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ASCL LAB Ejemplos en Pureza

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175 views65 pages

ASCL LAB Ejemplos en Pureza

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Dïö Val

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ASCLD/LAB-International

ASCLD/LAB Guidance on the

Estimation of Measurement
Uncertainty – ANNEX B
Drug Chemistry Discipline
Three Examples – Weight, Volume
and Purity Determination

ASCLD/LAB-International is a program of the

American Society of Crime Laboratory Directors / Laboratory Accreditation Board
ASCLD/LAB

Copyright © 2013 by ASCLD/LAB

Approval Date: May 22, 2013

Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
ASCLD/LAB Document Control Number: AL-PD-3063 Ver 1.0

NOTE ASCLD/LAB customers may find value in using this guidance document to better understand
and apply AL-PD-3060 ASCLD/LAB Policy on Measurement Uncertainty.
Document History / AL-PD-3063

Description of Activity or
Date Version Approved By Effective Date
Revision
ASCLD/LAB Executive
May 22, 2013 1.0 Reviewed and approved for distribution May 22, 2013
Director

All intellectual property rights in this publication are the property of the
American Society of Crime Laboratory Directors / Laboratory Accreditation Board ASCLD/LAB

ASCLD/LAB
139 J Technology Drive
Garner, North Carolina 27529
USA
919-773-2600

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 2 of 57

Purpose........................................................................................................................................................................... 5

Scope .............................................................................................................................................................................. 5

The NIST 8-Step Process for Estimating and Reporting Measurement Uncertainty ....................................................... 6

EXAMPLE 1: Measurement of the weight of controlled substance evidence .................................................................. 6

EXAMPLE 1, Step 1: Specify the measurement process ...................................................................................... 8

EXAMPLE 1, Step 2: Identify uncertainty components .......................................................................................... 9

EXAMPLE 1, Step 3: Quantify uncertainty components ...................................................................................... 10

EXAMPLE 1, Step 4: Convert quantities to standard uncertainties ..................................................................... 14

EXAMPLE 1, Step 5: Calculate the combined standard uncertainty ................................................................... 16

EXAMPLE 1, Step 5: Calculate the combined standard uncertainty continued – evaluation of bias ................... 17

EXAMPLE 1, Step 6: Expand the combined standard uncertainty by coverage factor (k) .................................. 18

EXAMPLE 1, Step 7: Evaluate the expanded uncertainty ................................................................................... 19

EXAMPLE 1, Step 8: Report the uncertainty ....................................................................................................... 21

EXAMPLE 2: Measurement of the volume of controlled substance evidence............................................................... 24

EXAMPLE 2, Step 1: Specify the measurement process .................................................................................... 24

EXAMPLE 2, Step 2: Identify uncertainty components ........................................................................................ 25

EXAMPLE 2, Step 3: Quantify uncertainty components ...................................................................................... 27

EXAMPLE 2, Step 4: Convert quantities to standard uncertainties ..................................................................... 28

EXAMPLE 2, Step 5: Calculate the combined standard uncertainty ................................................................... 30

EXAMPLE 2, Step 6: Expand the combined standard uncertainty by coverage factor (k) .................................. 30

EXAMPLE 2, Step 7: Evaluate the expanded uncertainty ................................................................................... 31

EXAMPLE 2, Step 8: Report the uncertainty ....................................................................................................... 33

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 3 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
EXAMPLE 3: The quantity of a controlled substance when reported as a weight or volume fraction (purity) of the whole
...................................................................................................................................................................................... 34

EXAMPLE 3, Step 1: Specify the measurement process .................................................................................... 37

EXAMPLE 3, Step 2: Identify uncertainty components ........................................................................................ 38

EXAMPLE 3, Step 3: Quantify uncertainty components ...................................................................................... 40

EXAMPLE 3, Step 4: Convert quantities to standard uncertainties ..................................................................... 46

EXAMPLE 3, Step 5: Calculate the combined standard uncertainty ................................................................... 50

EXAMPLE 3, Step 6: Expand the combined standard uncertainty by coverage factor (k) .................................. 51

EXAMPLE 3, Step 7: Evaluate the expanded uncertainty ................................................................................... 51

EXAMPLE 3, Step 8: Report the uncertainty ....................................................................................................... 53

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 4 of 57

To provide guidance to laboratories that must achieve compliance with the ASCLD/LAB Policy on Measurement
Uncertainty 1 as they prepare for and maintain accreditation under the ASCLD/LAB-International Testing Program.

Scope

This guidance document will cover:

• Use of the NIST 8-Step Process for Estimating and Reporting Measurement Uncertainty 2 for:
o a measurement of the weight of controlled substance evidence
o a measurement of the volume of controlled substance evidence
o a measurement of the quantity of a controlled substance when reported as a weight or volume fraction
(purity) of the whole
• This general framework conforms to the principles in the Guide to the Expression of Uncertainty in
Measurement (GUM)3

This guidance document is intended to be used by:

• Laboratories that are accredited or that are seeking accreditation under the ASCLD/LAB-International Testing
Program in the discipline of Drug Chemistry,
• Technical assessors for the ASCLD/LAB-International program, and
• Users of ASCLD/LAB-International accredited laboratory services.

For ease of use:

 Denotes a definition. The definition will be from the VIM 4 unless otherwise noted

 Denotes a requirement from the cited accreditation requirement document. Accreditation documents include, but
are not limited to: ISO/IEC 17025:2005, 5 ASCLD/LAB-International Supplemental Requirements for the Testing 6
program, ASCLD/LAB Policy on Measurement Uncertainty and ASCLD/LAB Board Interpretations 7. (A complete
listing of accreditation requirements is available at www.ascld-lab.org.)

Portions of the ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty - Overview8 and the
ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX A Details on the NIST 8-Step
Process 9 have been included in this document but the reader is encouraged to refer to both of these documents for
additional information.

Per the ASCLD/LAB Policy on Measurement Uncertainty, applicant and accredited laboratories in the Drug Chemistry
Discipline shall have and shall apply a procedure to estimate the uncertainty of measurement when values are
reported for the quantity (weight or volume) of controlled substance evidence or the quantity of a controlled substance
when reported as a weight or volume fraction (purity) of the whole. This guidance document will use the NIST 8-Step
Process to work through an example estimation of measurement uncertainty for each type of measurement. These
examples are meant to be illustrative only. The NIST 8-Step Process is a tool that can be used by a laboratory to
meet accreditation requirements but a laboratory is not required to use this process. ASCLD/LAB-International

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 5 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
accredited laboratories are required to be in compliance with all accreditation requirements including ASCLD/LAB
Policies.

The NIST 8-Step Process for Estimating and Reporting Measurement Uncertainty
The steps in the process are:

An estimation of measurement uncertainty is specific to the

measurement traceability that has been established for the
measurement, the measurement assurance processes that are in
place, the laboratory test method, the laboratory facility, etc.
Therefore, the example that follows must be evaluated and revised
by each laboratory to take into consideration the elements that are
specific to that laboratory.
EXAMPLE 1: Measurement of the weight of controlled substance evidence

The SWGDRUG Supplemental Document SD-3 for Part IVC – Quality Assurance/Uncertainty Measurement
Uncertainty for Weight Determinations in Seized Drug Analysis 10 has been referenced for this example. Readers
are encouraged to review the SWGDRUG document in its entirety.

Test Method Information:

• Multiple analysts perform this test method
o All analysts use the same type of balance for the test method
o The test method delineates the flexibility that is allowed (e.g., gross and net weight; use of weigh boats,
weigh paper or other containers)

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 6 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
o The test method specifies the taring of the weighing vessel followed by addition of the measurand to the
weighing vessel while it remains on the balance. (Defined by SWGDRUG10 as a dynamic, single
weighing event)

Measurement Traceability:
The traceability for this measurement process is established through the calibration of the measuring equipment,
the balance, and through the mass reference standards used to confirm the continued calibration status of the
balance.
• The calibration of the balance was determined to have a significant effect on the accuracy or validity of the
test result.
o The external calibration of all balances is performed by a calibration laboratory that meets Section 3.2.3
of the ASCLD/LAB Policy on Measurement Traceability 11
o The mass reference standards are calibrated by an external calibration laboratory that meets Section
3.2.3 of the ASCLD/LAB Policy on Measurement Traceability

Measurement Assurance:
• The laboratory determined that intermediate checks are needed to maintain confidence in the calibration
status of the balances during the interval between external calibrations. These checks are carried out
according to a defined schedule and procedure (ISO/IEC 17025:2005, Clause 5.5.10).
o The laboratory procedure includes the use of calibrated mass reference standards
• Data is available from both an initial study and ongoing quality control that evaluates the variation in the
measurement process using a check standard 12 surrogate. All analysts participate. All balances are used as
are all methods of weighing allowed by the test method procedure. The check standard used is a powder
material, packaged for stability that is sensitive to environmental changes in the laboratory.

 Measurand (VIM 2.3): quantity intended to be measured

 Quantity (VIM 1.1): property of a phenomenon, body, or substance, where the property has a magnitude that can
be expressed as a number and a reference

The statement defining the measurand can be a written statement, a visual diagram and/or a mathematical
expression. To be clear about what measurement process the estimation is being calculated for, it is important to be
as specific as possible when defining the measurand. To distinguish one measurement process from another in a
laboratory it may be necessary to include a reference to a specific type of equipment used, a specific procedure, etc.
in the statement defining the measurand.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 7 of 57

Drug Chemistry - Weight Determination Using Balance Model 123; Procedure No. XXXX, Revision ZZZZ

Weight Determination
• Weight determination of a solid (non-liquid) material using a balance with a readability of 0.01 gram.
• Range of measurement: laboratory determined minimum balance load to maximum balance load

A single measurement is made.

The measurement of weight is not made directly. Weight is determined through a functional relationship based on
the amount of force on the balance. The functional relationship can be expressed by the mathematical equation:

y = mx + b +/- U

Where,
y = the measurement result
m = slope or sensitivity of the measurement instrument linearity
x = the indication
b = bias; in this example, the scale error determined during the external calibration process or during
the intermediate checks, is a systematic bias in the measurement
U = expanded uncertainty

y can further be expressed mathematically as a function of the influences on the measurement process
identified by a laboratory.

 ISO/IEC 17025:2005, Clause 5.4.6.2 states “… the laboratory shall at least attempt to identify all the components
of uncertainty…”

 ISO/IEC 17025:2005, Clause 5.4.6.3 states “when estimating the uncertainty of measurement, all uncertainty
components which are of importance in the given situation shall be taken into account …”

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(b) Statement of how traceability is established for the measurement
(c) The equipment (e.g., measuring device[s] or instrument[s]) used
(d) All uncertainty components considered

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 5.3.2 requires that the specific measuring device or
instrument used for a reported test result to have been evaluated in the estimation of measurement uncertainty for
that test method.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 8 of 57

Traceability is established for this measurement through the calibration of the balance(s), the measuring
equipment, used to perform the measurement and through the mass reference standards used to confirm the
continued calibration status of the balance(s).

The equipment (e.g., measuring device[s] or instrument[s]) used in this test method is:
Top-loading balances Model 123; readability of 0.01 g

List of uncertainty components considered:

Measuring Equipment - Balance
Display Resolution – impact of rounding at zero and at load on the value displayed
Multiple equipment of the same model
Balance Calibration Uncertainty
Balance Linearity
Balance Bias
Calibrated mass reference standards used for this evaluation
Temperature Coefficient of Sensitivity
Staff
Multiple Analysts
Training
Experience
Test Method
Differences in centering of measurand on the balance
The buoyant effect of weighing the measurand in air
Facility
Temperature variation of laboratory and difference from the temperature during calibration
Drafts - air flow in the laboratory area of the balance
Location of balance(s) in the laboratory building
Vibration
Humidity
Static Electricity

NOTE: Residual sample not transferred to the weighing vessel during the performance of the test method to
obtain a weight is not included as a component of uncertainty in the measurement.

A laboratory may identify different uncertainty components when an evaluation of their specific measurement
process is performed.

This list of potential uncertainty components could also be compiled into a fishbone diagram or into any other format of
the laboratory’s choosing. Two fishbone diagram examples depicting possible uncertainty components and one blank
fishbone diagram are available on the ASCLD/LAB website at www.ascld-lab.org. Appendix A to this document
provides an example of using an Excel spreadsheet (available at www.ascld-lab.org) to display the information from
the NIST 8-Step Process.

NOTE: Regarding calculations in Excel:

Regardless of the number of digits that are shown in a cell, Excel carries the maximum number of digits in the
background and will use the entire number for further calculations.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 9 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
 ISO/IEC 17025:2005, Clause 5.4.6.3 states “when estimating the uncertainty of measurement, all uncertainty
components which are of importance in the given situation shall be taken into account using appropriate methods
of analysis.”

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(e) All uncertainty components of significance and how they were evaluated
(f) Data used to estimate repeatability and/or reproducibility
(g) All calculations performed

Review the list of uncertainty components created in Step 2. Identify which of the components listed can be quantified
by existing data from the measurement process.

The GUM (2.3.2) refers to this method of analysis of one or more uncertainty components as:

 Type A evaluation (of uncertainty): method of evaluation of uncertainty by the statistical analysis of series
of observations

The quantification of the remaining uncertainty components is performed by a different method of evaluation referred
to by the GUM (2.3.3) as:

 Type B evaluation (of uncertainty): method of evaluation of uncertainty by means other than the statistical
analysis of series of observations

EXAMPLE 1, Step 3: Quantify uncertainty components

Data is available from both an initial study and ongoing quality control that evaluates the variation in the
measurement process using a check standard surrogate that reasonably mimics the weight determination
process. All balances are used as are all methods of weighing allowed by the test method procedure. All analysts
participate. The laboratory has data spanning the work day, all days of the work week, and normal laboratory
environmental conditions over greater than a one year time period.

The uncertainty components and how they will be evaluated:

Uncertainty Component Method of Evaluation

Measuring Equipment - balance
Type B Evaluation
Display Resolution – impact of rounding at zero (Note: a position can be supported that this is
and at load on the value displayed covered by sufficient measurement assurance
program data)
Covered in Type A Evaluation of process
Multiple equipment of the same model
reproducibility data
Balance Calibration Uncertainty Type B Evaluation

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 10 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Balance Linearity Type B Evaluation
Calibrated mass reference standards are used to
confirm the continued calibration status of the
balances. This provides the laboratory with an
Balance Bias
ongoing evaluation of bias. The evaluation of bias
will be done after the calculation of combined
standard uncertainty.
Temperature Coefficient of Sensitivity Type B Evaluation
Staff
Covered in Type A Evaluation of process
Multiple Analysts
reproducibility data
Covered in Type A Evaluation of process
Training
reproducibility data
Covered in Type A Evaluation of process
Experience
reproducibility data
Test Method
Differences in centering of measurand on the Covered in Type A Evaluation of process
balance reproducibility data
The buoyant effect of weighing the measurand in
Type B Evaluation
air
Facility
The location of the equipment has not been altered
since the external calibration; Covered by the
Location Calibration Uncertainty. (Note: If the balance is
moved, the validity of the calibration may be
impacted due to variations in gravitational forces).
Covered in Type A Evaluation of process
Temperature variation
reproducibility data
Covered in Type A Evaluation of process
Air flow
reproducibility data
Covered in Type A Evaluation of process
Vibration
reproducibility data
Covered in Type A Evaluation of process
Humidity
reproducibility data
Covered in Type A Evaluation of process
Static Electricity
reproducibility data

Type A Evaluation of uncertainty components:

Measurement Process Reproducibility – Check Standard Measurement Data

The laboratory has existing data from the measurement process.

The number of observations from the initial study and ongoing data in this example is greater than 200.

The data was evaluated and appears to have a normal distribution.

The data, graphed as a histogram has a normal, non-skewed distribution.
The approximate percentage of data points fall within 1, 2, and 3 standard deviations of the mean

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 11 of 57

Standard Deviation (Sample):

∑ (x )
n
2
i −x
s= i =1
n −1
The standard deviation of the reproducibility data in this example = 0.031 g

Type B Evaluation of uncertainty components:

Display Resolution - rounding at zero and at load

The model of measuring equipment in use is a “single range” balance.
The display resolution is 0.01 g at both zero and at load.

The purpose of this uncertainty component is to account for the rounding that is automatically performed by the
balance. Because rounding automatically occurs at both zero (taring) and at load, two components will be
included.

Equal to one half of the display resolution 13 = ½ of 0.01 g = 0.005 g

The measurement process reproducibility data may double-count variation separately quantified for the display
resolution at zero and at load. Any double-counting will result in an over estimation of the measurement
uncertainty. (Note: a laboratory may be able to support a position that these components can be covered by
sufficient data from a measurement assurance program).

Balance Calibration Uncertainty:

A review of the calibration certificates from the accredited external calibration laboratory for all of the balances
that may be used by an analyst in the performance of this test method identified that the greatest calibration
expanded uncertainty over the usable range is 0.013 g.

Balance Linearity:
The laboratory procedure to confirm the continued calibration status of the balance (ISO/IEC 17025:2005, Clause
5.5.10) and procedures to ensure proper functioning of the balance (ISO/IEC 17025:2005, Clause 5.5.6) both
have set pre-defined performance criteria of +/- 0.01 g across the entire useable range of the balance(s) used for
this measurement.

Temperature Coefficient of Sensitivity:

A balance calibration is performed at a specified temperature. Operating the balance at any other temperature
will cause a difference between the value measured and the correct value. Room temperature as well as
placement of the balance in direct sunlight or in drafts will cause delays in stabilization and changes in the
temperature of the balance.

The value for the temperature coefficient is provided by the balance manufacturer based on the material(s) used
in the construction of the balance. It may be expressed as a nominal value or a percentage change per degree of
temperature (0C) in relation to the amount of load on the balance.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 12 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Some types of balances have a function to perform an “Internal Calibration” or “Autocal”. The function that the
equipment is performing is an adjustment, not a calibration, and is performed to assist in keeping the balance
performing accurately in a changing environment. Please refer to the ASCLD/LAB Guidance Document on
Measurement Traceability 14 for additional information on this topic.

The laboratory in this example, uses this function of the balance and per a defined schedule and procedure
performs a check of the calibration status of the balance to provide objective evidence that this adjustment has
had minimal impact on the calibration performed by the external calibration laboratory. The calibration status
check procedure, using calibrated mass reference standards, covers the weighing range of the balance.

The laboratory’s pre-defined criteria for the calibration status checks preclude use of the balance outside of the
pre-defined performance criteria. This criterion will control variation due to many aspects including temperature of
the balance. Within this operating criterion, variations in environmental conditions in the laboratory, including
temperature, are captured through the use of the measurement assurance check standard (Type A Evaluation).

NOTE: if a laboratory is not evaluating the impact of balance temperature through other laboratory processes and
therefore through other uncertainty components, then the manufacturer’s temperature coefficient of sensitivity
would be used to quantify this component. A laboratory can determine if the component will be quantified as a
worst case scenario for the entire range of the balance as below, quantified for specific weight ranges or as a
relative uncertainty percentage.

Temperature coefficient = 2.5 x 10 -6 / oC * i Where i is the balance indication

Widest variation in room temperature is +/- 5 oC.

Calculation of outside limit = 5 oC x 0.0000025 / oC * i
= 0.0000125 * i

Evaluating this at the upper limit of the balance will provide the largest possible impact
Upper limit of balance = 6000 g

Therefore, the largest impact = 0.0000125 * 6000 g

= 0.075 g

The buoyant effect of weighing the measurand in air: From the SWGDRUG document10
“Buoyancy is difficult to account for in seized drug cases because the density of the material being weighed must
be known. However, for material that has a lower density than the steel calibration weights (8.0 g/cm3) the bias
imparted is always negative and the weight displayed by the balance will be less than the true weight of the
material. Ignoring buoyancy contributes a small systematic error that represents no more than 0.1 % bias to the
weight. Therefore, buoyancy corrections are not made in any uncertainty computations shown in this document
(SD-3).”

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 13 of 57

All uncertainty components must be expressed as a standard uncertainty and in the same measurement unit.

 Standard uncertainty (VIM 2.30): measurement uncertainty expressed as a standard deviation

EXAMPLE 1, Step 4: Convert quantities to standard uncertainties

The measurement unit is the gram.

Type A Evaluation of uncertainty components:

Reproducibility data: Is in the correct measurement unit

Is expressed as one standard deviation
The standard deviation of the reproducibility data in this example = 0.031 g

Type B Evaluation of uncertainty components:

Display Resolution - rounding at zero and at load:

This component is evaluated as a rectangular distribution:

Upper limit = +a
Lower limit = -a
Possible range of values = (+a) - (-a) = 2a

For a rectangular distribution, the standard uncertainty is calculated by:

standard uncertainty = a / √3

The outside limit = ½ the readability of the balance at zero

= ½ (0.01 g)
= 0.005 g

standard uncertainty = 0.005 g / √3

= 0.003 g

The outside limit = ½ the readability of the balance at load

= ½ (0.01 g)
= 0.005 g

standard uncertainty = 0.005 g / √3

= 0.003 g

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 14 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Balance Calibration Uncertainty:
A review of the calibration certificates from the accredited external calibration laboratory for all of the balances
that may be used by an analyst in the performance of this test method identified that the greatest calibration
expanded uncertainty over the usable range is 0.013 g.

The certificate indicates this expanded uncertainty assumes a normal distribution, a coverage factor of k = 2 and
a coverage probability of approximately 95 %.

The uncertainty on the calibration certificate will be divided by the coverage factor, 2, to arrive at a standard
uncertainty.
standard uncertainty = 0.013 g / 2
= 0.007 g

Balance Linearity:
This component is evaluated as a rectangular distribution:

Upper limit = +a
Lower limit = -a
Possible range of values = (+a) - (-a) = 2a

The outside limit = 0.01 g

standard uncertainty = 0.01 g /√3

= 0.006 g

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(g) All calculations performed
(h) The combined standard uncertainty,…

Individual standard uncertainties quantified by Type A and Type B methods of evaluation are now combined to
calculate the combined standard uncertainty for the measurement process. The combined standard uncertainty is an
estimated standard deviation and characterizes the dispersion of the values that could reasonably be attributed to the
measurement result at the equivalent of one standard deviation, a coverage probability of 68.26 %.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 15 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
The combined standard uncertainty, denoted by uc(y), is the positive square root of the variance of all components
combined. Variance is equal to the Standard Deviation squared. This formula is commonly called the Root Sum of
the Squares or RSS.

∑(c u )
2
uc ( y ) = i i

uc ( y ) = s 2p + u02 + u12 + u22 + ..... + ui2

This is the RSS formula when the measurement result is the sum of a series of components. The formula also
assumes that the uncertainty components are independent or uncorrelated (a change in one component does not
cause a change in another component).

EXAMPLE 1, Step 5: Calculate the combined standard uncertainty

The estimation will assume that the uncertainty components are independent or uncorrelated and that the
measurement result is the sum of a series of components.

The measurement process reproducibility may double-count variation quantified by the scale readability at zero
and scale readability at load uncertainty components. This double-counting cannot be quantified. Any double-
counting will result in an over estimation of the measurement uncertainty.

uc ( y ) =s 2process + ureadabiltyzero
2
+ ureadabiltyload
2
+ ucalibrationunc
2
+ ulinearity
2

uc ( y ) =0.0312process + 0.003readabilityzero
2
+ 0.003readabilityload
2
+ 0.007calibrationunc
2
+ 0.006linearity
2

uc ( y ) = 0.001

uc ( y ) = 0.032 g

Evaluation of bias
Measurement accuracy 15 encompasses both precision 16 and bias 17. A measurement is more accurate when it has
less bias and greater precision. An assessment of bias requires the comparison of a measurement result to a
reference value.

The GUM3 in section 3.2.4 states “it is assumed that the result of a measurement has been corrected for all
recognized significant systematic effects and that every effort has been made to identify such effects.”

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 16 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
General approach to bias evaluation9, 18, 19:
• Estimate the combined uncertainty without considering the relevant bias.
• Compare the bias with the combined uncertainty.
• Where the bias is not significant compared to the combined uncertainty, the bias may be neglected or
included as a component in the estimation of uncertainty.
• Where the bias is significant compared to the combined uncertainty, additional action is required.
Appropriate actions might:
o Eliminate or correct for the bias, including the uncertainty of the correction in the estimation of
uncertainty.
o Report the observed bias and its uncertainty in addition to the result.

EXAMPLE 1, Evaluation of bias (Step 5 continued)

The laboratory in this example views the monitoring of bias as a component of ensuring the validity of the test
method (ISO/IEC 17025:2005, Clause 5.9.1). The laboratory routinely evaluates bias during the procedure for
confirmation of the calibration status of the balance through the use of multiple calibrated mass reference
standards.

The laboratory procedure requires that all calibration status checks be within 0.01 g of the reference value and
specifies what an analyst is to do if this does not occur (ISO/IEC 17025:2005, Clause 5.9.2). A review of the
data, including data points outside of this administrative limit with no known cause, yields a mean value of each
reference standard that is within the range of the reference value plus or minus the combined standard
uncertainty. The bias is viewed as insignificant by the laboratory.

Continuing to follow a conservative approach in this example, an additional component will be added to the
uncertainty estimation that will address the uncertainty in the reference value of the reference standards used for
the evaluation of bias.

Step 3 Quantify uncertainty components

The laboratory reviewed the calibration certificates from the accredited external calibration laboratory for all mass
reference standards used in the calibration status check procedure and identified that the greatest calibration
expanded uncertainty is 5.5 mg.

Step 4 Convert quantities to standard uncertainties

The certificate indicates this expanded uncertainty assumes a normal distribution, a coverage factor of k = 2 and
a coverage probability of approximately 95 %.
The uncertainty on the calibration certificate will be divided by the coverage factor, 2, to arrive at a standard
uncertainty.

standard uncertainty = 0.0055 g / 2

= 0.003 g

Step 5: Calculate combined standard uncertainty

The revised RSS calculation:

uc ( y ) = s 2process + ureadabiltyzero
2
+ ureadabiltyload
2
+ ucalibrationunc
2
+ ulinearity
2
+ ucalibrefstd
2

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 17 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
uc ( y ) = 0.0312process + 0.003readabilityzero
2
+ 0.003readabilityload
2
+ 0.007calibrationunc
2
+ 0.006linearity
2
+ 0.003calrefstd
2

uc ( y ) = 0.001

uc ( y ) = 0.033 g

The impact to the calculated combined standard uncertainty and can only be seen when additional digits are
shown in calculations.

Combined standard uncertainty no bias component = 0.03245381 g

Combined standard uncertainty with a bias component = 0.03257012 g

The combined standard uncertainty, calculated in Step 5, is an estimated standard deviation and characterizes the
dispersion of the values that could reasonably be attributed to the measurement result at the equivalent of one
standard deviation, a coverage probability of 68.26 %.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.2 requires the coverage probability to be a minimum
of 95.45 % (often referred to as approximately 95 %).

The coverage probability of the combined standard uncertainty must be expanded to comply with the ASCLD/LAB
Policy.

EXAMPLE 1, Step 6: Expand the combined standard uncertainty by coverage factor (k)

The data from the measurement process is assumed to follow a normal distribution.
The laboratory has objective evidence supporting this assumption. The data was graphed in a histogram and
was found to be symmetrical about the mean with the number of data points 1, 2 and 3 standard deviations
from the mean following the expected percentages.

The laboratory has greater than 200 measurements of the check standard.

Refer to the Student’s t-distribution, Table 1 in ASCLD/LAB Guidance on the Estimation of Measurement
Uncertainty – ANNEX A9 for the specific value of k. NOTE: The assumptions for a normal distribution are
modified when a limited number of measurements are used for repeatability data and/or reproducibility data.

To expand the uncertainty to a 95.45 % coverage probability the coverage factor k = 2.0003 will be used. A
laboratory can choose to increase the coverage probability. To increase the coverage probability to 99.73 %, a
coverage factor k=3.0003 will be used. NOTE: A laboratory could choose to use the more conservative values for
k for 100 degrees of freedom from the Student’s t-distribution table or could interpolate the values of the t-
distribution table for the number of measurements available.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 18 of 57

EXAMPLE 1, Step 7: Evaluate the expanded uncertainty

Step 7 is the time to critically evaluate the estimation of uncertainty and to determine if it “makes sense” and is
“reasonable.”

• The laboratory may identify calculation errors in this Step.

• The laboratory will decide if the uncertainty results are appropriate for the test method. If the laboratory
placed limits on the acceptable expanded uncertainty, does the calculated value meet the stated
requirement?
• Does the expanded uncertainty meet the customer’s needs?

If the laboratory determines that the expanded uncertainty is not acceptable, areas of method improvement (e.g.,
measurement method standardization, improved calibration of equipment, increased readability of the measuring
instrument, etc.) can be identified and evaluated for the impact that a change would have on the estimation of
uncertainty using the information available from Steps 3 and 4.

Once changes to a test method have been validated, the appropriate edits to Steps 1-6 can be made and the
estimation of uncertainty reevaluated.

Is there a requirement regarding the relationship between the calculated expanded uncertainty and the
measurement result or the minimum sample load of a test method?

 ISO/IEC 17025:2005, Clause 5.4.6.1 for calibration laboratories and Clause 5.4.6.2 for testing laboratories
requires laboratories to have and apply a procedure for estimating uncertainty of measurement.

Neither ISO/IEC 17025:2005 nor ASCLD/LAB-International Policy on Measurement Uncertainty specifies how large
the expanded uncertainty can be in relationship to the measurement result. It will be up to the laboratory to determine
what is acceptable as part of the laboratory procedure for estimating uncertainty of measurement.

The Eurachem/CITAC Guide on Quantifying Uncertainty in Analytical Measurement19 provides the following
information on this topic. Although written for analytical measurements, the points are applicable.
• At low concentration, an increasing number of effects become important
• The relative uncertainty associated with the result tends to increase, first to a substantial fraction of the result
and finally to the point where the (symmetric) uncertainty interval includes zero. This region is typically
associated with the practical limit of detection or limit of quantitation for a given method.
• The GUM does not give explicit instructions when the results are small and the uncertainties large compared
to the results. Indeed, the basic form of the ‘law of propagation of uncertainties’ may cease to apply
accurately in this region; one assumption on which the calculation is based is that the uncertainty is small
relative to the value of the measurand.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 19 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
• An additional, if philosophical, difficulty follows because values below zero cannot be reasonably ascribed to
the value of the measurand when the measurand is a concentration, because concentrations themselves
cannot be negative.
• These difficulties do not preclude the application of the estimation methods but some caution is required in
interpretation and reporting the results of measurement uncertainty estimation in this region.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.1 requires the laboratory to have a procedure for the
process of rounding the uncertainty.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.2 requires the coverage probability of the expanded
uncertainty to be a minimum of 95.45 % (often referred to as approximately 95 %).

 Coverage probability (VIM 2.37): probability that the set of true quantity values of a measurand is contained
within a specified coverage interval
Note 1 This definition pertains to the Uncertainty Approach as presented in the GUM.
Note 2 The coverage probability is also termed “level of confidence” in the GUM.

 ASCLD/LAB requirements for the reporting of measurement uncertainty can be found in the Policy on
Measurement Uncertainty in Clauses 5.1 - 5.3
 Clauses 5.1 and 5.3 apply to testing laboratories

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 5.3.1 states that the rounded expanded uncertainty
shall be reported to at most two significant digits, unless the laboratory has a documented rationale for reporting
additional significant figures. The need for reporting additional significant figures in a rounded expanded
uncertainty is rare.

Refer to the Policy for all reporting requirements as only selected reporting requirements are being covered in this
Guidance Document.

 For testing laboratories:

5.1. 2 When measurement uncertainty is reported, the value shall be reported in the test report or in an
attachment to the report, and shall be expressed as an expanded uncertainty and include the coverage
probability.

This measurement result shall include the measured quantity value, y, along with the associated
expanded uncertainty, U, and this measurement result shall be reported as y ± U where U is consistent
with the units of y.

NOTE 1 For asymmetrical uncertainties, it may be inappropriate to quote a single result for the
uncertainty and presentations other than y ± U may be needed.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 20 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
5.3.3 The measurement result and the rounded expanded uncertainty shall be reported to the same level of
significance.

EXAMPLE 1, Step 8: Report the uncertainty

k = 2.000 U= 2.000* 0.033 = 0.065 g

k = 3.000 U= 3.000* 0.033 = 0.098 g

As required in Section 3.1.1 of the ASCLD/LAB Policy on Measurement Uncertainty, the laboratory has
established a procedure for the process of rounding the expanded uncertainty. Following that procedure and
considering Section 5.3.3 of the Policy that requires the measurement result and the rounded expanded
uncertainty to be reported to the same level of significance, the expanded uncertainty will be reported as:

k = 2.000 U= 0.07 g
k = 3.000 U= 0.10 g

Example report statements:

The net weight of Item 1 was found to be 30.03 g +/- 0.07 g at a coverage probability of 95.45 %.

The net weight of Item 1 was found to be 30.03 g +/- 0.10 g at a coverage probability of 99.73 %.

A laboratory can include additional information regarding the test result and the relationship to a specification in the
test report but it must be additional information and not in place of that which is required by the ASCLD/LAB Policy on
Measurement Uncertainty. If a laboratory wishes to compare a test result to a specification (e.g., statute limit), the
expanded uncertainty is taken into account in evaluating compliance to the specification. The report must accurately,
clearly, unambiguously and objectively communicate this information.

Example report statements that include additional information regarding a specification:

The net weight of Item 1 was found to be 30.03 g +/- 0.07 g at a coverage probability of 95.45 %. Taking the
estimated measurement uncertainty into consideration, the weight of Item 1 is greater than one ounce (28.35 g).

The net weight of Item 1 was found to be 30.03 g +/- 0.10 g at a coverage probability of 99.73 %. Taking the
estimated measurement uncertainty into consideration, the weight of Item 1 is greater than one ounce (28.35 g)

If the laboratory, desires to include additional information in a test report regarding a specification but the
measurement result and the expanded uncertainty are not clearly outside (above or below) a specification,
can the laboratory still include this additional information?

A laboratory can still include additional information regarding a specification, a statute limit. The report must
accurately, clearly, unambiguously and objectively communicate this information.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 21 of 57

The measurement
result +/- the
expanded
uncertainty is above
The measurement the limit.
result +/- the
expanded
uncertainty is not
above the limit.

LIMIT

The measurement
result +/- the
expanded
uncertainty is not
The measurement below the limit.
result +/- the
expanded
uncertainty is below
the limit.

Example report statements that include additional information regarding a specification:

The net weight of Item 1 was found to be 28.43 g +/- 0.07 g at a coverage probability of 95.45 %. Taking the
estimated measurement uncertainty into consideration, the weight of Item 1 is greater than one ounce (28.35 g).

The net weight of Item 1 was found to be 28.43 g +/- 0.10 g at a coverage probability of 99.73 %. Taking the
estimated measurement uncertainty into consideration, there is a possibility that the weight of Item 1 is less than
one ounce (28.35 g).

If an item contains multiple sub-items and the laboratory desires to report a total weight, how is the
measurement uncertainty handled?

This example does make only one measurement of weight.

If a laboratory desires to issue an overall weight for an item containing two or more sub-items, then the uncertainty in
each measurement must be accounted for in the reported overall uncertainty. If the measurements are made using
the same equipment, the calibration of the equipment is also the same, and there is correlation between some
uncertainty components. The difficulty comes in quantifying the amount of correlation.

It is the laboratory’s responsibility to consult references or seek the advice of a statistician as necessary when
evaluating correlation of uncertainty components.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 22 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
A laboratory can refer to the SWGDRUG Supplemental Document SD-3 for Part IVC – Quality Assurance/Uncertainty
Measurement Uncertainty for Weight Determinations in Seized Drug Analysis10 for an example of multiple
measurements on the same balance.

If the measurements use different equipment, two different types of balances, these are viewed as independent
measurements. This position is supported based on the major components to uncertainty, measurement process
reproducibility and readability, being different. The weights and their respective uncertainties would be added
together.

Example: Laboratory obtains a gross weight on a balance that reads to 0.1 gram, obtains the weight of the
packaging on a balance that reads to 0.001 gram. Per laboratory procedure the net weight is truncated to the
level of significance of the least sensitive balance. The combined uncertainty is rounded per laboratory
procedure.

Item 1 GW = 205.6 g Expanded Uncertainty at 95.45 % = 0.9 g

TW = 31.123g Expanded Uncertainty at 95.45 % = 0.007 g
NW = 174.477g Expanded Uncertainty at 95.45 % = 0.907 g

Report statement:
The net weight of Item 1 was found to be 174.4 g +/- 1.0 g at a coverage probability of 95.45 %.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 23 of 57

Test Method Information:

• Multiple analysts perform this test method.
o All analysts use the same equipment, a graduated cylinder, for the test method.

Measurement Traceability:
The traceability for this measurement process is established through the calibration of the measuring equipment,
a graduated cylinder, used to perform the measurement.
• The calibration of the graduated cylinder was determined to have a significant effect on the accuracy or
validity of the test result.
o The calibration of the graduated cylinder is performed by an external calibration laboratory that meets
Section 3.2.3 of the ASCLD/LAB Policy on Measurement Traceability.11

Measurement Assurance:
• The laboratory determined that no intermediate checks are needed to maintain confidence in the calibration
status of the graduated cylinder during the interval between external calibrations of the equipment. (ISO/IEC
17025:2005, Clause 5.5.10). The graduated cylinder is inspected visually to ensure proper functioning
(ISO/IEC 17025:2005, Clause 5.5.6)
• Training and competency testing of each analyst as well as an intra-laboratory comparison where multiple
analysts read the volume of different types of liquid routinely encountered in casework provides data on the
variation of multiple analysts reading a volume of liquid using the graduated cylinder.

 Measurand (VIM 2.3): quantity intended to be measured

 Quantity (VIM 1.1): property of a phenomenon, body, or substance, where the property has a magnitude that can
be expressed as a number and a reference

EXAMPLE 2, Step 1: Specify the measurement process

Drug Chemistry Volume Determination - Test Method No. XXXX, Revision ZZZZ

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 24 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Volume Determination: The volume of a liquid is determined using a 100 mL graduated cylinder with a
scale in 1 mL increments.

Expressed by the mathematical equation:

Y = y + b +/-U

Where:
y is the best estimate of the measurand Y from the test method and is expressed by
y = f (x1, x2, ..., xN )
y is a function of the components of uncertainty
b = bias; in this example, the calibrated scale error is a systematic bias in the measurement
U = expanded uncertainty

 ISO/IEC 17025:2005, Clause 5.4.6.2 states “… the laboratory shall at least attempt to identify all the components
of uncertainty…”

EXAMPLE 2, Step 2: Identify uncertainty components

Traceability is established for this measurement through the calibration of the graduated cylinder used for the
measurement.

The equipment (e.g., measuring device[s] or instrument[s]) used in this test method is:
All measurements are made using one calibrated 100 mL graduated cylinder.

List of uncertainty components considered:

Equipment – graduated cylinder
Graduated Cylinder Calibration uncertainty
Scale Readability
Scale Error
Uncertainty in the stated error

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 25 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Staff
Multiple Analysts
Training
Experience
Test Method
Differences in establishing “eye level” to read the meniscus
Measurand
Differences in volatility
Facility
Lighting
Temperature variation of laboratory and difference from that during calibration of the graduated cylinder

A laboratory may identify different uncertainty components when an evaluation of their specific measurement
process is performed.

This list of potential uncertainty components could also be compiled into a fishbone diagram or into any other format of
the laboratory’s choosing. Two fishbone diagram examples depicting possible uncertainty components and one blank
fishbone diagram are available on the ASCLD/LAB website at www.ascld-lab.org. Appendix B to this document
provides an example of using an Excel spreadsheet (available at www.ascld-lab.org) to display the information from
the NIST 8-Step Process.

NOTE: Regarding calculations in Excel:

Regardless of the number of digits that are shown in a cell, Excel carries the maximum number of digits in the
background and will use the entire number for further calculations.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(e) All uncertainty components of significance and how they were evaluated
(f) Data used to estimate repeatability and/or reproducibility
(g) All calculations performed

Review the list of uncertainty components created in Step 2. Identify which of the components listed can be quantified
by existing data from the measurement process.

The GUM (2.3.2) refers to this method of evaluation of one or more uncertainty components as:

 Type A evaluation (of uncertainty): method of evaluation of uncertainty by the statistical analysis of series
of observations

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 26 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
The quantification of the remaining uncertainty components is performed by a different method of evaluation referred
to by the GUM (2.3.3) as:

 Type B evaluation (of uncertainty): method of evaluation of uncertainty by means other than the statistical
analysis of series of observations

EXAMPLE 2, Step 3: Quantify uncertainty components

The laboratory has existing data from the measurement process.

An intra-laboratory comparison requiring all analysts to measure the volume of typical liquids was conducted to
gather initial data. Prior to this initial study, the laboratory had standardized the procedure for reading the
meniscus. The procedure includes a meniscus reader that must be used. The procedure follows NIST GMP 3 -
Good Measurement Practice for Method of Reading A Meniscus Using Water or Other Wetting Liquid 20 (Type A
Evaluation).

The laboratory has determined that the largest difference between analysts is less than one increment on the
measurement scale of the graduated cylinder, 1 mL (Type B Evaluation).

Each new analyst during training practical exercises and competency testing must provide objective evidence that
their performance meets the laboratory pre-defined criteria for measurement competency.

The uncertainty components considered and how they will be evaluated:

Uncertainty Component Method of Evaluation

Equipment – graduated cylinder
Calibration uncertainty Type B Evaluation
Scale Readability Type B Evaluation
This known bias will be added or subtracted from
Scale Error
the measurement result itself.
Type B Evaluation - included in the calibration
Uncertainty in the stated error
uncertainty
Staff
Multiple Analysts Combination Type A and Type B Evaluation
Training Combination Type A and Type B Evaluation
Experience Combination Type A and Type B Evaluation
Test Method
Differences in establishing “eye level” to read the
Combination Type A and Type B Evaluation
meniscus
Measurand
Differences in volatility Combination Type A and Type B Evaluation
Facility
Lighting Combination Type A and Type B Evaluation

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 27 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Temperature variation of laboratory and difference
Combination Type A and Type B Evaluation
from that during calibration of the graduated cylinder

Combination Type A and Type B Evaluation of component:

Graduated Cylinder Scale readability:

Scale readability = 1.0 mL

Type B Evaluation of uncertainty component:

Graduated Cylinder Calibration Uncertainty

A review of the calibration certificate from the accredited external calibration laboratory identified that the greatest
calibration expanded uncertainty over the usable range is 50 µL.

All uncertainty components must be expressed as a standard uncertainty and in the same measurement unit.

 Standard uncertainty (VIM 2.30): measurement uncertainty expressed as a standard deviation

EXAMPLE 2, Step 4: Convert quantities to standard uncertainties

The measurement unit is the milliliter (mL).

Combination Type A and Type B Evaluation of component:

Graduated Cylinder Scale readability:

Scale readability = 1.0 mL

This component is evaluated as a rectangular distribution:

Upper limit = +a
Lower limit = -a

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 28 of 57

For a rectangular distribution, the standard uncertainty is calculated by:

standard uncertainty = a / √3

The outside limit = 1.0 mL

standard uncertainty = 1.0 mL / √3

= 0.577 mL

Type B Evaluation of uncertainty component:

Graduated Cylinder Calibration Uncertainty

A review of the calibration certificate from the accredited external calibration laboratory identified that the greatest
calibration expanded uncertainty over the usable range is 50 µL.

The certificate indicates this expanded uncertainty assumes a normal distribution, a coverage factor of k = 2 and a
coverage probability of approximately 95 %.
The uncertainty on the calibration certificate will be divided by the coverage factor, 2, to arrive at a standard
uncertainty.

standard uncertainty = 50 µL / 2
= 25 µL
= 0.025 mL

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(g) All calculations performed
(h) The combined standard uncertainty,…

The combined standard uncertainty, denoted by uc(y), is the positive square root of the variance of all components
combined. Variance is equal to the Standard Deviation squared. This formula is commonly called the Root Sum of
the Squares or RSS.

∑(c u )
2
uc ( y ) = i i

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 29 of 57

EXAMPLE 2, Step 5: Calculate the combined standard uncertainty

The estimation will assume that the uncertainty components are independent or uncorrelated and that the
measurement result is the sum of a series of components.

=uc ( y ) 2
uscalereadability + ucalibunc
2

=uc ( y ) 0.577 2scalereadability + 0.025calibunc

uc ( y ) = 0.334

uc ( y ) = 0.578 mL

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.2 requires the coverage probability to be a minimum
of 95.45 % (often referred to as approximately 95 %).

The coverage probability of the combined standard uncertainty must be expanded to comply with the ASCLD/LAB
Policy.

EXAMPLE 2, Step 6: Expand the combined standard uncertainty by coverage factor (k)

Both components in this example are based on an infinite number of observations. To expand the uncertainty to
a 95.45 % coverage probability the coverage factor k = 2.0003 will be used.
A laboratory can choose to increase the coverage probability to a greater percentage than that required in the
Policy. If, for example, a laboratory chooses to increase the coverage probability to 99.73 %, then the coverage
factor k = 3.0003 will be used.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 30 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
NOTE: The assumptions for a normal distribution are modified when a limited number of measurements are used
for repeatability data and/or reproducibility data. Refer to the Student’s t-distribution table, Table 1 in ASCLD/LAB
Guidance on the Estimation of Measurement Uncertainty – ANNEX A9 for the specific value of k.

k = 2.000 U= 2.000 * 0.578 = 1.156 mL

k = 3.000 U= 3.000 * 0.578 = 1.734 mL

EXAMPLE 2, Step 7: Evaluate the expanded uncertainty

Step 7 is the time to critically evaluate the estimation of uncertainty and to determine if it “makes sense” and is
“reasonable.”

• The laboratory may identify calculation errors in this Step.

Once changes to a test method have been validated, the appropriate edits to Steps 1-6 can be made and the
estimation of uncertainty reevaluated.

Is there a requirement regarding the relationship between the calculated expanded uncertainty and the
measurement result or the minimum sample load of a test method?

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 31 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
• The GUM does not give explicit instructions when the results are small and the uncertainties large compared
to the results. Indeed, the basic form of the ‘law of propagation of uncertainties’ may cease to apply
accurately in this region; one assumption on which the calculation is based is that the uncertainty is small
relative to the value of the measurand.
• An additional, if philosophical, difficulty follows because values below zero cannot be reasonably ascribed to
the value of the measurand when the measurand is a concentration, because concentrations themselves
cannot be negative.
• These difficulties do not preclude the application of the estimation methods but some caution is required in
interpretation and reporting the results of measurement uncertainty estimation in this region.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.1 requires the laboratory to have a procedure for the
process of rounding the uncertainty.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.2 requires the coverage probability of the expanded
uncertainty to be a minimum of 95.45 % (often referred to as approximately 95 %).

 ASCLD/LAB requirements for the reporting of measurement uncertainty can be found in the Section 5 of the
ASCLD/LAB Policy on Measurement Uncertainty.
 Clauses 5.1 and 5.3 apply to testing laboratories

Refer to the Policy for all reporting requirements as only selected reporting requirements are being covered in this
Guidance Document.

 For testing laboratories:

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 32 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
NOTE 1 For asymmetrical uncertainties, it may be inappropriate to quote a single result for the
uncertainty and presentations other than y ± U may be needed.

5.3.3 The measurement result and the rounded expanded uncertainty shall be reported to the same level of
significance.

EXAMPLE 2, Step 8: Report the uncertainty

k = 2.000 U= 2.000 * 0.578 = 1.156 mL

k = 3.000 U= 3.000 * 0.578 = 1.734 mL

As required in Clause 3.1.1 of the ASCLD/LAB Policy on Measurement Uncertainty, the laboratory has
established a procedure for the process of rounding the expanded uncertainty. Following that procedure and
considering Clause 5.3.3 of the Policy that requires the measurement result and the rounded expanded
uncertainty to be reported to the same level of significance, the expanded uncertainty will be:

k = 2.000 U = 1 mL
k = 3.000 U = 2 mL

Scale Error

The known scale error, a correction, must be taken into account prior to reporting the measurement result. A
review of the calibration certificate for the graduated cylinder indicates that the scale error is +0.080 mL. The
correction to the measurement result is -0.080 mL.

If the volume of Item 1 is measured to be 23 mL, then the corrected measurement result is:

23 mL – 0.080 mL = 22.92 mL

The laboratory procedure will need to address if the measurement result is rounded or truncated and if rounded
what the procedure for rounding will be. For this example the result will be rounded down.

Example report statements:

The volume of Item 1 was found to be 22 mL +/- 1 mL at a coverage probability of 95.45 %.

The volume of Item 1 was found to be 22 mL +/- 2 mL at a coverage probability of 99.73 %.

The volume of liquid to be measured is greater than the volume of the calibrated graduated cylinder so more
than one measurement is necessary. How is this handled?

This example does make only one measurement of volume. If the volume of liquid is greater than 100 mL requiring
two or more measurements, then the uncertainty in each measurement must be accounted for in the overall
uncertainty.

If the measurements are made using the same equipment, the calibration of the equipment is the same there is
correlation or dependence between the uncertainty components. The difficulty comes in quantifying the amount of

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 33 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
correlation. It is the laboratory’s responsibility to consult references or seek the advice of a statistician as necessary
when evaluating correlation of uncertainty components.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 34 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
EXAMPLE 3: The quantity of a controlled substance when reported as a weight or volume fraction
(purity) of the whole

The SWGDRUG has published Supplemental Document SD-4 for Part IVC – Quality Assurance/Uncertainty
Measurement Uncertainty for Purity Determinations in Seized Drug Analysis 21. Readers are encouraged to
review the SWGDRUG document in its entirety.

Test Method Information:

• Multiple analysts perform this test method
o All analysts use the same equipment for the test method
• The method is a chromatographic method that includes the use of an internal standard
o Sample introduction is by autosampler
o Preparation of calibrators 22 , quality control samples and measurand(s) follow the general procedure:
• Calibrators are prepared using a solid reference material of known purity
• Weigh out a known quantity of material (same approximate weight; exact weight recorded) into a
volumetric flask
o A single balance is used for this test method
• A specified volume of internal standard is added by pipette
• Bring all volumetric flasks to final volume with solvent
• Mix
• Place a sample of each into an analytical vial for analysis
o The internal standard is prepared from a solid reference material and diluted in the same solvent used to
prepare the calibrators and to dissolve the measurand
o The measurand is homogenized per the laboratory procedure and two aliquots are weighed out for
analysis
• Procedure administrative requirement of 10 % agreement between replicates
• The average of the two measurement results is reported
o The multi-point calibration curve covering the reportable concentration range is established each
analytical run.

Measurement Traceability:
The traceability for this measurement process is established through the calibrators used to establish the
calibration curve on the measuring system 23 as well as through the calibration of other equipment used in the
measurement process where the calibration of the equipment is viewed to have a significant effect on sampling or
the accuracy of the test result.
• All calibrations of measuring equipment are performed by external calibration laboratories that meet Section
3.2.3 of the ASCLD/LAB Policy on Measurement Traceability11
o The following equipment is calibrated:
 Balance
 Volumetric flasks
 Pipette used to aliquot the internal solution

Measurement Assurance
• This laboratory has prepared a measurement assurance sample to use as quality control to ensure the
ongoing performance of the analytical test method (ISO/IEC 17025:2005, Clause 5.9.1). The measurement
assurance check standard12 contains the analyte of interest and a common diluent. The reference material

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Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
used to prepare this quality control sample is from a different source than that used to prepare the calibrators.
When initially prepared, the entire material was homogenized following the laboratory procedure. This
measurement assurance check standard is prepared by the laboratory in a large batch, packaged and stored
in a manner to provide a long shelf-life for the material.
o Concentration is determined in-house through repeat measurements
o Pre-defined criteria for acceptable performance (ISO/IEC 17025:2005, Clause 5.9.2) are based on
historical data
o The laboratory has 26 measurements made using this check standard
• The laboratory has determined that intermediate checks of the calibration status of the balance are required
(ISO/IEC 17025:2005, Clause 5.5.10). The laboratory procedure uses calibrated mass reference standards
with established measurement traceability to perform the intermediate checks of the calibration status of the
balance.
• To ensure proper functioning of the balance (ISO/IEC 17025:2005, Clause 5.5.6) the laboratory routinely
uses a measurement check standard surrogate to ensure ongoing proper functioning. All analysts
participate. The check standard used is a powder material, packaged for stability that is sensitive to
environmental changes in the laboratory.
• The laboratory has determined that no intermediate checks of the calibration status of the volumetric flasks
are necessary (ISO/IEC 17025:2005, Clause 5.5.10). The laboratory test method does require a basic visual
check for cleanliness and general status (no breakage or cracks) prior to each use to ensure proper
functioning (ISO/IEC 17025:2005, Clause 5.5.6).
• The laboratory has determined that intermediate checks of the calibration status of the pipette used to
measure the volume of internal standard are required (ISO/IEC 17025:2005, Clause 5.5.10). This program is
viewed to cover the function check requirement also (ISO/IEC 17025:2005, Clause 5.5.6). Because this is an
internal standard method, the most important characteristic of the pipette is precision during the short time of
use to prepare the calibrators, quality control and measurand for analysis.

 Measurand (VIM 2.3): quantity intended to be measured

 Quantity (VIM 1.1): property of a phenomenon, body, or substance, where the property has a magnitude that can
be expressed as a number and a reference

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 36 of 57

Drug Chemistry – Purity Determination of Drug R using Procedure No. XXXX, Revision ZZZZ

The measurement process can be shown by the following mathematical expression:

Imeasurand
Cmeasurand = Ccalibratorsx + b +/- U
Icalibrators
Where,
I is the instrument response
C is the concentration
b is a bias
U = expanded uncertainty

Each of these influences (inputs) on the measuring process will have uncertainty components that will be
considered.

 ISO/IEC 17025:2005, Clause 5.4.6.2 states “… the laboratory shall at least attempt to identify all the components
of uncertainty…”

The Eurachem/CITAC Guide on Quantifying Uncertainty in Analytical Measurement19 suggests that for analytical
methods it is helpful to break the analytical procedure into a set of generic steps when identifying uncertainty
components. This reference includes the following steps that are then further broken down to individual components:
Sampling
Sample Preparation
Presentation of Certified Reference Materials to the measuring instrument
Calibration of the Instrument
Analysis (data acquisition)

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 37 of 57

Sample preparation may include, but may not be limited to extraction, concentration, and derivatization. Each of these
steps will have uncertainty components to consider.

EXAMPLE 3, Step 2: Identify uncertainty components

Traceability is established for this measurement through the preparation of the calibrators used to establish
the calibration curve on the measuring system and through the calibration of other equipment used in the
measurement process where the calibration of the equipment is viewed to have a significant effect on sampling or
the accuracy of the test result.
• Calibrators
o Prepared using a reference material of known purity, a calibrated balance and calibrated volumetric
flasks.
 Both the balance and the volumetric flasks are considered to be equipment that has a significant
effect on the accuracy or validity of the test result (ISO/IEC 17025:2005, Clause 5.6.1).
o The multi-point calibration curve covering the reportable concentration range is established each
analytical run.
• Internal Standard
o The pipette used to add the specified volume of internal standard is considered to be a piece of
equipment that has a significant effect on sampling (ISO/IEC 17025:2005, Clause 5.6.1).
 The laboratory has the pipette calibrated by an appropriately accredited external calibration
laboratory.
 The procedure used to both check the calibration status (ISO/IEC 17025:2005, Clause 5.5.10) and
to ensure proper functioning of the pipette (ISO/IEC 17025:2005, Clause 5.5.6) requires the use of a
calibrated balance.
• Balance
o The laboratory has determined that the measurements made in the procedure to ensure proper
functioning of the pipette are to have measurement traceability. This is a second reason, to that above,
that the laboratory has the balance calibrated by an appropriately accredited calibration laboratory.
 Intermediate checks performed to ensure continued confidence in the calibration status of the
balance, are performed using calibrated mass reference standards.

The equipment (e.g., measuring device[s] or instrument[s]) used in this test method is:
• Chromatographic measuring system including sampling system and data processing software
• Analytical balance used in the preparation of calibrators, quality control samples and measurand samples as
well as the procedure to ensure the proper functioning of the pipette
• Volumetric flask(s) used to prepare calibrators
• Pipette used to measure the specified volume of internal standard

List of uncertainty components considered:

Staff
Multiple analysts
Training
Experience

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Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Calibrators
Purity of reference material
Not matrix matched to measurand
Quality Control Samples
Matrix control – stability
Measurand
Homogenization – grinding
Effects of sampling strategy
Physical state (solid or liquid)
Temperature
Internal Standard Preparation
Components – solid reference material appropriate for analyte being quantitated and solvent used to
dissolve calibrators, quality control samples and measurand
Concentration
Preparation of Calibrators, Quality Control and Measurand samples for analysis
Weighing of sample
Dissolution
Addition of internal standard – pipette
Uncertainty in pipette calibration
Variation between analysts
Volumetric flask(s)
Bringing to final volume - reading of the meniscus on the volumetric flask
Uncertainty in calibration of the volumetric flask(s)
Error in the volume of the volumetric flask(s)
Calibration of measuring system
Uncertainty in the calibrator values used to set the indication
Matrix match of calibrators to measurand
Instrument precision
Analysis
Instrument parameter settings (e.g., oven temperature(s), gas flow, split ratios, aging of chromatographic
column, autosampler syringe, autosampler precision, etc.)
Interference from the matrix
Interference from reagents
Interference from other compounds
Stability of sample(s) from preparation through analysis
Data Processing
Calibration model
Integration parameters
Processing algorithms

A laboratory may identify different uncertainty components when an evaluation of their specific measurement
process is performed.

This list of potential uncertainty components could also be compiled into a fishbone diagram or into any other format of
the laboratory’s choosing. Two fishbone diagram examples depicting possible uncertainty components and one blank
fishbone diagram are available on the ASCLD/LAB website at www.ascld-lab.org. Appendix C to this document
provides an example of using an Excel spreadsheet (available at www.ascld-lab.org) to display the information from
the NIST 8-Step Process.

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Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
NOTE: Regarding calculations in Excel:
Regardless of the number of digits that are shown in a cell, Excel carries the maximum number of digits in the
background and will use the entire number for further calculations.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(e) All uncertainty components of significance and how they were evaluated
(f) Data used to estimate repeatability and/or reproducibility
(g) All calculations performed

Review the list of uncertainty components created in Step 2. Identify which of the components listed can be quantified
by existing data from the measurement process.

The GUM (2.3.2) refers to this method of evaluation of one or more uncertainty components as:

 Type A evaluation (of uncertainty): method of evaluation of uncertainty by the statistical analysis of series
of observations

The quantification of the remaining uncertainty components is performed by a different method of evaluation referred
to by the GUM (2.3.3) as:

 Type B evaluation (of uncertainty): method of evaluation of uncertainty by means other than the statistical
analysis of series of observations

EXAMPLE 3, Step 3: Quantify uncertainty components

The calibration model was determined during method validation and was shown through the use of residual plots
to have equal variation across the linear range. Therefore, the laboratory is going to calculate an estimation of
measurement uncertainty for the entire reportable concentration range.
(Note: if variation is not constant across the reportable range, a laboratory can still choose to estimate a
single measurement uncertainty but will have to base calculations on the widest variation seen in the
measurement process or a laboratory can choose to break the reportable concentration range into two or
more sections and estimate the measurement uncertainty for each concentration section.)

The laboratory has existing data from the measurement process.

Data is available from ongoing quality control using the same check standard over a long period of time. This
check standard contains the analyte at approximately 50 % purity mixed with a common diluent. The laboratory

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 40 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
has 26 measurements of this QC check standard spanning a one year time period. All analysts have made
measurements using this measurement process.

The analytical process involves the weighing of similar weight samples for all calibrators, quality control samples
and replicate samples of the measurand. This weighing process uses the same balance, the same operator, and
occurs at approximately the same time. Since the purity concentration of the measurand is relational to the purity
concentration of the calibrators, any impact due to uncertainty in the balance calibration, drift in linearity,
readability of the balance and impact of facility temperature (see Example #1) are viewed to be captured by the
quality control check standard that goes through the same process.

Two uncertainty components related to the internal standard were listed for consideration. Using professional
judgment and assuming that the same batch of internal standard is used for all samples in an analytical batch, the
only aspect of the internal standard that has an influence on the measurement result is variation in the amount of
internal standard added to each calibrator, quality control sample or measurand sample by the pipette.

The uncertainty components and how they will be evaluated:

Uncertainty Component Method of Evaluation

Staff
Covered in Type A Evaluation of process
Multiple analysts
reproducibility data
Covered in Type A Evaluation of process
Training
reproducibility data
Covered in Type A Evaluation of process
Experience
reproducibility data
Calibrators
Purity of reference material Type B Evaluation
Initially evaluated during method validation
Quantified in Type A Evaluation of process
Not Matrix matched to measurand reproducibility data QC sample and through the
procedure administrative requirement for
agreement of replicates (Type B Evaluation)
Quality Control Samples
Covered in Type A Evaluation of process
Matrix control – stability
reproducibility data
Measurand
Initially evaluated during method validation and
reflected in measurement procedure
requirements
Homogenization – grinding
Controlled through the procedure administrative
requirement for agreement of replicates (Type
B Evaluation)
Initially evaluated during method validation and
reflected in measurement procedure
requirements
Effects of sampling strategy
Controlled through the procedure administrative
requirement for agreement of replicates (Type
B Evaluation)

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 41 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Controlled through the procedure administrative
Physical state (solid or liquid) requirement for agreement of replicates (Type
B Evaluation)
Controlled through the procedure administrative
Temperature requirement for agreement of replicates (Type
B Evaluation)
Internal Standard
Initially evaluated during method validation and
reflected in measurement procedure
requirements
Components
The measurement result will only be impacted
by the volume of the internal standard added to
each sample
Initially evaluated during method validation and
reflected in measurement procedure
requirements
Concentration
The measurement result will only be impacted
by the volume of the internal standard added to
each sample
Preparation of Calibrators, Quality Control sample and Measurand
Quantified in Type A Evaluation of process
reproducibility data QC sample and through the
Weighing of sample
procedure administrative requirement for
agreement of replicates (Type B Evaluation)
Initially evaluated during method validation and
Dissolution reflected in measurement procedure
requirements
Addition of internal standard – pipette
Type B Evaluation
(Note: Because precision is the primary
concern, a position could be supported that this
Uncertainty in pipette calibration component is covered by Type A Evaluation of
process reproducibility data if the QC is
sampled throughout the preparation of the
batch and not all at one time)
Covered in Type A Evaluation of process
Variation between analysts
reproducibility data
Volumetric flask(s)
Quantified in Type A Evaluation of process
Bringing to final volume - reading of the meniscus reproducibility data QC sample and through the
on the volumetric flask procedure administrative requirement for
agreement of replicates (Type B Evaluation)
Uncertainty in calibration of the volumetric flask(s) Type B Evaluation
Error in the volume of the volumetric flask(s) Type B Evaluation
Calibration of measuring system
Uncertainty in the calibrator values used to set the Duplicate listing of component – see Calibrator
indication section above

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Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
Duplicate listing of component – see Calibrator
Matrix match of calibrators to measurand
section above
Instrument precision
Covered in Type A Evaluation of process
reproducibility data

Analysis
Instrument parameter settings (e.g. oven
temperature(s), gas flow, split ratios, integration Covered in Type A Evaluation of process
parameters, aging of chromatographic column, reproducibility data
autosampler syringe, autosampler precision, etc)
Duplicate listing of component – see
Interference from the matrix
Measurand section above
This component is not an uncertainty
component but is a quality control concern
The laboratory analyzes a matrix blank that
Interference from reagents contains no analyte but does evaluate all
reagents used in the analytical method. The
laboratory procedure specifies acceptable
criteria for this quality control sample
This component is not an uncertainty
component but is a quality control concern
The laboratory, as part of the procedure to
Interference from other compounds identify the analyte prior to quantitation, will
have ensured that specificity of the
chromatographic quantitation test method is
acceptable.
Quantified in Type A Evaluation of process
reproducibility data QC sample and through the
Stability of sample(s) from preparation through analysis
procedure administrative requirement for
agreement of replicates (Type B Evaluation)
Data Processing
Covered in Type A Evaluation of process
Calibration model
reproducibility data
Covered in Type A Evaluation of process
Integration parameters
reproducibility data
Covered in Type A Evaluation of process
Processing algorithms
reproducibility data

Type A Evaluation of uncertainty components:

Measurement Process Reproducibility

The number of measurements from ongoing quality control sample data in this example is 26.

The data was evaluated and appears to have a normal distribution.

The data, graphed as a histogram has a normal, non-skewed distribution.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 43 of 57

The statistic that will be calculated is the percent relative standard deviation.
To begin the mean (average) and standard deviation of the data will be calculated.

Mean (Sample):

1 n
x = ∑ xi
n i =1

( x1 + x2 + x3 + ...xn )
x=
n

The mean of the reproducibility data in this example = 49.58 %

Standard Deviation (Sample):

∑ (x )
n
2
i −x
s= i =1
n −1
The standard deviation of the reproducibility data in this example = 2.98 %

Relative Standard Deviation (RSD):

s
RSD =
x

2.98
RSD =
49.58

RSD = 0.060

% Relative Standard Deviation = RSD *100

% RSD = 0.060 * 100

= 6.0 %

Type B Evaluation of uncertainty components:

Interference from the matrix:

The laboratory did evaluate matrix effects during method validation which resulted in the dilution factor (volume of
flask) used in the test method. Dilution of the sample, in combination with the procedural requirements for

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 44 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
homogenization of the measurand minimizes matrix effects. The laboratory does acknowledge that it is
impossible to evaluate all variations in measurand matrix during method validation; therefore, the test method
does include a matrix control and a requirement for agreement between replicate samples to quantify the impact
of matrix on the measurement.

The laboratory procedural requirement for replicate agreement is an example of an administrative requirement
that restricts variation in the measurement method.
• It is up to a laboratory to determine if an administrative control such as this example will be used.
o The decision will be based on, but may not be limited to, knowledge of the measurement process, the
impact of repeat analysis on cost and process efficiency, and the required expanded uncertainty.
• Measurement data may at times exceed the set administrative limit and not be a statistical outlier.

For this example, the laboratory procedure requires:

 two samples be taken from the homogenized measurand and
 the analyte concentration of the two replicates must be within +/-10.0 % of the average or the measurand
is further homogenized and the analysis is repeated.

The two components, process reproducibility and interference from matrix, quantify a number of the same
uncertainty components. The matrix control, over a longer period of time, holds the impact from matrix constant
while the effects from equipment, calibration, operators, and the laboratory environmental conditions vary. The
replicate samples of the measurand provide information on the measurand matrix and a short–term evaluation of
the effect from equipment, calibration, operators, and the laboratory environment. Any double-counting of a
component will result in an over estimation of the measurement uncertainty.

Calibrators: Purity of reference material

The reference material was purchased from an authoritative source. Stated purity is >99 %.
99 % purity is the minimum and 100 % pure the maximum. Therefore, the range can be expressed as 99.5 % +/-
0.5 %.

Pipette Calibration Uncertainty:

A review of the calibration certificate from the accredited external calibration laboratory identified that the
calibration expanded uncertainty at the usable range of 1000 µL is 1.8 µL.

The relative percentage uncertainty is:

1.8 µL/1000 µL * 100 = 0.18 %

Volumetric Flask(s) Calibration Uncertainty:

A review of the calibration certificates from the accredited external calibration laboratory for all volumetric flasks
that are available for use in this procedure identified that the greatest calibration expanded uncertainty is
0.0086mL.

The relative percentage uncertainty is:

0.0086 mL / 25 mL * 100 = 0.0344 %

Error in the volume of the volumetric flask:

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 45 of 57

All uncertainty components must be expressed as a standard uncertainty and in the same measurement unit.

 Standard Uncertainty (VIM 2.30): measurement uncertainty expressed as a standard deviation

EXAMPLE 3, Step 4: Convert quantities to standard uncertainties

The measurement unit:

The estimate of measurement uncertainty will be a relative uncertainty expressed as a percentage.

Type A Evaluation of uncertainty components:

Measurement Process Reproducibility data: is in the correct measurement unit

is expressed as one standard deviation
The % relative standard deviation of the reproducibility data in this example = 6.0 %

In this example, the measurand is sampled in duplicate and the laboratory procedure for the reported purity is to
average the two measurement results. Repeat measurements of the measurand provide more information and
more confidence that the reported result is the best estimate of the true value. When multiple measurements are
made of the measurand and the average is reported and the measurement process reproducibility data is based
on single measurements of quality control samples, the standard deviation of the measurement process can be
divided by the square root of the number of measurements. This statistic is the standard deviation of the mean.
If a single measurement result for the measurand is selected to be reported (e.g., the lowest value), then the
standard deviation of the mean calculation is not applicable. If the laboratory makes an equal number of multiple
measurements of the quality control sample as it does of the measurand and averages the results to evaluate the
acceptability of the quality control sample, then the standard deviation of the mean calculation is not applicable.
The % relative standard deviation of the reproducibility data in this example = 6.0 %
The mathematical expression for relative standard deviation of the mean:

RSD
RSDmean =
n

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 46 of 57

RSDmean = 4.24%

Type B Evaluation of uncertainty components:

Interference from the matrix:

The laboratory procedure requires:
two samples be taken from the homogenized measurand and
the analyte concentration of the two aliquots must be within +/-10.0 % of the average or the analysis is
repeated.

This component is evaluated as a rectangular distribution:

Upper limit = +a
Lower limit = -a
Possible range of values = (+a) - (-a) = 2a

For a rectangular distribution, the standard uncertainty is calculated by:

standard uncertainty = a / √3

The outside limit = 10.0 %

standard uncertainty = 10.0 % / √3

= 5.77 %

Calibrators: Purity of reference material

This component is evaluated as a rectangular distribution:

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 47 of 57

For a rectangular distribution, the standard uncertainty is calculated by:

standard uncertainty = a / √3

The outside limit = 0.5 %

standard uncertainty = 0.5 % / √3

= 0.29 %

Pipette Calibration Uncertainty:

A review of the calibration certificate from the accredited external calibration laboratory identified that the
calibration expanded uncertainty at the usable range of 1000 µL is 1.8 µL.

The relative percentage uncertainty is:

1.8 µL / 1000 µL * 100 = 0.18 %

The certificate indicates this expanded uncertainty assumes a normal distribution, a coverage factor of k = 2 and
a coverage probability of approximately 95 %.

The uncertainty on the calibration certificate will be divided by the coverage factor, 2, to arrive at a standard
uncertainty.

standard uncertainty = 0.18 % / 2

= 0.09 %

Volumetric Flask(s) Calibration Uncertainty:

The relative percentage uncertainty is:

0.0086 mL / 25 mL * 100 = 0.0344 %

The certificate indicates this expanded uncertainty assumes a normal distribution, a coverage factor of k = 2 and
a coverage probability of approximately 95 %.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 48 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
The uncertainty on the calibration certificate will be divided by the coverage factor, 2, to arrive at a standard
uncertainty.

standard uncertainty = 0.0344 % / 2

= 0.02 %

Error in the volume of the volumetric flask:

The relative percentage error is:

0.0350 mL / 25 mL * 100 = 0.14 %

This component is evaluated as a rectangular distribution:

Upper limit = +a
Lower limit = -a
Possible range of values = (+a) - (-a) = 2a

For a rectangular distribution, the standard uncertainty is calculated by:

standard uncertainty = a / √3

The outside limit = 0.14 %

standard uncertainty = 0.14 % / √3

= 0.08 %

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 4.1 requires ASCLD/LAB-International applicant and
accredited testing laboratories to record for each estimation of measurement uncertainty:
(g) All calculations performed
(h) The combined standard uncertainty,…

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 49 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
estimated standard deviation and characterizes the dispersion of the values that could reasonably be attributed to the
measurement result at the equivalent of one standard deviation, a coverage probability of 68.26 %.

∑(c u )
2
uc ( y ) = i i

uc ( y ) = s 2p + u02 + u12 + u22 + ..... + ui2

EXAMPLE 3, Step 5: Calculate the combined standard uncertainty

The estimation will assume that the uncertainty components are independent or uncorrelated and that the
measurement result is the sum of a series of components.

Care must be taken if the measurement results lie over a range of values. If the laboratory has information that
an individual component does not vary consistently across the measurement range, then the laboratory must
decide how this will be handled. In this scenario, the calibration model was determined during method validation
and was shown through the use of residual plots to have equal variation across the linear range so a single
estimation of measurement uncertainty can be calculated for the entire concentration range. Another option is to
calculate a measurement uncertainty for different ranges of measurements.

As noted in Step 3, the two components, process reproducibility and interference from matrix, quantify a number
of the same uncertainty components. The matrix control, over a longer period of time, holds the impact from
matrix constant while the effects from equipment, calibration, operators, and the laboratory environmental
conditions vary. The replicate samples of the measurand provide information on the measurand matrix and a
short–term evaluation of the effect from equipment, calibration, operators, and the laboratory environment. Any
double-counting of a component will result in an over estimation of the measurement uncertainty.

u=
c ( y)
2
sreproducibility + uMatrix
2
+ uRMpurity
2
+ u 2pipettecal + u 2flaskcal + u 2flaskvolerr

u=
c ( y) 4.242reproducibility + 5.77 2Matrix + 0.292RMpurity + 0.092pipettecal + 0.022flaskcal + 0.082flaskvolerr

uc ( y ) = 51.44

uc ( y ) = 7.17 %

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 50 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
The combined standard uncertainty, calculated in Step 5, is an estimated standard deviation and characterizes the
dispersion of the values that could reasonably be attributed to the measurement result at the equivalent of one
standard deviation, a coverage probability of 68.26 %.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.2 requires the coverage probability to be a minimum
of 95.45 % (often referred to as approximately 95 %).

The coverage probability of the combined standard uncertainty must be expanded to comply with the ASCLD/LAB
Policy.

EXAMPLE 3, Step 6: Expand the combined standard uncertainty by coverage factor (k)

The laboratory data is based on 26 measurements which equal 25 degrees of freedom.

The assumptions for a normal distribution are modified when a limited number of measurements are used for
repeatability data and/or reproducibility data. Refer to the Student’s t-distribution table, Table 1 in ASCLD/LAB
Guidance on the Estimation of Measurement Uncertainty – ANNEX A9 for the specific values of k.

To expand the uncertainty to a 95.45 % coverage probability the coverage factor k = 2.113 will be used.
A laboratory can choose to increase the coverage probability. If a laboratory chose to increase the coverage
probability to 99.73 %, then the coverage factor k = 3.333 will be used.

k = 2.11 U= 2.11 * 7.17 = 15.13 %

k = 3.33 U= 3.33 * 7.17 = 23.88 %

EXAMPLE 3, Step 7: Evaluate the expanded uncertainty

Step 7 is the time to critically evaluate the estimation of uncertainty and to determine if it “makes sense” and is
“reasonable.”

• The laboratory may identify calculation errors in this Step.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 51 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
• The laboratory will decide if the uncertainty results are appropriate for the test method. If the laboratory
placed limits on the acceptable expanded uncertainty, does the calculated value meet the stated
requirement?
• Does the expanded uncertainty meet the customer’s needs?

If the laboratory determines that the expanded uncertainty is not acceptable, areas of method improvement (e.g.,
measurement method standardization, improved calibration of equipment, etc.) can be identified and evaluated for the
impact that a change would have on the estimation of uncertainty using the information available from Steps 3 and 4.

Once changes to a test method have been validated, the appropriate edits to Steps 1-6 can be made and the
estimation of uncertainty reevaluated.

Is there a requirement regarding the relationship between the calculated expanded uncertainty and the
measurement result or the limit of quantification of a test method?

Neither ISO/IEC 17025:2005 nor ASCLD/LAB-International Policy on Measurement Uncertainty specifies how large
the expanded uncertainty can be in relationship to the measurement result. It will be up to laboratory to determine
what is acceptable as part of the laboratory procedure for estimating uncertainty of measurement.

The Eurachem/CITAC Guide on Quantifying Uncertainty in Analytical Measurement19 provides the following
information on this topic.

• At low concentration, an increasing number of effects become important

• The relative uncertainty associated with the result tends to increase, first to a substantial fraction of the result
and finally to the point where the (symmetric) uncertainty interval includes zero. This region is typically
associated with the practical limit of detection or limit of quantitation for a given method.
• The GUM does not give explicit instructions when the results are small and the uncertainties large compared
to the results. Indeed, the basic form of the ‘law of propagation of uncertainties’ may cease to apply
accurately in this region; one assumption on which the calculation is based is that the uncertainty is small
relative to the value of the measurand.
• An additional, if philosophical, difficulty follows because values below zero cannot be reasonably ascribed to
the value of the measurand when the measurand is a concentration, because concentrations themselves
cannot be negative.
• These difficulties do not preclude the application of the estimation methods but some caution is required in
interpretation and reporting the results of measurement uncertainty estimation in this region.

 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.1 requires the laboratory to have a procedure for the
process of rounding the uncertainty.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 52 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
 ASCLD/LAB Policy on Measurement Uncertainty, Clause 3.1.2 requires the coverage probability of the expanded
uncertainty to be a minimum of 95.45 % (often referred to as approximately 95 %).

Refer to the Policy for all reporting requirements as only selected reporting requirements are being covered in this
Guidance Document.

 For testing laboratories:

NOTE 1 For asymmetrical uncertainties, it may be inappropriate to quote a single result for the
uncertainty and presentations other than y ± U may be needed.

5.3.3 The measurement result and the rounded expanded uncertainty shall be reported to the same level of
significance.

EXAMPLE 3, Step 8: Report the uncertainty

k = 2.11 U= 2.11 * 7.17 = 15.13 %

k = 3.33 U= 3.33 * 7.17 = 23.88 %

k = 2.11 U= 15 %
k = 3.33 U= 24 %

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 53 of 57

The percentage of Drug R in Item 1 was found to be 65 % +/- 15 % at a coverage probability of 95.45 %.

The percentage of Drug R in Item 1 was found to be 65 % +/- 24 % at a coverage probability of 99.73 %.

A laboratory can include additional information regarding the test result’s relationship to a specification in the test
report but it must be additional information and not in place of that which is required by the ASCLD/LAB Policy on
Measurement Uncertainty. If a laboratory wishes to compare a test result to a specification (e.g., statute limit), the
expanded uncertainty is taken into account in evaluating compliance to the specification. The report must accurately,
clearly, unambiguously and objectively communicate this information.

Example report statements that include additional information regarding a specification:

The percentage of Drug R in Item 1 was found to be 97 % +/- 15 % at a coverage probability of 95.45 %.
Taking the estimated measurement uncertainty into consideration the concentration of Drug R in Item 1 is greater
80 %.

The percentage of Drug R in Item 1 was found to be 97 % +/- 24 % at a coverage probability of 99.73 %.
Taking the estimated measurement uncertainty into consideration, there is a possibility that the concentration of
Drug R in Item 1 is less than 80 %.

In the scenario above, where the test result considering the expanded uncertainty is not clearly outside a specification,
the report will need to accurately, clearly, unambiguously and objectively report this information.

Possibly scenarios are depicted below:

The measurement
result +/- the
expanded
The measurement uncertainty is above
result +/- the the limit.
expanded
uncertainty is not
above the limit.

LIMIT

The measurement
result +/- the
expanded
uncertainty is not
The measurement
below the limit.
result +/- the
expanded
uncertainty is below
the limit.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 54 of 57

1 American Society of Crime Laboratory Directors / Laboratory Accreditation Board (ASCLD/LAB): ASCLD/LAB Policy on
Measurement Uncertainty (AL-PD-3060) (Garner, North Carolina: ASCLD/LAB, 2013). Available at www.ascld-lab.org.

2 Adapted from:
National Institute of Standards and Technology, SOP 29 – Standard Operating Procedure for the Assignment of
Uncertainty, (Gaithersburg, Maryland, February 2012). Available for download at
http://www.nist.gov/pml/wmd/labmetrology/upload/SOP_29_20120229.pdf
3
Joint Committee for Guides in Metrology (JCGM), Evaluation of measurement data – Guide to the expression of uncertainty
in measurement (GUM) (GUM 1995 with minor corrections). (Sèvres, France: International Bureau of Weights and Measures
[BIPM]-JCGM 100], September 2008). Available at http://www.bipm.org/en/publications/guides/gum.html.

Even though the electronic version of the 2008 edition of the GUM is available free of charge on the BIPM’s website,
copyright of that document is shared jointly by the JCGM member organizations (BIPM, IEC, IFCC, ILAC, ISO, IUPAC,
IUPAP and OIML).

4 Joint Committee for Guides in Metrology (JCGM), International vocabulary of metrology – Basic and general concepts and
associated terms (VIM), 3rd ed. (Sèvres, France: International Bureau of Weights and Measures [BIPM]-JCGM 200, 2012)
(2008 with minor corrections). Available for download at http://www.bipm.org/en/publications/guides/vim.html.

Even though the electronic version of the 3rd edition of the VIM is available free of charge on the BIPM’s website, copyright
of that document is shared jointly by the JCGM member organizations (BIPM, IEC, IFCC, ILAC, ISO, IUPAC, and OIML).

5 International Organization for Standardization (ISO), ISO/IEC 17025:2005 General requirements for the competence of
testing and calibration laboratories (Geneva, Switzerland: ISO, 2005). Available for purchase at
http://www.iso.org/iso/home/store/catalogue_ics.htm or from other authorized distributors.

Additional information about ISO is available at http://www.iso.org/iso/home.html.

6 ASCLD/LAB, ASCLD/LAB-International Supplemental Requirements for the Accreditation of Forensic Science

Testing Laboratories (AL-PD-3040) (Garner, North Carolina, 2011 Edition).

Acquisition and use of that document requires a User License Agreement with ASCLD/LAB and an ISO/IEC 17025
Certification Statement. Acquisition forms are available at www.ascld-lab.org or by contacting ASCLD/LAB. Contact
information for ASCLD/LAB is provided on page 2 of this document.

7 ASCLD/LAB, ASCLD/LAB-International Program Applications, Guidance and Board Interpretations [for] Forensic
Science Testing Laboratories (Web only access, available at www.ascld-lab.org).

8 ASCLD/LAB, ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty - Overview (AL-PD-3061) (Garner,
North Carolina: ASCLD/LAB, 2013). Available at www.ascld-lab.org.

9 ASCLD/LAB, ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty - Annex A Details on the NIST 8-
Step Process (AL-PD-3062) (Garner, North Carolina: ASCLD/LAB, 2013). Available at www.ascld-lab.org.

10 SWGDRUG, SUPPLEMENTAL DOCUMENT SD-3 FOR PART IVC – Quality Assurance/Uncertainty Measurement
Uncertainty for Weight Determinations in Seized Drug Analysis.(SWGDRUG 2011-07-07) Available at
http://www.swgdrug.org/supplemental.htm

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 55 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
11 ASCLD/LAB, ASCLD/LAB Policy on Measurement Traceability (AL-PD-3057) (Garner, North Carolina: ASCLD/LAB,
2013). Available at www.ascld-lab.org.

12 ASCLD/LAB, ASCLD/LAB Guidance on Measurement Traceability – Measurement Assurance (AL-PD-3059) (Garner,

North Carolina: ASCLD/LAB, 2013). Available at www.ascld-lab.org.

13 National Institute of Standards and Technology, NISTIR 6919 - Recommended Guide for Determining and reporting
Uncertainties for Balances and Scales, (Gaithersburg, Maryland, January 2002). Available for download at
http://www.nist.gov/pml/wmd/pubs/nistir.cfm

14 ASCLD/LAB, ASCLD/LAB Guidance on Measurement Traceability (AL-PD-3057) (Garner, North Carolina: ASCLD/LAB,
2013). Available at www.ascld-lab.org.

15 VIM Definition 2.13 – measurement accuracy: closeness of agreement between a measured quantity value and a true
quantity value of a measurand. NOTE 1: The concept ‘measurement accuracy’ is not a quantity and is not given a numerical
quantity value.

Source: Joint Committee for Guides in Metrology (JCGM), International vocabulary of metrology – Basic and general
concepts and associated terms (VIM), 3rd ed. (Sèvres, France: International Bureau of Weights and Measures [BIPM]-JCGM
200, 2012) (2008 with minor corrections).

16 VIM Definition 2.15- measurement precision: closeness of agreement between indications or measured quantity values
obtained by replicate measurements on the same or similar objects under specified conditions. NOTE 1: Measurement
precision is usually expressed numerically by measures of imprecision, such as standard deviation, variance, or coefficient of
variation under the specified conditions of measurement.

17 VIM Definition 2.18 - bias: estimate of a systematic measurement error

18 National Institute of Standards and Technology, SOP 29 – Standard Operating Procedure for the Assignment of
Uncertainty, (Gaithersburg, Maryland, February 2012). Available for download at
http://www.nist.gov/pml/wmd/labmetrology/upload/SOP_29_20120229.pdf

19 S L R Ellison and A Williams (Eds). Eurachem/CITAC Guide: Quantifying Uncertainty in Analytical Measurement, Third
edition, (QUAM: 2012 P1) Available for download at http://www.eurachem.org/index.php/publications/guides

Additional information about EURACHEM is available at http://www.eurachem.org/index.php/euintro.

Additional information about CITAC is available at http://www.citac.cc/.

20 National Institute of Standards and Technology, GMP 3 - Good Measurement Practice for Method of Reading A
Meniscus Using Water or Other Wetting Liquid, (Gaithersburg, Maryland, March 2012). Available for download at:
http://www.nist.gov/pml/wmd/labmetrology/upload/GMP_3_20120314.pdf

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 56 of 57

Drug Chemistry Discipline – Three Examples – Weight, Volume and Purity Determination
Approval Date: May 22, 2013 Effective Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director AL-PD-3063 Ver 1.0
21 SWGDRUG, SUPPLEMENTAL DOCUMENT SD-4 FOR PART IVC – Quality Assurance/Uncertainty Measurement
Uncertainty for Purity Determinations in Seized Drug Analysis.(SWGDRUG 2011-07-07) Available at
http://www.swgdrug.org/supplemental.htm

22 VIM Definition – 5.12 calibrator: measurement standard used in calibration. NOTE: The term “calibrator” is only used in
certain fields.

23 VIM Definition – 3.2 measuring system: set of one or more measuring instruments and often other devices, including any
reagent and supply, assembled and adapted to give information used to generate measured quantity values within specified
intervals for quantities of specified kinds

ASCLD/LAB NOTE: For interpreting and applying 3.3.2 of this policy, a gas chromatograph is an example of a measuring
system.

ASCLD/LAB Guidance on the Estimation of Measurement Uncertainty – ANNEX B Page 57 of 57

Measurement Uncertainty Estimation Form

Measurement: Weight Determination of a Controlled Substance
Range of measurement values: Enter appropriate range
Procedure name and revision: Drug Chemistry No. XXXX, Revision ZZZZ
Estimation prepared by: ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 70
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty % 60
1 Measurement Process Reproducibility 0.031 gram A normal 1.00 >200 0.031 63 50
2 Display Resolution - rounding at zero 0.005 gram B rectangular 1.73 ∞ 0.003 6 40
3 Display Resolution - rounding at load 0.005 gram B rectangular 1.73 ∞ 0.003 6 30
4 Balance calibration uncertainty 0.013 gram B normal 2.00 ∞ 0.007 13
20
5 Linearity - allowed tolerance of accuracy checks 0.01 gram B rectangular 1.73 ∞ 0.006 12
10
Combined Standard Unc u 0.032 100
0
Expanded Unc in grams U (k = 2.000) 0.065
1 2 3 4 5
Expanded Unc in grams U (k = 3.000) 0.097
Reported Uncertainty (gram): 0.07 gram k = 2.000
Reported Uncertainty (gram): 0.10 gram k = 3.000

NOTE: Regardless of the number of digits that are showing in a cell, Excel carries the maximum number of significant figures in the background and will use the entire number for further calculations

The basis for the data above:

Measurement Process Reproducibility - this entry is a combined estimation for uncertainty components listed in Step 3 as Type A method of evaluation
1 Assumes a normal distribution
2 Display Resolution at zero = 0.01 g; The impact on rounding will be = 1/2 of the least count of the instrument
Display Resolution at load = 0.01 g; The impact on rounding will be = 1/2 of the least count of the instrument
IF working with a dual-range balance the scale readability at zero and load will be different.
3 (Note: a position can be supported that these two components for Scale Readability can be covered by sufficient measurement assurance program data)
4 Balance calibration largest uncertainty = 0.013; assume a normal distribution; k =2; approximate 95% confidence level
5 Linearity - Maximum deviation permitted in calibration status check = 0.01 gram

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix A to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

Estimation - no bias component - with step annotations Page A2 Appendix A to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Weight Determination of a Controlled Substance
Range of measurement values: Enter appropriate range

Step 1
Procedure name and revision:
Step 2
Drug Chemistry No. XXXX, Revision ZZZZ
Estimation prepared by: StepASCLD/LAB
3 Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 70
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty % 60
1 Measurement Process Reproducibility 0.031 gram A normal 1.00 >200 0.031 63 50
2 Display Resolution - rounding at zero 0.005 gram B rectangular 1.73 ∞ 0.003 6 40
3 Display Resolution - rounding at load 0.005 gram B rectangular 1.73 ∞ 0.003 6 30
4 Balance calibration uncertainty 0.013 gram B normal 2.00 ∞ 0.007 13
20
5 Linearity - allowed tolerance of accuracy checks 0.01 gram B rectangular 1.73 ∞ 0.006 12
Step 5

10
Combined Standard Unc u 0.032 100
0
Expanded Unc in grams U (k = 2.000) 0.065
Step 6

1 2 3 4 5
Expanded Unc in grams U (k = 3.000) Step 4 0.097
Reported Uncertainty (gram): 0.07 gram k = 2.000

Step 8
Reported Uncertainty (gram): 0.10 gram k = 3.000
Step 7
NOTE: Regardless of the number of digits that are showing in a cell, Excel carries the maximum number of significant figures in the background and will use the entire number for further calculations

The basis for the data above:

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix A to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

Estimation with bias component - no annotations Page A3 Appendix A to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Weight Determination of a Controlled Substance
Range of measurement values: Enter appropriate range
Procedure name and revision: Drug Chemistry No. XXXX, Revision ZZZZ
Estimation prepared by: ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 70
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty % 60
1 Measurement Process Reproducibility 0.031 gram A normal 1.00 >200 0.031 60
50
2 Display Resolution - rounding at zero 0.005 gram B rectangular 1.73 ∞ 0.003 6
3 Display Resolution - rounding at load 0.005 gram B rectangular 1.73 ∞ 0.003 6 40
4 Balance calibration uncertainty 0.013 gram B normal 2.00 ∞ 0.007 13 30
5 Linearity - allowed tolerance of accuracy checks 0.01 gram B rectangular 1.73 ∞ 0.006 11 20
6 Mass reference standard calibration uncertainty 0.0055 gram B normal 2.00 ∞ 0.003 5 10
Combined Standard Unc u 0.033 100
0
Expanded Unc in grams U (k = 2.000) 0.065 1 2 3 4 5 6
Expanded Unc in grams U (k = 3.000) 0.098
Reported Uncertainty (gram): 0.07 gram k = 2.000
Reported Uncertainty (gram): 0.10 gram k = 3.000

NOTE: Regardless of the number of digits that are showing in a cell, Excel carries the maximum number of significant figures in the background and will use the entire number for further calculations

The basis for the data above:

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix A to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

Estimation with bias component - with step annotations Page A4 Appendix A to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Weight Determination of a Controlled Substance
Range of measurement values: Enter appropriate range

Step 1
Procedure name and revision: Drug Chemistry No. XXXX, Revision ZZZZ
Estimation prepared by: Step 2 Step 3ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 70
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty % 60
1 Measurement Process Reproducibility 0.031 gram A normal 1.00 >200 0.031 60
50
2 Display Resolution - rounding at zero 0.005 gram B rectangular 1.73 ∞ 0.003 6
3 Display Resolution - rounding at load 0.005 gram B rectangular 1.73 ∞ 0.003 6 40
4 Balance calibration uncertainty 0.013 gram B normal 2.00 ∞ 0.007 13 30
5 Linearity - allowed tolerance of accuracy checks 0.01 gram B rectangular 1.73 ∞ 0.006 11 20
6 Mass reference standard calibration uncertainty 0.0055 gram B normal 2.00 ∞ 0.003 5 10
Step 5

Combined Standard Unc u 0.033 100

0
Expanded Unc in grams U (k = 2.000) 0.065
Step 6

1 2 3 4 5 6
U (k = 3.000)
Step 4
Expanded Unc in grams 0.098
Reported Uncertainty (gram): 0.07 gram k = 2.000

Step 8
Reported Uncertainty (gram): 0.10 gram k = 3.000 Step 7

NOTE: Regardless of the number of digits that are showing in a cell, Excel carries the maximum number of significant figures in the background and will use the entire number for further calculations

The basis for the data above:

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix A to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

Estimation - no annotations Page B1 Appendix B to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Drug Chemistry - Volume Determination
Range of measurement values: 10 - 100 mL
Procedure name and revision: Test Method No. XXXX, Revision ZZZZ
Estimation prepared by: ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 150
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty %
100
1 Graduated Cylinder Scale Readability 1.0 mL Rectangular B 1.73 ∞ 0.577 96
2 Graduated Cylinder Calibration Uncertainty 0.050 mL Normal B 2.00 ∞ 0.025 4 50
Combined Standard Unc u 0.578 100
0
Expanded Unc U (k = 2.000) 1.156
1 2
Expanded Unc U (k = 3.000) 1.734
Reported Uncertainty: 1 mL k = 2.000
Reported Uncertainty: 2 mL k = 3.000

The basis for the data above:

1 Graduated Cylinder Scale Readability - 1 mL
2 Graduated Cylinder Calibration Uncertainty = 50 µL = 0.050 mL; assumes a normal distribution; k =2; approximate 95% confidence level

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix B to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

Estimation with step annotations Page B2 Appendix B to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Drug Chemistry - Volume Determination
Range of measurement values: 10 - 100 mL

Step 1
Procedure name and revision:
Step 2 Test Method No. XXXX, Revision ZZZZ
Step 3
Estimation prepared by: ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 150
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty %
100
1 Graduated Cylinder Scale Readability 1.0 mL Rectangular B 1.73 ∞ 0.577 96
2 Graduated Cylinder Calibration Uncertainty 0.050 mL Normal B 2.00 ∞ 0.025 4 50
Step 5

Combined Standard Unc u 0.578 100

0
Expanded Unc U (k = 2.000) 1.156
Step 6

1 2
Expanded Unc U (k = 3.000) Step 4 1.734
Reported Uncertainty: 1 mL k = 2.000

Step 8
Reported Uncertainty: 2 mL k = 3.000

The basis for the data above: Step 7

1 Graduated Cylinder Scale Readability - 1 mL

2 Graduated Cylinder Calibration Uncertainty = 50 µL = 0.050 mL; assumes a normal distribution; k =2; approximate 95% confidence level

Revision: 1

ASCLD/LAB Document Control Information:

A blank form is available at www.ascld-lab.org

Estimation - no annotations Page C1 Appendix C to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Purity Determination of Drug R
Range of measurement values: Enter reportable concentration Range
Procedure name and revision: Procedure No. XXXX, Revision ZZZZ
Estimation prepared by: ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 60
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty %
50
1 Measurement Process Reproducibility - %RSD 6.0 % normal A 1.41 25 4.24 40
2 Homogeneity 10.0 % rectangular B 1.73 ∞ 5.77 55 40
3 Purity of reference material 0.5 % rectangular B 1.73 ∞ 0.29 3 30
4 Uncertainty of pipette calibration 0.18 % normal B 2 ∞ 0.09 1
20
5 Uncertainty of volumetric flask calibration 0.0344 % normal B 2 ∞ 0.02 0
6 Error in volume of volumetric flask 0.14 % rectangular B 1.73 ∞ 0.08 1 10
Combined Standard Unc u 7.17 100
0
Expanded Unc U (k = 2.11 for n=26; degrees of freedom = 25) 15.13 1 2 3 4 5 6
Expanded Unc U (k = 3.33 for n=26; degrees of freedom = 25) 23.88
Reported Uncertainty: 15 % k = 2.11
Reported Uncertainty: 24 % k = 3.33

The basis for the data above:

1 Measurement Process Reproducibility - this entry is a combined estimation for uncertainty components listed in Step 3 as Type A method of evaluation
This calculation is also based on two replicate samples and the average of the two being reported
Assumes a normal distribution
2 Homogeneity - laboratory control of 10.0 %
3 Purity of reference material - stated purity is greater than or equal to 99%.
99% purity is the minimum and 100% pure the maximum. Therefore, the range can be expressed as 99.5% +/- 0.5%.
4 Uncertainty of pipette calibration = 1.8 µL; at useable volume of 1000 µL this equals a relative percentage uncertainty of 0.18%; certificate indicates k = 2; approximate
95% confidence level
5 Uncertainty of volumetric flask calibration = 0.0086 mL; at volume of 25 mL this equals a relative percentage uncertainty of 0.0344%; certificate indicates k = 2;
approximate 95% confidence level
6 Error in volume of volumetric flask = 0.0350 mL; Equals a relative percentage error for a 25 mL flask of 0.14%

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix C to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

Estimation with step annotations Page C2 Appendix C to AL-PD-3063

Measurement Uncertainty Estimation Form

Measurement: Purity Determination of Drug R
Range of measurement values: Enter reportable concentration Range

Step 1
Procedure name and revision: Procedure No. XXXX, Revision ZZZZ
Step 2
Estimation prepared by: Step 3 ASCLD/LAB Guidance Document Annex B Date Prepared: April 1, 2013
Degrees Component
Line Uncertainty Freedom Standard Contribution 60
Item Component Value Units Distribution Type Divisor (n-1) Uncertainty %
50
1 Measurement Process Reproducibility - %RSD 6.0 % normal A 1.41 25 4.24 40
2 Homogeneity 10.0 % rectangular B 1.73 ∞ 5.77 55 40
3 Purity of reference material 0.5 % rectangular B 1.73 ∞ 0.29 3 30
4 Uncertainty of pipette calibration 0.18 % normal B 2 ∞ 0.09 1
20
5 Uncertainty of volumetric flask calibration 0.0344 % normal B 2 ∞ 0.02 0
6 Error in volume of volumetric flask 0.14 % rectangular B 1.73 ∞ 0.08 1 10
Step 5

Combined Standard Unc u 7.17 100

0
Expanded Unc U (k = 2.11 for n=26; degrees of freedom = 25) 15.13
Step 6

Step 4 1 2 3 4 5 6
Expanded Unc U (k = 3.33 for n=26; degrees of freedom = 25) 23.88
Reported Uncertainty: 15 % k = 2.11

Step 8
Reported Uncertainty: 24 % k = 3.33
Step 7
The basis for the data above:
1 Measurement Process Reproducibility - this entry is a combined estimation for uncertainty components listed in Step 3 as Type A method of evaluation
This calculation is also based on two replicate samples and the average of the two being reported
Assumes a normal distribution
2 Homogeneity - laboratory control of 10.0 %
3 Purity of reference material - stated purity is greater than or equal to 99%.
99% purity is the minimum and 100% pure the maximum. Therefore, the range can be expressed as 99.5% +/- 0.5%.
4 Uncertainty of pipette calibration = 1.8 µL; at useable volume of 1000 µL this equals a relative percentage uncertainty of 0.18%; certificate indicates k = 2; approximate
95% confidence level
5 Uncertainty of volumetric flask calibration = 0.0086 mL; at volume of 25 mL this equals a relative percentage uncertainty of 0.0344%; certificate indicates k = 2;
approximate 95% confidence level
6 Error in volume of volumetric flask = 0.0350 mL; Equals a relative percentage error for a 25 mL flask of 0.14%

Revision: 1

ASCLD/LAB Document Control Information:

Approval Date: May 22, 2013
Approved By: ASCLD/LAB Executive Director
Effective Date: May 22, 2013
Appendix C to AL-PD-3063 Ver 1.0

A blank form is available at www.ascld-lab.org

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