Effect of process parameters and formulation properties on the lead-lag between in-line NIR tablet press feed frame and off-line NIR tablet measurements.

The use of in-line near-infrared (NIR) measurements for tablet potency monitoring and diversion was studied. First, the optimal sample size for in-line NIR measurements inside the feed chute and the dosing and filling chamber of the tablet press feed frame was determined to allow proper comparison between these different measurement positions. Because of the considerably longer measurement time needed to obtain the same sample size inside the feed chute compared to the feed frame, the possibility of powder segregation inside the feed chute and the additional powder mixing inside the feed frame, the latter is preferred over the feed chute for in-line blend potency monitoring. Next, a design of experiments (DoE) was performed to evaluate the effect of paddle speed, turret speed, overfill level and formulation properties upon the lead-lag and the time it takes before the powder blend that is expelled at the dosing station is measured by the NIR inside the dosing chamber. Lead-lag is defined as the difference in time and API concentration between the measured in-line NIR response inside the filling chamber of the feed frame and the off-line NIR tablet response. Paddle speed and turret speed were the only compression parameters affecting lead-lag. Lead-lag decreased with increasing paddle speed for the first formulation. For the second formulation, lead-lag decreased with decreasing paddle speed and/or increasing turret speed. Formulation properties did not have an effect on the lead-lag. The in-line NIR response inside the dosing chamber of the feed frame was found to be closely following the tablet NIR response. Therefore, the dosing chamber could be used as an additional in-line NIR position for tablet potency monitoring and diversion. It can provide an extra layer of confidence about the final tablet quality. To demonstrate this potential benefit of simultaneous in-line NIR measurements inside the filling and dosing chamber of the feed frame, a tableting experiment was performed where a surrogate API spike was introduced into the product stream to mimic a potential process disturbance. The in-line NIR measurements inside the filling chamber allow diverting tablets in-time when the blend potency crosses the predefined control limits. And because the NIR response inside the dosing chamber closely follows the tablet NIR response, tablet diversion can discontinue when the blend potency inside the dosing chamber is again within the control limits. This could increase the yield of the tableting process by avoiding a longer than needed wash-out period and rejecting tablets that meet the release limits.

Determination and understanding of lead-lag between in-line NIR tablet press feed frame and off-line NIR tablet measurements.

The influence of different tableting process parameters on lead-lag was studied by collecting in-line near-infrared (NIR) spectra in the filling chamber of the tablet press feed frame and off-line NIR tablet data. Lead-lag is defined as the difference in time and API concentration between the measured in-line feed frame NIR response and the off-line NIR tablet data. Lead-lag results from the product formulation blend undergoing additional mixing after passing the NIR probe inside the feed frame, before being filled into the dies of the tablet press. A design of experiments (DoE) was performed to evaluate the effect of the tableting process factors paddle speed, turret speed, overfill level, paddle speed ratio and feed frame type upon lead-lag. Paddle speed and turret speed were identified as the only tableting parameters affecting lead-lag. Lead-lag decreased with increasing paddle speed or turret speed and became negligible at high paddle speed and high turret speed. Overfill level, paddle speed ratio and feed frame type did not affect lead-lag, suggesting that the amount and the trajectory of the recirculating powder in the feed frame did not significantly vary and hence influence the lead-lag within the examined process factor ranges. Finally, a methodology was developed using the in-line feed frame NIR measurements for the continuous monitoring and control of blend potency and tablet content uniformity. Tablet diversion should start when the in-line feed frame monitored blend potency exceeds the predefined control limits and can discontinue when this blend potency is again within the control limits for a duration equal to the lead-lag time. A combination of continuous blend potency monitoring inside the feed frame and in-process tablet weight control allows real-time tablet content uniformity assurance. Although the findings of this study are restricted to the specific equipment, tableting parameter ranges and product formulation used, the suggested approach for lead-lag determination and continuous tablet content uniformity monitoring can be applied to any rotary tablet press and product formulation.

A hybrid model for multipoint real time potency observation in continuous direct compression manufacturing operations.

The ongoing transition from batch to continuous manufacturing offers both challenges and opportunities in the field of oral solid dosage form production. In turn, Process Analytical Technology (PAT) offers a path towards the successful deployment of continuous tablet manufacturing in rotary tablet presses. One promising PAT tool for this endeavour is the NIR-derived potency measurement. However, the high degree of noise in the data may hamper the extraction of useful information. For this reason, this work focused on the implementation of an adaptive Kalman filter algorithm that incorporates and reconciles the potency prediction given by one or more NIR probes with those of a semi-mechanistic compartmental model developed for the application at hand. This approach allowed for more robust concentration estimations. Furthermore, it was observed that potency levels in multiple locations in the studied tablet press (including those in the finished tablets) could be appropriately inferred using a single in-line measurement data stream. This methodology thus opens the door to advanced process control applications.

Soft sensor for real-time estimation of tablet potency in continuous direct compression manufacturing operation.

One of the critical quality attributes of the solid oral dosage forms produced in continuous direct compression operations is the tablet potency. A novel soft sensor comprising of a combination of first principle-based and empirical models has been developed to enable real-time monitoring of blend and tablet potency, and concentrations of other excipients at various stream levels along the direct compression line. The soft sensor model has only three adjustable parameters, primarily associated with the equipment design and operation, so the model is product agnostic which is key to enable flexible manufacturing. The estimation accuracy of the soft sensor is demonstrated through a series of real time experiments which include steady state and dynamic transitions of potency during the runs, compared with offline analytically tested tablet cores. The results indicate that the proposed soft sensor can be utilized as a robust tool for real-time monitoring of potency, suggesting an extension of its utilization to higher levels of control. Two potential applications of the soft sensor are: 1. An element of a control strategy for product diversion; 2. A predictive model for advanced process control strategy to minimize the variability in tablet composition.

A hybrid NIR-soft sensor method for real time in-process control during continuous direct compression manufacturing operations.

Near Infrared (NIR) spectroscopy is commonly utilized for continuous manufacturing as Process Analytical Technology (PAT) tool. This paper focus on a continuous direct compression manufacturing process, in which an NIR PAT probe is integrated into the tablet press feed frame and into the tablet diversion control system to ensure continuous monitoring of the potency and homogeneity of the blend within the process line. The quantification of NIR spectra is achieved through Partial Least-Squares (PLS) modeling, calibrated with offline analyzed tablet cores at different potency levels. Because the NIR measurements are often sensitive to sample physical properties caused by raw materials or process conditions, etc., adopting a data-driven approach will require a large amount of representative data throughout the method lifecycle. During the early stages of process development, whenever new uncaptured source of variability in the model space are encountered, the chemometric predictions can deviate from the offline reference, requiring frequent model updates. These deviations can be reduced by integrating process and physico-chemical knowledge in the on-line potency estimation. This paper presents a novel hybrid method combining the online NIR PLS and a potency soft sensor estimation, enabling a robust potency prediction whilst minimizing maintenance downtimes and facilitating cross-site method transfer.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.