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Page 1: Metrology and Calibration in GLP

www.eurofinsagro.com07/04/23 confidential

Metrology and Calibration in GLP

Technical and Practical Aspects for

Contract Research OrganisationsXIX SEGCIB Congress

Barcelona, 18 november 2010

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Topics

GLP Guidelines and Equipment Calibrations Basic Concepts in Metrology Calibrations and Uncertainty of Measurement Certificates of Calibration Practical Aspects when using values from certificates of

calibration within CRO’s

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GLP Guidelines and Equipment Calibrations

OECD Series No. 1 – Principles of Good Laboratory Practice

Point 4.2“Apparatus used in a study should be periodically inspected, cleaned, maintained, and calibrated according to Standard Operating Procedures. Records of these activities should be maintained. Calibration should, where appropriate, be traceable to national or international standards of measurement.”

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GLP Guidelines and Equipment Calibrations

International Vocabulary of Metrology (VIM)

Calibration

2.39 (6.11)

“operation that, under specified conditions, in a first step, establishes a relation between the quantity values with measurement uncertainties provided by measurement standards and corresponding indications with associated measurement uncertainties and, in a second step, uses this information to establish a relation for obtaining a measurement result from an indication”

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GLP Guidelines and Equipment Calibrations

NOTES:

1- A calibration may be expressed by a statement, calibration function, calibration diagram, calibration curve, or calibration table. In some cases, it may consist of an additive or multiplicative correction of the indication with associated measurement uncertainty.

2 - Calibration should not be confused with adjustment of a measuring system, often mistakenly called “self-calibration”, nor with verification of calibration.

3 - Often, the first step alone in the above definition is perceived as being calibration.

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GLP Guidelines and Equipment Calibrations

Verification (2.44)

“provision of objective evidence that a given item fulfils specified requirements”

NOTES:

1 — The item may be, e.g. a process, measurement procedure, material, compound, or measuring system.

2 — The specified requirements may be, e.g. that a manufacturer's specifications are met..

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GLP Guidelines and Equipment Calibrations

NOTES (Continued)

3 — Verification in legal metrology, as defined in VIML[53], and in conformity assessment in general, pertains to the examination and marking and/or issuing of a verification certificate for a measuring system.

4 — Verification should not be confused with calibration. Not every verification is a validation.

5 — In chemistry, verification of the identity of the entity involved, or of activity, requires a description of the structure or properties of that entity or activity.

6 - When applicable, measurement uncertainty should be taken into consideration.

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Basic Concepts in Metrology and Calibration

Tolerancetolerance is a condition imposed on a measurement and is defined as

the total permissible variation of a quantity from a designated value.”We could express it as: 20+/- 2, 75-80, >= 100, etc.

True Quantity Value vs Conventional Quantity ValueValue that characterises a magnitude perfectly defined in the conditions

when the magnitude is considered. It’s always an uthopy and cannot be never known. The second one is an approximation of the first. (In a CRO, the value assigned to a reference pattern may be considered as the True Quantity Value)

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Basic Concepts in Metrology and Calibration

Influence Quantityquantity that, in a direct measurement, does not affect the quantity that is actually measured, but affects the relation between the indication and the measurement result

Resolution of an instrumentsmallest change in a quantity being measured that causes a perceptible change in the corresponding indication. It is in fact a quantitative expression of the ability of a gauge to distinguish significantly between two values that are very close of the indicated quantity

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Basic Concepts in Metrology and Calibration

Instrumental Driftcontinuous or incremental change over time in indication, due to

changes in metrological properties of a measuring instrument

NOTE: Instrumental drift is related neither to a change in a quantity being measured nor to a change of any recognized influence quantity.It depends, mainly on the time and proper use of equipment. It can be determined by the manufacturer but if this is not the case we can estimate it bigger and correct it with time until its real value

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Basic Concepts in Metrology and Calibration

Correcctioncompensation for an estimated systematic effect. It’s a value that added to the result of a measurement compensates the systematic measurement error

NOTE:

The compensation can take different forms, such as an addend or a factor, or can be deduced from a table.Measurement Standard Instrument Correction100 95 -5

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Basic Concepts in Metrology and Calibration

Measurement Accuracy and PrecisionAccuracy is the closeness of agreement between a measured quantity value and a true quantity value of a measurandNOTE 1 The concept ‘measurement accuracy’ is not a quantity and is not given a numerical quantity value. A measurement is said to be more accurate when it offers a smaller measurement error.Precision is the closeness of agreement between indications or measured quantity values obtained by replicate measurements on the same or similar objects under specified conditions. It refers to the dispersion of values obtained after measuring repeatitively a quantity. As the dispersion is lower the accuracy is higher. Consequently the standard deviation is a good estimator of the accuracy and can be estimate in function of that

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Basic Concepts in Metrology and Calibration

Repeatability and y Reproducibility

Repeatability is the condition of measurement, out of a set of conditions that includes the same measurement procedure, same operators, same measuring system, same operating conditions and same location, and replicate measurements on the same or similar objects over a short period of time

Reproducibility is the condition of measurement, out of a set of conditions that includes different locations, operators, measuring systems, and replicate measurements on the same or similar objects

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Calibrations and Uncertainty of Measurements

MEASUREMENT UNCERTAINTY

It’s a non-negative parameter characterizing the dispersion of the quantity values being attributed to a measurand, based on the information used

NOTE 1 - Measurement uncertainty includes components arising from systematic effects, such as components associated with corrections and the assigned quantity values of measurement standards, as well as the definitional uncertainty. Sometimes estimated systematic effects are not corrected for but, instead, associated measurement uncertainty components are incorporated.

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Calibrations and Uncertainty of Measurements

NOTE 2 - The parameter may be, for example, a standard deviation called standard measurement uncertainty (or a specified multiple of it)

NOTE 3 - Measurement uncertainty comprises, in general, many components. Some of these may be evaluated by Type A evaluation of measurement uncertainty from the statistical distribution of the quantity values from series of measurements and can be characterized by standard deviations. The other components, which may be evaluated by Type B evaluation of measurement uncertainty, can also be characterized by standard deviations, evaluated from probability density functions based on experience or other information.

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Calibrations and Uncertainty of Measurements

Type A evaluationIt’s the evaluation of a component of measurement uncertainty by a statistical analysis of measured quantity values obtained under defined measurement conditions

NOTE 1 - For various types of measurement conditions, see repeatability condition of measurement, intermediate precision condition of measurement, and reproducibility condition of measurement.

NOTE 2 - For information about statistical analysis, see

e.g. ISO/IEC Guide 98-3, ISO/IEC Guide 98-3:2008, 2.3.2, ISO

5725, ISO 13528, ISO/TS 21748, ISO/TS 21749.

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Calibrations and Uncertainty of Measurements

Type B evaluationIt’s the evaluation of a component of measurement uncertainty determined by means other than a Type A evaluation of measurement uncertainty

EXAMPLES Evaluation based on information

— associated with authoritative published quantity values,— associated with the quantity value of a certified reference material,— obtained from a calibration certificate,

— about drift,

— obtained from the accuracy class of a verified measuring instrument,— obtained from limits deduced through personal experience.

NOTE: See also ISO/IEC Guide 98-3:2008, 2.3.3.

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Calibrations and Uncertainty of Measurements

Practical Approach (Considering Type A and B evaluation)

Main parameters to consider for calculation:- Calibration Uncertainty of the instrument- Drift from last calibration- Resolution- Influence Quantity- Variability

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Calibrations and Uncertainty of Measurements

2. How they can be calculated/estimated - - Calibration Uncertainty of the instrument. (From Certificate of Calibration- Drift from last calibration (Calculated from records/Estimated)- Resolution. (Must be estimated)- Influence Quantity. (Must be calculated)- Variability. It can be calculated by carrying out n measurements under repeatability conditions. The estimator to consider is in this case the standard deviation

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Calibrations and Uncertainty of Measurements

3. Approaches for calculation of Measurement Uncertainty- Adding Up:

U Drift (D) Correction (C) Total0.11 0.2 +0.3 0.61

- SQR of sum: SRQ (0.11^2+0.2^2+0.3^2) = 0.24

- EA-4/R2: 0.16 (Para K=2)

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Calibration Certificates

Electronic Balances Pressure Gauges Thermometers Calibration Weights

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Calibration: Practical Aspects for Field CROs

1. Relationship between Tolerance and UncertaintyIt is normally recommended that the following formula is followed:

3≤ T/2U ≤ 10

From that we can get that:

T = 4 U

So, firstly we have to define a value for Tolerance and then and Acceptance Criteria. Based on the Tolerance we setup the following scenarios may happen

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Calibration: Practical Aspects for Field CROs

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Calibration: Practical Aspects for Field CROs

1. External Calibration Periods based on• Applicable Guidelines• Usage frequency• Kind of Usage• Drift• Recommendations of the manufacturer / calibration lab

2.Internal Calibrations. Periodical CheckingsVIM defines calibration as an operation that, under specified

conditions, in a first step, establishes a relation between the quantity values with measurement uncertainties provided by measurement standards and corresponding indications with associated measurement uncertainties and, in a second step, uses this information to establish a relation for obtaining a measurement result from an indication

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Calibration: Practical Aspects for Field CROs

3. Practical Procedure of a periodical checking

3.1 - External Calibration of the Measurement Standard (eg. Thermometer)3.2 - Setting up the Tolerance3.3 - Carry out checking measurement standard - instrument3.4 - Setting up the Acceptance Criteria3.5 - Applying the Acceptance Criteria

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Calibration: Practical Aspects for Field CROs

(I) DATA FROM CERTIFICATE OF CALIBRATION

Temp Ref (ºC) Readings of Measurement Standard (ºC)

Correction (ºC) Uncertainty (ºC)

0,15 0,6 -0,45 0,09-19,9 -18,8 -1,1 0,1-10,07 -9,3 -0,77 0,120,01 19,7 0,31 0,135,18 34,4 0,78 0,10,16 0,6 -0,44 0,09

(II) Setting Up Tolerance: 0,4ºC

(III) Checking the new thermometer against the Measurement Standard (MS)

MS Readings of Thermometer (ºC) Corrección10 10,5 -0,520 19,4 0,635 35,3 -0,3

(IV) Seeting Up the Acceptance Criteria: ±0,4ºC

(V) Applying the method and determining if equipment is acceptable ¿EQUIPO APTO?

DUDOSO 10 + 0,1 + 0,4 = 10,5NO 20 - 0,1 - 0,4 = 19,5NO 35 + 0,1 + 0,4 = 35,5

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Calibration: Practical Aspects for Field CROs

4. Calculation of Typical Uncertainty (u)Type A and B evaluations

3.1 - Measurement Standard Uncertainty (u1)3.2 - Variability = standard deviation of the mean (u2)3.3 - Drift. It has to be calculated (u3)3.4 - Correction. It has to be calculated (u4)

u2 = (u1)2+(u2)2+(u3)2+(u4)2

In accordance with the guidelines the expanded uncertainty may be expressed as:U = k * u (Being K=2 for a level of confidence of 95%)

Let’s see a real example…

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Calibration: Practical Aspects for Field CROs

A field studies company buys a new soil thermometer to replace one that was broken. Before commissioning it for recording raw data, they wanted to make a proper calibration making calculations for getting values for the typical and the expanded uncertainty. They use an excel sheet.

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Calibration: Practical Aspects for Field CROs

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Equipment ID REPETIBILITY

Equipment Make Serial No. Nominal 6,80 10,40 21,00   

Soil Thermometer TESTO Measurement 1 6,90 10,30 21,80   

Measurement 2 6,90 10,30 21,80   

CALIBRATION METHOD Measurement 3 6,90 10,30 21,80   

Measurement 4 6,90 10,31 21,70   

MEASUREMENT STANDARD USED Measurement 5 6,80 10,30 21,90   

Refer. Patron Equipo Nº serie Certificado Measurement 6 6,90 10,30 21,80   

ASS/1133/S/E Termometro Digital con Sonda   C/082109I2Measurement Standard Uncertainty

x0 6,8000 10,4000 21,0000   

u0(y) 0,10000 0,10000 0,10000   

CONDICIONES AMBIENTALES            

Las condiciones ambientales durante la calibración fueron las siguientes: °C %HR Repetibility Mean 6,8833 10,3008 21,8000   22 45 u1(y) 0,0167 0,0008 0,0258   

Correction (y) -0,0833 0,0992 -0,8000   

Typical Uncertainty u(y) 0,13123 0,14084 0,80664   

K Factor   2,0000 2,0000 2,0000   

CRITERIO DE ACEPTACIÓN: 0,5 ºC RESULTADO NO APTO Expanded Uncertainty U(±) 0,262 0,282 1,613   

Nominal 6,80 10,40 21,00   

  Correctio (y) -0,0833 0,0992 -0,8000   

Global Uncertainty U(±) 0,26 0,28 1,61   Sum ±(U+y) 0,18 0,38 0,81   

All values expressed in ºC

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Thank you for your kind attention and now…

It’s your turn for questions