Thermal Protein Stability Assessment Correlated With SEC

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Solution Overview

Problem

Current methods for determining protein stability, such as Size Exclusion Chromatography (SEC), are time-consuming and costly, necessitating a more efficient and cost-effective approach to assess protein stability in therapeutic proteins.

Innovation Solution

Measuring thermal stability of therapeutic proteins using differential scanning calorimetry (DSC) or differential scanning fluorimetry (DSF) and correlating the unfolding temperature (Tm) with SEC results to predict protein stability, which requires less sample and time than traditional SEC methods.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If Size Exclusion Chromatography (SEC) is used to determine protein stability, then measurement precision is improved, but loss of time and productivity deteriorate

Engineering Contradiction:

Improveprotein stability measurement accuracyVSAvoidtime required for stability assessment

Core Design Contradiction:

Measurement precisionVSLoss of time

Solution Approach 1:

The patent replaces the mechanical SEC separation system with a thermal analysis system (DSC or DSF) that measures protein stability through thermal unfolding. DSC measures heat capacity changes during unfolding, while DSF uses fluorescence changes, both providing stability data without the time-consuming mechanical chromatography process.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent changes the measurement parameter from hydrodynamic radius (SEC) to thermal stability parameters (Tm, ΔH, ΔCp). By measuring the thermal unfolding temperature and heat capacity changes, the method obtains protein stability information through a different physical parameter that can be measured more rapidly.

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If Size Exclusion Chromatography (SEC) is used to determine protein stability, then measurement precision is improved, but manufacturing cost deteriorates

Engineering Contradiction:

Improveprotein stability measurement accuracyVSAvoidcost of stability assessment

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

The patent replaces the expensive SEC instrumentation and operational costs with more affordable thermal analysis equipment. DSC and especially DSF instruments are generally less costly to purchase and operate than HPLC-based SEC systems, reducing the manufacturing burden while maintaining measurement capability.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent employs disposable components in the thermal stability assays, such as single-use DSC pans or DSF plates, which eliminate the need for expensive column maintenance and regeneration required by SEC, thereby reducing overall manufacturing costs.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Productivity

If thermal stability analysis is used to assess protein stability, then productivity is improved, but measurement precision may deteriorate

Engineering Contradiction:

Improvespeed of stability assessmentVSAvoidcorrelation with SEC results

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The patent establishes a feedback relationship between thermal stability parameters (Tm, ΔH) and SEC-based stability measurements. By correlating these different measurement approaches and using thermal data to predict SEC outcomes, the method validates precision while maintaining speed advantages.

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The patent uses thermal stability parameters as an intermediary that correlates with protein stability. The Tm and other thermal parameters serve as intermediate measurements that can be rapidly obtained and then correlated to the gold standard SEC measurements, bridging the gap between speed and precision.

Inventive Principle:

Principle #24Intermediary (Mediator)

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

Thermal stability analysis provides a statistically significant correlation with SEC results, allowing for quicker and more cost-effective assessment of protein stability, facilitating early-stage drug development and formulation optimization.

Implementation Method 1

measuring thermal stability of the therapeutic protein

Methodology Applied

Scientific EffectCalorimetry: Calorimetry

Implementation Method 2

measuring thermal stability of the therapeutic protein

Methodology Applied

Scientific EffectFluorescence: Fluorescence

Data Source

PatentUS12493019B2Methods of determining protein stability

Publication Date: 2025.12.09 AMGEN INC

AI summary

The disclosure provides for a method of assessing stability of a therapeutic protein in a formulation comprising the steps of measuring thermal stability of the therapeutic protein wherein the value for thermal stability correlates with the main peak percent change determined by size exclusion chromatography in a statistically significant manner.