By Dr Daisuke Kawakami

What is the new EU In Vitro

Diagnostic Regulation?

The new In Vitro Diagnostic Medical Device Regulation (IVDR) (EU) 2017/746 was published in EU Official Journal in May 2017 in order to ensure a high level of safety and health while supporting innovation. It applies from 26 May 2022 and
replaced the previous IVD Directive (98/79/EC).

This regulation set rules for in vitro diagnostic devices including reagents, calibrators, kit, instrument and software intended by the manufacturer to be used for diagnostic purposes. IVDR retains some concepts of the IVD Directive such as CE marking or essential requirements (under IVDR called “general safety and performance requirements”). As in the past, manufacturers have to demonstrate that they and their devices meet the requirements through a conformity assessment procedure.

Different from the IVD Directive, however, IVDR introduced risk-based classification (Fig. 1). Under IVDR devices are classified into four categories. The devices with the highest risks are classified in class D. The class A devices have low risks and include products for general laboratory use, with accessories which possess no critical characteristics.

IVDR transition timeline announced in December 2021

As shown Figure 2, self-declaration of conformity by the manufacturer which meet the requirements of IVDR is necessary to place the class A devices* on the EU market from 26 May 2022. Class B**, C and D devices need the certification from the accredited Notified Body (NB) to be placed on the EU market. Although only 8% of devices required NB certification under the IVD Directive, 78% of devices require NB certification under IVDR [1]. Despite that fact, the number of NBs accredited in the EU is small [2].  For that reason, in December 2021, the transition period has been extended depending on the class (class B** until 26 May 2027, class C until 26 May 2026, and class D until 26 May 2025). The European Commission presented a further extension proposal in January 2024 [3]. If this amendment proposal is published in the official Journal as it is, the transition period of class B** devices will be extended until 31 December 2029, class C until 31 December 2028 and class D until 31 December 2027.

Figure 1. IVDR risk-based classification
IVDD, In Vitro Diagnostic Directive; IVDR, In Vitro Diagnostic Regulation; NB, Notified Body.

In-house devices and IVDR

Another big difference between the IVDR and the IVD Directive is that the IVDR governs so called ‘in-house devices’ – what you know as LDTs (lab-developed tests). IVD medical devices can be manufactured and used within EU health institutions (in-house devices), on a non-industrial scale, to address the specific needs of target patient groups which cannot be met, or cannot be met at the appropriate level of performance, by an equivalent CE-marked device available on the market. In-house devices are exempt from most of the provisions of IVDR, if the health institution fulfills the conditions laid out in IVDR Article 5(5). Here, ‘health institutions’ include not only hospitals but also laboratories and public health institutes which support the healthcare system and/or address patient needs, but do not treat or care for patients directly [4]. For the details, MDCG guidance is available [5].

Currently – during the transition period – use of an in-house device is possible for health institutions without justifying in their documentation that the specific needs of the target patient group cannot be met, or cannot be met at the appropriate level of performance, by an equivalent device available on the market. However, from 26 May 2028 justifying documentation will be necessary. Also here, the European Commission presented a further extension proposal. If this proposal is published as it is, this deadline will be extended to 31 December 2030 [3].

’Old’ devices

It is possible to continue using IVD Directive products already on the market. IVD devices that were placed on the market prior to 26 May 2022 in accordance with IVD Directive and are still on the market or in use after 26 May 2022 are called ‘old’ devices. These ‘old’ devices are, in principle, not subject to IVDR requirements. So, these ‘old’ devices can be further used in your laboratory. However, IVDR provisions which do not directly impact the device, its documentation or the conditions for the placing or making devices available on the market apply also for these ‘old’ devices. Concretely, rights and obligations of competent authorities with regard to market surveillance activities (IVDR Article 88 to 95) apply also to ‘old’ devices after 26 May 2022. Also, the reporting and analysis of serious incidents and field safety corrective actions occurring after 26 May 2022 should be also done in accordance with IVDR Article 82 and 84, except for reporting of incidents and market surveillance activities [6].

Figure 2. IVDR transition timeline
* Class A devices without requirements for sterility.
** This includes class A devices with requirements for sterility.

Shimadzu IVDR class A solutions for HPLC and LC/MS/MS

High performance liquid chromatography (HPLC) and liquid chromatography tandem mass spectrometry (LC-MS/MS) are used to measure blood concentrations of immunosuppressants, antibiotics, antimycotics, antiepileptics, other TDM (therapeutic drug monitoring), steroids, 25-hydroxy vitamin D, etc. If a Research Use Only (RUO) HPLC or LC-MS/MS is used for diagnostic purposes, it may be converted to an in-house device in accordance with Article 5(5) of IVDR.

However, the work required to meet the requirements of Article 5(5) is enormous. Therefore, we recommend the introduction of IVDR class A products for HPLC and LC-MS/MS to reduce the workload. Shimadzu has already launched IVDR class A devices for HPLC (LC-40 CL) and LC-MS/MS (LCMS-8045/8050/8060/8060NX CL) in 2022. HPLC IVDR class A (Fig. 3) is available without MS. Each unit [pump, autosampler, oven, valve, and detector (UV)] is IVDR class A, so the combination can be customized. For LC-MS/MS, the series can be selected according to required sensitivity (Fig. 4).
Shimadzu also launched an IVDR class A device, the CLAM-2040 CL (Fig. 5), a fully automated sample preparation module for Shimadzu LC-MS/MS that enables a seamless workflow from laborious pre-treatment to fully automated LC-MS/MS. The CLAM-2040 CL is not only seamless, but also flexible. Depending on the application, you can choose an IVDR class A compliant LC-MS/MS to be combined with the CLAM-2040 CL. The design also allows connection to LIS (laboratory information system) and LAS (laboratory automation system), enabling a wide range of tests and workflow improvements using LC-MS/MS.

These IVD devices, in combination with commercially available IVD kit, is expected to relieve the user from the enormous amount of work necessary to meet the requirements of Article 5(5) of IVDR. Only the validation by combination is still required.

Figure 3. Shimadzu HPLC (LC-40 XR/X3 CL)

Figure 4. Shimadzu LC-MS/MS (LCMS-8045/8050/8060/8060NX CL)

Disclaimer
This publication may contain references to products that are not available in your country. Please contact us to check the availability of these products in your country. Company names, products/service names and logos used in this publication are trademarks and trade names of Shimadzu Corporation, its subsidiaries or its affiliates, whether or not they are used with trademark symbol “TM” or “®”. Third-party trademarks and trade names may be used in this publication to refer to either
the entities or their products/services, whether or not they are used with trademark symbol “TM” or “®”. Shimadzu disclaims any proprietary interest in trademarks and trade names other than its own. The contents of this publication are provided to you “as is” without warranty of any kind, and are subject to change without notice. Shimadzu does not assume any responsibility or liability for any damage, whether direct or indirect, relating to the use of this publication.

Figure 5. Shimadzu fully automated sample preparation module for LCMS (CLAM-2040 CL)

The author

Daisuke KAWAKAMI PhD,
Shimadzu Europa GmbH

For further information see:
1. LC & LC-MS compliant with In Vitro Diagnostic Regulation (IVDR) (https://www.shimadzu.co.uk/products/liquid-chromatograph-mass-spectrometry/triple-quadrupole-lc-msms-ivdr-class-a/lc-ms-ivdr-compliant/index.html); and
2. CLAM applications (https://www.shimadzu.com/an/products/liquid-chromatograph-mass-spectrometry/lc-ms-option/clam-2040/applications.html#tbaleAnchor_more).

References

1. MedTech Europe Survey Report analysing the availability of in vitro diagnostic devices (IVDs) in May 2022 when the new EU IVD Regulation applies. MedTech Europe 8 September 2021; pp6–7 (https://www.medtecheurope.org/wp-content/uploads/2021/09/medtech-europe-survey-report-analysing-the-availability-of-in-vitro-diagnostic-medical-devices-ivds-in-may-2022-when-the-new-eu-ivd-regulation-applies-8-september-2021.pdf).
2. As of 16 February 2024, only 12 Notified Bodies exist. European Commission Single Market Compliance Space (https://webgate.ec.europa.eu/single-market-compliance-space/#/notified-bodies/notified-body-list?filter=legislationId:35,notificationStatusId:1).
3. Proposal for a Regulation of the European Parliament and of the Council amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards a gradual roll-out of Eudamed, information obligation in case of interruption of supply and the transitional provisions for certain in vitro diagnostic medical devices. European Commission 2024 (https://health.ec.europa.eu/system/files/2024-01/mdr_in-vitro-proposal.PDF).
4. MDCG 2023-1. Guidance on the health institution exemption under Article 5(5) of Regulation (EU) 2017/745 and Regulation (EU) 2017/746. Medical Device Coordination Group January 2023; p3 (https://health.ec.europa.eu/system/files/2023-01/mdcg_2023-1_en.pdf).
5. MDCG 2023-1. Guidance on the health institution exemption under Article 5(5) of Regulation (EU) 2017/745 and Regulation (EU) 2017/746. Medical Device Coordination Group January 2023 (https://health.ec.europa.eu/system/files/2023-01/mdcg_2023-1_en.pdf).
6. MDCG 2022-8. Regulation (EU) 2017/746 – application of IVDR requirements to ‘legacy devices’ and to devices placed on the market prior to 26 May 2022 in accordance with Directive 98/79/EC. Medical Device Coordination Group May 2022 (https://health.ec.europa.eu/system/files/2022-05/mdcg_2022-8_en.pdf).