Quality Attributes Of Final Product Research Articles

Mass Spectrometry Advances and Perspectives for the Characterization of Emerging Adoptive Cell Therapies.

Adoptive cell therapy is an emerging anti-cancer modality, whereby the patient’s own immune cells are engineered to express T-cell receptor (TCR) or chimeric antigen receptor (CAR). CAR-T cell therapies have advanced the furthest, with recent approvals of two treatments by the Food and Drug Administration of Kymriah (trisagenlecleucel) and Yescarta (axicabtagene ciloleucel). Recent developments in proteomic analysis by mass spectrometry (MS) make this technology uniquely suited to enable the comprehensive identification and quantification of the relevant biochemical architecture of CAR-T cell therapies and fulfill current unmet needs for CAR-T product knowledge. These advances include improved sample preparation methods, enhanced separation technologies, and extension of MS-based proteomic to single cells. Innovative technologies such as proteomic analysis of raw material quality attributes (MQA) and final product quality attributes (PQA) may provide insights that could ultimately fuel development strategies and lead to broad implementation.

Variation and Risk Analysis in Tablet Press Control for Continuous Manufacturing of Solid Dosage via Direct Compaction

A continuous rotary tablet press is a multi-stage process with many punch stations running in parallel, in which each punch undergoes the following steps: die filling and metering, pre-compaction, main-compaction, tablet ejection, and tablet take-off from lower punch. Process uncertainties or disturbances within a punch station or among stations in the tablet press are a major source of variation in final product quality attributes, e.g., hardness, weight, etc., which in turn imposes challenges for the real-time release in pharmaceutical continuous manufacturing of solid dosage. In this study, the direct compression line at Purdue University was investigated and a Natoli BLP-16 tablet press was used to characterize powder compressibility, system dynamics and variation, as well as the interaction effects on process control development. The compressibility of tablets made from a blend of Acetaminophen (API), Avicel Microcrystalline Cellulose PH-200 (excipient), and SiO2 (lubricant) was found to be largely independent of tableting speed. By contrast, filling depth or dosing level, turret speed, feed-frame speed, and compression force were interacting and significantly affected the die-filling process and the final product quality attributes. Thus, the design of the process control structure plays an important role in reducing process and product quality variations. A hierarchical three-level control design was proposed and evaluated, consisting of Level 0 Natoli built-in control, Level 1 decoupled Proportional Integral Derivative (PID) cascaded control loops for tablet weight and production rate control, and Level 2 advanced model predictive control. Process variations, e.g., in powder bulk density changes, during continuous steady-state operation were also investigated. Finally, a risk analysis of the effects of the process dynamics on variation on the product quality control was briefly discussed and summarized.

A drop penetration method to measure powder blend wettability

Water wettability of pharmaceutical blends affects important quality attributes of final products. We investigate the wetting properties of a pharmaceutical blend lubricated with Magnesium Stearate (MgSt) as a function of the mechanical shear strain applied to the blend. We measure the penetration dynamics of sessile drops deposited on slightly compressed powder beds. We consider a blend composed of 9% Acetaminophen 90% Lactose and 1% MgSt by weight. Comparing the penetration time of water and a reference liquid Polydimethylsiloxane (silicon oil) we obtain an effective cosine of the contact angle with water, based on a recently developed drop penetration method. We repeat the experiments for blends exposed to increasing levels of shear strain and demonstrate a significant decrease in water wettability (decrease in the cosine of the contact angle). The results are consistent with the development of a hydrophobic film coating the powder particles as a result of the increased shear strain. Finally, we show that, as expected dissolution times increase with the level of shear strain. Therefore, the proposed drop penetration method could be used to directly assess the state of lubrication of a pharmaceutical blend and act as a quality control on powder blend attributes before the blend is tableted.

Non-thermal hybrid drying of fruits and vegetables: A review of current technologies

Abstract Fruits and vegetables are very perishable commodities that have enormous industrial and commercial importance. To preserve its quality attributes, increase shelf life, and reduce transport weight, fruit and vegetable can be processed by drying. Over the years, conventional drying techniques have been widely applied, both industrially and commercially for the processing and preservation of fruits and vegetables. However, most of the conventional techniques are time and energy consuming, and affect important quality attributes of final products. Recently, there has been increased interest in the use of non-thermal drying methods in combination with other conventional drying techniques for preserving fruits and vegetables. These methods have been reported to enhance the quality attributes of dried products, reduce drying time and energy demand, and increase the overall drying efficiency. In this regard, the development of a cost effective non-thermal hybrid drying systems, such as combined ultrasound (US) and hot-air drying, ultraviolet (UV) and hot-air drying, and pulse electric field (PEF) and hot-air drying have recently been researched on. These drying techniques have become potential substitute for conventional industrial and commercial dryers, owing to their advantage of producing quality dried fruit and vegetable products, with reduced drying time and energy consumption. This study therefore attempts to highlight recent developments of the commonly used non-thermal combined convective hot-air drying (CHAD) techniques for fruits and vegetables, with emphasis on drying time, drying rate, quality attributes of products, and modelling approach. This study further highlights the primary constraints for industrial application of this technology as the inadequate medium of transmission for power ultrasound, cost of design and installation, and the limited study on (UV) and PEF assisted CHAD. The necessity for conducting more detailed studies on non-thermal assisted convective hot-air drying of fruits and vegetables was emphasized.

Evaluation of the Moisture Prediction Capability of Near-Infrared and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy Using Superdisintegrants as Model Compounds

The superdisintegrants (SDs) moisture content measurement by near-infrared (NIR) spectroscopy and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy has been evaluated against thermogravimetric analysis as a reference method. SDs with varying moisture content were used to build calibration and independent model verification data sets. Calibration models were developed based on the water-specific NIR and ATR-FTIR spectral regions using partial least-square regression methods. Because of the NIR water low molar absorptivity, NIR spectroscopy handled higher moisture content (∼81%, w/w) than ATR-FTIR (∼25%, w/w). A two-way ANOVA test was performed to compare R(2) values obtained from measured and predicted moisture content (5%-25%, w/w) of SDs. No statistically significant difference was observed between the predictability of NIR and ATR-FTIR methods (p = 0.3504). However, the interactions between the two independent variables, SDs, and analytical methods were statistically significant (p = 0.0002), indicating that the predictability of the analytical method is material dependent. Thus, it would be important to recognize this highly dependent material and analytical method interaction when using NIR moisture analysis in process analytical technology to analyze and control critical quality and performance attributes of raw materials during processing with the goal of ensuring final product quality attributes.

Investigation of the effects of process variables on derived properties of spray dried solid-dispersions using polymer based response surface model and ensemble artificial neural network models

The objective of this study was to use different statistical tools to understand and optimize the spray drying process to prepare solid dispersions. In this study we investigated the relationship between input variables (inlet temperature, feed concentration, flow rate, solvent and atomization parameters) and quality attributes (yield, outlet temperature and mean particle size) of spray dried solid dispersions (SSDs) using response surface model and ensemble artificial neural network. The Box Behnken design was developed to investigate the effect of various input variables on quality attributes of final products. Moreover, Pearson correlation analysis, self organizing map, contour plots and response surface plot were used to illustrate the relationship between input variables and quality attributes. The influence of different physicochemical properties of solvent on the quality attributes of spray dried products was also investigated. Final validation of prepared models was done using binary SSDs of six model drugs with PVP. Results demonstrated the effectiveness of proposed PVP based model which can help scientists to gain detailed understanding of spray drying process of solid dispersion using minimal resources and time during early formulation development stage. It will also help them to ensure consistent quality of SSDs using broad range of input variables.

EFFECT OF TEMPERATURE ON REHYDRATION KINETICS, FUNCTIONAL PROPERTIES, TEXTURE AND ANTIOXIDANT ACTIVITY OF RED PEPPER VAR. HUNGARIAN (CAPSICUM ANNUUM L.)

ABSTRACT Dehydrated peppers at 60C were rehydrated at three temperatures (20, 40 and 60C) to analyze the effect of processing temperature on rehydration kinetics and quality attributes of final products. Several empirical and diffusive models were applied to simulate rehydration kinetics. Based on statistical results (sum of square error, root mean square error and chi-square), Weibull and exponential models obtained the best fit quality for the experimental data. Water holding capacity and rehydration ratio presented a maximum and minimum value at 40C, respectively, indicating structural modifications of pepper due to thermal processing. Based on the glass transition temperature of the dried samples, it could be inferred that peppers are susceptible to structural disruption during rehydration at the three working temperatures. Increasing rehydration temperatures lead to a reduction in the pepper firmness. The radical scavenging activity showed higher antioxidant activity at high temperatures (e.g., 60C) rather than at low temperatures (e.g., 20 and 40C). PRACTICAL APPLICATIONS The main utility of this study is the appliance of diffusional, statistical and empirical models in food rehydration, which can be considered a basis for a very accurate estimation of rehydration time and the optimization of the rehydration process. The physicochemical analyses on food products can confirm that thermal processes modify the cell structure of food, reducing the rehydration ability due to cellular and structural disruption that takes place during dehydration. Also, families of most peppers are rich in antioxidants due to the presence of bioactive compounds, which are associated to reduction of biological complications such as aging, cardiovascular disease and carcinogenesis. In addition, dried red pepper var. Hungarian and other dried pepper exports from Chile have become especially important, because these products are consumed both dry and rehydrated. Major markets for these products include the U.S.A., the European community and Japan.

Modeling and Optimization of a Tablet Manufacturing Line

This paper investigates an approach to modeling and optimizing an industrial tablet manufacturing line for different API and excipient formulations. Multi-block partial lease square (PLS) models are built from historical data on a given class of drug products. The data blocks consisted of data on the mass fractions of API and 11 excipients used in the different formulations, the roller compaction process variables, the tablet press settings and the measured final product quality attributes (tablet weight, hardness, and disintegration time). More than 400 runs are used in the modeling. The multi-block PLS models are first used to show which process blocks and which variables in each of the process blocks are most influential on the product quality variables. An optimization is then performed in the latent variable space of the PLS model to find the optimal combination of settings to use for the critical to quality roller compaction and tablet press variables in order to achieve the desired final tablet properties for a specified drug formulation. This optimization can be used to set up the tableting line prior to running a new formulation or can be used in an on-line mode for making small corrections to the operation of the tablet presses in response to small variations in formulations, raw material properties, and roller compaction operation.

Optimization of Batch Operating Policies. Part II. Incorporating Process Constraints and Industrial Applications

In the first part of this series [Ind. Eng. Chem. Res. 2006, 45, 7856−7866], data-driven approaches, based on partial least squares (PLS) models built from historical batch data, were used to find optimal batch operating trajectories that would yield a desired vector of final product quality attributes. The method allowed for the inclusion of univariate and multivariate constraints on the set of desired final product quality attributes and presented approaches for handling multiple solutions. In this paper, the technology is further extended to include constraints in the process operating trajectories themselves. The methodology is successfully applied to an industrial batch polymerization process where the batch trajectories are designed to achieve specific properties of the final polymer while consuming the minimal amount of time for the batch run.