Overall Conclusions

An introductory background to the biopharmaceutical drug development and manufacturing pathway has been presented in Chapter 1. The recent surge in demand for antibodies has increased the need for large-scale efficient production of these biochemical entities. Early process development is necessary to enhance manufacturing operations in order to streamline timescales whilst containing costs.

The application of computer-aided design tools is critical to aid process design and development of biochemical processes. The need for a bioprocess simulator that captures both the business and process perspectives of biopharmaceutical manufacturing is becoming increasingly important. However, process performance is affected by the need to comply with regulatory practices and to cope with randomness inherent in the system. Existing simulators often lack the capabilities to reflect regulatory conformation and incorporate uncertainties. These factors provided part of the impetus and motivation for this research, which examines the capacity of a bioprocess simulator to provide a business-process interface, model regulatory-compliance activities and incorporate risks in processes subject to uncertainty.

In Chapter 2, the industrial production of Mabs for large-scale applications is described as this provided the basis for the case studies in Chapters 5 and 6. There exist various expression techniques and cell culture methods for the commercial production of protein-derived products. A review of published literature indicated that mammalian cell culture is the most common technology for the expression of such recombinant proteins. The industry has converged on using stirred tank bioreactors as the standard technology for large-scale production of antibodies. Fed- batch and perfusion cultures are the two dominant modes of operation used for such mammalian-based processes. Typical industrial issues concerning the manufacture of antibodies, which provide the foundation for the case studies in this thesis, are highlighted. An investigation of the commercial production methods for Mabs enabled generic mammalian-based processes to be identified that were subsequently used as the basis for the unit operations included in the tool domain. Recent technologies used in the development of antibodies were discussed so as to assess future trends in antibody production.

The development and implementation of a prototype tool, BioPharmKit, to model bioprocess operations in the manufacture of monoclonal antibodies is illustrated in Chapter 3. The main objective was to formulate a decision-support tool to compute cost measures, simulate resource handling, perform mass balance calculations and incorporate risks in order to facilitate the transparency and ease of decision-making in the biopharmaceutical industry. The conceptual framework seeks to integrate the technical, operational and economic aspects of biopharmaceutical manufacture. The hierarchical task-oriented approach employed in this work was adapted from previous work at University College London (UCL) and has been extended to include regulatory compliance activities. Such an approach enables the rapid modelling of information at different levels of details. The tool architecture also permits the explicit modelling of ancillary tasks such as equipment cleaning and regulatory activities, so as to estimate more accurately operative measures such as costs and resource utilisation. The graphical illustration and dynamic simulation of the process offers a comprehensive perspective of the modelling system. The economic feasibility and effectiveness of manufacturing options can be evaluated by examining key performance metrics such as the cost of goods, capital investment and net present value (NPV). Incorporating risk analysis permits the evaluation of potential risks associated with different manufacturing strategies and enhances the quality of decision-making within a company.

The usefulness of the simulation tool developed in this thesis is explored in Chapter 4. The tool can be employed to model a new plant during the early design stage. In addition, the tool can act as a platform to simulate optimal operating scenarios using existing plant capacity. It can also describe a range of case studies and help to address the typical problems facing the industry. Effective use of the simulation outcomes can contribute to improved process development, more efficient use of resources and result in worthwhile comparisons of manufacturing alternatives. The application of the prototype tool for accessing the impact of manufacturing alternatives on technical and financial performance metrics was demonstrated via industrial-related case studies in the subsequent chapters.

A typical issue in perfusion culture is how often to pool the fermentation broth in order to utilise fully resources while reducing operating costs. In the case study

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-Chapter 7. Conclusions and Future Work

described in Chapter 5, which assessed the most appropriate pooling strategies in perfusion mode using mammalian cell culture, the modelling tool indicates how manufacturing options affect the demands on resources and manufacturing costs. A deterministic case was initially carried out and validated by industrial experts to ensure the outputs were computed correctly. A sensitivity analysis was then performed to determine the impact of individual variables on key output parameters.

The effects of fluctuating titres, process yields and risk of contamination were analysed using the Monte Carlo simulation technique in order to reflect the inherent variability of process parameters during the operation of a biopharmaceutical plant.

The stochastic simulation forecasts a range of possible outcomes, determines the likelihood that the key performance metrics could exceed a critical threshold, and computes the expected performance of the model in order to facilitate process analysis. Possible scenarios regarding the stability of product cell line and downstream purification scale were analysed to gain further insight into relevant events and enhance the decision-making.

Fed-batch and perfusion cultures are capable of achieving large-scale production of antibodies. Although the fed-batch culture has predominated, there has been increasing use of perfusion culture in recent years due to the high productivity achieved in such culture system. The use of the decision-support tool to compare the economic feasibility of both culture modes was investigated in Chapter 6. In the deterministic analysis, the values of the key economic and process output parameters were determined. To take into account the inherent variability of process variables, the key uncertainties in the system were identified and a sensitivity analysis was then performed to investigate the impact on output parameters. Another objective of this chapter was to compare risk analysis methods, such as the decision tree and Monte Carlo simulation techniques, to account for risk factors with known probabilistic characteristics. An illustration of how to determine the probabilistic cases and compute the expected output values using a decision tree was provided. The decision tree analysis provided a simple and efficient approach to select between manufacturing alternatives based on the expected values of performance metrics.

The limitation of the decision tree analysis was found to be the inability to explicitly acknowledge the underlying uncertainty in the contributory estimates and to consider parallel events that could happen. A Monte Carlo analysis was then performed to

provide a more accurate estimation of the overall uncertainty. Such a technique incorporates input parameters with probability distributions, generates frequency distributions for each designated output and computes various statistical summaries featuring the outputs. However, unlike decision trees, the Monte Carlo technique is more time-consuming in terms of computation and does not explicitly make a decision.

The work carried out in this thesis presents the design and implementation of a decision-support tool that links both the process and business aspects of biopharmaceutical manufacture. The tool, BioPharmkit, has customised built-in features specific for bioprocesses including costing functions to determine plant cost, operating costs and profitability of manufacturing options, mass balance models to calculate process data, risk parameters to carry out risk assessment and a graphical interface to build model flowsheets. In addition, the tool offers the ability to create newer unit operation models. Key disadvantages of the approach are that significant effort was required to customise existing unit operations models. This is because BioPharmkit does not have the availability of bioprocess models and sufficient data required to accommodate more rigorous and sophisticated models. Despite the limitations mentioned, the potential rewards of such a bioprocess simulation tool are significant. The benefits of the simulation tool for strategic decision-making have been demonstrated through application to industrial-related case studies. It is envisaged that such a tool might be used during the early stage of process development, which can lead to faster time-to-market, more efficient use of resources and enhanced the economic performance of a company.