The strategic advantages of X-ray fluorescence for pharmaceutical elemental analysis

Executive summary 

X-ray fluorescence (XRF) spectroscopy provides many benefits over traditional elemental analysis techniques for pharmaceutical applications, including inductively coupled plasma (ICP) spectrometry. ICP techniques¹ require highly skilled operators as well as hazardous and time-consuming sample preparation. In contrast, XRF sample preparation is much faster, less complex, and doesn’t destroy the sampled material in the process. These improvements are particularly beneficial in the scale-up context, as specialized labor as well as drug substances and formulations are in short supply. XRF analysis therefore greatly improves the efficiency of scale-up and other pharmaceutical workflows, making them simpler, safer, faster, and more sustainable. 

Introduction

X-ray fluorescence (XRF) technology has been widely adopted as a quality control technique in many highly regulated industries, such as food, cement, and mining. Yet it has not been embraced by the pharmaceutical industry – even though it can provide many strategic and operational benefits in this context. While ICP spectroscopy provides a wealth of data on samples and plays a critical role in elemental analysis, its popularity can lead to bottlenecks and mounting costs as samples get held up in a queue and scientists wait for results. Incorporating XRF analysis into the pharmaceutical workflow – whether during early development, scale-up or manufacturing – can help relieve such bottlenecks. Furthermore, ICP instruments require highly specialized operators to perform the sample preparation, which involves dissolving the sample using hazardous chemicals and can take up to several days to complete. In contrast, sample preparation for XRF analysis is far less complex: no hazardous chemicals are used, operators do not require extensive training, and samples can be prepared and measured in under 30 minutes. In addition, pharmaceutical applications require orthogonal² analysis to confirm results, so XRF analysis can be a very effective complement to ICP spectroscopy for elemental analysis.

The basics of X-ray fluorescence technology 

Whereas ICP spectrometers strip ions from atoms in a sample and then measure those ions to identify the elements present, XRF instruments use high-energy radiation to excite the electrons around the atoms. At this point, the electrons emit fluorescent X-ray ‘fingerprints’ characteristic of their specific element. The key difference from ICP spectroscopy is that the electron excitation is non-destructive. Samples analyzed using XRF systems can be re-analyzed with the same or a different technique and even returned to production. This is a major benefit in any application where samples are precious, such as the development of active pharmaceutical ingredients (APIs). Indeed, the development of an API can be very expensive, and production capabilities in the early stages of drug development can be limited. 

Comparative analysis: XRF spectroscopy vs. ICP spectroscopy

When comparing XRF spectroscopy and ICP spectroscopy for drug development, the key features are ease of operation, speed of the analytical feedback loop, and instrument accuracy and sensitivity.  

• Ease of use: Sample preparation for ICP analysis is time-consuming, complex, and hazardous, so highly skilled operators are required – a major issue when such specialized labor is in short supply. When using XRF instrumentation, operators can obtain robust and reliable results with minimal training, quickly and safely. 
• Feedback loop speed: Sample preparation for ICP analysis can take up to several days, creating a lengthy delay between the time when measurements are required and the time when results are obtained. By contrast, sample preparation takes just a few minutes for XRF analysis, so results can be obtained in less than half an hour. Small companies must often outsource ICP analysis. This means sending the sample to an external lab (often a contract research organization), where results can take even longer (up to –several weeks). XRF technology is considerably more affordable than ICP systems, both in terms of the instruments and manpower required to run the measurements,  making it accessible to even small companies. 
• Accuracy & sensitivity: Although ICP spectroscopy has a higher sensitivity than XRF spectroscopy (up to parts per trillion vs. parts per million), XRF sensitivity falls well within the limits specified by the ICH  for elemental analysis. In fact, tablet coatings analysis with ICP instruments can be very inaccurate. Traditional silicon dioxide and titanium oxide coatings are very difficult to dissolve fully, which increases the likelihood of errors in sample preparation and hence, incorrect results. 

The benefits of XRF analysis according to pharmaceutical scientists

Salutas Pharma GmbH published a paper⁴ on the choice of benchtop XRF instrument over other techniques (including ICP-OES⁵ and LA-ICP-MS).⁶ Their reasons for choosing XRF technology included:

• The lower complexity, time consumption, and running costs of XRF technology.
• No need for toxic hydrofluoric acid (HF) to fully dissolve silicon dioxide or titanium dioxide during sample preparation for XRF analysis.
• The limitation of LA-ICP-MS instruments to analyze very small sample quantities compared to XRF systems, which does not lead to representative results, particularly in the case of a heterogeneous sample. 

Following a recent trial of Malvern Panalytical’s Revontium™ XRF instrument, a laboratory manager familiar with ICP analysis told us that XRF analysis provides better results than ICP analysis for drug products containing chlorine and bromine salts. 

In another case, the chief technical officer of a contract research organization highlighted the speed and ease of sample preparation for XRF analysis, which reduces the likelihood of errors. They also noted that because larger amounts of sample can be analyzed with an XRF system, it provides better sample representation. They added that the non-destructive analysis of XRF also allows for subsequent analysis with other techniques, further improving confidence in results. 

Cost-efficiency and operational advantages

As XRF instruments do not require the use of solvents, reagents, gases, or daily calibration, the running costs are substantially lower compared to ICP instruments. Overall, Malvern Panalytical XRF instruments have up to 50% lower operational costs compared to traditional ICP instruments. What’s more, because XRF spectrometers do not require dedicated and highly specialized operators to deliver robust results, users will quickly realize a return on their investment thanks to the simplicity of XRF technology.  One customer in the pharmaceutical industry told us that nine within nine months of introducing an XRF system into their workflow, they were able to save the costs of one full-time ICP operator. 

Operationally, XRF technology greatly speeds up analytical feedback loops by allowing samples to be measured directly or with minimal preparation, which also eases method transfer. Results are thus obtained faster, removing elemental analysis as a bottleneck to other processes in drug development and manufacturing workflows. 

Finally, the small footprint of some XRF instruments and the fact that they don’t require additional infrastructure (such as fume hoods and extraction equipment) mean it’s possible to place XRF instruments at-line for optimal efficiency. 

Environmental and safety benefits

The EFPIA⁷ has laid out several targets for more sustainable practices in the pharmaceutical industry, in line with the desires of stakeholders and industry leaders. Moving to more sustainable analytical techniques can help drug developers achieve these targets by reducing the use of non-renewable materials and synthetic chemicals. In one example, such green chemistry efforts resulted in a 19% reduction in waste and 56% improved productivity compared with past drug production standards.⁸ XRF technology can contribute to a sustainable chemistry strategy because it eliminates the need to use hazardous reagents

Removing the use of hazardous chemicals also greatly improves safety for operators. Effective management of chemical risks linked to the handling of these agents is mandatory for the safety of the workers in the industry, as per the rules and guidelines of various acts regulating the pharma industry.

Incorporating XRF analysis into your workflow can form part of a green chemistry strategy, helping to increase sustainability in terms of environmental impact and health and safety for operators. 

Malvern Panalytical’s XRF solutions

Malvern Panalytical’s XRF solutions are designed to provide precise and fast elemental analysis with a focus on ease of use, low implementation costs, and low operational costs. 

• The benchtop formats of the Epsilon 1 and Epsilon 4 enable easy implementation, allowing operators to swiftly start performing elemental analysis screening for more basic applications. 
• The Revontium is a new-to-market, best-in-class solution when complete elemental characterization is required.

Overview of solutions

* Suitable for pharmaceuticals where the total mass of drug product consumed by a patient daily does not exceed the given value.⁹

Quality control and regulatory compliance

Malvern Panalytical’s Revontium and Epsilon instruments comply with the US Pharmacopeia (USP <232>, USP <233>), where XRF spectroscopy is mentioned explicitly as a suitable technique for metal impurities testing (USP<735>). XRF spectroscopy is also described in  the European Pharmacopoeia (2.2.37) and complies with the ICH Guideline for Elemental Impurities (Q3D). 

Malvern Panalytical’s software supports customers working in a regulated environment across its range of XRF instruments, simplifying measurement auditing. Regulatory compliance and data integrity can thus be achieved quickly and with full confidence. 

Conclusion

An XRF instrument is an effective investment as an alternative, complementary, or orthogonal technique to traditional elemental analysis techniques, such as ICP spectroscopy for elemental analysis for pharmaceutical development and manufacturing. Compared to ICP instruments, XRF systems does not require extensive training, and the removal of hazardous materials for sample preparation greatly improves worker safety and sustainability. The much more direct analysis provided by XRF technology results in much faster sample preparation, easier and cheaper method transfer, and faster screening speeds. Overall, XRF analysis is well-adapted to pharmaceutical and API scale-up applications, complying with industry standards and providing key strategic and operational benefits. 

If you are interested in how applying XRF analysis to your pharmaceutical applications, please contact Malvern Panalytical for more information or to arrange a demonstration. 

References and footnotes

1. Such as Inductively coupled plasma optical emission spectrometry (ICP-OES), inductively coupled plasma atomic emission spectroscopy (ICP-AES), and inductively coupled plasma mass spectrometry (ICP-MS).
   
2. When a measurement is confirmed by using a different instrument that analyzes the same characteristic but with a different principle or technique. 
3. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.
4. Kroll C., Sauer B., Xiao Y., Zoontjes M., “Application of X-ray fluorescence spectrometry for screening pharmaceutical products for Elemental Impurities according to ICH guideline Q3D”, Journal of Pharmaceutical and Biomedical Analysis 179:5 (2020).
5. Inductively coupled plasma optical emission spectrometry.
6. Laser ablation inductively coupled plasma mass spectrometry.
7. European Federation of Pharmaceutical Industries and Associations.
   
8. Mishra, M., Sharma, M., Dubey, R., et al. Green synthesis interventions of pharmaceutical industries for sustainable development. Current Research in Green and Sustainable Chemistry. https://www.sciencedirect.com/science/article/pii/S2666086521001211
9. ICH, ICH guideline Q3D (R2) on elemental impurities (2022), 20.