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- Roch, Patricia, 1988-
(author)
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Monitoring of product variants in biopharmaceutical downstream processing : Mechanistic and data-driven modeling approaches
- 2019
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Doctoral thesis (other academic/artistic)abstract
- During the manufacturing of biopharmaceuticals, a multistep purification strategy is employed to remove process-related impurities and product variants, to achieve high product quality, assuring patients’ safety. To guarantee that biopharmaceuticals are safe and to accomplish quality, strict policies were established by regulatory agencies as well as guiding principles, such as Quality by Design and process analytical technology. To make the manufacturing process economical, relatively high product yield and productivity are also desirable.The removal of product variants often poses a challenge in downstream processing due to their structural similarity to the product resulting in similar behavior. One way of overcoming this issue is to employ additional monitoring tools capable to distinguish between the product and product variants.This thesis demonstrates the development of novel monitoring tools, based on existing monitoring and modeling approaches, to facilitate downstream processing.Existing techniques are evaluated and critically compared toward meeting the requirements on monitoring quality attributes in downstream processing.A mechanistic model-based monitoring tool was established for a reversed phase chromatography polishing step of insulin to predict the elution profile of insulin and two insulin variants. By relying on model-based monitoring a significant increase in product yield was achieved.Further, multi-wavelength fluorescence spectroscopy coupled with the multi-way algorithm parallel factor analysis was utilized to monitor product variants of biopharmaceuticals in downstream processing. This monitoring tool capitalizes on a shift in fluorescence emission between the product and its variant. Developed for monitoring aggregates during antibody purification, the transferability of the approach to other relevant biopharmaceuticals, such as factor VIII and erythropoietin, has been confirmed.The monitoring tools developed in this thesis, extend existing monitoring tools for downstream processing of biopharmaceuticals. When implementing these monitoring tools into the different phases of biopharmaceuticals’ lifespan, their potential could range from optimizing downstream processes during purification strategy development to supporting manufacturing by facilitating process decisions.
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| 3. |
- Randek, Judit, 1990-
(author)
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Advancement of sensor technology for monitoring and control of upstream bioprocesses
- 2020
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Doctoral thesis (other academic/artistic)abstract
- In bioprocesses, the upstream process part with cultivation and harvesting steps has decisive influence on the final process outcome, including the quality of the product, the productivity and the yield. To ensure stable product quality of biopharmaceuticals, the U.S. Food and Drug Administration (FDA) encourages the industry to apply the process analytical technology (PAT) guidelines. These guidelines strongly recommend advancements in sensor monitoring and control technology as the important means for improving performance of pharmaceutical manufacturing.The aim of this thesis is to contribute to this advancement of sensor technology, by proposing alternative ways to apply existing sensors for monitoring and control of upstream bioprocesses. Cutting-edge sensor technologies are evaluated with respect to their suitability for process monitoring of critical process parameters. The sensor technologies are compared with other analytical techniques, mainly based on their performance and applicability for monitoring as well as control of common bioprocesses.To cover diverse bioprocess conditions and requirements, a range of organisms, including bacteria, yeast and mammalian cells, have been used in the thesis. Through this, different needs, obstacles and challenges have been unraveled when culturing these organisms. One of these challenges is the wide span of growth rates of the cells used in production, which limits the number of the sensor technologies that are suitable for accomplishing efficient process monitoring and control. The mammalian cells for example, grow at a low rate, and may therefore allow the use of an at-line measurement technology as the presented screen-printed single-use enzyme biosensor for monitoring of metabolite formation. On the contrary, rapidly growing microorganisms, for example bacteria and yeasts, require faster analytical techniques, such as the in-line capacitance and near-infrared sensors used in the presented studies.This thesis emphasizes the current needs and the importance of providing new and more advanced sensor technology for upstream bioprocess monitoring. The parallel advancements of bioreactor designs, with both stainless steel and disposable bioreactors, further emphasizes the need for a high degree of adaptability of the sensors. As highlighted in the thesis, the advancement of the sensors should also contribute to improve process stability and quality of the product by applying process control methods that efficiently can handle unexpected variations in biological production systems.
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