Methods of manufacturing injectable sustained release formulations

A method of manufacturing an injectable sustained release formulation, wherein the injectable sustained release formulation comprises a luteinizing hormone releasing hormone (LHRH) agonist or a salt thereof, an N-methylpyrrolidone (NMP), and a biodegradable polymer, and wherein the method comprises:

• i. a compounding step that is conducted under a controlled humidity of less than 60% at 15-25° C., wherein the compounding step comprises a) introducing ≥70% of a total amount of the NMP into a compounding vessel;
• b) dividing the biodegradable polymer into multiple fractions and adding a first fraction of the biodegradable polymer to the compounding vessel, and mixing the first fraction of the biodegradable polymer with the NMP in the compounding vessel until the first fraction of the biodegradable polymer is wetted or dissolved, then separately and sequentially introducing each of the remaining fraction(s) of the biodegradable polymer to the compounding vessel and mixing until the newly added fraction of the biodegradable polymer is wetted or dissolved before introducing a next fraction of the biodegradable polymer;
• c) after all the fractions of the biodegradable polymer are wetted or dissolved, adding the LHRH agonist in 1 to 20 fractions separately and sequentially into the compounding vessel and mixing the fraction of LHRH agonist with the NMP and biodegradable polymer in the compounding vessel until the LHRH agonist is wetted or dissolved, wherein a subsequent fraction of the LHRH agonist, if any, is added after the LHRH agonist previously added into the compounding vessel is wetted or dissolved, and mixing the LHRH agonist with the NMP and biodegradable polymer in the compounding vessel to form the formulation;
• and
• ii. a degassing step that is performed by four (4) or more vacuum/vent cycles of applying a relative vacuum pressure between −300 mbar and −1000 mbar to the compounding vessel or a degassing vessel containing the formulation prepared in (i) above, maintaining the vacuum for a time period between 5 min and 720 min, and releasing the vacuum to allow venting;
• wherein the vacuum level maintained at each vacuum/vent cycle is at least as strong as or stronger than that maintained in an immediately previous cycle,
• wherein the formulation is a viscous suspension or emulsion of LHRH agonist rich phase having a droplet diameter of Dv50 of less than 50 pm suspended in a biodegradable polymer rich continuous phase and has a viscosity of greater than 10,000 centipoise (cPs).