Update on the Replacement Update on the Replacement of the HCV RNA of the HCV RNA International Standard International Standard Sally Baylis & Alan Heath, Sally Baylis & Alan Heath, NIBSC NIBSC SoGAT XX, Warsaw 12-13 June SoGAT XX, Warsaw 12-13 June 2007 2007
Update on the Replacement of the HCV RNA International Standard
Jan 31, 2016
Update on the Replacement of the HCV RNA International Standard. Sally Baylis & Alan Heath, NIBSC SoGAT XX, Warsaw 12-13 June 2007. Replacement of the 2 nd International Standard for HCV RNA (96/798). - PowerPoint PPT Presentation
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Update on the Replacement Update on the Replacement of the HCV RNA of the HCV RNA
International Standard International Standard
Sally Baylis & Alan Heath, NIBSCSally Baylis & Alan Heath, NIBSC
SoGAT XX, Warsaw 12-13 June SoGAT XX, Warsaw 12-13 June 20072007
Replacement of the 2Replacement of the 2ndnd International Standard for HCV International Standard for HCV
RNA (96/798)RNA (96/798)
Proposal made at SoGAT 2005 to replace the HCV Proposal made at SoGAT 2005 to replace the HCV RNA International Standard as requested by WHORNA International Standard as requested by WHO
Agreement that HCV 1a genotype would be Agreement that HCV 1a genotype would be sourced & would be anti-HCV negative and sourced & would be anti-HCV negative and diluted in plasma rather than cryosupernatant diluted in plasma rather than cryosupernatant
Candidate Standards for Candidate Standards for EvaluationEvaluation
3 anti-HCV negative window period genotype 1a 3 anti-HCV negative window period genotype 1a donations have been obtaineddonations have been obtained
The genotype of each has been confirmed by LiPA The genotype of each has been confirmed by LiPA & DNA sequencing& DNA sequencing
Absence of other viral markers confirmed in these Absence of other viral markers confirmed in these stocksstocks
Material has been freeze-dried in two batchesMaterial has been freeze-dried in two batches Batch 1 (NIBSC Code 06/100), 2085 vials, fill CV = 0.62%Batch 1 (NIBSC Code 06/100), 2085 vials, fill CV = 0.62% Batch 2 (NIBSC code 06/102), 2100 vials, fill CV = 1.82%Batch 2 (NIBSC code 06/102), 2100 vials, fill CV = 1.82%
Panel for Collaborative studyPanel for Collaborative study
Sample 1 – 2Sample 1 – 2ndnd International Standard for HCV International Standard for HCV RNA (96/798)RNA (96/798)
Sample 2 - new freeze-dried preparation 06/100Sample 2 - new freeze-dried preparation 06/100
Sample 3 - new freeze-dried preparation 06/102Sample 3 - new freeze-dried preparation 06/102
Sample 4 – liquid/frozen bulk material (NIBSC Sample 4 – liquid/frozen bulk material (NIBSC code 06/118) that was used to prepare Samples 2 code 06/118) that was used to prepare Samples 2 & 3& 3
Collaborative StudyCollaborative Study
Collaborative study commenced in November 2006Collaborative study commenced in November 2006
Participants requested to test samples in four Participants requested to test samples in four independent assaysindependent assays
33 laboratories from 14 countries participated in 33 laboratories from 14 countries participated in the studythe study
40 data sets received; 25 from quantitative assays 40 data sets received; 25 from quantitative assays & 15 from qualitative assays& 15 from qualitative assays
NIBSC collated & analysed dataNIBSC collated & analysed data
Types of Quantitative Assays Used Types of Quantitative Assays Used by Participantsby Participants
AssayCode
Assay Number ofData-sets
AB Abbott RealTime HCV 7
BA Bayer Versant HCV RNA 3.0(bDNA)
4
CTM COBAS Ampliprep/COBASTaqMan
6
CTMH HPS/COBAS TaqMan 1
IHRT In-house real-time 3
MO COBAS Amplicor HCV Monitor
4
Types of Qualitative Assays Used Types of Qualitative Assays Used by Participantsby Participants
AssayCode
Assay Number ofData-sets
A Amplicor HCV 2.0 2
AC COBAS Amplicor HCV 2.0 1
ASC COBAS Ampliscreen HCV 2.0 3
IHQ In-house qualitative 1
IHRTQ In-house real-time qualitative 3
P Procleix 1*
PU Procleix Ultrio 1
PUT Procleix Ultrio (TIGRIS) 1
TS COBAS TaqScreen MPX 1
Estimated IU/ml (logEstimated IU/ml (log1010) from ) from Quantitative Assays Quantitative Assays
Sample N Mean 95% CI SD %CV
1 25 5.10 5.02-5.17 0.19 3.73
2 25 5.32 5.22-5.42 0.24 4.51
3 25 5.51 5.44-5.58 0.17 3.10
4 25 5.74 5.65-5.83 0.22 3.84
N - Number of laboratory estimatesSD - Standard Deviation of log10 estimates across laboratories
Sample 1 - Quantitative Results (IU/ml)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
03
14
27
01
05
10
12
26
11
19
21
29
05
20
32
02
06
09
30
05
27
18
08
13
22
CTM
IHRT
MO
AB
AB
AB
AB
AB
BA
BA
BA
BA
CTMH
IHRT
IHRT
MO
MO
AB
AB
CTM
CTM
MO
CTM
CTM
CTM
Sample 2 - Quantitative Results (IU/ml)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
27 11
21
27
05
05
12
26
29
03
14
20
06
01
09
10
30
19
05
13
32
02
08
22
18
MO BA
BA
CTM
CTMH
AB
AB
AB
BA
CTM
IHRT
IHRT
MO
AB
AB
AB
AB
BA
CTM
CTM
IHRT
MO
CTM
CTM
MO
Sample 3 - Quantitative Results (IU/ml)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
30
11
19
21
32
27
05
10
12
26
29
03
05
13
27
05
14
20
02
01
09
22
06
18
08AB
BA
BA
BA
IHRT
MO
AB
AB
AB
AB
BA
CTM
CTM
CTM
CTM
CTMH
IHRT
IHRT
MO
AB
AB
CTM
MO
MO
CTM
Sample 4 - Quantitative Results (IU/ml)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
11 19
21
29
03
20
02
01
05
10
12
26
30
05
13
27
14
27
09
08
05
32
06
22
18
BA BA
BA
BA
CTM
IHRT
MO
AB
AB
AB
AB
AB
AB
CTM
CTM
CTM
IHRT
MO
AB
CTM
CTMH
IHRT
MO
CTM
MO
Estimated PCR Detectable Estimated PCR Detectable Units/ml (logUnits/ml (log1010) from Qualitative ) from Qualitative
Assays Assays
Sample N Mean 95% CI SD %CV
1 13 5.24 5.04-5.43 0.32 6.11
2 12 5.35 5.09-5.62 0.42 7.78
3 13 5.65 5.45-5.86 0.34 6.10
4 13 6.04 5.76-6.33 0.47 7.74
N - Number of laboratory estimatesSD - Standard Deviation of log10 estimates across laboratories
Sample 2 - Potencies Relative to sample 1: Qualitative Assays
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
25 31
16
04
23
23
28
27
24
15
32
07
33IHRTQ IHQ
IHRTQ
A
ASC
PU
PUT
TS
A
AC
ASC
IHRTQ
ASC
Sample 3 - Potencies Relative to sample 1: Qualitative Assays
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
23 25 23
07
16
27
24
32
31
17
28
15
33
04PU IHRTQ ASC
IHRTQ
IHRTQ
TS
A
ASC
IHQ
P
PUT
AC
ASC
A
Sample 4 - Potencies Relative to sample 1: Qualitative Assays
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
15
16
25
28
27
23
31
04
24
32
17
23
33
07
AC
IHRTQ
IHRTQ
PUT
TS
ASC
IHQ
A
A
ASC
P
PU
ASC
IHRTQ
Overall Mean Potencies (logOverall Mean Potencies (log1010 IU/ml) Relative to Sample 1 IU/ml) Relative to Sample 1
Sample N Mean 95% CI SD %CV
2 38 5.19 5.11-5.27 0.24 4.62
3 39 5.41 5.34-5.48 0.21 3.82
4 39 5.70 5.62-5.78 0.25 4.31
N - Number of laboratory estimatesSD - Standard Deviation of log10 estimates across laboratories
Sample 2 - Potencies Relative to sample 1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
25 27
31
16
04
23
11
21
13
05
27
23
28
27
24
01
05
09
10
12
26
30
15
19
29
05
08
22
14
20
02
06
18
32
03
32
07
33IHRTQ CTM
IHQ
IHRTQ
A
ASC
BA
BA
CTM
CTMH
MO
PU
PUT
TS
A
AB
AB
AB
AB
AB
AB
AB
AC
BA
BA
CTM
CTM
CTM
IHRT
IHRT
MO
MO
MO
ASC
CTM
IHRT
IHRTQ
ASC
Sample 3 - Potencies Relative to sample 1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
23 30
13
25
23
11
19
21
22
27
32
07
16
18
27
24
01
05
09
10
12
26
32
29
05
08
05
31
14
20
02
06
27
17
28
15
33
03
04PU AB
CTM
IHRTQ
ASC
BA
BA
BA
CTM
CTM
IHRT
IHRTQ
IHRTQ
MO
TS
A
AB
AB
AB
AB
AB
AB
ASC
BA
CTM
CTM
CTMH
IHQ
IHRT
IHRT
MO
MO
MO
P
PUT
AC
ASC
CTM
A
Sample 4 - Potencies Relative to sample 1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
IU/ml (log10)
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
15
13
16
30
11
19
21
29
03
05
08
27
20
25
02
28
27
01
05
09
10
12
26
23
22
31
14
06
04
24
32
05
32
18
27
17
23
33
07
AC
CTM
IHRTQ
AB
BA
BA
BA
BA
CTM
CTM
CTM
CTM
IHRT
IHRTQ
MO
PUT
TS
AB
AB
AB
AB
AB
AB
ASC
CTM
IHQ
IHRT
MO
A
A
ASC
CTMH
IHRT
MO
MO
P
PU
ASC
IHRTQ
Accelerated Degradation Studies Accelerated Degradation Studies Sample 2Sample 2
Relative potencies of accelerated degradation samples with respect to Sample 2 stored at -20ºC (log10 drop), qPCR analysis
Stability appears similar to 96/790 and 96/798; studies on-going
96/798 from this study has not lost potency after >10 years storage at -20 ºC
Incubation Time +4°C(10.5 months)
+20°C(1 month)
Sample 2 0.22 0.20
Proposal for 3Proposal for 3rdrd International International Standard for HCV RNAStandard for HCV RNA
Real-time & accelerated degradation data Real-time & accelerated degradation data indicate that Sample 2 (06/100) is stable & indicate that Sample 2 (06/100) is stable & suitable for long term usesuitable for long term use
Propose that 06/100 be established as the Propose that 06/100 be established as the 33rdrd International Standard for HCV RNA International Standard for HCV RNA with a unitage of 5.19 logwith a unitage of 5.19 log1010 IU/ml (4.89 IU/ml (4.89 loglog1010 IU/vial) IU/vial)
Report will be submitted to ECBS by JulyReport will be submitted to ECBS by July
AcknowledgementsAcknowledgements
Nita Shah & David Padley NIBSCNita Shah & David Padley NIBSC
Professor Ewa Brojer, Institute of Hematology & Professor Ewa Brojer, Institute of Hematology & BloodBlood Transfusion, WarsawTransfusion, Warsaw
Dr Richard Smith, National Genetics Institute, Dr Richard Smith, National Genetics Institute, Los AngelesLos Angeles
Dr Vivienne James, HPA, ColindaleDr Vivienne James, HPA, Colindale
Dr Michael Chudy, WHO, GenevaDr Michael Chudy, WHO, Geneva
Collaborative study participantsCollaborative study participants
HCV RNA Collaborative Study HCV RNA Collaborative Study ParticipantsParticipants
S Baylis, N ShahS Baylis, N Shah South Mimms, UKSouth Mimms, UK T Cuypers M KoppelmanT Cuypers M Koppelman Amsterdam, The NetherlandsAmsterdam, The Netherlands C DeferC Defer Lille, FranceLille, France L FanningL Fanning Cork, EireCork, Eire G GesuG Gesu Milan, ItalyMilan, Italy A GoglioA Goglio Bergamo, ItalyBergamo, Italy P GrantP Grant London, UKLondon, UK P IudiconeP Iudicone Rome, ItalyRome, Italy L Jarvis, A ClelandL Jarvis, A ClelandEdinburgh, UKEdinburgh, UK C JorkC Jork Springe, GermanySpringe, Germany S KerbyS Kerby Bethesda, USABethesda, USA A Klotz, M GessnerA Klotz, M Gessner Vienna, AustriaVienna, Austria R MadejR Madej Pleasanton, USAPleasanton, USA B MillerB Miller Karlsruhe, GermanyKarlsruhe, Germany S MizusawaS Mizusawa Tokyo, JapanTokyo, Japan C NegruC Negru TimişoaraTimişoara , Romania, Romania M NM Nüblingübling Langen, GermanyLangen, Germany
HCV RNA Collaborative Study HCV RNA Collaborative Study ParticipantsParticipants
JM PawlotskyJM Pawlotsky CrCréteil, Franceéteil, France M PecorariM Pecorari Modena, ItalyModena, Italy G PisaniG Pisani Rome, ItalyRome, Italy A Portela MoreiraA Portela Moreira Madrid, SpainMadrid, Spain S SauledaS Sauleda Barcelona, SpainBarcelona, Spain H SchindlH Schindl Vienna, AustriaVienna, Austria G SchneiderG Schneider Des Plaines, USADes Plaines, USA A da SilvaA da Silva Lisbon, PortugalLisbon, Portugal R SmithR Smith Los Angeles, USALos Angeles, USA S TassenS Tassen Brentwood, UKBrentwood, UK P TaylorP Taylor London, UKLondon, UK A van der ZandenA van der ZandenApeldoorn, The NetherlandsApeldoorn, The Netherlands YC YangYC Yang Taipei, TaiwanTaipei, Taiwan S YerlyS Yerly Geneva, SwitzerlandGeneva, Switzerland M ZaccanelliM Zaccanelli Treviglio, ItalyTreviglio, Italy
Update on the Stability of Update on the Stability of the HAV RNA International the HAV RNA International
Standard Standard
Sally Baylis, Nita Shah & Alan Heath, Sally Baylis, Nita Shah & Alan Heath, NIBSCNIBSC
SoGAT XX, Warsaw 12-13 June 2007SoGAT XX, Warsaw 12-13 June 2007
Background – Hepatitis A Virus Background – Hepatitis A Virus RNA ISRNA IS
The 1The 1stst International Standard for HAV RNA International Standard for HAV RNA (00/560) and a second batch (00/562) were (00/560) and a second batch (00/562) were prepared in Q1, 2001prepared in Q1, 2001
00/560 was evaluated in an international 00/560 was evaluated in an international
collaborative study, with data returned from 16 collaborative study, with data returned from 16 laboratorieslaboratories
The mean logThe mean log1010 equivalents/ml were 5.29 (00/560) equivalents/ml were 5.29 (00/560) and 5.07 (00/562)and 5.07 (00/562)
11stst International Standard (00/560) was established International Standard (00/560) was established in 2003 with 50,000 IU/vialin 2003 with 50,000 IU/vial
ECBS noted that 00/562 may be a replacement for ECBS noted that 00/562 may be a replacement for 00/56000/560
Stability Data 00/560 & 00/562Stability Data 00/560 & 00/562
Accelerated thermal degradation samples Accelerated thermal degradation samples for 00/560 and 00/562, stored at +4for 00/560 and 00/562, stored at +4ºC for ºC for ~6 years were tested in parallel with ~6 years were tested in parallel with samples of 00/560 stored at -20 ºCsamples of 00/560 stored at -20 ºC
00/560 – a drop on 0.1 log00/560 – a drop on 0.1 log1010
00/562 – a drop on 1.0 log00/562 – a drop on 1.0 log1010
Conclude that 00/560 is highly stable Conclude that 00/560 is highly stable
Proposal to Replace the Proposal to Replace the Parvovirus B19 DNA Parvovirus B19 DNA
International Standard International Standard
Sally Baylis, NIBSCSally Baylis, NIBSCSoGAT XX, Warsaw 12-13 June SoGAT XX, Warsaw 12-13 June
20072007
Replacement of the Replacement of the Parvovirus B19 DNA IS Parvovirus B19 DNA IS
99/800 99/800 The 1The 1stst International Standard for B19V DNA International Standard for B19V DNA
was established by the WHO ECBS in October was established by the WHO ECBS in October 20002000
Estimated date of exhaustion of the IS will be Estimated date of exhaustion of the IS will be 2008/9 at current rate of usage2008/9 at current rate of usage
Materials coded AA (99/800) & BB (99/802) Materials coded AA (99/800) & BB (99/802) showed no significant difference in potency in showed no significant difference in potency in the collaborative studythe collaborative study
ECBS noted that BB (made from the same stock ECBS noted that BB (made from the same stock as AA) could be reserved for potential future as AA) could be reserved for potential future use as a replacement standarduse as a replacement standard
Candidate 2Candidate 2ndnd International International StandardStandard
Materials coded AA (99/800) & BB (99/802) Materials coded AA (99/800) & BB (99/802) showed no significant difference in potency in the showed no significant difference in potency in the original collaborative studyoriginal collaborative study
ECBS noted that BB (prepared from the same ECBS noted that BB (prepared from the same stock as AA) could be reserved for potential stock as AA) could be reserved for potential future use as a replacement standardfuture use as a replacement standard
Current study designed to demonstrate the Current study designed to demonstrate the equivalence of the candidate replacement (BB) to equivalence of the candidate replacement (BB) to AAAA
Real-time data on samples AA & BBReal-time data on samples AA & BB Accelerated degradation data for samples AA & BBAccelerated degradation data for samples AA & BB
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