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Calibration Fundamentals Biometrix Corporation (800)-890-89 1

Calibration

Fundamentals

Calibration Fundamentals Biometrix Corporation (800)-890-89 1
Objectives  Understand why we calibrate  Understand 21 CFR Part 820  Introduce the

Objectives

Understand why we calibrate

Understand 21 CFR Part 820

Introduce the basis for the basic SI units

Explain the standards used in the calibration chain.

Explain uncertainty and the 4:1 ratio.

standards used in the calibration chain.  Explain uncertainty and the 4:1 ratio. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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Metrology  What is Metrology?  The science that deals with measurement  What does

Metrology

What is Metrology?

The science that deals with measurement

What does it mean to calibrate?

To check, adjust, or determine display accuracy by comparison with a standard (the graduations of a quantitative measuring instrument)
To make corrections in; adjust
a set of operations that establish, under specified conditions, the relationship between the values of quantities indicated by a measuring instrument or measuring system … and the corresponding values realized by standards

instrument or measuring system … and the corresponding values realized by standards Biometrix Corporation (800)-890-89 3

Biometrix Corporation (800)-890-89

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Metrology  Why Calibrate?  The quality of drug product is dependent upon certain conditions

Metrology

Why Calibrate?

The quality of drug product is dependent upon certain conditions of manufacture, including temperature, pressure, and pH. In order to ensure consistent and correct drug manufacture, instrumentation relating to the drug production must be calibrated.

In order to accurately describe the processes by which drugs are created, and gauge the effect of any deviations on the drug process

which drugs are created, and gauge the effect of any deviations on the drug process Biometrix

Biometrix Corporation (800)-890-89

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Metrology  and  21 CFR Part 820.72 governs Inspection, Measuring and Test Equipment. because

Metrology

and

21 CFR Part 820.72 governs Inspection, Measuring and Test Equipment.

because the government requires it.

governs Inspection, Measuring and Test Equipment. because the government requires it. Biometrix Corporation (800)-890-89 5

Biometrix Corporation (800)-890-89

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21 CFR Part 820  (a) Control of inspection, measuring, and test equipment. Each manufacturer

21 CFR Part 820

(a) Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained. The procedures shall include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained. These activities shall be documented.

accuracy and fitness for use are maintained. These activities shall be documented. Biometrix Corporation (800)-890-89 6

Biometrix Corporation (800)-890-89

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21 CFR Part 820  Calibration. Calibration procedures shall include specific directions and limits for

21 CFR Part 820

Calibration. Calibration procedures shall include specific directions and limits for accuracy and precision. When accuracy and precision limits are not met, there shall be provisions for remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device`s quality. These activities shall be documented.

was any adverse effect on the device`s quality. These activities shall be documented. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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21 CFR Part 820  Calibration standards. Calibration standards used for inspection, measuring, and test

21 CFR Part 820

Calibration standards. Calibration standards used for inspection, measuring, and test equipment shall be traceable to national or international standards. If national or international standards are not practical or available, the manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and maintain an in-house standard.

standard exists, the manufacturer shall establish and maintain an in-house standard. Biometrix Corporation (800)-890-89 8

Biometrix Corporation (800)-890-89

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21 CFR Part 820  Calibration records. The equipment identification, calibration dates, the individual performing

21 CFR Part 820

Calibration records. The equipment identification, calibration dates, the individual performing each calibration, and the next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment.

such equipment and to the individuals responsible for calibrating the equipment. Biometrix Corporation (800)-890-89 9

Biometrix Corporation (800)-890-89

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N.I.S.T.  As a non-regulatory agency of the United States Department of Commerce’s Technology Administration

N.I.S.T.

As a non-regulatory agency of the United States Department of Commerce’s Technology Administration, the National Institute of Standards (NIST) develops and promotes measurement, standards, and technology to enhance productivity, facilitate trade, and improve the quality of life. As part of this mission, NIST scientists and engineers continually refine the science of measurement, making possible the ultraprecise engineering and manufacturing required for today’s most advanced technologies. They also are directly involved in standards development and testing done by the private sector and government agencies.

NIST was originally called the National Bureau of Standards (NBS), a name that it had from 1901 until 1988

the National Bureau of Standards ( NBS ), a name that it had from 1901 until

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Definitions  Unit (of measurement)  Particular quantity, defined and adopted by convention, with which

Definitions

Unit (of measurement)

Particular quantity, defined and adopted by convention, with which other quantities of the same kind are compared in order to express their magnitudes relative to that quantity.

Value (of a quantity)

Magnitude of a particular quantity generally expressed as a unit of measurement multiplied by a number.

quantity generally expressed as a unit of measurement multiplied by a number. Biometrix Corporation (800)-890-89 11

Biometrix Corporation (800)-890-89

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Definitions  Measurement Set of operations having the object of determining a value of a

Definitions

Measurement Set of operations having the object of determining a value of a quantity.

Error (of measurement)

Result of a measurement minus a true value of the measured.

(of measurement)  Result of a measurement minus a true value of the measured. Biometrix Corporation

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Definitions  Accuracy  Conformity to fact.  Precision; exactness.  The ability of a

Definitions

Accuracy

Conformity to fact.

Precision; exactness.

The ability of a measurement to match the actual value of the quantity being measured

ability of a measurement to match the actual value of the quantity being measured Biometrix Corporation

Biometrix Corporation (800)-890-89

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Definitions  Traceability  Property of the result of a measurement or the value of

Definitions

Traceability

Property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties.

Includes conductivity solutions, pH solutions, viscosity solutions, and turbidity solutions.

conductivity solutions, pH solutions, viscosity solutions, and turbidity solutions. Biometrix Corporation (800)-890-89 14

Biometrix Corporation (800)-890-89

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Definitions  Standard Reference material (SRM)  Reference material, accompanied by a certificate, one or

Definitions

Standard Reference material (SRM)

Reference material, accompanied by a certificate, one or more of whose property values are certified by a procedure which establishes traceability to an accurate realization of the unit in which the property values are expressed, and for which each certified value is accompanied by an uncertainty at a stated level of confidence.

certified value is accompanied by an uncertainty at a stated level of confidence. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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Definitions  Reference Material (RM)  Material or substance one or more of whose property

Definitions

Reference Material (RM)

Material or substance one or more of whose property values are sufficiently homogeneous and well established to be used for the calibration of an apparatus, the assessment of a measurement method, or for assigning values to materials.

A reference material may be in the form of a pure or mixed gas, liquid or solid. Examples are water for the calibration of viscometers, sapphire as a heat-capacity calibrant in calorimetry, and solutions used for calibration in chemical analyses.

calibrant in calorimetry, and solutions used for calibration in chemical analyses. Biometrix Corporation (800)-890-89 16

Biometrix Corporation (800)-890-89

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Definitions  Working Standard  Standard that is used routinely to calibrate or check material

Definitions

Working Standard

Standard that is used routinely to calibrate or check material measures, measuring instruments or reference materials.

A working standard is usually calibrated against a reference standard.

 A working standard is usually calibrated against a reference standard. Biometrix Corporation (800)-890-89 17

Biometrix Corporation (800)-890-89

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Definitions  Reference Standard  Standard, generally having the highest metrological quality at a given

Definitions

Reference Standard

Standard, generally having the highest metrological quality at a given location or in a given organization, from which measurements made there are derived.

location or in a given organization, from which measurements made there are derived. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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Definitions  Primary Standard  Standard that is designated or widely acknowledged as having the

Definitions

Primary Standard

Standard that is designated or widely acknowledged as having the highest metrological qualities and whose value is accepted without reference to other standards of the same quantity.

whose value is accepted without reference to other standards of the same quantity. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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Definitions  Resolution  A measure of the smallest portion of the signal that can

Definitions

Resolution

A measure of the smallest portion of the signal that can be observed. For example, a thermometer with a display that reads to three decimal places would have a resolution of 0.001ºC. In general, the resolution of an instrument has a better rating than its accuracy.

In general, the resolution of an instrument has a better rating than its accuracy. Biometrix Corporation

Biometrix Corporation (800)-890-89

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Definitions  Repeatability  closeness of the agreement between the results of successive measurements of

Definitions

Repeatability

closeness of the agreement between the results of successive measurements of the measurand (eg mass value) carried out under the same conditions of measurement. Conditions include:

same procedure, observer, instrument, conditions, location; and carried out over a short period of time.

instrument, conditions, location; and carried out over a short period of time. Biometrix Corporation (800)-890-89 21

Biometrix Corporation (800)-890-89

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Definitions  Reproducibility  closeness of the agreement between the results of measurements of the

Definitions

Reproducibility

closeness of the agreement between the results of measurements of the measurand (eg mass value) carried out under changed conditions of measurement. Includes changing some of those conditions which are held constant for ‘repeatability’, and may refer to measurements carried out over a long period of time.

and may refer to measurements carried out over a long period of time. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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Definitions  Uncertainty  parameter, associated with the result of a measurement, that characterizes the

Definitions

Uncertainty

parameter, associated with the result of a measurement, that characterizes the dispersion of values that could reasonably be attributed to the measurand

the dispersion of values that could reasonably be attributed to the measurand Biometrix Corporation (800)-890-89 23

Biometrix Corporation (800)-890-89

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Definitions  Standard  Material measure, measuring instrument, reference material or measuring system intended to

Definitions

Standard

Material measure, measuring instrument, reference material or measuring system intended to define, realize, conserve or reproduce a unit or one or more values of a quantity to serve as a reference.

Examples

kg mass standard

100 Ω standard resistor

standard ammeter

cesium frequency standard

 100 Ω standard resistor  standard ammeter  cesium frequency standard Biometrix Corporation (800)-890-89 24

Biometrix Corporation (800)-890-89

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International System of Units (SI)  The SI is founded on seven SI base units

International System of Units (SI)

The SI is founded on seven SI base units for seven base quantities assumed to be mutually independent.

Length

Mass

Time

Temperature

Quantity of Substance

Luminous Intensity

Electric Current

Temperature  Quantity of Substance  Luminous Intensity  Electric Current Biometrix Corporation (800)-890-89 25

Biometrix Corporation (800)-890-89

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Length  Meter  The meter is the length of the path traveled by light

Length

Meter

The meter is the length of the path traveled by light in vacuum during a time interval of 1/299 792 458 of a second.

Symbol = m

It used to be one ten millionth of the distance of the meridian through Paris.

 It used to be one ten millionth of the distance of the meridian through Paris.

Biometrix Corporation (800)-890-89

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Mass  Kilogram  The kilogram is the unit of mass; it is equal to

Mass

Kilogram

The kilogram is the unit of mass; it is equal to the mass of the international prototype of the kilogram.

The international prototype is a large chunk of platinum-iridium in Paris.

The international prototype will soon be a sphere of pure Silicon with an exactly known number of atoms

Symbol = kg

be a sphere of pure Silicon with an exactly known number of atoms  Symbol =

Biometrix Corporation (800)-890-89

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Time  Second  The second is the duration of 9 192 631 770 periods

Time

Second

The second is the duration of 9 192 631 770 periods of the radiation corresponding to the transition between the two hyperfine levels of the ground state of the cesium 133 atom.

Symbol = s

It used to be 1/86400 of the astronomical day.

cesium 133 atom.  Symbol = s  It used to be 1/86400 of the astronomical

Biometrix Corporation (800)-890-89

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Temperature  Kelvin  The Kelvin, unit of thermodynamic temperature, is the fraction 1/273.16 of

Temperature

Kelvin

The Kelvin, unit of thermodynamic temperature, is the fraction 1/273.16 of the thermodynamic temperature of the triple point of water.

What is the triple point?

The temperature and pressure at which solid, liquid, and gaseous water coexist in equilibrium.

Symbol = K

at which solid, liquid, and gaseous water coexist in equilibrium.  Symbol = K Biometrix Corporation

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Electric Current  Ampere  The ampere is that constant current which, if maintained in

Electric Current

Ampere

The ampere is that constant current which, if maintained in two straight parallel conductors of infinite length, of negligible circular cross-section, and placed 1 meter apart in vacuum, would produce between these conductors a force equal to 2 x 10-7 Newton per meter of length.

between these conductors a force equal to 2 x 10-7 Newton per meter of length. Biometrix

Biometrix Corporation (800)-890-89

30

SI Derived Units  Examples of SI derived  Area square meter m2  Volume

SI Derived Units

Examples of SI derived

Area

square meter

m2

Volume

cubic meter

m3

Speed

velocity meter per second

m/s

Acceleration

meter per second squared

m/s2

Wave number

reciprocal meter

m-1

Mass density

kilogram per cubic meter

kg/m3

Specific volume

cubic meter per kilogram

m3/kg

Current density

ampere per square meter

A/m2

Magnetic field strength ampere per meter

A/m

Concentration

mole per cubic meter

mol/m3

Luminance

candela per square meter

cd/m2

Mass fraction

kilogram per kilogram

kg/km

per square meter cd/m2  Mass fraction kilogram per kilogram kg/km Biometrix Corporation (800)-890-89 31

Biometrix Corporation (800)-890-89

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CGMP Calibrations  CGMP Calibration must be traceable through all vendors and paperwork to the

CGMP Calibrations

CGMP Calibration must be traceable through all vendors and paperwork to the original NIST calibration

Example: NIST calibrates primary standard for primary standards lab

Primary Standards Lab calibrates Intelligent RTD for Biotech Manufacturing Facility

Biotech Manufacturing Facility calibrates HART temperature blocks with IRTD

Calibration Group calibrates bioreactor instrumentation using the HART temperature blocks.

Group calibrates bioreactor instrumentation using the HART temperature blocks. Biometrix Corporation (800)-890-89 32

Biometrix Corporation (800)-890-89

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4:1 Ratio  When using one instrument or standard to calibrate another, the ratio of

4:1 Ratio

When using one instrument or standard to calibrate another, the ratio of accuracies should be maintained at no lower than a 4:1 ratio. Example

Using an IRTD with an accuracy of +/- 0.01 K to calibrate a HART Block with an accuracy of +/- 0.05 K.

an accuracy of +/- 0.01 K to calibrate a HART Block with an accuracy of +/-

Biometrix Corporation (800)-890-89

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Uncertainty  To calculate the uncertainty of the overall test system, the uncertainties of the

Uncertainty

To calculate the uncertainty of the overall test system, the uncertainties of the individual components are combined using a statistical approach.

Each component is represented by a standard deviation (standard uncertainty).

The deviations are combined under the rule of Propagation of Uncertainty.

This rule is mathematically expressed as the root sum squared.

The square root of the sum of the squares.

When combined they are known as the

Combined Standard Uncertainty

the squares.  When combined they are known as the Combined Standard Uncertainty Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

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Combined Standard Uncertainty  Example  A pressure measurement system contains a pressure transducer, ma

Combined Standard Uncertainty

Example

A pressure measurement system contains a pressure transducer, ma transmitter, and PLC Analog Input.

The uncertainty of the pressure transducer is +/- 0.5%

The uncertainty of the ma transmitter is +/-0.2%

The uncertainty of the PLC Analog Input is +/- 0.1%

sqroot((0.5%) 2 + (0.2%) 2 + (0.1%) 2 )

Combined Standard Uncertainty =

0.547%

+ (0.2%) 2 + (0.1%) 2 )  Combined Standard Uncertainty =  0.547% Biometrix Corporation

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Expanded Uncertainty  The expanded uncertainty, suggested symbol U , is obtained by multiplying the

Expanded Uncertainty

The expanded uncertainty, suggested symbol U, is obtained by multiplying the combined standard

uncertainty by a coverage factor, suggested symbol

k,

which typically has a value between 2 and 3 (i.e.,

U

= kuc)

For a normal distribution and k = 2 or 3, the expanded uncertainty defines an interval having a level of confidence of 95.45% or 99.73%, respectively.

defines an interval having a level of confidence of 95.45% or 99.73%, respectively. Biometrix Corporation (800)-890-89

Biometrix Corporation (800)-890-89

36

Expanded Uncertainty  If we apply the 4:1 ratio on top of the expanded uncertainty,

Expanded Uncertainty

If we apply the 4:1 ratio on top of the expanded uncertainty, the maximum specification for accuracy with a 99.73% confidence level would be

0.547% Combined Standard Uncertainty

K Factor of 3 for 99.73& confidence

4:1 ratio

4 x 3 x 0.547%

= +/- 6.564 % Luckily most pressure transducers are significantly more accurate.

= +/- 6.564 % Luckily most pressure transducers are significantly more accurate. Biometrix Corporation (800)-890-89 37

Biometrix Corporation (800)-890-89

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