Presentation October 2010:  The State of Our Industry
Jeff W. Paslay, PhD.
Paslay Consulting

The BioPharma industry has been under increasing scrutiny over the last decade as R&D costs continue to rise and relative productivity has decreased. Our public image has deteriorated to a point where we are viewed as not trustworthy and we are a constant target of litigation. Whether these criticisms or perceptions are just or not, is not the key issue. The real issue that many of us ponder is “how did we get where we are today?” This presentation will discuss some of the underlying causes for these perceptions, actions and trends that the industry has pursued to address these issues, and project where the industry may head to regain productivity, efficiency and respect.
 

Presentation June 2009:  Considerations in Building a Compound Management Lab
Ted Peters; Compound Manager
Constellation Pharmaceuticals Inc.

The challenge of starting a compound management lab with the limited resources of a startup company has been a unique experience. Considerations of what is essential to the process including storage, automated pipetting needs, technician staffing and IT support. The focus of these consideration is to adopt new technologies and concepts for faster screening of assay ready plates. There is an ongoing effort to create a small scale lab with large scale expectations of HTS and hit to lead activities. The details at the one year mark of what has been accomplished and where we are striving to be.
 

Presentation June 2009:  Bringing a Compound Collection into the 21st Century: The Introduction of Automation and QC
Myra O'Leary;  Research Technician, Compound Management
The Broad Institute

The Broad compound management team previously worked in a fully walk up mode. With our previous setup, throughput was limited and mistakes could go undetected. Collaborating with HiRes Biosolutions we established a fully automated screening center and compound management system. We also implemented quality control by LC/MS throughout our entire existing collection creating thresholds for compound quality. Details of our current compound management system include increased throughput, improved automation capabilities and compound quality, and novel informatics tools and a bright outlook for our future.
 

Presentation June 2009:  Progressive Compound Management: Strategies and Pitfalls
Rhett L. Affleck, Ph. D.; V.P. Technology
Nexus Biosystems
 

Presentation April 2009:  The cancer Biomedical Informatics Grid^?/font> (caBIG^?/font>): Resources to support translational research
Donna Messersmith, PhD; Integrative Cancer Research Product Representative
National Cancer Institute - Center for Bioinformatics and Information Technology

The Biospecimen Research Database (BRD) is designed to address the problem of no reliable means to find well vetted, sufficiently expressed experimental protocols for creating biospecimens. This affects researchers in terms of the time to search for and find a relevant protocol to utilize. If one is not found then additional time and effort is required to develop their protocol. The impact of a solution would be to expedite scientific research. The ideal solution would be to provide a searchable, well-documented means to prepare a repeatable and consistent biospecimen through a curated protocol.

The BRD addresses this need by promoting the idea that data about biospecimen protocols should be structured in a way to allow easy search and use. Papers and studies are curated to identify technology platform, analyte, and biospecimen location. As the curated quantities that represent best practices increases the BRD will become a preferred starting point to find well annotated protocols. This will give rise to Standard Operating Protocols (SOPs) built from the meta-analysis of biospecimen protocols. By posting published SOPs in the BRD and making them searchable entities with the characteristics of being digitally unique, versioned, able to be referenced, and portable the BRD will fulfill part of the mission of the Office of Biorepositories and Biospecimen Research (OBBR).

Presentation April 2009:  Mixed phase 21st century, world class biobanking story
Steve Arsenault, directeur de l?xploitation
Biobanque G幯ome Qu嶵ec

Challenges of implementing a world class Biobank
Building a public resource: The Genome Quebec - Centre hospitalier affili? universitaire r嶲ional de Chicoutimi Biobank
Evaluating and choosing a cost-effective and sustainable infrastructure
Implementation Process and Timeline
Current Biobank Operations

Presented at LRIG Mid Atlantic, Automated Biorepositories: Enabling Technologies
 

Presentation April 2009:  DNA Extraction Technology Overview - Increasing Capacity 10X
Robert J.Corr
Pfizer Global Research & Development, DNA & BioFluids Center of Emphasis, Pfizer Inc., Kings Heights, Groton, CT

New protocols, extensive multiplexing, increased sensitivity of detection, and advances in miniaturization and automation have substantially reduced the amount of DNA required for downstream assays prompted the question: are we banking an appropriate amount of DNA?
The current DNA extraction platform at the DNA & BioFluids CoE was designed to extract large quantities of DNA from large volumes of human whole blood. After discussions with our colleagues in Exploratory Research, it was determined that decreasing banked DNA amounts while increasing throughput was preferable to the current model. This presentation describes the process of reviewing the current technology landscape with the intent of increasing daily DNA extraction capacity by ten fold while maintaining quality and reducing operating cost. The exploration of the technology landscape included the review of chemistry (solid-phase, precipitation, silica, and magnetic bead technologies) and various automation options. Additionally, in-house and outsourcing processing costs were compared.

Presented at LRIG Mid Atlantic, Automated Biorepositories: Enabling Technologies
 

Presentation April 2009:  Development of QC methods to monitor cross-contamination from fixed-tip automation used to extract DNA from clinical blood samples
Stephanie K. Hall¹, Jason Harraden² and Diane L. Johnson²
Pfizer Global Research & Development, ¹Groton Laboratories, Pfizer Inc., Groton, CT 06340 ²DNA/Biofluids BioBank, Pfizer Inc., Kings Heights, Groton, CT 06340

Clinical studies and gene-based target discovery require high quality DNA for genotyping, genetic association studies and resequencing efforts. Rigorous quality control (QC) procedures are required to assess the DNA extracted from our automated DNA extraction process to ensure high standards and sample integrity for the material used in our studies. Our DNA extraction process uses fixed-tip automation which could increase the potential of sample contamination. The QC procedures that have been developed to monitor cross-contamination will be discussed in our presentation.

Evaluating samples for cross contamination using water control samples is a critical step in our QC methodology. TaqMan genotyping assays were used initially to evaluate water samples from our DNA extraction process. Cross-contamination rates approaching 20% were detected in early development of the DNA extraction process. Enhanced tip washing procedures were implemented in addition to a tip bleaching step. These modifications significantly reduced observed cross-contamination levels to <2%. One limitation of the TaqMan assay is its inability to precisely quantitate the contamination that was detected. Copy number and plus/minus real-time PCR assays were developed and used with serially diluted DNA of known concentration to provide absolute quantitation of contamination levels. Using these assays, we have been able to detect contamination at levels of 1 pg/ul. A mixing experiment was performed to assess whether low level system contamination could alter the performance of extracted DNA samples in genotyping assays. A contaminated water sample from an individual homozygous for one SNP allele was combined in equal proportion with DNA from an individual homozygous for the other SNP allele. TaqMan genotyping assays were performed and no alteration in the genotype of the DNA sample was observed. The genotypes were always reflective of the DNA allele and were not affected by the presence of contamination from the combined water sample. Future enhancements are being developed to provide QC methods to evaluate clinical DNA samples extracted on our automated system.

Presented at LRIG Mid Atlantic, Automated Biorepositories: Enabling Technologies
 

Presentation 2/08:  Development and validation of the UK Biobank sample handling, processing and archiving protocol (also available as PDF)
Tim Peakman, Executive Director, UK Biobank

UK Biobank is a large prospective study established in the United Kingdom to determine the role of genetic factors, environmental exposures and lifestyle in the causes of major diseases of late and middle age. Extensive data and biological samples are being collected from 500,000 participants aged between 40 and 69 years. Which biological samples are collected and how they are processed and stored will have a major impact on the future value of the UK Biobank resource. The UK Biobank sample handling and storage protocol has been carefully designed to future proof the study (i.e. to avoid, as far as can be predicted, processing or storage approaches that will preclude current or future assays) and to provide a resource that would give the maximum scientific value within the available budget. The protocol was developed through a thorough review of the literature on sample handling and processing as well as wide consultation within the academic community. This approach addressed issues such as which samples should be collected, how and when they should be processed, and how the processed samples should be stored to ensure their long term integrity. The factors involved in developing the final protocol will be discussed. The recommended protocol was also extensively tested in a series of pilot studies conducted by collaborating groups throughout the UK. Using a variety of technologies to assay the genome, transcriptome, proteome and metabolome, these studies examined the stability of a wide range of components of blood and urine maintained at either 4?/font>C or 18?/font>C for varying times prior to processing and cryopreservation. An overview of the results of these pilots will be presented. The sample processing and archiving protocol adopted by UK Biobank provides a feasible approach to quality and throughput that reflects the size and aims of the project within the available funding.

Presentation 2/08:  Implementation of the UK Biobank (also available as PDF)
Paul Downey, Director of Operations, UK Biobank

UK Biobank is a new organisation, set up to facilitate efficient medical and scientific research. The project will recruit 500,000 volunteer members of the public over a period of three years. The volunteers provide detailed information about the health and lifestyle and consent to access to their health care records. This will form a valuable resource that can be rapidly accessed by research organisations.

In order to deliver the project, a national network of recruitment clinics has been established to receive and process the volunteer participants. A biological specimen processing factory has been constructed and an automated biological specimen repository developed, having the capacity to process and store the 14,000,000 sample aliquots that will be created.

The use and delivered benefits of utilising modern manufacturing practices to design implement and operate a sample processing facility will be discussed. The use of appropriate techniques during the evolving phases of the project: the research and design phase, the operations development phase and the operational phase will be covered. Selection and implementing appropriate culture and quality systems at the phases of the project to support the organisational objectives will be discussed.

Presented at LRIG Mid Atlantic, Automated Biorepositories: Successful Models
 

Presentation 2/08:   The Pfizer Liquid Store, DNA & BioFluids REMP Store (also available as PDF)
Craig Hines, Manager, Liquid Store Center of Emphasis, Pfizer - Kings Heights Technology Center
Diane Johnson, Head of DNA & BioFluids Center of Emphasis, Pfizer - Kings Heights Technology Center
Leonid Vodonos, Facility Manager, Pfizer - Kings Heights Technology Center

This presentation will discuss the Kings Heights Technology Center scientific business objectives in conjunction with the facility support infrastructure and operational service delivery model. The presenters will provide details of the unique relationship between the Kings Heights Scientific Lines and Global Operations that laid foundation for a dynamic and State-of-the-Art technological facility.

Recently Global Operations has collaboratively developed and implemented a wide variety of business specific services including Processing Labs humidity control, management of service contracts based on contractual partnership, scheduling and coordination of preventative maintenance, demand repair work, handling service related documentation, Facility Center asset management, 24/7 monitoring and equipment emergency response, production process consumable supply/tracking and lab support technical services. Global Operations has made a commitment to deliver cost-effective services and solutions that enhance scientific productivity.

The timelines for design, manufacture, and installation of the REMP Stores will be presented. As well as a number of functionalities that was developed for the Liquid Store, DNA & BioFluids REMP store & laboratories.

Presented at LRIG Mid Atlantic, Automated Biorepositories: Successful Models
 

Presentation 2/08:  The Rutgers University Cell and DNA Repository (also available as PDF)
Dr. Andrew Brooks, Associate Director of Technology Development for the Rutgers University Cell and DNA Repository (RUCDR)

The Rutgers University Cell and DNA Repository (RUCDR) is among the largest academic repositories in the world. The scope of the repository grows every year and includes service offerings that range from DNA extraction to cell line immortalization in addition to a considerable sample distribution program. Currently the RUCDR maintains several large federal respoitories for the following NIH institutes: NIAAA, NIDA, NIMH and NIDDK. Additionally, the RUCDR services several foundation projects that include and are not limited to the Simons Autism Foundation and the New Jersey Tourettes collection. In total the RUCDR currently manages over 60 different clinically based projects through these and other agencies which help geneticists around the world understand the genetic basis for over 25 different diseases. In order to coordinate the collection and processing of samples from over 400 collection sites worldwide and manage over 1 million cell line aliquots and 750,000 samples in mechanical storage the RUCDR has developed several sophisticated automation schemes to handle many aspects of the RUCDR workflow. The structure of the RUCDR, a description of its automation infrastructure and a detailed overview of the programs services will be discussed.

Presented at LRIG Mid Atlantic, Automated Biorepositories: Successful Models
 

DNA samples are stored in the -20˚C compartment that is a standard REMP store. DNA samples are thawed and refrozen after each access and are in the proprietary REMP 96-well 900ul tubes. Individual samples are replaced in their original locations to prevent store fragmentation. In contrast biofluid samples are in the same tubes but heat-sealed and used as single use samples to minimize freeze/thaw cycles.

The timelines for design, manufacture, and installation, will be presented. A number of functionalities that were developed for the earlier REMP stores and their reuse will be discussed, together with the rationale for a partial FAT at Oberdiessbach will be presented with respect to reduced time and cost versus potential issues.

Presented at LRIG Mid Atlantic, Biorepositories: An Automation Frontier
 

Presentation 02/06:   Samples in DMSO: What an end user needs to know (PDF file requires Adobe Reader)
Christopher Lipinski, Ph.D.; Adjunct Senior Research Fellow
Pfizer Global Research and Development, Pfizer, Inc., retired

The end user of samples in DMSO is someone who uses and stores samples for a relatively short period of time. The body of existing literature suggests storing samples in dry DMSO at room temperature for no more than three months and then discarding them. DMSO and water exhibit very non-ideal behavior when mixed together. This behavior is responsible for a range of property changes when the two solvents interact. These include; the hygroscopicity of DMSO; the viscosity increase when DMSO is wet and most importantly for this discussion: the marked solubility decrease of compounds in wet DMSO. When compounds precipitate from wet DMSO about half the time they can be resolubilized by sonication. The trend in chemistry to make amorphous compounds is an advantage in that initial solubilization in DMSO is easy. The downside is that the DMSO solutions have to be kept absolutely dry and freeze thaw cycles need to be minimized. Trifluoroacetic (TFA) contamination of samples in DMSO is a serious problem. TFA as low as 10 nM is cytotoxic in 24-hour cell cultures. This is not much of a problem in the typical short incubation HTS but it could be a problem as longer time interval safety assays get pushed into discovery. When TFA contaminated samples in DMSO become wet, acid hydrolysis becomes a serious concern. Many heterocycles made by a dehydration step are perfectly stable under neutral conditions but are hydrolyzed by TFA in wet DMSO.
 

Presentation 02/06:   Automation of compound management at Schering-Plough Research Institute (SPRI)
Marybeth Burton; Associate Director, Chemical Technologies
Schering-Plough Research Institute

Proprietary research sample collections are one of the most valuable assets for large pharmaceuticals companies. Investment in technology to store, retrieve, prepare, and analyze this key resource is critical for the support of current and future drug discovery screening efforts. This presentation describes the project undertaken by Schering-Plough Research Institute (SPRI) to automate compound management processes and highlights improvements in request processing cycle time resulting from this initiative.
 

Presentation 02/06:   Practical Considerations for Enlightened Compound Management (PDF file requires Adobe Reader)
Rhett Affleck, Ph.D.; V.P. Technology
Nexus Biosystems

Beyond the choices of storage systems, container types, and compound selection, many questions remain regarding how to best achieve a compound management facility? goal: delivering the proper amount of each requested compound - at the required throughput and at a reasonable cost. Precipitation and degradation of compounds in DMSO stocks is a known problem. Should compounds be stored dry, in DMSO, or both? If in DMSO, at what concentration? Should multiple copies of each compound be aliquotted and stored? These and other decisions will ultimately influence screening results and should be considered by compound managers and screeners before processes are put in place that needlessly waste or don? actually deliver a large fraction of the library.
 

Presentation 02/06:   GenVault: Dry-state DNA storage: Enabling Pharmacogenomics through Smart Biosample Management (PDF file requires Adobe Reader)
Dr. David Wellis, PhD; Senior Vice President Sales and Marketing
GenVault

The management of biosamples has become increasingly important for pharmaceutical companies and contract research organizations in light of access, traceability and cost requirements. Biosamples must be easily shipped, repeatedly accessed and conveniently distributed. Biosamples must also be stored in cost-effective, long term storage conditions that are secure and traceable. GenVault exceeds these demands with a fully integrated sample management system designed for optimizing storage and retrieval and quick accessibility of collected biological samples. The core of the platform, the GenPlate, enables long-term storage, high throughput access, standard shipment and recovery of high quality DNA all at room temperature. GenVault? state of the art system is automated and offers clinical informatics to meet the needs of both small and large repositories.
 

Getting a liquid handler “dialed in” for precise, reliable operation can consume many hours (and many cases of microplates). Having been through this discovery process on a number of instruments, Molecular Devices has developed some expertise in validating its liquid handlers. We will present some of the lessons we?e learned during the development and validation of fluidics instrumentation. Some topics covered in this presentation will include: How do you select an appropriate detection method (absorbance vs fluorescence)? How do you select an appropriate dye and concentration? What can you do to minimize detection artifacts? What can you do to minimize meniscus effects? Special considerations for air displacement dispensers. How to characterize carryover and tip washing effectiveness.

Presentation 02/04:  Stability of Compounds Stored in TekCel Plate Management System: Application of New Approaches for Ultra-High-Throughput Analysis of Compound Stability
James A. Connelly Ph.D.
Director of Library Production and QC
Aventis Combinatorial Technologies Center
Tucson, Arizona
 

Presentation 01/04:  Septa Applications for Compound Preparation
Sam Abdelhamid and Paul Blake
Purdue Pharma, Cranbury, NJ, USA

Controlling the amount of water in chemical samples has become a priority among compound preparation departments. It is well known that DMSO can quickly absorb water from the surrounding air. This can compromise screening samples by lowering the concentration of dissolved material, and or causing sample precipitation. The introduction of septa based applications cannot only save time, by eliminating de-capping steps; they can also reduce the amount of water absorbed by solvents. By using vented tips that are filled with nitrogen, it is now possible to aspirate and dispense solutions from vials and deep well plates, without allowing the sample to come in contact with air. The use of liquid handling systems that incorporate septa and vented tips can also be used for combinatorial chemistry methods that use water sensitive reactants (i.e. acid chlorides). Septa caps ensure that moisture does not come into contact with air sensitive reagents. Various customs racks, holders, and vented tips were integrated with our current liquid handling procedures to yield liquid transfers under an inert atmosphere. The equipment and supplies used to implement these procedures, along with results, will be discussed in detail.
 

Presentation 01/04:  Compound Solubility and HTS Screening
Christopher Lipinski, Ph.D., Adjunct Senior Research Fellow
Pfizer Global Research and Development, Pfizer, Inc., retired

Sessions on reproducibility in HTS screening appear in the 2003 and 2004 annual meetings of the Society for Biomolecular Screening. The focus has largely been on the biological aspect, i.e. how large is the overlap in screening results when the same library of compounds is tested against the same target but using different assay methods. What is only slowly being realized is that there is another dimension to the HTS screening quality issue. HTS assay quality is very much better if you really know the concentration of compound in DMSO stocks and if you really know the compound concentration when the DMSO stocks are diluted into aqueous assay medium. Relevant to this issue are the following sub-topics: 1) from the 1880? Oswalds “rules of stages” and why it explains many DMSO solubility issues; 2) the dependence of DMSO freezing point on water content; 3) what exactly is there about freeze thaw cycles that causes solubility problems; 4) why is there such erratic behavior in terms of precipitation from DMSO and 5) what is the evidence that globally about 20% of compounds might ultimately have a DMSO solubility problem. Additionally, what has changed in the last year in terms of software and hardware that could help with the compound in DMSO solubility problem will be discussed.
 

Poster 11/03: Drug-Likeness and Lead-Likeness: An Overview of Recent Studies
Zhengming (Jimmy) Chen, Purdue Pharma L.P., Cranbury, NJ

The distinction between drug-like and non drug-like molecules has been a hot research topic in recent years. The most well known early study in this field is the “Lipinski? rule of five” which was derived empirically from the analysis of the World Drug Index on the properties that maximize an oral drug candidate? probability of surviving clinical development: molecular weight (MW) < 500, number of hydrogen bond donors < 5, number of hydrogen bond acceptors < 10, and ClogP < 5. The rule of five is now widely used to filter out compounds likely to have poor pharmacokinetic properties early on in drug discovery. Lead-likeness (compounds??likelihood to be good lead candidates), as distinct from drug-likeness, is a new concept that is gaining acceptance in recent years. Lead-like molecules are generally smaller to allow for structural additions to enhance effectiveness during lead optimization, and is being incorporated into the library design and lead optimization processes. In this presentation, I am going to present an overview of recent studies on the topic of drug-likeness and lead-likeness. The presentation will provide a few intriguing insights into the influence of molecular properties on the likelihood of progression through the drug development process and trends in modern drug discovery.

Sample Handling Operation Wizard (SHOW) is a system developed to guide manual sample handling in the research laboratory. It comprises a sample tray mounted on a flat-panel computer monitor. Up to four transparent micro titer plates and up to 8 reagent vials may be placed on the sample tray. Images of the wells of the plates and vials are generated on the monitor and controlled by computer software. These images are directly aligned with the positions of the physical wells. By highlighting the wells or vials involved in a sample handling step of a pre-defined protocol, manual operation can be performed with precise guidance from the system. As a result, the risk of locating a wrong sample or placing a sample at a wrong location can be minimized, and sample handling operations become more efficient and less stressful.

Selection and optimization of candidates for activity and selectivity have traditionally played a dominant role in drug discovery. However, in recent years the complimentary nature of pharmaceutical properties in candidate success has been recognized. This has led to the implementation of pharmaceutical profiling as part of the discovery process. Several objectives of drug discovery pharmaceutical profiling can be met through strategies and tactics that involve automation: 1) The need for more information on in vivo delivery of the candidate to the therapeutic target has led to the implementation of assays that model key in vivo ADME barriers; 2) The need to improve discovery efficiency has led to accelerated analysis and early collection of data to avert ADMET problems that cause failure at later stages; 3) The need to perform discovery research more effectively has led to the application of pharmaceutical property information to better plan and interpret discovery activity assays. These applications require high capacity because of the large number of discovery compounds and speed because discovery moves quickly. This presentation describes the automation of pharmaceutical profiling assays for the properties: integrity, lipophilicity, solubility, permeability, metabolic stability, and CYP450 inhibition. The management of the resulting data and its delivery to discovery teams are also key elements of the pharmaceutical profiling workflow.

Presentation 09/03:  The Way of XML -- Saving time and increasing reliability with XML
Liam Quin, W3C XML Activity Lead, [email protected], http://www.w3.org/People/Quin/

The Extensible Markup Language (XML) has seen widespread use in industry, in government, in research, and seems still to be spreading. Its popularity lies partly in the fact that it's a relatively simple and open specification, freely downloadable; partly in the fact that it is an intuitive way to represent structured information; and partly in the fact that every new XML document and every new XML tool multiplies the usefulness of every other XML document and tool, through interoperability.

Liam Quin is XML Activity Lead at the World Wide Web Consortium, the organization that publishes and maintains the XML Specification. He will give a brief philosophical background to XML, show some ways in which use of XML can give unexpected benefits, and give an overview into how some XML specifications fit together.

Presentation 09/03:  Application of the Sotax AT70smart within a development laboratory
D鏮al J Murphy, Ph.D.; Analytical Development; AstraZeneca UK

In the pharmaceutical industry, Good Manufacturing Practice (GMP) guidelines require careful validation of automated processes so that fitness for purpose can be demonstrated. This is also true of automated dissolution where validation must be performed for each of the products to be tested to ensure reproducible and robust method operation. Key validation considerations are discussed including some which are specific to the Sotax AT70smart. Experiences with the Sotax AT70smart and its application within a development laboratory are also discussed.

Presentation 01/03:  Quality Perspectives for Compound Storage
Dania Yaskanin, Ph.D.; Manager, Johnson and Johnson Pharmaceutical Research and Development Corporate Compound Logistics Center

The Corporate Compound Logistics Center (CCLC) is actively investigating compound quality and storage issues. Several approaches are being used, including studies of production materials, process verifications, and storage environment.

Production material changes over the past year have included compound storage vials, microplate seals, and DMSO vendors. The compound vials were replaced with a different vial type to improve compound handling and data quality. At J&J PRD, solubilized compounds in DMSO are stored in microplates in a controlled environment. To optimize compound storage in this environment, seven different microplate seals were evaluated for seal integrity with physical stress tests and detection of materials leached into DMSO. A portion of the solubilized compound inventory is also being moved into sealed polypropylene tubes that will allow comparison of compound quality when stored in plates versus tubes.

Process verifications have shown that solvent handling during compound solubilization and dilution influences the quality of compounds in solution. Qualitative analysis of a representative portion of the compound library is underway, with the goal of repeating the analysis over several years to record compound deterioration over time. Additional procedures for evaluating compound quality are currently being added to department capabilities, such as quantitative analysis of compound concentration, percentage of water content, and detection of contaminating materials extracted by DMSO. 

Presentation 11/02: A Summary of Compound Stability Experiments Performed at GlaxoSmithKline
Zoe Heaton, GlaxoSmithKline

Presentation 11/02: Ensuring Compound Integrity With Modular, Scalable, Automated Solutions
Stuart Naylor, European Sales Manager, TekCel Inc.

Presentation 11/02: Synthesis and Screening in Micro Reactors
Paul Watts, University of Hull, UK

Presentation 11/02: Managing the ‘Crown Jewels??
Krystyna Holden, Millennium Pharmaceuticals

Presentation 11/02: Purification for Quality
Biotage, Inc.

Presentation 11/02: Automation Without Robotics, a Comparison of Common Approaches to Low Temperature Compound Storage
Ian Whitehall, TTP LabTech

Presentation 11/02:  Evaluation of Technologies for Potassium Channel Targets Compound Screening
Dr. Weimin Tang, Principal Scientist, Johnson and Johnson/Pharmaceutical Research Institute

We have seen a surge of research in development of fast and reliable HTS methods for ion channel targets. This is driven by the fact that hundreds of ion channel genes from the human genome project and their functional association with human diseases. Some of the channels have been proved to be important in the drug discovery process such as HERG and various calcium channels. Traditional potassium channel functional study has relied on Patch-Clamp electrophysiology and Rb86 efflux assay. However, those methods were not easily deployed for drug screening because of the concern for cost and speed. Pharmaceutical companies have relied on dye based ion channel readers such as FLIPR and VIPR for many years and the results are controversial. This talk will focus on the development of non-radioactive Rb+ efflux assay using ICR8000, a system designed for medium throughput functional HERG channel screening. The development of HTS ICR12000 will also be discussed.
 

Presentation 11/02: A Calcium Flux Assay for Drug Screening In The LabChip System
Abbie L. Esterman, Ph.D., Senior Applications Scientist, Caliper Technologies

A high throughput calcium flux assay was developed for the LabChip™ microfluidic system. The system accesses samples from a microplate, mixes the samples with cells flowing through a microchannel and reads out cellular responses using fluorescence detection. Calcium responses resulting from G-protein coupled receptor activation were measured. The ability to conduct screens for GPCR agonists and antagonists was demonstrated by screening for agonists and antagonists of the m1-muscarinic receptor mediated calcium response in CHO cells. The LabChip™ system uses as few as 50-100 cells per sample and less than 10 nl of sample and 10 nl of agonist per measurement. Because of the low cellular and reagent consumption, and high data quality obtained with the microfluidic device, the LabChip™ system should be widely applicable in high throughput screening.

Presentation 11/02: Count the Ways: Automated Biochemical Counter-Screening for Kinase Drug Discovery
Gordon Alton, Department of Biochemistry, Pfizer Global R and D, La Jolla Labs

One of the most critical issues for protein kinase drug discovery is selectivity. Since most kinase inhibitors are targeted to the ATP-binding site and there are more than 500 kinases in the Human genome off-target inhibition is a significant problem. As the potency of lead compounds increase through iterative cycles of medicinal chemistry and structure based drug design it is important to identify off-target inhibition. To facilitate counter-screening by individual project biochemists routine robust automation of dose response curve kinase assays are required. In contrast to an HTS assay these automated assays are designed to provide high precision data for a small number of compounds for multiple kinases. This presentation will outline some of the robotic assay development solutions that have been implemented in the Biochemistry Group at Pfizer La Jolla.
View / Download as PPT file

Presentation 10/02: The Human Genome Project: A view from the trenches
Dr. Bruce A. Roe George, Lynn Cross Research Professor, Advanced Center for Genome Technology, Department of Chemistry and Biochemistry, University of Oklahoma

Presentation 9/02: Issues in Compound Storage in DMSO
Christopher A. Lipinski, Adjunct Senior Research Fellow, Pfizer Global R&D, Groton Labs

Presentation 9/02: Through-Hole Microarrays: A High Throughput Platform for Synthesis, Storage and Screening (PDF file)
Tanya Kanigan, BioTrove Inc.

Presentation 9/02: Multilayer Soft Lithography MSL for Life Sciences
Rodney Turner, Fluidigm

Presentation 6/02: Design of a Laboratory for Cell-based High Throughput Screening
Jessica Rivers, Research Associate, Maxim Pharmaceuticals [www.Maxim.Com] San Diego, California

Presentation 5/02: Low Volume Liquid Handling By A Dispensing Well Plate™
Roland Zengerle, IMTEK Institute for Micro System Technology, University of Freiburg, Germany, http://www.imtek.de/anwendungen

Poster (PDF): High-Throughput Protein Crystallography with the Corning Protein Crystallography Plate on the Beckman Coulter Multimek 96 Automated 96- Channel Pipettor
Phillip Bradford, Dr. Rongbao Li, Jennifer Fiedler and Dr. Thomas Fletcher III (Southern Research Institute), Edwin Dario and Tom Harrison (Beckman Coulter), Dr. Ma Sha and Gerald Campbell, Jr. (Corning)

Poster (PDF): An Automated Platform for Miniaturized Protein Crystallization
Holger Eickhoff, Patrick Umbach, Lajos Nyarsik , Martin Horn, Thomas Przewieslik , Wolfram Saenger , Hans Lehrach , Gther Knebel , Peter Opfermann
The Protein Structure Factory, Free University of Berlin, Institute for Crystallographie, Max-Planck-Institute for Molecular Genetics, Greiner Bio-One GmbH

Poster (PDF) 1/02: Minimizing Compound Exposure
W. Steven Fillers, Ph.D., TekCel, Inc., Hopkinton, MA

Poster (PDF) 1/02: Automated Microplate Sealing and Unsealing with SealTite
W. Steven Fillers, Ph.D., TekCel, Inc., Hopkinton, MA

Presentation 1/02: Modular Strategies for Automated Storage and Retrieval
John Morin, Ph.D.; Biological Chemistry Section, Wyeth-Ayerst Research, Pearl River, NY, USA

The Wyeth-Ayerst Research (WAR) High Throughput Screening (HTS) group is responsible for supporting project teams from 6 different therapeutic areas and maintains HTS laboratories at 2 separate sites. In addition to providing assay development and HTS services, we are responsible for dissolving compounds in DMSO and formatting them into micro-titer plates for distribution inside and outside the company. The WAR corporate library has swollen over the past 10 years through merger activities and the acquisition of combinatorial chemistry collections. By mid-1999 we estimated that sample preparation, storage and retrieval were consuming more than half of our personnel and equipment resources, so we began a project to improve our sample management functions. We achieved greater efficiency almost immediately simply by consolidating responsibility for sample management to a small group of volunteer specialists. Further gains came from collapsing our old 96-well sample plate library into 384-well plates, but the manual storage and retrieval of sample plates in over 70 upright freezers was still a bottleneck. We therefore circulated a Request for Proposals to several leading vendors of automated storage and retrieval systems. After many presentations and extensive deliberation, we ultimately chose to avoid the standard approach of a large, complex, integrated system with multiple overlapping and interdependent functions and to invest instead in a novel hybrid system composed of modular units provided by 3 different vendors: (TekCel, The Technology Partnership and Packard/CCS)  I will describe what we?e building and why we chose this path. I will also update our progress as elements of the system have begun to arrive.
View / download as PDF file

Presentation 1/02:   SmartPlate integrates library management and assay platforms to increase throughput and preserve compound library
Jeffrey A. Karg, PE; Boston Innovation Inc.; Cambridge, MA

Assay miniaturization has pushed the limits of fluid handling. 384 and 1536 well screening requires accurate and reliable compound dispensing during the reformatting procedure. This time-consuming and wasteful step is eliminated with the SmartPlate™ shipping, storing, and dispensing technology that includes integral dilution. A new concept assigns a DMSO dissolved compound to an individually addressable sealed tap. The taps are the storage, metering, dispensing, and diluting elements and formatted in a 384-well plate-based array. Compound dispense volumes range from 5-200nl. Reformatting, disposable tips, and wash cycles are eliminated. This presentation will highlight how SmartPlate10 works, implementation examples, and current performance data.
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Poster (PDF): The Effect Of Sealing Versus Lidding Plates On Degradation And Water Uptake Of Compounds Held In DMSO At 4慢
Zoe Heaton, C廥ar Ram甏ez-Molina - Analytical Sciences, Dr Sue Holland, Rob Hughes, Dr Rob Lifely, Compound Management, Linda Robb, Statistical Sciences
GlaxoSmithKline, Stevenage, UK

Poster (PDF): The Effect Of Freeze Thawing And Storage Time On Degradation Of Compounds At 4慢 Under Humidity Control Using Experimental Design
Zoe Heaton, Analytical Sciences, Dr Sue Holland, Rob Hughes, Dr Rob Lifely, Compound Management, Linda Robb, Statistical Sciences
GlaxoSmithKline, Stevenage, UK

Poster (PDF): The Importance Of Karl Fischer In Quality Control For The Support Of Automated Liquid Stores
Zoe Heaton, Mark Connell, Analytical Sciences, Dr Sue Holland, Rob Hughes, Dr Rob Lifely, Compound Management
GlaxoSmithKline, Stevenage, UK

Poster (PDF): The Effect of Freeze/Thaw Cycles on the Stability of Compounds in DMSO
B. A. Kozikowski, L. E. Williams, D. Tirey, B. Kuzmak and K. L. Morand
Procter & Gamble Pharmaceuticals

Poster (PDF): High Throughput Screening Degradation Study: Determination Of Storage Options And Retention Limits
L.E. Williams, B.A. Kozikowski, T. Burt, B. Kuzmak, K. L. Morand Williams, B.A. Kozikowski, T. Burt, B. Kuzmak, K. L. Morand
Procter & Gamble Pharmaceuticals

Presentation 11/01: DNA microarray fabrication and processing - Automation in the laboratory
Gary Hardiman Ph.D., Director BIOGEM (BioMedical Genomics Microarray Facility), Division of Biology, University of California, San Diego, CA

Presentation 11/01: An Automated Approach to the Supply of Samples for Screening
Terry Wood, Pfizer Global Research & Development, Sandwich, UK
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Presentation 11/01: Liquid handling in Chemical Synthesis- The Celltech approach
Nick Ray - Celltech R&D, Granta Park, Cambridge  UK
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Presentation 9/01: A cost-effective way to pipet 384 samples simultaneously
John Herich, Manager- HTS, Maxim Pharmaceuticals

Poster (PDF): How Exposed Are Your Compounds?
W. Steven Fillers, Ph.D., Andr嶪 Proulx and Marsha Paul, TekCel, Inc., Hopkinton, MA

Presentation 6/01: Compound Management Automation at AstraZeneca
Ian Yates, Head, Compound Management & Automation, AstraZeneca HTS Centre Sweden

The AstraZeneca HTS Centre based in M闤ndal, Sweden is one in a network of four HTS centres that support the AstraZeneca drug discovery process. Integrated within the department is the Compound Management Team. This team, in partnership with compound management groups across the organisation, is responsible for managing the compound collection and ensure it? accessibility to both the local HTS group and scientists globally.
In common with many other companies in the pharmaceutical industry Astrazeneca has experienced a dramatic increase in both the size of it? compound collection and it? screening capacity. This has resulted in tremendous pressure being placed on compound management groups to manage and supply more compounds, and to do so quicker.
This presentation will look at the automated systems that have been, are currently being, and will be, used at the HTS Centre in Sweden to enable us to meet this high demand. It will start with an overview of the systems that were implemented when the Centre was founded five years ago. It will then cover the systems in use today and conclude with a preview of a new automated compound management facility planned for the Centre. This facility forms part of AstraZeneca? strategy for a more efficient and truly global compound collection.
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Presentation 6/01:  Conversion of manual access of 384 lidded plates to an automated storage and retrieval system
Pavel Rychetsky, Martha Ackerman, Patti Willson; Biology Automation
Selectide, a subsidiary of Aventis Pharmaceuticals Inc., Tucson, Arizona, USA

Compound management and logistic support is an integral part of high-throughput screening activities. Usually, intermediate microtiter plates with diluted compounds have to be prepared in advance of a screening run. We eliminated this step by implementing a procedure for compound transfer directly from 384-well compound storage plates into assay plates during a screening run using a pin tool. After the screening run the storage plates are stored in freezers and reused later in the next screen. As loading and unloading compound plates for routine HTS runs became the most time-consuming step in our lab operation, we felt that further efficiency could be achieved by integrating an automated storage and retrieval system by TekCel Corp. into the HTS robot. The storage system is capable of presentation of storage plates to the screening robot without human intervention. Two major areas of application for the refrigerated storage and retrieval system are HTS and "cherry-picking". The advantages of this storage system concept, with its unique plate sealing capability, compactness, and expandability, will be presented.
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Presentation 6/01:  Mass Storage / Retrieval of Chemical and Biological Libraries
Dr. Terry V. Iorns, Iorns Consulting, Inc., 6334 E. Viewmont Drive, Mesa, AZ 85215 USA, E-Mail: [email protected] , http://www.iorns.com

Storage, retrieval, and distribution of chemical and biological libraries is a critical activity in drug discovery. Successful high throughput screening requires careful coordination and interaction of screening technology with assay / reagent preparation and availability of screening libraries. Failure of any of these to come together leads to a problem in the discovery program.
What is a library? Consider a library as a collection of chemical compounds or biological substances that should be handled or screened together. Examples include:
?Compound Collection - all the compounds/substances a pharmaceutical company can put their hands on.
?Related compounds by activity in a class of assay - such as a kinase or protease library.
?Related by structure or synthesis - combinatorial libraries
?Purchased collections
How are libraries received, stored and exchanged? There are four major ways to handle libraries:
?Solubilized in plates
?Solubilized in tubes or microtubes
?Neat substances in vials
?Neat substances in tubes or plates
Neat substances are generally quite stable and are generally stored at room temperature. Sometimes neat substances must be stored cold, in an inert atmosphere, or protected from light. Solubilized substances are generally stored in 100% DMSO. Most organizations store these solutions cold, near the freezing point of DMSO. Source plates or tubes generally contain a fairly high concentration, usually in the range of 3 to 20 mM. Collections are generally distributed to screening laboratories at much lower concentrations, usually less than 1 mM and often in the mM range.
Handling issues to consider:
?Automation of processes to prepare and distribute libraries
?Vendor and equipment reliability
?Sealing tubes and plates to protect solutions from evaporation or water absorption
?Unsealing or piercing plate seals to allow sampling by screening robots
?Stability of substances in solution over long periods of time and conditions
This paper will conclude with a survey of equipment and techniques to make the handling of libraries easier and more reliable. Products from several vendors in the following categories will be mentioned:
?Storage and retrieval systems
?Sealing and piercing devices
?Replication systems
?Robotic systems
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Poster 6/01:  Comparison of Microplate Sealing Tapes Using Standardized Test Protocols
Terry W. Lewis, PhD, Maurice H. Kuypers, Mialena M. Walker Medical Specialties Department - 3M Health Care - St. Paul, Minnesota

Adhesive tapes have become an attractive option to cover microplates in bioanalytical, genomic, and pharmaceutical research. Primary performance criteria for microplate adhesive tape seals include: prevention of evaporation from the individual wells; low contamination of well contents by the tape adhesive; prevention of cross-contamination between individual wells, and clean tape removal for access to well contents. Depending on the particular research objective, other criteria for adhesive tape seals may be important. These include pierce-ability for access to individual wells without entire tape removal, good optical properties, for monitoring well contents through the tape, and temperature resistance over wide ranges to include compound storage and PCR. This poster will describe results of a wide variety of adhesive tape performance testing designed to mimic actual industry use conditions. The tests include evaporation data with water, DMSO, and aqueous mixtures of isopropanol, methanol, and acetonitrile. Microplate composition and manufacturer were also varied. Temperature conditions ranging from -70?C up to room temperature and actual PCR cycling were evaluated. Other testing results on adhesive extractables, tape optical properties, and tape application and removal will be presented.

Presentation 1/00:  The TekCel TekBench: An Innovative Tool for High Throughput Screening
Ben Knight
Millennium Pharmaceuticals
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Presentation 1/00:  A Novel Process for Completely Automating Microplate Sealing, Unsealing and Storage
Julian Warhurst; Chief Technical Officer
TekCel Corporation, Hopkinton, MA 01748

Over the past decade, the application of automation techniques to High Throughput Screening has made great strides. Automation has enabled HTS to increase productivity by ten-fold or more. Labs are now processing hundreds of plates per day. "A plate a minute with some automation strategies". Surprisingly enough, these advancements paid little attention to the way plates are handled before and after the actual screening process. Questions still remain about where and how to store these increased compound plates without compromising integrity.
Central to the concept of plate handling up and downstream is an effective way to automatically seal and unseal a microplate. Conventional approaches such as adhesive or thermal systems have been used with various levels of success in automated systems. However, neither of these technologies can be reused, once they have been removed from the plate or pierced by awaiting pipettors.
The SealTite* microplate cover is the cornerstone of a unique system that provides a reusable, fully automated sealing and unsealing technique that guarantees sample integrity under an inert gas tight seal. Used with the totally automated PlateServer Workstation, plates are retrieved from the PlateStore storage module, thawed, unsealed, logged through the barcode and delivered to any vendor's automated platform at rates up to 240 plates per hour.
TekCel's new model for plate handling, storage and sealing is destined to change how microplates are automatically delivered and retrieved to various screening platforms as well as moved to long term storage. This novel approach can draw and analogy to the migration path the computer industry took in moving away from the core main frame to the client server distributed architecture. In this model data is stored and work is performed in multiple places as opposed to one large, inflexible system.
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Presentation:  Molecular Braille: A Novel Technology for Identification and Characterization of Compounds that Modulate Receptor Function
Dale J. Christensen, PhD., Senior Scientist
Novalon Pharmaceutical Corporation

Poster 10/99: Automated Solubility Analysis of Small Quantities of Drug Substance
John Troisi, Research Assistant Automation
R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ

Presentation 10/99: Harnessing the Power of Computational Intelligence to Identify Leads in HTS
Susan I. Bassett, Ph.D., Executive Vice-President, Global Technology Operations
Bioreason, Inc.

Presentation 10/99: High-Throughput Screening Applications of a Novel Scanning Laser Imaging Technology
Sheri Miraglia, Ph.D., Senior Scientist
PE Biosystems

Presentation 5/99: Automated High Throughput Pharmacological System, HT-PS?100
Ilya Okun, Ph.D. - Vice President of Cell Pharmacology
AXIOM Biotechnologies, Inc.

Presentation 5/99: Assay Translation: Some guidelines for turning a manual laboratory process into an automated laboratory process
Douglas Gurevitch
Axys Pharmaceuticals

Presentation 4/99:  Development of Fluorescence Polarization and FRET Assays for Tyrosine and Serine/Threonine Kinases
Dr. Jinzi J. Wu
Novartis Institute for Biomedical Research
Summit, New Jersey
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Presentation 3/99:  96 to 384 - Challenges and Solutions
Seth P. Cohen Ph.D.
Associate Director, HTS
Millennium Pharmaceuticals, Inc.

Presentation 3/99:  Automation Architectures for HTS and Their Impact on Productivity
Julian Warhurst; Vice President, Research and Development
TekCel Corporation, Hopkinton, MA 01748
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Presentation 2/99:  A Web Based System for Data Management
Richard Kozack
Ares Advanced Technology

Presentation 1/99:  Strategies For The Successful Sourcing of Robotic Systems
Bob Trinka
Robocon Inc.

Presentation 12/98:  HTS and Lead Optimization Using FLIPR
Joseph Gunnet, Ph.D.
Principal Scientist, Endocrine Therapeutics
The R.W. Johnson Pharmaceutical Research Institute, Rt. 202, Raritan, NJ 08869

Presentation 12/98:  Automation of the assay development phase of drug discovery
Damien Dunnington (1), Anthony Lozada (1), Hsiu-Yu Tseng (1), Paul Taylor (2) and Frances Stewart (2)
1. Hoechst Marion Roussel, Route 202-206, Bridgewater NJ 08807
2. SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia PA 19406