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Helmut ★★★   Vienna, Austria, 2021-12-01 14:09 (1270 d 02:03 ago) Posting: # 22680 Views: 3,844 |
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Dear all, recently I saw a deficiency of a European agency: The Applicant should specify the integration method (automatic or manual) adopted to calculate chromatograms area for all submitted studies. If manual integration was adopted, the Applicant should specify the percentage of the total chromatograms and specify which samples (QC/calibrator or unknown) have been analysed. Sure, that’s according to the 2011 guideline stating:5.5. Integration 6.6 MANUAL INTEGRATION An experienced analyst outperformed the software easily (esp. at low concentrations). Even ‘normal’ ones did so on the average.* $$\small{CV\;(n=10)}$$$$\small{\begin{array}{lcc} \text{integration method} & \text{1 ng/mL} & \text{0.1 ng/mL}\\\hline \text{automated (smoothing 1, bunching 2)} & 6.5\% & 15.1\%\\ \text{manual correction (experienced analyst)} & 6.3\% & 11.1\%\\ \text{manual correction (ten analysts)} &5.2\% & 12.8\%\\ & (3.8\%-6.8\%) & (6.9\%-16.0\%)\\\hline \end{array}}$$ See also here (slides 26–29) and there (slides 24–31).
— 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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ElMaestro ★★★ Denmark, 2021-12-01 15:40 (1270 d 00:32 ago) @ Helmut Posting: # 22681 Views: 3,153 |
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Hi Helmut, As I see it, FDA have been completely adverse to manual integrations for a decade at least. Manual integrations not accepted. At all. In any form. And therefore many CROs have adopted similar policies - they have to run the validation and sample analysis without ever touching the MI function. Some CROs allow for MI if the intended submission is EU/ROW/WHO etc but do not open that option if the submission targets US. The approach is, as I see it, completely safe: If you can run the val. and the sample analysis without MI then you have a great setup and you are not disturbing anyone. But still runs need to be approved and still someone should somehow sign off for the peak identification and correct integration. Which also means that it is a bit demanding from the equipment perspective. You need something which has a noise-less baseline, which means equipment sensitivity, colums integrity and method development is paramount. I am aware of the wording in M10 which other suggests there may be a way for MI. I have not, hoever, heard of FDA taking any another stance in practice. Finally, everything evolves, including integration algorithms. Perhaps what was pretty bad in 2009 is pretty good in 2021? There is no good way to evaluate it. I don't have a way to import WIFF files from 2009 into Analyst 1.6.5 or whatever today's version is. But if someone has a way to it, let us see some results  So, I am fine with CROs trying to avoid MI as long as what it is meant is the aim to have a method that is so sensitive that even at low concs the integration is good. That also means the deficiency letter is a walk in the park. — Pass or fail! ElMaestro |
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Helmut ★★★ Vienna, Austria, 2021-12-01 18:38 (1269 d 21:35 ago) @ ElMaestro Posting: # 22682 Views: 3,206 |
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Hi ElMaestro, ❝ As I see it, FDA have been completely adverse to manual integrations for a decade at least. Manual integrations not accepted. At all. In any form. That’s bad. Well, it saves the assessor time. ❝ The approach is, as I see it, completely safe: If you can run the val. and the sample analysis without MI then you have a great setup and you are not disturbing anyone. But still runs need to be approved and still someone should somehow sign off for the peak identification and correct integration. Which also means that it is a bit demanding from the equipment perspective. You need something which has a noise-less baseline, which means equipment sensitivity, colums integrity and method development is paramount. Fully ACK. However, let’s face it: If you have to measure really (‼) low levels, ‘a noise-less baseline’ belongs still to the realm of science fiction. ❝ I am aware of the wording in M10 which other suggests there may be a way for MI. I’m absolutely fine with Section 3.6.3 of the GL: Chromatogram integration and reintegration should be described in a study plan, protocol or SOP. Any deviation from the procedures described a priori should be discussed in the Bioanalytical Report. The list of chromatograms that required reintegration, including any manual integrations, and the reasons for reintegration should be included in the Bioanalytical Report. Original and reintegrated chromatograms and initial and repeat integration results should be kept for future reference and submitted in the Bioanalytical Report for comparative BA/BE studies. ❝ I have not, hoever, heard of FDA taking any another stance in practice. I believe it. ❝ Finally, everything evolves, … All too true. ![[image]](img/uploaded/image783.png) ❝ … including integration algorithms. Perhaps what was pretty bad in 2009 is pretty good in 2021? There is no good way to evaluate it. No idea. A CDS is a pitch-black box with Schrödinger’s cat lurking inside. In my CRO I had access to all raw data (peak slices). Though the vendor claimed which Al Gore Rhythms were implemented (without giving great detail), I never was able to reproduce it. Tried a lot. Gave up. ❝ So, I am fine with CROs trying to avoid MI as long as what it is meant is the aim to have a method that is so sensitive that even at low concs the integration is good. Sure. I was only concerned about the sentence ‘Manual integration is PROHIBITED in any circumstance.’ Reminded me on: Medical statistician: One who will not accept that Columbus discovered America… ❝ That also means the deficiency letter is a walk in the park. It was. (1) for the EMA and (2) only automatic anyhow. — 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