West Nile Virus and Plasma-Derived Products FDA Blood Product Advisory Committee Meeting 18 September 2003

1. West Nile Virus and Plasma-Derived ProductsFDA Blood Product Advisory Committee Meeting18 September 2003 Mahmood Farshid, Ph.D. Division of Hematology OBRR, CBER

2. Current Review Approach for Viral Clearance Studies in Human Blood Derived Products • Manufacturing processes must contain at least two orthogonal and effective steps for removal/inactivation of viruses (effective is defined as achieving > 4 log clearance) • One of the clearance steps must be inactivation • The validated steps should remove/inactivate three to five orders of magnitude more virus than is estimated to be present in the starting materials ( for relevant viruses this is estimated to be 10 log total reduction)

3. Current Review Approach for Viral Clearance Studies in Human Blood Derived Products… cont. • The actual virus of concern should be used in viral validation studies if technically feasible • Specific model viruses can be used in validation studies if technical/ experimental limitations do not allow use of the relevant virus

4. In March 2003 BPAC addressed the following issues: • Whether viral validation data on model flaviviruses are sufficient to demonstrate WNV clearance 2. Whether the clearance steps in the manufacture of plasma derivatives obviate the need to screen donations of source plasma ( this issue will not be addressed further, pending FDA review of additional data requested of the plasma industry)

5. BPAC recommendation with respect to viral clearance data for WNV • Viral clearance studies should be conducted using WNV, as opposed to model viruses

6. Fllow up to BPAC Recommendation • FDA met with PPTA member representatives, at which time, WNV clearance studies were presented and validation data have been submitted for review • The data include WNV inactivation studies, for multiple plasma-derived products, using a variety of inactivation methodologies to demonstrate the comparability of WNV clearance to other flaviviruses.

7. Comparison of WNV and BVDV Clearance by Common Methodologies Heat Treatment* S/D Sponsor Virus IGIV -1 PI rF VIII Albumin F VIII IgG IGIV F VIII 1  6.4  7.2  6.1  5.9 WNV  4.8  5.9  5.2  4.2 BVDV 2  6.3  5.7  8.0  5.9 WNV  6.1  5.2  6.2  5.0 BVDV  5.1  5.0 WNV 3  6.2.  5.9 BVDV Source: Data Submitted to CBER by 3 Manufacturers of Plasma derived products * Pasteurization or vapor heat

8. Evaluation of WNV Clearance Data • Cretin common inactivation methodologies (s/d and heat) that have been used by multiple manufactures in multiple products, consistently provided significant level of inactivation (>5 logs) for WNV • The level of WNV inactivation is comparable to that of BVDV, an historical model for HCV

9. Current Thinking with respect to WNV Clearance • Available viral clearance data, comparing WNV to BVDV, have demonstrated comparable levels of clearance for these viruses following s/d or heat treatment in multiple products • BVDV inactivation data could be extrapolated to WNV for the aforementioned methodologies

10. Current Thinking…cont. • The level of inactivation shown in these studies, combined with the expected (but not yet determined) contribution of the removal steps in the manufacturing processes, are expected to be sufficient to demonstrate the safety of plasma derivatives with regard to WNV • Generation of validation data with regard to the removal steps, comparing WNV clearance to model flaviviruses, are needed to further establish WNV safety of plasma-derived products

11. Current Thinking…cont. • FDA intends to request that manufacturers, for all their products, document the adequacy of the clearance steps with respect to WNV: • WNV or BVDV data for well established clearance steps (s/d and heat) • WNV data for novel or less establish clearance steps