NIR Spectroscopy for Real-Time Protein A Chromatography Loading Control
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Solution Overview
Problem
Current continuous chromatography systems face challenges such as high manufacturing costs, complexity, suboptimal loading, potential product loss due to slow analysis times, and limitations in handling multiple columns and detector drifts, particularly in real-time monitoring and control of protein-A chromatography processes.
Innovation Solution
A system utilizing near-infrared spectroscopy (NIR) flow cells to measure protein concentration in real-time, allowing for dynamic control of chromatography processes, including loading, wash, elution, and equilibration, by adjusting valve configurations and pump actuations based on continuous data processing, thereby optimizing resin utilization and handling variations in feed material concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If analytical HPLC methods are used to determine column breakthrough, then measurement precision is improved, but analysis time increases leading to loss of time for real-time decision making
Solution Approach 1:
The patent replaces the mechanical/chemical analytical HPLC system with an optical detection system (NIR or UV-Vis spectroscopy) that provides real-time monitoring without the time-consuming analysis steps of traditional HPLC methods
Solution Approach 2:
The patent introduces an intermediary detection system (spectroscopic sensor) that indirectly measures column breakthrough by monitoring optical properties of the effluent, avoiding the need for direct analytical HPLC measurement while maintaining detection capability
2Manufacturing precision
If Protein-A resin is used for capture chromatography, then manufacturing precision is improved, but device complexity increases due to expensive resin and multiple cleaning cycles
Solution Approach 1:
The patent implements real-time feedback control by continuously monitoring effluent concentration and using this information to dynamically adjust loading parameters, optimizing resin utilization and reducing the need for frequent cleaning cycles
Solution Approach 2:
The patent introduces dynamic control of chromatography parameters (flow rate, loading concentration) based on real-time monitoring data, allowing the system to adapt to changing conditions and maximize resin performance without requiring overly complex fixed protocols
3Productivity
If dynamic binding capacity is optimized for each cycle, then productivity is improved, but device complexity increases due to dependence on residence time, flow rate and column cycles
Solution Approach 1:
The patent uses real-time effluent monitoring to provide feedback on binding capacity utilization, enabling dynamic adjustment of loading parameters without requiring complex pre-calculations of residence time and flow rate relationships
Solution Approach 2:
The system allows the chromatography process to self-regulate by using real-time concentration data to automatically determine when loading should be stopped or parameters adjusted, reducing the need for external control complexity
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
Enables real-time monitoring and control of protein concentration, ensuring maximum resin utilization, consistent elution times, and adaptability to varying process conditions, reducing costs and improving the efficiency and flexibility of continuous biopharmaceutical production.
Implementation Method 1
one or more NIR flow cells (7, 9), configured for analyzing spectra of the feed material to measure concentration of bio molecule in the feed material
Implementation Method 2
Protein-A chromatography is a key downstream unit operation for capturing a single target monoclonal antibody (mAb) product from clarified cell culture harvest fluid
Implementation Method 3
Protein-A resins cost nearly an order of magnitude more than other resins due to the difficulty of producing and immobilizing the Protein-A affinity ligand on the surface of the resin particles
Data Source
AI summary
The present invention relates to method of using spectroscopy for real time measuring of concentration of desired product and using measured data for monitoring and control of chromatography. It develops a method and system for measuring real-time concentration of clarified harvest and that of flow through of loading step of the chromatography and using measured data for determining breakthrough in real-time. The two modes of operation are used viz. first mode (Part A) uses a single near infrared spectroscopy (NIR) flow cell prior to the continuous chromatography column to ensure optimal loading in each cycle based on dynamic binding capacity studies carried out previously with the desired Protein A resin and second mode (Part B) uses two near infrared spectroscopy (NIR) flow cells, one before and one after the column, to detect the breakthrough curve (from 1% breakthrough onwards).