Balances and Scales Metrology and Fitness for Intended Use

Accurate weighing is key to pharmaceutical quality control (QC). While pharmacopeias have begun to set clear metrological rules for QC weighing, a lack of guidance remains for weighing in production. This can complicate the definition of weighing requirements that are commensurate with the quality attributes of an API or finished pharmaceutical product.

However, new regulations, along with established weighing standards, are helping to close these gaps in practice. Consequently, outdated concepts such as the daily balance check and the idea that weighing a test load without stating the associated measurnonement uncertainty constitutes calibration can be substituted with state-of-the-art, risk-based assessments. This should help steer the industry toward risk-based quality management built on proven metrology.

The recent emphasis that pharmacopeias are placing on metrologically sound requirements for assessing balances used for analytical purposes will help move this process forward, with as-found and as-left calibration embedded as a cornerstone of a holistic performance verification strategy.

These risk-based strategies should also be applied to weighing applications in production. While weighing requirements for manufacturing are not under pharmacopeial jurisdiction, fostering consistency across the industry will help assure the accuracy that is paramount for regulatory compliance, consumer safety, and commercial success.

Introduction

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 High-Performance Liquid Chromatography (HPLC) or Quantitative Nuclear Magnetic Resonance (qNMR) analysis. For several decades, the United States Pharmacopeia (USP) has set stringent requirements for balances used to weigh analytes for quantitative measures in its General Chapter 41, “Balances.”1  These requirements are intended to ensure that any weighing error is small or even negligible compared to the error potential of other process steps within an analysis. Other pharmacopeias have recently established requirements for balances used for analytical purposes as well. These requirements are closely aligned with the approach stipulated by the USP. General Chapter 2.1.7 within the European Pharmacopoeia (Ph. Eur.)2 and General Chapter 9.62 within the Japanese Pharmacopoeia (JP)3 became official in 2022 and 2024, respectively, and since then, the Indian Pharmacopoeia (IPC) and the Chinese Pharmacopoeia (ChP) have published drafts of general chapters for balances to solicit industry feedback that align with the same direction.4^, 5

All weighing chapters in the pharmacopeias set specific requirements for the performance verification of balances that consist of periodic calibration and routine testing activities. The purpose of these requirements is to ensure that the instrument remains fit for its intended use by providing accurate weighing results based on specific metrological criteria. While the basic procedures and acceptance criteria for routine testing activities in all compendia are the same, Ph. Eur. has started setting requirements that are much more explicit concerning the application of underlying metrological concepts for calibration.

In Ph. Eur. General Chapter 2.1.7, calibration of weighing instruments has been associated with the estimation of measurement uncertainty for the first time in pharmaceutical regulations. Furthermore, the concept of as-found and as-left calibration is elaborated, which ensures traceability of measurement results both before and after a service intervention when a balance is in routine operation. In addition, emphasis is placed on a risk-based approach for all weighing instrument performance verification activities as a basis for ensuring continuous fitness for intended use. This holistic metrological approach is also implemented in a new draft to revise USP General Chapter 416 and in the draft of the balance chapter issued by IPC.4 Therefore, the pharmacopeias are acting as strong ambassadors for implementing metrologically sound, risk-based strategies for the performance verification of weighing instruments globally.

Accurate weighing is also paramount for manufacturing to ensure that pharmaceutical products meet their predefined quality attributes. However, pharmaceutical regulations do not stipulate specific requirements for weighing in the production environment, instead leaving the definition of these requirements to the manufacturing organization. Still, the direction in which pharmaceutical QC regulations are developing might also serve as a solid example for updating metrological concepts for quality management of weighing within the production area. Specifically, the inclusion of measurement uncertainty in calibration activities and the consideration of as-found and as-left calibrations in production will help ensure traceability, and therefore the quality of measurement results.

Understanding Calibration

Regulatory Requirements for Calibration

Calibration is one of the key activities that must be performed periodically when instruments are used for quality-relevant measurements. Internationally, there are many standards that stipulate this requirement, e.g. ISO 9001, as well as pharmaceutical regulations such as Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP). As an example, US GMP7 requires that: “Automatic, mechanical, or electronic equipment…shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance.”

All major pharmacopeias require the use of a calibrated balance when weighing analytes for the purpose of quality control of pharmaceutical products, as stipulated in the respective general chapters for balances.1^, 2^,  3^, 4^, 5 Personnel who work in quality control and quality assurance, either in the laboratory or in the production environment, are generally aware that calibration is mandated by regulatory and compendial guidance. However, outside of an actual calibration laboratory, there is still little true understanding of how calibration is defined or implemented. As noted, in the pharmaceutical industry, it is still widely believed that a balance is calibrated when a test load is placed on the weighing pan and the indication is compared with the reference value of the mass of the test weight.

The European Pharmacopoeia was the first compendium specially set out to overcome this misconception in the General Chapter 2.1.7, “Balances for Analytical Purposes,” by spelling out the calibration requirement as follows: “Calibration is part of balance qualification and is performed by the user or by a suitable, competent body. Its aim is to establish traceability of measurement results to the [International System of Units] (metrological traceability). The calibration results include measurement uncertainty and are documented in a calibration certificate.”

This explicit statement that defines calibration in terms of traceability and measurement uncertainty is replicated by the latest draft to revise USP General Chapter 41.6 It has also been implemented in JP General Chapter 9.62 and the drafts issued by IPC and ChP, which have adopted this approach and require a statement on measurement uncertainty when a balance is calibrated.

For many years, the USP has referred to measurement uncertainty in the glossary of USP General Chapter 1058, “Analytical Instrument Qualification,”8 which contains the same definition of calibration that is presented in the International Vocabulary of Metrology (VIM).9 However, all USP general chapters with numbers between 1000 and 1999 are for information only and cannot be legally enforced. Therefore, the requirement for inclusion of measurement uncertainty in calibration, as per the recent updates of the pharmacopeial chapters on balances, is a big step towards a metrologically sound interpretation of calibration.

The quality of calibration activities, when performed according to the principles outlined in the VIM, can be supported by accreditation under the ISO/IEC 17025 standard.10 Accreditation by an accreditation body is the formal process that confirms a calibration competence and compliance with requirements stipulated by ISO/IEC 17025. While accreditation is not a formal requirement of pharmaceutical regulations, calibration activities executed by an accredited calibration laboratory are becoming widely recognized as a supportive element in achieving compliance with applicable clauses of GLP and GMP regulations. As per ISO/IEC 17025, measurement uncertainty is an integral part of any calibration activity and therefore complements the latest pharmacopeial requirements.

Harmonizing Calibration Practices for Non-Automatic Weighing Instruments

Pharmaceutical regulations do not stipulate a specific method for the calibration of weighing instruments, so users typically refer either to internal procedures or to widely available and generally accepted reference documents. For balances and scales, which can also be described as non-automatic weighing instruments, many calibration guidelines exist at the national level, most of them based on the concepts described in the “Guide to the Expression of Uncertainty in Measurement (GUM).”11 While these guidelines are generally quite similar, they differ in certain details, which has made it difficult, if not impossible, to develop and implement a single calibration guideline on a global level. Over the last decade, activities in the scientific community have addressed this issue by creating a harmonized approach for calibration of non-automatic weighing instruments based on EURAMET cg-18 “Calibration of Non-Automatic Weighing Instruments,” which is the most widespread guideline globally.12^, 13

While EURAMET Calibration Guidelines No.18 (cg-18)are globally recognized, local calibration guidelines have subsequently been developed based on its principles. In China, the national calibration specification JJF 1847 “Calibration Specification for Electronic Balances” was enacted in 202014 to address the calibration of balances for the first time. JJF 1847 is fully aligned with the procedures and uncertainty estimation of EURAMET cg-18. In the United States, the recently updated document ASTM E898 “Standard Practice for Calibration of Non-Automatic Weighing Instruments”15 is also fully commensurate with EURAMET cg-18 and supports the international harmonization of balance and scale calibration within the United States.

The approach of associating measurement uncertainty with calibration results in the general chapters on balances within the pharmacopeias fosters the global harmonization of calibrating weighing instruments using EURAMET cg-18 as the underlying guideline. Furthermore, in the draft to USP General Chapter 41, EURAMET cg-18 and ASTM E898 are specifically mentioned as calibration guidelines that fulfill pharmacopeial requirements for calibration.

As-Found and As-Left Calibration

In any discussion of calibration, it is essential to introduce the concept of adjustment as it relates to measuring instruments. Adjustment is defined in the International Vocabulary of Metrology (VIM) as a:

“Set of operations carried out on a measuring system so that it provides prescribed indications corresponding to given values of a quantity to be measured.”

In other words, adjusting an instrument involves modifying its indications so they correspond as closely as possible to the quantity values of the applied measurement standards. Unfortunately, many users apply the terms “calibration” and “adjustment” interchangeably or incorrectly. It is common for users to refer to calibrating a weighing instrument when they actually mean adjusting it. The VIM emphasizes this distinction, stating:”

“Adjustment of a measuring system should not be confused with calibration, which is a prerequisite for adjustment. After an adjustment of a measuring system, the measuring system must usually be recalibrated.”

This concept is reinforced in General Chapter 2.1.7 of the European Pharmacopoeia:

“To ensure traceability, it is recommended to perform calibration before any maintenance operation is carried out that significantly alters its measurement performance. Significant operations include repairs, transfer of the balance to another location or mechanical adjustment of one or more weighing parameters. The balance must be recalibrated after significant operations. Re-calibration is not necessary after less significant operations, which include levelling the balance or adjustment using built-in weights.”

With this statement, the European Pharmacopoeia establishes a solid foundation for promoting the concept of as-found and as-left calibration as essential components of ensuring the traceability and validity of measurement results obtained from balances during routine use in the pharmaceutical industry.

• As-found calibration ensures traceability of all measurements performed prior to any adjustment on the instrument.
• As-left calibration ensures traceability of all measurements performed after the intervention.

The USP has adopted this approach in its recent draft update of General Chapter 41, and the IPC has implemented similar language in its draft balance chapter in their compendium. It is anticipated that other pharmacopeias will evaluate this approach with respect to calibration and eventually set similar requirements in their compendia with the objective of harmonizing pharmaceutical requirements for the metrology of weighing at an international level.

It is important to analyze the requirements of ISO/IEC 17025 with respect to as-found and as-left calibration. Paragraph 7.8.4.1 states that calibration certificates should include “the results before and after any adjustment or repair, if available.”

This requirement is commensurate with the previously mentioned statement in the VIM and emphasizes the metrological importance of both calibration activities.

Calibration of scales in the production environment should follow the same principles, as measurement traceability during manufacturing is equally critical to traceability of measurements during analytical processes. Furthermore, in light of GMP requirements to ensure proper performance of electronic equipment, as-found calibration provides a basis for determining whether an instrument fulfilled metrological requirements prior to any performance modification (i.e., adjustment or repair see Figure 1).

Recently, the concept of Target Measurement Uncertainty (TMU) has come into frequent use as a fundamental metrological requirement for assessing whether an instrument is fit for its intended use.16^, 17 In other words, an instrument is considered fit for its intended use if its measurement uncertainty―derived during calibration―does not exceed a predefined threshold. This assessment enables users to determine whether an instrument needs to be adjusted.

If the measurement uncertainty estimated during the as-found calibration meets the TMU with a sufficiently high safety margin, an adjustment of the instrument may be unnecessary, rendering the subsequent as-left calibration obsolete. In such cases, the as-found calibration serves as the as-left calibration. It is worth noting that users often refer to “accurate measurement results” if they meet the TMU. However, TMU may not be the sole criterion for determining fitness for its intended use; additional requirements may need to be fulfilled.

For balances and scales, the measurement uncertainty derived from calibration results can be used to calculate the minimum weight― the smallest quantity of material that must be weighed to achieve a specified relative TMU. Minimum weight is therefore a critical factor in determining whether a balance is capable of producing the required accuracy for a given application. There are more details on the concept of minimum weight in the literature..12^, 13

Routine Testing

Defining Accuracy and Precision

Because calibrations are not carried out frequently―usually once or twice per year― it is considered best practice for users to conduct routine testing between calibration intervals. However, before analyzing routine testing as a critical part of weighing instrument performance verification in pharmaceutical regulations, it is essential to understand how accuracy and precision are defined within the pharmaceutical industry.

Specifically, the term “accuracy” has a different meaning within the pharmaceutical industry compared to its definition in VIM (see Figure 2). According to ICH Q2(R2),18 “accuracy” is defined as:

“The accuracy […] expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value or set of values measured.”

This concept is called “trueness” in all other fields of metrology and defined accordingly in the VIM. It characterizes the deviations of a series of measurements from a reference value.

“Precision,” by contrast, is defined similarly in both pharmaceutical and metrological contexts. ICH Q2(R2) states:

“The precision […] expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple samplings of the same homogeneous sample under the prescribed conditions […].”

Precision characterizes how close together a series of measurements are under defined measurement conditions.

These definitions are important in the context of routine testing for balances to ensure they remain fit for their intended use. Pharmacopeias define specific tests for assessing accuracy and precision in their general chapters on balances. These tests stipulated by the pharmacopeias are designed to evaluate both systematic and random errors, which are limited when specific acceptance criteria, for tests that assess systematic and random errors, are defined.

Assessment of Accuracy and Precision

Routine testing activities aim to verify that weighing instruments fulfills predefined acceptance criteria during routine operation . Routine testing activities are specifically required by pharmaceutical regulations. While GMP regulations do not prescribe specific tests or acceptance criteria, pharmacopeias usually provide more detailed guidance.

Figure 1: Flow diagram of calibration and adjustment activities. The assessment of calibration results confirms whether the instrument is fit for its intended use. As-found calibration ensures the traceability of all preceding measurements that have been carried out on the instrument, while the as-left calibration ensures traceability of all subsequent measurements.

Figure 2: Correlation between precision, trueness and accuracy based on their definitions in the VIM. Note that ICH uses the term “accuracy” instead of “trueness.” Furthermore, ICH does not provide an equivalent for the VIM definition of “accuracy.” In ICH terminology, the combination of accuracy and precision corresponds to what the VIM defines as accuracy.

Figure 3: Typical values for tolerances or target measurement uncertainties (TMU) in laboratory and production applications within the pharmaceutical industry. For laboratory applications, most cases are governed by pharmacopeial requirements (0.10 % limit value for accuracy and precision). In manufacturing, tolerances are generally wider and depend on the criticality of individual weighing applications. This figure is based on a 2025 survey conducted by Mettler-Toledo,covering 56260 balances installed in laboratory environments and 12257 scales installed in production environments.19

Historically, the USP has defined two specific tests, and associated acceptance criteria, to assess the systematic and random error of balances. With a relative limit value of 0.10 %, the acceptance criteria for random and systematic errors defined in the pharmacopeias are quite stringent and ensure that the weighing step within analytical procedures is not the limiting factor in the overall accuracy of analytical procedures.

As previously noted, GMP regulations do not stipulate specific weighing requirements for pharmaceutical production. Therefore, it is the responsibility of individual organizations to define appropriate acceptance criteria for weighing instruments used outside the quality control laboratory. These criteria are typically expressed as a tolerance or a target measurement uncertainty (TMU), ranging from 0.1 % to 1 %, depending on the criticality of the weighing process and the potential impact of inaccurate measurements on production quality (see Figure 3) . However, some organizations may still struggle to define appropriate weighing requirements that are commensurate with the quality attributes of the Active Pharmaceutical Ingredient (API) or the finished pharmaceutical product, due to limited regulatory guidance.

Rounding Rules for Assessment

IIt is important to understand the rounding rules that are applied throughout all chapters of the pharmacopeias. Considering the Ph. Eur. description of the rounding rules in the General Notices section under “Limits” as representative for all pharmacopeias, the rule reads:20

“In determining compliance with a numerical limit, the calculated result of a test or assay is first rounded to the number of significant figures stated […]. The limits, regardless of whether the values are expressed as percentages or absolute values, are considered significant to the last digit shown (for example, 140 indicates 3 significant figures). The last figure of the result is increased by one when the part rejected is equal to or exceeds one half-unit, whereas it is not modified when the part rejected is less than a half-unit.”

USP has implemented the same rounding rules, as described in the General Notices and Requirements section 7.20, which includes example illustrating how compendial requirements are applied.21 In practice, mathematical rounding rules are applied to observed or calculated values based on the number of decimal places of the limit expression (the acceptance criterion). For example, a relative standard deviation of 0.1049 %, determined during a repeatability test to assess the precision of the instrument, would be rounded to 0.10 % (which corresponds to the number of decimal places of the 0.10 % acceptance criterion). With this value, the balance would pass the repeatability test. However, a relative standard deviation of 0.1050 % would be rounded to 0.11 %, resulting in a failed test. Note that this rounding procedure differs significantly from rounding rules in other fields of applied and legal metrology, where the formatting of any given limit value has no influence on the rounding of a measurement result.

Risk-Based Approach for Performance Verification

As previously noted, regulations often lack specificity regarding how instruments should be calibrated and tested, and they typically do not indicate specific time intervals for the tests―other than stipulating that calibrations and tests should be performed periodically. In metrology, guidance documents, such as the International Organization of Legal Metrology (OIML)/International Laboratory Accreditation Cooperation (ILAC) co-publication Guidelines for the Determination of Recalibration Intervals of Measuring Equipment22 outline key factors to consider when determining calibration and testing intervals:

• A requirement for measurement uncertainty
• Risk exceeding predetermined limits or accuracy requirements in use
• Manufacturer’s recommendations
• Expected extent and severity of equipment use
• Environmental conditions
• Frequency, quality, and results of intermediate checks

One important consideration in defining appropriate calibration and testing methods and intervals is the risk associated with the specific application. According to ICH Q9, risk is defined as “the combination of the probability of occurrence of harm and the severity of that harm.23”

In weighing applications, it is assumed that the more stringent the accuracy requirements of a weighing process are, the higher the probability that the weighing result may not meet the requirements. In such cases, calibration and testing frequencies should be increased to mitigate risk. Similarly, when the potential impact of inaccurate weighing is severe―such as compromising product quality―more frequent calibrations and tests should be performed. By increasing the frequency of calibration and testing in high-risk scenarios, the probability of undetected measurement errors is reduced. This approach effectively offsets the elevated risk associated with critical weighing processes, thereby lowering the likelihood of occurrence of the impact, and hence, offsetting the increase of risk of inaccurate weighing processes that otherwise would occur.

Given the preceding discussion, , it is important to address a frequent misconception that is prevalent in the pharmaceutical industry when it comes to routine testing between calibration activities. Many quality control professionals refer to a “daily balance test,” which typically assesses sensitivity―that is, the systematic error near balance’s maximum capacity―without assessing its repeatability. Daily balance tests are anchored in the mindset of generations of operators who worked with mechanical balances, when daily checks were advisable due to wear, tear, and abrasion of critical mechanical components.

Figure 4: Example of the implementation of a risk-based approach for the performance verification of weighing instruments. The higher the impact of inaccurate weighings—and the smaller the required weighing tolerance or target measurement uncertainty— the higher the risk that the instrument may not be fit for its intended use. This risk is mitigated by increasing appropriate performance verification activities.

However, such daily balance checks are no longer required for electronic balances, and especially for electronic balances with built-in adjustment weights. This internal weight have rendered daily sensitivity testing with external reference weights largely obsolete. This shift is supported by guidance such as the United Kingdom Accreditation Service (UKAS) LAB 14 guidance document “Calibration of Weighing Machines.24 The guide states:

“Historically the best advice has been to perform daily checks, however, as is the case for calibration, the frequency of these checks should be determined on the basis of the risk associated with the weighing application.”

Further support for this approach is found in Ph. Eur. General Chapter 2.1.7, which states:

“In addition to testing weighing instruments with external weights, it is accepted practice to adjust the instruments by means of built-in weights. This makes it possible to reduce the frequency of sensitivity tests with external reference weights. For electronic balances with a built-in weight, daily sensitivity testing with an external reference weight is not considered necessary […].”

This position is also reflected in guidance issued by the US FDA,25 which states:

“For a scale with a built-in auto-calibrator, we recommend that external performance checks be performed on a periodic basis, but less frequently as compared to a scale without this feature. The frequency of performance checks depends on the frequency of use of the scale and the criticality and tolerance of the process or analytical step.”

Figure 5: Holistic approach for the performance verification of weighing instruments. The as-found and as-left calibration is supplemented by appropriate routine testing activities to ensure that the instrument is continuously fit for its intended use, such as maintaining measurement uncertainty below the required target measurement uncertainty (TMU).

Instead of stipulating a daily balance check, pharmaceutical reference documents now focus on a risk-based approach for performance verification. This approach considers factors such as the OIML/ILAC categories (see Figure 4). For example, USP General Chapter 1251 “Weighing on an Analytical Balance”26 states:

“The frequency of the balance check depends on the risk of the application and the required weighing tolerance.”

The literature provides more details on the lifecycle management of weighing instruments using a risk-based approach, highlighting its influence on accuracy, productivity, safety, and compliance.27^, 28

Relating As-Found and As-Left Calibration to Routine Testing

As previously noted, regulatory guidance requires an as-found calibration prior to a significant modification of the instrument (e.g., repair or adjustment with external test weights). Results of such a calibration are also used to assess whether an instrument is still fit for its intended use―specifically, whether all preceding measurements on the device fulfill the respective user requirements, such as a target measurement uncertainty TMU).

However, it would be detrimental to the weighing process to observe non-compliance based on an as-found calibration result, as it may impact the reliability of an undetermined number of preceding measurements―extending back to the last as-left calibration in the absence of routine testing. Therefore, periodic routine testing activities between calibrations are imperative to ensure that the instrument remains fit for its intended use. Routine testing can provide an early warning about a potential drift of the instrument that could lead to measurements that no longer fulfill user requirements.

Pharmacopeial standards support this approach by prescribing specific tests for assessing accuracy and precision, which serve this purpose exactly. Therefore, as-found and as-left calibrations and routine testing are all indispensable parts of a state-of-the-art approach for the quality management of weighing instruments. Combining them into this holistic practice ensures fitness for intended use across the lifetime of the instrument (see Figure 5). Ensuring these activities are well-understood in analytical and QC laboratories and extending them to production will help to assure the quality of weight-based measurements across the pharmaceutical value chain for easier compliance, better product quality, and heightened consumer safety.

Discussion and Conclusion

With respect to the lifecycle management of weighing instruments, the pharmaceutical industry has begun implementing concepts that are ever more anchored in metrology. While the outdated concept of a daily balance check remains prevalent in the minds of many users, a growing number of reference documents applicable to the pharmaceutical industry are embracing state-of-the-art methods for the testing and calibration of balances and scales based on risk assessment and management. Within a risk-based approach, the likelihood of inaccurate measurements and the potential impact of such errors would be assessed and offset by appropriate performance verification activities to reduce the risk to an acceptable level.

Recent interpretations of calibration within the pharmacopeias―aligned with the definition in the International Vocabulary of Metrology (VIM)―constitutes a quantum leap concerning the adoption of a more scientific interpretation of metrology within the pharmaceutical industry. Furthermore, the importance of as-found and as-left calibrations in ensuring the traceability of measurement results obtained by an instrument during routine use is being incorporated into pharmaceutical quality management systems.

In recent years, more pharmacopeias have expanded their regulatory frameworks with the objective of following the metrological approach initiated by Ph. Eur. in General Chapter 2.1.7, “Balances for Analytical Purposes.” This trend is serving to foster a globally harmonized approach on metrology for balances used within the pharmaceutical industry.

These concepts should be applied in a similar way to weighing instruments across all pharmaceutical applications, as scales in the production area constitute a critical link in the pharmaceutical value chain. A holistic approach to the quality management of weighing instruments will help to ensure that balances and scales remain fit for their intended use, and that they are capable of promoting weighing accuracy, production quality, and consumer safety.

The consideration of measurement uncertainty for weighing processes may encourage its broader application across analytical and production workflows. By defining quality attributes for the final product and incorporating applicable quality control activities that consider measurement uncertainty, pharmaceutical companies could validate process outcomes on a more scientifically rigorous basis.