Automated Biomanufacturing with Single-Use Perfusion and Continuous Chromatography
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Solution Overview
Problem
The biopharmaceutical industry faces challenges in integrating upstream biologics manufacturing processes with downstream processes, particularly due to dimensional limitations in chromatography columns and the need for robust viral clearance and automation strategies to ensure high product quality, especially in continuous manufacturing systems.
Innovation Solution
An automated facility and process for manufacturing purified proteins using single-use perfusion bioreactors with continuous or periodic addition of fresh sterile culture medium, integrated with chromatography systems, viral inactivation, and ultrafiltration/diafiltration systems, to maintain constant culture volume and manage fluid flow rates, ensuring high product quality and viral clearance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional batch processing platforms are used for biologics manufacturing, then operational flexibility and product quality are maintained, but throughput is limited and manufacturing costs are higher
Solution Approach 1:
The patent implements continuous processing systems where upstream bioreactor operations are directly integrated with downstream purification processes, eliminating batch-to-batch transitions and enabling uninterrupted material flow. This continuous operation mode increases throughput while reducing manual intervention and manufacturing costs compared to traditional batch processing.
Solution Approach 2:
The patent merges upstream and downstream processing operations into an integrated continuous manufacturing system. The direct connection between bioreactors and purification trains allows seamless transition from production to purification, improving overall productivity and reducing the dimensional limitations that constrain separate batch operations.
2Productivity
If continuous perfusion technologies are implemented to increase throughput, then productivity improves, but integration with downstream processes becomes more complex
Solution Approach 1:
The patent segments the continuous manufacturing system into modular functional units including upstream perfusion bioreactors, intermediate holding vessels, and downstream purification modules. Each module can be independently optimized and maintained, reducing overall system integration complexity while preserving continuous operation benefits.
Solution Approach 2:
The patent introduces intermediate holding vessels and buffer systems as mediators between upstream perfusion operations and downstream purification processes. These intermediaries buffer flow rate variations and enable smooth integration between different processing stages, simplifying the overall system architecture.
3Manufacturing precision
If chromatography columns are used for purification, then product purity is achieved, but dimensional limitations restrict processing capacity
Solution Approach 1:
The patent transitions from traditional batch chromatography to continuous chromatography operations, adding the time dimension to the purification process. Multiple chromatography columns operate in sequence or parallel with continuous flow, effectively increasing processing capacity while maintaining purity requirements through optimized column dimensions and flow rates.
Solution Approach 2:
The patent optimizes chromatography operating parameters including flow rates, column dimensions, and resin characteristics to maximize processing capacity within available dimensional constraints. Continuous operation allows for higher linear flow rates and reduced column sizes while maintaining equivalent purification performance.
4Productivity
If long-duration perfusion culture is conducted to increase protein production, then productivity improves, but contamination risk increases
Solution Approach 1:
The patent implements closed continuous systems where sterile barriers are maintained throughout the extended perfusion culture period. Continuous operation with sealed connections and automated processing minimizes human intervention and exposure to contamination risks that increase with longer batch durations.
Solution Approach 2:
The patent employs single-use sterile consumables including disposable bioreactor bags, filters, and chromatography columns that are pre-sterilized and sealed. These single-use components eliminate sterilization validation requirements and reduce contamination risk during long-duration operations by providing inherent sterile barriers.
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 enables long-duration perfusion culture with reduced waste management costs, minimized contamination risk, and efficient protein production, addressing the integration challenges and scalability issues in biologics manufacturing by maintaining high viability and purity of the protein product.
Implementation Method 1
culturing mammalian cells in one or more single-use perfusion bioreactors comprising a liquid culture medium under conditions that allow the cells to secrete the protein into the liquid culture medium for a production cultivation period of at least 10 days; wherein, periodically or continuously, during the production cultivation period, fresh sterile liquid culture medium is added into the one or more perfusion bioreactors
Implementation Method 2
the removed volumes of permeate are automatically and fluidly fed from the one or more single-use perfusion bioreactor(s) into a single-use surge vessel and thence into a first chromatography system, whereby the protein is collected in a protein isolate fraction
Implementation Method 3
an ultrafiltration/diafiltration system adapted to fluidly receive the virus-free filtrate from the second chromatography system or from the third chromatography system and/or the viral filtration system, whereby the purified protein of interest is obtained
Data Source
AI summary
Disclosed are a process and an automated facility for manufacturing a purified protein of interest. The protein of interest can be a recombinant or naturally occurring protein and/or a therapeutic or other medically useful protein. For example, the disclosed process and automated facility are useful for manufacturing a purified protein drug substance.