Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations.

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition. Initial API-substrate screening revealed best printing results for gelatin films with TiO2 filling. For calibration of the NIR-HSI system, escalating drug doses were printed on the substrate. After spectral pre-treatments, including standard normal variate (SNV) and Savitzky-Golay filtering for noise reduction and enhancement of spectral features, principal component analysis (PCA) and partial least squares (PLS) regression were applied to create predictive models for the quantification of independent printed metformin hydrochloride samples. It could be shown that the concentration distribution maps provided by the developed HSI models were capable of clustering and predicting the drug dose in the formulations. HSI model prediction showed significant better correlation to the reference (HPLC) compared to on-board monitoring of dispensed volume of the printer. Overall, the results emphasize the capability of NIR-HSI as a fast and non-destructive method for the quantification and quality control of the deposited API in drug-printing applications.

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.

Filling of lactose-based formulations in a tamping-pin capsule filler.

We studied three lactose-based formulations in terms of bulk powder properties and capsule-filling behavior in a tamping-pin capsule filling system, to which several mechanical adaptions were made for process optimization in light of future continuous production. The model formulations were thoroughly characterized and filled into size 1 capsules according a well-defined design of experiments (DoE). Overall, the three entirely different formulations were successfully filled within the selected design space. The fill weight and fill weight variability can be adjusted by fine-tuning the process settings, like the pin immersion depth and the maximum compaction pressure (pneumatic or spring-controlled), and by using the appropriate powder bed height and mechanical adaptions. This study demonstrated that selection of process parameters and mechanical adaptions could enhance the filling performance, especially in continuous production, since they reduce the powder volume in the process. Moreover, we showed that a tamping-pin system is capable of successfully filling a broad range of powders with various material characteristics and can potentially be used in a continuous production mode.

Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch.

This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-of-the-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation. The predicted optimal process setup can be validated quickly in the pilot plant. Lastly, a transfer of the process to any GMP-certified manufacturing site can be performed in silico for any extruder based on our validated computational framework. In summary, the proposed workflow massively reduces the risk in product and process development and shortens the drug-to-market time for enabling formulations.

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.

Validating a Numerical Simulation of the ConsiGma(R) Coater.

Continuous manufacturing is increasingly used in the pharmaceutical industry, as it promises to deliver better product quality while simultaneously increasing production flexibility. GEA developed a semi-continuous tablet coater which can be integrated into a continuous tableting line, accelerating the switch from traditional batch production to the continuous mode of operation. The latter offers certain advantages over batch production, e.g., operational flexibility, increased process/product quality, and decreased cost. However, process understanding is the key element for process control. In this regard, computational tools can improve the fundamental understanding and process performance, especially those related to new processes, such as continuous tablet coating where process mechanics remain unclear. The discrete element method (DEM) and computational fluid dynamics (CFD) are two methods that allow transition from empirical process design to a mechanistic understanding of the individual process units. The developed coupling model allows to track the heat, mass, and momentum exchange between the tablet and fluid phase. The goal of this work was to develop and validate a high-fidelity CFD-DEM simulation model of the tablet coating process in the GEA ConsiGma® coater. After the model development, simulation results for the tablet movement, coating quality, and heat and mass transfer during the coating process were validated and compared to the experimental outcomes. The experimental and simulation results agreed well on all accounts measured, indicating that the model can be used in further studies to investigate the operating space of the continuous tablet coating process.

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.

The effect of saliva on the fate of nanoparticles.

OBJECTIVES: The design of nanocarriers for local drug administration to the lining mucosa requires a sound knowledge of how nanoparticles (NPs) interact with saliva. This contact determines whether NPs agglomerate and become immobile due to size- and interaction-filtering effects or adsorb on the cell surface and are internalized by epithelial cells. The aim of this study was to examine the behavior of NPs in saliva considering physicochemical NP properties. MATERIALS AND METHODS: The salivary pore-size distribution was determined, and the viscosity of the fluid inside of the pores was studied with optical tweezers. Distinct functionalized NPs (20 and 200 nm) were dispersed in saliva and salivary buffers and characterized, and surface-bound MUC5B and MUC7 were analyzed by 1D electrophoresis and immunoblotting. NP mobility was recorded, and cellular uptake studies were performed with TR146 cells. RESULTS: The mode diameter of the salivary mesh pores is 0.7 µm with a peak width of 1.9 µm, and pores are filled with a low-viscosity fluid. The physicochemical properties of the NPs affected the colloidal stability and mobility: compared with non-functionalized particles, which did not agglomerate and showed a cellular uptake rate of 2.8%, functionalized particles were immobilized, which was correlated with agglomeration and increased binding to mucins. CONCLUSION: The present study showed that the salivary microstructure facilitates NP adsorption. However, NP size and surface functionalization determine the colloidal stability and cellular interactions. CLINICAL RELEVANCE: The sound knowledge of NP interactions with saliva enables the improvement of current treatment strategies for inflammatory oral diseases.

Drug-Excipient Interactions in the Solid State: The Role of Different Stress Factors.

Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.

Establishment of a Molding Procedure to Facilitate Formulation Development for Co-extrudates.

Co-extrusion offers a number of advantages over conventional manufacturing techniques. However, the setup of a co-extrusion line is cost- and time-intense and formulation development is challenging. This work introduces a novel procedure to test the applicability of a co-extruded reservoir-type system at an early product development stage. We propose vacuum compression molding (VCM), a fast procedure that requires only small material amounts, for the manufacturing of cylindrical reservoir-type system. To this end, the commercially available co-extruded product NuvaRing® and variations thereof were used as test systems. All VCM systems showed a homogeneous skin thickness that adhered well to the core, thereby providing a precise core/skin interface. As drug release is a key criterion for pharmaceutical products, a modified in vitro dissolution method was set up to test the VCM systems. The drug release from the VCM systems was in the same order of magnitude as the corresponding co-extruded strands and followed the same release kinetics. Moreover, the VCM systems were capable of indicating the relative effect of formulation-related modifications on drug release. Overall, this shows that this system is a powerful tool that facilitates formulation tailoring and co-extrusion process setup at the earliest stage.

Condensation reaction between carbohydrazide and salicylaldehyde: in-line vibrational spectroscopy monitoring and characterization of the reaction products in solution and solid state.

The condensation reaction between carbohydrazide and salicylaldehyde was monitored in-line by using vibrational NIR and Raman spectroscopies and statistical methods. Prior to in-line data analysis the reaction products were fully characterized in solution and solid state in order to check the potential of the in-line approach as a tool for in-process Schiff bases reaction control. It was demonstrated that a combination of vibrational spectroscopy and principal component analysis made it possible to detect and identify the reaction products, e.g. mono(salicylidene)carbohydrazide (1) and bis(salicylidene)carbohydrazide (2) in different solvents, and to determine the reaction end points in real time. Owing to complexity of the reaction mixtures and band overlapping, it was not possible to determine the relative ratio of the reaction products in-line. The off-line analysis showed that 1 was predominant in methanol while the highest portion of 2 was obtained in ethanol.

Extending the Use of Optical Coherence Tomography to Scattering Coatings Containing Pigments.

Coating thickness is a critical quality attribute of many coated tablets. Functional coatings ensure correct drug release kinetics or protection from light, while non-functional coatings are generally applied for cosmetic reasons. Traditionally, coating thickness is assessed indirectly via offline methods, such as weight gain or diameter growth. In the past decade, several methods, including optical coherence tomography (OCT) and Raman spectroscopy, have emerged to perform in-line measurements of various subclasses of coating formulations. However, there are some obstacles. For example, when using OCT, a major challenge is scattering pigments, such as titanium dioxide and iron oxide, which make the interface between the coating and the tablet core difficult to detect. This work explores novel OCT image evaluation techniques using unsupervised machine learning to compute image metrics. Certain image metrics of highly scattering coatings are correlated with the tablet thickness, and hence indirectly with the coating thickness. The method was demonstrated using a titanium dioxide rich coating formulation. The results are expected to be applicable to other scattering coatings and will significantly broaden the applicability of OCT to at-line and in-line coating thickness measurements of a much larger class of coating formulations.

In-situ monitoring of in vitro drug release processes in tablets using optical coherence tomography.

Film-coated modified-release tablets are an important dosage form amenable to targeted, controlled, or delayed drug release in the specific region of the gastrointestinal (GI) tract. Depending on the film composition and interaction with the GI fluid, such coated products can modulate the local bioavailability, systemic absorption, protection as an enteric barrier, etc. Although the interaction of a dosage form with the surrounding dissolution medium is vital for the resulting release behavior, the underlying physicochemical phenomena at the film and core levels occurring during the drug release process have not yet been well described. In this work, we attempted to tackle this limitation by introducing a novel in vitro test based on optical coherence tomography (OCT) that allows an in-situ investigation of the sub-surface processes occurring during the drug release. Using a commercially available tablet based on osmotic-controlled release oral delivery systems (OROS), we demonstrated the performance of the presented prototype in terms of monitoring the membrane thickness and thickness variability, the surface roughness, the core swelling behavior, and the porosity of the core matrix throughout the in vitro drug release process from OROS. The superior spatial (micron scale) and temporal (less than 10 ms between the subsequent tomograms) resolution achieved in the proposed setup provides an improved understanding of the dynamics inside the microstructure at any given time during the dissolution procedure with the previously unattainable resolution, offering new opportunities for the design and testing of patient-centric dosage forms.

Monitoring blending of pharmaceutical powders with multipoint NIR spectroscopy.

Blending of powders is a crucial step in the production of pharmaceutical solid dosage forms. The active pharmaceutical ingredient (API) is often a powder that is blended with other powders (excipients) in order to produce tablets. The blending efficiency is influenced by several external factors, such as the desired degree of homogeneity and the required blending time, which mainly depend on the properties of the blended materials and on the geometry of the blender. This experimental study investigates the mixing behavior of acetyl salicylic acid as an API and α-lactose monohydrate as an excipient for different filling orders and filling levels in a blender. A multiple near-infrared probe setup on a laboratory-scale blender is used to observe the powder composition quasi-simultaneously and in-line in up to six different positions of the blender. Partial least squares regression modeling was used for a quantitative analysis of the powder compositions in the different measurement positions. The end point for the investigated mixtures and measurement positions was determined via moving block standard deviation. Observing blending in different positions helped to detect good and poor mixing positions inside the blender that are affected by convective and diffusive mixing.

Supervisory control system for monitoring a pharmaceutical hot melt extrusion process.

Continuous pharmaceutical manufacturing processes are of increased industrial interest and require uni- and multivariate Process Analytical Technology (PAT) data from different unit operations to be aligned and explored within the Quality by Design (QbD) context. Real-time pharmaceutical process verification is accomplished by monitoring univariate (temperature, pressure, etc.) and multivariate (spectra, images, etc.) process parameters and quality attributes, to provide an accurate state estimation of the process, required for advanced control strategies. This paper describes the development and use of such tools for a continuous hot melt extrusion (HME) process, monitored with generic sensors and a near-infrared (NIR) spectrometer in real-time, using SIPAT (Siemens platform to collect, display, and extract process information) and additional components developed as needed. The IT architecture of such a monitoring procedure based on uni- and multivariate sensor systems and their integration in SIPAT is shown. SIPAT aligned spectra from the extrudate (in the die section) with univariate measurements (screw speed, barrel temperatures, material pressure, etc.). A multivariate supervisory quality control strategy was developed for the process to monitor the hot melt extrusion process on the basis of principal component analysis (PCA) of the NIR spectra. Monitoring the first principal component and the time-aligned reference feed rate enables the determination of the residence time in real-time.

A DEM model to evaluate refill strategies of a twin-screw feeder.

Residence time distribution (RTD) modeling has proven to be a valuable tool for material tracking in continuous pharmaceutical processes. Refilling is thoroughly studied in the literature, but the main focus lies on the feed rate disturbances. The impact of the feeders themselves on intermixing of different material batches is often overlooked. Since the experimental methods to measure the RTD feeder discharging processes feeder are complex and material intensive, there is only limited experimental RTD data available in the literature. A DEM (discrete element method) simulation of a discharge of a twin-screw feeder shows that a large fraction of material that is moved and intermixed by the agitator. In addition to the intermixing, there is a tendency to discharge material located above the agitator early. In order to predict the behavior during multiple refill events, three models in order of increasing complexity are presented: (1) A simple exponential RTD assuming perfect intermixing of material batches; (2) a RTD model based on DEM results; (3) particle-level material tracking by extrapolation of the DEM results. All three of these models are able to predict the survival function of old material for late refills at low fill levels, however, earlier refills at high fill levels require more complex models to accurately represent the dynamics inside the hopper of the feeder.

Single-tablet-scale direct-compression: An on-demand manufacturing route for personalized tablets.

Today's pharmaceutical industry is facing various challenges. Two of them are issues with supply chain security and the increasing demand for personalized medicine. Both can be addressed by increasing flexibility and a more decentralized approach to pharmaceutical manufacturing. In this study, we present a setup that provides flexibility in terms of supplied raw materials and the product, i.e., a direct-compression setup for personalized tablets operating at a single-tablet-scale. The performance of the implemented single-tablet-scale technology for dosing and mixing was investigated. In addition, an analysis of the critical quality attributes (CQAs) of immediate release ibuprofen and loratadine tablets was performed. The developed dosing device achieved acceptance rates of > 90 % for doses ≥ 20 mg for various pharmaceutical powders. Regarding the vibratory mixing process, a dependency of the performance on the applied frequencies and acceleration was observed, with 100 Hz and âˆ¼ 90 G performing best, yet still exhibiting varying mixing efficacies depending on the granular system. The tablets produced met U.S. Pharmacopeia requirements regarding mechanical stability and dissolution characteristics. Given these results, we consider the developed setup a proof of concept of a tool to provide personalized tablets to patients while minimizing the dependency on complex supply chains.

A multi-step machine learning approach for accelerating QbD-based process development of protein spray drying.

This study proposes a new material-efficient multi-step machine learning (ML) approach for the development of a design space (DS) for spray drying proteins. Typically, a DS is developed by performing a design of experiments (DoE) with the spray dryer and the protein of interest, followed by deriving the DoE models via multi-variate regression. This approach was followed as a benchmark to the ML approach. The more complex the process and required accuracy of the final model is, the more experiments are necessary. However, most biologics are expensive and thus experiments should be kept to a minimum. Therefore, the suitability of using a surrogate material and ML for the development of a DS was investigated. To this end, a DoE was performed with the surrogate and the data used for training the ML approach. The ML and DoE model predictions were compared to measurements of three protein-based validation runs. The suitability of using lactose as surrogate was investigated and advantages of the proposed approach were demonstrated. Limitations were identified at protein concentrations >35 mg/ml and particle sizes of x50>6 µm. Within the investigated DS protein secondary structure was preserved, and most process settings, resulted in yields >75% and residual moisture <10 wt%.

Carrier particle emission and dispersion in transient CFD-DEM simulations of a capsule-based DPI.

The dispersion of carrier-based formulations in capsule-based dry powder inhalers depends on several factors, including the patient's inhalation profile and the motion of capsule within the device. In the present study, coupled computational fluid dynamics and discrete element method simulations of a polydisperse cohesive lactose carrier in an Aerolizer® inhaler were conducted at a constant flow rate of 100 L/min and considering an inhalation profile of asthmatic children between 5 and 17 years approximated from literature data. In relevant high-speed photography experiments, it was observed that the powder was distributed to both capsule ends before being ejected from the capsule. Several methods of ensuring similar behavior in the simulations were presented. Both the constant flow rate simulation and the profile simulations showed a high powder retention in the capsule (7.37-19.00%). Although the inhaler retention was negligible in the constant flow rate simulation due to consistently high air velocities in the device, it reached values of around 7% in most of the profile simulations. In all simulations, some of the carrier powder was ejected from the capsule as particle clusters. These clusters were larger in the profile simulation than in the constant flow rate simulation. Of the powder discharged from the capsule, a high percentage was bound in clusters in the profile simulation in the beginning and at the end of the inhalation profile while no more than 10% of the powder ejected from the capsule in the 100 L/min constant flow rate simulation were in clusters at any time. The powder emission from the capsule was studied, indicating a strong dependency of the powder mass flow from the capsule on the angular capsule position. When the capsule holes face the inhaler's air inlets, the air flow into the capsule restricts the powder discharge. The presented results provide a detailed view of some aspects of the powder flow and dispersion of a cohesive carrier in a capsule-based inhaler device. Furthermore, the importance of considering inhalation profiles in addition to conventional constant flow rate simulations was confirmed.