Stable High-Concentration Lyophilized Anti-CD38 Antibody Formulation
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Solution Overview
Problem
Therapeutic antibodies, such as anti-CD38 antibodies, face challenges in formulation stability, including protein aggregation, deamidation, oxidation, and high viscosity, which affect their biological activity and administration ease, particularly in high-concentration formulations.
Innovation Solution
A stable lyophilized pharmaceutical formulation of anti-CD38 antibody (MOR202) is developed, comprising a pH 5.5-6.5 histidine buffer, polysorbate surfactant, and sucrose stabilizer, allowing reconstitution for administration, with concentrations up to 65 mg/ml and viscosity optimized for subcutaneous or intravenous use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high protein concentration formulations are used, then the dosage volume is reduced and administration efficiency is improved, but the viscosity increases and syringability deteriorates
Solution Approach 1:
The patent optimizes formulation parameters including pH (adjusted to specific ranges using buffers), ionic strength, and excipient concentrations to reduce viscosity. By changing these physical-chemical parameters, the formulation achieves lower viscosity at high protein concentrations, improving syringability while maintaining administration efficiency.
Solution Approach 2:
The patent uses composite formulation systems combining the therapeutic antibody with multiple excipients (surfactants like polysorbate, stabilizers like sucrose or trehalose, buffers). This composite approach creates a synergistic effect where each component contributes to reducing protein-protein interactions and lowering viscosity, enabling high concentration formulations that remain syringable.
2Duration of action of stationary object
If high protein concentration formulations are used, then the shelf life and storage stability are improved, but protein aggregation and physical instability increase
Solution Approach 1:
The patent introduces intermediary substances (excipients) that mediate between the high protein concentration and the protein molecules. Surfactants adsorb at protein interfaces preventing aggregation, while stabilizers like sugars form protective matrices during lyophilization. These intermediaries enable high concentration formulations to maintain physical stability and extend shelf life.
Solution Approach 2:
The patent employs lyophilization (freeze-drying) which utilizes phase transitions of water (freezing then sublimation) to create a stable solid matrix. This phase transition removes liquid water that could facilitate aggregation, locking the protein in a stable conformational state and preventing physical instability during long-term storage.
3Duration of action of stationary object
If lyophilized formulations are used, then the storage stability and shelf life are improved, but the formulation complexity and manufacturing process difficulty increase
Solution Approach 1:
The patent performs preliminary optimization of the formulation composition before lyophilization. By pre-selecting appropriate excipients and adjusting formulation parameters (pH, concentration, buffer composition), the patent ensures that the lyophilization process proceeds smoothly with consistent results. This preliminary action simplifies the manufacturing process by preventing issues like cake collapse, deliquescence, or incomplete drying.
4Reliability
If antibody formulations are stabilized against degradation, then the biological activity is preserved, but the formulation composition becomes more complex
Solution Approach 1:
The patent selects excipients that perform multiple functions simultaneously. For example, phosphate or acetate buffers not only maintain pH to prevent deamidation but also provide ionic strength control. Surfactants like polysorbate prevent aggregation while also stabilizing the protein surface. This multi-functionality reduces the need for additional separate stabilizing agents, keeping the formulation relatively simple while maintaining biological activity.
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 formulation maintains biological activity and stability, reducing immune response risks and improving administration ease, suitable for treating conditions like multiple myeloma and other cancers.
Implementation Method 1
comprising a pH 5.5-6.5 histidine buffer
Implementation Method 2
polysorbate surfactant
Implementation Method 3
sucrose stabilizer
Implementation Method 4
stable lyophilized pharmaceutical formulation
Data Source
AI summary
The present disclosure relates to formulations of a pharmaceutically active antigen binding protein, such as a monoclonal antibody. In particular, the present disclosure relates to a stable lyophilized pharmaceutical formulation of an anti-CD38 antibody, a reconstituted liquid formulation of such lyophilized formulation, and to methods of making and using such lyophilized and reconstituted formulations.