Lyophilized Anti-CD20 Antibody Formulation with Controlled Moisture
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Solution Overview
Problem
Current methods for providing high-concentration lyophilized antibody formulations face challenges due to increased viscosity and protein aggregation, which can lead to stability issues and unwanted immune responses, necessitating the development of a stable and efficient method for producing lyophilized anti-CD 20 antibodies with controlled residual moisture content.
Innovation Solution
A method involving the steps of providing an anti-CD 20 antibody solution, freezing it, and subjecting it to a drying process at shelf temperatures between -10°C to 30°C to achieve a lyophilized formulation with a residual moisture content of 1% to 10%, optionally 1% to 5%, using buffering agents like histidine, tonicity modifying agents such as sucrose, and surfactants like polysorbate 20 to enhance stability and reduce aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If high concentration formulations of therapeutic proteins are used, then the volume necessary for administration decreases and convenience increases, but viscosity increases dramatically and protein aggregation occurs
Solution Approach 1:
The patent applies parameter changes by controlling the residual moisture content to a specific range (1-10%) through optimized lyophilization parameters including shelf temperature, drying time, and pressure conditions. This parameter optimization prevents protein aggregation while maintaining high concentration (100 mg/mL or higher), thereby resolving the contradiction between achieving small administration volume and preventing protein instability
Solution Approach 2:
The patent uses composite formulations combining the therapeutic protein with stabilizing excipients such as sugars (sucrose, trehalose), amino acids (arginine, histidine), and buffers. These composite materials work synergistically to maintain protein stability at high concentrations during lyophilization and storage, preventing aggregation while enabling reduced administration volume
2Stability of the object's composition
If lyophilization is used to prevent protein aggregation, then stability increases, but residual moisture content must be precisely controlled to avoid degradation
Solution Approach 1:
The patent implements feedback control during the lyophilization process by monitoring residual moisture content at various stages and adjusting drying parameters accordingly. The method specifies precise drying conditions (shelf temperature of -10°C to 30°C, controlled vacuum pressure) that automatically guide the process toward achieving the target moisture range (1-10%), ensuring both stability and manufacturing precision
Solution Approach 2:
The patent applies preliminary action by pre-freezing the formulation to specific temperatures and maintaining it in the frozen state during primary drying. This preliminary freezing step ensures proper ice crystal formation and prevents premature thawing that could lead to moisture condensation, thereby facilitating precise residual moisture control while maintaining formulation stability
3Productivity
If high concentration formulations are prepared, then fewer administrations are needed, but the tendency to form aggregates increases
Solution Approach 1:
The patent introduces intermediary substances (excipients) such as surfactants (polysorbate 20, polysorbate 80), sugars, and amino acids that mediate between the high concentration requirement and aggregate prevention. These intermediaries interact with the protein surface and solvent to stabilize the formulation at high concentrations, enabling reduced administration frequency without harmful aggregation
Solution Approach 2:
The patent creates an inert environment during lyophilization by conducting the drying process under controlled vacuum conditions with limited oxygen exposure. This inert atmosphere prevents oxidative degradation and reduces protein-protein interactions that could lead to aggregation, allowing high concentration formulations to be prepared with minimal aggregate formation
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 results in a stable lyophilized formulation with reduced aggregation and increased stability during storage, allowing for convenient reconstitution and administration, particularly suitable for subcutaneous use in treating various cancers and autoimmune diseases.
Implementation Method 1
freezing the antibody solution
Implementation Method 2
subjecting the antibody solution to at least one drying step at a shelf temperature of −10° C. to 30° C. in order to obtain the lyophilized formulation
Data Source
AI summary
The present invention provides a method for preparation of a lyophilized formulation of an anti-CD 20 antibody as well as to a lyophilized formulation of an anti-CD 20 antibody, comprising an anti-CD 20 antibody and having a residual moisture content in the range of 1% to 10%. The present invention also relates to the reconstituted formulation obtained by the method described herein, the use of said antibody formulation as a medicament, the use of the lyophilized formulation for the preparation of a medicament and a method of treating a patient.