1. ISA
TRANSACTIONS®
ISA Transactions 41 ͑2002͒ 245–254
Batch control system project for a pharmaceutical plant
´ ˇ
Roman Holy, Jaroslav Pozivil*
Department of Computing and Control Engineering, Faculty of Chemical Engineering, Prague Institute of Chemical Technology,
´
Technicka 1905, CZ-166 28 Praha 6, Czech Republic
͑Received 23 August 2000; accepted 25 March 2001͒
Abstract
This paper describes a case study of a control system design for a batch pharmaceutical process. The ISA standard
S88.01 batch control models and terminology were used as the main guidelines for the implementation. As the S88 is
not a guide for how to apply the definitions/structures, etc., one of the main goals of our work was to create a
methodology for decomposition of functional requirements in terms of S88 models and structures. This methodology
was tested on a real problem, described in the case study. Also presented are some remarks on project methodology and
Food and Drug Administration validation. © 2002 ISA—The Instrumentation, Systems, and Automation Society.
Keywords: Batch plant; Process model; Procedural control; S88 standard; FDA validation
1. Introduction within a programmable logical controller ͑PLC͒;
more modern setups are even rarer. This situation
Batch processes are the ones most often used in usually causes greater variations in both the pro-
the manufacture of pharmaceuticals, specialty duction quality and quantity, problems with pro-
chemicals, pure substances, and other high-value- cess precision and repeatability ͑in the first case͒,
added products. Such processes are characterized or problems with the process flexibility—there
by frequent changes of technology and continuous exists the necessity to modify parameters or even
introduction of new or modified products. This all the programs in the PLC’s when some product
places high demands on process control and pro- or process changes are needed ͑in the second
duction planning. case͒.
The current state in most batch manufacturing In order to improve this situation companies
plants in the Czech Republic is based on old- should implement new control systems with better
fashioned methods. This means many of them still functionality. The best guideline for how these
use paper standard operation procedures or paper new batch control systems should be organized
‘‘operation sheets’’ for production control and data seems to be provided in the ISA S88 standard
logs, and mostly they control their batch processes models. Moreover, in the pharmaceutical industry,
manually. In the better case, they have a supervi- when companies wish to export their products to
sory control and data acquisition system for pro- the USA, then their batch control systems should
cess visualization and basic control implemented be compliant with Food and Drug Administration
͑FDA͒ requirements ͓1͔. Such a batch control sys-
*Corresponding author. Tel.: ϩ420-2-2435-4259; fax: tem design and implementation project is then a
ϩ420-2-2435-5053. E-mail address: very complex activity that needs an appropriate
jaroslav.pozivil@vscht.cz scientific and methodological approach.
0019-0578/2002/$ - see front matter © 2002 ISA—The Instrumentation, Systems, and Automation Society.

2. 246 ´ ˇ
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2. The aim of the paper means of S88’s well-structured modularization
and its split of process equipment from procedural
The S88 standard, Part 1 ͓2͔, defines models and control. The advantages and suitability of the use
terminology for physical plants, procedures, and of S88 principles for FDA validation is well docu-
recipes. As the standard has already been intro- mented in literature, for example, in Refs. ͓7–9͔
duced in most of the cited references, we do not where validation system life cycles can also be
think it is necessary to reprint it here. For more found.
detailed references, we recommend reviewing the The validation effort is needed to prove that the
standard itself or the following articles: Refs. ͓3͔, final equipment performance and capabilities meet
͓4͔, or our paper ͓5͔. the requirements. Systematic quality control dur-
S88 establishes a framework for specification of ing the creation process can establish a traceable
requirements for the batch process control, and for control mechanism confirming whether the design
their subsequent translation into application soft- meets the requirements, and the installation corre-
ware. The framework consists of a variety of defi- sponds to the design. If the design process is under
nitions, models, and structures. It is not, however, control and well documented, confirming quality
a guide for how to apply the definitions/structures, control may require substantially lower validation
etc. Therefore, the main goal of our work was to effort.
create a methodology for decomposition of func-
tional requirements in terms of S88 models and
structures, as this is something the ISA standard
lacks. This methodology was tested on a real prob-
lem described in the case study below. 4. Case study
3. Problem analysis We have been involved in a pilot project at ICN
Czech Republic, Inc., a manufacturer of pharma-
Existence of a good project methodology is a ceuticals. The main goal of our pilot project at
necessity for any large project, and the methodol- ICN was to design a prototype of a new batch
ogy should provide a tool for allocating the re- control system for Nystatin separation ͑a batch
sources and information in an organized and effi- process producing the pharmaceutical substance
cient way. In our project we have followed ͑with Nystatin from the intermediate product manufac-
some adjustments depending on our specific tured by a fermentation process͒ that would be in
needs͒ the methodology described in the S88 accordance with current standards, would use
Implementation Guide by Fleming and Pillai ͓6͔. modern technology, and would demonstrate feasi-
The project methodology has six phases and sev- bility and benefits of such a system.
eral key attributes—some of which are described For implementation of the control system we
below. have used the software InBatch™ Wonderware®
The automation engineering effort is heavily ͓10͔. InBatch is a flexible batch management soft-
front-end loaded. The entire methodology is de- ware designed to be consistent with the ISA stan-
signed to make changes easier to implement. At dard S88. It is integrated within the framework of
any given time, the current version of documents the Wonderware FactorySuite 2000 package; for
should be able to describe the state of the process visualization the package offers InTouch ͑human-
control. Any change is evaluated against the im- machine interface software͒, and we have used
pact on all the previous phases of the project and this tool too.
is fully documented before it is implemented. Fi- The aim of the case study was to apply the ISA
nally, testing and validation of the installed system S88-based methodology to an existing industrial
forms a part of the overall control system design. plant manufacturing Nystatin.
As the process is being designed, the critical pa-
rameters are defined along with the protocol for
testing and the acceptance criteria for each param- 4.1. Plant description
eter.
The use of the S88 standard enables and helps to The new control system is intended for only a
pass FDA validation. This is done mainly by part of the whole Nystatin production, its separa-

3. ´ ˇ
Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254 247
Fig. 1. Schematics of the case study plant.
tion. To protect what ICN viewed as sensitive kieselguhr, and activated carbon is prepared, and
data, some of the following, such as compositions its content is then poured into A121. After this,
of some solutions, is replaced by anonymous des- formic acid is added. The content of A121 is trans-
ignations or is omitted. The technology can be di- ferred into filtrating centrifuge O123.
vided into five sections listed below ͑simple sche-
matics are shown in Fig. 1͒.
4.1.2. Filtration of extraction
4.1.1. Extraction of dry mycel Filtration in O123 is performed through a layer
Solvent A is charged into extraction vessel A121 of fabric coated with kieselguhr, and the filter cake
͑cooled using brine͒, then oxalic acid is added is washed using solvent A. Filtrate is collected in
while stirring. A barrel of a mixture of dry mycel, an H126 tank; filtration cake is considered waste,

4. 248 ´ ˇ
Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254
Fig. 2. Systems hierarchy.
although samples are taken for analysis from ev- 4.2. Aims of the project
ery batch. Filtrate from H126 is next filtered in
plate filter F122A and membrane filter F122B and • Automation of the process;
then transferred into A122 for pH adjusting. • reduction of paperwork and computerized
data logging; and
4.1.3. Treatment of extraction • easier validation of the control system by
A sample is taken from A122, and then the ex- FDA regulations.
tract is treated by solvent B ͑filtered through the The proposed integration of information and con-
bacterial filter͒ to reach the required pH. trol systems from the crystallization reactor to the
manager’s personal computer is shown in Fig. 2.
4.1.4. Crystallization The level we have been operating on was that of
Crystallization is performed in either A123A or procedural and operator control.
A123B. An amount of RO water specified by the
recipe is added into the vessel and the content of
the vessel is then slowly heated. Addition of the
extract starts upon reaching the required tempera- 5. Control system specification and
ture, and during this time solvent C and Syntron B decomposition
are also added. The content of the vessel is heated
to another recipe-defined temperature, and, after it Batch control projects usually involve other lay-
is reached and samples are taken, it is then cooled. ers existing above S88 models and terminology.
Although terms such as recipes, units, operations,
4.1.5. Separation and washing of the product phases, and equipment modules have been de-
Mother liquor is centrifuged from the product in fined, S88 is unsatisfactory in providing design
O122, and suspension and washing of the product guides and examples. Fortunately, a lot of effort
takes place in A131. The washing liquid is re- was directed towards this since the publication of
moved from the product in centrifugal separator the S88 standard. For the more complex decompo-
O131. sition methodologies and examples we would like

5. ´ ˇ
Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254 249
Fig. 3. Framework of S88 models in the presented methodology.
to recommend Refs. ͓6͔ or ͓11͔, the latter based on odology is shown in Fig. 3. There are two main
the PhD/thesis of Bunch ͓12͔. Both of these meth- differences expanding the S88 mapping:
odologies have strong and weak aspects in their
structure and description. Inspired by these efforts, 1. Connections ͑defined in the framework of
and in order to avoid some of their weak points, transfer classes͒ have been added to the
we have defined our own decomposition approach. physical model in order to simplify the defi-
This approach better suits our needs and is in good nition of procedures.
agreement with both the S88 standard itself and 2. Process phases have been defined and used
the batch management software used—InBatch. as a common element both to the physical
The structure of application of S88 models in the model and to the procedural control model,
framework of the proposed decomposition meth- and they link these two models together.
Fig. 4. Algorithm of the proposed methodology.

6. 250 ´ ˇ
Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254
The algorithm of the proposed methodology is different types of phases—automatic, semiauto-
shown in Fig. 4. More detailed descriptions of all matic, and manual—with three different levels of
steps in the algorithm, together with examples connections to low level control systems. All nec-
from the process in which it was used, follows. essary phases for each process and transfer class
have been identified resulting in a total of 59 pro-
cess phases and 15 transfer phases.
5.1. Physical model 6. The sixth step should produce phase logic
controlling and connected equipment modules. In
1. The first step defines the boundaries between the best case, this should be done in parallel with
cell͑s͒ of interest and the rest of the site/area. In phase development in the above step. This step, as
our case, the solved problem was the part of the well as the seventh step below, was not applied in
process between process stages of weighing ͑fer- our prototype.
mentation cell͒ and drying—the Nystatin separa- 7. The seventh step defines control modules and
tion. In this process, only one product is being their elements.
manufactured—Nystatin.
2. The second step establishes the definitions of
trains and process stages. Two trains can be de- 5.2. Procedural control model
fined for our process cell as the cell contains two
parallel crystallization reactors. In our model only 8. The eighth step of the algorithm is a logical
one train has been defined, because there was no continuation of the seven previous steps and starts
special need to distinguish between the two reac- the definition and decomposition of the procedural
tors and the definition, and use of two trains would control model, using outputs of previous steps, es-
decrease the flexibility of the designed control sys- pecially phases. In this step, the number of proce-
tem. Five process stages, mentioned in the plant dures is determined. In our case, two procedures
description, have been also defined—extraction, were defined ͑the procedure for Nystatin produc-
filtration, extract treatment, crystallization, and tion and another one for the cleaning in place pro-
separation, as well as the washing process stage. cess, sterilization͒. In the following text we deal
3. The third step includes identifying process only with the first procedure.
units. Here is another expansion of the S88 stan- 9. The ninth step establishes unit procedures,
dard, because the unit definition involves not only which are usually related to the process stages and
processing of one batch ͑or partial batch͒ of mate- process classes defined above, although we cannot
rial but also a storage of materials, e.g., hold tanks exclude exceptions. Seven unit procedures were
or bulk storage vessels. This approach was par- defined in the framework of our prototype.
tially enforced by selected software. Fifteen units 10. The tenth step of this methodology is the
were defined—eight process units and seven most subjective. The S88 standard’s definition of
units—tanks. In this step, connections describing operation is very general and it enables different
transfer of materials between units must be also explanations and implementations. The software
defined. The case study contains a total of 23 con- we selected supports this kind of flexibility. This
nections. enables us to define boundaries between opera-
4. The fourth step is designed to classify all the tions in the framework of one unit procedure at
units and connections into process classes and any chosen point. The objective was to divide unit
transfer classes. This object-oriented approach procedures into logical pieces—operations—
shows its advantages mainly during decomposi- whenever it seemed suitable, with the aim of mak-
tion of large models with many same or similar ing procedures more clear and structured. As an
units and/or connections, once a class is defined it example, the unit procedure, extraction, is in our
is not necessary to define each object separately. A implementation divided into three operations:
total of eight process classes and 15 transfer setup, the extraction itself, and transfer. In this
classes were defined. way, 12 operations were defined.
5. The fifth step involves identifying specific 11. The eleventh step uses the above-defined
process phases ͑in the framework of process phases to implement demanded process actions.
classes͒ and transfer phases ͑in the framework of Displaying the phases by means of sequential
transfer classes͒. The methodology distinguishes function charts ͑SFC’s͒ made this easier and more

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Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254 251
flexible ͑it enables use of both serial and parallel and MichVypn͒, manual charge of the mate-
sequencing, and logical transitions͒. rial ͑RucnPrid͒ and some others, and their
12. The twelfth step establishes necessary steps ͑phase͒ formula parameters ͑e.g., tempera-
to implement defined phases. This and the next ture for the cooling phase with the default
step were not applied in our prototype. value 8.5 °C and high and low limits 12 °C
13. The thirteenth step establishes necessary ac- and 5 °C, respectively͒, and their tags
͑A – 121-ChlaZapn-Teplota-ACT for a cur-
tions to implement the steps defined above.
rent value of the temperature͒.
14. The fourteenth and final step is a ‘‘debug-
• Units that have the same processing capa-
ging’’ step that allows returning to previous defi-
bilities are assigned to the same process
nitions and modifying them or adding new ones. class. Each unit has processing capabilities
In the end, the result should be a perfect physical that are defined by phases of the process
model and procedural control model—structured class. There is only one unit ͑A121͒ for the
according to the S88 structured models/ process class A – 121.
recommendations and functional/system require- • Transfer classes and their phases are defined
ments. in a similar way—within them, connections
͑e.g., pipes, hoses, filters͒ are defined.
6. Batch software implementation For readers who would like to go into more
implementation-specific details we would recom-
6.1. Process model—equipment mend Wonderware materials as the primary source
͓10͔.
The plant’s ͑or only one process cell’s͒ equip-
ment and its processing capabilities, as well as its
control and information requirements, are defined 6.2. Recipe—procedural control model
in the framework of the process model. The model
establishes the rules by which the plant’s equip- Procedural control is typical for batch processes.
ment and control systems are configured to pro- In order to carry out a process-oriented task it di-
duce batches. rects equipment-oriented actions so that they occur
In this part, confusion can arise between the in an ordered sequence. In InBatch, there are no
views of S88 and those of InBatch. InBatch ties ‘‘independent’’ procedures ͑the highest element of
both S88 models ͑physical model and process the procedural control model͒, because they are
model͒ together in one editor ͑Process Modeling created in the framework of recipes. This is logical
Editor͒, as this is the simplest way of describing because the recipe is in the end the place where
the characteristics of the equipment in the physical the procedures are used. The procedure consists of
plant. It becomes logical when one realizes that user-defined operations required to produce one
every unit ͑sometimes also a connection—e.g., a batch of a final product or an intermediate product.
filter͒ has some processing capabilities. The pro- The recipe’s equipment requirements necessitate
cess model itself is an abstract construct, as it be- linking to available processing capabilities ͑i.e.,
comes a reality at the time the procedure ͑as a part phases͒. Each operation and its phases are associ-
of the control recipe—the procedural control ated with a process class. In addition to the proce-
model͒ is applied to the equipment ͑physical dure, the recipe editor allows us to define the
model͒, and it starts the batch processing ͑or just a header, equipment requirements, and the formula.
simulation͒. Main characteristics of recipes can be described as
The process model uses an object-oriented ap- follows:
proach with advantages:
• Procedures for both operations ͑e.g.,
• All the characteristics of the units are de- charge—extraction—PlneniExtrakce͒ and
fined in the framework of process classes phases ͑e.g., process phases: the start of
͑e.g., A – 121 or O – 131͒, together with their cooling—ChlaZapn, the start of stirring—
process phases ͑for A – 121 the following MichZapn, and manual charge of material—
phases have been defined—the start and the RucnPrid; transfer phase: acknowledged
end of cooling ͑ChlaZapn and ChlaVypn͒, charge—PotvPrid͒ are edited in a SFC for-
the start and the end of stirring ͑MichZapn mat to allow for parallel and/or sequential

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Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254
operations and phases. Phase properties can selected phases by enabling the ‘‘check
be also edited ͑e.g., temperature of the phase by’’ check box during the configuration of
ChlaZapn͒. the phase. During recipe execution, this
• The master recipe is equipment and path in- option requires the operator and the super-
dependent, and it allows scaling of batch visor, or another person with a compa-
sizes. The master recipe is transformed into rable security level, to enter his/her secu-
a control recipe dynamically during run rity identification and password before the
time. The master recipe is edited in the
recipe editor. phase can end. Enabling ‘‘check by’’ auto-
matically enables the ‘‘acknowledge’’ and
• The control recipe starts as a copy of a spe-
cific version of the master recipe and is then the ‘‘done by’’ check boxes.
modified as necessary with scheduling and ͑2͒ Entry of numeric data, where the batch con-
operational information specific to a single trol system checks the validity of values, and
batch. It contains product-specific process if they are not in the predefined range ͑de-
information necessary to manufacture a par- termined by high and low deviations and/or
ticular batch of the product. It may be modi- high and low limits͒ it does not allow
fied to account for momentary raw material completion of the phase in a standard way.
qualities and actual equipment to be utilized. In such a case it is necessary to correct the
The control recipe is used during batch pro- appropriate value or to abort the phase. All
duction or simulation in the framework of events and corrections are logged and easily
the batch display editor. reported.
This allows very flexible recipe modeling and
batch management ͑including on-line parameter
changes͒. We can define a different sequence of 6.4. Flexible batch simulation and production
operations and phases and their parameters with-
out changing the process model or even recoding This describes the way in which process func-
the PLC. It is usually called a ‘‘recipe-driven’’ tionality and procedural functionality are linked
process. together into a flexible batch production or simu-
lation. General process classes ͑master recipe͒ are
6.3. Security clearances and safety transformed into actual process units ͑control
recipe͒:
In our prototype of the control system, we have • General procedure ( master recipe) ⇒actual
concentrated mainly on two security and safety is- process in the equipment ͑according to the
sues. control recipe͒.
͑1͒ The three levels of access authorization in- • Process class extraction reactors
clude the following A – 121⇒unit A121.
͑a͒ Acknowledging prior to the end of the
phase by using the ‘‘acknowledge’’ but- • Transfer class H1XXA121⇒connection
H134A121.
ton, without an operator’s security identi-
fication. • Phase: the start of cooling ͑ChlaZapn͒ of
process class extraction reactors ͑A – 121͒
͑b͒ Verification of the data entry and/or the
and default parameters⇒cooling in the reac-
start or the end of the phase by enabling tor A121 to the required temperature
the ‘‘done by’’ check box during the con- ( 8.5 °C) .
figuration of the phase. During recipe ex-
• Phase: acknowledged charge ͑PotvPrid͒—
ecution, this option requires the operator, add 650 l of methanol ͑default value͒ into a
or another person with a necessary secu- reactor ͑transfer class H1XXA121͒
rity level, to press the ‘‘acknowledge’’ ⇒ adding 650 l of methanol ͑actual value͒
button and then enter his/her security with the lot code 1548/8989 into the reactor
identification and password before the A121.
phase can end. • Security clearance request ͑for the phase, ac-
͑c͒ Verification and confirmation of critical knowledged charge–PotvPrid͒ for the opera-
data entry and/or the start or the end of tor is also shown.

9. ´ ˇ
Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254 253
Table 1 stopping pumps, and changing the setpoints
Comparison of our results with those of Love and Bunch of controllers. The number of such actions
͓11͔. should decrease by 70% after the batch con-
Methodology of Bunch, Our methodology trol system is implemented.
1998 • Product quality improvement—a reduc-
tion of operator-induced variability should
Lacks precise instructions Defines algorithms for
for decomposition at decomposition at physical
occur. This improvement is also supported
physical model and model and procedural
by easy and automated data acquisition, by
procedural control model control model level
better processing of the data, and by faster
level control interventions.
Contains unnecessary and Defines and uses the term • Cycle time reduction and yield
questionable rules phase as shared by two improvements—based on our experience
models with implementation of these and similar
Is not tied to SW Suitable for SW control systems in real plants, there should
implementation implementation ͑in InBatch͒ appear at least some cycle time reduction. In
Allows only sequential Allows use of SFC’s and a manually controlled process, there are
operations and phases parallel phases and many occasions where an operator does not
operations execute a phase at the earliest possible time
Does not define connections Uses the term connection because of outside reasons ͑e.g., he wants to
between units defined within transfer drink his coffee first͒. Through one batch, all
class of these delays can add up to a significant
Defines and differentiates amount of wasted time. Automation also
manual phases usually results in yield improvements. Auto-
matic recording of all events, actions, and
time makes operators more precise and
prompt.
This system of linking of the control recipe pro-
• Flexibility—when the procedural control is
cedure to the equipment control remains formally
separated from the equipment control, the
the same both for simulation and for actual control process becomes much more flexible. Most
͑manufacturing͒. After the process model and the changes in the recipe procedure do not re-
recipes are simulated, and successfully tested and quire either changes in physical model or
validated, the process model ͑namely, its phases code changes in PLC’s.
and their control/status tags͒ can be connected to • Reliability—ensuring that all necessary in-
programmable logic controllers or to any other put and output parameters are within pre-
control system used to perform phase logic and/or defined ranges is one of the most important
interface functions with the manufacturing equip- benefits. It is not possible to complete a
ment, and the production can start. phase, an operation, or a whole batch with
wrong parameter values anymore, or to for-
7. Discussion get about the signature on the operation
sheet. This is very important for FDA audits.
The results of this work are compared to results • Validation—many batch control systems
based on InBatch have already been vali-
published in Love and Bunch ͓11͔. The main ad-
dated by the FDA, and this documents the
vantages of our new methodology over the old one suitability of this software. By designing the
are described in Table 1. phase logic so that the phases are indepen-
Aside from well measurable benefits of intro- dent of one another, validation of the soft-
ducing the new control system, such as lower ware ͑whether built on InBatch or on other
manpower requirements, the system can cause software͒ is greatly simplified. Documenta-
other not precisely predictable effects. Among tion and testing of each phase’s functionality
those ‘‘non-tangible’’ benefits are need to be done only once. The recipe pro-
cedure is created and documented separately
• Operator efficiency—a good measure of from the phase definitions and tested only to
the workload on operators is to count the ensure that these phases are called upon in a
number of operator actions, which include, proper sequence and with correct param-
e.g., opening and closing valves, starting and eters. Consequently, changes to the recipe/

10. 254 ´ ˇ
Roman Holy, Jaroslav Pozivil / ISA Transactions 41 (2002) 245–254
procedure do not necessitate testing or docu- Guidelines for the application of ISO 9001:1994 to the
mentation changes at the phase level. development, supply, installation and maintenance of
ˇ
computer software ͑ISO 9000-3:1997͒, CNI, Praha,
• Data availability—this is enabled by auto-
matic saving of both process and procedural 1998.
͓2͔ ISA—The International Society for Measurement and
data to prepared databases on the MS-SQL
Control, ANSI/ISA-S88.01, Batch Control, Part 1:
server. These data are available for other Models and Terminology, ISA standard, 1995.
processing. The benefits of such availability ͓3͔ Bastiaan, H.K., Process model and recipe structure,
of data are not directly quantifiable, but the the conceptual design for a flexible batch plant. ISA
effect on the optimization effort can be sig- Trans. 36, 249–255 ͑1998͒.
nificant. ͓4͔ Crowl, T.E., S88.01 Concepts Streamline Control
Software Application for Biotech Plant, ISA technical
8. Conclusions paper, 1998.
͓5͔ ´ ˇ
Holy, R. and Pozivil, J., How to Apply S88 Models to
This paper shows how the models of the ISA a Complex Manufacturing Process, Proceedings of the
12th International Conference on Process Control PC
S88 standard can be implemented in new batch ´
99, Tatranske Matliare, Slovakia, 1999.
control systems, with special attention to the phar- ͓6͔ Fleming, D.W. and Pillai, V., S88 Implementation
maceutical industry. The approach defined by us Guide. McGraw-Hill, New York, 1998.
was described in the paper, and the new suggested ͓7͔ Salazar, J., Batch standards enable computer valida-
decomposition methodology was also presented. tion. Pharm. Dev. Technol. 20, 46 –52 ͑1996͒.
Our case study and all other published papers ͓8͔ Webb, M., Computer system implementation, batch
prove that the S88 standard has large potential to standards and validation. ISA Trans. 34, 379–385
͑1995͒.
significantly improve the performance of the batch ͓9͔ Nelson, P.R. and Shull, R.S., Organizing for an initial
pharmaceutical industry. Software vendors who implementation of S88. ISA Trans. 36, 189–195
supply better packages for batch control systems ͑1997͒.
compliant with the ISA standard, larger function- ͓10͔ Wonderware, InBatch User’s Guide, Wonderware, Ir-
ality, and higher reliability support this potential. vine, 1999.
͓11͔ Love, J. and Bunch, M., Decomposition of require-
ment specifications for batch process control. Trans.
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Inst. Chem. Eng., Part A 76, 973–979 ͑1998͒.
͓1͔ FDA, 21 CFR 11, Electronic Records, Electronic Sig- ͓12͔ Bunch, M., A Specification Methodology for Applica-
natures, Final Rule, March 1997. EN ISO 9000-3, tion Software for Batch Process Control Consistent
Quality management and quality standards—Part 3: with S88, PhD thesis, University of Leeds, 1998.