LOQ limit impurities

[centraing]

Hello,

In the european pharmacopee, one of the system suitability items is the control of the s/n ratio of the disregard limit by the determination of related substances. The s/n of the disregard limit must be >10:1!

Now I work at an generic farmaceutical laboratory and in the specified document for an tablet product, there is only the LOQ described. The determination of related substances is based on the total area of all impurities + the area of the principle peak. The known impurity is calculated as follows:

(area imp * 100%/((sum area imp)+area API))*Factor

The pre-determinated LOQ is <0.02%
When I calculated a sample, the known impurities has an percentage of 0.04%
This peak has an s/n ratio of 4. This is to low in observing the SS-limit of minimum 10 LOQ.
The method is set up by an other laboratorium, with possible an sensitiver detector.

Is it correct to control the s/n ratio here? Or because of no information in the analyse method, I just close my eys . Anyway I can not do this
Can I, within the requiremends of the european pharmacopee and ICH guidlines, raise the injectionvolume so that the s/n ratio will be >10:1 ?
I can only find something about decrease the injection volume.

When I rais the injectionvolume do I have to validate this method?

Sorry for the many quenstions , but I can not conform this with some one else within my company

Thanks a lot

Ing

[DSP007]

Hi
a) 10:1 -to good determine peak area.
b) "Za scale" (peak on a scale beyond the operating range) major peak - yes or no ? If "yes"- may be mistake
c) Dissolve (dilute) you sample in 10000 and inject. And see "What admixture peak dimension right"
d) For peak/nouse-
Increase the concentration or volume of the sample three times - and you will be happy.

[krickos]

Hi

Well think you really have to dig into the history of this procedure finding the validation report, when was it validated, how was LOQ determined and so on. Why?
-LOQ can be determined by S/N (2*H/h) or other means as per ICH Q2 guideline

-If procedure was developed before ICH guideline came into play (1996-7) maybe S/N was calculated as H/h?!

-LOQ may have been determined by using dilutions of the main peak which may have considerble better peak shape than your impurity.

and so on.

From a compliance point of view I am not sure you really has to comply with the Ph Eur general demand. Ph Eur covers drug substances and excipients in general but lack monographs for products which USP,BP and JP have. Sure ICH Q2 refers to pharmacopieas in general for suitble SSTs but again it boils down to how and when the LOQ was determined in the first place.

[yanyan]

It looks like that the system of the validation someone performed with is at least 5 folds sensitive to the one in your laboratory. There are so many factors can affect the s/n ratio, such as instrument brand, detector lamp aging, mobile phase(s) and system cleanness, column extra volume, and so on... I would focus on improving the system to max its sensitivity if I was you. There is always a possibility that you can improve it. Good luck!

[yanyan]

By the way, it may not be 5 folds sensitive than yours, depends on what mean they used in the method validation.

[krickos]

The method is set up by an other laboratorium, with possible an sensitiver detector.

Should be fairly easy and quick if both labs could do a serie of diluted solutions 0,1-0,02% including a couple of blanks for noise and compare S/N ratios for those to confirm any significat differences in noise and/or sensitivity issues.

[Peter Apps]

If the s:n of 4 was measured as the peak height vs short-term baseline noise (which is possible) and if the analysis is calibrated using peak area (which is likely) then the repeatability will be better (i.e. smaller) than 25%, and might even reach 10%. So the critical question for the OP is; How did you determine signal:noise ?

Peter

[centraing]

Hey,

Thank you all for your response

The s/n ratio was determend by 2H/h. We already have made an solution of 0.05% of the mayor peak.
That solution gives an s/n ratio of 2.5. So for unknown peaks the LOD is anyway <0.05 the LOQ is in theory <0.2. Our specification is <0.2 so here I have a problem
I shall try to get some information by our contracter. But the problem is that we alreay perform this method for some time now. There was no one in my company who notice this problem. Because I transferd the Ph eur. SST requirements in to our HPLC procedure for related substances, we now see some problems with this method. Maybe I work now to critical.

I also think that the first method was sensitiver than at our laboratory.What can i do about this.
What is nesseccary by method trasfer? Method transfer was really needful here, but never done.

thank you
Ing