calibration fundamentals

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Calibration Fundamentals


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.


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


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


Metrology

..and because the government requires it. 21 CFR Part 820.72 governs Inspection,

Measuring and Test Equipment.


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.


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.


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.


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.


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


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.


Definitions

MeasurementSet 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.


Definitions

Accuracy Conformity to fact. Precision; exactness. The ability of a measurement to match the

actual value of the quantity being measured


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.


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.


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.


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.


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.


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.


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.


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.


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.


Definitions

Uncertainty parameter, associated with the result of a

measurement, that characterizes the dispersion of values that could reasonably be attributed to the measurand


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


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


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.


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


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.


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


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.


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


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.


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.


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


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%


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.


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.

calibration fundamentals

Documents

calibration standards

test equipment

calibration procedures

calibration records

calibration dates

calibration chain

equipment identification

storage of equipment