Analytical Applications - Pharmaceutical Technology

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PharmTech Europe

Analytical Applications
Several industry experts describe applications in pharmaceutical applications, including on-line total organic carbon analysis, ultra-fast liquid chromatography, rapid microbial testing, and differential scanning calorimetry-Raman Spectroscopy.


Pharmaceutical Technology
Volume 34, pp. s36-s30

On-line TOC analysis

Jonathan Yourkin, global pharmaceutical product manager GE Analytical Instruments (Boulder, CO)


APOSTROPHE PRODUCTIONS, PHOTODISC, GETTY IMAGES
Total organic carbon (TOC) is a critical water-quality attribute. Reliance on periodic laboratory grab samples taken from the process is comparatively inefficient and less reliable than using on-line TOC analyzers located at critical locations within the water-distribution system. An important element of implementing on-line TOC is ensuring that the process analyzers use an analytical method that is equivalent to or better than the established laboratory method. Recognizing that most compendial methods were never intended for, nor designed to qualify continuous-process analyzers, the US Food and Drug Administration's guidance on process analytical technology (PAT) suggests that users consider any process analyzer used for real-time data as an "alternate analytical method" (1). Simply stated, the user must establish the suitability of the process analyzer for the intended use through prescribed method-validation procedures. Beyond establishing the suitability of on-line TOC methods, several important process-validation elements should be considered for complying to current good manufacturing practices, including evaluating variables within a measurement system.

Evaluating variables in a measurement system. A key challenge in any shift to on-line TOC analysis is ensuring that the measurement system that measures an analyte on-line provides the same or better data quality as the laboratory-based measurement system. Often, analytical methods used to produce on-line and laboratory data are different. These challenges can be solved when all analytical methods used are essentially the same or the analytical capabilities of the laboratory-based and on-line TOC methods have proven to be like-for-like. Once method comparability is established, any variability observed between laboratory and on-line TOC results can be attributed to different sampling processes.

When comparing TOC data from similar samples analyzed by on-line and laboratory TOC instruments, observed variation can be attributed to two major sources: the sampling process used to introduce the sample to the measuring device and the inherent analytical capabilities of the analytical method. Given the ubiquitous presence of organics in the environment, grab-sample collection of TOC samples is subject to numerous error sources. With the on-line method, sampling-process variability is minimized or eliminated because the analyzer is physically integrated within the process-water stream for continuous quality-assurance monitoring. In addition, this evaluation quantifies sampling-process variation at TOC concentrations produced by the pharmaceutical water system, which are typically an order of magnitude lower than the TOC standard concentrations used to validate the analytical method. Sampling process variation is generally much more pronounced at these lower TOC concentrations.

Equivalency testing. Equivalency testing demonstrates the sameness of two measurement systems based upon the analytical results the methods produce. This type of testing differs from instrument-validation testing, which typically assesses various attributes using standards of known concentration. Validation protocols are not designed to identify differences in the test-sample data quality. Therefore, it is possible to validate two methods with the same protocols using the same criteria, yet have the methods yield nonequivalent analytical results under actual conditions of use. It is particularly important in on-line TOC implementations to augment validation protocols with equivalency testing. The fundamental hypothesis supporting the justification for measurment-system equivalency testing is that, given the sameness of on-line and laboratory analytical methods, any lack of equivalency observed between the two data sets can be attributed to aspects of the measurement system rather than the core analytical method.

This type of analysis is typically performed using a Gage Repeatability and Reproducibility (Gage R&R) study to quantify measurement-system variation relative to variation of the process as a whole. The Gage R&R addresses several components affecting variability, including the gauge (the instrument), the operator, and the sample itself. Ordinarily, a full-scale Gage R&R would be used to assess variability contributed by all components. This example uses a simplified Gage R&R approach based on the degree of sameness of the analytical methods and the unique differences in the operational or environmental conditions associated with laboratory and on-line measurements. By pairing the on-line and laboratory data collection, process water variability remains common between the two systems. In addition, the inherent accuracy of the instruments remains common, based on like-for-like methods that have been validated appropriately.


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