Evaluation of Pharmacopeial Methods

[Santosh Gandhi]

Hi,
Last week I was evaluating a pharmacoepial method for an API, there were two methods given for related substances, the difference between the two chromatographic conditions was only the in the concentration of Acetonitrile. In the second method ( Both isocratic) the concentration of ACN was 67% compared to the first 45%. The second method is ofcourse used for quantifying late eluters. The problem that I had was in the second method because of higher conc of ACN some of the impurities eluting after the main peak co-elutes with the main peak and the main peak is eluting very early ( the RT as been specified). I found that the problem was finding the right column . Moreover some of the impurities that may be present in the API that I use for evaluating the method may not be present in the sample with which the pharmacoepial method was developed.
My question is what is the best way or approach for evaluating pharmacoepial methods.

[krickos]

Hi
Well there are not a simple answer to your question. Ph Eur at least list those impurities that are supposed to be resolved on the specified chromatographic system.
From a GMP point of view you need to documented it but there are no really mandatory tests "verify that the method is suiteble under actual conditions".

A couple of pointers/ideas:

1. Obviously the SSTs needs to be fulfilled, a decent indicator (do not forget the general ones).

2. Review the impurities, does the one listed (hopefully) in the monograph mathc the ones that are likely in your API or your suppliers API (can be found in open part of Drug Master File). Ideally you would have acess to all relevant impurities but that is not always the case, and here you might end up with some kind of risk assesment (test done sufficient or should we spend $$$ on getting some/all impurities of intrest?).

In worst case you will find that the new method is not suiteble for your API and an alternative method (or your old one) have to be used (the pharmacopieas appreciate such feedback). Can also cause some regulatory work in worst case ie submitting an alternative method.

3. Recall that the pharmacopieas allows for some modification (see relvant general chapters regarding chromatography) to obtain appropiate resolution/peak form/RT.

4. Yes, finding the "right" column manaufacture can still be an issue.

5. Compare results between new and old mehod, does the results match? Also consider spike tests depending on availble impurities. If you expect regulatory questions comparing three batch results are typically a good idea as they tend to ask for that.

6. If things seems to work I would also recommend some reduced "intermediate precision" and robustness testing.
-Let a second person test the method, ideally on another instrument brand and column batch.
-Spend some time on stability of solutions (sample and standard solutions), always appriciated by those who run the method on a daily basis and usually not listed in the pharmacopiea.
-Depending on what you have found out so far some additional testing/verification might be needed.

Might have forgotten something but should be a good start.

As a side note:

"Column" problems may also appear with GC methods.

Have also faced issues with seemingly easy methods such as heavy metals and sulphated ash when changes have been made in pharmacopieas.

Conclusion: Do not assume it works (paper review), always test it.

[aceto_81]

...
4. Yes, finding the "right" column manaufacture can still be an issue.

For the European Pharmacopea there is a link were you sometimes the column used can find:
http://extranet.pheur.org/publications/ ... s_sw.shtml

Ace

[krickos]

...
4. Yes, finding the "right" column manaufacture can still be an issue.

For the European Pharmacopea there is a link were you sometimes the column used can find:
http://extranet.pheur.org/publications/ ... s_sw.shtml

Ace

Yes that link works fine and additionaly you can also sometimes find a chromatogram there.

If you have an online subscription of Ph Eur you can also reach the "knowledge database" via a link in the monograph.

[JM]

USP also publish a book of columns used in monographs but it is not free .

For that matter nothing is free from USP.

JM