Manufacturing of bupivacaine multivesicular liposomes
Embodiments of the present application relate to commercial manufacturing processes for making bupivacaine multivesicular liposomes (MVLs) using independently operating dual tangential flow filtration modules.
1. A process for preparing bupivacaine encapsulated multivesicular liposomes in a commercial scale, the process comprising:
(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a water-in-oil first emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, at least one amphipathic lipid comprising 1, 2-dierucoylphosphatidylcholine (DEPC), and at least one neutral lipid;
(b) mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion, wherein the second aqueous solution comprises lysine and dextrose;
(c) removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion to form a first aqueous suspension of bupivacaine encapsulated multivesicular liposomes having a first volume;
(d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated multivesicular liposomes by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated multivesicular liposomes having a second volume;
(e) exchanging the aqueous supernatant of the second aqueous suspension with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated multivesicular liposomes having a third volume; and
(f) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated multivesicular liposomes having a target concentration of bupivacaine from about 11.3 mg/mL to about 17.0 mg/mL;
wherein all steps are carried out under aseptic conditions;
wherein the erucic acid concentration in the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is about 23 μg/mL or less after the final aqueous suspension is stored at 25° C. for one month;
wherein the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes has a volume of about 150 L to about 250 L; and
wherein the internal pH of the bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 5.5.
2. The process of claim 1 , wherein the mixing of step (a) is performed using a mixer at a high shear speed from about 1100 rpm to about 1200 rpm.
3. The process of claim 2 , wherein the high shear speed is about 1150 rpm.
4. The process of claim 1 , wherein the mixing of step (a) is performed for about 65-75 minutes.
5. The process of claim 1 , wherein the mixing of step (b) is performed using two mixers at a low shear speed from about 450 rpm to about 510 rpm.
6. The process of claim 5 , wherein the low shear speed is about 495 rpm.
7. The process of claim 1 , wherein the mixing of step (b) is performed for about 60 to 65 seconds.
8. The process of claim 1 , wherein step (e) is performed using two sets of filtration modules, wherein each set of the filtration modules operate independently of the other.
9. The process of claim 8 , where each set of filtration modules comprise five or more individual hollow fiber filters, wherein each individual hollow fiber filter has a membrane pore size from about 0.1 μm to about 0.2 μm.
10. The process of claim 1 , wherein the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes has a volume of about 200 L to about 225 L.
11. The process of claim 1 , wherein the target concentration of bupivacaine in the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is about 13.3 mg/mL.
12. The process of claim 1 , wherein the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes comprises less than 5% unencapsulated bupivacaine.
13. The process of claim 1 , wherein the d 50 of bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 24 μm to about 31 μm.
14. The process of claim 13 , wherein the d 50 of bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 27 μm.
15. The process of claim 1 , wherein the encapsulated lysine concentration of bupivacaine multivesicular liposomes in the final aqueous suspension is about 0.03 mg/mL.
16. The process of claim 1 , wherein final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is suitable for direct human administration.
17. The process of claim 1 , wherein the volatile water-immiscible solvent solution of step (a) further comprises 1,2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG).