Eliminating catalytic residues as you scale up APIs

Impurities can find their way into drug substances and pharmaceutical formulations at every step of the drug manufacturing process. For example, the metal catalysts used in the synthesis of certain compounds, which must be removed due to their toxicity. ?

In the final webinar of our four-part API scale-up strategies series, XRF’s expert Lieven Kempenaers, Ph.D. presented the benefits of Revontium, an X-ray fluorescence (XRF) spectrometer, for elemental impurity screening. The Q&A session that followed was filled with great questions – read on for the highlights!?

What can be measured with XRF??

Many viewers wanted to find out more about the kinds of samples XRF can analyze. Here are the questions they asked, and the answers Lieven provided:?

Q: Can liquid samples be analyzed with XRF??

A: Yes, liquids can be measured in the same sample cup as loose powders, making XRF a highly flexible solution that can analyze different types of samples with minimal sample preparation.?

Q: What is the maximum quantification level for metals???

XRF can measure metals from sub-parts per million (ppm) levels up to 100wt%, without the need to dissolve the sample. It can therefore analyze even pure metals, although you’ll always find traces of other metals while doing this analysis with XRF.??

Q: Is there a minimum amount of sample – solid or liquid, for example, 5mg of powder sample or 1 mL of liquid??

A: The principle with XRF is that the more samples you have, the more photons are produced during the experiment, which leads to higher intensities in the XRF spectrum and/or shorter measurement times. We recommend at least 5mL for liquid samples and 50-100 mg for powder samples, but a smaller sample quantity can be analyzed – it will just take more time to measure. ?

Q: Can XRF measure the percentage of counter ions, like nitrate or carbonate ions??

A: Unfortunately, XRF analysis is not able to perform element speciation. Nitrogen and carbon are also too challenging to analyze with XRF.? ?

Q: Can XRF provide quality and identification testing??

Yes - with just a quick screening against a known database, users can create a “fingerprint application”, where the combination of different elements is compared to a database instead of the elements being measured individually. Some of our clients use this functionality to quickly compare the quality and even the origin of different raw materials.?

We also offer ‘Omnian’, a screening tool that works together with Epsilon 4 and Revontium, and screens your solids and liquids in a few minutes measuring time. After the measurement, all the elements present in the sample are reported and semi-quantitative concentrations are provided in a nice overview.??

How do XRF instruments compare to ICP??

Viewers also wanted to know how XRF compares to inductively coupled plasma (ICP) spectroscopy, and how Malvern Panalytical’s XRF instruments compare to each other:?

Q: How is XRF superior to ICP??

For elemental impurities detection, the sensitivity of XRF is sufficient to meet the sensitivity levels required by regulators like ICH. But XRF has further benefits to ICP. Most importantly, samples don’t need to be dissolved in acids and can instead be analyzed in solid form. This means sample preparation time is cut from days to minutes. And since XRF does not require any acids, operators are in no danger during sample preparation. ?

Q: How time-consuming is recalibration??

XRF systems are very stable, so calibration is only needed annually; unlike ICP which daily requires time-consuming calibration. XRF is also very simple: it will typically involve measuring one or two samples to check if the calibration is valid, and if not, it takes just one or two measurements of monitor samples to update the calibration. ?

Q: How does Revontium compare with Epsilon 4? What makes it different??

This is not about defining the best instrument, but about identifying what is right for the task at hand. Both Epsilon and Revontium comply to the ICH guideline for detection of catalyst residue, but Revontium can achieve it for a higher daily dose (10 g) due to its higher sensitivity. Revontium would allow one to measure faster and is equipped with a higher capacity sample changer (32 positions), hence is more fit in a high-throughput environment.?

The Revontium is our best-in-class compact XRF instrument. It has a more powerful X-ray tube and more sensitive detection chain than the Epsilon 4, enabling users to optimize their sample throughput and push their detection limits for elemental impurities. If we look at Omnian, which enables XRF analysis even when no dedicated reference materials are available, the Revontium’s increased sensitivity will result in the detection of additional traces that would not be visible with the Epsilon 4. ?

Learn more about XRF technology for pharmaceutical applications here ?

Visit the solid-state analysis webinar hub to watch Lieven’s full webinar and more!?