Related substance methods

[AdrianF]

At the moment many of our related substance methods are calculated by reference to a 1 in 1000 dilution of the solution being examined. The impurity peaks are then compared to the 0.1% solution.

We are considering changing to a system which uses a dilute standard made from the pure active instead of the 0.1% solution.

What is your view of the validation implications of such a change.

[bookoon]

Using a working/ refernce standard (pure active) is always a better idea and that is what we follow in our labs.
However I would like to know the other viewpoints too.

[shaun78]

I have always used reference standards in these types of assays. Please note that these "reference standards" do not have to be of exceptional purity if it is not obtainable (see below).

Commercially available, purchased, characterized standards are best (simply because it saved YOU work). If that can not be obtained, then you are allowed to classify an aliquot of your raw material as a reference standard. How much testing you do is up to you, but generally I have evaluated: chromatographic purity, moisture (Karl-Fischer), IR, appearance, melting point, optical rotation, and NMR (both proton an carbon).

Side note here: one of the pharma companies I worked for made a tracer of about 75% purity for a diagnostic kit; it was the best we could do. The FDA had no problems with the fact that we characterized an aliquot of about 80% pure (manufacturing team took a hard cut of the product, lost about 40% more and gained an extra 5% purity) material as our reference standard.

Validation implications would be minimal if anything at all. You have already validated for the solution matrix, you have had to show specificity by diluent blanks/placebo, you have shown the nominal working concentration and linear range .... so basically as long as you do not change the diluent and keep the concentration/range the same, you have nothing to revalidate.

[AdrianF]

I completely agree with Shaun78 however I am having problems persuading others that this is a logical step and doesn't involve any essential change in the method.

I think part of the problem is a risk adverse culture where one can never be blamed for doing too much.

Can anyone one else agree or disagree with shaun78 and/or comment on the culture which exists in the pharmaceutical industry due to the regulatory environment.