The main hypothesis of this research project was that optimisation of treatment based on pharmacokinetic principles is on its own a powerful approach in improvement of treatment outcomes. This work therefore focused on optimisation of treatment of cancer based on principles of pharmacokinetics using two main approaches 1) lipophilic prodrug approach to specifically target the intestinal lymphatic system following oral administration and 2) identification of orally bioavailable candidate anticancer agents and biopharmaceutical development to increase the bioavailability for sufficient systemic exposure to the drug. The first approach was the prodrug derivatisation to take advantage of the physiological process of intestinal lymphatic transport in order to deliver anticancer agents to the mesenteric lymph nodes. Similar prodrug approaches have been researched by other groups but the main focus previously was on increasing the overall bioavailability where they mostly used long-chain or triglyceride mimetic prodrug moieties. However, in this project, through a series of stability and chylomicron association studies, it was revealed that activated ester prodrugs are the most suitable forms for yielding high concentrations of active drugs in the mesenteric lymph nodes. It was remarkable that using this novel approach significantly higher concentrations of the active drugs were achievable in the intestinal lymphatics without affecting the systemic exposure. The second approach taken in this PhD project was achieving sufficient systemic exposure of anticancer agents by identification of orally bioavailable candidate and improvement of oral bioavailability by biopharmaceutical development. The candidates with promising pharmacokinetic properties were rank-ordered by application of a rational drug discovery and development approach of integrated in vitro-in silico assessments. Following in vivo confirmation studies, oral bioavailability was further enhanced for a compound that exhibited a double-peak phenomenon. The results of the two approaches indicate that pharmacokinetic optimisation can be useful in development of anticancer agents to improve the treatment outcomes of cancer.

In order to achieve drug delivery via the respiratory route, an understanding of particulate interactions is of vital importance. For successful delivery to the distal airways, an aerodynamic diameter of less than 5 μm must be achieved. However, particles of this size presents a difficult formulation challenge, due to the inherent cohesiveness between particles and adhesion to the device, due to the high surface to volume ratio of such small particles, causing the particles to clump together. This tendency will thereby cause a reduction in dispersion, aerosolisation and device efficiency; for this reason dry powder inhalers (DPIs) invariably fail to achieve a fine particle fraction efficiency above 15%. There are a wide variety of factors which affect particulate interactions including; surface roughness, surface chemistry, particle size or shape and particle mechanical properties. However, these factors are highly interrelated and so previous attempts to investigate their effect on particle adhesion generally have difficulty isolating the impact of each factor. For instance, investigating the effect of morphology on particulate interactions invariably utilise destructive techniques to alter the roughness, which is likely to alter other factors like surface energy and provide limited control for optimisation. With the rise of 3D printing (additive manufacturing) there is now the capability to produce sub- micron morphologies, and so a bottom-up approach to studying the effect of morphology on particulate interactions can be achieved. The aims of this thesis are therefore twofold. Firstly, to identify, optimise and evaluate a suitable additive manufacturing technique to produce well-defined micron scale morphologies appropriate for furthering the understanding of the importance of morphology on particle adhesion. This is a scale which is at least two orders of magnitude improvement on current state of the art 3D inkjet printers. Secondly, to measure the effect on particle adhesion and deposition to these morphologies, both on an individual particle and on a bulk powder basis, allowing elucidation and understanding of the effect of surface roughness on particle adhesion, with a specific focus on respiratory drug delivery. Printing well defined geometries of an appropriate micron scale size range for particle adhesion testing has been achieved, using two photon polymerisation (TPP). TPP is a novel 3D printing technique which as its name suggests involves the curing of usually acrylate containing polymer resins by the absorption of two infra-red photons in the focus of the laser beam. TPP has been shown to produce a sub-diffraction limit lateral resolution of 120 nm. By optimising the printer parameters and experimentation with differing structure fill and input settings the creation of a well- defined curve on a micron scale was achieved. The initial test morphologies comprised of a ridge with a semi-circular top with a diameter of 1 μm, which were shown to be reproducibly printed. These morphologies were then varied in a controllable fashion with varying ridge height and spacing between the ridges. A uniform and consistent surface chemistry was created using a plasma polymerised hexane (ppHex) coating. In order to evaluate particulate interactions relevant to pulmonary drug delivery both an understanding of the effect of morphology on both individual particle adhesion and bulk powder deposition in a fluid environment is needed. Individual particle-surface adhesion was achieved by testing the TPP structures against three particle types using single particle colloidal probe microscopy (polystyrene beads diameter 10 μm and 5 μm and a lactose particle designed for inhalation formulations). The analysis of this data provides evidence of a clear trend between particle contact area and adhesion recorded both on the ppHex control and the TPP coated morphologies. The TPP morphologies are shown to locally reduce the overall adhesion, in comparison to the flat substrate. The ridge height is also seen to have a significant effect on particle adhesion, with 5 μm < 3 μm < 1 μm for the polystyrene beads, but 3 μm < 5 μm < 1 μm for the Respitose SV003 lactose particle for all ridge spacings. Varying the ridge spacing produced two differing trends in adhesion to the polystyrene beads. If the particle was unable to penetrate the valleys of the roughness, for the 1 μm high ridges, a significant effect on particle adhesion was seen with 3 μm < 1 μm for the polystyrene beads. In contrast, the 3 μm and 5 μm high ridges showed the opposite trend when the particle is unable to descend between the ridges with 1 μm < 3 μm < 8 μm for the polystyrene beads. Investigation of the bulk powder deposition of the particles on the TPP structures and any subsequent re-entrainment in a fluid environment was then achieved using a novel methodology developed during the course of this work. This combines the use of a standard next generation impactor, which generally is used to separate out a respiratory formulation based on aerodynamic diameter, with the TPP substrates. This shows that ridge height has a significant effect on particle adhesion with 3 μm < 1 μm < 5 μm. In contrast, the different spacings of the ridges were not shown to produce a significant difference in particle deposition. This is likely due to the conflicting effect of asperity spacing on the processes of particle deposition and re-entrainment. This thesis therefore highlights the capability of TPP, to produce well-defined micron scale structures with varying morphologies. It then shows that these can be successfully utilised to provide valuable insight into the effect of surface morphology on particle- surface interactions, specifically; adhesion, deposition and re-entrainment.

The pharmaceutical industry has experienced an increase in the amount of development candidates with low aqueous solubility and accordingly poor bioavailability. In order for this problem to be solved, amorphisation is thought to be the most favourable solution. The amorphous state is higher in free energy thus higher in solubility when compared to the crystalline form. Milling and specially cryomilling is a very unique technique for providing of the crystalline to amorphous transformation since there are no heat or solvents involved. Phthalic acid, isophthalic acid and terephthalic acid, individual and pair mixtures, are crystalline organic non medicinal compounds, which have been used for the first time as model compounds to investigate whether cryogenic milling can induce crystal to amorphous transformation and if the preparation of pair mixtures could affect the recrystallization rate of the subjected materials or not. The materials were cryomilled and analysed by DSC, XRPD, and FTIR. It was found that only terephthalic acid become amorphous after cryomilling, and even after the cryomilled sample been stored for three weeks DSC thermogram still detects recrystallization exothermic along with the XRPD pattern, which shows a very broad peaks indicative of particle size reduction. Pair mixtures were also studied and analysed by DSC and XRPD. Phthalic acid/isophthalic acid, isophthalic acid/terephthalic acid, phthalic acid/terephthalic acid were cryomilled together and mixed physically after been cryomilled separately. XRPD results show that unlike the cryomilled separately mixtures, phthalic acid/ isophthalic acid, isophthalic acid/terephthalic acid, terephthalic acid/phthalic acid cryomilled together samples produces a synergistic effect in which the Bragg peaks of both phthalic acid and isophthalic acid are suppressed. It appears that co cryomilling of these pair mixtures together resulted in the production of a new material that could potentially either be two-component single phase (nano-sized co-crystal), or a new polymorphic form of either phthalic acid, isophthalic acid or terephthalic acid. Single-component of aspirin (ASP), paracetamol (PCM) and caffeine (CAFF), along with multi-component systems of paracetamol/aspirin, paracetamol/caffeine and aspirin/caffeine were milled at room temperature and by a cryomill. The milled samples were analysed using DSC, XRPD and FTIR. It was noted that there are no clear indications of crystal to amorphous transformation in all three materials. When milling aspirin at room temperature a marked reduction in the melting point was observed. Generally, a reduction in the melting point is either attributed to particle size effects, polymorphism, impurities and decomposition. In this case, the decrease in the melting point was only noticed when aspirin was milled at room temperature, so it is possible that the heat generated during the milling process resulted in chemical decomposition of aspirin to salicylic acid. Anhydrous caffeine is acknowledged to have two polymorphic forms, Form II which is considered to be stable at room temperature until ~145 °C. Form I is stable from ~145 °C to its melting point ~ 236 °C. This polymorphic transformation was detected by DSC, XRPD and hot stage microscope and it was noticed only with the as received and the room temperature milled samples. Cryomilled caffeine data showed only the presence of Form I. On the other hand, for the cryomilled multi-component systems DSC and hot stage microscope images confirmed the eutectic formation with a composition of 45:55% w/w (PCM:ASP), 50:50% (ASP:CAFF) AND 50:50% (PCM:CAFF). The obtained data were compared with room temperature milled and the theoretical values resulted from Van Laar equation. Solid pharmaceuticals represent heterogeneous systems that typically consist of one or more active pharmaceutical ingredients (APIs) and a number of excipients. Multi-component systems from mixing aspirin, paracetamol and caffeine with different excipients, which included sucrose, lactose monohydrate, xylitol and trehalose dihydrate were prepared by the use of a cryomill and were analyesd by DSC and XRPD. It was found from the XRPD data that mixing both sucrose and lactose monohydrate respectively with ASP, PCM and CAFF would produce more of a synergistic effect than xylitol and trehalose dihydrate. Cryomilling caffeine/sucrose and caffeine/lactose resulted in a production of a new XRPD trace that cannot be described in terms of a linear combination of caffeine, sucrose and lactose monohydrate. A new material was therefore formed as a result of cryomilling which has not been reported before.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia de Elétrica. / Made available in DSpace on 2012-10-21T04:03:24Z (GMT). No. of bitstreams: 1 196807.pdf: 1106436 bytes, checksum: a82849ec23bac8e937c1350891f21dbf (MD5) / A presente pesquisa desenvolve uma proposta de metodologia para identificar os impactos adversos potenciais dos subprodutos resultantes de processos que utilizam tecnologia médico-hospitalar (TMH). O objetivo é auxiliar às estruturas de engenharia clínica (EEC) no aprimoramento da segurança e da qualidade no ambiente hospitalar. Para a construção desta proposta, o sistema de prestação de serviços de saúde foi representado por meio da teoria geral de sistema e foi modelado utilizando-se a metodologia gerenciamento por processo, adaptada e modificada para a área da saúde. Esta proposta está constituída por cinco fases. Na primeira fase - Base metodológica - composta por quatro etapas, busca-se conhecer e uniformizar conceitos relacionados ao processo tecnológico em estudo. Na segunda fase - Modelagem do processo tecnológico - composta por oito etapas, busca-se estabelecer as fronteiras e a descrição do processo, evidenciando a ampla perspectiva das funções e como elas afetam direta ou indiretamente as funções e/ou outros processos dos estabelecimentos assistências de saúde. Na terceira fase - Análise do processo tecnológico - composta por quatro etapas, oportunidades de melhoria são identificadas por meio de análises do processo modelado e uso de ferramentas da qualidade, sendo os subprodutos e as causas que contribuem para a sua geração identificados. Na quarta fase - Avaliação do processo tecnológico - composta por quatro etapas, são avaliados parâmetros que poderiam minimizar a produção de subprodutos com o objetivo de diminuir o impacto adverso potencial. Finalmente, na quinta fase - Aperfeiçoamento contínuo - composta por quatro etapas, busca-se apontar sugestões para que, melhorias no processo possam ser alcançadas. A metodologia foi aplicada no serviço de radiologia de um hospital público de Florianópolis - SC, como um estudo de caso e, a partir da identificação de desperdícios no setor, não conformidades com as regulamentações vigentes e subprodutos gerados que podem causar risco físico e químico, foram apresentadas sugestões para melhoria do processo radiológico. A metodologia proposta, nesta pesquisa, constitui uma importante ferramenta para o aprimoramento da gestão da tecnologia médico-hospitalar (GTMH), no que diz respeito ao gerenciamento da mesma em todo o seu ciclo de vida, especialmente nas fases de utilização e obsolescência. Esta metodologia apresenta uma visão diferenciada de gerenciamento e procura a adequação ao uso da tecnologia, possibilitando a melhoria da eficiência de EEC na GTMH como parte de um processo tecnológico.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia Elétrica. / Made available in DSpace on 2012-10-21T05:16:17Z (GMT). No. of bitstreams: 1 195543.pdf: 1749398 bytes, checksum: 3dada08baabfd8e4592afb34c2d34c04 (MD5) / A gestão de tecnologia médico-hospitalar (GTMH) é um processo macro, desencadeado pelas necessidades de incorporação do elemento tecnológico na assistência à saúde. Dentre essas necessidades, a produção e o suprimento de oxigênio ao estabelecimento assistencial de saúde (EAS) podem ser realizados através de sistemas concentradores de oxigênio (SCO). Sua incorporação visa à geração in loco e à redução de custos desse insumo. Insere, no entanto, uma série de variáveis de risco

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em Saúde Pública. / Made available in DSpace on 2012-10-20T08:50:32Z (GMT). No. of bitstreams: 1 186099.pdf: 206311 bytes, checksum: 8fc8b50e5c6c970ec30fa2b7e7c0aff5 (MD5) / O objetivo deste estudo foi identificar as causas do "estrangulamento" das consultas especializadas na Central de Marcação de Consultas - C.M.C. da Grande Florianópolis, no período de 1998 a 2000. A C.M.C. é gerenciada pela Secretaria de Estado da Saúde e se caracteriza como um centro aglutinador das consultas médicas especializadas, que administra as consultas geradas pelas unidades públicas e privadas conveniadas do SUS, disponibilizando-as para as unidades básicas de saúde. Para tanto, realizamos um estudo de caso, descritivo. Usamos dados secundários, obtidos através da Internet, site do Ministério da Saúde, onde se trabalhou com o Boletim de Produção Ambulatorial - BPA para obtermos a produção das consultas básicas dos municípios. Os dados das consultas especializadas foram buscados junto a C.M.C. Partimos do princípio que as causas do estrangulamento das consultas especializadas deviam estar relacionadas com a pouca oferta das consultas básicas da rede municipal, e/ou com o número de encaminhamentos realizados pelos municípios a C.M.C. e/ou com a pouca oferta de consultas especializadas ofertadas na C.M.C. Trabalhamos com três categorias de análise, que foram aprofundadas com base no referencial teórico. Foram elas, acesso, regionalização/hierarquização e regulação da assistência. A partir da análise dos dados pudemos perceber que a rede municipal não está ofertando com suficiência as consultas básicas, nem está encaminhando mais do que o esperado (20% do total de consultas realizadas), o que nos permite inferir que o motivo do estrangulamento das consultas especializadas não está, a priori, no funcionamento da rede básica. Verificamos também que a C.M.C. atende basicamente a região da Grande Florianópolis, o que significa estar cumprindo o princípio da regionalização. Na análise da oferta das consultas especializadas, percebemos que há pouca oferta destas consultas, por falta de profissionais ou por baixa produção dos profissionais existentes. Nos últimos três anos 50% das especialidades médicas da CMC estão no patamar de "estrangulada", ou seja, 100% de ocupação o que dificulta o acesso e gera filas de espera. Donde pudemos inferir que a causa básica do estrangulamento da CMC está na pouca oferta de consultas especializadas frente à demanda. Percebemos que a C.M.C., enquanto instrumento de regulação, deveria estar apontando as suas deficiências, as necessidades dos usuários, identificando claramente os déficits e as disfunções do sistema. O uso pelo Gestor Estadual de tais informações como base para o planejamento da assistência, assegura o acesso da população e, permite a construção de parâmetros assistenciais mais próximos da real necessidade da população. Para tanto, o Gestor Estadual deve reconhecer na C.M.C.um instrumento de regulação que organiza o fluxo de pacientes no sistema, a partir da necessidade do usuário, pois os dados produzidos pela C.M.C. estão relacionados com a resolubilidade real e não burocrática do sistema.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico.Programa de Pós-Graduação em Ciência da Computação / Made available in DSpace on 2012-10-19T05:05:48Z (GMT). No. of bitstreams: 0Bitstream added on 2014-09-25T21:06:22Z : No. of bitstreams: 1 179624.pdf: 5713780 bytes, checksum: 2af82a22175af5bcc9a6af31d87527d4 (MD5)

The prediction of percutaneous absorption is of enormous importance for the effective design, development and quality assessment of topical and transdermal formulations. In vitro diffusion experiments are widely carried out for such predictions and are of substantial interest across the pharmaceutical and cosmetic industries. Human or animal skin, usually excised, are often used in in vitro drug diffusion studies. However, difficulties in obtaining the mammalian skin and variation in their permeability directed researchers towards using synthetic membranes as skin mimics in preformulation screening experiments, where a large number of experiments are required. Polydimethylsiloxane (PDMS) membranes have been accepted as the most commonly used in vitro skin mimic because of their homogeneity, uniformity and skin-analogous rate-limiting permeation properties. This thesis investigates the effects of ionisation and surfactants on the permeation of pharmaceutical compounds of varied physicochemical properties through PDMS membranes using a flow-through diffusion cell system. Data suggests that drug permeation had a dependency on the extent of its ionisation, with the permeation being more favourable for the more unionised form of a drug. All of the surfactants studied were found to reduce the permeation of the drugs, with an inverse relationship being observed between the surfactant concentration and the amount of drug permeated. DSC (differential scanning calorimetry), SEM (scanning electron microscopy), FTIR (Fourier transform infrared) and NMR (nuclear magnetic resonance) spectroscopy were employed to study the interactions between the membrane and the surfactants. Results indicated that the permeation effects of the surfactants are a consequence of the interactions between the drugs and surfactant micelles, and/or the membrane and the surfactants. Air plasma treatment was used to modify the PDMS surfaces to become hydrophilic, which was confirmed by water contact angle (WCA) and SEM-EDX analysis. The permeation data for the modified membranes revealed that the plasma-induced hydrophilicity significantly reduced the fluxes of the hydrophobic compounds, while not affecting that of the hydrophilic drug. Aging studies of the plasma-treated membranes showed that the hydrophilic surfaces were maintained even after 8 weeks under airtight storage conditions. In summary, ionisation and surfactant effects on drug permeation across PDMS were thoroughly investigated, and plasma treatment was found to be a stable, economic and convenient method of modifying PDMS to offer skin-like slower drug permeation i.e. to produce a potential in vitro skin mimic.

An investigation into the aspects of innovation within the downstream domain of the pharmaceutical supply chain This research evaluates the implementation of innovative programmes within the downstream domain of the Pharmaceutical Supply Chain (PSC). Pharmacies are considered as key links between healthcare services and patients because they are responsible for dispensing and managing pharmaceuticals in order to prolong life. Considering the healthcare organisations‘ crucial role and that they face the challenge of minimising the cost of healthcare services while enhancing service quality, healthcare organisations tend to try improvement approaches and innovative interventions to enhance their efficiency and effectiveness. Specifically, they tend to focus on improving their Supply Chain Management (SCM) in order to reduce waste, in particular with regards to their medicine expenditure, and to provide improved services. However, implementing innovation within the Pharmaceutical Supply Chain (PSC) is not yet adequate; at present there appears to be a lack of experience and knowledge of how such initiatives should be undertaken. Research that examines potential innovative contributions might therefore make a defined contribution to the sector. This research, therefore, aims to assess the current medicine delivery process and identify the issues responsible for weak process performances and the factors that influence pharmacies‘ innovativeness within two diverse European contexts, the UK and Greece. An exploratory research design, embracing a mixed-methods approach, was used to analyse the issues associated with PSC inefficiency and assess to what extent innovation could be adopted by hospital and community pharmacies to improve the delivery process of pharmaceutical products. The qualitative data was gathered through 30 interviews with key professionals working within the downstream domain of the PSC in the two selected geographical areas. A total of 21 in-depth interviews in the UK and 9 in Greece were conducted to examine the elements preventing the effective and efficient delivery of medicines. Simultaneously, an online survey was developed to collect the quantitative data. The final sample (N=130) consisted of specialists working within the down stream domain of the PSC in Greece and the UK. The quantitative data analysis aimed to identify the factors that support or prevent innovation within this specific and complex environment. The analysis and combination of these two sets of data enabled the researcher to gain a comprehensive understanding and recommend innovative solutions that are suitable to the system under investigation, leading to continuous improvement. This research contriputes to academic literature as it adds more theoritical insights to innovative delively processes, especially those that have been characterised as highly complex. The results led to the generation of the Innovative Pharmaceutical Supply Chain Framework (IPSCF) that provides guidelines to healthcare organisations about how the identified problems can be overcome by implementing suitable innovative techniques. The implementation of Lean and Reverse Logistics practices, which are supported by integrated Information Technology (IT) systems, are suggested as a means for healthcare organisations to enhance their delivery system in terms of quality (products and service quality), visibility (knowledge and information sharing), speed (respond to customers and suppliers needs) and cost (minimisation of cost and waste) and therefore generate a competitive edge. The study‘s recommendations have important implications for pharmacies, as they provide guidance regards suitable innovative programmes that can be adopted. The outputs of this research are specifically relevant to the pharmacy sectors of the UK and Greece, but may have also relevance for European healthcare organisations.

Chemical risk assessment for human health effects is performed in order to establish safe exposure levels of chemicals to which individuals are exposed. The process of risk assessment traditionally involves the generation of toxicological studies from which health based guidance values are derived for a specific chemical. For low level exposures to chemicals, where there are no or limited chemical specific toxicity data, the application of the Threshold of Toxicological Concern (TTC) approach may estimate whether the exposure levels can be considered safe. The TTC approach has recently gained increasing interest as new requirements, under different regulatory frameworks, emerge for the safety assessment of chemicals and to assess chemicals for which testing is not routinely required. The application of TTC relies heavily on computational (in silico) methods. In silico tools are computer implemented models that, based on commonalities in the toxicity of “similar” chemical structures, may predict hazard. In silico methods are rapidly evolving and gaining importance within the context of Integrated Approaches to Testing and Assessment (IATA) and their acceptance for regulatory purposes is expanding. The work presented in this thesis has focused on the use and applicability of a wide range of computational approaches to assist in the application of the TTC concept. In the TTC approach, the identification of genotoxic chemicals is a primary requirement. In silico approaches apply expert knowledge and/or statistical methods to either predict genotoxicity or to identify structural alerts associated with it. This thesis focused, in part, on a group of important environmental pollutants, nitrobenzenes, to assess the applicability of in silico tools to predict genotoxicity. For this purpose a dataset containing 252 nitrobenzenes including Ames test results was compiled. Based on these test results a case study for sodium nitro-guaiacolate, a pesticide active substance, was developed. The case study demonstrated that (Q)SAR and a category approach incorporating read-across, are applicable for the prediction of genotoxicity and supports their use within a weight of evidence approach. Another aspect of the TTC approach is the evaluation of repeat dose, non-cancer endpoints. For that purpose chemicals are separated into groups related to three levels of concern based on the Cramer classification. For each level, namely the Cramer Classes (I, II and III), a safe exposure level has been established. Therefore, as interest to apply TTC expands to new groups of chemicals, the reliability and conservativeness of the established thresholds relative to Cramer Classes for the new chemistries must be established. In this thesis the TTC approach was evaluated for 385 cosmetic ingredients, 77 biocides and 102 compounds classified as reproductive and developmental toxicants. To support the evaluation at different levels, chemical datasets containing toxicological data were utilised and computational tools were applied to compare datasets. The results indicated, that the historical “Munro” dataset is broadly representative for cosmetics and biocides. In addition, that the threshold levels for Cramer Class III are within the range of Munro’s threshold further supports the validity of the TTC approach and its conservativeness for the groups of chemicals analysed. Cramer Class I thresholds were found to be valid only for classified developmental and reproductive toxicants. The results also supported the validity of the classification of chemicals into Cramer class III. It is foreseen that the TTC approach will gain increasing acceptance in the risk assessment of different groups of chemicals. Therefore it is emphasised that the future work should focus on the identification of the limitations of the application of TTC, including the identification of groups of chemicals to which TTC cannot be applied, the expansion of the underlying toxicological datasets, and the development of tools to support the application of TTC so that is transparent and acceptable for regulatory purposes.