As part of the method validation we usually perform a stress study of the substance the method is used for. As far as I know, there is no guideline that tells how to perform this study. Does anybody know where can I find more information obout forced degradation, or does anyobody have experience in it?
I would much apreciate your answers!

Yes, we do very extensive forced degradation study as a part of our validation for stability-indicating assay methods. Email me, so that I can send you some information. I really dont want to use the message board for this purpose.

I know of no such guidelines either.

I did find an interesting reference:
Guidance on Conduct of Stress Tests to Determine Inherent Stability of Drugs, by S. Singh and M. Bakshi, Pharmaceutical Technology On-Line, April 2000, p. 1. This reference gives some useful procedural advice.

As the title says, the subject is NOT stress testing for method validation, so they go to extremes that are probably not warranted for method validation.

For validation purposes, it is my opinion that under no circumstances would you want to degrade a drug to below an acceptable potency. For example, if the drug potence must be 100+or-10%, then a 10% degradation would be the maximum to consider. We often shoot for 5% to 10% degradation of the drug substance.

For a drug formulation I'm working on I used the following conditions:
ACID. Refluxing one hour with 2 parts 0.1 N HCl (followed by neutralization); result: 96% residual drug.
BASE. Refluxing about 24 hours with one part 2 N NaOH (followed by neutralization); result: 94% residual drug.
LIGHT. Exposure to 0.25 w/m^2 UV/Vis. light (at ambient temperature) for 36 hours; result: 94% residual drug.
HEAT. ~8 hr at ~130 degrees C (under nitrogen); result: 95% residual drug.
OXIDATION. ~12 hr at ~115 degrees C (under air); result: 97% residual drug.

Of course, these are only the conditions that worked for the drug I happen to be working on.

There is indeed a guideline for photostability testing. Please chcke out this link:

http://www.fda.gov/cder/guidance/1318fnl.pdf

Normally I've tested drug substances at the following conditions:
Acidic: Solved in 0.1 M HCl. Tested up to 4 hours at 60° C.
Basic: Solved in 1 M NaOH. Tested up to 4 hours at 60 °C
Oxidation: Solved in 1 % H2O2. Tested up to 2 hours at 60 °C
Heat: As dry substance 60° for 24 hours
And often tested solved in water at 60 °C for 4 hours.

For these degradation studies I too know of no guidelines, but would like to be enlightened.

That photostability testing guideline is interesting, but it isn't directly relevant to method validation. Rather, it is for testing of the drugs themselves.

In method validation, what is needed is to produce a reasonable degree of degradation by any appropriate means. This is usually taken to mean acid hydrolysis, base hydrolysis, photolysis, thermolysis and oxidation. Conceivably a neutral hydrolysis could be added to that if useful.

Having tested the drugs for stability, we are in a much better position to judge what sort of stresses should be used in validating a method. However, often this information is not available to the analyst, so we have to wing it.

All posted in the posting above is absolutely correct, except from the fact that it isn't directly relevant. What is neede isn't a reasonable degree of degradation, but what is thought to be a realistic picture of the degradation developing through f.i. a stability study.

And it is well known that a lot of compounds gives different degraadation products from light exposure than the Other degradation methods.

That's the point: what is the purpose of stress study? To degrade the drug substance by any "appropiate means" or to study the forced degradation with somewhat "realistic conditions". Our policy is "to keep the degradation conditions untill more or less 20% degradation of the drug substance or during a maximum of 2 weeks period of time." But what if the drug does not degrade with HCl 1 N in 2 weeks? Shall we use more concentrated acid (base, H2O2) or we simply accept that it does not degrade and stop to try to degrade it. (in one of our studies we used conc. HCl and the drug did not degrade...)

You should be able to detect any impurity due to a degradation process. !!!!
You should prove that your HPLC method is stability indicating and that's why you are doing first an stress testing. And for that you need to degrade your compound !!!

I believe that it is unreasonable to degrade your compound by any means necessary. I think that the purpose of a stress study is to account for degradants produced by reasonable stress such as those that might be encountered during a stability study or during a products shelf-life. Once you start getting secondary and tertiary degradation into the picture, I think you are losing touch with the scope of method validation. Method validation is performed to ensure that the method is capable of perfoming with respect the intended application. It is not meant to ensure that all conceivable scenarios are covered. Just my opinion.

The FDA document that refers to the stress studies is the FDA Stability Guidance. The web address can be found below.

http://www.fda.gov/cder/guidance/1707dft.pdf

The purpose of stress testing is to ensure that the methods used in stability studies are stability indicating. If you read the guidance, the FDA acknowledges that not all peaks may be relevant. I hope this gives you the regulatory reference that you desired.

The documents referenced above (in separate responses) are very interesting and potentially useful.

However, they apply to stability testing of drug substances, and not directly to method validation.

If anyone knows of more relevant documents, I would be very interested.

The idea is to degrade your drug substances. There are several methods like exposing to heat sunlight acid degradation alkaline degradation and oxidation. the basic idea is to degrade the compound and see the stability of the compound and working out the impurity profiles.