Assessment of drug delivery devices working at microflow rates.

Almost every medical department in hospitals around the world uses infusion devices to administer fluids, nutrition, and medications to patients to treat many different diseases and ailments. There have been several reports on adverse incidents caused by medication errors associated with infusion equipment. Such errors can result from malfunction or improper use, or even inaccuracy of the equipment, and can cause harm to patients' health. Depending on the intended use of the equipment, e.g. if it is used for anaesthesia of adults or for medical treatment of premature infants, the accuracy of the equipment may be more or less important. A well-defined metrological infrastructure can help to ensure that infusion devices function properly and are as accurate as needed for their use. However, establishing a metrological infrastructure requires adequate knowledge of the performance of infusion devices in use. This paper presents the results of various tests conducted with two types of devices.

Metrology in health: challenges and solutions in infusion therapy and diagnostics.

The significance of Metrology in infusion therapy and diagnostics, both critical in health care safety and quality, is discussed in this article. Although infusion therapy is the most used form of drug administration, infusion errors are often made with reported dramatic effects in different applications, especially in neonatology. Adverse incidents, morbidity, and mortality have often been traced back to poor or inaccurate dosing. For critical infusion applications to vulnerable patients, well-controlled medication administration might be accomplished by improved dosing accuracy, traceable measurement of volume, flow, and pressure in existing drug delivery devices and in-line sensors operating at very low flow rates. To this end, the contribution of recently upgraded metrological infrastructures in European Metrology Institutes to a safer infusion therapy in health care is described in detail. Diagnostics, on the other hand is a sector characterized by rapid developments further triggered recently by the necessity for the management and prevention of infectious diseases like COVID-19. In this context, the impact of metrology in future large-scale commercialization of next generation diagnostics (e.g., point-of-care) is highlighted. Moreover, the latest contributions of Metrology in the development of traceable testing methods and protocols to ensure the sensitivity and accuracy of these devices are described.

In-line measurements of the physical and thermodynamic properties of single and multicomponent liquids.

Microfluidic devices are becoming increasingly important in various fields of pharmacy, flow chemistry and healthcare. In the embedded microchannel, the flow rates, the dynamic viscosity of the transported liquids and the fluid dynamic properties play an important role. Various functional auxiliary components of microfluidic devices such as flow restrictors, valves and flow meters need to be characterised with liquids used in several microfluidic applications. However, calibration with water does not always reflect the behaviour of the liquids used in the different applications. Therefore, several National Metrology Institutes (NMI) have developed micro-pipe viscometers for traceable inline measurement of the dynamic viscosity of liquids used in flow applications as part of the EMPIR 18HLT08 MeDDII project. These micro-pipe viscometers allow the calibration of any flow device at different flow rates and the calibration of the dynamic viscosity of the liquid or liquid mixture used under actual flow conditions. The validation of the micro-pipe viscometers has been performed either with traceable reference oils or with different liquids typically administered in hospitals, such as saline and/or glucose solutions or even glycerol-water mixtures for higher dynamic viscosities. Furthermore, measurement results of a commercially available device and a technology demonstrator for the inline measurement of dynamic viscosity and density are presented in this paper.

Calibration methods for flow rates down to 5 nL/min and validation methodology.

Improving the accuracy and enabling traceable measurements of volume, flow, and pressure in existing drug delivery devices and in-line sensors operating at very low flow rates is essential in several fields of activities and specially in medical applications. This can only be achieved through the development of new calibrationmethods and by expanding the existing metrological infrastructure to perform micro-flow and nano-flow measurements. In this paper, we will investigate new traceable techniques for measuring flow rate, from 5 nL/min to 1,500 nL/min and present the results of an inter-comparison between nine laboratories for the calibration of two different flow meters and a syringe pump.

Calibration of insulin pumps based on discrete doses at given cycle times.

One application in the medical treatment at very small flow rates is the usage of an Insulin pump that delivers doses of insulin at constant cycle times for a specific basal rate as quasi-continuous insulin delivery, which is an important cornerstone in diabetes management. The calibration of these basal rates are performed by either gravimetric or optical methods, which have been developed within the European Metrology Program for Innovation and Research (EMPIR) Joint Research Project (JRP) 18HLT08 Metrology for drug delivery II (MeDDII). These measurement techniques are described in this paper, and an improved approach of the analytical procedure given in the standard IEC 60601-2-24:2012 for determining the discrete doses and the corresponding basal rates is discussed in detail. These improvements allow detailed follow up of dose cycle time and delivered doses as a function of time to identify some artefacts of the measurement method or malfunctioning of the insulin pump. Moreover, the calibration results of different basal rates and bolus deliveries for the gravimetric and the optical methods are also presented. Some analysis issues that should be addressed to prevent misinterpreting of the calibration results are discussed. One of the main issues is the average over a period of time which is an integer multiple of the cycle time to determine the basal rate with the analytical methods described in this paper.

Accelerating innovation and commercialization through standardization of microfluidic-based medical devices.

Worldwide, the microfluidics industry has grown steadily over the last 5 years, with the market for microfluidic medical devices experiencing a compound growth rate of 22%. The number of submissions of microfluidic-based devices to regulatory agencies such as the U.S. Food & Drug Administration (FDA) has also steadily increased, creating a strong demand for the development of consistent and accessible tools for evaluating microfluidics-based devices. The microfluidics community has been slow, or even reluctant, to adopt standards and guidelines, which are needed for harmonization and for assisting academia, researchers, designers, and industry across all stages of product development. Appropriate assessments of device performance also remain a bottleneck for microfluidic devices. Standards reside at the core of mature supply chains generating economies of scale and forging a consistent pathway to match stakeholder expectations, thus creating a foundation for successful commercialization. This article provides a unique perspective on the need for the development of standards specific to the emerging biomedical field of microfluidics. Our aim is to facilitate innovation by encouraging the microfluidics community to work together to help bridge knowledge gaps and improve efficiency in getting high-quality microfluidic medical devices to market faster. We start by acknowledging the progress that has been made in various areas over the past decade. We then describe the existing gaps in the standardization of flow control, interconnections, component integration, manufacturing, assembly, packaging, reliability, performance of microfluidic elements and safety testing of microfluidic devices throughout the entire product life cycle.

Improving Process Quality by Means of Accurate and Traceable Calibration of Flow Devices with Process-oriented Liquids.

Calibration of flow devices is important in several areas of pharmaceutical, flow chemistry and health care applications where volumetric dosage or delivery at given flow rates are crucial for the process. Although most of the flow devices are measuring flow rates of process-oriented liquids, their calibrations are often performed with water as calibration liquid. It is recommended to perform the calibrations of the flow devices with process-oriented liquids as the liquid itself might influence the performance of the flow devices. Therefore, METAS has developed facilities with METAS flow generators to address the issue of measuring with process-oriented liquids for flow rates from 400 ml/min down to 50 nl/min with uncertainties from 0.07-0.9 %. Traceability is guaranteed through the calibration of the generated flow rates of the METAS flow generators by means of the dynamic gravimetric method where a liquid of well-known density and a well-controlled evaporation rate is used. The design of the milli-flow facility will be discussed as well as first measurement results of the METAS flow generators in the range of micro-flow and milli-flow using water and other liquids.

Primary standards for measuring flow rates from 100 nl/min to 1 ml/min - gravimetric principle.

Microflow and nanoflow rate calibrations are important in several applications such as liquid chromatography, (scaled-down) process technology, and special health-care applications. However, traceability in the microflow and nanoflow range does not go below 16 µl/min in Europe. Furthermore, the European metrology organization EURAMET did not yet validate this traceability by means of an intercomparison between different National Metrology Institutes (NMIs). The NMIs METAS, Centre Technique des Industries Aérauliques et Thermiques, IPQ, Danish Technological Institute, and VSL have therefore developed and validated primary standards to cover the flow rate range from 0.1 µl/min to at least 1 ml/min. In this article, we describe the different designs and methods of the primary standards of the gravimetric principle and the results obtained at the intercomparison for the upper flow rate range for the various NMIs and Bronkhorst High-Tech, the manufacturer of the transfer standards used.

Time-resolved-correlation measurements of temporally heterogeneous dynamics.

Time resolved correlation (TRC) is a recently introduced light scattering technique that allows one to detect and quantify dynamic heterogeneities. The technique is based on the analysis of the temporal evolution of the speckle pattern generated by the light scattered by a sample, which is quantified by cI(t, tau), the degree of correlation between speckle images recorded at time t and t + tau. Heterogeneous dynamics results in significant fluctuations of cI(t,tau) with time t. We describe how to optimize TRC measurements and how to detect and avoid possible artifacts. The statistical properties of the fluctuations of cI are analyzed by studying their variance, probability distribution function, and time autocorrelation function. We show that these quantities are affected by a noise contribution due to the finite number N of detected speckles. We propose and demonstrate a method to correct for the noise contribution, based on a N--> infinity extrapolation scheme. Examples from both homogeneous and heterogeneous dynamics are provided. Connections with recent numerical and analytical works on heterogeneous glassy dynamics are briefly discussed.