GWP® - The Weighing StandardWhy We Should Challenge the Established Way We

Calibrate and Test Weighing Instruments

NCSLI Nashville July 2013

Dr. Klaus FritschManager Compliance

Weighing – Essential for all Processes

Regulations affecting Scales and Balances - ISO

3

“Measuring equipment shall be calibrated and/or verified at specified intervals … against measurement standards traceable to international or national measurement standards.”

ISO 9001:2008, 7.6 Control of Monitoring and Measuring Devices

How do we put this into practice?

“Automatic, mechanical or electronic equipment […]shall be routinely calibrated, inspected or checked according to a written program designed to assure proper performance.”

21 CFR part 211.68 (a), US GMP for Pharma

How do we put this into practice?

Regulations Affecting Scales & Balances - cGMP

Regulations affecting Balances - USP

5

"Weighing shall be performed using a balance that is calibrated […] and meets the requirements defined for repeatability and accuracy."

"Repeatability is satisfactory if two times the standard deviation of the weighed value, divided by the nominal value of the weight used, does not exceed 0.10%."

USP 36–NF 31 Second Supplement, General Chapter 41 “Balances“

What does this mean for my balances?

6

New USP General Chapters 41 & 1251

Publication in the Second Supplement to USP 36–NF 31 June 3rd 2013 General Chapter 41 "Balances"

General Chapter 1251 "Weighing on an Analytical Balance"

After a six month transition period the new chapters will be official from December 1st 2013 onwards.

The science-based global standard for efficient life cyclemanagement of weighinginstruments.

It applies a risk-based approach that allows improving control of the whole measuring process, which in turn helps to avoid costly OoS.

GWP® gives clear answers to questions such as how to specify or calibrate balances correctly. It covers every relevant step of the instrument's life cycle from evaluation to routine operation.

GWP® - The Weighing Standard

The Weighing Instrument is being Calibrated…

Repeatability RP

Readability RD

Nonlinearity NL

Eccentricity EC

Sensitivity SE

Uncertainty of Weighing Instruments

Nominal Property:

Measurement Properties:

All these properties contribute to the overall measurement uncertainty of the respective weighing instrument.

The Perfect Weighing Instrument…

…Impaired by Readability, … (RD)

…Sensitivity Offset, … (SE)

…Nonlinearity, … (NL)

…Eccentricity, … (EC)

…and Repeatability (RP)

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2

0 1 2 3 4 5 6 7 8 9 10

Absolute Measurement Uncertainty [mg]

Relative Measurement Uncertainty [%] (= Absolute measurement uncertainty / weight)

Relative measurement uncertainty increases as sample mass decreases

Unc

erta

inty

U [m

g or

%]

U [g] = U0 + Constant x Weight

For small sample weights, the relative uncertainty can become so high that the weighing results cannot be trusted anymore!

MaxLoad [g]

Behavior of Weighing Uncertainty

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0 1 2 3 4 5 6 7 8 9 10Unc

erta

inty

U [m

g]

MaxLoad [g]

Example of a Calibration Certificate

Semi-micro balance

Example of a Calibration Certificate

XP205

The examples show the increase of the relative measurement uncertainty upon decrease of load.

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0 1 2 3 4 5 6 7 8 9 10

Unc

erta

inty

U [m

g or

%]

MaxLoad [g]

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0 1 2 3 4 5 6 7 8 9 10

Relative Measurement Uncertainty [%] U

ncer

tain

ty U

[mg

or %

]

Required weighing accuracy [%]

MaxLoad [g]

When weighing below the minimum weight, the measurement un-certainty is larger than the accuracy required: Inaccurate results

Accuracy limit: Minimum sample weight

The Accuracy Limit = Minimum Weight

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0 1 2 3 4 5 6 7 8 9 10

Relative Measurement Uncertainty [%] U

ncer

tain

ty U

[gm

or %

]

MaxLoad [g]Accuracy limit: Minimum sample weight

MaxWeight [g]When weighing above the minimum weight, the measurement un-certainty is smaller than the accuracy required: Accurate results

Required weighing accuracy [%]Required weighing accuracy [%]

The Accuracy Limit = Minimum Weight

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0 1 2 3 4 5 6 7 8 9 10

1%

Minimum weight foran accuracy of 1%

More stringent accuracy = Increased minimum sample weight

Relative Measurement Uncertainty [%]

0.1%Required weighing accuracy [%]

Load [g]

Required weighing accuracy [%]

Minimum weight foran accuracy of 0.1%

Minimum Weight is a Function of the Accuracy

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0 1 2 3 4 5 6 7 8 9 10MaxLoad [g]

Relative Measurement Uncertainty [%]

Weighing accuracy [%]

MaxWeight [g]The minimum weight depends on its environment, the operator, and varies over time => Apply a safety factor

Unc

erta

inty

U [m

g or

%]

Safety

Minimum Weight varies over Time

Minimum Weight from Calibration Certificate

Variability of Minimum Weight – Safety Factor

time

Minimum weight

Smallest net weight

Calibration at Installation

adjustment (by service)

As-left calibrationAs-found calibration

calibration period

SAFETY

calibration period

"Factors that can influence repeatability while the balance is in use include:

- The performance of the balance and thus the minimum weight can vary over time because of changing environmental conditions

- Different operators may weigh differently on the balance—i.e., the minimum weight determined by different operators may be different

- The standard deviation of a finite number of replicate weighings is only an estimation of the true standard deviation, which is unknown

- The determination of the minimum weight with a test weight may not be completely representative for the weighing application

- The tare vessel may also influence minimum weight […]."

"For these reasons, when possible, weighings should be made at larger values than the minimum weight."

USP General Chapter 1251 suggests the application of a "safety factor".

USP <1251>: Variability of Minimum Weight

Accuracy = Weighing above Minimum Weight

Most important measure for accurate weighing:

Know the minimum weight of your instruments and always weigh above it, considering a safety factor!

Minimum weight unknown

Minimum weight unknown

200 g20 mg

A Risk-based Approach of Testing

USP General Chapter 1251: "The balance check is performed at appropriate intervals based on applicable standard operating procedures. The frequency of the balance check depends on the risk of the application and the required weighing tolerance."

FDA – Questions and Answers on cGMPs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124777.htm

Supplier's Question“Many leading analytical balance manufacturers provide built-in "auto calibration" features in their balances. Are such auto-calibration procedures acceptable instead of external performance checks? If not, then what should the schedule for calibration be?”

FDA Answer External performance checks still have to be carried out, but less

frequently. Risk analysis (criticality and tolerance of the process) and frequency

of use determine the frequency of performance checks. The calibration of an “auto-calibrator” should be periodically verified –

usual frequency is once per year - using […] traceable standards.

Log scale is better suited to depict uncertainties

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0 1 2 3 4 5 6 7 8 9 10

Unc

erta

inty

U [m

g or

%]

MaxLoad [g]

U_absU_rel

Rela

tive

Expa

nded

Wei

ghin

g Un

certa

inty

[%

]

0.00001

0.0001

0.001

0.01

0.1

1

0.01 0.1 1 10 100 1000

U_totU_RPU_ECU_NLU_SE

Balance XP204: Individual Uncertainty Contributions (@k=2)

Sample Mass [g]

Repeatability dominates uncertaintySensitivity & Eccentricitydominate uncertainty

Analytical balance

Balance Contributions to Uncertainty

Test Weights for User Tests

Weight 1: Largest OIML or ASTM nomination which equals or is smaller than the capacity of the balance or scale

Weight 2: Largest OIML or ASTM nomination which equals or is smaller than 5% of the capacity of the balance or scale

Semi-micro balanceCapacity 220 g

200 g and 10 g 50 kg and 2 kg

Ind. bench scaleCapacity 60 kg

Using a very small test weight results in the sensitivity deviation to becompletely buried within repeatability.

Assessing Systematic Deviations with Weight 1

Test sensitivity with a test weight close to nominal capacity (Weight 1).

Capacity5%< 5%

Not allowed

Load

Characteristic curve withsensitivity deviation

Correct sensitivity

Indication

Stipulated

USP General Chapter 41: "A test weight is suitable if it has a mass between 5% and 100% of the balance's capacity."

No accuracy test at working point.

Indication

Load

Assessing Repeatability with Weight 2

USP <41>: "To facilitate handling, the test weight that is used for the repeatability test does not need to be at the minimum weight value but can be larger because the standard deviation of repeatability is only a weak function of the test weight value."

Test weight up to a few percent of the balance's capacity.

5%

At the lower end of the measurement range, the repeatability is almost constant.

« 5%

Smaller weight: Feasible, butdifficult to handle (especially for micro and analytical balances)

Repeatability Test Performed with a Robot

Working point Test point

Maintain Accuracy with Performance Verification

To maintain continuous accuracy, it is important to carry out regular performance verification.

However, perform only meaningful tests and avoid unnecessary testing!

Doing the wrong tests? Quality Risk!Doing too much testing? Waste of Money!

The science-based global standard for efficient life cyclemanagement of weighinginstruments.

It applies a risk-based approach that allows improving control of the whole measuring process, which in turn helps to avoid costly OoS.

GWP® gives clear answers to questions such as how to specify or calibrate balances correctly. It covers every relevant step of the instrument's life cycle from evaluation to routine operation.

GWP® - The Weighing Standard

Publications in Journals

Pharmaceutical Engineering, November/December 2009 Pharmaceutical Engineering, January/February 2012 Pharmaceutical Formulation & Quality, February/March 2012

Publication in September 2013 Edition of MEASURE.

GWP® - The Weighing StandardWhy We Should Challenge the Established Way We

Calibrate and Test Weighing Instruments

NCSLI Nashville July 2013

Dr. Klaus FritschManager Compliance