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Master of Science / Department of Chemical Engineering / James Edgar / The bio-pharmaceutical industry began over 30 years ago with the production of human insulin and has shown incredible growth ever since. With forecasted annual worldwide sales of over $450B in 2025 for biopharmaceuticals, they are expected to be at least 25% of the entire pharmaceutical market. Therapeutics based on monoclonal antibodies (mAbs) make up roughly a third of all biopharmaceutical sales with indications from asthma, to cancer, to Parkinson’s disease. The recent approval of the first biosimilar mAb products in the US and Europe has exposed up to 20 of the top grossing biologic products to competition for the first time, while 75% of the US market is expected to lose patent exclusivity by 2020. With the increased competition from biosimilars, the costs associated with producing mAb based therapeutics will be a constraint on maintaining market share going forward. The majority of the total manufacturing costs for mAbs resides in the downstream processing where Protein A chromatography is the predominantly employed technology for the primary capture step. With Protein A’s high unit cost of up to $15,000 per liter and susceptibility to deamidification when exposed to high pH cleaning and sanitization chemicals, it is no surprise that many mAb manufacturers are considering alternatives. The objective of this work is to review the production process of mAb therapeutics, with a specific focus on the advantages, disadvantages, and alternatives to Protein A affinity chromatography as the primary capture step in downstream processing.

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This thesis describes the evaluation and application of the atomic emission detector as a detector for capillary gas chromatography. Chapter 1 is a general introduction to the technique, describing the development of the atomic emission detector, the theory of its operation, and some of its applications. This chapter also includes a detailed description of chromatography theory. Chapter 2 describes the experimental conditions used throughout the course of this work. Chapter 3 concentrates on compound independent calibration, beginning with a general introduction to the area and a discussion of studies already made. Four groups of compounds were used to determine the ability of the atomic emission detector to perform compound independent calibration. Initial studies with a group of similar hydrocarbons showed little or no compound/structure dependence. However, results from the same study with a group of phenols did indicate some structure dependence for carbon and oxygen, but when chloroanisoles were tested, this compound dependence was not apparent. A group of different nitrogen-containing compounds was then studied. Here structure dependence was observed on all channels, ie carbon, oxygen and nitrogen. It was also noted that the responses became non-linear at higher concentrations. This would normally indicate detector overload, but not in this case as non-linearity occurred to different extents for the same element in different compounds. A study was also made on the effect of discharge tube ageing on response. Clean and dirty discharge tubes were used for the phenols and the nitrogen-containing compounds. The phenol, carbon and chlorine results showed a decreased sensitivity with the old tube, but the oxygen responses were not affected. The same drop in sensitivity was seen with the nitrogen-containing compounds, but here oxygen was also affected. Chapter 4 describes the use of the atomic emission detector and mass spectrometry as complementary techniques. Perfume samples were analysed using both instruments. A comparison of 'real' and 'fake' perfumes was also made. Results indicated that the atomic emission data was useful in deciding whether to accept or reject mass spectral library guesses. Chapter 5 describes the application of the atomic emission detector for the analysis of refinery streams. The use of the 'backamount' correction facility was also effectively demonstrated. Chapter 6 is a general discussion of the instrument including operational problems encountered and possible modifications to overcome these problems. The overall objective of the thesis is to place the GC-AED combination in the context of the commonly used chromatographic techniques.

First the method of gas-liquid chromatography (GLC) has been used to obtain partition coefficients, K, at infinite dilution on polymeric and non-polymeric phases. About 30-40 solutes were studied per stationary phase. Secondly the method of gas-solid chromatography has been used to obtain adsorption isotherms for a series of adsorbents by the technique of elution by characteristic point (ECP). A single injection of a gas or vapour suffices to obtain the isotherm, and then the limiting Henry's law constant, Kh, for adsorption at low surface coverage. About 20-30 solutes were studied per adsorbent. Experiments were carried out at several levels of relative humidity (RH) 0%, 31% and 53%. The solute compounds used were chosen so as to have a wide range of properties such as polarity (pi*2), hydrogen-bond acidity (alpha[H]2), and hydrogen-bond basicity (beta[H]2). The results as log partition coefficients or -log Henry's constants were analysed by multiple linear regression analysis using equations such as: -LogK[H] or LogK = SPo + s.pi* 2 + a.alpha[H]2 + b.beta[H]2 + 1. LogL[18] where L[18] is the solute Ostwald absorption coefficient on n-hexadecane. In this way, the selectivity of the liquid polymeric phase or solid adsorbent towards classes of compound was investigated and equations for the prediction of further values of LogK or LogK[H] formulated. In parallel with the measurement of partition coefficients on liquid polymeric phases by GLC in this work, partition coefficients for the polymers have been determined using surface acoustic wave (SAW) devices by coworkers at the Naval Research Laboratory, Washington. The results for a series of 8-9 solutes in six polymeric phases show that partition coefficients and patterns of responses predicted through GLC experiments are the same as those found experimentally using coated SAW devices. Hence GLC can be used to evaluate possible coating materials, and by the technique of multiple linear regression analysis, to predict SAW responses for a multitude of vapours.

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Orientador: Natália Soares Janzantti / Banca: Maria Regina Bueno Franco / Banca: Magali C. Monteiro da Silva / Resumo: A uvaia (Eugenia pyriformis cambess) é uma fruta exótica que apresenta sabor adocicado e ácido, típica da Mata Atlântica. A revisão da literatura mostrou que, até o presente momento, não existe estudo sobre a composição de voláteis de uvaia, assim como não se conhece os compostos voláteis odoríferos importantes para a sua qualidade sensorial. Os parâmetros físico-quimicos da polpa da uvaia foram avaliados. A polpa de uvaia apresentou teor de sólidos solúveis de 5,0 ºBrix, pH 3,80, ratio de 4,65, teor de ácido ascórbico 54,06 mg/100 mL de polpa, teor de compostos fenólicos totais de 79,94 mg de ácido gálico/100 mL e foi caracterizada como uma fruta de baixa acidez (1,08 g de ácido cítrico/100 mL), conteúdo de açúcares predominantemente de açúcares redutores (açúcares redutores 2,81 g de glicose/100 mL, açúcares totais 2,81 g de glicose/100 mL) e elevada atividade antioxidante total (656,29 μmol de Trolox/100 mL de polpa). Os compostos voláteis da uvaia foram isolados usando a técnica de headspace dinâmico. As condições para o isolamento dos compostos voláteis de uvaia foram a captura por 3 horas e eluição com hexano. O isolado obtido foi representativo da amostra original de uvaia. Os compostos voláteis foram separados por cromatografia gasosa de alta resolução e identificados por cromatografia gasosa-espectrometria de massas, índices de retenção e uso de padrões puros. Foram detectados 55 compostos voláteis, dos quais 43 foram identificados, compreendendo 19 terpenos, 16 ésteres, 3 álcoois, 1 cetona e 4 compostos pertencentes a outras classes químicas. Os compostos majoritários na uvaia foram butanoato de etila com 27,82% da área relativa total do cromatograma, hexanoato de etila com 20,04%, octanol com 8,56%, D-limoneno com 7,16% e vinilbenzeno com 6,57%. Os compostos voláteis do headspace da uvaia foram avaliados por análise... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The uvaia (Eugenia pyriformis cambess) is a Brazilian exotic fruit that presents a sweet and sour flavor, native to the Mata Atlântica. A review of the literature shows that no research has been conducted on the volatile composition of uvaia, as well as on its sensory quality. The physicochemical parameters were analyzed in the uvaia pulp. The uvaia pulp showed 5,0 ºBrix for soluble solids, pH 3,80, ratio 4,65, 54,06 mg ascorbic acid/100 mL pulp, 79,94 mg acid galic/100 mL pulp for phenolic compounds, and was characterized as a low acidic fruit (1,08 g citric acid/100 mL), sugar content predominantly of reducing sugars (2,81 g glucose/100 mL for reducing sugars, 2,81 g glucose/100 mL for total sugars), high antioxidant activity (656,29 μmol Trolox/100 mL pulp). The volatile compounds from the headspace of the uvaia were isolated using the dynamic headspace technique. The conditions fixed for the isolation were three hours of trapping and elution with hexane. The isolate obtained was representative of the original uvaia sample. The volatile compounds were separated by high resolution gas chromatography and identified by gas chromatography/mass spectrometry, retention indices and pure reference compounds. Fifty-five compounds were detected, from which forty-three were identified, comprising 19 terpenes, 16 esters, 3 alcohols, 1 ketone and 4 miscellaneous. Major compounds were ethyl butanoate (27,82% of the chromatogram's total area), ethyl hexanoate (20,04%), octanol (8,56%), D-limonene (7,16%) and vinylbenzene (6,57%). The volatile compounds from the headspace of the uvaia pulp were evaluated by five trained judges using the OSME olfactometry technique. Forty-nine odorants were found in the sample, twenty-eight of which were identified. The most important odorant were ethyl hexanoate, ethyl butanoate, methyl butanoate, ethyl 2-butenoate and hexyl hexanoate... (Complete abstract click electronic access below) / Mestre