Chromatography Forum

Hi, dear all

I got stuck in another problem about residual solvent method validation , I hope some one can help me out .

There are 4 residual solvents that are likely to be present in the drug substance, but actually, only the solvent is detected in the authentic drug substance, others are absent.

Do I have to spike the absent solvents to the authentic sample while performing intermediate precision test?

Thanks in advance

Terry

Hi Terry

Well the ICH Q2a guideline do not directly require it, but when reading chapter 5.4 "Recommended data". it states " The standard deviation,............should be reported for each type of precision investigated".
A bit open it would seem, but data should cover all solvents of intrest so I read it as it is necessary to include the data.

Personally I mostly encounters the same "problem" and usually I spike samples at the intended specification limit to obtain the data.

Also please note that depending how you performed the validation, you may "reuse" data from the accuracy test, meaning that you not always have to do an extra analysis for the intermediate precision as you already may have data from the Accuracy investigation that can be used. Of course a second person/instrument and so forth still have to provide data.
However giving the nature of residual solvents, I still tend to redo it and provide a common spike solution in order to simulate a homogenous sample as far as possible.


Cheers Chris

Hello, Chris

Thanks for your prompt and helpful reply.

If a spike solution is prepared, and it is tested in various days, do you perform stability study of the spike solution?

Terry

Hi Terry

Well I guess would have to know the stability. I have the luxery of having help from several people/GC instruments located in different buildings so typically I would do the "different" people/instrument/column variation during one day from a common solution. And get "day to day" variations from other validation data if possible to avoid the stability issue unless I have gathered enough stability data already.

The ICH guidelines states that you do not have examine the "intermediate precision parameters" individually, and even encourages experimental design, but personally I tend to break out the "day to day" variation and study it individually as I find it convienient to study the same time as I look at variation of potential SSTs (System Suitability Tests).

Cheers Chris

Hi, Chris

In my opinion, the day-to-day variation study should test identical and homogeous sample.

So how do you do it by the following procedure?

break out the "day to day" variation and study it individually as I find it convienient to study the same time as I look at variation of potential SSTs (System Suitability Tests)

Regards

Hi Terry

I certainly agree with you, perhaps my "non-perfect" english caused some confusion.

Yes, ideally I do the same as you do, using an identical and homogenous sample.

The problem I sometimes have had with day-to-day variations when in need of spiking in residual solvents is that particulary water based spike solutions sometimes have a poor stability even when stored in 2-8°C. Perhaps I sometimes is a bit "over ethuastic" when doing day-to-day studies
In any case, this was what I meant ie water based spike solution may have to be redone on daily basis due to fast evaporation and hence me sometimes doing the day-to-day variation separately.

Cheers Chris

PS
Have a nice summer I am off to a four week holiday from Monday

DS

Hi Chris

Wish you a lovely summer holiday

Terry