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Weighty matters for the European Pharmacopoeia

A new General Chapter addresses balances for analytical purposes

Dr. Klaus Fritsch (Mettler-Toledo GmbH)

Weighing is one of the key activities carried out in every quality control (QC) laboratory. Usually it is one of the first steps in a whole analysis chain, e.g. when a sample or a standard is prepared for subsequent dilution and HPLC or qNMR analysis.

For many decades the United States Pharmacopeia (USP) has set stringent requirements for balances used for weighing analytes for quantitative measures in its General Chapter 41 “Balances” [1, 2]. These requirements ensure that weighing errors are small or even negligible for the result of the analysis. Other Pharmacopoeias have not previously set similar requirements. This situation will change from July 2021, when a General Chapter for balances is published in the European Pharmacopoeia (Ph. Eur.) [3]. The European Pharmacopoeia is the single reference compendium for the quality control of medicines in 39 European countries [4]. It is legally binding for pharmaceutical companies that intend to bring pharmaceutical products onto the market in one of the 39 countries, and is therefore not only relevant for European pharmaceutical companies but for pharmaceutical companies in other regions of the world which intend to export to Europe. The new General Chapter 2.1.7 “Balances for Analytical Purposes” stipulates requirements that are very closely aligned with the respective requirements of the USP. The new chapter is mandatory for any weighing procedure described in a Ph. Eur. monograph from January 1, 2022 and legally enforceable from that date onwards.  

Requirements for equipment performance – overview

Within its Equipment Performance section, General Chapter 2.1.7 sets three distinct requirements for balances used to weigh materials according to Ph. Eur. monographs:

i) Balances must be periodically calibrated.

Between calibrations, performance checks must be carried out periodically to assess the
ii) random error (precision) and
iii) systematic error (accuracy) of the balances.

Before analyzing in detail the three requirements on calibration, precision and accuracy, it is important to understand how accuracy and precision are defined in pharmaceutical regulations. Accuracy is defined in ICH Q2(R1) [5] and describes the systematic error of measurements. This concept is called “trueness” in all other fields of metrology, and defined as such in the International Vocabulary of Metrology (VIM) [6]. Precision is defined similarly in ICH Q2(R1) and the VIM, and describes the random error of measurements.

By defining specific acceptance criteria for both performance checks, it is ensured that the random and systematic errors of an instrument are minimized. Both acceptance criteria are expressed as relative limit values of 0.10 %.

It is worthwhile noting that the performance requirements set in Ph. Eur. General Chapter 2.1.7 are commensurate with those in USP General Chapter 41.

Calibration

According to the General Chapter 2.1.7, balances need to be calibrated periodically. Calibration covers a set of activities carried out on a measuring instrument to understand its behavior. This is done by establishing a relationship between known values (measurement standards) and the associated measured values (indications) of the instrument being calibrated. The chapter stresses the importance of including a statement of measurement uncertainty that allows metrological traceability of the measurement results.

Besides being calibrated, an instrument can also be adjusted. When adjusting an instrument, its indications are modified in a way as to correspond – as far as possible – to the values of the measurement standards applied. General Chapter 2.1.7 stresses the importance of performing calibration before (“as found”) and after (“as left”) an adjustment or any significant operation on the balance, for example upon repair or transfer to another location. This concept ensures the traceability and validity of measurement results performed on the balance during routine use.

Performance checks

After discussing the requirement of calibration, the following paragraphs will focus on the requirements of the two performance checks concerning precision and accuracy that must be carried out periodically between calibrations.

A. Repeatability requirement – minimum weight

Ph. Eur. General Chapter 2.1.7 requires a repeatability test to be carried out with no less than 10 replicate measurements. The repeatability is satisfactory if ( 2 × s / msnw ) × 100 ≤ 0,10, with s being the standard deviation of the indicated values, and msnw the smallest net weight defined by the user as the smallest net amount of substance that will be weighed on the balance. If s < 0.41 × d , in which d is the readability (scale interval) of the balance, s is replaced by 0.41 × d  for the assessment.

A very important consequence of the repeatability requirement is the concept of minimum weight. The minimum weight is the smallest net sample mass that can be weighed on the balance, whilst continuing to comply with the repeatability test criterion. All masses equal or larger than (2 × s × 100) / 0.10 conform to this requirement, and the smallest mass that satisfies this criterion is called minimum weight:

mmin = (2 × s × 100) / 0,10 = 2,000 × s

When calculating the minimum weight, s is replaced by 0.41 × d if s < 0.41 × d.

While the smallest net weight is a user requirement and defined as the smallest quantity that the user wants to weigh on the device on a day-to-day basis, it should not be confused with the minimum weight that is a property of the instrument and is calculated as described above. With these two definitions, the following statement applies: when the smallest net weight (that 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 2.1.7 is satisfied.

Fig. 1 Test weight selection for repeatability testing. The test weight does not need to be at the working point of the balance. Ph. Eur. Chapter 2.1.7 recommends choosing a test weight that is 5 % of the balance capacity or slightly below. This is consistent with the recommendations of USP General Chapter 1251 [7].

For the repeatability test, General Chapter 2.1.7 suggests taking a test load of no more than 5 percent of the nominal capacity of the balance, so a 10 g load for a balance with a nominal capacity of 200 g would be appropriate (see Fig. 1). A test load that is sufficiently larger than the expected minimum weight is easier to handle and avoids human errors being introduced during the repeatability test that could negatively influence the assessment of the instrument's performance.

B. Accuracy Requirement

Further to repeatability, Ph. Eur. General Chapter 2.1.7 stipulates how to assess the accuracy of the balance. Three major weighing parameters may affect the accuracy of the balance: sensitivity, linearity and eccentricity. The weighing parameter that most significantly affects accuracy is sensitivity. Sensitivity characterizes the change of indication of the balance divided by the change in load, so a balance without sensitivity deviation would indicate exactly the weighing value that corresponds to an applied test load at nominal capacity [8]. As sensitivity is the weighing parameter that most significantly affects the accuracy of the balance, it is considered sufficient to only assess sensitivity when carrying out performance checks. However, the acceptance criterion for sensitivity is set to 0.05 %, i.e. half of the overall accuracy acceptance criterion of 0.10 %. This takes into consideration that the other weighing parameters also influencing the accuracy of the balance might also contribute to the systematic error. All added up must not jeopardize the overall accuracy requirement of 0.10 %.

Fig. 2 Test weight selection for accuracy testing. The test weight must be between 5 % and 100 % of the balance’s capacity.

It needs to be noted that at the lower end of an analytical balance's measurement range, repeatability is the most dominant contributing factor to balance errors. Therefore, it is not meaningful to assess accuracy with a small test weight, as a potential systematic error would be masked entirely by the limited precision of the instrument, expressed by its repeatability. To avoid using small loads for testing systematic deviations, Ph. Eur. General Chapter 2.1.7 stipulates that the mass of the test load must be at least 5 % of the balance's capacity (see Fig. 2).

C. Usage of built-in adjustment weights

In addition to testing weighing instruments with external weights, it is accepted practice to adjust the instruments by means of built-in reference weights. Such practice allows reducing the frequency of sensitivity tests with external reference weights [7, 9, 10], and is also described in Ph. Eur. General Chapter 2.1.7.

At this point, it is important to point out a very frequent misconception that has prevailed in the industry for decades. Almost everybody in the pharmaceutical industry who works in quality control speaks of a “daily balance test” which assesses the accuracy of a balance. For electronic balances with a built-in weight, a daily test of sensitivity with an external reference weight is an outdated practice that does not need to be performed. Ph. Eur. General Chapter 2.1.7 focuses on a testing approach where it is the quality management system of the user that defines the frequencies of calibration and the individual performance checks.

Conclusion

Accurate weighing is key for any quality relevant weighing application. The European Pharmacopoeia has defined in its General Chapter 2.1.7 clear requirements to ensure that any weighing application within a Ph. Eur. monograph does not significantly contribute to the overall error of the analysis. Besides using a calibrated balance, requirements to ensure repeatability and accuracy are established and characterized by an assessment against a specified tolerance of 0.10%. As an important consequence of the repeatability test, the minimum weight is calculated. It establishes the smallest amount of net substance that must be weighed in order to comply with the permitted tolerance. The weighing requirements of Ph. Eur. General Chapter 2.1.7 are commensurate with the requirements set in USP General Chapter 41. Therefore, the European Pharmacopoeia has made an important step towards the international harmonization of weighing requirements between different pharmaceutical compendia.

________________________________________________________________________________________

Category: Pharmaceutical Quality Control | Compliance

Literature:
[1] USP General Chapter 41 “Balances”, United States Pharmacopeial Convention, Rockville, USA, USP-NF 2021, 2021
[2] Fritsch, K. (2019) Weighing in the US Pharmacopeia – Minimum Weight and Routine Testing According General Chapters 41 and 1251, 2019 Aug 26, https://q-more.chemeurope.com/q-more-articles/296/weiging-in-the-us-pharmacopeia.html (Ger.: Die US-Pharmakopöe auf der Waagschale – Mindesteinwaage und Routineprüfung gemäß den USP-Kapiteln 41 und 1251, 2019 Aug 26, https://q-more.chemie.de/q-more-artikel/296/die-us-pharmakopoee-auf-der-waagschale.html)
[3] Ph. Eur. 10.6, General Chapter 2.1.7 “Balances for Analytical Purposes”, EDQM Council of Europe, Strasbourg, France, European Pharmacopoeia (Ph. Eur.) 10th Edition, Supplement 10.6., July 2021
[4] European Directorate for the Quality of Medicines & HealthCare (EDQM), https://www.edqm.eu/en/news/european-pharmacopoeia-supplement-106-now-available, accessed on 2021 May 11
[5] ICH Q2 (R1), “Validation of Analytical Procedures: Text and Methodology”, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2005
[6] 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 2021 May 11
[7] USP General Chapter 1251 “Weighing on an Analytical Balance”, United States Pharmacopeial Convention, Rockville, USA, USP-NF 2021, 2021
[8] R. Nater, A. Reichmuth, R. Schwartz, M. Borys, P. Zervos, “Dictionary of Weighing Terms - A Guide to the Terminology of Weighing”, Springer Berlin Heidelberg, 2009, ISBN 978-3-64202013-1
[9] Questions and Answers to Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance – Equipment, U.S. Food and Drug Administration, Rockville, USA, retrieved from http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm124777.htm
[10] LAB 14, “Guidance on the calibration of weighing machines used in testing and calibration laboratories”, 6th ed., United Kingdom Accreditation Service UKAS, Feltham, UK, 2019

Date of publication: 22-Jun-2021

Facts, background information, dossiers

  • United States Pharmacopeia
  • laboratory weighing
  • analysis
  • measurement accuracy
  • metrology
  • measurement uncertainty
  • metrological traceability
  • minimum weight
  • repeatability

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