Target Measurement

Uncertainty
Dimitris Papamatthaiakis
Pharma Life-cycle Consultancy
  Guidance and regulatory
 In analytical target profile
 Inputs for TMU
 Case study: Quantification of the uncertainty according

Outline Eurachem/CITAC Guide CG4

 Estimated uncertainty vs TMU
 Measurement uncertainty optimization
 Setting acceptance criteria in method validation
 Decision rules for OOS
Target Measurement
Uncertainty
Guidance and regulatory
  The upper limit of the uncertainty decided on the basis
of the intended use of measurement results designated
Target
Measurement International Vocabulary of Metrology

Uncertainty Joint Committee for Guides in Metrology, International

vocabulary of metrology – basic and general concepts and
Guidance and regulatory associated terms (VIM), 3rd edition – 2008 edition with
minor corrections, JCGM 200, BIPM, 2012 (www.bipm.org).
  ICH Q12 “ There is some consideration of the analytical
method for the product”
 Method uncertainty defines the link between the
performance of the analytical procedure and its
Target "fitness for purpose" which is the outcome for the
product.
Measurement  In other words: Investigate method uncertainty
Uncertainty during development → adjust method to reduce
uncertainty to an acceptable level
Guidance and regulatory
Develop starting conditions via comprehensive screening using
risk assessment
Identify parameters to study
Screen DoEs & evaluate performance
Verify DoEs
  ISO/IEC Guide 98-1:2009 Uncertainty of measurement
 Proposed New USP General Chapter: The Analytical
Target Procedure Lifecycle <1220>;USP PF 42(6)

Measurement  Fitness for Use: Decision Rules and Target Measurement

Uncertainty; USP PF 42(2)
Uncertainty  Setting and Using Target Measurement Uncertainty;
Guidance and regulatory https://www.eurachem.org/index.php/publications/gui
des
Target Measurement
Uncertainty
In analytical target profile
  States performance requirements for analytical method
 Based on propability of result being within a given
range from the TRUE VALUE

Target  The reportable result must be fit for its purpose

Measurement
Uncertainty EXAMPLE
Specificity
In analytical target profile Linearity
“The assay procedure must be able to Accuracy
quantify RM5061 in presence of (Boc- Precision+Int. Precision
RM, TZA,..) over a range of 80% to Target measurement
120% of the nominal concentration uncertainty
with a bias of 2% and uncertainty so Acceptable risk
Confidence interval
that the reportable result falls within
±3,0% of the true value with at least
90% probability determined with 95%
confidence”.
  …range of 80% to 120% of the nominal
concentration

Target  …bias of 2%
Measurement  …reportable result within ±3.0% of true
Uncertainty value
In analytical target profile
 …90% probability
 …95% confidence”
 Analytical Target Profile
The ATP is derived from external
The ATP states the required quality of the
requirements (not from performance of the
results produced by a procedure
measureing system)

Target Critical Quality Attributes of the Reportable Result

Measurement
Uncertainty
Accuracy Precision

In analytical target profile

Target Measurement Uncertainty

Measurement uncertainty specified as the The target measurement uncertainty can be
upper limit and decided on the basis of the used as a measure of the “fitness for
intended use of measurement results intended use” of a measurement result
International Vocabulary of Metrology the International Vocabulary of
Metrology-VIM edition 3 Guide JCGM 200:2008 [ISO/IEC Guide 99-2007]
Target Measurement
Uncertainty
Inputs for TMU
  EURACHEM CITAC QUAM2012 “..Typical sources of
uncertainty..”
o Sampling
o Storage conditions

Target o Instrument effects

o Reagent purity
Measurement o Assumed stoichiometry

Uncertainty o Measurement conditions

o Sample effects (recovery/stability of sample)
Inputs for TMU
o Computational effects (calibration model)
o Blank correction (important for trace analysis)
o Operator effects (objective observation)
o Random effects
  The compliance interval, defined by a minimum and a
maximum limit or from the quantity value, above or
below a single limit, beyond which there should be a
low probability of an incorrect compliance decision.
Target  Limit of detection, precision and accuracy can be
Measurement converted into a target uncertainty.

Uncertainty  The results of collaborative studies or other

interlaboratory comparisons can be used to define the
Inputs for TMU
target uncertainty if it is concluded that the agreement
between results is adequate for the purpose of the
analysis.
  How to calculate uncertainty (practical
approach)
1. Precision study
2. Bias study
3. Additional factors

Target Standard deviation→𝛔(𝒙) =

𝛔(𝒙)

Measurement
𝒏

𝑺(𝒙)
Precision → S(𝒙) =
𝒏

Uncertainty Bias →𝐮𝒃 𝐱 = 𝛔(𝒙)𝟐 + 𝒖(𝒙𝒓𝒆𝒇 )𝟐

Inputs for TMU Addi onal factors → 𝒚𝒄𝒐𝒓 = 𝒚 − 𝒃

uncertainty → 𝐮 𝐱 = 𝑺𝟐 + 𝐮𝒃 𝐱 𝟐

combine uncertain es →expanded uncertainty → 𝑼 = 𝒌 × S(𝒙)𝟐 + 𝒖𝟐𝒃

Reportable result→ 𝒀𝒄𝒐𝒓 = 𝒚 − 𝒃 ± 𝒌 × S(𝒙)𝟐 + 𝒖𝟐𝒃

 Target Measurement
Uncertainty
Case study: Quantification of the uncertainty
according Eurachem/CITAC Guide CG4
  EURACHEM CITAC QUAM2012
Target o Specify measurand
Measurement o Identify uncertainty sources

Uncertainty o Standard uncertainty calculation

Case study: Quantification of the o Combined standard uncertainty calculation
uncertainty according Eurachem/CITAC o Expanded uncertainty calculation
Guide CG4
 Specify measurand

Sample solution – Accurately weigh 50 mg sample into a 50 ml volumetric flask. Dilute 5ml to 100ml with solvent.

Standard solution – Accurately weigh 50 mg sample into a 100 ml volumetric flask. Dilute 5ml to 50ml with solvent.

Measure sample solution – Inject 20 µl of standard solution. Record peak area.

Target Measure standard solution – Inject 20 µl of standard solution. Record peak area.

Measurement
Determine potency of XYZ in sample

Uncertainty
𝒘 𝑨𝑺𝑷𝑳 𝒎𝑺𝑻𝑫 𝑽𝑺𝑷𝑳
% = × × 𝑷 × 𝟏𝟎𝟎
𝒘 𝑨𝑺𝑻𝑫 𝒎𝑺𝑷𝑳 𝑽𝑺𝑻𝑫

Case study: Quantification of the Where

uncertainty according Eurachem/CITAC 𝑨𝑺𝑷𝑳 = Peak area for the sample solution
Guide CG4 𝒎𝑺𝑻𝑫 = Mass of the sample (mg)

𝑽𝑺𝑷𝑳 = Volume of sample solution (ml)

𝑨𝑺𝑻𝑫 = Peak area for the standard solution, average of measurements

𝒎𝑺𝑷𝑳 = Mass of the standard (mg)

𝑽𝑺𝑻𝑫 = Volume of standard solution (ml)

𝑷 = Purity of standard
 Source of Quantify Procedure
Uncertainty

Uncertainty of A spl Repeatability of sample: standard deviation of peak area of

sample solution

Uncertainty of A std Repeatability of standard: standard deviation of peak area

Target of standard solution

Measurement
Uncertainty of M spl Uncertainty of balance

Uncertainty Uncertainty of M std Uncertainty of balance

Case study: Quantification of the Uncertainty of V spl Tolerance of volumetric flask

uncertainty according Eurachem/CITAC Temperature effect
Guide CG4
Uncertainty of V std Tolerance of volumetric flask
Temperature effect

Uncertainty of Repeatability of sample: relative standard deviation of

Method Precision potency of sample

𝟐 𝟐 𝟐 𝟐 𝟐 𝟐 𝟐
( ) 𝒖𝑨𝑺𝑷𝑳 𝒖𝑨𝑺𝑻𝑫 𝒖𝒎𝑺𝑷𝑳 𝒖𝒎𝑺𝑻𝑫 𝒖𝑽𝑺𝑷𝑳 𝒖𝑽𝑺𝑻𝑫 𝒖𝒎𝑺𝑷𝑳
% = + + + + + + + 𝒖𝒑𝒓𝒆𝒄 𝟐 =….
𝑨𝑺𝑷𝑳 𝑨𝑺𝑻𝑫 𝒎𝑺𝑷𝑳 𝒎𝑺𝑻𝑫 𝑽𝑺𝑷𝑳 𝑽𝑺𝑻𝑫 𝒎𝑺𝑷𝑳
This is a free preview copy of the original training “Target Measurement Uncertainty”
Are you looking for a personalized solution towards your own needs?

Please contact us: https://pharmalifecycle.kartra.com/page/contactus