to be notified: all parties involved in the graduated plan procedure. Annexes

Transcription

1 Paul-Ehrlich-Institut Postfach Langen, Germany To all marketing authorisation holders of cellular blood preparations and therapeutic single plasmas as well as authorisation holders of stem cells for haematopoietic reconstitution PD Dr. med. M. Funk Telefon / Phone: 0+49 (0) Fax: +49 (0) Markus.Funk@pei.de to be notified: all parties involved in the graduated plan procedure Annexes Annex 1: Requirements for determining the sensitivity and specificity of screening tests used in the manufacture of blood and stem cell products for donor screening for HIV-1/2, HBV and HCV Annex 2: Requirements for the batch control testing of the screening kits listed in Annex 1 Annex 3: Requirements for determining the seroconversion sensitivity of HIV-1/2, HBV and HCV tests used as screening tests in the manufacture of blood and stem cell products Subject: Hearing for a provision pursuant to Section 28 (3c) AMG (Arzneimittelgesetz, German Medicinal Products Act) to guarantee an appropriate quality for risk prevention designed to assure the safety of blood components for transfusion and stem cell preparations for haematopoietic reconstitution tested using in vitro diagnostic devices (IVDs) for donor screening for HIV, HBV, and HCV Dear Sir or Madam, After entering into an exchange of information with marketing authorisation holders of blood components within the framework of a graduated plan, Level I on 20 January 2010, the Paul-Ehrlich- Institut now intends to order the following action to be taken: 1. In the manufacture of cellular blood components, therapeutic single plasmas and stem cell preparations for haematopoietic reconstitution, only those in vitro diagnostic devices (IVDs) may be used for testing donors for the infection markers of HIV, HBV, and HCV (so-called donor screening), for which proof has been provided that they fulfil the requirements listed in Annex 1 of this letter by submitting the appropriate proof, and for which batch release has been performed pursuant to Annex All IVDs used in the manufacture of cellular blood components, therapeutic single plasmas, and stem cell preparations for haematopoietic reconstitutions to screen donors for infection markers must be reported to the Paul-Ehrlich-Institut by the pharmaceutical manufacturer under 3. Screening tests for HIV, HBV, and HCV other than those accepted by the Paul-Ehrlich-Institut and stored in the database for donor screening may be used in the manufacture of cellular blood components, therapeutic single plasmas, and stem cell preparations for haematopoietic reconstitution only after prior agreement by the Paul-Ehrlich-Institut.

2 4. Documents on the above mentioned screening kits currently used must be submitted to the Paul- Ehrlich-Institut by 30 June 2012, which prove that the requirements for the determination of the sensitivity and specificity (Annex 1) as well as the batch testing procedure (Annex 2) have been fulfilled. After a favourable completion of the assessment, the tests will be stored in the database for "donor screening", and the applicants shall receive a written confirmation that the above mentioned conditions have been fulfilled. Justification The action ordered is based on Section 28 (3c) of the AMG. According to this section, the Paul- Ehrlich-Institut can order, among other things, that in testing the starting material of biological medicinal products, specific requirements must be fulfilled if this is necessary to guarantee the appropriate quality or for preventing risks. This measure is designed to assure that a high safety standard in manufacturing blood components and stem cell products is assured. Screening systems for the detection of infections with HIV, HBV and HCV must have a high sensitivity level in conformity with the current state of science and technology. In addition, consistent quality for each IVD batch must be assured. To assure this consistence of the batches used, it is necessary to perform independent and conforming batch testing. The Paul-Ehrlich-Institut considers this measure as required for the purpose of risk prevention, since it assures that the IVDs used will meet the specific requirements for screening test in the manufacture of blood and stem cell preparations for donor testing. Annex 1 states the requirements which screening tests designed for use in the manufacture of cellular blood components, therapeutic single plasmas and stem cell preparations for haematopoietic reconstitution (short: single blood and stem cell preparations) must fulfil. The criteria listed agree with the current "Common Technical Specifications" (CTS) of Directive 98/79/EC (COMMISSION DECISION of 27 November 2009 (9009/886/EC)). The Annex contains requirements which specify how the current state of technology is defined, and how the adherence to the standard must be assured. Annex 2 describes the requirements for testing the batches in the screening tests listed in Annex 1. For NAT screening tests manufactured in-house, i.e. in vitro diagnostic devices manufactured inhouse pursuant to Section 3 (21) Medical Devices Act (Medizinproduktegesetz, MPG) or IVDs manufactured in laboratories of health care facilities not marketed and not manufactured on a large scale, as well as CE marked quantitative NAT testing systems ("off-label use") used for donor screening, the validation requirements of the Paul-Ehrlich-Institut ( zulassung-human/06-blut/validierung-hcv-nat.html) still apply. All in-house NAT tests and/or CElabelled quantitative NAT testing systems currently used for donor screening have been reported, tested and accepted by the Paul-Ehrlich-Institut. They are monitored within collaborative studies. The batches of the above mentioned CE-labelled quantitative NAT test systems are tested by an accredited testing laboratory. The screening tests pursuant to number 2 of the notification must be reported, as ordered, online via an application on the internet ("Donor screening" database). The data are transmitted in encrypted form using the link and cannot be accessed by third parties. An application must be made by the person authorised for communication with the Paul-Ehrlich-Institut by using the address transfusionsmedizin@pei.de to obtain access to the "Donor screening" database. For this purpose, the person authorised for communication with the Paul-Ehrlich-Institut must indicate the full name, phone number with the extension and the address in addition to the name of the pharmaceutical company. Page 2/8

3 A manual is available for the donor screening databank. It can be downloaded on the homepage of the Paul-Ehrlich-Institut from this web address: If a facility intends to use tests other than those stored in the Donor screening database, a variation notification must be submitted stating the full description of the test together with the article number, and the name of the manufacturer of the test must be entered into the database by the person authorized (see above). In addition to the variation notification, documents must be submitted in conformity with the requirements contained in the annexes as described above. For NAT tests an additional written variation notification must be submitted taking into account the Requirements for the validation and/or the routine operation of NAT for the identification of virus nucleic acids in blood donations ( The screening tests stored in the database are continuously verified by the Paul-Ehrlich-Institut in conformity with the state of technology. The method used for this and the definition of the current state of technology for the individual testing parameters are described in Annex 3. If a test no longer fulfils the criteria defined and has to be removed from the database of accepted tests, the graduated plan representatives and other parties involved in the graduated plan are informed that the non-fulfilment of the condition pursuant to Section 30 (2) No 2 AMG which has thus occurred will lead to a withdrawal of the marketing authorisation if the test involved is not replaced by a different one which is suitable to fulfil the requirements in conformity with this provision. This is to give you the opportunity to make a comment on the action to be taken by Yours sincerely Dr. med. M. Funk Head of Unit S2 Pharmacovigilance II, Paul-Ehrlich-Institut Page 3/8

4 Annex 1: Requirements for the determination of the sensitivity of screening tests used in the manufacture of blood and stem cell preparations for donor testing Parameters Seroconversion sensitivity Diagnostic sensitivity Analytical sensitivity Anti-HIV-1/2 Ab Not applicable HIV Ag/Ab Anti-HCV Ab and HCV Ag/Ab HBsAg For all HIV, HCV and HBsAg screening tests, the sensitivity must be determined during the early infection phase (seroconversion) by testing 30 seroconversion panels with short intervals between the blood collections in the range in which the seroconversion takes place in comparison with a CE marked test with acceptable performance (cf. Annex 3). The sensitivity determined must conform to the state of the art determined by the Paul-Ehrlich-Institut (cf. Annex 3). In the case of anti-hcv Ab and HCV Ag/Ab tests, a welladjusted recognition of anti-core and anti-ns3 must also exist. The diagnostic sensitivity must be tested on 400 positive samples, and for HIV also on 100 anti-hiv-2 Ab positive samples at different stages of the disease and taking into account the pathogen variability pursuant to CTS Table 1. The test must show a positive result for all samples confirmed positive in a Western Blot or Line Assay. For HBsAg, the test should show an overall performance in conformity with the state of the art. HIV-1 p24 antigen 2 IE/ml referred to the WHO Standard (90/636) Not applicable < 0.1 IU/ml referred to WHO Standard (00/588) Genotype, subtype-, mutant recognition Sensitivity for HIV-1 subtype group M comparable with subtype B For HIV-1 group O and for HIV-2, the test must be positive at least for samples serologically confirmed as positive. Sensitivity for HIV-1 p24 Ag of subtype group M comparable with subtype B, Reactivity for HIV-1 group O must be present Proof must be provided for detection of HIV-2 Recognition of HCV genotypes 1-6 Sensitivity for HBV-genotypes and/or HBsAg subtypes must be comparable with genotype A Recognition of known HBsAg mutants. Page 4/8

5 Parameters Seroconversion sensitivity Diagnostic sensitivity Analytical sensitivity Anti-HBc Ab HCV-RNA HIV-1-RNA HBV-DNA Testing of 10 seroconversion panels minimum with an Anti-HBc Ab course. The sensitivity determined must meet the requirements of the state of the art determined by the Paul-Ehrlich-Institut (cf. column 4, analytical sensitivity). The diagnostic sensitivity must be tested on 400 positive samples pursuant to CTS Table 1. All samples which are simultaneously positive for anti-hbe Ab and/or anti- HBs Ab, must be recognised (100% sensitivity). Isolated anti-hbc Ab positive samples must be examined comparatively for clarification using at least 2 additional anti-hbc Ab tests. Samples from the pre-seroconversion Samples from the routine in comparison phase analogous with the requirements with another CE marked method. No laid down in the CTS for qualitative virus genome positive samples with a NAT tests (10 seroconversion panels, concentration above the declared each beginning with a negative sample sensitivity limit should be missed. and intervals < 7 days between the Testing of the influence of potentially collections) NAT inhibiting agents/substances. Regular identification of IU HCV- RNA/ml or 10,000 IU HIV1-RNA in a single donation. For the calculation of this sensitivity, triple the 95% LOD is used as a basis. < 1.40 IU/ml referred to the WHO standard (95/522) To be determined as 95 % LOD in IU/ml (WHO Standards) Genotype, subtype-, mutant recognition Not applicable Recognition of prevalent virus genotypes and subtypes with a sensitivity analogues with the appropriate WHO standards * With regard to the specific requirements in the manufacture of blood and stem cell preparations, the Paul-Ehrlich-Institut continuously determines the state of the art on the basis of comparative studies of available testing systems and develops new testing criteria. These criteria are published. Ag = antigen; Ab = antibody, CTS = Common Technical Specifications Page 5/8

6 Annex 2. Requirements for the batch testing of the screening tests listed in Annex 1 Requirements Ensuring a consistent quality by a batch-wise, manufacturer-independent, and experimental Documents to be submitted Exact description of test methods, samples to be tested and testing criteria Sensitivity: Analytical detection limit (e.g. NAT, Ag tests) or Accuracy (e.g. in antibody tests) Precision product testing with the involvement of a (contract) laboratory of the Notified Body or an ISO 17025/ISO accredited or recognized contract laboratory of the manufacturer in conformity with the following testing criteria: CTS, general principle 3.4 Page 6/8

7 Annex 3: Requirements for the determination of the seroconversion sensitivity of HIV-1/2, HCV and HBV tests used as screening tests in the manufacture of blood and stem cell preparations. The sensitivity of tests used for the screening of blood donations used in the manufacture of blood and stem cell preparations must be determined using a minimum of 30 suitable seroconversion panels. The minimum sensitivity must conform to the state of the art as laid down by the Paul-Ehrlich-Institut. The panels must be selected pursuant to the requirements of the CTS (Annex 1), and in addition the panels must fulfil the CTS requirements , for HIV also the CTS requirements Minimum sensitivity of HIV tests (Anti-HIV-1/2 and HIV-Ag/Ab combination tests) with seroconversions: Examples of suitable HIV seroconversion panels which can be used to determine the minimum sensitivity: SeraCare/BBI PRB927, PRB929, PRB930, PRB932, PRB939 Ext, PRB952, PRB965, PRB966 as well as ZeptoMetrix 6240, 6243, 6244, 6245, 6246, 6247, 6248, 9022, 9010, 9012, 9014, 9017, 9018, 9034, 9033, 9021, 9020, 9023, 9025, 9032, 9030, and Altogether, these panels contain 341 single collections. With the exception of Panel PRB930, all panels begin with at least one HIV-1 p24 antigen and HIV antibody negative blood collection. 29 panels contain HIV-1 p24 and/or antibody containing samples and are thus suitable for both HIV Ag/Ab combination tests and Anti-HIV- 1/2 tests. Solely Panel 9025 does not contain any antibody-reactive samples. For the panels listed, up to 134 samples can be determined as reactive for HIV-1 p24 antigen and/or HIV antibodies with very sensitive HIV- Ag/Ab tests. Sensitive anti-hiv-1/2 test can recognize up to 89 single collections. An Anti-HIV-1/2 test which would still be acceptable would have to recognise at least 65 samples as reactive in the case of this panel selection (this is equivalent to 49% of the samples detectable with HIV Ag/Ab tests or 73% of the anti-hiv-1/2 Ab positive samples). The requirement for the analytical sensitivity of HIV Ag/Ab combination tests for HIV-1 p24 antigen is described in Annex Minimum sensitivity of HBsAg tests with seroconversions: Examples of suitable HBV seroconversion courses SeraCare/BBI PHM903, PHM911, PHM914, PHM916, PHM925, PHM926, PHM927, PHM928, PHM929, PHM930, PHM931, PHM932, PHM934, ZeptoMetrix 6271, 6272, 6273, 6274, 6275, 6279, 11000, 11001, 11002, 11003, 11006, 11007, 11008, 11009, 11011, 11012, and Altogether, these panels contain 331 single collections. With sensitive HBsAg tests, 184 samples can be determined as reactive with these panels. A test which would still be acceptable would have to recognise at least 107 samples (58%) as positive in the case of this panel selection. The requirement for the analytical sensitivity of HBsAg tests is described in Annex Minimum sensitivity of Anti-HCV Ab tests: For the determination of the minimum sensitivity of Anti-HCV Ab tests, seroconversion panels must be selected which show different antibody patterns (e.g. anti-ns3 first, anti-core first and mixed antibody profiles). Panels which show exclusively antibodies against NS3 in the early phase of infection should be present in a representative quantity. Suitable HCV seroconversion panels include: HCV panels which show only antibodies against Core: SeraCare/ BBI PHV#: 909, 912, 913, 914, 918, ZeptoMetrix 6216, donor HCV panels which show only antibodies against NS3: Page 7/8

8 SeraCare/ BBI PHV#: 904, 905, 915; ZeptoMetrix 6212, 6224, 6225, 6228, 9047, donor 65345, donor HCV panels which show mixed antibody profiles in the seroconversion phase: SeraCare/ BBI PHV#: 906 (NS3/NS4), 907 (Core/NS3), 908 (NS3/NS4), 910 (Core/NS3/NS4), 916 (NS3/NS4), 919 (Core/NS3), 920 (Core/NS3); ZeptoMetrix 6211 (NS3/NS4), 6213 (NS3/Core), 6214 (NS3/NS4), 6222 (NS3/Core), 6226 (NS3/NS4/Core), 6227 (NS3/Core/NS5/NS4), 6229 (NS3/Core/NS5), 9045 (donor 64150; Core/NS4), 9054 (donor 66626; Core/NS3), 9055 (donor 66732; Core/NS3/NS4), and Donor (Core/NS3/NS4). The antibody profiles of the seroconversion panels were determined by means of CHIRON RIBA HCV 3.0 SIA. The order of the antigens indicated in brackets reflects the order of the antibodies which occurred in the course of the seroconversion. Altogether, all HCV panels contain 337 single collections. With very sensitive Anti-HCV-Ab tests, 128 samples (100%) maximum can be determined as reactive with this panel. An Anti-HCV-Ab test which would still be acceptable would have to recognise at least 90 samples (70%) as positive in the case of this panel selection. Since there are Anti-HCV tests which exhibit a weakness in recognising samples and seroconversions which only develop antibodies against NS3 in the course, these "NS3 panels" are evaluated again separately. Altogether, the so-called NS3 panels contain 87 single collections of which 37 (100%) can be recognised as positive using the most sensitive Anti-HCV tests. A test acceptable for blood donation should recognise at least 26 (70%) of the anit-ns3 positive samples as reactive. The definition of analytical sensitivity of HCV Ag/Ab tests is currently not possible. Page 8/8