Regulation (EU) 2017/746 (IVDR): practical implementation of annex I in pathology

“Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (Text with EEA relevance.)” [15] (short: IVDR) entered into force on 26 May 2017 and applied from 26 May 2022. The main objective of the regulation, which applies throughout the EU, is to ensure the highest possible level of patient health protection combined with a high level of user safety through harmonized requirements for the manufacture and use of in vitro diagnostic medical devices (IVD).

This article describes the procedure for implementing the currently applicable requirements of the IVDR for health institutions and the “General Safety and Performance Requirements” (IVDR, Annex I) into the established quality management (QM) system of the Institute of Pathology at the University Hospital of Heidelberg (IPH).

The IVDR distinguishes between two types of IVDR-compliant in vitro diagnostic medical devices (IVD; Table 1): CE-marked IVDs (CE-IVDs) from economic operators and in-house IVDs (IH-IVDs) from health institutions (see Table 2 for definitions of terms). For complex diagnostics in pathology, both types of IVDs, also in combination, are used to ensure optimal patient care.

Recital 29 of the IVDR describes the special importance of health institutions and the IVDs they develop themselves. According to this, health institutions—and thus pathology departments—should continue to have the possibility to manufacture, modify and use devices in-house, in order to be able to respond to the specific needs of the patient target groups. For this purpose, however, the IVDR is to prescribe EU-wide harmonized rules (Recital 28), which are described in Article 5 (5).

This article sets out several conditions for health institutions developing and using IH-IVDs. If all of the conditions described herein are met, any additional requirements of the IVDR do not apply to IH-IVDs. These conditions for health institutions are coming into effect gradually, following an amending regulation in January 2022 ([16]; Fig. 1).

The requirements summarized below must already be followed since 26 May 2022:

The term “industrial scale” is not defined in the IVDR. However, the guideline document MDCG-2023‑1, which was prepared specifically for IH-IVDs by the Medical Device Coordination Group (MDCG) and published in January 2023, comments on this [13]. This guideline states that no more than the estimated number of required devices should be produced in the manufacturing process.

For the requirements (2)–(5) listed above, there is therefore no immediate need for pathology departments to act. However, pathology departments must address point (1), the “general safety and performance requirements”, which are described in Annex I of the IVDR.

Pathology departments in Germany are accredited as inspection bodies by the Deutsche Akkreditierungsstelle GmbH (DAkkS)—the national accreditation body of the Federal Republic of Germany—according to standard DIN EN ISO/IEC 17020. The accreditation focuses on the expert assessment of the pathologist and thus the confirmation of the professional competence of the inspection body [7]. The requirements of the standard EN ISO 15189 must also be considered [4]. The Institute of Pathology at the University Hospital Heidelberg (IPH) has been accredited since 2007. This provides an established, sound and independently audited quality management structure into which the requirements of the IVDR can be integrated. Article 5 (5) (c) of the IVDR requires a quality management system in accordance with the standard EN ISO 15189 but does not stipulate accreditation [8].

All IVDs, whether commercial CE-IVDs or IH-IVDs manufactured in-house, must meet the general safety and performance requirements (Article 5 (5)). These requirements are intended to ensure and demonstrate that the devices are safe for patients and users, that potential risks are known and controlled, and that the devices are fit for their intended purpose. As a manufacturer and user of IH-IVDs, pathology departments must ensure and demonstrate compliance with Annex I. Annex I is divided into three chapters (Fig. 2):

The intended purpose forms the basis for the requirements from Annex I. It thus determines the effort required for the requirements of Chapters I, II and III and the amount of the associated documentation.

Chapter I focuses on device-specific risk management for the manufacture and use of IH-IVDs. IH-IVDs must be fit for purpose and safe; they must not compromise the safety of patients, users or third parties. Any risk associated with their manufacture and use must be acceptable in relation to the benefit to the patient and consistent with a high level of health protection and safety (IVDR, Annex I (1)). The IVDR defines risk as the combination of the probability of occurrence of harm and the severity of that harm (Table 2).

For the implementation of device-specific risk management, a new SOP was created for the IPH QM documentation. This SOP describes creation of a device-specific risk management file (Fig. 4a). The risk management file contains the required risk management plan, the risk assessment with its subcomponents and a risk management report.

Chapter II describes requirements for performance, design and manufacture of IVDs. The safe design and manufacture of IH-IVDs have already been considered and assessed in the risk management file. According to the IVDR, the performance of a device is the ability “to achieve its intended purpose as claimed by the manufacturer” (note: for IH-IVDs → pathology departments; Table 2). Through the analysis and evaluation of defined performance characteristics, the scientific validity, analytical performance and, if applicable, clinical performance are determined and verified before the devices are used (= performance evaluation; Table 2). Examples of the performance characteristics to be considered are listed in Chapter II, 9.1. and are determined on the basis of the device-specific intended purpose defined “by the manufacturer” (see below and Fig. 3). The intended purpose thus significantly influences the scope of the validation and decides which of the performance characteristics listed in Chapter II, 9.1., must be demonstrated and which can be excluded. A publication of the IVDR subgroup of the German Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF; Association of the Scientific Medical Societies in Germany) provides guidance on the performance evaluation of in-house methods for the detection of infectious pathogens [14].

Method validation at IPH is based on guidelines of the Pathology/Neuropathology Sector Committee, which is responsible for the interpretation of the accreditation requirements according to DIN EN ISO/IEC 17020 in the field of pathology [2, 3]:

The concluding performance evaluation is made in the device-specific validation report. This requires qualified personnel to decide whether the quality requirements for the method have been met and whether it can be used for the intended investigations in accordance with the intended purpose. Ongoing verification of the validated procedure is ensured by appropriate control mechanisms during operation. This ensures that the procedure is reproducibly stable and robust. The established QM system with its correction and improvement processes described above also applies here.

Chapter III specifies requirements for the information supplied with the device. “Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user or any other person, as appropriate” (Annex I, Chapter III, 20.1.). This is done through labelling and instructions for use, for which Chapter III provides specifications. Instructions for use are defined as follows: “‘instructions for use’ means the information provided by the manufacturer to inform the user of a device’s intended purpose and proper use and of any precautions to be taken” (Table 2).

In accordance with the requirements for IH-IVDs set out in Article 5 (5), pathology departments are both manufacturer and user, as the devices may not be transferred to another legal entity. Thus, all relevant information on the manufacture, safety and performance of the IH-IVD is available to the user group at all times. Within the QM system, the intended purpose, risk assessment and performance evaluation/validation documents are available to the user group at all times. In addition, there are device-/process-specific SOPs in the QM documentation. These are either prepared by the user group itself or the users are trained on them as part of the training program. These SOPs cover important aspects of the safe use of in-house methods and, like risk management, are regularly and systematically updated. The safe use of IH-IVDs in the laboratory, which is necessary to meet safety requirements, also includes relevant information on substances or mixtures classified as hazardous, e.g., in the form of safety datasheets and laboratory safety instructions.

Commercial CE-IVDs and IH-IVDs are specifically used in pathology for optimal diagnosis and individualized therapy [8]. With Recital 29 and its concretization in Article 5 of the IVDR, the legislator recognizes the benefit and necessity of in-house developed tests and allows their use for optimal patient care under certain conditions [8, 17]. As manufacturers and at the same time users of IH-IVDs, health institutions like pathology departments must ensure compliance with Article 5 (5) of the IVDR and fulfil the safety and performance requirements listed in Annex I. Then, all other requirements of the IVDR do not apply to IH-IVDs.

In January 2023, the Medical Device Coordination Group (MDCG) document MDCG-2023‑1 was published for health institutions, providing guidance on some of the requirements of Article 5 (5) [13]. The MDCG and its tasks are described in Articles 98 and 99 of the IVDR. According to Article 99 (c), it has the task of developing guidelines for an effective and harmonized implementation of the IVDR, but these are not legally binding.

Many professional societies and associations are committed to the practical implementation and content shaping of definitional gaps and vagueness in the requirements, and new networks have formed to use their academic knowledge and expertise to provide assistance. They provide support, for example, through guidelines and templates, as well as through discussion events, workshops and the exchange of experiences. The IVDR subgroup of the AWMF provides numerous templates and supporting documents in German and English (e.g., on risk management and performance evaluation) on its website [1]. The recommendations of the Bundesverband Deutscher Pathologen e. V. (BDP; Federal Association of German Pathologists) [9‐11], which describe the implementation of IVDR in pathology during the implementation phase, are also helpful.

Such information sources are an important step for institutions to implement and harmonize compliance with the requirements of Article 5(5). Academic networking structures are also important for interpretation of the IVDR and its practical implementation.

In Germany, around 100 institutes for pathology or neuropathology are accredited according to DIN EN ISO/IEC 17020 [7]. The implementation of the requirements of the IVDR for IH-IVD thus takes place within a solid, established and independently audited quality management structure, in which many requirements have already been implemented (e.g., continuous verification of methods by quality controls, user training or failure management). To comply with Annex I of the IVDR, the Institute of Pathology in Heidelberg (IPH) has created several new operating procedures and integrated them into the existing DIN EN ISO/IEC 17020-compliant QM documentation (Fig. 7). In some cases, existing QM documents were used, but these had to be adapted to the requirements of Annex I.

The intensive internal examination of the requirements of the IVDR (e.g., through gap analysis), the preparation of the QM documents listed in Fig. 7 (SOPs and forms), their implementation in the existing QM system, the necessary training and, above all, the device-specific documentation provided for in the IVDR through the expertise of the specialist staff are very resource intensive. For the device-specific documentation, the IH-IVD must first be defined and the area of application specified. Depending on the strategy, this can be done for an entire process chain, or modularly for individual links or elements, and takes the form of a documented intended purpose. Based on this determination, the device-specific risk management, which goes beyond general risk management within the scope of accreditation, performance evaluation and instructions for use (as SOPs) are established in accordance with the QM manual. A new challenge is posed by in-house software solutions, which now also fall under the definition of an IVD according to the IVDR.

For a university institution like IPH, ensuring compliance with the IVDR—in addition to the core tasks of patient care, teaching and research, the further development of methods for optimal and targeted personalized diagnostics and maintenance of the constantly evolving QM system—represents an additional major challenge in terms of personnel and time.