Stability-Indicating MV – peak purity of degradant peaks

[Lanon]

I am interested in getting feedback from others regarding the methodology normally used for demonstration of peak homogeneity of degradant peaks. My question does NOT concern peak homogeneity of the parent compound as I am more familiar with addressing that issue.

Here are the details -

Our drug product is expected to produce two impurities at levels that will exceed the ICH identification and qualification thresholds during ICH stability studies. These impurities will be qualified in tox studies. Standard materials of each impurity will be prepared and the standards will be used during the method validations studies to determine linearity, specificity, precision, accuracy, LOQ/LOD, etc for each impurity.

My question is with respect to the specificity evaluation. Should I include a requirement for DAD peak purity for these degradant peaks during the forced degradation study? In other words, I can generate the degradation products at significant (but realistic) levels under heat stress, so should I require these peaks to pass peak purity by DAD to show that these impurities are indeed one peak? I’ve never made this requirement in a MV study before but it seems logical. Has anyone else done something similar or do you usually handle this problem of peak purity separately from the method validation studies and in a method development-type study?

Thanks for reading and I really do look forward to any feedback that you can provide!

[krickos]

Hi

Doubt there are so much rights or wrongs here, more like keeping things apart a bit, so in other words your own suggestion to keept it separeted "feels" better.
Just like you caracterize the drug substance and your reference standards with assay, purity, Identity (IR, NMR, MS...) etcetera why not include a DAD spektrum from a well defined procedure? I think is it helpful but nothing I would normally add in a validation protocol for a related substances procedure if I have isolated and caracterized impurities/degradation products on the shelf.


For the the evaluation of the stress study on the other hand why not? It is an additional tool for evalution that may help you if you experiance something unexpected.

[cody84]

I'm using the spectrum for ID only as all of the impurities I'm working on are unknowns. I got the sprecta from a prep of USP standard that had them all in it and then try to match them to a degraded sample.

[Alfred88]

Dear chromatographers:

I was asked about peak purity recently by an auditor. For one validation, we acquired data with our UV detector.
We did not use orthogonal method or use a PDA to monitor possible degradant(s) in the validation.

Could we use data acquired by a second channel (different wavelength) to justify peak purity? We only have UVD, but no PDA.

I am thinking about a simple remedy, like scanning the potential degradants (and stressed product) in 10nm increments, e.g. 230, 240, 250, 260nm.
Please advise.

Thank you.

alfred

[sanS]

Hi krickos


It is good thing to have the peak purity test for the spiked impurities. But what if during the forced degradation studies you find that the main peak is pure but the impurities peak is not?

Will you go for changes in method to resolve the merged peaks or for other techniques like mass etc? What ultimately will be achieved by checking the purity of these impurities peaks.

[krickos]

Hi Sans

I would not go for a yes or no answer here as it is case by case. ICH 3B, chapter II includes a scientific rational apart from the recommended reporting limits etc.

It is also discussed in ICH Q1A (R2) (chapter 2.1.2 stress testing drug substance):
"Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. However, it may not be necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed under accelerated or long term storage conditions."

So unless you use H2O2 in your process I would say a degradation product originating from H2O2 exposure in a stress study that is not present in long term/accelerated stability studies would be less likely to need more examination.
While pH ajustments which is quite common can be critical process parameters in both drug substance manufacturing and drug product formulation, consequently a degration product from high/low pH exposure in stress study may be more likely to need further investigation and analytical procedure adjustments.

So what you achieve is a better understanding and information for your justifications.

[Rob Burgess]

You may find that DAD peak purity is just not sensitive enough to determine peak purity for low level impurities (i've never been able to do it especially for impurities in the 0.1 to 10% range of main peak from previous experience).

Personally I'd always recommend a LC-MS over a LC-DAD for a more accurate and definitive peak purity assessment be they main peak or impurity components.