luvblooms
★★  

India,
2014-09-04 11:47
(3494 d 02:23 ago)

Posting: # 13456
Views: 8,694
 

 Alcohol Dose Dumping: Requirments? [Regulatives / Guidelines]

Dear Gurus

Need some suggestions for Alcohol dose dumping issue!!!:crying:

For Alcohol dose dumping (for FDA submission) my understanding is as given below:

Requirement:
Testing Conditions: 900 mL/500 mL, 0.1 N HCl, Apparatus II (Paddle) at 50 rpm, with and without the alcohol:
  1. Test 1: 12 units tested according to the proposed method (with 0.1 N HCl), with data collected every 15 minutes for a total of 2 hours.
  2. Test 2: 12 units analysed by substituting 5% (v/v) of test medium with Alcohol USP, and data collection every 15 minutes for a total of 2 hours.
  3. Test 3: 12 units analysed by substituting 20% (v/v) of test medium with Alcohol USP, and data collection every 15 minutes for a total of 2 hours.
  4. Test 4: 12 units analysed by substituting 40% (v/v) of test medium with Alcohol USP, and data collection every 15 minutes for a total of 2 hours.
Both test and RLD products must be tested accordingly and data must be provided on individual unit, means, range and %CV on both strengths.

Criteria to be met: The dissolution of Test product should be either similar or slower to that of Reference product. (this is as per QBD MR guidance and also as per the Wockhardt Metoprolol Approval)

Now coming to the questions:
  1. Does one need to match the F2 for dose dumping? (In my opinion NO, would love to hear others experience and understanding on the same)
  2. Should I need to worry if RLD is releasing 90% in 2hrs in 40% alcohol where as my bioequivalent product is releasing almost 20%? (As per my limited knowledge, lower release in 40% alcohol will always mean lesser chance of dose dumping and increased safety. Am I right or just being knuckle head?)
  3. If there are multiple strengths available one need to compare
    1. Higher strengths of test product vs other strengths (IMHO, this makes sense as since test formulations are dose proportional, I need to show the similarity with Test product only)
    2. Individual strengths of test product vs individual reference strengths

Thanks a ton in Advance!!

P.S: HS, There were some threads for ADD studies but I couldn't find the relevant answers over there so starting a new thread. If required you can merge them

~A happy Soul~
jag009
★★★

NJ,
2014-09-04 22:23
(3493 d 15:47 ago)

@ luvblooms
Posting: # 13457
Views: 7,644
 

 Alcohol Dose Dumping: Requirments?

Hi Bloom,

❝ Dear Gurus


Not yet! Maybe in 10! (factorial) years.

❝ a. Does one need to match the F2 for dose dumping? (In my opinion NO, would love to hear others experience and understanding on the same)


F2(test and RLD)? Why? This alcohol business is a safety issue. What puzzles me (unless guidance is updated recently) is that Amphetamine ER (Adderall XR) does not require EtOH testing in-vitro.

❝ b. Should I need to worry if RLD is releasing 90% in 2hrs in 40% alcohol where as my bioequivalent product is releasing almost 20%? (As per my limited knowledge, lower release in 40% alcohol will always mean lesser chance of dose dumping and increased safety. Am I right or just being knuckle head?)


You meant to write "my BE product is releasing almost 20% at 40% EtOH while RLD is release 90% at 40% EtOH"? If so, that means your product is safer, no? So what do you need to worry? You just demonstrated that your product is safer than the reference.

❝ c. If there are multiple strengths available one need to compare...


Hmm... We did it for all strengths filed (as in test every strengths) and yes ours are dosage strength proportional... Maybe we were playing it safe?

John
luvblooms
★★  

India,
2014-09-05 08:28
(3493 d 05:42 ago)

@ jag009
Posting: # 13458
Views: 7,545
 

 Alcohol Dose Dumping: Requirments?

Hey John,

❝ F2(test and RLD)? Why? This alcohol business is a safety issue.


That is what I am trying to explain to some adamants who want to have similar dissolution. Apple vs Apple comparison and what not :blahblah:


❝ You meant to write "my BE product is releasing almost 20% at 40% EtOH while RLD is release 90% at 40% EtOH"? If so, that means your product is safer, no? So what do you need to worry? You just demonstrated that your product is safer than the reference.


Yes, I have a BE product but it is releasing almost 20% at 40% EtOH while RLD is release 90% at 40% EtOH and I know that my product is safer but "adamants" wants 90% release in 40% EtOH from test product too.

❝ Hmm... We did it for all strengths filed (as in test every strengths) and yes ours are dosage strength proportional... Maybe we were playing it safe?


This is what I proposed but again here people want to match each strength of test with each strength of reference. :smoke:

Thanks for clarifying it to me :thumb up:. Even I got confused after listening to their blabbering.

~A happy Soul~
nobody
nothing

2014-09-05 10:47
(3493 d 03:23 ago)

@ luvblooms
Posting: # 13459
Views: 7,517
 

 Alcohol Dose Dumping: Requirments?

❝ Yes, I have a BE product but it is releasing almost 20% at 40% EtOH while RLD is release 90% at 40% EtOH and I know that my product is safer but "adamants" wants 90% release in 40% EtOH from test product too.


AB-SO-LUTELY cool! Made my day!

Kindest regards, nobody
jag009
★★★

NJ,
2014-09-05 17:44
(3492 d 20:26 ago)

@ luvblooms
Posting: # 13462
Views: 7,472
 

 Alcohol Dose Dumping: Requirments?

Hi Bloom,

Don't they understand this statement from the guidance? "Due to a concern of dose dumping of drug from this drug product when taken with alcohol, the Agency currently requests that additional in vitro dissolution testing be conducted using various concentrations of ethanol in the dissolution medium"

It's a safety issue. You want to demonstrate that your product does not dose dump due to the coating being "damaged" by EtOH. So if RLD dose dumps and your BE product also dose dumps, you think FDA will give you the green light because your product is BE?

❝ ❝ Hmm... We did it for all strengths filed (as in test every strengths) and yes ours are dosage strength proportional... Maybe we were playing it safe?


❝ This is what I proposed but again here people want to match each strength of test with each strength of reference. :smoke:


No I meant we did the EtOH test on all strengths, not just at the highest strength. I was against this but then again the RA wanted a safe passage.

John
luvblooms
★★  

India,
2014-09-10 08:25
(3488 d 05:45 ago)

@ jag009
Posting: # 13470
Views: 7,420
 

 Alcohol Dose Dumping: Requirments?

Hey John


❝ Don't they understand this statement from the guidance? "Due to a concern of dose dumping of drug from this drug product when taken with alcohol, the Agency currently requests that additional in vitro dissolution testing be conducted using various concentrations of ethanol in the dissolution medium"


Tried my best but....!!

❝ No I meant we did the EtOH test on all strengths, not just at the highest strength. I was against this but then again the RA wanted a safe passage.



RA always want a safe passage ;-)

Just few more questions
a) Does one need to match the dissolution rate (At all time points 15, 30, 45, 60 , 90 and 120 min)or end release at 2 hrs will suffice the need???

b) What if my formulation is faster at 15 min and 30 min (let's BE product is relasing 15% in 15 min in 40% alcohol where as Innovator is releasing only 5%, at 30 min release from test is 40% from reference it is 30%) but after 30 min time point release from trest poduct is slower till end.

~A happy Soul~
nobody
nothing

2014-09-10 12:31
(3488 d 01:39 ago)

@ luvblooms
Posting: # 13471
Views: 7,403
 

 Alcohol Dose Dumping: Requirments?

If the reference has say 5% incidence for dose dumping with food do these people even want to match this with their new product?

Send these guys back to university to learn something, uhh, btw, have they ever been there?

Kindest regards, nobody
Shuanghe
★★  

Spain,
2014-09-10 13:39
(3488 d 00:32 ago)

@ luvblooms
Posting: # 13472
Views: 7,420
 

 OGD's article in AAPS J may help

Hi,

❝ Just few more questions

❝ a) Does one need to match the dissolution rate (At all time points 15, 30, 45, 60 , 90 and 120 min)or end release at 2 hrs will suffice the need???


❝ b) What if my formulation is faster at 15 min and 30 min (let's BE product is relasing 15% in 15 min in 40% alcohol where as Innovator is releasing only 5%, at 30 min release from test is 40% from reference it is 30%) but after 30 min time point release from trest poduct is slower till end.


According to the authors from OGD (published in AAPS J. 2008):
Methods.
The assay was implemented for several MR drug products under review at the Office of Generic Drugs (OGD). The assay
employs USP Apparatus I or II and 900 mL of 0.1 N HCl media containing ethanol (v/v) at: 0%; 5%; 20%; and 40%,
sampling every 15 minutes until 2 hours. Applicants conduct these studies on all drug product strengths.

The dissolution results are categorized as
Case I: If at 2 hours, % dissolved of the generic product in 40% ethanol is ≤ in 0% ethanol, the generic product is considered
robust (does not dose-dump); if not
Case II: at 2 hours, % dissolved of the generic product in ethanol solution is less or comparable to that of the reference, the
potential for dose-dumping is similar for the two products and the generic product is acceptable; if not
Case III: the generic product releases more drug in ethanol than the reference and is unacceptable.


You can download the abstract here

I guess that your is case II.

All the best,
Shuanghe
luvblooms
★★  

India,
2014-09-11 07:56
(3487 d 06:14 ago)

@ Shuanghe
Posting: # 13480
Views: 7,394
 

 OGD's article in AAPS J may help

Hi Shuanghe

❝ According to the authors from OGD (published in AAPS J. 2008):

❝ ....

❝ You can download the abstract here


Bingo!!!! This was the paper I was looking for but was unable to find it. Thanks a ton for pointing it out!! :clap:

❝ I guess that your is case II.


Yes!! Ours is Case II.

Thanks again :-D

~A happy Soul~
bharathi
☆    

India,
2016-08-17 15:10
(2780 d 23:00 ago)

@ luvblooms
Posting: # 16554
Views: 5,788
 

 OGD's article in AAPS J may help

HI,

Today I have seen BE recommendation of Levomilnacipran ER capsules, the dissolution medium to be used in in-vitro dose dumping in alcohol test is water in testing conditions and 0.1N HCl in the proposed method of test 1.

Dissolution media mentioned in OGD is water.

I believe that the in-vitro dose dumping in alcohol test compares the dissolution performance of the generic (test) product and the RLD by substituting various concentrations (0%, 5%, 20% and 40% (v/v)) of test medium [0.1N HCl] with Alcohol USP and 0.1N HCl is used as baseline medium to approximate conditions in the stomach, since most of a dose of alcohol is absorbed through the gastric mucosa.

I have seen almost all the BE recommendations which recommends to use 0.1N HCL for these studies. Then what might be the basis of water as test medium for this product. If it is water then what is the significance of using 0.1N HCl in test 1. These are the questions raised when i have seen this guideline.

Looking for other opinions too.

Regards,
Bharathi
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,636 registered users;
102 visitors (0 registered, 102 guests [including 7 identified bots]).
Forum time: 13:11 CET (Europe/Vienna)

With four parameters I can fit an elephant,
and with five I can make him wiggle his trunk.    John von Neumann

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5