Target residual moisture content for lyophilized drug product

Patent metadata

Field	Value
Publication number	US-12449198-B2
Application number	US-202418755396-A
Country	US
Kind code	B2
Filing date	Jun 26, 2024
Priority date	Feb 4, 2020
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

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.

First claim

What is claimed is:

1. A method for producing a lyophilized drug product, comprising:
obtaining a formulation comprising a formulated drug substance; and
subjecting the formulation to lyophilization to produce a lyophilized drug product, wherein the lyophilization comprises a first drying step and a secondary drying step, wherein the secondary drying step is conducted at a temperature below about 0° C., and the lyophilized drug product comprises a moisture content from about 3% to about 5%.

2. The method of claim 1 , wherein the formulated drug substance comprises an antibody, an antibody fragment, a Fab region of an antibody, an antibody-drug conjugate, or a fusion protein.

3. The method of claim 1 , wherein the moisture content is from 4% to 4.5%.

4. The method of claim 1 , wherein the lyophilized drug product has improved stability when stored at about 20-25° C.

5. The method of claim 1 , wherein the method further comprises determining an ending of the first drying step based on a change of a pressure in the chamber of the freeze-dryer.

6. The method of claim 1 , wherein the temperature of the secondary drying step is not above the about the temperature of the first drying step.

7. The method of claim 1 , wherein a temperature of the secondary drying step is from about 0° C. to about −30° C.

8. The method of claim 1 , wherein a temperature of the secondary drying step is about −10° C. to about −30° C.

9. The method of claim 1 , wherein a duration of the secondary drying step is about 10 to about 150 hours.

10. The method of claim 1 , wherein the formulation further comprises at least one buffer, at least one excipient, at least one stabilizer, at least one cryo-protectant, at least one bulking agent, at least one plasticizer, or a combination thereof.

11. The method of claim 10 , wherein the at least one buffer comprises acetate and/or histidine hydrochloride.

12. The method of claim 10 , wherein the at least one buffer has a pH value of about 5.3 to about 6.

13. The method of claim 10 , wherein the at least one excipient comprises polysorbate 80.

14. The method of claim 10 , wherein the at least one stabilizer comprises sucrose.

15. The method of claim 10 , wherein the at least one stabilizer comprises a polyol, sucrose, mannitol, trehalose, sorbitol, an amino acid, or a combination thereof.

16. The method of claim 10 , wherein the at least one cryo-protectant comprises a surfactant, sugar, salt, an amino acid, or a combination thereof.

17. The method of claim 10 , wherein the formulation comprises:
a. sucrose at a concentration of above 0% to about 5%;
b. arginine at a concentration of above 0% to about 2%;
c. acetate at a concentration of above 0 mM to about 10 mM;
d. histidine; and/or
e. polysorbate 80 at a concentration of above 0% to about 0.2%.

18. The method according to claim 1 , wherein the lyophilized drug product has improved stability when stored at about 2 to 8° C.

19. The method according to claim 6 , wherein the temperature of the secondary drying step is lower than the temperature of the first drying step.

Assignees

• Regeneron Pharma

Inventors

• Tang Xiaolin
• Kleppe Mary
• Chari Ravi
• Tzul Franco

Classifications

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• F26B25/22

  Controlling the drying process in dependence on liquid content of solid materials or objects · CPC title

• F26B5/044

  for drying materials in a batch operation in an enclosure having a plurality of shelves which may be heated (F26B5/045 takes precedence) · CPC title

• F26B5/06 Primary

  the process involving freezing · CPC title