2020-03-16 17:40
(1099 d 14:50 ago)

Posting: # 21282
Views: 3,643

 MR generic application [Regulatives / Guidelines]

Dear everyone,

I have a question regarding the number of studies to be performed to get the MA for a MR formulation following a generic application.
Indeed, we are developing a generic formulation of a marketed modified release form. This MR forms is marketed with three dosages strengths X1, X2 and X3.

According to the section 6 of the Guideline on the pharmacokinetic and clinical evaluation
of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr1), the following studies are required to demonstrate BE:
- a single-dose fasting study comparing test and reference drug product
- a single-dose fed study using a high-fat meal comparing test and reference drug product
- a multiple-dose study comparing test and reference drug product.

Furthermore, according to the section 6.1.2 "strength to be evaluated", the SD studies under fasting conditions should be performed for ALL strengths.

So, the question is, even if the product is eligible for the bracketing approach, is it necessary to perform the SD study with the lowest strength considering that the PK is linear for all the considered strengths?

Thanks in advance,
Best regards,

2020-03-23 20:40
(1092 d 11:51 ago)

@ Mikkabel
Posting: # 21296
Views: 1,893

 MR generic application

Hi Mikkabel,
More details are needed to determine what we are dealing with here:
- presumably it's an application for Europe?
- is it a single or multiple unit formulation?
- what does the reference SmPC say about intake with/without food?
- is accumulation expected?
- do all three strengths meet the general biowaiver criteria per section 4.1.6 of the Guideline on the investigation of bioequivalence?
- is the shape of all three strengths similar?
- which two strengths represent the extremes? consider it separately for each of the factors listed by section 6.6. of EMA MR Guideline.

Are you familiar with Annex IV to the EMA Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms?


2020-03-27 14:03
(1088 d 18:27 ago)

@ vixen
Posting: # 21302
Views: 1,356

 MR generic application

Hi Vixen,

Thank you for your reply!

I confirm that it is an application for Europe. Regarding the product's characteristics, it is a single unit formulation that can be administrated under fasting or fed conditons and accumulation is expected. Therefore, we meet the following pattern presented in the annex IV of the guidelines on the MR dosage forms.

Strength   Single dose     Single dose   Multiple dose
           Fasting study   fed study     Fasting study
high       yes             yes           yes
middle     yes             Waiver        waiver
low        yes             Waiver        waiver

Considering that the general biowaiver are met, it allows us to perform only studies with the high and low does following the bracketing approach defined in section 6.6 of the guidelines. However, we Wonder if it would be acceptable not to perform the study with the lowest dosage considering that the Pk of the product is linear.


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. Tabulators changed to spaces and BBcoded; see also this post #6[Helmut]

2020-03-27 22:20
(1088 d 10:11 ago)

@ Mikkabel
Posting: # 21304
Views: 1,327

 MR generic application

Hello Mikkabel,

I'd say no chance for that. The guideline is pretty clear about it - you have to test at least two strengths in fasting conditions (no "bracketing" possible without testing two extremes). I guess you will be lucky if you are able to bracket one of the three strengths anyway (what if the extremes selected according to the different factors are not always the same two strengths?).

Of note, the waiver for lower strength is possible in case of multiple unit formulations. Should you wonder why the requirements differ for single vs multiple unit formulations, the following article may offer some insights:

"Except for the multiple-unit dosage forms where various strengths differ only in the number of units, a lower strength of an ER drug product made either by making proportional change in composition or by only matching in vitro drug release may or may not be bioequivalent to the higher strength. Hence, allowing biowaiver for lower strengths of ER products based on in vitro drug release in the absence of an IVIVC or IVIVR (...) can result in compromised product performance and increased risks to the patients. (...)
For a monolithic dosage form, smaller dosage unit size of the proportionally similar lower strength generally results in a shorter diffusional pathlength and/or time for complete hydration in a matrix system, thinner coating film in the membrane-controlled reservoir, or semipermeable membrane in the osmotic devices because higher S/V provides larger normalized surface. As a result, drug release is usually faster than that of the higher strength counterpart."

Best regards,
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