Development of a Controlled Continuous Low-Dose Feeding Process.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle <10 µm, high density). A significant improvement in the feeding performance was achieved for all investigated materials. The feed rate deviation from the set-point and its relative standard deviation were minimal compared to operations without the control strategy.

Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow*.

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine. This synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions, as well as three inline separations. Advanced data analysis models were developed (indirect hard modeling, deep learning and partial least squares regression), to quantify the desired products, intermediates and impurities in real time, at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents a significant step forward in data-driven continuous flow synthesis.

Performance Evaluation of a High-Precision Low-Dose Powder Feeder.

Highly potent active pharmaceutical ingredients (APIs) and low-dose excipients, or excipients with very low density, are notoriously hard to feed with currently available commercial technology. The micro-feeder system presented in this work is capable of feeding low-dose rates of powders with different particle sizes and flow properties. Two different grades of lactose, di-calcium phosphate, croscarmellose sodium, silicon dioxide, a spray-dried intermediate, and an active ingredient were studied to vary material properties to test performance of the system. The current micro-feeder system is a volumetric feeder combined with a weighing balance at the outlet that measures feeder output rates. Feeding results are shown as a so-called "displacement-feed factor" curve for each material. Since the powder mass and volume are known in the micro-feeder system, in this work, we characterized an observed density variation during processing via a "displacement-feed factor" profile for each of the fed powders. This curve can be later used for calibrating the system to ensure an accurate, constant feed rate and in addition predicting feeding performance for that material at any feed rate. There is a relation between powder properties and feeding performance. Powders with finer particles and higher compressibility show densification during their feeding process. However, powders with larger particles and lower compressibility show both "densification" and "powder bed expansion," which is the manifestation of dilation and elastic recovery of particles during the micro-feeding process. Through the application of the displacement-feed factor, it is possible to provide precise feeding accuracy of low-dose materials.

The need for new control strategies for particulate matter in parenterals.

An undesirable characteristic in lyophilized parenteral products is the potential presence of particulate matter in the final product, which may affect patient safety. In this study, quality risk management tools described in the International Conference on Harmonization Guideline Q9 were used to estimate the risks for a pharmaceutical manufacturing line, based on three critical quality attributes: (1) visible particulate matter; (2) lyo-cake collapse traces; and (3) lyo-cake melt-back traces. Together with a Process Failure Mode Effect Analysis (PFMEA), an input-output analysis of the individual unit operations identified seven major material classes of extrinsic particulate matter. In addition to the process assessment, an experimental investigation of the location of impurities in lyophilized products was performed. To that end, intentionally contaminated vials were examined to locate the particulate matter and its possible migration. The results emphasize the importance of a full transmission mode release testing since the particles may enter the interior of the lyo-cake. A theoretical explanation of the observed impurity locations is provided.

Effect of Technically Relevant X-Ray Doses on the Structure and Function of Alcohol Dehydrogenase and Hen Egg-White Lysozyme.

PURPOSE: The effect of different irradiation doses on the structure and activity of lyophilized powders of Hen Egg-White Lysozyme (HEWL) and alcohol dehydrogenase (ADH) was investigated using these substances as models for robust and sensitive proteins, respectively. Three doses were selected to cover the ranges of radio-sterilization (25kGy), treatment of blood products (25Gy) and annual background radiation dose (approximately 2mGy). The results offer an initial screening of different irradiation doses and support the development of X-ray imaging methods as non-destructive process analytical technology (PAT) tools for detecting the visible particulate matters in such products. METHODS: HEWL and ADH were exposed to X-rays in the solid state. The effect of irradiation was determined directly after irradiation and after storage. Structural changes and degradation were investigated using SAXS, SDS-PAGE and HPLC-MS. Protein functionality was assessed via activity assays. RESULTS: Lower irradiation doses of 25Gy and 2mGy had no significant impact on the structure and enzyme activity. The dose of 25kGy caused a significant decrease in the enzyme activity and structural changes immediately after irradiation of ADH and after storage of irradiated HEWL at -20°C. CONCLUSION: The results emphasize the importance of careful selection of radiation doses for development of X-ray imaging methods as PAT tools inspection of solid biopharmaceutical products.

Monitoring of a Hot Melt Coating Process via a Novel Multipoint Near-Infrared Spectrometer.

The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly.

Prediction of in-vitro dissolution and tablet hardness from optical porosity measurements.

Advanced manufacturing technologies such as continuous processing require fast information on the quality of intermediates and products. Process analytical technologies (PAT) to monitor many critical quality attributes (CQAs) have been developed and successfully implemented in pharmaceutical industry. However, there are some CQAs, which still have to be measured off-line with significant effort due to the lack of suitable PAT sensors. Two prominent examples are the in-vitro dissolution and the tablet hardness. Both are obtained via destructive measurement, and the dissolution is tedious and time-consuming to determine. In this study, these two CQAs were predicted via correlation with the optical porosity of tablets. The optical porosity was measured via a novel combination of gas in scattering media absorption spectroscopy (GASMAS) and photon time of flight spectroscopy (pTOFS) with a SpectraPore instrument. The approach was tested in a continuous tableting line and showed promising results in predicting the amount of drug released after specific dissolution times as well as the tablet hardness. This indicates that the measurement of optical porosity can support control strategies within the real-time release testing (RTRT) concept.

Liquid API feeding in pharmaceutical HME: Novel options in solid dosage manufacturing.

Hot melt extrusion (HME) is a common unit operation. It is broadly applicable in the pharmaceutical industry and can be implemented in a continuous manufacturing line. However, the conventional way of active pharmaceutical ingredient (API) feeding with a pre-blend consisting of a powdered API and a polymer does not allow the flexibility and agility to adjust the process parameters, which is generally an essential part of continuous manufacturing. In addition, this method of API feeding may result in the segregation of the individual powder components or agglomeration of highly cohesive materials, leading to an inhomogeneous API content in the extrudates, especially at low doses. In this study, the universal applicability of liquid side feeding in pharmaceutical HME was demonstrated using various APIs suspended or dissolved in water and fed as suspension or undersaturated, supersaturated, and highly concentrated solutions into anterior parts of the extruder. The extrudates were characterized in terms of their API content, residual moisture content, and solid-state of the API embedded in the polymer. The results show that a uniform API content without major deviations can be obtained via this method. Furthermore, the residual moisture content of the extrudates was low enough to have no significant influence on further processing of the final dosage form. In summary, this advanced way of feeding allows an accurate, flexible, and agile feeding of APIs, facilitating the production of personalized final dosage forms and a novel option to link the manufacturing of the drug substance and the drug product.

Process analytical technology in Downstream-Processing of Drug Substances- A review.

Process Analytical Technology (PAT) has revolutionized pharmaceutical manufacturing by providing real-time monitoring and control capabilities throughout the production process. This review paper comprehensively examines the application of PAT methodologies specifically in the production of solid active pharmaceutical ingredients (APIs). Beginning with an overview of PAT principles and objectives, the paper explores the integration of advanced analytical techniques such as spectroscopy, imaging modalities and others into solid API substance production processes. Novel developments in in-line monitoring at academic level are also discussed. Emphasis is placed on the role of PAT in ensuring product quality, consistency, and compliance with regulatory requirements. Examples from existing literature illustrate the practical implementation of PAT in solid API substance production, including work-up, crystallization, filtration, and drying processes. The review addresses the quality and reliability of the measurement technologies, aspects of process implementation and handling, the integration of data treatment algorithms and current challenges. Overall, this review provides valuable insights into the transformative impact of PAT on enhancing pharmaceutical manufacturing processes for solid API substances.

Prediction of dissolution performance of uncoated solid oral dosage forms via optical coherence tomography.

Real-time prediction of the dissolution behavior of solid oral dosage forms is an important research topic. Although methods such as Terahertz and Raman can provide measurements that can be linked to the dissolution performance, they typically require a longer time off-line for analysis. In this paper, we present a novel strategy for analyzing uncoated compressed tablets by means of optical coherence tomography (OCT). Using OCT, which is fast and in-line capable, makes it possible to predict the dissolution behavior of tablets based on images. In our study, OCT images were obtained of individual tablets from differently produced batches. Differences between tablets or batches in these images were hardly visible to the human eye. Advanced image analysis metrics were developed to quantify the light scattering behavior captured by the OCT probe and depicted in the OCT images. Detailed investigations assured the repeatability and robustness of the measurements. A correlation between these measurements and the dissolution behavior was established. A tree-based machine learning model was used to predict the amount of dissolved active pharmaceutical ingredient (API) at certain time points for each immediate-release tablet. Our results indicate that OCT, which is a non-destructive and real-time technology, can be used for in-line monitoring of tableting processes.

On the influence of raw material attributes on process behaviour and product quality in a continuous WET granulation tableting line.

Continuous manufacturing of oral solids is a complex process in which critical material attributes (CMAs), formulation and critical process parameters (CPPs) play a fundamental role. However, assessing their effect on the intermediate and final product's critical quality attributes (CQAs) remains challenging. The aim of this study was to tackle this shortcoming by evaluating the influence of raw material properties and formulation composition on the processability and quality of granules and tablets on a continuous manufacturing line. Powder-to-tablet manufacturing was performed using four formulations in various process settings. Pre-blends of different drug loadings (2.5 % w/w and 25% w/w) and two BCS classes (Class I and II) were continuously processed on an integrated process line ConsiGmaTM 25, including twin screw wet granulation, fluid bed drying, milling, sieving, in-line lubrication and tableting. The liquid-to-solid ratio and the granule drying time were varied to process granules under nominal, dry and wet conditions. It was shown that the BCS class and the drug dosage influenced the processability. Intermediate quality attributes, such as the loss on drying and the particle size distribution, directly correlated with the raw material's properties and process parameters. Process settings had a profound impact on the tablet's hardness, disintegration time, wettability and porosity.

PAT implementation for advanced process control in solid dosage manufacturing - A practical guide.

The implementation of continuous pharmaceutical manufacturing requires advanced control strategies rather than traditional end product testing or an operation within a small range of controlled parameters. A high level of automation based on process models and hierarchical control concepts is desired. The relevant tools that have been developed and successfully tested in academic and industrial environments in recent years are now ready for utilization on the commercial scale. To date, the focus in Process Analytical Technology (PAT) has mainly been on achieving process understanding and quality control with the ultimate goal of real-time release testing (RTRT). This work describes the workflow for the development of an in-line monitoring strategy to support PAT-based real-time control actions and its integration into solid dosage manufacturing. All stages are discussed in this paper, from process analysis and definition of the monitoring task to technology assessment and selection, its process integration and the development of data acquisition.

Feasibility of In-line monitoring of critical coating quality attributes via OCT: Thickness, variability, film homogeneity and roughness.

The feasibility of Optical Coherence Tomography (OCT) for in-line monitoring of pharmaceutical film coating processes has recently been demonstrated. OCT enables real-time acquisition of high-resolution cross-sectional images of coating layers and computation of coating thickness. In addition, coating quality attributes can be computed based on in-line data. This study assesses the in-line applicability of OCT to various coating functionalities and formulations. Several types of commercial film-coated tablets containing the most common ingredients were investigated. To that end, the tablets were placed into a miniaturized perforated drum. An in-line OCT system was used to monitor the tablet bed. This set-up resembles the final stage of an industrial pan coating process. All investigated coatings were measured, and the coating thickness, homogeneity and roughness were computed. The rotation rate was varied in a range comparable to large-scale coating operations, and no influence on the outcome was observed. The results indicate that OCT can be used to determine end-point and establish in-process control for a wide range of coating formulations. The real-time computation of coating homogeneity and roughness can support process optimization and formulation development.

X-ray imaging: A potential enabler of automated particulate detection and cake-structure analysis in lyophilized products?

The presence of particulate matter in parenteral products is a major concern since it affects the patients' safety and is one of the main reasons for product recalls. Conventional quality control is based on a visual inspection, which is a labour-intensive task. Limited to clear solutions and the surface of lyophilised products, it cannot be applied to opaque containers. This study assesses the application of X-ray imaging for detecting the particulate matter in a pharmaceutical lyophilized product. The most common types of particulates (i.e., steel, glass, lyo stopper, polymers and organics in different size classes) were intentionally spiked in vials. After optimizing all relevant parameters of the X-ray set-up, all classes of particulates were detected. At the same time, due to contrast enhancement, the inherent structures of lyophilized cake became obvious. This work addresses the potential and limits of X-ray technology in that regard, paving the way for automated image-based particulate matter detection. Moreover, this paper discusses using this approach to predict critical quality attributes (CQAs) of the drug product based on the cake structure attributes.

End-Point Prediction of Granule Moisture in a ConsiGma™-25 Segmented Fluid Bed Dryer.

Continuously operated pharmaceutical manufacturing lines often consist of a wet granulation unit operation, followed by a (semi-) continuous dryer. The operating conditions of the dryer are crucial for obtaining a desired final granule moisture. Commercially available dryers lack of a thorough online measurement of granule moisture during the drying process. However, this information could improve the operation of the equipment considerably, yielding a granule moisture close to the desired value (e.g., by drying time and process parameter adjustments in real-time). The paper at hand proposes a process model, which can be parameterized from a very limited number of experiments and then be used as a so-called soft sensor for predicting granule moisture. It utilizes available process measurements for the estimation of the granule moisture. The development of the model as well as parameter identification and validation experiments are provided. The proposed model paves the way for the application of sophisticated observer concepts. Possible future activities on that topic are outlined in the paper.

A solution for low-dose feeding in continuous pharmaceutical processes.

Continuous feeding of small quantities of powder is increasingly applied in pharmaceutical manufacturing. With that regard, what is crucial is not only the feasibility, but also the accuracy and stability. To enable stable processing, low amounts of various agents, e.g., lubricants, can be used. Even more important is the exact dosage of highly potent active pharmaceutical ingredients (APIs), which require feed rates within the range of grams per hour. Conventional feeders cannot supply powder at such rates, especially when the material properties are challenging. In this work, a novel micro-feeder was integrated into a continuous manufacturing line and its capability to supply API at feed rates down to one gram per hour was tested. The micro-feeder system is based on the principle of active volumetric displacement: a piston pushes the powder out of the cartridge upwards to the end of a plate, where a scraper places it into the process inlet. In this study, a hot melt extrusion process was used, during which the API was dissolved in a polymer matrix. Samples of the strand were analysed with regard to their content by means of HPLC. The results showed that the novel micro-feeder system can feed powder with good accuracy and reproducibility, indicating its high potential for continuous process implementation.

Towards a novel continuous HME-Tableting line: Process development and control concept.

The objective of this study was to develop a novel closed-loop controlled continuous tablet manufacturing line, which first uses hot melt extrusion (HME) to produce pellets based on API and a polymer matrix. Such systems can be used to make complex pharmaceutical formulations, e.g., amorphous solid dispersions of poorly soluble APIs. The pellets are then fed to a direct compaction (DC) line blended with an external phase and tableted continuously. Fully-automated processing requires advanced control strategies, e.g., for reacting to raw material variations and process events. While many tools have been proposed for in-line process monitoring and real-time data acquisition, establishing real-time automated feedback control based on in-process control strategies remains a challenge. Control loops were implemented to assess the quality attributes of intermediates and product and to coordinate the mass flow rate between the unit operations. Feedback control for the blend concentration, strand temperature and pellet thickness was accomplished via proportional integral derivative (PID) controllers. The tablet press hopper level was controlled using a model predictive controller. To control the mass flow rates in all unit operations, several concepts were developed, with the tablet press, the extruder or none assigned to be the master unit of the line, and compared via the simulation.

Ensuring tablet quality via model-based control of a continuous direct compaction process.

Switching from batch to continuous pharmaceutical production offers several advantages, such as an increased productivity, a steady product quality, and decreased costs. This paper presents a control strategy for direct compaction on a continuous tablet production line consisting of two feeders, one blender, and a tablet press (TP). A data-driven, linear modeling approach is applied in order to develop a Smith predictor for active pharmaceutical ingredient concentration control and a model predictive controller responsible for the TP hopper level. Additionally, in case of severe concentration variations out-of-specification material can be discarded before it enters the TP. The effectiveness of the control concept is tested not only in simulations but also by implementing it on a real pilot plant.

Shedding light on coatings: Real-time monitoring of coating quality at industrial scale.

Optical Coherence Tomography (OCT) is increasingly being used for studies of pharmaceutical film coating. OCT allows fast and non-destructive analysis of the coating thickness and quality via high-resolution cross-sectional images. Information about both the coating thickness and the coating quality can be extracted. Most studies and OCT applications performed to date have been limited to off-line measurements and off-line computations of coating features based on data acquired in-line. This study examines OCT's applicability to an industrial-scale pan coating process. Automated layer detection, classification and thickness calculation were executed in real time. To evaluate the system's performance, runs with various tablet size, coating solution concentration and operating parameters were carried out and monitored. Our results indicate that, in addition to correct end-point determination, OCT enables real-time monitoring of the coating processes (thickness, homogeneity and roughness) and can support active process control by supplying information about the coating thickness and quality.

Characterization of the coating and tablet core roughness by means of 3D optical coherence tomography.

This study demonstrates the use of optical coherence tomography (OCT) to simultaneously characterize the roughness of the tablet core and coating of pharmaceutical tablets. OCT is a high resolution non-destructive and contactless imaging methodology to characterize structural properties of solid dosage forms. Besides measuring the coating thickness, it also facilitates the analysis of the tablet core and coating roughness. An automated data evaluation algorithm extracts information about coating thickness, as well as tablet core and coating roughness. Samples removed periodically from a pan coating process were investigated, on the basis of thickness and profile maps of the tablet core and coating computed from about 480,000 depth measurements (i.e., 3D data) per sample. This data enables the calculation of the root mean square deviation, the skewness and the kurtosis of the assessed profiles. Analyzing these roughness parameters revealed that, for the given coating formulation, small valleys in the tablet core are filled with coating, whereas coarse features of the tablet core are still visible on the final film-coated tablet. Moreover, the impact of the tablet core roughness on the coating thickness is analyzed by correlating the tablet core profile and the coating thickness map. The presented measurement method and processing could be in the future transferred to in-line OCT measurements, to investigate core and coating roughness during the production of film-coated tablets.