We all know that anti oxidants helps to decrease the generation of NDSRI impurities in many products and FDA already gave clarity on the requirement of bioequivalence after reformulating the drug product using antioxidant and alkalizer. But What is EMA’s thinking on the same change is still not clear. Does anyone is having experience on addition of antioxidant/alkalizer by changing granulating solvent fall under which type of variation? Is this call for new BE study?
Dear @nirav0904
Have you checked Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** section 4.4. ?
You may also refer to Antioxidant as a risk mitigation strategy - a couple of interesting papers are already posted there.
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Dear Nirav,
could you please elaborate on your comment that FDA gave clarity on the requirement of bio equivalence after reformulating the drug product using antioxidant and alkalizer? Is there any defined quantity of antioxidant or alkalizer from which over this a bioequivalence should be performed?
christos
thanks in advance
Couple of things to keep on the radar:
- pH is a mitigation pathway that is commonly overseeing. Keep this as part of your mitigation tools.
- Do not miss the upcoming FDA-CRCG workshop, where FDA will present research about the use of scavengers and pH as mitigation tool. (I saw some of the preliminary data, and the outcome will be unexpected!)
Dear Chrischar,
In latest guidance, USFDA gave clarity that if reformulation done by adding antioxidant/alkalizer, the bioequivalence is not required in below conditions.
- If Drug is BCS Class I, II or III
- Antioxidant/alkalizer used from FDA evaluated list i.e. Ascorbic acid, sodium ascorbate, propyl gallate, cysteine hydrochloride or sodium carbonate.
- Quantity of antioxidant/alkalizer used is less than 10 mg/day.
So, my question was no such clarity till date from EMA and if anyone from the community is having experience with EMA, can share their experience.
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Dear nirav,
thank you very much for your quick response!!
with regards
Christos
Dear Nirav,
could i ask a clarification on the FDAs guidance?
The relative paragraph for the allowable quantity of antioxidants/alkalizers in order to avoid a new BE, is the below:
‘’ If the product contains an API that is classified as BCS I, II, or III and the reformulation incorporates a pH modifier or one of the specific antioxidants studied in FDA-supported research (ascorbic acid, α-tocopherol, propyl gallate, or cysteine hydrochloride), in an amount no more than 10 mg per dose or maximum daily exposure (whichever is lower)’’
My question is the following:
The maximum daily exposure is refereed to the exposure from the tablet or to the maximum daily dose of the additive?
to make this more clear, lets say that we want to reformulate a product with an addition of an antioxidant (X) with MDD:50mg/day.
The quantity of X which will added will be: 6mg/tablet.
The maximum daily dose of the final product is two tablets/day.
This means that the sum of X will be 12mg/day.
Is this reformulation in line with the above guidance or not?
thank you
Christos
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Dear Chrischar,
The maximum daily exposure is referred to the maximum daily dose of the additive.
Your mentioned reformulation is not in-line with the guidance. it should be below 10 mg/day.
Thanks,
Nirav Bhavsar
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dear Nirav,
thank you very much for your clarification, it is much appreciated
best regards
@chrischar - my interpretation of this was different, taken from the conference last week, where the question was asked specifically - was the 10mg per dose or per day? The response from the panel was that the limit was 10 mg per dose.
In your example you are adding 6mg per dose, which is within the 10mg per dose stipulated, with a total dose of 12mg, which is within the 50mg MDD.
Therefore, from my point of view, this level is acceptable.
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Dear Mark,
this was also my initial point of view but the opinion of our CMC was different. Actually their interpretation was similar to nirav.
That’s why i asked for further clarification.
I hope you are right, this would be of course better.
thanks for your input, it is much appreciated
Christos
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Christos - I guess that the interpretation comes down to whether your 2 tablets a day are taken as a single dose, or if it is 2 tablets that are taken, for example, 12 hours apart.
If it is a single dose, then the reading could be that the 10mg limit is to be applied across the dose, and so a maximum of 5mg per tablet.
If it is 2 separate doses, then the limit is 10mg for each of the doses.
There wasn’t a lot of info in the conference last week on exactly where the 10mg had come from, it seemed to be that this was a level that had been tested and shown to have no impact from a bioavailability/bioequivalence perspective. It could be possible to go higher, if there is data to support that level having no impact in that respect. 10mg scavenger in a small tablet weighing 150mg and containing 5mg of API is very different from 10mg in a large tablet weighing 1500+mg containing 1000+mg of API.
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nope, their interpretation has been done, knowing that the two tablets are taken apart.
I agree with your suggestion that the ‘‘10mg’’ of scavenger/alkaline medium is from the BE/BA perspective.
And of course i agree with the differentiation of the API content in the tablet, good point Mark
thanx
Christos
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