Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe

1/9 Paul-Ehrlich-Institut Bundesamt für Sera und Impfstoffe To all pharmaceutical centres collecting blood or producing blood products S/2-23 600 +49 (0) 6103/77-3115 +49 (0) 6103/77-1268 20 January 2010 Prevention of risks of medicinal products in the graduated plan, Step 1: Subject: Scientific exchange of information to safeguard the quality standard of in vitro diagnostic medical devices (IVD) in the blood donation system and for risk prevention in donor testing Dear Sir or Madam, The Paul-Ehrlich-Institut (PEI) has initiated a graduated plan procedure in order to exchange information with you on how to guarantee quality standards of CE-marked screening tests in blood donation systems. To guarantee the best possible safety in the manufacture of blood components, only tests which meet the appropriate technical requirements shall be authorised for blood donor screening in Germany. Current experience with the CE marking of high risk IVD has shown that some tests which do not meet the state-of-the-art have been granted the CE mark. Therefore, there is reason to assume that the quality standard within the European Union (EU), as laid down in the Common Technical Specifications (CTS) and EU Directive 98/79/EC, is not implemented in a consistent manner. Additionally, experience gained by the PEI has shown that despite the quality assurance applied by the IVD manufacturers, inconsistencies between different batches of a certain product may occur. Another deficiency, in the view of the PEI, is that independent batch testing is not performed in a consistent manner throughout the EU, so that there is no guarantee that only batches of consistent quality are introduced into the market. The Paul-Ehrlich-Institut therefore considers the necessity of taking action in order to prevent test systems from being used which are of insufficient sensitivity or insufficiently consistent quality, as such test systems might not be suitable to

2/9 guarantee the safety standard required in the collection of blood and the preparation of blood components. The PEI intends to prepare a list of those IVDs for the detection of HIV, HBV, and HCV, which meet both the state of the art and the particular requirements for donor screening. In future, only IVD which have been included in this list ( IVD list ) shall be permitted to be used for testing blood and blood components. The aim of this risk prevention measure is to define sufficient sensitivity of the tests, and to achieve sufficient quality for each batch of the IVD. If new, previously unevaluated test systems are intended to be introduced in a donor centre, the PEI can include these test kits in the existing list, if the criteria defined below are fulfilled. These criteria largely conform to the current CTS applied to the state of technology reached since the last re-evaluation in 1998 under the German legislation for medicinal products and continuously updated in accordance with Directive 98/79/EC. The data for the serological tests are based on comparative testing of all screening tests known to the PEI using at least 30 seroconversion panels. Besides, the IVD list contains only those products of which it is known to the PEI that they are subject to independent batch testing. The list of test kits authorised for blood products shall be continuously updated and adapted to the state of technology at regular intervals. The minimum quality standard required shall be laid down using the following criteria: The sensitivity of the serological tests in the early phase of infection shall be controlled using follow-up samples from acutely infected donors (seroconversion panels). The seroconversion panels shall be chosen in such a way that they are suitable to judge differences in the test sensitivity (the follow-up should begin with negative samples, time intervals between samples should be short). Each test kit to be examined shall be compared with a test kit from the IVD list which has already been evaluated. The most sensitive test shall be used as reference (with a value of zero assigned to it). For all other tests, the number of samples not detected as positive shall be determined. Then an index shall be calculated for all panels examined (false negative samples/number of seroconversion panels). Based on this, the delay (given in days) in identifying the respective marker in comparison with the most sensitive test can also be calculated (missed days/seroconversion panel). The sensitivity is considered as sufficient if the sensitivity index corresponds to that of at least one test kit on the IVD list.

3/9 For some markers (e.g. HBsAg, anti-hbc, HIV-1 p24 antigen, HCV RNA, HIV-1 RNA), the analytical sensitivity shall be determined by means of national or international standards. Reliable diagnostic sensitivity of serological tests for samples which were detected and confirmed as positive (serologically confirmed positive samples shall not be missed). Detection of prevalent virus genotypes/variants and detection of major mutants (e.g. HBsAg G145R mutation). To guarantee sufficient consistency of the batch quality pursuant to Directive 98/79/EC, evidence must be provided for the quality of each batch by means of a manufacturer-independent experimental test. The batch control tests performed by the manufacturer (quality control) are deemed insufficient to assure batch to batch consistency. Batch control testing must be performed independently from the manufacturer s testing by the Notified Body or by a testing laboratory contracted by the Notified Body or the manufacturer. Testing by the Notified Body or the contracted testing laboratory must be carried out experimentally (what is known as wettesting ). Reviewing the manufacturer s batch documentation only and just observing of the manufacturer s batch testing procedure by the Notified Body or the contracted testing laboratory (what is known as witness testing ) are deemed insufficient. If the Notified Body does not perform batch testing or has not sub-contracted a laboratory for this purpose, the IVD manufacturer should have the batches tested by a laboratory of his own choice. This laboratory must be accredited to ISO 17025 or ISO 15189. The contract with the testing laboratory must lay down that the manufacturer should not have any influence on the interpretation of the test results, and should receive a certificate of these results. The conditions and modalities of the batch testing performed by the contract laboratory must be described in the contract as accurately as possible (test method, samples used for testing, test criteria applied). The independent batch testing to be submitted must fulfil the following requirements: 1. In the experimental testing at the Notified Body or the sub-contracted testing laboratory, each batch shall be tested for its sensitivity in the form

4/9 of an analytical detection limit (e.g. NAT, Ag tests) or accuracy (e.g. antibody testing) and its precision. 2. The testing laboratory, or the Notified Body involved, should define the criteria which are relevant for the acceptance or the release of the batch tested. 3. The results shall be analysed using a chronological documentation of the analysis results obtained, so that systematic deviations from the batch quality can be identified. 4. The manufacturer s QC documents shall be reviewed in conformity with the general principles of performance evaluation pursuant to paragraph 3.4 of the Annex of the CTS. To be included in the list of permitted screening tests (IVD list), the manufacturer of the respective test kit must provide the PEI with proof that the above described criteria have been fulfilled. For the purpose of inclusion in the list, the PEI shall check once whether the tests performed at the contract laboratory are suitable to provide proof of a consistent batch quality in accordance with the state of science. The blood donation centres must request and archive the positive test certificate from the manufacturer and the external contract laboratory for each batch of a test kit bought and used by them. Pursuant to the Medizinproduktegesetz (German Medical Devices Act) Section 3, 21, in vitro diagnostic medical devices from in-house production are IVDs which have been prepared in health centres, are not marketed, and are not manufactured on an industrial scale. The validation requirements of the PEI are also applicable to these in-house tests (in practice, only NAT tests are affected, see also: http://www.pei.de/cln_180/nn_154580/de/infos/pu/03-zulassunghuman/06-blut/validierung-hcv-nat.html? nnn=true) Table 1 lists the test-specific requirements which must be fulfilled by the screening tests. The criteria described in Table 1 essentially refer to sufficient sensitivity and regular batch control. Test specificity should comply with the CTS and fulfil the criteria laid down in these specifications. Table 2 lists test systems already evaluated by the PEI which meet the above mentioned requirements. This list is preliminary and makes no claim to be exhaustive. The tests are listed in alphabetical order without further rating (ranking,

5/9 for example). The list will be published and regularly updated on the website of the PEI (www.pei.de). Implementing the measure planned would mean that all pharmaceutical companies and centres collecting or producing blood or blood components would be obliged to use exclusively test systems which fulfil the minimum standard required and are subject to regular independent batch testing. In addition, the PEI would have to be notified if establishing a new test is planned so that this test kit might be evaluated and included in the list (if the requirements are met). To help us decide how to implement this measure, please answer the following questions by 28 February 2010 and send them to the PEI: 1) Does your blood donation centre use test kits not included in the enclosed (provisional) list? 2) Do you have any objections against the procedure planned by the Paul- Ehrlich-Institut? 3) Which other questions should be clarified before implementing the measure planned? 4) Which transition period(s) do you consider as appropriate? Yours sincerely PD Dr. Markus Funk Head of Unit S2 Pharmacovigilance II Annex: Table 1: Minimum standards required Table 2a/2b: Provisional lists of the test kits currently evaluated by the PEI-IVD Testing Laboratory

6/9 Table 1: Minimum standards required for blood donor screening tests Parameter Seroconversion sensitivity State of the art: Testing of 30 suitable seroconversion panels and index calculation in relation to a test within the acceptable sensitivity range: N false negative / N panels or N days missed /N panels Diagnostic sensitivity Analytical sensitivity Genotype, subtype, mutant recognition Anti-HIV 1/2 Serologically confirmed positive samples should not be missed Not applicable Identification of HIV 1 subtypes, including group O, Identification of HIV-2 HIV Ag/Ab Anti-HCV HBsAg anti-hbc HCV-RNA HIV-1-RNA HBV-DNA In addition, for anti-hcv wellbalanced detection for anticore and anti-ns3 Seroconversion panel, if available Samples from the preseroconversion phase Sufficient sensitivity in prolonged infection, and in the case of a chronic course, in comparison to an acceptable test. 100% sensitivity for anti-hbc samples, which are at the same time positive for anti- HBs and/or anti-hbe Sufficient sensitivity for weakly positive samples which are anti-hbc alone compared with other anti-hbc tests Examination of the influence of potentially NAT-inhibiting agents/substances HIV-Ag WHO standard (90/636) Not applicable <0.1 IU/ml WHO standard (00/588) <1.40 IU/ml WHO standard (95/522) 95 % LOD in IU/ml (WHO standards) Identification of HIV-1 subtypes Identification of HCV genotypes 1-6 Identification of HBVgenotypes A-F and HBsAg subtypes, as well as important mutants Not applicable Identification of prevalent virus genotypes and subtypes with a sensitivity analogous with the appropriate WHO standards Batch control testing Verification of consistent quality according to the approved design and performance: batch by batch, manufacturer independent and experimental product testing performed by the Notified Body, a sub-contracted laboratory of the Notified Body or a contract laboratory independent of the manufacturer and accredited according to ISO 17025 or ISO 15189 conforming to the following testing criteria: CTS general principle, article 3.4 exact description of the test methodology, samples, and acceptance criteria Sensitivity: analytical detection limit (e.g. NAT, Ag-tests) or accuracy (e.g. in antibody tests) Precision

7/9 The following validation requirements of the PEI are applicable to in-house NAT tests: Evaluation and acceptance by the PEI for the validation submitted, Simultaneous use of run-controls Participation and passing of the PEI ring trials The CE-marked quantitative NAT test systems (off-label use) currently accepted by the PEI have been accepted by the PEI without any exceptions. They are monitored as part of ring trials, and the batches are tested by an accredited test laboratory. Table 2a: Provisional list of the serological test kits evaluated by the PEI-IVD Testing Laboratory which are acceptable for blood screening in Germany (in alphabetical order) Marker In vitro diagnostic device Manufacturer ID no. HIV Ag/Ab ADVIA Centaur HIV Ag/Ab Combo (CHIV) Siemens Diagnostics 06520528 HIV 1/2 Ab ADVIA Centaur HIV1/0/2 Enhanced 200 T Siemens Diagnostics 3718237 HIV 1/2 Ab Anti-HIV 1/2 ELISA Human GmbH 51205 HIV 1/2 Ab Anti-HIV TETRA ELISA Biotest AG 807007/-8 HIV Ag/Ab ARCHITECT HIV Ag/Ab Combo Reagent Kit Abbott GmbH & Co. KG 4J27/-20/-25/-30 HIV 1/2 Ab AxSYM HIV 1/2 go Reagent Pack Abbott GmbH & Co. KG 3D41-22 HIV 1/2 Ab AxSYM HIV Ag/Ab Combo Reagent Pack Abbott GmbH & Co. KG 2G83-20 HIV 1/2 Ab Dia-HIV 1/2 JSC Diaproph-Med T-0106 HIV Ag/Ab DS-EIA-HIV-AG/AB-Screen RPC Diagnostic Systems I-1652/-4/-5 HIV Ag/Ab Elecsys HIV combi Roche Diagnostics 04860446 HIV 1/2 Ab Enzygnost Anti-HIV 1/2 Plus Siemens Diagnostics OQFK HIV Ag/Ab Enzygnost HIV Integral II Siemens Diagnostics OPAA HIV 1/2 Ab IMx HIV-1/HIV-2 III Plus Reagent Pack Abbott GmbH & Co. KG 8C98-20 HIV Ag/Ab Murex HIV Ag/Ab Combination Abbott/Murex Biotech Ltd. GE41/42 HIV 1/2 Ab Murex HIV-1.2.0 Abbott/Murex Biotech Ltd. GE94/95 (9E25) HIV Ag/Ab PRISM HIV Ag/Ab Combo Assay Kit Abbott GmbH & Co. KG 7G46-48 HIV 1/2 Ab PRISM HIV O Plus Reagent Kit Abbott GmbH & Co. KG 3D34-48

8/9 Marker In vitro diagnostic device Manufacturer ID no. HCV Ab ADVIA Centaur HCV ReadyPack Siemens Diagnostics 03438099 HCV Ab anti-hcv ELISA Human GmbH 51250 HCV Ab ARCHITECT Anti-HCV Reagent Kit Abbott GmbH & Co. KG 6C37-20/-25/-30 HCV Ab AxSYM HCV 3.0 Reagent Pack Abbott GmbH & Co. KG 3B44-20 HCV Ab Elecsys Anti-HCV Roche Diagnostics 03290352 HCV Ab IMx HCV version 3.0 Reagent Pack Abbott GmbH & Co. KG 5C71-20 HCV Ab Murex anti-hcv Version 4.0 HCV Ag/Ab HCV Ab Murex HCV Ag/Ab Combination Ortho HCV 3.0 ELISA Test System with Enhanced SAVe Murex Biotech South Africa Murex Biotech South Africa Ortho-Clinical Diagnostics VK47/48 4J24-01/-03/-04 930800/-20 HCV Ab PRISM HCV Assay Kit Abbott GmbH & Co. KG 6A52-48 HCV Ag ARCHITECT HCV Ag Abbott Japan Co., Ltd. 6L47-25 Marker In vitro diagnostic device Manufacturer ID no. HBsAg ARCHITECT HBsAg Reagent Kit Abbott GmbH & Co. KG 6C36/-22/-27/-32 HBsAg ARCHITECT HBsAg Qualitative Reagent Kit Abbott GmbH & Co. KG 1P97-25/-30/-35 HBsAg AxSYM HBsAg (V2) Reagent Pack Abbott GmbH & Co. KG 7A40-22 HBsAg DS-EIA-HBsAg-0,01 RPC Diagnostic Systems B-1256 HBsAg Elecsys HBsAg II Roche Diagnostics 04687787 HBsAg Enzygnost HBsAg 6.0 Siemens Diagnostics OPFM HBsAg Immulite 2000 (2500) HBsAg Siemens Diagnostics L2KHB2, L2KHB6 HBsAg Immulite HBsAg Siemens Diagnostics LKHB1, LKHB5 HBsAg IMx HBsAg (V2) Reagent Pack Abbott GmbH & Co. KG 2228-22 HBsAg Murex HBsAg Version 3 Abbott/Murex Biotech Ltd. GE34/36 9F80 HBsAg PRISM HBsAg Assay Kit Abbott GmbH & Co. KG 3A47-48

9/9 Marker In vitro diagnostic device Manufacturer ID no. Anti-HBc ADVIA Centaur HBc Total Siemens Diagnostics 07566733 Anti-HBc ARCHITECT Anti-HBc II Reagent Pack Abbott GmbH & Co. KG 8L44-25/-30/-35 Anti-HBc AxSYM Core Reagent Pack Abbott GmbH & Co. KG 7A41-20 Anti-HBc bioelisa anti-hbc Biokit S. A. 3000-1102 Anti-HBc Elecsys Anti-HBc Roche Diagnostics 11820559 Anti-HBc Enzygnost Anti-HBc monoclonal Siemens Diagnostics OUWE Anti-HBc Immulite 2000 (2500) Anti-HBc Siemens Diagnostics L2KHC2, L2KHC6 Anti-HBc Immulite Anti-HBc Siemens Diagnostics LKHC1, LKHC5 Anti-HBc IMx Core Reagent Pack Abbott GmbH & Co. KG 2259-20 Anti-HBc Murex Anti-HBc (total) Anti-HBc Ortho HBc ELISA Test System 3 Abbott/Murex Biotech, Ltd. Ortho-Clinical Diagnostics GE65 6902015 Anti-HBc PRISM HBcore Abbott GmbH & Co. KG 1A77-48 Table 2b: Provisional list of the NAT tests evaluated by PEI-IVD Testing Laboratory which are acceptable for blood screening in Germany (in alphabetical order) Product name Manufacturer ID-No. Marker COBAS AmpliScreen HCV Test, v2.0 COBAS AmpliScreen HIV-1 Test, v1.5 COBAS AmpliScreen HBV Test cobas TaqScreen MPX Test Roche Molecular Systems, Inc. Roche Molecular Systems, Inc. Roche Molecular Systems, Inc. Roche Molecular Systems, Inc. 03577074190 HCV-RNA 03577066190 HIV-1-RNA 21118323123 HBV-DNA 04584244190 HCV-RNA, HIV-1- RNA, HIV-2-RNA, HBV-DNA Procleix Ultrio Assay Gen-Probe Inc. 301118/301117 HCV-RNA, HIV-1- RNA, HBV-DNA Procleix Ultrio Plus Assay Gen-Probe Inc. 302573/ 302574 HCV-RNA, HIV-1- RNA, HBV-DNA Virus Screening PCR Kit GFE Blut mbh 001-24-10 HCV-RNA, HIV-1- RNA, HIV-2-RNA, HBV-DNA * The maximum number of donations for the test pool is referred to the detection limits for HCV- and HIV-1 RNA in a single donation (see http://www.pei.de/cln_180/nn_154580/de/infos/pu/03-zulassung-human/06-blut/validierunghcvnat. html? nnn=true)