Log in
Register|
kamblpa2 ● 2012-08-13 12:33 (5068 d 09:27 ago) Posting: # 9056 Views: 6,171 |
|
|
Dear All, Kindly provide your inputs for the response for the following deficiency received from France Regulatory agency, i) As per the current EMEA guideline 2012, Incurred sample reanalysis was not performed. Since the study was conducted in year 2007, that time ISR was not given in the guideline. We need to provide the justification to avoid rejection from authority Thanks |
|
Ohlbe ★★★ France, 2012-08-14 02:17 (5067 d 19:43 ago) @ kamblpa2 Posting: # 9058 Views: 5,353 |
|
|
Dear kamblpa2, ❝ Since the study was conducted in year 2007, that time ISR was not given in the guideline. True. So the lab did their job correctly at that time: ISR was not required for EU submissions in 2007. The guideline only came in force on 1st February 2012. The problem is that the date that matters is not the date when you did the trial, but the date the application was submitted to the Agency. To quote Annex 1 to Directive 2001/83/EC: In assembling the dossier for application for marketing authorisation, applicants shall also take into account the scientific guidelines relating to the quality, safety and efficacy of medicinal products for human use as adopted by the Committee for Proprietary Medicinal Products (CPMP) and published by the European Medicine Evaluation Agency (EMEA) and the other pharmaceutical Community guidelines published by the Commission in the different volumes of The rules governing medicinal products in the European Community. Translation: it is not just that the lab has to follow the guidelines. But also the applicants should make sure that the studies they submit follow the "state of the art" when they are submitted. Submitting now studies performed more than 2-3 years ago will now be difficult. If your dossier was submitted after 1st February 2012, you're in trouble. Regards Ohlbe — Regards Ohlbe |
|
Ohlbe ★★★ France, 2012-09-25 21:01 (5025 d 00:59 ago) @ kamblpa2 Posting: # 9253 Views: 5,339 |
|
|
Dear all, The CMDh just published a "kind reminder" in the report of their September meeting: The CMDh would like to remind Applicants that the Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009) came into force on 1st February 2012. New marketing authorisation applications are therefore expected to be submitted in compliance with the requirements of this guideline. Any deviations from the criteria adopted in this guideline should be fully justified within the application. I don't think "we are using an old study" will be considered a full justification... Regards Ohlbe — Regards Ohlbe |
|
ElMaestro ★★★ Denmark, 2012-09-25 22:21 (5024 d 23:39 ago) @ Ohlbe Posting: # 9255 Views: 5,077 |
|
|
Hi Ohlbe, ❝ I don't think "we are using an old study" will be considered a full justification...  Oh my, I think I am having a déjà-vu... Somehow I imagine there must be some borderline frustrated regulators out there since they feel a need to publish such a reminder. My gut feeling is that it is the incurred sample reanalysis that is troubling the most applicants. — Pass or fail! ElMaestro |
|
Ohlbe ★★★ France, 2012-09-26 00:06 (5024 d 21:54 ago) @ ElMaestro Posting: # 9256 Views: 5,176 |
|
|
Hi Maestro, ❝ My gut feeling is that it is the incurred sample reanalysis that is troubling the most applicants. Agreed. Basically all studies over 2-3 years old can be thrown away. They have finally found a way to set an expiry date to BE studies... Regards Ohlbe — Regards Ohlbe |
|
Dr_Dan ★★ Germany, 2012-09-26 13:35 (5024 d 08:24 ago) @ Ohlbe Posting: # 9261 Views: 5,078 |
|
|
Dear all, incurred sample reanalysis is troubling me like most applicants. We have a lot of studies with a (even according to the new guideline) validated method but with no ISR. IMHO ISR is a kind of performance indicator. Of course you can point out the results for QCs and standard curves but how can you justify deviations from the criteria adopted in this guideline (= missing ISR)? Looking forward to a fruitful discussion. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
|
Helmut ★★★   Vienna, Austria, 2012-09-26 16:48 (5024 d 05:12 ago) @ Dr_Dan Posting: # 9264 Views: 5,127 |
|
|
Dear Dan! ❝ IMHO ISR is a kind of performance indicator. Yep. ❝ Of course you can point out the results for QCs and standard curves… In the ‘spirit’ of ISR irrelevant because these are spiked samples. ❝ …but how can you justify deviations from the criteria adopted in this guideline (= missing ISR)? The only possible bail-out procedure I can imagine is reference to historic data. Some CROs store study samples for a quite long time. Give it a try. See also this thread. I guess that ‘hard-core assessors’ would not accept it (validation has to be done before the study,  ). On the other hand, when FDA’s 2001 guidance was published, many methods were partly revalidated (i.e., sumfink missing) and these studies were accepted.— 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 |
|
ElMaestro ★★★ Denmark, 2012-09-26 19:30 (5024 d 02:30 ago) @ Dr_Dan Posting: # 9266 Views: 5,029 |
|
|
Hi Dr_Dan, Hi all, I was thinking something along the lines of what Helmut wrote, and now I am just thinking loud: Let's say the CRO has stored the samples in a freezer. Ok they are now XYZ months old and their content of the API may due to stability issues and a ton of other factors no longer be exactly what they were when the samples were analysed for the study report, but they do have some content and they are still real samples. So let's say we take then out and re-analyse them. And then we re-analyse them again for ISR purposes. We do not try to make any inference re. the differences between the first analysis and the first re-analysis - we only deal with the difference between first re-analysis and second re-analysis. Would that be acceptable? Perhaps not but it might be the best we can do?! After all, ISR gives us info about reproducibility (week-to-week or month-to-month) in real samples rather than in spiked samples as those that are used in validation. An argument for rejecting this approach could be to claim that ISR on post-study samples may not reflect ISR when done at the study time, but on the other hand we need to bear in mind that there is sometimes also a considerable time between validation and study production (yes, I know reval comes into play but still there is sometimes a real time gap), so this could be tried. Now punish me! — Pass or fail! ElMaestro |
|
Ohlbe ★★★ France, 2012-09-28 01:15 (5022 d 20:45 ago) @ ElMaestro Posting: # 9272 Views: 5,034 |
|
|
Dear ElMaestro, ❝ Let's say the CRO has stored the samples in a freezer. Ok they are now XYZ months old and their content of the API may due to stability issues and a ton of other factors no longer be exactly what they were when the samples were analysed for the study report, but they do have some content and they are still real samples. Hopefully the CRO has kept some QC samples along with the study samples. This way they will be able to extend their long-term stability data. ❝ So let's say we take then out and re-analyse them. And then we re-analyse them again for ISR purposes. We do not try to make any inference re. the differences between the first analysis and the first re-analysis - we only deal with the difference between first re-analysis and second re-analysis. Would that be acceptable? I would say no. Not without a comparison to the initial analysis. ❝ After all, ISR gives us info about reproducibility (week-to-week or month-to-month) in real samples rather than in spiked samples as those that are used in validation. Not only that. A major concern is the back-conversion of unstable metabolites, such as acyl-glucuronides, N-oxides etc., back to parent during sample processing. You won't see anything with ISR if you have 100 % back-conversion during processing, of course. But if you have a partial back-conversion, it is likely to vary from run to run and to be detectable with ISR (at least that's the theory). But if your unstable metabolite has turned back to parent, or has dramatically decreased, during the 3 years your samples will have spent at -20°C, you are unlikely to detect anything if you only compare a first re-analysis to a second re-analysis. Regards Ohlbe — Regards Ohlbe |
|
Dr_Dan ★★ Germany, 2012-09-28 17:32 (5022 d 04:27 ago) @ Ohlbe Posting: # 9275 Views: 5,055 |
|
|
Dear Ohlbe, dear ElMaestro Thank you very much for your valuable input ❝ I would say no. Not without a comparison to the initial analysis. I totally agree ❝ Not only that. A major concern is the back-conversion of unstable metabolites, such as acyl-glucuronides, N-oxides etc., back to parent during sample processing. You won't see anything with ISR if you have 100 % back-conversion during processing, of course. But if you have a partial back-conversion, it is likely to vary from run to run and to be detectable with ISR (at least that's the theory). But if your unstable metabolite has turned back to parent, or has dramatically decreased, during the 3 years your samples will have spent at -20°C, you are unlikely to detect anything if you only compare a first re-analysis to a second re-analysis. I once made the experience that one lab did not pass the acceptance criterion for ISR. The second aliquot was transferred to the biggest competitor who analysed the samples with exactly the same method and this time the analysis passed. An investigation for the reason was without any result. Maybe because the second aliquot was used? Better performance of the second lab? All other parameters were ok. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
|
ElMaestro ★★★ Denmark, 2012-09-28 19:04 (5022 d 02:56 ago) @ Dr_Dan Posting: # 9276 Views: 4,977 |
|
|
Hi Dr_Dan, ❝ I once made the experience that one lab did not pass the acceptance criterion for ISR. The second aliquot was transferred to the biggest competitor who analysed the samples with exactly the same method and this time the analysis passed. An investigation for the reason was without any result. Maybe because the second aliquot was used? Better performance of the second lab? All other parameters were ok. There could be a ton of reasons for it. Other analysts, other equipment, difference in age of columns, etc. In perspective, my girlfriend and I both cook and we occasionally use the same recipes. When she makes a steak it usually comes out as a five star meal that makes me hear the angels sing. But when I use the same recipe the result is often a charred chunk of material with the hardness and density of granite and which has the potential to make people like agent Scully somewhat worried. I never was able to figure out exactly what causes this difference in outcome; I think it is one of life's great mysteries. Now, out of curiosity: Which result did you report? — Pass or fail! ElMaestro |
|
Helmut ★★★ Vienna, Austria, 2012-09-28 19:48 (5022 d 02:12 ago) @ ElMaestro Posting: # 9277 Views: 4,944 |
|
|
Hi ElMaestro, great remarks about theory (recipes, SOPs, …) and practice (we and our girlfriends, bioanalysis, …). Even more mysterious that some stuff my girlfriend can to better, and some the other way ’round. Learning curve turned out too steep for the both us – division of work was required. Back in 2004 the new BE guideline was announced as a sort of “cookbook”. Nice, but what to do if you are only a mediocre cook? — 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 |
|
ElMaestro ★★★ Denmark, 2012-09-29 11:30 (5021 d 10:29 ago) @ Helmut Posting: # 9279 Views: 4,946 |
|
|
Hi Helmut, ❝ Back in 2004 the new BE guideline was announced as a sort of “cookbook”. Nice, but what to do if you are only a mediocre cook? I don't know. I consider that question purely hypothetical. As you know "There are no stupid questions, just stupid answers". Along these lines I will claim that there are no lousy cooks, only silly recipes. Now, I apologise for this very short post today, but I have to leave for the nuclear waste facility in order to get rid of the leftovers from the dinner I prepared yesterday, so please have me excused. — Pass or fail! ElMaestro |
Ing. Helmut Schütz