Helmut
★★★

Vienna, Austria,
2013-12-10 14:05
(3165 d 02:08 ago)

Posting: # 12028
Views: 13,168

## FDA: Size of bio-batch [Regulatives / Guidelines]

Dear all,

for pivotal BE studies EMA requires that

The test product should usually originate from a batch of ≥1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified.

Do you know of a corresponding requirement by the FDA? In the Summary Table 11 sizes of the bio-batch and production batch have to be reported.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2013-12-10 20:03
(3164 d 20:11 ago)

(edited by jag009 on 2013-12-11 16:21)
@ Helmut
Posting: # 12032
Views: 10,636

## FDA: Size of bio-batch

Hi Helmut,

» Do you know of a corresponding requirement by the FDA? In the Summary Table 11 sizes of the bio-batch and production batch have to be reported.

We always make > 100,000 tablets. See page 2 of FDA Guidance I know it's old...

Hope that helps...

John
Helmut
★★★

Vienna, Austria,
2013-12-10 23:32
(3164 d 16:42 ago)

@ jag009
Posting: # 12033
Views: 10,055

## FDA: antique of ’93

Hi John,

» See page 2 of FDA Guidance I know it's old...

Oh boy, I completely have forgotten this one!
Now I know where the Europeans copypasted from. Nothing was stated in the ’91 version. Appeared for the first time in the ’98 draft and was carried over ever since.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2013-12-11 15:23
(3164 d 00:50 ago)

@ Helmut
Posting: # 12036
Views: 10,092

## FDA: antique of ’93

Hi Helmut,

» Oh boy, I completely have forgotten this one!

I confirmed with my formulators for you as well They can't be wrong hehe.

John
Helmut
★★★

Vienna, Austria,
2013-12-11 15:26
(3164 d 00:48 ago)

@ jag009
Posting: # 12037
Views: 10,054

## FDA: antique of ’93

Hi John,

» I confirmed with my formulators for you as well They can't be wrong hehe.

THX! Did you ask the guy with the Buster Keaton face again?

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2013-12-11 16:21
(3163 d 23:53 ago)

@ Helmut
Posting: # 12038
Views: 10,066

## FDA: antique of ’93

Hi Helmut,

» THX! Did you ask the guy with the Buster Keaton face again?

Nope, I asked the chefs (formulators) and RA.

Nope. I emailed him two questions and no feedback so far (2nd one was about stats for a partial rep study having 2 groups).

John
Helmut
★★★

Vienna, Austria,
2013-12-11 16:29
(3163 d 23:45 ago)

@ jag009
Posting: # 12039
Views: 9,940

## FDA: antique of ’93

Hi John,

»
» Nope. I emailed him two questions and no feedback so far (2nd one was about stats for a partial rep study having 2 groups).

So far? Unbelievable. Ask your legal department to get refund from the FDA for the study you performed exactly following the guidance only to get from SAS:

WARNING: Did not converge. WARNING: Output 'Estimates' was not created.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
jag009
★★★

NJ,
2013-12-11 23:16
(3163 d 16:58 ago)

@ Helmut
Posting: # 12041
Views: 10,026

## FDA: antique of ’93

Hi Helmut!

» So far? Unbelievable. Ask your legal department to get refund from the FDA for the study you performed exactly following the guidance only to get from SAS: WARNING: Did not converge...

They don't give refund... The govt just went through "sequester" this year...

Also it was a pilot study.

Strangely, I emailed FDA about stability and they replied back the next day!
Very responsive from that group!

John
Helmut
★★★

Vienna, Austria,
2013-12-12 14:34
(3163 d 01:40 ago)

@ jag009
Posting: # 12047
Views: 9,989

## Patience

Hi John,

» […] The govt just went through "sequester" this year...

… and avoided another one this week… So you are sitting in the anteroom for more then ½ a year.

» Also it was a pilot study.

Nevertheless, you got no direct estimates from the ABE code – only from the RSABE part.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Beholder
★

Russia,
2018-06-21 09:21
(1511 d 07:52 ago)

@ Helmut
Posting: # 18936
Views: 7,757

## FDA: antique of ’93

Hi Helmut and all!

» Now I know where the Europeans copypasted from.

I went through the forum but still could not find the information. Ok, we know that it is "highly likely" () that the EMA took "1/10 or 100,000 rule" from FDA. But why did FDA deside to use 1/10 or 100,000 rule? Why not, for instance, "1/15 and 150,000" or 100,000 is just round number and that's all?

Best regards
Beholder
Helmut
★★★

Vienna, Austria,
2018-06-21 15:05
(1511 d 02:09 ago)

@ Beholder
Posting: # 18944
Views: 7,572

## Nice numbers

Hi Beholder,

» But why did FDA deside to use 1/10 or 100,000 rule? […] 100,000 is just round number and that's all?

We find nice numbers which are “easy to remember” everywhere.
• When the transition from analysis of untransformed [limits 80–120%] to log-transformed data was made, we had serious discussions about how the new limits should be defined. There were three parties (all considering a ∆ of 20% as not clinically relevant):
1. L=1–∆, U=(1–∆)–1 or 80–125%.
2. U=1+∆, L=(1+∆)–1 or 83⅓–120%.
3. U–L 0.4 as the old one or ~81.98043–121.98033%.
The 1st party won because of the nice numbers.
• Critical dose drugs in Canada. ∆ 10% (like for the EMA). Lower limit 1–∆=90.0% (only one decimal place); upper limit not 111.11% but 112.0%.
• k in ABEL based on the switching CVwR 30% not $$\log{(1.25)}/\sqrt{\log{(0.30^2+1)}} = 0.7601283\ldots$$ but rounded to 0.76.
1. The test product should usually originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified.
2. The production of batches used should provide a high level of assurance that the product and process will be feasible on an industrial scale.
In case of a production batch smaller than 100,000 units, a full production batch will be
required.
(my emphasis)

prod. scale  full batch    10%    rule  biobatch     50,000      yes        5,000    b     50,000    100,000       no       10,000    a    100,000  1,000,000       no      100,000    a    100,000  5,000,000       no      500,000    a    500,000

Duno which justification you could give for a smaller biobatch under condition a).

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Beholder
★

Russia,
2018-06-22 10:33
(1510 d 06:40 ago)

@ Helmut
Posting: # 18946
Views: 7,508

## Nice numbers

Hi, Helmut!

» We find nice numbers which are “easy to remember” everywhere.

Thx a lot for clarification.

Im just comparing the EU legislation and EEU legislation because it is very similar. May be you or other members of the forum know how can one understand whether we need to perform BEQ study in case of changes in amount of tablets in production batch or not? I refer to the table B.II.b.4 Change in the batch size (including batch size ranges) of the finished product which says (point c):
c) The change requires assessment of the comparability of a biological/immunological medicinal product or the change in batch size requires a new bioequivalence study
(my emphasis)

Best regards
Beholder
Helmut
★★★

Vienna, Austria,
2018-06-22 15:12
(1510 d 02:01 ago)

@ Beholder
Posting: # 18948
Views: 7,480

## Type II variation

Hi Beholder,

» […] whether we need to perform BEQ study in case of changes in amount of tablets in production batch or not? I refer to the table B.II.b.4 Change in the batch size (including batch size ranges) of the finished product

Yes because that’s a Type II (i.e., a major) variation. Only if the conditions for a bio­waiver are applicable you could get around an in vivo study.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Denmark,
2018-06-22 10:10
(1510 d 07:03 ago)

@ Beholder
Posting: # 18945
Views: 7,508

## Birdsong's third law of BE

Hi Beholder,

» I went through the forum but still could not find the information. Ok, we know that it is "highly likely" () that the EMA took "1/10 or 100 000 rule" from FDA. But why did FDA deside to use 1/10 or 100 000 rule? Why not, for instance, "1/15 and 150 000" or 100 000 is just round number and thats all?

Not actually an answer to your question but a remark. Empirically, in the field of BE it is exceedingly rare that the answer to a question starting with "why?" about guideline requirements will change anything in practice for the person or entity trying to comply.
"Why?", simply stated, often is somewhat founded in frustration or initiates it, but "Why?"" rarely leads to solutions.

Having been a regulator myself, I am aware of all the effort it takes to revise a single sentence in a guideline. What you read in guidelines is the product of science and scientific compromise. The latter is a very significant part of it all.

Pass or fail!
ElMaestro
Beholder
★

Russia,
2018-06-22 11:04
(1510 d 06:10 ago)

(edited by Beholder on 2018-06-22 13:54)
@ ElMaestro
Posting: # 18947
Views: 7,437

## Experience

Hi, ElMaestro,

Thanks for your remark. I like it and would make a remark to your remark as well.

» Empirically, in the field of BE it is exceedingly rare that the answer to a question starting with "why?" about guideline requirements will change anything in practice for the person or entity trying to comply.

IMHO, the answer very often gives the understanding of the possibly hidden things which are behind simple sentence in the GL in order to plan the activities accordingly. Most probably the knowledge obtained now will be linked with another fact in future and will give the opportunity to undertand requirements deeper in case of not clear situation with unpredictable outcome.

» "Why?", simply stated, often is somewhat founded in frustration or initiates it, but "Why?"" rarely leads to solutions.

Questions, by the nature, and particularly "Why?" often lead the scientific process. Asking "Why?" the brightest minds from the begining of development of humankind gave us almost all discoveries and made our picture of the world more detailed and precise. Now based on these achivements we can go further.

And as it was said: "Well, I tried, didn't I? Goddamnit, at least I did that."

Best regards
Beholder
Helmut
★★★

Vienna, Austria,
2018-06-22 15:17
(1510 d 01:56 ago)

@ Beholder
Posting: # 18949
Views: 7,492

## Why, oh why?

Hi Beholder,

» Questions, by the nature, and particularly "Why?" often lead the scientific process. Asking "Why?" the brightest minds from the begining of development of humankind gave us almost all discoveries and made our picture of the world more detailed and precise.

Are you sure?

Science is wonderfully equipped to answer the question “How?”
but it gets terribly confused when you ask the question “Why?”
Erwin Chargaff

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Beholder
★

Russia,
2018-10-18 09:40
(1392 d 07:34 ago)

@ Helmut
Posting: # 19465
Views: 6,694

## Sorry for the delay

Hi Helmut!
I thought that carved in stone dogmas from sacramental person would not be in favour here. But nevertheless. Yes, I’m sure.
 Asking why is the root of a scientific mindset.  Eraldo Banovac
But what do you think?!

Best regards
Beholder