Professional Documents
Culture Documents
White Paper Quantos Gravimetric en
White Paper Quantos Gravimetric en
White Paper Quantos Gravimetric en
White Paper
Reducing Sample Size and OOS Errors
Contents
4.3 Mixing
4.4 Labelling
6 Conclusion
7 References
1 What is gravimetric sample preparation?
White Paper
Out-of-Specification (OOS) results have had a significant impact in the pharmaceutical industry for many years,
but in particular since a court ruling in 1993. In this case, the court ruled in favor of Barr Labs which upheld their
view that an OOS result does not necessarily constitute a batch failure (1). They felt that an OOS result should be
investigated to determine if there are other causes such as a laboratory error. However, the court did not like the
way Barr Labs was conducting their laboratory investigations. As a consequence, the FDA updated their guide-
lines concerning how to handle an OOS result and how to perform a proper investigation in October 2006 (2).
Since then, the FDA has issued a significant number of 483 observations concerning poor investigations.
Furthermore, in the FDA guidance concerning OOS investigations, the FDA states that:
“Laboratory errors should be relatively rare. Frequent errors suggest a problem that might
be due to inadequate training of analysts, poorly maintained or improperly calibrated
equipment, or careless work.”
However, as there are a significant number of FDA 483 observations relating to poor investigations, the incidence
of laboratory errors may not be as rare as it should. Unfortunately, there is no published data which shows that
for every OOS result generated there were many more minor errors that didn’t lead to an OOS result. These errors
may have been classified as a “Note to Record”, or simply noted in the laboratory notebook as an error. Many
companies don’t investigate these errors even though they are probably symptoms of potentially more serious
issues with the analysis method or process.
An article was published some years ago in LC/GC magazine concerning OOS results (3). The article discussed
two aspects of laboratory work: firstly, what are the sources of OOS errors and secondly, what activities con-
sume laboratory personnel’s time in an analytical workflow (Full Time Equivalent (FTE) spend in the laboratory).
Analysis (6%)
Calibration (9%)
Operator (19%)
The results from this survey indicated that the two largest sources of OOS results are sample processing followed
by human error and the most time-consuming (manual) task is sample processing (Figure 1). Even though no
follow-up survey has been published since, it appears that these results are still valid today. In fact, the instru-
mentation, data systems, and columns have improved significantly during the last 10 years, whilst the sample
processing has remained essentially the same. Since these other developments have saved a significant amount
of time in the workflow, it is fair to assume that the sample processing aspect of the laboratory work is likely to
account for even more than 61% of the FTE.
Figure 2 illustrates the accepted formal process for how to investigate OOS results:
Out-of-Specification Result
Laboratory Investigation
Checklist Approach: Investigation of standards used,
analytical techniques, etc.
No Yes
Lab Error Identified ?
No
Variation or Error in Manu- Retesting According to SOP Repeat Test to Substitute
facturing or Sampling or Protocol the OOS Result
Besides trying to determine the root cause, the other significant issue seems to be the mounting Corrective and
Preventative Actions or CAPAs that a company generates over a number of years as a result of these laboratory
investigations. These CAPAs typically cause procedural changes to SOPs and other documents and over time
they become unmanageable and difficult to follow which has the potential to cause even more issues.
The overriding problem with CAPAs is that, in the vast majority of cases, the assumption tends to be made that
it is an isolated incident and so only a specific item in a workflow or process is addressed. In other cases, there
is a tendency to blame a single employee or a simple laboratory error. In some cases, this simple error may be
the only thing that that needs to be addressed but in many, if not most cases, it is the whole process or workflow
that needs to addressed instead of one step. This is especially true of sample preparation in the laboratory.
Before we elaborate further on the sample preparation process and its individual steps, we would like to highlight
the scientific background of one of the most important steps of the whole process – weighing. Weighing is a key
activity in most laboratories but it isn’t always sufficiently understood and its complexity is often underestimated.
As the quality of weighing strongly influences the quality of the whole sample and standard preparation process,
USP specifically requires in its General Chapter <41> highly accurate weighing results used for quantitative
analysis (4).
“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%.”
Such a stringent requirement is not implemented for other instruments, where quite often the analytical develop-
ment group sets the method requirements.
State-of-the-art strategies for adhering to consistently accurate and reliable weighing processes comprise of sci-
entific methodologies on balance selection and testing (5, 6, 7). The weighing standard GWP takes these prin-
ciples into account, and furthermore addresses typical misconceptions on weighing which are very widespread
in the industry.
One of them is that many users believe “what you see is what you get”. What do we mean by that? Here is an
example: A user weighs a standard on a semi-micro balance and gets a reading of 50.13 mg which he believes
is the true amount of material that he was weighing. However, this reading might not exactly reflect the amount
weighed, in other words, the amount weighed might differ slightly from the indication. This is due to the so-called
measurement uncertainty which is inherent for every instrument you might think of.
Measurement uncertainty of instruments is determined by calibration, and the results issued in appropriate cali-
bration certificates. In general, measurement uncertainty of weighing systems can be approximated by a straight
line – the higher the load on the balance, the larger the (absolute) measurement uncertainty becomes, as shown
in Figure 3.
Figure 3: Measurement Uncertainty: Absolute (green line) and relative (blue line) measurement uncertainty of a weighing instrument.
The accuracy limit of the balance, the so-called minimum weight, is the intersection point between relative measurement uncertainty
and the required weighing accuracy.
Looking at the relative measurement uncertainty, which is the absolute measurement uncertainty divided by
the load, and usually indicated in per cent, we clearly see that the smaller the load is, the larger the relative
measurement uncertainty becomes. If you weigh at the very low end of the balance‘s measurement range, the
relative uncertainty can become so high that the weighing result cannot be trusted anymore. It is good practice
to define accuracy (tolerance) requirements for every weighing process. For quantitative analysis this is even
stipulated by USP General Chapter <41>. Weighing in the red area as indicated in the figure will result in inaccu-
rate measurements, as here the measurement uncertainty of the instrument is larger than the required accuracy
of the weighing process. Consequently, there is a specific accuracy limit for every weighing instrument – the
so-called minimum sample weight, or short, minimum weight, and you have to weigh at least this amount of
sample in order to have a sufficiently small uncertainty that satisfies the specific weighing accuracy requirement.
While measurement uncertainty is described in much detail in the respective literature (8, 9), we want to
emphasize that for weighing small loads on analytical and microbalances – and samples and standards usu-
ally are small loads as compared to the capacity of the balance – the dominant contribution factor to weighing
uncertainty stems from repeatability (expressed as the standard deviation of a series of weighings). This is also
reflected in USP General Chapter <41> as discussed above.
Even though adherence to this USP requirement seems to be straightforward, many companies still have issues
with the correct interpretation. While environmental influences and operator variability which contribute to inde-
terminate errors and consequently to possible changes or fluctuations of the reading of a weighing device are
discussed later, another misconception which is prevalent in the industry is briefly discussed now. Many compa-
nies wrongly believe that the weight of the tare also accounts for the adherence to the minimum weight. In other
words, if the tare weighs more than the minimum weight, any sample quantity can be added and USP<41> is
automatically fulfilled. This would mean that with a large enough tare container you might believe that you could
even weigh a microgram on a 5-place balance and still comply with the uncertainty requirement of 0.1%. Such
an extreme example clearly shows us that this widespread misinterpretation indeed does not make any sense.
For this reason USP has attempted to clarify this issue in the latest revision of General Chapter <1251> (10):
“The minimum weight applies to the sample weight, not to the tare or gross weight.”
The minimum weight of balances is furthermore not constant, but varies over time. This is due to changing
environmental conditions that affect the performance of the instrument, as for example vibrations or draft. The
operator himself also adds variability to the minimum weight, as different people might weigh differently or with
a different skill level on the balance. In order to ensure that you always weigh above the minimum weight as
determined at calibration (at a particular time with particular environmental conditions by a particular qualified
person), it is highly recommended to apply a safety factor, see Figure 4.
Accuracy limit:
“Minimum weight”
Load
Figure 4: Safety Factor: Variability of the relative measurement uncertainty due to changing environmental conditions and influences
introduced by the operator. Weighing in the green area guarantees adherence to the weighing accuracy requirements (application of a
safety factor).
The safety factor describes that you would only weigh sufficiently above the minimum weight as determined at
calibration. For manual weighing, a safety factor of 2 is commonly used, provided you have reasonably stable
environmental conditions and trained operators. For very critical applications or a very unstable environment, an
even higher safety factor is recommended.
Later in this paper we will elaborate more in detail about typical minimum weight values and recommended
safety factors for automated gravimetric sample preparation as compared to manual weighing (see 5.5 How can
a gravimetric approach reduce the sample volume?).
To be able to deal with variability in the laboratory, it is important to first understand the types of variability and
where they occur. Variability in the data generated comes from two sources, determinate and indeterminate
errors. A determinate error has a definite direction and magnitude and has an assignable cause, their cause can
be determined. Determinate error is also called systematic error. Determinate errors can (theoretically) be elimi-
nated through instrument adjustments. Indeterminate errors are also called random errors, or noise. Indetermi-
nate errors can be minimized but cannot be eliminated. Examples of these types of errors are described in more
detail in 5.6 Volumetric vs. gravimetric comparison.
The largest cause of indeterminate errors in the laboratory is from manual operations where the human element
is involved. Figures 1 highlights the issue that sample processing and human operations are the biggest source
of laboratory errors.
• Fill with specific amount of diluent, mix / sonicate and cool to room temperature
• Fill to the line with diluent
• Successive dilution, if required, fill to the line and mix
• Record data and label volumetric flasks
• Transfer to vials and label vials
• Repeat steps for each preparation
The steps are grouped into four distinct activities. The first concerns gathering materials and ensuring the equip-
ment is clean and calibrated. There are a number of steps at the beginning that would not necessarily cause an
OOS result but would certainly feature in both GxP and safety audits. Resolving these audit issues can consume
a significant amount of time and effort and should also be avoided as they may lead to future OOS results.
The second activity involves weighing and labeling steps. Typically, these are manual time consuming opera-
tions and the weighing steps can contribute to OOS results. An additional difficulty is that these steps are manu-
ally intensive, so it can potentially be very difficult to determine the root cause of this operation.
Finally, the samples are analysed and the materials and equipment are tidied up. This requires disposal of
unused solutions, rinsing of flasks and pipettes, and other resupply steps.
Therefore, a simple sample preparation takes ten or more steps with an additional ten miscellaneous steps. If
two standards and a sample were prepared, approximately 40 steps would need to be carried out. A 40 step
process has a significant number of areas where problems could potentially occur. Furthermore, some of these
steps can be expanded and a detailed analysis with more complex steps, including operations such as extrac-
tion and filtering, might result in a process with one hundred or more steps. Given this number of manual steps
where indeterminate errors occur, it is surprising that OOS results are not even more frequent. Fortunately, many
but not all of these errors are found before the final results are obtained but they do significantly impact the pro-
ductivity of the laboratory operation and the overall quality of the data.
Some of the key steps in sample preparations involve the use of volumetric glassware.
The production process which created flasks with accuracies similar to those in use today has been in operation
for the last 75 years. It is astonishing to consider that sample preparation methods have not advanced signifi-
cantly during the last century. Especially when compared to the advances in instrumentation and software that
have provided dramatic improvements in analysis and data processing.
What are some of the errors that are associated with volumetric glassware?
4.2.4 Revalidation
Coleman and Harris also suggested in their paper (11) that the calibration of the glassware should be verified at
least every 10 years. This could potentially be a very expensive process considering that the number of volumet-
ric flasks in a typical pharmaceutical analytical or QA/QC department can be very large. It could potentially be
cheaper to throw them all away and start again.
4.2.5 Tolerances
In Table 1, the published NIST relative percent errors associated with each size of volumetric glassware are listed.
In each case as the size (volume) of the glassware decreases, the error risk (tolerance) increases significantly.
Pipettes Flasks
Volume (mL) Relative % error Volume (mL) Relative % error
1 0.60 5 0.40
2 0.30 10 0.20
3 0.33 25 0.12
4 0.25 50 0.10
5 0.20 100 0.08
10 0.20 200 0.05
Any errors associated with the Class A glassware that does not meet the specification would be even larger, as
mentioned previously in 4.2.1 concerning the high failure rates.
Aside from the significant increase in the relative percent error, the smaller glassware is also very technique
dependent when it comes to manual manipulations. For example, in one company, it was found that many of the
analysts could not properly use a pipette below 2 mL and errors as high as 5% were noted in some cases (13).
4.2.6 Cost
The cost of using volumetric glassware is an issue that is often taken for granted. A great deal of effort goes
into keeping glassware organized and stored in a laboratory. Everyone who has worked in the lab has probably
been charged with ordering and putting away the clean glassware at some point in their career. This is costing
a proportion of a FTE. The pre and post rinsing on a company wide basis, assuming a very conservative 25 mL
use per flask and 10,000 sample preparations, might be costing the company $10,000 or more each year at a
$40/liter average solvent cost. These annually recurring costs can add up to a substantial amount, especially
when you include the rising cost of waste disposal. Additional costs can be incurred by lab services groups that
transport the flasks to and from the washing facility; and attrition due to breakage and damage, which results in
approx. 10% loss each year at a cost of about $20 per flask.
4.3 Mixing
Most samples are sonicated to expedite the breakup of tablets, capsules, or powders. Sonication can cause OOS
results when there is a lack of robustness in the method. The lack of robustness arises from the improper use
of the sonicator and whether or not the instrument is tuned properly. Most sonicators have the following instruc-
tions on them:
However, from industry feedback it seems that few people follow those instructions. The pictures in Figure 6
illustrate the difference between a tuned sonicator on the left and an untuned sonicator on the right.
The untuned system has most of its energy focused in the middle of the bath, where you can see the large hole
in the foil (on the right). Therefore, the energy of the system can vary significantly depending on the placement of
the sample into the bath.
Many methods need to have better instructions for the final mixing step. Most methods only state to mix well
without realizing that a volumetric flask is an extremely poor mixing vessel that requires it to be inverted a num-
ber of times to ensure proper mixing.
4.4 Labeling
Labeling can potentially cause OOS results due to label mix ups but the most significant issues with labeling
are usually identified at safety and GxP audit times. Regardless of what a labeling SOP in the company states,
when flasks in laboratories are examined, the labeling content usually ranges from the absolute minimum to
the very detailed. Of course, all of these permanent marker labels must be removed before sending them out to
be washed and that necessitates the use of methanol or acetone to wipe down the flasks which takes time and
wastes more solvent.
Gravimetric sample preparation, as described in USP General Chapter 1251, involves automated weighing and
dispensing of the solid and of the diluent and can reduce laboratory errors and increase laboratory efficiency (14).
Using this method, weighing papers, weighing boats and volumetric flasks are no longer necessary.
There are a number of systems available which support the technique of gravimetric sample preparation.
These are described in more detail in this section and listed in Table 2.
In all of the systems, a gravimetric approach is used to deliver both powders and liquids into a small, dispos-
able target container (vial) which is positioned on an analytical or a micro-analytical balance (see Figure 7).
The user has to define the concentration required and the target amount of solution to be prepared. The software
calculates the target amount of solid to dispense and then, according to the actual amount of solid dispensed,
delivers the appropriate amount of diluent to prepare an extremely accurate and precise concentration. Serial
dilutions can be reached efficiently, without multiple dilution series, as the XPR Automatic Balance can achieve a
dilution factor of even 10,000 in a single step.
Individual dosing heads are used for each substance. The powder dosing heads are disposable and designed
for use with a single substance only. The solvent dispensing heads are also exclusively used for a single solvent,
and no valves or switching or washing of lines is employed. This means that all potential sources of cross con-
tamination risk are eliminated.
The dosing enables automated powder and liquid dispensing processes. The appropriate powder dispensing
head has to be selected and manually inserted into the system. Each dosing head is identified by RFID chip for
process security. This head has to be manually removed and replaced by the appropriate liquid dosing head at
the “Add diluent“ step. All data is recorded electronically and can be automatically printed onto labels.
* = Automated powder dispensing for free-flowing powders. Manual dispensing for sticky powders, pastes, gels, liquid samples, etc.
** = typical value
These automated gravimetric systems are being adopted by analytical and QA/QC laboratories in the pharma-
ceutical industry.
We have already discussed how the addition of the diluent by volumetric measurement introduces a manifold of
indeterminate handling errors, such as reading the meniscus incorrectly or using the glassware at temperatures
where thermal expansion causes the limit of error to be exceeded. Gravimetric liquid dispensing avoids these
non-quantifiable handling errors, and furthermore weighing liquids at gram levels is very accurate because it
results in a completely negligible measurement uncertainty contribution of this process step. The amount of
diluent is typically far above the minimum weight of the balance, where the hyperbolic shape of the relative mea-
surement uncertainty curve flattens out to almost zero (see Figure 3).
With gravimetric sample preparation the exact amount of substance dispensed (whether dispensed manually by
spatula or using an automated dosing head) is recorded and used to accurately calculate the amount of solvent
to weigh in to the container. Any under or overshoot in powder weighing doesn’t require you to waste time add-
ing a tiny amount more or scooping material off the weighing paper with your spatula. The automated liquid
dispensing compensates for this and delivers the correct amount of diluent to achieve the required concentration.
The sample can then be sonicated and used without the need to be concerned about temperature and mixing.
In terms of data management there are also distinct advantages of automated gravimetric sample preparation
in comparison with the manual volumetric approach. The manual approach requires hand transcription which
has a high error-risk, and it relies on the diligence of each individual analyst. It is simply not possible to digitally
record which size of volumetric flask was used automatically.
With an automated approach the data transcription is automated. All samples and solvents are identified by RFID
(radio frequency identification) to eliminate the possibility of weighing the wrong sample. All weighed samples
are documented electronically (target weights, actual weights and concentrations achieved) and the data is fully
traceable.
The simplified gravimetric sample preparation workflow is shown in Figure 8. This workflow has approximately
30% fewer steps than the volumetric workflow, described in Figure 3, which is a significant reduction. This
makes the process much more efficient and results in a significant amount of time saved in the sample prepara-
tion workflow. More importantly, the steps that have greatest potential to cause OOS results have been eliminated.
Let us now look at the typical USP minimum weight and the recommended safety factor for automated gravimet-
ric dispensing systems as compared to manual weighing systems. Provided the same weighing module is used
in both instruments, generally the minimum weight for the automated system is significantly lower as compared
to the equivalent conventional weighing system. One main reason is that environmental effects – especially
drafts and temperature differences between balance and sample – are more efficiently prevented when using
automated dispensing. Furthermore, the variability introduced by the operator is completely removed.
XPR205 XPR226DRQ
analytical balance Automatic Balance
(Minimum weight (Minimum weight
× safety factor) × safety factor)
= 14 mg × 2 = 28 mg = 7 mg × 1.5 = 10.5 mg
Solvent volume
5.3 ×
substance
& solvent
& waste
Concentration prepared
Figure 9: Comparison of volumetric and gravimetric sample preparation on the amount of solvent used.
Being constrained to Class A volumetric glassware forces an analyst to use much more substance than neces-
sary because they are limited to the capacity of the flasks available. The amount of solvent used when preparing
samples using a manual volumetric approach is indicated by the red line in Figure 8. The sharp vertical drops in
the red line on the graph indicate the four discrete points at which the minimum weight of the substance matches
an available volumetric flask size (10 mL, 25 mL, 50 mL, 100 mL) and thus the only concentrations at which
the actual minimum weight can be used to achieve the desired concentration. In all other cases, the amount of
sample must be rounded up to match the next size of volumetric flask available.
Automated gravimetric sample preparation is not limited to these discrete intervals, as the smooth green curve
indicates. With this method, the minimum amount of sample (10.5 mg) can be weighed at every point on the
curve, and the corresponding amount of solvent can be added, to achieve the required concentration.
At the point indicated by the blue arrow (which corresponds to a concentration of 1.1 mg/mL), over five times
less substance and solvent is used to achieve the same concentration gravimetrically. This is due to an equal
contribution from both of the factors mentioned previously: the minimum amount of sample that can be weighed
on the XPR Automatic Balance is just over 2.5 times smaller; also, the total sample volume has been rounded up
to the next available size of volumetric flask (50 mL).
For example, Table 3 illustrates the preparation of three concentrations of solution manually (volumetrically)
compared to automatically (gravimetrically) using either (a) an XPR205 balance and an 50 mL or 100 mL volu-
metric flask; (b) a XPR205 Automatic Balance for automated sample preparation; (c) a XPR226DRQ Automatic
Balance for automated sample preparation. The amounts of substance and solvent consumed for each method
are listing along with the savings.
* = typical value
** = The safety factor quoted is that recommended for stable environments and trained operators. For unstable environmental conditions
or insufficiently trained operators higher safety factors should be used.
So, if a 1.0 mg/mL solution is prepared manually in a volumetric flask, 50 mL of solvent and 50 mg of
substance are consumed. When the solution is prepared using an automated gravimetric method with an
XPE206DR-PL system, 10.5 mL of solvent and 10.5 mg of substance are sufficient (assuming a solvent density
of 1 g/mL).
A saving of 79% in both substance and solvent can be realized whilst remaining compliant with USP General
Chapter <41>.
To directly compare the manual volumetric and the automated gravimetric methods, let’s look at a simple prepa-
ration comparing the two techniques. If the method requires a 0.25 mg/mL concentration then using a volumet-
ric system, one would use a 200 mL volumetric flask and weigh out 50 mg of material. Table 4 shows some of
the determinate and indeterminate errors that may be found in this simple procedure.
As you can see in Table 4, with gravimetric sample preparation the number of determinate errors is reduced and
the indeterminate errors which tend to be much larger than the determinate ones are essentially eliminated or
accounted for.
For the nine individual samples, the weight of solid dispensed is shown in column 2. The weight of solvent dis-
pensed is shown in column 3 and the concentrations achieved are shown in column 4. Accurate solvent weigh-
ing compensates for any variation in the amount of solid dispensed (which is already within a narrow range –
10.040 and 10.320 mg), to achieve an accurate concentration of 0.603 mg/g in every case. The repeatability of
the concentrations is excellent, as indicated by the low standard deviation, RSD = 0.001% (pale blue highlighted
cell). When the peak area is correlated after analysis, the RSD across these nine solutions is 0.19% (dark blue
highlighted cell).
The two columns at the right hand side of Table 5 show ten injections of the same solution, with the aim of
eliminating the contribution of the analytical system to the overall variability. The RSD of these samples is 0.21%
(green highlighted cell). So, in conclusion, automated standard preparation with solvent weighing shows no sig-
nificant variability in the solution concentrations, that can’t be attributed to the analytical instrumentation itself.
When the same experiment was repeated by preparing the individual standards manually, the results in table
6 were obtained. The RSD on the correlated areas was 0.57% (compared to 0.19% for automated). This IS
significant compared to the accuracy of the analytical instrumentation, and means that the variability can be
almost only attributed to the manual preparation process. As the weighing process and the HPLC analysis are
independent from each other, the associated %RSD are not added arithmetically but quadratically in order to
determine the %RSD of the peak area. As the %RSD of the peak area is 0.57% (sample weighed manually),
and the %RSD for the overall variability of the analytical instrumentation is 0.21%, the calculated %RSD for the
manual sample preparation is 0.54%, which fits nicely to the experimentally determined %RSD of 0.60% of
the manual weighing process. In other words, for this experiment the limiting factor for the overall accuracy of
the HPLC analysis was the manual sample preparation, whereas for automated sample preparation the limiting
factor for the overall accuracy is the HPLC itself.
6 Conclusion
The most important measure to guarantee accurate weighing – and consequently to avoid the possibility of OOS
due to weighing – is the determination of the minimum weight of the balances. Consequently, it is important
to always weigh above the minimum weight in order to comply with the respective accuracy requirements. For
automated dispensing systems, the minimum weight is significantly smaller as compared to manual weighing.
It is good practice to apply a safety factor in order to compensate the variability of the minimum weight due to
different operators and changing environmental conditions, however, the safety factor can be chosen significantly
smaller for automated weighing systems as environmental effects are reduced and the variability introduced by
the operator is completely removed.
Reducing the occurrence of OOS results in the laboratory requires close attention to the details of where errors
can occur, a critical evaluation of the overall process workflow, and a concerted effort to change those practices
that lead to OOS results or errors in the data. New technologies must be brought into the laboratory to finally
improve the data quality that is being generated by laboratories around the world. In addition, most companies
want and need to achieve higher productivity with the same or less resources. This efficiency cannot occur with-
out a fundamental change in the way sample preparation is currently performed which has had little improve-
ment for the best part of a century and still accounts for more than 60% of our time spent in the laboratory.
Gravimetric sample preparation, which is defined as automated weighing and dispensing of both the solid and
the solvent, is based on the weighing standard GWP®. Furthermore, it has several important benefits in a mod-
ern laboratory: it improves user safety due to reduced exposure risk; it improves process safety via electronic
recording and tracking of data; and it can save substance and solvent due to reduced minimum weight and
elimination of volumetric flasks.
However, the most important benefit of gravimetric sample preparation is its innovative ability to enhance the
accuracy and drastically reduce the variability in sample processing steps, which is the major source of out-
of-specification results. Some areas of high error risk in the process, such as those involving use of volumetric
flasks, are eliminated completely. Gravimetric sample preparation has the effect of reducing laboratory errors and
increasing laboratory efficiency.