Obinoscopy ★ USA, 20180422 15:11 (1372 d 14:59 ago) Posting: # 18718 Views: 10,697 

Dear All, Even though I have not come across this scenario in practice, I am imagining a situation where a test product is rapidly dissolving (>85% in 30 mins) while the comparator product is very rapidly dissolving (>85% in 15 mins) and vice versa. Is f2 calculation necessary? If it is, which time points will be used? I am aware, the requirements are different for different NRAs (USFDA, EMEA, WHO, etc). I will appreciate if these are taken into account when answering this question. Regards, — Scopy 
Helmut ★★★ Vienna, Austria, 20180422 16:56 (1372 d 13:14 ago) @ Obinoscopy Posting: # 18719 Views: 9,355 

Hi Scopy, » […] a situation where a test product is rapidly dissolving (>85% in 30 mins) while the comparator product is very rapidly dissolving (>85% in 15 mins) and vice versa. Is f2 calculation necessary? If it is, which time points will be used? Tricky. ƒ_{2} is generally not required if product(s!) release ≥85% in all three media. In the calculation of ƒ_{2} the devil is in the details. There are different restrictions on samples after 85% release:
BTW, what is an FFP? — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
wienui ★ Germany, Oman, 20180422 21:39 (1372 d 08:31 ago) @ Helmut Posting: # 18720 Views: 9,302 

Hi Scopy & Helmut, » » […] a situation where a test product is rapidly dissolving (>85% in 30 mins) while the comparator product is very rapidly dissolving (>85% in 15 mins) and vice versa. Is f2 calculation necessary? If it is, which time points will be used? I think in this case a calculation of f2 is necessary, as the condition for not required calculation of f2 is not exist. when both test and reference products dissolve 85 percent or more of the label amount of the drug in 15 minutes using all three dissolution media recommended above, the profile comparison with an f2 test is unnecessary. The differences in the GL's as mentioned in the reply of Helmut concerned how and when an additional time point after reaching the 85% release amount can be included in the calculation. As not more than 1 time point is allowed to be added in the calculation of f2 after reaching the 85% releasing time point (can be at time points 45min, 60min, ...). Best regards, Osama — Cheers, Osama 
Obinoscopy ★ USA, 20180423 00:53 (1372 d 05:17 ago) @ Helmut Posting: # 18721 Views: 9,315 

» ƒ_{2} is generally not required if product(s!) release ≥85% in all three media. You said Product(s) and not Products. So that means there are instances where f2 calculation can be shelved when only one product (either test or comparator product) releases >85% of API in 15 minutes? Maybe it's better I present some hypothetical data to help me present my case: If the 5, 10, 15, 20, 25, 30 and 45 mins dissolution values for the test product were 32%, 63%, 88%, 91%, 95%, 96% and 97% respectively. And that of the Comparator were 23%, 44%, 52%, 65%, 76%, 89% and 92% respectively. Is f2 calculation required going by USFDA, EMA and WHO GLs? If it is, how's the calculation done? » In the calculation of ƒ_{2} the devil is in the details. There are different restrictions on samples after 85% release:
I really don't understand. Please can you explain further. I'm still a beginner in this field. » BTW, what is an FFP? Oops. Thought I wrote FPP. apologies for the typo. Regards — Scopy 
wienui ★ Germany, Oman, 20180423 03:32 (1372 d 02:38 ago) @ Obinoscopy Posting: # 18722 Views: 9,253 

Dear Scopy, » If the 5, 10, 15, 20, 25, 30 and 45 mins dissolution values for the test product were 32%, 63%, 88%, 91%, 95%, 96% and 97% respectively. And that of the Comparator were 23%, 44%, 52%, 65%, 76%, 89% and 92% respectively. » » Is f2 calculation required going by USFDA, EMA and WHO GLs? If it is, how's the calculation done? Yes, you need to calculate the f2 value regardless the GL's, as your Comparator didn't achieve a release of ≥85% at the time point 15 min. How? as normal via the f2 equation, please have a look here https://www.fda.gov/downloads/drugs/guidances/ucm070237.pdf Regards, Osama — Cheers, Osama 
Obinoscopy ★ USA, 20180424 13:00 (1370 d 17:10 ago) (edited by Obinoscopy on 20180424 13:11) @ wienui Posting: # 18728 Views: 9,088 

» Yes, you need to calculate the f2 value regardless the GL's, as your Comparator didn't achieve a release of ≥85% at the time point 15 min. How about if its the other way? That is: If the dissolution values for the Comparator product were 32%, 63%, 88%, 91%, 95%, 96% and 97% respectively. And that of the Test product were 23%, 44%, 52%, 65%, 76%, 89% and 92% respectively. Want to know what USFDA, EMA and WHO recommends in the above case scenario. » How? as normal via the f2 equation I actually did the calculation and got an f2 of 99.5. However the reason I wanted someone else to the calculation is to know the time points to use. I used time points of 5, 10, 15, 20, 25, 30 mins because the comparator product was able to achieve >85% dissolution at 30 mins. Wanted to know if I'm right. Regards — Scopy 
wienui ★ Germany, Oman, 20180425 18:46 (1369 d 11:24 ago) @ Obinoscopy Posting: # 18730 Views: 8,966 

Dear scopy, » How about if its the other way? That is: » If the dissolution values for the Comparator product were 32%, 63%, 88%, 91%, 95%, 96% and 97% respectively. And that of the Test product were 23%, 44%, 52%, 65%, 76%, 89% and 92% respectively. Here also you have to calculate the f2 factor as your test drug didn't achieve a release of ≥85% at the time point 15 min.. both test and reference products dissolve 85 percent or more of the label amount of the drug in 15 minutes » Want to know what USFDA, EMA and WHO recommends in the above case scenario. » I actually did the calculation and got an f2 of 99.5. However the reason I wanted someone else to the calculation is to know the time points to use. I used time points of 5, 10, 15, 20, 25, 30 mins because the comparator product was able to achieve >85% dissolution at 30 mins. Wanted to know if I'm right. Now comes the difference in the GL'S, in this case (your second case scenario) as Helmut mentioned above:
Regards, Osama — Cheers, Osama 
Obinoscopy ★ USA, 20180427 02:51 (1368 d 03:19 ago) @ wienui Posting: # 18735 Views: 9,013 

» Here also you have to calculate the f2 factor as your test drug didn't achieve a release of ≥85% at the time point 15 min.. » » both test and reference products dissolve 85 percent or more of the label amount of the drug in 15 minutes Awesome. Thanks! » Now comes the difference in the GL'S, in this case ( your second case scenario) as Helmut mentioned above: » – according to WHO your time points (till to 30 min.) included in the calculations of f2 are not correct as you have to add only one time point after reaching the 85% release for your reference drug, i.e only till 20 min. » – but according to FDA & EMA you have to include the 45min time point too. For the second scenario, I thought it should be till 15 mins for WHO and till 30 mins for FDA and EMA. This because the time point for the comparator at 15 mins was 88% while the time point for the test product at 30 mins was 89%. These were the points when >85% was first achieved. Please confirm if I'm right. Thanks so much for your time. I appreciate. Regards, — Scopy 
wienui ★ Germany, Oman, 20180427 03:23 (1368 d 02:47 ago) @ Obinoscopy Posting: # 18736 Views: 8,966 

Dear Scopy, » For the second scenario, I thought it should be till 15 mins for WHO and till 30 mins for FDA and EMA. This because the time point for the comparator at 15 mins was 88% while the time point for the test product at 30 mins was 89%. These were the points when >85% was first achieved. Please confirm if I'm right. 1 time point have to be added in the calculation of f2 after reaching the 85% releasing time point, i.e WHO: 20 min EMA & FDA: 45 Regards, Osama — Cheers, Osama 
Obinoscopy ★ USA, 20180428 20:30 (1366 d 09:41 ago) @ wienui Posting: # 18739 Views: 8,868 

Dear Osama, Thanks so much for your assistance. Regarding your last post, I had a different understanding of the last time point to use when calculating for f2. » 1 time point have to be added in the calculation of f2 after reaching the 85% releasing time point, i.e » WHO: 20 min » EMA & FDA: 45 I had thought the next time point after achieving 85% release (or time point at asymptote) should be used. For reference product, exactly 85% release was achieved at a timepoint in between 10 and 15mins (even though this timepoint was not measured) thus the closest measured timepoint of 15mins should be the additional timepoint after 85% release has been achieved (ie >85% release will achieved at that timepoint). Similarly, for the test product, exactly 85% release will be achieved at a timepoint in between 25 and 30mins. Thus the minimal timepoint when greater than 85% was achieved becomes 30 mins. I had to read the guidelines over again and I couldn't find anything wrong with my mine. But I also couldn't disprove yours either. Perhaps Ohlbe, Helmut as well as others could weigh in their thoughts on this. Regards — Scopy 
Helmut ★★★ Vienna, Austria, 20180429 13:53 (1365 d 16:17 ago) @ Obinoscopy Posting: # 18740 Views: 8,917 

Hi Scopy, I’m not sure which approach is the ‘correct’ one. Your last example’s data:
FDA (1^{st} time >85% for T at 30 min, one sample after at 45 min): ƒ_{1} 21.53, ƒ_{2} 34.73 FDA (1^{st} time >85% for T at 28.46 min, one sample after at 30 min): ƒ_{1} 24.95, ƒ_{2} 33.16 WHO (1^{st} time >85% for R at 15 min, one sample after at 20 min): ƒ_{1} 32.85, ƒ_{2} 30.47 WHO (1^{st} time >85% for R at 14.40 min, one sample after at 15 min): ƒ_{1} 34.97, ƒ_{2} 30.19 Quoting the FDA’s guidance: For curves to be considered similar, ƒ_{1} values should be close to 0, and ƒ_{2} values should be close to 100. Generally, ƒ_{1} values up to 15 (0–15) and ƒ_{2} values greater than 50 (50–100) ensure sameness or equivalence of the two curves […] Can you elaborate how you arrived in this post at an ƒ_{2} of 99.5? Just by looking at the curves such a high ƒ_{2} does not seem to be possible.
My calculation by including all data showing intermediate results. Note that I simplified the original equation to get rid of the stupid nested brackets: \(\small{\\ — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Obinoscopy ★ USA, 20180429 22:08 (1365 d 08:02 ago) (edited by Obinoscopy on 20180429 22:30) @ Helmut Posting: # 18742 Views: 8,905 

Hi Helmut, I'm glad seeing your response. » FDA (1^{st} time >85% for T at 30 min, one sample after at 45 min): ƒ_{1} 21.53, ƒ_{2} 34.73 » FDA (1^{st} time >85% for T at 28.46 min, one sample after at 30 min): ƒ_{1} 24.95, ƒ_{2} 33.16 » WHO (1^{st} time >85% for R at 15 min, one sample after at 20 min): ƒ_{1} 32.85, ƒ_{2} 30.47 » WHO (1^{st} time >85% for R at 14.40 min, one sample after at 15 min): ƒ_{1} 34.97, ƒ_{2} 30.19 I noticed you used two case scenarios when calculating for f1 and f2. Is it that the guidelines are very specific as to the last timepoint to use when calculating for f1 and f2? I had thought the last time point to use in f1 and f2 calculation should be the timepoint when more than 85% dissolution has been achieved. Also if the values were switched between Test and Reference, what will be the decision to take using both FDA and WHO guidelines? I'm guessing both FDA and WHO will use the timepoint 30 minutes (ƒ_{1} 24.95, ƒ_{2} 33.16). » Can you elaborate how you arrived in this post at an ƒ_{2} of 99.5? Just by looking at the curves such a high ƒ_{2} does not seem to be possible. Seen your calculation. Now I know where I got it wrong. I transformed the percentages to decimals (ie 23% to 0.23) before doing the calculations which is wrong. Thanks. Regards, — Scopy 
Ohlbe ★★★ France, 20180423 11:10 (1371 d 19:00 ago) @ Helmut Posting: # 18723 Views: 9,201 

Dear Helmut, » BTW, what is an FFP? FPP, not FFP: finished pharmaceutical product (=formulation). (Well, FFP could stand for finished farmaceutical product, following a bold proposal for revised spelling rules sticking to the pronunciation). — Regards Ohlbe 
Helmut ★★★ Vienna, Austria, 20180424 00:24 (1371 d 05:46 ago) @ Ohlbe Posting: # 18725 Views: 9,141 

Oh dear, am I developing dislexia? — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
JMCardot ☆ France, 20180519 10:12 (1345 d 19:59 ago) @ Helmut Posting: # 18789 Views: 8,360 

Dear all Except if I mistaken I think that the we can simplify it as follow EMA: Not more than one mean value of > 85% dissolved for any of the formulations. FDA: Only one measurement should be considered after 85 percent dissolution of both products. best regards, 