vol. therole ofthe automation development group in...

Journal of Automatic Chemistry, Vol. 16, No. 4 (July-August 199,4), pp. 131-133

The role of the automation developmentgroup in analytical research anddevelopment at Dupont Merck

John C. Lynch, Jonathan S. Green, Paul K.Hovsepian, Kathleen L. Reilly and Joseph A. ShortAnalytical R & D, Pharmaceutical Development The DuPont Merck Pharma-ceutical Company E353 Experimental Station Wilmington, Delaware 190000353,USA

Laboratory robotics has been firmly established in many non-QClaboratories as a valuable tool for automating pharmaceuticaldosageform analysis. Often a single project or product line is usedto justify an initial robot purchase thus intr.oducing robotics to thelaboratoryfor thefirst time. However, to gain widespread acceptancewithin the laboratory and to justify further investment in robotics,existing robots must be used to develop analysesfor existing manualmethods as well as new projects beyond the scope off the originalpurchase justfcation. The Automation Development Group inAnalytical Research and Development is a team of analystsprimarily devoted to developing new methods and adapting existingmethodsfor the robot. This team approach developed the expertiseand synergy necessary to significantly expand the contribution 9frobotics to automation in the authors’ laboratory.

Introduction

This paper will discuss how a small to mid-sizedpharmaceutical company is successfully using automationduring the early 1990s, a period of considerable andfast-paced change.

research environment. In today’s business climate, R & Dcosts must be not only contained but reduced. Projecttimelines are getting tighter; a few years ago analystsmight have a year to develop methods and acquire andvalidate data. Now they must do that same work in atmost six to nine months, with no compromise in quality.Especially in pharmaceutical R & D, there are frequentstaff reorganizations which further limit the ongoingsupport of individuals and management for robotics,automation and new technologies in general. Automationis no longer a ’sacred cow’; it must earn its keep just likeeverything else in the budget by contributing to thebottom line through increases in sample throughput andproductivity. Since robots have the potential to displaceor change certain job functions, especially where routinesample preparation is concerned, enthusiasm amonglaboratory workers for robots may be severely limited in a

downsizing’ environment where everybody worries aboutjob security. In a regulated industry like pharmaceuticals,it is necessary to constantly improve the quality andamount of the data supplied to the FDA, and with theadvent of the Clinton health plan we will need to furtherimprove cycle times if development costs are to be cutand the organization to prosper in a new era of drug costcontainment.

The role of robotics

It is difficult to overemphasize how much things havechanged in the research and development environmentduring the last 10 to !5 years. During the late 1970s andearly 1980s, many research organizations experiencedsignificant growth in their budgets for both personnel andequipment. In the areas of automation and computers,it was relatively easy to justify the purchase of newequipment if one suggested that this would help’automate’ or ’computerize’ an application or function.During that same period a number ofindustries, includingpetroleum and pharmaceuticals, were enjoying a rapidincrease in profits which made purchasing new equipmenteasier. This scenario often leads to the anecdote about theresearcher who orders an expensive piece of equipment,only to leave it packed in its original box to be trippedover and eventually discarded by his replacement whenthe original owner is promoted or retires.

The research environment is different today. This paperwill discuss the role of robotics in a pharmaceuticaldevelopment organization in the midst of a changing

This paper was presented at the 1993 ISLAR, organized by theZymark Corporation.

About two years ago it was decided to bring robotics intoAnalytical Research and Development at DuPont Merck.Since it is relatively new company and the analyticalsection was mid-sized (less than 100 people) it could notsupport a specialized department nor could it justify thepurchase of a lot of equipment. Instead robotics had to

improve productivity within the constraints of thelaboratory environment.

The department was responsible for developing methodsand specifications for bulk drugs, dosage forms andreference standards as well as testing stability and releasesamples and providing fbr the transfer of method andtechnology to production sites in anticipation of NDAapproval. Based on this it seemed that robotics could makethe greatest impact if it could assist in the Phase II andPhase III project development.

By the time a pharmaceutical company decides to take a

drug candidate into costly Phase II/III clinical trials, ithas already taken a big financial gamble that it willsucceed. However, even at this stage many drugs fail toshow efficacy or show undesirable side-effects. Dependingon the size of the clinical study, several dozen lots ofvarious strengths, packaging and tablet shapes may be on

(C) Zymark Corporation 1994131

J. c. Lynch et al. The role of the automation development group at Dupont Merck

stability. Stability data is not only used to establish shelflife of the various packages under different conditions(which will eventually be used in the NDA submissionand in the market label) but to ensure that the varioustablets which are being given to patients in the clinicmeet the specifications for potency and purity. It isvitally important that samples are analysed promptlyand correctly the first time to protect patients and toalert the company to possible stability and storageproblems. Since samples are pulled at various intervalsspecified in the stability protocol for each lot, only asmall time window is allowed for each analysis and itsreporting. All of these factors combine for high visibilityfor analysts who decided to provide automated analysesto assist in these projects.

Initial successes

During 1992 a Zymark Tablet Processing Workstation(TPW) was installed. In conjunction with the RegulatoryCompliance Department and Metrologist the authorsdeveloped and carried out the validation plan, wrote andinstituted metrology operating procedures, and budgetedfor the training of three operators. Due to this effort over500 sample preparations were performed during athree-month period with the TPW operators performingthe HPLC analysis as well. As the original project movedtoward the end ofPhase III, a second TPW was purchasedand installed to handle the workload anticipated as thedrug moved into production and in support of otherphase II/III projects. However, just as the automationeffort was moving into high gear, the project wascancelled!

Early lessons

In order to be knowledgeable about robotics, the authorslearned about the technology. It is not enough to learnthe basic operation for the TPW, for example it is vitalto have expertise in troubleshooting, maintenance, andcustomizing. The authors developed partnerships with thevendor, the scientists who developed the manual methods,and with internal or external consultants.

One aspect that has deservedly received attention inseveral recent papers has been the importance ofrecruitingand developing the right staff to work with robotics. Noteveryone is able to be successful in this field. People whodevelop and troubleshoot methods must be extremelypatient but persistent. They must pay great attention todetail but still be able to see each component ofthe analysisas a small part of the whole. They must also be skilledanalysts and have good people skills since they have tointeract with many laboratory personnel who may notappreciate or understand what we do.

Major challenges

To be successful, the authors had to overcome a numberof major challenges. There was a phase II project waitingto be automated but there only was a short time--four

months--in which to develop and validate the methodsand issue all the required documentation. There was awide range of strengths, and since our TPW was notequipped to do analytical dilutions, this presented aproblem. There was also evidence that the solvent in themanual method caused foaming when the tablets werehomogenized and that the proposed internal standard wasunstable in solution. In addition, a new operator had tobe trained.

This project presented another major challenge which wasto the authors’ advantage: the management had decidedto concurrently develop a combinaton tablet as well as thesingle entity. Because of the similarity in products, theauthors were able to use the solvent system alreadydeveloped for the combination tablet manual method forboth single entity and combination product automatedmethods. This suggestion was made by the newoperator/analyst!

The purpose of this chronology is to illustrate theenvironment that the automation group worked in.Synergy is extremely important in an automation group.Analysts must be able to work independently but theymust also communicate fully with each other and withtheir customers in the laboratory. There is often notenough time to develop elegant and totally novelapproaches to problems. By sharing information, andusing it effectively, the job gets done on time and everyone’owns’ the problem and the solution.

During 1993, in support of this project, over 400 samplepreparations were performed, and three automatedmethods, a validation plan and report were issued andincluded as alternate methods in the CMC filing. Thisfurther increases our visibility and credibility. Thecombination product methods were issued in October1993. However, the project chemists felt that the internalstandard we were using took too long to elute. So, at theirrequest the authors developed and validated alternateautomated methods using external standard calibration.These were issued soon after the other methods, and thefirst samples were analysed the week before ISLAR 93.

Path forward

With both robots busy and two of the phase III projectsautomated, the initial goals were met. In order to grow,the first goal was to continue to educate the department,management, and regulatory and documentation depart-ments about the group’s work. The authors also neededto continue training and developing their staff; thismeant allocating funds to send them to basic andadvanced Zymark training and to allow them the timeto take on new tasks that would challenge them and allowthem to master new skills. It was important to continueto build synergy within the group, within the departmentand with robotics users in other departments and sitesthroughout the company. There was the ongoingresponsibility of managing the technology. Since bothrobots had been used for over a year, maintenance andtroubleshooting became very important if we were to relyon them for consistent performance. Parts and suppliesneeded to be stocked and organized. Large quantities of

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j. c. Lynch el al. The role of the automation development group at Dupont Merck

reagents also needed to be stocked and stored. In addition,the authors began to work with our industrial hygienedepartment to monitor and limit analysts’ exposure tosolvents used in these analyses, as well as the noisegenerated by the robots. In some cases this meant makingmodifications to the rooms. Finally, special spill-controlprocedures were written and equipment ordered tominimize danger to staff and damage to equipment if anyof the systems should malfunction during unattendedoperation. To shorten cycle times and improve quality ofanalyses it is necessary to constantly upgrade equipmentand improve procedures, whether this is as simple asreteaching a rack position, relocating a station or workingwith building engineers to improve the performance ofhoods or the chilled water system.

Technology and new applications

For the longer term development of robotics in theauthors’ department there are two things that areimportant: keeping abreast ofnew technology and findingnew niches or applications for robotics. Keeping abreastof new technology may be as simple as inviting a vendorin to demonstrate a new robot or autosampler. During1992, the group had the opportunity to evaluate a

non-Zymark workstation during a three-week period.During that time each member of our group was able tolearn the rudiments of the system and prepare severalsamples. This experience will enable the group tocomment intelligently on this vendor’s product. Keepingabreast of new technology also means purchasing robotsthat have new or different features that may be helpfulin project development. These new products may openup new applications for robotics in the lab as well asimproving the automation of current ones.

The authors have found that developing new niches forrobotics is a neverending task and one that is full ofsurprises as well. A current project challenge is to developa robotic method for the preparation and analysis of acombination drug that is contained in a multi-layer tablet.It is a perfect application for a robot because the manualmethod uses large amounts of chloroform and involves alot of repetitive motion. Using a robot can reduce thechloroform exposure and the amount of human repetitivemotion. The relatively short solution stability of theproduct can be minimized by using the robot to prepare

each sample immediately before injection. In fact, thiswill allow the assay for degradation products to becombined with the potency assay, saving a separatesample preparation and analysis for each sample.However, there are many challenges: the multilayer tabletis difficult to dissolve, the high rpms required forhomogenization represent a noise hazard. The chloroformfumes must be contained and vented, and, finally, one ofthe compounds is water sensitive. To deal with theseproblems a Lucite containment hood has been built, whichis vented to the roof scrubbers. This serves to contain thechloroform, as well as acting as a sound barrier. However,there have been problems with additional chloroformdripping from the wash line into the Fleaker duringhomogenization, causing dilution of the sample. In thiscase, the path of the tubing has been modified and a checkvalve added. This is a good example of how investingin new technology can help the robotics effort inunanticipated ways--the purchase was originally justifiedfor making direct injections after sample preparation.However, several features of the robot--its smaller size,the option of using multiple solvents to wash the Fleakerrather than just water and its unique probe and Fleakerdesign have also helped method development in ways thatwere not originally foreseen.

Conclusion

There are two lessons we have learned t?om our roboticsgroup that we feel are valuable for any laboratorycontemplating using robotics in an analytical research anddevelopment lab. First, as with any new technique, themore experience you have the better you become at usingrobotics and finding new applications. Finally, the methoddevelopment process is cyclical. You return to the sameissue and challenges better equipped to deal with themas well as the new challenges not previously encountered.

Acknowledgements

The authors wish to thank K. Rick Lung, Senior ResearchChemist, Mickey Schoenauer, Regulatory ComplianceManager for Information Systems, and Nancy Read,Analytical R & D’s Metrologist, for their advice and help.

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