Development of a robotic cluster for automated and scalable cell therapy manufacturing.

BACKGROUND AIMS: The production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products. METHODS: We present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster's expansion module was demonstrated by expanding human CD8+ T cells. RESULTS: The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. In addition, the robotic system was able to maintain culture sterility. CONCLUSIONS: Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies. This approach offers a pathway for overcoming manufacturing challenges associated with manual processes, ultimately contributing to the broader accessibility and affordability for personalized immunotherapies.

Development of a multi-component gastroretentive expandable drug delivery system (GREDDS) for personalized administration of metformin.

OBJECTIVES: Efficacy and compliance of type II diabetes treatment would greatly benefit from dosage forms providing controlled release of metformin in the upper gastrointestinal tract. In this respect, the feasibility of a new system ensuring stomach-retention and personalized release of this drug at its absorption window for multiple days was investigated. METHODS: The system proposed comprised of a drug-containing core and a viscoelastic umbrella-like skeleton, which were manufactured by melt-casting and 3D printing. Prototypes, alone or upon assembly and insertion into commercially-available capsules, were characterized for key parameters: thermo-mechanical properties, accelerated stability, degradation, drug release, deployment performance, and resistance to simulated gastric contractions. RESULTS: Each part of the system was successfully manufactured using purposely-selected materials and the performance of final prototypes matched the desired one. This included: i) easy folding of the skeleton against the core in the collapsed administered shape, ii) rapid recovery of the cumbersome configuration at the target site, even upon storage, and iii) prolonged release of metformin. CONCLUSIONS: Composition, geometry, and performance of the system developed in this work were deemed acceptable for stomach-retention and prolonged as well as customizable release of metformin in its absorption window, laying promising bases for further development steps.

Electrospinning of pullulan-based orodispersible films containing sildenafil.

Feasibility of electrospinning in the manufacturing of sildenafil-containing orodispersible films (ODFs) intended to enhance oxygenation and to reduce pulmonary arterial pressure in pediatric patients was evaluated. Given the targeted subjects, the simplest and safest formulation was chosen, using water as the only solvent and pullulan, a natural polymer, as the sole fiber-forming agent. A systematic characterization in terms of shear and extensional viscosity as well as surface tension of solutions containing different amounts of pullulan and sildenafil was carried out. Accordingly, electrospinning parameters enabling the continuous production, at the highest possible rate, of defect-free fibers with uniform diameter in the nanometer range were assessed. Morphology, microstructure, drug content and relevant solid state as well as ability of the resulting non-woven films to interact with aqueous fluids were evaluated. To better define the role of the fibrous nanostructure on the performance of ODFs, analogous films were produced by spin- and blade-coating and tested. Interestingly, the disintegration process of electrospun products turned out to be the fastest (i.e. occurring within few s) and compliant with Ph. Eur. and USP limits, making relevant ODFs particularly promising for increasing sildenafil bioavailability, thus lowering its dosages.

Insights into the Safety and Versatility of 4D Printed Intravesical Drug Delivery Systems.

This paper focuses on recent advancements in the development of 4D printed drug delivery systems (DDSs) for the intravesical administration of drugs. By coupling the effectiveness of local treatments with major compliance and long-lasting performance, they would represent a promising innovation for the current treatment of bladder pathologies. Being based on a shape-memory pharmaceutical-grade polyvinyl alcohol (PVA), these DDSs are manufactured in a bulky shape, can be programmed to take on a collapsed one suitable for insertion into a catheter and re-expand inside the target organ, following exposure to biological fluids at body temperature, while releasing their content. The biocompatibility of prototypes made of PVAs of different molecular weight, either uncoated or coated with Eudragit®-based formulations, was assessed by excluding relevant in vitro toxicity and inflammatory response using bladder cancer and human monocytic cell lines. Moreover, the feasibility of a novel configuration was preliminarily investigated, targeting the development of prototypes provided with inner reservoirs to be filled with different drug-containing formulations. Samples entailing two cavities, filled during the printing process, were successfully fabricated and showed, in simulated urine at body temperature, potential for controlled release, while maintaining the ability to recover about 70% of their original shape within 3 min.

Investigation on the use of fused deposition modeling for the production of IR dosage forms containing Timapiprant.

The present work focused on evaluating the feasibility of fused deposition modeling (FDM) in the development of a dosage form containing Timapiprant (TMP), also known as CHF6532, which is a novel active molecule indicated in the potential treatment of eosinophilic asthma upon oral administration. The resulting product could be an alternative, with potential towards personalization, of immediate release (IR) tablets used in the clinical studies. Formulations based on different polymeric carriers were screened, leading to the identification of a polyvinyl alcohol-based one, which turned out acceptable for versatility in terms of active ingredient content, printability and dissolution performance (i.e. capability to meet the dissolution specification set, envisaging >80% of the drug dissolved within 30 min). Following an in-depth evaluation on the influence of TMP solid state and of the voids volume resulting from printing on dissolution, few prototypes with shapes especially devised for therapy customization were successfully printed and were compliant with the dissolution specification set.

Expandable Drug Delivery Systems Based on Shape Memory Polymers: Impact of Film Coating on Mechanical Properties and Release and Recovery Performance.

Retentive drug delivery systems (DDSs) are intended for prolonged residence and release inside hollow muscular organs, to achieve either local or systemic therapeutic goals. Recently, formulations based on shape memory polymers (SMPs) have gained attention in view of their special ability to recover a shape with greater spatial encumbrance at the target organ (e.g., urinary bladder or stomach), triggered by contact with biological fluids at body temperature. In this work, poly(vinyl alcohol) (PVA), a pharmaceutical-grade SMP previously shown to be an interesting 4D printing candidate, was employed to fabricate expandable organ-retentive prototypes by hot melt extrusion. With the aim of improving the mechanical resistance of the expandable DDS and slowing down relevant drug release, the application of insoluble permeable coatings based on either Eudragit® RS/RL or Eudragit® NE was evaluated using simple I-shaped specimens. The impact of the composition and thickness of the coating on the shape memory, swelling, and release behavior as well as on the mechanical properties of these specimens was thoroughly investigated and the effectiveness of the proposed strategy was demonstrated by the results obtained.

Administration strategies and smart devices for drug release in specific sites of the upper GI tract.

Targeting the release of drugs in specific sites of the upper GI tract would meet local therapeutic goals, improve the bioavailability of specific drugs and help overcoming compliance-related limitations, especially in chronic illnesses of great social/economic impact and involving polytherapies (e.g. Parkinson's and Alzeimer's disease, tubercolosis, malaria, HIV, HCV). It has been traditionally pursued using gastroretentive (GR) systems, i.e. low-density, high-density, magnetic, adhesive and expandable devices. More recently, the interest towards oral administration of biologics has prompted the development of novel drug delivery systems (DDSs) provided with needles and able to inject different formulations in the mucosa of the upper GI tract and particularly of esophagus, stomach or small intestine. Besides comprehensive literature analysis, DDSs identified as smart devices in view of their high degree of complexity in terms of design, working mechanism, materials employed and manufacturing steps were discussed making use of graphic tools.

What's next in the use of opacifiers for cosmetic coatings of solid dosage forms? Insights on current titanium dioxide alternatives.

The consolidated use of coatings containing E171 (i.e. titanium dioxide, TiO2) as an opacifier has made the white color of the resulting dosage forms a quality standard in the pharmaceutical and dietary supplement fields. This color is also associated with the efficiency of the coating layer in protecting the substrate from the effects of UV rays. However, health risks related to diet exposure to TiO2 has recently been advanced and its addition in coating formulations has been seriously questioned. As a consequence, in principle safer TiO2-free formulations have been recently launched on the market, especially for coatings of dietary supplements. In this work, we evaluated the overall physico-technological characteristics and performance of immediate release tablets coated with a variety of commercial cosmetic formulations free of E171. Moreover, a quantitative method based on the CIELab color space was proposed for the first time for studying the covering/coloring performance of the coating formulations. Based on the results obtained, the possibility to achieve a satisfactory covering capability and a degree of white comparable to that of a standard TiO2-containing reference with all the commercially-available ready-to-use TiO2-free products considered, without affecting the dissolution performance, was demonstrated.

Intravesical drug delivery approaches for improved therapy of urinary bladder diseases.

Diseases of the urinary bladder have high incidence rates and burden healthcare costs. Their pharmacological treatment involves systemic and local drug administration. The latter is generally accomplished through instillation of liquid formulations and requires repeated or long-term catheterization that is associated with discomfort, inflammation and bacterial infections. Consequently, compliance issues and dropouts are frequently reported. Moreover, instilled drugs are progressively diluted as the urine volume increases and rapidly excreted. When penetration of drugs into the bladder wall is needed, the poor permeability of the urothelium has also to be accounted for. Therefore, much research effort is spent to overcome these hurdles, thereby improving the efficacy of available therapies. Particularly, indwelling delivery systems suited for i) insertion into the bladder through the urethra, ii) intra-organ retention and prolonged release for the desired time lapse, iii) final elimination, either spontaneous or by manual removal, have been proposed to reduce the number of catheterization procedures and reach higher drug levels at the target site. Vesical retention of such devices is allowed by the relevant expansion that can either be triggered from the outside or achieved exploiting elastic and purposely 4D printed shape memory materials. In this article, the main rationales and strategies for improved intravesical delivery are reviewed.

The Chronotopic™ System for Pulsatile and Colonic Delivery of Active Molecules in the Era of Precision Medicine: Feasibility by 3D Printing via Fused Deposition Modeling (FDM).

The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, entailing a gastroresistant film to prevent early interaction of the inner coat with gastric fluids and enabling the attainment of a lag phase matching the small intestinal transit time. Over the years, various multiple-step manufacturing processes have been tested for the fabrication of the Chronotopic™ system in both its configurations. This work focused on the evaluation of 3D printing by fused deposition modeling in view of its potential towards product personalization, on demand one-step manufacturing and efficient scale down of batches. The feasibility of each part of the Chronotopic™ system was independently investigated starting from in-house made filaments, characterizing the resulting specimens for physico-technological and performance characteristics. The printing parameters identified as suitable during the set-up phase were then used to fabricate prototypes either in a single step for the pulsatile configuration or following two different fabrication approaches for the colon-targeting one.

Shape memory materials and 4D printing in pharmaceutics.

Shape memory materials (SMMs), including alloys and polymers, can be programmed into a temporary configuration and then recover the original shape in which they were processed in response to a triggering external stimulus (e.g. change in temperature or pH, contact with water). For this behavior, SMMs are currently raising a lot of attention in the pharmaceutical field where they could bring about important innovations in the current treatments. 4D printing involves processing of SMMs by 3D printing, thus adding shape evolution over time to the already numerous customization possibilities of this new manufacturing technology. SMM-based drug delivery systems (DDSs) proposed in the scientific literature were here reviewed and classified according to the target pursued through the shape recovery process. Administration route, therapeutic goal, temporary and original shape, triggering stimulus, main innovation features and possible room for improvement of the DDSs were especially highlighted.

Quality considerations on the pharmaceutical applications of fused deposition modeling 3D printing.

3D printing, and particularly fused deposition modeling (FDM), has rapidly brought the possibility of personalizing drug therapies to the forefront of pharmaceutical research and media attention. Applications for this technology, described in published articles, are expected to grow significantly in 2020. Where are we on this path, and what needs to be done to develop a FDM 2.0 process and make personalized medicines available to patients? Based on literature analysis, this manuscript aims to answer these questions and highlight the critical technical aspects of FDM as an emerging technology for manufacturing safe, high-quality personalized oral drug products. In this collaborative paper, experts from different fields contribute strategies for ensuring the quality of starting materials and discuss the design phase, printer hardware and software, the process, the environment and the resulting products, from the perspectives of both patients and operators.

A Graphical Review on the Escalation of Fused Deposition Modeling (FDM) 3D Printing in the Pharmaceutical Field.

Fused deposition modeling 3D printing is currently one of the hot topics in pharmaceutics and has shown a 2000% increase in the number of research articles published in the last 5 years. In the prospect of a new era of fused deposition modeling focused on the industrial development of this technique applied to the fabrication of personalized medicines, a conceptual map to move through the evolution of the design of the printed dosage forms/drug delivery systems was conceived and mainly discussed by means of graphical tools.

Lego-Inspired Capsular Devices for the Development of Personalized Dietary Supplements: Proof of Concept With Multimodal Release of Caffeine.

Dietary supplement companies have recently started to focus on the personalization of products and the improvement of the relevant performance. In this respect, a versatile, easy-to-handle capsular delivery platform with customizable content and release kinetics was here proposed and evaluated after filling with caffeine as a model dietary ingredient. In particular, capsular devices comprising 1 to 3 independent inner compartments were attained by Lego-inspired assembly of matching modular units with different wall compositions, manufactured by injection molding and fused deposition modeling 3D printing. Accordingly, one-, two- and three-pulse release profiles of the dietary ingredient were obtained from differently assembled devices following the breakup of the compartments occurring promptly (immediate-release), on pH change (delayed-release) or after tunable lag times (pulsatile-release). The latter release mode would enable the onset of the stimulating effect of caffeine at different times of the day after a single administration when convenient. The performance of each individual compartment only depended on the composition (i.e., promptly soluble, swellable/soluble or enteric soluble polymers) and thickness of its own wall, while it was not affected by the composition and number of joined modular units. Moreover, the delivery platform was extended to include an external gastroresistant shell enclosing previously assembled devices.

3D printing by fused deposition modeling of single- and multi-compartment hollow systems for oral delivery - A review.

Feasibility of fused deposition modeling in 3D printing of hollow systems intended to convey different formulations for oral administration has recently been investigated. A major advantage of such printed devices is represented by the possibility of separately undertaking the development of the inner core from that of the outer shell, which could also act as a release-controlling barrier. Systems either composed of parts to be filled and assembled after fabrication or fabricated and filled in a single manufacturing process represent the main focus of this review. Devices having relatively simple (e.g. single-compartment capsule-like) configuration were first proposed followed by systems entailing multiple inner compartments. The latter were meant to be filled with different formulations, left empty for ensuring floatation or achieve combined release kinetics. For each of the reviewed systems, design, formulation approaches, manufacturing as well as release performance obtained were critically described. Versatility of FDM, especially in terms of geometric freedom provided, was highlighted together with some limitations that still need to be addressed, as expected for a newly-adopted fabrication technique that holds potential for being implemented in the pharmaceutical field.

Expandable drug delivery system for gastric retention based on shape memory polymers: Development via 4D printing and extrusion.

Several diseases would benefit from prolonged drug release provided by systems retained in the stomach for extended time periods. Expandable gastroretentive devices are administered in a collapsed configuration enabling swallowing and regain in situ their native shape having larger spatial encumbrance, thus hindering voidance through the wide open pylorus. An expandable system for gastric retention was here proposed relying on the shape memory behavior of pharmaceutical-grade poly(vinyl alcohol). Different original configurations to be recovered upon exposure to aqueous fluids at 37 °C, potentially enabling gastric retention, were conceived. Prototypes containing allopurinol were directly manufactured by fused deposition modeling or shaped by purposely-designed templates from hot melt extruded rods immediately after production. Various temporary shapes, in principle suitable for administration, were programmed by manual deformation of samples by means of specific templates, under defined temperature conditions. In 0.1 N hydrochloric solution at 37 °C, the prototypes recovered their original shape, reaching the desired spatial encumbrance within few minutes. Release from the samples, although of relatively short duration, was independent of the original shape and processing undergone, and was noticeably slowed down by application of Eudragit® RS/RL-based coatings.

Effect of Polyethylene Glycol Content and Molar Mass on Injection Molding of Hydroxypropyl Methylcellulose Acetate Succinate-Based Gastroresistant Capsular Devices for Oral Drug Delivery.

Capsular devices for oral drug delivery were recently proposed and manufactured by injection molding (IM) as an evolution of traditional reservoir systems comprising a core and a functional coating. IM allowed the fabrication of capsule shells with release-controlling features based on the employed materials and the design characteristics. These features are independent of the drug, with significant savings in development time and costs. In previous work, IM was used to produce enteric-soluble capsules from blends of hydroxypropyl methylcellulose acetate succinate, with polyethylene glycol (PEG) as the plasticizer. In this work, the range of plasticizer concentrations and molar mass was broadened to evaluate in-depth how those parameters affect material processability and capsule performance over time. As expected, increasing the amount of the low molar mass plasticizer decreased the viscosity and modulus of the material. This simplified the molding process and enhanced the mechanical resistance of the shell, as observed during assembly. However, some samples turned out translucent, depending on several factors including storage conditions. This was attributed to plasticizer migration issues. Such results indicate that higher molar mass PEGs, while not significantly impacting on processability, lead to capsular devices with consistent performance in the investigated time lapse.