Target residual moisture content for lyophilized drug product
Lyophilization methods for preparing protein formulations for long-term storage at room temperature or improved stability at refrigeration storage are provided. Specifically, the present application provides lyophilization methods to obtain a target percentage of residual moisture of a lyophilized product, such as 3-5% residual moisture. The secondary drying of the lyophilization can be conducted under controlling rate of desorption under a temperature which is similar to the shelf temperature of the primary drying. Alternatively, the lyophilization can be conducted without a distinguished secondary drying step.
1. A method of preparing a lyophilized cake, comprising:
preparing a formulation, wherein the formulation comprises at least one solvent molecule and a peptide or protein;
subjecting the formulation to lyophilization to obtain the lyophilized cake, including:
placing the formulation in a chamber of a freeze-dryer,
freezing the formulation,
conducting first drying on the formulation to remove the at least one frozen solvent molecule by sublimation, wherein the first drying is conducted at a shelf temperature of the freeze-dryer that is equal to or below about 0° C., and
conducting second drying on the formulation to remove the at least one solvent molecule to obtain a target weight percentage of the at least one solvent molecule in the lyophilized cake, wherein the second drying is conducted at the shelf temperature of the freeze-dryer that is equal to or below 0° C.
2. The method of claim 1 , wherein the target weight percentage of the at least one solvent molecule in the lyophilized cake is controlled by the shelf temperature of the freeze-dryer for the second drying with a controlled drying rate.
3. The method of claim 1 , wherein the target weight percentage of the at least one solvent molecule in the lyophilized cake is controlled by a duration time for the second drying.
4. The method of claim 1 , wherein the shelf temperature of the freeze-dryer for the second drying is equal to or slightly higher than the shelf temperature of the freeze-dryer for the first drying.
5. The method of claim 1 , wherein the shelf temperature of the freeze-dryer for the second drying is same as the shelf temperature of the freeze-dryer for the first drying.
6. The method of claim 1 , wherein the shelf temperature of the freeze-dryer for the second drying is higher than the shelf temperature of the freeze-dryer for the first drying.
7. The method of claim 1 , wherein the shelf temperature of the freeze-dryer for the second drying is lower than the shelf temperature of the freeze-dryer for the first drying.
8. The method of claim 1 , wherein the target weight percentage of the at least one solvent molecule in the lyophilized cake is about 3-5%, about 4% or about 4.5%.
9. The method of claim 1 , wherein the peptide or protein is an antibody, an antibody fragment, a Fab region of an antibody, an antibody-drug conjugate, a fusion protein, a protein pharmaceutical product or a drug.
10. The method of claim 1 , wherein the lyophilized cake is stable under the storage condition at room temperature or has improved stability for refrigeration storage.
11. The method of claim 1 , the at least one solvent molecule is a water molecule.
12. The method of claim 1 further comprising determining an ending of the first drying based on a change of a pressure in the chamber of the freeze-dryer.
13. The method of claim 1 , wherein a temperature of the lyophilized cake is below a collapse temperature of the lyophilized cake in the first drying.
14. The method of claim 1 , wherein the formulation further comprises a buffer, an excipient, a stabilizer, a cryo-protectant, a bulking agent, a plasticizer, or a combination thereof.
15. The method of claim 14 , wherein the buffer comprises acetate and/or histidine hydrochloride.
16. The method of claim 14 , wherein the buffer has a pH value of about 5.3 or about 6.
17. The method of claim 14 , wherein the excipient is polysorbate 80.
18. The method of claim 14 , wherein the stabilizer is sucrose, wherein the ratio of sucrose to the peptide or protein is about 1:1, about 3:1, about 10:1, or about from 1:1 to 10:1.
19. The method of claim 14 , wherein the stabilizer is polyol, sucrose, mannitol, trehalose, sorbitol, amino acid, or a combination thereof.
20. The method of claim 14 , wherein the cryo-protectant is surfactant, sugar, salt, amino acid, or a combination thereof.