RAMS69
☆    

Madruai, Tamilnadu, India,
2021-05-12 06:57
(40 d 02:11 ago)

Posting: # 22340
Views: 478
 

 Doubts regarding IS variation, ISR failure & SEL/SPE Acceptance criteria [Regulatives / Guidelines]

Dear All,

Greetings,

I have few doubts regarding the following,

1) Why we are fixing IS variation range ±50% from the average IS response of accepted CCs &
QCs. (while using a dutrated IS why we not keeping ±15% or ±20% or some other range).
2) If in one project ISR failure observed frequently/continuesly means what will go to next
actions and please give some exaples with clarification for the reasons for those
failures.
3) As per new guideline in Selectivity and Specificity for analyte interference in blank
samples were comparing with the speific lot LLOQ response (Which lot used for BLK & LLOQ
Preparation) but why the ISTD response of the balnk samples were comparing with the
average response of accepted CCs & QCs why not comparing with respective LLOQ ISTD
response.Please clarify.

Thank You,

Information is Wealth,
Thangairulappan S
ElMaestro
★★★

Denmark,
2021-05-12 09:10
(39 d 23:58 ago)

(edited by ElMaestro on 2021-05-12 12:48)
@ RAMS69
Posting: # 22342
Views: 415
 

 Doubts regarding IS variation, ISR failure & SEL/SPE Acceptance criteria

Hello Rams,

(typo in my first post, edited)

how right you are when you say that information is wealth. :-)
On the very general level I am kind of trying not to ask questions starting with "Why" or words to this effect, when it comes to guidelines and guidances. Though we have FOI acts and public consultations and symposia with regulatory attendance, the true answers to the questions starting with "Why" are not often in the public domain.

» 1) Why we are fixing IS variation range ±50% from the average IS response of accepted CCs &
» QCs. (while using a dutrated IS why we not keeping ±15% or ±20% or some other range).

I don't know why you or your company follows this practice. Ask internally.:-D
There is no requirement to follow exactly this rule, and you are free to decide on rules that make more sense.
±50% is common, ±80% is not unusual. Both may be acceptable.
Lots of it may be equipment-dependent and it is always a bit analyte and IS-dependent, too. So, sometimes you need an assay-specific rule for IS-variation rather than a system-wide rule.

» 2) If in one project ISR failure observed frequently/continuesly means what will go to next
» actions and please give some exaples with clarification for the reasons for those
» failures.

Scenario: When you fail, investigate. If no root cause (which is most comm,on) perhaps you can re-inject or re-extract once. If failing again and there was no root cause, the method may not be good. A run failed and a run passed should be assessed with caution. Discuss. Make very clear on source why the passing run was a more true reflection of assay performance than the failing run.
Variations in internal voltage, static phenomena, matrix effect, there are all sorts of weird things that can affect your IS variation, many of which you have no way of knowing when investigating.

» 3) As per new guideline in Selectivity and Specificity for analyte interference in blank
» samples were comparing with the speific lot LLOQ response (Which lot used for BLK & LLOQ
» Preparation) but why the ISTD response of the balnk samples were comparing with the
» average response of accepted CCs & QCs why not comparing with respective LLOQ ISTD
» response.Please clarify.

The rhetorical answer must be that this approach is suggested in FDA's guideline e.g. Table 1.
Why FDA wrote their propposal that way, I have no idea, see above. When I write "I have no idea" it does not mean "I disagree" or "I agree". It just means "I have no idea" as I was not following these discussions so closely and I would not have been privy to the true reason anyway.

Pass or fail!
ElMaestro
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2021-05-12 10:46
(39 d 22:22 ago)

@ ElMaestro
Posting: # 22343
Views: 388
 

 Why, oh why?

Hi ElMaestro,

» On the very general level I am kind of trying to ask questions starting with "Why" or words to this effect, when it comes to guidelines and guidances.

SCNR:

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
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
RAMS69
☆    

Madruai, Tamilnadu, India,
2021-05-13 04:08
(39 d 05:00 ago)

@ ElMaestro
Posting: # 22348
Views: 363
 

 Doubts regarding IS variation, ISR failure & SEL/SPE Acceptance criteria

Thank you

Information is Wealth,
Thangairulappan S
Ohlbe
★★★

France,
2021-05-12 10:51
(39 d 22:17 ago)

@ RAMS69
Posting: # 22344
Views: 402
 

 Doubts regarding IS variation, ISR failure & SEL/SPE Acceptance criteria

Dear Thangairulappan S,

» 1) Why we are fixing IS variation range ±50% from the average IS response of accepted CCs &
» QCs.

Your choice. Guidelines say you should monitor IS response, but do not specify how. Bear in mind that ±x% limits are useful, but not sufficient. Tons of reasons why in this issue of Bioanalysis.

» (while using a deuterated IS why we not keeping ±15% or ±20% or some other range).

Actually, a number of labs are pleading that you could use wider acceptance limits if using a stable isotope labelled IS. The tighter the limits you set, the higher the number of samples you will have to re-analyse because of IS variation, with little or no added value.

» 2) If in one project ISR failure observed frequently/continuously means what will go to next
» actions and please give some examples with clarification for the reasons for those
» failures.

Some good reading material:

Aimin Tan, Sofi Gagnon-Carignan, Sylvain Lachance et al.
Beyond successful ISR: case-by-case investigations for unmatched reassay results when ISR passed
Bioanalysis (2011) 3(9), 1031–1038

Manish Yadav, Pranav S Shrivastav
Incurred sample reanalysis (ISR): a decisive tool in bioanalytical research
Bioanalysis (2011) 3(9), 1007–1024

Some interesting information also in this more recent paper. However I would not follow all of their proposals and recommendations, as they may not be accepted by regulators:

Morten Anders Kall, Marco Michi, Barry van der Strate et al.
Incurred sample reproducibility: 10 years of experiences: views and recommendations from the European Bioanalysis Forum
Bioanalysis (2018) 10(21), 1723–1732

Regards
Ohlbe
RAMS69
☆    

Madruai, Tamilnadu, India,
2021-05-13 04:09
(39 d 04:59 ago)

@ Ohlbe
Posting: # 22349
Views: 359
 

 Doubts regarding IS variation, ISR failure & SEL/SPE Acceptance criteria

Thank you

Information is Wealth,
Thangairulappan S
Activity
 Admin contact
21,530 posts in 4,499 threads, 1,524 registered users;
online 5 (0 registered, 5 guests [including 3 identified bots]).
Forum time: Monday 09:08 CEST (Europe/Vienna)

Young man, in mathematics you don’t understand things.
You just get used to them.    John von Neumann

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