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.

Development of a tablet press feed frame lead lag determination model using in-line and off-line NIR measurements.

For continuous pharmaceutical manufacturing of oral solid dosages, it is essential that product quality is measured inline. In this application, a continuous rotary tablet press is used. The goal is a model-based assessment of the quality of the blend in the feed frame to determine whether the concentration of the active pharmaceutical ingredient (API) will be within the prescribed limits. This is to achieve a better quality assurance than by offline testing of a small sample of tablets. In this way, product quality for real-time release (RTR) could be implemented. With a near-infrared (NIR) probe, the concentration of the API in the feed chute and the feed-frame were measured, as well as the API concentration of the tablets by an offline NIR measurement. These different data sets are connected and used for the residence time distribution characterization of the mixing dynamic of the tablet press. A residence time distribution model is fitted to the data, and is further used to compute the lead-lag time. This yields information on how long it takes for a quantity of product to go from being measured in the feed frame until ending up in tablets. Further, it gives information on the occurrence of mixing in the feed-frame itself. These models allow making accurate predictions of whether tablets fall within specified concentration range in real-time. The real-time prediction can be used in combination with a control system both to maintain the quality of the blend as well as to know which tablets to discard. This real-time quality assurance will lead to less material waste and fewer declined batches of tablets.

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.

Benchtop NIR method development for continuous manufacturing scale to enable efficient PAT application for solid oral dosage form.

A Near Infrared (NIR) method was developed using a small benchtop feed frame system to quantify Saccharin potency in a powder blend during continuous manufacturing process. A 15-point Design of Experiments (DoE) was created based on the NIR spectral response and compositions of the formulation to develop a calibration set. The calibration set was designed to create compositional and raw material lots variation using minimum resources. The calibration experiments utilized around 0.5 kg Saccharin (Active Pharmaceutical Ingredient (API) surrogate) and 1.8 kg of excipients. Partial Least Square (PLS) modeling was used to develop a quantitative NIR method from the calibration data. The NIR method was implemented during 5 test batches in two different manufacturing sites across different potency levels at a continuous manufacturing platform for direction compression. Acceptable prediction performance was achieved from the NIR method at both sites. The NIR method was robust against changes in process scale and NIR instruments. The variance information built into the calibration set was found to be critical to successful model performance. This study shows a benchtop feed frame can be used for material sparing calibration method development without operating at a full-scale process line and applied across multiple sites, instruments at different potency levels.

Development and validation of an in-line NIR spectroscopic method for continuous blend potency determination in the feed frame of a tablet press.

A calibration model for in-line API quantification based on near infrared (NIR) spectra collection during tableting in the tablet press feed frame was developed and validated. First, the measurement set-up was optimised and the effect of filling degree of the feed frame on the NIR spectra was investigated. Secondly, a predictive API quantification model was developed and validated by calculating the accuracy profile based on the analysis results of validation experiments. Furthermore, based on the data of the accuracy profile, the measurement uncertainty was determined. Finally, the robustness of the API quantification model was evaluated. An NIR probe (SentroPAT FO) was implemented into the feed frame of a rotary tablet press (Modul™ P) to monitor physical mixtures of a model API (sodium saccharine) and excipients with two different API target concentrations: 5 and 20% (w/w). Cutting notches into the paddle wheel fingers did avoid disturbances of the NIR signal caused by the rotating paddle wheel fingers and hence allowed better and more complete feed frame monitoring. The effect of the design of the notched paddle wheel fingers was also investigated and elucidated that straight paddle wheel fingers did cause less variation in NIR signal compared to curved paddle wheel fingers. The filling degree of the feed frame was reflected in the raw NIR spectra. Several different calibration models for the prediction of the API content were developed, based on the use of single spectra or averaged spectra, and using partial least squares (PLS) regression or ratio models. These predictive models were then evaluated and validated by processing physical mixtures with different API concentrations not used in the calibration models (validation set). The ß-expectation tolerance intervals were calculated for each model and for each of the validated API concentration levels (ß was set at 95%). PLS models showed the best predictive performance. For each examined saccharine concentration range (i.e., between 4.5 and 6.5% and between 15 and 25%), at least 95% of future measurements will not deviate more than 15% from the true value.

Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press.

CONTEXT: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected. OBJECTIVE: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS). MATERIALS AND METHODS: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder. RESULTS AND DISCUSSION: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures. CONCLUSION: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.

Reduction of tablet weight variability by optimizing paddle speed in the forced feeder of a high-speed rotary tablet press.

CONTEXT: Tableting is a complex process due to the large number of process parameters that can be varied. Knowledge and understanding of the influence of these parameters on the final product quality is of great importance for the industry, allowing economic efficiency and parametric release. OBJECTIVE: The aim of this study was to investigate the influence of paddle speeds and fill depth at different tableting speeds on the weight and weight variability of tablets. MATERIALS AND METHODS: Two excipients possessing different flow behavior, microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate (DCP), were selected as model powders. Tablets were manufactured via a high-speed rotary tablet press using design of experiments (DoE). During each experiment also the volume of powder in the forced feeder was measured. RESULTS AND DISCUSSION: Analysis of the DoE revealed that paddle speeds are of minor importance for tablet weight but significantly affect volume of powder inside the feeder in case of powders with excellent flowability (DCP). The opposite effect of paddle speed was observed for fairly flowing powders (MCC). Tableting speed played a role in weight and weight variability, whereas changing fill depth exclusively influenced tablet weight. CONCLUSION: The DoE approach allowed predicting the optimum combination of process parameters leading to minimum tablet weight variability. Monte Carlo simulations allowed assessing the probability to exceed the acceptable response limits if factor settings were varied around their optimum. This multi-dimensional combination and interaction of input variables leading to response criteria with acceptable probability reflected the design space.

Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets.

Continuous manufacturing gains more and more interest within the pharmaceutical industry. The International Conference of Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of raw material attributes, manufacturing process options and process parameters. This fits further into the Process Analytical Technology (PAT) and Quality by Design (QbD) framework. The present study evaluates the effect of variation in critical raw material properties on the critical quality attributes of granules and tablets, produced by a continuous from-powder-to-tablet wet granulation line. The granulation process parameters were kept constant to examine the differences in the end product quality caused by the variability of the raw materials properties only. Theophylline-Lactose-PVP (30-67.5-2.5%) was used as model formulation. Seven different grades of theophylline were granulated. Afterward, the obtained granules were tableted. Both the characteristics of granules and tablets were determined. The results show that differences in raw material properties both affect their processability and several critical quality attributes of the resulting granules and tablets.

Moisture and drug solid-state monitoring during a continuous drying process using empirical and mass balance models.

Classically, the end point detection during fluid bed drying has been performed using indirect parameters, such as the product temperature or the humidity of the outlet drying air. This paper aims at comparing those classic methods to both in-line moisture and solid-state determination by means of Process Analytical Technology (PAT) tools (Raman and NIR spectroscopy) and a mass balance approach. The six-segmented fluid bed drying system being part of a fully continuous from-powder-to-tablet production line (ConsiGma™-25) was used for this study. A theophylline:lactose:PVP (30:67.5:2.5) blend was chosen as model formulation. For the development of the NIR-based moisture determination model, 15 calibration experiments in the fluid bed dryer were performed. Six test experiments were conducted afterwards, and the product was monitored in-line with NIR and Raman spectroscopy during drying. The results (drying endpoint and residual moisture) obtained via the NIR-based moisture determination model, the classical approach by means of indirect parameters and the mass balance model were then compared. Our conclusion is that the PAT-based method is most suited for use in a production set-up. Secondly, the different size fractions of the dried granules obtained during different experiments (fines, yield and oversized granules) were compared separately, revealing differences in both solid state of theophylline and moisture content between the different granule size fractions.

Prediction of quality attributes of continuously produced granules using complementary pat tools.

Manufacturers of pharmaceutical solid dosage forms aim for a reduced production time and a shorter "time-to-market." Therefore, continuous manufacturing gains increasing interest in the pharmaceutical industry. For continuous manufacturing, the quality of produced pharmaceuticals should be assessed in real-time (in-line, on-line, and at-line) and not via the traditional off-line, often destructive and time-consuming analysis methods that supply the desired information only hours after sampling. This research paper evaluates three Process Analytical Technology (PAT) tools for the real-time at-line analysis of granules, which were produced using a continuous wet twin-screw granulator being part of a from powder-to-tablet production line (ConsiGma™-25). A Raman and NIR spectrometer were used together with a photometric imaging technique in order to acquire solid-state information and granule size data. These multivariate data were then used to predict the granules' moisture content, tapped and bulk density, and flowability. The three PAT tools provided complementary information for predicting these quality attributes of the continuously produced granules. The residual moisture content was mostly correlated with the spectroscopic data, whereas the imaging data had the highest predictive capability for the flowability of the granules.