Ensuring USP Compliance with

Revised Chapters on Weighing

Presenters:
Mr. Gregory Martin
Dr. Martin Huber
Dr. Joanne Ratcliff

Webinar

Speakers
Moderator:
Patricia Van Arnum
Executive Editor
Pharmaceutical Technology

Speakers:
"Recent Revisions to USP Chapters <41> and <1251>"
Gregory Martin
President, Complectors Consulting
Chair of the USP Expert Panel on Balances
"Practical Guidance on how to Achieve USP & GMP Compliance"
Martin Huber, Ph.D
Good Weighing Practice Competence Center
Mettler-Toledo AG
"Introducing Gravimetric Sample Preparation"
Joanne Ratcliff, Ph.D
Laboratory Weighing
Mettler-Toledo AG

Gregory P. Martin
President, Complectors Consulting
greg.martin@complectors.com
484-942-3200

<41> Weights and Balances

<1251> Weighing on an Analytical Balance

Among the oldest chapters in USP

No substantial revision since 2000

Changes recently introduced in June 2013

in USP 36/NF 31 Second Supplement
Became official on 1 Dec 2013

Chapter <41>

Name changed to Balances

Elimination of references to standardized weights,
which are controlled by other organizations
Added clarity on Repeatability and Accuracy

Chapter <1251>

Major overhaul
Focus on Qualification and Operation

Chapter <41>

Users have freedom to use any appropriately

calibrated weights
Repeatability limit changed to 0.10% with 2 SD
from 0.1% with 3 SD (no practical impact), to
harmonize with current metrology practices
Accuracy limit of 0.10% added explicitly

Chapter <1251>

Added information on balance qualification

Balance checks and minimum weight addressed
More flexible language for types of weighing
Valuable information regarding problem samples
and safety consideration
5

Scope

This chapter states the requirements for materials

that must be accurately weighed
USP General Notices 6.50.20 states Solutions for
quantitative measures shall be prepared using
accurately weighed or accurately measured analytes

For other applications, the balance repeatability and

accuracy should be commensurate with the
requirements for its use

Requirements

Weighing should be done using a calibrated balance

that meets the requirements for repeatability and
accuracy
6

Repeatability is assessed by weighing one

test weight not less than 10 times

Because repeatability is virtually independent of

mass, use of a small test weight is not required

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 less than 0.41d,

where d is the display increment, replace it with
0.41d
The smallest allowed standard deviation

of 0.41 d accounts for the rounding error

of a digital indication and provides a
lower limit for the minimum weight

Is 2 x s / m < 0.10 % ?

Where:
2 = k, coverage factor
s = standard deviation of not less than 10
determinations
m = desired smallest net weight

Example:

Consider the application

s = 0.007 mg, m = 20 mg
2 x 0.007 / 20 x 100 = 0.07%, which is < 0.10%
Balance is suitable for weighing 20 mg

The accuracy of a balance is satisfactory if its

weighing value, when tested with a suitable
weight, is within 0.10% of the test weight
value
A test weight is suitable if it has a nominal
mass between 5% and 100% of the balance's
capacity, and its maximum permissible error
(mpe) is NMT one-third of the applied test
limit of the accuracy test
Select a weight class so that the uncertainty is
negligible compared to the accuracy test limit
9

Summary of Changes

Major overhaul
Focus on Qualification and Operation
Qualification

IQ, OQ, PQ
Balance checks, minimum weight

Operation

Receivers
Types of weighing
Problem Samples
10

The general information described here

applies directly to electronic balances used in
analytical procedures
This chapter should not be considered allinclusive
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
11

The balance should be installed on a solid, level,

nonmagnetic surface that minimizes the
transmission of vibration
If a metallic support surface is
used, the surface should be
Issues to be avoided
grounded in order to prevent

Air currents
the buildup of static electricity
Excessive temperature variations
Humidity extremes (very low or very high)
Adjacent operations cause vibration
The balance is located within a fume hood or near corrosive
materials
The balance is adjacent to equipment that produces a
magnetic field (e.g. a magnetic stirrer)
Direct sunlight strikes the balance

12

Demonstrate the instrument is operating

properly

All moveable parts are able to move as intended

Reading is stable
Built-in weights for manually triggered or
automatic adjustment are working properly
Ancillary equipment performs as intended
Tare function is operational
Initial calibration passes

13

Performance Qualification should be performed regularly as described in SOPs

Property

Examples

Acceptance
Criteria*

Sensitivity

The test load at or sufficiently close to the

nominal capacity of the balance

NMT 0.05%
deviation

Linearity

From 3 to 6 points over the range of the

balance

NMT 0.05%
deviation

Performed in the center and the four

quadrants with test load usually is
NMT 0.05%
Eccentricity
between 30% and 100% of the capacity of
deviation
the balance
10 replicate weighings with a test weight
Requirement
Repeatability
that is a few percent of the nominal
from <41>
capacity of the balance
* Based on accurately weighed; other criteria may apply

14

A balance check using an external weight

helps ensure that the balance meets weighing
tolerance requirements
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 weighing tolerance
More about this later

Balance checks with external weights can be

replaced partially using automatic or manually
triggered adjustment by means of built-in weights
15

min

= k s/required weighing tolerance

Since k = 2 and tolerance is 0.10% or .0010,

m min = 2000 s

As an example, if s = 0.009 mg, then m min = 18 mg

The minimum weight applies to the sample weight,
not the tare or gross weight
Weighings should preferably be made at larger
values than the minimum weight [more about safety
factor later]

16

Receivers

Practical advice; fairly straightforward

Types of Weighing

Addition (e.g. to a weighing paper)

Dispense (e.g. from a syringe)
Gravimetric (e.g. using a dosing unit)

17

Problem Samples
Electrically charged samples and receivers (static electricity)
Volatile samples
Warm or cool samples
Hygroscopic samples
Aseptic or biohazardous samples

Air flow within the biosafety cabinet, isolator or similar device potentially
can cause balance instability
After the balance has been installed under a hood, a rigorous qualification
should be performed to assess balance performance in this environment

Safety Considerations
Analysts may be exposed to high concentrations of materials
which may be toxic or allergenic during the weighing process

18

greg.martin@complectors.com
19

Practical Guidance on
how to Achieve USP & GMP Compliance
Dr. Martin Huber
Good Weighing Practice
Competence Center
Mettler-Toledo AG

Consequences of New Chapters <41> & <1251>

3.
Minimum Weight

General Chapter 41 "Balances"

GC <41> "Balances"

Requirements

1. "Weighing shall be performed using a balance that is

calibrated []"

2. "[] and meets the requirements defined for repeatability

and accuracy."

22

Chapter <41>: Repeatability Requirements

23

Chapter <41>: Accuracy Requirements

24

Chapter <41>: Performance Criteria

25

Chapter <41>: Test Weights for Repeatability

2 s

m

0.10%

m = desired smallest
net weight

0.10%
2

"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."
26

Chapter <41>: Test Weights for Accuracy

"A test weight is suitable if it has a nominal

mass between 5% and 100% of the balance's
capacity."

Today's widespread practice of accuracy testing with a small weight

at the "working point" is not allowed anymore.

27

Chapter <41>: Test Weights for Accuracy

Accuracy Test Tolerance

28

CL

mtest weight 0.10%

2

Chapter <41>: Test Weights Summary

Repeatability:
Minimum Weight mTW 5%

Accuracy:
5% mTW 100%
mTW = mass of test weight

Weight 1 Accuracy. Largest OIML/ASTM

weight below balance capacity ( 100%)

CarePac
Weights for
Routine Testing

Weight 2 Repeatability. Largest OIML/ASTM

weight 5% of the capacity
29

Contributors of Measurement Uncertainty

Measurement properties
contributing to the
measurement uncertainty

Sensitivity
Non-linearity

"Systematic
Error"
~ USP <41>
"Accuracy"

Eccentricity
Repeatability

"Random Error"

Chapter <1251> Performance Qualification

"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."
30

Importance of Uncertainty Contributors

Balance XP204: Individual Uncertainty Contributions (@k=2)
Relative Measurement Uncertainty [%]

0.1

U_tot
U_RP
U_EC
U_NL
U_SE

0.01

0.001

0.0001

0.00001
0.01

0.1

10

Sample Mass [g]

Repeatability dominates uncertainty

100

1000

Sensitivity & Eccentricity

dominate uncertainty

Summary: Influence of Uncertainty Contributors

Repeatability
Dominant influence with samples of small mass

Sensitivity & Eccentricity

Dominant influence with samples of large mass;
negligible influence with samples of small mass

Nonlinearity
Not dominant with samples of small mass; generally not
dominant throughout the entire sample mass range

It is normally not necessary for the user to assess nonlinearity in

routine tests; this is done during calibration by the service technician.
32

General Chapter 41 "Balances"

Requirements

1. "Weighing shall be performed using a

balance that is calibrated []"

Calibration

"Operation that [] establishes a relation between the

quantity values with measurement uncertainties []
and uses this information to establish a relation for
obtaining a measurement result from an indication."
International Vocabulary Of Basic And General Terms In
Metrology (VIM) JCGM 200:2012, item 2.39

In simple words: During calibration, the measurement uncertainty

of the instrument is determined.
33

Example of a Calibration Certificate

U=(

)
Simplified formula

34

Measurement uncertainty [g or %]

Behavior of Measurement Uncertainty

U = U0 + C x l

Weight [g or kg]

Max.

Relative measurement uncertainty [%] =

Absolute measurement uncertainty / weight

35

Measurement uncertainty [%]

Behavior of Measurement Uncertainty

Weighing tolerance [%] (e.g. 0.10%)

Weight [g or kg]

Max.

Minimum weight

Weighing below the minimum weight delivers inaccurate results

which can lead to OOS, rework and disposal.
36

2. How Often Should Balances Be Tested?

37

Chapter <1251> Frequency of Balance Checks

Performance Qualification

"Performance qualification should be performed periodically [], 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."

GC 1251 does not describe a daily balance assessment or check

anymore. Risk analysis determines the frequency of any test.
38

Chapter <1251>: Risk-Based Test Frequencies

Weighing Tolerance

0.10%

Impact

39

3. Handling Minimum Weight

40

Chapter <1251>: 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 according USP <41>

the equation 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 is the first official introduction of minimum weight within a
Pharma compendium and not restricted to applications of USP <41>.
41

Minimum Weight beyond USP <41>

42

Chapter <1251>: Environmental Factors

"The performance of the balance and thus the minimum weight can vary over
time because of changing environmental conditions []
For these reasons, when possible, weighings should be made at larger values
than the minimum weight."
USP newly stipulates the application of a "safety factor".
43

Variability of Minimum Weight Safety Factor

Net weight

Smallest net weight

24 mg

SAFETY
FACTOR

e.g. 30 mg
adjustment
(by service)

21 mg

16mg

Minimum weight
determined

14 mg
calibration period

calibration period

time
Calibration
at Installation

As-found
calibration

44

As-left
calibration

4. How to Achieve Compliance ?

3.
Minimum Weight

GWP - The Global Weighing Standard

Scientific, risk-based
methodology

Clear guidance how

to specify and qualify
balances & scales

Applicable to all
weighing equipment
of any manufacturer

USP and GMP auditproof documentation

46

Benefits of GWP Verification Documentation 1/2

Documents the performance of each
balance versus process & compliance
requirements

47

Benefits of GWP Verification Documentation 2/2

Recommended calibration and

routine tests, including SOPs
and test frequencies

Appropriate test weights and

weight classes

Test tolerances and acceptance

criteria (warning & control limits)

Only meaningful and necessary tests are recommended.

In many cases, efforts can be reduced.
48

Easy Compliance with GWP Verification

Includes:

Calibration (Measurement Uncertainty)

Minimum Weight determined
Safety Factor determined
Risk Analysis
Routine Test SOPs
Test Frequencies
Test Weights and Classes
Test Tolerances
Training
Scientific rational and publications

All relevant information to update your SOPs for new compliance

Available for Lab and Production weighing devices of any brand
49

GWP Publications in Pharma Journals

Pharmaceutical Engineering, November/December 2009

Pharmaceutical Engineering, January/February 2012
Pharmaceutical Formulation & Quality, February/March 2012

Also watch the USP Movie Tutorial

www.mt.com/lab-usp-tutorial
50

Introducing Gravimetric Sample

Preparation
Dr. Joanne Ratcliff
Laboratory Weighing
Mettler-Toledo AG

USP <1251>: Weighing on an Analytical Balance

"Gravimetric DosingGravimetric dosing typically is used for sample
and standard preparations or capsule filling. For such weighing the
analyst places the volumetric flask, vial, or capsule shell on the balance;
tares the balance after the balance display stabilizes; adds the solid or
liquid components into the receiver by means of dosing units; and
records the respective weights."

52

Introducing Gravimetric Sample Preparation

1. What is Gravimetric Sample Preparation?

2. Why change to a Gravimetric Approach?

3. How to implement Gravimetric Methods?

53

What is Gravimetric Sample Preparation?

The definition of Gravimetric Sample Preparation is:
Weighing not only the solid but also the solvent to
prepare a precise concentration of solution
Weigh solid & diluent directly into
the same (disposable) vial

Amount of diluent is precisely

calculated from ACTUAL amount
of solid dispensed

Prepare solution in mg/g,

mg

supported by USP Chapter 841

(official 1 Aug 2013)

54

Why Change to a Gravimetric Approach?

STEP 1: WEIGH SOLID (Sample or Standard)

Manual /Volumetric

Automated /Gravimetric

Potential for substance to be lost in

transfer from weigh boat or paper

Weigh directly into vial

No weigh boats/papers required

User in close contact with the substance

Safety precautions must be taken

User exposure minimized

Solid contained in closed dosing system

Reduces weighing errors and enhances operator safety

55

Reduce Errors and Out-of-Spec Results

STEP 2: ADD DILUENT

Manual /Volumetric

Automated /Gravimetric

Meniscus reading is subjective (cause of variability)

No meniscus reading error

Published accuracy/tolerance

Dosing of diluent (g) has negligible uncertainty

(far above the minimum weight)

Calibrated at 20C but used at @?

Method not temperature dependent

Risk of cross contamination with rinse and re-use

Disposable vials used

Cross contamination risk eliminated

User error in selecting the wrong flask/pipette?

Amount of solvent to add calculated automatically

Volumetric flasks have failure rates up to 50% (NIST)

Should be recalibrated every 10 years (NIST)

Volumetric flasks not required

Eliminates volumetric flasks and associated errors

56

Peace of Mind with a Reliable Process

RFID chip in dosing

heads

Amount of diluent
calculated automatically

Labels printed
automatically

Eliminates selection of

Eliminates manual

Eliminates data

the wrong sample

calculation errors

transcription errors

Eliminates human error in

choice of flask and/or
pipette

Reduces risk - data is electronically recorded and fully traceable

57

Lower Minimum Weight with Automated Weighing

XP205

QB5

Manual (5-place balance): 14 mg

Safety factor of 2 28 mg

Automated system: 6 mg
Safety factor of 1.5 9 mg

Downscaling by using automated weighing

Automated weighing systems have smaller minimum weight

A smaller safety factor can be applied due to reduced environmental
influences and elimination of operator interaction
Weight [g]

Max

means that up to three times less sample can be used!

58

Save > 80% of solvent and substance

120

1
AmountofSolid
(mg)

100

100

0.8
AmountofSolvent
(mLorg)

80
0.6
60

50
0.4

40
0.2

18

20

9
2.1

4.2
0

0
ManualVolumetric
(MW14mg)

QuantosQB5
(MW6mg)

QuantosQX7
(MW1.4mg)

Gravimetric sample preparation systems

Quantos QB5

59

Quantos QX7

Save > 80% of solvent and substance

120

120%
100%

AmountofSolid
(mg)

80

80%

AmountofSolvent
(mLorg)

60

60%

Substancesavings
(%)

100

100

96%
82%

50

40

40%
18

20

20%

0%

2.1

4.2

0%
ManualVolumetric
(MW14mg)

QuantosQB5
(MW6mg)

QuantosQX7
(MW1.4mg)

Gravimetric sample preparation systems

Quantos QB5

Quantos QX7

Gravimetric dosing systems support Green Chemistry

60

Reproducibility and Precision Study

Experiment:

Repeatability and precision study

- Sample: Caffeine; Diluent: 30:70 MeOH:H2O
Aim:

Compare existing manual volumetric method with

new automated gravimetric method

Method:

Gravimetric method using Quantos QX7 fully

automated sample preparation workstation

Quantos QX7 [Mettler Toledo]

Results:
Method

Solid
amount

Diluent
amount

Time

Precision
(% RSD)

Manual
Volumetric

20 mg

50 mL

35 mins operator
(50 mins total)

1.67%

Automated
Gravimetric

5 mg

12.5 g

10 mins operator
(30 mins total)

0.49%

Automation improved precision x 3.4

75% less substance & solvent used
Labour time reduced by > 70%
61

How to implement gravimetric methods?

For an existing method:
Convert between mg/g and mg/ml using specific gravity conversion
described in USP Chapter <841> which states:
"Where the density is known, mass can be converted to volume, or
volume converted to mass, by the formula: volume = mass/density."
(First Supplement to USP36-NF31, Official since Aug 1, 2013)
If a new method is being developed:
Use gravimetric procedures (mg/g) for solution preparation and
document in the method
Or add the use of specific gravity for conversion to mg/mL (for
comparison to previous methods) into the method
Then validate in accordance with General Chapter <1225> as you
would for any new method

Note: If concentration remains the same, but total volume is changed, no

additional validation may be required, as compendial procedures are routinely
scaled up or down
62

Summary of Gravimetric Sample Preparation

Reduce ERRORS

Reduce RISK

Reduces OOS &

Enhances user
errors associated with
safety by reducing
"weighing" & "dilution"
exposure
steps
Increases process
security / reliability
Volumetric flasks and
Data electronically
weigh boats / papers
recorded and
no longer required
traceable

63

Reduce COST

Lower minimum
weight & safety
factor
Reduces substance
& solvent use by
>80%
Supports Green
Chemistry

Summary of revised GC 41 and 1251

Weighing shall be performed using a
calibrated balance

Repeatability & accuracy each with 0.10%

criteria

Minimum repeatability of 0.41d

Minimum weight can be calculated from s
using a test weight > minimum weight

Accuracy test with a weight 5% of capacity

Risk analysis determines the frequency of any test

Tests with built-in weights can partially replace external checks
Minimum weight applies to the net sample weight
Smallest net weight > minimum weight (safety factor)
Concept of minimum weight applicable beyond USP <41>

For more information

Contact us at
Mettler-Toledo AG
GWP and Laboratory Weighing
CH-8606 Greifensee / Switzerland
Joanne Ratcliff joanne.ratcliff@mt.com
Martin Huber martin.huber@mt.com

For more information on the USP changes visit www.mt.com/lab-usp

- Video tutorials, e-Learning, white paper, further on-demand webinars

View webinars on automated weighing at www.mt.com/q-webinars

View the current webinar schedule at www.mt.com/webinars
Thank you for your interest!
All rights reserved. 2013,
METTLER TOLEDO