IVD


In-vitro Diagnostic Medical Device

1. IN-VITRO DIAGNOSTICS DIRECTIVE IVD 98/79/EC

1.1. Scope of the In-Vitro Diagnostics Directive

The In-Vitro Directive relates to medical devices for in vitro diagnostics and their accessories. Each medical appliance that is;
   Reagent
   Reactive product
   Calibration material
   Control material
   Kit
   Instrument
   Device
   or a system

that shall be used for the in vitro investigation of specimens originating from the human body (saliva, perspiration, excrements, blood, tissue samples) with the aim to provide information
   Concerning a physiological or pathological state
   Concerning a congenital (inherited) abnormality
   to determine the safety and compatibility with potential recipients
   to monitor therapeutic processes.

In addition, specimen receptacles (containers for in-vitro tested samples) are IVD.

Excluded from the scope of IVD are;
   Products for general laboratory use, provided that the manufacturer did not appointed t     hose products as specialised for In-vitro testing
   Invasive sampling devices for collecting samples for In-vitro diagnostic
   IVD devices produced and used in the same institution, without any transport or sale      to other bodies

:Examples of products which are the IVD medical devices include:
   Specialised spectrophotometric analysers including reference materials for calibration of      them
   Reagent papers for the saliva pH estimation
   Reagent sets for the blood group identification
   Sets for detection of HIV markers in a human samples
   Self-diagnostic device for blood sugar
   Pregnancy test (gravidity)
   Reagent papers for occult blood in feces
   Receptacle for sputum

Examples of products which are not the IVD medical devices include:
   Syringes and needles for the blood collection

1.2. Classification of IVD

The Directive recognises 4 categories of IVDs. The level of regulatory control applied to an IVD is proportional to the degree of risk connected with the IVD application.
  1. General IVDs
  2. IVDs for self testing, i.e. test kits used in a home environment (excluding self test      devices covered by Annex II)
  3. IVDs in Annex II, List B of the Directive, e.g. test kits for rubella, Chlamydia, CMV,      PSA, or the major tissue typing groups
  4. IVDs in Annex II List A of the Directive, e.g. test kits for HIV, hepatitis B, C, or D,       HTLV and the major blood groups.

Lists A and B in the Annex II are in detail described in following articles

List A
    Reagents, related calibrators and control materials, for determining the following blood      groups:
      - ABO system
      - Rhesus (C, c, D, E, e)
      - Anti-Kell,

    Reagents, related calibrators and control materials, 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.

List B
   IVD for determining the following blood groups: anti-Duffy and anti-Kidd
   IVD for determining irregular anti-erythrocytic antibodies
   IVD for the detection of the congenital infections: rubella, toxoplasmosis
   IVD for diagnosing of phenylketonuria
   IVD for determining infections by cytomegalovirus Chlamydia
   IVD for determining the HLA tissue groups: DR, A, B
   IVD for detection tumoral marker PSA
   IVD for evaluating the risk of trisomy 21
   IVD for self-diagnosis of blood sugar content

1.3. Essential requirements and supplier registration:

As in the case of general MD Directive, the IVD manufacturer or his authorised representative in the EU has the obligation to register at the appropriate authority itself together with the products introduced on the market. The manufacturers from third countries must have in EU authorized representative, if they wish to sell products in soever EU Member State.

The safety requirements are specified n the Annex I of the 98/79/EC. Basically, they are derived from the safety requirements of Medical devices directive, but specialized parts related to IVD shall apply (e.g. requirements for self-testing IVD).

1.4. Vigilance procedures

IVD products are as well as other medical devices a subject of vigilance procedure, as the essential requirement of the administrative type. In the frame of vigilance, the manufacturer shall have a procedure for post market surveillance and reporting of adverse incidents. It means that documentation system should be established, where any positive, but especially negative information from users, physicians and another person or bodies are collected and archived. Acquired information shall the manufacturer immediately send to national authority, responsible for the vigilance. As a rule, it is mostly the same authority, which asked the manufacturer for the registration, commonly the Health Ministry.

1.5. Conformity Assessment procedures

The different risk classes of IVD are subject to different processes of conformity assessment, as described in the Article 9 of the IVD Directive. Schematically the individual cases are described by the flow chart diagrams on the following pages.

However, the conformity to harmonized standards is accepted as the presumption of fulfilling of essential requirements.

The list of harmonized standards is possible download from internet pages, e.g.:

1 A) IVD that are not covered by Annex II and that are not the IVD devices for    self testing nor performance evaluation:
   The manufacturer follows the procedure of Annex III (excluding point 6)
   Draws up the EC declaration of conformity
   and affix the CE marking before placing the IVD on the market

It is a typical Module A procedure (Internal Production Control), the NB is not necessary. Only service of ITC (and its foreign partner, eventually) is a voluntary product certification and/or certification of QMS according to standard EN ISO 13485 and/or EN ISO 9001.

1 B) IVD for self-testing other than those covered by Annex II and devices for    performance evaluation, the manufacturer shall, prior to the drawing up of the    declaration of conformity, fulfil the supplementary requirements set out in    Annex III, point 6. Instead of applying this procedure, the manufacturer may    follow the procedure referred to in paragraphs 2 or 3.
   The manufacturer follows the procedure of Annex III (including point 6)
   Draws up the EC declaration of conformity
   and affix the CE marking before placing the IVD on the market
   or the manufacturer could follow the procedure of Annex IV
   or the manufacturer could apply the combined procedures of Annex V + Annex VI or      Annex V + Annex VII

For these types of IVD, the NB assistance is necessary even in the case of the simplest way (the left branch of the flow chart.

2. For IVD referred to in List A in Annex II (other than for performance    evaluation), the manufacturer shall
   (a) follow the procedure set out in Annex IV (full quality assurance), or
   (b) follow the procedure of Annex V (EC type-examination) coupled with the         Annex VII (production quality assurance).

In relevance to higher level of risk, the “list A IVDs” are assessed at full assistance of Notified Body, independently which branch of the flow chart is chosen by manufacturer. Moreover, no one clause of the Annexes IV or VII is omitted.

3. For IVD devices referred to in List B in Annex II not for performance    evaluation, the manufacturer shall for the purposes of affixing the CE marking,    follow either:
   (a) the procedure in Annex IV (full quality assurance) or
   (b) the procedure in Annex V (EC type-examination) coupled with:
     (i) the EC verification set out in Annex VI, o
     (ii) the production quality assurance set out in Annex VII.

Even in the case of “list B IVDs”, the Notified Body assistance is necessary. Differently from list A IVDs, a few clauses of the Annexes IV and VII are omitted.

4. For IVD intended for performance evaluation, the simplified procedure according to Annex VIII shall apply, as this type is not introduced on the market.

1.6. COMMON TECHNICAL SPECIFICATIONS FOR IVD

The Commission Decision No. 2002/364/EC has been issued to reach higher level of harmonisation in the field of IVD. It establish Common Technical Specifications (CTS) applicable both by manufacturer (in the phase of research, clinical trials and design development) and by Notified Body (the processes containing design evaluation or type evaluation). The necessary sensitivities and other performance characteristics are specified mainly by the form of tables consisting of required statistical data.

2.7. ITC AND ITS FOREIGN PARTNER'S ROLE IN THE IVD FIELD

The notification scope of ITC includes all kinds and classes of In-Vitro diagnostics. The limitations are given by the description of tasks according to relevant Annexes of the 98/79/EEC Directive. Therefore, possibilities of ITC/foreign partner co-operation are fairly large in the IVD field:

1.7.1. Voluntary certification
Only the simplest IVDs (not listed in Annex II and simultaneously not intended for self-testing) are CE-marked and introduced on the market by manufacturer without any obligatory participation of the Notified Body. Nevertheless, ITC offers even in this case testing and product certification on the voluntary basis. The manufacturers wish to make more evident the quality of their products especially in this very sensitive sector of production.

However, the quality system evaluation and certification according to standard EN ISO 13485 is also frequently asked. Especially in this voluntary region, the subcontracting activity of foreign partner and certificate issuing by ITC could be profitable for both partners.

1.7.2. Notified Body's participation
All remaining types IVD introduced on the market are before CE marking subject of conformity assessment tasks performed by Notified Body. As it is shown, the manufacturer has in the most cases the chance of choice between different procedures.

It is highly recommended, to offer to manufacturer especially the procedure described in the Annex IV (Full Quality Assurance ? Module H). For the intended co-operation, ITC/foreign partner takes advantage the necessary quality management system approval and audits, which could be conducted by close co-operation of ITC and the partner. At present, it is impossible to perform this task without physical attendance of ITC expert.

On the other hand, this module is also favourable for many manufacturers, as it is applicable for any IVD products. In the most common case, the manufacturer is producing more than one IVD device and the Full quality assurance procedure could be applied for all produced items together.