(International Symposium on Laboratory Automation and Robotics) 1996

Journal of Automatic Chemistry, Vol. 19, No. 3 (May-June 1997) pp. 61-89

Abstracts of papers presented at the ISLAR (International Symposium on Laboratory Automation and Robotics) 1996

The fourteenth International Symposium on Laboratory Automation and Robotics was held from 20-23 October 1996 in Boston, MA, USA, and proved the largest number of technical presentations ever offered at this meeting. State-of-the art developments in laboratory automation and robotics were reflected in the symposium programme, including papers and posters on all aspects of the technology--drug discovery research, data handling and data management, chemical analysis, custom automation, laboratory workstations, bioanalytical assays, managing laboratory automation, dissolution testing, pharmaceutical analysis, automation and combinatorial chemistry, validating automated methods, and advanced topics. Several new workshops and discussion sessions were also provided. Zymark should be congratulated on their continuing commitment to this programme of seminars and technical sessions. The programme provided a valuable insight to the use of robotics as well as the problems experienced. We hope to include some of these articles as technical papers in the journal in the near future. The 1997 ISLAR will once again be held in Boston, MA, from 19-22 October 1997. Speakers' abstracts should be submitted by 14 March and Poster abstracts by 14 July. Session topics will be similar to previous years but will also include High Throughput Screening, Re-Engineering the Laboratory and Increasing Productivity. For more information, contact Christine O'Neil at 508497 2224; fax on 508435 3439; send an E-mail to [email protected] or visit the ISLAR pages at http://www.islar.com.

Drug discovery meets biotech: how automation These issues and the roles they play in painting the enables the 'better-faster-cheaper' paradigm opportunities/challenges picture of outsourced bioanalytical support for drug development on the five yea.r Walter H. Moos horizon were discussed. Chiton Corporation, Emeryville, CA, USA Pharmaceutical and biotechnology companies have faced The automated synthesis of organic compounds significant new challenges in the 1990s. Health care cost- some newcomers have some success containment, mergers and acquisitions, venture-capital funded technology development, and other forces have Christopher Floyd, Christopher Lewis, Sanjay catalysed important paradigm shifts in therapeutic re- Patel and Mark Whittaker search and development. The resulting efforts to per- British Biotech Pharmaceuticals Ltd, Oxford, UK form drug discovery and preclinical development better, The search for useful drug substances is accelerating. The faster, and cheaper, are being aided by new approaches increasing speed and reliability of automated assays using in the design, synthesis, screening, and optimization of microtitre plates has led to a situation where traditional product candidates. Core competencies in automation one-by-one organic synthesis can no longer keep up, and underpin a major portion of this new wave of unprece- automated devices are required for organic synthesis, dented productivity. Several examples of Chiron's cluster purification, and distribution for assay. By deliberately of combinatorial technologies were discussed. avoiding over-automation the authors have a flexible system in which the devices can be used in the most appropriate way, as different therapeutic project areas The strategic direction of bioanalytical support have different, and changing, needs. In particular they for drug development work at a scale that provides enough material for follow- up in vivo testing, as well as initial screening. James E. McClurg Harris Life Science, Lincoln, NE, USA A key part of the system is a Zymark XP Zymate laboratory robot. It is equipped with custom-built work The types and volume of bioanalytical support of drug stations to enable it to cleave small molecules into development being outsourced by pharmaceutical com- solution after solid phase synthesis, to evaporate the panies is changing rapidly. There are a number of forces acidic solutions to near dryness, and to dilute, dissolve causing this change: bioanalytical technology, cost and and distribute into 96-well plates. All of these functions time pressures, the proportion of drug development being may be used independently, or chained together for a done by 'start-up' ventures, compliance issues, geo- complete processing run. A MultiSyn Tech Syro I is used graphic locations, sample logistics, clinical study designs, for the solid phase syntheses and a Gilson Preparative types of therapeutic molecules, competition, use of tox- HPLC using an Aspec XL as an autoinjector and fraction icokinetic data to design early clinical trials, etc. collector is used for purification, if required.

The presentation described the synthesis and subsequent trollers. In case of a robotic error, it is always possible to treatment of some sulphonamides and small peptides, control the reaction vessels. Programming is through a demonstrating how some of the disparate needs of the software program developed in house, running on a different projects were met. standard 486 computer. The recipes for reactions are constructed from unit operations where variables like temperature, reaction time can be introduced. Acclerating drug discovery by high-throughput combinatorial synthesis The automated synthesis system has been operational since January 1995. Since then some 250 reactions have Steven C. Banville and Ronald N. Zuckermann been done successfully; some typical examples in the field Chiton Corporation, Emeryville, CA, USA of steroid/carbohydrate/heterocyclic chemistry were shown. From these experiments some drawbacks of the A fully automated organic synthesizer has been con- synthesis system could be identified; improvements that structed to generate diverse chemical libraries for use in will been introduced, were discussed. drug screening programmes. This high-throughput be/have chemical synthesizer is based on proprietary robotic synthesis hardware and software. The robotic synthesizer Adaptation of liquid handlers to the automation of is able to transform a small set of low-cost starting organic and combinatorial chemistry materials into an equimolar mixture of tens of thousands of novel diverse chemical structures. These mixtures can William Neil, Harold N. Weller, Michael Lawrence then be screened against a wide variety of pharmaceuti- and Marian G. Young cally relevant receptors. Reptoids (N-substituted gly- The Bristol-Myers Squibb Pharmaceutical Research Institute, cines), as well as peptides, can be synthesized in very Princeton, NJ, USA have the added advantage that they high yields. Peptoids High throughput screening has been at the forefront of can be from an of synthesized incredibly large pool laboratory automation for several years, resulting in available amines. commercially primary Highly potent rapid and efficient biological testing. Recent efforts have trimers have been discovered with this technol- peptoid focused on automating the synthesis of new candidate More chemical structures are also ogy. complex being molecules for screening, particularly through the use of has in the made; this prompted significant design changes combinatorial methods. Traditional robotic liquid hand- hardware. a new synthesis Recently, generation synthe- lers have been designed for delivery of aqueous samples sizer has been constructed that features a high tempera- for biological assays, and are not necessarily suitable for ture heat block as well as more flexible software. This delivery of organic solvents and solutes. Additionally, automated system has thus evolved from peptide synthe- screening applications are often run by a dedicated sizer into a more general purpose organic synthesizer. operator or team of operators, while apparatus for combinatorial organic synthesis may be used by a large Automated organic chemical synthesis at and heterogeneous group often located at more than one Organon site. Several of the problems and solutions related to conversion of conventional robotic liquid handlers to P. Hilberink, S. v. Aelst, F. Kaspersen use in organic synthesis were discussed. Scientific Development Group, N.V. Organon, The Netherlands T. Vink The Hamilton Microlab 2200 liquid handler is used by Automation, N.V. Diosynth, The Netherlands the authors to perform many liquid handling tasks, E/I/A and for and E. v. Gool including product distribution, reagent delivery Labotec SA/NV, Teralfene, Belgium both solution and solid phase chemistry. Many hardware and software modifications have been incorporated into This presentation described Organon's synthesis robot the system to adequately support the needs of organic which is used for reaction optimization for the synthesis of and combinatorial chemistry. By using a universal deck biologically active compounds. Some results of the ex- layout and common carriers identical systems can be periments performed with this system were also pre- provided at several sites. The methods are not specific to sented. The automated synthesis system is centred the Hamilton Microlab, and application to other liquid around a Zymark XP-robot. With the use of a number handlers was discussed. of working stations (vortex; capping-station, cleaning station, solvents-station, balance), storage racks for reagents/samples and four different robot-hands, the sys- Managing laboratory automation--historical ret- tem is capable of performing (this means starting, actual rospective and future view chemical reaction, sampling, partial work up and clean- Keith D. Holmes ing) automatically a great variety of organic reactions in Inc., Groton, CT, USA two reaction vessels. The reaction vessels have a working Pfizer volume of 25-125 ml (so experiments on preparative scale A retrospective view of automation and management can be done), the temperature can be varied from -40C from the late 1970s until today shows that industry and to 140C (reflux is possible) in either N2 or Ar-atmos- instrument companies have made tremendous strides in phere with controlled stirring. The system is set up in a automation. However, the management of laboratory vented hood and the power supply is backed up by a automation in future will probably be dramatically battery pack. Control of the robot and the reaction different from today's management. The 'virtual labora- vessels is separated by the use of two System V con- tory' may be a real possibility and rapid chemical screen-

62 Abstracts of papers presented at the 1996 ISLAR ing of hundreds of compounds a month may be common- (1) Automation allowed the product to be released in place. The relationship between industry and academia less time, considerably reducing the lead time of (at all levels) will become much more collaborative. In products. this presentation, the author discussed the preparations Reduction of investigations due to human errors and that be made to meet these (2) might challenges. reduced re-testing of products. More accurate results (no human intervention, for Relocating and re-establishing a robotics labora- example in dilutions). tory (4) Use of people's expertise in tasks other than sample Stephen Scypinski, Theodore Sadlowski and preparation. John Baiano (5) Reductiori of waste generated by sample preparation Hoffmann-La Roche Inc., Nutley, dV, USA with a saving in waste disposition. Over the past several years, there have been many (6) A partnership relation with Zymark that gave an presentations at various ISLAR meetings devoted to opportunity to solve any situation and help improve the trials and tribulations of establishing a robotics the methods. facility in an existing laboratory environment. The considerations necessary to properly fit out such a laboratory have been discussed. Recently, the Analytical Automated acetyl analysis of cellulose acetates R&D Department at Hoffmann-La Roche has had the Ralph Bandy good fortune (or painful task) or moving out of an Eastman Chemical, Kingsport, TN, USA existing laboratory into a newly constructed building. The new laboratory was specifically designed to accom- The acetyl analysis of cellulose acetates has been auto- modate robotic systems and was not 'converted' from a mated utilizing a Zymark robot for sample preparation laboratory already in use. This allowed the greatest and potentiometric titration to detect and quantify the efficiency in the use of space and in design of services acetate ion formed by saponification of the ester samples. needed for the systems. It was also a learning experience, The procedure for the acetyl analysis of cellulose acetates with regard to areas such as building, utility and involves solvation of the ester sample in a suitable solvent municipal codes. The room was even fitted with its own followed by hydrolysis of the acetyl groups using a strong high-pressure hot water system to supply the cleaning base. Any residual base is titrated to an initial end-point, stations on the robots. followed by titration of the acetate ion at the second endpoint. The manual potentiometric procedure is both time Once the laboratory had been completed and a certifi- consuming and very technique dependent, making an cate of occupancy was obtained, the robotic systems had excellent candidate for automation. The system incorpo- to be moved. The monumental task of disassembling, rates a Visual Basic Graphical User Interface (VB-GUI) packing, moving and then reassembling three Py systems, developed in-house to serve as an interface between the as well as the various workstations along with their analyst and the robot system. The VB-GUI also serves as supporting instrumentation (HPLC pumps and detec- an interface between the analyst and the laboratory tors), took several months to completely accomplish. LIMS system allowing automated data transfer. After reinstallation, the process of revalidation was undertaken. Automated immersion testing This presentation offered tips and information to anyone faced with, or contemplating, moving their robotic Alex W. Gutierrez systems to a new location. US Army Research Laboratory, Weapons and Materials Research Directorate, Aberdeen Proving Ground, MD, USA An intelligent robotic work cell has been developed to automation--successful Laboratory approach perform immersion testing of polymer composite test Myriam L. Martinez specimens. Immersion testing involves measuring weight McNeil Consumer Products, Las Piedras, PR, USA changes in the composite specimens as a function of the time that they are immersed in water at a particular McNeil Consumer Products (PR) Inc. is a manufactur- temperature. The robot automatically handles test speci- ing site for solid dosages of Tylenol (all adult products), mens, operates equipment, and measures the amount of Children Chewables, Tylenol PM and Tylenol Sinus. water absorbed by each specimen. Traditionally, immer- The Analytical Laboratory is under quality assurance sion testing is a labour intensive procedure that involves a and is responsible for the release of all products after repetitive sequence of operations such as transferring testing. An important factor is that it works in a 'just in liquids; blotting and weighing specimens; measuring time' environment, where the releases have to be done specimen thickness and recording data. Through auto- immediately to have the product always available in the mation, the robot can handle many test specimens and market. The initial approaches for the acquisition of immersion testing can be done 24 hours per day, and automated systems were to release Tylenol PM products seven days per week. This not only improves the accuracy as quickly as possible without adding headcount. When and reproducibility of results, but can facilitate the the new equipment was installed and running the follow- production of an enormous amount of data. This quanti- ing resulted. tative information is required to assess environmental

63 Abstracts of papers presented at the 1996 ISLAR durability and to guide the specification, design and Strategies for integration of combinatorial chem- manufacture of composite materials. istry synthesis and screening Richard Kris Selectide/HMR, Tucson, AZ, USA Automated titration system for the assay of Combinatorial chemistry has grown to become an im- absorbent gel materials in diapers portant part of the biotechnology and pharmaceutical industries. Combi-chem raises some specific concerns for Kyoko IdA, Shunji Ishigam and Dean L. DuVal high-throughput screening programmes. One is flexibil- Procter & Gamble Far East Inc., Kobe, apan ity. As unique libraries are produced each week or each for some one will be screened in The present manual method to quantitatively determine month, only project tested for each Absorbent Gel Materials (AGM) in diapers (nappies) detail (with multiple concentrations compound) while for others several selected projects will involves an extraction procedure followed by an acid- be screened at concentrations. Hence the author's base titration. However, this method is laborious and single application of high throughput combi-chem screening time-consuming. It requires six hours for two people to has implemented a fairly large integrated system analyse 40 diapers. To overcome this situation, Procter & equipped with the hardware necessary for running assays Gamble Far East has introduced a fully automated for all current projects. Another concern is integration of titration a robot, automated ex- system by integrating screening with synthesis. Selectide/HMR is complemen- traction baths and an autotitrator. The novel system tary microplate-based Zymate systems for synthesis and contains a XP three racks Zymate robot, sample (36 screening. Selectide/HMR's experience in automation pads/rack), a Mettler titrator, three bubbling extraction and integration of combinatorial screening and synthesis balances and a waste container. baths, pumps, was the focus of this presentation and of the next A paddle mixer was previously used to facilitate extrac- presentation by Stephen Felder. tion of the AGM out of diapers. However, this method requires skilled personnel and a fairly long sample- Strategies for automated microplate synthesis of preparation time. A new bubbling air method was combinatorial libraries developed and the results give more than 98% recovery after 6min bubbling. Three bubbling extraction baths Stephen Felder are used simultaneously, providing a greater number of Selectide/HMR, Tucson, AZ, USA unit of time. sample preparations per The presentation reported on a system for synthesis of This robotic system was developed to automatically Combi-Chem libraries in microplates. Libraries are prepare samples, react AGM with excess HC1, and titrate produced either as large collections of individual com- the excess HC1 with NaOH. The amount of AGM in the pounds-useful for profiling and optimization of an diaper is automatically calculated. existing lead compound, or as a large collection of mixtures--to help search for novel chemical leads. The system uses a work-station approach. One station is for down-stream processing of synthesized compounds- Use of a Zymark robotic system for acid-digestion washing, deprotection, either cleavage from resin or with microwave technology extraction of product, and preparation of the compounds for use. The other station is a multi-functional work- Norbert E. W. Mueller and Bernhard Ciommer station for synthesis. Each function is run as a batch Hoechst AG, Frankfurt, Germany process for all of the microplates according to library design. Use of this approach for production of Non- The digestion of mineral and organic samples is the most Iterative Deconvolution Libraries was presented. important preparation step for element specific analysis by means of AAS- and I CP-techniques. It forms the essential basis for reliable results; errors in this stage of Implementation of an automated preparatory analysis cannot be corrected later. So these marginal purification verification system requirements initiate the development of a universal Michael Routburg, Roll Swenson, Jill Hochlowski, digestion robot to get qualitative high grade reproducible Philip Serole, Bob Schmitt, Gene Maslana, digestions of organic substances for the atomspectro- A1 Washington, Boris Minin, Sandra Mueller and metric measurement. Ken Matuszak Abbott Abbott USA The automation should certainly not be realized at the Laboratories, Park, IL, expense of flexible handling of samples and digestion Abbott Laboratories is involved in creating single com- conditions. Many pilot tests had to be made for combin- pound libraries by parallel synthesis. It has been found ing test sample series and single individual samples. The that the samples often lack the desired purity. There- final result was a flexible automated system, which is able fore, a purification process is sometimes required. This to do quite varied samples series but also a single sample presentation focused on Abbott's approach to the auto- in one digestion cycle. The system was designed in co- mation of the purification of parallel synthesized com- operation with Zymark and Maassen/Berghof (specialists pounds, and the integration of that process with the mass in microwave techniques). spectrum verification of compounds, which have been

64 Abstracts of papers presented at the 1996 ISLAR prescreened through an analytical HPLC and subdivided over a linear range of 0"5-100nm/ml in human plasma by purity and by quantity. The development and im- and 2-2500ng/ml in human urine with coefficients of plementation process of the system were discussed, along variant < 10% and bias < +15%. The validation results with the methodology, selection criteria, direction of the of the robotic extraction compared favourably to the automation, what worked and what did not, what was validation results of the manual method. The advantages suitable and what was not. of using the Zymate robotic system in bioanalysis include uniformity of sample processing and treatment, minimiz- ing analyst contact with biological and chemical hazards and improvement in laboratory productivity by freeing Efficient high throughput quantitative analysis in up the analyst's time from tedious and repetitive sample Division of and Glaxo Wellcome's Bioanalysis preparation steps. Drug Metabolism Julie Tomlinson Glaxo Wellcome, Research Triangle Park, ArC, USA for During Glaxo-Wellcome's post-merger integration ef- Enhancing productivity bioanalytical assays: utilization of automated SPE isolation and forts, a project was undertaken to examine efficiency in the international division of Bioanalysis and Drug Meta- MS for steroid analysis That and team were bolism. project its called High Timothy Getek, Walter Mei and The divi- Throughput Quantitative Analysis (HTQA). Shankar Hariharan sion of and Metabolism is made of Bioanalysis Drug up Forest Labs, Inc., Farmingdale, ArT, USA departments that perform analytical support for discovery, ADME and clinical, plus a strategic technology Advanced state-of-the-art analytical instrumentation, group and a systems support group. A 14-member team such as LC/MS/MS, has allowed the analyst to run a of scientists was formed with UK and US representatives large number of samples (100 to 300) in one day by from each of those five departments. The HTQA team utilizing shorter chromatographic times. In order to keep collaborated to perform an evaluation, decide on solu- up with the pace of the analysis speed, a rapid procedure tions and make short-term and long-term implementa- of extracting the analyte from biomatrices was needed; tion recommendations to management. They evaluated this meant automating the process by which samples instruments detection automated and procedures, sys- were prepared. In this presentation, a case study of the tems and across two US and three UK sites. work-flow analysis of several steroids from biomatrices was dis- Their recommendations--which were unanimous--took cussed. The analytical protocols were rapidly developed into account similarities and differences in needs HTQA (typically, less than three days) at levels of 150 pg/ml in between the sites and applications. plasma. The combination of an automated SPE system and LC/MS/MS permitted the rapid analysis of a large number of samples in a few days. Rapid throughput of Automated HPLC methods for the analysis of the data was complemented using a computer network Zaleplon and metabolites in human plasma and which allowed for speedy data processing via commer- urine cially available database software. D. M. Rushworth, R. Unczowsky, P. Amorusi and S. Tse Wyeth-Ayerst Research, Pearl River, ArY, USA The RapidTrace in the contact bioanalytical lab- Zaleplon is a non-benzodiazepine sedatime/hypnotic oratory: impact on data quality and sample agent currently in clinical development. The analysis throughput for Zaleplon and the des-ethyl metabolite in human plasma and urine was conducted using a high perfor- P. Zavitsanos and Joe Palantra mance liquid chromatography (HPLC) method. The Biovail Corporation International, Toronto, Ontario, Canada assay was initially validated using a manual extraction is an antiviral currently under procedure which was tedious and labour intensive. Since Acyclovir compound at Biovail International. The Zaleplon and the des-ethyl metabolite are stable in analysis Corporation assay is HPLC-UV with a Level of of human plasma and urine, this assay was an ideal analysed by Quantitation candidate for automation. The HPLC method for the 5 nanograms per millilitre. Extensive data for the manual analysis of Zaleplon and the des-ethyl metabolite in extraction of this compound exists in the laboratory and plasma and urine was validated with automatic sample serves as a good baseline for comparison to the newly processing using a Zymate II Plus robot. In this method, implemented automated technique, solid phase extrac- sample aliquots were loaded into refrigerated racks on tion using the RapidTrace Workstation. The presenta- the robotic system. The Zymate robot was configured tion compared the precision and accuracy data of with the following modules: Dilute and Dissolve; Cen- manual to automated techniques, as well as average trifuge; Test Tube Dispenser, TurboVap Evaporator and comparative time lines per batch. Impact on sample Reodyne Injector. The analytes were separated with a throughput of the automated system was examined, in Beckman LC-8 column and monitored by fluorescence addition to projection of future sample throughput (460nm). This method has been successfully validated improvements.

65 Abstracts of papers presented at the 1996 ISLAR

Automated ion exchange extraction for quantifica- biological matrices such as plasma, urine, and blood. The tion of a synthetic amino-acid drug candidate by dialysis membrane used on the ASTED has a molecular LC-MS-MS weight cut-off of 15000. High molecular weight compounds, such as proteins, that normally interfere with the Christopher Guy Whiffin and Payne, Carter, Gary HPLC separation and quantitation of analytes are ex- Richard Lachno cluded from the 'filtered' recipient side of the membrane Research Centre, UK Lilly Surrey, containing the dialysates. Since this one-line deproteini- LY35470 monohydrate is a synthetic amino acid ana- zation process dilutes the dialysates, a trace enrichment logue of glutamate that is being investigated for utility in column (TEC) is used to concentrate the analytes of various CNS disorders through activation of mGluR2 interest just before injection. The TEC is typically a small and mGluR3 receptor subtypes. An LC-MS-MS assay column containing a suitable packing material that has a has been developed to quantify levels of Ly354740 in high affinity for the compounds of interest. The HPLC plasma from human volunteers. Deproteinized plasma mobile phase is then used to selectively elute the retained extracts were purified by automated strong anion ex- analytes from the TEC onto an analytical HPLC col- change chromatography using a Zymark RapidTrace umn. The ASTED system has been used as an automated solid phase extraction workstation. The positive fluid on-line sample preparation procedure for biological displacement design of this apparatus, where eluent samples that normally require tedious extraction, con- delivery is controlled by syringe pump, allows the low centration, and clean-up procedures before HPLC injec- flow rates necessary for efficient ion exchange. Batches of tion. This system has been validated and used for the up to 150 samples have been processed in approximately routine analysis of Zaleplon (a no-benzodiazepine seda- 4h. Further purification of samples is performed chro- tive/hypnotic agent) and several metabolites in human matographically by an on-line column switching system plasma and urine. The linear concentration range for prior to quantification of LY35470 using a Sciex AP Zaleplon and the desethyl metabolite in plasma and III+ with heated nebulizer interface. The assay is urine was 0-5 to 100ng/ml. The concentration range extremely robust in operation, as well as being accurate for the M1 and M2 metabolites in plasma was 25 to and precise. To date over 1000 clinical samples have been 5000ng/ml. Inter-day precision (SD) and accuracy analysed in the range of 2-100 ng/ml. (%bias) were < 10% and < 16%, respectively, for all analytes. High throughput solid phase extraction for bioanalytical applications Extraction of broad range compounds using solid George Hutchinson phase technology Anachem Ltd, Luton, UK Margaret Raisglid and Michael F. Burke Fraudeau Christopher University Arizona, Tucson, USA Gilson Medical Electronics, France of AZ, and Marisue Paulus Solid phase extraction has proven to be an effective Gilson Inc., Middleton, WI, USA technique for isolating and concentrating a broad range of compounds from a variety of matrices, one of the The power and reliability of solid phase extraction (SPE) challenges has been selecting sorbents and solvents that is now well proven and this sample preparation tech- are suitable to extract a broad range of compounds from nique is widely used for a variety of compounds in an a single sample. Although it is possible to select a phase extensive range of biological matrices. As modern analy- and conditions that will optimize overall recoveries for a tical techniques, such as LC/MS, enable shorter run given type of sample, the recoveries of some of the times the throughput of the sample preparation becomes individual compounds may be compromised. For an important goal in method optimization. This pres- example, a sample may contain analytes that range from entation described a novel approach to the automation of small polar molecules to large hydrophobic molecules. If conventional solid phase extraction cartridges using new a short chain modified silica, such as C2, is chosen as the hardware. By taking a minimal list approach to method bonded phase, the large compounds can be retained, and design, optimization of chemistry, correction selection of subsequently eluted, but the small, polar compounds will sorbent mass and identification of critical extraction pass through the extraction bed unretained. Alterna- parameters, a throughput of more than 50 biological tively, a long chain modified silica, such as C18, may samples per hour can be achieved. be used for the extraction. Although the full range of compounds may be retained, it is often difficult to elute Automation of extraction procedures for Zaleplon the large, hydrophobic compounds. An alternative to and various metabolites in biological fluids using using an extraction cartridge containing a single bonded the ASTED (Automated Sequential Trace Enrich- phase is to layer different sorbents in a single cartridge. ment of Dialysates Sample Processor) coupled to The remaining challenge is to characterize the sorbent HPLC and solvents using stacked columns and then optimize the layered column for use with automation. Examples using M. Milisci, K. Tantillo, P. Amorusi and S. Tse segeral unique combinations, which are compatible with Wyeth-Ayerst Research, Pearl River, NY, USA the AutoTrace unit, were presented. Layered columns The Gilson ASTED system employs a dialysis technique have proved to be an effective approach for optimizing to separate low molecular weight analytes from complex recoveries for broad range analytes.

66 Abstracts of papers presented at the 1996 ISLAR

In vitro drug interaction studies in drug discov- phoric acid and fortified with internal standard, 24DP, ery-higher throughput methods each at a concentration of 100ng/ml. The calibration urines were blank urine samples fortified with herbicide Diane Johnson, John Janiszewski and standards. The herbicides and internal standard were Donald Tweedle extracted from the urine samples using C18 SPE car- Pzer Inc., Groton, CT, USA tridges, and eluted with acetone into tubes containing Drug metabolism studies are providing key information pentafluorobenzyl bromide and cesium carbonate. After in drug discovery to assist in the selection of new drug 10 minutes of reaction time, the solutions were trans- candidates. The challenges of analysing large numbers of ferred to tubes containing hordenine that quenched the compounds in a timely manner have necessitated new reaction, by consuming the excess pentafluorobenzyl approaches. Technologies used for high throughput bromide. Dilute sulphuric acid was added to the pharmacology screens are being applied to conduct quenched reaction mixture, and the 35% aqueous solu- metabolism studies. Initial metabolism screens have been tion was passed through a second C18 SPE cartridge, the estabished to conduct in vitro drug interaction studies. pentafluorobenzyle esters were retained on the columns, These studies can be used to predict the potential for in and were eluted off with toluene. 2-(1-Methylpropyl)- vivo drug-drug interactions and can also indicate which 4,6-dinitrophenol (dinoseb) methyl ether was added to individual enzymes may be involved in the metabolism of each final extract as an internal instrument performance discovery compounds. These inhibition studies generate check. The extracts were analysed by capillary GC with IC50 values (drug concentration to inhibit enzyme electron capture detection. activity in the absence of inhibitor by 50%). Routine Urine samples were analysed in batches of 30 7"0ml assays have been established in 96 well plates to measure samples consisting of 16 field urine samples, eight cali- inhibition of the major isoforms of cytochrome P450, the bration urines, three quality control urines, a blank family of enzymes primarily responsible for the metabo- urine, and a water blank. Quality control was main- lism of drugs. Conducting these assays has presented tained for each sample by monitoring the peak height problems related to enzyme lability, sensitivity to organic response (mV/ng) of the internal standard and the solvent concentration, and timely analysis of large num- internal instrument performance standard. Shewhart's bers of samples. Examples of the approaches being taken control charts of the dinoseb response and chromato- and the data generated were provided. graphic efficiency (N, theoretical plates) monitored the performance of the instrument for each sample, and detected instrument failure. Control charts of the internal Benchmate assisted-chlorophenoxy acid herbi- standard response monitored the performance of sample cides urinalysis method for biological monitoring preparation for each sample. If the internal standard of field exposed applicators response was out of control, the robotic data audit trail K. K. Brown, A. W. Teass, L. E. Stettler and allowed for diagnosis at the sample preparation step. c. J. Hines Traditional batch quality control was also obtained by U.S. National Institute for Occupation Safety and Health, monitoring the response of quality control samples, Cincinnati, OH, USA replicates, and water blanks. Thus, the quality of each data was assured. Data processing and record keeping A biological monitoring method was developed for the was facilitated by the direct linkage of Benchmate and determination of the chlorophenoxy acid herbicides, 2, chromatographic data files to a preprogrammed spread- 4-dichloro-t-methoxybenzoic acid [dicamba], 3-(2,4-di- sheet, which were stored on optimal disks. chlorophenoxy)propanoic acid [dichlorprop], 2,4-di- chlorophenoxyacetic acid [24D], 3-(2,4,5-trichlorophen- The present method produced a linear detector response oxy)propanoic acid [245TP], (2,4,5-trichlorophenoxy) from to 1000ng/ml. Percentage relative standard acetic acid [245T], and 4-(2,4-dichlorophenoxy)butanoic deviation for 24D averaged 7% above the LOD. Batch acid [24DB] in urine. Chlorophenoxy acid herbicides are limits of detection for dicamba, dichlorprop, 24D, difficult to analyse by broad multi-residue analytical 245TP, 245T, and 24DB averaged 34, 6, 9, 24, 19, and methods because of their high polarity and ionic proper- 18 ng/ml, respectively. Thus far, field samples ranged in ties. These compounds required derivatization for GC 2,4-D concentration from the LOD to 326 ng/ml. analysis, and the derivatizing reagent varies among published methods. This present method derivatized Automation in the oligonucleotide synthesis lab--- using pentafluorobenzyl bromide [PEB]. Unique to the the workstation approach method was the use of solid phase extraction [SPE] that made it amenable to automation. BenchmateTM auto- Burr Goodman, Joel Boymel, Cheryl Johnson, mation allowed for overnight unattended sample pre- Brian Governski, Julie Ross-Kramer, paration assistance with computer file documentation of David Van Ausdall, Ted Jones and each step. An internal standard [IS], the PFB ester, of William S. Marshall 2,4-dichlorophenyl acetic acid [24DP], was used for Amgen Inc., Boulder, CO, USA quantification and quality control, and an internal The DNA at is instrument performance standard [IIPS], dinoseb methyl Technology Group Amgen-Boulder for the of all for ether was used to monitor instrument performance. responsible synthesis oligonucleotides Amgen Inc. The process of automated DNA synthesis Sample preparation was assisted using a BenchmateTM was approached using a 'workstation' rather than a robotic workstation. Samples were acidifed with phos- 'system' approach. Using this approach, and integrating

67 Abstracts of papers presented at the 1996 ISLAR the use of commercially available DNA synthesizers, A robotic system for agar diffusion testing flexible workstations were developed that perform the following functions: vial sorting and decapping, solid Morten Heide phase extraction, and liquid transfer. The entire process Novo Nordisk A/S, Novo Alle, DK 2880 Bagsvaerd, Denmark is tracked by a database system developed in-house. The Jan Madsen and Nils B. Jensen process of oligonucleotide synthesis, as well as the func- Novo Nordisk Engineering A/S, Krogshoejvej 55 DK 2880 tion and performance of these workstations, was exam- Bagsvaerd, Denmark ined. A robotic system for screening for anti-microbial activities against agar imbedded target micro-organisms has The development of an automated high through- been developed and implemented at Novo Nordisk A/S. put screening system The system can carry out high throughput screening of extract collections for anti-microbial activity against up D. Harding to 40 different target organisms per run. An Adept One Thurnall plc, Manchester, UK robot is used for moving the sample racks and the target plates between the two storage hotels and the working The automation of high throughput screening is rapidly platforms. On each target plate a 9 x 9 array of holes is gaining acceptance in the drug discovery world. This punched by the robot using a custom designed tool. To paper described how one such facility was developed, the avoid carry over between plates with different target flexibility of the final system, and the design process organisms, the tool is cleaned in a solvent between the required to produce an 'industrial' level of reliability plates. The solvent and the surplus agar from the plates and robustness. The facility was developed for Glaxo are removed using vacuum and collected in a freeze trap. Wellcome's Medicines Research Centre in the UK. It The samples are distributed to the target plates by the consists of two robot systems, one handling isotopic robot using a high performance pipetting system with assays, the other non-isotopic work. The facility is nine individual syringes. The pipetting tool is equipped designed to handle both 96 and 384 microtitre plates. with needles for penetrating the septa on the sample vials. Standard instruments are used, with the exception of To avoid carry over, the pipetting tool is cleaned in a incubators and the bulk reagent dispenser where instru- solvent between samples. ments were developed especially for the application. The two systems are controlled by Thurnall's SPRINT After incubation the clearing zones are scored with software system--a WindowsTM based scheduling system regard to size, shape and turbidity using a vision system. providing significant user flexibility, while remaining The images and scores are transferred to a database. To user friendly. The facility was developed to meet specific protect the targets against foreign organisms, the system customer requirements within a short timescale. The is enclosed in a hood with a sterile laminar airflow. project lifecycle was described to show how the initial were converted into a requirements working system. Eight steps for non-programmers to write a Windows-based instrument controller The use of reactive fragment structure transfor- Michael J. Shea mations for automated structure generation in Recombinant BioCatalysis Inc., Sharon Hill, PA, USA automated combinatorial chemistry with applications to diversity analysis To unite an instrument controller with a Windows interface it is not necessary to be an expert programmer. John Cargill With the aid of Visual Basic, and other design tools and Ontogen Corporation, Carlsbad, CA, USA techniques, instrument control programs can be written with little programming background. An eight-step Computer programs for the automated generation of approach for writing control programs was described. A molecular structures are required to handle the volume terminal program that can help in understanding the of data produced by recent advances in combinatorial instrument was discussed. This also includes codes that chemistry. Typically a list of reagents and a reaction can be reused for the implementation of new instrument template are provided as input to these programs and a control programs. This presentation described the com- set of structures is generated as output. One demon- plete creation of an instrument control program for an strated approach to this problem is based upon a SLT Spectra Shell Reader instrument. parent-substituent model. In the Ontogen approach, the structure of each reagent is specified to the graph structure of the reactive fragment that is incorporated Automated high throughput mass spectral analy- into the desired structure post-synthesis. By specifying the sis of oligonucleotides the the final struc- connection points among fragments, David Van Ausdall and William S. Marshall ture can be generated without the limitation of an Amgen Inc., Boulder, CO, USA invariant parent fragment. The reactive fragment approach is universally applicable for the many reactions in The DNA Technology Group at Amgen, Inc. currently which a parent-substituent approach fails. In addition, produces an average of 10 synthetic oligomers per day, the application demonstrates a method of diversity analy- all requiring quality assurance analysis. The addition of sis utilizing reactive fragments which has several desir- Delayed Extraction (DE) technology to Matrix Assisted able features. Laser Desorption Ionization-Time of Flight (MALDI-

68 Abstracts of papers presented at the 1996 ISLAR

TOF) mass spectrometry enables the rapid mass analysis robotic workcells. Although they are intended for usage of multiple oligonucleotide samples. A Bohdan liquid with a Zymate controller, these devices are intelligent spotting Automated Work Station (AWS) has been used and can be controlled by an external computer provided for precise and repeatable sample placement, and a that their non-standard interface is translated to standard PerSeptive Biosystems Voyager DE MALDI Mass Spec- RS-232 specifications. In this case, a system using non- trometer (MS) provides high throughput analysis of invasive hardware and providing a graphical user inter- synthetic oligonucleotides. Prior to the development of face was desired to enable the use of Zymark peripherals these systems, the only methods of analysis with sufficient outside of the traditional Zymark robotic workcell. The throughput were trityl cation analysis and polyacryla- first phase of this project entailed the design and im- mide gel electrophoresis (PAGE). Unfortunately, PAGE plementation of an interface to the Zymate Master can only give a qualitative analysis of the product and is Laboratory Station (MLS). The interface comprises a unable to unambiguously verify the identity of the hardware serial communications bridge to translate RS- oligomers. The DE MALDI MS is able to determine 232 signals to Zymate electrical specifications and a PC- the mass of each sample within approximately 0"1% of based device software driver which adheres to the per- the expected mass. This accuracy means that the identity ipheral command protocol. and purity of all oligonucleotides produced can be determined with an unprecedented degree of confidence. Using this automation suite, sample preparation, spot- Automated inert atomosphere synthesis using the ting and analysis of 100 samples can be completed in less Tecan CombiTec System than 90 minutes. Stefan Loren, Robert J. Schmitt, Lisa M. Frey and Thomas J. Sowin A comparison of the Waters Tablet Processing Abbott Laboratories, Abbott Park, IL, USA System and Zymark Table Processing Work- station II A series of 48 oxygen sensitive solid phase organic reactions were carried out using the Tecan CombiTec John R. Stanley combinatorial chemistry workstation. Despite the need SmithKline Beecham Pharmaceuticals, Hertfordshire, UK for different incubation temperatures, 24 Suzuki and 24 Heck were run in parallel in a single reaction The Waters Tablet Processing System (TPS) is the only couplings block to produce a library consisting of biaryls and all-in tablet analysis package on the market which is not stilbenes. Prior to the introduction of the palladium a customized system and, as such, is the main competitor catalyst, the inert atmosphere of each indvidual reaction to the Zymark Tablet Processing Workstation II (TPW vessel was measured by GC-MS. All experimental results II). In both cases, the end result is the processing of were reported. tablets and capsules but these two instruments are very different beasts. The TPS consists of a Source for Automation tablet processor married to a Waters HPLC Design, development and implementation of auto- set-up. The tablet processing control software and data mated screening methods at Hoechst Marion analysis software (Waters Millenium) are inter-linked, Roussel Research Institute which, in theory, allows the operator to obtain quantitative data in one seamless process. The TPW II, on the Brent T. Butler other hand, exists as an extraction tool and can be linked Glaxo Wellcome Research, Research Triangle Park, NC, USA to most HPLC (or UV detectors) and data analysis packages which will have to be purchased separately from the TPW II. Jan R. Davis, Steve Busch and Robert Singleton, Hoechst Marion Roussel, Cincinnati, OH, USA To compare the extraction, ease of use and robustness of these instruments, a tablet and capsule formulation were In the past several years there has been increased analysed. The table extraction process was optimized external and internal pressures on the part of the using a fractional factorial approach (using Design Ease pharmaceutical industry to expedite the discovery and software), which highlighted not only the optimal but the thus the time to market of new chemical entities. This is critical extraction parameters. Ease of use and robustness being accomplished with the use of robotics technology to were determined by user friendliness and reliability. The screen thousands of compounds for searching for that advantages and disadvantages of the TPS and TPW II next blockbuster drug. In 1994, Hoechst Marion Roussel were discussed. Research Institute, HMR (formerly Marion Merrell Dow), invested in an automation laboratory and robotics system for directed and profile screening. The automa- Remote control of Zymate peripheral devices with tion laboratory that was designed employs two Beckman a PC Biomek 1000 robots with side loaders and a Zymark cell- based robotic that uses a Packard Multiprobe Steve Semanchik system iichalczyk, Jeff Russell, Jennifr 104DT for These handle a and Yeo liquid handling. systems Kyeong variety of assays including cell-based reporter gene Bristol-Myers Squibb, Princeton, USA NJ, assays, ELISAs and enzyme assays. The Biomeks are also Zymark Corporation currently offers several peripheral used for creating daughter plates from compound stocks. devices to provide controllable syringe pumps, valves, The facility has a separate cell culture lab which main- relays and other electro-mechanical functions to the tains and supplies the cells for cell-based assays. The cell

69 Abstracts of papers presented at the 1996 ISLAR culture room has a Zymark robot designed for plating were discussed. The cross-validation between the Zy- cells into 96-well plates. mate-TPW and BenchMate TPW was also presented. The automated laboratory is currently capable of screening approximately 10000 compounds/week for directed A break-even analysis model for the evaluation of screens and 500 compounds/week for profile screening. capital spending in laboratory automation The data generated from these assays are downloaded to an Oracle data base and analysed using ActivityBase. K. R. Lung, Cheryl Umbles and John DeMay The results are readily accessible to scientists throughout The DuPont Merck Pharmaceutical Company, Wilmington, DE, HMR USA A finance model often used for the justification of capital spending in laboratory robotics and automation is the Payback Model. Although this model is simple and Evaluating the feasibility of automated analytical intuitive, it is too one-dimensional and fails to capture methods for the determination of drugs in medi- the dynamics among initial capital costs, efficiency cated animal feeds improvements and sample load in an automation project. In addition, the Payback Model implicitly assumes the Mark M. Walstead, Brian Mazur, Yacoob Haroon replacement of laboratory personnel with robotic equip- Hoffmann-La Roche Inc., Fair Lawn, NJ, USA ment. However, the authors' experience demonstrates and Ed Yapchanyk that the replacement of personnel with equipment does Zymark Corporation, Hopkinton, MA, USA not necessarily take place. Automation certainly improves the efficiency of analyti- An automated method based on the Zymark Tablet cal laboratories the use of robotic Processing Workstation has been developed through sample prep- (TPW II) aration and data tools. for extracting Frenolicin-B from poultry feed. The pro- equipment laboratory processing of these robotic and automation cedure weighs ground feed samples, adds solvents, and Unfortunately, many tools are and the high initial capital investments extracts Frenolicin-B by homogenization. After auto- costly often have to be evaluated and justified from a financial mated filtration, the samples are injected and analysed using liquid chromatography. perspective. The Break-Even Model presents an automation project Automation of this application reduced analyst time from as an X-Y graph, in which the cost of the project is 3-5h to 30min for 25 The accuracy and samples. plotted on the Y-axis and the volume of samples is plotted precision data for this analysis were similar to those found on the X-axis. Improvement in efficiency due to auto- when samples were extracted employing more traditional mation is represented by a lower slope in the cost-volume methodologies. curve. At the same time, the cost-volume curve for Implementation of this technique for routine extraction automation is handicapped by a high initial intercept of Frenolicin B from Type C medicated feeds was associated with up front capital investment. The break- described. even point is where the cost-volume curve for a non- automated project (with a higher slope and lower intercept) crosses the cost-volume curve for the automated Validation of automated methods for ReVia tab- project. lets The Break-Even Model summarizes the financial as- j. A. Short and K. R. Lung sumptions of a typical, automation project and can assist The DuPont Merck Pharmaceutical Company, Wilmington, DE, R&D Management in making investment decisions that USA are both technically and financially sound. Representa- (R) tive examples of improvements in efficiency, comparing Revia (Naltrexone Hydrochloride) is a DuPont Merck projects that used automated sample preparation versus drug that has been approved in the US and Canada for projects that used manual sample preparation, were the treatment of alcoholism. This drug is formulated in presented. the form of a coated capsule-shaped tablet. Due to the high volume of release and stability testing required to support the NDA activities, automated sample prepara- Using the Biomek 2000 to automate an EIA for the tion methods were develo]ed for assay and content quantitation of polysaccharides uniformity testing of ReVia. R. Charbonneau, W. Long, J. Hennessey and Initially, the automated sample preparation methods L. Rubinstein were developed on the XP-arm based Zymate Tablet Merck & Company, West Point, PA, USA Processing Workstation (Zymate-TPW). Eventually, the A Beckman Biomek 2000 utiliz- assay method was adapted to the BenchMate Tablet liquid handling system, Processing Workstation (BenchMate TPW). ing a Zymark robotic arm, was used to replace a manual EIA (enzyme immune assay) procedure for the quantita- These automated methods have been validated and were tion of Pneumoccocal polysaccharides. The procedure is shown to be equivalent to the manual method. The complex, involving the simultaneous microplate analyses validation of the method on the Zymate TPW and of eight different polysaccharide antigens and includes: cross-validation of this method with the manual method serial dilution of samples, plate washing, sequential

7O Abstracts of papers presented at the 1996 ISLAR addition of reagents and optical quantitation of a colori- preparation time per sample can range from minutes to metric reaction. The manual procedure is tedious, time- hours. These lengthy procedures result in inefficient use consuming, and prone to operator error. The robotic of the analyst's time and training. procedure is fully automated, requiring operator interaction only for initial setup and final data download into This presentation demonstrated the potential time and cost manual an Excell spreadsheet for analysis. The Bioworks software savings benefits in converting lengthy meth- to methods for two forms. allows a variable number of plates to be manipulated ods automated solid dosage without program alteration. The robotic arm provides One product required over three hours to manually the Biomek 2000 with labware, including pipette tips and prepare one sample for content uniformity analysis. With some the method was to 10 min of reagents. Additional reagents, including a detection modification, reduced time for onto reagent stored on ice, are provided via a peristaltic pump preparation time, including injection the TPW II. second connected to a multiport valve. HPLC, using A product required over one hour of sample preparation. Again, with some modification, the preparation time was reduced to minutes. Comparison of the cost savings using the automated Robotic system for the analysis of semi-solids in a versus manual methods was discussed. quality control laboratory M. Mercenari Schering S.p.A., Milan, Italy BenchMate automates DNPH preparation of PPM Robotics can decrease analytical costs and thus increases aldehydes in aqueous samples the profit margins of drug manufacturers. Therefore Stephen L. Wellons et aL Schering S.p.A. and FKV, Sorisole (BG), representative Union Carbide Corporation, South Charleston, WVA, USA of Zymark Corporation, USA, co-operated to try to obtain an automated system for the analysis of semi- A Zymark Benchmate has been used to automate the solids. sample dilution and 2,4-dinitrophenylhydrazine derivations previously done manually. This The development of the robotic system involved four (DNPH) labour intensive procedure took an experienced techni- steps: cian about 15 min per sample. The Benchmate procedure Study: the parameters of the methods used for the analysis only takes about 3 min (per sample) of technician in- of semi-solids were examined to check the necessity and volvement and requires less expertise on the operator's the frequency of the changes to be made for analysing part. The procedure is applicable to samples that are different products. Then the feasibility of dosing the aqueous or miscible in water. The automated procedure components of most of the products without human was found to be equivalent to the manual one and works intervention was checked. for concentrations of aliphatic aldehydes (glycolalde- and have been tested Project: foundations were laid for the realization of the hyde, formaldehyde acetaldehyde so from several hundred down to The robotic system by checking the compliance of the tech- far) ppm. reactants are cleaned on C-18 solid phase extractions nical answers to the requirements in the study phase. up (SPE) cartridges. The resulting solutions are analysed by Realization: various working stations of the robotic system liquid chromatography (LC). Fractional factorial de- were built and assembled to verify the connection signed experiments were used to determine the principal between the different devices. This phase was realized effects of the procedural steps. The components of by FKV and ended only when every working station variance between the Benchmate and LC portions were worked perfectly, either separately or connected with the estimated using nested designed experiments. other. Validation: this began after the definitive installation in and involved the meth- Schering's laboratory checking PGB determination in transformer oils sample od's which was done ruggedness, product by product, by preparation with BenchMateTM SPE-Workstation means of statistical calculations. This was the most and TurboVap (R) SPE-Workstation delicate phase, where the practical, 'not robotic' problems occur and have to be solved, because they cause Andrea Joeris-Viethen and Regine Weber difficulties in the use of the automated system. GEW KO'ln, Germany According to the PCB-Verbotsverordnung of 1989, which is now part of the Chemikaliengesetz, it is no Comparison of manual versus automated content longer permitted to operate transformers with cool and uniformity analysis of pharmaceutical solid do- isolation oils that have more than 50mg/kg total PCB sage forms using the Zymark TPW II content according to LAGA. The determination of the content follows DIN 51 There are six PCBs Kerr PCB 527. John specified, which are determined vicarious for the total Glaxo Wellcome, Inc., Greenville, NC, USA PCB content given by LAGA (sum of six PCBs multiplied One of the most common tests requested during devel- by five). The samples of transformer oils are cleaned up opment of new solid dosage forms of a particular drug is by liquid chromatographic preparation and the sample content uniformity. Depending on the matrix, manual concentration can be automated conveniently and reli-

71 Abstracts of papers presented at the 1996 ISLAR ably by the BenchMate SPE Workstation and TurboVap The modification of standard methods of analysis LV Evaporator. of water for automation on a dual robotic system Michael J. Tutor, A. P. Gehring and Development of a fully automated flow injection Aaron M. Hamilton system VMI Research Laboratories, Lexington, VA, USA Michael J. Tutor and Seth Gilmore One of the primary reasons that laboratories are auto- VMI Research Laboratories, Lexington, VA, USA mated is to increase the sample throughput by increasing the speed and by reducing the human error that can Flow Injection Analysis(FIA) is a very popular tech- result in inconsistent data or the need to rerun samples. nique. It is inexpensive compared with batch automation Automation also has the potential of around-the-clock methods and it requires relatively simple equipment; it is operation. Many standard methods are not excessively amenable to a variety of analyses, conserves reagents, difficult to automate, but extensive procedures can reduces contact with possibly hazardous chemicals, and is actually take longer on a robotics system than if done often many times faster than batch methods of analysis. mutually. It is often beneficial to consider adapting The VMI Intelligent Automation Group is developing a certain methods to the robotic system as opposed to fully automated FIA system. With the use of the Lab- adapting the robot to run these methods. View 4.0 graphical interface programming software, a The VMI Intelligent Automation Group is using an in- point and click interface has been created to allow house colorimetric analysis program (SPECTRO) to minimal training to operate the system. The system optimize and modify standard analytical methods for consists of a variable size syringe pump, an automatic use on a dual robotics system. The Spectro program is sample injector, a digital I/O board that controls a set of designed to be broad and universal so that several new solenoid valves, and a spectrophotometer. The FIA types of analytes could simply be added to the system system has been used to automate the analysis of several without reprogramming the basic procedure. Several ions metal ions, including Co(II), Fe(II), Pb(II), and Hg(II). (including lead, zinc, mercury, copper, cadmium, cya- nide, aluminium, chromium, and cobalt) have been optimized for automation. Certain methods, such as Modification of standard methods of water analy- aluminium and cobalt, underwent extensive modification sis to simplify the adaptation to flow injection to ease the adaptation of these methods to automation analysis using the in-house program. Michael J. Tutor, Seth Gilmore and Aaron M. The Eriochrome Cyanine R method for determination of Hamilton aluminium is published as a procedure that involved VMI Research Laboratories, Lexington, VA, USA adding four separate reagents to the test solution to Flow Injection Analysis(FIA) is a popular means of produce the desired colour for detection. This procedure laboratory automation. It is fast, economical, conserves was not compatible with the in-house colorimetric analy- reagents, reduces contact with dangerous materials, and sis program. It was modified so that the reagents is also flexible in the types of analyses that can be responsible for the development of colour were combined, performed. A system consists of a pump for the reagents, and the combined 'colouring solution' was then added to an injection valve to inject the analyte and a reaction coil the test solution, and then analysed after the required that leads to a spectrophotometer. FIA can also accom- time. This modified procedure is now compatible with modate in line extraction cells for hazardous or complex the in-house program. separations. The complexing agent 4-(2-pyridilazo)resorcinol(PAR) Standard methods that require heating or waiting peri- is used in many standard colorimetric methods of analy- ods to allow a complexing reaction, or extraction tech- sis. Cobalt analysis with PAR requires heating and niques involving organic reagents make the use of FIA waiting periods, along with addition of masking agents impossible or extremely difficult. It is often much easier after the complexing reaction has occurred. This made to adapt methods to FIA than try to accommodate a new the automation difficult and time consuming. The meth- or complex technique to the method. Methods that od was modified using the surface active agent Triton X require extraction, heating or waiting periods to allow 100 to catalyze the reaction and eliminate the need for the complex to form can possibly be catalysed or heating and waiting periods (Tutor M. J., VMI Under- solubilized by the use of surface active agents. graduate Research Review, vol. II, 3, 1996). These modifications made the method much easier to adapt to the in- The VMI Intelligent Automation Group is developing a house system. fully automated FIA system. Several batch methods have been modified with the use of surfactants to accommodate the use of FIA. The standard dithizone method for The design, construction and testing of a dual lead, mercury, cadmium, zinc, and copper requires a robotic system extraction with a solvent; surfac- liquid-liquid nonpolar Michael (3. Zirkle tants have been used to eliminate this Surfactants step. VMI Research Laboratories, Lexington, VA, USA have also been used to eliminate heating and waiting periods in the standard methods of cobalt and nickel. Two primary reasons for automating analytical methods Such modifications have made these methods easily in a chemistry laboratory are to save time and to decrease adapted to FIA. human interaction. Software packages are constantly

72 Abstracts of papers presented at the 1996 ISLAR being updated to include new scheduling algorithms and ceutical dosages into disposable syringes and placing other programs that allow the user to do more with less. them into lead shields. There comes a point where complex software solutions no longer make significant improvements in performance, This system has been in operation for several months at and a new path needs to be followed. Rethinking the the Chicago facility of Medi-Physics, Inc. It is capable of hardware configuration is the next logical step. drawing 60 + doses per hour. Future modifications will increase the throughput to 120+ doses per hour. The The VMI Research Laboratories Intelligent Automation system is based upon the Mitsubishi RV-M2 articulated Group, a multidisciplinary team composed of chemists arm robot and custom hardware and software designed and programmers, has combined the Zymate II and (in conjunction with Medi-Physics personnel) by SLR Zymate XP robotic systems, with in-house and commer- Systems. Manufacture of the system was performed at cial software systems, to create a dual robotic system for SLR Systems' facilities in Richland, WA. versatile colorimetric analysis under a Windows NTTM environment. The system is controlled via a 486 computer, pro- grammed in Microsoft Visual Basic. Two microcontrol- A description of the automated system was presented lers (BS2 from Parallax, Inc.) are incorporated to here, along with the requirements posed to the system provide intelligent digital I/O for sensors, pneumatic and the software and hardware utilized. slides, conveyors, and turntables.

Custom engineered automation for scientific re- A novel microwave autoclave for automation of a search pharmaceutical research application W. Lautenschlager, W. G. Engelhart and Ed Ball and Dave McCampbell M. Metzger Midwest Research Institute, St. Louis, MO, USA Milestone MLS, Riviera Beach, FL, USA MidWest Research Institute (MRI) has been providing Hundreds of laboratories currently utilize microwave contact scientific research for 50 years, in fields such as systems to accelerate the preparation of samples for energy, environmental, health, and transportation. Auto- research purposes, quality control and process control mation solutions have been provided for the laboratory analyses. Conventional microwave systems with multi- research scientist for almost 10 years. The automation code cavities and doors are designed for manual opera- group is a multidisciplinary group with backgrounds in tion. mechanical engineering, engineering design, artificial intelligence, computer programming, machine vision, A new microwave autoclave eliminates the impediments analytical chemistry, and biology. to automating microwave chemistry procedures. The ultra CLAVE system combines microwave heating and Automation specialists at MRI have developed robotic high pressure vessel technology allowing chemical reac- systems to increase the throughput and precision of such tions to be conducted at pressures and temperatures up to tasks as natural pesticide screening, oncogene inhibitor 200 bar (2 900 psig) and 350C. The system is specifically screening, biological matrix extraction, and mineral designed for semi-automated batch processing of multiple content determination of food products. Some of the samples. Full automation is achieved for interfacing a custom systems and modules developed by the automa- laboratory robot arm to load/unload sample racks. tion group at MRI were described. Fundamental design and operating principles of the system were presented along with examples of pharma- Dimensional analysis of rigid polyurethanes with ceutical research applications performed in the system, Windows '95 synthesis reactions, solvent extractions, peptide/protein hydrolyses, acid digestion of implant materials, etc. Steven E. Robbins and Michael E. Rusak Air Products & Chemicals Inc., Allentown, PA, USA Rapid polyurethanes are used primarily as insulation and Radiopharmaceutical automated dosage system subjected to a variety of environmental conditions, typically from 20 in commercial refrigerators to 160C Rodney Stockton in ovens. The dimensional stability, or resistance to SLR Systems, Richland, WA, USA deformation, is a key material property, indicative of James w. Pancy and Mark Nybo the material's long term behaviour in the specific applica- Medi-Physics, Inc., @ring Lake, MI, USA tion. Radiopharmaceuticals are used in nuclear medicine for A Windows '95 platform has been used to automate various diagnostic and therapeutic procedures. Nor- sample manipulation, instrument control and data mally, the radiopharmaceutical is drawn into a dispos- acquisition. The system includes several controllable able syringe by a pharmacist. Although single dosages do sample carousel racks, dimensional measurement gauges, not present a health hazard to the patient, the prepara- positional control devices, optical sensors, and a mass tion of 300 + dosages per day by the pharmacist presents balance. This presentation described the operational a considerable exposure hazard. This presentation de- simplicity of a complex customized system as well as scribed an automated system for drawing radiopharma- some of the key building blocks used.

73 Abstracts of papers presented at the 1996 ISLAR

Challenges and opportunities in high throughput High throughput screening for novel lead com- screening: implications for new technologies pounds using defined biochemical assays John Major Berta Strulovici and Sarkiz Daniel-Issakani ZENECA Pharmaceuticals, Macclesfield, UK Tularik Inc., S. San Francisco, CA, USA The approach Tularik has taken to the discovery of novel In response to mounting competitive pressures, the lead compounds is the screening of hundreds and thou- current trend in the pharmaceutical industry is to shorten sands of test materials from various sources against a the time scale for all aspects of drug discovery. While diversity of biochemical assays in robotic format. This is advances in computation, structural chemistry and mol- achieved by integrating the organization of the test ecular modelling are facilitating rational design activities, compound library with a relational database, the devel- empirical screening continues to play a crucial role in opment of biochemical assays in a robotic-friendly format lead identification. Because the ability to test large and high throughput screening. Particular attention is numbers of compounds quickly and efficiently can pro- being paid to the use of automation in all aspects of the vide a competitive advantage, high throughput screening drug discovery operation. (HTS) has become a key goal. To achieve the necessary productivity, effective integration of compound supply, To ensure structural diversity, Tularik has assembled a of of known assay operation and data management is essential. HTS large library consisting compounds structure, and natural extracts from various sources such as is a high technology enterprise that must take full product and marine extracts. To fulfil immediate advantage of the latest advances in bioscience, biotech- microbial, plant screening requirements and at the same time ensure nology, engineering and electronics. There is a constant longevity, our libraries are aliquoted in replicate 96 well dilemma, however, in relation to when well established, plates. All compound information is electronically up- mature should be new methods technologies replaced by loaded into a relational database. that promise to deliver spectacular advantages. The final decision must be based on weighing up the promised Automated data analysis software has been created, benefit against the cost and risk. While huge challenges which is based on the 4D program for Macintosh, to face the pharmaceutical industry, there are also oppor- handle the vast amount of data generated. This is a tunities for those companies that can identify and imple- relationally integrated custom application. The data ment new technology effectively. The requirements for from robotic screening is electronically uploaded, and efficient HTS and the implications in relation to assay so are the follow up results. Virtually every endpoint 96 technology and automation were discussed. well reader exports data in a different format. A driver was designed for each detection system to convert raw plate data to a single format for analysis. The database flags the 'hits' for quick recognition and generates comparative reports. Transforming robotics into an infrastructure for the future The targets in which Tularik is interested are novel. Therefore, a major challenge is the design of biochemi- John Babiak cally sound, valid assays, the ability to automate them Wyeth-Ayerst Research, Princeton, NJ, USA and implement screening expediently. At present, several types of assays are running simultaneously in robotic Advances in high throughput screening frequently occur format: protein kinases, a variety of enzymes involved by interfacing new automated peripheral devices or in gene replication, protein/peptide interaction assays, workstations which perform critical functions onto an and protein/DNA interaction assays. The assays are fully existing robotic core system. In the past, these interfaced automated using Zymark robotic systems on which we devices have included liquid handlers, incubators and integrate and customize all the hardware and software detectors. As new peripherals are integrated to a core required by the assay flow chart. This includes the robotics system, new opportunities and higher productiv- integration of one or two different detection systems such ity are realized. The key to successful progress in robotic- as a luminometer, fluorescence spectrophotometer on the based automation is the perception and utilization of the same robotic system. Using these systems, a throughput core robotic communications and operating systems as an of 1-2 million data points per year is achieved. infrastructure upon which all workstation interfaces are In terms it is necessary to answer developed. practical Management of a centralized high throughput a Can three questions when interfacing new device. (1) screening facility the device be made compatible with the dexterity of the robotic arm? (2)Is it possible to communicate with Mark D. Lister the device using standard protocols consistent with the Sphinx Pharmaceuticals, Durham, NC, USA existing robotic operations and scheduling architecture? High throughput screening programs have seen a resur- (3) Are the benefits derived from interfacing the device gence as the preferred method for lead generation in drug significant? As the three questions imply, a robotic arm discovery. Due to recent technological advances, such as will only become an infrastructure tbr future develop- liquid handling automation, assay miniaturization and ment and success if it is part of an open architecture imaging plate readers, the length of time to run a screen which supports expansion both physically and operation- on any given target has gone from years to a few months ally. or weeks. There are two prominent approaches to screen-

74 Abstracts of papers presented at the 1996 ISLAR ing: a single centralized laboratory or a number of compounds move to formulation selection and phase III decentralized laboratories, often divided by therapeutic testing the analytical efforts to produce data in a GMP areas. Through its acquisition of Sphinx Pharmaceuti- manner tax the capacity of manual instrumentation. cals, Eli Lilly and Company has established a centralized Automation presents a challenge because of the diversity screening approach to its drug discovery program. In the of compounds, the unique requirements, and the level of past, screens were run by personnel trained to do a training within each development team. specific task where little or no scientific foundation was necessary. The present paradigm requires personnel with A flexible approach to automated dissolution was pre- which a higher skill levels. These include a solid background in sented, employs segmented workstations and dissolution device of other dissolution biology, an aptitude for automation and computers, and Zymark automated Each unit under an ability to work in a team atmosphere. The operations samplers. dosage development employs those stations for the each station is group at Sphinx consists of 10 people who run, over the only required task, to use or and little course of the year, 15 or more screens of all types (i.e., easy program requires training. Stations not in for the unit under receptor, enzymatic, cellular, etc.). Methodologies em- use dosage investigation are free to other tasks. to increase ployed range from semi- to fully-automated. Along with perform Strategies and assure of the dissolution validating the automation and running the screen at high throughput quality Zymark device were described. collection and volume, managing screen operations involves input on Data automated technical feasibility of assay protocols of upcoming reporting of non-routine dosage testing were discussed. screens. Furthermore, it is necessary to continually seek out new technologies that will not only increase throughput Automated dissolution testing using the Zymark but increase the probability of finding good drug candidates. Multidose Joseph L. Schmitt, Ruben Lozano, Steve Conder The versatile TPW llmfrom powder to liquids and John M. Joseph Simon Smith Bristol-Myers Squibb Company, New Brunswick, NJ, USA SmithKline Beecham Pharmaceuticals, Crawley, UK The Zymark MultiDose is a non-robotic dissolution Following on from the success of two BenchMate Table workstation for the automation of USP Apparatus 2 Processing Workstations, the TPW II laboratory up- (paddle) dissolution profiles. MultiDose can automate grade programme was developed and executed with the up to eight standard 6-vessel dissolution tests without omission of any instrument downtime. The existing two operator assistance. Analysis can be performed using on- systems have been replaced with two TPW II systems line UV or off-line by HPLC. and a third was purchased primarily to support new MultiDose frees up analyst's time by automating crucial product introductions. steps in dissolution testing such as; media sparging (using The main justification for the purchase of the TPW II helium), preheating and dispensing into two vessels; was for the analyses of powders, namely compression verification of vessel temperature; dropping of dosage mixes during the quantification of the manufacturing forms (either in batch mode 'all at the same time' or process. The notion that liquid samples, for example serial mode 'one at a time'); collection and filtration of viscous syrups, could be analysed using the quantitative sample aliquots at prescribed times; and cleaning of powder handling module did not occur until after vessels at the end of the test. These steps can be repeated installation. The powder module was extensively tested for up to eight batches of tablets. within our laboratory environment during Zymark's beta testing programme. The experience gained here and also Automated dissolution in subsequent development validation efforts was described testing pharmaceutical in this paper. development Several key automated analytical method validation Christine Hecht routines have been developed for the TPW II encom- F. Homann-La Roche Ltd, Basel, Switzerland passing all types of product formulations. This has aided Requirements regarding time to market, cost effective- the development of automated methods both within the ness and cGMP compliance in pharmaceutical develop- laboratory and the R&D environment where the major- ment have dramatically increased in the last few years ity of method development and validation occurs before and will continue to do so. This means, among other transfer to the Crawley New Production Introduction things, that different dosage forms, dosage strengths and facility. packaging configurations of a new drug product are to be developed in parallel and before efficacy and dose range have been established. Segmented automation techniques in a develop- finally ment environment One of the most important aspects in the characterization Harnath Doddapaneni, Nagesh Palepu and of a new drug product is its dissolution behaviour. Multi- Jushchyshyn point dissolution profiles are consistently required for John the whole devel- SmithKline Beecham Pharmaceuticals, Upper Merion, PA, USA release and stability testing throughout opment. Together with the increased number of samples SmithKline Beecham Pharmaceuticals currently enjoys a and the time and cost constraints, this means that the large pipeline of commercializable compounds, as these automation of dissolution testing is mandatory for most

75 Abstracts of papers presented at the 1996 ISLAR analytical laboratories working in the field of pharma- from EPA-mandated soil dissipation and ground water ceutical development. monitoring studies must be analysed promptly and To meet shortened For the above reasons, a Zymate System with the efficiently. product development schedules without custom robotics capability to perform fully automated dissolution testing increasing staffing, of solid oral dosage forms using USP Apparatus or 2 systems were purchased. including online spectrophotometric or HPLC assay of The conflicting needs of a high throughput for efficient the samples has been installed in the area of Development sample analysis and adaptability for yet-to-be developed Products of the Pharmaceutical Con- Analytics Quality residue methods led to the initial design and construction trol and Assurance of F. Hoffmann-La Department of a functional, but unreliable robotic system. Using a Roche Ltd. This described technical presentation design, 'Win-Win' approach, Zymark and Bayer abandoned the operational environment, validation and practical ex- initial designs, costs and deadlines and redefined all goals perience acquired in routine operation of the Zymate and operating constraints. New robotic which Dissolution System. systems, are much more efficient, flexible and reliable, have been constructed and installed. It is believed that the rede- signed systems, with updates and modifications, will play Ten years of robotics and laboratory automation an important role in the soil and water analysis method in a production control laboratory development work for many years to come. Julius Brown Eastman Chemical Company, Columbia, SC, USA Carolina Eastman Division (CED) of Eastman Chemical Versatility--the key for success of automation Company produces polyethylene terephthalate (PET) at systems in research & development laboratories the world largest single site PET production facility located in Columbia, South Carolina. CED Polymers Ramasamy Tamilarasan, Paul L. Morabito, Laboratory operates 24 hours per day performing analy- John J. Zieman and P. D. Hazelwood tical testing of products and process samples for monitor- The Dow Chemical Company, Midland, MI, USA The an ing production processes. laboratory analyses Research and development (R&D) laboratories and average of 1800 samples per day 3800 using (> results) Quality Control (QC) laboratory represents contrasting a variety of analytical techniques. Because most results paradigms of operation with different modes of success are used by process operators in real-time to control or for automation systems. QC laboratories typically have monitor processes, most samples are processed through numbers of similar to be the laboratory in to 4 hours. In order to meet the large samples analysed using well defined and thus demands for efficient, accurate, and timely testing CED procedures, high sample through- has operated Zymark Robots and other laboratory put is the major impact of automation systems. R&D laboratories have various of to automation since 1986. These systems are operated 24 commonly types samples hours a day seven days a week. CED has realized gains in analyse and analysis procedures often must be developed. labour efficiency, as well as reduced exposure to noxious The automated system should be simple and flexible for chemicals through the use of automation. The robot multiple users with several different procedures. This systems have evolved from Zymate I to Zymate II to presentation described such a versatile system recently XP Robots with System V controllers. The robots per- developed for preparing samples in an analytical R&D form sample preparations for different product analyses laboratory. The system is capable of preparing samples and are interfaced to an MIS system for automatic data using seven different predefined methods and one user reporting resulting in completely automated analyses. configurable method. User-friendly graphical interface This presentation described robot and other automated provides easier data input and output. applications, the evolutionary process for their improvements, and discussed the benefits and challenges to implementing and maintaining these systems. Managing automation in an environmental testing laboratory Management's view of the design, construction Lars W. Lindquist and installation of a custom robotic system WMX Technology Center, Inc., Geneva, IL, USA V. E. Clay, P. Y. Yen and S. L. Widmer Today, more than ever, there is a need to automate Bayer Corporation, Stilwell, KS, USA processes to drive costs lower while improving efficiency. The Environmental Fate Team at Bayer Corporation Automating projects requires careful thought and plan- Agriculture Division is responsible for the development of ning to obtain success. Often a project can be better pesticide residue methods and the annual analysis of addressed if a phased in approach is used in the devel- thousands of soil and water samples. Unique residue opment stage. One approach used at the WMX Tech- methods are required for each active ingredient and its nology Center over an eight year period to develop an major environmental degradates. The methods must ongoing successful automation program was described. provide separate quantitation of each analyte in the New workstations and system enhancements were also part-per-billion to sub-part-per-billion range. Samples discussed.

76 Abstracts of papers presented at the 1996 ISLAR

The creation of an integrated data handling sys- Electronic laboratory notebooks: The R&D team tem for automated organic synthesis computing and the needs, the systems and the consortium Chris Green ZENECA Pharmaceutical, UK Rich Lysakowski Team Science, Inc., Sudbury, MA, USA Automated chemical synthesis, of novel chemical entities An multi-company study was started in Octo- for biological screening, has been carried out in the intensive, called 'R&D Team R&D author's laboratory for four years. To undertake effective ber 1994, Computing Study'. Team Computing Systems contain a large number of organic synthesis on a Zymate XP Robotic system subsystems or components, including electronic records, requires a considerable amount of data manipulation. management systems, electronic record keeping, project Originally, this was a tedious process involving file data and document management systems, workflow, transfers to and from a VAX system. With recent PC and other of collaboration and network advances, software packages (Excel, Word, groupware, types systems. The of an R&D Team Computing System is to Isisbase, Isisdraw, Project Library) can be run which purpose foster better Collaboration of professionals working on enable the data to be managed effectively. complex product research and development projects, in order to greatly reduce cycle times and improve the Data management in the oligonucleotide synthesis quality of both products and customer services. laboratory The R&D Team Computing Study started with surveys of hundreds of users' needs in the pharmaceutical, Joel L. Boymel, Butt Goodman, Cheryl Johnson, chemical, biotechnology, and materials industries, and Brian Governski, Juli Ross-Kramer, resulted in a master list of requirements for R&D team David Van Ausdall, Ted Jones and computing systems for FDA--and EPA--regulated in- William S. Marshall dustries where applications are routinely filed to USA patent Amgen Inc., Boulder, CO, obtain proprietary advantage. The next step was to The DNA Technology Group at Amgen has the respon- profile the most popular vendors and systems in the sibility of synthesizing the oligonucleotides necessary for marketplace, based on demand and priorities set by Amgen's research needs. In the last five years the demand users. Finally, a multi-volume report was written that for oligonucleotides has grown exponentially. From 1991 outlines the background for the business, regulatory, to 1994 the DNA manufacturing process changed dras- legal, technical, and social needs, the profiles of fit for tically. The constant state of flux made a traditional various vendors and systems, along with summaries for database system too slow to respond to changing needs. various levels of management and end users. As a first iteration, it was decided that a user modifiable, The R&D Team Computing Study represents the culmi- flat file system would be used. Over the next few years the nation of several years of work to understand and specify manufacturing process settled and the data system the broad range of requirements of global, collaborative evolved to handle the increasing load. Orders were electronic notebook systems, which operate at the inter- electronically cut and pasted from e-mail and macro section of law, commerce, sociology, science, and technol- utilities were utilized to automate redundant processes. ogy. The results of the study pave the way for better The data system was able to adapt quickly, but quickly integrated systems to be built that significantly enhance became a difficult to manage conglomeration of sofware global collaboration on complex R&D projects, while packages from many different vendors, loosely held addressing the needs for reliable and trustworthy record together by macro tools that were stretched to their keeping and records management. limits. Eventually, excessive time was spent ensuring data integrity, indicating that this system's limits had been This presentation described the results from this compre- reached. hensive study including: the needs survey; vendor technology profiling project; bottom-line results; and the In 1995 the next iterative change in the data manage- R&D team computing consortium. ment system occurred. Since a workable system was in place, an open, expandable system could be designed. Computer platforms were chosen to best fit the authors' Increasing analytical laboratory productivity by situation. A client-server system was chosen to ensure simplifying complex processes that work could be done from any location. Touch Richard G. Poser screens and barcode scanners were used to speed the Dura Pharmaceuticals, San Diego, CA, USA processing of oligonucleotides. Orders were placed di- has become the fashion. As com- rectly into the sytem over the network using a small Process re-engineering external interface, elimnating operator manipulation of panies are compelled to do more with less, they have to science of in the of sequences. File servers are used to transfer data to and turned the re-engineering hope of their from external robotic systems. More information is enhancing the productivity precious remaining and facil- tracked, and reported, with less operator input and error. resources. Research, development production ities have become more efficient and productive by The only thing constant is change itself. The best we can implementing new technologies. Regulatory require- strive for is to manage that change as best we can. The ments demand additional testing in support of stability, modularity and connectivity of the current system will cleaning and validation programs. These factors have allow seamless upgrades when the need arises. created tremendous new demands on the analytical

77 Abstracts of papers presented at the 1996 ISLAR testing and control laboratories that support these opera- Meeting a client's needs using a Zymark Multi- tions. Lab managers with limited resources constantly dose in a contract laboratory setting face increasing workloads, shorter deadlines, and a D. Rhines demand for more rapid sample turnaround. Timothy BAS Analytics, West Lafayette, IN, USA It is a common oversimplification to equate laboratory BAS Analytics, a contract laboratory for the pharmaceu- re-engineering with introducing automation. Re-enginer- tical industry, was challenged by a client to perform a ing is about improving efficiency and productivity of a large scale stability program. Each method required two system. While re-engineering analysts frequently recom- sample pulls and two dilutions before injection into an mend automating a manual process, automation is only HPLC. At the time the project was presented, BAS one of several solutions a skilled system analyst may Analytics had two manual dissolution units. The pro- utilize to improve the productivity of a system. gram required potency, dissolution, TLC impurity screening, tablet hardness, tablet thickness, and moisture. Re-engineering should begin with a thorough analysis of Through the multiples of tablet potencies and packagings the process, paying particular attention to how work and a total of 96 samples were set on stability. The task facing information flow through the system. This may reveal BAS Analytics was how to complete the required dissolu- redundant, archaic or that can be unnecessary steps tion work for the three-month stability time point within simplified or eliminated. Only the system is simpli- after a three week testing window. This stability protocol fied as far as possible should automation then be con- requires two dissolution methods to be performed. Pre- sidered, and only then if further gains are cost effective. viously, most of the work was done manually. BAS A case study was presented, showing how an analytical Analytics identified that automation was the best means support laboratory was able to permanently increase for growth, without adding excessive staff. Zymark was testing capacity and improve test quality while reducing contacted in late April of 1995 and an order was placed average sample turnaround from 60 to four days. This with them for a MultiDose Automated Dissolution Work- was achieved following a thorough process analysis that station, and a BenchMate II. Instrument performance revealed how data flow could be simplified, delegation of validation of the systems was performed in June, as was sampling responsibility and sequential testing to elim- the automated method validation. BAS Analytics was inate unnecessary testing. A second case study illustrated ready to test the samples when they arrived. The co- how process analysis and simplification accelerate docu- operative effort between Zymark, the client, and BAS resulted in data delivered on time for submis- ment review and approval prior to automation of a Analytics and regulatory document routine system. sion. The validation process, time schedule, issues benefits experienced at BAS Analytics were discussed.

Rosie the robot. Laboratory automation during the war years, 1941 to 1945 The role of automated systems in laboratory re- Kevin Olsen engineering Wyeth-Ayerst/Lederle Labs, Pearl River, NY, USA Michael L. Rutherford In our own day, managers often cite the gains in Eli Lilly and Company, Indianapolis, IN, USA productivity as the primary reason to automate laboratory operations. This is hardly new. During the Second As more and more emphasis is being placed on improving World War, shortages of skilled labour and materials laboratory efficiency in order to provide more analytical were felt in the chemistry laboratory. Doing more with data at reduced costs, provide higher levels of customer less was not a matter of corporate policy, it was a matter service, and generate more timely results, many labora- of national survival. tories are forced to change how they are doing business. Re-engineering the workflow of the laboratory by reor- An amazing variety of automated devices were created ganizing the functional group is one approach to this between 1941 and 1945. Some were designed to save situation. This approach can provide better focus, ded- labour, such as the automated distillation units seen in la- ication of resources, improved customer service, and the petroleum industry or other organic chemistry reduced cycle times. However, this approach often does boratories. Certain automatic titrators, polographs, re- instruments and water still also fall into this not reduce resource requirements and costs since some cording Other was intended to conserve replication is necessary to meet the customer service category. equipment requirements. For years, robotics and automated work- strategic materials, like an all-glass constant-rate reagent addition control and a constant stations have been utilized to improve staff utilization, as device, specialized relays bath that was made out of a lamp globe, well as improve the quality of results. Incorporating temperature thermostat, and heating device, all for less than four automated systems into the workflow improvements can dollars. Still others improved assay performance by provide even greater benefits in many cases, whether part automating steps that were prone to human error. of the original re-engineering process, or as further enhancement to the plan. To demonstrate the benefits Although the technology has changed, the reasons to of incorporating automated systems in the re-engineer- automate have not. These devices were largely con- ing process, several scenarios within Eli Lilly were structed by end users who were working alone. This fact presented. illustrates something else that has not changed, the most

78 Abstracts of papers presented at the 1996 ISLAR important ingredient in automation is not the hardware, A modified HPLC autosampler (Gilson 233) is used to it is the imagination. inject samples directly from the collection plates. The autosampler has a capacity of six blocks which even with a 2 min run time allows around the clock operation of PE Solid phase extraction of antidepressants from Sciex API-III mass spectrometer. mouse, rat and human plasma utilizing robotic workstations This approach offers many advantages, speed (96 samples in approximately 50min), no manual liquid Patrick J. Faustiano, Christopher D. Ellison and handling, no vial capping or labelling and true high Karl P. Flora throughput quantitative mass spectrometry (sequential U.S. Food & Drug Administration, Laurel, MD, USA injection of up to 576 samples). The format has also Antidepressants are used clinically to treat mental illness. proved amenable to different packing materials and Their widespread use and the large range of dosed packing volumes. A strategy for the complete automation utilized for the treatment of depression have currently of the system using a Zymark robot was also outlined. revealed and expanded need for monitoring of plasma drug levels because of inter-individual differences in both Design and evaluation of an automated solid- steady state plasma levels and metabolism. Drug mon- phase extraction method-development system for itoring of patients undergoing long-term treatment with use with biological fluids antidepressants may provide a more accurate determina- toin of an individual's appropriate therapeutic dose. Tresavon D. Parker III, D. Scott Wright and Recent FDA studies required monitoring antidepressant David T. Rossi plasma drug levels in rodents for pharmacokinetics Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA scaling to humans. Automated methods that are reproducible and accurate have proved essential for the An automated solid-phase extraction method develop- preparation of large numbers of pre-clinical and clinical ment system, utilizing a Zymate XP robot and a custom- samples. designed solid-phase extraction (SPE) manifold, has been developed and validated. This system spikes blank liquid The authors have developed and evaluated automated matrix, such as plasma serum or urine, with solutions solid phase extraction methods for two antidepressant containing drug, internal standard, and up to two compounds and their pharmacological active metabolites metabolites. Samples are then buffered or diluted with from plasma: a first generation tricyclic antidepressant, an appropriate reagent. After these samples and corre- amitriptyline, and a second generation selective from sponding blanks have been prepared, solid-phase car- mouse, rat and human plasma using BenchMate robotic tridges containing selected sorbents are automatically workstations. Plasma drug levels, pharmacokinetics and conditioned. Samples are robotically vortexed and trans- metabolism of relevant clinical doses from native and ferred to the conditioned cartridges, and analytes are chronically treated animals were determined by high extracted. Validation of this robotic system demonstrated pressure liquid chromatography with ultra-violet detec- acceptable precision and accuracy for two types of liquid tion. Robotic workstations now occupy a central role in transfer including metering pump (< 6%RSD and RE the rapid development of automated methods for the for > 2"0ml dispensation), syringe-based laboratory sta- preparation of bioanalytical samples. tion (< 2-9%RSD and 0"5%RE for volumes between 0-25 and 1.00ml and syringe hands (< I%RSD and RE for volumes between 0"25 and For two model Microlute a semi-automated solid phase extrac- l'00ml). compounds and PD the system effec- tion system in the 96 well format (CI-988 135158), tively distinguished good solid-phase sorbents from mar- R. A. Biddlecombe and S. Pleasance ginal ones through precision, recovery and Glaxo Wellcome, Beckenham, UK chromatographic selectivity. Solid-phase extraction of these compounds from human plasma gave precision The use of tandem mass liquid chromatography spectro- to and extraction efficiency in with (2% 4%RSD) (96 +6%) metry (LC-MS-MS) quantitative bioanalysis, comparable to results obtained from manual extractions analysis times typically less than 4 min, has made sample (92 + 11%). preparation the rate determining step, particularly when using solid phase extraction (SPE). The use of SPE in the 96 well format, coupled with a Packard Multiprobe Use of the Rapid TraceTM SPE workstation for robotic sample processor (RSP), allows rapid processing accelerated methods development of samples in the batch mode. A modified vacuum manifold positioned on the deck of the Multiprobe is Xialoi Ren and Allan Witkowski used to control the flow rate of the liquids through the BAS Analytics, West Lafayette, IN, USA block. The Multiprobe is used to prime, load, wash and elute the blocks. After each step, a post run customized Due to its high throughput and ability to process samples program activates the vacuum by switching a valve. The unattended, automated solid phase extraction (SPE) RSP aspirates sample, buffer and internal standard should enable accelerated methods development for sequentially and adds them to the block, the dispensing analytes in biological matrices. To explore this possibility speed giving adequate mixing. The placement of the further, a generalized approach to SPE methods devel- collecting plate in the vacuum manifold, prior to the opment was designed and implemented using the Rapid elution step is the only manual intervention required. Trace Workstation. The model beings with pre-develop-

79 Abstracts of papers presented at the 1996 ISLAR ment groundwork, leading to an initial extraction meth- reaction vessels and also preparation of diversity elements od. The methods development phase is broken down into in a standard format. Another workstation is devoted to two portions, extraction optimization and time reduc- transferring solvents and diversity elements into reaction tion. The automated variation of key variables (such as vessels. A third is used for solvent washing as well as sorbent material and bed size, solvents, pH, volumes, cleavage of compounds from solid supports. A separate speed, etc.) allows for a comprehensive range of para- heat/shake/cooling incubator is used for reaction incuba- meters to be quickly evaluated. Finally, the optimized tion. To complement these systems, off-the-shelf compo- method is used to perform a full method validation. This nents such as TurboVaps and speedvacs have been experimental approach is illustrated through the devel- modified to support downstream sample processing. opment of an automated SPE assay for proprietary drug The function and performance of these workstations in human serum, focusing on the rational behind the was examined. methodology, the impact on assay ruggedness, and time savings achieved.

ACID for the Tecan: an automated combinatorial interface demonstration Managing compound library production through modular automated workstation-based system Robert M. Kennedy Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA B. and Richard A. James Campbell Wildonger Automated workstations for Pharmaceuticals, Inc., Wilmington, DE, USA liquid handling performing Zeneca combinatorial organic synthesis are recent additions to The advent of combinatorial libraries has infused the the organic laboratory. Many of these robots are mod- pharmaceutical industry with a novel set of tools to ifications of those used for biological work. Much of the expedite drug discovery. Thus, parallel methods of recent literature describing these newly developed ma- synthesis and combinatorial, or mixture synthesis, chines has focused on hardware. coupled with high-throughput screening have greatly Described in this presentation was a software suite, enhanced capabilities in identifying novel drug candi- ACID, which was developed for the Tecan. This software dates of higher quality, and with greater rapidity, than arose from a need to simplify a typical organic chemist's ever before. Automation is central to the efficient im- interaction with the liquid handling robots performing plementation of compound library synthesis. The authors parallel synthesis. Prior to this, much of the available described some of their initiatives to develop compound software had been designed for biological work in which library production systems for managing the numerous most samples are treated identically. It is the definition of processes involved in high through-put chemical syn- combinatorial work that all samples are treated differ- thesis. Single and multi-tasking automated modules can ently, hence a new approach was needed. systematize and increase the efficiency of the various processes which provide the framework of chemical The 20 programs written for ACID consist of four basic library synthesis system. Thus, modules used for reagent groups: Reactions, Extractions, Chromatography and preparation, barcode labelling of reagent and reaction Archival. The user launches a program within Integrator containers, reagent transfer modules, off-line incubation and is presented with a series of menus specific to that stations and post-reaction processing stations can all be program. This program then creates a command file. integrated to define a library synthesis system. Progress ACID then uses a single program. This program then on implementation of such synthesis systems dedicated to creates a command file. ACID then uses a single program library production was reviewed. to read and interpret the command file for the Tecan. In the course of the execution of this program a log file and an error file are generated. Programs executing reactions also generate a tag file which describes the synthetic Developing a high speed synthesis paradigmmthe history of well locations. The tag file provides the links workstation approach to the SD file containing structures. Butt Goodman, Kirsten Bjergarde, Joel Boymel, Ted Jone and Larry Melvin Amgen Inc., Boulder, CO, USA A fully automated stacking microplate lumino- The New Leads Discovery department at Amgen- meter for high throughput screening of libraries of Boulder is responsible for the synthesis Steven Lenz, Ed Marples and Mel Reichman in an automated fashion. After compounds evaluating Ligand Pharmaceuticals Inc., San Diego, CA, USA commercially available synthesis automation, instrumentation was developed using a 'workstation' rather than a The Torcon Stacking Luminometer incorporates a Dy- 'system' approach. The key to this strategy is a modular natech ML 1000 luminometer, reagent dispenser, com- reaction block design that is portable between instru- puter, barcode reader and a plate stacking/shuttle device ments. Reaction block modules insure that valuable equipped with a mechanical gripper. The system is instrument time is not tied up during reaction incubation capable of reading stacks of up to 25 plates with a three periods. Using this approach, several flexible worksta- fold increase in detection sensitivity. A plate is removed tions which perform specific functions have been devel- from the stack, placed on the plate shuttle and its barcode oped. One workstation performs resin loading into is read. The shuttle positions the plate under the reagent

8O Abstracts of papers presented at the 1996 ISLAR addition station, which is capable of dispensing between assay validation were discussed. Examples of situations 10 and 300 gl of reagent. After reagent addition, the plate from the pharmaceutical industry were presented. is shuttled to the luminometer loading position, where a robotic hand grips the plate and places it into the luminometer. The plate is read and the data analysed Establishing a high throughput screening core for out of range messages. If any are found, the gain is group at Procter & Gamble Pharmaceuticals automatically adjusted and the plate read with the new Jonathan Cook, Barbara Hynd, gain. After the data is acquired the plate is placed into Barbara Kozikowski, Kathy Rasmusen, the output stack. The barcode on the plate is encoded Deborah Paugh, Julie Whitten, Jennifer Sway with a unique identifier for storing the data and the Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA default gain setting to be used by the luminometer. Data is written locally, then automatically uploaded to Oracle Scott Atkin, Tim Bruemmer and Bryan Wildman at the end of the run. The system failure rate is 0" 1% of Sagian Incorporated, Indianapolis, IN, USA the plates processed and costs under $40K. I CN's plate About two the authors started assembling a stack magazines are used by the Torcon and can be years ago at Procter & Gamble Pharmaceuticals. interchanged with the stacking reader and platewasher screening group The was and efficiently, and devices used in the lab. This system will be modified for process completed quickly the group did not affect overall head count, although use with a CRS Robotics arm as part of a plate stacking some occurred. In order to robot personnel re-assignments system. accomplish this, all expertise gaps in automation, database management, and screening facility operation have been filled through contracts and by consultation with recognized leaders. Automated compound dissolution Transferring and validating a biochemical assay and distribution, and a capability for both cell-based into a high throughput screening assay and biochemical assays are now in place. The group, Richard Harrison located with the compound repository as one of its Rhone Poulenc Rorer, Collegeville, PA, USA primary customers, has integrated software and tracking systems. Handling the high volume of data generated by The drug discovery process is a multi-discipline, multi- HTS, associating results with the correct compound and faceted operation utilizing expertise from scientific back- integrating with company databases has been accom- grounds as diverse as genetics and chemistry. The process plished using CSAPTM from MLT Automation. The begins as biologists and geneticists discover new pathways process of identifying and implementing the key compo- and targets. Next, chemists synthesize small molecule nents of the core facility formed the basis of this presenta- inhibitors, agonists, or antagonists of these define targets. tion. Finally, biologists and pharmacologists test these compounds in animal models for in vivo efficacy. Each step in the process is a transfer of information and technology from one scientific discipline to another. However, the Use of a two armed Zymark robot for high process is a slow one, typically taking up to 10 years to throughput screening identify and market a new drug entity. Historically, the Mark Beggs slow step in the drug discovery process has been collect- ZENECA Pharmaceuticals, Macclesfield, UK ing and synthesizing compounds as potential drug candidates. With the advent of high speed parallel synthesis, a High throughput screening is a key component of the vast array of chemically diverse structures, previously pharmaceutical lead identification process at ZENECA. unattainable, are created daily for biological character- Robotic systems have been employed throughout the ization. Now, the slow step in the process becomes industry to perform the initial compound dilution and the characterization of compounds through biological distribution processes that form a common front end to assays. many high throughput screens, and the assay assembly and signal detection steps that comprise an individual Biological assays are generally crude systems designed to screen. Although the use of manipulative arm system in understand the workings of a protein or receptor, and for formulating and replicating test compounds is well its initial characterization and purification. Such assays established, robotic throughput rates have been signifi- are inherently laborious, time consuming tests not gen- cantly slower than those which can be maintained by erally suitable for screening a large number of compound human operatives and consequently the use of robots for variables such as cost reagent availability, reliability, performing assays has been limited. Over recent years the limits of detection, and speed are not of paramount industry has experienced significant increases in the rate importance. Yet, these are the most important variables of compound screening and throughput rates are now when designing a high throughput screening assay. It is approaching the upper limit that human operatives can therefore necessary to modify existing biological assays to be expected to achieve in a working day. To permit fit in a high throughput environment. Still, no rules exist future increases in the rate of screening, a novel automa- to guide this modification. This presentation focused on tion system was designed based on the use of two Zymark the steps used to transfer biological assays into a high arms. The rationale behind automation of the screening throughput environment. The choice of assay, kinetic process, the capabilities provided by the system and the and thermodynamic characterization of the reagents, and resulting benefits were described.

81 Abstracts of papers presented at the 1996 ISLAR

Automated high throughput screening to aid the ing: an ability to easily reuse software modules, better drug hunter at GlaxoWellcome debugging capabilities, and increased robustness. M. N. Banks, S. Fogarty, M. Valler, K. Mills, Making use of OOP concepts for the development of an S. O'Brien, A. Binnie and J. G. Houston interface to a laboratory instrument is appealing. This Glaxo Wellcome, Stevenage, UK 'instrument' object can be saved and easily re-used by other laboratory software applications. In this paper the Lead within at GlaxoWell- discovery drug discovery authors discussed methods for creating objects for data come's Medicines Research Centre a role in plays key acquisition and instrument control in Visual Basic 4.0. the company's high throughput screening programme. Strategies for managing and re-using user created instru- This presentation described how automation has been ment objects were presented, which enabled the creation used to facilitate this programme and the various ap- of an instrument object library proaches used. High throughput screening involves the testing of a range of different chemical entities in An additional step in the development of a library of biochemical assays. Typically, these samples include instrument objects is to reformat them as OLE (Object single entity compounds, combinatorial compound li- Linking and Embedding) objects. OLE is the foundation braries and partially or fully characterized natural of the 'plug and play' concept that is currently popular in products. The storage and preparation of these materials the computing industry. Methods for creating OLE are performed by the Compound Diversity Unit and objects from a library of instrument objects were also microtitre plates are provided for automated screening. discussed. For the last two years a Robolab 9600 has been used, and recently a second screening system has been commis- Visual basic applications in a laboratory environ- sioned that will dramatically increase our high through- ment put screening capacity. This second system, R2, contains Juan Cadavid and Marie Sabo two robotic cells, one for performing isotopic assays and Clairol, Inc., Stamford, C T, USA the second for non-isotopic work. This presentation described how this system was designed, built and In the last several years there has been a strong emphasis commissioned to run on both 96 and 384 well microtitre on doing things more efficiently. To accomplish this plates. objective, the analytical group has been searching for productivity enhancement tools to apply in a laboratory environment. Small computer programs written in Vi- Developing smart robotic stations with embedded sual Basic have been found to be one of those tools. These controllers programs take advantage of the many capabilities of Stephen Dokoupil Visual Basic, especially its ability to create intuitive Helen Curtis, Inc., Rolling Meadows, IL, USA graphical user interfaces. One of the applications implemented was a program which predicts the final result Often there is a need for the addition of extra sensors or of a titration based on the theoretical contributions of the control in a robotic station. At the same time the I/O different raw materials in a consumer product. This available through the Zymate Power & Event Controller program is intuitive enough that the formulators can may be exhausted by existing system complexity. The use use it independently of their computer skills. The theore- of simple embedded controllers or small single board tical value obtained can also be used to verify the validity computers can help expand the I/O capabilities of the of the experimental results and to develop finished robot system. A basic overview of embedded controllers product specifications. Another important application was presented. This included the different types of implemented is capturing the data coming from a controllers currently available, their cost and their use titration system and storing it in a database utilizing in a typical robotics or instrument application. Basic Visual Basic as the front end interface. This program interfacing techniques and programming the controller allows the data to be reviewed at any time after the were also covered. sample has been analysed. Creating reusable instrument objects with Visual The trials and tribulations of writing these computer Basic programs were presented, as was the resulting impact of productivity. Martin Echols SmithKline Beecham, Inc., King of Prussia, PA, USA Reaction screening and optimization in chemical and Mark F. Russo process research and development Bristol-Myers Squibb, Princeton, NJ, USA Barbara M. Ciaramella The new relatively object-oriented programming (OOP) Bristol-Myers Squibb Pharmaceutical Research Institute, New paradigm has had a dramatic impact on software devel- Brunswick, NJ, USA opment. Yet, few examples of OOP applied to laboratory automation exist. Visual Basic 4.0 now supports many The shortening of drug development timelines has caused elements of OOP through the creation of objects. An pharmaceutical companies to rethink their strategies for object is a simple mechanism for encapsulating the product development. One facet of Bristol-Myers properties and functions of a discrete software entity. Squibb's approach has been to incorporate robotics and The OOP approach can result in many benefits, includ- automation into new discovery and development para-

82 Abstracts of papers presented at the 1996 ISLAR digms. Within the Process Research and Development molecular weight determination and in structure elucida- department of Pharmaceutical Development, a robotic tion using LC/MS techniques. The role of standard apparatus has been configured to run and monitor up to methods, template structure analysis, predictive profiles, 16 reactions simultaneously, enabling faster data regen- structure profile libraries and candidate analytical pro- eration and reaction assessment, including route scouting files were discussed. These were illustrated with recent and reaction optimization. This presentation discussed applications from candidate proof of structure, combina- the hardware and custom software configuration and torial chemistry, natural product discovery, drug meta- presented results to date. bolism, impurities, and degradation products.

New approaches for material handling at Glaxo An automated system for the purification of com- Wellcome binatorial libraries by semi-preparative HPLC Brenda Johnson Ray Christopher E. Kibbey, Greg A. Robertson, GlaxoWellcome Inc., Research Triangle Park, NC, USA Alasdair MacDonald and Sheila H. DeWitt Parke-Davis Pharmaceutical USA Chemical sample dispensing at GlaxoWellcome has Research, Ann Arbor, MI, undergone a major shift in recent years. Previously, solid Combinatorial chemistry has emerged as a powerful tool sample weighing was one of the major functions of the for the rapid generation of new pharmaceutical candi- Materials Management group, which has responsibility dates. Improvements in laboratory robotics and informa- for the distribution of samples for discovery research. tion management systems have contributed to the field's Now, high-throughput screening and combinatorial rapid growth. While several systems are available for chemistry programs have been developed in order to performing automated compound synthesis, there are synthesize and test more compounds, find better leads, comparatively fewer systems which automate the efficient and ultimately get a drug on to the market in less time. purification of milligram quantities of compounds from Consequently, the Materials Management Group has combinatorial libraries. The high separation efficiencies had to re-evaluate its role. First, the solid sample afforded by commercial packed columns and level of weighing bottleneck was eased with the routine provision automation inherent in modern liquid chromatographic of samples in liquid format. Next, repetitive manual steps equipment make HPLC well suited to the purification of were automated with stand-alone instrumentation or just combinatorial libraries. This presentation described an simple changes in work practices. Finally, the Group automated, semi-preparative HPLC system designed for evaluated options for linking the old solid handling the isolation of milligram quantities of single compounds practices to the new liquid handling procedures in order from combinatorial arrays produced using solid-phase, or to transition smoothly from one to the other. The benefits solution-phase techniques. and the process were described. Purification of a sample library is performed in two chromatographic steps. First, a portion of the crude Recent applications of accelerated structure sample is chromatographed on an analytical-scale HPLC analysis protocols column and elution of the sample components is monitored by UV and mass spectrometric detection. The Edward H. Kevin L. Kerns, J. Volks, Jeff Whitney, chromatogram from this scouting run is then imported Robyn A. Rourick into a custom program, where an intelligent peak track- Bristol-Myers Squibb Pharmaceutical Research Institute, Wall- the isolation of selected C USA ing algorithm guides product ingford, T, component(s) fom the crude sample by semi-preparative Mark E. Hail and Mike S. Lee HPLC. Because positive identification of each component Bristol-Myers Squibb Pharmaceuticals Research Institute, in the crude sample may be performed via an LC/MS Princeton, NJ, USA scouting run, the system provides MS identification of the product component in the crude sample prior to chro- Current trends in research and product development matographic purification the need to collect and analyse have focused on accelerated cycles (for example, pre- multiple sample fractions during semi-preparative pur- clinical development) and increased sample generation ification is eliminated. Further, the LC/MS data sets may example, combinatorial chemistry). At the same (for be used to verify failed syntheses, and thereby speed the resources for internal of these initiatives time, support purification process by excluding these samples from traditional have not increased at the using paradigms further processing. same rate, leading to the necessity for a new paradigm. In this environment, mass spectrometry is the emerging The purification system is compatible with both reversed- analytical technology for meeting current and future phase and normal-phase methods, and only requires that needs, based on its sensitivity, selectivity, universal the same chromatographic support be packed in both the applicability, speed and cost-effectiveness. Integration analytical and semi-preparative HPLC columns. Scaling of advanced mass spectrometry technology, development a set of analytical chromatographic conditions to their of new methodology and novel implementation strategies semi-preparative equivalent is straight forward. The have provided increased levels of support and informa- chromatographic methods employed may be tailored to tion generation consistent with current and future trends. meet the specifications imposed by the sample library. These strategies, once developed, have been automated This becomes especially important when dealing with for optimum productivity. This presentation described compound classes which are susceptible to hydrolysis, recent development in structure characterization using thermal degradation, or transesterification.

83 Abstracts of papers presented at the 1996 ISLAR

Integrated drug discovery: thriving on organiza- The true pre-emptive multi-tasking provided by Win- tional and technological improvements dows NT prevents the collapse of one piece of software from affecting others controlling an automated system. Peter Eckard, Juergen Delzer, Franz Emling, The built-in security features of Windows NT allow the Siegmund Guhl, Reinhold Claus Markert, Janocha, of a robotics to the users Gerhard Paul, Juergen Seega and administrators system prevent Wolfgang Weruet from accidentally deleting files and data important to the Windows NT also allows a Knoll AG, BASF Pharma, Ludwigshafen, Germany operation of the system. degree of flexibility and modularity unavailable in most High throughput screening (HTS) has been established operating systems. Computer hardware devices (such as as a standard technology in the drug discovery process of multi-port serial cards and IEEE cards) are handled by BASF Pharma. With the HTS set-up presented at the operating system rather than separate device drivers. ISLAR 94, the authors have screened their chemical This allows for software design that is truly hardware library in various enzyme or cell-based assays or ELISAs independent. Windows NT offers some additional bene- on different molecular targets. As a result, promising fits, including a limit of 256 serial ports per computer, leads have been identified and some of these screening remote system maintenance, and increased system re- assays are now in an advanced stage of preclinical sources. development. However, the routine use of HTS revealed several shortcomings which have been taken into account Designing a robotics system on an object-based operating in a new version of the authors' HTS concept. system allows the use of object based programming to software tools for automation. The demands on HTS have steadily been increasing over languages develop a it can time. The number of compounds to be tested, as well as When defining a component in robotics system, the number of targets to be screened, were boosted by include both the instrumentation and software required combinatorial chemistry and Genomics respectively. In for its operation. Object based programming languages the decentralized HTS approach, where several labora- such as Microsoft Visual Basic 4.0 allow for a modular tories in different units perform HTS and secondary approach to instrument control. The instrument control screening, the HTS equipment could be improved. To software can also be used without the automated system. match the needs resulting from these increasing demands This allows the users to become used to the look and feel and time constraints, technological improvements and of the instruments integrated with their software drivers organizational measures are mandatory. in a stand alone mode. The future of modular laboratory automation includes a modular software approach, as The presentation described the authors' experiences of well as modular instrumentation. The authors have HTS at Knoll AG and addressed the future establishing begun development of such a system and presented some new for perspectives covered by the concept integrated of their experiences. drug discovery (single compounds versus mixtures, preparation of samples, highly integrated robotic systems, HTS core unit versus decentralized approach and work- High throughput screening through the use of ing time models). robotics and a high performance data handling system A component based approach to laboratory auto- Hiromichi Kotaki and mation Shin-Ichi Nihira, Atsuko Nakano Mark N. Feiglin and Bruce J. Russell Nippon Roche Research Centre, Kamakura, Kanagawa, Japan Merck Research Laboratories, Rahway, NJ, USA High throughput screening (HTS) using various auto- While laboratory automation projects have grown in mated devices including robots has expanded the cap- complexity, there has been a move towards using mod- abilities of random screening of natural products and ular approaches in selecting instruments for automated chemical libraries for drug discovery during the past Rather than a instrument systems. using single complex several years. It is a promising approach in the rapid to a a modular perform variety of tasks, approach and efficient identification of compounds. The utilization to divide the tasks among a number of specia- attempts of robotics coupled with a high throughput data handling lized instruments. Each instrument is often designed for a system allows hundreds of thousands of screening samples specific role and is able to work independently of the (natural products as well as synthetic chemical com- other instruments on a system. In this manner, the failure pounds) to be processed in a realistic screening period. of one instrument does not necessarily mean the collapse For further in of the entire of the entire system. A modular system also follows for improvement performance of the following issues must be addressed: easy modifications to the system as needs change. process HTS, logistics of assay samples; informatics; screening automa- During the authors' work in laboratory automation, they tion. have further developed this concept. In addition to using modular instrumentation, a design has been developed The authors' group is responsible for HTS and for that also stresses a modular approach to software design. implementation of HTS related technologies. During In designing a modular software approach to laboratory the past few years, the screening process has been automation, it is important to select an operating system developed to accommodate extremely large number of that is flexible, robust, secure, and itself modular. One samples derived from chemical compound libraries and such operating system is Microsoft Windows NT. natural products.

84 Abstracts of papers presented at the 1996 ISLAR

This presentation focused on the authors' practical Experiences with fibre optic technology in auto- experience and presented some issues related to interfa- matic dissolution testing cing of both systems. H. D. Friedel and D. Wortig Bayer AG, Leverkusen, Germany Automation of assays for nuclear receptors In recent years, dissolution testing has become increas- Steven G. Blanchard, Cole O. Harris, ingly important in the development of new solid dosage James S. Nichols and Derek J. Parks forms. Dissolution results also indicate batch homogene- GlaxoWellcome Inc., Research Triangle Park, jVC, USA ity and conformity. Samples are generally removed from the dissolution vessel through a filter at specified inter- The development and automation of functional and vals. The active ingredient content is determined by ligand binding assays for members of the steroid/thyroid HPLC or UV spectroscopy, both with manual sampling superfamily of nuclear hormone receptors was described. and in automatic systems. The use of stand-alone instrumentation and assay stream- lining allowed for rapid automation without any result- Precipitation or adsorption of the drug on the filters or ing delay. The assay formats utilized are generic and tubes may occur when the sample is taken. The amount have been verified for multiple nuclear receptors. As a of released active ingredient is best determined in situ result, implementation of additional assays for members directly in the vessel. The reading is taken very quickly, of the nuclear receptor superfamily can be accomplished enabling release kinetics from very quickly releasing with minimal assay development. tablets to be recorded. A direct measurement is carried out using a dipping probe connected via a fibre optic cable to a UV/VIS spectrometer. The detector is inte- Implementation of the TPW II Powder Pouring grated into an automatic system. A robot, manufactured Workstation for on-line analysis of process valida- by Zymark, moves on a linear axis and dips the measur- tion samples ing probe in the solution at the times stipulated. The system carries out dissolution tests fully automatically. All Thomas D. Groeschner steps are automated, from preparing the media, filling Schein Pharmaceutical, Inc., Carmel, NY, USA the dissolution vessels and adding the tablet, to calibration, measuring, and cleaning the vessels. Robot systems The current analysis of process validation samples by with fibre optic detection, which allow several tablet current manual analytical procedures has demonstrated batches to be analysed without supervision, have been the need for automation due to the large sample load and working in the authors' laboratory since 1992. the labour intensive nature of the manual preparation procedure. At Schein Pharmaceutical, the idea of automating the procedures to analyse process validation A Q.A robotic system to perform chemical samples (powdered samples) was taken to Zymark analyses Corporation. In conjunction with Schein Pharmaceuti- cal, a TPW II workstation was developed to handle all Marie Sabo and Juan Cadavid the parameters required to process powdered process Clairol, Inc., Stamford, C T, USA validation samples. A robotic system has been designed for and implemented Schein demonstrated automation for a number of rea- in the chemical quality assurance laboratory, which sons. First, the FDA requires that all of the contents of a supports consumer product production operations. The process validation sample be analysed. To accomplish initial decision was made to automate chemical testing of this manually, the bottle must first be weighed, the the largest volume manufactured products, both as in- contents of a bottle must then be emptied and the bottle process and final package samples, which are in five rinsed several times. Then, after drying, the bottle must aluminium tubes. A proposal was presented for a Zymark be reweighed to obtain the sample weight. This process custom-designed Zymate robotic system capable of ad- takes one analyst approximately 30min per powdered dressing the highest throughput analyses performed: two blend sample. Second, the large number of powdered titrations (acid-base type) and a viscosity measurement. samples associated with a process validation (20-50 blend These titrations have historically been performed manu- samples) is extremely labour intensive and requires 10 ally in QA, although Analytical had used Brinkmann man hours to prepare only 20 powdered samples. Third, autotitrators for some time. Since the chemistry was well in the generic industry there is a high demand for known and the autotritrator methods had already proven maximum throughput with minimum manpower. There- to be accurate and precise, these appeared to be ideal fore the need was to increase the efficiency of the testing analyses for robotic automation. The viscosity determina- of process validation samples and it was determined that tions would not be as straightforward; since the samples automation was the avenue to take to accomplish this had only been prepared manually no automation had yet goal. been developed. It was felt that the sample preparation could be automated with some effort, and in fact, would This presentation described the requirements of a system probably be more reproducible than the manual proce- to handle powdered process validation samples. The dure. The actual viscosity measurement is made using a benefits of an automated procedure as opposed to a Brookfield viscometer. The system would also need to manual procedure were explained. contain and dispense at least 10 different reagents and be

85 Abstracts of papers presented at the 1996 ISLAR able to move, manipulate, and clean-up materials with a required development of custom hardware modules to range of viscosities from water-thin to thick gels. provide automation for both high and low temperature dissolution techniques, for solution filtration and concen- it would be used the Although initially by QA analysts, tration techniques, analytical instruments interfaces and system was designed with a non-scientist operator in multi-method capabilities. Because of the complexity mind. The is for a worker to long-term goal production associated with the polymer preparation and lack of be able to a to the be bring sample robot, computer suitable on-line analysers, laboratory robotics were into the and some prompted through sample entry sytem, chosen as the automation platforms. Recently, two time later receive an or 'not result. 'approved' approved' robotics automation systems were developed and in- latter situation would then (The require QA-human stalled in the high Density Polyethylene and Polystyrene It to a intervention.) was, therefore, necessary develop Samia production facilities. This presentation described database of all test products, product specifications, the technical merits of the hardware automation, as well methods, method and calculations parameters, variables, as the complex flexible operating protocols required to for into the The user should incorporation system. only rapidly support production. need to know and enter two pieces of information into the system: a product number and whether the sample is in- process or in a final package. The computer should tell The care and feeding of robot Jock the operation exactly where to place the sample in the system racks. The database would need to contain Norman E. Fraley, Jr. information and specs for over 500 products to be Kelly Scientific Resources, Des Plaines, IL, USA analysed using about 30 method variations. This presentation took a light-hearted look at the issues The robotic system which meets these requirements was involved with robots and personnel. The introduction of presented and discussed. Recent enhancements made to the robot tends to generate the amazing transmogrifica- the original operation design, which have expanded the tion of normal chemists into the robot Jock. This new use of the system, were also described. species of scientist has its own unique set of needs and feeds. This creature was examined both in the wild and in its natural habitat. Some of the fears and favours of this It's 1.00a.m.mdo you know how your robot is entity were explained and ways to ensure that this rare, performing? and extremely valuable, creature is well cared for were outlined. j. R. Ormand The Dow Chemical Company, Midland, MI, USA Open access mass spectrometry in combinatorial For several years, the author's laboratory has been chemistry focusing on improving the efficiency of its work processes. A key measurement is cycle-time for sample sets. Large Lester C. Taylor, Jeremy Batt, Robert L. Johnson cycle-time reductions have been achieved through stan- and Melanie Traynor dardization of sample preparation, analysis, data reduc- GlaxoWellcome, Research Triangle Park, NC, USA tion, report writing, and data review. Further reduction The introduction of open access mass spectrometry has of sample set cycle-time has been investigated by examin- changed the way in which the synthetic ing the effectiveness of the automated significantly systems. chemist undertakes routine sample analysis. The avail- This presentation described the performance of a Zymate ability of walk-up instruments allows the chemist to carry XP robot which has been used for the five years to out sample analysis usually within a few minutes. As a perform a complex liquid/solid extraction process. The result, mass spectrometry is used routinely for reaction system's performance has been studied for approximately monitoring, analysis of analytical and preparative HPLC two years, focusing on the number of sample preparations fractions, synthetic intermediates and final products. The that are completed without operator intervention. The development of atmospheric pressure ionization (API) details of these measurements, comparisons to other has facilitated routine and reliable operation of such applications and systems, as well as the implementation general access instruments. This includes the use of of process improvements were discussed. electrospray (ES) and atmospheric pressure chemical ionization (APCI) sources which provide molecular weight information (often with some degree of fragmen- Application of automated polymer analysis tation) for the vast majority of polar, thermally labile Paul L. Morabito, John J. Zieman, molecules. However, there are compound classes (for Ramasamy Tamilarasan, Ward L. Rigor example, less polar, volatile compounds) which do not The Dow Chemical Company, Midland, MI, USA give molecular weight information by API and for which chemical ionization is a more appropriate ionization Paul D. Hazelwood, Mark (]ranch and mode. As a result the authors have also introduced an Roger Gagnon Open Access GC-MS instrument for the analysis of such The Dow Chemical Company, Samia, Ontario, Canada compounds. Over the past three years, laboratory robotic automation Combinatorial synthesis is being adopted as a routine efforts within Dow Chemical have been directed towards approach for the generation of large numbers of com- developing systems to prepare a variety of different pounds in the drug discovery process. This has placed an polymer samples for subsequent analysis. These systems increased burden on analytical methods to support

86 Abstracts of papers presented at the 1996 ISLAR characterization and synthesis validation. A mass spec- information obtained from the laboratory information trometer has been acquired which utilizes a Gilson 215 management system (LIMS). Modules associated with autosampler directly sample 96-well microtiter plates at this system include barcode reader, solvent dispensing the rate of approximately one sample per minute. This station, vortex mixer, pipetter, and turbidity check and system utilizes computer software to facilitate data analy- filtration stations. The dissolved sample solution is dis- sis and rapidly validate the chemistries for each plate. pensed into an NMR tube or MS vial, which is then Target compound molecular weights can be searched capped, and placed into an autosampler rack on the and compared automatically to the data for each well respective spectrometer. analysis, providing the chemistry with a quick evaluation Some is in a batch on auto- of library synthesis. analysis performed mode mated NMR and mass spectrometers using instrument worklists download from the LIMS. Data acquisition and processing occur without analyst intervention. Data file Adding value to enterprise-wide research and transfer and loading completed results into the LIMS are development programs through automated NMR triggered by the analyst. spectroscopy Data files are archived on a file server equipped with an William C. Hutton optical jukebox and indexed in a relational database. Corporate Research, Monsanto Company, St. Louis, MO, USA Data files are retrieved through querying the database and transferring files back to a spectrometer. Information NMR spectroscopy generates information vital to busi- system features include sample login front-end for custo- nesses who use chemistry and biology to invent and mer use, e-mail notification of results, intranet access to develop new products. NMR spectroscopy is resource sample and instrument status, and results through Net- intensive as well. Laboratory automation brings value by scape. The careful integration of analytical instrumenta- maximizing the quantity and quality of NMR data tion, robotics and information systems results in an throughput and R&D enterprise. This paper presented efficiently operating laboratory that can meet the ever a unique robotics system used to collect NMR data. The increasing demands of a research environment. approach provides the efficiency of automated measurement without sacrificing flexibility. The impact on the NMR laboratory as well as the technical community were addressed. The technical and cultural obstacles High throughput cell based assay robotics system encountered during this project were discussed. Informa- with integrated diagnostics and data management tion technology is no less important than productive measurement of spectra. An NMR information system Steven Lenz, Ed Marples and Mel Reichman based on a UNIX/TCP-IP/X-Windows computer net- Ligand Pharmaceuticals Inc., San Diego, CA, USA work was presented. Cell based assays are performed in a high throughput mode for drug screening at Ligand. A robotics system for automatically performing these assays in the evening, and functional as a series of independent workstations Automation of structure analysis in pharmaceu- for use the was built and The tical R&D during day, implemented. system integrates a 96-well pipettor, plate washer, re- Gary A. McClusky, Brian Tobias, Robert Short, agent addition station, luminometer and a tissue culture Dana E. Dejohn, Leslie McMacken, incubator with a CRS Robotics A265 arm and flexible Carmen Faraianu and Bryan Judge data management software by MLR Automation. The Parke-David Pharmaceutical Research, Ann Arbor, MI, USA 96-well pipettor is a Robbin's Hydra that was modified with a wash station and plate shuttling device. It is used The analytical chemistry laboratory in pharmaceutical to pipette gl of compound directly into the assay plates research continues to be challenged to structural perform at better than 7% CV. The incubator was modified with characterization rapidly and This is fuelled accurately. miniature pneumatically actuated doors and rotating 120 by improvements in organic synthesis, such as automated plate carousel. These modifications and the slowly rotat- synthesis and combinatorial and the avail- chemistry, ing carousel, minimize environmental disturbances and ability of better structural tools and methods. Advances edge effects caused by the robot accessing the incubator. in instrumentation, robotics and computer technology Reagents, compound and assay plates are barcoded with have enabled automation of the associated such as tasks, identifiers. This information is read the robot data unique by sample preparation, sample introduction, acquisi- and written into the data file headers. MLR Automa- tion and procession, and data and retrieval. The storage tion's CSAP software has been modified to interface with integration of these with informa- components laboratory Oracle. It automatically processes and uploads the data tion systems results in improved overall efficiency of based on the file headers. CSAP then generates a list of laboratory operation. This, in turn, allows the laboratory retests to be submitted to the compound handling system. analyst to direct significant time to challenging structural A vision system and modem have been integrated into characterization projects and away from standard analy- the This allows the robot or an sis. system's computer. operator to transmit still photos of the robot when the Laboratory robotics have been used to automate sample system halts due to an error. The operator may then preparation for NMR and MS analysis. Barcoded sample remotely diagnose the problem and attempt corrective vials are delivered to the robot and are prepared using action.

87 Abstracts of papers presented at the 1996 ISLAR

High-throughput screening by remote control tains all production data). The integration process required many trials, and custom equipment was needed Aimi and Michael Kozlowski Junko R. for several robot functions. The current system consists of Geron Menlo Corporation., Park, CA, USA two Zymate XP robots performing solution viscosity Laboratory automation is an essential component of the analysis on a 24 hour basis, 365 days per year. high-throughput screening laboratory. The robotics systems are used to perform repetitive functions and free To or not to Peripherals from robot humans for more creative activities. Major limitations of buy buy? suppliers automated systems are: errors occur during the course of a large run; software programs available for performing Michael R. Kozlowski high-throughput screens are not flexible enough to Geron Corporation, Menlo Park, CA, USA accommodate special needs within an assay; and changes are faced need to be implemented in a timely manner. High-throughput screening groups frequently with difficult decisions concerning the most effective ways This presentation discussed approaches designed for of automating drug discovery processes. These decisions monitoring automated screens and for performing real- generally do not involve which robotic arm to use, since time modifications of protocols and error corrections. the number of choices in this area is still relatively small, This included a simple baby-sitting program that con- but the type of instruments that the robotic arm will serve tacts individuals when an interruption in an automated (peripherals). There are two broad types of robot per- run is detected; a video monitoring system that allows an ipherals. The first are stand alone instruments--these are individual to survey multiple systems and/or supervise often automated but are not integrated with a robotic robotics operations from a remote location; and an arm. The integration is left as an exercise for the interactive system (under development) which allows purchases. The second class is integrated instruments. monitoring of robot modules and error corrections in These are designed to be used with a robotic arm (often real-time. exclusively) and are available from suppliers of robotic arms as modules or as part of a turn-key robotic platform. Each of these types of peripherals has its strengths and Automated for dilute solution systems viscosity weaknesses, some of which are related to the type of task measurement of a Robot polymers using Zymate being performed, as well as the laboratory environment. and a Viscotek Differential Viscometer Because of the time and expense involved in setting up a Sador S. Black, Tab Crawford and Harold Kinder robotic screening laboratory, an incorrect choice of robot Eastman Chemical Company, Kingsport, TN, USA peripherals can cause, for the laboratory manager, considerable loss of efficiency, face, and often another Solution viscosity analysis is a fast, simple, and reliable anatomical feature. This paper discussed options in method for determining the molecular weight of a choosing robot peripherals, and how to select the correct polymer. The polymer molecular weight is an important instruments. property since it reflects the ability of the polymer to be processed and the polymer's fitness for use in various applications. In the Polymers Division of Eastman Robotic control of whole blood processing in a Chemical Company, the Analytical Services Laboratory clinical laboratory for functional brain imaging is responsible for determining the Inherent Viscosity (IV) David L. Alexoff, Payton King and S. Gatley of all production process samples. IV determination can John Brookhaven National Laboratory, Upton, NY, USA be broken down into several steps: sample preparation; sample analysis; sample cleanup; and data reporting. Clinical and basic research protocols using functional Each of these steps was previously performed by labora- imaging techniques like Positron Emission Tomography tory analysts in the Analytical Services lab. The motiva- (PET) or Single Photon Emission Tomography (SPET) tion to automate IV testing came from several sources. often require a significant personnel commitment to the The first incentive was an increasing sample load. It was sampling and processing of whole blood samples from believed that automation, coupled with the use of human and non-human primate subjects. Blood gas, different viscometers, could increase laboratory sample plasma glucose, and radioactivity concentrations must capacity. Safety was another incentive. The solvent be determined for each imaging study. Faced with de- which is used to dissolve the polymer sample is very creasing research operating budgets and the anticipated hazardous. Automation was expected to greatly reduce addition of a second tomograph, the authors' labor- the analysts' exposure to the solvent. There was also an atory has begun investigating the utility of using labora- economic incentive. Two analysts were required to per- tory robots to carry out some of these routine clinical form the manual IV test. It was felt that automation of laboratory tasks necessary for clinical and basic research the system would reduce this number to one and free the protocols using PET. second analyst to perform other jobs. This presentation described the routine clinical labora- The process of transferring the manual operation to an tory tasks needed in PET research and how these tasks automated one required hardware and software integra- have been automated using a commercially available tion between the Zymate robot, the PC used to control laboratory robot system. The system is based on standard the differential viscometer, the LIMS computer in the components of Zymark Corporation's (Hopkinton, MA, Analytical Services Lab and the Polymers Manufactur- USA) PyTechnology systems. No custom robot hardware ing Information System (a VAX computer which main- was used, and all software was developed at Brookhaven

88 Abstracts of papers presented at the 1996 ISLAR

National Laboratory. An algorithmic approach to sol- business strategies. Those who excel will gain competitive ving the problem of pipetting plasma from small-volume advantage, grow and prosper. whole blood samples (< 0"04ml) was described. The system automatically centrifuges small-volume whole blood samples, pipettes and weighs plasma, and assays The use of robotics in a cosmetic microbiology 511 KeV photon radioactivity in the plasma. Steady state laboratory robotic throughput is 143 samples/hour for auto-sampled whole blood. Results and performance of the robotic Steven F. Schnittger system were compared with those obtained manually Estee Lauder Companies, Melville, NY, USA by an experienced laboratory technician. The preservative challenge test is a method used to This research was carried out at Brookhaven National determine the efficacy of a preservation system in a laboratory under contract DE-AC02-76CH00016 with cosmetic formulation. The method of testing is a labour the US Department of Energy and supported by its intensive, repetitive task. Product testing entails a large Office of Health and Environmental Research and also volume of samples which are analysed repeatedly under supported by the National Institutes of Health Grant NS- the same conditions and protocol. For this reason, an 15380. automated robotic system was developed to perform this testing and to free the cosmetic microbiologist to perform It's only a matter of time more meaningful and creative tasks. F. H. Zenie Two hundred and fourteen different formulations totall- Zymark Corporation, Hopkinton, MA, USA ing 1039 samples were evaluated, comparing the automated robotic system to the manual count method Columbus set out for China and discovered America. plate of testing. The samples comprised make-ups, shampoos, Was the journey a success or failure? It has to be a failure conditioners, oil in water emulsions, mascaras and pow- unless you redefine the goals. We are surrounded by ders. The selection of tested are similar opportunities, the challenge is recognizing them and then micro-organisms to those recommended by the CTFA Guideline for the redefining our goals to capitalize on the new opportunity. Preservation Testing of Eye Area Products. Changing markets and economics demand business innovation. We are learning that new technologies enable The results showed that there was a greater than 98% change, but management must lead business innovation. correlation in results when comparing the automated Today's managers must shift from directing work to plating system to the manual method of testing. It has translating business strategies into action plans and also been determined that the robot can save between energizing people to implement the plans. Simplistic two to three man hours per day. accounting measurements are being replaced by business The unattended sample preparation of the robot, allows impact analysis, and judgment. for testing to continue beyond the normal work day of the Over the past 15 years, laboratory automation has grown job. By programming the robot to run 24 hours per day, from a novel new technology to a powerful management the microbiologist or technician is able to perform other tool to help leading organizations become more innova- functions in the lab. It also allows for an increase in the tive, productive and competitive. The greatest value workload of the lab, improving the throughput of the lab, comes from applying automation in the context of without additional personel.

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