EVOLVING - 8 Pages

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Disposables Development and Qualification of a Scalable, Disposable Bioreactor for GMP-Compliant Cell Culture Suppliers Put Quality By Design Concepts into Practice by Anne Weber, Ute Husemann, Sebastien Chaussin, Thorsten Adams, Davy De Wilde, Susanne Gerighausen, Gerhard Greller, and Christel Fenge During the past decade, singleuse bioreactors have become widely accepted for use in cell culture process development and clinical manufacturing. Their key benefits over stainless steel bioreactors are flexibility, cost, and time savings associated with the reduction of crosscontamination risks (l). Here, we describe our approach to development and qualification of the Biostat STR single-use, stirred-tank bioreactor. Unlike other stirred single-use bioreactors, it offers a similar design to that of well-established, conventional (stainless steel) stirred-tank bioreactors. Disposability of the single-use cultivation chamber gives it robustness, reliability, and reproducibility of biological results together with a supply assurance needed to meet biopharmaceutical industry requirements. Development of a single-use bioreactor involves different phases of work (Figure 1). The starting point should be a clear definition of the product’s intended application. Typically, related requirements are captured in a user requirement specification (URS). On the basis of that initial input, the bioreactor design and material selection are then initiated. The proof-of-concept phase establishes component- and product- based tests that are predictive of the final application. Mechanical, chemical, and biological tests can be used to verify compliance with the URS during the prototype feasibility phase. Ideally, the production process should be qualified as well: Qualification efforts should cover production equipment, procedures, and parameters. Final product qualification can be based either on qualification of the individual components or the whole final product (or a combination of both) using mechanical and biological Key User Requirements Key user requirements for the Biostat STR stirred, single-use bioreactor: • Robustness and reliability • Ease of handling • Assurance of supply • Superior cell growth and productivity • Scalability • Oxygen transfer and CO2 removal • Safety of the medicinal product tests that emulate a specific intended application. Typically, this evaluation should be performed using bioreactor bags derived from regular manufacturing. All changes brought about (e.g., performance or robustness improvements) should be controlled by a stringent change-control process. User Requirement Specification When we initiated development of our new bioreactor, we started by defining the ultimate requirements that users of a disposable cultivation platform might expect from such a technology. Single-use bioreactors are increasingly used not only to make biological drugs for research purposes, but also for clinical trials and even commercial sale. Key 6 BioProcess International 11(4)s April 2013

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Relevant Guidelines Biocompatibility ISO 10993-5: Biological Evaluation of Medical Devices — In Vitro Cytotoxicity US Pharmacopeia <87>: Biological Reactivity test, In Vitro US Pharmacopeia <88>: Biological Reactivity Test, In Vivo TSE/BSE European Medicines Agency A410_01 (rev2) or european Pharmacopoeia 5.2.8: Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products requirements for such uses are listed in the box above. Limiting release of leachables from plastic materials into cell cultures and investigating their effects on...

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disposable bag (4). Finally, a doublewall jacket in the lower part of the stainless steel bag holder provides effective heating and cooling. The Biostat STR system comes with fluorescence-based, single-use sensors for oxygen and pH measurement and control. Sensor patches are installed and sterilized with the cultivation bag. Modern single-use sensor technology ensures the same level of control that traditional sensors provide while preventing risky insertions of classical probes (5). But reusable probes can be inserted into a single-use bag through special probe assemblies for a...

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Table 1: Agitation rates applied during robustness trials Table 2: Final assessment of the robustness trial damage (26, 27), Nienow suggests a higher range of <250 W/m3 (28). Mixing: Efficient mixing in large-scale single-use bioreactors is mandatory to prevent formation of concentration gradients and to ensure a homogeneous cell suspension. Inhomogeneous mixing contributes to formation of pH and nutrient gradients (29), which can reduce cell growth and protein expression (30-32). We determined mixing times using either the decolorization or the conductivity method (4, 5). For all scales of...

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Cultivation Parameters: Seed Expansion in CultiBag RM 10-L Optical Format Working Volume: 5 L Temperature: 36.8 °C pH: 7.15 (controlled by CO2 addition) pO2 Set Point: 60% (controlled using nitrogen, air, and pure oxygen) Rocking Rate: 17-23 rocks/minute Rocking Angle: 6° Aeration: Overlay Inoculum Cell Density: 0.2 x 106 cells/mL bioreactors. Because Stedim 40 film has been successfully established in biopharmaceutical applications such as media and intermediate storage for years, we use it for the CultiBag STR family as well. In addition to the US Pharmacopeia chapters <87> and <88>, we...

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