General laboratory equipment: What manufacturers and laboratories need to know to avoid problems and unnecessary expense

One assumption persists: General laboratory equipment such as PCR cyclers, NGS devices, fragment analyzers, centrifuges, pipetting robots, and extraction kits must bear a CE-IVD marking. Is this correct?

There is often a lack of clarity about

• what counts as general laboratory equipment and
• whether these must meet the requirements of Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR).

Hence, there are uncertainties,

• what manufacturers of IVDs and manufacturers of general laboratory equipment are allowed to advertise,
• what requirements the respective manufacturers must fulfill, and
• for what purposes medical laboratories are allowed to use these devices,

in order not to make themselves liable to prosecution.

This article provides clarity and gives manufacturers and operators (e.g., medical laboratories) specific tips to avoid regulatory hassle and unnecessary expense.

1. General laboratory equipment: A regulatory classification

The first step is to clarify how the general laboratory equipment is to be qualified. If it falls into the category of IVD medical devices, classification is also necessary.

a) Qualification (overview)

The IVDR distinguishes between several "types" of devices:

1. In vitro diagnostic (IVDs) medical devices, which must bear a CE marking (CE-IVD devices)

2. Devices for performance studies

3. Devices that are manufactured and used only within health institutions established in the Union (in-house IVDs)

4. Devices for General Laboratory Use (GLU)

5. Devices exclusively for research purposes (Research Use Only, RUO)

The IVDR regulates the first three types. The last two, i.e., GLU and RUO, do not fall within the scope of the regulation in accordance with Article 1 (3) a) IVDR.

An exception exists if devices for general laboratory use, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examination.

RUO devices are devices that are intended exclusively for analysis in the context of scientific research.

b) Qualification as "general laboratory equipment"

As with RUO devices, there is no uniform definition for GLU devices.

However, the IVDR provides guidance in Article 1 (3) a): If the device in question has no characteristics that make it suitable for a specific IVD investigation, it is not an IVD. Such devices should be intended for general laboratory use.

Two guidelines are to be considered

Specific examples of general laboratory equipment can be found in two guidelines:

• Guidance document MEDDEV 2.14/ revision 2
• Manual on borderline and classification in the community regulatory framework for medical devices

In the future, the Manual on borderline and classification for medical devices under Regulation (EU) 2017/745 on medical devices and Regulation (EU) 2017/746 on in vitro diagnostic medical devices should contribute to clarification. A chapter on "Borderline between IVDs and general laboratory equipment" has already been created, but unfortunately, it still has no content.

As a revision regarding the IVDR is still outstanding, the two documents mentioned above can still be regarded as the state of the art.

MEDDEV 2.14 provides examples

MEDDEV 2.14/revision 2 provides a comparison of when certain product types qualify as GLU and when they qualify as IVD medical device:

Tab. 1: Comparison of devices for general laboratory use and IVD devices. Non-exhaustive list. Source: MEDDEV 2.14/1 revision 2

This comparison confirms that it depends on the specific characteristics of the devices for general laboratory use whether they qualify as IVDs.

Further examples

However, devices for general laboratory use become IVD medical devices if they are specifically intended by their manufacturer to be used for a specific in vitro diagnostic examination. This is anchored in classification rule 5 of the IVDR (Annex VIII) in particular.

c) Classification

If a device qualifies as an IVD medical device, the manufacturer must assign a class to it.

Classification rule 5 of the IVDR states:

Example qPCR cycler

The above-mentioned qPCR cycler for in vitro diagnostic testing for the detection of C. difficile with a specific IVD kit and associated analysis software falls into class A.

Further examples of class A devices can be found in the MDCG 2020-16:

The guideline provides examples of devices but not in the context of a specific application. As soon as these devices are used for a specific application, they are no longer considered general laboratory equipment.

• “Solutions like cleaners, buffer solutions, lysing solutions, diluents specified for use with an IVD.
• Pipette with a specific fixed one volume specifically intended for a particular IVD test with specified human sample […].
• Kits for Isolation and purification of nucleic acids from human specimens.
• Nucleic acid quantitation kits.“

The last two examples (extraction kit and quantification kit) do neither list specific product characteristics, nor is any reference made to a specific in vitro diagnostic examination. Nevertheless, Rule 5a of Annex VIII of the IVDR states:

Without this connection, these are devices for general laboratory use.

MEDDEV 2.14/revision 2 is much clearer in its comparison (see Tab. 1) than the MDCG document.

2. Tips for manufacturers

Tip 1: Define the intended purpose precisely

Manufacturers should first know or define their product description, including the intended purpose, because qualification depends on this.

Tip 2: Weigh up the benefits of certification

For devices in the "gray area," it is conceivable to start with the desired qualification and then formulate the intended purpose accordingly. You can be guided by the question of whether CE-IVD marking actually offers added value for the customer or whether it entails higher effort and costs for the operators.

Tip 3: Do not use the CE mark for marketing purposes

Summary

Manufacturers should not use the CE-IVD marking for marketing purposes. The CE IVD marking has far-reaching regulatory and legal consequences. If it is an IVD medical device, the manufacturer must also provide the corresponding evidence. If he is unable to do so, the manufacturer must expect legal consequences.

Derivation Part 1: Specific uses

If it is an IVD medical device, the IVD must possess specific properties that make it suitable for one or more specific in vitro diagnostic applications. MEDDEV 2.14/1 rev. 2 stipulates this:

The guideline further specifies:

Accordingly, the manufacturer is even prohibited from CE-IVD marking a device if it does not have characteristics that make it suitable for one or more specific in vitro diagnostic examinations.

Derivation Part 2: Sample preparation

Specifically, MEDDEV 2.14/1 rev. 2 addresses devices used in connection with the preparation of human specimen materials. These are generally not considered to be IVD medical devices:

Derivation Part 3: Regulatory requirements

Irrespective of whether the products are reagents, instruments, or other pieces of equipment or apparatus for general laboratory use, the following applies:

Suppose the manufacturer claims that the device is intended for in vitro diagnostic use, he must provide evidence of these specific properties and the link to the particular in vitro diagnostic procedure.

The Manual on borderline and classification in the community regulatory framework for medical devices writes:

This means that if the device is an IVD medical device, the manufacturer must comply with the associated regulatory requirements: He must provide evidence that the device meets the general safety and performance requirements set out in Annex I, considering its intended purpose, and prepare and maintain a technical documentation in accordance with Annexes II and III.

However, if the device does not fall within the scope of the IVDR, this saves the manufacturer a lot of effort.

Tip 4: Prefer GLU to RUO

Create clarity and use the term "General Laboratory Use" (GLU) instead of "Research Use Only" (ROU).

While doing so, manufacturers will not have to explain why they sell RUO devices to medical laboratories. As general laboratory reagents or devices for general laboratory use may be used for in vitro diagnostic procedures.

Tip 5: Consider further legal requirements

Irrespective of qualification as an IVD medical device, manufacturers may have to comply with other EU requirements that are not specifically intended for IVD medical devices. GLU devices, in particular, are subject to the Machinery Directive or Machinery Regulation and must, therefore, be CE-marked to proof conformity.

4. Tips for medical laboratories

Tip 1: Avoid off-label use

General: If medical laboratories use devices for general laboratory use in in-house procedures, they are responsible for the conformity of the examination with the IVDR.

This also applies if they use devices outside their intended purpose or outside their intended use.

Therefore, laboratories should always check the manufacturer's exact intended purpose for CE-IVD-marked devices. This includes information on the combination in which devices shall be used, i.e., device A with kit B and software C.

The CE-IVD marking refers exclusively to the intended purpose stated by the manufacturer.

Suppose a device is used in a different context (i.e., different product combinations, different indications, etc.), the laboratory quickly becomes the manufacturer of an in-house IVD with all resulting consequences.

Therefore, the blanket use of CE-IVD-marked devices is not always appropriate.

Tip 2: Be careful with in-house manufacturing

If a medical laboratory manufactures an IVD medical device "in-house," it must demonstrate conformity with the general safety and performance requirements for this in-house IVD in accordance with Annex I of the IVDR.

This applies regardless of whether the laboratory applies a "misused" CE IVD device or a GLU device.

Reference is made in particular to Annex I of the IVDR:

Tip 3: Carefully check the manufacturer's marketing claims

Medical laboratories should carefully check the information provided by manufacturers of CE-IVD-marked devices:

Is the CE-IVD marking non-specific?

Does the manufacturer neither provide specific product properties nor a reference to a specific examination? The device is illegally marked as CE-IVD.

What do the instructions for use and product information say?

Does the in-vitro diagnostic application relate to a specific procedure with specific product combinations? If these do not correspond to the laboratory routine, the CE-IVD marking is worthless for the laboratory.

Tip 4: Keep a list of what devices are used for

Keep a list of all devices (medical devices, IVD medical devices, GLU, RUO) and refer to the intended purposes and examinations that are used in your laboratory in connection with the respective device.

This provides an overview of all the procedures used and allows you to check whether the intended purposes specified by the manufacturer match your intended use. If not, it is an in-house development.

For the procedure - as an in-house IVD - you must check and document that the procedure meets the general safety and performance requirements and the additional requirements of Article 5 (5) of the IVDR.

Furthermore, this list can be used to identify examination procedures for which no adequate CE-IVD device is available on the market. It thus provides you with a basis for building justifications regarding the requirement arising from Article 5 (5) d) of the IVDR.

5. Summary and conclusion

a) Devices without specific characteristics often count as GLU

Many devices used in in-vitro diagnostic applications fall within the scope of devices for general laboratory use (GLU).

However, if these devices have specific properties that make them demonstrably suitable for a particular in-vitro diagnostic examination, manufacturers must mark them with a CE-IVD mark, with the resulting regulatory consequences.

Devices for general laboratory use without these specific properties do not fall within the scope of the IVDR but may still be used for in vitro diagnostic examination.

b) The intended purpose has consequences for manufacturers and laboratories

When combining devices for general laboratory use and IVD medical devices as part of a laboratory-specific procedure, the intended purpose of the individual devices must always be considered: The laboratory may have (unknowingly) developed an in-house IVD and is fully responsible for the procedure.

Medical laboratories should know the intended purpose of the devices they use and compare this with the intended purpose of their own examination procedures. This will enable them to determine whether the use of a CE-IVD-labeled device is appropriate or useful at all.

c) A certified device is not better per se

With the involvement of customer requirements, manufacturers should consider whether qualification as an IVD medical device actually provides added value.

If the device is not an IVD medical device, it contributes to clarity and legal safety if manufacturers refer to it as a "GLU" device instead of the RUO marking.

Support

The IVD team at the Johner Institute will support you:

• It helps you qualify your devices or examination procedures, for example, with in-house workshops on approval strategy and in-house IVDs.
• It provides you with expert opinions on the qualification of your device, which you can submit to your customers and/or notified bodies.
• It supports you in all activities up to the "certification" of your device (e.g., performance evaluation) and beyond (e.g., post-market surveillance).

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