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auditor ★ India, 2012-02-10 07:45 (4859 d 02:40 ago) Posting: # 8090 Views: 8,005 |
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Dear All, This is something regarding the practice deference between Indian CRO and over sea's. In India we prefer to prepare calibration curve within the establish calibration curve. however in some of the over sea's data we have observed that they are some times using higher values of ULOQ then the establish one in the validation due to differences in weight taken. As a part of justification they said that till date agency has not raised any question on that as the difference is very less. Kindly advice me on above mentioned case. is it acceptable? is regulatory accept if prepared ULOQ is slightly higher then the established during validation? Regards, Auditor |
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Ohlbe ★★★ France, 2012-02-10 13:05 (4858 d 21:20 ago) @ auditor Posting: # 8097 Views: 7,188 |
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Dear Auditor, If the difference is really only due to the difference in the exact weight taken to prepare the stock solution, it will be very minimal (usually less than 1 or 2 %) and it shouldn't be an issue. Regards Ohlbe — Regards Ohlbe |
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auditor ★ India, 2012-02-10 16:54 (4858 d 17:31 ago) @ Ohlbe Posting: # 8101 Views: 7,152 |
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Dear Ohlbe, Did the agency accept it? Can you please provide me any reference which says something about this practical issue? |
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Helmut ★★★   Vienna, Austria, 2012-02-10 18:33 (4858 d 15:52 ago) @ auditor Posting: # 8103 Views: 7,189 |
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Dear Auditor, just my two cents. ❝ Did the agency accept it? I never heard about any problems in this respect. Let me put it another way: It would made me suspicious if an analyst claims that he/she could reproduce a weighing to ±0.1 mg. ❝ Can you please provide me any reference which says something about this practical issue? Sorry. What about common sense? — 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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Ohlbe ★★★ France, 2012-02-10 19:10 (4858 d 15:15 ago) @ auditor Posting: # 8105 Views: 7,161 |
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Dear Auditor, ❝ Did the agency accept it? I never heard of any agency rejecting data for this reason. As long, of course, as the difference is indeed minimal and really due to differences in weighing. If you get a difference of 30 % don't pretend it's due to weighing. Or change the way you weigh... Regards Ohlbe — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2012-02-10 20:15 (4858 d 14:10 ago) @ Ohlbe Posting: # 8106 Views: 7,214 |
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Dear Ohlbe! ❝ […] change the way you weigh...  Great poetry! Chinese origin?— 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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auditor ★ India, 2012-02-11 07:49 (4858 d 02:36 ago) (edited on 2012-02-11 11:59) @ Helmut Posting: # 8108 Views: 7,152 |
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Dear Both, you mean to say that up to some of the extent variation in nominal concentration is accepted. In India we always tried to give appropriate dilution to the taken weight to get the concentration of nominal within the validated range. Might be regulatory having different approach while auditing data generated in India and over sea's. We believes that if some thing is not cover by establish calibration curve we have to generate some supporting data for the same. And we believe that such kind of issue will not add any value to establish validated range. Still i am not clear about reply given by you. Regards, Auditor |
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Helmut ★★★ Vienna, Austria, 2012-02-11 13:59 (4857 d 20:26 ago) @ auditor Posting: # 8109 Views: 7,162 |
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Dear Auditor! ❝ you mean to say that up to some of the extent variation in nominal concentration is accepted. Yes. ❝ In India we always tried to give appropriate dilution to the taken weight to get the concentration of nominal within the validated range. How to you do that (“appropriate dilution”)? ❝ Might be regulatory having different approach while auditing data generated in India and over sea's. Can you give an example of regulatory problems by the CDSCO/DCGI? ❝ We believes that if some thing is not cover by establish calibration curve we have to generate some supporting data for the same. And we believe that such kind of issue will not add any value to establish validated range. Believes cannot be challenged. Have nothing to do with science. ❝ Still i am not clear about reply given by you. Example:
— 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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ElMaestro ★★★ Denmark, 2012-02-11 21:20 (4857 d 13:05 ago) @ Helmut Posting: # 8110 Views: 7,132 |
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Hi auditor, ❝ Example:
I agree with the views of HS and Ohlbe expressed here and would like to point out that in any method development you have a specification of how much the technician should weigh (like 0.1150 g or sumfin like that). You are dealing with a situation where the actually weighed amount is a little higher than it has been previously during the development but it could still be weighed correctly according to the method description. That in itself opens another can of worms; if you wish to avoid the situation of concern then you somehow need to ascertain that the study analyst never uses an amount literally exceeding the largest amount used during method development/validation ("weigh not more than 0.1142 grams") which one can argue imposes a change to the method and that's not what you wish to do at that stage. I totally see your concern, but I think this case is best solved by practical thinking. — Pass or fail! ElMaestro |
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auditor ★ India, 2012-02-13 06:35 (4856 d 03:50 ago) @ Helmut Posting: # 8112 Views: 7,088 |
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❝ ❝ In India we always tried to give appropriate dilution to the taken weight to get the concentration of nominal within the validated range. ❝ How to you do that (“appropriate dilution”)? in that we are targeting required concentration. After acheiving that concentration we prepare remaining level of the curve by serial dilution. this way we always prepare all the level within the establish calibration curve. ❝ ❝ Might be regulatory having different approach while auditing data generated in India and over sea's. ❝ ❝ Can you give an example of regulatory problems by the CDSCO/DCGI? I am no talking about CDSCO/ DCGI. I am talking about US FDA. In one of the meeting we have discuss this point and they suggest to have all the level within the establish calibration curve. (Sorry i can not give name of the agency inspector) ❝ Deviation –1%: no problem. this will allow us to prepare calibration curve level within the range. ❝ In validation you weighed in 19.9 mg and in the study 20.1 mg. ❝ Deviation +1%: problem. Why? We do not worry about +1% deviation. as we are adjusting concentration by dilution. |
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Helmut ★★★ Vienna, Austria, 2012-02-13 14:29 (4855 d 19:56 ago) @ auditor Posting: # 8118 Views: 7,066 |
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Dear Auditor! ❝ ❝ How to you do that (“appropriate dilution”)? ❝ in that we are targeting required concentration. After acheiving that concentration we prepare remaining level of the curve by serial dilution. this way we always prepare all the level within the establish calibration curve. Do you mean something like this? Validation: 20.1 mg → 100 mL (primary stock 201 µg/mL) 500 µl → 100 mL (spiking stock 1.005 µg/mL) 1 ml plasma + 2/4/8/16/32 µL → 2.010/4.020/8.040/16.08/32.16 ng/mL Study 1: 19.9 mg → 100 mL (primary stock 199 µg/mL) 505 µl → 100 mL (spiking stock 1.00495 µg/mL); 1 ml plasma + 2/4/8/16/32 µL → 2.010/4.020/8.040/16.08/32.16 ng/mL Study 2: 20.2 mg → 100 mL (primary stock 202 µg/mL) 497 µl → 100 mL (spiking stock 1.00394 µg/mL); 1 ml plasma + 2/4/8/16/32 µL → 2.008/4.016/8.032/16.06/32.13 ng/mL or 498 µl → 100 mL (spiking stock 1.00596 µg/mL); 1 ml plasma + 2/4/8/16/32 µL → 2.012/4.024/8.048/16.10/32.19 ng/mL Don’t you see problems with the resolution of pipettes? In the second study you can either go with 497 µl keeping the calibration within the range at the upper end (32.13<32.16) but failing at the lower end (2.008<2.010) – or with 498 µl overrunning slightly at the upper end (32.19>32.16). I would be more concerned about the former (< validated LLOQ). ❝ I am no talking about CDSCO/ DCGI. I am talking about US FDA. In one of the meeting we have discuss this point and they suggest to have all the level within the establish calibration curve. Nice. ❝ We do not worry about +1% deviation. as we are adjusting concentration by dilution. Might not work all the time (see above). — 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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Aceto81 ★ Belgium, 2012-02-16 11:50 (4852 d 22:35 ago) @ auditor Posting: # 8128 Views: 6,893 |
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In European Pharmacopea and / or USP is a statement that it is allowed to maximum deviate 5% from the stated weight in the monographs. eg if you have to weigh 50mg, you are allowed to weigh 45–55mg. We use this rule for all our analysis, and never had problems with regulatories (at least not on this topic). Ace |
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auditor ★ India, 2012-02-16 13:23 (4852 d 21:02 ago) @ Aceto81 Posting: # 8129 Views: 6,984 |
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❝ In European Pharmacopea and / or USP is a statement that it is allowed to maximum deviate 5% from the stated weight in the monographs. I do agree with you. but here the topic is what to do if some thing is prepared high then the establish one. I just want to say we need to inject one P&A to justify slightly increased ULOQ. Here we are not changing the range but using of ULOQ which is just slightly beyond the establish one in method validation. |
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Helmut ★★★ Vienna, Austria, 2012-02-16 14:24 (4852 d 20:01 ago) @ Aceto81 Posting: # 8131 Views: 7,007 |
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Hi Ace! ❝ […] it is allowed to maximum deviate 5% from the stated weight in the monographs. eg if you have to weigh 50mg, you are allowed to weigh 45–55mg. 50mg ± 5% = 47.5mg – 52.5mg. ![[image]](https://forum.bebac.at/img/uploaded/image28.png)  — 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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pharmino ☆ 2012-02-17 22:24 (4851 d 12:02 ago) @ Helmut Posting: # 8141 Views: 6,930 |
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Hi all! First of all: nice page. 2nd: By the weight... A technologist colleague asked me about her doubts about the interpretation of the GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE (sorry for the caps, I was lazy not to paste it as it was written on the front page). So the guideline states in the c/i biowaiver criterion: "the amount of the active substance(s) is less than 5 % of the tablet core weight, the weight of the capsule content". Question is: the weight of the salt counts (I guess this is the case) or only the weight of the active cation? Further formulation strategy depends on the answer. And yes, I'm quite a newbie in this field. Thanks. |
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Helmut ★★★ Vienna, Austria, 2012-02-18 14:34 (4850 d 19:51 ago) @ pharmino Posting: # 8142 Views: 6,993 |
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Dear pharmino! ❝ […] (sorry for the caps, I was lazy not to paste it as it was written on the front page). I would appreciate it if you try to overcome your laziness retyping six words in the future. ❝ Question is: the weight of the salt counts (I guess this is the case) IMHO you are right. See this thread and especially Jean-Michel’s telling example. — 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