National Standards for Blood Viruses in Taiwan Yi-Chen

National Standards for Blood Viruses in Taiwan 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 So. GAT XXI May 2009

Current Status of NAT Regulations • 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 (-) • B 19 NAT on plasma pool or mini-pool is suggested ~ the cut-off limit of B 19 DNA should be < 105 IU/m. L 2

Regulatory Framework of Medical Device 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 Registration and Market approval* * 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. 3

HBV DNA National Standard and Working Reagent • 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 ü 4℃ , -20 ℃ , -80 ℃ Product Item Conc. (IU/m. L) Genotype Lot number HBV DNA National Standard 106 genotype B BFDA lot 92 -08 HBV DNA Working Reagent 103 genotype B BFDA lot 92 -08 W 4

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

HCV RNA National Standard and Working Reagent • 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 ü 4 ℃ , -20 ℃ , -80 ℃ Product Item Conc. (IU/m. L) Genotype Lot number HCV RNA National Standard 5. 2 × 104 genotype 1 b BFDA lot 93 -09 HCV RNA Working Reagent 890 genotype 1 b BFDA lot 93 -09 W 6

p Exclude the data out of the range of mean ± 2 SD 7

B 19 DNA National Standard and Working Reagent • High titer B 19 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 ü 25℃, 4 ℃ , -20 ℃ , -80 ℃ Product Item Conc. (IU/m. L) Genotype Lot number B 19 DNA National Standard 1. 9 × 106 genotype 1 BFDA lot 94 -08 B 19 DNA Working Reagent 2. 0 × 104 genotype 1 BFDA lot 94 -08 W 8

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

National Standards and Working Reagents for NAT Assays No. Item 1 1 st National Standard for HBV DNA* Lot 92 -08 Note 2 1 st Working Reagent for HBV DNA* 92 -08 W 103 IU/m. L 3 1 st. National Standard for HCV RNA* 93 -09 5. 2× 104 IU/m. L 4 1 st Working Reagent for HCV RNA* 93 -09 W 890 IU/m. L 5 1 st National Standard for Parvovirus B 19 DNA 94 -08 1. 9× 106 IU/m. L 6 1 st Working Reagent for Parvovirus B 19 DNA 94 -08 W 2× 104 IU/m. L 106 IU/m. L • Candidate Standard for HIV-1 RNA being formulated National Standards and Reference Panels for Serological Assays No. Item Lot Note 106 IU/m. L 1 1 st National Standard for HBs. Ag (subtype ad)* 89 -06 2 Anti-HCV Reference Panel 92 -01 3 HBs. Ag Sensitivity Panel 94 -12 4 Anti-HIV-1 Reference Panel 96 -11 10

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 ü 25℃, 4 ℃ , -20 ℃ , -80 ℃ • The panel contains 6 characterized specimens – Include strong-reactive, weak-reactive, and negative samples 11

Current Status of National Standards Used in Taiwan • Class III IVD licensing test (BFDA) • Post-market surveillance for high risk class III IVD (BFDA) – HBs. Ag 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. ) 12

Quantitative Data from Users (I) HBV STD (Lot 92 -08) Lab-Sample code Log IU/m. L HBV WR (Lot 92 -08 W) TCD-BAbm 1 5. 699 103 IU/m. L TCD-BAbm 2 Log IU/m. L TCD-BWAbm 1 3. 146 5. 580 TCD-BWRo. T 1 3. 326 TCD-BAbm 3 5. 505 Med-BWRo. T 1 3. 049 TCD-BRo. T 1 6. 041 Med-BWRo. T 2 3. 021 TCD-BRo. T 2 6. 215 Med-BWRo. T 3 3. 196 BFD-BRo. T 1 106 IU/m. L Lab-Sample code 6. 371 Med-BWRo. T 4 3. 253 Med-BWRo. T 5 3. 212 Med-BWRo. T 6 3. 161 Med-BWRo. T 7 3. 299 BFD-BWRo. T 1 3. 146 BFD-BWRo. T 2 3. 079 BFD-BWRo. T 3 3. 255 BFD-BWRo. T 4 3. 079 BFD-BWRo. T 5 3. 176 • Collaborative study result Mean ± 2 SD: 6 ± 0. 38 Log IU/m. L • Collaborative study result Mean ± 2 SD: 3 ± 0. 44 Log IU/m. L 13

Quantitative Data from Users (II) Lab-Sample code Log IU/m. L TCD-CWAbm 1 2. 389 3. 700 TCD-CWRo. T 1 3. 243 TCD-CAbm 3 4. 155 Reg-CWRo. T 1 2. 807 TCD-CRo. T 1 4. 869 Reg-CWRo. T 2 2. 455 TCD-CRo. T 2 4. 913 Med-CWRo. T 1 2. 799 TCD-CRo. T 3 5. 045 Med-CWRo. T 2 2. 736 Med-CWRo. T 3 2. 732 Com-CWRo. T 1 2. 600 Com-CWRo. T 2 2. 630 HCV STD (Lot 93 -09) Lab-Sample code Log IU/m. L 5. 2 × 104 U/m. L TCD-CAbm 1 4. 199 TCD-CAbm 2 • Collaborative study result Mean ± 2 SD: 4. 719 ± 0. 192 Log IU/m. L HCV WR (Lot 93 -09 W) 890 IU/m. L • Collaborative study result Mean ± 2 SD: 2. 949 ± 0. 486 Log IU/m. L 14

Summary • We have established HBV, HCV, and B 19 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 15

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