1. Yi-Chen Yang, Yu-Hsuan Chen, Show-Lan Chiu, Hwei-Fang Cheng Drug Biology Division, Bureau of Food and Drug Analysis Department of Health, Taiwan, ROC National Standards for Blood Viruses in Taiwan SoGAT XXI May 2009

2. 2 To improve the safety of plasma products –NAT requirements in Taiwan (2002) The plasma pool or mini-pool should be HBV NAT (-), HCV NAT (-), and HIV NAT (-) For S/D treated blood products, one additional VI/R step should be performed, or the plasma pool should be HAV NAT (-) B19 NAT on plasma pool or mini-pool is suggested ~ the cut-off limit of B19 DNA should be < 10 5 IU/mL Current Status of NAT Regulations

3. 3 Class I low risk Class II higher risk Class III highest risk Most exempt from the Medical Device GMP/QSD Sterile products shall still comply with Medical Device GMP/QSD Medical Device GMP/QSD Medical Device GMP/QSD Registration and Market approval Registration and Market approval* Regulatory Framework of Medical Device * Special Requirements for Class III IVD ~Submit sample to BFDA for licensing tests The current focus of BFDA’s work in biological standards is for IVDs that are either used in blood screening or plasma pool testing for further fractionation process.

4. 4 High titer HBV DNA (+) plasma –Screening for other blood viruses –Quantitative analysis and genotyping Diluted with pooled human plasma* –*Screening for all major blood viruses Calibrate the titers of candidates against the IS (97/746) by a collaborative study –11 Labs from 7 countries Official Medicine Control Laboratories (OMCL) & CDC (Taiwan) Hospital laboratory & Reference laboratory Blood Service Manufacturers of in vitro diagnostics Stability study 4 ℃, -20 ℃, -80 ℃ HBV DNA National Standard and Working Reagent Product Item HBV DNA National StandardHBV DNA Working Reagent Conc. (IU/mL) 10 6 10 3 Genotypegenotype B Lot numberBFDA lot 92-08BFDA lot 92-08W

5. 5  Exclude the data out of the range of mean ± 2 SD HBV DNA standard HBV DNA working reagent

6. 6 HCV RNA National Standard and Working Reagent Product Item HCV RNA National StandardHCV RNA Working Reagent Conc. (IU/mL) 5.2 × 10 4 890 Genotypegenotype 1b Lot numberBFDA lot 93-09BFDA lot 93-09W High titer HCV RNA (+) plasma –Screening for other blood viruses –Quantitative analysis and genotyping Diluted with pooled human cryosupernatant* –*Screening for all major blood viruses Calibrate the titers of candidates against the IS (96/790) by a collaborative study –8 Labs from 6 countries Official Medicine Control Laboratories (OMCL) & CDC (Taiwan) Hospital laboratory & Reference laboratory Blood Service Manufacturers of in vitro diagnostics Stability study 4 ℃, -20 ℃, -80 ℃

7. 7  Exclude the data out of the range of mean ± 2 SD

8. 8 B19 DNA National Standard and Working Reagent Product Item B19 DNA National StandardB19 DNA Working Reagent Conc. (IU/mL) 1.9 × 10 6 2.0 × 10 4 Genotype genotype 1 Lot numberBFDA lot 94-08BFDA lot 94-08W High titer B19 DNA (+) plasma –Screening for other blood viruses –Quantitative analysis and genotyping Diluted with pooled human cryosupernatant* –*Screening for all major blood viruses Calibrate the titers of candidates against the IS (99/800) by a collaborative study –10 Labs from 7 countries Official Medicine Control Laboratories (OMCL) NAT testing laboratory Manufacturers of plasma products Manufacturers of in vitro diagnostics Stability study 25 ℃, 4 ℃, -20 ℃, -80 ℃

9. 9  All data were within the range (mean ± 2 SD), showed that all laboratories are in good agreement with the results.

10. 10 National Standards and Reference Panels for Serological Assays No.ItemLotNote 1 1 st National Standard for HBsAg (subtype ad)* 89-06 106 IU/mL 2 Anti-HCV Reference Panel 92-01 3 HBsAg Sensitivity Panel 94-12 4 Anti-HIV-1 Reference Panel 96-11 National Standards and Working Reagents for NAT Assays No.ItemLotNote 1 1 st National Standard for HBV DNA* 92-08 10 6 IU/mL 2 1 st Working Reagent for HBV DNA* 92-08W 10 3 IU/mL 3 1 st National Standard for HCV RNA* 93-09 5.2×10 4 IU/mL 4 1 st Working Reagent for HCV RNA* 93-09W 890 IU/mL 5 1 st National Standard for Parvovirus B19 DNA 94-08 1.9×10 6 IU/mL 6 1 st Working Reagent for Parvovirus B19 DNA 94-08W 2×10 4 IU/mL Candidate Standard for HIV-1 RNA being formulated

11. 11 Anti-HIV-1 Reference Panel Anti-HIV-1 (+) plasma selection –Screening for other blood viruses –Characterized with anti-HIV diagnostic kits, HIV viral-load kit Panel members characterization by a collaborative study –12 Labs from 5 countries Official Medicine Control Laboratories (OMCL) & CDC (Taiwan) Hospital laboratory & Reference laboratory Blood Service Manufacturers of in vitro diagnostics –Include 22 anti-HIV diagnostic kits & Lab. in-house WB assay Stability study 25 ℃, 4 ℃, -20 ℃, -80 ℃ The panel contains 6 characterized specimens –Include strong-reactive, weak-reactive, and negative samples

12. 12 Class III IVD licensing test (BFDA) Post-market surveillance for high risk class III IVD (BFDA) –HBsAg diagnostic kits (2008) Pick up 2 products fail to meet the sensitivity requirement –Anti-HCV diagnostic kits (2009) kits receiving test in blood service & hospital lab. (IVD manufactures) R&D and quality control for diagnostic kits (IVD/Biotech manufactures) Sensitivity evaluation for purchasing diagnostic kits (Taiwan CDC) Research (BFDA & Hospital lab.) Current Status of National Standards Used in Taiwan

13. 13 Quantitative Data from Users (I) HBV STD (Lot 92-08) Lab-Sample code Log IU/mL 10 6 IU/mLTCD-BAbm15.699 TCD-BAbm25.580 TCD-BAbm35.505 TCD-BRoT16.041 TCD-BRoT26.215 BFD-BRoT16.371 HBV WR (Lot 92-08W) Lab-Sample code Log IU/mL 10 3 IU/mLTCD-BWAbm13.146 TCD-BWRoT13.326 Med-BWRoT13.049 Med-BWRoT23.021 Med-BWRoT33.196 Med-BWRoT43.253 Med-BWRoT53.212 Med-BWRoT63.161 Med-BWRoT73.299 BFD-BWRoT13.146 BFD-BWRoT23.079 BFD-BWRoT33.255 BFD-BWRoT43.079 BFD-BWRoT53.176 Collaborative study result Mean ± 2SD: 6 ± 0.38 Log IU/mL Collaborative study result Mean ± 2SD: 3 ± 0.44 Log IU/mL

14. 14 Quantitative Data from Users (II) HCV STD (Lot 93-09) Lab-Sample code Log IU/mL 5.2 ×10 4 U/mL TCD-CAbm14.199 TCD-CAbm23.700 TCD-CAbm34.155 TCD-CRoT14.869 TCD-CRoT24.913 TCD-CRoT35.045 HCV WR (Lot 93-09W) Lab-Sample code Log IU/mL 890 IU/mLTCD-CWAbm12.389 TCD-CWRoT13.243 Reg-CWRoT12.807 Reg-CWRoT22.455 Med-CWRoT12.799 Med-CWRoT22.736 Med-CWRoT32.732 Com-CWRoT12.600 Com-CWRoT22.630 Collaborative study result Mean ± 2SD: 4.719 ± 0.192 Log IU/mL Collaborative study result Mean ± 2SD: 2.949 ± 0.486 Log IU/mL

15. 15 We have established HBV, HCV, and B19 national standards and working reagents for NAT assays. –The standards were prepared by BFDA, and established through the international collaborative studies. Candidate standard for HIV-1 RNA being formulated. These NAT standards are currently used for evaluation of the molecular diagnostics market in Taiwan. –Licensing test & post-market surveillance for high risk class III IVD –Kits receiving test in blood service & hospital lab –R&D and quality control for diagnostic kits –Sensitivity evaluation for purchasing diagnostic kits Summary

16. Thank you for your attention Acknowledgements Thanks to all participants of the collaborative study groups Thanks to all data-feedback users