Method of filling a container with no headspace
The present invention is directed to methods for filling a container wherein the filled container has no headspace. The present invention is further directed to methods for stabilizing an aqueous drug substance solution by filling a container with the aqueous drug substance solution wherein the filled container has no headspace. The present invention is further directed to methods for detecting headspace in a container.
1. A method for preparing a container with zero headspace comprising an aqueous solution, the method comprising:
a) providing a container with an open end;
b) providing a degassed aqueous solution that is free of a polyol, a sugar, and a surfactant;
c) filling the container via the open end with the degassed aqueous solution;
d) purging the container with carbon dioxide;
e) inserting a stopper into the open end of the container creating a headspace of carbon dioxide; and
f) storing the container at about less than 10° C. for at least about 18 hours,
wherein the stopper can move within the container while maintaining an airtight seal; and the storing step results in the container having zero headspace.
2. The method of claim 1 , wherein prior to the purging step or prior to inserting the stopper, the container is subjected to a vacuum.
3. The method of claim 2 , wherein the vacuum applies a pressure to the container of at least 27.5 inHg.
4. The method of claim 1 , wherein the step of purging the container with carbon dioxide comprises providing carbon dioxide to the container at a flow rate of about 10 milliliters/minute for 0.5 minutes.
5. The method of claim 1 , wherein the container is stored for at least about 2 days.
6. The method of claim 1 , wherein the container is stored at about less than 10° C. for at least about 3 days.
7. The method of claim 1 , wherein the container is stored at about less than 10° C. for at least about 4 days.
8. The method of claim 1 , wherein the container is stored at about 4° C.
9. The method of claim 1 , wherein the stopper is coated with silicone oil.
10. The method of claim 9 , wherein the stopper is coated with about 0.4 mg of silicone oil.
11. The method of claim 1 , wherein, following the storing step, the aqueous solution comprises less than about 6,000 subvisible particles having a size of ≥10 μm per 0.8 mL of the aqueous solution and less than about 600 subvisible particles having a size of ≥25 μm per 0.8 mL of the aqueous solution.
12. The method of claim 1 , wherein the container is a syringe or a cartridge.
13. The method of claim 1 , wherein the aqueous solution is further free or substantially free of a buffer, a salt, a stabilizer, or any combination thereof.