Evaluation of Viral Clearance Studies.ppt

Evaluation of Viral Clearance Studies Mahmood Farshid, Ph.D. Div. Of Hematology OBRR/ CBER/FDA Biologics Monoclonal antibodies and recombinant products produced in cell culture Blood and blood products and other human derived products Animal derived products Risk Reduction Strategies Donor Screening: donor history assessment, written and oral questionnaire Donors Testing: Anti- HIV-1/2, HIV-1 p24 Ag ,anti-HCV, HBsAg , anti HBc, anti-HTLV-1/2, syphilis (NAT for HCV and HIV) Pharmacovigilance/ look back studies Inactivation/Removal Validating the manufacturing processes for removal / inactivation of viruses The Aim of Viral Validation To provide evidence that the production process will effectively inactivate/remove viruses which could potentially be transmitted by the product To provide indirect evidence that the production process has the capacity to inactivate/remove novel or yet undetermined virus contamination Common Virus Clearance Methods Virus inactivation: Chemical:organic solvents; pH extremes; solvent detergent; alcohol Physical: Heat treatment (dry heat or pasteurization) Virus removal Precipitation: ammonium sulfate etc. Chromatography: ion exchange; gel filtration; affinity; reverse phase Membrane filtration: Omega, Planova, DV50 Validation of Virus Removal/inactivation Include: Scaling down process steps Spiking appropriate steps with high titer of infectious virus (relevant or model) Determining virus reduction factors for each step Summing reduction factors to give a total log10 reduction value (LRV) Evaluation of the Effectiveness of Viral Clearance Step Test viruses used The design of the validation studies The validity of scaled-down process The kinetics of inactivation Susceptibility to small variations in process parameters (robustness) The limits of assay sensitivity The log reduction achieved Virus Selection Viruses that can potentially be transmitted by the product (relevant or specific model viruses) Viruses with a wide ra