Open-Circuit Cell Culture Filtration With Reversible TFF Flow
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Solution Overview
Problem
Conventional perfusion bioreactor methods result in prolonged external residence time of cell culture outside controlled growth conditions, leading to decreased viable cell density, percent viability, and culture productivity, along with filter fouling issues.
Innovation Solution
An open circuit filtration system with reversible tangential fluid flow across a cross-flow filter, utilizing a reservoir, TFF unit, and bi-directional pump flow to minimize external residence time and improve filter flushing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional unidirectional tangential flow filtration is used, then filter fouling occurs, but filter flushing is incomplete
Solution Approach 1:
The patent applies reverse flow filtration by alternating the flow direction through the filter. After filtering in one direction, the flow is reversed to flush the filter surface, removing accumulated fouling materials. This inversion of flow direction enables complete filter flushing that conventional unidirectional systems cannot achieve.
Solution Approach 2:
The system employs periodic alternation between forward flow filtration and reverse flow flushing cycles. This periodic action allows the filter to be continuously cleaned during operation, preventing fouling accumulation and maintaining filtration efficiency over time.
2Ease of manufacture
If cell culture is removed from bioreactor for filtration, then filtration can be performed, but external residence time increases
Solution Approach 1:
The patent merges the filtration operation with the perfusion cycle by implementing in-line filtration within the bioreactor system. The filter is positioned such that cell culture flows through it during the perfusion process, combining filtration with the existing culture maintenance operations and eliminating separate external filtration steps.
Solution Approach 2:
The system maintains continuous cell culture circulation through the bioreactor and filter system without interrupting the perfusion process. The filter is designed to handle the continuous flow, eliminating the need to stop or slow down the culture medium circulation for filtration operations.
3Ease of manufacture
If conventional filtration systems are used, then cell culture can be filtered, but viable cell density and productivity decrease
Solution Approach 1:
The patent employs a cross-flow filter configuration where the flow direction is tangential to the filter surface rather than perpendicular to it. This local quality change in flow pattern reduces the shear stress and mechanical damage to cells during filtration, preserving viable cell density while still achieving effective filtration.
Solution Approach 2:
By implementing reverse flow cycles, the system prevents filter fouling that would otherwise require more aggressive filtration conditions or frequent filter replacements. This maintains consistent filtration performance and cell viability over extended operation periods.
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
Increases viable cell density, percentage viable cells, specific and volumetric productivity, and reduces filter fouling, while maintaining optimal conditions for recombinant protein production.
Implementation Method 1
an open circuit filtration system providing reversible tangential fluid flow across a surface of a cross-flow filter
Implementation Method 2
reversing the first flow direction and flowing the cell culture through the TFF unit in a second flow direction for a second period of time
Data Source
AI summary
Provided herein are methods of processing a cell culture and open circuit filtration systems.