How to Carry Out SIFT-MS Analysis and How it Can Speed up Workflow

Volatile compounds are common impurities in pharmaceutical products and are often of concern due to their toxicity. They can also represent a health and comfort hazard, both indoors and out. However, analysis using conventional chromatographic methods is slow, due to both sample preparation and chromatography.

Selected ion flow tube mass spectrometry (SIFT-MS) is a new analytical tool for real-time, selective, and economical trace gas and headspace quantification of volatile compounds, including chromatographically challenging ones, such as formaldehyde, formic acid, and ammonia. But how do you approach analytical method validation for SIFT-MS so that the data can be used to support regulatory requirements? By applying a strategic method in accordance with ICH Q2(R1) Guidelines to direct SIFT-MS methods – and utilizing formaldehyde analysis as a case study – successful validation is readily achieved.

In a webinar now available on demand, scientific experts Mark Perkins, from Anatune, and Dr. Vaughan Langford, from Syft Technologies, explain how SIFT-MS works; how it speeds up analysis; and how it can be validated successfully in accordance with ICH Q2(R1) guidelines suitable for pharmaceutical applications, such as regulatory submissions where GMP compliance is essential.

If you missed the webinar, you can now watch it on demand whenever you feel like it. Read on for highlights from the webinar’s Q&A session.

Q: How long did the entire validation take?

A: Considerably shorter than a standard chromatography method would take – from start to end, the entire process was about two weeks, but in that two weeks, we had to work out how to do some of the processes. Now we know how to do this, we could definitely generate the validation data probably within five to seven working days. The technique is that fast.

Q: What sample types can be analyzed with SIFT-MS? Or is it just applicable to packaging headspace?

A: SIFT-MS is a gas phase sampler – your sample has to be in the gas phase for it to be analyzed. So pretty much any sort of material that generates VOCs can be analyzed, for example, you can generate VOCs from packaging or you can look at aqueous solutions. By looking at dissolved VOCs in aqueous solutions, you can analyze pharmaceuticals directly.

We've seen some good analysis techniques being developed on aqueous headspace, where we can generate some calibration standards in water and run some swift calibration curves off the back of that.

Q: How is work being carried out on pressurized metered-dose inhalers?

A: One of the obvious things we looked at early on was could we see formaldehyde in MDIs, because that's a difficult analysis to carry out — and we can. But I've also done some more recent work looking for some other volatile compounds that were expected to be present as part of the product. So, actuation into a headspace file followed by sampling of that headspace, and we could see the VOCs we were interested in. We did do some direct sampling where we just actuated the device in front of the system and got it to show responses to these VOCs.

Q: Do you need or should you use internal standards?

A: If you look at the data generated in this webinar, it would suggest to you that you don't need internal standards, because those RSDs generated for the precision exercise and the accuracy exercise were less than 0.5%. That suggests that the instrument is very stable and as long as your sample type is stable also, then I don't see the need for internal standards. There are some cases where maybe we're looking at slightly more tricky compounds, or we're looking at a tricky matrix, or we're looking at trying to drive some more polar compounds out, then you might want to look at internal standards.

But the thing to remember with these is we wouldn't need to use deuterated standards, because we're not trying to find some sort of separation on the mass specs and on the column. We can do the separation using the multiple gradient ions.

Q: Would SIFT-MS be useful for pre-screening packaging materials, i.e., a quality-by-design approach?

A: Absolutely. These measurements can be made in 25 seconds using this technique. You can run that continuously in real time and see changes to your packaging and VOCs, depending on the batch of those packaging materials that's coming through. The other thing we’re doing quite a lot of work on now, in collaboration with Strathclyde University, is looking at whether we can use SIFT-MS as part of continuous manufacturing type processes. So, where we batch process the pharmaceuticals, we do continuous process manufacturing pharmaceuticals.

That requires real-time inline continuous measurement to control the output of those products; a sort of quality by design approach, because it means that if we can continually see these inline processes and keep this continuous manufacturing going, we're not dumping bad batches, because we're constantly making sure that everything stays within its accepted parameters. So, we are absolutely perfect for that type of application.

Q: How has SIFT-MS been used for residual solvent analysis?

A: It has in my lab, yes. Another pharmaceutical application that seems to be directly applicable to this type of technique is residual solvents. I'm currently working on developing that method further and looking at validating a method to cover 29 analytes within one method.

Q: Could you use SIFT-MS to measure the release of volatiles in real time as polymer seed stock is extruded?

A: Yes, I'm sure you can. In this type of work where you're having to extrude polymers, the heat generated from the extrusion process releases VOCs from unpolymerized monomers remaining in that plastic, but could also release potential degradation byproducts.

If we're talking about elastomeric materials, you will have the residual accelerators and degradation of residual accelerators in those compounds as well, which tend to be compounds that are sulfurous or nitrogenous, for example, nitrosamines. These are difficult compounds but are perfectly analyzable by SIFT-MS. You could again just tap into the exhaust pool on a twin-screw extruder and examine changes in VOCs, revealing information about degradation and about what's happening within that process.

Q: Is there a way that you measure absolute quantities of volatiles in materials?

A: Yes, there is. When you're looking at headspace above a compound, what you're basically looking at is a partition from whatever the matrix is, whether it's solid or liquid in the headspace. And that partition isn't 100% — some of your VOCs stay in the matrix. Your headspace measurement is only telling you what's in the headspace and you might want to know what's in the solid material. Therefore, you can go through a process called a multiple headspace extraction, where you measure — as the technique suggests — multiple headspace measurements.

So, you measure a headspace, then get rid of it, and then you regenerate a new headspace from the same sample and measure that one, then you generate the next one. Over time, you deplete headspace and the concentration in the sample. If you add all of them together, you would get the concentration in the sample, the total concentration. But, of course, we don’t want to do all of that, as it will take ages. So, you can do maybe the first three or four points, extrapolate it, because it does tend to follow a pseudo-exponential decay, and then just fit it using maths and extrapolate back, giving you your total concentration.

This is done not as often as you might imagine, simply because it takes such a long time using standard chromatography. But if you could measure a headspace every 25 or 50 seconds then, short of having to regenerate headspace, these techniques become much more applicable.

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