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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
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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.
119
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