Weighing is Critical

w/ focus on USP GCs41, 1251

US New Weighing Chapters <41> & <1251>
New Weighing Chapters <41> & <1251>
New Weighing Chapters <41> & <1251>
4 Simple Questions to Answer
Am I doing too much or
Are my balances/scales accurate?
too little testing?

Is our documentation complete? Do I have an overview of

the status of all equipment?
Customer Processes Weighing is Critical

Solutions to support customer processes

Drug Quality
R&D
Discovery Control

Logistics Retail

Laboratory Solutions
Manufacturing Packaging Industrial Solutions
Retail Solutions

Customer Benefits Accelerate processes Increase efficiency

Improve product quality Comply with regulations

6
Guaranteed Accuracy Reduced Costs Secure Audits

We want to produce high-grade products.

We want to save costs and reduce expenses.
We want to meet ISO and other regulations.

How can your weighing systems help and

meet the above requirements?
Avoid the following pain points.
7
Customers' Pain Points

Problem source:
How to prevent bad
Inaccurate weighing
batches and OOS*?
-QUALITY-

Auditor: Prove that Missing adequate

your scales are documentation
consistently accurate!
-COMPLIANCE-

Testing is costly
Do we test too little and a lot of effort
or too often?
-COST-
Good Manufacturing Practice

Say what you do, do what you say,

and be able to prove it.

Courtesy Novartis Courtesy Roche Courtesy Nocartis Courtesy Nocartis

Good People + Good Equipment + Good Processes = Good Products

9
Regulations Affecting Scales & Balances: cGMP

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

Regulations Affecting Scales & Balances - cGMP

How do we put this

into practice?

Balances and measuring equipment of an

appropriate range and precision should be available
for production and control operations. Measuring,
weighing, recording and control equipment should be
calibrated and checked at defined intervals by
appropriate methods.
Orange Guide, EC Guide to Good Manufacturing Practice,
Chapter 3.40/3.41
Steps to Ensure Quality and Minimize Costs

Steps must be taken

to ensure quality and
Quality compliance and to
Compliance minimize costs
Costs throughout the whole
weighing instrument
life cycle.
Using Estimated Uncertainty to help.
The weighing community should have a science-based standard for
efficient life-cycle management of weighing equipment.
Clear answers should be available on: how you calibrate each device,
how you establish of limits, and sound scientific rationale covering
every step in the life cycle management of a weighing device
4 Simple Questions to Answer
Am I doing too much or
Are my balances/scales accurate?
too little testing?

Is our documentation complete? Do I have an overview of

the status of all equipment?
Weighing A Small Sample is Critical

Capacity: 3'000kg
Readability: 1kg

min. 50%
Uncertainty

Typical minimum weight

for a weighing tolerance
of maximum 1 %:
80 kg

What you read on the display is not what you get!

Every measurement comes with uncertainty.
In order to weigh reproducibly you need to know this uncertainty.
GC <41>

History
Revision of USP General Chapter 41
Revision of USP General Chapter 1251
Reference to General Chapter 841 and 1251

16 Internal usage only

New General Chapter 41 "Balances"

Scope
"States the requirements for balances used for materials that must be
accurately weighed (see General Notices, 8.20)."
Weighing of analytes for quantitative measures
Scope unchanged but better defined/explained
Requirements
"Weighing shall be performed using a balance that is calibrated []"
"[] and meets the requirements defined for repeatability and
accuracy."
"For balances used for other applications the balance repeatability and
accuracy should be commensurate with the requirements of its use."

It is made evident that GC 41 is applicable for weighing of

analytes for quantitative measures. However, other weighings should
also have clearly defined repeatability and accuracy requirements.
17 Internal usage only
Requirement for Repeatability

Requirement
"Repeatability is assessed by weighing one test weight NLT 10 times."
"Repeatability is satisfactory if two times the standard deviation of the
weighed value, divided by the desired smallest net weight, does not
exceed 0.10%."
"If the repeatability obtained is smaller than 0.41 d, where d is the scale
interval, replace this standard deviation with 0.41 d."
Additional Statement
"Because repeatability is virtually independent of sample mass within the
balances capacity, use of a small test weight, which may be difficult to
handle, is not required."

GC 1251 provides more information how the repeatability require-

ment can be put into practice when using larger test weights.
18 Internal usage only
 Requirement Repeatability

Indication

At the lower end of the

measurement range, the
Smaller weight:
Feasible, but repeatability is almost
difficult to handle constant.
(especially for micro
and analytical Test weight up to a few percent of
balances) the balance's capacity.

Load
5% 5%
"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." Internal usage only
Requirement for Repeatability

Example: Repeatability test with a semi-micro (AX205 for example)

balance using a weight with a nominal mass of 20 mg

Standard Existing USP Pass / Proposed new USP Pass /

deviation criterion Fail criterion Fail
s 3*s/m 0.1% 2*s/m 0.10%

0.005 mg 0.08% (0.1%) Pass 0.05% Pass

0.007 mg 0.11% (0.1%) Pass 0.07% Pass
0.009 mg 0.14% (0.1%) Pass 0.09% Pass
0.010 mg 0.15% (0.2%) Failed 0.10% Pass
0.011 mg 0.17% (0.2%) Failed 0.11% Failed

The effective requirement for repeatability essentially remains

unchanged from a practical perspective (changed coverage factor
and different rounding essentially compensate each other).
20 Internal usage only
USP <41>: Repeatability Requirements

Internal usage only

Requirement for Accuracy
"The accuracy of a balance is satisfactory if its weighing value, when
tested with a suitable weight(s) is within 0.10% of the test weight
value."
"A test weight is suitable if it has a mass between 5% and 100% of the
balance's capacity."
Characteristic curve with
sensitivity deviation

Correct sensitivity
Indication

Not allowed

Stipulated

Load
< 5% 5% Capacity Internal usage only
USP <41>: Accuracy Requirements

Internal usage only

USP <41>: Performance Criteria

Internal usage only

New General Chapter 41 "Balances"

Scope
"States the requirements for balances used for materials that must be
accurately weighed (see General Notices, 8.20)."
Weighing of analytes for quantitative measures
Scope unchanged but better defined/explained
Requirements
"Weighing shall be performed using a balance that is calibrated []"
"[] and meets the requirements defined for repeatability and
accuracy."
"For balances used for other applications the balance repeatability and
accuracy should be commensurate with the requirements of its use."

It is made evident that GC 41 is applicable for weighing of

analytes for quantitative measures. However, other weighings should
also have clearly defined repeatability and accuracy requirements.
25 Internal usage only
Agenda

History
Revision of USP General Chapter 41
Revision of USP General Chapter 1251
Reference to General Chapter 841

26 Internal usage only

USP General Chapter 1251

All USP Generel Chapters with a number equal or larger than 1000 are
for information only and not legally binding.
A proposal to change General Chapter 1251 "Weighing on an Analytical
Balance" was made by the USP Expert Panel in parallel to the proposal
to change General Chapter 41 "Weights and Balances"
Provides information on
- Installation and Operational Qualification
- Performance Qualification and Balance Checks
- Minimum Weight
- Balance Operation

Important Statement at the beginning of the chapter: "The information

given in this chapter is applicable not only to balances used for materials
that must be accurately weighed (see Balances 41) but also to balances
used in all analytical procedures."

General Chapter 1251 is considered as an information chapter for

essentially all laboratory weighing applications.
27 Internal usage only
Performance Qualification as per GC 1251

"Table 1 provides a list of the most important balance properties that should be
assessed during performance qualification. Depending on the risk of the
application and the required weighing process tolerance, some of these tests
may be omitted. Tests also can be omitted if there is evidence that the property
in question has only minimal effect on the weighing performance."

Property Examples
Sensitivity The test load at or sufficiently close
to the capacity of the balance.

Linearity From 3 to 6 points over the range of the balance.

Eccentricity Performed in the center of gravity and the four quadrants [].
Test load usually should be 30% of the capacity of the balance
or higher.

Repeatability 10 replicate weighings (using a test weight that is a few

percent of the nominal capacity of the balance).

28 Internal usage only

Frequency of PQ and of Balance Checks

Performance Qualification
"Performance qualification should be performed periodically as described
in standard operating procedures, and the frequency of each of the
individual tests can vary depending on the criticality of the property."
Balance Check
"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."
"Checks with external weights can be replaced partially using (automatic
or manually triggered) adjustment by means of built-in weights."

GC 1251 does not describe anymore a daily balance assess-

ment or check. Risk analysis determines the frequency of any test.
29 Internal usage only
A Risk-Based Approach of Testing
The Concept of Minimum Weight

"The minimum net sample weight, mmin, of a balance can be expressed

by the equation:
mmin = k*s/required weighing tolerance
For materials that must be accurately weighed, Balances 41 stipulates
that 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%. For this criterion the equation above simplifies to:
mmin = 2000*s
If not subject to the requirements of Balances 41, the minimum weight
value may vary depending on the required weighing tolerance and the
specific use of the balance."

This methodology describes an alternative for determining the

minimum weight of balances.
31 Internal usage only
 Test Weight for Repeatability/Minimum Weight?

Indication

At the lower end of the

measurement range, the
Smaller weight:
Feasible, but repeatability is almost
difficult to handle constant.
(especially for micro
and analytical Test weight up to a few percent of
balances) the balance's capacity.

Load
5% 5%

Internal usage only

The Concept of Minimum Weight (1251)

"In order to satisfy the required weighing tolerance, when samples are
weighed the amount of sample mass (i.e., the net weight) must be equal
to or larger than the minimum weight. The minimum weight applies to
the sample weight, not to the tare or gross weight."

The net sample weight

has to fulfill the
minimum weight
requirement.

GC 1251 wants to overcome the misconception that a tare weight

can be used to fulfill the minimum weight requirement.
33 Internal usage only
The Concept of Minimum Weight

"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 balancei.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 also may influence minimum weight because of the
interaction of the environment with the surface of the tare vessel."
"For these reasons, when possible, weighings should be made at larger
values than the minimum weight."

The above information stipulates the application of a "safety factor".

34 Internal usage only
What is the Safety Factor?

Safety Factor < 1

Weighing results are inaccurate
and process will fail

Safety Factor = 1
Weighing process is currently OK,
but reproducibility may fail over time.

Safety Factor 2
(depending on risk)
Assured accuracy over time
US Minimum Weight beyond USP <41>
What we have evolved to....
Minimum Weight?
Testing Parameters?
Training
Certified weights
Tolerances
Uncertainty
Service
Calibration Departments
4 Simple Questions to Answer
Am I doing too much or
Are my balances/scales accurate?
too little testing?

Is our documentation complete? Do I have an overview of

the status of all equipment?
The Measurement Uncertainty of a
Weighing Device
Cut open view of a semi-micro balance (0.01mg)

40
Copyright 2009 Mettler-Toledo, Inc.
Electromagnetic compensating analytical balance
1 weighing pan
2 hanger
3 guide
4 flexible joint
5 coupling
6 lever
7 lever bearing
8 compensation coil
9 permanent magnet
10 magnetic flux
11 optical position sensor
12 position vane
13 temperature sensor

41
Copyright 2009 Mettler-Toledo, Inc.
Measurement Uncertainty what is it?

Measurement uncertainty
[] Parameter that describes the dispersion of the quantity values
that is assigned to a scale [].
International Vocabulary Of Basic And General Terms In Metrology (VIM) JCGM
200:2008, entry 2.26

The measurement uncertainty takes of account of the circumstance

that no measurement is perfect
The measurement uncertainty indicates how accurate the measured
value is how close it is to the destination
The indication of the measurement uncertainty is a part of quality
systems, such as ISO, GLP/GMP or pharmacopoeia such as the USP
The accuracy of measurements can be checked during an inspection
and needs to be documented
Accuracy = Readability?
Or do I need a scale with a higher readability,
such as 10 g or even 1 g?

But what about

the accuracy?
Accuracy Readability

Display: The readability of a scale

can be electronically set to different
values.

Sensor: To increase the accuracy, a

better sensor must be selected
(e.g. EMFR instead Strain Gauge
technology)

The accuracy of a scale is expressed by its measurement

uncertainty.
What Accuracy Means

A scale is ACCURATE
if it satisfies the requirements of the user.

In other words:

MEASUREMENT UNCERTAINTY < PROCESS

TOLERANCE
Accurate, reliable Measurement results
Measurement Measurement Measurement
uncertainty of m1 uncertainty of m2 uncertainty of m3
Process tolerance

OK Fair Not OK

m1 kg m2 kg m3 kg Display [kg]

Accuracy means that the MEASUREMENT UNCERTAINTY of the

instrument is always less than/equal to the PROCESS TOLERANCE.
 Essential Balance and Scale Properties

Nominal Property: Readability RD

Measurement Properties: Sensitivity SE

Nonlinearity NL

Eccentricity EC

Repeatability RP

All these properties contribute to the measurement

uncertainty of the respective weighing instrument.
The Perfect Weighing Instrument
Measurement uncertainty By readability, (RD)
Sensitivity Deviation, (SE)
Non-linearity, (NL)
Corner Load/Eccentricity/Shift (EC)
Repeatability (RP)
 Influence of Weighing Parameters on Accuracy

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

Relative Expanded Weighing Uncertainty [%]

Sample Mass [g]

Sensitivity & Eccentricity
Repeatability dominates uncertainty dominate uncertainty
Measurement Uncertainty behavior

Measurement uncertainty [kg or %]

Weight [kg] Max.

Relative measurement uncertainty [%] =

Absolute measurement uncertainty / weight
Behavior of Measurement Uncertainty
U [g] = U0 + Constant x Weight
Relative measurement uncertainty [%] Absolute measurement
(= Absolute measurement uncertainty / weight) uncertainty [g]
Uncertainty U [g or %]

Relative measurement uncertainty

increases as sample mass decreases

Weight [g] Max

Max
For small sample weights,Weight
the [g]
relative uncertainty can become
so high that the weighing results cannot be trusted anymore!
Accuracy limit = Minimum weight

Measurement uncertainty %]

Process tolerance [%]

(Accuracy requirements of the customer)

Weight [kg] Max.

Accuracy limit:
Minimum weight

When weighing above the minimum weight, the measurement

uncertainty is always smaller than the accuracy required:
Accurate results
Minimum weight increases as process % gets tighter

Measurement uncertainty %]

1%

0.5%

0.1%

Minimum Minimum Minimum Weight [kg]

weight weight weight
for 1% for 0.5% for 0.1%

The greater the accuracy, the tighter the process tolerance -

the higher the minimum weight
 Scope of USP and GMP

USP41 USP1251 USP41 GMP

"Quantitative "All analytical Statement All weighing
"For balances used for other
Analysis" procedures" applications the balance processes
repeatability and accuracy
should be commensurate
with the requirements
of its use."

Scope of USP: Quality Control of Drugs

Lab balances only

Scope of GMP: Consistent Manufacturing and Quality Control

All weighing equipment 59 Internal usage only
GWP - The Global Weighing Standard

Metrology
Quality
management

Process
requirements
Content of GWP Verification: Per Instrument

For each weighing instrument:

Calibration with minimum weight certificate
GWP Verification performance verification, containing:
Required / achieved accuracy statement for minimum weight and safety factor
Optimal Performance verification activities and frequencies, weights, and limits
GWP Verification Document
GWP Verification Document

Accurate results at all times:

Suitability and accuracy of the instrument

based on minimum weight and safety factor
Recommended installation, calibration
and maintenance services

Recommended performance
verification activities and frequencies

Appropriate test weights and weight

classes

Warning and control limits that ensure

quality of weighing processes
Content of GWP Verification: Per Site

For each site:

Weighing accuracy summary with color coded interpretation
Comprehensive summary report providing inventory status at a glance
Recommendations for optimization and cost savings
Page 1 Accuracy Status Result