Reference standards are intermediates/standards used to calibrate instrumentation or methodologies that can be applied for characterization, quantitation, or identification purposes. Since the early 1980s, pharmaceutical impurity reference standards have been developed within governmental agencies and academia with the intent of providing quality control for pharmaceutical manufacturing. The availability of high-quality reference materials is important because it allows end-users to monitor their performance against an industry standard during routine operation. Reference materials do not replace the need for control over drug substances and formulations during production stages, but they provide a possibility to monitor development processes. They are also useful in cases where it would be difficult to monitor key process steps directly, e.g., due to too possible reaction pathways leading back to a starting material.

The need for pharmaceutical impurity reference standards can be divided into 1) efficacy, 2) contamination/analysis methods, and 3) substitution.

Efficacy-related issues are related to the pharmaceutical product itself. Still, it should be noted that typically only one key active drug substance is present in a pharmaceutical formulation/drug product.

Contamination/methodology problems could arise from the loss of any of the intermediates used during manufacturing or by insufficient purification steps that affect how compounds are identified or quantified during analysis. The use of substitution challenges has been implemented within certain branches of industry as part of an overall control strategy to ensure accuracy in measurements.

Substitution testing takes advantage of modern instrumentation where higher sensitivities and increased selectivity are available to provide the end-user with a better idea of where they stand in terms of impurities. The pharmaceutical industry is currently able to detect laser light scattering, UV/Vis absorbance, fluorescence, and chromatographic properties, all at lower limits than what used to be available fifteen years ago.

The Future of Pharmaceutical Impurity Reference Standards

Although pharmaceutical impurity reference standards are already established in the industry, there is still room for improvement. It is not uncommon for end-users to create their impurity reference standard using raw materials that go into the production of drugs. Unfortunately, many of these approaches have led to questionable comparisons between different measurements or reagents by end-users that did not perform within an acceptable range when compared against a “known” standard.

There is much room for improvement in developing and maintaining regulated reference materials such as pharmaceutical impurity reference standards because the technology used in many cases may not be applicable everywhere due to interdependencies on other equipment and costly acquisition of software packages needed for data processing and calibration. In addition, the lack of standardization within the pharmaceutical industry makes comparisons between batches difficult and time-consuming, even when a reference material is used.

The future for pharmaceutical impurity reference standards looks interesting as new requirements continue being put in place. At the same time, it becomes harder to perform desired analyses. Data processing capabilities have improved over the last few years due to better instrumentation. However, there are still key problems that must be addressed before becoming more widely accepted by end-users.