govardhanpillari
☆

India,
2009-03-04 11:30

Posting: # 3314
Views: 22,704

## F1 and F2 values and dissolution profile [Dissolution / BCS / IVIVC]

Dear All,

We planned to develop one generic formulation (one formula) for both US and EU submissions. For this, we have done the comparative dissolution studies for both RLD (US and EU). The dissolution data as follows,

S.no  Time  %of drug release              US RLD  EU RLD  1     15      62     86  2     30      94     95  3     45      98     96  4     60      99     95 f1   8.78 f2  45.58
Can any one suggest us that if we are matching our test product dissolution profile in between these two RLD profile, Can we succeed in BE with two RLDs.

Sorry for my english....

Regards,
Govardhan

Edit: Table reformatted using BBCodes. [Helmut]

Govardhan.P
drcampos
★

Brazil,
2009-03-04 12:51
(edited by drcampos on 2009-03-04 20:18)

@ govardhanpillari
Posting: # 3317
Views: 20,150

## F1 and F2 values and dissolution profile

Dear Govardhan,

First of all, I don't know of which drug you are talking about. You haven't also presented the dissolution con­ditions. Moreover, it's very difficult to predict the BE result from dissolution profile. I suggest you to do a pilot study (n = 8 or 12) to evalute the formulations in vivo.

Regards,

Daniel Rossi de Campos
Aceto81
★

Belgium,
2009-03-05 11:30

@ govardhanpillari
Posting: # 3320
Views: 20,426

## F1 and F2 values and dissolution profile

Hi,

if you want to use F1 and F2 values for you comparison of your generic formulation with a reference formulation, you may only have 1 point after 85%, so you need 3 - 4 points before 85% release.
Also you need to test 12 samples.
If your component is rapid dissolving (> 85% in <=15min), you don't have to perform F1 and F2 comparison.
Besides this: F2 should be between 50 - 100, so based on your calculations: equivalence isn't shown.

For a reference about dissolution comparison: http://www.dissolutiontech.com/DTresour/899Art/DissProfile.html

Kind regards

Ace
Helmut
★★★

Vienna, Austria,
2009-03-05 13:01

@ Aceto81
Posting: # 3323
Views: 20,123

## F1 and F2 values and dissolution profile

Dear Ace!

Agree with your points. To my understanding Govardhan wants to develop a generic formulation, which might have a chance to be bioequivalent to both the US RDL and an European Reference.

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
govardhanpillari
☆

India,
2009-03-06 05:04

@ Aceto81
Posting: # 3328
Views: 21,975

## F1 and F2 values and dissolution profile

Dear Ace, HS, Daniel and ohlbe,

Thank you very much for your information.

My product is Hydroxychloroquine sulfate 200 mg tablets.. The dissolution data of US and EU are as follows,
 Type : USP Type - II (paddle) RPM   50, Temp: 37C Medium : Purified water Volume :  900 ml,  S.No     time (min)    US RLD      EU RLD  1            5           13          21 2           10           40          64 3           15           62          86 4           20           78          94 5           30           94          95 6           45           98          96 7           60           99          95 F1 value is 16.3 f2 value is 41.7

This drug may comes under BCS class III drug. Usally Invitro -Invivo correlation is only possible for BCS II and slightly for BCS IV drugs...

My question is, Does the invivo activity of these RLDs depend on dissolution? (it is highly soluble drug)...

Thanks & Regards,

Govardhan

Edit: Full quote removed. Please see this post, and here for instructions to construct simple tables in the forum. [Helmut]

Govardhan.P
drcampos
★

Brazil,
2009-03-06 13:31

@ govardhanpillari
Posting: # 3333
Views: 20,459

## F1 and F2 values and dissolution profile

Dear Govardhan,

If your drug is a BCS class III so the permeability is the limitant factor for absorption. Some authors* have concluded that differences in dissolution rates observed earlier than 30 min have negligible consequences in vivo for BCS class III drugs. Moreover, you should evalute if excipients may influence either the permeability or solubility of the drug. Therefore, I should ensure if your formulation is BCS class III too.

Considering the issue about IVIVC for formulations with BCS class III drugs generally is possible to establish a nonlinear IVIV relationship. This relationship might ensure that your formulation has a BCS class III behaviour (http://www.dissolutiontech.com/DTresour/800Articles/800_art1.html) but this model is not applied to predict the in vivo disposition of the formulation.

Best regards,

Daniel Rossi de Campos

* 1. Polli JE. 1997. In vitro-in vivo relationships of several "immediate" release tablets containing a low permeability drug. Adv Exp Med Biol 423:191-
198.
2. Cheng CL, Yu LX, Lee HL, Yang CY, Lue CS, Chou CH. 2004. Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: Bridging evidence for metformin immediaterelease tablet. Eur J Pharm Sci 22:297-304.
3. Blume HH, Schug BS. 1999. The biopharmaceutics classification system (BCS): Class III drugs - Better candidates for BA/BE waiver? Eur J Pharm Sci 9:117-121.
govardhanpillari
☆

India,
2009-03-07 04:47

@ drcampos
Posting: # 3338
Views: 20,089

## F1 and F2 values and dissolution profile

Dear drcampos,

Thank you very much for your information..

Regards,

Govardhan

Govardhan.P
Helmut
★★★

Vienna, Austria,
2009-03-05 13:15

@ govardhanpillari
Posting: # 3324
Views: 20,243

## US RLD / European reference

Dear Govardhan!

First have a look at Ace's reply. It looks the the US and the EU product differ in the first 15 minutes...

» [...] we have done the comparative dissolution studies for both RLD (US and EU).

There's no 'EU RLD'! For a European submission for marketing authorisation an innovator's product from any European member state may be used as a reference. It is well known that innovator's products may differ from country to country... So maybe you just picked a 'bad' one...
CROs make their (good?) living from in vivo studies; you can place a bet that all sponsors have done a lot to match the reference's in vitro profile. If the dissolution is not triggered by the formulation (i.e., MR), trying to match the reference is nice - but you will have to perform a biostudy anyway. Maybe if criteria are fulfilled (f2, ), studies for different strengths will be waived.

Cheers,
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Ohlbe
★★★

France,
2009-03-05 18:09

@ Helmut
Posting: # 3325
Views: 20,021

## European reference

Dear Helmut,

» There's no 'EU RLD'

True... except if the product was authorised through the centralised procedure. In such a case the product is identical in all EU Member States.

Regards
Ohlbe
jayeshd
●

2010-04-17 06:58
(edited by Ohlbe on 2010-04-17 18:12)

@ govardhanpillari
Posting: # 5159
Views: 19,483

## F1 and F2 values and dissolution profile

Hi Govardhan,

We are also planning to do a single BE study for EU and USA market. Now we dont know how to go about bio studies.

I would like to know about;
1. How to select Reference drug for EU market ? Is ther any system/website just like orange book for USFDA ?
2. Can we plan a single 3WC study using RLD from USA and EU ?
3. If our product fail to bioequivalent to USFDA, but it is bioequivalent to EU then does EU accept our dossier ?
4. Is there any regularoty issue for conducting this study ?

thanks
Jayesh

Ohlbe
★★★

France,
2010-04-17 18:19

@ jayeshd
Posting: # 5161
Views: 19,311

## EU + US

Dear Jayesh,

» 1. How to select Reference drug for EU market ? Is ther any system/website just like orange book for USFDA ?

No "Orange book" here. See Helmut's message in this thread and my response.

» 2. Can we plan a single 3WC study using RLD from USA and EU ?

Yes, as long as you manage to comply with all requirements from both sides. Until now I have seen trials with reference products from EU and Switzerland and EU + Australia, but never with EU + US.

» 3. If our product fail to bioequivalent to USFDA, but it is bioequivalent to EU then does EU accept our dossier ?

No reason why they should not.

» 4. Is there any regulatory issue for conducting this study ?

You have to comply with both the EU and US BE guidelines and all regulations. See the guidance page.

Regards
Ohlbe

Regards
Ohlbe
Dr_Dan
★★

2010-04-19 12:51

@ jayeshd
Posting: # 5171
Views: 19,433

## F1 and F2 values and dissolution profile

Dear Jayesh
How do you know that the US reference product has the same formulation as the European reference product? You will never know! I also tried once but the agencies did not accept the argument US RLD= EU RLD although there was worlwide only one production site and the qualitative composition was the same. A single 3WC study using RLD from USA and EU bears the risk that one comparison fails. The consequence would be that you present unfavourable data to the agency. In case when everything is fine nobody would ask, in case of failure you have to find strong arguments how you selected your reference batches. This might lead to endless discussions. I strongly recommend to perform two studies, one for the US market and one for Europe.
O.K. I agree that it is more expensive but you are on the safe side.
Kind regards
Dan

Kind regards and have a nice day
Dr_Dan
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