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This presentation presents the impact of project MeDDII.

This White paper was written as part of activity A3.1.4 from the EMPIR Establishing Metrology Standards in Microfluidic Devices (MFMET) project. The three-year European project commenced on 1st June 2021 and focused on providing a generic methodology of accurate measurement of a particular quantity in a microfluidic device by utilising standardised methods and reference documents, e.g. VIM & GUM. For more details about this project, please visit www.mfmet.eu

This document presents guidelines and a test protocol for leakage and burst pressure of microfluidic devices. The guidelines and the protocol in this document aim to operate within the following parametric range: non-hazardous water-based flow media, temperature (4-50) °C, pressure below 200 kPa (2000 mbar), and flow rates between 1 and 100 µL/min. The reasoning behind these operational parameters is to frame a subset without risks to safety or the environment. The testing of this document applies to device types that are not capillary flow devices. Furthermore, the testing was demonstrated with a microfluidic device made of COC (cyclic olefin copolymer) and mini Luer connectors. This test protocol originated from the discussions found in activity A1.2.2 (Heeren et al., 2022) and the work by Silverio et al. (Silverio, Guha, et al., 2022). Furthermore, this test protocol was created from the work of activity A1.2.3, which performed documented examples of leakage testing and burst pressure testing in the liquid flow laboratory at CETIAT (Villeurbanne, France). Activities A1.1.1 and A1.1.2, also contributed to this test protocol with vocabulary for microfluidic components and definitions of flow control terminology (Kartmann et al., 2022; Silverio, Metaxiotou, et al., 2022).

This document provides test protocols for specific microfluidic measurements of the quantities: flow resistivity flow volume volume of droplets The EMPIR innitiative is co-funded by the European Union's Horizon 2020 research and innovation programme and the EMPIR Participating States

This document presents the results of the project MeDDII - Metrology for drug delivery regarding the four technical objectives.&nbsp

This document presents the final results and dissimination activities of project EMPIR MeDDII - Metrology for drug delivery.

This document presents the development of EMPIR project 18HLT08 MeDDII in M30 (November 2021), its a summary of all activities performed so far.

This document provides a compilation of basic and general concepts and associated terms related to flow control whose definitions are currently lacking harmonisation. A proposal of definitions and symbols has been produced as well as a Vocabulary of Flow Control (containing terms such as repeatability, stability, settling time, liquid properties, dead volume, volume dispensed, accuracy, range, etc). This compilation is drawn on existing symbols and standards for flow control. Activity number Activity description Partners (Lead in bold) A1.1.2 M6 Using input from A1.1.1, IPQ, CETIAT, NEL, INESC MN, NQIS, HSG IMIT and BHT will identify basic and general concepts and associated terms related to flow control whose definitions are currently lacking harmonisation. A proposal of definitions and symbols will be produced as well as a Vocabulary of Flow Control (containing terms such as repeatability, stability, settling time, liquid properties, dead volume, volume dispensed, accuracy, range, etc). This compilation will draw on existing symbols and standards for flow control where appropriate. IPQ, CETIAT, NEL, INESC MN, NQIS, HSG IMIT, BHT

This report was written as part of activity 1.1.1 from the EMPIR Establishing Metrology Standards in Microfluidic Devices (MFMET) project. The three-year European project commenced on 1st June 2021 and focused on providing a generic methodology of accurate measurement of a particular quantity in a microfluidic device by utilising standardised methods and reference documents, e.g. VIM & GUM. For more details about this project, please visit www.mfmet.eu The document provides a literature and market research in order to compile and classify flow control components (such as reservoirs, valves, chambers, external connectors, tubing). Within this research, the partners investigated the definitions, characteristics (such as flow range), specifications (such as accuracy), application and function (such as droplet generation) of the components., This project (20NRM02 MFMET) has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme.

How will microfluidic standards improve and ease organ-on-chip development and studies ? By the Improvement of device availability, reliability and accessibility; by encouraging large-scale adoption; by speeding up development; by improving time-to-market; by lower production costs &nbsp

Infusion is the most used technology in hospitals. Because of its widespread application, often in critical situations and by many users, many infusion errors are made, with some having severe effects. Part of these errors can be avoided if the users of infusion technology have a better understanding of the specific equipment they use. Furthermore, even more could be achieved, if the exact consequences of technical choices made on dosing accuracy could be clarified to the healthcare provider. We have found in our project that these everyday choices, like flow rate adaptations or the choice to use a specific disposable, can have influence on dosing accuracy. Current systems or user settings are not often traceable to the exact dosing which can lead to complicities, morbidities and mortality. Though this is especially the case in neonatology, where multiple pump infusion is typically combined with low flow rates. The complex interplay arising is counterintuitive to the user and give incentive to make flowrate adaptations that unwillingly lead to inaccurate dosing. There is therefore an urging need to prevent device related dosing errors and related incidents, morbidity and mortality, by tracing back the dose effects of flowrate adaptations with accurate measurement of the entire multi-infusion system. In order to improve measurement procedures of infusion devices, National Metrology Institutes, Manufacturers and Academia have been involved in research projects since 2015. The latest project MeDDII- Metrology for drug delivery, co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation program, was focus on accuracy and traceability of low flow rates. Highlighted the role of the regulation 2017/745 on medical devices that into force on 26th May 2021, MEDD II consortium gives an outlook and a quick landscape review within the relevance of metrological requirements of infusion devices to provide a better shared understanding of this issue. &nbsp

This document provides a literature review of existing metrology and normative standards related to the flow properties and microfluidic devices. The flow quantities input from A2.1.3: Flow rate (including fast changing flow rates) Flow resistivity 3- Volume, such as internal volume, dead volume and droplet size Activity number Activity description Partners (Lead in bold) A2.2.1 M11 Using the flow quantities identified in A2.1.3, TUBITAK, DTI, NQIS, CETIAT, IPQ, CMI and BHT will perform a literature review of existing metrology and normative standards related to the flow properties and microfluidic devices. TUBITAK, DTI, NQIS, CETIAT, IPQ, CMI, BHT, "This project (20NRM02 MFMET) has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme."

Opening, lecturers and program of the DOSEtrace Training Course, This project 17RPT01 DOSEtrace has received funding from the EMPIR programme cofinanced by the Participating States and from the European Union's Horizon 2020 research and innovation programme.

Flow measurement is critical in healthcare, chemistry and pharmaceutics, to mention a few. In fact, there are several applications in the microflow and nanoflow range, such as scaled-down process technology, drug development, and special health-care applications, as organ-on-a- chip technology. Nevertheless, the majority of the instruments used for the specified applica- tions are not sufficiently studied regarding their flow accuracy and traceability. Hence these fluid applications at the micro and nanoscale still lack well defined calibration methodologies for the devices working at the mentioned flow range with adequate uncertainty values. The work presented in this thesis focuses on the development and improvement of in- novative applications of calibration methodologies for microflow measuring instruments. The gravimetric method already implemented at IPQ from 120 L/h to 2000 mL/h was used and improved for low flow rates down to 10 L/h. Additionally, other 4 methods were developed to enable the calibration of micro/nano flows in a non-intrusive way. They are interferometry, pending drop, front track and comparison method (where a calibrated flow generator is used as the reference standard). The methodology that is best suited for each specific instrument and each measurement range, with the lowest uncertainty, was successfully identified along with the relevant influence factors in microflow measurements. A specific objective of this work was to increase the measuring range of IPQ-LVC down to 5 nL/min (0.3 L/h) with a 3% target uncertainty (k=2). This objective was possible to achieve and even surpass with the use of the interferometric method, where measurements were per- formed down to 1.6 nL/min (0.1 L/h) with 2 % uncertainty(k=2). This method was internally validated by comparison with the gravimetric method and is now in the process of external validation by EURAMET project 1508. A medição de caudal é extremamente importante em áreas como a saúde, a indústria química ou farmacêutica. Caudais à escala micro/nanométrica são já utilizados em várias aplicações, nomeadamente, processos tecnológicos de redução de escala, desenvolvimento de fármacos e especialmente em novas aplicações na área da saúde, tais como a tecnologia de órgãos-em- chip. Os sistemas de medição utilizados nas aplicações indicadas, por serem relativamente recentes, não estão ainda suficientemente estudados quanto a sua exatidão e rastreabilidade. É, assim, necessário desenvolver metodologias de calibração específicas para os referidos cau- dais com incertezas de medição adequadas. Este trabalho irá focar-se no desenvolvimento e melhoramento de metodologias de cali- bração de instrumentos utilizados na medição de micro/nanocaudal de fluidos. O método gra- vimétrico já implementado no IPQ numa gama de medição de 120 L/h a 2000 mL/h foi me- lhorado de forma se realizarem calibrações até 10 L/h. Foram ainda desenvolvidos 4 novos métodos, a interferometria, o método da gota pendente, o método do deslocamento de me- nisco e o método comparativo (onde um gerador de caudal é utilizado como referência). A metodologia que melhor se aplica a cada instrumento e a gama de medição, com a melhor incerteza foi identificada, assim como fatores de influência na medição de microcaudal. Um objetivo específico deste trabalho foi aumentar o intervalo de medição do IPQ-LVC para 5 nL/min (0.3 L/h) com uma incerteza de (k=2). Isso foi possível e até ultrapassável com a utilização do método interferométrico, em que as foram realizadas medições até 1.6 nL/min (0.1 L/h) com 2% de incerteza (k=2). Este método foi validado internamente por comparação com o método gravimétrico e está agora em processo de validação externa através do projeto EURAMET 1508.

In 2021, an new EURAMET EMPIR-funded project, MFMET – Establishing metrology standards in microfluidic devices- will start. The goal of this project is to contribute to the development of globally accepted standards for microfluidic devices and disseminate them to end users in industry, particularly Life Science and Diagnostics Companies, and in academia. This project will focus on testing and metrology strategies that are essential to ensure measurement accuracy and traceability of microfluidic devices and will aid product developers in advancing the field of microfluidics. The project partners will interact with ISO/TC48/WG3 for the development of microfluidic standards, covering metrology for the methodologies and fabrication processes. This project will also develop protocols for measuring different quantities, interface, connectivity, modularity and sensor integration of microfluidic devices based on experimental test results obtained by the new microfluidic transfer standards fabricated by the consortium and literature surveys. The overall objective of this project is to focus on metrology research necessary to support standardisation for microfluidics used in the health and pharmaceutical industry. This project will develop protocols for measuring different quantities, interfaces, connectivity, modularity and sensor integration in microfluidic devices. The protocols implemented in new transfer standards fabricated under this project and literature surveys will integrate the standards prepared by ISO/TC48/WG3. The specific objectives, are: 1. To investigate, evaluate and formulate consensus-based flow control specifications to enhance the manufacturing capability of the microfluidics industry supply chain through voluntary compliance. 2. To develop measurement protocols for different quantities, (e.g. flow rate and liquid properties) in different microfluidics devices to be used in pharmaceuticals, biomedical and mechanobiology applications. A EURAMET guide on these measurement protocols will be developed. 3. To define general standards and guidelines for interfaces and connectivity between fluidic passages and optical/electrical connections of microfluidics components and corresponding measurement standards, from micro to macro size scales. 4. To define guidelines for the standardisation of dimensions and accuracy for modularity (either moduleto-module or module-to-world) and sensor integration (combination of sensing elements/materials with microfluidic modules). 5. To contribute to the standards development work of ISO/TC 48/WG3 to ensure that the outputs of the project are aligned with their needs. The project outputs from objective 1-4 will be communicated and disseminated quickly to those developing the standards and to those who will use them (health and pharmaceutical industry), and in a form (e.g. specifications, guidelines and white papers) that can be incorporated into the standards (e.g. new technical guides, ISO 10991 and ISO/CD 22916) at the earliest opportunity. The present publication will detail the state of the art, the underlying needs, the objectives, and the means implemented to establish new metrology standards in microfluidic devices. This work performed under MFMET project has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme, This project (Euramet 20NRM02 MFMET) has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme.

Microfluidics, concerned with fluid-handling in the nano-to-millilitre scale, has major applications in biomedical and chemical analysis however global standards are lacking. ISO/TC48/WG3 has been established to address the standardisation of microfluidic components, interfaces, protocols for associated testing and protocols for microflow control to be applied in the development and the fabrication processes (manufacturing, testing and assembly) of microfluidic devices. This project aims to contribute to the development of globally accepted standards for microfluidics and disseminate them to end users in industry (health and pharmaceutical sectors) and academia. &nbsp

Overall Objective: Using input from A1.2.1-A1.2.4, CETIAT, NEL, IPQ, CMI, RISE, METAS and THL will write a report on calibration methods for measuring the response or delay time of drug delivery devices using Newtonian liquids for flow rates from 5 nL/min to 100 nL/min. Once agreed by the consortium, the coordinator will then submit the report to EURAMET as D1: ‘Report on calibration methods for measuring the response or delay time of drug delivery devices using Newtonian liquids for flow rates from 5 nL/min to 100 nL/min’.

Nowadays, several types of infusion pumps are commonly used for medical drug delivery, such as insulin pumps, and present different measuring features and capacities according to their use and therapeutic application. In order to ensure the metrological traceability of these equipment, it is necessary to use suitable calibration methods and standards. During the research herein presented, two different calibration methods were used to determine the flow rates of an insulin pump. One of these was the gravimetric method, considered as a primary method, and commonly used by the National Metrology Institutes; the other calibration method used was an optical method, which relies on the measurement of the variation of volume of a drop during a period of time. The suitability of each calibration method mentioned earlier was assessed by testing an insulin pump at a flow rate of 10 μL/h and for a volume of 10 μL, that in the tested device corresponds to 1 unit of insulin. Experimental results revealed a non-continuous functioning of the insulin pumping device under test, which was unexpected, and could lead the patient not to receive a continuous dose of medicine.

In the human body, the circulatory system is responsible for the process of transporting blood, which among many other functions delivers nutrients to the cells. In accordance with this physiological principle, supporting methodologies for therapeutic processes were developed that have enabled medical measuring instruments to be developed. It was within this context that the first infusion pumps appeared in the 60 s and 70 s, that by using a pressure higher than the blood pressure allowed fluids to be administered directly into the human body, including medications, blood components, and nutrients amongst others. Currently and according to the international standard IEC 60601-2-24 these devices are designated by infusion pumps. Because it is an infusion pump with the respective accessories, the term perfusion systems is also used as nomenclature throughout this document.

No corpo humano, o processo de transporte do sangue é assegurado pelo sistema circulatório que tem a função, entre outras, de distribuir os nutrientes pelas células. De acordo com este princípio fisiológico, foram desenvolvidas metodologias coadjuvantes de processos terapêuticos, que permitiram o desenvolvimento de instrumentos médicos com função de medição. Neste contexto, as primeiras bombas de perfusão surgiram nas décadas de 60 e de 70, que ao utilizarem uma pressão superior à pressão sanguínea, possibilitaram a administração de fluidos diretamente no corpo humano, incluindo fármacos, componentes do sangue, nutrientes, entre outros. Atualmente, e de acordo com a norma internacional IEC 60601-2-24, a estes dispositivos é atribuída a designação de bombas de perfusão, habitualmente designados por bombas infusoras. Tratando-se de uma bomba de perfusão com os respetivos acessórios, o termo sistemas de perfusão é também atribuído como nomenclatura ao longo do presente documento.