New USP Chapters 41 and 1251 on Balances –

Choose the Fast Lane to Compliance

Dr. Klaus Fritsch

Manager Compliance
Global Business Area LabTec

Expert

Dr. Klaus Fritsch

 Manager Compliance
 Global Business Area “Laboratory & Weighing
Technologies” at METTLER TOLEDO
 Actively involved in USP, ASTM and
EURAMET Expert Panels

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Agenda

 Objective of Revision
 Revision of USP General Chapter 41
 Revision of USP General Chapter 1251
 Summary and Conclusions
 GWP® – The Weighing Standard

US Pharmacopeia

 Founded 1820 by 11 physicians

 The United States Pharmacopeia and The
National Formulary (USP–NF) is a book of
public pharmacopeial standards. It contains
standards for chemical & biological drug
substances, dosage forms, compounded
preparations, excipients, medical devices,
and dietary supplements.
 A drug product in the U.S. market or
imported in the U.S. must conform to the
standards in USP–NF
 1938 Federal Food, Drug & Cosmetics Act:
USP standards recognized, enforced by FDA
 Scientific non-profit and non-governmental
organization
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New USP General Chapters 41 & 1251
Publication in the Second Supplement to USP 36–NF 31 June 3rd 2013

After a six month transition period the new chapters will be official
from December 1st 2013 onwards.
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Weighing Results: Essential for Your Processes

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 How do You Assure Good Weighing Results?

Problem:
 “What you see is what you get”
 Inaccurate results and OoS
 Erroneous testing generates
unnecessary costs
Solution:
 Use the right instrument and know its
accuracy limit = minimum weight
 Risk-based performance verification
with only the necessary testing

Agenda

 Objective of Revision
 Revision of USP General Chapter 41
 Revision of USP General Chapter 1251
 Summary and Conclusions
 GWP® – The Weighing Standard

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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."

Weighing applications beyond USP General Chapter 41 should also

have clearly defined repeatability and accuracy requirements.
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Requirement for Repeatability

Requirement
 "Repeatability is assessed by weighing one test weight not less than 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."

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.
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Requirement for Repeatability
Example: Repeatability test with a semi-micro balance using a weight
with a nominal mass of 20 mg

Standard Old USP criterion Pass / New USP criterion Pass /

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

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).
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Requirement for Accuracy

Requirement
 "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."

 "The test weight's maximum permissible error (mpe), or alternatively its

calibration uncertainty, shall be not more than one-third of the applied
test limit of the accuracy test."

The test weights are selected large enough to efficiently detect

systematic deviations. The weight class is selected to have a weight
uncertainty which is negligible compared to the accuracy test limit.
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Which Test Weight for Accuracy?
 Test for accuracy (systematic deviations) with a test weight between
5% and 100% of the capacity.
 Using a smaller test weight results in systematic deviations to be
buried within repeatability.

Indication Characteristic curve with

sensitivity deviation

Correct sensitivity

Not allowed

Stipulated

Load
< 5% 5% Capacity

Agenda

 Objective of Revision
 Revision of USP General Chapter 41
 Revision of USP General Chapter 1251
 Summary and Conclusions
 GWP® – The Weighing Standard

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Scope of USP General Chapter 1251
 All USP Generel Chapters with a number equal or larger than 1000 are
for information only and not legally binding.

 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 weighing applications.
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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).

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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 no longer describes a daily balance assessment or check.

Risk analysis determines the frequency of any test.
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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 desired smallest net weight, 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.
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 Which Test Weight for 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%

It is much easier to assess repeatability with a larger test weight

than with a test weight reflecting the minimum weight of the balance.

Which Test Weight for Repeatability?

 "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."

Indication

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

Load
« 5% 5%
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Tare Vessel and Minimum Weight
 "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.

General Chapter 1251 wants to overcome the misconception that a

tare weight can be used to fulfill the minimum weight requirement.
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Variability of Minimum Weight – Safety Factor

 "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 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 suggests the application of a "safety factor".

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 Variability of Minimum Weight – Safety Factor
Minimum weight
Smallest net weight

SAFETY adjustment
(by service)

calibration period calibration period

time
Calibration
at Installation As-found calibration As-left calibration

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Types of Weighing – Selected Example

 "Gravimetric Dosing—Gravimetric 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."

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Environmental Influences
 "Potential facility issues:"
- Air currents
- Temperature changes
- Low or high humidity; electrostatics
- Vibration
- Corrosive materials
- Fume hood
- Magnetic influences
- Direct sunlight
 "In situations when the balance is located near equipment or systems
that induce vibration, drafts, electromagnetic radiation, magnetic fields,
or changes in temperature or humidity, the assessment should be
conducted with those systems operating in order to duplicate a worst-
case scenario."

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Agenda

 Objective of Revision
 Revision of USP General Chapter 41
 Revision of USP General Chapter 1251
 Summary and Conclusions
 GWP® – The Weighing Standard

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Impact of the Proposed New Chapters 41 and 1251

 The applicability of GC 41 ("…used for materials that must be accurately

weighed…") is now clearly defined.
 Use of calibrated balances is required; furthermore two tests with their
respective test limits are described (repeatability and accuracy).
 Change of the coverage factor k from three to two reflects current
metrology practice (as e.g. in calibration certificates).
 The change of the repeatability test limit from 0.1% to 0.10% affects the
rounding of the test result.
 The effective requirement for the repeatability essentially remains
unchanged from a practical perspective (changed coverage factor and
rounding essentially compensate each other).
 The use of 0.41d as the minimum repeatability value accounts for the
rounding error of digital indications as already incorporated in
international guidance documents for calibration of non-automatic
weighing systems.

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Impact of the Proposed New Chapters 41 and 1251

 An alternative method is described to determine the minimum weight of

balances, using a larger test weight than the minimum weight.
 It is clearly stated that the minimum weight applies to the sample weight,
not to the tare or gross weight.
 As repeatability fluctuates over time, when possible, the net sample
weight should be larger than the minimum weight (safety factor).
 It is not permitted to carry out an accuracy test using a test weight with a
mass of smaller than 5% of the balance's capacity.
 A daily balance assessment or check is not described anymore. Risk
analysis determines the frequency of any test.
 Checks with external weights can be replaced partially using (automatic
or manually triggered) adjustment by means of built-in weights.

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Agenda

 Objective of Revision
 Revision of USP General Chapter 41
 Revision of USP General Chapter 1251
 Summary and Conclusions
 GWP® – The Weighing Standard

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Accuracy = Weighing above Minimum Weight

Most important measure for accurate weighing:

Know the minimum weight of your instruments and
always weigh above it!

Minimum weight
unknown

20 mg

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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!

GWP® - The Weighing Standard

The only science-based global standard for efficient life cycle

management of weighing systems.

A risk-based approach that allows

to improve 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.

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Benefits of GWP® Verification Documentation 1/2

Certifies the accuracy of the

balance for the weighing process

For each balance:

 Documentation whether the accuracy
of the balance complies with the
process requirements, based on
minimum weight and safety factor

 Determines the minimum weight

of the balance at its location

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Benefits of GWP® Verification Documentation 2/2

Roadmap for accurate

weighing throughout the
life cycle of the instrument

 Recommended calibration
and maintenance services
 Optimal routine testing including
tests, frequencies and SOP’s

 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.

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Quality Assurance with GWP® Verification

 Accurate weighing at all times in

order to avoid OoS and costly
investigations in laboratory and
production areas

 Clear guidance on optimization

of weighing quality system

 Act only where it really matters -

no unnecessary investments

 Recommendations for inventory

optimization and cost savings

 Applicable to all types of

balances and scales from any
manufacturer

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If you want to know more about…

Compliance & USP chapters GWP Europe and Americas

Dr. Klaus Fritsch Jean-Luc Quenot
 Klaus.Fritsch@mt.com  Jean-Luc.Quenot@mt.com

GWP Asia Pacific

Jeik Tong Tan
 JeikTong.Tan@mt.com

Request a quote for METTLER TOLEDO GWP® Verification or ask for

an inhouse seminar.

Call 1-800-METTLER or visit www.mt.com/GWP-Verification

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New USP Chapters 41 and 1251 on Balances –
Choose the Fast Lane to Compliance

Dr. Klaus Fritsch

Manager Compliance
Global Business Area LabTec

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