The Metrology for Drug Delivery project, funded by the EMRP (European Metrology Research Programme), started in 2012.

The initial joint research project (JRP) aimed to develop:

  • traceable calibration services for drug delivery systems for flow rates down to 1 nl/min transfer standards for onsite calibration
  • assessment of the drug delivery devices
  • a best practice guide for drug delivery

This JRP was finalized in 2015 – see report for a full description. As part of the development of the metrological infrastructure, the researchers also investigated parameters that influence the accuracy of the treatment, related to human behavior and equipment. This knowledge was disseminated in a first e-learning.

Metrological infrastructure and best practices

To improve the accuracy and efficiency of patient treatment, methods needed to be developed for the reliable and accurate delivery of drugs to patients. In order to do this, the metrological infrastructure for pharmaceutical drug delivery needed improvement. Between 2012 and 2015, the consortium improved the infrastructure, consisting of traceable calibration services for drug delivery systems for flow rates down to 10-100 nl/min. This is several orders of magnitude lower than the lowest calibration service available in Europe at that time; the primary standard went down to 16 ul/min, however below 100 ml/min there had never been a formal validation of primary standards by means of a (key) comparison. Read more about the new metrological infrastructure.

The Best Practice Guide that resulted from the project is based on the assessment carried out for drug delivery devices. It focuses on the safe and sound usage of various types of drug delivery devices. Read more about the assessment and the Best Practice Guide.

Why was the project initiated?

There are various examples where adverse incidents, morbidity and/or mortality, can be traced back to poor drug delivery. Consequently, the health community using (multi-pump) infusion technology needed new calibration services and improved knowledge and understanding of the equipment they are using. Infusion technology suppliers needed traceability and lower calibration uncertainties in order to improve their products. Finally, hospital technicians in charge of the maintenance of the infusion pumps needed a better understanding of the impact of the physical parameters and needed better equipment for their cross checks.

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The following partners contributed to the initial project as part of the consortium:

VSL is the Dutch Metrology Institute. The flow laboratories include a broad range of primary and secondary flow standards.

Dr Peter Lucas, Research Scientist at VSL, explains why this project is important: “For special drug delivery applications the required accuracy on the dosing is not met with current infusion devices. In this project we will address the potentially inaccurate dosings by infusion devices, by means of an elaborated test program. Especially for very low flow rate applications, say lower than 1 ml/h, as well as for multi-pump infusion applications, it is a challenge to deliver the right amount of medication. Furthermore, we will work together with (academic) hospitals to make them more aware of the importance of metrology.”

VSL is the coordinator of this project, “hence VSL is responsible for the final results and outcomes. But of course, VSL will also have technical contribution to the project: “VSL is involved in developing a standard for ultra low flow rates (lower than 1 ul/min), testing of (commercial) flow meters and testing of infusion devices”. Furthermore, VSL works together with a flow manufacturer to test and develop a flow meter for ultra-low flow rates.”

Mr Lucas emphasizes that the results of this project not only improves drug delivery: “There is an increasing demand for liquid flow rate calibrations in the low flow range. Applications include amongst others infusion technology, HPLC and general requests from flow meter manufactures. Currently, we cannot meet the demands of our clients.”

LNE-CETIAT (Centre Technique des Industries Aérauliques et Thermiques) is a study, testing and calibration laboratory in the fields of aerodynamics and fluid mechanics, heat sciences and acoustics. LNE-CETIAT calibration range cover 1 ml/h to 36 m3/h for water flow. With its calibration facilities and expertise in small flow of liquid, LNE-CETIAT was an evident partner for the MeDD project.

Dr. Ing. Christopher David: “With the increasing needs for efficiency and to overcome the environmental issues (lower the waste), miniaturization of all processes is a true challenge. Health is not drawn aside and the control of low liquid flows is now a key parameter for research activities, dosing of medicines and stabilization of patients.”

In the MeDD-project, LNE-CETIAT will contribute by harmonization of practices and results obtained by the different National Metrological Institutes (organization of inter-laboratories comparisons), the characterization of drug delivery devices and accessories and the dissemination of knowledge via scientific papers and congress organization

Mr David: “The main challenge for LNE-CETIAT related to this project is to overcome the differences in technical practices of flow measurement within the MeDD group in order to be able to compare calibration results. This experience will help in the harmonization of flow measurement uncertainties and offer the possibility to disseminate this knowledge to others calibration facilities.”

The Czech Metrology Institute (CMI) is a governmental organisation with long experience in technical and legal questions in liquid flow measurement. Using its gravimetric and volumetric flow standards CMI offers calibrations and verifications of all types of flow-meters in a wide range of flow-rates for various kinds of fluids.

Mr Jan Gersl (research worker at the Department of flow and heat) thinks the results of the MeDD-project will have impact in real life situations: “…and it potentially can improve quality of life for people who depend on permanent medication”. He explains: “Metrology for drug delivery is an interesting and important topic and at the same time it gives us the opportunity to work together with other institutes and to learn in the fields of micro and nano flow and in the field of computational fluid dynamics.”

CMI will contribute to the project mainly by supporting other project partners in their developments: “Our company helps other participants by means of computer simulations of flow and heat transfer in physical situations that occur in their standards. E.g. we make a simulation of temperature distribution and temperature evolution in the flow standard of VSL, based on thermal expansion of a fluid. Or we simulate an interaction of a pipe with weighing systems in case of DTI. We use OpenFoam software for the simulations. The biggest challenge is to obtain realistic predictions with sufficient accuracy from the numerical model.”

Danish Technological Institute (DTI) is a self-owned and not-for-profit institution with over 1000 employees. DTI develops, applies and disseminates research and technologically-based knowledge for the Danish and international business sectors. DTI has been working with flow calibration for more than 30 years, with micro flow calibration since 2008 and in general with micro- and nano fluidic systems since 2006.

Mr. Claus Melvad, project leader and consultant at DTI: “Our current customers in the micro and nano flow laboratory are mainly the pharmaceutical industry and manufacturers of medical devices. We have chosen to participate in this promising project to meet the increasing demands below our current range which goes down to 16 µl/min as well as to learn more about the health care sector in other countries.”

“The correct use of the different infusion pumps and systems is often experience-based and the experiences and procedures vary a lot internationally and even nationally” says Mr. Melvad. “MeDD is an initiative to reduce variances in critical patient care across different manufacturers which could help save lives. But without SI traceability it is difficult to compare procedures and measurement results.”

“DTI has strong connections to several stakeholders within national and international manufacturers of medical devices and will lead the impact work package.” DTI is also involved in the development of a new gravimetric standard with nano flow measurement capabilities and with the unique feature to include the dynamic behavior. Using this new gravimetric standard DTI will carry out a number of tests of commercially available flow meters and infusion pumps to characterize their behavior under real conditions. DTI also participates in the development of a flow meter for ultra-low flow rates.

IPQ (Instituto Português da Qualidade) is the national metrology institute of Portugal and partner of the Joint Research Project “Metrology for Drug Delivery”.

Mrs Elsa Batista, Head of Volume Laboratory at IPQ, explains why IPQ participates in the project: “There is a national and international need for traceability in the microflow range. For us, achieving the low measurement range of 1nl/min is a real challenge, but in a broader context this project will have an impact on all of us as it will make drug delivery more reliable and robust through the traceability assurance and performance analysis of drug delivery systems.The results of this project will be very useful to the medical community in order to be more familiar with the problems and solutions of performance of drug delivery devices.”

IPQ will participate in the method comparisons and improvement of the gravimetric measurement setup down to 100nl/min. This will result in a gravimetric primary standard with an weighing scale evaporation trap. IPQ will also participate in the performance tests of several drug delivery devices and it will participate in the dissemination of results.

The Federal Office of Metrology (METAS), part of the Department of Justice and Police (EJPD) realises and disseminates internationally harmonised and recognised units of measurement with the necessary accuracy. It supervises the deployment of measuring instruments in the fields of commerce, traffic, public safety, health and environment. One of its technical fields is Flow.

METAS has been working in the domain of micro flow for two years. Dr Hugo Bissig (Scientist) of METAS: “We have developed a system to determine liquid flow down to a few μl/min with an accuracy of a few percent. Therefore, it was evident for METAS to participate in this project.”

Calibration services at ultra-low flow rates need to be harmonized and improved to lower the measurement uncertainty. According to Mr Bissig this is not only important for hospitals, but in the first place for manufacturers of drug delivery devices to improve the products: “Products like applications and flow sensors can be improved if we can offer calibration services and the knowledge in this field at ultra-low flow rates in order to increase the accuracy of their measurements.”

METAS will contribute to the development of the primary standard. Mr Bissig: “the primary standard will cover flow rate ranges from 1 ml/min down to 100 nl/min with the aim of 10 nl/min and with the possibility of investigating the influence of pulsating flow.”

TUBITAK is the National Metrology Institute of Turkey. By participating to the MeDD-project they hope to extend their knowledge about micro flow rates and also to be able to service the health sector for accurate drug delivery.

Mrs Başak AKSELLİ has noticed an increasing demand of calibration and testing services for medical devices from hospitals and suppliers of medical equipment in Turkey. “To be able to satisfy this grooving demand we need to expand our calibration range. This project will lead to better primary and secondary standards for micro and nano flow rates.”

But according to Mrs Akselli, the project will also show the importance of metrology to the health sector: “We have noticed that people in the health sector do not know much about metrology and the importance of accurate measurement. MeDD will show the importance of flow metrology to both suppliers and end users of drug delivery devices.”

TUBITAK will contribute to the MeDD-project by developing a new standard based on the so-called micro-PIV technique: “We have developed a micro-PIV system which is an optical flow measurement technique. For PIV measurements, the fluid of interest is seeded with tracer particles that are illuminated by a sheet of bright light. The positions of these particles at different times are recorded by a camera. By measuring the particle displacements, the motion of the fluid can be ascertained.  We will employ this technique to measure the flow rates in micro channels/pipes for steady and unsteady flow conditions. Unsteady flow investigations, which are mainly the pulsations created by pumps, is one of the challenges when talking about Metrology for Drug Delivery.”

]The Medical Devices and Sensor Technology department of the Luebeck university is part of the joint Competence Center for Technology and Engineering in Medicine (TANDEM). They develop medical devices and relevant components.

Dr. Stephan Klein and Dr. Bodo Nestler (project leaders) are happy to join the MeDD project: “Flow standards for low flows of drugs are required e.g. to improve implantable infusion pumps and patient treatment. Moreover, it offers a great opportunity to compare our method with other approaches from other groups and develop a reliable measuring device for the characterisation of microflow components.”

Luebeck University will develop a new test set-up to apply an optical method to measure low flows down to 1 nl/min. “It is a great challenge to meet the technical requirements.”

Medication errors constitute one of the highest risks to patient safety. Dr. Annemoon Timmerman (Clinical Physicist and Patient Safety Officer at the Medical technology and Clinical Physics department) of UMC Utrecht: “In the past few years international authorities have reported numerous adverse events concerning the incorrect use or application of infusion technology in hospitals.”

Mrs. Timmerman explains the challenge: “Flow rates can be unpredictable and deviate from its set point, especially in multi-infusion set ups. MeDD gave us the opportunity to fine tune our measurement methods and develop a model to predict the actual flow rate to the patients blood stream. With the research we can help medical personnel to get to the bottom of how drug delivery really works. This helps our patients to get the right drug delivery treatment at the right time.”

“The model we developed was validated using in vitro experiments. Now we are ready for the next step: to help infusion pump users to learn how their multi-infusion systems work in clinical practice, what the pitfalls are and how they should use them. Therefore, we will use our knowledge to make a user friendly e-learning in close cooperation with the European Society for Intensive Care Medicine and clinical users. We hope we can collect as many relevant clinical cases as possible, to tie in with clinical practice and really improve the care for our patients.”

As an academic hospital, UMC Utrecht adds important experience to the MeDD-project: “We have substantial experience in multi-infusion measurement and research. However, the measurement system used has its drawbacks. With the current UMC method we can simulate up to four infusion pump flows, but it remains uncertain how the properties of these dyes relate to the flow of actual drugs. Our multidisciplinary and experienced team of clinicians, nurses, physicists and engineers contributes to the ultimate goal: to make drug delivery more reliable and robust. We will participate in the collection of measurement and investigate which clinical cases are most relevant to improvement.”