MALS UV Signal Correction for Macromolecule Purification
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Solution Overview
Problem
Current methods for purifying therapeutic proteins like monoclonal antibodies struggle to effectively separate monomeric proteins from aggregates in real-time during chromatographic purification, leading to inefficiencies and potential contamination due to the lack of sensitive online detection of aggregates.
Innovation Solution
A computer-implemented method and system that utilizes real-time multi-angle light scattering (MALS) to monitor and correct UV absorption and conductivity signals, enabling the determination of aggregate presence and concentration, thereby optimizing the collection of pure monomeric proteins by diverting the process stream accordingly.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional UV absorption detection is used to monitor chromatographic purification, then the system is simple and easy to operate, but it lacks the sensitivity to effectively detect and separate aggregates from monomeric proteins in real-time
Solution Approach 1:
The patent combines UV absorption detection with multi-angle light scattering (MALS) detection into a unified chromatographic purification system. The UV detector provides concentration information while the MALS detector provides aggregate detection capability. By merging these two detection methods and analyzing their signals together through a unified control algorithm, the system achieves both high aggregate detection sensitivity and maintains operational simplicity.
Solution Approach 2:
The patent introduces a computer system with control algorithms as an intermediary that processes and integrates signals from both UV and MALS detectors. This intermediary component analyzes the combined signals in real-time, applies correction factors, and generates control decisions for the fraction collector. The intermediary enables the complex task of aggregate detection and separation to be automated, reducing the operational burden on users while maintaining high measurement precision.
2Measurement precision
If real-time multi-angle light scattering is implemented to detect aggregates, then aggregate identification accuracy improves, but the system complexity and computational requirements increase
Solution Approach 1:
The patent applies preliminary correction factors to the UV absorption signals before they are used in aggregate detection algorithms. These correction factors account for known sources of error such as buffer composition variations and detector response differences. By pre-correcting the signals, the system reduces the computational complexity required for real-time analysis while maintaining high aggregate identification accuracy. The correction factors are determined beforehand through calibration procedures.
Solution Approach 2:
The patent implements a feedback control system where the computer continuously monitors both UV and MALS signals, compares them against reference values, and adjusts the fraction collection decisions in real-time. The system uses the MALS signal as feedback to identify aggregates and adjusts the fraction collector accordingly. This closed-loop feedback mechanism enables accurate aggregate detection while automating the control process, reducing the need for complex manual intervention.
3Measurement precision
If UV absorption alignment corrections and band broadening corrections are applied, then concentration measurement accuracy improves, but the computational processing time increases
Solution Approach 1:
The patent performs UV absorption alignment corrections and band broadening corrections using pre-determined correction factors and algorithms. These corrections are applied based on calibration data obtained before the actual purification run. By preparing the correction parameters in advance, the system minimizes real-time computational requirements while ensuring high concentration measurement accuracy. The corrections are applied automatically as the chromatogram passes through each detection point.
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 enhances the chromatographic purification process by enabling real-time identification and separation of aggregates, improving the yield and purity of monomeric proteins by ensuring optimal fraction collection and reducing the risk of contamination.
Implementation Method 1
receiving, by the computer system, from the MALS instrument scattering intensity values of a sample solution flowed from the chromatographic purification system to the MALS instrument over a time series
Implementation Method 2
receiving, by the computer system, from the UV detector UV absorption values of the sample solution flowed from the chromatographic purification system to the UV detector over the time series
Implementation Method 3
calculating, by the computer system, concentration values of the sample solution, cj, with respect to the UV time series of excess UV absorption values and an absorption coefficient of the sample solution according to Beer's Law
Data Source
AI summary
The present disclosure describes a computer implemented method, a system, and a computer program product of controlling the purification of a macromolecule solution via real-time multi-angle light scattering.