Bioequivalence and Bioavailability Forum

Dear Dipesh,

If you are planning for submissions to USFDA may I suggest you to have a look at this http://www.fda.gov/foi/warning_letters/archive/m2483n.pdf warning letter (see bottom of page 1 and top of page 2). Particularly, "Contrary to your response, values outside acceptance limits do not automatically qualify as outliers for precision analysis, unless there is an identifiable cause. It is imperative that such unfavorable data be included when evaluating the performance of analytical methods".

It seems that inspectors from the French agency (Afssaps) have a similar attitude during their BE trials inspections. The reasonning is based on section 3.4 of the EU Note for Guidance, which states that the method validation also comprises the study phase itself, to confirm the method's precision and accuracy. QC samples are used to validate each analytical run, according to the usual rules (67 % of all QC results in the run within 15 % of nominal, including at least 50 % at each level of concentration). But they are also used to check the method's precision and accuracy. If you exclude from the calculations all failing results, or even results identified after an outlier test, your QC results are no longer representative of the P&A of your method as applied to the subjects samples. There is no outlier test for subject samples, the only thing is that you may decide to re-analyse some samples for PK reasons if you have an SOP for this. But PK repeats would only be for samples with a rather important deviation from the concentration expected from the PK curve (especially during the absorption phase), not just 15 %.

As already stressed upon by HS if you decide to exclude outliers you should present the results with and without the outliers.

Regards
Ohlbe

---

Edit: Link corrected for new FDA site. [Helmut]