Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties

Thermophysical Phenomena in Metal Additive Manufacturing by Selective Laser Melting: Fundamentals, Modeling, Simulation and Experimentation

Among the many additive manufacturing (AM) processes for metallic materials, selective laser melting (SLM) is arguably the most versatile in terms of its potential to realize complex geometries along with tailored microstructure. However, the complexity of the SLM process, and the need for predictive relation of powder and process parameters to the part properties, demands further development of computational and experimental methods. This review addresses the fundamental physical phenomena of SLM, with a special emphasis on the associated thermal behavior. Simulation and experimental methods are discussed according to three primary categories. First, macroscopic approaches aim to answer questions at the component level and consider for example the determination of residual stresses or dimensional distortion effects prevalent in SLM. Second, mesoscopic approaches focus on the detection of defects such as excessive surface roughness, residual porosity or inclusions that occur at the mesoscopic length scale of individual powder particles. Third, microscopic approaches investigate the metallurgical microstructure evolution resulting from the high temperature gradients and extreme heating and cooling rates induced by the SLM process. Consideration of physical phenomena on all of these three length scales is mandatory to establish the understanding needed to realize high part quality in many applications, and to fully exploit the potential of SLM and related metal AM processes

Structural fluctuations in thin cohesive particle layers in powder-based additive manufacturing

Producing dense and homogeneous powder layers with smooth free surface is challenging in additive manufacturing, as interparticle cohesion can strongly affect the powder packing structure and therefore influence the quality of the end product. We use the Discrete Element Method to simulate the spreading process of spherical powders and examine how cohesion influences the characteristics of the packing structure with a focus on the fluctuation of the local morphology. As cohesion increases, the overall packing density decreases, and the free surface roughness increases, which is calculated from digitized surface height distributions. Local structural fluctuations for both quantities are examined through the local packing anisotropy on the particle scale, obtained from Vorono\"{\i} tessellation. The distributions of these particle-level metrics quantify the increasingly heterogeneous packing structure with clustering and changing surface morphology.Comment: 17 pages, 8 figure

In-line Monitoring of Lubricant Addition Through Passive Vibration Measurements in a V-blender

Process analytical technologies can improve product monitoring and process efficiency in pharmaceutical manufacturing. Passive vibration measurements were evaluated for their potential as a technique to monitor lubricant dispersal in a V-blender. An accelerometer was attached to the lid of a V-blender shell to measure vibrations from particle collisions. Lubricants formed a layer around the surface of particles, altering energy dissipation upon impact. With mixing, vibrational amplitudes approached a stable value indicating a mixing end-point. Mixing profiles were sensitive to changes in particle type, particle size and distribution, and lubricant concentrations for ideal particles and pharmaceutical granules. Axial loading configurations provided better mixing performance compared to radial configurations. An optimal fill level for effective convective mixing was determined through vibration measurements. Overall, this research demonstrated the potential of using passive vibration measurements as a monitoring technique for lubricant dispersal in pharmaceutical manufacturing to improve control and efficiency of the mixing process

Passive Acoustic Emissions in a V-blender

The pharmaceutical manufacturing process consists of a number of batch steps; each step must be monitored and controlled to ensure quality standards are met. The development of process analytical technologies (PAT) can improve product monitoring with the aim of increasing efficiency, product quality and consistency and creating a better understanding of the manufacturing process. This work investigates the feasibility of using passive acoustic emissions (PAE) to monitor particulates in a V-blender. An accelerometer was attached to the lid of a V-blender to measure vibrations from the tumbling solids. A wavelet filter removed the oscillations in the signals from the motion of the shell, focusing on the emissions from the particle interactions. The particle size, fill level and scale affected the acoustic emissions through changes in the particle momentum. Changes in particle cohesiveness and flowability were also reflected in the measured emissions. Powder properties and behavior are critical to efficient and successful manufacturing of pharmaceutical tablets. As the powders must be transferred between the different manufacturing stages, the flowability of powders is critical. Trials were conducted to investigate the effect of moisture content of a powder on its flowability. Through avalanche behavior, it was found that the flowability and the dynamic density of a powder change with moisture content. PAEs were used to detect changes in solids moisture content as solids tumbled within the V-blender. It was found that particle mass, coefficient of restitution (COR) and flowability impacted the amplitude of the acoustic emissions. To further investigate the effects of particle flowability, PAEs were used to monitor lubricant addition. The amplitudes of the acoustic emissions were sensitive to the lubricant addition due to changes in the flowability. A trend in the emission amplitude allowed for the progression of the lubricant mixing to be followed. Overall, the research supports the feasibility of PAEs as a PAT for mixing in a tumbling blender to increase process knowledge and improve product quality

Development and validation of process analytical methods for a continuous pharmaceutical manufacturing process of tablets based on wet granulation

Continuous processing is well established in the chemical, cosmetics and food industry, whilst it is still in its infancy in the pharmaceutical industry. However, there exists the intention to shift pharmaceutical manufacturing from traditional batch production towards continuous production. Continuous pharmaceutical manufacturing has several advantages, but with its implementation one major question rises as well: “How to assure the quality of both the in-process materials and the end product?”. Indeed, the quality of pharmaceutical products obtained via traditional batch-wise processes is generally assessed via sampling and time-consuming off-line analyses in analytical laboratories. These quality evaluation methods would annul the advantages of continuous processing. It is clear that real-time quality assessment and control is indispensable for continuous production by means of Process Analytical Technology (PAT) tools. In this dissertation, the strengths and weaknesses of several complementary PAT tools, implemented in a continuous wet granulation process, which is part of a fully continuous from powder-to-tablet production line, were evaluated. Furthermore, the influence of raw material variability upon processability, intermediates and end products was investigated. Process understanding is gained and the presented approach fits in the Quality by Design (QbD) framework as it is presented by the Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH)

Application of Process Analytical Technology for Investigation of Fluid Bed Granulation and Active Coating during Process Development and Scale-up

This thesis discusses the potential applications of process analytical techniques (PAT) and associated benefits of exploiting such in-line and at-line measurement tools during process development of solid dosage forms using case studies of two different development projects. The most critical unit operations of the manufacturing process affecting downstream processability and Critical Quality Attributes of the final drug product to a great extent were fluid bed granulation for the first project (Project A) and active coating of tablets for the second project (Project B). In Project A, fluid bed granulation processes were investigated by in-line particle size measurements using spatial filtering velocimetry and in-line moisture determination by near infrared spectroscopy (NIRS). Implementation of these in-line tools significantly enhanced process understanding during development. In-line particle sizing provided insight into the dynamics of particle growth during different phases of fluid bed granulation process: wetting and nucleation, agglomeration and finally a steady-state phase, when agglomeration and attrition are at par. Furthermore, different technologies for particle sizing were compared. The effect of varying process parameters on resulting granulate particle size was systematically investigated by means of a Design of Experiments (DoE) study, performed as several fractional factorial designs. The developed statistical model obtained from this study could accurately predict the median granulate size (D50) in dependence on the process parameters inlet air temperature and product temperature in the investigated ranges. Higher inlet air temperature has a positive correlation with particle size resulting in increased D50 values, while lower product temperatures yield larger granules. Besides, a NIRS calibration model applying a fibre optic probe and diffuse reflection measuring mode was developed for in-line moisture monitoring during the granulation process. The calibration is built upon Partial Least Squares regression of NIR spectra and reference values generated by loss on drying on a halogen dryer. It is possible to predict the water content in the calibrated range with a precision comparable to the one of the reference method. Finally, in-line moisture monitoring by NIRS turned out to effectively support the scale-up activities to commercial scale. The added value of application of PAT during process development in this project did not save development time, but increased the required understanding of the (inter-) relationships between process parameters and attributes of the produced granulates. Based on this knowledge, reasonable specifications for routine manufacturing can be selected and process windows or design spaces for single unit operations can be implemented. Project B involves an active coating process of tablet cores in a drum coater, where tablets are layered by a film-coating liquid containing the Active Pharmaceutical Ingredient (API). Critical process parameters affecting content uniformity of the API in the final drug product were assessed by means of a DoE study. It was found that content uniformity could be improved by reducing the spray rate, reducing the solid content of the coating suspension by adding water or by increasing the rotation speed of the drum coater. One of the objectives of this study was to perform a feasibility assessment regarding the development of a NIRS method for end-point determination of the coating process in real time. Currently, the end-point is estimated by indirect measurements. An appropriate at-line measurement procedure and a NIR calibration model were established for determination of the actual API content. The calibration is based on time-consuming HPLC reference values, which is the current standard release test. Two distinct models were developed: one focusing on measurements of individual tablets and one using a rotating sample cup as a measuring device, which allows the simultaneous measurement of a larger surface area of several tablets. Principal Component Analysis proves the specificity of both final models for the API. A complete validation approach including further validation parameters i.e. linearity, precision, accuracy as well as robustness was exemplarily realised for the NIR method considering individual tablets. In conclusion, near infrared spectroscopy is found to be an appropriate tool for end-point determination of the active coating process, but further optimisation of the manufacturing process itself might be necessary for reducing variability in content uniformity of the film-coated tablets. The benefit of applying NIRS as a PAT tool in active coating processes compared to conventional HPLC analysis is mainly related to saving of time because the bulk product can directly be processed further without delay between completion of a unit operation and sampling, analysis and release. In the last section, important regulatory requirements concerning the submission of PAT data and specifics for NIR data are summarised

Estimation and Control of Robotic Radiation-Based Processes

This dissertation presents a closed-loop control and state estimation framework for a class of distributed-parameter processes employing a moving radiant actuator. These radiation-based processes have the potential to significantly reduce the energy consumption and environmental impact of traditional industrial processes. Successful implementation of these approaches in large-scale applications requires precise control systems. This dissertation provides a comprehensive framework for: 1) integration of trajectory generation and feedback control, 2) online distributed state and parameter estimation, and 3) optimal coordination of multiple manipulated variables, so as to achieve elaborate control of these radiation-based processes for improved process quality and energy efficiency. The developed framework addresses important issues for estimation and control of processes employing a moving radiant actuator from both practical and theoretical aspects. For practical systems, an integrated motion and process control approach is first developed to compensate for disturbances by adjusting either the radiant power of the actuator or the speed of the robot end effector based on available process measurements, such as temperature distribution. The control problem is then generalized by using a 1D scanning formulation that describes common characteristics of typical radiant source actuated processes. Based on this 1D scanning formulation, a distributed state and parameter estimation scheme that incorporates a dual extended Kalman filter (DEKF) approach is developed to provide real-time process estimation. In this estimation scheme, an activating policy accompanying the moving actuator is applied in order to reduce the computational cost and compensate for observability changes caused by the actuator\u27s movement. To achieve further improvements in process quality, a static optimization and a rule-based feedback control strategy are used to coordinate multiple manipulated variables in open-loop and closed-loop manners. Finally, a distributed model predictive control (MPC) framework is developed to integrate process optimization and closed-loop coordination of manipulated variables. Simulation studies conducted on a robotic ultraviolet (UV) paint curing process show that the developed estimation and control framework for radiant source actuated processes provide improved process quality and energy efficiency by adaptively compensating for disturbances and optimally coordinating multiple manipulated variables

Process analytical technology tools for process control of roller compaction in solid pharmaceuticals manufacturing

This article presents an overview of using process analytical technology in monitoring the roller compaction process. In the past two decades, near-infrared spectroscopy, near-infrared spectroscopy coupled with chemical imaging, microwave resonance technology, thermal effusivity and various particle imaging techniques have been used for developing at-, off-, on- and in-line models for predicting critical quality attributes of ribbons and subsequent granules and tablets. The common goal of all these methods is improved process understanding and process control, and thus improved production of high-quality products. This article reviews the work of several researchers in this field, comparing and critically evaluating their achievements