Huiquan Wu

Quality-By-Design (QbD): An Integrated Approach for Evaluation of Powder Blending Process Kinetics and Determination of Powder Blending End-point

The objective of this study was to develop an integrated process monitoring approach for evaluating powder blending process kinetics and determining blending process end-point. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients (HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near-infrared spectroscopy scan of the powder mixture for obtaining the time course of the blending process. The evaluation of the blending process kinetics and process end-point was studied through three quantitative approaches: (1) Spectra linear superposition method; (2) Characteristic peak method; (3) Moving block standard deviation method. It was found that the powder blending experienced an initial rapid process to reach a quasi- end point within the first few minutes. Afterwards, a demixing occurred. Then, a real blending end-point was reached as characterized by an inflection point. ANOVA shows that the compositions of ibuprofen and MCC are the most statistically significant variables that impact the time required to reach the blending end-point. This highlighted the critical importance of developing quantitative chemometric approaches to extract critical process information and generate essential process knowledge to enable real-time release of the blending process.

Quality-by-Design (QbD): Effects of Testing Parameters and Formulation Variables on the Segregation Tendency of Pharmaceutical Powder Measured by the ASTM D 6940-04 Segregation Tester

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and without magnesium stearate (MgS). The segregation tendency of a blend was determined by measuring the last/first (L/F) ratio, the ratio of aspirin concentrations between the first and last samples discharged from the tester. A 2(2) factorial design was used to determine the effects of measurement parameters [amount of material loaded (W), number of segregation cycles] with number of replicates 6. ANOVA showed that W was a critical parameter for segregation testing. The L/F value deviated further from 1 (greater segregation tendency) with increasing W. A 2(3) full factorial design was used to assess the effects of formulation variables: grade of ASP (unmilled, milled), grade of MCC, and amount of lubricant, MgS. MLR and ANOVA showed that the grade of ASP was the main effect contributing to segregation tendency. Principal Component Regression Analysis established a correlation between L/F and the physical properties of the blend related to ASP and MCC, the ASP/MCC particle size ratio (PSR) and powder cohesion. The physical properties of the blend related to density and flow were not influenced by the grade of ASP and were not related to the segregation tendency of the blend. The direct relationship between L/F and PSR was determined by univariate analysis. Segregation tendency increased as the ASP to MCC particle size increased. This study highlighted critical test parameters for segregation testing and identified critical physical properties of the blends that influence segregation tendency.

Robust Calibration Design in the Pharmaceutical Quantitative Measurements with Near-Infrared (NIR) Spectroscopy: Avoiding the Chemometric Pitfalls

Quantification analysis with near-infrared (NIR) spectroscopy typically requires utilizing chemometric techniques, such as partial least squares (PLS) method, to achieve the desired selectivity. This article points out a major limitation of these statistical-based calibration methods. The limitation is that the techniques suffer from the potential for chance correlation. In this article, the impact of chance correlation on the robustness of PLS model was illustrated via a pharmaceutical application with NIR to the content uniformity determination of tablets. The procedure involves evaluating the PLS models generated with two sets of calibration tablets incorporated with distinct degree of concentration correlation between the active pharmaceutical ingredient (API) and excipients. The selectivity and robustness of the two models were examined by using a series of data sets associated with placebo tablets and tablets incorporated with variations from excipient content, hardness and particle size. The result clearly revealed that the strong correlation observed in the PLS model created by the correlated design was not solely based on the API information, and there was an intrinsic difference in the variances described by the two calibration models. Diagnostic tools that enable the characterization of the chemical selectivity of the calibration model were also proposed for pharmaceutical quantitative analysis.

Quality‐by‐Design (QbD): An Integrated Process Analytical Technology (PAT) Approach for Real‐Time Monitoring and Mapping the State of a Pharmaceutical Coprecipitation Process

In this work, an integrated PAT approach was developed for monitoring a pharmaceutical (naproxen) and a polymer (eudragit) coprecipitation process: real-time in-line near-infrared (NIR) absorbance monitoring, real-time on-line turbidity monitoring, and in situ crystal size monitoring. The data and information obtained through these three monitoring techniques confirmed the observation of the onsets of three distinct stages: incubation, nucleation, and crystal growth. The process trajectory constructed based on results of applying principal component analysis (PCA) to either process NIR spectra data or process turbidity profile, clearly demonstrated that various distinguishable process events, including incubation, nucleation, and crystal growth, could be accurately tracked and differentiated. These findings were further supported by process knowledge and information, such as process design, process sequence, thermodynamic and mass-transfer analysis. Therefore, this work provides a case study that illustrated a rational approach to develop a science-based and knowledge-based process monitoring strategy, which is essential for establishing both a suitable process control strategy and an operational process space for a pharmaceutical unit operation.

Population Balance Model Development, Validation, and Prediction of CQAs of a High-Shear Wet Granulation Process: Towards QbD in Drug Product Pharmaceutical Manufacturing

This paper focuses on the predictive model development for a pharmaceutically relevant model granulation process. A population balance modeling (PBM) framework has been employed for modeling purposes which is then utilized to obtain accurate predictions of the process. The model is aligned to adequately describe the high-shear mode of granulation operation in a batch process. The model is calibrated using the particle swarm algorithm (PSA) in the form of a multiobjective optimization problem. The multiobjective optimization problem was implemented based on the ε-constraint method which involves the handling of multiple cost functions in the form of constraints with the minimization of one primary objective function from the entire set of cost functions. The resultant solutions obtained from the model are Pareto optimal. The effects of the impeller speed, liquid-to-solid ratio, and wet massing time on the particle size distributions were characterized, and predicted size distributions were in agreement with experimental results. The predictive model framework lends itself to the quality by design (QbD) initiative undertaken by the US Food and Drug Administration (US FDA).

Evaluation of Transmission and Reflection Modalities for Measuring Content Uniformity of Pharmaceutical Tablets with Near-Infrared Spectroscopy

This paper examines how one may assess spectral changes with instrument configuration (or composition), in combination with the spectral changes in the measurement that are caused by experimental effects, and subsequently select an appropriate measurement modality for tablet content uniformity determination with near-infrared (NIR) spectroscopy. Two NIR spectrometers furnished with three configurations in the sample measurement interface were evaluated. One spectrometer, Bruker MPA (multiple purpose analyzer), was equipped with two measurement modalities, diffuse transmission (DT) and diffuse reflection based on integrating sphere optics (DR/IS). The other spectrometer, Bruker StepOne, was equipped only with diffuse reflection mode based on a fiber-optic probe (DR/FO). The data were collected with each of the configurations for the tablets associated with two dosage strengths differing significantly in diameter and thickness. Spectral diagnosis was performed in terms of sensitivity and selectivity. The signal-to-noise ratio computed for the data collected with the DT and DR/IS spectrometers was approximately an order of magnitude greater than that computed for the DR/FO spectrometer. The net-analyte-signal-based selectivity analysis of NIR spectra associated with the sample tablet and the placebo tablet indicated that both transmission and reflection mode provided similar selectivity when the optimal spectral range was chosen. A partial least squares (PLS) calibration model was developed for each data set. The overall standard error of calibration for each DT and DR/IS measurement was approximately 0.3% in weight for each strength, significantly better than the value of 1.0% in weight produced by the DR/FO measurement. This result was consistent with the sensitivity analysis based on spectral noise characterization. The poor analytical performance of the DR/FO spectrometer was attributed to the small illumination spot size of the reflection probe and thus the sensitivity of the measurements to the tablet engraving. The PLS analysis and spectral diagnostics both showed that transmission and reflection modes based on the Bruker MPA provided similar measurement accuracy for each strength. However, the robustness study clearly revealed that the transmission mode would be more robust than the reflection mode when there is considerable variability in the chemical composition and physical properties of tablets.