MEASUREMENT UNCERTAINTY
Laboratory workflow Centrifuge speed
Autoclave sterilisation cycles
Pipette calibration and volume dispensing
Where MU can impact patient results
Variation in centrifugation speed and failure of monitoring systems to measure them accurately may give false assurance that equipment is running within specification
MU in temperature and pressure settings of autoclaves can affect the sterilisation of equipment and media
Variability of pipette measurements can introduce MU in volume dispensed, affecting reagent and QC concentrations
Balances and mass measurement Weighing reagents or samples introduces MU that can affect reagent preparation or sample analysis Timer calibration
Electrical equipment calibration (voltage, current, resistance)
pH meter calibration Water quality monitoring
(conductivity, resistivity) Gas flow rate and pressure
monitoring
MU in time-controlled processes, such as incubation or reaction times, can affect test consistency Variations in power supply or instrument output can introduce MU affecting devices such as
electrophoresis units or PCR machines
MU in pH measurement can impact sample or reagent preparation where precise pH control is required MU in the monitoring of laboratory water quality (eg deionised or distilled water) can influence the purity used
MU in the delivery of gases, such as carbon dioxide for incubators or nitrogen for cryopreservation, could affect equipment performance
Table 1. A breakdown of the wider impact of MU on laboratory result.
contexts beyond assays – temperature monitoring, incubator performance, reagent storage, and environmental controls – while aligning with ISO 15189. We will also consider the need for external calibration by accredited services to ensure compliance with relevant ISO standards.
Measurement uncertainty beyond assays Measurement uncertainty is frequently discussed in the context of assays, but laboratories often overlook its importance in non-assay processes. The advantage of new guidelines recommending the use of the top-down method is that it simplifies the process of calculating MU. Using imprecision, calibration and bias data as necessary, we capture most common sources of variability in a single QC result, and the variability of repeated QC results represents the system variation. As a reminder, prior to ISO/TS 20914:2019, the GUM method required each uncertainty source to be quantified and combined – often using very complicated maths. Using ISO/TS 20914:2019 does not mean we forget about those uncertainty sources we would previously have measured, and controlled. Importantly, some of those contributors themselves are subject to
MU, and they may not be captured by our internal quality control (IQC). In fact, careful control of these processes, and the impact of MU on them, is required for reliable estimation of MU from our IQC.
Temperature monitoring of freezers and refrigerators Maintaining stable storage conditions for reagents, controls, and patient samples is critical. Even slight temperature deviations can cause degradation or denaturation, affecting assay performance. Temperature monitoring is now well embedded in routine laboratory practice. A common step missed though is assuming that monitoring the temperature alone is sufficient without accounting for the MU associated with the monitoring system. For example, if a thermometer has a ±0.5°C uncertainty, and the freezer is set to –20°C, the actual temperature could vary between –19.5°C and –20.5°C. Over time, this small discrepancy could affect the stability of stored samples. To mitigate this risk, laboratories must ensure that monitoring systems are regularly calibrated, ideally by external services accredited to ISO standards, which guarantees the accuracy of calibration processes. Where this practically makes a difference is with setting limits for alarming excursion from the range set.
There are a range of aspects of laboratory practice where MU comes into play, and it is often these applications that present challenges during audits and compliance assessments
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A common range for a refrigerator for example may be 2–8°C. In times gone by, we would have set the alarms at exactly that, 2–8°C. However, appreciating the MU of the temperature monitoring system, and considering the impact of a temperature deviation using a risk-based approach, the alarm should be set narrower than the extremes of temperature we permit. So, rather than 2–8°C, we would set the alarms for 2.5–7.5°C.
Incubator and heat block monitoring
Incubators and heat blocks have many uses including being used for sample and blood product preparation. Activities may range from defrosting samples after storage, thawing bags of fresh frozen plasma (FFP) or incubation of assays at constant temperatures over time to optimise reaction conditions. Some techniques still even use water baths. Maintaining temperature in these pieces of equipment are challenging depending on how they are used. Doors opening, conduction of heat through metallic heat blocks, or the variability in temperature in water baths relative to the heat source. All of these factors may be influenced by equipment age and maintenance schedules. Of course, the same as for refrigerators and freezers, the thermometer used for checking the temperature also must be calibrated to ISO standards. As before, alarms or monitoring of the equipment takes the form of including the MU to set limits.
Stock and reagent storage The potency and stability of reagents are often affected by storage conditions.
OCTOBER 2024
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