Download pdf - Vol. Key issues for establishing a robotics laboratory in the ...JournalofAutomaticChemistry,Vol. 16, No.4 (July-August 1994), pp. 117-119 Keyissues for establishing a robotics laboratoryin

Journal of Automatic Chemistry, Vol. 16, No. 4 (July-August 1994), pp. 117-119

Key issues for establishing a roboticslaboratory in the pharmaceutical industry

Steve ConderBristol-Myers Squibb Company, PO Box 191, New Brunswick, New Jersey08903-0191, USA

The Analytical Research and Development Department ofBristol-Myers Squibb has a laboratory dedicated to robotic analysisof solid doseforms. It consists of eight individuals responsiblefor 191nine robotic systems. The laboratory is dedicated to the support ofPhase III stability studies that require dissolution, potency, content.uniformity and Karl Fischer moisture assays. The group performsabout 15 000 assays ayearfor approximately six long-term stability 92programs. The key issues for success were personnel selection,methods development (methods transfer), routine assay support,documentation, validation, training and support services. Thispaper discusses the establishment of the laboratory and the future 3issues important to continued success.

Phase III Stability

Introduction

The Analytical Research & Development Departmentof the Bristol-Myers Squibb (BMS) PharmaceuticalResearch Institute has developed a robotics laboratory toprovide automated assay support of its Phase III clinicaland stability programes within pharmaceutical develop-ment.

10

Thousands

Potency

Karl Fisher

Dissolution

Totals

Figure 1. Semple handling steps.

12 14 16

The typical assays within pharmaceutical analysis thatconstitute the majority of the work in a Phase Ill stabilityprogramme are:

(1) Potency/degradants.

(2) Dissolution.

(3) Karl Fischer moisture.

The routine Phase III sample load can often exceed theresources available within the non-automated laboratoryand the robotics laboratory at BMS has been designed toprovide automated support for each of these assays.

The robotics laboratory houses nine robots, twoworkstations and has a staff of eight (including thelaboratory manager). The majority of the robots aredissolution due to the labour intensive nature ofthis assay, while the remainder are predominantly tabletassay robots or workstations. One robot is used for allKarl Fischer moisture determinations. The laboratoryincludes:

(1) Nine Robots (Zymark Corporation): five dissolution;three tablet assay; and one Karl Fischer Titration..

This paper was presented at the 1993 International Symposium onLaboratory Automation and Robotics (ISLAR) organized by theZymark Corporation.

(2) Two workstations: BenchMate (Zymark Corporation);and SmartPREP (Source for Automation).

(3) Personnel: four system managers; and three chemicaltechnicians.

A history of the productivity of the laboratory over thepast three years is provided in figure 1. The laboratoryassayed over 15 000 samples in 1991 ofwhich the majoritywere dissolution assays. The totals have decreased steadilyover the past two years due to the reduced sample loads forolder Phase III programmes and the lack of new PhaseIII programmes that were started during this time. The15 000 samples assayed in 1991 represent less than 50%of the laboratory’s capacity, and there is significant roomfor expansion.

Key issues for success

Before discussing the key issues necessary for success indeveloping a robotics laboratory, it is instructive to reviewsome of the inherent obstacles to success. Several obstaclesare presented in table that are worth mentioning here.The first two acknowledge the high cost and demand onresources that an automated laboratory requires,especially during the initial phase. This inevitably leadsto special needs for education of the users or systemmanagers for each robotic system. Furthermore, thecomplexity of robotic systems for total automation of the

(C) Zymark Corporation 1994117

$. Conder Key issues for establishing a robotics laboratory in the pharmaceutical industry

Table 1. Inherent Obstacles to success.

High cost

High demand for resources

User education

Complexity

Long automation design cycle

GLP/GMP requirements

Table 2. Key issues for success.

Personnel selection

Methods development

Routine assay s.upport

Training

Documentation/validation

Support services

typical assays can lead to extended design cycles. Rarelyis success achieved immediately upon installation. Finally,a special requirement particular to the PharmaceuticalIndustry is the need for adherence to current GoodLaboratory Practices (GLP) and Good ManufacturingPractices (GMP) regulations within the operatinglaboratories.

The key issues for success are shown in table 2. Theassumption here is that management support andadequate funding and facilities are available for thelaboratory.

The most important factor is personnel selection. Manyobstacles or inadequate support in the other areas listedin table can be overcome by a creative and highlymotivated staff. The ideal candidate has strong analyticalskills, is computer literate and is detail oriented.Understanding the key steps in an analytical method isessential to its successful automation. Successful auto-mation chemists are also part engineer (both mechanicaland software) since they pertbrm the translation of themanual procedure into an automated one to be performedby a blind, deafand dumb robot. This can be a frustratingexperience that requires perserverance, creativity and awillingness to experiment and question assumptions.However, perfictionist tendencies can be t;atal because atsome point development steps and routine samples needto be run.

A key area for success in assay support is methodsdevelopment. Experience has taught BMS to follow anexperimental plan that has developed over time for eachassay type that is automated. Initially, this did not existas experience was gained about the importance of certainassay requirements. For automation ofmanual dissolutionassays, the appropriateness of the method for use on the

robot is assessed and, if suitable, the validation plan isdeveloped to transfer the assay. This allows templates tobe built which are followed during method developmentand speeds the whole process to completion. This isparticularly important for stability assays where it isnecessary to make the transition from development toheavy support for routine assays very quickly andsmoothly. It is critical to develop efficient procedures forhandling sample and data management very early in thedevelopment cycle. This is necessary to avoid the classicautomation bottleneck that occurs when robots stand idlewhile results are calculated and notebook entries arecompleted.

A tedious and time-consuming task that can be viewedas unproductive is the GLP/GMP validation anddocumentation of a system. The documentation iscomprised of a considerable volume of paper on thehardware and software that constitutes a robotic system.This is not provided with most installations and mustbe prepared by the user. Validation requires anunderstanding of the key procedures or processes underthe control of the robot that must be tested to ensureaccuracy, suitability and adherence to any GMPrequirements. This may be as simple as validating thedetermination of the vessel temperature in a dissolutiontest that must meet USP criteria. Since it is onlyrecently that this information can be provided bythe manufacturer, the users generally decided whatdocumentation was necessary. Furtheremore, provisionsfor system security and software change control need tobe addressed as a part of computer system validation.

Technical support services are needed both from thevendor and in-house to adequately service, maintain andintegrate the robotic system within the data managementsystems of the development. Robots that perform LCinjections can create a heavy workload for a chromato-graphic data processing system; it is a key requirement tohave sufficient capacity for each robot. Furthermore,development of custom assay methodologies may requireengineering services, such as mechnical or electrical todevelop custom hardware for each application. Onceagain, this is a labour intensive and iterative process.

Future plans

BMS has shifted from late stage development projects withheavy Phase III support requirements to early stageprojects that have vastly different dynamics than PhaseIII programmes. Experiences with Phase III programshas provided a substantial amount of informationabout methods development strategies and sample/datamanagement for high-load projects. However, toparticipate and contribute to early stage developmentprojects, it is important to be flexible and expand thelaboratory’s capabilities. For example, early stagedevelopment dose forms are typically dry-filled capsulesthat pose different challenges for dissolution and potencyassays than tablets. It is necessary to rely on our methodsdevelopment strategies to respond quickly and continueto expand the laboratory’s technological capability toassay dry-filled capsules. Furthermore, it demands moreof the laboratory’s analytical capabilities, since less is

118

S. Conder Key issues for establishing a robotics laboratory in the pharmaceutical industry

known about the compound and dose form behavior. Theability to automate at an early stage will be a bonus if theproject moves to the latter stages of development, since arobot-friendly analytical method is available.

AcknowledgementsThe author would like to thank the following tbr

their valuable contributions to the success of thisproject. Current and past management ofARD including:Drs Berry J. Kline, Glenn A. Brewer and Jerry R. Allison.The current members of the robotics laboratoryteam: Dan Barrow, Scott Jennings, Rich Vol Culin,John Rumney, Jim Wysocki, Alma Johnson and KhanhHa.

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