Development of an In-Line Near-Infrared Method for Blend Content Uniformity Assessment in a Tablet Feed Frame

Abstract

Process analytical technology (PAT) has shown great potential for in-line tableting process monitoring. 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 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 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. Spectral averaging, integration time, and feed frame paddle wheel speed were found to influence the effective sample size measured by the NIR probe. The effective sampling size was also estimated by comparing the distribution of predicted values with the reference values. The development of a robust, in-line PAT method was facilitated by thorough understanding of the sensitivity of PAT sensors to factors affecting pharmaceutical processes and products.

Sample Mass Estimate for the Use of Near-Infrared and Raman Spectroscopy to Monitor Content Uniformity in a Tablet Press Feed Frame of a Drug Product Continuous Manufacturing Process

“…Specifically, the sample mass is no more than one to three times a dosage unit regardless of the assumed depth of penetration used in the calculation. 17,25 This ensures that the measurement is appropriate for content uniformity of the blend in the feed frame.…”

“…This conclusion is consistent with the recent work of other researchers who have also estimated the sample size of NIR measurements in a tablet press feed frame. 16 In that work, the effective NIR sample size was determined both mathematically and based on a simulation approach where the variability of the active content based on the NIR monitoring of the blend was compared to the variability of the batch based on high-performance liquid chromatography (HPLC) analysis of compressed tablet cores, with different simulated sample sizes ranging from one to three tablets. With respect to the calculation-based approach, the authors included blend density, radius of the NIR beam, NIR acquisition time, distance from the center of the NIR beam to the center of the feed frame, an assumed penetration depth of 0.5 mm, and the feed frame angular velocity.…”

“…The Raman penetration depth reported in relevant literature 23,24 was taken into consideration. According to the similar depth of penetration reported for NIR and Raman in feed-frame applications, 7,25 an intermediate value of 1.0 mm was used here for Raman, similar to what was used in the NIR Case Study: A Commercial Deployment section above for NIR.…”

“…The use of the feed frame as a spectroscopic PAT monitoring location preceded the advent of continuous manufacturing. 6–16 The FF sits on top of a tablet press and contains rotating paddles that convey powder blend to the tablet press punches and dies. The proximity of the feed frame to the tablet compression location and its effectiveness as a point for characterizing powder mixing make it an ideal location for not only process monitoring of active pharmaceutical ingredient (API) concentration (i.e., common cause variability) and detecting transient disturbance (i.e., special cause variability) in final blends, but also as an input to real-time tablet accept/reject decisions.…”