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cakhatri ★ India, 2013-03-10 10:41 (4462 d 13:18 ago) Posting: # 10180 Views: 5,304 |
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Dear Members, I have a situation as below and need your opinion; " We have a method for simultaneous estimation of drug and metabolite. During the course of analysis 4 subjects failed to meet acceptance criteria for metabolite but accepted for drug.According to the guidelines the data for drug should be accepted and used for PK & Stat. The batches were repeated for the metabolite after a gap of 30 days due to large sample size. The repeated batches were accepted for metabolite and data used for PK&Stat. With this repeat analysis, data for drug also was generated.According to in-house SOP the data for drug will not be used for PK analysis. When the initial and repeat data of drug was compared, the difference observed was about +/- 30%.This was the case with 3 subjects out of more than 65 subjects ISR passed with more than 95% acceptance criteria Does this cause concern where the difference between initial and repeat analysis data is more than 30% and ISR is still meeting the acceptance criteria. From our own experience, the final analysis was done with initial as well as repeat values and the BE was met with repeat values for drug as well as metabolite The study was a partial replicate. How would FDA look at such a situation. Pl share your views Regards Chirag |
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Ohlbe ★★★ France, 2013-03-11 19:58 (4461 d 04:01 ago) @ cakhatri Posting: # 10188 Views: 4,251 |
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Dear Chirag, ❝ When the initial and repeat data of drug was compared, the difference observed was about +/- 30%. This was the case with 3 subjects out of more than 65 subjects ❝ ❝ ISR passed with more than 95% acceptance criteria ❝ ❝ Does this cause concern where the difference between initial and repeat analysis data is more than 30% and ISR is still meeting the acceptance criteria. Some questions: - in how many runs were the samples of these 3 subjects analysed initially ? How many runs for re-analysis ? - was the difference always in the same direction for all samples for each subject ? If yes, it just looks like an accuracy issue (one run may be 15 % too high, the second 15 % too low). - was the difference in the same direction for the 3 subjects ? Higher, or lower than the initial result ? If the difference was systematically in the same direction, with 3 independent runs, you may have an issue with stability (either of the parent analyte, or of a metabolite). Did you analyse your ISR runs only at the end of the study, or on an ongoing basis each time you had enough samples to re-analyse in a run ? Regards Ohlbe — Regards Ohlbe |
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cakhatri ★ India, 2013-03-12 06:24 (4460 d 17:35 ago) @ Ohlbe Posting: # 10189 Views: 4,194 |
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Dear ohlbe, Pl read my response in blue ❝ - in how many runs were the samples of these 3 subjects analysed initially ? How many runs for re-analysis ? Each subject(three period) was analysed against a calibration curve and similarly for the repeat subjects ❝ - was the difference always in the same direction for all samples for each subject ? If yes, it just looks like an accuracy issue (one run may be 15 % too high, the second 15 % too low). Yes, it was either -25 to -30% or + 25-30% ❝ - was the difference in the same direction for the 3 subjects ? Higher, or lower than the initial result ? If the difference was systematically in the same direction, with 3 independent runs, you may have an issue with stability (either of the parent analyte, or of a metabolite). Did you analyse your ISR runs only at the end of the study, or on an ongoing basis each time you had enough samples to re-analyse in a run ? The difference was consistently on higher for two repeat subjects and lower for the other. ISR was performed at the end of the study. |
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Ken Peh ★ Malaysia, 2013-03-16 15:40 (4456 d 08:20 ago) @ cakhatri Posting: # 10206 Views: 4,001 |
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Dear Cakhatri, According to EMEA Guideline on Bioanalytical Method Validation (2011), the concentration obtained for the initial analysis and reanalysis should be within 20% of their mean for at least 67% of the repeats. Large differences between results may indicate analytical issues and should be investigated. If I interpret the guideline correctly, as long as you have more than 67% of the repeats within 20% of their means, you are safe. What do you mean when you mentioned "ISR passed with more than 95% acceptance criteria" ? I have no experience dealing with FDA on ISR. Any guideline by FDA on this matter ?? Regards, Ken |
Ing. Helmut Schütz