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Document 02002D0364-20091201

    Consolidated text: Commission Decision of 7 May 2002 on common technical specifications for in vitro -diagnostic medical devices (notified under document number C(2002) 1344) (Text with EEA relevance) (2002/364/EC)

    ELI: http://data.europa.eu/eli/dec/2002/364/2009-12-01

    2002D0364 — EN — 01.12.2009 — 001.002


    This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents

    ►B

    COMMISSION DECISION

    of 7 May 2002

    on common technical specifications for in vitro-diagnostic medical devices

    (notified under document number C(2002) 1344)

    (Text with EEA relevance)

    (2002/364/EC)

    (OJ L 131, 16.5.2002, p.17)

    Amended by:

     

     

    Official Journal

      No

    page

    date

     M1

    COMMISSION DECISION of 3 February 2009

      L 39

    34

    10.2.2009

    ►M2

    COMMISSION DECISION of 27 November 2009

      L 318

    25

    4.12.2009


    Corrected by:

    ►C1

    Corrigendum, OJ L 348, 29.12.2009, p. 94  (886/2009)




    ▼B

    COMMISSION DECISION

    of 7 May 2002

    on common technical specifications for in vitro-diagnostic medical devices

    (notified under document number C(2002) 1344)

    (Text with EEA relevance)

    (2002/364/EC)



    THE COMMISSION OF THE EUROPEAN COMMUNITIES,

    Having regard to the Treaty establishing the European Community,

    Having regard to Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices ( 1 ), and in particular the second subparagraph of Article 5(3) thereof,

    Whereas:

    (1)

    Directive 98/79/EC sets out the essential requirements that in vitro diagnostic medical devices must meet when they are placed on the market and conformity with harmonised standards provides a presumption of conformity with the relevant essential requirements.

    (2)

    By way of exception to these general principles, the drawing up of common technical specifications takes account of a current practice in some Member States whereby for selected devices mainly used for the evaluation of the safety of blood supply and of organ donation, such specifications are adopted by the public authorities. These common technical specifications can be used for performance evaluation and re-evaluation.

    (3)

    Scientific experts from various interested parties have been involved in the drafting of the common technical specifications.

    (4)

    Directive 98/79/EC provides that Member States are to presume compliance with the essential requirements in respect of devices designed and manufactured in conformity with common technical specifications drawn up for certain devices in the highest risk category. These specifications are to establish appropriate performance evaluation and re-evaluation criteria, batch release criteria, reference methods and reference materials.

    (5)

    Manufacturers are, as a general rule, to be required to comply with the common technical specifications. If, for duly justified reasons, manufacturers do not comply with those specifications they must adopt solutions of a level at least equivalent thereto.

    (6)

    The measures provided for in this Decision are in accordance with the opinion of the committee set up by Article 6(2) of Council Directive 90/385/EEC ( 2 ),

    HAS ADOPTED THIS DECISION:



    Article 1

    The technical specifications set out in the Annex to this Decision are adopted as common technical specifications for in vitro diagnostic medical devices in list A of Annex II to Directive 98/79/EC.

    Article 2

    This Decision is addressed to the Member States.

    ▼M2




    ANNEX

    COMMON TECHNICAL SPECIFICATIONS (CTS) FOR IN VITRO DIAGNOSTIC MEDICAL DEVICES

    1.   SCOPE

    The common technical specifications set out in this Annex shall apply for the purposes of Annex II List A to Directive 98/79/EC.

    2.   DEFINITIONS AND TERMS

    (Diagnostic) sensitivity

    The probability that the device gives a positive result in the presence of the target marker.

    True positive

    A specimen known to be positive for the target marker and correctly classified by the device.

    False negative

    A specimen known to be positive for the target marker and misclassified by the device.

    (Diagnostic) specificity

    The probability that the device gives a negative result in the absence of the target marker.

    False positive

    A specimen known to be negative for the target marker and misclassified by the device.

    True negative

    A specimen known to be negative for the target marker and correctly classified by the device.

    Analytical sensitivity

    Analytical sensitivity may be expressed as the limit of detection, i.e. the smallest amount of the target marker that can be precisely detected.

    Analytical specificity

    Analytical specificity means the ability of the method to determine solely the target marker.

    Nucleic acid amplification techniques (NAT)

    The term ‘NAT’ is used for tests for the detection and/or quantification of nucleic acids by either amplification of a target sequence, by amplification of a signal or by hybridisation.

    Rapid test

    ‘Rapid test’ means qualitative or semi-quantitative in vitro diagnostic medical devices, used singly or in a small series, which involve non-automated procedures and have been designed to give a fast result.

    Robustness

    The robustness of an analytical procedure means the capacity of an analytical procedure to remain unaffected by small but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

    Whole system failure rate

    The whole system failure rate means the frequency of failures when the entire process is performed as prescribed by the manufacturer.

    Confirmation assay

    Confirmation assay means an assay used for the confirmation of a reactive result from a screening assay.

    Virus typing assay

    Virus typing assay means an assay used for typing with already known positive samples, not used for primary diagnosis of infection or for screening.

    Sero-conversion HIV samples

    Sero-conversion HIV samples mean:

     p24 antigen and/or HIV RNA positive, and

     recognised by all of the antibody screening tests, and

     positive or indeterminate confirmatory assays.

    Early sero-conversion HIV samples

    Early seroconversion HIV samples mean:

     p24 antigen and/or HIV RNA positive, and

     not recognised by all of the antibody screening tests, and

     indeterminate or negative confirmatory assays.

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

    3.1.    CTS 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

    General principles

    3.1.1.

    Devices which detect virus infections placed on the market for use as either screening or diagnostic tests, shall meet the requirements for sensitivity and specificity set out in Table 1. See also principle 3.1.11 for screening assays.

    3.1.2.

    Devices intended by the manufacturer for testing body fluids other than serum or plasma, e.g. urine, saliva, etc., shall meet the same CTS requirements for sensitivity and specificity as serum or plasma tests. The performance evaluation shall test samples from the same individuals in both the tests to be approved and in a respective serum or plasma assay.

    3.1.3.

    Devices intended by the manufacturer for self-test, i.e. home use, shall meet the same CTS requirements for sensitivity and specificity as respective devices for professional use. Relevant parts of the performance evaluation shall be carried out (or repeated) by appropriate lay users to validate the operation of the device and the instructions for use.

    3.1.4.

    All performance evaluations shall be carried out in direct comparison with an established state-of-the-art device. The device used for comparison shall be one bearing CE marking, if on the market at the time of the performance evaluation.

    3.1.5.

    If discrepant test results are identified as part of an evaluation, these results shall be resolved as far as possible, for example:

     by evaluation of the discrepant sample in further test systems,

     by use of an alternative method or marker,

     by a review of the clinical status and diagnosis of the patient, and

     by the testing of follow-up-samples.

    3.1.6.

    Performance evaluations shall be performed on a population equivalent to the European population.

    3.1.7.

    Positive specimens used in the performance evaluation shall be selected to reflect different stages of the respective disease(s), different antibody patterns, different genotypes, different subtypes, mutants, etc.

    3.1.8.

    Sensitivity with true positives and sero-conversion samples shall be evaluated as follows:

    3.1.8.1. Diagnostic test sensitivity during sero-conversion has to represent the state of the art. Whether further testing of the same or additional sero-conversion panels is conducted by the notified body or by the manufacturer the results shall confirm the initial performance evaluation data (see Table 1). Sero-conversion panels should start with a negative bleed(s) and should have narrow bleeding intervals.

    3.1.8.2. For blood screening devices (with the exception of HBsAg and anti-HBc tests), all true positive samples shall be identified as positive by the device to be CE marked (Table 1). For HBsAg and anti-HBc tests the new device shall have an overall performance at least equivalent to that of the established device (see 3.1.4).

    3.1.8.3. Regarding HIV tests:

     all sero-conversion HIV samples shall be identified as positive, and

     at least 40 early sero-conversion HIV samples shall be tested. Results should conform to the state of the art.

    3.1.9.

    Performance evaluation of screening assays shall include 25 positive (if available in the case of rare infections) ‘same day’ fresh serum and/or plasma samples (≤ 1 day after sampling).

    3.1.10.

    Negative specimens used in a performance evaluation shall be defined so as to reflect the target population for which the test is intended, for example blood donors, hospitalised patients, pregnant women, etc.

    3.1.11.

    For performance evaluations for screening assays (Table 1) blood donor populations shall be investigated from at least two blood donation centres and consist of consecutive blood donations, which have not been selected to exclude first time donors.

    3.1.12.

    Devices shall have a specificity of at least 99,5 % on blood donations, unless otherwise indicated in the accompanying tables. Specificity shall be calculated using the frequency of repeatedly reactive (i.e. false positive) results in blood donors negative for the target marker.

    3.1.13.

    Devices shall be evaluated to establish the effect of potential interfering substances, as part of the performance evaluation. The potential interfering substances to be evaluated will depend to some extent on the composition of the reagent and configuration of the assay. Potential interfering substances shall be identified as part of the risk analysis required by the essential requirements for each new device but may include, for example:

     specimens representing ‘related’ infections,

     specimens from multipara, i.e. women who have had more than one pregnancy, or rheumatoid factor positive patients,

     for recombinant antigens, human antibodies to components of the expression system, for example anti-E. coli, or anti-yeast.

    3.1.14.

    For devices intended by the manufacturer to be used with serum and plasma the performance evaluation must demonstrate serum to plasma equivalency. This shall be demonstrated for at least 50 donations (25 positive and 25 negative).

    3.1.15.

    For devices intended for use with plasma the performance evaluation shall verify the performance of the device using all anticoagulants which the manufacturer indicates for use with the device. This shall be demonstrated for at least 50 donations (25 positive and 25 negative).

    3.1.16.

    As part of the required risk analysis the whole system failure rate leading to false-negative results shall be determined in repeat assays on low-positive specimens.

    3.1.17.

    If a new in vitro diagnostic medical device belonging to Annex II List A is not specifically covered by the common technical specification, the common technical specification for a related device should be taken into account. Related devices may be identified on different grounds, e.g. by the same or similar intended use or by similar risks.

    3.2.    Additional requirements for HIV antibody/antigen combined tests

    3.2.1.

    HIV antibody/antigen combined tests intended for anti-HIV and p24 antigen detection which include claims for single p24 antigen detection shall follow Table 1 and Table 5, including criteria for analytical sensitivity for p24 antigen.

    3.2.2.

    HIV antibody/antigen combined tests intended for anti-HIV and p24 detection which do not include claims for single p24 detection shall follow Table 1 and Table 5, excluding criteria for analytical sensitivity for p24.

    3.3.    Additional requirements for nucleic acid amplification techniques (NAT)

    The performance evaluation criteria for NAT assays can be found in Table 2.

    3.3.1.

    For target sequence amplification assays, a functionality control for each test sample (internal control) shall reflect the state of the art. This control shall as far as possible be used throughout the whole process, i.e. extraction, amplification/hybridisation, detection.

    3.3.2.

    The analytical sensitivity or detection limit for NAT assays shall be expressed by the 95 % positive cut-off value. This is the analyte concentration where 95 % of test runs give positive results following serial dilutions of an international reference material for example a WHO standard or calibrated reference material.

    3.3.3.

    Genotype detection shall be demonstrated by appropriate primer or probe design validation and shall also be validated by testing characterised genotyped samples.

    3.3.4.

    Results of quantitative NAT assays shall be traceable to international standards or calibrated reference materials, if available, and be expressed in international units utilised in the specific field of application.

    3.3.5.

    NAT assays may be used to detect virus in antibody negative samples, i.e. pre-sero-conversion samples. Viruses within immune-complexes may behave differently in comparison to free viruses, for example during a centrifugation step. It is therefore important that during robustness studies, antibody-negative (pre-sero-conversion) samples are included.

    3.3.6.

    For investigation of potential carry-over, at least five runs with alternating high-positive and negative specimens shall be performed during robustness studies. The high positive samples shall comprise samples with naturally occurring high virus titres.

    3.3.7.

    The whole system failure rate leading to false-negative results shall be determined by testing low-positive specimens. Low-positive specimens shall contain a virus concentration equivalent to three times the 95 % positive cut-off virus concentration.

    3.4.    CTS 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)

    3.4.1.

    The manufacturer’s release testing criteria shall ensure that every batch consistently identifies the relevant antigens, epitopes, and antibodies.

    3.4.2.

    The manufacturer’s batch release testing for screening assays shall include at least 100 specimens negative for the relevant analyte.

    3.5.    CTS 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)

    Criteria for performance evaluation of reagents and reagent products for determining the blood groups 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) can be found in Table 9.

    3.5.1.

    All performance evaluations shall be carried out in direct comparison with an established state-of-the-art device. The device used for comparison shall be one bearing CE marking, if on the market at the time of the performance evaluation.

    3.5.2.

    If discrepant test results are identified as part of an evaluation, these results shall be resolved as far as possible, for example:

     by evaluation of the discrepant sample in further test systems,

     by use of an alternative method,

    3.5.3.

    Performance evaluations shall be performed on a population equivalent to the European population.

    3.5.4.

    Positive specimens used in the performance evaluation shall be selected to reflect variant and weak antigen expression.

    3.5.5.

    Devices shall be evaluated to establish the effect of potential interfering substances, as part of the performance evaluation. The potential interfering substances to be evaluated will depend to some extent on the composition of the reagent and configuration of the assay. Potential interfering substances shall be identified as part of the risk analysis required by the essential requirements for each new device.

    3.5.6.

    For devices intended for use with plasma the performance evaluation shall verify the performance of the device using all anticoagulants which the manufacturer indicates for use with the device. This shall be demonstrated for at least 50 donations.

    3.6.    CTS 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)

    3.6.1.

    The manufacturer’s release testing criteria shall ensure that every batch consistently identifies the relevant antigens, epitopes, and antibodies.

    3.6.2.

    Requirements for manufacturers batch release testing are outlined in Table 10.



    Table 1

    ‘Screening’ assays: anti-HIV 1 and 2, anti-HTLV I and II, anti-HCV, HBsAg, anti-HBc

     
     

    Anti-HIV-1/2

    Anti-HTLV-I/II

    Anti-HCV

    HBsAg

    Anti-HBc

    Diagnostic sensitivity

    Positive specimens

    400 HIV-1

    100 HIV-2

    including 40 non-B subtypes, all available HIV/1 subtypes should 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 subtypeconsideration

    400

    Including evaluation of other HBV-markers

    Sero-conversion panels

    20 panels

    10 further panels (at Notified Body or manufacturer)

    To be defined when available

    20 panels

    10 further panels (at Notified Body or manufacturer)

    20 panels

    10 further panels (at Notified Body or manufacturer)

    To be defined when available

    Analytical sensitivity

    Standards

     
     
     

    0,130 IU/ml (Second International Standard for HBsAg, subtype adw2, genotype A, NIBSC code: 00/588)

     

    Specificity

    Unselected donors (including first-time donors)

    5 000

    5 000

    5 000

    5 000

    5 000

    Hospitalised 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)

    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 (1): 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 (1): 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 (1): 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 (1): 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 (1)as far as calibrated subtype reference materials are available; in vitro transcripts could be an option

     

    According to EP validation guideline (1)as far as calibrated subtype reference materials are available; in vitro transcripts could be an option

     

    According to EP validation guideline (1)as far as calibrated subtype reference materials are available; in vitro transcripts could be an option

     

    According to EP validation guideline (1)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

    (1)   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.



    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

     
     

    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 (1).

    No false-positive results/ (1) 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

     

    (1)   Acceptance criteria no neutralisation for HBsAg confirmatory assay.



    Table 5

    HIV 1 antigen

     

    HIV-1 antigen assay

    Acceptance criteria

    Diagnostic sensitivity

    Positive specimens

    50 HIV-1 Ag-positive

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

    Correct identification (after neutralisation)

    Sero-conversion panels

    20 sero-conversion panels/low titre panels

     

    Analytical sensitivity

    Standards

    HIV-1 p24 Antigen, First International Reference Reagent, NIBSC code: 90/636

    ≤ 2 IU/ml

    Diagnostic specificity

     

    200 blood donations

    200 clinical samples

    50 potentially interfering samples

    ≥ 99,5 % after neutralisation



    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

    ►C1  

    > 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

    Acceptance criteria:

    All of the above reagents shall show comparable test results with established reagents with acceptable performance with regard to claimed reactivity of the device. For established reagents, where the application or use has been changed or extended, further testing should be carried out in accordance with the requirements outlined in column 1 (above).

    Performance evaluation of anti-D reagents shall include tests against a range of weak RH1 (D) and partial RH1 (D) samples, depending on the intended use of the product.

    Qualifications:

    Clinical samples

    :

    10 % of the test population

    Neonatal specimens

    :

    > 2 % of the test population

    ABO samples

    :

    > 40 % A, B positives

    ‘weak D’

    :

    > 2 % of RH1 (D) positives

    Table 10

    Batch release criteria for reagents and reagent products to determine blood group antigens in the ABO, Rh and Kell blood group systems

    Specificity testing requirements on each reagent

    1.    Test reagents



    Blood group reagents

    Minimum number of control cells to be tested

     

    Positive reactions

     

    Negative reactions

     

    A1

    A2B

    Ax

     
     

    B

    0

     

    Anti-ABO1 (anti-A)

    2

    2

    (1)

     

    2

    2

     
     

    B

    A1B

     
     

    A1

    0

     

    Anti-ABO2 (anti-B)

    2

    2

     
     

    2

    2

     
     

    A1

    A2

    Ax

    B

    0

     
     

    Anti-ABO3 (anti-A,B)

    2

    2

    2

    2

    4

     
     
     

    R1r

    R2r

    WeakD

     

    r’r

    r’r

    rr

    Anti-RH1 (anti-D)

    2

    2

    (1)

     

    1

    1

    1

     

    R1R2

    R1r

    r’r

     

    R2R2

    r’r

    rr

    Anti-RH2 (anti-C)

    2

    1

    1

     

    1

    1

    1

     

    R1R2

    R1r

    r’r

     

    R1R1

     
     

    Anti-RH4 (anti-c)

    1

    2

    1

     

    3

     
     
     

    R1R2

    R2r

    r’r

     

    R1R1

    r’r

    rr

    Anti-RH 3 (anti-E)

    2

    1

    1

     

    1

    1

    1

     

    R1R2

    R2r

    r’r

     

    R2R2

     
     

    Anti-RH5 (anti-e)

    2

    1

    1

     

    3

     
     
     

    Kk

     
     
     

    kk

     
     

    Anti-KEL1 (anti-K)

    4

     
     
     

    3

     
     

    (1)   Only by recommended techniques where reactivity against these antigens is claimed.

    Note: Polyclonal reagents must be tested against a wider panel of cells to confirm specificity and exclude presence of unwanted contaminating antibodies.

    Each batch of reagent must exhibit unequivocal positive or negative results by all recommended techniques in accordance with the results obtained from the performance evaluation data.

    2.    Control materials (red cells)

    The phenotype of red cells used in the control of blood typing reagents listed above should be confirmed using established device.



    ( 1 ) OJ L 331, 7.12.1998, p. 1.

    ( 2 ) OJ L 189, 20.7.1990, p. 17.

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