Scale-up & Design Finalization
for Ultrafiltration

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Scale-up and Large-Scale Design

The goal of TFF scale-up is to create reproducible product yield, quality and purity. Remember that the device type you choose will impact the ease of the scale-up step. Flat sheet devices will scale linearly.

Learn about Pellicon® ultrafiltration cassettes for demanding ultrafiltration processes.

Large-Scale Process Control Options and Considerations

Throughout a TFF process, as protein is concentrated or exchanged into different buffers, the process parameters need to be adjusted so that they remain at their setpoints. Several methods of process control are used to accomplish this. The tangential flow can be controlled to maintain either

• Constant feed flow rate (recommended)
• Constant pressure drop

The applied pressure can be controlled to maintain a constant

• Retentate pressure
• TMP
• Flux
• Cwall

The cost/benefit analysis of these control options are discussed in more detail in Protein Concentration and Diafiltration by Tangential Flow Filtration -- An Overview.

Plant-related considerations

• Clean-in-place (CIP)
• Hardware requirements
• Disposable flow path opportunities

Operating procedure-related considerations

• SOP development
• Equipment and operator qualification (training)
• Automated and/or manual integrity testing

Other ultrafiltration-related considerations

• Operating sequence: A typical sequence of operations in an ultrafiltration process includes the following steps:
  
  
  • Filter installation, flushing
  • Pre-use air integrity test
  • CIP (sanitization optional based on bioburden)
  • Normalized Water Permeability (NWP)
  • Buffer pre-conditioning and permeability measurement
  • Processing and product recovery (the process of removing the product from the TFF system and placing it into a vessel appropriate for storage or further processing; a well-designed system has minimal deadlegs in the piping and is sloped to a collection port at the lowest point in the piping to improve drainage)
  • CIP (sanitization optional based on bioburden)
  • NWP
  • Post-production integrity testing (optional)
  • Storage

Best Practice: To ensure that the installed membranes have not sustained damage during storage and handling, Merck recommends air integrity testing all TFF assemblies pre- and post- use. An air diffusion test identifies such problems as macroscopic holes in the membrane, cracks in the seals or improperly seated modules. Determine baseline NWP post first exposure to CIP. Re-measure NWP after each process batch to determine cleaning effectiveness.

Contact the Ultrafiltration Team to explore how we can help you avoid costly errors by verifying that your design falls within Merck’s guidelines (actual process performance to be verified with optimization and process simulation trials).