The Relevance of Device Stability Studies to IVDR Performance Evaluation

April 18, 2023

5 mins

EU IVDR General

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Under the IVDR, the performance evaluation report (PER) is supported by three “sub-reports” comprising the scientific validity report (SVR), analytical performance report (APR), and clinical performance report (CPR). APR is among the technical documentation file (TDF) information on device analytical performance required under Section 6.1 of Annex II. In addition, all four reports are among the TDF information on clinical performance and clinical evidence required under Section 6.2 of Annex II. 

The role of stability studies in device performance evaluation under the IVDR

Although General Safety & Performance Requirement (GSPR) 9.2 establishes that “The performance characteristics of the device shall be maintained during the lifetime of the device as indicated by the manufacturer”, thereby indicating that device stability is a device “performance characteristic”, stability is listed separately under Section 6.3 of Annex II with no clear indication as to whether this is within the scope of analytical performance or clinical performance. Evidence of device stability includes claimed shelf-life, in-use stability, and shipping stability studies, as relevant.

To further compound potential confusion, within Annex XIII Section 1.2.2 (Demonstration of the analytical performance) and Section 1.2.3 (Demonstration of the clinical performance) only reference the parameters described in GSPR 9.1(a) and 9.1(b), respectively.

Are stability studies relevant to IVDR performance evaluation?

The short answer to this question is “Yes”.

Section 1.1, Annex XIII of the IVDR establishes that the performance evaluation plan (PEP) shall include at least “…an identification of the general safety and performance requirements as laid down in Sections 1 to 9 of Annex I that require support from relevant scientific validity, analytical and clinical performance data.”

Which GSPRs directly impact IVDR stability studies to performance evaluations?

Among GSPRs 1-9 under Annex I of the regulation, the following directly concern device stability:

GSPR 6: The characteristics and performance of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer’s instructions.

This GSPR is relevant to both device-claimed shelf-life and in-use stability studies.

GSPR 7: Devices shall be designed, manufactured, and packaged in such a way that their characteristics and performance during their intended use are not adversely affected during transport and storage, for example, through fluctuations of temperature and humidity, taking account of the instructions and information provided by the manufacturer.”

This GSPR is relevant to both device-claimed shelf-life and shipping stability studies.

These GSPRs do not require support from scientific validity data, as stability studies are not performed to demonstrate the association of an analyte with a clinical condition or a physiological state. However, manufacturers may be confused as to whether these GSPRs require support from relevant analytical and/or clinical performance data. 

In which IVDR performance evaluation-related report should stability studies be described?

To answer this question, we need to review current MDCG guidance. While MDCG 2022-2 describes sample stability considerations as falling within the scope of analytical performance under Section 6.2 of the guidance (among the examples of analytical performance indicators listed in this section is “stability”), there is no clear distinction as to whether this is in reference to sample stability or device stability. This contrasts with Section 6.3, Annex II of the IVDR which explicitly excludes specimen stability from its scope. Therefore, as the reference to “stability” could be understood to refer to both sample and device stability, current guidance indicates stability studies fall within the scope of analytical performance and therefore would be best described in the APR.

This approach would be aligned with the manner in which stability studies are performed. Despite not yet being harmonized under the IVDR, EN ISO 23640:2015 In vitro diagnostic medical devices – Evaluation of the stability of in vitro diagnostic reagents is harmonized under the IVDD and is aligned with CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents, 1st Edition. Stability studies require manufacturers to select metrics that are most likely to reveal potentially important changes to a product’s quality, safety, and/or efficacy during storage, use, and transport. Such metrics typically reflect physical, biological, chemical, and/or microbiological characteristics of the product itself or the analytical performance of the product (Remembering that GSPRs 6 and 7 require that both device characteristics and performance are not adversely impacted). Clinical performance characteristics are not among the metrics investigated in stability studies, despite the possibility that pooled human specimens (neat, diluted, or spiked) may be used to determine measurand drift in such studies.

Why are stability studies relevant?

Stability studies are relevant to performance evaluation, and they are most appropriately described in the APR. Although, where a device does not possess any specific analytical performance characteristics (e.g. diluent/sample buffer for IVD purposes) and the manufacturer has subsequently used this as justification for the absence of analytical performance data, it would be reasonable to describe the device stability studies in the PER. These approaches are also aligned with performance evaluation reviews that we have observed with Notified Bodies under the IVDR and MDCG 2022-2.

Consulting services regarding performance evaluations

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