AMYLIN PHARMACEUTICALS
Evaluation of alternative methods for Leptin production
Over the past decade, several advances have been made in recombinant DNA technology and heterologous protein expression. Such advances have had a direct impact on the efficiency with which pharmaceutical and biotechnology companies can produce therapeutic protein products, thus fueling growth for a market which now accounts for 10% of all pharmaceutical sales. Leptin is a naturally occurring protein hormone secreted by adipose tissue and acts as a signal to the hypothalamus to regulate food intake and energy expenditure. Studies have shown that leptin given in combination with amylin, a second hormone linked to fat metabolism, results in sustained, fat-specific weight loss in a leptin-resistant animal model of obesity. Thus, leptin, in combination with pramlintide, an amylin analog, is currently being investigated by Amylin Pharmaceuticals as a treatment for obesity. The primary objective of the project undertaken by the KGI team was to evaluate the yeast Pichia pastoris as a possible manufacturing cell line and analyze the commercial feasibility of using a P. pastoris expression system for the production of human leptin.

Since the company is investigating leptin for use in a combination therapy, a crucial factor is to minimize the drug substance cost of goods manufactured (COGM). One way to keep COGM low is to find an efficient expression host that may also minimize downstream processing. The project helped Amylin determine whether P. pastoris can be a commercially acceptable alternative to the current system for producing the leptin protein. The technical assessment provided results for product titer, yield, and quality, as well as data that can be used to perform a matrix analysis to estimate cost of goods manufactured. The report also included an intellectual property analysis, a contract manufacturing assessment, evaluation of regulatory issues, and bioprocess models produced using SuperPro™. Combined, this information provides Amylin with the information necessary to begin assessing P. pastoris as an alternative expression system for the manufacture of human leptin.

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Students: Naomi Arana, Shi Yu Chang, Tianhao Han, Sarah Moore (HMC), Kimberly Sevilla
Corporate Liaison: Dr. David Litzinger
Faculty Advisor: Prof. Karen Moynihan

AMYLIN PHARMACEUTICALS
Evaluation of Implantable Delivery Systems for Continuous Therapy in Diabetes and Obesity
Amylin Pharmaceuticals Inc. is committed to the discovery, development and commercialization of novel medicines for the treatment of metabolic diseases. With two first-in-class products on the market, SYMLIN® (pramlintide acetate) and BYETTA® (exenatide), Amylin is continually striving to meet the therapeutic needs of patients. The goal of the project was to apply novel drug delivery technologies to Amylin's active pharmaceutical ingredients, yielding a new generation of products that reduce the frequency of patient-driven dosing while enhancing patient compliance.

Using a comprehensive, multidisciplinary approach, several implantable drug delivery systems were evaluated for potential inclusion as treatment options within the diabetes and obesity therapeutics market. Historically, implantable drug delivery devices have been developed for a variety of therapeutic areas including pain management, viral infection, delivery of hormones and cancer treatment. The drug delivery systems investigated for Amylin were generally small devices designed to be subcutaneously implanted in patients. The devices provide controlled and sustained delivery of drug for extended periods of time. To assess the market for implantable devices, the team evaluated the compatibility and feasibility of each type of implant with Amylin's compounds and also investigated the implants from a financial and market acceptance point of view. The implications of launching a drug delivery product of this nature for the diabetes and obesity markets were evaluated based on several factors including patient, physician and payer acceptance, along with the reimbursement landscape and product utility.

Other delivery technologies that prolong drug action were examined to explore changing the treatments for diabetics and obese patients. Summaries of the team's findings, including analysis of regulatory issues and development of a commercialization strategy, were organized into traditional marketing frameworks. Ultimately, a final recommendation detailing the most effective drug delivery systems was given.

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Students: Sanket Acharya, Justin Custer, Krishnalekha Datta, Tezus Naidu, Jeremy Six, Alissa Sole (CMC)
Corporate Liasons Dr. Jim Osborne, Dr. Stephen Pentoney, Betty Tuggle, Dr. Craig Adams, Dr. Jerald Feitelson
Faculty Advisor: Prof. Bulbul Chakravarti

BECKMAN COULTER
Current and Future Role of Mass Spectrometry and Multiplex Assays in Human Diagnostic Testing
Beckman Coulter, Inc. is a leading manufacturer of biomedical instruments, tests and supplies that simplify and automate laboratory processes. Beckman Coulter was interested in the need for mass spectrometry for use in clinical diagnostic testing systems.

The goals of this TMP were to provide Beckman Coulter with a background of mass spectrometry clinical diagnostic information, identify key customer practices and drivers for the adoption of clinical mass spectrometry technology, and evaluate the competitive landscape for this technology. Background information and an analysis of the competitive landscape were provided using summarized secondary web-site and Internet research. Background information included current uses of mass spectrometry in the lab, information on sample preparation, and current technologies available. Customer practices and requirements were identified through the use of an intricate on-line survey given to various hospitals across the United States. The survey was designed such that both hospitals that do and do not currently offer or perform mass spectrometry-based clinical tests were able to give meaningful input. All of the information gathered will be used to generate a report that answers the following questions regarding the use of mass spectrometry in the clinic: Why Mass Spectrometry? What tests are done? Where? Who is using it? Whose equipment is being used? What's next? ▲ Top     

Students: AnGee Baldini (CMC), Victor Chiu, Anita Kurien, Jennifer Wong
Corporate Liasons: Dr. Elvir Causevic, Rich Watt
Faculty Advisor: Prof. John Milton (CMC)

BRAINSCOPE
Assessment of Market Opportunities for Electroencephalography Applied to Neurological Disease
The BrainScope Company, Inc. is the developer of a radically new generation of hand-held devices that act as digital translators of the electrical activity of the brain. With a BrainScope device, medical professionals can quickly have an objective, accurate, and evidence-based assessment of a patient's need for further examination in cases of concussion, stroke and other brain dysfunctions. The technology rests on more than 30 years of clinical data and combines cutting edge, patented algorithms developed against the world's largest database of brainwave recordings, with advanced miniaturized hardware, an easy-to-use user interface and a disposable headset.

Students worked with BrainScope to identify and characterize various markets for clinical use of BrainScope's revolutionary, proprietary and non-invasive technology. The students assessed neurological diseases for which Brainscope technology could prove most useful in diagnosis and they developed business models for a number of the diseases identified. The TMP effort provided analysis and recommendations that aid Brainscope in the mission to provide medical professionals with effective new tools to assist in the assessment of brain injuries and brain disorders and to provide appropriate and timely treatment

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Students: Rajesh Chitta, Alex Clayton, Paul Schultz, Timothy Iafe (CMC)
Corporate Liason: Fred Boling
Faculty Advisor: Prof. Matthew Croughan
Consulting Scientist: KiriLynn Svay

CLEAR SPRINGS
Biofuel Feedstocks: Economics of Algae and Switchgrass
Clear Springs owns 18,000 acres of rolling land located in Polk County, Florida, which is midway between Tampa and Orlando. Founded as a new eco-friendly community by Stanford N Phelps, Clear Springs plans to dedicate 6,000 acres of land to renewable energy feedstock production.

The objective of this TMP was to analyze the renewable energy market and determine the optimal energy feedstock for this new community. Working directly with Clear Springs, the team identified algae and switchgrass as the two best suited energy feedstock options. For the analysis of the algae biofuels market, the team investigated all the companies currently involved in the field, conducted extensive interviews, created financial models, and developed detailed market reports. In addition, switchgrass strains and biofuel production technology were investigated and a final report and recommendation were provided.

The team also succeeded in developing a laboratory analysis of algae composition and growth characteristics. The algae and switchgrass financial valuations were supported by Crystal Ball risk and valuation software, which was utilized to forecast outcomes for the different investment proposals and provide reports to conduct a return on investment analysis.

The team successfully recommended several business proposals to Clear Springs with supporting marketing, financial, and laboratory information. The recommendations provided Clear Springs with the knowledge and resources necessary to make a final decision on how to proceed with their renewable energy venture.

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Students: Matthew Grunseth, Pavan Kolli, Daniel Spurgin, Andrew Zepfel (CMC)
Corporate Liason: Dr. Gregory Bradfisch
Faculty Advisor: Prof. Kathrin Schrick
Consulting Scientist: Dr. Bala K.P. Venkata

DOW AGROSCIENCES
Market assessment of stress tolerant traits for field production of corn and development of proof-of-concept assays for rapid screening of targeted traits
Dow AgroSciences LLC (DAS), based in Indianapolis, Indiana, USA, is a top tier agricultural company providing innovative crop protection, pest and vegetation management, and seed and biotechnology solutions to serve the world's growing population. A wholly owned subsidiary of The Dow Chemical Company, Dow AgroSciences contributed $3.4 billion in global sales for its parent company in 2006.

Average corn yield rarely matches the genetic potential because of stresses imposed by the environment. Drought stress is perceived to be the most common contributor to yield loss. With the majority of the crop reliant on rainfall, a drought resistant corn product would help farmers stabilize yields. The goal behind the Dow AgroSciences (DAS) Team Masters Project is to refine product definition and screening strategies for developing drought resistant corn traits for the United States and global marketplaces.

The DAS TMP approached product definition and screening development for drought tolerant traits in three ways: (1) established a database of competitive intelligence, (2) statistically assessed the non-irrigated corn market by correlating soil moisture to yield, and (3) designed an experimental proof-of-concept screening assay to identify drought resistance. In aggregate this tripartite assessment will refine DAS product discovery strategies for drought tolerance in corn, coupled with a high throughput means of identifying targeted traits.

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Students: Joanna Kang, Theodore Nguyen, Jacqueline Rosselle, Satish Vammi
Corporate Liason: Bruce Kisner
Faculty Advisor Prof. James Sterling

GILEAD SCIENCES
Manufacturing Transaction Processing Using Wireless Technology and Bar Codes
Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines primarily for antiviral and cardiovascular conditions and respiratory diseases. The objective of the Gilead Work Order (WO) TMP was to improve the accuracy and efficiency of warehouse and manufacturing operations, including data entry, to ensure real-time issuance of components for the operations at the San Dimas site. Our project, the fourth phase of an ongoing Gilead program, was titled Bar Code Automated System—IV (BCAS IV).

Incorporating dcLink, JDEdwards and Optio Software, we designed a software program that would barcode and automatically generate a WO. Our TMP also created a revised WO format using feedback received from user interviews and developed and tested test scripts which were used to validate the new system that was implemented. In addition, we developed several important scripting and verification documents including the User Requirements Specification (URS), Functional Requirements Specification (FRS), Validation Master Plan (VMP) and several Standard Operating Procedures (SOPs). Finally, we successfully validated the software system and transitioned this system into manufacturing and production processes within the San Dimas facility in April 2008, also known as our “Go Live” date.

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Students: Sanket Borad, Aanchal Kamra, Jayasri Prabakaran, Parvin Rastegar, Tirso Alvarez Carrera (PTZ), Oliver Johnson (HMC), Autumn Petros-Good (HMC), Natt Supab (HMC)
Corporate Liasons: Dr. Gerard Jensen, Tark Bunch
Faculty Advisors: Prof. James Sterling, Prof. Ruye Wang (HMC)

GILEAD SCIENCES
Automated Inspection for Pharmaceutical Products
Testing of pharmaceutical product components in the manufacturing process is required to ensure quality. Automated and trainable machines could eliminate human variability in characterizing components such as glass vials for parenteral dosages, stoppers for use with vials, and other dimension-critical items. The technology for automated dimensional analysis and defect detection has undergone rapid improvement and development in recent years. Implementation of automated inspection systems could improve efficiency and reduce operating costs at the manufacturing plant of Gilead Sciences in San Dimas.

Currently, there are two levels of inspection performed in the industry – 100% inspection of all incoming and final products by the manufacturing department, and a separate verification of batch quality by discrete sampling inspection by the quality assurance department.

This project was a joint effort between Harvey Mudd College and Keck Graduate Institute. There were two goals of this project. The first objective was to evaluate and make recommendations for the purchase of a manufacturing-scale automated inspection system for parenteral products. The scope of this evaluation included a risk assessment and an economic justification for the recommended system. The second objective was to design a system to detect and quantify cosmetic defects in pills for quality assurance purposes. The developed prototype is able to detect and classify cosmetic defects in pills using image analysis software and serves as a proof-of-concept for the development an automated inspection system for pill defect detection.

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Students: Stephanie Brecheisen, Eureka Dias, Andrew Hopkins, Santosh Kuruvilla, Raghavan Vasudevan
Corporate Liasons: Dr. Ray Goodrich, Dr. Helena Buneksn
Faculty Advisor: Prof. Steven Casper

GAMBRO BCT
Pursuing a "Better Blood" Indication Based on the Ability of the Mirasol Pathogen Reduction Technology to Inactivate White Blood Cells in Transfused Blood Products
Navigant Biotechnologies, a wholly-owned subsidiary of Gambro BCT, is focused on developing pathogen reduction methods that are based on the addition of riboflavin to blood products followed by exposure to light before transfusion. Navigant’s flagship product, the Mirasol Pathogen Reduction Technology (PRT) system has recently received CE marking, indicating that it has met certain requirements for sale in Europe for platelet products, and other applications of this technology are now being sought. Navigant is currently generating clinical data for FDA approval of Mirasol.

The focus of this TMP was to assess the viability of various business strategies and approaches intended to expand and accelerate global market penetration of Mirasol beyond 2008. The team focused on determining a potential positioning strategy primarily based on white cell inactivation by Mirasol. The team investigated:

• The clinical benefits over current techniques of white cell inactivation
• The overall incidence of adverse transfusion events as an indication of potential market size
• Potential target patient populations
• The cost-to-benefit requirements for system implementation
• Reimbursement issues
• The UK as a model for US market entry

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Students: Kristina Roskos, Marcia Soriano, Sean Tsai, Chris Warner
Corporate Liasons: Michael Fiske, Barbara Dwyer
Faculty Advisors: Prof. Angelika Niemz, Prof. Deb Chakravarti
Consulting Scientist: Tanya Ferguson

ORTHO-CLINICAL DIAGNOSTICS
Optimizing Reagents for Homogenous EMIT Immunoassays
Ortho-Clinical diagnostics (OCD) is a Johnson & Johnson company known for its clinical chemistry, immunodiagnostics, immunohematology and blood screening products and services. OCD has reported less than optimal on-analyzer stability profiles for some of their Enzyme Multiplied Immunoassay Technique (EMIT) assays, in particular Valproic Acid (VALP). The current work-around wastes company supplies and money. Therefore, the OCD Team Masters Project at KGI has been charged with further investigating the cause of this phenomenon, and has focused primarily on the enzyme-conjugate used in the assays. Several avenues to improve reagent on-analyzer stability were explored by implementing wet lab techniques, engineering devices, and Design of Experiments (DOE) methodology.

The team developed several methods for isolating and characterizing the enzyme-conjugate when it is aged on the analyzer. They compared the aged enzyme-conjugate to its native state using SDS-PAGE, Western Blots, and Size Exclusion Chromatography. A temperature gradient in the reagent storage carousel was characterized and a small device was subsequently built to replicate the gradient. Finally, using DOE studies, the addition of excipients to help mitigate the observed instability was examined. The team’s studies have increased knowledge of the biophysical properties of the enzyme-conjugate and the VALP assay, which may lead to more cost effective solutions for EMIT assays.

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Students: Sebastien Brasseur, Ye-won Cho, Thi Nguyen, Peter Vandeventer
Corporate Liason: Jason Abbas
Faculty Advisor: Dr. Robert Doebler

SYNGENTA
Design and Development of an In-line, Rapid-cycling PCR System
As a leading agribusiness committed to sustainable agriculture through innovative research and technology, Syngenta is interested in large-scale, high-throughput, sensitive, and low-cost screening of plant materials, in support of their plant breeding effort. The goal of the Syngenta Team Masters Project was to develop and test strategies to amplify target DNA using PCR, in a continuous high-throughput fashion that is compatible with a novel microwell substrate and its automated system.

The team evaluated and tested different methods of heating and cooling that can be used to amplify the sample DNA much more rapidly than the current thermocycling times. Speed of amplification and cost were considered when designing and building a small scale prototype. The design was constantly modified and improved throughout the project based on results from extensive laboratory experiments. The final design provided Syngenta with a starting point to assess the feasibility of replacing their current system with a scaled up in-line PCR system based upon the results of our prototype. p>

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Students: J.P. Doyle (CMC), Sunitha Jagannathan, James Lu, Isaac Middendorf, Brianna Schuetz
Corporate Liason: Dr. Kenneth Pitzer
Faculty Advisor: Prof. Molly Schmid

THERAVANCE
Leveraging Global Capabilities to Speed Drug Discovery and Early Development
Theravance is a pharmaceutical company located in San Francisco that specializes in discovery and commercialization of small molecule drugs for several conditions including respiratory disease, bacterial infections and gastrointestinal dysfunction. The objective of the Theravance Team Masters Project was to explore emerging global resources to speed drug discovery and early development. Globalization has presented a series of opportunities for US-based pharmaceutical and biotechnology companies in processes such as contract manufacturing and clinical trials. Cost savings has been an important factor that has promoted outsourcing of such scale-dependent processes. This project, however, focused on how global resources can be used to reduce the time needed to discover candidate molecules meeting a specified preclinical profile. The implications of reduced time to market are longer market exclusivity and increased revenues.

The assessment took the perspective of a mid-sized firm such as Theravance, Inc. which currently has one location in the United States. After gaining an understanding of the current Theravance approach to drug discovery and early development, the project team identified several alternative opportunities to use global resources to speed the R&D process. Through interviewing key opinion leaders and senior members at Theravance, the team quantified the potential benefits and risks associated with pursuing these opportunities. Using a structured decision analysis process, the team evaluated and ranked these options. The top three alternatives were developed into detailed strategic plans including key actions, timelines and budgets. These detailed strategic plans also highlighted the important success factors and associated risks (regulatory, operational, cultural, etc.). The results of the project and the detailed strategic plans were presented to the Theravance senior management.

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