Diafiltration for Antibody Formulation Stability
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Solution Overview
Problem
Pharmaceutical protein formulations face challenges in maintaining protein stability and solubility, especially at high concentrations, due to physical and chemical instabilities, which can lead to aggregation, precipitation, and degradation during storage and delivery, requiring additional excipients that may cause unwanted effects.
Innovation Solution
Aqueous protein formulations are developed using a diafiltration process with water to reduce the concentration of excipients by at least 95-99%, allowing proteins to remain stable and soluble at high concentrations without the need for additional stabilizing agents, such as surfactants and buffering systems, while maintaining biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional excipients (surfactants, buffering systems) are added to maintain protein stability, then protein stability and solubility are improved, but formulation complexity and potential immunogenicity increase
Solution Approach 1:
The patent removes traditional excipients (surfactants, buffering systems, salts) from the formulation through a diafiltration process, extracting only the necessary components while eliminating complex additives that contribute to formulation complexity and potential immunogenicity
Solution Approach 2:
The protein formulation achieves self-stabilization through controlled water addition and diafiltration, where the protein itself maintains its stability without requiring external excipients, enabling the formulation to serve its own stabilization needs
2Quantity of substance
If protein concentration is increased to improve therapeutic efficacy, then dosage volume is reduced, but aggregation and precipitation risks increase
Solution Approach 1:
The patent changes the formulation parameters by using ultra-pure water with controlled conductivity (0.05-0.5 µS/cm) and specific resistivity (2-20 MΩ·cm), allowing high protein concentrations to be achieved while maintaining stability through precise control of water quality parameters rather than relying on stabilizing excipients
3Duration of action of stationary object
If freezing is used for long-term storage to maintain stability, then shelf-life is extended, but localized concentration extremes and aggregation may occur
Solution Approach 1:
The patent performs preliminary diafiltration and ultra-purification of water before formulation, removing all excipients and impurities in advance, which prevents the formation of localized concentration extremes during freezing and thawing cycles, maintaining homogeneity throughout storage
4Reliability
If multiple excipients are added to prevent degradation, then chemical and physical stability are improved, but toxicity risks and immunogenicity increase
Solution Approach 1:
The patent extracts and removes all potential toxic excipients through diafiltration against ultra-pure water, eliminating harmful substances while retaining the therapeutic protein, thereby achieving degradation resistance without toxicity risks
Solution Approach 2:
The patent uses disposable ultra-pure water with extremely low conductivity (0.05-0.5 µS/cm) as a temporary medium during diafiltration that is subsequently removed, serving its stabilization function during manufacturing and then being eliminated from the final formulation to avoid long-term toxicity
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 achieves stable protein formulations with minimal aggregation and low osmolality, suitable for long-term storage and delivery, including freeze/thaw cycles, with improved stability and reduced immunogenicity, enabling high protein concentrations without the use of traditional excipients.
Implementation Method 1
Aqueous protein formulations are developed using a diafiltration process with water to reduce the concentration of excipients by at least 95-99%
Implementation Method 2
Protein stability can be improved by including excipients that interact with the protein in solution to keep the protein stable, soluble and unaggregated
Data Source
AI summary
The invention provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductivity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.