Ken Peh
★    

Malaysia,
2014-08-18 20:43
(3509 d 21:26 ago)

Posting: # 13402
Views: 7,186
 

 Non-weighting to weighting method [Bioanalytics]

Dear Members,

Would highly appreciate your input and kind sharing for the following scenario.

Method validation has been carried out on the drug where standard calibration curve was quantified without using weighting factor. We were told (later) that weighting factor was allowed.
  1. Can we recalculate the data using weighting factor for MV and then use this weighting method in the analysis of study samples ?
  2. Do we need to qualify by running partial validation ? Why ? :confused:

We found that using weighting factor is easier to pass the standard calibration curve.

Thank you.

Regards,
Ken
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-08-19 15:51
(3509 d 02:18 ago)

@ Ken Peh
Posting: # 13405
Views: 6,365
 

 Non-weighting to weighting method

Hi Ken,

❝ Method validation has been carried out on the drug where standard calibration curve was quantified without using weighting factor.


Bad idea. Unweighted regression is a valid model only for constant variances (homoscedasticity: variance of responses independent from concentration).

❝ We were told (later) that weighting factor was allowed.


In your posts you regularly use the phrase “We were told…” It would help to know who told you some­thing. A colleague, a regulator/inspector, the sponsor?

Correct – not only allowed, but mandatory in most cases. Do you remember this thread? In chroma­to­graphy (not necessarily in LBAs) we see more or less constant CVs – variances increase with con­cen­tration (heteroscedasticity). It is up to you to find a suitable weighting factor in method develop­ment/ validation (see Almeida et al. 2002).
  1. You have to stick to what you stated in the protocol. You can recalculate samples as an additional analysis. No idea how regulators like that. In the future, go for a weighted calibration.
  2. No. You could use the raw data of the MV and update the validation/SOP.

❝ We found that using weighting factor is easier to pass the standard calibration curve.


Sure, as expected – especially at the lower end.


PS: See this post.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Malaysia,
2014-08-19 21:33
(3508 d 20:36 ago)

@ Helmut
Posting: # 13407
Views: 6,282
 

 Non-weighting to weighting method

Dear Helmut,

❝ In your posts you regularly use the phrase “We were told…” It would help to know who told you some­thing. A colleague, a regulator/inspector, the sponsor?


Inspector. The inspector of the recent inspection is kind enough to accept the use of weighting factor in BE study.

❝ Correct – not only allowed, but mandatory in most cases. Do you remember this thread?


Yes. I remember. I learned a lot from the thread and have started using weighting factor after that.

❝ You have to stick to what you stated in the protocol. You can recalculate samples as an additional analysis. No idea how regulators like that. In the future, go for a weighted calibration.


The protocol you refer to is study protocol or method validation protocol? :confused: We do not explain in detail the analytical method in the study protocol, which is submitted to ethical committee.

❝ No. You could use the raw data of the MV and update the validation/SOP.


Kindly explain "update the validation".

Thank you for your kind sharing.

Regards,
Ken
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-08-20 13:50
(3508 d 04:19 ago)

@ Ken Peh
Posting: # 13413
Views: 6,312
 

 Non-weighting to weighting method

Hi Ken,

❝ ❝ It would help to know who told you some­thing. A colleague, a regulator/inspector, the sponsor?


❝ Inspector.


THX for clarifying.

❝ The inspector of the recent inspection is kind enough to accept the use of weighting factor in BE study.


Makes sense.

❝ ❝ You have to stick to what you stated in the protocol. You can recalculate samples as an additional analysis. No idea how regulators like that. In the future, go for a weighted calibration.


❝ The protocol you refer to is study protocol or method validation protocol? :confused:


Neither nor. IMHO, the analytical protocol of the study should describe how the calibration will be performed. I think that’s better (and more transparent) than to refer to the method’s SOP.

❝ We do not explain in detail the analytical method in the study protocol, which is submitted to ethical committee.


OK. It is sufficient to submit the goalposts (validated working range, accuracy/precison).

❝ ❝ No. You could use the raw data of the MV and update the validation/SOP.


❝ Kindly explain "update the validation".


The validation consist of the protocol, the actual work, and the report (giving all relevant data necessary to track the outcome). I suggest to write a protocol stating in the purpose something like “Validation of method XYZ by weighted calibration”. Make clear in the method section that you will use the raw data of the original validation. In the report everything will be calculated by the weighted method. You should also update the SOP of the method. If you have a general SOP for calibration, update this one as well.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
nobody
nothing

2014-08-19 18:32
(3508 d 23:37 ago)

@ Ken Peh
Posting: # 13406
Views: 6,374
 

 Non-weighting to weighting method

Time-warp, 20 years back...

Bubert H. und R. Klockenkämper, Fresenius Z Anal Chem, 316 (1983) 186, "Precision-Dependent Calibration in Instrumental Analysis"

Buick A.R., M.V. Doig, S.C. Jeal, G.S. Land und R.D. McDowall, J Pharm Biomed Anal, 8 (1990) 629, "Method Validation in the bioanalytical laboratory"

Causey A.G., H.M. Hills und L.J. Phillips, J Pharm Biomed Anal, 8 (1990) 625, "Evaluation of criteria for the acceptance of bioanalytical data"

Garden J.S., D.G. Mitchell und W.N. Mills, Anal Chem, 52 (1980) 2310, "Nonconstant Variance Regression Techniques for Calibration-Curve-Based Analysis"

Karnes T.H., G. Shiu und V.P. Shah, Pharm Res, 8 (1991) 421, "Validation of Bioanalytical Methods"

Karnes H.T. und C. March, J Pharm Biomed Anal, 9 (1991a) 911, "Calibration and validation of linearity in chromatographic biopharmaceutical analysis"

Lang J.R. und S. Bolton, J Pharm Biomed Anal, 9 (1991a) 435, "A comprehensive method validation strategy for bioanalytical applications in the pharmaceutical industry - 2. Statistical analyses"

Levie R. de, J Chem Educ, 63 (1986) 10, "When, Why and How to Use Weighted Least Squares"

McLean A.M., D.A. Ruggirello, C. Banfield, M.A. Gonzalez und M. Bialer, J Pharm Sci, 79 (1990) 1005, "Application of a Variance-Stabilizing Transformation Approach to Linear Regression of Calibration Lines"

Sands D.E., J Chem Educ, 51 (1974) 473, "Weighting Factors in Least Squares"

Shah V.P., K.K. Midha, S. Dighe, I.J. McGilveray, J.P. Skelly, A. Yacobi, T. Layloff, C.T. Viswanathan, C.E. Cook, R.D. McDowall, K.A. Pittmann und S. Spector, J Pharm Sci, 81 (1992) 309, "Analytical Method Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies"

...if your German is good I can provide you some text on this issue, too... ;-)

Kindest regards, nobody
Ohlbe
★★★

France,
2014-08-25 02:10
(3503 d 15:59 ago)

@ Ken Peh
Posting: # 13425
Views: 6,198
 

 Non-weighting to weighting method

Dear Ken,

❝ Can we recalculate the data using weighting factor for MV and then use this weighting method in the analysis of study samples ?


I would say yes. You can even try several weighting factors to decide which one fits your data best (and then stick to it for your study). But remember to recalculate the data of all experiments in you method validation (including stability in matrix), not just the precision and accuracy runs !

Regards
Ohlbe
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,638 registered users;
76 visitors (0 registered, 76 guests [including 7 identified bots]).
Forum time: 17:10 CET (Europe/Vienna)

Nothing shows a lack of mathematical education more
than an overly precise calculation.    Carl Friedrich Gauß

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