Resolving Poor Recovery and Memory Effects in Trace Metal Analysis by Inductively Coupled Plasma Mass Spectrometry (ICP-MS): A Method Transfer Case Study

Abstract

During the transfer of an ICP-MS method for palladium determination in a complex solid matrix, poor spike recovery and significant memory effects were observed. A systematic investigation was performed to identify the root cause and establish a robust method. Key variables evaluated included the microwave digestion vessel type, the microwave digestion temperature, acid chemistry and rinse conditions and sample preparation approach. The ability of the digestion vessels to operate safely at higher temperatures and pressures together with digestion temperature (≥ 230 °C) and acid composition were identified as critical factors influencing recovery, while extended rinse times effectively removed memory effects. The optimised method achieved consistent recoveries (98–100%) with good precision and no observable carryover. This study highlights the importance of digestion conditions in successful ICP-MS method development for challenging matrices.

Introduction

The transfer of an ICP-MS method for trace metal determination can be challenging, particularly for samples that require robust digestion² (such as those containing molecules with unsaturated ring structures) to achieve complete analyte recovery. In general, challenges may arise when the receiving laboratory has different instrumentation compared with the transferring laboratory. Differences in sample preparation equipment, digestion vessels or digestion conditions between laboratories may influence digestion efficiency and method performance. Microwave digestion systems from different manufacturers can provide slightly altered digestion conditions resulting in poor analyte recovery, high variability and carryover effects. ICP-MS instruments from different manufacturers can also provide differing sample introduction and interference removal technologies, all of which can impact the results obtained during a method transfer.

This case study describes a comprehensive investigation carried out following unsuccessful method transfer attempts for trace palladium determination by ICP-MS. The receiving laboratory used an Agilent 7900 ICP-MS instrument and MARS microwave, whilst the original laboratory used an Agilent 7700 ICP-MS instrument and an Anton Paar microwave. The work focused on identifying the root cause of low recovery and memory effects and on defining digestion and instrumental parameters capable of delivering consistent and reliable performance, while maintaining alignment with the customer method where possible.

Initial Method Transfer and Problem Statement

The initial method transfer employed microwave digestion using standard high-pressure vessels at a digestion temperature of 200 °C and an oxidising hydrochloric acid/nitric acid mixture, followed by ICP-MS analysis using both collision and non-collision modes. The original laboratory used a temperature of 250 °C; however, the 200 °C on the MARS system typically results in full digestion of samples; therefore, it was not anticipated to cause an issue. Spike recovery was consistently low (approximately 40–50%), with acceptable repeatability; however, there was clear evidence of incomplete digestion. In addition, significant memory effects were observed as demonstrated by the elevated independent quality control standard (IQC) responses and signal drift. The prepared samples were also run on a separate Thermo Scientific iCAP RQ ICP-MS instrument; however, the results were the same. These observations showed that the issues were not ICP-MS instrument specific and indicated that sample preparation and digestion efficiency were likely the primary contributors to poor performance.

Investigation Strategy

A phased investigation strategy was adopted to systematically assess the potential causes of poor recovery and memory effects. The following parameters were evaluated: digestion vessel type, microwave digestion temperature and acid chemistry, instrument rinse time and sample preparation approach (with and without sonication).

Each change was assessed using spiked samples with performance checked against predefined acceptance criteria for accuracy, precision, system suitability and carryover control.

Investigation Findings

Digestion Vessel Evaluation

Multiple digestion vessel types were evaluated. Standard MARS Xpress vessels (maximum operating temperature 200 °C and lower pressure capability) consistently produced low and variable recoveries despite optimisation of temperature and acid composition, and were deemed unsuitable due to temperature and pressure limitations. In contrast, high-performance MARS Easy Prep vessels, which are designed to operate at higher temperatures and pressures than MARS Xpress vessels, enabled more complete digestion and resulted in higher and more reproducible recoveries (Figure 1).

Figure 1 includes recovery data generated across the range of acid compositions, microwave digestion parameters and post-digestion dilutions evaluated during the investigation, demonstrating the overall impact of vessel type on method performance. MARS Xpress vessels showed lower recoveries (approximately 45–80%). In comparison, MARS Easy Prep vessels achieved consistently higher recoveries (approximately 70–100%) with tighter clustering of results. The consistently improved performance observed with MARS Easy Prep vessels suggests that their ability to operate at higher temperatures and pressures enables more complete sample digestion and improved analyte recovery.

These findings demonstrate that digestion vessel capability is a critical factor influencing method performance.

Figure 1. Comparison of Pd spike recovery (%) for MARS Xpress and MARS Easy Prep microwave digestion vessels (Note: Jitter applied to improve visibility; underlying values are unchanged). [Chart image pending upload]

Digestion Temperature and Acid Chemistry

Digestion temperature was identified as a critical parameter influencing recovery. Small changes in the temperature from 200 °C to 230 °C resulted in significant improvement in recovery. Temperatures above 230 °C were not investigated further because higher temperatures may increase vessel venting and the risk of analyte loss from MARS Easy Prep vessels. All temperature evaluations were performed using MARS Easy Prep and MARS Xpress vessels.

Palladium spike recovery (%) as a function of microwave digestion temperature (200–230 °C) is shown in Figure 2. Recoveries were low and highly variable at 200 °C, with several results below the acceptance threshold. Improved performance was observed at 220 °C; however, some variability remained. At 230 °C, recoveries were consistently within an acceptable range and showed tight clustering, indicating improved method performance.

Although the data were generated across a range of digestion conditions evaluated during the investigation, the overall trend demonstrated that digestion temperature had a significant impact on recovery. The higher temperatures resulted in higher and more consistent recoveries, indicating that more effective digestion was achieved at elevated temperatures.

Figure 2. Palladium spike recovery (%) as a function of microwave digestion temperature (200–230 °C). [Chart image pending upload]

Several hydrochloric acid/nitric acid mixtures, with and without hydrogen peroxide and with and without perchloric acid were evaluated to optimise digestion performance (Figure 3). Hydrogen peroxide addition made no significant difference; therefore, the results are not shown. While increased nitric acid volumes and alternative acid combinations provided partial improvements, these conditions resulted in variable recoveries.

Although the data presented in Figure 3 were generated across a range of digestion conditions evaluated during the investigation, including different digestion vessels, temperatures, and acid compositions, the overall trend demonstrated the impact of acid chemistry on method performance. The introduction of perchloric acid resulted in higher recoveries, suggesting that stronger oxidising conditions enabled more complete digestion of the sample and improved palladium recovery.

Figure 3. Summary of recovery achieved using different acid compositions evaluated during the investigation. [Chart image pending upload]

Sonication Assessment

Sonication was evaluated as a potential pre-digestion step to improve spike recovery. No improvement in recovery was observed, and the approach introduced an increased risk of sample loss and variability. Direct transfer of the sample into digestion vessels without sonication was therefore selected as the preferred approach.

Memory Effects Assessment

Significant palladium memory effects were observed during the initial method transfer as evidenced by elevated IQC responses following sample analysis. The investigation confirmed that inadequate rinse time was the primary contributing factor. Increasing the rinse time to 250 seconds in combination with appropriate wash steps effectively mitigated carryover, resulting in stable IQC responses within acceptable limits. No residual memory effects were observed following optimisation.

Summary

The investigation confirmed that poor palladium recovery was primarily due to incomplete sample digestion. The use of digestion vessels capable of operating at higher temperatures and pressures together with optimisation of digestion temperature and acid chemistry with the addition of perchloric acid resulted in consistent recoveries of 98–100%, while optimisation of rinse conditions successfully eliminated memory effects. The final method demonstrated robust performance with accurate recovery, good precision and no observable carryover. The changes in the method from the original laboratory will, however, require some additional validation parameters to be included in the method transfer.

Conclusion

At Almac, we have the necessary experience and instrumentation to overcome challenging samples and can establish robust methods for elemental impurities analysis by ICP-MS in accordance with current regulatory guidance¹ using our state-of-the-art ICP-MS instruments. This study demonstrates Almac's ability to overcome complex analytical challenges and provide robust, regulatory-compliant solutions, ensuring reliable data for our clients.

References

1. Ramamoorthy, S. Impurity Characterization Across Drug Development Stages: Analytical Methodologies and Regulatory Perspectives. Pharm. Res. 2026, 43 (6), 1799–1820. DOI: https://doi.org/10.1007/s11095-026-04054-y.
2. Belmiro, C. M.; Gomes, M. C.; Ferreira, F. N.; Neves, M. A. F. S.; Gois, J. S. Microwave-Assisted Digestion Method and Dispersive Magnetic Solid-Phase Microextraction for the Determination of Major and Trace Elements in Lignocellulosic Biomass by ICP-OES. ACS Omega 2025, 10 (28), 30443–30449. DOI: https://doi.org/10.1021/acsomega.5c02196.

About the Author

Dr. Andrei Izmer is Analytical Technical Leader – Mass Spectrometry at Almac Sciences. He obtained his PhD in Analytical Chemistry in 2006 from Mainz University (Germany). He was a Postdoctoral Researcher at Paul Scherrer Institute (Switzerland), Trent University (Canada) and Ghent University (Belgium). He has a background in the development of analytical methods for the determination of elemental impurities by ICP-MS in a wide range of materials including radioactive materials, biological, environmental and pharmaceutical samples.