
pmid: 29802761
We propose a standard protocol for integrity testing the residence‐time distribution (RTD) in a “Jig in a Box” design (JIB)—a previously described tortuous‐path, tubular, low‐pH, continuous viral inactivation reactor, ensuring that biopharmaceutical products will be incubated for the required minimum residence time, tmin . tmin is the time by which just 0.001% of the total product containing virus has exited the incubation chamber (i.e., t0.00001). This t0.00001 is selected to ensure a >4‐log reduction in viral load. As current tracers and in‐line analytical technologies may not be able to detect tracers at the 0.001% level, an alternative approach is required. The authors describe a method for deriving tmin from t0.005 (i.e., the time at which 0.5% of the product has emerged from the reactor outlet) and an experimentally confirmed offset value, toffset = t0.005−t0.00001. The authors also evaluate tracer candidates—including 100‐nm‐diameter gold nanoparticles, dextrose, monoclonal antibody, and riboflavin—for pre‐process acceptability and the effects of viscosity, molecular diffusion coefficient, and particle size. The authors show that a JIB will yield tmin and RTDs that are nearly identical for multiple tracers due to Dean vortex induced mixing. Results indicate that almost any small‐molecule tracer that is generally recognized as safe can be used in pre‐use integrity testing of a continuous viral inactivation reactor under the Deans values (De) of 119–595.
Quality Control, Bioreactors, Time Factors, Batch Cell Culture Techniques, Hydrodynamics, Virus Inactivation, Models, Theoretical
Quality Control, Bioreactors, Time Factors, Batch Cell Culture Techniques, Hydrodynamics, Virus Inactivation, Models, Theoretical
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