Variable Tangential Flow Filtration for Immunoglobulin Concentration
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Solution Overview
Problem
Current tangential flow filtration (TFF) methods for immunoglobulin concentration often result in aggregate formation and prolonged processing times due to constant transmembrane pressure and cross-flow, which can damage drug products and affect purity and yield.
Innovation Solution
A method involving variable transmembrane pressure and cross-flow rates during TFF, specifically adjusting between 1.4-1.6 bar and 75-90 ml/min, 0.8-0.9 bar and 140-160 ml/min, and 0.8-0.9 bar with 120-140 ml/min, depending on the immunoglobulin concentration, to minimize shear stress and aggregate formation while achieving high concentration in a short time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If constant transmembrane pressure and cross-flow are used in TFF, then process simplicity is maintained, but aggregate formation increases and processing time is prolonged
Solution Approach 1:
The patent applies dynamics by transitioning from constant to variable transmembrane pressure and cross-flow rates during the TFF process. The pressure and flow rates are dynamically adjusted based on real-time monitoring of flux decline and concentration levels, allowing the system to adapt to changing conditions and minimize aggregate formation while maintaining efficiency.
Solution Approach 2:
The patent implements parameter changes by systematically varying transmembrane pressure and cross-flow rates throughout the concentration process. Different pressure and flow parameter combinations are applied at different stages (e.g., higher pressure initially, then reduced as concentration increases), optimizing both flux performance and product integrity.
2Productivity
If higher transmembrane pressure is applied to increase flux, then concentration speed improves, but shear stress increases causing aggregate formation
Solution Approach 1:
The patent applies periodic action by implementing cyclic adjustments in pressure and flow rates. The process involves alternating between higher pressure phases (to maintain flux) and lower pressure phases (to reduce shear stress), creating a periodic pattern that balances concentration speed with aggregate minimization.
Solution Approach 2:
The patent uses dynamic pressure adjustment where transmembrane pressure is continuously modified based on real-time process conditions. The pressure profile is not static but evolves throughout the concentration process, increasing or decreasing as needed to maintain optimal flux while preventing excessive shear stress.
3Manufacturing precision
If extended concentration time is used to achieve low volumes, then concentration completeness improves, but process efficiency decreases and product exposure to stress increases
Solution Approach 1:
The patent implements feedback control by continuously monitoring flux, concentration levels, and process parameters throughout the TFF operation. Real-time feedback allows the system to detect when concentration targets are approached and automatically adjust pressure and flow rates to complete the process efficiently without unnecessary extensions.
Solution Approach 2:
The patent applies self-service through automated process control systems that monitor and adjust parameters without manual intervention. The system independently determines when concentration is complete based on predefined criteria and automatically terminates or adjusts the process, eliminating the need for extended processing times.
4Object-generated harmful factors
If higher cross-flow rate is applied to reduce aggregation, then shear stress increases, but processing time is prolonged
Solution Approach 1:
The patent applies dynamics by making cross-flow rate a variable parameter that changes throughout the concentration process. The cross-flow rate is dynamically adjusted based on concentration level, flux conditions, and aggregate formation trends, allowing optimal balance between aggregation prevention and processing efficiency at each stage.
Solution Approach 2:
The patent implements parameter changes in cross-flow rate alongside transmembrane pressure adjustments. Different cross-flow parameters are applied at different concentration stages, with higher rates used when aggregation risk is elevated and lower rates applied when the process is stable, optimizing both product integrity and time efficiency.
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
This approach allows for efficient concentration of immunoglobulin solutions up to 100 mg/ml with low aggregate formation and reduced processing time, improving flux performance and maintaining product integrity.
Implementation Method 1
concentrating an immunoglobulin solution by tangential flow filtration wherein the transmembrane pressure and the cross-flow, which are applied, are variable
Implementation Method 2
The correlation between shear stress and aggregation in tangential flow concentration processes for monoclonal antibody (mAb) intermediate solutions was investigated
Data Source
AI summary
The current invention reports a method for concentrating an immunoglobulin solution by tangential flow filtration wherein the transmembrane pressure and the cross-flow are variable.