excerpts

Bioprocess-Int_Single-Use-Bioreactors - 1

Superior Scalability of Single-Use Bioreactors by Davy De Wilde, Thomas Dreher, Christian Zahnow, Ute Husemann, Gerhard Greller, Thorsten Adams, and Christel Fenge uring the past several years, single-use bioreactors have been gradually established in modern biopharmaceutical processes (1, 2). This adoption is directly linked to their unique ability to enhance flexibility and reduce investment and operational costs. Furthermore, production output can be increased, and time to market is shortened (3). Today a wide variety of single-use bioreactors exists for the cultivation of mammalian and insect cells (4), whereas only limited solutions are available for microbial cultures (5). Typically, processes are established and optimized in stirred-tank benchtop bioreactor systems. One challenge during the development of a robust cell culture process is the straightforward scale-up to final production scale. This is especially critical when using less-characterized bioreactor designs that deviate from the well-known and understood classical stirred-tank principle. Scale-up is an important and potentially time-consuming step in the development of industrial processes. It involves much more than just doing the same at a larger volume. It requires the generation of solid process understanding at different scales to ensure consistent quality and titer throughout scale-up from early clinical trials to final production scale (6). Today, many companies use chemometric tools such as design of experiments and multivariate data analysis to establish critical process parameter ranges that define the design space of a robust production process. Especially during late-phase development of a commercial process, the availability of a properly representative scale-down model of full production scale is essential to allow efficient process development (7). Detailed understanding of bioreactor characteristics at different scales significantly facilitates the development and scale-up of robust production processes (6). Typical parameters of concern are oxygen transfer, mixing, and heat-transfer characteristics as well as the generated shear forces. During the past 30 years, stainless‑steel stirred-tank bioreactors have evolved as the gold standard, especially as a result of their straightforward scale-up. Multiple times, their well‑understood design principles have proven successful in development and scale-up to safe and robust commercial processes. Furthermore, they enable users to implement their existing knowledge — especially with platform processes — into production processes of new drugs and to set-up experiments in a way that can shorten development timelines. However, many commercially available single-use bioreactors differ from this gold standard. Vessel design, stirrer design, and gassing strategy especially may differ from the classical Figure 1:  ambr250, UniVessel SU, and BIOSTAT STR family; working volume ranges from 250 mL to 2000 L ambr250 UniVessel SU 2L Supplement, Preprint BioProcess Internati

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Bioprocess-Int_Single-Use-Bioreactors - 2

Table 1: Summary of geometrical dimensions of the AMBR250, UniVessel SU, and BIOSTAT STR family Table 2: Comparison of process engineering parameters suitable for scale-up from the BIOSTAT STR 50 to the BIOSTAT STR 2000; for scale-up, a CHO process performed at 50 L scale was assumed, which was performed at 150 rpm equivalent to a tip speed of 1.1 m/s, a commonly used tip speed for cell culture applications Process Engineering Parameter Equal tip speed for BIOSTAT STR 2000    42    1.1    171,936    6.7 stirred-tank design principles and do not necessarily offer consistency and geometrical...

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Bioprocess-Int_Single-Use-Bioreactors - 3

Figure 3:  Stirrer speed as a function of the tip speed for the UniVessel SU and BIOSTAT STR reactors. BIOSTAT  STR  500 BIOSTAT  STR  1000 Figure 4:  Power input per volume (P/VL) for the UniVessel® SU and BIOSTAT® STR family 400 350 UniVessel SU filling volume, which enables an improved gas exchange at the gas– liquid interface. On the other hand, a larger aspect ratio offers advantages in case of direct sparging due to the longer residence time of gas bubbles in the liquid and hence a higher oxygentransfer rate (12). For animal cell cultivations, often a ratio of 2:1 is recommended (13)....

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Bioprocess-Int_Single-Use-Bioreactors - 4

Figure 5:  Mixing times for the different scales of the UniVessel SU and BIOSTAT STR family as a function of the tip speed for 2 x 3-blade-segment impeller configuration 70 60 50 has developed a special microsparger design with 150 µm holes that provides a uniform bubble swarm of small bubbles for effective gas transfer. Spargers with large holes have a relatively low oxygen transfer but offer improved performance for CO2 stripping because bigger bubbles typically rise to the gas–liquid interface and carry excessive CO2 from the cell suspension to the headspace. At small-scale, CO2...

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Bioprocess-Int_Single-Use-Bioreactors - 5

Figure 6:  Characteristics of the volumetric mass transfer for the different scales of the UniVessel SU and BIOSTAT STR family using 2 × 3-blade-segment impellers; (a) results of the ringsparger and (b) results of the microsparger 20 UniVessel SU ring (0.5 mm) BIOSTAT STR 50 ring (0.8 mm) BIOSTAT STR 200 ring (0.8 mm) BIOSTAT STR 500 ring (0.8 mm) BIOSTAT STR 1000 ring (0.8 mm) BIOSTAT STR 2000 ring (0.8 mm) BIOSTAT STR 200 micro (0.15 mm) BIOSTAT STR 500 micro (0.15 mm) BIOSTAT STR 1000 micro (0.15 mm) BIOSTAT STR 2000 micro (0.15 mm) Bareither et al. used tip speeds ranging from 0.27 m/s...

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Bioprocess-Int_Single-Use-Bioreactors - 6

resulting in a more efficient oxygen transfer (22). The AMBR system had kLa values of 8.5 h-1 at a tip speed of 1.02 m/s (20). For the other bioreactor families ^a values >10 h-1 can be easily achieved at all scales for both microsparger and ringsparger. Hence, the AMBR, UniVessel SU, and BIOSTAT STR bioreactors meet the oxygen-transfer requirements of mammalian cell cultures. With a microsparger, ^a values up to 40 h-1 can be reached at 2,000 L scale, thereby demonstrating the superior performance of this bioreactor type and making this bioreactor type the ideal choice for high...

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