Bioequivalence and Bioavailability Forum

In-vitro equivalence

martin — Sat, 19 May 2012 10:28:54 +0200

Reply from martin, 2012-05-19 10:28:

Dear ElMaestro!

We were asked by a regulator to examine a random sample of k>25 lots produced (including also already formally "released" lots) each evaluated with at least 3 replicates. The information that I have is that we have to show (whatever that means) that the lots are "comparable" to the reference lot (i.e. kind of standard) and superior to the negative control lot (also a kind of standard without biological activity).

I would be really glad to get some ideas and suggestions!

best regards

martin

PS.: I do not like the word comparable: apple and oranges

PPS.: it's a biologic - QbD :smoke:

FDA regulation on Overage of drug product

HS — Sat, 19 May 2012 02:02:40 +0200

Reply from HS, 2012-05-19 02:02:

Hi John!

» Does anyone know if FDA has a guidance on overage of a drug product?

None I'm aware of.

» Example, OROS drug products have overage.

Didn’t know that! The NDA of Concerta (01/2000) states in the first label:

Each extended release tablet for once-a-day oral administration contains 18 or 36 mg of methylphenidate HCl USP […]

In the Clinical Pharmacology Biopharmaceutics Reviews we read:

The OROS^® system delivers 18 or 36 mg of methylphenidate HCl […]

So my first idea was that – by design – not the entire dose is released. But in three studies (18 mg, fasting and fed) retrieved capsules were analysed for drug content, which was <1.2%.
So: how much overage have you measured? We have just finished a study with 36 mg; I’ll have a look into the CoAs. :-D

» Is there a limit as to how much overage is allowed?

No idea.

In-vitro equivalence

ElMaestro — Sat, 19 May 2012 01:35:11 +0200

Reply from ElMaestro, 2012-05-19 01:35:

Hi Martin,

which of the following questions are you trying to answer:
1. Can this lot I just produced be released?
2. Is the production process stable?

Without being fully sure I get the idea that your situation isn't classical (batch release is based on floating criteria?) and that you are perhaps entering the world of GMP, Six Sigma, DoE and QbD and then it quickly gets extremely complex. Could you provide a bit more context?

FDA regulation on Overage of drug product

jag009 — Fri, 18 May 2012 21:05:34 +0200

Post by jag009, 2012-05-18 21:05:

Hi everyone,

Does anyone know if FDA has a guidance on overage of a drug product? Example, OROS drug products have overage. Is there a limit as to how much overage is allowed?

Thanks

John

Bioequivalence study on Psychotropic drugs

swapnil.kuche — Fri, 18 May 2012 13:41:35 +0200

Reply from swapnil.kuche, 2012-05-18 13:41:

Dear All,

Is it required to obtain Transport permit from state excise to transport the Narcotic drug consignment from one place to another intra state or inter state in India?

Regards,
Swapnil Kuche

how to use Loo Riegelman method and deconvolution

SDavis — Fri, 18 May 2012 12:32:39 +0200

Reply from SDavis, 2012-05-18 12:32:

Dear Laili,

Loo-Riegelman PK model assumes two-compartment PK. I think you may need to refine your question a little as to what you need clarifying.

What are you trying to achieve and with what source data
What software is your LR model implemented in?

I would, (working as I do for Pharsight :surprised:), suggest taking a look at the Numerical Deconvolution implemented in WinNonlin and Phoenix WinNonlin if you have access to these software as I've had much more comfortable results with this tool for extravascular administration. Nonetheless I understand that some people prefer the LR and WN models so these are implemented within the IVIVC module which is an additional purchase.

Phoenix (and WNL 5.x) have detailed example datasets and Guides;

C:\Program Files (x86)\Pharsight\Phoenix\application\Examples

to help step you through using these functions. And of course there is our own software forum (login required).

Simon

Edit: Extranet linked. [Helmut]

Bioequivalence study on Psychotropic drugs

drchilkoti — Fri, 18 May 2012 08:24:53 +0200

Reply from drchilkoti, 2012-05-18 08:24:

Dear All,

Thanks a lot for your valuable inputs. It was helpful.

Regards,

Dr. Deepak

Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post --> 550! [Ohlbe]

Forced Degradation study of Hydrocortisone

Ravindran S — Fri, 18 May 2012 06:13:18 +0200

Post by Ravindran S, 2012-05-18 06:13:

how to conduct forced degradation study of hydrocortisone, kindly help me in preparing the acid, base and oxidation stress condition sample of the forced degradation study of hydrocortisone

In-vitro equivalence

martin — Thu, 17 May 2012 15:10:12 +0200

Post by martin, 2012-05-17 15:10:

dear all!

I have a questions regarding testing for equivalence and acceptance criteria for lot releases. In these kind of studies several lots (test) and one reference lot are investigated in-vitro each with replicated measurements (typically 3 replicates per lot are available).

For an overall statement (i.e. combined lots) the R package mratios may be used to model the lot and potential day and/or operator effects assuming normal distribution and independent replicates and use corresponding contrasts to get the ratio and corresponding CIs for an overall statement. However, I do not really understand the comparison of individual lots with the reference lot. In statistics, CIs are used get an idea regarding the population average. By comparing individual lots with the reference lot the statistical unit reflects only the assay variability.

I would be happy if you can help me in answering the following questions:

Is anyone aware of acceptance criteria for these kind of evaluations (I think the scaled average approach may be also applicable as the CV of the assay is known and a parallel group design is adequate).
What is the interpretation (i.e. statement regarding the population) when equivalence is shown (for a given acceptance criteria) for a specific test lot compared to the reference lot.

best regards

martin

FDA: In-Vitro Alcohol testing of modified release product

Shuanghe — Thu, 17 May 2012 10:08:04 +0200

Reply from Shuanghe, 2012-05-17 10:08:

» Is it required to compare against the reference product? If so, is it based on f2?

yes. If you go to FDA's guidance page looking for new individual BE guidance for MR product, almost all of them require this test and:

"Both test and reference listed drug (RLD) products should be tested accordingly and data should be provided on individual unit, means, range and %CV on all strengths."

» If the rate of in-vitro release in EtOH is not similar (i.e., faster but not the point of dose dumping) to that of the reference, then what?

check this link.

http://www.aapsj.org/abstracts/am_2008/aaps2008-001832.pdf

I hope this helps.

Shuanghe

Thai FDA

boonchai_l — Wed, 16 May 2012 19:02:36 +0200

Reply from boonchai_l, 2012-05-16 19:02:

Dear HS,

» Yeah – was in your nice country more than once… Took me ages to pronounce even simple words like ชา – almost – correctly. ;-)

Ha Ha Ha, it is usual for foreigners and thanks for the admiration my country.

Refer to that announcement, let me add more 1 thing.

4. All groups must have equal number of subjects.

BTW, refer to #3, why I said stupid? I have an example.

If you are going to run BE study with high CV drug on 2x2 standard design and the number of subject, 80 to reach the desired power and your max capacity of the facility is 34. You decide to separate them into 3 groups, 27, 27 and 26 (because of #1). During the study, you have dropout 1, 2 and 4 subjects in each group, respectively. So you analyze 26, 25 and 22 in each and 73 subjects in total (Is it in conflict with #4?). However, you pool them to evaluate BE and the result shows equivalence with 84% power but the ANOVA found the significant group effect (It is possible to occur because the group effect is nested with subject effect, you never know which subject is good, poor, fast or slow metabolizer, assuming you bad luck in this case, the first group was filled with the slow metabolizers and the second group was filled with the fast metabolizers). So you can not pool them according to #3. The results from the separated analyses show inequivalence for all 3 evaluations with 60, 62 and 58% power.

My question: Is it reasonable?

Regards,
Boonchai_l

FDA: In-Vitro Alcohol testing of modified release product

jag009 — Wed, 16 May 2012 16:22:46 +0200

Post by jag009, 2012-05-16 16:22:

Hi everyone,

Does anyone have experience with the in-vitro EtOH testing on modified release drug product as per FDA for the assessment of dose dumping? Is it required to compare against the reference product? If so, is it based on f2?

If the rate of in-vitro release in EtOH is not similar (i.e., faster but not the point of dose dumping) to that of the reference, then what?

Thanks

John

Thai FDA

HS — Wed, 16 May 2012 13:55:47 +0200

Reply from HS, 2012-05-16 13:55:

Dear Boonchai!

» Ha Ha Ha amazing for your สวัสดี HS!,

Yeah – was in your nice country more than once… Took me ages to pronounce even simple words like ชา – almost – correctly. ;-)

» http://drug.fda.moph.go.th/zone_bioequivalence/files/doc210.pdf

Wow, a scan… Bad luck for people depending on Google Translate.

Thai FDA

boonchai_l — Wed, 16 May 2012 13:37:43 +0200

Reply from boonchai_l, 2012-05-16 13:37:

Ha Ha Ha amazing for your สวัสดี HS!,

» Interesting. If the announcement is available online can you provide us the URL?

http://drug.fda.moph.go.th/zone_bioequivalence/files/doc210.pdf

I will reply your comment tomorrow because I have to go now.

Regards,
Boonchai_l

Thai FDA

HS — Wed, 16 May 2012 13:01:14 +0200

Reply from HS, 2012-05-16 13:01:

สวัสดี Boonchai!

» Let see announcement number สธ1009.4/ว.11243 from Thai FDA date 13 Sep 2011.

Interesting. If the announcement is available online can you provide us the URL?

Resonable.
Hhm; that’s nitpicking. We plan studies in such a way that we don’t expect carry-over with the minimum washout stated in the protocol. Even if there is a small carry-over it would be even lower for subjects in the group(s) with longer washouts. BE is based on within-subject comparisons – so what?
I wouldn’t call that stupid but consistent. BTW, testing for a group effect is based on a between-subject comparison which has very low statistical power.