Developing a Modular Continuous Drug Product Manufacturing System with Real Time Quality Assurance for Producing Pharmaceutical Mini-Tablets.

The pharmaceutical industry has shown keen interest in developing small-scale modular manufacturing systems for producing medicinal products. These systems offer agile and flexible manufacturing, and are well-suited for use in situations requiring rapid production of drugs such as pandemics and humanitarian disasters. The creation of such systems requires the development of modular facilities for making solid oral drug products. In recent years, however, the development of such facilities has seen limited progress. This study presents a development of a prototype modular system that uses drop on demand (DoD) printing to produce personalized solid oral drug products. The system's operation is demonstrated for manufacturing mini-tablets, a category of pediatric drug products, in continuous and semi-batch modes. In this process, the DoD printer is used to generate molten formulation drops that are solidified into mini-tablets. These dosages are then extracted, washed and dried in a continuous filtration and drying unit which is integrated with the printer. Process monitoring tools are also incorporated in the system to track the critical quality attributes of the product and the critical process parameters of the manufacturing operation in real time. Future areas of innovation are also proposed to improve this prototype unit and to enable the development of advanced drug manufacturing systems based on this platform.

Manufacturing pharmaceutical mini-tablets for pediatric patients using drop-on-demand printing.

The pharmaceutical industry has traditionally manufactured medicines in a limited range of dose strengths, with an emphasis on addressing the needs of the largest patient subgroups. This has disadvantaged smaller patient subsets, such as children, who often cannot find drug products in dosage levels suitable for their requirements. In recent years, development of pharmaceutical mini-tablets has emerged as an attractive solution to this problem. These are small-size dosages that offer attractive features such as flexible and personalized drug dosing, ease of swallowing, and tailored drug release, making them an excellent choice for administering medicines to children. This study presents a novel technique for manufacturing pharmaceutical mini-tablets, using a drop-on-demand (DoD) printing system. In this method, a DoD system is used to generate precise droplets of a melt-based formulation, which are then captured and solidified in an inert solvent bath to produce individual mini-tablets. The study also evaluates the performance of this technique for various formulations, and quantifies two critical quality attributes (CQAs) of the resulting mini-tablets: content uniformity and dissolution behavior. The findings demonstrate that the manufactured mini-tablets can meet regulatory specifications for both CQAs, and that their release profiles can be customized by modifying the excipients used. The study also discusses promising areas of application and limitations of this technique.

Developing a machine learning enabled integrated formulation and process design framework for a pharmaceutical dropwise additive manufacturing printer.

The pharmaceutical manufacturing sector needs to rapidly evolve to absorb the next wave of disruptive industrial innovations - Industry 4.0. This involves incorporating technologies like artificial intelligence, smart factories and 3D printing to automate, miniaturize and personalize the production processes. The goal of this study is to build a formulation and process design (FPD) framework for a pharmaceutical 3D printing technique called drop-on-demand (DoD) printing. FPD can automate the determination of formulation properties and printing conditions (input conditions) for DoD operation that can guarantee production of drug products with desired functional attributes. This study proposes to build the FPD framework in two parts: the first part involves building a machine learning model to simulate the forward problem - predicting DoD operation based on input conditions and the second part seeks to solve and experimentally validate the inverse problem - predicting input conditions that can yield desired DoD operation.

Small-Scale Continuous Drug Product Manufacturing using Dropwise Additive Manufacturing and Three Phase Settling for Integration with Upstream Drug Substance Production.

The pharmaceutical industry has traditionally relied on mass manufacturing to make its products. This has created multiple problems in the drug supply network, including long production times, inflexible and sluggish manufacturing and lack of personalized dosing. The industry is gradually adapting to these challenges and is developing novel technologies to address them. Continuous manufacturing and 3D printing are two promising techniques that can revolutionize pharmaceutical manufacturing. However, most research studies into these methods tend to treat them separately. This study seeks to develop a new processing route to continuously integrate a 3D printing platform (Drop-on-Demand, DoD, printing) with crystallization that is generally the final step of the active ingredient manufacturing. Accomplishing this integration would enable harnessing the benefits of each method- personalized dosing of 3D printing and flexibility and speed of continuous manufacturing. A novel unit operation, three-phase settling (TPS), is developed to integrate DoD with the upstream crystallizer. To ensure on-spec production of each printed dosage, two process analytical technology tools are incorporated in the printer to monitor drug loading in manufactured drug products in real time. Experimental demonstration of this system is carried out via two case studies: the first study uses an active ingredient celecoxib to test the standalone operation of TPS; the second study demonstrates the operation of the integrated system (crystallizer - TPS - DoD) to continuously make drug products for the active ingredient- lomustine. A dissolution test is also performed on the manufactured and commercial lomustine drug products to compare their dissolution behavior.