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The latest revisions to the United States Pharmacopeia (USP) General Chapters <41> Balances and <1251> Weighing on an Analytical Balance became official on Dec. 1, 2013. These revisions aim to ensure weighing accuracy and eliminate unnecessary over-testing for US pharmaceutical manufacturers and suppliers. The chapters attempt to simplify previous descriptions and reflect current state-of-the-art weighing practices. Revisions include modified balance test procedures, which focus on the determination of minimum weight, and the execution of routine testing.
The new requirements of General Chapter <41> are mandatory. The revised chapter now states that accurate weighing must be performed using a calibrated balance. It also details a relatively demanding balance assessment, describing accuracy and repeatability tests with new acceptance limits. These requirements apply for balances used to weigh analytes for quantitative measures.
For accuracy testing, using a test weight of 5–100% of the balance capacity is now applicable. Accuracy, defined by USP as the systematic error, must be determined at higher loads close to the balance capacity (i.e., largest systematic error), as it cannot be detected reliably below 5%. Hence, accuracy testing below 5% is no longer allowed. In the lower weighing range, repeatability is the dominant source of error.
In contrast, repeatability testing and minimum-weight determination should be carried out using a small weight below 5% of the balance capacity. In this lower range, the repeatability is virtually independent of the test weight. With higher weights (i.e., above 5%), repeatability will increase, leading to higher minimum weight values. For more information on balance testing, the USP video tutorial can be viewed at: www.mt.com/lab-usp-tutorial.
Advisory Chapter <1251> provides additional clarification and extends the scope to any balance used for an analytical procedure. These major revisions focus on balance qualification and operation. For example, performance verification should be carried out using a risk-based approach. Crucially, weighing net samples sufficiently above the minimum weight is recommended to take balance performance fluctuations into account. This requirement is clearly applied to the sample weight, not including the tare vessel. Every balance has an individual minimum weight, depending on the type and performance of the load cell, the location, and the environmental conditions. The minimum weight of every balance should be periodically assessed for conformance.
Applying a safety factor minimizes the risk of out-of-calibration, out-of-specification (OOS), or out-of-tolerance (OOT) results. The safety factor is the quotient between the smallest net weight and the experimentally determined minimum weight. It accounts for environmental influences and variations in operators, samples, and statistical factors. The safety factor applied should depend on the risk. It should be higher for more critical applications and unstable environments.
Another consequence of the USP revisions is that a daily balance check, typical in the pharmaceutical industry, is no longer a requirement. Instead, the type and frequency of balance checks should be determined by the risk and process tolerance of the application. The more critical the impact of an incorrect result, the more testing should be carried out, to reduce the risk of OOS or OOT results. In any case, it should contain at least a regular calibration with determination of measurement uncertainty and periodic sensitivity and repeatability testing. Performing the right tests at the right intervals will ensure quality results. During a webinar in December 2013, a majority of balance users (77% of those surveyed) admitted to still carrying out balance checks daily or before every use (1). This result indicates that many companies could potentially benefit from eliminating unnecessary testing, which brings significant time and cost savings.
Commercially available programs, like Mettler Toledo’s Good Weighing Practice, can help pharmaceutical manufacturers and suppliers to comply with the new USP guidelines by putting the guidelines into practice in a structured and effective way. Services can, for example, perform risk assessments and provide test methods and frequencies based on specific risks.
Further educational resources relating to these USP revisions can be accessed at: www.mt.com/lab-usp.
To learn more about this topic, view the full recording of the webinar at: www.pharmtech.com/uspcompliance.
1. G. Martin, M. Huber, and J. Ratcliff, “Ensuring USP Compliance with Revised Chapters on Weighing,” webinar (Dec. 3, 2013).