High-throughput, aseptic production of injectable Tetra-PEG hydrogel microspheres for delivery of releasable covalently bound drugs

The purpose of this work was to develop equipment and procedures for large-scale aseptic production of injectable microsphere (MS) drug conjugates. The two major challenges were (a) to prepare sufficient amounts of MSs for clinical trials, and (b) to prepare the MS-drug product under aseptic conditions. The approach was to prepare the MS-drug conjugate in two stages. Stage 1 was the preparation of monodisperse tetra-PEG amine derivatized MSs (amino-MS) from two soluble PEG prepolymers under low to no bioburden conditions. To accomplish this, custom-engineered equipment compatible with both aqueous and organic solvents was fabricated for parallel microfluidic preparation of amino-MS. The system was capable of preparing up to similar to 2 L of high quality 50 mu m diameter amino-MS per day. Stage 2 was the sterilization of the starting amino-MS and aseptic production of the MS-drug conjugate. The amino-MS were first sterilized by autoclaving then transferred to a custom-engineered autoclave-sterilized washer-reactor. This apparatus allowed for activation of the amino-MS and attachment of a linker-drug under aseptic conditions to give the sterile MS-drug conjugate drug substance. The final drug product was produced by addition of excipients to form a homogeneous suspension. The entire process is exemplified by an engineering production run of a sterile MS-peptide drug product.