Single-Pass Tangential Flow Filtration for Antibody Drug Conjugate Purification
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Solution Overview
Problem
Current methods for producing antibody drug conjugates (ADCs) are bottlenecked by the removal of impurities and buffer exchange, which are costly and inefficient, particularly in large-scale manufacturing, due to the need for recirculation over TFF membranes, leading to high processing volumes and times with potential shear exposure.
Innovation Solution
The implementation of single-pass tangential flow filtration (SPTFF) and countercurrent diafiltration for continuous ADC production, enabling simultaneous concentration, purification, and buffer exchange, reducing processing time and improving yield and consistency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If bulk diafiltration by tangential flow filtration is used for ADC purification and buffer exchange, then the ADC can be purified and exchanged into stable buffer, but the processing time is long (4-5 days) and processing volumes are high due to recirculation requirements
Solution Approach 1:
The patent implements continuous processing where the ADC flows continuously through the TFF membrane in a single pass, eliminating the batch recirculation cycles. The conjugate flows from the conjugation reactor directly through the TFF system for purification and buffer exchange, maintaining continuous operation throughout the process rather than stopping and recirculating multiple times.
Solution Approach 2:
The patent divides the purification process into distinct functional zones within the TFF system, including a dilution zone where buffer is added, a filtration zone where separation occurs, and a collection zone where purified ADC is gathered. This segmentation allows each zone to perform its specific function efficiently without requiring recirculation.
2Manufacturing precision
If bulk diafiltration by tangential flow filtration is used for ADC purification, then the ADC can be concentrated and purified, but the cost is high and the process is not optimal for large-scale manufacturing
Solution Approach 1:
The continuous TFF process allows for uninterrupted processing of large volumes of ADC, eliminating the stopping and starting inherent in batch operations. The system maintains steady-state operation with continuous feed, filtration, and product collection, significantly improving throughput for large-scale manufacturing.
Solution Approach 2:
The patent incorporates a dilution zone before the filtration zone where buffer is pre-added to the conjugate stream. This preliminary dilution reduces the viscosity and concentration of the feed entering the filtration zone, improving flow characteristics and filtration efficiency without requiring multiple recirculation cycles.
3Manufacturing precision
If recirculation over TFF membranes is used for ADC purification, then the ADC can be purified through multiple cycles, but the ADC is exposed to potentially high shear zones increasing the risk of damage
Solution Approach 1:
The single-pass continuous filtration eliminates repeated exposure to high-shear recirculation zones. The ADC flows through the system once in a gentle, controlled manner, minimizing mechanical stress and shear forces that could damage the conjugate structure while still achieving effective purification.
4Manufacturing precision
If bind and elute column chromatography is used for ADC purification, then the ADC can be purified and buffer exchanged, but the process is costly and time-consuming
Solution Approach 1:
The patent replaces the chemical-based column chromatography system with a physical-based TFF system. Instead of relying on chemical interactions between the ADC and chromatography media, the process uses physical size-based separation through the TFF membrane, combined with continuous buffer exchange, achieving purification without the time and cost associated with chromatography.
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 a more efficient and consistent production of ADCs by eliminating the need for recirculation, decreasing processing time, and minimizing shear exposure, thereby enhancing the manufacturing efficiency and product quality.
Implementation Method 1
single-pass tangential flow filtration (SPTFF) is used to remove the unconjugated drug
Implementation Method 2
SPTFF can be linked to antibody drug conjugation reactions to facilitate, not only the concentration of antibody drug conjugates (ADCs)
Implementation Method 3
countercurrent diafilitration can also be used in antibody drug conjugation reactions for similar purposes
Data Source
AI summary
Methods of producing, purifying, and formulating antibody drug conjugates (ADCs) are provided herein. The methods use continuous conjugation processes, single-pass tangential flow filtration, countercurrent diafiltration, and/or in-line process automation technologies. The methods decrease process times and costs and improve product consistency.