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Amalia
Junior

Greece,
2018-10-01 11:04

Posting: # 19350
Views: 469
 

 Solubility based Biowaiver [Dissolution / BCS / IVIVC]

Dear all,

we are trying to built a biowaiver justification for the lowest strength of a products.
According to the guideline "The pH-solubility profile of the drug substance should be determined and discussed. The drug substance is considered highly soluble if the highest single dose administered as immediate release formulation(s) is completely dissolved in 250 ml of buffers within the range of pH 1 – 6.8 at 37±1 °C. This demonstration requires the investigation in at least three buffers within this range (preferably at pH 1.2, 4.5 and 6.8) and in addition at the pKa, if it is within the specified pH range. Replicate determinations at each pH condition may be necessary to achieve an unequivocal solubility classification (e.g. shake-flask method or other justified method). Solution pH should be verified prior and after addition of the drug substance to a buffer."

Could you please let me know whether the solubility studies refer to the API, or to the FDF?
If we demonstrate that the FDF of the lowest strength is highly soluble in all relevant media, will it be sufficient to claim a biowaiver?

Thank you in advance.

Kind Regards,
Amalia


Edit: Category changed; see also this post #1[Helmut]
Obinoscopy
Regular

Nigeria,
2018-10-01 15:03

@ Amalia
Posting: # 19352
Views: 438
 

 Solubility based Biowaiver

Dear Amalia,

There are basically two biowaiver pathways. One is Additional Strength Biowaivers while the other is BCS-Based Biowaivers. Which pathway do you intend following?

If BCS, then you need to first classify your API as to whether it's BCS Class I or Class III. this will require performing the prescribed experiment or referring to literature as spelt out in the guideline.

It is then that you can now demonstrate dissolution rate of your FPP (in 15 or 30 minutes) and then go ahead with comparative dissolution studies. The classification determines the dissolution requirements for your FPP.

Regards,

Scopy
Amalia
Junior

Greece,
2018-10-01 15:59

@ Obinoscopy
Posting: # 19354
Views: 426
 

 Solubility based Biowaiver

Thank you very much for your reply!

Basically it is an additional strength biowaiver. The molecule is classified as BCS Class II. However we were advised that considering solely the lowest strength, it is very close to being considered as highly soluble. As per the Guideline of BE "the drug substance i considered highly soluble if the highest single dose administered as immediate release formulation is completely dissolved in 250ml of buffers within certain pH range". In other words for a highly soluble drug, the dose number (D0) is equal or lower than 1.

Therefore, my question here is whether the solubility test should be done at the API or the final formulation (lowest strength) in order to support a biowaiver for the lowest stength.

I hope I have not confused you more!

Awaiting your response!

Thank you in advance,

Amalia
Obinoscopy
Regular

Nigeria,
2018-10-01 19:05

@ Amalia
Posting: # 19357
Views: 411
 

 Solubility based Biowaiver

Dear Amalia

» Basically it is an additional strength biowaiver.

Okay

» The molecule is classified as BCS Class II.

Okay. I'll like to point out that BCS classification is irrelevant when following the Additional Strength Biowaiver pathway. What's relevant is to confirm if Invivo Bioequivalence was established for the Highest Strength of your formulation. And that both strengths are in the same proportion in terms of excipients.

» However we were advised that considering solely the lowest strength, it is very close to being considered as highly soluble.

Who gave the advice? A Regulatory Agency? A CRO?

» As per the Guideline of BE "the drug substance i considered highly soluble if the highest single dose administered as immediate release formulation is completely dissolved in 250ml of buffers within certain pH range". In other words for a highly soluble drug, the dose number (D0) is equal or lower than 1.

Again I'll reiterate that solubility of the drug substance is irrelevant. See above.

» Therefore, my question here is whether the solubility test should be done at the API or the final formulation (lowest strength) in order to support a biowaiver for the lowest stength.

Following the Additional Strength Biowaivers pathway, you don't need to perform solubility test for the API. what you do is to perform a comparative dissolution profile study for your low strength formulation against the high strength formulation after you've ensured that the requirements I stated above have been met.

» I hope I have not confused you more!

Lol, I think not. I hope i haven't confused you as well.

Regards,

Scopy
wienui
Regular

Germany, Oman,
2018-10-02 04:52
(edited by wienui on 2018-10-02 05:14)

@ Obinoscopy
Posting: # 19358
Views: 397
 

 Solubility based Biowaiver

Dear Amalia & Scopy,

I agree with Scopy only an important point to mention that the dissolution tests of the lower strength must be conducted against the same Biobatch (the batch which approved via BE study) of the higher strength, otherwise it will not be accepted from the regulatory.

Best regards,

Osama
Amalia
Junior

Greece,
2018-10-02 08:59

@ Obinoscopy
Posting: # 19360
Views: 370
 

 Solubility based Biowaiver

Dear Obinoscopy,

what I guess I should have clarified is that the reason we are trying to use this justification is because the lower strength is not proportional in terms of excipients.

» The advise was given by an "external clinical expert".

I presume this is why we were advised to follow the solubility path for a biowaiver? That is why we are wondering whether we should perform the solubility tests at the API or the final formulation.
What do you think?

Kind Regards,

Amalia
The Outlaw Torn
Regular

Europe,
2018-10-02 09:51

@ Amalia
Posting: # 19361
Views: 356
 

 Solubility based Biowaiver

» what I guess I should have clarified is that the reason we are trying to use this justification is because the lower strength is not proportional in terms of excipients.
»
» » The advise was given by an "external clinical expert".

Where is the difference coming from?

Is the API less than 5% of the total weight of the tablet?

Take a look at the General biowaiver criteria on page 12 of the guideline. If you don't meet the conditions stated in c), you'll need to conduct a BE study at the lower strength too.
Amalia
Junior

Greece,
2018-10-02 10:35

@ The Outlaw Torn
Posting: # 19362
Views: 349
 

 Solubility based Biowaiver

» Where is the difference coming from?

None of the excipients are proportional.

» Is the API less than 5% of the total weight of the tablet?

The API of the lowest strength is less than 5%. But not of the highest strength for which a BE study was performed.

» Take a look at the General biowaiver criteria on page 12 of the guideline. If you don't meet the conditions stated in c), you'll need to conduct a BE study at the lower strength too.

I Know. The most probable scenario is that we will perform a BE study. We are just trying to see if a justification can be made.


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! Please follow the Forum’s Policy[Helmut]
Obinoscopy
Regular

Nigeria,
2018-10-06 19:59

@ Amalia
Posting: # 19413
Views: 240
 

 Solubility based Biowaiver

Dear Amalia,

» what I guess I should have clarified is that the reason we are trying to use this justification is because the lower strength is not proportional in terms of excipients.

Okay thanks for the clarification.

Hmm, I think you are in a quagmire here. If the lower strength isn't proportional then you can't go through the Additional Strength Pathway. You can't go through the BCS-Based Biowaiver Pathway either as you mentioned that the API is BCS class II.

» The advise was given by an "external clinical expert".

Okay

» I presume this is why we were advised to follow the solubility path for a biowaiver? That is why we are wondering whether we should perform the solubility tests at the API or the final formulation.

You cannot follow both of the Biowaiver Pathways because of the reasons I mentioned above. If an API is BCS Class II, then it's not eligible for BCS Biowaiver, plain and simple.

But if you think you can perform experiments that will demonstrate the solubility (and permeability) of the API such that it is classified as BCS Class I or III, then be my guest. However you will have to explain to the regulators why you didn't follow he same pathway for the higher strength.

» What do you think?

If you ask me, I'd recommend you conduct an Invivo BE study. The solubility and permeability experiment on the lower strength API is a waste of energy and resources IMHO. But if asked, don't quote me as the "external clinical expert." I'm just me :-).

Regards,

Scopy
The Outlaw Torn
Regular

Europe,
2018-10-02 08:56

@ Amalia
Posting: # 19359
Views: 373
 

 Solubility based Biowaiver

Do as others have said, Amalia.

Follow section 4.2 of the Guideline. When it points you to appendix III, ignore the BCS-biowaiver stuff. Focus on the first third of the information on page 27 only (about experimental conditions). In other words, don't think BCS or solubility or permeability or API or anything else. Do the standard comparative dissolution testing at 3 pH values for your finished drug product at all strengths, etc.
lukamar
Junior

Poland,
2018-10-05 09:30

@ Amalia
Posting: # 19410
Views: 279
 

 Solubility based Biowaiver

» we are trying to built a biowaiver justification for the lowest strength of a products.

If I understand correctly you have BE study for highest strength and want to justify biowaiver for lower strenght(s). However this lower strength does not fullfil general biowaiver criteria (as described in 4.1.6 of BE guideline) so you consider BCS-based biowaiver instead.
Such approach is theoretically possible, assuming that drug substance is considered as highly soluble i.e. highest single dose is completely dissolved in 250 ml of buffers accross 1 - 6.8 pH range. This in turn depends on posology of given strenght. I think there are 2 scenarios. Let's say the product is of 10 mg and 5 mg:
1 - you have same posology for both strengths i.e. highest dose is 10 mg and patient can take it either as 1x10 or 2x5 mg. Then 10 mg has to be proven as highly soluble in order to apply BCS-based biowaiver for 5 mg
2 - posology is different i.e. for 5 mg strenght - 5 mg is highest dose (i.e. you cannot use as multiplication for higher dose), and for 10 mg - 10 mg. Then it would be suffcient to prove high solubility for 5 mg of active substance to apply BCS-based biowaiver for this strength.
Hope I helped.
Best regards,
Łukasz
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