Chromatography Forum

We recently validated a method for a client for an impurity related to a specific API, to determine related % This had a specific linear range, and had all the usual validation parameters, linearity precision, recovery etc etc. The client then got back to us, and they wanted to extend the calibration line, and in effect double it for certain samples that would have higher amounts, and to do some.of the validation parameters.

It was during a call that it was suggested that because we had shown that recovery was pretty much 100% during validation at high middle and low spikes, that the additional experiments would not be required, (as we have shown that amount impurity recovered between 0 concerned API to XX concentration is the same)and those samples that at would be expected to have impurity at higher levels could be diluted further, or to inject samples at different API concentrations (but no higher than the concentration API was validated at), so that we would acquire impurity within the linear range, and as %relative impurity to API is the information, then this makes scientific sense.

Both quality teams at the different companies agreed this was fine, the principal scientists were all in agreement, with there decades of experience. So I am not early career but still early thirties, and so I thought that any change including extra dilutions would need to be revalidated?. I did look at the ICH guidelines and it does say something along the lines of "should consider". Is this one of those things were the scientific justification is enough to negate the need for additional work. The method has not changed it is just that additional dilutions may be required between routine analysis to the next.

What are your thoughts??

Logically, you've validated a method so that it works if the sample contains a minimum of X and a maximum of Y of the API, and a minimum of A and a maximum of B of the impurity. If you've got a sample that contains a little less than Y of the API, but a bit more than B of the impurity, then if you dilute it, it falls in the range over which your assay is validated.

So the only question is whether you need to revalidate an entire analytical method because you're using a diluted sample.

If you were suddenly diluting your sample in a radically different, weird solvent, it could mess up your analytical method, but if you dilute it in the solvent that it's already in, there is no way the analytical method can distinguish between this sample and a sample that just happened to be dilute anyway, by its nature. So dilution really should be a very, very low concern; there are probably lots of ways that the analysis can go wrong that are far more likely to happen.

I wouldn't do a full validation. I'd do a couple of studies and document that in a report. Should be less than a week of work.

My last boss would've wanted us to start from scratch, he didn't believe that ANY parameters could be modified as stated in USP <621> or FDA ORA documents despite those being stated in plain English....