Reverse Sparger Dissolved Oxygen Control in Bioreactors

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Existing methods for controlling dissolved oxygen levels during the harvest and downstream processing of recombinant proteins, such as monoclonal antibodies, are limited in accessibility and effectiveness, particularly in Single Use Mixers, leading to protein degradation due to disulfide bond reduction and oxidation.

Innovation Solution

A reverse sparger method is introduced, which recirculates the solution through a tube connected to a curved nozzle, directing the flow along the container wall, and refreshes the air overlay with gases like oxygen, nitrogen, or argon, to efficiently control dissolved oxygen levels in storage containers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If traditional sparger method is used to control dissolved oxygen, then oxygen transfer can be achieved, but accessibility for implementation in downstream product-hold vessels is limited

Engineering Contradiction:

Improveaccessibility for implementation in downstream product-hold vesselsVSAvoidimplementation complexity in SUM vessels

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent inverts the traditional sparger approach by using a recirculation system with a nozzle that directs liquid flow along the container wall, creating a thin liquid film that enhances oxygen transfer from the headspace. This reverse approach enables effective DO control in previously inaccessible downstream product-hold vessels like Single Use Mixers.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention transitions from conventional bulk sparging to a surface-based oxygen transfer mechanism by creating a thin liquid film along the container wall. This dimensional change from volumetric to surface-based mass transfer enables implementation in vessels with limited mixing capability.

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

2Reliability

If dissolved oxygen levels are not controlled, then protein degradation occurs through disulfide bond reduction and oxidation, but implementing control methods increases process complexity

Engineering Contradiction:

Improveprotein quality stabilityVSAvoidprocess parameter control complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The recirculation system automatically maintains dissolved oxygen levels by continuously drawing liquid through the nozzle and allowing oxygen transfer at the liquid film interface. The system self-regulates without requiring complex control algorithms or multiple process parameters, simplifying implementation while ensuring protein stability.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The invention changes the physical state and flow characteristics of the liquid by creating a thin film flow regime instead of bulk mixing. This parameter change in flow dynamics enhances oxygen transfer efficiency and simplifies the control strategy for maintaining protein quality.

Inventive Principle:

Principle #35Parameter changes

3Stability of the object's composition

If high dissolved oxygen levels are maintained to prevent protein degradation, then oxidation of other residues may occur, but reducing oxygen leads to disulfide bond reduction

Engineering Contradiction:

Improveprotein structural integrityVSAvoidoxidation of methionine residues

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The continuous recirculation creates a dynamic equilibrium at the liquid film interface, allowing controlled oxygen transfer that maintains dissolved oxygen levels within an optimal range. This feedback-like continuous adjustment prevents both excessive oxygen accumulation (which causes oxidation) and oxygen depletion (which causes disulfide bond reduction), thereby protecting protein structural integrity.

Inventive Principle:

Principle #23Feedback

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 method effectively maintains high dissolved oxygen levels, reducing protein degradation by minimizing disulfide bond reduction and oxidation, outperforming traditional methods in oxygen transfer rates and stability of protein quality over time.

Implementation Method 1

directing the flow along the container wall

Methodology Applied

Scientific EffectThin film flow:

Implementation Method 2

directing the flow along the container wall

Methodology Applied

Scientific EffectSurface area enhancement:

Implementation Method 3

air overlay of the top of the container

Methodology Applied

Scientific EffectGas-liquid mass transfer:

Implementation Method 4

dissolved oxygen control

Methodology Applied

Scientific EffectDiffusion: Diffusion

Implementation Method 5

the recirculation is driven by a pump

Methodology Applied

Scientific EffectPumping: Pump

Data Source

PatentUS20240390869A1Methods of controlling the level of dissolved oxygen (DO) in a solution comprising a recombinant protein in a storage container

Publication Date: 2024.11.28 BRISTOL MYERS SQUIBB CO

AI summary

This invention provides a method of controlling the level of dissolved oxygen in a solution comprising a recombinant protein in a storage container.