1. FDA Update: Particulate Matter Task Force Sharyn Orton, Ph.D. OBRR/CBER/FDA Blood Products Advisory Committee Meeting June 19, 2003

2. Background In February 2003, the American Red Cross Southern Region (Atlanta, GA) reported unusual particulate matter (PM) in red blood cells (rbc) prepared from whole blood drawn in bags manufactured by Baxter. This was followed by reports from other blood centers, and in bags manufactured by Terumo and Medsep as well.

3. continued PM was reported primarily in rbc’s prepared using a hard spin. PM was found less frequently in rbc’s prepared using a soft spin, or after leukofiltration.

4. continued FDA requires visual inspection procedures during storage and immediately before distribution [21 CFR 606.160(b)(3)(ii) and 640.5(e)]. Current thinking is that as part of this visual inspection, Blood Centers should perform an enhanced visual inspection (10-minute hold) of rbc’s after preparation [FDA Talk Paper/FAQ (February 2003)].

5. continued Suspect units should be either leuko-filtered prior to release to Transfusion Services, or quarantined. These recommendations are still in effect.

6. Studies Baxter Within FDA: –Forensic Chemistry Center (FCC) –Center for Devices and Radiologic Health

7. Studies –Center for Biologics Evaluation and Research Division of Hematology –ARC Holland Laboratory –NIH Transfusion Service Division of Blood Applications –Gulfcoast Regional Blood Center –Florida Blood Services –Centers for Disease Control

8. FCC Analyzed anticoagulants –Citrate, sodium, phosphate, chloride and adenine –Anticoagulants and rbc’s for zinc and iron Tested fill volumes Analyzed for impurities, degradation products or exotic elements Examined interior surfaces of bags; raw material and sheeting Examined particles to identify “seed material”

9. CDRH Examined and compared bag materials from control, heated and cooled bags

10. CBER Division of Hematology –Photographed and classified particle types –ARC Holland Laboratory evaluated PM formation and donor, blood-related and blood-processing factors Influence of leukoreduction on PM removal Total protein, total fibrinogen and lipid profiles Donor medications and meals in 24 hours prior to donation

11. CBER Platelet and plasma parameters: – D-Dimer, platelet factor 4, soluble P- Selectin, CD41 positive platelet derived microparticle (PDMP), CD41, CD42b positive PDMP, Thromboxane B2, IgG, IgA, IgM, Fibrinogen, Fibronectin, Prothrombin time and Partial Thromboplastin time, Prothrombin fragment 1.2

12. CBER Division of Blood Applications –Infectious agents CDC –Pre/post filtration wbc and plt counts Gulfcoast Regional Blood Center, and Florida Blood Services –Adverse event (AE) rates CDC; Gulfcoast Regional Blood Center, and Florida Blood Services (FBS)

13. Results Particles appeared to be comprised of normal blood constituents. Reports from some Blood Centers that PM can be normally found in rbc preparation.

14. continued Baxter –No process or material abnormalities identified FCC –All anticoagulants/associated solutions as expected –All fill volumes as stated on the label –No impurities, degradation products or exotic elements identified –No “seed material” identified

15. continued CDRH –Control, heated and cooled bags showed no differences; suspect lots not measurably different from non-implicated lots. Consistent molecular weight between bag lots Consistent plasticizer weight fractions Bulk material confirmed

16. continued CBER: ARC Holland Laboratory for DH (preliminary) –No apparent association between PM and high plt or wbc counts –Leukofiltration removed observable PM –Subsequent filtration with 170μ mesh filter did not isolate additional material –Additional PM development not observed during subsequent 42 day storage –Comparable plt and plasma parameters

17. continued CBER: DBA –Infectious agents: CDC No evidence of infectious agents –Pre/post plt and wbc count of PM leukofiltered rbc’s: FBS wbc counts all < 5 x 10 6 80% plt removal

18. continued CBER: DBA –AE: CDC GA Dept. of PH: –No increase in adverse event reporting for transfused rbc’s comparing January 2002 with January 2003 –No trend in adverse event reporting for transfused rbc’s between January 2002 through January 2003

19. continued CBER: DBA –AE: Gulfcoast Regional Blood Center and FBS No AE reported: PM rbc’s: –135 LF; 187 non-LF Non-PM rbc’s: –176 LF; 695 non-LF

20. Conclusion There were no detectable aberrant results associated with the collection bags. There does not appear to be an increase in AE rates associated with transfusion of rbc’s with “normal” PM, or PM rbc that are subsequently leukofiltered. Note: the sample size is still small relative to the power required to detect a difference.