Validation question

[scottythree]

I am looking for opinions. I have an assay/CU method and a separate impurity method. Do I need to perform force degradation studies on both these methods in order to fulfill ICH guidelines stability indicating assay method?

[danko]

In my opinion, you'll need to document the degree of specificity of each of the methods. That includes the ability to separate and potentially quontitate degradation products and impurities in general.

Best Regards

[shaun78]

It all really depends upon the intended use of the assay.

If it serves as an inprocess test and a release test, then all you need to know is where the probable process impurities are.

If this assay is to be used to test product that has been put up on stability, then you need to run through the acid, base, light, heat, and oxidative degradations.

[Rob Burgess]

I'd be more conservative as to what "degradation" is required to support ICH stability studies.

I tend to just look at "forced degs" in the solid state of your API or drug product arising from light, heat alone (60 or 80°C) heat/humidity (60/75 or 80/75).

Personally I think acid. base and oxidative (H2O2 or similar) is overkill to support ICH stabilty as your solid stored samples are never likely to "see" these conditions.

[shaun78]

Personally I think acid. base and oxidative (H2O2 or similar) is overkill to support ICH stabilty as your solid stored samples are never likely to "see" these conditions.

I have been specifically asked to perform the acid/base/oxidative degradations when I worked for companies that deal with the final dosage form. When I was asked to do this, I gave a very similar argument.

The answer I was given was product pH can change over time; when product gets consumed from a tube it can be exposed to oxidative stress. I hard a hard time coming up with some way to argue that.

Anymore, it's just habit ...

[Consumer Products Guy]

Our products are buffered, and have their pH measured as part of their OTC Stability. So to even approach the "degradation" conditions the pH measurement would be out of specifications.

But our QA group never lets us leave ANYTHING out or bridge anything, guess they need some power....so we do that as well....

[danko]

It’s not a question of whether or not it’s possible for you to observe product degradation by means of pH measurement or whatever. It’s a question of capabilities – is your method capable of detecting (potentially quantitating) possible degradation? Just in case!
Besides I’ve never heard of a test for degradation/impurities that is derived from measuring of the product's pH.
Safety is an important thing – in the context of medicine anyway.

Best Regrds

[Rob Burgess]

To be honest with all the cutbacks the pharma industry is doing we are taking a more risk-based approach to all our work activities.

The reason we don't employ aggresive stressing conditions (acid/base/oxidative) to support solid state stability of API and drug products is that we don't want to be chasing impurities that we are never likely to see or indeed "secondary" impurities of impurities.

We are taking this approach through to our regulatory departments and haven't encountered any push-back so far.

If it is explained properly then there really shouldn't be any debate

[danko]

Rob,

What are you talking about - the product or the analytical method? If it’s the product you may be able to explain and justify a potential omission of a certain test. But the method you’re using for documentation of your thesis and in the end the quality and efficacy of your product has to be capable of detection and quantitation of possible degradation products, such as oxides, desamides, aggregates etc.
The original question was about analytical methods.

Finally: Cost reduction initiatives are not and cannot be regarded as an excuse for filling patients with unsafe junk!

Best Regards

[Rob Burgess]

In truth it refers to both doesn't it - the product and the method. They go hand in hand.

The method is suitable in that it will be specific for impurities you will only ever see from ICH storage conditions.

Why would you need a method to support degradtion products such as oxides, desamides etc. if you will never see them from the solid state storage? The method needs to be fit for purpose. If things do oxidise from heat/humidity under solid state storage then fine - obviously you need a method to track them.

But if something oxidises only with H2O2 but NOT on storage in solid state - why would you go hunting for a deg. imp that you would never see?

[danko]

But if something oxidises only with H2O2 but NOT on storage in solid state - why would you go hunting for a deg. imp that you would never see?

But how will you know what happens on storage if your method isn’t capable of answering that question.
So, in the context of this particular topic, the forced degradation’s relevance is to the method and once you’ve shown you can detect and quantitate the possible impurities, you may begin thinking of the possible stability parameters.

Remember the outcome of the cost reduction initiatives undertaken by BP? And there are thousands upon thousands of examples one can learn from.

Ever thought of who benefits from all those cost reductions? I bet it’s not the scientists, technicians and all other hard working people, which I assume you’re a part of.

Best Regards

[Rob Burgess]

But how will you know what happens on storage if your method isn’t capable of answering that question.

I'm not sure I understand your point. Your method will be able to pick up all the relevant imps as you would have stressed appropriately i.e. 60/75 or 80/75 to mimic ICH conditions and developed the method as normal to pick up all the potential impurities. Often smashing a molecule to bits with H2O2 is meaningless (from experience) as it generates to many imps that will never be seen and "you can't see the wood through the trees" to coin an expression.

Often "possible impurities" does not equate to actual real impurties. Look at your molecule from a risk based approach. Say if there is less than 0.05% chance of seeing an imp ever with your storage conditions (ICH) why include it as a part of method dev. sampe set?

There is no risk here as I see it. [/quote]

[danko]

The role of H2O2 is to mimic the long-term exposure of a given product to air/oxygen. The results of that test are later compared to what really happened over time (2 – 3 years or whatever). The point is; you don’t know what will happen unless you can detect it. If you’ve had a bad experience with H2O2 you might have been using too concentrated solution of that.
I personally never came across a drug (I’ve been working mostly with proteins) that wasn’t oxidized over time – despite sealed containers, storage at low temperature etc.

Besides, you might like to re-read the original question?

Best Regards

[yanyan]

If it is for stability testing, I would check samples, either from a forced degradation study or from old (passed expiration date), on both methods.

For assay method, I would only need to separate all impurities from the active peak. For impurity method, I would not only need to separate all impurities from the active peak, but also to each of others.

[Alex Buske]

If it is for stability testing, I would check samples, either from a forced degradation study or from old (passed expiration date), on both methods.

How do you know that there are no additional peaks below the others, before or after the chromatogram or at other detection conditions?

For assay method, I would only need to separate all impurities from the active peak. For impurity method, I would not only need to separate all impurities from the active peak, but also to each of others.

Note: synthsis impurities that can not formed under normal conditions (i.e. methylated API, something with a C7 instead a C6 side chain) dont have to be monitored in stability studies.