ATF Microfilter Bioreactor System for Polypeptide Concentration
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Solution Overview
Problem
Current methods for producing polypeptide products, such as monoclonal antibodies, through cell culture face challenges in achieving high product concentrations and compatibility with downstream purification processes, particularly due to the complexity of continuous cell culture and perfusion techniques which complicate clarification and batch definition.
Innovation Solution
The use of a system comprising a production bioreactor connected to an alternating tangential flow (ATF) microfilter and a harvest vessel with an ATF ultrafilter allows for the concentration of polypeptides over extended periods before downstream purification, reducing the need for additional clarification steps and maintaining batch integrity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If continuous perfusion techniques are used for process intensification, then productivity is improved, but device complexity and difficulty of clarification increase
Solution Approach 1:
The system divides the continuous production process into two distinct batches: Batch 1 in the production bioreactor for cell culture and Batch 2 in the harvest vessel for product concentration. This segmentation allows continuous product accumulation while maintaining batch processing simplicity for downstream operations, resolving the contradiction between productivity improvement and process complexity.
Solution Approach 2:
The patent extracts the product concentration function from the production bioreactor by introducing a separate harvest vessel. The ATF microfilter continuously transfers polypeptide-containing medium from the production bioreactor to the harvest vessel, where concentration occurs. This extraction eliminates the need for continuous clarification during purification while maintaining process intensification benefits.
2Productivity
If perfusion process is used to achieve high product concentration, then productivity is improved, but the need for massive cell clarification increases operational difficulty
Solution Approach 1:
The ATF microfilter performs preliminary continuous filtration of cells during the production phase, separating cells from the polypeptide-containing medium before harvest. This preliminary action eliminates the need for massive cell clarification during downstream processing, as the harvest vessel receives already clarified medium containing accumulated product.
Solution Approach 2:
The ATF microfilter acts as an intermediary device between the production bioreactor and harvest vessel. It continuously filters the medium, allowing polypeptides and small molecules to pass while retaining cells in the production bioreactor. This intermediary function achieves both high product concentration and simplified downstream operations.
3Productivity
If break tank with continuous chromatography is used for extended period production, then productivity is improved, but quality and regulatory compliance become difficult to maintain
Solution Approach 1:
The system segments the production process into distinct batches (Batch 1 in production bioreactor, Batch 2 in harvest vessel) with clear temporal and spatial boundaries. Each batch has defined start and end points, enabling precise lot definition and traceability. This segmentation maintains regulatory compliance while allowing extended production periods through continuous product accumulation in Batch 2.
Solution Approach 2:
The system employs periodic batch operations rather than continuous chromatography. Production occurs in defined batches with clear beginning and end points, allowing for proper lot release and quality control. The ATF microfilter operates continuously within these periodic batches to accumulate product, combining the benefits of both continuous and batch processing.
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 higher polypeptide concentrations and simplifies downstream operations by concentrating the product in a separate harvest vessel, reducing costs and maintaining batch integrity, while allowing for continuous production without the need for extensive cell clarification.
Implementation Method 1
a first bioreactor in fluid connection with an alternating tangential flow (ATF) microfilter such that the host cell, the culture medium, and the polypeptide from the first bioreactor contact the ATF microfilter
Implementation Method 2
contacting the polypeptide and the portion of the culture medium in the second bioreactor with an ATF ultrafilter, wherein the ATF ultrafilter causes the polypeptide to be retained in the second bioreactor and allows culture medium to exit the second bioreactor
Data Source
AI summary
Provided herein are methods and systems for production (e.g., batch production) of a polypeptide product via cell culture. In some embodiments, the methods and systems use a first bioreactor (e.g., for cell culturing), an alternating tangential flow (ATF) microfilter (e.g., for removing a polypeptide product and culture medium from the cell culture while retaining cells), a second bioreactor (e.g., for concentrating the product), and an ATF ultrafilter (e.g., for retaining product in the second bioreactor and allowing culture medium to exit).