Does the new, long-awaited MDCG Guidance 2023-1 deliver what it promises? Does it really clarify the practical implementation of Article 5(5) of EU Regulation 2017/746 on in vitro diagnostic medical devices?

So-called in-house products or in-house IVDs are widely used in medical laboratories and are an important component for patient care. In-house IVDs are exempt from most of the requirements of the IVDR, according to the new MDCG Guidance 2023-1. However, they must meet the requirements of Article 5(5) of the IVDR. The MDCG Guidance promises to provide guidance on how to apply some of these rules. The Guidance is written specifically for healthcare professionals and researchers in healthcare facilities within the EU* who intend to design, manufacture, or modify and use in-house devices. It is also intended to promote the harmonized application of Article 5(5) by the various national authorities.

In these 10 points, we have summarized for you the new information on Art. 5(5) brought by MDCG Guideline 2023-1:

1. General aspects
2. With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of this Regulation shall not apply to devices manufactured and used only within health institutions established in the Union, provided that all of the following conditions are met:
3. Regarding Art. 5(5) a) he devices are not transferred to another legal entity;
4. [SP 4]Regarding Art. 5(5) b) manufacture and use of the devices occur under appropriate quality management systems/ c) he laboratory of the health institution is compliant with standard EN ISO 15189 or where applicable national provisions, including national provisions regarding accreditation;
5. Regarding Art. 5(5) d) the health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market;
6. Regarding Art. 5(5) e) the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use;
7. Regarding Art. 5(5) f) the health institution draws up a declaration which it shall make publicly available …;
8. Regarding Art. 5(5) g) as regards class D devices in accordance with the rules set out in Annex VIII, the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met. Member States may apply this provision also to class A, B or C devices in accordance with the rules set out in Annex VII;
9. Regarding Art. 5(5) i) the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions.
10. Regarding Art. 5(5) Sentence 3: This paragraph shall not apply to devices that are manufactured on an industrial scale.

1 General aspects

To which products does Article 5(5) refer?
According to the definition of the IVDR, an IVD is a medical device that is "... intended b y the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following ..." (Art. 2(2)).

In this regard, the MDCG 2023-1 clarifies that any device or combination of devices that fall within the IVD Regulation definition must be either

• a CE-marked IVD,
• an in-house IVD as defined in Art. 5(5),
• a device for performance evaluation studies, or
• a device that is exceptionally allowed by the competent authority to deviate from the CE marking.

This means that only CE-marked IVDs and in-house IVDs according to Art. 5(5) may be used for the diagnosis of human patient samples (apart from rare exceptions that must be agreed with the competent authorities).
The terms "research use only" (RUO) and "off-label use" (use of devices, deviating from their intended purpose) refer to test systems that are not devices according to the IVDR and thus may not be used for diagnostics.

Once the healthcare facility

• changes the intended purpose or design of a CE-marked device, and wishes to use this device for diagnostics, it falls under Art. 5(5) of the IVDR.
• ascribes a purpose to a RUO product, thereby bringing it within the definition of IVD, Art. 5(5) applies.

In both cases, measures must be taken by the healthcare facility so that these tests comply with the requirements of Article 5(5) and become an in-house IVD. Only when the healthcare facility has documented that the requirements of Art. 5(5) are met for such a test, the product may be used as an in-house IVD for diagnostic purposes.
The MDCG Guidance provides other general examples of what is meant by manufacturing" of in-house IVDs by healthcare facilities:

• Manufacturing of a product
• from raw materials,
• from parts or components of a CE-marked product, or
• from another type of product (e.g., from an RUO assay).
• Combination of a product with another product, where the combination results in a new product.
• Modification of an existing product to generate a new product (this includes, for example, changing the intended purpose, keyword "off-label use").

No devices in the sense of the IVDR (and therefore not covered by Art. 5(5)) are protocols describing the manufacturing or use of an in-house IVD, patient samples as well as the results of an in-house IVD. Results of an in-house IVD must be recorded at the healthcare facility where the in-house IVD was manufactured. This does not preclude sharing the result with other healthcare facilities or patients. Similarly, protocols and patient samples may be shared between different healthcare facilities.

IVD products that are not covered by Art 5(5) and therefore require full compliance with the IVDR include for example self-tests applied outside the legal entity of the healthcare facility.

However: a self-test that is manufactured in-house may be used within the healthcare facility by lay persons. In addition, in-house products may also be used within the healthcare facility to analyze samples obtained by the patient and subsequently sent to the laboratory.

2 With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of this Regulation shall not apply to devices manufactured and used only within health institutions established in the Union, provided that all of the following conditions are met :

In-house products must comply with Annex I of the IVDR. The MDCG document addresses important aspects in this regard: In particular, it emphasizes that a risk management system must be established, and a regular update of the risk-benefit study must be made (Chapter I, Annex I). Besides the risks for patients also risks affecting the user and user errors must be considered throughout the life cycle of the in-house product. The regular update of the benefit-risk ratio also implies the regular update of the performance evaluation.

Furthermore, the MDCG document states that the requirements in Chapter II on design, manufacture and performance are also particularly relevant for in-house products - especially when demonstrating that no like CE-marked product is available on the market. No proper (technical) documentation - no meaningful evidence.

Not all requirements of Chapter III are applicable to in-house products. Applicable are those that are relevant for the safe use of the product, so that the product can fulfill its intended purpose. Based on this, the MDCG lists the following exemplary documents and information that you must provide:

• instructions for use and/or protocols,
• information on substances or mixtures that may be considered hazardous,
• shelf life or production date of the manufactured product or batch,
• storage and handling conditions, and
• batch or serial number, or similar identification measures for traceability purposes.

The MDCG 2023-1 does not say anything about labeling. We assume that in most cases adequate labeling of the product and its components is also a prerequisite for its safe and correct use.

Conclusion: Annex I evidence for in-house IVDs initially includes as many requirements as for CE-marked IVDs. Even for CE-marked IVDs, not all requirements always apply. Therefore, always check individually for a specific product which of the requirements are applicable or not.

3 Regarding Art. 5(5) a) the devices are not transferred to another legal entity;

The third requirement regulates that in-house IVD may not be transferred to other legal entities. The MDCG gives examples of what a legal entity may be. Some EU member states have differently organized healthcare systems, so there may be differences in the concept of legal entity. Here, the respective national competent authorities should/can provide clarification.

4 Regarding Art. 5(5) b) manufacture and use of the devices occur under appropriate quality management systems/ c) he laboratory of the health institution is compliant with standard EN ISO 15189 or where applicable national provisions, including national provisions regarding accreditation;

Here, the MDCG document clarifies the minimum requirements for a QMS (quality management system) for in-house IVDs, referring to Art. 10(8) of the IVDR. In particular, ISO standards, especially harmonized standards, are to be used where applicable (e.g. manufacturing or risk management). Examples of topics to be covered by the QMS are also given. At this point, a note is made here that ISO 15189 alone will not be sufficient as it does not cover, for example, IVD manufacturing. This indicates that other standards need to be considered, such as ISO 13485 (or ISO 9001).

5 Regarding Art. 5(5) d) the health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market;

This requirement has already provided some points of controversy for interpretation and discussion. The MDCG explains its view on this.
"Market" in this context is understood as "market of CE-marked products in the corresponding member state". The like product must be available to the respective healthcare facility according to EU, national and local rules, and regulations. Depending on where the healthcare facility is located, this may result in different availabilities of the same type of CE-marked product.

"Specific requirements" can be a specific product, or a specified level of performance for specific performance characteristics. The following scenario is possible: a CE-IVD is marketed exclusively for a specific patient population (e.g., adults), although the laboratory may wish to consider other patient populations (e.g., pediatric) for which the CE-IVD is not suitable. A lack of suitability may be that, for example, the critical analyte concentration of the second patient group is in a different range. Interestingly, the avoidance or reduction of (especially painful) sample collection is also admitted as an argument for combining certain products, and thus for the manufacturing and use of an in-house IVD.

There is no definition of "equivalent products" in the IVDR. Therefore, it is worthwhile to have a look at the MDR. There can be technical, biological, or clinical reasons for non-equivalence. This includes, for example, differences in

• intended purpose,
• clinical condition,
• patient groups,
• conditions of use,
• principle of operation,
• sample material, and
• critical performance characteristics or critical technical features.

This justification according to Art. 5(5) d) is the prerequisite or the raison d'être for your in-house IVD. Therefore, appropriate searches must be performed before an In-house IVD is manufactured for the first time.

Note: This requirement will not become effective until 2028. For in-house IVDs that are already in service or will be in service before 2028, this justification does not need to be in place until May 2028. This still gives healthcare facilities sufficient time to integrate an appropriate process for this in the QMS.

In the document of MDCG, the European Database for Medical Devices (EUDAMED) is mentioned as a source for the identification of like CE-marked IVDs. In addition, other sources of information are to be consulted, such as information from manufacturers, distributors, scientific conferences, etc. When the in-house IVD is put into operation after the initial research, it is still necessary to continuously collect information to monitor the market’s developments, and to keep the rationale for your in-house IVD up to date. You have probably already noticed: A well thought-out research strategy is required here (keyword QM processes).

If a CE IVD comes on the market that is like your in-house IVD and meets the specific patient needs with the required performance, you will need to start a transition process to use the CE-marked product.

Conclusion: There are many reasons why a specific requirement of a patient target group is not met, or why there is no like product on the market. Good research and documentation of the facts is the basis of adequate justification for your in-house IVD.

6 Regarding Art. 5(5) e) the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use;

For this purpose, the Guidance gives examples of documents and information that could be requested by the competent authority. You already have most of this information if you properly implement and document compliance with the Annex I requirements for your in-house product.

This includes:

• product description incl. intended purpose and intended use,
• data on the design, manufacturing process, safety, and performance as well as expected benefits,
• justification that no like product exists,
• description of modifications made to the product (change management!),
• overview of the number of units or batches manufactured, including justification, and
• data on the product’s performance during use: performance characteristics, incidents, complaints, and corrective actions taken.

Depending on national requirements, the competent authority must be informed when an in-house IVD is commissioned, modified, or decommissioned/shut down.

7 Regarding Art. 5(5) f) the health institution draws up a declaration which it shall make publicly available …

While the contents of the required public declaration are specified in the requirement itself, it is not yet clear where or how this declaration is to be made public. This may be regulated differently at national level, which is why national laws and regulations must be consulted as well. In Germany, the state authorities are responsible for monitoring the laboratories. In Annex A of the MDCG Guidance you will find a template that you can use for your declaration.

8 Regarding Art. 5(5) g) as regards class D devices in accordance with the rules set out in Annex VIII, the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met. Member States may apply this provision also to class A, B or C devices in accordance with the rules set out in Annex VII;

Here, the data and information required for class D products are mentioned separately. In our experience, you will have this information available if you properly provide and document the evidence of compliance with Annex I. Just as with CE-marked IVDs, the documentation and provision of evidence for in-house IVDs is adapted to the risk class of the product: More risk - more evidence. Moreover, the note that you can follow the structure of Annex II of the IVD Regulation for the technical documentation is applicable to all risk classes. This will help you to create a clear, organized, searchable, and unambiguous technical documentation.

9 Regarding Art. 5(5) i) the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions.

This is about processes, how clinical and performance data are collected, and how incidents and corrective actions are handled. Here, too, national regulations must be observed if you expand your QM system to include this.

10 Regarding Art. 5(5) Sentence 3: This paragraph shall not apply to devices that are manufactured on an industrial scale.

The IVDR does not provide a definition for the term "industrial scale". In this regard, the MDCG states that the exemption of Art. 5(5) only applies to products manufactured in healthcare facilities to meet specific needs of patients. Therefore, the manufacturing process of an in-house IVD should not provide more than the estimated number of products needed.

Final discussion:

Are in-house manufacturers really exempt from most of the requirements of the IVDR, as the MDCG claims? We see this statement as critical. With the obligation to comply with Annex I, a complete technical documentation is finally required, including a system for Post-Market Surveillance (PMS) and Vigilance. You must adapt your QMS accordingly as well as establish and live a risk management system for your products. For your justification that no like CE-marked product is available, you need to update your research permanently, as well as the risk analysis and performance evaluation for your in-house product.

As an in-house manufacturer you do not need an audit of your technical documentation by a notified body. Likewise, the UDI and EUDAMED requirements for in-house products do not apply.

Conclusion

The statement exempt from most of the requirements of the IVDR" is misleading. The implementation of the Annex I compliance requirement will place a large documentation burden on laboratories.

It is open to question whether the MDCG is really helpful for healthcare professionals and researchers whose main focus/main activity is not the development and documentation of products and the implementation of regulatory requirements . At least, it sheds light on some definitions and wording.

If you are interested in an overview of the Art. 5(5) requirements and implementation, see our posts Laboratory Developed Tests (LDT) under the IVDR: New Challenges for Medical Laboratories and IVDR: Shifted Effective Date of Conditions for In-house Products.

Are you unsure what you need to do as a manufacturer of in-house products? We will work with you to develop an individual roadmap for the implementation of the IVDR and Art. 5(5). We are also happy to support you in adapting your QMS and creating the necessary processes. With our help, you will succeed in translating the regulatory requirements into efficient and straightforward documentation. We look forward to getting to know you during a free initial consultation.

Best Regards