Robust freeze-drying process re-design of a legacy product based on risk analysis and design of experiments.

In this study, a QbD freeze-drying process re-design applied to a lyophilized injectable drug product is presented. The main objective was to assess the freeze-drying process robustness using risk analysis and a proper experimental design. First, the product's thermal fingerprint was characterized by thermal analysis and freeze-drying microscopy. Then, according to the output of the risk analysis, primary drying temperature and pressure were studied by a Doehlert DoE design with four responses; primary drying time, appearance, residual moisture content, and reconstitution time. Statistically significant MLR models were obtained for residual moisture content and primary drying time. In the latter, the temperature factor was the predominant factor to predict the duration of the primary drying stage. Two additional lab-scale batches were run to confirm the mathematical model predictions. Finally, optimal primary drying conditions (30 °C, 0.400 mbar) were selected to minimize the duration of the primary drying stage, while preserving the quality of the product. It was possible to set high temperature and pressure values because no collapse temperature was found during the thermal characterization of the product. Secondary drying temperature and time were defined based on the residual moisture content results. It was shown that secondary drying is robust between 30 °C and 50 °C and from 3 to 16 h. In conclusion, we were able to define a robust freeze-drying process which was further validated at an industrial scale with satisfactory results and approved by the health authorities in different countries around Europe.

Finding a reliable limit of detection in the NIR determination of residual moisture in a freeze-dried drug product.

The validation of an analytical method in the pharmaceutical industry follows strictly regulated guidelines. The introduction of multivariable calibration methods requires a revision of these recommendations, since some of them are contradictory regarding the limit of detection (LOD). This work compares the LOD values obtained using pseudounivariate and multivariate procedures in the PLS-NIR determination of residual moisture content (RMC) in a freeze-dried drug. As NIR has proved to be more precise than Karl-Fischer at low RMC values, LOD has been estimated by ordinary and by orthogonal least squares regression. The precision of the RMC determination in approx. 2000 industrial vials was used as an indirect evidence of the reliability of the LOD values obtained. The effect of reducing the number of calibration samples and increasing the RMC values have also been studied. No significant differences were observed using a number of calibration samples ≥ 20. Based on our findings, when the size of the calibration sample set is high and the range of RMC values is close to the limit, the LOD estimated with the ICH formula and using orthogonal regression should be recommended. If water content moves away, the ICH formula should be replaced by the LODOS equation as a practical, reliable and simple procedure.

The role of SeDeM for characterizing the active substance and polyvinyilpyrrolidone eliminating metastable forms in an oral lyophilizate-A preformulation study.

A preformulation study of an oral lyophilisate with cetirizine dihydrochloride (CTZ) as active ingredient, mannitol and PVP K30 as bulking agents is presented. CTZ shown a humidity content of 0.150% and a spontaneous hygroscopicity of 0.200% (both determined by SeDeM diagram), demonstrating an adequate stability behavior in solid form. A design of experiments (DoE) performed with both mannitol and PVP K30, followed by a simple factorial design (32) has determined the optimum combination of excipients and CTZ, and showed that a higher proportion of PVP K30 was able to prevent metastable forms generated by mannitol.

Determination of stress-induced degradation products of cetirizine dihydrochloride by a stability-indicating RP-HPLC method.

BACKGROUND: A new, simple and accurate stability-indicating reverse phase high performance liquid chromatography method was developed and validated during the early stage of drug development of an oral lyophilizate dosage form of cetirizine dihydrochloride. METHODS: For RP-HPLC analysis it was used an Eclipse XDB C8 column 150 mm × 4.6 mm, 5 µm (Agilent columns, Barcelona, Spain) as the stationary phase with a mobile phase consisted of a mixture of 0.2 M K2HPO4 pH 7.00 and acetonitrile (65:35, v/v) at a flow rate of 1 mL min (-1). Detection was performed at 230 nm using diode array detector. The method was validated in accordance with ICH guidelines with respect to linearity, accuracy, precision, specificity, limit of detection and quantification. RESULTS: The method results in excellent separation between the drug substance and its stress-induced degradation products. The peak purity factor is >950 for the drug substance after all types of stress, which confirms the complete separation of the drug substance peak from its stress induced degradation products. Regression analysis showed r(2) > 0.999 for cetirizine dihydrochloride in the concentration range of 650 µg mL (-1) to 350 µg mL(-1) for drug substance assay and a r(2) > 0.999 in the concentration range of 0.25 µg mL(-1) to 5 µg mL(-1) for degradation products. The method presents a limit of detection of 0.056 µg mL (-1) and a limit of quantification of 0.25 µg mL(-1). The obtained results for precision and accuracy for drug substance and degradation products are within the specifications established for the validation of the method. CONCLUSIONS: The proposed stability-indicating method developed in the early phase of drug development proved to be a simple, sensitive, accurate, precise, reproducible and therefore useful for the following stages of the cetirizine dihydrochloride oral lyophilizate dosage form development.