On 26 May 2022, Regulation (EU) 2017/746, or the In Vitro Diagnostic Regulation (IVDR), finally came into force. One of the most compelling requirements in this EU regulation deals with two important aspects of conformity assessments of Class D IVD medical products: namely, the batch verification process and the involvement of EU reference laboratories that conduct these processes.
In February 2022, a new guidance document was released by the Medical Devices Coordination Group (MDCG) that allows a more precise interpretation of these requirements: MDCG—Verification of Manufactured Class D IVDs by Notified Bodies.
- MDCG 2022-3: MDCG—Verification of Manufactured Class D IVDs by Notified Bodies
In addition, it is important to note that additional MDCG documents were published in April 2021 and August 2021, dealing with the transitional provisions for the same category of devices:
- MDCG 2021-4: Application of Transitional Provisions for Certification of Class D In Vitro Diagnostic Medical Devices According to Regulation (EU) 2017/746
- MDCG 2021-22: Clarification on “First Certification for that Type of Device” and Corresponding Procedures to be Followed by Notified Bodies, In Context of the Consultation of the Expert Panel Referred to in Article 48(6) of Regulation EU 2017/746.
MDCG 2021-4: Involvement of EURL
Before we take a deep dive into the batch verification requirements for Class D IVDs in the IVDR, we first need to describe the narrative with the aforementioned MDCG 2021-4 and MDCG 2021-22 document in mind.
According to the IVDR, as part of conformity assessments of class D IVDs, manufacturers must submit an application to an EU Notified Body (NB). In addition to the assessment by the NB, under certain conditions, particular elements may be reviewed by an expert panel and/or tested by an EU reference laboratory (EURL).
The establishment of EURLs for a range of class D devices has been identified as an important priority by MDCG. For class D devices for which no common specifications exist, and where “it is the first certification for that specific type of device” and there is no similar device on the market having the same intended purpose and based on similar technology, NBs should, in addition to the laboratory testing of the performance claimed by the manufacturer and the compliance of the device by the EU reference laboratories (EURLs), be obliged to request expert panels to scrutinise their performance evaluation assessment reports.
Although the document very much delves into the roles and responsibilities of expert panels for the first certification of innovative class D IVD devices that meet the above mentioned criteria, EU Reference Laboratories must also be involved. While discussions on practical aspects of such laboratories are ongoing and their requirements have been drafted, the structures selected as EURLs are expected to be defined only at the beginning of 2023 (at the time of writing this blog, an EU Reference Laboratory has yet to be designated for the responsibilities mentioned in article 100 of the IVDR).
At the moment, this is not considered a large issue since the MDCG 2021-4 allows NBs to issue certificates irrespective of this designation.
- On sample or batch testing, an NB and manufacturer should follow the EURL-related provisions of Section 4.12 of Annex IX or Section 5 of Annex XI from the time that the EURL becomes operational.
- For performance verification, an NB should follow the EURL-related provisions of Section 4.9 of Annex IX or Section 3 (j) of Annex X at the time of the re-certification in line with Section 4.11 (f) of Annex VII. So, the procedure set out in paragraph 5 of Article 48 involving a EURL will be also be applied at the time of the re-certification.
Once the EU Reference Laboratories are designated, then these laboratories will also have an active role in supporting the initial certification of class D IVDs by an NB. This is especially important, since for IVD Class D devices where, until recently, no Common Specifications were available—and where it is also the first certification for that type of device—the batch release criteria may not be fully defined…yet. And, the appointed EU expert panels involved in the review of performance evaluation review reports of Class D IVDs may also set the conditions for the batch release if one reviews the MDCG document more closely.
MDCG 2022-3: A One Size Fits All for Class D IVDs?
The MDCG 2022-3 is more specific on what the batch verification process of class D IVDs entails. By the way, the batch verification process is not a new regulatory requirement for IVDs in the EU; it has always been a requirement for certification of so called Annex II List A devices per the IVD Directive (98/79/EC).
In the past, an NB recommendations were made available by an NB-MED that describes the modalities of a batch verification process conducted by NBs: NB-MED/2.5.4/Rec2. Now, under the IVDR, Class D IVDs now basically replace the Annex II List A devices listed in the IVDD and the batch verification process has, for the most part, been transferred to EU Reference Laboratories that act independently from NBs.
The latter still takes the ultimate decision on the approval on the EU market for a class D IVD batch, but the actual batch verification and testing is carried out by the EU Reference Laboratory. In order to fulfil the requirements of a solid and compliant batch release process, per IVDR, the following needs to be arranged between an NB, the IVD manufacturer and the EU Reference Laboratory. Mind you, that the IVD manufacturer does not have a direct relationship with the EU Reference Lab, although a formal agreement exists between the IVD manufacturer and the NB and between the NB and the EU Reference Laboratory (an actual contract needs to be established).
The central piece that is common to both the NB agreement and the EURL contract is the “test plan.” The test plan will need to be approved first by the EURL and is device-specific; certainly not a one size fits all approach.
For example, the test plan at least needs to contain the following elements:
- Relevant and critical parameters to be tested
- Decision making criteria for success or failure of the batch
- Samples to be tested
- Specimens to be tested
- Other specific materials provided by the manufacturer
- Testing frequency
- Test platform and protocol used
- Reference to any applicable common specifications and relevant standards or other solutions chosen by the manufacturer
- Reference to the designation scope of the EURL
The document goes on to list the important elements to be included in the NB IVD manufacturer agreement and the NB EURL contract. These elements are very important for all parties involved, but covering these separately goes beyond this blog.
Another important element that is covered in the document deals with the provision of samples to the EURL and the batch verification process itself. Along the same lines as the earlier mentioned NB MED document, there are sampling criteria mentioned that are risk-based; the higher the impact of device failure, the higher number of batches that have to be tested. When determining the frequency of sending samples of batches to the EURL considerations are given to the relative risk/impact of the device based on the type of intended use, making a distinction between tests determining transmittable agents and blood grouping tests.
The document goes on to state that for first-line assays and devices intended for diagnosis, every batch has to be tested. For other devices, the number of batches to initially be tested should be determined by the NB. The NB will take into account the batch-testing regime defined by the manufacturer and the views expressed in the scientific opinion of the EURL and, where applicable, the views expressed by the aforementioned expert panels (the document states actual testing). The frequency of testing can be conducted through a risk-based approach, which is sensible. However, for first-line assays, there is no possibility of adjusting the frequency. Again, for blood grouping tests and tests detecting transmissible agents, the sampling criteria are different.
NBs are responsible for conducting the verification of batches of manufactured class D IVDs through review of a manufacturer’s Quality Control release data and considering the findings from EURL. Although this document does give clarity on what to look for, when conducting batch reviews, it may still be a challenging process.
Sponsors must understand that the NB and manufacturer will have a timeframe of no later than 30 days after reception of samples for the communication of the decision to either approve or disapprove the documentation. Following this verification procedure, manufacturers may place class D IVDs on the market unless the NB communicates to the manufacturer within this agreed timeframe of any other decision. When there is no communication of the decision reached within the agreed timeframe, the manufacturer may assume there are no issues with the documentation and that the batch may be released to the market.
When reviewing these new documents, a “one size fits all” approach is not applicable for the batch verification process for class D IVDs (per IVDR). But, this is not necessarily make this a bad thing. This process provides clarity regarding the majority of class D IVDs and what information should be covered in the agreement and contract between an IVD manufacturer, the NB and the EURL.
Also, the good thing regarding these new guidance documents is that they are consistent with the best practice documents that many NBs work with at the present moment (at the writing of this blog). These practices are even in line with the old Common Technical Specifications document that states performance and batch release criteria for the majority of the old Annex II List A and new class D IVD devices. The wait is now on the first EURL to be designated and prepared to carry out most of the tests they are designated to.
Finally, it should be mentioned that Implementing Acts have been published that further detail the roles and responsibilities for EU Reference Labs:
- 2022/944 of 17 June 2022 laying down rules for the application of Regulation (EU) 2017/746 of the European Parliament and of the Council as regards the tasks of and criteria for European Union reference laboratories in the field of in vitro diagnostic medical devices and 2022/945 of 17 June 2022 laying down rules for the application of Regulation (EU) 2017/746 of the European Parliament and the Council with regard to fees that may be levied by EU reference laboratories in the field of in vitro diagnostic medical devices (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32022R0944); and
- Common Specifications for Class D IVD’s; COMMISSION IMPLEMENTING REGULATION (EU) 2022/1107 of 4 July 2022 laying down common specifications for certain class D in vitro diagnostic medical devices in accordance with Regulation (EU) 2017/746 of the European Parliament and of the Council. https://eur-lex.europa.eu/eli/reg_impl/2022/1107/oj
How Can NAMSA Help?
At NAMSA, our European regulatory team can help guide you through this complex regulatory environment and help determine the correct regulatory pathway for your IVD product. We not only understand how to accurately interpret the complicated regulatory challenges that IVD manufacturers sometimes face, but we also help you simplify the development and implementation of effective development strategies. Whether supporting IVD regulatory assessments and submissions, developing IVDR compliant technical files, designing and managing clinical trials or building ISO 13485:2016 and 21 CFR part 820 compliant quality systems… we’ve got you covered.
To learn about NAMSA’s full suite of IVD services and solutions, including IVDR compliance planning, please visit: https://namsa.com/services/ivd/. Or, if you’re ready to set up a complimentary consultation, get in touch with one of our IVD experts here: https://namsa.com/namsa-expertise/subject-matter-experts.
Alex Laan has been in the IVD and Medical Device industry for a total of 20 years with 12 years spent working for a respectable EU Notified Body. Alex has held the position of Principal Certification Manager at DEKRA Certification BV, a Notified Body for IVDs and Medical Devices located in Arnhem, The Netherlands. Mr. Laan also worked for KEMA Quality, beginning in 2006, where he was qualified for Lead Assessor for Medical Devices and IVD devices, Device Specialist reviewer in IVDs and Medical Devices, including drug-device combinations. In these roles, Alex managed projects with large multinationals (e.g., Boston Scientific), as well as small start-up companies. Alex has been an active member of IVD working group within EU Notified Bodies and TEAM-NB and acting as direct contact for EU competent authorities and EMA on implementation of the EU IVDR (2017/746) and EU MDR (2017/745).