In Focus
In-Vitro Diagnostic Regulation (IVDR) and laboratory developed tests/reagents
A grip on in-house tests
Sofia Lejon-Crottet
Swiss National Immunohematology Reference Laboratory, Interregional Blood Transfusion SRC, Berne, Switzerland
The requirements of regulations worldwide is a challenge for both commercial in vitro diagnostic medical device (IVD) manufacturers and laboratories that develop and manufacture IVDs.
Due to a lack of suitable commercially available tests, medical laboratories often use in-house developed tests or modify commercial tests adapted to specific requirements (e.g. anticoagulant, sample volumes). The field of transfusion medicine is not an exception.
The impact of the IVD regulation in the immunohaematology laboratory was discussed during a recent Working Party meeting break-out session. Which laboratory developed tests/reagents are used in the immunohaematology reference laboratory, how can they be authorised (e.g. in-house IVD) or what are the options?
The impact of IVDR in the Immunohaematology Laboratory
The introduction of in-vitro diagnostic regulations (IVDR) has a profound impact on immunohaematology reagents. Currently, IVD regulations are not harmonised globally, and this results in variable requirements and increased costs to manufacturers when registering reagents in different markets. Where the local market is small, companies may choose not to register products if the cost and work required for local registration outweighs the return from the market. This significantly limits competition and increases costs for routine reagents used primarily in pre-transfusion testing.
IVDR has resulted in a significant rationalisation of products, with some low volume products being removed from the market. For example, commercial lectin kits are no longer available for the investigation of red cell polyagglutination. There are also some benefits from this rationalisation, with harmonisation of manufacturing processes in global companies that have multiple manufacturing sites. This improves consistency and ensures there is a genuine alternative for business continuity.
The impact has been greater in the immunohaematology reference laboratories as many reagents used in this area are laboratory developed (in-house) or commercial products only for research use. The best example for this impact is the valuable source of a wide variety of well characterised donor test cells and patient’s antisera, which do not fulfill the requirements per se (e.g. rare reagent test cells, rare antisera, etc). Commercially registered IVDD are also restricted to use according to the manufacturer’s instructions. This includes sample type, transport, and storage conditions. These may limit the suitability of a sample for testing. For example, if a non-anticoagulated sample is collected and serum is not specified as a valid material, testing of serum becomes an in-house application and requires time consuming validation and method registration by the laboratory.
Laboratory Developed Test/Reagents
Reagent red cells and antisera derived from patient and donor samples that are not readily available from commercial companies are used routinely for antibody investigations in the reference laboratory and are considered laboratory developed (in-house) and require a method registration. Many other routine reagents used in the reference laboratories, including chemicals (DTT, AET), enzymes (trypsin, α-chymotrypsin) and recombinant blood group proteins also require registration. Whilst IVDR provides structure and guidance to manage risk and ensure safety and quality of the manufacturing process, this has imposed a significant increase in work and costs to obtain and maintain registration.
In molecular testing, further challenges are found. The sample type may be the first hurdle to be encountered. If the registered commercial IVDD lists whole blood EDTA as the sample type for DNA extraction, then DNA extracted from an alternate source, e.g. buccal swab, amniocytes etc., would require validation and registration as an in-house method.
Summary
In summary, the implementation of IVDR offers the opportunity for better control of the medical devices of the diagnostics industry and sets minimum standards for laboratory developed tests. On the other hand, this implementation may include supply bottlenecks for niche tests, as well as barriers for innovation, both in industry as well as in the area of medical laboratories that develop innovative tests themselves.
Another problematic consequence is/could be that reagents have been/will be withdrawn from the market due to considerably increasing documentation requirements, which in the end could have a significant impact on patient safety.
Finally, due to the absence of commercially available IVDR conformed reagents for the immunohematology reference laboratory, the need for laboratory developed tests will remain indispensable.
