Replacement / Alternate methods - Need Guidance

[HPLCer]

Hi,

I am looking for any regulatory guidelines or any advice for establishing a newer replacement or alternate method.

For instance, suppose a particular HPLC method for a drug product was filed 15 or 20 years ago. The method was fine and considered "robust" when initially filed with FDA, but technology and agency expectations have changed.

If I were to propose a newer more "state of the art" method I would obviously want to demonstrate that the replacement method is equivalent if not superior to the existing method.

One concern I have is the possibility of a new “improved” method revealing new impurities that have never before been detected and or identified? This is both a good and bad “thing”. Good because detecting and identifying any new impurities in a drug product improves the overall quality and thus safety to the patient. Bad because detecting new impurities can also be a show stopper for from a regulatory stand point and could potentially disrupt the supply of product to patients.

If anyone knows of guidelines and or papers / presentations that have been published regarding replacement / alternate methods on established API or drug Product please post a link.

Thanks for any feedback.

[Consumer Products Guy]

I'm not "an expert" in validation, but it sounds like you will need to re-validate. Moving to a modern HPLC system alone should not require re-validation.

However - big however - in those old days maybe assays and validation was done on an HPLC with integrator, and no small peaks were observed. These days electronic datastations allow for zooming-in and thus showing tiny peaks in the matrix, which must be resolved away from the API.

We have similar issues...

[Gerhard Kratz]

I agree with Consumer Products Guy. If you will get more peaks with a new method, a "new" column, with different pH etc. you will need to do re-validation. You should ask the question what will be the advantage of the new method for product safty, consumer safty, advantage over the competition, and what will be the costs for re-validation.

[Mattias]

Everything usually boils down to that you will need to do a "method comparison study". There you will have task to show that the methods are equivalent, even if the old method gives the wrong result or has terrible precision.

I have many times had the impossible task to develop a new better method "that gives the same result as the old one"...

[unmgvar]

HPLCer,

what is a newer more "state of the art" method?

there are several reasons to R&D a new method for an existing method.
most of them truly have a financial related issue that would make it worth while to refile the method for approval.
or because you were requested to make a change by a regulatory body or very important customer QA audit, and that of course also comes down to a financial reason as well.

from talks i heard from FDA people, they simply say:
risk assess the scope of the changes you intend to do and re-validate in accordance so that you fulfill all regulatory requirements expected
with answers like that what we see is that we simply re-validate from scratch everything, and with IDDs we try like Mattias to keep it looking as much like in the old format.
i have heard of a case where a try to shorten a method, brought a change in the placebo profile in the chromatogram, and one peak that moved out to a new RT, failed the project. it was not cost effective to try to prove that the peak in question was a placebo and not a new or unexpected IDD. so the application stayed 30 minutes and was not shorten to be 8 minutes