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CE MARKING OF IVDDsCE MARKING OF IVDDs- the NIBSC perspective- the NIBSC perspective

Morag FergusonMorag FergusonDivision of VirologyDivision of Virology

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Issues to be consideredIssues to be considered

The IVD directiveThe IVD directive IVDDsIVDDs Why NIBSC has CE marked some of its Why NIBSC has CE marked some of its

working standardsworking standards Process of CE markingProcess of CE marking

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The IVD DirectiveThe IVD Directive

This is a European Directive aimed at This is a European Directive aimed at creating a single market and reducing creating a single market and reducing technical barriers to trade for medical technical barriers to trade for medical devices.devices.

The IVD directive came into force on 7 The IVD directive came into force on 7 June 2000June 2000

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The IVD Directive - key dates

7 December 2003 7 December 2003 End of the transitional period - batches End of the transitional period - batches of non-CE products cannot be placed on of non-CE products cannot be placed on the market. However, batches that are the market. However, batches that are already in the distribution chain on this already in the distribution chain on this date can continue to be supplied to the date can continue to be supplied to the end user end user

7 December 20057 December 2005Full implementation – all IVDs supplied Full implementation – all IVDs supplied to the end user must be CE markedto the end user must be CE marked

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Key Elements of the IVD Key Elements of the IVD DirectiveDirective

Classification of IVDsClassification of IVDs Essential requirementsEssential requirements Technical DocumentationTechnical Documentation Conformity assessment proceduresConformity assessment procedures Written Declaration of ConformityWritten Declaration of Conformity

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What is an IVDD?What is an IVDD?

An An in vitroin vitro diagnostic device is defined diagnostic device is defined as a reagent, product, calibrator, as a reagent, product, calibrator, control control materialmaterial, kit or instrument, apparatus or , kit or instrument, apparatus or equipment, specimen receptacles equipment, specimen receptacles that that is used is used in vitroin vitro for the examination of for the examination of specimens for diagnostic purposes. specimens for diagnostic purposes.

Specimens would include: tissue, blood, Specimens would include: tissue, blood, fluid. fluid.

In addition, dIn addition, devices an iVD needs to evices an iVD needs to function as intended are iVDs, including function as intended are iVDs, including software.software.

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ExclusionsExclusions

Internationally certified ivDs Internationally certified ivDs

eg WHO International Standards.eg WHO International Standards. In-house use In-house use

ie ivDs manufactured and used only ie ivDs manufactured and used only within the same health institution and within the same health institution and onon the premises of their manufacture or the premises of their manufacture or used on premises in the immediate used on premises in the immediate vicinity without being transferred to vicinity without being transferred to another legal entity.another legal entity.

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At NIBSC we considered whether our At NIBSC we considered whether our serology and NAT working standards fall serology and NAT working standards fall within the IVD Directivewithin the IVD DirectiveQuestions we asked in order to decide Questions we asked in order to decide whether we are producing an IVD or not whether we are producing an IVD or not – –

How are the standards used?How are the standards used? Does the inclusion of the working Does the inclusion of the working

standard affect the outcome of the test standard affect the outcome of the test on the patient/donor?on the patient/donor?

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Use of NIBSC serology Use of NIBSC serology working standards in the UK working standards in the UK

BTSBTS Working standards for HBsAg, anti-HCV, Working standards for HBsAg, anti-HCV,

anti-HIV 1 +2 and anti-HTLV 1 serve as the anti-HIV 1 +2 and anti-HTLV 1 serve as the UK Working Standards cited in Annex 4, UK Working Standards cited in Annex 4, General Specifications for Laboratory Test General Specifications for Laboratory Test Procedures, of the Guidelines for the Blood Procedures, of the Guidelines for the Blood Transfusion Services in the United Transfusion Services in the United Kingdom, 6Kingdom, 6thth Edition 2002 (The ‘Red Book’) Edition 2002 (The ‘Red Book’) and have done so since their establishment and have done so since their establishment in the early to mid 1990s. in the early to mid 1990s.

If these working standards are not If these working standards are not detected, the test run is repeated.detected, the test run is repeated.

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Does the inclusion of the Does the inclusion of the working standard affect the working standard affect the outcome of the test on the outcome of the test on the

patient/donor?patient/donor? The result of the test on the working standard The result of the test on the working standard

is not impacting on declaring a donor positive is not impacting on declaring a donor positive as such samples will go through additional as such samples will go through additional confirmatory testing, but it is validating them confirmatory testing, but it is validating them as being negative/non-reactive.as being negative/non-reactive.

We therefore decided that the working We therefore decided that the working standards produced and supplied by NIBSC to standards produced and supplied by NIBSC to the UK BTS are IVDs and in accordance with the UK BTS are IVDs and in accordance with the IVD Directive have to be CE marked.the IVD Directive have to be CE marked.

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NIBSC standards which have NIBSC standards which have already been CE markedalready been CE marked

HBsAg working standard and monitor HBsAg working standard and monitor samplesample

Anti-HCV working standardAnti-HCV working standard Anti-HIV 1 working standardAnti-HIV 1 working standard Anti- HIV 2 working standardAnti- HIV 2 working standard

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Are the NAT working Are the NAT working standards also IVDs?standards also IVDs?

Possible uses of NAT working standardsPossible uses of NAT working standards For research purposes onlyFor research purposes only By plasma fractionators to standardise By plasma fractionators to standardise

assays on plasma poolsassays on plasma pools By diagnostic or laboratories By diagnostic or laboratories

screening blood donors to validate screening blood donors to validate the sensitivity of their assaysthe sensitivity of their assays

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Use of NIBSC HCV NAT Use of NIBSC HCV NAT working standard by the UK working standard by the UK

BTSBTS UK BTS laboratories include a dilution of UK BTS laboratories include a dilution of

the NIBSC HCV RNA working standard in the NIBSC HCV RNA working standard in every test runevery test run

The sensitivity of each test run is The sensitivity of each test run is validated through the detection of this validated through the detection of this dilution of the NIBSC working standarddilution of the NIBSC working standard

This is in addition to validating their This is in addition to validating their assays on the basis of the results of the assays on the basis of the results of the kit manufacturer’s controlskit manufacturer’s controls

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Is this different from the use Is this different from the use of NAT working standards of NAT working standards

elsewhere in Europe?elsewhere in Europe? Council of Europe guide to the Council of Europe guide to the

preparation, use and quality assurance preparation, use and quality assurance of blood components (10th edition, of blood components (10th edition, 2004) and the UK Guidelines for Blood 2004) and the UK Guidelines for Blood Transfusion (The ‘Red Book’) requireTransfusion (The ‘Red Book’) require

……for the release of blood components, for the release of blood components, HCV RNA NAT assays should detect a HCV RNA NAT assays should detect a run control of 5000IU/ml HCV RNA per run control of 5000IU/ml HCV RNA per donation ie that in a mini-pool of 100 donation ie that in a mini-pool of 100 samples you should detect 50IU/ml.samples you should detect 50IU/ml.

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NAT Working standards NAT Working standards which NIBSC is in the which NIBSC is in the process of CE markingprocess of CE marking

HCV RNAHCV RNA HIV RNAHIV RNA

HBV DNA - to be considered if use HBV DNA - to be considered if use within the next 9-12 months increaseswithin the next 9-12 months increases

Probably not HAV RNA and B19 DNA Probably not HAV RNA and B19 DNA which are not used by the UK BTSwhich are not used by the UK BTS

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Conformity AssessmentConformity Assessment

There are various routes that There are various routes that manufacturers can take to demonstrate manufacturers can take to demonstrate compliance with the Directivecompliance with the Directive

Dependent on class of device – self Dependent on class of device – self certification unless devices are in high risk certification unless devices are in high risk categories (Annex II Lists A and list B)categories (Annex II Lists A and list B)

Combination of quality systems and Combination of quality systems and product evaluationproduct evaluation

Essentially if the production and Essentially if the production and characterisation meets ISO 13485:characterisation meets ISO 13485:20032003, , they meet the directive.they meet the directive.

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List of devices referred to in List of devices referred to in Annex II list AAnnex II list A

Reagents and reagent products, Reagents and reagent products, including related calibrators and control including related calibrators and control materialsmaterials

for determining blood groups - ABO for determining blood groups - ABO system, rhesus (C, c, D, E, e) anti-Kell,system, rhesus (C, c, D, E, e) anti-Kell,

for the detection, confirmation and for the detection, confirmation and quantification in human specimens of quantification in human specimens of markers of HIV infection (HIV 1 and 2), markers of HIV infection (HIV 1 and 2), HTLV I and II, and hepatitis B, C and DHTLV I and II, and hepatitis B, C and D

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The Directive Requirements The Directive Requirements For Annex II List A devicesFor Annex II List A devices

A Notified Body must audit the quality A Notified Body must audit the quality system to determine whether it meets the system to determine whether it meets the requirements referred to in the relevant requirements referred to in the relevant quality assurance annex of the Directive quality assurance annex of the Directive and the design certificationand the design certification

This would include an audit of the full This would include an audit of the full quality assurance system and review of the quality assurance system and review of the design dossierdesign dossier

Once the Notified Body has issued a Once the Notified Body has issued a certificate of conformity the CE mark can certificate of conformity the CE mark can be affixed on the productbe affixed on the product

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Notified BodyNotified Body

Third party certification body, system Third party certification body, system registrar, testing agencyregistrar, testing agency

Designated to conduct conformity Designated to conduct conformity assessmentsassessments

They are required to meet the They are required to meet the requirements of the Directive (audited requirements of the Directive (audited by competent authoritiesby competent authorities

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Common Technical Common Technical Specifications (CTSs)Specifications (CTSs)

The IVD Directive requires that devices The IVD Directive requires that devices must be designed and manufactured in must be designed and manufactured in conformity with the essential conformity with the essential requirements. requirements.

In order to assist manufacturers meet In order to assist manufacturers meet the essential requirements and ensure the essential requirements and ensure consistency of the review process across consistency of the review process across Member States, article 5 of the Directive Member States, article 5 of the Directive proposes that CTSs should be prepared.proposes that CTSs should be prepared.

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Common Technical Common Technical Specifications cont’dSpecifications cont’d

The Directive states that CTS will be The Directive states that CTS will be prepared for the devices in List A of prepared for the devices in List A of Annex II, and where necessary, the Annex II, and where necessary, the devices in List B of Annex II. devices in List B of Annex II.

At present there are no Common At present there are no Common Technical Specifications for quality Technical Specifications for quality control materials or calibrantscontrol materials or calibrants