Mandatory requirement for quality control of medicinal products in the European Member States who exported to the European market more
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Weighing is one of the key activities carried out in every QC laboratory. Usually, it is one of the first parts of a whole analysis chain, such as when a sample or a standard is prepared for HPLC or qNMR analysis. As any weighing errors have the potential to propagate through the whole analysis and deliver an inaccurate final result, the United States Pharmacopeia (USP) has set stringent requirements for balances used for weighing analytes for quantitative measures. A recent update effective August 1, 2019 underscores the need for accuracy and emphasizes the concept of minimum weight as basis for accurate weighing processes.
Fig. 1 Foundation of the United States Pharmacopeial Convention on January 1, 1820 in the Old Senate Chamber of the U.S. Capitol (11 of the 16 delegates – all physicians – present) . The first USP was published on December 21, 1820. Artist: Robert Thom. Painting commissioned by USP, 1957.
The pharmacopeias are central documents for the pharmaceutical industry. These documents are collections of published standards describing requirements for testing chemical and biological drug substances and dosage forms, as well as methods of analysis for medicines. The standards themselves are defined to ensure pharmaceutical products are of the appropriate identity, strength, quality, purity and consistency. While pharmacopeias describe requirements for the testing of drug substances and dosage forms, they do not apply to the manufacturing of the respective products.
One of the oldest and most widely applied pharmacopeias is the U.S. Pharmacopeia (USP) (Fig. 1). The weighing requirements defined in its General Chapter 41 , together with state-of-the-art performance verification activities described in the informational General Chapter 1251 , are quite often regarded as a de facto standard to ensure consistently accurate weighing results in QC across the pharmaceutical industry.
It is important to refer to the USP General Notices and Requirements  to understand the exact scope of General Chapter 41. Section 6.50.20 states (text shortened):
“Solutions for quantitative measures shall be prepared using accurately weighed or accurately measured analytes (see section 8.20).”
Section 8.20 stipulates (text shortened):
“If the measurement is stated to be ‘accurately weighed’, follow the statements in Balances ⟨41⟩.”
With these two requirements, it is evident that whenever a monograph requires material to be “accurately weighed,” the balance on which the weighing process is carried out needs to comply with the requirements described in General Chapter 41.
General Chapter 41 sets three distinct requirements to be applied to materials that must be accurately weighed.
“The weighing shall be performed using a balance that is calibrated over the operating range and meets the requirements defined for repeatability and accuracy.”
Fig. 2 Systematic and random errors of the balance are assessed by specific tests with an acceptance criterion of 0.10 %. The systematic errors have to be tested with a test load between 5 % and 100 % of the balance capacity. The repeatability test load is usually selected at a few percent of the balance capacity.
Two of the three requirements for balances expressed in the above are repeatability and accuracy. By defining specific acceptance criteria for the repeatability and accuracy test, it is ensured that both random and systematic errors of the instrument are minimized. Both acceptance criteria are expressed as relative limit values, 0.10 % (Fig. 2). From a practical perspective, this requirement is quite stringent and ensures that the weighing error is usually small, if not negligible, compared to errors in the subsequent process steps described in the individual monographs when drug substances are tested.
Calibration, the third requirement, is defined in the International Vocabulary of Metrology (VIM) , and it establishes, for weighing instruments, a relationship between the mass value of reference weights and the balance indication including the associated measurement uncertainties.
Of specific practical relevance to balance performance is the repeatability requirement stipulated by USP General Chapter 41 (text shortened):
“Repeatability is assessed by weighing one test weight not less than 10 times. Repeatability is satisfactory if twice the standard deviation of the weighed value, divided by the desired smallest net weight (i.e. the smallest net weight that the users plan to use on that balance), does not exceed 0.10 %.”
A very important consequence of the repeatability requirement is the concept of minimum weight, which has already been described for many years in the informational General Chapter 1251. During the minor revision of USP General Chapter 41 that came into effect August 1, 2019, this description of minimum weight has been moved from General Chapter 1251 to this mandatory chapter. While the repeatability test and assessment have not changed in the revision, the importance of minimum weight for the practical application of the balance in day-to-day use was enforced by this revision.
The new revised General Chapter 41 states:
“The repeatability measurement establishes the smallest net amount of material that may be weighed on the balance in conformance with the 0.10 % limit.”
Based on the repeatability acceptance criterion, (2 x s) / (smallest net weight) ≤ 0.10 %, all masses equal or larger than (2 x s) / (0.10 %) conform with this requirement. The smallest mass that satisfies this criterion is called minimum weight:
mmin = (2 x s) / (0.10 %) = 2,000 x s
Note that the smallest standard deviation (s) that may be used for the assessment against the 0.10 % repeatability requirement and for the calculation of minimum weight is 0.41 d, where d is the digital increment (readability) of the balance. This lower limit is based on the rounding error of a digital indication.
As stated in the repeatability requirement, the smallest net weight is defined as the smallest quantity that the user wants to weigh on the device on a day-to-day basis. This smallest net weight is a user requirement and should not be confused with the minimum weight that is a property of the instrument and which is calculated as described above.
With the two preceding definitions for smallest net weight and minimum weight, the following statement applies: When the smallest net weight (the user wants to weigh) equals or is larger than the minimum weight (as calculated from the repeatability of the balance), then the repeatability criterion of General Chapter 41 is satisfied.
USP General Chapter 1251 provides detailed information regarding qualification and operation of the instrument. While the chapter is specifically written for analytical balances, most of the information presented can also be applied to balances of higher capacity, such as precision balances or bench scales.
Fig. 3 Variability of the minimum weight over time due to changing environmental conditions. To ensure traceability of the weighing results, an as-found calibration is carried out before servicing or adjusting the instrument.
An important part of this chapter is a detailed presentation of state-of-the-art strategies for routine testing of the instrument. The frequency and type of routine testing activities depends on the risk and the required weighing process tolerance. Daily tests are not prescribed, and the usage of built-in adjustment weights in the balance allows the reduction of testing frequency using external weights. However, it is left to the user to specifically define performance verification activities based on the above considerations.
Another important consideration of General Chapter 1251 details the variability of the balance's performance over time triggered by changing environmental conditions and operator influence on weighing accuracy (Fig. 3). To mitigate these influences, it is recommended that the smallest net weight, i.e. the smallest quantity that the operator would like to weigh using the balance, is sufficiently larger than the minimum weight as derived through the repeatability test at a particular moment in time. In other words, applying a safety factor to ensure consistent adherence to the pre-defined weighing tolerance at all times is recommended.
Accurate weighing is key for any quality-relevant weighing application. The USP has defined in its General Chapter 41 clear requirements that should ensure that any weighing application within its scope does not significantly contribute to any overall analytical error. Besides using a calibrated balance, requirements for repeatability and accuracy are established and characterized by an assessment against a specified tolerance (0.10 %). As an important consequence of the repeatability test, the minimum weight can be calculated. This minimum weight describes the smallest amount of net substance that can be weighed while complying with the tolerance requirement.
USP General Chapter 1251 elaborates more fully on routine balance tests by applying a risk-based approach on performance verification activities. Furthermore, it elaborates on the variability of the balance's performance over time, which leads to the concept of the safety factor.
Applying the requirements of USP General Chapter 41 and best practices from General Chapter 1251 ensures that the user can rely on the accuracy of the instrument over time.
Category: Pharmaceutical Quality Control | Compliance
 USP General Chapter 41 “Balances”, United States Pharmacopeial Convention, Rockville, USA, USP42-NF37 Supplement 1, August 2019
 USP General Chapter 1251 “Weighing on an Analytical Balance”, United States Pharmacopeial Convention, Rockville, USA, USP42-NF37 Supplement 1, August 2019
 Tirumalai, G., Long, A. “United States Pharmacopeial Convention: Respecting the past, moving confidently into the future”, United States Pharmacopeial Convention, Rockville, USA, retrieved from https://www.usp.org/sites/default/files/usp/document/about/usp-history.pdf, accessed on 2019 Aug 9
 USP General Notices and Requirements, United States Pharmacopeial Convention, Rockville, USA, USP42-NF37 Supplement 1, August 2019
 JCGM 200 (VIM), “International Vocabulary of Metrology – Basic and General Concepts and Associated Terms”, 3rd ed., JCGM, 2010, https://www.bipm.org/utils/common/documents/jcgm/JCGM_200_2012.pdf, accessed on 2019 Aug 9
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USP Chapter 41 weighing requirements are mandatory in a Pharmaceutical Quality Control laboratory, where weighing is a fundamental step. (…)
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