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The municipal association Norrvatten produces drinking water at Görväln WTP for approximately 700,000 residents in 14 member municipalities in the northern Stockholm region. To ensure the drinking water meets quality criteria, the water must be carefully monitored by the WTP. At Norrvatten there are several rapid filters that remove different types of particles, mainly residues from the previous flocculation step. The running time of the filters can be limited by a filter breakthrough, which means that the filter must be regenerated through backwashing. To detect a filter breakthrough, turbidity measurement is used. A new advanced AI method, a particle meter, from the manufacturer Uponor is installed at several locations at Görväln WTP. The particle meter is being evaluated as a possible complement to the standard turbidity measurement. The particle meter is a type of advanced image interpretation software that measures and categorizes particles that may indicate disturbances in the drinking water production.I n this project, particle meters placed on-line in three different rapid filtrates were compared with existing on-line turbidity measurements. The aim was to investigate whether the particle meter could detect a filter breakthrough earlier than a turbidimeter and whether the particle meter added any additional valuable information for drinking water production. Data from the period 1 May 2022–30 April 2023 was evaluated in Acurve and Excel. Periods where filter breakthrough occurred in filters denoted A, B and C were evaluated to see which method indicates a filter breakthrough the fastest. During the studied period, eight filter breakthroughs occurred in filter C (quartz sand), three in filter A (Filtralite NC 0,8-1,6 mm) and none in filter B (Filtralite 70% NC 0,8-1,6 mm and 30% HC 0,5-1 mm. Rapid filter B has a lower flow rate than filter A and C, which contributes to no breakthroughs being found. The particle meter could not detect a filter breakthrough faster than existing turbidimeters. However, total particles correlated with the trend of turbidity between March–June, which could be explained by the higher abundance of B-particles. During the remaining months, turbidity and total particles followed completely different trends. Therefore, the particle meter could potentially be used to detect algal blooms online early during spring, compared to the weekly laboratory analysis of algae. This is also supported by algae in raw water correlating with the trend of B-particles in the rapid filtrate. Periods where the turbidity was below 0,10 FTU and total particles exceeded 100,000 pcs/ml in filters A, B and C were selected to investigate whether the particle meter provided any additional valuable information. Six events for total particles exceeding 100,000 pcs/ml were found in filter C, two in filter A and none in filter B during the examined period. The lower flow rate as well as the material combination in Filter B could contribute to no events being found. The material in Filter A could also contribute to a lower number of events compared to Filter C. The small particle category, 3 𝜇𝑚 , dominated during these periods and is prone to false detections due to fouling of the particle meter. The particle category that correlated with total particles was small particles in filter A and a mixture of B-and F-particles in filter C. B-and F-particles often followed the same trend which could be because particles, mainly algae, have been categorized into both categories at the same time. Events where total particles >100,000 pcs/ml occur means that there are particles in the filtrate periodically which the rapid filters cannot separate, and which are not detected by the turbidimeter. However, these results could be a consequence of false detections. The particle categorization of the particle meter does not seem to be finished, as only a few of the total particles have been categorized as either B-, C-, F- or small particles. This leads to difficulty in interpreting and using the produced data. / Kommunalförbundet Norrvatten producerar dricksvatten på Görvälnverket till ungefär 700 000 invånare i 14 medlemskommuner i norra Stockholmsregionen. För att säkerställa att dricksvattnet uppfyller de kvalitetskriterier som finns måste vattnet noggrant kontrolleras av vattenverket. Hos Norrvatten finns flertalet snabbfilter som avlägsnar olika typer av partiklar, främst rester från den föregående flockningssteget. Filtrets gångtid kan begränsas av ett filtergenombrott, som leder till att filtret måste regenereras genom backspolning. För att upptäcka ett filtergenombrott används turbiditetsmätning. En ny avancerad AI-metod, en partikelmätare, från tillverkaren Uponor är installerad på flertalet platser i Görvälnverket. Partikelmätaren utvärderas som ett möjligt komplement till den vanliga turbiditetsmätningen. Partikelmätaren är en typ av avancerat bildtolkningsprogram som mäter och kategoriserar partiklar som kan indikera störningar i dricksvattenberedningen. I det här arbetet jämfördes partikelmätare placerad on-line i tre olika snabbfiltrat med existerade on-line turbiditetsmätning. Målet var att undersöka om partikelmätaren kunde upptäcka ett filtergenombrott snabbare än en turbidimeter samt om partikelmätaren tillförde någon ytterligare värdefull information för dricksvattenberedningen. Data från perioden 1 maj 2022–30 april 2023 utvärderades i Acurve och Excel. Perioder där filtergenombrott skett i filter benämnda A, B och C utvärderades för att se vilken mätare som indikerar ett filtergenombrott snabbast. Under den studerade perioden inträffade åtta filtergenombrott i snabbfilter C (kvartssand), tre i snabbfilter A (Filtralite NC 0,8–1,6 mm) och inga i snabbfilter B (Filtralite 70% NC 0,8–1,6 mm och 30% HC 0,5–1 mm. Snabbfilter B har lägre flöde än filter A och C, vilket kan vara en orsak till att inga genombrott hittades. Partikelmätaren kunde inte påvisa ett filtergenombrott snabbare än redan existerande turbidimeter. Däremot korrelerade totala partiklar med trenden för turbiditet mellan mars–juni, vilket kan förklaras av den högre förekomsten av B-partiklar. Under resterande månader följde turbiditet och totala partiklar helt olika trender. Därför skulle partikelmätaren potentiellt kunna användas för att upptäcka algblomningar on-line tidigt under våren, jämfört med de veckovisa laboratorieanalyserna av alger. Detta stöds också av alger i råvatten som korrelerar med trenden av B-partiklar i det samlade snabbfiltratet. Perioder där turbiditeten var lägre än 0,10 FTU och totala partiklar översteg 100 000 pcs/ml i filter A, B och C valdes ut i syftet att undersöka om partikelmätaren tillförde någon ytterligare värdefull information för dricksvattenberedningen. I den undersökta perioden hittades sex event där totala partiklar översteg 100 000 pcs/ml i filter C, två i filter A och inga i filter B. Den lägre flödeshastigheten samt materialkombinationen i filter B skulle kunna vara orsaken till att inga event hittades. Materialet i filter A skulle också kunna bidra till det lägre antalet event jämfört med filter C. Små partiklar, <3 μm, dominerade under dessa perioder som är en kategori där felavläsningar är vanligt vid fouling av partikelmätaren. Den partikelkategori som korrelerade med totala partiklar var små partiklar i filter A och en blandning av B-och F-partiklar i filter C. B-och F-partiklar följde ofta samma trend vilket skulle kunna bero på att partiklar, främst alger, har blivit indelade i båda kategorierna samtidigt. Att totala partiklar >100 000 pcs/ml förekommer i perioder innebär att det finns partiklar i filtratet periodvis som snabbfiltren inte kan avskilja och som inte detekteras av turbidimetern. Dessa resultat skulle dock kunna vara en konsekvens av feldetektion. Partikelkategoriseringen hos partikelmätaren verkar inte vara helt färdig hos Norrvatten då endast ett fåtal av de totala partiklarna har blivit kategoriserade som antingen B-, C-, F- eller små partiklar. Detta leder till en svårighet i att tolka och använda framtagna data.

A general, non-iterative design technique for low shapefactor, transversal filters is presented. This design approach uses two cosine series to specify appropriate eigenfunctions. An infinite set of such eigenfunctions are defined and the method for choosing the coefficients is discussed. The total filter response is specified as the product of two individual frequency responses. The impulse response of each is then determined by applying the superposition of appropriate eigenfunctions. The criteria for choosing the appropriate eigenfunctions is discussed. A synthesis procedure for designing surface acoustic wave filters is presented. The effects of truncating the impulse response are also explored. A design example is shown for a filter with 10 percent fractional bandwidth and a shapefactor of 1.15.

In dieser Arbeit werden mit einem Raumtemperatur-Modellsystem die Wechselwirkungen und Überlagerungen der verschiedenen Einflussparameter auf die Partikelabscheidung in keramischen Tiefenfiltern dargestellt. Aussagen zum zeitlichen Beladungsverhalten, dem Einfluss der Strukturparameter und der Oberflächenrauheit der Filter auf die Abscheidung werden diskutiert. Außerdem wird die Abscheideeffizienz in Abhängigkeit der Eigenschaften der Verunreinigungen (Größe, Agglomeratzustand, Dichte), sowie dem Vorhandensein von Mikro- oder Nanogasblasen untersucht. Mit Hilfe der Computertomografie können die im Filter abgeschiedenen Verunreinigungen lokal abgebildet werden, was zum Verständnis der in schaumkeramischen Filtern ablaufenden Prozesse bei der Aluminium-Schmelzefiltration beiträgt. Ergebnisse einer dynamischen Bildanalyse lassen Rückschlüsse auf den Fraktionsabscheidegrad der Filter zu.

Therapeutic viruses are a class of biotherapeutic which have enabled new treatments and medical advances in the areas of vaccines, cancer treatment, gene therapy, and more. In the production and purification of these products, the sterile filtration unit operation is known to have poor yields and contribute to the high cost of the final product, significantly hampering the large-scale production of some therapeutic viruses. Thus, this thesis seeks to explore various aspects of process development and fundamental understanding in the sterile filtration of therapeutic viruses. This thesis explores the mechanisms and membrane properties which govern how bacteria are retained during filtration, and applies these insights to improve the sterile filtration recovery of a therapeutic virus through proper membrane selection. To better understand the factors which cause membrane fouling and loss of virus during sterile filtration, the effect of host cell impurities on filtration performance was investigated. This revealed that small amounts of host cell protein are a major factor in both membrane fouling and reduced virus yield, and that there is a synergistic effect between the virus and the host cell protein adsorbing to the membrane surface. Recognizing that conventional polymeric membranes have many limitations, a novel ultrathin, isoporous, microfabricated silicon nitride membrane was tested for suitability as a sterile filter. Finally, the application of nanoparticles as model virus particles in filtration testing was examined, and a process was developed through which nanoparticles could be fused together to create controlled amounts of particle aggregates, similar to how viruses can be prone to aggregation. The work described here will help enable the development of next generation sterile filtration membranes and provides both insights and methodologies for improving sterile filtration performance. / Thesis / Doctor of Philosophy (PhD) / While many people are aware that viruses can be used in medicine as vaccines, there are even more new and developing ways they can be used, such as in fighting cancer or treating previously uncurable diseases. However, testing of and patient access to these new treatments is often limited due to the challenges in producing and purifying enough of the virus. Viruses are highly complex and large relative to other products, and so many of the common methods and manufacturing processes which are standard in the industry need to be significantly adapted or improved to suit the production of viruses. This study investigates one step of the purification process, sterile filtration, and considers how a variety of factors from the materials used to the properties of the virus solution can be optimized to improve performance. With a deeper understanding of the sterile filtration process, recommendations can be made to help improve the production of future virus-based therapies.

Oncolytic viruses (OVs) are a class of cancer therapy that is currently undergoing clinical trials on its way to full regulatory approval. At present, the downstream processing of OVs relies on a combination of chromatography and membrane-based processes to remove process-related (e.g. host-cell proteins and nucleic acids) and product-related impurities (e.g. aggregated virus particles). This thesis explores various methods that can potentially be used to address the challenges associated with downstream processing during the production of OVs. To this end, the Rhabdoviral vector, which is currently undergoing clinical trials (phase I/II) for use in treating advanced or metastatic solid tumors, was selected as a promising oncolytic virus. One potential improvement in the downstream process that was investigated was the use of monolithic column chromatography for Rhabdovirus purification. Two monolithic anion-exchange columns (2 and 6 µm pore size) and one hydrophobic interaction column (6 µm pore size) were used to examine how column pore size affects virus recovery and contaminant removal. This investigation ultimately inspired the development of a purification process based on monolithic hydrophobic interaction column chromatography. Furthermore, this work is also the first to investigate how additives, namely glycerol, impact the hydrophobic interaction chromatography of virus particles. The developed process could be readily implemented for the scaled-up purification of the Rhabdoviral vector. Another challenge associated with the downstream processing of OVs is membrane fouling, which is characterized by a dramatic rise in transmembrane pressure (TMP) and low virus recovery. Indeed, membrane fouling poses a significant challenge, as some recent studies have reported that it can result in viral vector titer losses of over 80%. One critical use of membranes in downstream processing is for the sterile filtration of OVs, which is a required final step that is conducted right before vialing and involves passing the virus particles through a validated sterile filter. One of the main objectives of this thesis was to develop a fundamental understanding of the sterile filtration process and to optimize it in order to achieve higher throughput and lower losses, which are both essential to the large-scale production of OVs. To this end, a dead-end sterile filtration setup was designed, and various commercially available filters were evaluated to examine how membrane morphology affects fouling and product recovery. The results of these tests showed that double-layered composite filters enabled higher virus recovery and filtration capacity compared to single-layered sterile filters. Another cause of membrane fouling is the aggregation of virus particles, which is mediated by various interactions in the solution. To study this, the above-described setup was re-designed to create an effective procedure that utilizes minimal volumes of virus solution, while also enabling the rapid assessment of microscale filtration performance and a comprehensive understanding of virus-virus and virus-membrane interactions. This setup was used to study how different additives, including various proteins (bovine serum albumin and α-lactalbumin) and polymers (polyethylene glycol and polyvinylpyrrolidone), affect the microfiltration of the Rhabdoviral vector and, consequently, the TMP profile. Furthermore, the correlation between the membrane fouling rate (via TMP profiles) and virus recovery was also investigated. This investigation revealed that proteins significantly increase virus transmission and that polymers are incapable of mimicking the effects of the proteins. To explain this phenomenon, a theory based on the biophysical structure of proteins, mainly heterogenicity in charge distribution, was proposed. Moreover, membrane surface modification tests were conducted using bovine serum albumin, with the results indicating that this approach has considerable potential for enhancing virus transmission. Due to the similarities between the test setup and actual downstream processing unit operations, the results from this part of the thesis could be easily and accurately applied to process optimization. / Thesis / Candidate in Philosophy / There is considerable interest in the development of oncolytic viruses for cancer immunotherapy. Indeed, at the time of this thesis’ writing, a Canadian team of researchers is conducting the world’s first clinical trial using a combination of two viruses to kill cancer cells and stimulate an immune response. The process of manufacturing oncolytic viruses is generally divided into two major steps: upstream processing and downstream processing. While upstream processing focuses on virus propagation, downstream processing aims at removing process-related and product-related impurities. However, research into downstream process design and optimization has largely been neglected in favour of a focus on upstream processing, aimed at increasing bioreactor yields and achieving high viral titers. Consequently, downstream processing has become the main bottleneck in virus manufacturing processes, accounting for as much as 70% production costs. This thesis aims to identify and develop a fundamental understanding of the main challenges associated with the downstream processing of oncolytic viruses and to investigate methods for addressing them. Specifically, the present work focuses on the purification and final sterile filtration steps in the manufacturing of oncolytic Rhabdoviral vectors.