1. CE MARKING OF IVDDs - the NIBSC perspective Morag Ferguson Division of Virology

2. Issues to be considered  The IVD directive  IVDDs  Why NIBSC has CE marked some of its working standards  Process of CE marking

3. The IVD Directive  This is a European Directive aimed at creating a single market and reducing technical barriers to trade for medical devices.  The IVD directive came into force on 7 June 2000

4. The IVD Directive - key dates  7 December 2003 End of the transitional period - batches of non-CE products cannot be placed on the market. However, batches that are already in the distribution chain on this date can continue to be supplied to the end user  7 December 2005 Full implementation – all IVDs supplied to the end user must be CE marked

5. Key Elements of the IVD Directive  Classification of IVDs  Essential requirements  Technical Documentation  Conformity assessment procedures  Written Declaration of Conformity

6. What is an IVDD? An in vitro diagnostic device is defined as a reagent, product, calibrator, control material, kit or instrument, apparatus or equipment, specimen receptacles that is used in vitro for the examination of specimens for diagnostic purposes. Specimens would include: tissue, blood, fluid. In addition, devices an iVD needs to function as intended are iVDs, including software.

7. Exclusions  Internationally certified ivDs eg WHO International Standards.  In-house use ie ivDs manufactured and used only within the same health institution and on the premises of their manufacture or used on premises in the immediate vicinity without being transferred to another legal entity.

8. At NIBSC we considered whether our serology and NAT working standards fall within the IVD Directive Questions we asked in order to decide whether we are producing an IVD or not –  How are the standards used?  Does the inclusion of the working standard affect the outcome of the test on the patient/donor?

9. Use of NIBSC serology working standards in the UK BTS  Working standards for HBsAg, anti-HCV, anti-HIV 1 +2 and anti-HTLV 1 serve as the UK Working Standards cited in Annex 4, General Specifications for Laboratory Test Procedures, of the Guidelines for the Blood Transfusion Services in the United Kingdom, 6 th Edition 2002 (The ‘Red Book’) and have done so since their establishment in the early to mid 1990s.  If these working standards are not detected, the test run is repeated.

10. Does the inclusion of the working standard affect the outcome of the test on the patient/donor?  The result of the test on the working standard is not impacting on declaring a donor positive as such samples will go through additional confirmatory testing, but it is validating them as being negative/non-reactive.  We therefore decided that the working standards produced and supplied by NIBSC to the UK BTS are IVDs and in accordance with the IVD Directive have to be CE marked.

11. NIBSC standards which have already been CE marked  HBsAg working standard and monitor sample  Anti-HCV working standard  Anti-HIV 1 working standard  Anti- HIV 2 working standard

12. Are the NAT working standards also IVDs? Possible uses of NAT working standards  For research purposes only  By plasma fractionators to standardise assays on plasma pools  By diagnostic or laboratories screening blood donors to validate the sensitivity of their assays

13. Use of NIBSC HCV NAT working standard by the UK BTS  UK BTS laboratories include a dilution of the NIBSC HCV RNA working standard in every test run  The sensitivity of each test run is validated through the detection of this dilution of the NIBSC working standard  This is in addition to validating their assays on the basis of the results of the kit manufacturer’s controls

14. Is this different from the use of NAT working standards elsewhere in Europe?  Council of Europe guide to the preparation, use and quality assurance of blood components (10th edition, 2004) and the UK Guidelines for Blood Transfusion (The ‘Red Book’) require  …for the release of blood components, HCV RNA NAT assays should detect a run control of 5000IU/ml HCV RNA per donation ie that in a mini-pool of 100 samples you should detect 50IU/ml.

15. NAT Working standards which NIBSC is in the process of CE marking  HCV RNA  HIV RNA  HBV DNA - to be considered if use within the next 9-12 months increases  Probably not HAV RNA and B19 DNA which are not used by the UK BTS

16. Conformity Assessment  There are various routes that manufacturers can take to demonstrate compliance with the Directive  Dependent on class of device – self certification unless devices are in high risk categories (Annex II Lists A and list B)  Combination of quality systems and product evaluation  Essentially if the production and characterisation meets ISO 13485:2003, they meet the directive.

17. List of devices referred to in Annex II list A Reagents and reagent products, including related calibrators and control materials  for determining blood groups - ABO system, rhesus (C, c, D, E, e) anti-Kell,  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 and D

18. The Directive Requirements For Annex II List A devices  A Notified Body must audit the quality system to determine whether it meets the requirements referred to in the relevant quality assurance annex of the Directive and the design certification  This would include an audit of the full quality assurance system and review of the design dossier  Once the Notified Body has issued a certificate of conformity the CE mark can be affixed on the product

19. Notified Body  Third party certification body, system registrar, testing agency  Designated to conduct conformity assessments  They are required to meet the requirements of the Directive (audited by competent authorities

20. Common Technical Specifications (CTSs)  The IVD Directive requires that devices must be designed and manufactured in conformity with the essential requirements.  In order to assist manufacturers meet the essential requirements and ensure consistency of the review process across Member States, article 5 of the Directive proposes that CTSs should be prepared.

21. Common Technical Specifications cont’d  The Directive states that CTS will be prepared for the devices in List A of Annex II, and where necessary, the devices in List B of Annex II.  At present there are no Common Technical Specifications for quality control materials or calibrants