• Development of Real Time Release Testing of Controlled Release Multiparticulate Drug Delivery System Using the Principles of Quality by Design

      Kothari, Bhaveshkumar H.; Hoag, Stephen W. (2014)
      To develop a control system, for real time release testing of a controlled release multiparticulate drug delivery system, an adequate understanding of polymer film formation and effect of processing parameters on the quality of film formation is essential. Presently, the curing of pseudolatex films is not well understood, and without a proper understanding of film formation mechanisms products without highly variable dissolution cannot be developed. To better understand film formation, the material attributes and process parameters were systematically assessed using risk analysis models like Ishikawa and failure mode and effect analysis (FMEA). This was followed up by a resolution V fractional factorial design to gain process understanding. Information gained was further evaluated using a resolution IV fractional factorial design to identify the critical process parameters that can significantly influence drug dissolution due to poor film formation. The design space was evaluated using different statistical approaches and experiments were conducted using central composite response surface methodology design to map the response surface and determine edge of failure. The in-process control strategy models were developed using diffuse reflectance near infrared spectroscopic technique. The risk assessment models and the statistical experimental designs helped to elucidate the effect of process efficiency and variation of extent of curing during the coating process. The design space was established using two different statistical models and were in close agreement to each other with statistical least square approach being more conservative than the Bayesian approach. The coating process was optimized and design space was built with product temperature, curing temperature and curing time deemed as the most critical process parameters. The effect of humidity on the extent of curing was also characterized and the in-process control strategy models helped determine process trajectory which could serve as the basis for a process control chart and actual endpoint measurement of the coating process. The intrinsic process variability associated with the coating process was successfully studied and in-process models were developed using near infrared spectroscopy and the data fusion method provided new insights into the prediction of dissolution from coated beads.
    • Excipient Screening and Spray Drying Process Optimization of Cell-based and Protein-based Biologics with Feasibility Demonstration of Oral Delivery

      Lu, Yuwei; Hoag, Stephen W.; 0000-0001-7081-3611 (2021)
      Biologics-based therapeutics, such as proteins and cells, have gained increasing popularity over the past few years. Formulation and process strategies have been applied to achieve quality biologics products, prioritizing desired efficacy and safety over shelf –life. In this thesis research, spray drying formulation development strategies were developed for a novel biotherapeutics ABAB antibody producing Sb-ABAB cells for the treatment of Clostridium difficile infection (CDI) and a recombinant human serum albumin (rHSA) using carbohydrate, protein-based, or other excipients and excipient combinations. Excipient functionality was explored using spectroscopy-based chemometrics investigation. In addition, novel mass spectroscopy based in cell-fast photochemical oxidation of proteins (ICFPOP-MS) was used in combination with homology labeling to probe the excipient - protein interactions. In addition, excipients and water activity effects on the storage stability of the Sb-ABAB spray dried product were explored to optimize shelf life. Subsequently, multivariate data analysis and design of experiments (DOE) were applied to explore the effects of spray dry process parameters on critical quality attributes of the protein- based and cell-based biological products. The spray dried protein/cell powders were further developed into oral dosage forms acceptable for patient use, such as tablets and capsules. The feasibility of developing oral protein tablets using IgG as model protein and enteric-coated Sb-ABAB capsules were explored. For example, compression force, particle size and storage relative humidity effects on the stability of the IgG tablets were investigated via analytical and biophysical analysis. In addition, colon targeted delivery of the Sb-ABAB minicapsules was developed and in vitro release assay was conducted to evaluate the enteric coating efficiency. In conclusion, cell-based and protein-based therapeutics were successfully spray dried while achieving desirable stability during the drying process. Furthermore, protein tablets and controlled release Sb-ABAB capsules were successfully developed, offering a novel alternative delivery approach to biologics products.