A Validatible Porosimetric Technique for Verifying the Integrity of Virus-Retentive Membranes

Abstract

Abstract.The verification of membrane integrity for filtration processes specifically designed for the removal of adventitious virus from biotherapeutics is of the utmost importance to both biomanu-facturers and regulatory agencies. Although conventional bubble-point and air-diffusion tests are widely accepted for integrity testing of bacteria-retentive membranes, these tests have severe limitations in their ability to assess the integrity of virus-retentive membranes. A novel membrane integrity test based upon liquid—liquid porosimetric principles (CorrTest™) has been specifically designed to correlate and predict the virus retention capabilities of Viresolve™ virus removing membranes. To optimize test sensitivity for both Viresolve/70™ and Viresolve/180™ membrane types, two distinct porosimetric correlations at different transmembrane pressures have been developed. Based upon an 80% prediction interval, an integrity test performed at either test pressure can reliably predict the ability of Viresolve™ membranes to remove the bacteriophage φX174 to within 0·4 log removal value (LRV) units. To maintain test sensitivity and provide greater flexibility for conducting the liquid—liquid intrusion integrity test, appropriate pressure- and temperature-correction equations have been established. The two immiscible fluids employed in the developed technology are easily flushed from the membrane structure and are generally regarded as acceptable, non-toxic reagents for pharmaceutical applications. Consequently, the CorrTest™ integrity test can reliably and non-destructively measure both pre- and post-use membrane integrity to verify virus removal performance with the Viresolve™ module.