In any organisation processes can be seen evolving throughout their lifecycle and play a deciding role in the efficiency of organisational activities. Tender processes are no different and with growing competitiveness and globalisation it has become the responsibility of managerial staff to ensure continuous improvement is applied to processes so organisational goals are consistently met and knowledge, talents and other success factors are institutionalised therein. The objective of this study was to perform an iteration of process re-engineering on the tender process within Tubular Track, so that a tender could be performed more efficiently and more competitively, and be more manageable. The investigation was carried out by means of a literature review and interviews. This was done to establish an accurate baseline from the current process and then re-engineer the system in its entirety. Verification of the investigation method was done through application of the PMBOK proven project management methods, while validation was done by comparison of processes through process improvement methodology principles as relationship. Process improvement and its management is a continuous procedure but because this study only focuses on the design of a new tender process for Tubular Track the conclusion that was made through literature application and comparison was that the newly designed process is expected to improve efficiency, manageability and time to complete. In the final conclusion stage recommendations were also made that re-engineering phases be planned and followed with corresponding risk and change management plans. Training needed for personnel so that implementation would be optimally applied and continuous improvement institutionalised would also need inspecting. / MIng (Development and Management Engineering), North-West University, Potchefstroom Campus, 2015

In any organisation processes can be seen evolving throughout their lifecycle and play a deciding role in the efficiency of organisational activities. Tender processes are no different and with growing competitiveness and globalisation it has become the responsibility of managerial staff to ensure continuous improvement is applied to processes so organisational goals are consistently met and knowledge, talents and other success factors are institutionalised therein. The objective of this study was to perform an iteration of process re-engineering on the tender process within Tubular Track, so that a tender could be performed more efficiently and more competitively, and be more manageable. The investigation was carried out by means of a literature review and interviews. This was done to establish an accurate baseline from the current process and then re-engineer the system in its entirety. Verification of the investigation method was done through application of the PMBOK proven project management methods, while validation was done by comparison of processes through process improvement methodology principles as relationship. Process improvement and its management is a continuous procedure but because this study only focuses on the design of a new tender process for Tubular Track the conclusion that was made through literature application and comparison was that the newly designed process is expected to improve efficiency, manageability and time to complete. In the final conclusion stage recommendations were also made that re-engineering phases be planned and followed with corresponding risk and change management plans. Training needed for personnel so that implementation would be optimally applied and continuous improvement institutionalised would also need inspecting. / MIng (Development and Management Engineering), North-West University, Potchefstroom Campus, 2015

Thesis (MEng)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: The main purpose of the base metal refinery (BMR) as operated by Lonmin at their Western Platinum Ltd BMR, is to remove base metals – such as copper and nickel – from a platinum group metal (PGM) containing matte. The leaching processes in which this is done pose several challenges to the control of the process. The most significant of these is the slow dynamics of the process, due to large process units, as well as the continuously changing composition of the first stage leach residue, which is not measured on-line. This is aggravated by the fact that the exact leaching kinetics (and therefore the effect of the disturbances) are not understood well fundamentally. The slow process dynamics mean that controllers cannot be tuned aggressively, resulting in slow control action. The large residence times and off-line composition analyses of major controlled variables also mean that the effects of operator set point changes are visible only the following day, often by a different shift of operators. Dorfling (2012) recently developed a fundamental dynamic model of the pressure leach process at Lonmin‟s BMR. This dynamic model incorporates 21 chemical reactions, as well as mass and energy balances, into a system of 217 differential equations. The model provides a simulation framework within which improved control strategies can be investigated. The primary aims of this study are twofold. The first is to validate the model for the purpose of the investigation and development of control structure improvements. This is done by comparing the model to plant data, and adapting it if necessary. The second aim to reconsider the current control philosophy to the extent that is allowed by the model‟s determined validity. The current plant control philosophy aims to maintain a PGM grade of 65%, while the copper in the solids products of the second and third leaching stages should be below 25% and 3.5% by mass, respectively. Two areas of particular concern in this process that have been raised by Lonmin are the control of the temperature of the first compartment and the addition of pure sulphuric acid to control the acid concentration in the second stage leach. Dynamic plant data were used to calibrate the model, which was migrated from its received MATLAB platform to Simulink, to assist with control development. Flow rates were imported from the data, with some data values adapted for this purpose, due to mass balance inconsistencies. The outputs from the calibrated model were compared with corresponding data values. The model was found to be suitable for the investigation and development of the control structures of pressure, temperatures and inventories (termed basic regulatory control) and the acid concentration and solids fraction in the preparation tanks (termed compositional regulatory control). It was, however, found to be inadequate for the investigation and development of supervisory control, since it does not provide accurate compositional results. The leaching of copper is especially under-predicted, with the predicted copper concentration in the second stage product being approximately 46% lower than data values. The basic and compositional regulatory control structures were investigated. For each of these a base case was developed which aimed to represent the relevant current control structure, assuming optimal tuning. The variable pairings for the basic regulatory control were reconsidered using a method proposed by Luyben and Luyben (1997), since this part of the process does not permit the generation of a relative gain array (RGA) for variable pairing. The resulting pairing corresponds with Lonmin‟s current practice. Considering the temperature control of compartment 1, it was found that the addition of feed-forward control to the feedback control of the level of the flash tank improves the temperature control. More specifically, during an evaluation where the temperature‟s set point is varied up to 1%, the IAE of the temperature of compartment 1 was decreased with 7.5% from the base case, without disturbing the flash tank. The addition of feed-forward control allows for more rapid control and more aggressive tuning of this temperature, removing the current limit on ratio between the flash recycle stream and the autoclave feed. The compositional control was investigated for the second stage leach only, due to insufficient flow rate and compositional information around the third stage preparation tank. Variable pairing showed that three additive streams are available for the preparation tanks of the second and third stage leach to control the acid concentration and solids fraction in those tanks. Focussing on the second stage, the aim was to determine whether the acid concentration in the flash tank can be successfully controlled without the addition of pure acid to the tank. With four streams available around the second stage preparation tank to control its mass/level, the acid concentration and solids fraction, three manipulated variables were derived from these streams. The resulting pairings were affirmed by an RGA. Control loops for the control of acid concentration and solids fraction in the flash tank were added as cascade controllers, using the preparation tank‟s control as secondary loops. The added compositional control was evaluated in two tests. The first of these entailed the adding of typical disturbances, being the flash recycle rate, the solids and water in the feed to the second stage preparation tank and the acid concentration in copper spent electrolyte. In the second test the control system was tested for tracking an acid concentration set point. It was found that the cascade structure controls the acid concentration in the flash tank less tightly than the base case (with an IAE that is 124% and 80.6% higher for the two tests), but that it decreases the variation of solids fraction (lowering the IAE with 40.8% with the first test) in the same tank and of the temperature in the first compartment (lowering the IAE with 73.6% in the second test). It is recommended that the relative effects of these three variables on leaching behaviour should be investigated with an improved model that is proven to accurately predict leaching reactions in the autoclave. / AFRIKAANSE OPSOMMING: Die hoofdoel van die basismetaal-raffinadery (BMR), soos dit bestuur word deur Lonmin by hulle Western Platinum Ltd BMR, is om basismetale – soos koper en nikkel – te verwyder uit 'n mat wat platinum groep metale (PGM) bevat. Die logingsprosesse waarin dit gedoen word hou talle uitdagings in vir die beheer van die proses. Die mees beduidende hiervan is die proses se stadige dinamika, wat veroorsaak word deur groot proseseenhede, sowel as die deurlopend veranderende samestelling van die eerste stadium residue (wat nie aanlyn gemeet word nie). Dit word vererger deur die feit dat die presiese logingskinetika (en daarom ook die effek van versteurings) nie fundamenteel goed verstaan word nie. Die stadige dinamika beteken dat die beheerders die aggressief verstel kan word nie, en dit lei tot stadige beheeraksies. Die groot verblyftye en aflyn samestellingsanalises van die belangrikste beheerde veranderlikes beteken dat die gevolge van 'n operateur se stelpunt veranderinge slegs die volgende dag sigbaar is – dikwels in die skof van 'n ander operateur. Dorfling (2012) het onlangs 'n fundamentele, dinamiese model van die drukloog proses by Lonmin se BMR ontwikkel. Hierdie dinamiese model inkorporeer 21 chemiese reaksies, sowel as massa- en energiebalanse, in ‟n stelsel van 217 differensiaalvergelykings. Die model bied 'n simulasie-raamwerk waarbinne verbeterde beheerstrategieë ondersoek kan word. Die hoofdoel van hierdie studie is tweeledig. Die eerste hiervan is om die model te valideer vir die ondersoek en ontwikkelling van beheerstruktuur verbeteringe. Dit is gedoen deur die model met aanlegdata te vergelyk en dit aan te pas, indien nodig. Die tweede doel is om die huidige beheerfilosofie te heroorweeg tot op 'n punt wat toegelaat word deur die bepaalde geldigheid van die model. Die huidige beheerfilosofie van die aanleg mik om 'n gehalte van 65% te handhaaf, terwyl die koper in die vastestof produk van die tweede en derde logingsstadia onderskeidelik onder 25% en 3.5% op 'n massa basis moet wees. Twee probleem-areas, soos ge-opper deur Lonmin, is die beheer van die temperatuur in die eerste kompartement en die byvoeging van suiwer swaelsuur om die suurkonsentrasie van die tweede stadium te beheer. Dinamiese aanlegdata is gebruik om die model te kalibreer. Hierdie model is van die oorspronklike MATLAB platform na Simulink gemigreer, ten einde beheerontwikkelling te vergemaklik. Vloeitempo's is van die data af ingevoer na die model toe, met sekere data waardes wat aangepas is vanweë massabalans inkonsekwenthede. Die uitsette van die gekalibreerde model is met die ooreenstemmende data waardes vergelyk. Daar is bevind dat die model geskik is vir die ondersoek en ontwikkelling van die beheer van druk, temperature en tenks (basiese reguleringsbeheer), sowel as die beheer van suurkonsentrasies en vastestoffraksies in die bereidingstenks (reguleringsbeheer van die samestelling). Daar is egter bevind dat die model nie geskik is vir die ondersoek en ontwikkelling van toesigbeheer nie, aangesien dit nie akkurate samestellingsresultate genereer nie. Die voorspelde loging van koper is veral te laag, met die model wat koperkonsentrasies vir die tweede stadium voorspel wat ongeveer 46% laer is as ooreenstemmende data waardes. Die basiese en samestelling reguleringsbeheer strukture is ondersoek. Vir elkeen is ‟n basisgeval ontwikkel wat poog om die huidige beheerstruktuur te verteenwoordig, met optimale verstellings aanvaar. Die paring van veranderlikes vir die basiese reguleringsbeheer is heroorweeg met deur middel van ‟n metode wat deur Luyben en Luyben (1997) voorgestel is, aangesien hierdie deel van die proses nie die opstel van ‟n relatiewe winsmatriks (RWM) vir die paring toelaat nie. Die uiteindelike paring stem ooreen met Lonmin se huidige praktyk. Met die heroorweging van die temperatuurbeheer van kompartement 1 is daar bevind that die byvoeging van vooruitvoer beheer by die terugvoerbeheer van die flitstenk die temperatuurbeheer verbeter. Meer spesifiek het die IAE van hierdie temperatuur met 7.5% verlaag van die basisgeval af nadat die temperatuur se stelpunt tot met 1% gevariëer is – sonder om die flitstenk te versteur. Die byvoeging van vooruitvoer beheer laat vinniger beheer en meer aggressiewe verstellings van die temperatuur toe, aangesien die huidige beperking op die verhouding tussen die flitsstroom en die outoklaaf voer verwyder word. Die samestellingsbeheer is slegs ondersoek in die geval van die tweede loogstadium as gevolg van onvoldoende vloeitempo- en samestellingsinligting om die bereidingstenk van die derde stadium. Die paring van veranderlikes het gewys dat drie voerstrome onderskeidelik beskikbaar is vir beide die bereidingstenks van die tweede en derde stadia, om die suurkonsenstrasies en vastestoffraksies in hierdie tenks te beheer. Met die fokus op die tweede stadium was die doel om te bepaal of die suurkonsentrasie in die flitstenk suksesvol beheer kan word sonder dat suiwer suur by hierdie tenk gevoeg word. Met vier strome beskikbaar rondom die bereidingstenk van die tweede stadium om die massa/vlak, die suurkonsentrasie en die vastestoffraksie te beheer, is drie manipuleerde veranderlikes vanuit hierdie strome afgelei. Die uiteindelike paring is bevestig deur 'n RWM. Beheerlusse is ingevoeg vir die beheer van die suurkonsentrasie en vastestoffraksie in die flitstenk, met die bereidingstenk se beheer wat dien as sekondêre lusse in kaskadebeheer. Die kaskadebeheer is geëvalueer in twee toetse. Die eerste hiervan behels die invoer van tipiese versteurings, soos die vloeitempo van die flitsstroom, die vastestof en water in die voer na die tweede stadium se bereidingstenk en die suurkonsentrasie in die gebruikte elektroliet. In die tweede toets is die vermoë van die beheerstelsel om 'n suurkonsentrasie stelpunt te volg getoets. Daar is bevind dat die kaskadestruktuur die suurkonsentrasie minder nougeset beheer as die basisgeval (met 'n IAE wat 124% en 80.6% hoër is vir die twee toetse), maar dat dit die variasie in die vastestoffraksie in dieselfde tenk (40.8% vermindering van die IAE in die eerste toets) en in die temperatuur van die eerste kompartement (73.6% vermindering van die IAE in die tweede toets) beduidend verminder. Daar word aanbeveel dat die relatiewe effekte van hierdie drie veranderlikes op logingsoptrede ondersoek moet word, met die gebruik van 'n model wat logingsreaksies in die outoklaaf akkuraat voorspel.

One of the most used for separation of alcohol and water is distillation. Traditionally the production of hydrated ethanol fuel is produced by large distilleries, which were freestanding or attached. A problem found for production of ethyl alcohol in small properties is related to the type of equipment used and the breaking of the paradigm of food production with energy production in case the fuel. Usually the equipment for small scale production process both in batch or continuous processes by the system relate to the low quality of ethyl alcohol, since most equipment does not provide quality were considered low income, made by hand. A key question for this system is no interference of the production system for joint production of food perfectly integrated into the system. Thus, this study proposes to validate statistically the equipment designed for obtaining alcohol fuel under discontinuous (batch) for small scale production, to evaluate the alcohol obtained is within the regulatory standards of ANP on the alcohol content. To validate the system software was used for specific simulation models also using the Response Surface Methodology, verifying that it is possible to obtain ethanol-grade and quantity for the producer of family farming cooperatives, so that works. / Um dos processos mais utilizados para separação do álcool e da água é a destilação. Tradicionalmente a produção de álcool etílico hidratado carburante é produzida pelas grandes destilarias, sendo elas autônomas ou anexas. Uma problemática verificada para produção de álcool etílico em pequenas propriedades está relacionada ao tipo de equipamento utilizado e a quebra do paradigma da produção de alimentos juntamente com a produção de energia no caso o combustível. Geralmente os equipamentos para produção em pequena escala tanto em processo de batelada ou em processos pelo sistema contínuo referem-se à baixa qualidade do álcool etílico obtido, visto que a maioria dos equipamentos não apresenta qualidade sendo considerados de baixo rendimento, fabricados de forma artesanal. Uma questão chave para este sistema é a não interferência do sistema produtivo para produção conjunta de alimentos perfeitamente integrada ao sistema. Assim, o presente estudo propõe-se a validar, estatisticamente, o equipamento projetado para obtenção de álcool combustível em regime descontínuo (batelada), para produção em pequena escala, avaliando-se que o álcool obtido está dentro das normas regulamentadoras da ANP quanto ao teor alcoólico. Para validação do sistema foi utilizado o software específico para simulação dos modelos utilizando-se também a Metodologia da Superfície de Resposta, verificando-se que é possível obter álcool etílico com graduação e quantidades para o produtor da agricultura familiar que trabalha de forma cooperativada.

Estudos de qualificação e validação de processos são amplamente requisitados por agências regulatórias na produção de medicamentos. Entretando, uma abordagem pouco explorada pela literatura é o emprego de equipamentos qualificados e processos validados em estudos de formulação. O presente trabalho objetiva desenvolver uma proposta de qualificação do desempenho e validação do processo de compressão direta em escala piloto e aplicar o processo validado, como uma ferramenta de garantia da qualidade, com auxílio de um fármaco-modelo. Primeiramente, foi obtida e caracterizada uma mistura padronizada de adjuvantes farmacêuticos de referência. Em seguida, realizou-se a qualificação de uma máquina de comprimir rotativa instrumentada pela avaliação dos principais parâmetros, sejam eles Altura do Rodete Superior, Volume da Câmara de Compressão, Velocidade da Platina, e Pré-compressão, em condições reais de produção. Após análise estatística, concluiu-se que os parâmetros avaliados produzem o efeito esperado sobre as variáveis Peso, Dureza, Espessura, Forças de Compressão, Ejeção e Précompressão dos compactos produzidos, de maneira reprodutível e que o processo de compressão direta demonstrou estabilidade estatística e elevada capacidade em originar comprimidos com características de qualidade previamente definidas. O processo validado foi, então, aplicado a um estudo de formulação de comprimidos de carbamazepina obtidos pela compressão direta de nove misturas físicas, binárias e ternárias, com celulose microcristalina e macrogol 8000, em diferentes proporções. A carbamazepina utilizada foi caracterizada como a forma cristalina B. Os estudos físico-químicos dos componentes, misturas, e comprimidos revelou manutenção da forma cristalina da carbamazepina durante o processo de compressão. A avaliação dos perfis de liberação in vitro do fármaco corroborou com o apresentado na literatura para as formulações binárias. Os perfis de dissolução inesperados das formulações ternárias, com cinética de liberação semelhante a de ordem zero, puderam ser explicados pela formação de diferentes cristais de CBZ diidrato com hábito cristalino isométrico. / Qualification and process validation studies are currently required by regulatory agencies in pharmaceutical manufacturing. However, little attention has been given to the way How these procedures should be conduced and the lack of more specific literature become evident. Thus, in the present work a practicable approach for a rotary press qualification and its insertion in a direct compression process validation strategy are described. Additionally, the equipment performance qualification was assessed in the tabletting of the model-drug carbamazepine at pilotscale production. Thus, a standard powders mixture was obtained and characterized. The qualification of a rotary tablet press was conducted concerning the main equipment parameters, namely Upper Compaction Roll Height, Die Cavity Volume, Compression Rate and Pre-compression, at real manufacturing situations. After proper statistical analysis, it was observed that the equipment parameters had the expected effect over the variables Weight, Hardness, Thickness, Compression, Ejection and Pre-compression force, in a reproducible manner and that the tabletting process undergoes with statistical stability and has elevated capability in originate tablets with previous determined specifications. The validated process was then applied to a CBZ tablet formulation study. The tablets were obtained by the direct compression of nine binary and ternary physical mixtures of CBZ, microcrystalline cellulose and polyoxyethylene glycol 8000. The CBZ raw material was characterized as the monoclinic form B. The physico-chemical studies of the components, mixtures and tablets revealed no CBZ polymorphic transition during the tabletting process. The evaluation of the in vitro dissolution profiles corroborated with the literature concerning the binary physical mixtures. The unexpected dissolution behavior of the ternary formulations, with apparent zero-order kinetic process, was ascribed to the formation of new and large CBZ dihydrate crystals, with an unusual isomeric crystal habit.

Estudos de qualificação e validação de processos são amplamente requisitados por agências regulatórias na produção de medicamentos. Entretando, uma abordagem pouco explorada pela literatura é o emprego de equipamentos qualificados e processos validados em estudos de formulação. O presente trabalho objetiva desenvolver uma proposta de qualificação do desempenho e validação do processo de compressão direta em escala piloto e aplicar o processo validado, como uma ferramenta de garantia da qualidade, com auxílio de um fármaco-modelo. Primeiramente, foi obtida e caracterizada uma mistura padronizada de adjuvantes farmacêuticos de referência. Em seguida, realizou-se a qualificação de uma máquina de comprimir rotativa instrumentada pela avaliação dos principais parâmetros, sejam eles Altura do Rodete Superior, Volume da Câmara de Compressão, Velocidade da Platina, e Pré-compressão, em condições reais de produção. Após análise estatística, concluiu-se que os parâmetros avaliados produzem o efeito esperado sobre as variáveis Peso, Dureza, Espessura, Forças de Compressão, Ejeção e Précompressão dos compactos produzidos, de maneira reprodutível e que o processo de compressão direta demonstrou estabilidade estatística e elevada capacidade em originar comprimidos com características de qualidade previamente definidas. O processo validado foi, então, aplicado a um estudo de formulação de comprimidos de carbamazepina obtidos pela compressão direta de nove misturas físicas, binárias e ternárias, com celulose microcristalina e macrogol 8000, em diferentes proporções. A carbamazepina utilizada foi caracterizada como a forma cristalina B. Os estudos físico-químicos dos componentes, misturas, e comprimidos revelou manutenção da forma cristalina da carbamazepina durante o processo de compressão. A avaliação dos perfis de liberação in vitro do fármaco corroborou com o apresentado na literatura para as formulações binárias. Os perfis de dissolução inesperados das formulações ternárias, com cinética de liberação semelhante a de ordem zero, puderam ser explicados pela formação de diferentes cristais de CBZ diidrato com hábito cristalino isométrico. / Qualification and process validation studies are currently required by regulatory agencies in pharmaceutical manufacturing. However, little attention has been given to the way How these procedures should be conduced and the lack of more specific literature become evident. Thus, in the present work a practicable approach for a rotary press qualification and its insertion in a direct compression process validation strategy are described. Additionally, the equipment performance qualification was assessed in the tabletting of the model-drug carbamazepine at pilotscale production. Thus, a standard powders mixture was obtained and characterized. The qualification of a rotary tablet press was conducted concerning the main equipment parameters, namely Upper Compaction Roll Height, Die Cavity Volume, Compression Rate and Pre-compression, at real manufacturing situations. After proper statistical analysis, it was observed that the equipment parameters had the expected effect over the variables Weight, Hardness, Thickness, Compression, Ejection and Pre-compression force, in a reproducible manner and that the tabletting process undergoes with statistical stability and has elevated capability in originate tablets with previous determined specifications. The validated process was then applied to a CBZ tablet formulation study. The tablets were obtained by the direct compression of nine binary and ternary physical mixtures of CBZ, microcrystalline cellulose and polyoxyethylene glycol 8000. The CBZ raw material was characterized as the monoclinic form B. The physico-chemical studies of the components, mixtures and tablets revealed no CBZ polymorphic transition during the tabletting process. The evaluation of the in vitro dissolution profiles corroborated with the literature concerning the binary physical mixtures. The unexpected dissolution behavior of the ternary formulations, with apparent zero-order kinetic process, was ascribed to the formation of new and large CBZ dihydrate crystals, with an unusual isomeric crystal habit.

Estudos de qualificação e validação de processos são amplamente requisitados por agências regulatórias na produção de medicamentos. Entretando, uma abordagem pouco explorada pela literatura é o emprego de equipamentos qualificados e processos validados em estudos de formulação. O presente trabalho objetiva desenvolver uma proposta de qualificação do desempenho e validação do processo de compressão direta em escala piloto e aplicar o processo validado, como uma ferramenta de garantia da qualidade, com auxílio de um fármaco-modelo. Primeiramente, foi obtida e caracterizada uma mistura padronizada de adjuvantes farmacêuticos de referência. Em seguida, realizou-se a qualificação de uma máquina de comprimir rotativa instrumentada pela avaliação dos principais parâmetros, sejam eles Altura do Rodete Superior, Volume da Câmara de Compressão, Velocidade da Platina, e Pré-compressão, em condições reais de produção. Após análise estatística, concluiu-se que os parâmetros avaliados produzem o efeito esperado sobre as variáveis Peso, Dureza, Espessura, Forças de Compressão, Ejeção e Précompressão dos compactos produzidos, de maneira reprodutível e que o processo de compressão direta demonstrou estabilidade estatística e elevada capacidade em originar comprimidos com características de qualidade previamente definidas. O processo validado foi, então, aplicado a um estudo de formulação de comprimidos de carbamazepina obtidos pela compressão direta de nove misturas físicas, binárias e ternárias, com celulose microcristalina e macrogol 8000, em diferentes proporções. A carbamazepina utilizada foi caracterizada como a forma cristalina B. Os estudos físico-químicos dos componentes, misturas, e comprimidos revelou manutenção da forma cristalina da carbamazepina durante o processo de compressão. A avaliação dos perfis de liberação in vitro do fármaco corroborou com o apresentado na literatura para as formulações binárias. Os perfis de dissolução inesperados das formulações ternárias, com cinética de liberação semelhante a de ordem zero, puderam ser explicados pela formação de diferentes cristais de CBZ diidrato com hábito cristalino isométrico. / Qualification and process validation studies are currently required by regulatory agencies in pharmaceutical manufacturing. However, little attention has been given to the way How these procedures should be conduced and the lack of more specific literature become evident. Thus, in the present work a practicable approach for a rotary press qualification and its insertion in a direct compression process validation strategy are described. Additionally, the equipment performance qualification was assessed in the tabletting of the model-drug carbamazepine at pilotscale production. Thus, a standard powders mixture was obtained and characterized. The qualification of a rotary tablet press was conducted concerning the main equipment parameters, namely Upper Compaction Roll Height, Die Cavity Volume, Compression Rate and Pre-compression, at real manufacturing situations. After proper statistical analysis, it was observed that the equipment parameters had the expected effect over the variables Weight, Hardness, Thickness, Compression, Ejection and Pre-compression force, in a reproducible manner and that the tabletting process undergoes with statistical stability and has elevated capability in originate tablets with previous determined specifications. The validated process was then applied to a CBZ tablet formulation study. The tablets were obtained by the direct compression of nine binary and ternary physical mixtures of CBZ, microcrystalline cellulose and polyoxyethylene glycol 8000. The CBZ raw material was characterized as the monoclinic form B. The physico-chemical studies of the components, mixtures and tablets revealed no CBZ polymorphic transition during the tabletting process. The evaluation of the in vitro dissolution profiles corroborated with the literature concerning the binary physical mixtures. The unexpected dissolution behavior of the ternary formulations, with apparent zero-order kinetic process, was ascribed to the formation of new and large CBZ dihydrate crystals, with an unusual isomeric crystal habit.

As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.

As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.

Vibrio parahaemolyticus is a Gram-negative, halophilic pathogen that occurs naturally in coastal and estuarine environments. This human pathogen is frequently isolated from a variety of seafood, particular oysters, and is the leading cause of gastroenteritis associated with seafood consumption. Several outbreaks of V. parahaemolyticus infections linked to consumption of raw oysters have been documented. Contamination of oysters with V. parahaemolyticus is a concern for public health. This study investigated the efficacy of high pressure processing (HPP) in inactivating V. parahaemolyticus in raw Pacific oysters (Crassostrea gigas) and identified a process condition capable of achieving greater than 3.52-log reductions of V. parahaemolyticus in raw oysters for commercial application. Raw Pacific oysters were inoculated with a clinical strain of V. parahaemolyticus 10293 (O1:K56) to levels of 10⁴⁻⁵ cells per gram and processed at 293 MPa (43K PSI) for 90, 120, 150, 180 and 210 s. Populations of V. parahaemolyticus in oysters after processes were analyzed with the 5-tube most probable number (MPN) method. A minimum HPP of 293 MPa for 120 s at groundwater temperature (8±1 °C) was identified capable of achieving greater than 3.52-log reductions of V. parahaemolyticus in Pacific oysters. The HPP (293 MPa for 120 s at 8±1 °C) was validated at a commercial scale according to the FDA's National Shellfish Sanitation Program Post Harvest Processing (PHP) Validation/Verification Interim Guidance for Vibrio vulnificus and Vibrio parahaemolyticus. Negative results obtained by the MPN method were confirmed with a multiplex PCR detecting genes encoding thermolabile hemolysin (tl), thermostable direct hemolysin (tdh) and TDH-related hemolysin (trh). Oysters processed at 293 MPa for 120 sec had a shelf life of 6-8 days when stored at 5 °C or 16-18 days when stored in ice. This validated HPP was accepted by the FDA as a post harvest process to eliminate V. parahaemolyticus in raw oysters. / Graduation date: 2012