High-Concentration IgG Purification for Stable Subcutaneous Use
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Solution Overview
Problem
Existing methods for producing immunoglobulin preparations are inadequate for achieving high concentrations suitable for subcutaneous and intramuscular administration, and there is a need for stable, highly purified, virus-inactivated products with improved safety and yield.
Innovation Solution
A manufacturing method involving ultrafiltration and diafiltration steps to achieve a highly concentrated IgG composition with at least 95% purity, using a process that includes ethanol precipitation, cation and anion exchange chromatography, and nanofiltration, followed by sterilization and storage at elevated temperatures to inactivate viruses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If traditional IVIG production methods are used, then virus safety and basic purity are achieved, but IgG concentration remains insufficient for effective treatment of certain conditions
Solution Approach 1:
The production process is divided into multiple sequential purification steps including ammonium sulfate precipitation, cation exchange chromatography, anion exchange chromatography, and nanofiltration. Each step targets specific contaminants while progressively concentrating IgG, allowing the process to achieve both high concentration and virus safety through cumulative effect of multiple specialized operations.
Solution Approach 2:
The process utilizes controlled changes in pH, ionic strength, and temperature parameters throughout the purification steps. Ammonium sulfate precipitation uses controlled salt concentration changes, while chromatography steps use pH gradients for selective elution. These parameter changes enable selective separation of IgG from contaminants and achieve both concentration and purification simultaneously.
2Quantity of substance
If IgG concentration is increased to 200 mg/mL for subcutaneous administration, then treatment efficacy and home-care possibility improve, but storage stability deteriorates
Solution Approach 1:
Glycine buffer is introduced as an intermediary substance to stabilize the high-concentration IgG formulation. The glycine maintains pH control and prevents aggregation that would otherwise occur at 200 mg/mL concentration. This intermediary agent enables the formulation to achieve both high concentration for subcutaneous administration and adequate storage stability.
Solution Approach 2:
The formulation uses controlled pH adjustment to a specific range (pH 4.5-5.5) to optimize both solubility and stability of IgG at high concentration. This parameter optimization prevents precipitation and aggregation while maintaining the desired 200 mg/mL concentration level for subcutaneous injection.
3Manufacturing precision
If multiple purification steps are added to achieve higher purity and concentration, then IgG quality improves, but manufacturing complexity increases
Solution Approach 1:
Multiple purification functions are merged into integrated chromatography columns and filtration systems. The cation and anion exchange chromatography steps are combined in sequence within a single processing train, and nanofiltration is integrated as the final polishing step. This merging reduces the number of separate operations and simplifies manufacturing while maintaining high purity and concentration.
Solution Approach 2:
The purification process is designed as a continuous flow system where each step feeds directly into the next without interruption. Ammonium sulfate precipitation followed by cation exchange, then anion exchange, and finally nanofiltration creates an uninterrupted purification train that maintains product quality while reducing batch processing complexity and improving manufacturing efficiency.
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
The method produces a stable, highly concentrated IgG preparation suitable for subcutaneous and intravenous administration, with improved stability and safety, and can be stored for extended periods without significant protein loss.
Implementation Method 1
The composition is produced by a process leading to a product suitable for subcutaneous and intravenous administration... passing the nanofiltrate through an ultrafiltration membrane to generate an ultrafiltrate
Implementation Method 2
mixing pre-cooled ethanol with the liquid from (1) to form a mixture... separating liquid and precipitate from the mixture of (2) by centrifugation
Implementation Method 3
passing the solution after (9) through a cation exchange chromatography column and eluting proteins absorbed on the column in an eluate
Implementation Method 4
passing the eluate from (10) through an anion exchange chromatography column to generate an effluent
Implementation Method 5
separating liquid and precipitate from the mixture of (2) by centrifugation... separating liquid and precipitate from the mixture of (4) by centrifugation
Implementation Method 6
passing the effluent through a nanofilter to generate a nanofiltrate
Implementation Method 7
mixing a detergent and cold alcohol with the filtrate of (7) and obtaining a precipitate by centrifugation... dissolving the precipitate in an aqueous solution comprising a solvent or detergent
Data Source
AI summary
The present invention relates to a new and improved method for preparing a highly concentrated immunoglobulin composition from pooled plasma for subcutaneous injection. A composition comprising 20% or more immunoglobulin suitable for subcutaneous use is also described.