Pseudo-Batch Ultrafiltration for High-Concentration Protein Production
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Solution Overview
Problem
The challenge in protein manufacturing is the inefficiency of current methods in achieving high concentration protein solutions due to increased viscosity and protein aggregation caused by shear and interfacial stresses during ultrafiltration/diafiltration processes, which limits the maximum achievable protein concentration and prolongs process times.
Innovation Solution
A method involving a pseudo-batch configuration for ultrafiltration/diafiltration that recirculates the retentate through a feed tank and retentate vessel, maintaining a constant liquid volume ratio, and using a three-way valve to direct retentate flow between the tanks, effectively converting the process to a batch-like operation, reducing process time and minimizing protein aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If ultrafiltration/diafiltration is used to concentrate proteins to high concentrations, then the protein concentration increases, but the solution viscosity increases significantly leading to high system pressures that limit the maximum achievable concentration
Solution Approach 1:
The patent implements a dynamic fed-batch process where the feed tank is continuously loaded with retentate during the ultrafiltration process. This dynamic approach allows the system to maintain optimal concentration gradients and control the rate of concentration increase, preventing excessive viscosity buildup and system pressure spikes that would occur with static batch processing.
Solution Approach 2:
The patent changes the operational parameters by maintaining a constant liquid volume ratio between the feed tank and retentate vessel throughout the process. This parameter control strategy ensures that the system operates within optimal pressure and viscosity ranges while achieving the desired high protein concentration, resolving the contradiction between concentration and pressure.
2Quantity of substance
If ultrafiltration/diafiltration is used to concentrate proteins to high concentrations, then the protein concentration increases, but the process time is prolonged due to decreased permeate flux from increased viscosity
Solution Approach 1:
The patent implements continuous loading of the feed tank with retentate throughout the ultrafiltration process, ensuring that the useful action of concentration continues without interruption. This continuous operation maintains optimal flow conditions and permeate flux throughout the process, achieving high protein concentration without the time penalties associated with batch processing and viscosity increases.
3Quantity of substance
If proteins are exposed to prolonged shear and interfacial stresses during ultrafiltration, then high concentration is achieved, but protein aggregation increases
Solution Approach 1:
The dynamic fed-batch process with continuous retentate loading creates more favorable flow conditions that reduce shear stress exposure. The constant volume ratio maintenance ensures smooth flow transitions and minimizes interfacial stresses, protecting protein quality while achieving high concentration through extended but gentler processing.
4Quantity of substance
If significant volume reduction is achieved through concentration, then high concentration drug substance is produced, but facility fit and capacity challenges arise
Solution Approach 1:
The patent maintains a constant liquid volume ratio parameter throughout the concentration process, which optimizes the use of available facility volume. This parameter control allows the system to achieve high protein concentration while efficiently utilizing the stationary facility capacity, avoiding volume-related operational challenges.
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 significantly reduces process time by up to 40% compared to fed-batch methods, while maintaining or improving protein quality by minimizing shear-induced aggregation and facility fit-dependent variability, leading to more consistent and efficient high-concentration protein production.
Implementation Method 1
a filter, a three way valve comprising a feed tank valve connecting the filter to the feed tank
Implementation Method 2
a three way valve comprising a feed tank valve connecting the filter to the feed tank and the reservoir tank valve connecting the filter to the reservoir tank
Data Source
AI summary
Provided herein are optimized methods for concentrating large volumes of antibody feedstocks to generate concentrated drug substances by ultrafiltration in a batch-like mode using a fed-batch setup.