Bioequivalence and Bioavailability Forum

Dear Ram,

❝ But the study failed because of the Bioanalytical issues which were not able to define the stability of the molecule.

When you say that the study failed, do you mean to say that it failed to demonstrate bioequivalence ? Or just that as the bioanalytical results are not reliable you can't use them for PK / stats ? If you performed the stats and the study failed it will become difficult to convince the regulators that you are repeating the study because of a bioanalytical issue unseen before.

❝ The molecule showed stability until 55 days, where after it showed degradation.

Shit happens. But storage over 55 days in a BE study is already quite long.

❝ Possible reasons incurred are - (1) improper mixing of blood and anti-coagulant at time of blood collection,(2) samples where not stored at prescribed temperature, (3) method was not robust.

(1): OK, could be, but not my first hypothesis. And you would not see it with your stability QC samples. (2): yes, possible. You're supposed to have temperature records to confirm the storage conditions. (3): unless the problems happened during sample processing (bench top stability, dry extract stability) or added up to the degradation over time during long term storage, no. Stability is a characteristic of the analyte under specific conditions and is independent from the method used.

I would add reason 4: the analyte is not stable for more than 55 days in matrix at that temperature... Solutions: analyse faster; store at lower temperatures; add agents to stabilise.

❝ ❝ That will be the more tricky part. You'll have to prove, and to convince them, that the problem indeed was a lack of stability - and to explain why you did not identify it initially. You can expect questions - and probably an inspection of both studies.

❝

❝ Are there any guidelines related to this part.

I don't think this is a matter of guideline... It also goes back to the first question:
- if you did not run the PK / stats but just stopped the analysis because of the stability issues, the study did not really "fail";
- if you did the PK / stats and the study failed to show BE, and now you say there were stability issues, you can expect questions. Especially if there were no problems in your temperature records, the drug is described as stable in the literature, and you now have 80 days stability data.