In Focus
The transition to non-DEHP blood bags
Replacing plasticizers by 2030 - the search for viable alternatives
The paradox of the blood bag plasticiser di(2-ethylhexyl) phthalate (DEHP) is well-known these days: there are both advantages and concerns with DEHP usage.
For more than 70 years, the use of DEHP in blood bags has been a central factor in preserving the red blood cell (RBC) quality during storage. In addition to making the blood bags soft, flexible and resistant to mechanical forces during processing, DEHP comes with a bonus feature: stabilisation of the RBC membrane. Conversely, storage in a non-DEHP environment has previously been linked to unacceptable haemolysis levels, increased microvesicle formation and reduced post-transfusion RBC survival.
However, there are also concerns related to DEHP; foremost to potential endocrine-disruptive toxicity. Although a solid body of evidence of toxic impact on the human species has not been presented, concerns remain for extensive exposure, such as repeated transfusions or frequent apheresis donation. A series of regulatory provisions led by the publishment of Regulation (EU) 2017/745 on Medical Devices, therefore ban the use of DEHP in blood bags within the EU and beyond, with the sunset date set to July 1st, 2030.
Three main non-DEHP plasticiser candidates
Removing DEHP from blood bags while maintaining acceptable RBC component quality has proven to be a challenge. Numerous potential plasticisers have been investigated, but few seem to live up to basic requirements such as not introducing new (known) toxicity, not leaching excessively into the component, and not reducing RBC quality. So far, there seem to be three realistic options: di(2-ethylhexyl) terephthalate (DEHT), 1,2-Cyclohexanedicarboxylic acid, diisononyl ester (DINCH) and n-butyryl tri-n-hexyl citrate (BTHC). All of these seem to provide satisfactory RBC quality, on the condition that the additive solution is simultaneously upgraded to the next-generation phosphate-adenine-glucose-guanosine-saline-mannitol (PAGGSM).1-5 Storage of RBCs using DEHT+PAGGSM or DINCH+PAGGSM has been shown to provide red cell quality comparable to storage in DEHP blood bags with traditional saline-adenine-glucose-mannitol (SAGM) additive solution.
BTHC was for some time considered inferior compared to DEHT and DINCH for RBC storage, but more recent studies, where a combination of DINCH and BTHC was used, suggest RBC quality is more or less similar to storage in DEHT or DINCH alone.4, 6 In other words, at least according to in vitro data, the transition to non-DEHP blood bags appears possible.
Yeah, in vivo studies would be nice, but…
The relevance of in vivo studies to ensure the quality, safety and efficacy of RBCs stored with new plasticisers, is currently being debated. Unarguably, in vivo data adds another piece to the overall assessment of a plasticiser’s suitability to replace DEHP, such as 24-hours post-transfusion survival of the RBCs6, 7. However, in vivo studies are both costly and time-consuming, and in practice, very few blood establishments have the capacity to conduct them. The Biomedical Excellence for Safer Transfusion (BEST) Collaborative recently published a position paper where a mandatory requirement for in vivo data was discouraged8. A key limitation of in vivo studies is that any potential toxicity of the alternative plasticisers will likely, just like for DEHP, only show as long-term effects, and events may be too rare to be captured.
…clinical monitoring may be more beneficial to capture the foreseen risks
An alternative approach may be a clinical monitoring programme; an option supported by the EuroGTP II Risk Assessment Guide9. When assessing the risk of switching to non-DEHP blood bags using the associated tool, the outcome (definition of extent of studies needed) will likely correspond to “low” or “medium” risk, i.e. recommendation of a follow up programme complemented by, where needed, collection of a specified data set. Furthermore, serious transfusion reactions and adverse events reporting will be pivotal. It may therefore be considered to extend conventional reporting parameters to reflect the plasticiser used, to enable long-term following up on whether specific adverse events can be related to blood bag plasticiser.
Huge validation pressure on the blood establishments
Once new blood bags are commercially available, a huge validation effort is foreseen for the blood establishments. All components downstream of whole blood will need to be revalidated, even though platelet- and plasma components will likely only need minor qualification. As the blood bag manufacturers are anticipated to choose different plasticisers, several combinations of plasticisers and additive solution will need to be assessed. To facilitate the work, blood establishments will likely need to collaborate and exchange validation data. For this purpose, a working group under European Blood Alliance has published recommendations for in vitro validations for blood components collected, prepared and stored in non-DEHP blood bags.10 A harmonised approach is encouraged, including which parameters to assess, number of units and which processing parameters to monitor. The latter will be key to document, as sharing of validation results will only be possible between blood establishments that have similar preparation processes. Communication with the competent authorities to ensure that leaning on other blood establishments’ results is accepted, will also be elemental.
Figure 2: Plasticiser and AS combinations
What can we do to prepare for the transition?
While waiting for DEHP-free blood bags to enter the market, numerous activities can be performed to prepare for the upcoming transition:
- Create evaluation plans! Prepare for the required validations (time, resources, methods, staff training…) and clinical monitoring.
- Liaise with blood services using similar manufacturers, processes and/or blood components! Start discussions of sharing data/cooperation on the validations.
- Create a plan B if the blood component quality turns out to be non-satisfactory. Are there elements of the processing strategy that can be changed?
- Consider flexible contracts with the blood bag manufacturers. Is it possible to switch to corresponding non-DEHP disposables whenever available?
- Communicate with the competent authorities around legislative requirements. In the EU, this may be extra important in light of the new SoHO regulation and the associated SoHO preparation authorisations, as well as distribution, import and expert of blood components of different plasticisers between blood establishments.
- Finally, stay up-to-date with information and be ready to go earlier than 2030 – manufacturers may choose to transition to DEHP-free blood bags ahead of the final sunset date!
References
1. Larsson L, Sandgren P, Ohlsson S, Derving J, Friis-Christensen T, Daggert F et al. Non-phthalate plasticizer DEHT preserves adequate blood component quality during storage in PVC blood bags. Vox Sang, 2021. 2. Lagerberg JW, Gouwerok E, Vlaar R, Go M, de Korte D. In vitro evaluation of the quality of blood products collected and stored in systems completely free of di(2-ethylhexyl)phthalate-plasticized materials. Transfusion, 2015. 3. van Wonderen SF, Vermeulen C, Lagerberg J, Vlaar APJ, Klei TRL. Combinations of Non-di(2-ethylhexyl) Phthalate Collection Sets, Storage Bags and Additive Solutions for Red Blood Cells. Transfus Med Rev, 2025. 4. Vermeulen C, den Besten G, van den Bos AG, Go M, Gouwerok E, Vlaar R et al. Clinical and in vitro evaluation of red blood cells collected and stored in a non-DEHP plasticized bag system. Vox Sang, 2022. 5. Stephenson T, Howell A, Olafson C, Sumain C, Reichenberg S, Brebant Q et al. In vitro quality of whole blood-derived red cell concentrates collected, processed and stored in a blood bag set plasticized with di (2-ethylhexyl) terephthalate. Vox Sang, 2025. 6. van Wonderen SF, Vermeulen C, Lagerberg J, cvan Amstel RBE, Ribble L, Sedjo RL et al. In vitro and in vivo evaluation of leukoreduced red cell concentrates stored in non-DEHP storage bags. Vox Sang, 2026. 7. Brown BL, Mack SM, Mason E, Wellington M, Rugg N, Marschner S et al. In vivo recovery and in vitro quality assessment of apheresis red blood cells stored for 42 days in non-DEHP disposable sets. Vox Sang, 2026. 8. Brown B, Klei TRL, Kanias T, de Korte D, Cancelas JA, Cardigan R. Clinical evaluation of novel blood collection and storage bags containing alternative plasticizers to DEHP: Recommendations from the BEST collaborative. Transfusion, 2025. 9. Good practices for evaluating quality, safety and efficacy of novel SoHO preparations, Blood component specific chapter. 2021–2023, European Directorate for the Quality of Medicines and Healthcare, co-funded by the European Union and the Council of Europe. 10. Klei TRL, Begue S, Lotens A, Sigurjónsson ÓE, Wiltshire MD, George C et al., Recommendations for in vitro evaluation of blood components collected, prepared and stored in non-DEHP medical devices. Vox Sang, 2023.
