New Developments in Weighing Technology That Meet the Needs of Advanced Pharmaceutical and Manufacturing Compliance Protocols

One of the worst-case scenarios for a pharmaceutical laboratory is to have a government inspector close down the facility because it cannot provide regulatory compliance documentation, much less follow safety and maintenance procedures. The requirements for controlling and monitoring the accuracy of inspection, measuring, and test equipment used in quality systems and those of the United States Pharmacopeia place exceptionally high demands on laboratory equipment and operators alike. For the regulated facility that needs to integrate its balances into a quality system, for example, today’s scale manufacturers have designed and developed new technology that offers the user convenience, speed, accuracy, modularity, and of course, accurate documentation of results.

Figure 1 - An analytical balance that can support advanced
pharmaceutical applications including static elimination.

As will be shown in this article, it is imperative that each function and feature of these new laboratory balances support compliance with monitoring, control, and documentation requirements that can translate into specific user benefits. In addition, the balances must not only meet today’s requirements, but also be upgradeable for future government regulations and safety procedures (see Figure 1).

It is also important that many of today’s balances be able to integrate seamlessly into a facility’s processes. The new balances of today can provide the user with valuable support in implementing and documenting both customized standard operating procedure (SOP) protocols as well as Good Manufacturing Practice (GMP)-/Good Laboratory Practice (GLP)-compliant procedures. An added benefit of the balances is that the resulting data, especially for advanced pharmaceutical compliance, can be measured for both safety and reliability. The user can now provide the best possible results for compliance to the government agency without any loss of down time and additional verification procedures.

How new technology balances improve quality manufacturing operations in a pharmaceutical plant

Figure 2 - Quality system map.

The documentation capability of the new balance instruments (as a test and measuring device) offers many advantages for a pharmaceutical manufacturer’s verification needs. First of all, documenting and controlling inspection, measuring, and testing are key elements of a functional quality management system (Figure 2). Secondly, it is a prerequisite for objectively demonstrating the performance of a laboratory in the aforementioned quality system. Failure to provide this information can result in a shut-down of the laboratory facility and, even worse, the whole production process.

Quality system protocols often begin with the selection of a suitable balance device based on the tolerances to be tested, which, for instance, are indicated in the laboratory’s SOPs. Balances suitable for this purpose have an overall uncertainty of measurement that is much lower than the sample with respect to the specifications of the equipment and all factors that have an influence on the measurement.

In addition, extreme ranges of resolution have been attained in the field of analytical weighing technology. Reaching these new limits, however, has affected the competence of individual laboratories both inside and outside of the manufacturer’s facility. For this reason, most laboratories must keep certificates, accreditation documents, and written results on file. These credentials provide objective evidence of the laboratory’s performance and assure those using their services that questions will be expertly answered with the proper documentation.

Figure 3 - Plant diagram showing incoming/outgoing goods with weighing stations.

Another factor is that the flood of analytical data provided by today’s instrumentation has been a problem for laboratory technicians. Namely, they must test and validate many measured values for plausibility and accuracy to conform to quality system and SOP protocols. Here, again, quality assurance measures provided by today’s balance and scale manufacturers are essential for correct, comparable, and verifiable results from incoming inspection to outgoing goods in a modern plant facility (Figure 3). 

USP requirements according to Section 41

Figure 4 - USP book, weights, and calibration certificate.

A key factor of advanced pharmaceutical compliance is the minimum sample weight verification protocols according to the United States Pharmacopoeia (USP) (Figure 4). Section 41 specifies that the minimum sample amount measured on a balance may not be less than 1000 times the uncertainty of measurement (or the uncertainty of measurement must not be greater than 0.1% of the minimum sample weight). To be more exact, the original text is as follows:

“Pharmacopeial tests and assays require balances that vary in capacity, sensitivity, and reproducibility. Unless otherwise specified, when substances are to be ‘accurately weighed’ for Assay the weighing is to be performed with a weighing device whose measurement uncertainty (random plus systematic error) does not exceed 0.1% of the reading. For example, a quantity of 50 mg is to weighed so that the absolute error does not exceed 50 µg. Measurement uncertainty is satisfactory if three times the standard deviation of not less than ten replicate weighings divided by the amount weighed, does not exceed 0.001.”

Figure 5 - The standard deviation, s, is used to evaluate a balance with regard to its reproducibility. For a confidence interval of ±3σ, 99.7% of the values measured lie within these limits around the mean.

The standard deviation (repeatability) describes the ability of an instrument to obtain corresponding results under constant testing conditions (Figure 5). Therefore, this can be designated as the most important metrological feature of a modern electronic weighing instrument. For this reason, the repeatability (also called reproducibility) is always given in the specifications for a balance.

The simple standard deviation (1s) is mostly used to quantify the repeatability. With this specification, the minimum sample weight can be calculated using the following equation:

Repeatability * 3000 = minimum sample weight

The factor 3000 is calculated based on the USP requirement that three times the standard deviation (= measurement uncertainty according to the USP) must be used and that the measurement uncertainty may not exceed 0.1% of the reading of the minimum sample weight (0.1% corresponds to the factor 1000). Focal points are:

Figure 6 - SQmin display on a balance showing the required minimum weight, and clearly indicating whether or not the sample is within USP requirements.

  • Ten replicate weighings using traceable weights
  • Three times the standard deviation of those weighings
  • U = 3 * sd
  • Because USP uses a tolerance limit of 0.1%, the minimum sample quantity can be determined as: Minimum Sample Quantity = U * 1000.

Therefore, it is imperative in advanced pharmaceutical applications that the user’s balance can specify the correct sample weight so that it is within legal requirements (Figure 6).