DDEBUNKINGEBUNKING TTHEHE TTWOWO GGREATREATMMYTHSYTHS AABOUTBOUT CCALIBRATIONALIBRATION::

TTRACEABILITYRACEABILITY TOTO NISTNISTTTRACEABILITYRACEABILITY TOTO NISTNISTIIFF YYOUOU CCANNOTANNOT AADJUSTDJUST, , II YYOUOU A OA O AA JUJU ,,YYOUOU CCANNOTANNOT CCALIBRATEALIBRATE!!

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AACRONYMSCRONYMS

• International System of Units (abbreviated SISIfrom the French Le Système International yd'Unités – Seven Base Units: meter, kilogram, second, ampere, kelvin, mole, & candela), p , , , )

• Bureau International des Poids et Mesures (BIPM). The task of the BIPM is to ensure ( ) fworld-wide uniformity of measurements and their traceability to the International System of y y fUnits (SI)

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AACRONYMSCRONYMS

• National Metrology Institute (NMI)• National Institute of Standards and Technology gy(NIST)

• Food and Drug Administration (FDA) g ( )• Code of Federal Regulations (CFR)• current Good Manufacturing Practice (cGMP)g ( )• Quality System Regulation (QSR - 21CFR Part 820))

• Quality Calibration Program (QCP)

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BBYY DEFINITIONDEFINITION ……

Traceability is the property of the resulty p p yof a measurement or the value of astandard whereby it can be related tostandard whereby it can be related tostated references, usually national ori t ti l t d d (SI) th hinternational standards (SI), through anunbrokenunbroken chainchain ofof calibrationscalibrations (thethe paperpapertrailtrail) all having statedstated uncertaintiesuncertainties.

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BBYY DEFINITIONDEFINITION ……

Calibration is a comparisoncomparison of twomeasurement devices or systems, one ofknown uncertainty (youryour standardstandard) andy (yy )one of unknown uncertainty (youryour testtestequipmentequipment)equipmentequipment).

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TTRACEABILITYRACEABILITY PYRAMIDPYRAMID

BIPM

NMIs

Reference standards

Third-party Calibration labs

Metrology/Calibration Department(inside a company)

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User’s test equipment

TTRACEABILITYRACEABILITY PYRAMIDPYRAMID

SI units

Primary standards

Secondary standards

Reference standards

Working standards

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User’s test equipment

AASS PERPER N.I.S.T. …N.I.S.T. …

You can state: This test instrument wascalibrated against Standards that aretraceable to the SI via NIST (or anyyNMI).

Y t t t Thi t t i t tYou cannot state: This test instrumentwas calibrated against Standards thatare NIST traceable to the SI (unlessthey were actually calibrated at NIST).

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y y )

DDIDID YOUYOU KNOWKNOW??

The FDA regulates ~ 25% of theU. S. Gross Domestic Product (GDP)U. S. Gross Domestic Product (GDP)

As of February 15th 2012As of February 15th, 2012,the US GDP was

$15 294 300 000 000 00 ($15 294 T)$15,294,300,000,000.00 ($15.294 T)

The FDA regulatedThe FDA regulated~ $3.824 Trillion of

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the US GDP

DDIDID YOUYOU KNOWKNOW??

And none of this couldAnd none of this couldAnd none of this couldAnd none of this couldhappened without the use of happened without the use of calibrated test equipment!calibrated test equipment!

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WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .Several references that you might be interested in: 21 CFR . . .• Part 58 (Good Laboratory Practice [GLP] for Nonclinical Laboratory Studies)

P t 110 ( GMP i M f t i ki• Part 110 (cGMP in Manufacturing, packing, or holding human food equipment and utensil maintenance)maintenance)• Part 211 (cGMP for Finished Pharmaceuticals)• Part 606 (cGMP for Blood and Blood Components)( p )• Part 820 Part 820 (cGMP for Medical Devices)(cGMP for Medical Devices)

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WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .

Title 21--Food and Drugsg

PART 820--QUALITY SYSTEM REGULATION (QSR)PART 820 QUALITY SYSTEM REGULATION (QSR)(cGMP for Medical Devices)

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WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .The QSRThe QSR

820.1 Scope.820.3 Definitions.820.5 Quality system.

820.86 Acceptance status.820.90 Nonconforming product.820.100 Corrective and preventive action.820.5 Quality system.

820.20 Management responsibility. 820.22 Quality audit.820.25 Personnel.820 30 D i t l

820.100 Corrective and preventive action.820.120 Device labeling.820.130 Device packaging.820.140 Handling.820 150 St820.30 Design controls.

820.40 Document controls.820.50 Purchasing controls.820.60 Identification.

820.150 Storage.820.160 Distribution.820.170 Installation.820.180 General requirements.

820.65 Traceability.820.70 Production and process controls.

q820.181 Device master record.820.184 Device history record.820.186 Quality system record.820 198 Complaint files

820.72 Inspection, measuring, and test 820.72 Inspection, measuring, and test equipmentequipment820.75 Process validation.820.80 Receiving, in-process, and finished device acceptance.

820.198 Complaint files.820.200 Servicing.820.250 Statistical techniques.

equipment.equipment.

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PPARTART 820.72820.72Why discuss the requirements of 21 CFR Part 820.72? Because, of all the stated calibration requirements in 21 CFR Part XXX, Part 820.72 is the most specific and detailed relating to calibration requirements.The bottom line is this, when it comes to a ,quality calibration program, it doesn’t cost any more to go first-class (to exceed the y g (standard), than it does to ride in coach (just meeting the standard).

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g )

A BA BASICASIC QCPQCP“Say what you do”

Written procedures

“Do what you say”Follow proceduresp

“Record what you did”Keep recordsKeep records

“Check the results”Did ‘it’ pass or fail

“Act on the difference”

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Act on the differenceProcedures for OOT conditions

WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .Sec. 820.72 Inspection, measuring, and test equipment.

(a) Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all inspection measuringEach manufacturer shall ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its i t d d d i bl f d i lid ltintended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain procedures (Administrative SOPs and scheduling protocols – software) to

h i i i l lib d i densure 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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WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .Sec. 820.72 Inspection, measuring, and test equipment

(b) Calibration. Calibration procedures (‘say what you do do what you say’) shall include specific directions and limitsdo, do what you say’) 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 (‘check th lt ’ d ‘ t th diff ’) t t bli h th li itthe results’ and ‘act on the difference’) to reestablish the limits and to evaluate whether there was any adverse effect on the device's quality. These activities shall be documented (calibration

d ‘ d h did’)records – ‘record what you did’).

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WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .Sec. 820.72 Inspection, measuring, and test equipment.

(1) Calibration standards. Calibration standards used for inspection measuring and test equipment shallused for inspection, measuring, and test equipment shall be traceable to national or international standards (the SI). If national or international standards are not

ti l il bl th f t h llpractical or available, the manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and

i i i h d dmaintain an in-house standard.

Note: Nothing here refers to traceability to NIST in the USA, or to ISO standards in Europe. Also, both ISO 9001-2008 and ISO 13485:2003 require traceability to international or national standards.

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WWHATHAT THETHE FDA FDA SAYSSAYS . . .. . .Sec. 820.72 Inspection, measuring, and test equipment.

(2) Calibration records. The equipment identification calibration dates the individualidentification, calibration dates, the individual performing each calibration, and the next calibration date shall be documented. These records shall be di l d h i f i t h ll bdisplayed 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

iequipment.

Note: this paragraph is referring to calibration labels that should be attached to each piece of test equipment that has been calibrated.

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TTHEHE BOTTOMBOTTOM LINELINE ISIS THISTHIS . . .. . .

All test equipment that All test equipment that makes a quantitative makes a quantitative

measurement requires measurement requires measurement requires measurement requires periodic periodic calibration!calibration!pp

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CCALIBRATIONALIBRATION MYTHSMYTHS ……• If test equipment ‘As Found’ was within tolerance then calibration is not required.

•• WRONG! WRONG! Every time a calibration is performed, the UUT’s ‘As Found’ readings, and the readings of your Standard must be recorded.

• If test equipment cannot be adjusted or aligned, it q p j g ,cannot be calibrated (e.g. a glass thermometer).

•• WRONG!WRONG! Calibration is a comparison only - AWRONG!WRONG! Calibration is a comparison only A complete calibration is performed irrelevant of the ability to adjust the test instrument.

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y j

CCALIBRATIONALIBRATION MYTHSMYTHS ……• A calibration laboratory, with a controlled environment is required for traceable calibrations.

•• WRONG! WRONG! Calibration occurs whenever a standard with know uncertainty is compared to a UUT with unknown uncertainty.

• Traceability in the USA must be to NIST.y

•• WRONG!WRONG! Traceability is to a national or international standard (the SI) not to an organization or NMI NISTstandard (the SI), not to an organization or NMI. NIST might maintain a standard/artifact to which your calibrations are traceable, but it’s not traceable to NIST.

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TTHEHE PAPERPAPER TRAILTRAIL ……

S h d t bilit d thSo how does traceability and the paper trail really work? Here’s an example of traceability back to the SI when calibrating a common waterbath used by g yany biotech, pharmaceutical or medical device companydevice company . . .

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EEXAMPLEXAMPLE OFOF TRACEABILITYTRACEABILITYΩ BIPM

NIST Standard (P i S d)

Ω (ohm) BIPMDerived Unit of the International System (SI)

NIST Standard (Primary Std)

Hart Scientific Std.(Secondary Std)

SPRT & Black Stack (Ref Std)( f )

4600 (Working Std)g

Waterbaths

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(Unit Under Test)

BBESTEST PRACTICESPRACTICES/L/LESSONSESSONS LEARNEDLEARNED

Calibration certificates*• Title• Name & address of the calibration laboratory• Unique ID of the certificate• Name & address of the client• Identification of the method used• Description and condition of the item calibrated• The date(s) of calibration• The date(s) of calibration• Calibration results and units of measurement• Name, function, and signature of authorizing person• Environmental conditions during calibration• Uncertainty of measurementUncertainty of measurement• Evidence that the measurements are traceableEvidence that the measurements are traceable

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*IAW ISO/IEC 17025

TTHEHE 4:1 4:1 RULERULE

To show your uncertainty, withouty y,performing calculations, you mustensure the uncertainty of your standardsensure the uncertainty of your standardsare at least four times (4:1) more

t th th t l f th t taccurate than the tolerance of the testequipment being calibrated.Author’s note: This refers to the TUR, or TestUncertainty Ratio.

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TTESTEST UUNCERTAINTYNCERTAINTY RRATIOATIOA i N ti lAmerican National

Standard for Calibration –

“Where calibrations provide for verification

(ANSI/NCSL Z540.3-2006)

Where calibrations provide for verification that measurement quantities are within specified tolerances Where it is not practicalspecified tolerances…Where it is not practical to estimate this probability, the TUR shall be equal to or greater than 4:1 ”equal to or greater than 4:1.

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TTRACEABILITYRACEABILITY & U& UNCERTAINTYNCERTAINTY

SI unitsuuu ccc bb

22

Primary standardsukU

ccc baab

TUR 4:1Combined Uncertainty

4:1 Rule

Secondary standardscukU

Expanded Uncertainty

4:1 Rule

Reference standards

Working standards

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User’s test equipment

A BA BASICASIC QCPQCP“Say what you do”

Written procedures

“Do what you say”Follow proceduresp

“Record what you did”Keep records

“Record Record what you didwhat you did”Keep recordsKeep recordsKeep records

“Check the results”Keep recordsKeep records

Did ‘it’ pass or fail

“Act on the difference”

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Act on the differenceProcedures for OOT conditions

RRECORDECORD WHATWHAT YOUYOU DIDDID

This means recording the results This means recording the results of your measurements, as you f d h d h h f found them, and what they were if you had to adjust them, and keeping those records in a secure location.location.

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EEXAMPLEXAMPLE OFOF AA CALIBRATIONCALIBRATION FFORMORM

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RRECORDECORD WHATWHAT YOUYOU DIDDID

16913 5016913 50

Ambient +5 °C ~ 70 ± 1 °C

5-25-2010 5-20-2011 5-20-2012

SM-13 1369 SM 13 1369

30.01 30.037.03 37.0

N/A N/A N/A N/AN/A N/AN/A N/ATraceability37.03 37.0

42.02 42.070.01 70.0

N/A N/AN/A N/AN/A N/A

N/A N/A N/A N/AN/A N/A N/A N/AN/A N/A N/A N/A

TraceabilityStatement

N/A N/A N/A N/A

1-16-2011

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N/A

03

RRECORDECORD WHATWHAT YOUYOU DIDDID

03

UncertaintyBudget

Joe Bagadonuts / Noxious Gas Area / x1369

N/A or a detail description of all events as they happened, and the actions taken.

p y pp ,

5-20-2011 Ayumi Jane Deaux5-20-2011 Jay L. Bucher

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LLEARNINGEARNING OBJECTIVESOBJECTIVES

In order to maintain traceability, you must be In order to maintain traceability, you must be able to show the ‘paper trail’ from your UUT all theable to show the ‘paper trail’ from your UUT all theable to show the paper trail from your UUT all the able to show the paper trail from your UUT all the way back to the SI, with appropriate uncertainty way back to the SI, with appropriate uncertainty budgets during each calibrationbudgets during each calibrationbudgets during each calibrationbudgets during each calibration

Calibration Calibration is simply a comparison of two is simply a comparison of two measurement devices or systems, one of known measurement devices or systems, one of known uncertainty, and one of unknown uncertainty; uncertainty, and one of unknown uncertainty; adjustment, alignment, and/or repair of the UUT is adjustment, alignment, and/or repair of the UUT is irrelevant to the calibration process irrelevant to the calibration process

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B MB M

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