Bioanalytical automatlon: history and future plans --]JournalofAutomaticChemistry,Vol. 16, No. 4 (July-August 1994), pp. 121-123 Bioanalytical au future plans tomatlon: history and

Journal of Automatic Chemistry, Vol. 16, No. 4 (July-August 1994), pp. 121-123

Bioanalytical aufuture plans

tomatlon: history and

Raymond H. FarmenBioanalylical & Radiochemical R & D, Bristol-Myers Squibb, 675 College RoadEast, Princeton, New Jersey 08543-4500, USA

Bioanalysis is determining the concentration of drugs andmetabolites in biological fluids (i.e. plasma and urine). Duringthe past 15years tremendous advances in bioanalysis, for exampleHPLC, auto injectors, data collection systems and robotics hasenabled the productivity of,the bioanalyst to increase but it stillrequires considerable manual intervention. This paper describes therationale, the justification and the plans Bristol-MyersSquibb has to completely automate the entire bioanalytical process.

Fifteen years ago bioanalysis was extremely tedious.Q.uantitating drugs in plasma and urine was accomplishedby either RIA or GC. Although RIA was non-specific, andraising appropriate antibodies bordered on black magic,this was often preferred over the labour-intensive GC.GC required tedious chemical derivatization withmanual injection, followed by manual chromatographicintegration. When HPLC was introduced in the 1970s, itproved to be a fantastic technological advance inbioanalysis because it offered specificity without the needtbr chemical derivatization. Unfortunately, HPLC stillrequired manual injection and manual chromatographicintegratio.n. When autoinjectors and chromatographicintegrators became available they quickly increased theproductivity of both GC and HPLC. These advances onlyaddressed the obvious needs of the chromatographicportion ofsample bioanalysis. However, sample extractionand preparation was still performed manually. Theintroduction of fast LC systems with air bubbles asseparators was an attempt to automate the sampleextraction portion of bioanalyis. Unfortunately, thistechnology did not prove to be robust. Zymark’s roboticstations were successthl at automating the sampleextraction steps.

Many people consider their bioanalytical laboratoriesautomated if they have Zymark robots, automaticinjectors and data reduction systems. As shown in figure1, there are many steps involved in bioanalysis and thecommercially available equipment will only address thesample analysis step. Clearly, considerably more can beautomated in this bioanalytical process. In fact, the entiresystem should be able to be automated if it wereeconomically beneficial.

--] Sample Receiptmple Login

contamination (?)Sample Storage

Transfer Samples to Lab

reate an Analytical Run

"]arnple Analysis[_mple Re-st0rage

Figure 1. Sample handling steps.

laboratories. Without the use of robotics the typicalin-house analyst can prepare a bioanalytical run everyother day. The average bioanalytical run contains about90 injections, 20 of which are standards and qualitycontrol samples. Therefore, the typical analyst can processabout 175 unknown samples per week. During 1992 about63000 samples were sent to contract bioanalyticallaboratories for bioanalysis for two reasons.-First,Bristol-Myers Squibb has inadequate facilities forhandling samples known to be HIV+. Therefore, anyknown HIV + sample is sent out for bioanalysis. Second,with the current level of automation within thebioanalytical department it was impossible to handle thetremendous quantity of samples. It should be stressed thatsending samples to contract laboratories for bioanalysisonly saves about two thirds of the resources that wouldbe used for in-house bioanalysis. The analyst inBristol-Myers Squibb is still responsible for verifying thebioanalytical results and for getting the data in a formatfor subsequent pharmacokinetic analysis. It costs onaverage about $38 per sample for outside contractbioanalysis. However, the real.cost of sending samples tocontract laboratories for bioanalysis is $60 per sample,taking into account both the contract and in-house costs.During 1992, Bristol-Myers Squibb spent $2.4 M dollarson bioanalytical contracts.

Total automation

During 1992 Bristol-Myers Squibb generated about200 000 bioanalytical samples that needed to be analysed.Of these samples about two-thirds of them were analysedin-house and the remainder were sent to contract

This paper was presented at the 1-993 ISLAR, organized by the ZymarkCorporation.

If the entire bioanalytical process were to be automatedat Bristol-Myers Squibb, the goals would be:

(1) Increase productivity--go from 175 to 1500 samples/week/analyst.

(2) Increase capacity--plan to process 400 000 samples/year.

’,) Z "k Cot "ati 1994 121

R. H. Farmen Bioanalytical automation" history and future plans

100 Feet

Area Office Storage

A,

I, AS/RS]B FreezerA 16’x20’xlO’

AS/RSRack

Analysis Robot

XY Robotlifts rackto & fromanayisis

robot bench

Analysis Robot

Figure 4. Sample transport conveyor system.

4’ HoodsAS/RS Automated Storage/Retrieval System

A Rack Storage Area Rack Building Area

Figure 2. Bioanalytical laboratory layout.

(_ (YZ Robot

Feeder Tubes Reader SampleStorage Bleach BathRack

Figure 3. Sample login and decontamination station.

(3) Reduce reliance on contract laboratories and savemillions of dollars each year.

(4) Improve analyst safety from blood-born diseases andbe able to bring HIV+ samples in-house forbioanalysis.

(5) Maximize the time that expensive equipment isutilized by continuously feeding it samples.

(6) Accelerate drug development by processing samplesat a faster rate.

(7) Improve our sample tracking capabilities that areoften done manually.

(8) Improve worker morale.

A 40 ft x 100 ft automation bioanalytical laboratory thataddresses all of the sample processing steps described infigure is shown in figure 2. Sample flow in this laboratorymoves from right to left. Sample receipt and its subsequentdecontamination occur in the room on the right.

A schematic for the automated sample login anddecontamination station is shown in figure 3. Followingdecontamination the samples are sent into a large freezerfor storage at -20C. This freezer has been named the’AS/RS’--the automatic storage and retrieval system.The freezer has two linear tracks on which robots moveto place on and pick off 50 tube trays from storage racks.This process can be viewed very much like an automatedwarehouse, only it is smaller and colder. During samplebioanalysis, selected samples are removed from their traysin the freezer and placed into 20 tube trays for transportto the bioanalysis stations. The trays are transported to

the bioanalysis stations by simple conveyor belts. Thetrays are removed from the conveyor belts by a robot andplaced on the bioanalysis station. After an aliquot hasbeen taken from each sample in the tray, the tray is thenplaced back on the conveyor belt for transport back tothe AS/RS for storage. A schematic ofthe transport systemshown in figure 4. The final step in the automationprocess (sample bioanalysis) has already been fullyautomated. The sample bioanalysis process consists ofextraction, chromatographic separation, measurementand quantitation.

Managing this automation laboratory will requireconsiderably different skills than are currently envisionedin a research environment. For example, the goal of thislaboratory is to run 24 hours a day, seven days a week.Managing that work will require production managementas well as scientific management training. It is anticipatedthat the entire automation laboratory with 12 bioanalysisstations will require a staff of six bioanalytical scientists,two computer scientists, one decontamination technicianand one manager. That is two bioanalysis stations perscientist. Handling the current sample workload wouldbe simple in this laboratory. For example, if 11 of the 12bioanalysis stations process one sample every 15 minutes,24 hours a day, five days per week and 40 weeks per year,the result would be well over 200000 samples beinganalysed. Sample capacity could easily be increased byeither increasing sample throughput per bioanalysisstation, and/or by working more days/week, and/or byadding more bioanalysis stations. Clearly, increasingsample throughput would be the preferred choice.

The entire cost estimate of this automation laboratoryranges from $4 500 000 to $7 000 000. The hardware alonewill cost about $2500000 with software/engineeringcosting between $2 000 000 to $4 500 000. The large rangein software expense is dependent upon what internalresources can be devoted to this project. The questionthat is often asked is whether this automation laboratorywill be economically justifiable? Figures 5 and 6 addressthis question. Figure 5 compares the per samplebioanalytical cost between automated sample bioanalysisversus manual sample bioanalysis. As the number ofsamples increases, the cost of performing automatedbioanalysis decreases to about $38 per sample. The figureof $38 per sample amount represents the high side of totalsample bioanalysis because the scientist performing thebioanalysis was still responsible for manually logging inthe samples, for tracking the samples, for transporting the

122

R. H. Farmen Bioanalytical automation: history and future plans

S300

S250

$200

S150

$1oo

$50

In-house / Contract labs,, Automation

2000 13000 15000

# Samples Analyzed Person

Actual data for automating sample an,,sis wzth one Zymark robot

21000

$30 t In-house + contract Dabs ./

$25

$20

$15

$10

$5

$050000 100000 200000 300000 400000 500000

Annual # Samples Analyzed

Figure 6. Bioanalytical cost comparison.

samples to the laboratory and for s.etting up the analyticalrun. In figure 6 the total sample bioanalysis cost inmillions of dollars, versus the annual number of samplesanalysed in-house, is plotted comparing the in-hour/contract cost of $60 per sample against the automationsample bioanalysis cost of $38 per sample. These costcomparisons were used to perform a return on investmentanalysis. Under the worst case scenario that the total cost

of the automation laboratory was 35 more than$7000000, that the efficiency of the automation labwas 35 less than projected (efficiency was onesample processed every 15 minutes per sample bioanalysisstation) and that the sample capacity stayed the same,this system would pay for itself in less than three years.Creating this bioanalytical automation laboratoryproduced several new and excisting challenges. First, thislaboratory will force the company to redefine abioanatytical experiment. For example, today’s bio-analytical experiment consists of 11-12 standards, 6-8quality control (QC) samples and 60-100 unknown studysamples. In the continuous feed automation laboratorythe potential exists for a bioanalytical experiment tocontain 500-1000 samples. In an experiment of this sizehow many standards and QCs are appropriate? Also, howshould the standards and QCs be placed in therun? Second, chromatographic software will need tobe developed that can diagnose problems with theexperiment and can then terminate that experiment.Third, LCMS machines will be interfaced with thissystem. This equipment has the ability to accept a newsample every four minutes. With the continuous-feedautomation laboratory, the rate limiting step is the sampleextraction process. Manufacturers will need to developtechnology that greatly increases the speed of thatbioanalytical step.

Conclusion

In conclusion, a vision for automating bioanalysis hasbeen presented. This vision moves away from the historicalperspective that the only steps in bioanalysis that need tobe automated are the sample extraction step, the sampleseparation and measurement step and the samplequantitation step. This vision offers the potential forincreased productivity, increased capacity and increased"worker safety. This vision was turned into a plan; albeitan expensive plan but with the potential for big monetarysavings. This plan in a relatively low-risk plan, becausesimilar systems have been successtially implemented suchas warehousing and clinical chemistry operations.

123

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Bioanalytical automatlon: history and future plans --]JournalofAutomaticChemistry,Vol. 16, No. 4 (July-August 1994), pp. 121-123 Bioanalytical au future plans tomatlon: history and