Antibody Formulation Viscosity Reduction via Calcium Buffer Exchange
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Solution Overview
Problem
Highly concentrated antibody formulations face instability due to particulate formation and increased viscosity, making them difficult to manufacture, draw into syringes, and inject without causing denaturation and inactivation of active biologics.
Innovation Solution
A method involving buffer exchange with a diafiltration buffer containing a calcium salt at a temperature greater than 30°C, specifically using calcium acetate, to reduce viscosity to 10 cP or less, facilitating the concentration of antibodies to 70 mg/mL or higher, thereby improving manufacturing and injection processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If antibody concentration is increased to improve dosing efficiency, then patient dosing regimes are enhanced with smaller injection volumes, but viscosity increases making the formulation difficult to manufacture and inject
Solution Approach 1:
The patent applies parameter changes by adjusting the buffer composition (switching from standard buffer to calcium-containing buffer) and processing conditions (temperature, pH) to modify the physical properties of the antibody formulation. This resolves the contradiction by enabling high concentration (70-210 mg/mL) while maintaining viscosity below 10 cP through specific buffer exchange conditions with calcium salts at elevated temperatures
Solution Approach 2:
The patent uses a diafiltration buffer containing calcium salt as an intermediary medium to facilitate buffer exchange. This intermediary buffer allows the antibody to be concentrated while the calcium ions act as a mediator to control intermolecular interactions and prevent excessive viscosity buildup, enabling smooth injection at high concentrations
2Quantity of substance
If antibody concentration is increased to reduce injection volume, then dosing efficiency improves, but particulate formation increases leading to instability
Solution Approach 1:
The patent changes critical formulation parameters including buffer composition (introduction of calcium salts), temperature (greater than 30°C during buffer exchange), and pH to stabilize the high-concentration antibody formulation. These parameter changes prevent particulate formation and maintain composition stability at concentrations of 70-210 mg/mL
Solution Approach 2:
The calcium-containing diafiltration buffer serves as an intermediary that stabilizes the antibody during concentration. The calcium ions act as a stabilizing agent that prevents aggregation and particulate formation, allowing high concentration without compromising formulation stability
3Quantity of substance
If force is applied to manipulate viscous formulations to achieve desired concentration, then antibody concentration increases, but excessive frothing occurs leading to denaturation and inactivation
Solution Approach 1:
The patent changes the buffer composition parameter (introduction of calcium salts) and processing temperature parameter (greater than 30°C) to reduce the viscosity of the formulation. This parameter change allows concentration to be achieved with minimal mechanical force, preventing frothing and denaturation while maintaining antibody biologic activity and reliability
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 enhances patient dosing regimes by reducing viscosity, allowing for smaller injection volumes, wider device options, and improved supply chain considerations, while maintaining the stability and effectiveness of the antibodies.
Implementation Method 1
buffer exchanging a composition comprising the antibody with a diafiltration buffer comprising a calcium salt at a temperature greater than 30° C.
Implementation Method 2
the exchanging step occurs via ultrafiltration/diafiltration
Data Source
AI summary
The present disclosure provides materials and methods for preparing an antibody pharmaceutical formulation having a viscosity of 10 cP or less comprising exchanging a composition comprising the antigen binding protein with a diafiltration buffer comprising calcium at a temperature greater than 30° C.