(32f) High Throughput Sterile Filtration of Highly Viscous Pharmaceutical Formulations

Sterile filtration using 0.2um membranes is a widely used method to eliminate the microbial load in a wide range of pharmaceutical formulations. However, sterile filtration of highly viscous solutions is challenging due to low throughput and potential concentration changes stemming from solution viscosity, retention or adsorption. Due to the inherent difficulty in filtration of relatively large molecular weight polymers or highly concentrated biologics, other sterilization methods such as e-beam, gamma radiation, dry heat, autoclave and others are usually implemented, if applicable. These methods may result in undesirable product attribute changes. Sterile filtration is usually restricted by manufacturer operating ranges and set points of single use cartridges and capsules. The limitation of using such filters are usually low operating pressure up to 60 to 90 psi in addition to significant holdup or concentration changes by size exclusion or adsorption.

In this work, we present high pressure sterile filtration (HPSF) as a method to increase yield without compromise on safety or quality. A validated HPSF system that adheres to PDA and ASTM sterile filtration guidance was utilized. This system has been used to filter sterilize sodium hyaluronate (NaHy) solutions used as ophthalmic visco-devices, which are used in cataract surgery (nominal viscosities of 50,000 cps). Recently, we have started to expand the use of HPSF to other highly viscous solutions. The HPSF system runs up to a 900 psi for filtration of highly viscous formulations of NaHy, sodium carboxymethyl cellulose(Na-CMC), and other widely used excipients.

Formulations of NaHy with molecular weights ranging from 800 up to 2,000 kDa with concentrations as high as 20g/L were examined. When comparing the filtration yield of a 1% NaHy solution with 1,000kDa molecular weight on a capsule filter at the maximum operating pressure (60 psi) set by the manufacturer to a HPSF with nearly equivalent filtration surface area of 200cm², the flux on the high pressure filter was about three orders of magnitude faster for the same solution. Furthermore, when comparing the NaHy concentration of filtrate to the feed using the HPSF to off the shelf filter cartridges, the HPSF maintained the concentration and viscosity of the feed solution while a single cartridge caused 7% drop in concentration and up to 15% when redundant filtration was used. This clearly demonstrate the benefits of HPSF when filtering NaHy formulations.

Formulations of Na-CMC with molecular weights of 250kDa and 700 kDa with 0.7-1.2 degree of substitution of carboxymethyl and up to 20g/L in concentration were also examined. A 2% CMC formulation has on average a one order of magnitude higher throughput utilizing a HPSF system operated at 600 psi in comparison to filtration at 95 psi utilizing equivalent filtration surface areas in a cartridge.

In summary, sterile filtration of highly viscous pharmaceutical formulations using HPSF system can have clear advantages in terms of higher throughput, higher flux, and reproducibility in terms of concentration, and lower material holdup which can be beneficial when handling costly formulations. High pressure sterile filtration can fast track development effort and accelerate bringing early phase formulations to into the clinic.