Specs setting on an HPLC method for impurities

[an_k]

I work on a product specification regarding related substances. Please help me with the following:

PhEur monograph - Imp.: A, B nmt: 0.4%
BP monograph (final product).: Imp A nmt: 0.4%
Imp B nmt: 6%

MDD of the product 1200mg, acc. to ich q3(b): identification threshold: 0.16%
Qualification threshold: 0.20%


So acc. to that, a first optimization for the specs: Imp A: nmt 0.4% (acc. to EP)
Imp B: nmt 0.4% (acc. to EP)
Any other specified / unspecified: nmt 0.16% (acc. to ICH)

The API manufacturer is a cep holder, so the only comment for imps is: ‘’any other impurity except those listed in the monograph and detected by test for related substances of the monograph should not be more than 0.1%.
What do you think about that? Does the 6% limit for impurity B of the BP fp product monograph is upsetting?
I have to ask for a characterization of impurities, but what do you think of this consideration?

Thank you.

[krickos]

Hi

Well very generally speakning, not necessarly upsetting at all. Many might only be used to see certain antibiotics/penicillins with high spec limits for impurities, but they do exists for other products. Tox studies/clinical etc studies concludes if impurity (or degradation product) is safe enough or not.

The API manufacturer is more or less correct, any other non specfied impurity has a limit set to 0,10% (not 0,1%, was an update in general chapter 5.10 a few years ago together with general monograph 2084, so all 0,1% limits for any unspecified should read 0,10% even if 0,1% is still left in EP monographs, this is auto changed when a monograph is updated).
Guess you purchase the API from external supplier so you have some info acess to their file/CEP regarding impurities, but you can also request an impurity profile with impurties between 0,10-loq of monograph tabulated (with RRT values if not identified)as the required to have a fairly updated one according ICHq7a.

[prepcolumn]

I work on a product specification regarding related substances. Please help me with the following:

PhEur monograph - Imp.: A, B nmt: 0.4%
BP monograph (final product).: Imp A nmt: 0.4%
Imp B nmt: 6%

MDD of the product 1200mg, acc. to ich q3(b): identification threshold: 0.16%
Qualification threshold: 0.20%


So acc. to that, a first optimization for the specs: Imp A: nmt 0.4% (acc. to EP)
Imp B: nmt 0.4% (acc. to EP)
Any other specified / unspecified: nmt 0.16% (acc. to ICH)

The API manufacturer is a cep holder, so the only comment for imps is: ‘’any other impurity except those listed in the monograph and detected by test for related substances of the monograph should not be more than 0.1%.
What do you think about that? Does the 6% limit for impurity B of the BP fp product monograph is upsetting?
I have to ask for a characterization of impurities, but what do you think of this consideration?

Thank you.

If i were u i would do forced degradation or observe 40 C/75RH conditions before setting limits especially for impurity B..

[rickmartink]

Hi there i saw your id in Chromatography forum. I am sure you are a Liquid chromatography expert. I have the following issue. can you please advice

Dear Forum
I count upon your knowledge and hope to get a solution.

I have a tablet with composition Paracetamol ( 500mg ) + Aceclofenac ( 100mg) and caffeine ( 25mg).

Normally for HPLC related substance test , the Final test solution concentration is kept as 1mg/ml. Hence in my case i crush 20 tablets and weigh equivalent quantity of Caffeine to get final concentration of 1mg/ml of Caffeine then the concentration of paracetamol and Aceclofenac will be way too high.

What should i do and which API out of three should i consider to make my test solution.

The HPLC method we have developed is Gradient and we have acheived resolution for all three API so there is no issue with the method we want to use. We have dont on test solution to be prepared.

PL. advice.

Regards
Rick Martink

[krickos]

If i were u i would do forced degradation or observe 40 C/75RH conditions before setting limits especially for impurity B..

Agree forgot to comment on that. You need to consider was is a suiteble release limit versus a limit at end of shelflife/stability. This also likely will have impact on assay at release testing versus end shelflife. Normally you would expect +/- 5% of claimed assay, but will likely not be possible at end of shelflife.

[an_k]

Hi there i saw your id in Chromatography forum. I am sure you are a Liquid chromatography expert. I have the following issue. can you please advice

Dear Forum
I count upon your knowledge and hope to get a solution.

I have a tablet with composition Paracetamol ( 500mg ) + Aceclofenac ( 100mg) and caffeine ( 25mg).

Normally for HPLC related substance test , the Final test solution concentration is kept as 1mg/ml. Hence in my case i crush 20 tablets and weigh equivalent quantity of Caffeine to get final concentration of 1mg/ml of Caffeine then the concentration of paracetamol and Aceclofenac will be way too high.

What should i do and which API out of three should i consider to make my test solution.

The HPLC method we have developed is Gradient and we have acheived resolution for all three API so there is no issue with the method we want to use. We have dont on test solution to be prepared.

PL. advice.

Regards
Rick Martink

Hello,

If i understand correctly, you have an analytical hplc method that determines all three apis at the same time (not three different methods).

Do you consider it as a problem to work with different concentration in the same dilution? I suggest you should work for the lower possible concentration for caffeine so that you can perform dilution also for the other two (not too dense solutions) and then validate at different concentrations for three apis.