Evaluation of the financial and technical impacts of changing commercial-scale pharmaceutical manufacturing processes.

Growing pressures in the pharmaceutical industry are driving the need to optimise processes used for the manufacture of drugs at commercial-scale, in order to improve cost of goods, product throughput and production times. Evaluating the impacts of process optimisation upon these metrics presents a challenge due to complexities and trade-offs that are often encountered when developing a typical bioprocess. Such factors have resulted in a range of novel simulation- and experimental- based techniques being developed which enable rapid, accurate and cost effective assessment of manufacturing options for commercial-scale production. This thesis proposes a combination of modelling and experimental methods for evaluating the business- and process-related impacts of implementing changes to pre-existing commercial-scale pharmaceutical manufacturing processes. The approaches are illustrated through an industrial case study, focusing upon a process operated by Protherics U.K. Limited for the manufacture of the FDA-approved rattlesnake anti-venom CroFab (Crotalidae Polyvalent Immune Fab (Ovine)). The novel methods developed and illustrated in this thesis include: Investigating the effects of process changes upon calculated yields and processing times within the production framework for a pre-existing FDA-approved bio-manufacturing process Evaluating the impacts of both developing and implementing process changes, combining output metrics into a single value to simplify the assessment Developing a multi-layered simulation methodology for the rapid and efficient evaluation of bio- manufacturing process options Applying advanced sensitivity analysis techniques to identify the most critical factors that influence product yield and throughput Evaluating a novel synthetic Protein A matrix for the recovery and purification of polyclonal antibodies from hyperimmunised ovine serum Developing decision-support software to aid the design of chromatography steps for antibody purification at industrial scale Demonstrating the utility of such models by application to data and constraints derived from a full-scale industrial facility

The Simplex Algorithm for the Rapid Identification of Operating Conditions During Early Bioprocess Development: Case Studies in FAb' Precipitation and Multimodal Chromatography

This study describes a data-driven algorithm as a rapid alternative to conventional Design of Experiments (DoE) approaches for identifying feasible operating conditions during early bioprocess development. In general, DoE methods involve fitting regression models to experimental data, but if model fitness is inadequate then further experimentation is required to gain more confidence in the location of an optimum. This can be undesirable during very early process development when feedstock is in limited supply and especially if a significant percentage of the tested conditions are ultimately found to be sub-optimal. An alternative approach involves focusing solely upon the feasible regions by using the knowledge gained from each condition to direct the choice of subsequent test locations that lead towards an optimum. To illustrate the principle, this study describes the application of the Simplex algorithm which uses accumulated knowledge from previous test points to direct the choice of successive conditions towards better regions. The method is illustrated by two case studies; a two variable precipitation example investigating how salt concentration and pH affect FAb' recovery from E. coli homogenate and a three-variable chromatography example identifying the optimal pH and concentrations of two salts in an elution buffer used to recover ovine antibody bound to a multimodal cation exchange matrix. Two-level and face-centered central composite regression models were constructed for each study and statistical analysis showed that they provided a poor fit to the data, necessitating additional experimentation to confirm the robust regions of the search space. By comparison, the Simplex algorithm identified a good operating point using 50% and 70% fewer conditions for the precipitation and chromatography studies, respectively. Hence, data-driven approaches have significant potential for early process development when material supply is at a premium

Designing liquid repellent surfaces for fabrics, feathers and fog

Thesis (Ph. D. in Chemical Engineering Practice)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis. "December 2012."Includes bibliographical references.Omniphobicity refers to a property of surfaces which are not wetted by water, oils, alcohols and other low surface tension liquids. Robust omniphobic surfaces can be applied in many areas including fabrics with chemical / biological protection and dirt / fingerprint resistant touch screens. The main aim of this thesis is to develop rules for the systematic design of omniphobic surfaces with a focus on textiles. First, a design chart is developed to help us understand the impact of surface chemistry and surface topography on the wettability of a textured surface. A smaller characteristic length scale of a re-entrant surface topography, tighter weave and a coating with inherently low wettability are better for producing omniphobic surfaces that resist wetting by liquids with low surface tension. This framework is applied to textile fabrics and bird feathers to test their wettability. Using this framework, wettability of low surface tension liquids on a polyester fabric is tuned or switched using either thermal annealing or biaxial stretching. Army Combat Uniform fabrics are rendered oleophobic, thus opening the way to optimize omniphobic army uniforms. The wettability of molecules similar to fluorodecyl POSS is investigated by measuring the contact angles with liquids of a broad range of surface tension and polarity. Of the molecules tested so far, fluorodecyl POSS has the lowest solid surface energy (9.3 mN/m) and the lowest increment in solid surface energy (7 mN/m). The wetting aspects of the hierarchical topography of bird feathers are captured using contact angle measurements in terms of a spacing ratio. Thermodynamics of the wetting of feathers and the robustness against wetting during the course of a dive are correlated to the wing spreading behavior. Our understanding of surface wettability of woven meshes is applied to optimize their fog collection ability. A business case for fog harvesting is developed and strategies to decrease asset and cash flow risks are proposed. The contributions presented here provide means to better characterize surfaces with complex topography, tune and a priori predict their wettability and recommend a design strategy both at a molecular and a macroscopic level to maximize their non-wettability.by Shreerang S. Chhatre.Ph.D.in Chemical Engineering Practic

Solution spraying of poly(methyl methacrylate) blends to fabricate microtextured, superoleophobic surfaces

We describe a simple technique to prepare superhydrophobic and superoleophobic microtextured surfaces by spray coating a blend of poly(methyl methacrylate) (PMMA) and the low surface energy molecule 1H,1H,2H,2H-heptadecafluorodecyl polyhedral oligomeric silsesquioxane (fluorodecyl POSS, γ[subscript sv] ≈ 10 mN/m) using an air brush with a pressurized nitrogen stream. Scanning electron micrographs show the formation of microtextured surfaces possessing re-entrant curvature; a critical feature for obtaining liquid repellency with low surface tension liquids. The surface morphology can be tuned systematically from a corpuscular or spherical microstructure to a beads-on-string structure and finally to bundled fibers by controlling the solution concentration and molecular weight of the sprayed polymer. The oleophobicity of the resulting structures is characterized by advancing and receding contact angle measurements with liquids of a range of surface tensions.United States. Army Research Office (Contract W911NF-07-D-0004)Air Force Research Laboratory (Wright-Patterson Air Force Base, Ohio). Propulsion DirectorateUnited States. Air Force Office of Scientific Researc

The hybrid experimental simplex algorithm – An alternative method for ‘sweet spot’ identification in early bioprocess development: Case studies in ion exchange chromatography

The capacity to locate efficiently a subset of experimental conditions necessary for the identification of an operating envelope is a key objective in many studies. We have shown previously how this can be performed by using the simplex algorithm and this paper now extends the approach by augmenting the established simplex method to form a novel hybrid experimental simplex algorithm (HESA) for identifying ‘sweet spots’ during scouting development studies. The paper describes the new algorithm and illustrates its use in two bioprocessing case studies conducted in a 96-well filter plate format. The first investigates the effect of pH and salt concentration on the binding of green fluorescent protein, isolated from Escherichia coli homogenate, to a weak anion exchange resin and the second examines the impact of salt concentration, pH and initial feed concentration upon the binding capacities of a FAb′, isolated from E. coli lysate, to a strong cation exchange resin. Compared with the established algorithm, HESA was better at delivering valuable information regarding the size, shape and location of operating ‘sweet spots’ that could then be further investigated and optimized with follow up studies. To test how favorably these features of HESA compared with conventional DoE (design of experiments) methods, HESA results were also compared with approaches including response surface modeling experimental designs. The results show that HESA can return ‘sweet spots’ that are equivalently or better defined than those obtained from DoE approaches. At the same time the deployment of HESA to identify bioprocess-relevant operating boundaries was accompanied by comparable experimental costs to those of DoE methods. HESA is therefore a viable and valuable alternative route for identifying ‘sweet spots’ during scouting studies in bioprocess development

Including a pen and/or cover letter, containing social incentive text, had no effect on questionnaire response rate : a factorial randomised controlled Study within a Trial [version 1; peer review: awaiting peer review]

Background: Postal questionnaires are frequently used in randomised controlled trials to collect outcome data on participants; however, poor response can introduce bias, affect generalisability and validity, and reduce statistical power. The objective of this study was to assess whether a pen and/or social incentive text cover letter sent with a postal follow-up questionnaire increased response rates in a trial. Method: A two-by-two factorial randomised controlled trial was embedded within the OTIS host trial. Participants due their 12-month (final) follow-up questionnaire were randomised to be sent: a pen; a social incentive text cover letter; both; or neither. The primary outcome measure was the proportion of participants in each group who returned the questionnaire. Secondary outcomes were: time to return, completeness of the questionnaire, necessity of a reminder letter, and the cost effectiveness. Results: The overall 12-month questionnaire response rate was 721 out of 755 (95.5%). Neither the pen nor social incentive cover letter had a statistically significant effect on response rate: pen 95.2% vs. no pen 95.8%, adjusted OR 0.90 (95% CI 0.45 to 1.80; p=0.77); social incentive cover letter 95.2% vs. no social incentive cover letter 95.8%, adjusted OR 0.84 (95% CI 0.42 to 1.69, p=0.63). No statistically significant differences were observed between either of the intervention groups on time to response, need for a reminder or completeness. Therefore, neither intervention was cost-effective. Conclusions: We found no evidence of a difference in response rates associated with the inclusion of a pen and/or social incentive cover letter with the final follow-up postal questionnaire of the host trial. However, when these results are combined with previous SWATs, the meta-analysis evidence remains that including a pen increases response rates. The social incentive cover letter warrants further investigation to determine effectiveness

Climate resilience of dry season cereals in India

India is the world’s second largest producer of wheat, with more than 40% increase in production since 2000. Increasing temperatures raise concerns about wheat’s sensitivity to heat. Traditionally-grown sorghum is an alternative rabi (winter season) cereal, but area under sorghum production has declined more than 20% since 2000. We examine sensitivity of wheat and sorghum yields to historical temperature and compare water requirements in districts where both cereals are cultivated. Wheat yields are sensitive to increases in maximum daily temperature in multiple stages of the growing season, while sorghum does not display the same sensitivity. Crop water requirements (mm) are 1.4 times greater for wheat than sorghum, mainly due to extension of its growing season into summer. However, water footprints (m3 per ton) are approximately 15% less for wheat due to its higher yields. Sensitivity to future climate projections, without changes in management, suggests 5% decline in wheat yields and 12% increase in water footprints by 2040, compared with 4% increase in water footprint for sorghum. On balance, sorghum provides a climate-resilient alternative to wheat for expansion in rabi cereals. However, yields need to increase to make sorghum competitive for farmer profits and efficient use of land to provide nutrients

Alternative cereals can improve water use and nutrient supply in India

open7siHumanity faces the grand challenge of feeding a growing, more affluent population in the coming decades while reducing the environmental burden of agriculture. Approaches that integrate food security and environmental goals offer promise for achieving a more sustainable global food system, yet little work has been done to link potential solutions with agricultural policies. Taking the case of cereal production in India, we use a process-based crop water model and government data on food production and nutrient content to assess the implications of various crop-shifting scenarios on consumptive water demand and nutrient production. We find that historical growth in wheat production during the rabi (non-monsoon) season has been the main driver of the country’s increased consumptive irrigation water demand and that rice is the least water-efficient cereal for the production of key nutrients, especially for iron, zinc, and fiber. By replacing rice areas in each district with the alternative cereal (maize, finger millet, pearl millet, or sorghum) with the lowest irrigation (blue) water footprint (WFP), we show that it is possible to reduce irrigation water demand by 33% and improve the production of protein (+1%), iron (+27%), and zinc (+13%) with only a modest reduction in calories. Replacing rice areas with the lowest total (rainfall + irrigation) WFP alternative cereal or the cereal with the highest nutritional yield (metric tons of protein per hectare or kilograms of iron per hectare) yielded similar benefits. By adopting a similar multidimensional framework, India and other nations can identify food security solutions that can achieve multiple sustainability goals simultaneously.openDavis, Kyle Frankel; Chiarelli, Davide Danilo; Rulli, Maria Cristina; Chhatre, Ashwini; Richter, Brian; Singh, Deepti; DeFries, RuthDavis, Kyle Frankel; Chiarelli, Davide Danilo; Rulli, Maria Cristina; Chhatre, Ashwini; Richter, Brian; Singh, Deepti; Defries, Rut

Assessing the sustainability of post-Green Revolution cereals in India

Sustainable food systems aim to provide sufficient and nutritious food, while maximizing climate resilience and minimizing resource demands as well as negative environmental impacts. Historical practices, notably the Green Revolution, prioritized the single objective to maximize production over other nutritional and environmental dimensions. We quantitatively assess outcomes of alternative production decisions across multiple objectives using India’s ricedominated monsoon cereal production as an example. We perform a series of optimizations to maximize nutrient production (i.e., protein and iron), minimize greenhouse gas (GHG) emissions and resource use (i.e., water and energy), ormaximize resilience to climate extremes.We find that increasing the area under coarse cereals (i.e., millets, sorghum) improves nutritional supply (on average, +1% to +5% protein and +5% to +49% iron), increases climate resilience (1% to 13% fewer calories lost during an extreme dry year), and reduces GHGs (−2% to −13%) and demand for irrigation water (−3% to −21%) and energy (−2% to −12%) while maintaining calorie production and cropped area. The extent of these benefits partly depends on the feasibility of switching cropped area from rice to coarse cereals. Based on current production practices in 2 states, supporting these cobenefits could require greater manure and draft power but similar or less labor, fertilizer, and machinery. Nationaland state-level strategies considering multiple objectives in decisions about cereal production can move beyond many shortcomings of the Green Revolution while reinforcing the benefits. This ability to realistically incorporate multiple dimensions into intervention planning and implementation is the crux of sustainable food production systems worldwide