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Interference from Deuterated IS [Bioanalytics]

posted by Ohlbe - France, 2019-01-10 23:41  - Posting: # 19770
Views: 224

Dear Chirag,

» 2.During method development we observed around 12-16% interference from Digoxin deuterated (D3) IS at the RT of Digoxin drug.

That's a rather high level of interference. I'm quite surprised, that's more than I would expect just from isotopic contribution. It does not look like it could be due to another type of adduct, figures do not really match, but I'm not expert enough. Did you check that the deuterium substitution was not done at a labile position, causing deuterium exchange ?

There are several papers describing the use of D3 digoxin as IS. Do the authors report similar levels of interference ? Was their IS marked at the same position ?

Did you try and modify your ion source parameters (e.g. declustering potential) ? Any influence on this % interference ?

Any improvement with an increased MS resolution ? I know it will spoil the LLOQ, but it could help to understand what's going on.

» 3. Inspite of this interference, all the QCs (100%) (Spiked with only Digoxin & Digoxin + X) are meeting the acceptance criteria.

Yes, the interference is compensated by the intercept in your calibration curve. But I would be worried regarding the ruggedness of the method and the reproducibility of the results at low levels of concentration, close to the LLOQ.

» My question
» 1. Would it be advisable to proceed with the validation and will this have impact during sample analysis since all the samples will be spiked with IS.

I would first try and understand what's happening, and reduce this % interference as much as possible.

» 2. Is there an alternate approach to this scenario ?

If the authors of published papers report the same issues and there is no possible correction, I would either:
- try and find a provider who would accept to manufacture digoxin marked with more deuterium, or C13,
- or try a structural analogue IS rather than stable-labelled,
- or decrease the interference by decreasing the amount of IS added to the samples.

Or you can try your luck, perform a full validation and see whether it passes, but there is always a risk that any Agency the results will be submitted to will not like it.

If you could keep us informed, it would be appreciated. That's an interesting topic :-)


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