xtianbadillo
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Mexico,
2018-01-16 15:02
(1099 d 22:49 ago)

Posting: # 18185
Views: 2,964
 

 Is a Chiral method required? [Regulatives / Guidelines]

A Clinical study is going to be with an enantiomer (not racemate).
The enantiomers exhibit different pharmacodynamic characteristics but only the active enantiomer is going to be in the formulation.
There is no in-vivo interconversion.
The reference standard is going to be the enantiomer (not racemate).

Is a chiral method required? Can I go with a simple achiral method?


Edit: Please follow the Forum’s Policy. [Helmut]
Helmut
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Vienna, Austria,
2018-01-17 13:40
(1099 d 00:12 ago)

@ xtianbadillo
Posting: # 18190
Views: 2,611
 

 Racemate vs. enantiomer?

Hi Christian,

» A Clinical study is going to be with an enantiomer (not racemate).

Are you talking about bioequivalence?

» The enantiomers exhibit different pharmacodynamic characteristics but only the active enantiomer is going to be in the formulation.
» There is no in-vivo interconversion.
» The reference standard is going to be the enantiomer (not racemate).

» Is a chiral method required? Can I go with a simple achiral method?

Which regulation? F.i. the FDA’s requirements concerning chiral methods are diametral to the EMA’s (see also here and there). Can’t find anything in the Mexican one.
One of the prerequisites in BE is that same molar doses of the active ingredient are administered. If the enantiomeric ratio* of the reference is 1:1, IMHO, you would have to administer twice the dose of the test and use a chiral method (assessing only the active enantiomer for BE).

Other opinions are welcome.


  • In sterochemistry, by definition a racemate contains the enantiomers in an equimolar mixture. When it comes to APIs this must not necessarily be the case.
    I once faced this situation: The reference was not declared as a racemate (though only the d-enantiomer was known to be active). It was also known that in purification of the API, the d-enantiomer is enriched. It turned out that the reference product contained 95% d and the test (API of another manufacturer) >99%. Since at that time we had no data about in vivo interconversion and were bound to the EMA’s GL, we used a chiral method. The d-enantiomer passed BE easily and the l-enantiomer would have failed (already expected based on the enantiomeric ratio and therefore, only descriptive according to the protocol). The test was approved in most member states of the EU. However, we received a deficiency letter of the swissmedic (Switzerland is a member of the EEA…) asking to re-evalute the study for the sum of d- and l. :-D

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xtianbadillo
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Mexico,
2018-01-17 18:31
(1098 d 19:20 ago)

@ Helmut
Posting: # 18194
Views: 2,592
 

 Racemate vs. enantiomer?

Dear Helmut

» Are you talking about bioequivalence?

Is a Bioavailability study 3x6x3: FDC (NSAID active-enantiomer + Opioid racemate) vs (NSAID active-enantiomer or Opioid racemate)

» » The enantiomers exhibit different pharmacodynamic characteristics but only the active enantiomer is going to be in the formulation.
» » There is no in-vivo interconversion.
» » The reference standard is going to be the enantiomer (not racemate).

» » Is a chiral method required? Can I go with a simple achiral method?
»
» Which regulation? F.i. the FDA’s requirements concerning chiral methods are diametral to the EMA’s (see also here and there). Can’t find anything in the Mexican one.

Neither do I, so State of the art regulation

» One of the prerequisites in BE is that same molar doses of the active ingredient are administered. If the enantiomeric ratio* of the reference is 1:1, IMHO, you would have to administer twice the dose of the test and use a chiral method (assessing only the active enantiomer for BE).

Thank you


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! [Helmut]
Relaxation
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Germany,
2018-01-18 09:37
(1098 d 04:15 ago)

@ Helmut
Posting: # 18205
Views: 2,533
 

 Racemate vs. enantiomer?

Hi everybody.

» Other opinions are welcome.

Then I just have to add some quick thoughts. Taking the risk of having misunderstood the post.
I am not sure I agree with the interpretation here:

» One of the prerequisites in BE is that same molar doses of the active ingredient are administered. If the enantiomeric ratio* of the reference is 1:1, IMHO, you would have to administer twice the dose of the test and use a chiral method (assessing only the active enantiomer for BE).

I would focus here on the wording "active ingredient". Either both enantiomers are active, then you need to administer both anyway or have some long discussions on substituting one enatiomer with the other or whatever. I cannot think of an example, but that's my theory.
If there is only one active enantiomer, I would guess the other one is simply an inactive ingredient.
So in conclusion, proposing 50 mg of the pure active enantiomer as a generic to a product containing 100 mg of the 1:1 racemate would work for me.
But I am not an assessor and I have no example. Got involved in a discussion on dexibuprofen briefly, but there it is more complicated due to interconversion and still some discussion of a contribution of both enantiomers to efficacy.
Helmut
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Vienna, Austria,
2018-01-18 09:55
(1098 d 03:57 ago)

@ Relaxation
Posting: # 18207
Views: 2,547
 

 Racemate vs. enantiomer?

Hi Relaxation,

» I am not sure I agree with the interpretation here:
»
» » One of the prerequisites in BE is that same molar doses of the active ingredient are administered. If the enantiomeric ratio* of the reference is 1:1, IMHO, you would have to administer twice the dose of the test and use a chiral method (assessing only the active enantiomer for BE).
»
» I would focus here on the wording "active ingredient". […] If there is only one active enantiomer, I would guess the other one is simply an inactive ingredient.

Ariëns’ isomeric ballast.* :-D

» So in conclusion, proposing 50 mg of the pure active enantiomer as a generic to a product containing 100 mg of the 1:1 racemate would work for me.

You are right and I stand corrected! I doubt that such a product falls in the definition of a generic. However, Christian is interested in a new FDC.

» Got involved in a discussion on dexibuprofen briefly, but there it is more complicated due to interconversion and still some discussion of a contribution of both enantiomers to efficacy.

IMHO, dexibuprofen products are – to a large extent – marketing gimmicks.


  • Ariëns EJ. Racemic therapeutics — ethical and regulatory aspects. Eur J Clin Pharmacol. 1991;41(2):89–93. doi:10.1007/BF00265897.

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