Calibration

Fundamentals

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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.

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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

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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

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Metrology
 ..and because the government requires it.
 21 CFR Part 820.72 governs Inspection,
Measuring and Test Equipment.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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Definitions
 Accuracy
 Conformity to fact.
 Precision; exactness.
 The ability of a measurement to match the
actual value of the quantity being measured

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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

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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

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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

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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.

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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
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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.

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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

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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.

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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

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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.

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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.

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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

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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%

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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.

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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.

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