Comparing ICP-MS, ICP-OES and XRF techniques for elemental impurity testing of pharmaceuticals

In active pharmaceutical ingredient (API) manufacturing, every opportunity to streamline process steps is invaluable. Of course, certain steps can’t be cut – for instance, regulations like USP 232/233 and ICH Q3D set strict limits concerning the presence of metal impurities in drug formulations. As a result, elemental analysis is always a crucial process.  

While inductively coupled plasma spectroscopy, using optical emission spectroscopy (ICP-OES) or mass spectrometry (ICP-MS), provide accurate results, they’re time-consuming, causing bottle necks in workflows and delaying decisions. As a faster, more cost-effective alternative, X-ray fluorescence (XRF) can simplify and accelerate elemental analysis. 

What is Inductively Coupled Plasma Mass Spectrometry (ICP-MS)? 

ICP-MS is an analytical technique used to detect and quantify trace elements and isotopes with detection limits in the parts per trillion (ppt) range, making it one of the most precise techniques for elemental analysis. Samples are dissolved using hazardous acids for several days, then ionized by an inductively coupled plasma. A mass spectrometer then detects and separates the stripped ions based on their mass-to-charge ratio, thereby identifying and quantifying the elements in the sample.  

What is Inductively Coupled Optical Emission Spectroscopy (ICP-OES)? 

ICP-OES is another powerful technique for elemental analysis, although it provides a lower level of sensitivity (typically parts per million) compared to ICP-MS. Instead of a mass spectrometer, it uses optical emission to detect elements. A high-temperature plasma excites atoms in the dissolved sample, causing them to emit light at characteristic wavelengths. A spectrometer then measures the emitted light to determine the concentration of elements in the sample.  

Challenges of ICP-based elemental analysis 

For many pharmaceutical companies, ICP-MS is the go-to technology for fulfilling their elemental analysis needs, either in-house or by outsourcing to a contract research organization (CRO). However, ICP is not always the best tool for the job when it comes to active pharmaceutical ingredients (APIs): 

• Hazardous and time-consuming sample preparation:  Samples must be dissolved in aggressive chemicals such as hydrofluoric acid, which takes hours to days, and must be prepared by a dedicated ICP specialist.  

• This lengthy sample preparation results in long feedback loops: This means you can expect to wait at least 24 hours and sometimes several days to get results. 

• The precision provided by ICP is not always used effectively: For example, during the early stages of metal scavenging, ICP’s sensitivity far exceeds what is necessary do the job. 

In contrast, XRF-based elemental analysis requires almost no sample preparation or training, is non-destructive, and is listed in USP 232/233 and ICH Q3D as a suitable alternative to ICP-MS or ICP-OES.  

Why XRF is ideal for pharmaceutical applications 

XRF is an analytical technique used to determine the elemental composition of materials. It exposes a sample to high-energy X-rays, which excite the atoms in the material. These atoms then emit secondary (fluorescent) X-rays, which are characteristic of specific elements. By measuring the wavelengths and intensities of these emissions, an XRF spectrometer can identify and quantify the elements present in the sample. 

XRF is widely used in industries such as mining, environmental testing, and increasingly in pharmaceuticals. In fact, its ability to analyze solids, liquids and powders with minimal sample preparation makes it particularly attractive for drug and excipient testing.  

With XRF for pharmaceutical development, elemental analysis is faster, easier, and more cost-effective – while maintaining compliance with USP 232/233 and ICH Q3D.  

How to select the right solution for you 

Malvern Panalytical offers three XRF spectrometers fit for use in pharmaceutical research and manufacturing: 

• Epsilon 1 is a portable XRF analyzer that provides straightforward analysis of residue elements and efficient raw materials inspection.  

• Epsilon 4 is a benchtop XRF instrument suitable for elemental impurities analysis in APIs and excipients, in line with the recommendations of ICH Q3D and USP 232/233. 

• Revontium™ is a compact XRF analyzer that delivers high-quality elemental analysis in a compact, tabletop format, fusing the performance of floor-standing XRF and the versatility of table-top instruments. 

If you’d like to discuss how XRF can add value to your pharmaceutical processes or book a demo to see it for yourself, please contact our experts.