CLR
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Singapore,
2016-04-11 12:12
(2908 d 09:10 ago)

Posting: # 16181
Views: 10,559
 

 What is the point of IVIVCs for generics? [Dissolution / BCS / IVIVC]

Hi everyone,

I was recently involved in some discussions about BE training and the topic of IVIVCs came up. I also came across a publication from last year by a bunch of USFDA reviewers about applying IVIVCs in generic drug development. Based on my rather limited experience, despite the benefits that an IVIVC brings, many generic companies either don't do them for their oral extended-release products or don't do them correctly. As many of you have direct working experience either with or within generic drug companies, could you perhaps share why you think this is the case? If it's such an uphill climb, is there any point in trying to sell IVIVCs to the generic drug companies?

Looking forward to hearing your views :-D
jag009
★★★

NJ,
2016-04-12 18:24
(2907 d 02:59 ago)

@ CLR
Posting: # 16191
Views: 9,493
 

 What is the point of IVIVCs for generics?

Hi,

Some hints:
  1. IVIVC allows you to claim biowaiver for biostudy for SUPAC (manufacturing site transfer)
  2. IVIVC is a great tool in formulation development, optimization.
Why not many IVIVC?
  1. It's not easy to do unless your compound is BCS class 1 or 2.
  2. Not many generic companies do manufacturing site transfers (?)

John
CLR
☆    

Singapore,
2016-04-19 07:29
(2900 d 13:53 ago)

@ jag009
Posting: # 16217
Views: 9,170
 

 What is the point of IVIVCs for generics?

Hi John,

Valid points! However, generic companies do sometimes have to make formulation changes (e.g. problems with a functional coating in a modified-release tablet) and if they happen to be SUPAC level 3, then the BE studies would be required by the USFDA in the absence of an acceptable IVIVC. I'm not very clear on how the EMA assesses such changes but if an IVIVC is not submitted, then it means that 3 BE studies have to be submitted for a modified-release oral solid dosage form? This seems like a lot but I guess generic companies may consider the risks of such formulation problems to be fairly low? :confused:

I am asking out of academic interest - I have not come across IVIVCs performed in this part of the world so far and there is no push for this to change anytime soon.
luvblooms
★★  

India,
2016-04-19 18:43
(2900 d 02:40 ago)

@ jag009
Posting: # 16221
Views: 9,133
 

 What is the point of IVIVCs for generics?

Hi John,

❝ Some hints:

❝    1. IVIVC allows you to claim biowaiver for biostudy for SUPAC (manufacturing site transfer)

❝    2. IVIVC is a great tool in formulation development, optimization.

❝ Why not many IVIVC?


IVIVC has also been used to
  1. set the dissolution specification during development
  2. to modify dissolution specification during stability (been there, done that and got approval on the changed specification setting ;-) )

Regards

~A happy Soul~
Dr_Dan
★★  

Germany,
2016-04-20 16:17
(2899 d 05:06 ago)

@ luvblooms
Posting: # 16222
Views: 9,083
 

 What is the point of IVIVCs for generics?

Dear all
IVIVC = in-vitro in-vivo correlation, i.e. you need to have more than one set of clinical data. For generic products you need to demonstrate bioequivalence (= one set of clinical data). Therefore IVIVC is not applicable (provided that you do not fail several times in BE :-D)
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Helmut
★★★
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Homepage
Vienna, Austria,
2016-04-20 18:04
(2899 d 03:19 ago)

@ Dr_Dan
Posting: # 16223
Views: 9,088
 

 Education needed

Dear Dan & all

❝ IVIVC = in-vitro in-vivo correlation, i.e. you need to have more than one set of clinical data.


Yep. I agree with [msg]John’s #2[/msg]:

❝    IVIVC is a great tool in formulation development, optimization.


IMHO many (most?) generic companies are still lacking experience with IVIVC. Formulators forget that at the end of the day the formulation should match the reference in vivo. They fiddle around with dissolution media for quality control instead of trying to find discriminatory and/or biorelevant media. I have seen too many fruitless pilot studies of candidate formulations – which were developed by “gut feeling”… But it is not too late! The best way to set up a successful IVIVC is in vivo first and then find a discriminatory dissolution method. Hence, with all the available in vivo data the first step is already done!
Quoting Jean-Michel Cardot:

“If Earl Grey with sugar and a sip of milk turns out to be discriminatory – use it!”


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jag009
★★★

NJ,
2016-04-20 23:29
(2898 d 21:54 ago)

@ Dr_Dan
Posting: # 16228
Views: 9,016
 

 What is the point of IVIVCs for generics?

Hi Dr. Dan,

IVIVC is applicable for a generic company in terms formulation development, post pilot bio-study formulation optimization (ie: if established, the model allows you to predict a target disso profile which can result in a product BE to reference).

Of course then you have specification, site transfer, stability, yada yada...

John
Dr_Dan
★★  

Germany,
2016-04-21 10:35
(2898 d 10:47 ago)

@ jag009
Posting: # 16230
Views: 9,058
 

 What is the point of IVIVCs for generics?

Dear John & Helmut
Maybe I worked for the wrong generic companies but I never faced a problem which needed to be solved by IVIVC....
However, IMHO the general practice for a generic is as follows: You develop a formulation which is stable and shows similar dissolution profiles compared to the reference product. Then you conduct a BE study which passes and that´s it. (Lucky shot?) You have your generic product and you can sell it. No post pilot bio-study formulation. In my opinion IVIVC is extra money no one wants to spent in the generic industry. Yes, you are right this would increase the knowledge about your product, but who cares? As long as you have a bioequivalent product and do not want to change anything there is no need for IVIVC. IMHO IVIVC is a nice intellectual game. For the originator industry this is of course different since the reference product is not established.
I know my attitudy will raise your protest...
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
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