Pharmacopoeial Methods

Quality control of active ingredients in drug development: Pharmacopoeia testing and physicochemical characterization of APIs and excipients

For the quality control of medicinal products, the primary focus is on the galenical formulations of one or more active pharmaceutical ingredients (APIs) together with their excipients in the finished, marketable product. However, considering that both APIs and excipients undergo separate upstream manufacturing processes, it becomes evident—particularly during the development of a galenical formulation for the intended dosage form—that the quality of the raw materials must also be controlled.
Within this upstream level of quality-related testing (pharmacopoeial testing), potential inputs of unwanted by-products or impurities from manufacturing processes are addressed. In addition, these tests are complemented by assays and identification tests as well as analyses of further physicochemical parameters, such as viscosity, in order to verify and control various specific properties of the raw materials. The pharmacopoeial tests to be applied and their corresponding test parameters are specified in the relevant monographs of the respective pharmacopoeias (USP, Ph. Eur., JP, ChP, etc.).

Use case: monograph for Croscarmellose Sodium

As an example of a pharmacopoeial test, the monograph for Croscarmellose Sodium according to the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP) is considered here. Owing to the high level of harmonisation between Ph. Eur. and USP methods, most tests can be performed according to the Ph. Eur. procedures. Croscarmellose is primarily used as a disintegrant and can significantly accelerate the disintegration of dosage forms such as tablets, thereby facilitating the release of the active ingredient.
First of all, for routine testing it should be ensured that the validated pharmacopoeial method also delivers reliable and robust results in the specific application environment. This is achieved through verification of the validated pharmacopoeial method in the applying laboratory. Critical parameters are evaluated to assess whether the method can be applied in the current laboratory setting—potentially with necessary adjustments—using the available equipment and reference standards/chemicals by trained personnel. Such parameters can be derived from Ph. Eur. chapter 5.26 or USP <1226>. In the present case, an assay is performed that is corrected for the dry weight of the excipient Croscarmellose Sodium; therefore, a recently determined loss on drying must be included in the subsequent calculation. If individual tests consist of routine determinations, such as loss on drying and sulphated ash, which are frequently conducted in the laboratory, separate method verification may be omitted and the measurements may be carried out directly.

In this context, the assay is used to assess the degree of substitution of the cellulose structures within the croscarmellose. For this purpose, the contents of sodium carboxymethyl cellulose and acidic carboxymethyl cellulose groups are summed up. Both contents are determined by acid–base titration in two consecutive steps and subsequently evaluated using two interrelated calculation formulas. The sulphated ash must also be considered in the calculation and corrected for loss on drying. As part of method verification, precision may be determined, for example, using six independent sample preparations. Taking into account the upper and lower specification limits as well as the analytical procedure applied, a requirement for the relative standard deviation of the determined values from the mean must be defined. During method establishment, it is then verified whether this requirement can be met and whether routine analysis can be carried out meaningfully, considering the actual variability observed in the current laboratory environment and with the applied method—including any pharmacopoeia-compliant adjustments. This ensures reliable differentiation between results within and outside the specification. Once all requirements are fulfilled, the results can be reported, and routine testing can be performed accordingly. Subsequently, the quality of the excipient Croscarmellose Sodium can be demonstrated by comparison with the specifications defined in the pharmacopoeial monograph. Additional tests address the content of sodium glycolate and sodium chloride (also as a sum), as well as sedimentation volume, pH value, water-soluble substances, and microbiological quality (TAMC, TYMC, absence of E. coli).

Pharmacopoeial tests represent the current technical standard and accumulated knowledge in pharmaceutical analysis. Nevertheless, due to the lengthy harmonisation process prior to publication and the rapid development of analytical techniques, methods may quickly become outdated. In such cases, users are free to validate alternative methods and statistically compare them with the locally verified pharmacopoeial method (see Ph. Eur. chapter 5.27). If this comparison demonstrates good agreement between the methods, the alternative method may subsequently be used exclusively.

In general, pharmacopoeial testing fills a critical gap upstream of the analysis of finished medicinal products. Depending on the target market, the appropriate pharmacopoeia must be selected to ensure regulatory compliance. The correct classification in individual cases can be complex.

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