Hassan, I; (2012) A Techno-Economic Framework for Assessing Manufacturing Process Changes in the Biopharmaceutical Industry. Doctoral thesis , UCL (University College London).

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Abstract

Industry pressures encourage and sometimes ‘force’ biopharmaceutical companies to implement process changes throughout a product’s lifecycle, so as to enhance yields, purity, robustness and cost-effectiveness. However, making a change involves technical, regulatory, and clinical risks. Possible changes to a product’s quality mean that all changes must be backed-up either with non-clinical bioequivalence studies or with lengthy and costly clinical trials and approved by regulatory authorities. These hurdles combined with the upfront costs can results in a tendency to avoid changes, whereas they may represent economic opportunity if evaluated holistically. This thesis explores the possibility of creating a systematic evaluation framework that captures the technical and regulatory activities involved in process changes to rapidly gauge the potential cost and risk implications. Fundamentaldrivers and consequencesof making bioprocesses changes were benchmarked in a survey to help create the framework model. Key technical activities were captured, namely development, manufacturing, retrofitting and validation at all stages of development. Impacts of changes were linked to regulatory activities needed to assess comparability. Resulting uncertainties such as the likelihood of repeating clinical trials, market losses, delays to market from retrofit, revalidation, or regulatory approval disruptions, and the costs involved in proving product equivalence were captured. The framework was translated into Microsoft Excel with macros for Monte Carlo simulations to account for the uncertainties. Minor and major change scenarios based on the purification of polyclonal IVIG by means of a blood-plasma fractionation process were used to demonstrate the usefulness of the proposed framework. The impact of ‘forced’ and optional changes were compared at different stages of development. Changes made during late-phase development resulted in market share losses and delays that outweighed any yield improvement modifications. The model predicted that it would be more profitable to make process modifications either during early phase development or post-product approval assuming stockpiling of approved product was feasible. The feasibility of purifying a new product, alpha-1 antitrypsin (AAT) from a waste fraction, Fraction IV precipitate, was another process change scenario explored using scale-down studies. Experimental trials of the preliminary filtration and anion exchange purification steps were carried out, yielding low recoveries of AAT. Ciphergen®’s SELDI-TOF-MS ProteinChip technology was used to investigate the value of using a high throughput optimisation method to improve the isolation of AAT. Quantitative analysis of the protein samples using the Ciphergen® was compared to well-established protein concentration determination methods, eliminating variability in samples and differences in MS intensity by normalising the data. The work in this thesis has demonstrated the usefulness of a combined business, technical and risk approach for evaluating the risks and benefits of implementing process changes.

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