OpenLegislation

Division 3 COMMON TECHNICAL SPECIFICATIONS (CTS) FOR PRODUCTS REFERRED TO IN ANNEX II, LIST A OF DIRECTIVE 98/79/ECF1

United Kingdom

Original text. Later amendments are not shown.

F2Table 1

Screening assays: anti-HIV 1/2, HIV 1/2 Ag/Ab, anti-HTLV I/II, anti-HCV, HCV Ag/Ab, HBsAg, anti-HBc

anti-HIV 1/2, HIV 1/2 Ag/Ab Anti-HTLV-I/II anti-HCV, HCV Ag/Ab HBsAg Anti-HBc
Diagnostic sensitivity Positive specimens

400 HIV-1

100 HIV-2

including 40 non-B-subtypes, all available HIV/1 subtypes shall be represented by at least 3 samples per subtype

300 HTLV-I

100 HTLV-II

400 (positive samples)

Including samples from different stages of infection and reflecting different antibody patterns.

Genotype 1-4: > 20 samples per genotype (including non-a subtypes of genotype 4);

5: > 5 samples;

6: if available

400

including subtype-consideration

400

including evaluation of other HBV-markers

Sero-conversion panels

20 panels

10 further panels (at F3Approved Body or manufacturer)

 To be defined when available

20 panels

10 further panels (at Approved Body or manufacturer)

20 panels

10 further panels (at Approved Body or manufacturer)

 To be defined when available
Analytical sensitivity Standards 0,130 IU/ml (WHO International Standard: Third International Standard for HBsAg, subtypes ayw1/adw2, HBV genotype B4, NIBSC code: 12/226)
Specificity Unselected donors (including first-time donors) 5 000 5 000 5 000 5 000 5 000
Hospitalized patients 200 200 200 200 200
Potentially cross-reacting blood-specimens (RF+, related viruses, pregnant women, etc.) 100 100 100 100 100

Table 2

NAT assays for HIV1, HCV, HBV, HTLV I/II (qualitative and quantitative; not molecular typing)

European Pharmacopoeia guideline.

Notes: Acceptance criteria for ‘whole system failure rate leading to false-neg results’ is 99/100 assays positive.

For quantitative NATs a study shall be performed on at least 100 positive specimens reflecting the routine conditions of users (e.g. no pre-selection of specimens). Comparative results with another NAT test system shall be generated in parallel.

For qualitative NATs a study on diagnostic sensitivity shall be performed using at least 10 sero-conversion panels. Comparative results with another NAT test system shall be generated in parallel.

HIV1 HCV HBV HTLV I/II Acceptance criteria
NAT qualitative quantitative qualitative quantitative qualitative quantitative qualitative quantitative
As for HIV quantitative As for HIV quantitative As for HIV quantitative

Sensitivity

Detection limit

Detection of analytical sensitivity (IU/ml; defined on WHO standards or calibrated reference materials)

 According to EP validation guideline f1 : several dilution series into borderline concentration; statistical analysis (e.g. Probit analysis) on the basis of at least 24 replicates; calculation of 95 % cut-off value Detection limit: as for qualitative tests; Quantification limit: dilutions (half-log10 or less) of calibrated reference preparations, definition of lower, upper quantification limit, precision, accuracy, ‘ linear ’ measuring range, ‘ dynamic range ’ . Reproducibility at different concentration levels to be shown According to EP validation guideline : several dilution series into borderline concentration; statistical analysis (e.g. Probit analysis) on the basis of at least 24 replicates; calculation of 95 % cut-off value According to EP validation guideline : several dilution series into borderline concentration; statistical analysis (e.g. Probit analysis) on the basis of at least 24 replicates; calculation of 95 % cut-off value According to EP validation guideline : several dilution series into borderline concentration; statistical analysis (e.g. Probit analysis) on the basis of at least 24 replicates; calculation of 95 % cut-off value
Genotype/subtype detection/quantification efficiency At least 10 samples per subtype (as far as available) Dilution series of all relevant genotypes/subtypes, preferably of reference materials, as far as available At least 10 samples per genotype (as far as available) As far as calibrated genotype reference materials are available As far as calibrated genotype reference materials are available
Cell culture supernatants (could substitute for rare HIV-1 subtypes) Transcripts or plasmids quantified by appropriate methods may be used.
According to EP validation guideline as far as calibrated subtype reference materials are available; in vitro transcripts could be an option According to EP validation guideline as far as calibrated subtype reference materials are available; in vitro transcripts could be an option According to EP validation guideline as far as calibrated subtype reference materials are available; in vitro transcripts could be an option According to EP validation guideline as far as calibrated subtype reference materials are available; in vitro transcripts could be an option
Diagnostic specificity negative samples 500 blood donors 100 blood donors 500 blood donors 500 blood donors 500 individual blood donations
Potential cross-reactive markers By suitable assay design evidence (e.g. sequence comparison) and/or testing of at least 10 human retrovirus (e.g. HTLV)-positive samples As for qualitative tests By assays design and/or testing of at least 10 human flavivirus (e.g. HGV, YFV) positive samples By assays design and/or testing of at least 10 other DNA-virus positive samples By assay design and/or testing of at least 10 human retrovirus (e.g. HIV-) positive samples
Robustness As for qualitative tests
Cross-contamination At least 5 runs using alternating high positive (known to occur naturally) and negative samples At least 5 runs using alternating high positive (known to occur naturally) and negative samples At least 5 runs using alternating high positive (known to occur naturally) and negative samples At least 5 runs using alternating high positive (known to occur naturally) and negative samples
Inhibition Internal control preferably to go through the whole NAT procedure Internal control preferably to go through the whole NAT procedure Internal control preferably to go through the whole NAT procedure Internal control preferably to go through the whole NAT procedure
Whole system failure rate leading to false-neg results At least 100 samples virus-spiked with 3 × the 95 % pos cut-off concentration At least 100 samples virus-spiked with 3 × the 95 % pos cut-off concentration At least 100 samples virus-spiked with 3 × the 95 % pos cut-off concentration At least 100 samples virus-spiked with 3 × the 95 % pos cut-off concentration 99/100 assays positive

Table 3

Rapid tests: anti-HIV 1 and 2, anti-HCV, HBsAg, anti-HBc, anti-HTLV I and II

Anti-HIV 1/2 Anti-HCV HBsAg Anti-HBc Anti-HTLV I/II Acceptance criteria
Diagnostic sensitivity Positive specimens Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays
Sero-conversion panels Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays Same criteria as for screening assays
Diagnostic specificity Negative specimens 1 000 blood donations 1 000 blood donations 1 000 blood donations 1 000 blood donations 1 000 blood donations ≥ 99 % (anti-HBc: ≥ 96 %)
200 clinical specimens 200 clinical specimens 200 clinical specimens 200 clinical specimens 200 clinical specimens
200 samples from pregnant women 200 samples from pregnant women 200 samples from pregnant women 200 samples from pregnant women
100 potentially interfering samples 100 potentially interfering samples 100 potentially interfering samples 100 potentially interfering samples 100 potentially interfering samples

Table 4

Confirmatory/supplementary assays for anti-HIV 1 and 2, anti-HTLV I and II, anti-HCV, HBsAg

Acceptance criteria no neutralisation for HBsAg confirmatory assay.

Anti-HIV confirmatory assay Anti-HTLV confirmatory assay HCV supplementary assay HBsAg confirmatory assay Acceptance criteria
Diagnostic sensitivity Positive specimens 200 HIV-1 and 100 HIV-2 200 HTLV-I and 100 HTLV-II 300 HCV (positive samples) 300 HBsAg Correct identification as positive (or indeterminate), not negative
Including samples from different stages of infection and reflecting different antibody patterns

Including samples from different stages of infection and reflecting different antibody patterns.

Genotypes 1 – 4: > 20 samples (including non-a subtypes of genotype 4);

5: > 5 samples;

6: if available

Including samples from different stages of infection

20 ‘high pos’ samples (> 26 IU/ml); 20 samples in the cut-off range

Sero-conversion panels 15 sero-conversion panels/low titre panels 15 sero-conversion panels/low titre panels 15 sero-conversion panels/low titre panels
Analytical sensitivity Standards Second International Standard for HBsAg, subtype adw2, genotype A, NIBSC code: 00/588
Diagnostic specificity Negative specimens 200 blood donations 200 blood donation 200 blood donations 10 false positives as available from the performance evaluation of the screening assay f2 . No false-positive results/ no neutralisation
200 clinical samples including pregnant women 200 clinical samples including pregnant women 200 clinical samples including pregnant women
50 potentially interfering samples, including samples with indeterminate results in other confirmatory assays 50 potentially interfering samples including samples with indeterminate results in other confirmatory assays 50 potentially interfering samples including samples with indeterminate results in other supplementary assays 50 potentially interfering samples

Table 5

HIV 1 antigen, HIV Ag/Ab, HCV antigen, HCV Ag/Ab

The total number of seroconversion panels for combined Ag/Ab assays (from tables 1 and 5) need not be greater than 30.

HIV-1 antigen and HIV Ag/Ab assays HCV antigen and HCV Ag/Ab assays Acceptance criteria
Diagnostic sensitivity Positive specimens

50 HIV-1 antigen positive

50 cell culture supernatants including different HIV-1 subtypes and HIV-2

 25 HCV core antigen and/or HCV RNA positive but anti-HCV negative samples, comprising HCV genotypes 1-6 (if a genotype is not available, a justification shall be made) See general principle in § 3.1.8
Sero-conversion panels f3 20 sero-conversion panels/low titre panels 20 sero-conversion panels/low titre panels
Analytical sensitivity Standards HIV-1 p24 Antigen, First International Reference Reagent, NIBSC code: 90/636 HCV core antigen detection limit shall be investigated using dilutions of the WHO International HCV core antigen Standard: (HCV core Ag product code: PEI 129096/12) For HIV-1 p24 antigen: ≤ 2 IU/ml
Diagnostic specificity

200 blood donations

200 clinical samples

50 potentially interfering samples

 200 blood donations, 200 clinical samples, 50 potentially interfering samples ≥ 99,5 % after neutralisation or, if no neutralisation test available, after resolution of the sample status according to general principles in § 3.1.5

Table 6

Serotyping and genotyping assay: HCV

HCV serotyping and genotyping assay Acceptance criteria
Diagnostic sensitivity Positive specimens

200 (positive samples)

Including samples from different stages of infection and reflecting different antibody patterns.

Genotypes 1 – 4: > 20 samples (including non-a subtypes of genotype 4);

5: > 5 samples;

6: if available

≥ 95 % agreement between serotyping and genotyping

X1> 95 % agreement between genotyping and sequencing

Diagnostic specificity Negative specimens 100

Table 7

HBV markers: anti-HBs, anti HBc IgM, anti-HBe, HBeAg

Anti-HBs Anti-HBc IgM Anti-HBe HBeAg Acceptance criteria
Diagnostic sensitivity Positive specimens 100 vaccinees 200 200 200 ≥ 98 %
100 naturally infected persons

Including samples from different stages of infection (acute/chronic, etc.)

The acceptance criteria should only be applied on samples from acute infection stage.

 Including samples from different stages of infection (acute/chronic, etc.) Including samples from different stages of infection (acute/chronic, etc.)
Sero-conversion panels 10 follow-ups or anti-HBs sero-conversions When available
Analytical sensitivity Standards WHO First International Reference Preparation 1977; NIBSC, United Kingdom HBe — Referenzantigen 82; PEI Germany Anti-HBs: < 10 mIU/ml
Diagnostic specificity Negative specimens 500 200 blood donations 200 blood donation 200 blood donations ≥ 98 %
Including clinical samples 200 clinical samples 200 clinical samples 200 clinical samples
50 potentially interfering samples 50 potentially interfering samples 50 potentially interfering samples 50 potentially interfering samples

Table 8

HDV markers: anti-HDV, anti-HDV IgM, delta antigen

Anti-HDV Anti-HDV IgM Delta antigen Acceptance criteria
Diagnostic sensitivity Positive specimens 100 50 10 ≥ 98 %
Specifying HBV markers Specifying HBV markers Specifying HBV markers
Diagnostic specificity Negative specimens 200 200 200 ≥ 98 %
Including clinical samples Including clinical samples Including clinical samples
50 potentially interfering samples 50 potentially interfering samples 50 potentially interfering samples

Table 9

Blood group antigens in the ABO, Rh and Kell blood group systems

1 2 3
Specificity Number of tests per recommended method Total number of samples to be tested for a launch product Total number of samples to be tested for a new formulation, or use of well-characterised reagents
Anti-ABO1 (anti-A), anti-ABO2 (anti-B), anti-ABO3 (anti-A,B) 500 3 000 1 000
Anti-RH1 (anti-D) 500 3 000 1 000
Anti-RH2 (anti-C), anti-RH4 (anti-c), anti-RH3 (anti-E) 100 1 000 200
Anti-RH5 (anti-e) 100 500 200
Anti-KEL1 (anti-K) 100 500 200

F4Table 11

Variant Creutzfeldt-Jakob disease (vCJD) assays for blood screening

Material Number of specimens Acceptance Criteria
Analytical sensitivity vCJD brain spikes in human plasma (WHO reference number NHBY0/0003)

24 replicates of each of three dilutions of the material WHO number NHBY0/0003

(1×10 4 , 1×10 5 , 1×10 6 )

23 of the 24 replicates detected at

1×10 4

vCJD spleen spikes in human plasma (10 % spleen homogenate — NIBSC reference number NHSY0/0009)

24 replicates of each of three dilutions of the material NIBSC number NHSY0/0009

(1×10, 1×10 2 , 1×10 3 )

23 of the 24 replicates detected at

1×10

Diagnostic sensitivity

A)

Specimen from appropriate animal models

 As many specimen as reasonably possible and available, and at least 10 specimens 90 %

B)

Specimen from humans with known clinical vCJD

 As many specimen as reasonably possible and available, and at least 10 specimens 90 %

Only in case where 10 specimens are not available:

  • the number of specimens tested shall be comprised between 6 and 9

  • all available specimens shall be tested

 no more than one false negative result
Analytical specificity Potentially cross-reacting blood-specimens 100
Diagnostic specificity Normal human plasma samples from area of low BSE exposure 5 000 At least 99,5 %
  1. 3.1CTS for performance evaluation of reagents and reagent products for the detection, confirmation and quantification in human specimens of markers of HIV infection (HIV 1 and 2), HTLV I and II, and hepatitis B, C, D
  2. 3.2Additional requirements for HIV and HCV antigen and antibody combined tests
  3. 3.3Additional requirements for nucleic acid amplification techniques (NAT)
  4. 3.4CTS for the manufacturer’s release testing of reagents and reagent products for the detection, confirmation and quantification in human specimens of markers of HIV infection (HIV 1 and 2), HTLV I and II, and hepatitis B, C, D (immunological assays only)
  5. 3.5CTS for performance evaluation of reagents and reagent products for determining the following blood group antigens: ABO blood group system ABO1 (A), ABO2 (B), ABO3 (A,B); Rh blood group system RH1 (D), RH2 (C), RH3 (E), RH4 (c), RH5 (e); Kell blood group system KEL1 (K)
  6. 3.6CTS for the manufacturer’s release testing of reagents and reagent products for determining the blood group antigens: ABO blood group system ABO1 (A), ABO2 (B), ABO3 (A,B); Rh blood group system RH1 (D), RH2 (C), RH3 (E), RH4 (c), RH5 (e); Kell blood group system KEL1 (K)
  7. 3.7CTS for Variant Creutzfeldt-Jakob disease (vCJD) assays for blood screening
  8. Acceptance criteria:
  9. Qualifications:
  10. Table 10

Annotations

Textual amendments

F1

Substituted by Commission Decision of 27 November 2009 amending Decision 2002/364/EC on common technical specifications for in vitro diagnostic medical devices (notified under document C(2009) 9464) (Text with EEA relevance) (2009/886/EC).

F2

Substituted by Commission Implementing Decision (EU) 2019/1244 of 1 July 2019 amending Decision 2002/364/EC as regards requirements for HIV and HCV antigen and antibody combined tests and as regards requirements for nucleic acid amplification techniques with respect to reference materials and qualitative HIV assays (notified under document C(2019) 4632) (Text with EEA relevance).

F3

Words in Annex Table 1 substituted (E.W.S.) (11.8.2021) by The Medical Devices (Amendment) (EU Exit) Regulations 2021 (S.I. 2021/873), reg. 1(1), Sch. 2 para. 3(d)

F4

Inserted by Commission Decision of 20 December 2011 amending Decision 2002/364/EC on common technical specifications for in vitro diagnostic medical devices (notified under document C(2011) 9398) (Text with EEA relevance) (2011/869/EU).

Editorial notes

X1

Substituted by Corrigendum to Commission Decision 2009/886/EC of 27 November 2009 amending Decision 2002/364/EC on common technical specifications for in vitro diagnostic medical devices (Official Journal of the European Union L 318 of 4 December 2009).

Footnotes

f1

European Pharmacopoeia guideline.

f2

Acceptance criteria no neutralisation for HBsAg confirmatory assay.

f3

The total number of seroconversion panels for combined Ag/Ab assays (from tables 1 and 5) need not be greater than 30.