Good Weighing Practices
in
Pharmaceutical Industry
Presented by:
Md. Tayfuzzaman
Senior Executive, ARD
SCOPE
The general information described here applies
directly to electronic balances used in analytical
procedures.
Many portions of the information are applicable to all
types balances also.
REFERENCES
The following USP Chapters and regulatory guidelines
were considered when composing this data:
〈41〉 Balances
〈1251〉 Weighing on an Analytical Balance
〈1058〉 Analytical Instrument Qualification
Industrial Guidelines
NIST Hand Book on specifications, Tolerances and other
Technical Requirements for Weighing and Measuring Devices.
21CFR211.160-US FDA
Definitions of Balances
Electronic Balance:
A balance that generates a current proportional to the
displacement of the pan.
Analytical Balances: An analytical balance is a class of balance
designed to measure small mass in the sub-milligram range.
The measuring pan of an analytical balance is inside a
transparent enclosure with doors so that dust does not collect
and so any air currents in the room do not affect the balance's
operation. This enclosure is often called a draft shield. The use
of a mechanically vented balance safety enclosure which has
uniquely designed acrylic airfoils, allows a smooth turbulence-
free airflow that prevents balance fluctuation and the measure
of mass down to 1 μg without fluctuations or loss of product.
Schematic Diagram of Electronic Balance
Different type of Analytical Balances
Class Balance name Resolution Quantity of
decimal digits
1 Ultra- 0,1µg 0,0000001
microbalances
2 Microbalances 1µg 0,000001
3 Semi- 0,01mg 0,00001
microbalances
4 Analytical balances 0,1mg 0,0001
5 Precision balances 1g ÷ 1mg 1g ÷ 1mg
Accurately Weighing
Measuring of weight of a specimen with an Qualified,
Calibrated and specified Analytical Balance maintaining all
conditions of GLP.
In generally we have a wrong concept regarding accurately
weighing that we have take a weight very close to the target
weight.
As per USP: The initial step for many quantitative analyses
is to accurately weigh a specified amount of a sample.
stipulates that solutions for quantitative measures must be
prepared using accurately weighed analytes: i.e., analysts
must use a balance that meets the criteria in USP 〈41 〉.
Importance of Accurate weighing
Weighing is the starting and heart of an analysis.
A statistics shows that about 30% of the analytical
errors occurring from weighing error.
Wrong analytical results produces misleading
evaluation data of DS and DP, consequently increase
the risk of Patient safety.
Prerequisite of Weighing Room
Controlled temperature: As weighing results are influenced by
temperature, user should ensure a constant temperature is maintained
in weighing rooms/laboratories. The typical drift of balances of types 1
and 2 is 1-2 ppm/°C. The deviation should not exceed more than 5 °C
per hour.
Humidity: The optimum relative humidity (% RH) during a weighing
process is between 40 % to 60 % for balances of class I and II (see Table
1). The relative humidity may be expanded to 20 % to 80 % in cases
where the accuracy and linearity of measurements are not affected
Air Flow: Balances should not placed in the flow of air conditioners or
devices with ventilators (such as computers or large laboratory
equipment), next to doorways or in areas of high traffic. This is
because in addition to the potential temperature drift, strong air
currents can interfere with the functioning of balances. If a balance is
placed in a laminar flow workstation, e. g. for weighing of toxic
material, the cabinet should be suitable for the intended use.
Prerequisite of Weighing Room
Free from all types of dust and residuals of previous
weighing
Vibration free table.
Sufficient area for movement
Controlled entrance of personnel
Nearer to the analytical Laboratory.
Free from strong external Electrical and magnetic
field.
Balance should be protected from direct sunlight
Qualification/Calibration of Analytical Balances
As per the USP Chapter <1251> and <41> following parameters
should evaluate during Qualification/Calibration.
Sensitivity (The test load at or sufficiently close to the capacity
of the balance. AC: NMT 0.05%)
Linearity (From 3 to 6 points over the range of the balance.
AC: NMT0.05%)
Eccentricity (Performed in the center of gravity and the four
quadrants (for rectangular platter shapes) or at analogous
locations for other platter shapes. Test load usually should be
30% of the capacity of the balance or higher (refer to the
manufacturer's manual for any possible upper limit AC; NMT
0.05%)
Repeatability
Select a test weight of few percent of the Balance
capacity
Perform 10 measurements with this weight
Calculate 2 x standard deviation (std. dev.) / desired
smallest net weight≤ 0.10%
If the std. dev. < 0.41 d, replace it by 0.41d (minimum
error).
Calculation of Minimum Weight
Calculate the starting point of the operating range:
2 x SD x 1000
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.
Factors that can influence repeatability while the Balance is in Use
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.
Accuracy
Based on the frequency of use and risk analysis
Electronic Balance accuracy should be check at regular
interval.
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.
Quality Risk Analysis
Risk Identification → Define your own balance analysis
What are you weighing?
What is the expected analysis precision?
How big is the sample?
What weighing containers do you use?
What are the external conditions of analysis realization?
Risk Analysis
Should catalogue data be estimated?
Should measurement data be estimated?
Risk Estimation
Estimate mass measurement error influence on product
quality Then the most important stage of risk management
should be performed, which helps in decrease it.
Balances risk reduction is finding an answer to the question:
how to reduce measurement error:
Risk Reduction → how to reduce weighing errors?
suitable balance choice
Using balance self-adjustment
weighing techniques internal training
Using standard operational procedures ,,SOP”?
Using authorized service – service reviews
Risk Acceptance → is balance precision sufficient?
•Estimate weighing errors influence on the whole process
risk.
• Next stage of risk management process is performed
process data monitoring. At this stage balance precision is
estimated with regard to requirements and effectiveness of
carried out operations. Risk Management Process Review
is a system procedure. It aims at receiving new ideas and
using them in order to reduce risk. When using risk
management in reference to balances, it should be
remembered that legal requirements have to be observed.
Risk management is designed as a process that supports
making decisions based on scientific knowledge and
practice.
Measurement Errors
In practice, there are no ideal measurements, each
measurement is afflicted by an error.
Errors are divided into:
Gross (mistakes),
Systematic,
Random
Gross Error
Gross error in most cases occurs because operator’s inattention or in
result of sudden change of measuring conditions (e.g. shocks, breeze
of air). An instance of a gross error is presented on below collection
of data:
1. 45,5010
2. 45,5009
3. 45,5012
4. 45,5080 ← gross error / noticeable change of + 70 units
5. 45,5012
Gross error should not be taken into account in a series of
measurements. In most cases it is removed, and the selected
measurement is recognized as incorrect. The gross error occurrence
cause and corrective activities should be analyzed, to eliminate this
error in future measuring processes.
Systematic Error
Measurement error component, that remains stable or changes in predictable way during
measurement repetition and result of devices and measuring methods imperfection. Systematic
errors should be considered if corrections (adjustments) are introduced to measuring result. A
correction is a compensation of estimated systematic result. It can have a form of correction,
multiplier or a value from a table.
With reference to balances, a correction can have a form of constant movement of zero, for
instance, if a balance does not display exact zero after removing a load from its weighing pan, but
it ALWAYS stops on e.g. 0,0012g. In such case, measuring result should be corrected according to
below instance
-reference mass:100g
−reference mass error: + 0,2mg
−measuring result: 99,9996g
−actual value: 99,9996g – 0,2mg = 99,9994g
−actual value corrected by systematic error: 99,9994g – 0,0012g = 99,9982g
In practice, balances that are not characterized by ideal return to zero, can be used successfully.
However, such balance should have stable and repeatable characteristics with regard to corrective
parameter
Random Error
Random error is a measurement error component, which
changes in unpredictable way during repeatable
measurements. Random measurement error is equal to:
measurement error minus systematic measurement error.
Random error results from various incidental factors
(like for instance: temperature oscillations, air
movements in close distance from the measuring
instrument). If measuring results of the same quantity
are not repeatable, than it is caused by random error
occurrence.
Different Type of Weighing
Addition Weighing
Addition weighings typically are used for solid samples or
liquid samples for which volatility is not an issue. The
receiver is placed on the balance. After the balance display
stabilizes, the analyst should tare the balance; add the
desired amount of material to the receiver; allow the
balance display to stabilize; record the weight; and
quantitatively transfer the material to an appropriate
vessel or, if it cannot be guaranteed that the entire amount
has been transferred, weigh the receiver again and note the
weight difference.
Dispense Weighing
Dispense weighing typically is used for weighing emulsions or
viscous liquids such as ointments. In these situations it is not
practical to weigh the material into a typical receiver.
Accordingly, the analyst should tare the balance; place the
sample on the balance in a suitable container (e.g., a
bottle, tube, transfer pipette, or syringe) that has been wiped
clean on the outside; record the weight after the balance display
stabilizes; transfer the desired amount of sample to an
appropriate receiving vessel, such as a volumetric flask; and
place the pipette or syringe back onto the balance.
The difference in the two weighings is equal to the weight of the
transferred specimen.
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.
Weighing of Problem Samples
Electrically Charged Samples And Receivers
Dry, finely divided powders may be charged with static electricity that can make the
powder either attracted to or repelled by the receiver or the balance, causing
inaccurate weight measurements and specimen loss during transfer.
Commercially available balances with a builtin antistatic device can be used to
remedy the problem. Such devices may use piezoelectric components or a very
small amount of a radioactive element (typically polonium) to generate a stream of
ions that dissipate the static charge when passed over the powder being weighed.
Antistatic weigh boats, antistatic guns, and antistatic screens also are commercially
available. The static charge depends also on the relative humidity of the laboratory,
which in turn depends on atmospheric conditions. Under certain conditions, static
charge is caused by the type of clothing worn by the operator and this charge can
cause large errors in the weighing. Borosilicate glassware and plastic receivers have a
wellknown propensity for picking up static charge, especially at low relative
humidity. The gloves used to protect the operator also may increase the potential for
a static charge problem. Placing the container in a metal holder may help to shield
the static charge, and antistatic gloves also can help to alleviate the problem.
Volatile Samples
When weighing a liquid that has a low boiling point,
analysts must receive the specimen in a vessel
with a gastight enclosure of small diameter. The
analyst then tares the vessel and enclosure, adds
the desired amount of sample, and replaces the
enclosure. After the balance display stabilizes, the
analyst records the specimen weight.
Warm or Cool Samples
Samples that are warm or cool should be equilibrated in
the laboratory, or the weight readings may be erroneous.
With regard to warm samples, the apparent weight is
smaller than the true weight because of heat convection.
For example, a flask that is warmer than ambient air
warms up this air, which then flows upward along the
flask and reduces the apparent weight of the contents by
viscous friction.
Hygroscopic Samples
Hygroscopic materials readily absorb moisture from
the atmosphere and steadily gain weight if left
exposed. Therefore, hygroscopic samples must be
either weighed promptly or placed in a vessel with
a gastight enclosure. For a gastight vessel, analysts
should tare the vessel and enclosure, add the
desired amount of sample, and replace the enclosure.
After the balance display stabilizes, the analyst
can record the specimen weight.
Aseptic or Bio Hazardous Samples
The weighing of sterile or bio hazardous samples
should take place within the confines of a clean bench,
bio safety cabinet, isolator, or similar containment
device. Air flow within the hood potentially can cause
balance instability, so after a balance has been installed
under a hood, analysts should perform a rigorous
qualification study with suitable weight artifacts in
order to determine the acceptability of the balance
performance in this environment.
Corrosive Materials
Many chemicals, such as salts, are corrosive, and
materials of this nature should not be spilled on
the balance pan or inside the balance housing. Extra
care is essential when materials of this nature
are weighed. Analysts should consider the use of
sealed containers such as weighing bottles or
syringes. In the event of a spill, requalification of
balance may be necessary, depending on the
nature of the spill.
Toxic Materials
Hazardous materials should be handled in an
enclosure that has appropriate air filtration. Many
toxic—and possibly allergenic—substances present as
liquids or finely divided particles. When weighing
these substances, analysts should use a mask that
covers the nose and mouth to prevent any inhalation
of the substance, and they should use gloves to prevent
any contact with the skin.
Recommendations
One SOP to be Prepared as “ Good Weighing Practices
in ARD Laboratory”
Proper Hands on training to be provides to minimize
the weighing error.
A Quality Risk Analysis need to Perform to Justify the
Calibration, Accuracy Check frequency and minimum
weight.
An Microbalance need to procure to weigh 2-5 mg
One more Fume hood need to install for weighing the
hazardous and toxic chemicals.
Thank You
