Continuous wet granulation using a twin-screw extruder has attracted considerable attentions in pharmaceutical industry as it ensures consistent tablet quality at a high production rate. However, challenge still exists in controlling desired granule properties especially when different sized twin-screw granulators are used. This study therefore explored the potential of scalability of two sized twin-screw extruders and the how raw materials affect granules properties in two twin-screw extruders. The first study focuses on aspects of scaling using two twin-screw extruders, 18mm and 27mm. Dimensionless groups including Fr Number, Powder Feed Number and Degree of Fill (<30%) were studied to observe their influences on granule attributes. It was found that these dimensionless groups demonstrated inconsistent effects on granule properties and the effect of Powder Feed Number was highly dependent on Degree of Fill. Different extruder still exerts significant impact on granule properties. A scaling rule was established for median granule size (d50) only, but only moderate degree of fit was found. Although a considerable number of studies have been published on controlled-release and extended-release excipients, little attentions have been given to the influence of microcrystalline cellulose (MCC) grades in twin-screw wet granulation. The second study therefore investigated the processability of five grades MCC from the Avicel® PH family using two twin-screw extruders again, 18mm and 27mm. Granule attributes including particle size, density, moisture, and strength were tested and it was found that MCC inherent density has the most significant impact on granule properties while particle size of MCC has minor positive effect on granule size. This study also concluded that better granule flowability and uniformity can be achieved by using low moisture, larger particle size and high density MCC as excipients. / Thesis / Master of Applied Science (MASc)

Yes / Solid state shear milling (S3M) is reported as a scalable, continuous, polymer-assisted cocrystallization technique. A specially designed milling pan was employed to provide high levels of applied shear, and the addition of a polymeric processing aid enabled generation of high stress fields. Carbamazepine–salicylic acid cocrystals were produced with 5–25 wt % of poly(ethylene oxide) (PEO). A systematic study was carried out to understand the effect of process variables on properties and performance of the cocrystals. S3M offers an important new route for continuous manufacturing of pharmaceutical cocrystals.

<p>In recent years, the pharmaceutical industry has embarked on an extensive program to modernize its manufacturing resources. Recognizing the limitations of traditional mass manufacturing, the industry is now focused on developing new production systems that can deliver high-quality medicines with enhanced efficiency, flexibility, agility, and reliability. To realize this vision, innovations in three key areas are being pursued: continuous processing, personalized medicine, and Industry 4.0.</p> <p>This thesis contributes towards the industry’s goal by focusing on the development of an advanced system to manufacture solid oral drug products. This system is centered around a pharmaceutical additive manufacturing technology called drop on demand (DoD) printing. This technology is highly effective in making personalized drug products, which allow for customizing dose attributes such as drug loading, release behavior, formulation type, and dosage form, based on patient requirements. To develop the DoD printer into an advanced production system, technologies such as end-to-end continuous processing, real time quality assurance, and automated operation need to be incorporated into it. </p> <p>The studies presented in this thesis implement different aspects of these technologies in the printer. To enable end to end operation, a novel solvent switch process called three phase settling is developed to integrate the DoD system with upstream steps for synthesizing the active ingredient. To facilitate automated processing of formulations with different active ingredients, excipients, and particle concentrations, a model framework is developed to recommend operating conditions for the DoD platform that can deliver on-spec printer operation. To expand the range of personalized dosage forms offered by the system, the manufacturing of a new category of drug products, called mini-tablets, is demonstrated. To provide reconfigurability and quality assurance capabilities in the platform, modular design and process monitoring tools are implemented. To aid optimization and control of drug production processes, a digital twin is developed by combining the models developed for DoD, solvent switch, synthesis, and crystallization operations. </p> <p>The research presented in this thesis lays the foundation for developing the next generation of manufacturing systems for drug products. Incorporation of scalability, autonomous operation, and real time release prediction are critical steps in facilitating the next phase of its development – deployment in real-world manufacturing scenarios.  </p>

Recent research and development has resulted in a working prototype of an automated process for manufacturing IsoTruss® and other innovative open lattice composite structures which yields faster, and more predictable and consistent parts, while automatically consolidating individual members. This machine is sufficiently versatile to manufacture any type of open lattice structure fabricated from filamentary composite materials. The objectives of the research in this thesis were two-fold: (1) to validate this new process for making IsoTruss structures; and (2) to measure the compression strength and stiffness of specimens produced on the machine. In order to accomplish the first purpose, various parts were manufactured on this prototype machine, including: a six-node IsoTruss structure with single outer longitudinal members, a three-longitudinal member section of an inner longitudinal IsoTruss structure with consolidated members, and a two-bay IsoTruss panel structure. By creating and running patterns to make these parts, the hypothesis that the machine will make any geometry of IsoTruss structure was validated. The second objective of this research was accomplished by testing the compression strength and stiffness of specimens manufactured with this automated process. Buckling versus compression failure of members was examined by varying member aspect ratios. The effect of intersecting helical members was also explored, as was the effect of changing the number of braiding bobbins used to consolidate members. Testing showed that increasing the number of braiders increases consistency of the braided sleeves and reduces scatter in the results. The ratio of helical to longitudinal tows at a joint is directly related to the percent decrease in member strength at the joint. Compression failure of individual members is the preferred method of failure, because this type of failure absorbs significantly more energy. This research proves that the manufacturing process will produce even the most complex IsoTruss geometries, with the necessary consolidation of individual members. Findings also indicate that a few modifications -- such as improved bobbins, more reliable switches, more accurate pulling system, etc. -- will enable this automated process to produce composite lattice structures with superior mechanical properties.

The high specific strength and stiffness characteristics of composite materials such as carbon fiber-reinforced plastic (CFRP) allow a significant weight reduction of the structural machine components such as automobile driveshafts. But high material cost and rather low productivity of the established manufacturing processes (e.g., filament winding) often inhibit the use of CFRP components in a high-volume car series. In this paper, a novel composite driveshaft system based on a profiled CFRP tube is presented. This system is designed to be produced by a continuous pultrusion process to achieve a significant reduction of the manufacturing costs. A cost assessment study was conducted to quantify the benefit of the developed continuous manufacturing process. In comparison with the state-of-the-art filament winding process, a cost reduction of 36% for the composite shaft body can be obtained. Moreover, the proposed fiber layup processes – braiding and continuous winding – offer the potential to manipulate the reinforcement architecture to maximize material utilization without reducing the manufacturing efficiency. This potential is investigated and validated by experimental tests. A difference in the load bearing capacity of more than 100% between different reinforcing architectures is shown.

<p dir="ltr">We present a systematic approach for integrating reduced-order models of tableting with upstream pharmaceutical unit operations. This method identifies critical material attributes (CMAs) and process parameters (CPPs) from upstream operations, describing their coupling to both first and second orders, while selecting the appropriate mathematical forms and estimating parameters. The coupling is modeled using normalized bivariate rational functions.</p><p dir="ltr">The approach is demonstrated for dry granulation, a process that enhances powder flowability but compromises tabletability by reducing particle porosity and increasing plastic work. Using a formulation of 10\% w/w acetaminophen and 90\% w/w microcrystalline cellulose, granules with varying densities and size distributions are produced, and tablets of different relative densities are fabricated. This work provides essential insights for end-to-end process integration, control, and optimization of dry granulation and tableting. It also identifies granule properties that predominantly influence the four stages of powder compaction: die filling, compaction, unloading, and ejection.</p><p dir="ltr">Furthermore, we examine the effects of excipients such as lubricants (magnesium stearate) and glidants (silica) on tablet critical quality attributes (CQAs) in continuous manufacturing. Lubricants were found to affect all compaction stages, with sensitivity to mixing time, while glidants influenced bulk density and tensile strength without significantly impacting tablet density or compaction force. Reduced-order models are developed to predict tablet weight, density, and tensile strength based on excipient concentration and mixing time. These models are integral to implementing real-time control under the quality-by-control paradigm.</p>

<p>  </p> <p>In the pharmaceutical industry, special care must be taken by companies to guarantee high quality medications that are free from byproducts and impurities. The development process involves various considerations including solvent selection, solubility screening, unit operation selection, environmental, and health impact evaluations. Traditionally, pharmaceutical manufacturing consisted of large, centralized facilities to meet pharmaceutical demands; however, there has been a recent shift toward distributed manufacturing. With distributed manufacturing platforms, rapidly changing supply chain needs can be met regionally in addition to supplying small-volume medications and personalized medicines to hospitals and pharmacies. To produce quality pharmaceuticals, distributed manufacturing platforms should integrate digital design, novel unit operations, and process analytical technology (PAT) tools for quality monitoring and control. In this dissertation, a process design and development framework is proposed and implemented for a small-scale pharmaceutical manufacturing platform: MiniPharm.</p> <p>Various approaches to process design are detailed in this dissertation, which include heuristic-based and digital or simulation-based design. For heuristic-based design, the knowledge of the researchers was utilized to provide unit operation evaluation and screening of process alternatives. In cases when unit operations were highly complex, digital or simulation-based design was utilized to conduct sensitivity analyses and simulation-based design of experiments. With the implementation of simulation-based design, material and time needs were reduced while gaining knowledge about the system. The integration of various unit operations comes with increased understanding of start-up dynamics and operational constraints. What was found to be the most successful approach was the combination of heuristics and digital design to combine researcher knowledge and experience with the information gained from process modeling and simulation to create process alternatives that utilized system dynamics to reach desired process outcomes. </p> <p>Additionally, MiniPharm was used for process model development at the small-scale. Various software packages have been made commercially available that focus on production scale; however, models for small-scale operations are not typically implemented in these packages. Models for unit operations were fit with collected experimental data to estimate model parameters for small-scale synthesis, liquid-liquid extraction, and crystallization unit operations. The models were implemented to better capture the heat and mass transfer of the milli-fluidic scale platform, which consist of unit operations housed within microchannels. MATLAB was utilized for estimation of parameters such as kinetic rate constants and overall mass transfer coefficients. These parameters were used for design space determination and process disturbance simulation. The exploration of the impact of various process parameters on quality attributes helps researchers gain a deeper understanding about the manufacturing process and helps to demonstrate how to control the process. </p> <p>An important aspect of MiniPharm is the process development progress that has been demonstrated. With the construction of a modular and reconfigurable platform, various process alternatives can now be experimentally validated. The integration of unit operations operated at a decreased scale makes MiniPharm an example of process intensification. The implementation of integrated unit operations decreases handling time of intermediates and reduces the overall footprint for manufacturing. Designed to allow for increased flexibility of operation, perfluoroalkoxy alkane (PFA) tubing was used for synthesis and purification. With PFA tubing clean in place procedures can be implemented using continuous solvent flow or the low cost, PFA tubing can be replaced. The modular nature of the platform also allows for the investigation of individual unit operations for performance evaluation. </p> <p>Finally, a novel continuous solvent switch distillation unit operation was designed and constructed along with customized reactor and crystallizers for process alternative screening for the synthesis and purification of two compounds: Diphenhydramine hydrochloride and Lomustine. Diphenhydramine hydrochloride is a low-value, high volume allergy medication commonly found in Benadryl and Lomustine is a high-value, low volume cancer medication used to treat glioblastoma and Hodgkin Lymphoma. The production of the compounds demonstrated the flexibility of the manufacturing platform to produce both a generic and a specialty medication. A versatile platform is needed for distributed manufacturing because of quickly changing supply chain needs. Overall, this dissertation successfully demonstrates the process design, development, and simulation for small-scale manufacturing.</p>