Chelators Prevent Visible Particle Formation in Protein Formulations
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Solution Overview
Problem
The formation of visible particles in aqueous protein compositions, particularly in pharmaceutical antibody formulations, due to the degradation of polysorbate, poses a significant challenge as it can lead to safety risks and product recalls, with unpredictable occurrence and limited solutions for preventing free fatty acid particle formation.
Innovation Solution
The use of chelators such as EDTA or DTPA is introduced to complex multivalent cations, preventing their interaction with free fatty acids resulting from polysorbate degradation, thereby mitigating the formation of visible particles below their solubility limit.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polysorbate is added to protect protein against interfacial stress, then protein stability is improved, but polysorbate degradation occurs leading to free fatty acid particle formation
Solution Approach 1:
Chelators serve as intermediary substances that bind to multivalent cations, preventing these cations from interacting with free fatty acids and forming particles. The chelator acts as a mediator between the harmful free fatty acids and the cations, converting the harmful interaction into a controlled complexation process that prevents particle formation.
Solution Approach 2:
The degradation of polysorbate, which initially produces harmful free fatty acids, is converted into a beneficial scenario by adding chelators. The chelators bind the multivalent cations that would otherwise catalyze further degradation or form particles with FFAs, thus converting the harmful degradation pathway into a controlled process that maintains formulation stability.
2Reliability
If chelators are added to prevent particle formation, then formulation stability is improved, but formulation complexity increases
Solution Approach 1:
The invention changes the chemical environment parameters of the formulation by introducing chelators that alter the availability and reactivity of multivalent cations. This parameter change prevents particle formation without requiring fundamental changes to the formulation structure or manufacturing process.
3Loss of substance
If polysorbate degradation is allowed to occur, then surfactant functionality is lost, but free fatty acids are released which can form particles
Solution Approach 1:
Chelators act as intermediary substances that intercept the interaction between free fatty acids and multivalent cations, preventing particle formation even when polysorbate degradation has occurred. The chelator mediates the system by binding cations, thus preventing the harmful FFA-cation interaction that leads to visible particles.
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 addition of chelators effectively stabilizes aqueous protein formulations by preventing the formation of visible particles, ensuring the quality and safety of parenteral pharmaceutical products by maintaining their stability throughout their authorized shelf life.
Implementation Method 1
the addition of excipients (chelators), which can complex multivalent cations and prevent their interaction with fatty acids resulting from polysorbate degradation
Implementation Method 2
Hydrolytic degradation of PS20 does not only result in a loss of surfactant functionality but furthermore leads to the release of free fatty acids (FFA)
Implementation Method 3
Trace levels of metal ions like Al3+ have been previously shown to interact with FFAs resulting from hydrolytic PS degradation, leading to FFA-metal complexes which eventually precipitate out of aqueous formulations
Data Source
AI summary
The present invention provides methods to prevent the formation of visible particles in aqueous protein formulations, in particular the use of certain chelators, as well as compositions and pharmaceutical products obtained with said method.