Continuous Recombinant Protein Production via Integrated Chromatography
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Solution Overview
Problem
Continuous manufacturing techniques have not been widely implemented in the biopharmaceutical industry due to differences in upstream and downstream technological needs, resulting in limited experience with extended, minimally interactive continuous downstream operations.
Innovation Solution
A continuous method and system integrating capture chromatography, post-capture chromatography, virus filtration, and ultrafiltration/diafiltration for the production of recombinant proteins, which includes capturing the protein using capture chromatography systems, subjecting the eluates to post-capture systems, and purifying through ultrafiltration and diafiltration, enabling a steady and efficient production process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If continuous downstream operations are implemented in biopharmaceutical manufacturing, then productivity and volumetric efficiency are improved, but device complexity and operational difficulty increase due to the need for integrated multi-step processes running for extended periods
Solution Approach 1:
The continuous downstream process is divided into distinct functional modules: capture chromatography system, post-capture chromatography system, virus filtration system, and ultrafiltration/diafiltration system. Each module performs a specific purification function and can be independently optimized, controlled, and maintained, reducing overall system complexity while enabling continuous operation.
Solution Approach 2:
The system employs dynamic flow control and automated switching mechanisms that allow the process to adapt to varying production conditions. The continuous operation capability is achieved through dynamic coordination between multiple chromatography columns and filtration systems, enabling extended runtime with minimal intervention.
2Productivity
If multiple chromatography systems and filtration steps are integrated continuously, then manufacturing efficiency is improved, but the extent of automation required increases significantly
Solution Approach 1:
The system maintains continuous operation through coordinated cycling between multiple chromatography columns while others are being regenerated or cleaned. This continuous action eliminates idle time and maximizes productivity without requiring complex batch-to-batch automation transitions, as the process flows continuously through different operational phases.
Solution Approach 2:
Column regeneration, cleaning, and preparation steps are performed preliminarily and concurrently with other columns in the continuous process. This allows the system to maintain continuous production while automation handles the preparatory tasks for the next operational cycle, reducing the burden on real-time automation control.
3Loss of time
If continuous operation for extended periods is implemented, then steady state operation and reduced cycle times are achieved, but reliability and stability of the process become more challenging to maintain
Solution Approach 1:
The multi-column chromatography system allows segmentation of operational tasks across parallel units. While one column is in service, others can be regenerated or maintained, ensuring continuous reliable operation without interruption. This segmentation prevents single-point failures and maintains process stability over extended periods.
Solution Approach 2:
The system implements continuous regeneration and recovery of chromatography columns during operation. Used columns are automatically regenerated and recovered for reuse, maintaining consistent performance and reliability. This continuous recovery process ensures that purification capacity is constantly replenished without stopping production, maintaining both speed and reliability.
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 the continuous production of recombinant proteins with high yield and purity over extended periods with minimal operator intervention, achieving a net yield of at least 5 kg of drug substance over 25 days, demonstrating streamlined process flow and reduced capital costs.
Implementation Method 1
capturing the recombinant protein from a substantially cell-free sample using one or a plurality of capture chromatography systems
Implementation Method 2
subjecting the product output to ultrafiltration and diafiltration to purify the recombinant protein
Implementation Method 3
subjecting the product output to ultrafiltration and diafiltration to purify the recombinant protein
Data Source
AI summary
The present disclosure relates to methods and systems for the continuous production of recombinant proteins. In particular embodiments, the disclosure relates to methods and systems using capture chromatography, post-capture chromatography, virus filtration, and ultrafiltration/diafiltration for the continuous production of recombinant proteins.