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:
- In vitro diagnostic medical devices (IVDs), which must bear a CE marking (CE-IVD devices)
- Devices for performance studies
- Devices that are manufactured and used only within health institutions established in the Union (in-house IVDs)
- Devices for General Laboratory Use (GLU)
- 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.
“This Regulation does not apply to:
(a) products for general laboratory use or research-use only products, unless such products, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examination;”
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.
Devices for general laboratory use either do not fall within the scope of the IVDR (general case) or they count as “CE-IVD” and are assigned to class A (more on this later).
RUO devices are devices that are intended exclusively for analysis in the context of scientific research.
Read more here: Laboratory products for “Research Use Only” (RUO) – often a dangerous claim.
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.
Nevertheless, these devices may be used in the context of in-vitro diagnostic examination procedures, even if they are not IVDs themselves.
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
Both documents still refer to the EU Directive 98/79/EC on in vitro diagnostic medical devices (IVDD). Nevertheless, they introduce essential concepts for the definition of “general laboratory equipment,” contribute to a general understanding of the regulatory requirements, and standardize their interpretation.
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:
| Laboratory use product | Covered by IVD Directive | |
| Centrifuges | General centrifuges, cytospin | Hematocrite centrifuge |
| Pipettes | General purpose pipettes (e.g., single or multiple pipettes, plastic pipettes, Pasteur pipettes) | Blood coagulation pipettes with automatic timing (Accessory of coagulometer) |
| Tubes and flasks | Erlenmeyers, plastic tubes | Blood collection tubes, urine sample containers |
| Plates | Empty ELISA plates, empty Petri dishes | Coated microtiter plates for the diagnosis of Lyme’s disease |
| Nucleic Acid extraction products | DNA and RNA extraction kits that only provide a specimen without an intended IVD detection combination | DNA and RNA extraction kits intended to provide a specimen to be used with an IVD device (validation for at least one combination is to be provided) |
| General equipment | Scales, balances, microtomes, incubators, sterilizers for laboratory equipment, paraffin embedding machine | |
| HPLC products | size-exclusion HPLC columns | HPLC columns for IVD purposes: e.g., HbA1c |
| Detection equipment | Mass spectrometer, spectrophotometers, ELISA readers providing raw data which is not readily readable and understandable by the user (e.g., peaks, OD) | McFarland bacteria density testing |
| Others | Foetal calf serum, cell culture media, fixation solution, mounting media, buffers (e.g., PBS), chemicals (e.g., sulphuric acid, formol, water) |
This comparison confirms that it depends on the specific characteristics of the devices for general laboratory use whether they qualify as IVDs.
Further examples
A non-specific centrifuge does not fall under the IVDR as general laboratory equipment.
However, a hematocrit centrifuge whose rotor has been specially designed so that it can be loaded with hematocrit capillaries in accordance with EN ISO 12772 and which enables the hematocrit value to be read directly from the device is an IVD medical device.
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.
Extraction kit A for the extraction of RNA and DNA from EDTA blood is specially intended by manufacturer X for the qPCR-based in-vitro diagnostic examination in combination with qPCR kit B on the C system from manufacturer X. This extraction kit is an IVD and bears a CE mark.
A qPCR cycler without specific properties that can be used with any qPCR kit from any manufacturer (if the channel for the corresponding probe labeling is available) and provides raw data as output (e.g., melting curve diagrams) is a device for general laboratory use. CE-IVD labeling is not permitted (see chapter 2.a).
Suppose the qPCR cycler is intended by the manufacturer to be used for in vitro diagnostic testing to detect C. difficile with a specific IVD kit and associated evaluation software, the cycler becomes a CE-IVD medical device.
Please note: If a kit other than the one declared by the manufacturer is used on this particular CE-IVD cycler, even though it is also used for the detection of C. difficile, the cycler is used off-label and the CE-IVD marking no longer offers the operator any advantage (see chapter 2.b).
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:
“The following devices are classified as class A:
(a) products for general laboratory use, accessories which possess no critical characteristics, buffer solutions, washing solutions, and general culture media and histological stains, intended by the manufacturer to make them suitable for in vitro diagnostic procedures relating to a specific examination;
(b) instruments intended by the manufacturer specifically to be used for in vitro diagnostic procedures; […]”
IVDR, Annex VIII, Rule 5
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:
„Rule 5a applies to general laboratory products like pipettes, stain powders, glass microscope slides, centrifuges, pipette tips or instrument liquid collection containers, buffers which usually do not fall under the definition of an IVD medical device.”
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:
“[…] intended by the manufacturer to make them suitable for in vitro diagnostic procedures relating to a specific examination;”
IVDR, Annex VIII, Rule 5a
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.
However, certain device dependencies must also be considered in this context. A higher classification may be necessary if an analysis software is embedded in the device.
An example is a qPCR-based point-of-care devices. The device is not only capable of performing qPCR and generating melting curve diagrams but also provides diagnostic information directly via the embedded analysis software, e.g., the amount of one or more specific pathogens in the human sample examined.
Read more about this topic here: Classification of in vitro diagnostic medical devices: How to avoid over-classification
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 qualification provided for in the Directive is where, on the basis of its characteristics, a manufacturer specifically intends that the product should be used for in vitro diagnostic examination. In this case, the product becomes an IVD and must comply with the applicable essential requirements of the IVDD and therefore must be CE marked.”
MEDDEV 2.14/1 rev. 2
The guideline further specifies:
“If, however, the product does not possess specific characteristics that make it suitable for one or more identified in vitro diagnostic examination procedures, then the manufacturer is not allowed to qualify its product as an IVD. A manufacturer is not allowed to affix the CE mark on a piece of general laboratory equipment as a marketing claim. Merely adding the statement “for in vitro diagnostic use“ to a product is not sufficient to qualify a product as an IVD.”
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:
“Products used in vitro in the preparation of samples that have been obtained for examination are considered neither as IVD nor as accessories and fall outside the scope of the Directive unless, based on their characteristics, they are specifically intended for a particular IVD test. The validation of this specific combination shall be clearly documented in the technical documentation.”
MEDDEV 2.14/1 rev. 2
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:
“If this [product] possesses such specific characteristics, the manufacturer will have to demonstrate these specific characteristics and the link with one or more identified in vitro examination procedures.”
Manual on borderline and classification in the community regulatory framework for medical devices, Part 1.5
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.
Read more on the topic here: Machinery Directive: What applies to medical devices
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.
If a laboratory uses a CE-IVD-labeled NGS device, then, according to the manufacturer’s intended purpose, the in vitro diagnostic application is related to a specific examination procedure, such as the detection of CFTR mutations with a corresponding kit and the associated analysis software from the same manufacturer.
If the laboratory now uses exactly this NGS device to detect mutations in entirely different genes, for example, a breast cancer panel analyzed with a different NGS kit (perhaps even from a different manufacturer) and an in-house developed NGS pipeline, then the CE-IVD mark is worthless for the laboratory.
Under these circumstances, the laboratory could have purchased a cheaper GLU NGS device from the manufacturer, as the laboratory is responsible for the conformity of the procedure anyway.
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:
“If the device is intended for use in combination with other devices or equipment, the whole combination, including the connection system, shall be safe and shall not impair the specified performances of the devices. Any restrictions on use applying to such combinations shall be indicated on the label and/or in the instructions for use.”
Annex I, Chapter II, Part 13.1 of the IVDR
Read more on the topic here: The EU regulates medical laboratories. Are in-house IVDs (LDTs) still allowed?
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.
Read more on the topic here: The EU regulates medical laboratories. Are in-house IVDs (LDTs) still allowed?
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.
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).
