## Is ƒ2 dead as well – always bootstrapping? [Dissolution / BCS / IVIVC]

Hi ElMaestro and all,

I’ve read the Q&A again. Here the last paragraph in all of its beauty:

Any approach based upon confidence intervals for ƒ2 would, however, be considered appropriate whether the validity criteria outlined in CHMP guidance are met or not [CPMP/EWP/QWP/1401/98 Rev. 1/Corr**]. Similarity could then be declared if the confidence interval for ƒ2 were entirely above 50. However, regardless of whether the conditions to adequately apply ƒ2 in a dissolution experiment are fulfilled or not, the properties of the ƒ2 sampling distribution do not allow the derivation of exact confidence intervals to adequately quantify the uncertainty of the ƒ2 estimate. To address this, bootstrap methodology could be used to derive confidence intervals for ƒ2 based on quantiles of re-sampling distributions, and this approach could actually be considered the preferred method over ƒ2 and MD.

(my emphases)

Do I get this right? Bootstrapping is preferred over ƒ2 even if the validity criteria* are met?
I expect ‘regulatory creep’. Preferred will turn into mandatory. Will it be required retrospectively? I know some minor variations supported by ƒ2, where it was say, only 53 in one pH. Will not pass the lower confidence limit.
IMHO, the only way to decrease the CV – and hence, the width of the bootstrapped CI – is to substantially increase the number of units.

CV units ──────── ♫    12 ¾    21 ⅔    27 ½    48 ⅓   108

No risk, no fun.

• ≥12 units of T and R, CV ≤20% at ≤15 minutes, CV ≤10% at >15 minutes, not more than one mean value of >85% dissolved for each formulation.

Dif-tor heh smusma 🖖
Helmut Schütz

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