deepakpangavhane
Junior

India,
2019-01-09 13:54
(edited by mittyri on 2019-01-09 15:56)

Posting: # 19762
Views: 860
 

 Long term stability [Bioanalytics]

Dear Experts

I have required long term stability data proved with an old method. However during validation of old method, second analyte i.e. metabolite was not spiked in presence of parent analyte.
Whereas study plasma samples contains both parent analyte and metabolite in them.

I have developed and validated new method (changes primarily include: SPE cartridge make change; change in concentration range from 10-5000 pg/mL to 10-4000 pg/mL; parent analyte spiked in plasma in presence of metabolite for all experiments) and perfromed study sample analysis with new method.

However I am unable to finish LTS experiment for required duration with new method.

Can I use long term stability data of old method as supportive data for my usfda study submission?

Regards

Deepak


Edit: Category changed; see also this post #1[Mittyri]
VKB2207
Junior

Portugal,
2019-01-10 20:55

@ deepakpangavhane
Posting: # 19768
Views: 738
 

 Long term stability

Hi,

Highly unlikely because:

1. You do not have LTPS data for metabolite

Otherwise if no major changes in method, LTPS data may be accepted as you are going from high to low range.

Regards


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe]
deepakpangavhane
Junior

India,
2019-01-14 11:17

@ VKB2207
Posting: # 19775
Views: 659
 

 Long term stability

Hi...

Thanks VKB2207 first of all.

I do have LTS data for metabolite (in presence of analyte) for required duration as there is separate method for metabolite quantitation.

My concern is that I dont have LTS data of analyte in presence of metabolite.

If I submit LTS data of analyte (in absence of metabolite), then is it acceptable?

Regards
Deepak Pangavhane.
Ohlbe
Hero

France,
2019-01-11 00:00

@ deepakpangavhane
Posting: # 19771
Views: 730
 

 Long term stability

Dear Deepak,

» I have developed and validated new method (changes primarily include [...] parent analyte spiked in plasma in presence of metabolite for all experiments) and performed study sample analysis with new method.

I'm not sure I understand. Did you measure the metabolite too ? If yes and as rightly pointed out by VKB2207, you need long-term stability data for the metabolite anyway, so you old data will not save you. If not, why did you add the metabolite for all experiments ? Can you give us more details on the structure of the metabolite compared to the parent compound (primary or secondary metabolite, risk of back-conversion etc.), and the levels of concentration of the metabolite compared with the parent ?

» However I am unable to finish LTS experiment for required duration with new method.

Is this just because the sponsor is in a hurry and wants the report last week, or are there other reasons ?

» Can I use long term stability data of old method as supportive data for my usfda study submission?

Long-term stability in matrix is independent from the bioanalytical method used: if the analyte is stable for 3 months with method A it will also be stable for 3 months with method B. The FDA and EMA requirement to test for the stability of all analytes spiked together in case several drugs are given to a subject, even if stability data are available for each analyte separately (e.g. drug/drug interaction studies), is highly disputed by industry and regularly discussed at bioanalytical conferences. I didn't hear of an extension of this FDA/EMA requirement to non-measured metabolites.

However the storage conditions are important (not just the temperature, also the type of tubes used due to possible adsorption), and you should check they were the same in the old and new method.

But the final answer to your questions depends on your answer to some of mine ;-)

Regards
Ohlbe
deepakpangavhane
Junior

India,
2019-01-14 12:05

@ Ohlbe
Posting: # 19776
Views: 657
 

 Long term stability

» Dear Ohlbe

Thanks for your reply.
»
» » I have developed and validated new method (changes primarily include [...] parent analyte spiked in plasma in presence of metabolite for all experiments) and performed study sample analysis with new method.
»
» I'm not sure I understand. Did you measure the metabolite too ? If yes and as rightly pointed out by VKB2207, you need long-term stability data for the metabolite anyway, so you old data will not save you. If not, why did you add the metabolite for all experiments ? Can you give us more details on the structure of the metabolite compared to the parent compound (primary or secondary metabolite, risk of back-conversion etc.), and the levels of concentration of the metabolite compared with the parent ?

Yes. Metabolite was also measured with different method. I have LTS data for metabolite (in presence of analyte) for required duration. I spiked metabolite for new validated method as study samples contain analyte and metabolite. HQC level of metabolite is spiked in parent analyte during method validation.


»
» » However I am unable to finish LTS experiment for required duration with new method.
»
» Is this just because the sponsor is in a hurry and wants the report last week, or are there other reasons ?

Sponsor want to achieve targeted timelines of submission.
»
» » Can I use long term stability data of old method as supportive data for my usfda study submission?
»
» Long-term stability in matrix is independent from the bioanalytical method used: if the analyte is stable for 3 months with method A it will also be stable for 3 months with method B. The FDA and EMA requirement to test for the stability of all analytes spiked together in case several drugs are given to a subject, even if stability data are available for each analyte separately (e.g. drug/drug interaction studies), is highly disputed by industry and regularly discussed at bioanalytical conferences. I didn't hear of an extension of this FDA/EMA requirement to non-measured metabolites.
»
I have measured analyte and metabolite also with two different methods.

» However the storage conditions are important (not just the temperature, also the type of tubes used due to possible adsorption), and you should check they were the same in the old and new method.

Storage conditions and types of tubes used are same in both methods.
Only major difference and point of concern is that:
Old method: parent analyte is only present in stability QC samplpes.
New method: parent analyte and metabolite is also spiked in stability QC samples.


Whether LTS data of old method is acceptable for parent analyte as per usfda?

Awaiting your response.

Regards
Deepak Pangavahne
Ohlbe
Hero

France,
2019-01-14 12:41

@ deepakpangavhane
Posting: # 19777
Views: 660
 

 Long term stability

Dear Deepak,

» I spiked metabolite for new validated method as study samples contain analyte and metabolite. HQC level of metabolite is spiked in parent analyte during method validation.

It is good to do it at least once, analysing QCs spiked only with the parent + QCs containing parent and metabolite, against calibration samples containing only the parent. This way you can demonstrate the selectivity of your method and the lack of back-conversion during the analysis. But I would not necessarily expect the whole validation to be performed with samples spiked with the metabolite if you don't measure it with the method being validated.

» Sponsor want to achieve targeted timelines of submission.

Yeah... Unfortunately The Man In The Armani Suit is always in a hurry...

» Only major difference and point of concern is that:
» Old method: parent analyte is only present in stability QC samples.
» New method: parent analyte and metabolite is also spiked in stability QC samples.
»
» Whether LTS data of old method is acceptable for parent analyte as per usfda?

You did not answer my question on the type of metabolite and risk of back-conversion... If you have long-term stability data of your metabolite showing that there is no back-conversion during storage, I would think you can provide reasonable justification. I would also look at the results of the other stability experiments, particularly freeze/thaw (passing easily, or borderline ?). If in doubt, start a controlled correspondence with the FDA. But with the shutdown, running the stability might be faster :-(

Regards
Ohlbe
deepakpangavhane
Junior

India,
2019-01-14 13:18

@ Ohlbe
Posting: # 19778
Views: 652
 

 Long term stability

Dear Ohlbe,

» » I spiked metabolite for new validated method as study samples contain analyte and metabolite. HQC level of metabolite is spiked in parent analyte during method validation.
»
» It is good to do it at least once, analysing QCs spiked only with the parent + QCs containing parent and metabolite, against calibration samples containing only the parent. This way you can demonstrate the selectivity of your method and the lack of back-conversion during the analysis. But I would not necessarily expect the whole validation to be performed with samples spiked with the metabolite if you don't measure it with the method being validated.

We perform complete validation taking into account fact that- SPE cartridge make change; change in concentration range from 10-5000 pg/mL to 10-4000 pg/mL; parent analyte spiked in plasma in presence of metabolite to mimic study sample plasma conditions; to incorporate recent validation guidance recommendations. To be on safer side...


» You did not answer my question on the type of metabolite and risk of back-conversion...

Metabolite is hydroxy form of parent analyte. As evident from validation data, back-conversion during storage was not observed.

» If you have long-term stability data of your metabolite showing that there is no back-conversion during storage, I would think you can provide reasonable justification. I would also look at the results of the other stability experiments, particularly freeze/thaw (passing easily, or borderline ?). If in doubt, start a controlled correspondence with the FDA. But with the shutdown, running the stability might be faster

We have LTS data of metabolite showing no back-conversion i.e. LTS data within acceptance to initial day analysis.
We are also thinking to proceed for long term stability experiment for parent analyte with new method for analyte.


Regards
Deepak Pangavahne
Ohlbe
Hero

France,
2019-01-14 14:04

@ deepakpangavhane
Posting: # 19779
Views: 646
 

 Long term stability

Dear Deepak,

» We perform complete validation taking into account [...]
Oh, you're absolutely right to perform a full validation, considering the changes made. My comment was rather that I personally would not have considered it necessary to have the metabolite in each and everyone of the new experiments performed.

» We are also thinking to proceed for long term stability experiment for parent analyte with new method for analyte.

Well, if you're unsure that the data you currently have will be sufficient, you should indeed start generating new long-term stability data. This way by the time the sponsor submits the data and gets the question from the FDA, you'll have your answer ready.

Regards
Ohlbe
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