How infusion drug delivery can reduce medical error

Dr Tracy Brown, head of Life Sciences and Healthcare at TÜV SÜD National Engineering Laboratory explores the advances being made to reduce medical error with improved infusion drug delivery.

Infusion is the most common form of therapy in a clinical setting, but its widespread use in critical healthcare settings means errors are often made. Whilst the monitoring of a patient’s vital signs can indicate potential dosing errors, they cannot be relied upon as they only indicate the error after it has occurred, and it is too late.

Growing focus on personalised healthcare brings with it a commensurate impetus for greater metrological understanding. Precision medicine is expected to change fundamentally the delivery of medical treatments and is predicated on the idea that different sizes of dose can be delivered accurately. The journey towards therapeutic and prophylactic interventions tailored to individuals that take into account their genetic blueprint, environment and lifestyle is underway. Intrinsically, this will require enhanced measurement capability to ensure the accurate dosing of infusions containing novel complex therapeutics designed to treat niche illnesses.

We are part of a consortium of European National Measurement and Designated Institutes, universities and manufacturers that is conducting a three-year project aimed at improving dosing accuracy and enabling the traceable measurement of volume, flow and pressure of drug delivery devices used in infusion therapy. 

The research project will develop traceable calibration procedures for medical flow devices such as infusion pumps, down to very challenging low flow rates in the nanolitre (nL) per minute range necessary for infusions in certain patient groups, e.g. neonates. Techniques will be developed for generating and measuring the response or delay time of these devices and examining the influence of fast-changing flow rates and innovative approaches to make these challenging measurements, for example, optical methods.  

The research programme will also investigate how mixtures of liquids with different viscosities mix and flow in multi-infusion systems and how this affects the therapeutic drug concentration over the course of an infusion. It is intended that such rigorous metrology will prevent harm to patients arising from inappropriate mixing such as therapeutic failure or toxicity.

The primary infusion devices used for administration have a significant impact on metrology.  In the case of intravenous administration, for example, various devices with different purposes may be used (syringe pumps, peristaltic pumps, insulin pumps). Each method must be capable of delivering traceable, accurate and reproducible metered doses of drug. Understanding the sources of, and minimising, measurement uncertainties attributable to the operation of each device is key to achieving this and is a fundamental aspect of the work being undertaken in this multi-partner project where uncertainties of one to two per cent are being targeted.

The Coronavirus pandemic has created unprecedented conditions and challenges for hospitals - bringing accurate, traceable flow measurement for drug delivery more acutely into focus. These extraordinary times have seen new measures being implemented in some healthcare settings, including the use of drug delivery devices outside the patient’s room and the postponement of maintenance and calibration schedules. In response to these changes, the consortium published a document highlighting specific metrological and clinical physics guidance on newly-adopted Covid-19-related measures implemented in some European hospitals for patients receiving drug therapies through infusion pumps. These provide clinicians and nursing staff with practical solutions which can be implemented easily to safeguard confidence in the use of these drug delivery devices during these challenging times. This Metrology for Drug Delivery 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.

Organ On A Chip (OOAC) microfluidic devices are evolving rapidly and present exciting opportunities across the drug discovery pipeline from candidate identification to efficacy, toxicity and safety. These microscale in vitro human physiological models are efficient and cost-effective with their added potential to reduce the use of animal models offering an ethical alternative to conventional pre-clinical drug discovery approaches. Moreover, OOAC technology can be used as implantable drug delivery devices capable of producing continuous, non-continuous or pulsatile delivery patterns by less painful means. Fluid flow measurement has an integral role to play in the translational journey of these novel microfluidic applications from bench to clinic. For example, the interconnection by microfluidic flow of single organ models enabling the study of biological interactions between organs.

The burgeoning adoption of technologies such as OOAC in healthcare will necessitate the development of a metrological infrastructure to validate their accuracy and reproducibility. Accordingly, a further aim of the collaborative European metrology project is the development of a proof-of-concept microfluidic microchip flow pump for use as a moveable traceable transfer standard for the calibration of drug delivery devices used in drug discovery and OOAC for ultra-low flow rates (below 100 nL/min).

Regulatory compliance underpins every innovation or innovative methodology within the medical device sector; an obligation which is set to increase when the new Medical Devices Regulation (MDR 2017/745) and In Vitro Diagnostic Regulation (IVDR 2017/746) come into full effect in May 2021 and May 2022, respectively.  Conformity leads to CE marking of devices enabling them to be sold within the EU. Additionally, with the UK having left the EU as of 1 January this year, device manufacturers will also be required to comply with the new UK Conformity Assessment (UKCA) from July 2023 if they want to sell their device to the UK market.

The move towards greater regulation and increased innovation and complexity of drug infusion systems will inevitably see metrology form an essential part of the regulatory approval process for these medical devices. Not only will this entail the development of existing standards, it will also require the creation of new ones to address their diversity and increasing complexity. Whilst at an embryonic stage, microfluidic technology is progressing apace. In parallel, work is needed to define measurement standards for microfluidic devices covering areas such as the control and quantification of fluid flows. Developing microfluidics measurement standards will facilitate their uptake across the pharmaceutical and health sectors by providing the necessary accuracy and reliability in their manufacture and performance.

The advantages of microfluidic devices as drug discovery and delivery platforms cannot be underestimated; they are quick, inexpensive, portable and effective. Developing a robust flow metrology infrastructure to validate their quality, reduce dosing errors and ensure efficacy and safety will be key to unlocking their potential.