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2018-07-11 06:44

Posting: # 19028
Views: 525

 BA/BE study - internal standard response variability [Bioanalytics]

Dear Members,
In BA/BE study bio-analysis, is high internal standard response variability is a cause for LC-MS data batch rejection? (for example more than 20% of the unknown samples showing more than ±50% difference etc..)
General practice is only one scenario is considered for IS variation (±50% difference from the mean), is there any other scenario to be considered?
Trend analysis for Internal standard area response? Please comment.
Thanks & regards,
Avinash Jain M V

2018-07-11 08:14

@ avinash
Posting: # 19029
Views: 422

 BA/BE study - internal standard response variability

Hello Avinash,

there is no particular requirement specified, but you need to have an objectiv rule.

You can for example check if more than X percent of the samples deviate more than Y percent from the mean calibrator and QC IS response, and reinject the run when it happens. Pick X and Y wisely, as in, according to your own opinion, experience and performance ambitions/needs.

A good question is what to do -if anything- with individual values falling outside and when they are too few to merit a complete run re-injection. Again, there are no rules, but I think it is ok to repeat those individuals as well, possibly with a root cause analysis. They never show much, do they, those investigations?

Note that, unfortunately, if you take FDA's guideline verbatim then there can be no repeats until (before) a root cause has been established: "Repeat analysis is acceptable only for assignable causes (e.g., the samples are above the ULOQ, there are sample processing errors, there is an equipment failure, the chromatography is poor)", and you might wish to make a deviating IS response as an assignable cause in its own right. I have not heard anyone from FDA express an opinion on this.

You can do trending but note that it may be a bit questionable to use statistical objectivity for it (the correct one would be Spearman's rank, and note you may not just go by a p-value) and your mileage will vary if the number of samples differ between runs (and it will do when you take missings, repeats and ISR into consideration). I personally think it is better if you have a reliable to lab employee who can eyeball the data and check trend or no trend.

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Best regards,

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2018-07-12 00:24

@ avinash
Posting: # 19036
Views: 362

 BA/BE study - internal standard response variability

Dear Avinash,

The issue of IS variation has been discussed multiple times at the WRIB. This year they even had a full day on this topic, with speakers from the FDA and other regulators + industry.

I would suggest you to have a look at the White Papers of the WRIB meeting of 2015 and 2017, published in Bioanalysis, and wait for this year's to be published.

There were also some presentations at EBF meetings in the past. According to my dear friend Google some slides are supposed to be available here but I'm getting a 503 error message, dunno if it's temporary or permanent. Same slides copied there, not sure they have an authorisation for it.

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