Bidirectional TFF Perfusion Bioreactor for High Cell Density
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Solution Overview
Problem
Current Tangential Flow Filtration (TFF) perfusion bioreactor systems face challenges with filter fouling and cell viability decline at high cell densities, particularly in continuous or semi-continuous biologics manufacturing platforms, due to high shear and filter fouling issues.
Innovation Solution
An automated TFF perfusion bioreactor with a recirculation loop and low-shear pump system that periodically switches the flow direction through a hollow fiber filter, using centrifugal pumps to minimize shear stress and prevent filter fouling, allowing operation at high cell densities for extended production periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If Tangential Flow Filtration (TFF) is used for perfusion at high cell densities, then productivity and cell retention are improved, but filter fouling increases and cell viability declines
Solution Approach 1:
The patent implements periodic reversal of flow direction through the hollow fiber filter. The system alternates between forward flow and reverse flow modes, preventing debris and cell aggregates from accumulating on the filter surface. This periodic action maintains sustainable perfusion operation at high cell densities by continuously clearing the filter, thereby preventing filter fouling and maintaining cell viability while preserving productivity
2Speed
If high crossflow rates are used in TFF to maintain flow at high viscosities, then flow capability is improved, but filter fouling and cell debris increase
Solution Approach 1:
The patent reverses the flow direction through the hollow fiber filter periodically. By switching from forward flow to reverse flow, the system prevents the accumulation of debris and cell aggregates on the filter surface that would otherwise occur at high crossflow rates. This inversion strategy maintains flow capability at high viscosities while preventing filter fouling and reducing cell debris generation
3Reliability
If Alternating Tangential Flow (ATF) is used to prevent debris build-up, then filter maintenance is improved, but residence time increases and viability declines
Solution Approach 1:
The patent optimizes the flow rates and reversal timing parameters to achieve effective filter maintenance with minimized residence time. By carefully controlling the crossflow rate and the duration of each flow direction cycle, the system prevents debris build-up while reducing the time cells spend outside the controlled bioreactor environment, thereby maintaining cell viability
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The solution significantly improves sieving efficiency and maintains viable cell densities over 13-90 days, reducing filter fouling and cell viability decline, thereby enhancing the productivity and sustainability of biologics manufacturing.
Implementation Method 1
a hollow fiber filter comprising a lumen having a porous surface capable of preventing the passage of whole cells but allowing volumes of conditioned cell culture medium to pass
Implementation Method 2
a low-shear pump system comprising at least one pump head that directs the flow of the conditioned medium containing cells through the recirculation loop
Data Source
AI summary
Disclosed is an automated tangential flow filtration (TFF) perfusion bioreactor for culturing eukaryotic cells, useful for manufacturing a purified protein of interest, such as, but not limited to, a recombinant or naturally occurring protein and/or a therapeutic or other medically useful protein. The disclosed TFF perfusion bioreactor system can operate at high cell densities for long production cultivation periods (13-90 days) that provide the greatest efficiencies, whether in batch mode, continuous, or semi-continuous biologics manufacturing platforms.