Adapting an in-line PAT method, such as a near-infrared (NIR) spectroscopic method, for analyzing content uniformity of powder in the feed frame provides opportunities to assure the quality of tablets in the late stages of tablet manufacturing. Feed frame has been identified as a reliable location to achieve representative sampling of blends. It is closest to the die cavities and positioning the probe above the paddle fingers helps to avoid probing the ‘dead zones’ of powder in the feed frame. One of the challenges associated with real-time monitoring of compression blend content uniformity in the feed frame is the lack of ‘sample volume’ definition. The calculation of sample mass analyzed by NIRS for a particular pharmaceutical process requires information regarding the penetration depth of the NIR beam, bulk or tapped density of powder, cross-section area of light and powder velocity. Once the appropriate sample size is determined for the intended use of an analytical method, the integration time and number of co-adds of the PAT sensors need to be specified to meet the sampling needs of the process and product. In the framework of continuous manufacturing, measurements in the feed frame may be essential to ensure the homogeneity of blends after the API and excipients are discharged from the blender and fed into the press.
The study focuses on the development and validation of an in-line near-infrared (NIR) spectroscopic method for the determination of content uniformity of blends in a tablet feed frame. An in-line NIR method was developed after a careful evaluation of the impact of potential experimental factors on the robustness and model accuracy and precision. The NIR method was validated according to the principles outlined in International Conference on Harmonization - Q2(ICH-Q2) and accuracy profiles for validation of analytical procedures and was demonstrated to be suitable for monitoring blend content for the formulation under evaluation. Reliable measurements of blend homogeneity rely on representative sampling. To reach the appropriate scale of scrutiny for a unit dose, the study assessed factors that influence the effective sample size measured by NIR. Bootstrap sampling was used to compare the standard deviations of reference values and NIR measurements with changing sample sizes.
The importance of experimental factors was assessed by how much the model metrics deteriorated after each factor was removed from the model. When the level of variability of a factor was fixed and no risk is associated with exceeding the operation ranges, removal of that factor had no impact on the model performance and yielded a model with decreased, yet sufficient robustness. Otherwise, global modelling, where most of the relevant sources of variability are included, was preferred. The developed NIR method demonstrated sufficient accuracy, precision, specificity and robustness to minor press speed variation. The selection of a proper NIR sample mass was critical to the content uniformity assessment. An optimum similarity between the distributions of the API content was demonstrated when a sample size of one tablet was used. Spectral averaging, integration time and feed frame paddle wheel speed were found to influence the effective sample size measured by the NIR probe.
An in-line NIR method was developed and validated for real-time API content determination in the tablet feed frame. Development of a robust, in-line PAT method was facilitated by thorough understanding of the sensitivity of PAT sensors to factors impacting pharmaceutical processes and products.