Quality by Design Procedure for Continuous Pharmaceutical Manufacturing: An Integrated Flowsheet Model Approach

Pharmaceutical manufacturing is crucial to global healthcare and requires a higher, more consistent level of quality than any other industry. Yet, the traditional pharmaceutical batch manufacturing has remained largely unchanged in the last fifty years due to high R&D costs, shorter patent durations, and regulatory uncertainty. This has led regulatory bodies to promote modernization of manufacturing process to continuous pharmaceutical manufacturing (CPM) by introducing new methodologies including quality by design, design space, and process analytical technology (PAT). This represents a shift away from the traditional pharmaceutical manufacturing way of thinking towards a risk based approach that promotes increased product and process knowledge through a data-rich environment. While both literature and regulatory bodies acknowledge the need for modernization, manufacturers have been slow to modernize due to uncertainty and lack of confidence in the applications of these methodologies. This paper aims to describe the current applications of QbD principles in literature and the current regulatory environment to identify gaps in literature through leveraging regulatory guidelines and CPM literature. To aid in closing the gap between QbD theory and QbD application, a QbD algorithm for CPM using an integrated flowsheet models is also developed and analyzed. This will help to increase manufacturing confidence in CPM by providing answers to questions about the CPM business case, applications of QbD tools, process validation and sensitivity, and process and equipment characteristics. An integrated flowsheet model will aid in the decision-making process and process optimization, breaking away from ex silico methods extensively covered in literature

Strategic Biopharmaceutical Production Planning for Batch and Perfusion Processes

Capacity planning for multiple biopharmaceutical therapeutics across a large network of manufacturing facilities, including contract manufacturers, is a complex task. Production planning is further complicated by portfolios of products requiring different modes of manufacture: batch and continuous. Capacity planning decisions each have their own costs and risks which must be carefully considered when determining manufacturing schedules. Hence, this work describes a framework which can assimilate various input data and provide intelligent capacity planning solutions. First of all, a mathematical model was created with the objective of minimising total cost. Various challenges surrounding the biomanufacturing of both perfusion and fed-batch products were solved. Sequence-dependent changeover times and full decoupling between upstream and downstream production suites were incorporated into the mixed integer linear program, which was used on an industrial case study to determine optimal manufacturing schedules and capital expenditure requirements. The effect of varying demands and fermentation titres was investigated via scenario analysis. To improve computational performance of the model, a rolling time horizon was introduced, and was shown to not only improve performance but also solution quality. The performance of the model was then improved via appropriate reformulations which consider the state task network (STN) topology of the problem domain. Two industrial case studies were used to demonstrate the merits of using the new formulation, and results showed that the STN improved performance in all test cases, and even performed better than the rolling time horizon approach from the previous model in one test case. Various strategic options regarding capacity expansion were analysed, in addition to an illustration of how the framework could be used to de-bottleneck existing capacity issues. Finally, a multi-objective component is added to the model, enabling the consideration of strategic multi-criteria decision making. The ε-constraint method was shown to be the superior multi-objective technique, and was used to demonstrate how uncertain input parameters could affect the different objectives and capacity plans in question

Setting up new chemical engineering degree programmes: Exercises in design and retrofit within constraints

The rise in popularity of chemical engineering among students entering university has prompted expansion of the UK provision, through increased intake into current degree programmes and with the rise of new providers. The former entails logistical challenges of processing larger numbers through existing infrastructures whilst maintaining the student experience. The latter entails challenges of designing and introducing programmes that build harmoniously on existing non-chemical engineering provision, within the constraints of university validation procedures and physical resources, and in the face of uncertainty around student and staff recruitment, while aspiring to implement best practice in chemical engineering content and pedagogy. Following a review of the UK chemical engineering landscape and a critique of literature guidance on the appropriate content of chemical engineering curricula, this paper illustrates the issues of new programme development through the approaches and experiences of a new provider, the University of Huddersfield, which introduced new chemical engineering programmes from academic year 2013-14. The paper addresses specifying the content of chemical engineering programmes to align with accreditation requirements and literature advice while maintaining distinctiveness. The constraints imposed by the need to specify and validate courses internally and to minimise substantive programme changes subsequently, whilst responding to the opportunities that arise as staff are recruited and to external developments and unplanned incidents, are highlighted and illustrated, in order to draw lessons that might help to guide other new entrants

Synthesis and evaluation of pharmaceutical and fine chemicals processes for intensification and sustainability benefits

PhD ThesisIn the face of global competition and tighter safety and environmental regulations, the pharmaceutical industry is exploring new areas and technologies that could potentially bring about step change in process performance. Process intensification has the potential to improve early development by introducing new process options, which are capable of achieving green and sustainable benefits in production. In this thesis, the objective is to demonstrate the synthesis and evaluation of pharmaceutical processes for intensification and sustainability benefits. This is illustrated with two main processes – the amidation process and the ortho-lithiation process. Based on the experiences gained at the end of the case studies, a general framework that summarizes the approach to Process Intensification (PI) for pharmaceutical processes is developed. Firstly, the amidation process has been successfully intensified with the implementation of a number of PI options, which are proven feasible in lab-scale experiments. These options are represented in terms of three intensified cases - the intensified batch case, the continuous reaction case and the continuous process case, are compared to the batch base case. To compare their sustainability performance, the respective plants are designed at a hypothetical throughput of 3 tons per year. Overall, the intensified batch case provided the most benefits, with cost savings of up to 40%, and more than 70% improvements in total material efficiency and E-factor compared to the batch base case. This also indicates that batch mode operation in this particular process is more suitable than continuous mode. The second case study on the ortho-lithiation process consists of three parts. The first part investigates ortho-lithiation reaction in continuous flow reactors at ambient temperature. The findings demonstrated that the highest reaction yield of 99% was obtained in a T-reactor as a result of short residence time and good mixing. The Spinning Disc Reactor (SDR) also showed distinct advantage in handling this reaction with mild solid precipitation. The second part focuses on the comparison of the T-reactor, the SDR and the Stirred Tank Reactor (STR) based on the sustainability metrics. The results showed that the T-reactor process achieved 66% and 11% reduction in energy consumption and operating expenditure respectively as compared to the STR process. The last part of the ortho-lithiation process focuses on the study of the whole process including workup. To avoid dealing with inefficient separation process, consecutive reaction has been attempted by avoiding the isolation of ortho-lithiation crude product and directly transferring it into the next reactor for subsequent reaction. This is experimentally proven feasible and resulted in a greener process.GSK-EDB Singapor

Process intensification for post combustion CO₂ capture with chemical absorption: a critical review

The concentration of CO₂ in the atmosphere is increasing rapidly. CO₂ emissions may have an impact on global climate change. Effective CO₂ emission abatement strategies such as carbon capture and storage (CCS) are required to combat this trend. Compared with pre-combustion carbon capture and oxy-fuel carbon capture approaches, post-combustion CO₂ capture (PCC) using solvent process is one of the most mature carbon capture technologies. There are two main barriers for the PCC process using solvent to be commercially deployed: (a) high capital cost; (b) high thermal efficiency penalty due to solvent regeneration. Applying process intensification (PI) technology into PCC with solvent process has the potential to significantly reduce capital costs compared with conventional technology using packed columns. This paper intends to evaluate different PI technologies for their suitability in PCC process. The study shows that rotating packed bed (RPB) absorber/stripper has attracted much interest due to its high mass transfer capability. Currently experimental studies on CO₂ capture using RPB are based on standalone absorber or stripper. Therefore a schematic process flow diagram of intensified PCC process is proposed so as to motivate other researches for possible optimal design, operation and control. To intensify heat transfer in reboiler, spinning disc technology is recommended. To replace cross heat exchanger in conventional PCC (with packed column) process, printed circuit heat exchanger will be preferred. Solvent selection for conventional PCC process has been studied extensively. However, it needs more studies for solvent selection in intensified PCC process. The authors also predicted research challenges in intensified PCC process and potential new breakthrough from different aspects