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Helmut ★★★   Vienna, Austria, 2010-06-10 16:43 (5858 d 22:27 ago) Posting: # 5492 Views: 7,854 |
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Dear all, the draft guideline states in Section 4.1.5 Accuracy, lines 196-198: To enable evaluation of any trends over time within one run, it is recommended to demonstrate accuracy of QC samples over at least one of the runs with a size equivalent to a prospective analytical run. According to the EUFEPS/EBF-workshop last April I would expect that this statement will 'make it' to the final version.We have one validated method (GC/MS stable isotope IS) which is in routine use for numerous years. Until now we have analyzed ~8300 samples and had not a single batch rejected (86 batches, size 72-108 study samples/batch, average 96 samples without calibrators/QCs). What do you think? Will regulators insist in performing a new validation run in ~110 samples or would it be sufficient to refer to historical data? — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Helmut ★★★ Vienna, Austria, 2010-09-07 14:54 (5770 d 00:15 ago) @ Helmut Posting: # 5889 Views: 6,533 |
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Dear all, any opinions on this issue? — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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vajra123 ☆ India, 2010-09-08 07:34 (5769 d 07:35 ago) @ Helmut Posting: # 5891 Views: 6,555 |
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Hi HS, To enable evaluation of any trends over time within one run, it is recommended to demonstrate accuracy of QC samples over at least one of the runs with a size equivalent to a prospective analytical run. As per the statement we need to demonstrate the accuracy of the QC representing the sample size of the batch during the routine analysis. This means that, during your validation run the batch with samples equivalent to size of sample analysis. It doesn't mean that it should exactly matches the batch size during the sample analysis. As per your example you have analyzed the 86 batches with 72-108 samples that was in one study. Let consider the study was carried for IR (Immediate release) formulation with two periods. if the same method is used for the study with ER (Rxtended release) formulation with three periods then the sample size of the batch will vary (sample size will be more...  ).So, I don't think again we have to prove for the accuracy of the QC's as the batch size is increased. This is my opinion, if i am wrong please correct me.  Regards, Vajra. — Vajra |
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Helmut ★★★ Vienna, Austria, 2010-09-08 14:36 (5769 d 00:33 ago) @ vajra123 Posting: # 5892 Views: 6,382 |
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Dear Vajra, THX for the response! ❝ […] we need to demonstrate the accuracy of the QC representing the sample size of the batch during the routine analysis. This means that, during your validation run the batch with samples equivalent to size of sample analysis. It doesn't mean that it should exactly matches the batch size during the sample analysis. Agree. ❝ As per your example you have analyzed the 86 batches with 72-108 samples that was in one study. OK, I was ambiguous. When I stated 'We have one validated method […] which is in routine use for numerous years', I meant that ~8300 samples from >15 studies were analysed. ❝ Let consider the study was carried for IR (Immediate release) formulation with two periods. if the same method is used for the study with ER (Rxtended release) formulation with three periods then the sample size of the batch will vary (sample size will be more...). Right guess; we had 2-period and 3-period studies in the past. That's why the batch sizes varied. ❝ So, I don't think again we have to prove for the accuracy of the QC's as the batch size is increased. I'm not so sure for a new method. But specifically I'm interested whether a reference to historical data (performance of the method in real batches) will suffice, or will European regulators insist on partial revalidation (one batch of calibrators / QCs / blanks). Additional question: The method is GC/MS - only 2 µl are injected. Since the idea of the 'batch validation' is essentially to show stability of the column (RT shift, peak shape, etc.) if loaded with extracted matrix, would it be sufficient to repetitively inject from a single vial? — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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vajra123 ☆ India, 2010-09-08 15:19 (5768 d 23:51 ago) @ Helmut Posting: # 5893 Views: 6,348 |
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Hi HS, ❝ Additional question: The method is GC/MS - only 2 µl are injected. Since the idea of the 'batch validation' is essentially to show stability of the column (RT shift, peak shape, etc.) if loaded with extracted matrix, would it be sufficient to repetitively inject from a single vial? sorry i am not able to get the point of question for the above said. regards, Vajra. — Vajra |
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Helmut ★★★ Vienna, Austria, 2010-09-08 15:32 (5768 d 23:37 ago) @ vajra123 Posting: # 5894 Views: 6,368 |
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Dear Vajra! ❝ ❝ The method is GC/MS - only 2 µl are injected. Since the idea of the 'batch validation' is essentially to show stability of the column (RT shift, peak shape, etc.) if loaded with extracted matrix, would it be sufficient to repetitively inject from a single vial? ❝ ❝ sorry i am not able to get the point of question for the above said. I'm just trying to read tea leaves - or in other words, regulator's minds. Let's say we are able to inject 25 times from a single vial; would you say that it's possible to extract only four blank samples → four vials → 25 injections / vial → 100 chromatograms or extract 100 blank samples → 100 vials → chromatograms? — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Ohlbe ★★★ France, 2010-09-08 20:03 (5768 d 19:07 ago) @ Helmut Posting: # 5896 Views: 6,368 |
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Dear Helmut, ❝ I'm just trying to read tea leaves - or in other words, regulator's minds. Good luck OK, regarding your question: I think the idea is that a validation performed with runs of maximum 30-40 samples may not predict what will happen with longer runs. This was mentioned several times by various regulators in presentations (CT Viswanathan had that in a presentation at the BSAT in November 2005, if I'm not mistaken). The difference in run size between method validation and study phase was identified as one of the reasons why shit eventually happened during study sample analysis but was not identified during the validation. I'm sure it must be also in a white paper somewhere but I'm afraid I can't find it right now. In your case I wouldn't be too worried unless you had a large number of rejected runs in your previous studies: you have tons of historical data to show that your method performs correctly also with full-size runs. I'm sure your QC samples were nicely placed within the runs to show that there was no drift or trend of any kind. Maybe you could compile these data and build a document with nice figures, to be appended to the validation report in the final report of any new trial, to justify why you don't need to do it again. ❝ Let's say we are able to inject 25 times from a single vial; would you say that it's possible to extract only four blank samples → four vials → 25 injections / vial → 100 chromatograms or extract 100 blank samples → 100 vials → chromatograms? Not blank samples: 3 levels of QCs (or rather 4 with LLOQ ?). I don't think this would be OK. Problems do not come only from the injector/column/detector, but may also come from sample handling and extraction, depending on the extraction method. It takes more time to extract 120 samples than a handful. In addition I suppose you would also be expected to report precision, though this is not clear in the draft (according to line 217 precision should be calculated using the data obtained for accuracy. Hopefully this will be clarified in the final version). Multiple injections of a single extract would not provide relevant information on the precision of the method. Regards Ohlbe — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2010-09-08 20:16 (5768 d 18:53 ago) @ Ohlbe Posting: # 5897 Views: 6,394 |
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Dear Ohlbe! ❝ I think the idea is […] Agree with your statement. This would also be my understanding. ❝ In your case I wouldn't be too worried unless you had a large number of rejected runs in your previous studies: Yeah, not a single one…  ❝ Maybe you could compile these data and build a document with nice figures, to be appended to the validation report in the final report of any new trial, to justify why you don't need to do it again. Good idea. ❝ ❝ Let's say we are able to inject 25 times from a single vial; would you say that it's possible to extract only four blank samples → four vials → 25 injections / vial → 100 chromatograms or extract 100 blank samples → 100 vials → chromatograms? ❝ ❝ Not blank samples: 3 levels of QCs (or rather 4 with LLOQ ?). Sure. I meant a full batch (calibrators, QCs) and extracted blanks within. ❝ I don't think this would be OK. Problems do not come only from the injector/column/detector, but may also come from sample handling and extraction, depending on the extraction method. It takes more time to extract 120 samples than a handful. In addition I suppose you would also be expected to report precision, though this is not clear in the draft (according to line 217 precision should be calculated using the data obtained for accuracy. Hopefully this will be clarified in the final version). ❝ Multiple injections of a single extract would not provide relevant information on the precision of the method. Oh.  — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Ohlbe ★★★ France, 2010-09-08 21:03 (5768 d 18:06 ago) @ Helmut Posting: # 5898 Views: 6,317 |
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Dear Helmut, ❝ Sure. I meant a full batch (calibrators, QCs) and extracted blanks within. Oh, I see, sorry I misunderstood what you intended to do. In that case you would of course have the data for the calculation of precision. But the concern regarding sample handling and extraction remains. Regards Ohlbe — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2010-09-08 21:07 (5768 d 18:03 ago) @ Ohlbe Posting: # 5899 Views: 6,370 |
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Dear Ohlbe! ❝ […] But the concern regarding sample handling and extraction remains. I see. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz