
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, 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,
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 as that Annex applied before IP completion day and as modified by Schedule 2A to the Medical Devices Regulations 2002.
Article 2 
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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 shall meet the requirements for sensitivity and specificity set out in Table 1 and Table 5 according to virus type and entities detected (antigen and/or antibody). 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  UK or 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  approved 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  UK or 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 and HCV antigen and antibody combined tests
                         
 3.2.1. HIV antigen and antibody combined tests intended for the detection of HIV-1 p24 antigen and HIV-1/2 antibody shall meet the requirements for sensitivity and specificity set out in Table 1 and Table 5.
 3.2.2. Hepatitis C virus (HCV) antigen and antibody combined tests intended for the detection of HCV antigen and HCV antibody shall meet the requirements for sensitivity and specificity set out in Table 1 and Table 5. HCV seroconversion panels for the evaluation of HCV antigen and antibody combined tests shall start with one or more negative bleeds and comprise panel members from early HCV infection (HCV core antigen and/or HCV RNA positive but anti-HCV negative). HCV antigen and antibody combined tests shall demonstrate enhanced sensitivity in early HCV infection when compared to HCV antibody only tests.
 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, where available, such as a World Health Organisation (WHO) International Standard or reference material calibrated against a WHO International Standard.
 3.3.2a. Qualitative HIV NAT assays intended to be used to detect the presence of HIV in blood, blood components, cells, tissues or organs, or in any of their derivatives, in order to assess their suitability for transfusion, transplantation or cell administration shall be designed to detect both HIV-1 and HIV-2.
 3.3.2b. Qualitative HIV NAT assays, other than virus typing assays, shall be designed to compensate for the potential failure of a HIV-1 NAT target region, e.g. by using two independent target regions.
 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.
 3.7. 
                           CTS for Variant Creutzfeldt-Jakob disease (vCJD) assays for blood screening
                         

CTS for Variant Creutzfeldt-Jakob disease (vCJD) assays for blood screening are set out in Table 11.



Table 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-1100 HIV-2including 40 non-B-subtypes, all available HIV/1 subtypes shall be represented by at least 3 samples per subtype 300 HTLV-I100 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 400including subtype-consideration 400including evaluation of other HBV-markers

                                    Sero-conversion panels
                                  20 panels10 further panels (at  Approved Body  or manufacturer) 
                                    To be defined when available
                                  20 panels10 further panels (at Approved Body or manufacturer) 20 panels10 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)
                           
                                    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
                                 
SensitivityDetection limitDetection of analytical sensitivity (IU/ml; defined on WHO standards or calibrated reference materials) 
                                    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
                                  
                                    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
                                 


                                             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 infection20 ‘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
                                    
                                    .
                                  
                                    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
                            
                                    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 positive50 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
                                     
                                    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 donations200 clinical samples50 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> 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
                                        
                                          2
                                            
                                          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
                                        
                                          2
                                            
                                          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
                                         


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

                              Acceptance criteria:
                            

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.



Table 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 at1×10
                                             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 at1×10

                                    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 %
