Reference Paper

Complying with USP 41 and 1251

Balance Calibration and Testing

If companies are still carrying out the former widespread practice of checking balances daily
or even before every use, they could potentially benefit from an optimized risk-based testing
schedule which could eliminate unnecessary testing and bring about significant time, costs
and material savings.

The United States Pharmacopeia (USP) General Chapters <41> Balances and <1251> Weigh-
ing on an Analytical Balance aim to ensure weighing accuracy and eliminate unnecessary
over-testing for US pharmaceutical manufacturers and suppliers. Chapter <41> focuses on
accuracy and balance assessment, whilst <1251> suggests that the type and frequency of
balance checks should be determined by the risk and process tolerance of the application.
 USP General Chapters <41> Balances and <1251> Weighing on an Analytical Balance reflect current state-of-
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the-art weighing practices, including modified balance test procedures, which focus on the determination of
minimum weight, and the execution of routine testing. The requirements of General Chapter <41> are mandatory
and state that accurate weighing must be performed using a calibrated balance. This applies for balances used
to weigh analytes for quantitative measures. Chapter <41> details a practical balance assessment, describing
accuracy and repeatability tests with new acceptance limits.

Accuracy Testing

For accuracy testing, a test weight of 5–100% of the balance capacity must be used. Accuracy, defined by USP as
the systematic error, must be determined at higher loads close to the balance capacity (i.e. largest systematic er-
ror) as it cannot be detected reliably below 5%. Hence, accuracy testing below 5% is not allowed (see Figure 1).

Figure 1: For accuracy testing, the test weight should be between 5 and 100% of balance capacity

Repeatability Testing and Minimum Weight Determination

In contrast, repeatability testing and minimum-weight determination should be carried out using a small weight
below 5% of the balance capacity (see Figure 2). In this lower range, the repeatability is the dominant source
of error and is virtually independent of the test weight. With higher weights (i.e. above 5%), the repeatability is a
weak function of the test weight and so the repeatability will increase, leading to higher minimum weight values.

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Figure 2: For repeatability testing, the test weight should be < 5% of balance capacity.

www.mt.com/balance-routine-testing

Advisory Chapter <1251> provides additional clarification and extends the scope to any balance used for an
analytical procedure and has a focus on balance qualification and operation. Installation Qualification (IQ),
Operational Qualification (OQ) and Performance Qualification (PQ) recommendations are given. For example,
performance qualification should be carried out using a risk-based approach.

Minimum Weight

“Minimum weight” refers to the smallest sample size that can be accurately weighed on a balance. Every bal-
ance has an individual minimum weight that is unique to the balance and depends on the type and performance
of the load cell, the location of the balance, and the environmental conditions. The minimum weight applies to
the net sample weight and does not include the tare vessel. The minimum weight of every balance should be
periodically assessed for conformance.

USP also gives recommendations on how to establish the minimum weight for applications outside of USP <41>
with the phrase “If not subject to the requirements of General Chapter <41>, the minimum weight value may vary
depending on the required weighing tolerance and the specific use of the balance.”

Chapter <1251> provides practical recommendations for the installation qualification and operation of balances.
Amongst others, it describes several environmental factors that can influence the performance of a balance,
such as: air currents (drafts), temperature variations (e.g. direct sunlight), vibrations, and electrostatic effects.
These can all affect the minimum weight of a balance at any time.

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 Safety Factor
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Crucially, weighing net samples sufficiently above the minimum weight is recommended in order to take balance
performance fluctuations into account. The implication is that a safety factor should be used when weighing. The
use of a safety factor ensures that the smallest net weight is sufficiently larger than the minimum weight deter-
mined at a particular time by a particular person.

1 Required weighing tolerance: 1%

2 Accuracy limit of the balance, minimum weight determined: 8.44 g
3 Minimum weight with a safety factor of 2: 17.47 g
4 Smallest net weight in the Safe Weighing Range

Weighing Range (g)

Figure 3: Safe Weighing Range

There are three areas in the device’s weighing range:
• RED AREA: Lowest weighing range, below the minimum weight of the balance or scale, indicates that the results are inaccurate.
• YELLOW AREA: This range indicates that the weighing tolerance is still met but there is a potential for inaccuracies caused by other influ-
ence factors such as the environment, object to be weighed, operator, etc. In other words it may not be safe to weigh in this yellow zone.
• GREEN AREA: Indicates the Safe Weighing Range in which it is safe to weigh, even if conditions vary and may influence the performance
of the instrument.
www.mt.com/lab-weighing-range

Applying a safety factor minimizes the risk of out of specification (OOS) results. The safety factor is the quotient
between the smallest net weight and the experimentally determined minimum weight. The safety factor accounts
for environmental influences and variations in operators, samples, and statistical factors. The safety factor ap-
plied should depend on the risk. It should be higher for more critical applications and unstable environments.
Figure 3 illustrates how the safe weighing range applies in action.

Optimizing Routine Testing

USP Chapter <1251> suggests that the former widespread routine of a daily balance check in the pharmaceutical
industry is no longer a state-of-the-art requirement. Instead, the type and frequency of balance checks should be
determined by the risk and process tolerance of the application. The more critical the impact of an incorrect re-
sult, the more testing should be carried out to reduce the risk of OOS results. In any case, balance checks should
contain at least a regular calibration with determination of measurement uncertainty, and periodic sensitivity and
repeatability testing. Performing the right tests at the right intervals will ensure quality results. If companies are
still carrying out balance checks daily or even before every use, they could potentially benefit from an optimized
risk-based testing schedule which could eliminate unnecessary testing and bring about significant time and cost
savings.

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METTLER TOLEDO
Accuracy Calibration Certificate

METTLER TOLEDO’s Accuracy Calibration Certificate (ACC) calibrates balances and scales according to a com-
pany’s individual weighing process tolerances and ensures that local and global regulations are adhered to. By
following the guidance in the ACC, companies can be sure that weighing always takes place in the safe weighing
range of the balance, i.e. the minimum weight is not breached and an appropriate risk-based safety factor is ap-
plied. Companies benefit through improved quality, and reduced waste and rework.

www.mt.com/acc-expert

USP FAQs

The USP chapters focus primarily on analytical balances in laboratories. Do they also apply to balances in
a production or manufacturing environment?

The scope of USP is quality control of drugs. If the procedure referred to in a USP monograph requires materials
to be “accurately” weighed, a balance which weighs “accurately” (meeting 0.10% requirements for repeatability
and accuracy) is needed. If not, the balance repeatability and accuracy should meet other defined weighing
tolerances commensurate with the requirements of the application. Production scales can also have a critical
impact on the quality of drugs and thus need to meet GMP requirements. GMP requires scales to be consistently
accurate and to be periodically calibrated and tested. Thus, the same scientific principles of managing weighing
equipment apply for production and quality control. The difference is that USP <41> explicitly requires a weighing
tolerance of 0.10%, whereas the weighing tolerance in production can be chosen and defined based on specific
quality and process requirements. Most pharmaceutical companies typically use weighing tolerances between
0.1% and 2%.

For all applications, weighing should be carried out using a calibrated balance that meets the requirements for
repeatability and accuracy. The scientific principles are summarized in METTLER TOLEDO’s Good Weighing
Practice™ (GWP®).
www.mt.com/gwp

What do USP mean when they say that balance checks with external weights can be partially replaced by
using automatic or manually triggered adjustment by means of built-in weights?

With some limitations, the internal test can be considered as a sensitivity test. It detects systematic deviations
and adjusts for it. However, since the internal weights are not traceable, an external, traceable weight must be
used periodically. In practice, “partially” means that if the internal test is performed on a daily basis, the external
frequency can be extended to once a week or once a month, for example. It is recommended to activate the in-
built automatic adjustment function using the internal weights and to program (or trigger manually) the balance
for a daily adjustment. Depending on the risk of the application, further measures may be recommended.

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 Do we need to establish the minimum weight for each
balance or can we just set a nominal minimum weight
for all 5-place balances?

Every balance has an individual minimum weight, depending on

the type and performance of the load cell, the location and the
environmental conditions. This means that ten different balances
of an identical model may have ten different minimum weights. In
theory, it is possible to set the smallest net weight to a relatively
high threshold to cover a family of identical balances. However, this
would eventually mean that some of the weighing range is lost with
those balances that perform better - and potentially weighing more
material than is actually necessary could mean wasted sample and
higher costs. Nevertheless, if the smallest net weight for a series of
instruments is set to 50 mg, for example, then the minimum weight
of every balance must still be periodically assessed for confor-
mance.

What is a safety factor and how is it determined?

The safety factor is the quotient between the smallest net weight to
be weighed and the determined minimum weight and accounts for
environmental influences and variations in operators, samples and
statistical factors. The safety factor depends on the risk. It should be
higher for more critical applications and unstable environments. It is
recommended to measure the current, actual safety factor through
a GWP® Verification and then define it based on the results and the
risk analysis.

METTLER TOLEDO’s Good Weighing Practice™ can help phar-

maceutical manufacturers and suppliers to comply with the USP
Chapters by putting the guidelines into practice in a structured and
effective way. The GWP® Verification service includes a risk assess-
ment and provides an appropriate testing schedule detailing test
methods, frequencies and weights based on the specific risks.

www.mt.com/gwp

METTLER TOLEDO Group

Laboratory Weighing
www.mt.com/lab-usp
For more information
Local contact: www.mt.com/contacts

Subject to technical changes

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