Challenges and Opportunities of Implementing Data Fusion in Process Analytical Technology-A Review.

The release of the FDA's guidance on Process Analytical Technology has motivated and supported the pharmaceutical industry to deliver consistent quality medicine by acquiring a deeper understanding of the product performance and process interplay. The technical opportunities to reach this high-level control have considerably evolved since 2004 due to the development of advanced analytical sensors and chemometric tools. However, their transfer to the highly regulated pharmaceutical sector has been limited. To this respect, data fusion strategies have been extensively applied in different sectors, such as food or chemical, to provide a more robust performance of the analytical platforms. This survey evaluates the challenges and opportunities of implementing data fusion within the PAT concept by identifying transfer opportunities from other sectors. Special attention is given to the data types available from pharmaceutical manufacturing and their compatibility with data fusion strategies. Furthermore, the integration into Pharma 4.0 is discussed.

Testing the Limits of a Portable NIR Spectrometer: Content Uniformity of Complex Powder Mixtures Followed by Calibration Transfer for In-Line Blend Monitoring.

(1) Background: Portable NIR spectrometers gain more and more ground in the field of Process Analytical Technology due to the easy on-site flexibility and interfacing versatility. These advantages that originate from the instrument miniaturization, also come with a downside with respect to performance compared to benchtop devices. The objective of this work was to evaluate the performance of MicroNIR in a pharmaceutical powder blend application, having three active ingredients and 5 excipients. (2) Methods: Spectral data was recorded in reflectance mode using static and dynamic acquisition, on calibration set samples developed using an experimental design. (3) Results: The developed method accurately predicted the content uniformity of these complex mixtures, moreover it was validated in the entire calibration range using ±10% acceptance limits. With respect to at-line prediction, the method presented lower performance compared to a previously studied benchtop spectrometer. Regarding the in-line monitoring of the blending process, it was shown that the spectral variability-induced by dynamic acquisition could be efficiently managed using spectral pre-processing. (4) Conclusions: The in-line process monitoring resulted in accurate concentration profiles, highlighting differences in the mixing behaviour of the investigated ingredients. For the low dose component homogeneity was not reached due to an inefficient dispersive mixing.

Liposomal simvastatin sensitizes C26 murine colon carcinoma to the antitumor effects of liposomal 5-fluorouracil in vivo.

5-Fluorouracil-based therapy remains the main approach in colorectal cancer, even though there are still some drawbacks, such as chemoresistance. In this study we combined 5-fluorouracil encapsulated in long-circulating liposomes with simvastatin, also encapsulated in long-circulating liposomes, that was previously proved to exert antitumor actions on the same tumor model. The production of angiogenic/inflammatory proteins was assessed by protein array and the production of markers for tumor aggressiveness (Bcl-2, Bax, and nuclear factor [NF]-κB) were determined by western blot analysis. Intratumor oxidative stress was evaluated through measurement of malondialdehyde level by HPLC, and through spectrophotometric analysis of catalytic activity of catalase and of total antioxidant capacity. Immunohistochemical analysis of tumors for CD31 expression was assessed. Intratumor activity of MMP-2 by gelatin zymography was also carried out. Our results revealed that combined therapies based on liposomal formulations exerted enhanced antitumor activities compared with combined treatment with free drugs. Sequential treatment with liposomal simvastatin and liposomal 5-fluorouracil showed the strongest antitumor activity in C26 colon carcinoma in vivo, mainly through inhibition of tumor angiogenesis. Important markers for cancer progression (Bcl-2, Bax, NF-κB, and intratumor antioxidants) showed that liposomal simvastatin might sensitize C26 cells to liposomal 5-fluorouracil treatment in both regimens tested. The outcome of simultaneous treatment with liposomal formulations was superior to sequential treatment with both liposomal types as the invasive capacity of C26 tumors was strongly increased after the latest treatment. The antitumor efficacy of combined therapy in C26 colon carcinoma might be linked to the restorative effects on proteins balance involved in tumor angiogenesis.

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization.

OBJECTIVE: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach. METHODS: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes. RESULTS: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product's disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load). CONCLUSIONS: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.

Selection of a Digitalis purpurea Cell Line with Improved Bioconversion Capacity of Hydroquinone into Arbutin.

This study aimed to investigate the biotransformation capabilities of a hydroquinone-tolerant Digitalis purpurea cell line (DpHQ) for bioconverting hydroquinone (HQ) into arbutin, a compound with significant therapeutic and cosmetic applications. The research evaluated the influence of various HQ concentrations, feeding protocols, and carbon sources on arbutin bioconversion yield. By using HPLC-MS for the quantification of arbutin in biomass and medium, the study revealed that higher precursor (HQ) concentration led to a more pronounced growth inhibition under single dosing than sequential dosing. At lower sugar (3%) and precursor (4 mM HQ) levels, arbutin predominantly remained within the cells, whereas higher sugar (6%) and HQ (5-6 mM) levels promoted its release into the medium. Arbutin production ranged from 591 mg/L under single dosing to 3049 mg/L with sequential dosing, with the highest yield being achieved with 5 mM HQ in divided doses and 6% glucose. This study holds novelty for being the first to demonstrate the DpHQ's tolerance to high concentrations of HQ and its efficient capabilities to bioconvert HQ to arbutin, indicating that D. purpurea is equipped with the enzymes required for this process. These aspects highlight its potential as a biotechnological source for arbutin synthesis.

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation-From the Lab Scale to the Pilot Scale.

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up.

Polyvinyl Alcohol, a Versatile Excipient for Pharmaceutical 3D Printing.

Three-dimensional (3D) printing in the pharmaceutical field allows rapid manufacturing of a diverse range of pharmaceutical dosage forms, including personalized items. The application of this technology in dosage form manufacturing requires the judicious selection of excipients because the selected materials must be appropriate to the working principle of each technique. Most techniques rely on the use of polymers as the main material. Among the pharmaceutically approved polymers, polyvinyl alcohol (PVA) is one of the most used, especially for fused deposition modeling (FDM) technology. This review summarizes the physical and chemical properties of pharmaceutical-grade PVA and its applications in the manufacturing of dosage forms, with a particular focus on those fabricated through FDM. The work provides evidence on the diversity of dosage forms created using this polymer, highlighting how formulation and processing difficulties may be overcome to get the dosage forms with a suitable design and release profile.

Testing the disintegration and texture-related palatability predictions for orodispersible tablets using an instrumental tool coupled with multivariate analysis: Focus on process variables and analysis settings.

Orodispersible tablets (ODTs) represent a growing category of dosage forms intended to increase the treatment acceptability for special groups of patients. ODTs are designed to rapidly disintegrate in the oral cavity and to be administered without water. In addition, ODTs are easy to manufacture using standard excipients and pharmaceutical equipment. This study adds to previously published research that developed an instrumental tool to predict oral disintegration and texture-related palatability of ODTs with different formulations. The current study aimed to challenge the predictive capacity of the models under variable process conditions. The studied process parameters with potential impact on the pharmaceutical properties, texture profiles, and palatability were the compression pressure, punch shape and diameter. Subsequently, for all the placebo and drug-loaded ODTs, the in vivo disintegration time and texture-related palatability were determined with healthy volunteers. Previously developed regression models were applied to predict the formulation's disintegration time and texture-related palatability characteristics of ODTs obtained under different experimental conditions. The influence of process variables on the predictive performance of the models was estimated by calculating the residuals as the difference between the predicted and observed values for the investigated response. Increasing the speed of the analyser`s probe from 0.01 mm/s to 0.02 mm/s led to an improved differentiation of the texture profiles. The in vivo disintegration time and texture-related palatability scores were only influenced by the mechanical resistance and the tablet shape. Lower score was observed for the larger diameter tablets (10 mm). Overall, the prediction of the disintegration time at 0.02 mm/s was more accurate, except for stronger tablets. The best prediction of texture-related palatability was achieved for the 10 mm tablets, tested at 0.01 mm/s speed. The same model achieved good predictions of the oral disintegration time for all API-loaded formulations, which confirmed the ability of the texture analysis to capture process-related variability. Drug loading decreased the predictive capacity of the texture-related palatability because of the taste effect.

Expanding the Manufacturing Approaches for Gastroretentive Drug Delivery Systems with 3D Printing Technology.

Gastroretentive drug delivery systems (GRDDSs) have gained substantial attention in the last 20 years due to their ability to retain the drug in the stomach for an extended time, thus promoting an extended release and high bioavailability for a broad range of active pharmaceutical ingredients (APIs) that are pH-sensitive and/or have a narrow absorption window. The currently existing GRDDSs include floating, expanding, mucoadhesive, magnetic, raft-forming, ion-exchanging, and high-density systems. Although there are seven types of systems, the main focus is on floating, expanding, and mucoadhesive systems produced by various techniques, 3D printing being one of the most revolutionary and currently studied ones. This review assesses the newest production technologies and briefly describes the in vitro and in vivo evaluation methods, with the aim of providing a better overall understanding of GRDDSs as a novel emerging strategy for targeted drug delivery.

Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films.

In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients.

Investigation of Epilobium hirsutum L. Optimized Extract's Anti-Inflammatory and Antitumor Potential.

Epilobium hirsutum L., commonly known as hairy willowherb, is a perennial herbaceous plant native to Europe and Asia. In Romania, the Epilobium genus includes 17 species that are used in folk medicine for various purposes. This study aimed to investigate the anti-inflammatory and antitumor potential of the optimized extract of Epilobium hirsutum (EH) in animal models. The first study investigated the anti-inflammatory properties of EH optimized extract and the model used was carrageenan-induced paw inflammation. Wistar rats were divided into three groups: negative control, positive control treated with indomethacin, and a group treated with the extract. Oxidative stress markers, cytokine levels, and protein expressions were assessed. The extract demonstrated anti-inflammatory properties comparable to those of the control group. In the second study, the antitumor effects of the extract were assessed using the tumor model of Ehrlich ascites carcinoma. Swiss albino mice with Ehrlich ascites were divided into four groups: negative, positive treated with cyclophosphamide (Cph), Group 3 treated with Cph and EH optimized extract, and Group 4 treated with extract alone. Samples from the ascites fluid, liver, and heart were analyzed to evaluate oxidative stress, inflammation, and cancer markers. The extract showed a reduction in tumor-associated inflammation and oxidative stress. Overall, the EH optimized extract exhibited promising anti-inflammatory and antitumor effects in the animal models studied. These findings suggest its potential as a natural adjuvant therapeutic agent for addressing inflammation and oxidative stress induced by different pathologies.

Texture analysis - A versatile tool for pharmaceutical evaluation of solid oral dosage forms.

In the past few decades, texture analysis (TA) has gained importance as a valuable method for the characterization of solid oral dosage forms. As a result, an increasing number of scientific publications describe the textural methods that evaluate the extremely diverse category of solid pharmaceutical products. Within the current work, the use of texture analysis in the characterization of solid oral dosage forms is summarised with a focus on the evaluation of intermediate and finished oral pharmaceutical products. Several texture methods are reviewed regarding the applications in mechanical characterization, and mucoadhesion testing, but also in estimating the disintegration time and in vivo specific features of oral dosage forms. As there are no pharmacopoeial standards for pharmaceutical products tested through texture analysis, and there are important differences between reported results due to different experimental conditions, the choice of testing protocol and parameters is challenging. Thereby, this work aims to guide the research scientists and quality assurance professionals involved in different stages of drug development into the selection of optimal texture methodologies depending on the product characteristics and quality control needs.

Development of a PAT platform for the prediction of granule tableting properties.

In this work, the feasibility of implementing a process analytical technology (PAT) platform consisting of Near Infrared Spectroscopy (NIR) and particle size distribution (PSD) analysis was evaluated for the prediction of granule downstream processability. A Design of Experiments-based calibration set was prepared using a fluid bed melt granulation process by varying the binder content, granulation time, and granulation temperature. The granule samples were characterized using PAT tools and a compaction simulator in the 100-500 kg load range. Comparing the systematic variability in NIR and PSD data, their complementarity was demonstrated by identifying joint and unique sources of variation. These particularities of the data explained some differences in the performance of individual models. Regarding the fusion of data sources, the input data structure for partial least squares (PLS) based models did not significantly impact the predictive performance, as the root mean squared error of prediction (RMSEP) values were similar. Comparing PLS and artificial neural network (ANN) models, it was observed that the ANNs systematically provided superior model performance. For example, the best tensile strength, ejection stress, and detachment stress prediction with ANN resulted in an RMSEP of 0.119, 0.256, and 0.293 as opposed to the 0.180, 0.395, and 0.430 RMSEPs of the PLS models, respectively. Finally, the robustness of the developed models was assessed.

In-Depth Understanding of Granule Compression Behavior under Variable Raw Material and Processing Conditions.

Tablet manufacturing involves the processing of raw materials through several unit operations. Thus, the mitigation of input-induced variability should also consider the downstream processability of intermediary products. The objective of the present work was to study the effect of variable raw materials and processing conditions on the compression properties of granules containing two active pharmaceutical ingredients (APIs) and microcrystalline cellulose. Differences in compressibility and tabletability of granules were highlighted in function of the initial particle size of the first API, granule polydispersity and fragmentation. Moreover, interactions were underlined with the atomizing pressure. Changing the supplier of the second API was efficiently controlled by adapting the binder addition rate and atomizing pressure during granulation, considering the starting crystal size. By fitting mathematical models on the available compression data, the influence of diluent source on granule compactibility and tabletability was identified. These differences resumed to the ease of compaction, tableting capacity and pressure sensitivity index due to variable water binding capacity of microcrystalline cellulose. Building the design space enabled the identification of suitable API types and the appropriate processing conditions (spray rate, atomizing pressure, compression force) required to ensure the desired tableting performance.

QbD guided development of immediate release FDM-3D printed tablets with customizable API doses.

The objective of this work was to develop a fused deposition modeling (FDM) 3D printed immediate release (IR) tablet with flexibility in adjusting the dose of the active pharmaceutical ingredient (API) by scaling the size of the dosage form and appropriate drug release profile steadiness to the variation of dimensions or thickness of the deposited layers throughout the printing process. Polyvinyl alcohol-based filaments with elevated API content (50% w/w) were prepared by hot melt extrusion (HME), through systematic screening of polymeric formulations with different drug loadings, and their printability was evaluated by means of mechanical characterization. For the tablet fabrication step by 3D printing (3DP), the Quality by Design (QbD) approach was implemented by employing risk management strategies and Design of Experiments (DoE). The effects of the tablet design, tablet size and the layer height settings on the drug release and the API content were investigated. Between the two proposed original tablet architectures, the honeycomb configuration was found to be a suitable candidate for the preparation of IR dosage forms with readily customizable API doses. Also, a predictive model was obtained, which assists the optimization of variables involved in the printing phase and thereby facilitates the tailoring process.

Epilobium Species: From Optimization of the Extraction Process to Evaluation of Biological Properties.

Epilobium species are used in Romanian folk medicine as tinctures, tea, or tablets for ameliorating the symptoms of benign prostate hyperplasia (BPH), but scientific-based evidence is scarce for this species or other endemic plants of the same genus. Therefore, the aims of this research were to evaluate the phytochemical profile of five endemic Epilobium species (E. hirsutum L., E. parviflorum Schreb., E. palustre L. E. dodonaei Vill., and E. angustifolium L.) and to assess their in vitro biological activity. For enhanced recovery of polyphenols, a D-optimal experimental plan was developed using Modde software and the optimal working conditions were ultra-turrax-assisted extraction, for 8 min, with 30% ethanol in water. The optimized extracts were obtained from various plant parts and were further characterized by LC-MS analysis, with the major compound being oenothein B. All extracts demonstrated good antioxidant activity, evaluated by DPPH and TEAC assays. The most prominent antimicrobial potency of optimized extracts was displayed against Bacillus cereus, while against Gram-(+) bacteria, a moderate efficacy was observed. Furthermore, anti-cancer, anti-inflammatory, and antioxidant potential were assessed on normal fibroblasts and prostate carcinoma cell lines. From the evaluated optimized extracts, E. angustifolium aerial parts had the highest selectivity toward killing cancerous cells, followed by E. hirsutum aerial parts extract. For the antioxidant effect, E. hirsutum leaves and E. hirstum aerial parts extracts displayed the highest potency, decreasing ROS at the level observed for the positive control. The highest anti-inflammatory potential, based on the IL-6 and IL-8 levels, was displayed by E. dodonaei aerial parts and E. angustifolium leaves extracts. In conclusion, all five endemic species of Epilobium harvested from Romanian flora possess a diverse phytochemical composition, which supports complex biological activities.

The Use of the QbD Approach to Optimize the Co-Loading of Simvastatin and Doxorubicin in Liposomes for a Synergistic Anticancer Effect.

The present study aimed to optimize a liposomal formulation co-encapsulating simvastatin (SIM) and doxorubicin (DOX) that has future perspectives in anticancer therapy. The optimization process was performed by implementing the Quality by Design concept and by considering the results of a previous screening study. Failure Mode and Effects Analysis was used for the identification of the potential critical factors, i.e., phospholipid, SIM and DOX concentration, which were assessed in an optimization experimental design with the purpose of designing an optimal formulation. The optimal formulation, meeting the established quality profile, was additionally characterized in terms of the release profile and antiproliferative effects. During dissolution studies, a novel chronoamperometric method was used for the simultaneous quantification of SIM and DOX. The obtained data confirmed the similarity of this method with a validated HPLC method. The anticancer potential of the optimal formulation was tested against two human cancerous cell lines, namely T47D-KBluc human mammary ductal carcinoma cell line and A549 human pulmonary cancer cell line. The results highlighted that the antiproliferative effect of the optimal formulation is concentration dependent and favors a synergistic effect of the two drugs.

Multivariate feed forward process control and optimization of an industrial, granulation based tablet manufacturing line using historical data.

The purpose of this work was to understand the variability in disintegration time and tableting yield of high drug load (>60%) tablets prepared by batch-wise high shear wet granulation. The novelty of the study is the use of multivariate methods (Batch Evolution Models - BEMs and Batch Level Models - BLMs) to enhance process control, with a feed forward component, using prediction models built from a historical dataset acquired for 95 industrial scale batches. Time dependent process variables and significant influences on investigated parameters were identified. Prediction of output from input was tested with Partial Least Squares (PLS) and Artificial Neural Network (ANN) modeling. A reliable prediction ability was achieved for granulation water amount (±2 kg in a 16-31 kg range), tableting speed (±5000 tablets/h in a 23,000-72,500 tabl./h range) and disintegration time of cores (±100 s; in a 250-900 s range). Offsets from the optimal process evolution and certain raw material properties were correlated with differences observed in the output variables. Improvement options were identified for 80% of the batches with high disintegration time. Hence, the trained models can be applied for systematic process improvement, enabling feed forward control.

Fluidised bed granulation of two APIs: QbD approach and development of a NIR in-line monitoring method.

The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients, intended for coated tablets preparation and further transfer to industrial scale. The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy. Moreover, an in-line Near-Infrared monitoring method was developed, which offered a real time overview of the moisture level along the granulation process, thus a reliable supervision and control process analytical technology (PAT) tool. The experimental design's results showed that the use of apparently interchangeable active pharmaceutical ingredients (APIs) and filler sorts that comply with pharmacopoeial specifications, lead to different end-product critical attributes. By adapting critical granulation parameters (i.e. binder spray rate and atomising pressure) as a function of material characteristics, led to granules with average sizes comprised in a narrow range of 280-320 µm and low non-granulated fraction of under 5%. Therefore, the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability. To complete the Quality by design (QbD) strategy, despite its limited spectral domain, the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process.

Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis.

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles were successfully monitored in real-time by the developed videometric system consisting of a high-speed process camera coupled with an image analysis software. The system was also tested in feedback control mode to automatically reach the desired mass flow values by adjusting the feeder speed based on the mass flow measured by the image analysis system. Based on these features, the developed videometric system can serve as a multi-purpose PAT-tool and can provide valuable real-time information about the process which is indispensable for modern continuous pharmaceutical manufacturing.