ISA TRANSACTIONS

ISA Transactions 41 2002 245254

Batch control system project for a pharmaceutical plant

, Jaroslav Poz ivil* Roman Holy
Department of Computing and Control Engineering, Faculty of Chemical Engineering, Prague Institute of Chemical Technology, 1905, CZ-166 28 Praha 6, Czech Republic Technicka

Received 23 August 2000; accepted 25 March 2001

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 denitions/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 ISAThe Instrumentation, Systems, and Automation Society.
Keywords: Batch plant; Process model; Procedural control; S88 standard; FDA validation

1. Introduction Batch processes are the ones most often used in the manufacture of pharmaceuticals, specialty chemicals, pure substances, and other high-valueadded products. Such processes are characterized by frequent changes of technology and continuous introduction of new or modied products. This places high demands on process control and production planning. The current state in most batch manufacturing plants in the Czech Republic is based on oldfashioned methods. This means many of them still use paper standard operation procedures or paper operation sheets for production control and data logs, and mostly they control their batch processes manually. In the better case, they have a supervisory control and data acquisition system for process visualization and basic control implemented
*Corresponding author. Tel.: 420-2-2435-4259; fax: 420-2-2435-5053. E-mail address: jaroslav.pozivil@vscht.cz

within a programmable logical controller PLC; more modern setups are even rarer. This situation usually causes greater variations in both the production quality and quantity, problems with process precision and repeatability in the rst case, or problems with the process exibilitythere exists the necessity to modify parameters or even all the programs in the PLCs when some product or process changes are needed in the second case. In order to improve this situation companies should implement new control systems with better functionality. The best guideline for how these new batch control systems should be organized seems to be provided in the ISA S88 standard models. Moreover, in the pharmaceutical industry, when companies wish to export their products to the USA, then their batch control systems should be compliant with Food and Drug Administration FDA requirements 1. Such a batch control system design and implementation project is then a very complex activity that needs an appropriate scientic and methodological approach.

0019-0578/2002/$ - see front matter 2002 ISAThe Instrumentation, Systems, and Automation Society.

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2. The aim of the paper The S88 standard, Part 1 2, denes models and terminology for physical plants, procedures, and recipes. As the standard has already been introduced in most of the cited references, we do not think it is necessary to reprint it here. For more detailed references, we recommend reviewing the standard itself or the following articles: Refs. 3, 4, or our paper 5. S88 establishes a framework for specication of requirements for the batch process control, and for their subsequent translation into application software. The framework consists of a variety of denitions, models, and structures. It is not, however, a guide for how to apply the denitions/structures, etc. Therefore, the main goal of our work was to create a methodology for decomposition of functional requirements in terms of S88 models and structures, as this is something the ISA standard lacks. This methodology was tested on a real problem described in the case study below. 3. Problem analysis Existence of a good project methodology is a necessity for any large project, and the methodology should provide a tool for allocating the resources and information in an organized and efcient way. In our project we have followed with some adjustments depending on our specic needs the methodology described in the S88 Implementation Guide by Fleming and Pillai 6. The project methodology has six phases and several key attributessome of which are described below. The automation engineering effort is heavily front-end loaded. The entire methodology is designed to make changes easier to implement. At any given time, the current version of documents should be able to describe the state of the process control. Any change is evaluated against the impact on all the previous phases of the project and is fully documented before it is implemented. Finally, testing and validation of the installed system forms a part of the overall control system design. As the process is being designed, the critical parameters are dened along with the protocol for testing and the acceptance criteria for each parameter. The use of the S88 standard enables and helps to pass FDA validation. This is done mainly by

means of S88s well-structured modularization and its split of process equipment from procedural control. The advantages and suitability of the use of S88 principles for FDA validation is well documented in literature, for example, in Refs. 79 where validation system life cycles can also be found. The validation effort is needed to prove that the nal equipment performance and capabilities meet the requirements. Systematic quality control during the creation process can establish a traceable control mechanism conrming whether the design meets the requirements, and the installation corresponds to the design. If the design process is under control and well documented, conrming quality control may require substantially lower validation effort.

4. Case study We have been involved in a pilot project at ICN Czech Republic, Inc., a manufacturer of pharmaceuticals. The main goal of our pilot project at ICN was to design a prototype of a new batch control system for Nystatin separation a batch process producing the pharmaceutical substance Nystatin from the intermediate product manufactured by a fermentation process that would be in accordance with current standards, would use modern technology, and would demonstrate feasibility and benets of such a system. For implementation of the control system we have used the software InBatch Wonderware 10. InBatch is a exible batch management software designed to be consistent with the ISA standard S88. It is integrated within the framework of the Wonderware FactorySuite 2000 package; for visualization the package offers InTouch humanmachine interface software, and we have used this tool too. The aim of the case study was to apply the ISA S88-based methodology to an existing industrial plant manufacturing Nystatin. 4.1. Plant description The new control system is intended for only a part of the whole Nystatin production, its separa-

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Fig. 1. Schematics of the case study plant.

tion. To protect what ICN viewed as sensitive data, some of the following, such as compositions of some solutions, is replaced by anonymous designations or is omitted. The technology can be divided into ve sections listed below simple schematics are shown in Fig. 1. 4.1.1. Extraction of dry mycel Solvent A is charged into extraction vessel A121 cooled using brine, then oxalic acid is added while stirring. A barrel of a mixture of dry mycel,

kieselguhr, and activated carbon is prepared, and its content is then poured into A121. After this, formic acid is added. The content of A121 is transferred into ltrating centrifuge O123.

4.1.2. Filtration of extraction Filtration in O123 is performed through a layer of fabric coated with kieselguhr, and the lter cake is washed using solvent A. Filtrate is collected in an H126 tank; ltration cake is considered waste,

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Fig. 2. Systems hierarchy.

although samples are taken for analysis from every batch. Filtrate from H126 is next ltered in plate lter F122A and membrane lter F122B and then transferred into A122 for p H adjusting. 4.1.3. Treatment of extraction A sample is taken from A122, and then the extract is treated by solvent B ltered through the bacterial lter to reach the required p H. 4.1.4. Crystallization Crystallization is performed in either A123A or A123B. An amount of RO water specied 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 temperature, and during this time solvent C and Syntron B are also added. The content of the vessel is heated to another recipe-dened temperature, and, after it is reached and samples are taken, it is then cooled. 4.1.5. Separation and washing of the product Mother liquor is centrifuged from the product in O122, and suspension and washing of the product takes place in A131. The washing liquid is removed from the product in centrifugal separator O131.

4.2. Aims of the project Automation of the process; reduction of paperwork and computerized data logging; and easier validation of the control system by FDA regulations. The proposed integration of information and control systems from the crystallization reactor to the managers personal computer is shown in Fig. 2. The level we have been operating on was that of procedural and operator control.

5. Control system specication and decomposition Batch control projects usually involve other layers existing above S88 models and terminology. Although terms such as recipes, units, operations, phases, and equipment modules have been dened, S88 is unsatisfactory in providing design guides and examples. Fortunately, a lot of effort was directed towards this since the publication of the S88 standard. For the more complex decomposition methodologies and examples we would like

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Fig. 3. Framework of S88 models in the presented methodology.

to recommend Refs. 6 or 11, the latter based on the PhD/thesis of Bunch 12. Both of these methodologies have strong and weak aspects in their structure and description. Inspired by these efforts, and in order to avoid some of their weak points, we have dened our own decomposition approach. This approach better suits our needs and is in good agreement with both the S88 standard itself and the batch management software usedInBatch. The structure of application of S88 models in the framework of the proposed decomposition meth-

odology is shown in Fig. 3. There are two main differences expanding the S88 mapping: 1. Connections dened in the framework of transfer classes have been added to the physical model in order to simplify the denition of procedures. 2. Process phases have been dened and used as a common element both to the physical model and to the procedural control model, and they link these two models together.

Fig. 4. Algorithm of the proposed methodology.

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The algorithm of the proposed methodology is shown in Fig. 4. More detailed descriptions of all steps in the algorithm, together with examples from the process in which it was used, follows. 5.1. Physical model 1. The rst step denes the boundaries between cells of interest and the rest of the site/area. In our case, the solved problem was the part of the process between process stages of weighing fermentation cell and dryingthe Nystatin separation. In this process, only one product is being manufacturedNystatin. 2. The second step establishes the denitions of trains and process stages. Two trains can be dened for our process cell as the cell contains two parallel crystallization reactors. In our model only one train has been dened, because there was no special need to distinguish between the two reactors and the denition, and use of two trains would decrease the exibility of the designed control system. Five process stages, mentioned in the plant description, have been also denedextraction, ltration, extract treatment, crystallization, and separation, as well as the washing process stage. 3. The third step includes identifying process units. Here is another expansion of the S88 standard, because the unit denition involves not only processing of one batch or partial batch of material but also a storage of materials, e.g., hold tanks or bulk storage vessels. This approach was partially enforced by selected software. Fifteen units were denedeight process units and seven unitstanks. In this step, connections describing transfer of materials between units must be also dened. The case study contains a total of 23 connections. 4. The fourth step is designed to classify all the units and connections into process classes and transfer classes. This object-oriented approach shows its advantages mainly during decomposition of large models with many same or similar units and/or connections, once a class is dened it is not necessary to dene each object separately. A total of eight process classes and 15 transfer classes were dened. 5. The fth step involves identifying specic process phases in the framework of process classes and transfer phases in the framework of transfer classes. The methodology distinguishes

different types of phasesautomatic, semiautomatic, and manualwith three different levels of connections to low level control systems. All necessary phases for each process and transfer class have been identied resulting in a total of 59 process phases and 15 transfer phases. 6. The sixth step should produce phase logic controlling and connected equipment modules. In the best case, this should be done in parallel with phase development in the above step. This step, as well as the seventh step below, was not applied in our prototype. 7. The seventh step denes control modules and their elements. 5.2. Procedural control model 8. The eighth step of the algorithm is a logical continuation of the seven previous steps and starts the denition and decomposition of the procedural control model, using outputs of previous steps, especially phases. In this step, the number of procedures is determined. In our case, two procedures were dened the procedure for Nystatin production and another one for the cleaning in place process, sterilization. In the following text we deal only with the rst procedure. 9. The ninth step establishes unit procedures, which are usually related to the process stages and process classes dened above, although we cannot exclude exceptions. Seven unit procedures were dened in the framework of our prototype. 10. The tenth step of this methodology is the most subjective. The S88 standards denition of operation is very general and it enables different explanations and implementations. The software we selected supports this kind of exibility. This enables us to dene boundaries between operations in the framework of one unit procedure at any chosen point. The objective was to divide unit procedures into logical piecesoperations whenever it seemed suitable, with the aim of making procedures more clear and structured. As an example, the unit procedure, extraction, is in our implementation divided into three operations: setup, the extraction itself, and transfer. In this way, 12 operations were dened. 11. The eleventh step uses the above-dened phases to implement demanded process actions. Displaying the phases by means of sequential function charts SFCs made this easier and more

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exible it enables use of both serial and parallel sequencing, and logical transitions. 12. The twelfth step establishes necessary steps to implement dened phases. This and the next step were not applied in our prototype. 13. The thirteenth step establishes necessary actions to implement the steps dened above. 14. The fourteenth and nal step is a debugging step that allows returning to previous denitions and modifying them or adding new ones. In the end, the result should be a perfect physical model and procedural control modelstructured according to the S88 structured models/ recommendations and functional/system requirements. 6. Batch software implementation 6.1. Process modelequipment The plants or only one process cells equipment and its processing capabilities, as well as its control and information requirements, are dened in the framework of the process model. The model establishes the rules by which the plants equipment and control systems are congured to produce batches. In this part, confusion can arise between the views of S88 and those of InBatch. InBatch ties both S88 models physical model and process model together in one editor Process Modeling Editor, as this is the simplest way of describing the characteristics of the equipment in the physical plant. It becomes logical when one realizes that every unit sometimes also a connectione.g., a lter has some processing capabilities. The process model itself is an abstract construct, as it becomes a reality at the time the procedure as a part of the control recipethe procedural control model is applied to the equipment physical model, and it starts the batch processing or just a simulation. The process model uses an object-oriented approach with advantages: All the characteristics of the units are dened in the framework of process classes e.g., A 121 or O 131, together with their process phases for A 121 the following phases have been denedthe start and the end of cooling ChlaZapn and ChlaVypn, the start and the end of stirring MichZapn

and MichVypn, manual charge of the material RucnPrid and some others, and their phase formula parameters e.g., temperature for the cooling phase with the default value 8.5 C and high and low limits 12 C and 5 C, respectively, and their tags A 121-ChlaZapn-Teplota-ACT for a current value of the temperature. Units that have the same processing capabilities are assigned to the same process class. Each unit has processing capabilities that are dened by phases of the process class. There is only one unit A121 for the process class A 121. Transfer classes and their phases are dened in a similar waywithin them, connections e.g., pipes, hoses, lters are dened. For readers who would like to go into more implementation-specic details we would recommend Wonderware materials as the primary source 10. 6.2. Recipeprocedural control model Procedural control is typical for batch processes. In order to carry out a process-oriented task it directs equipment-oriented actions so that they occur in an ordered sequence. In InBatch, there are no independent procedures the highest element of the procedural control model, because they are created in the framework of recipes. This is logical because the recipe is in the end the place where the procedures are used. The procedure consists of user-dened operations required to produce one batch of a nal product or an intermediate product. The recipes equipment requirements necessitate linking to available processing capabilities i.e., phases. Each operation and its phases are associated with a process class. In addition to the procedure, the recipe editor allows us to dene the header, equipment requirements, and the formula. Main characteristics of recipes can be described as follows: Procedures for both operations e.g., chargeextractionPlneniExtrakce and phases e.g., process phases: the start of coolingChlaZapn, the start of stirring MichZapn, and manual charge of material RucnPrid; transfer phase: acknowledged chargePotvPrid are edited in a SFC format to allow for parallel and/or sequential

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operations and phases. Phase properties can be also edited e.g., temperature of the phase ChlaZapn. The master recipe is equipment and path independent, and it allows scaling of batch sizes. The master recipe is transformed into a control recipe dynamically during run time. The master recipe is edited in the recipe editor. The control recipe starts as a copy of a specic version of the master recipe and is then modied as necessary with scheduling and operational information specic to a single batch. It contains product-specic process information necessary to manufacture a particular batch of the product. It may be modied to account for momentary raw material qualities and actual equipment to be utilized. The control recipe is used during batch production or simulation in the framework of the batch display editor. This allows very exible recipe modeling and batch management including on-line parameter changes. We can dene a different sequence of operations and phases and their parameters without changing the process model or even recoding the PLC. It is usually called a recipe-driven process. 6.3. Security clearances and safety In our prototype of the control system, we have concentrated mainly on two security and safety issues. 1 The three levels of access authorization include the following a Acknowledging prior to the end of the phase by using the acknowledge button, without an operators security identication. b Verication of the data entry and/or the start or the end of the phase by enabling the done by check box during the conguration of the phase. During recipe execution, this option requires the operator, or another person with a necessary security level, to press the acknowledge button and then enter his/her security identication and password before the phase can end. c Verication and conrmation of critical data entry and/or the start or the end of

selected phases by enabling the check by check box during the conguration of the phase. During recipe execution, this option requires the operator and the supervisor, or another person with a comparable security level, to enter his/her security identication and password before the phase can end. Enabling check by automatically enables the acknowledge and the done by check boxes. 2 Entry of numeric data, where the batch control system checks the validity of values, and if they are not in the predened range determined by high and low deviations and/or high and low limits it does not allow completion of the phase in a standard way. In such a case it is necessary to correct the appropriate value or to abort the phase. All events and corrections are logged and easily reported.

6.4. Flexible batch simulation and production This describes the way in which process functionality and procedural functionality are linked together into a exible batch production or simulation. General process classes master recipe are transformed into actual process units control recipe: General procedure ( master recipe) actual process in the equipment according to the control recipe. Process class extraction reactors A 121 unit A121. Transfer class H1XXA121 connection H134A121. Phase: the start of cooling ChlaZapn of process class extraction reactors A 121 and default parameters cooling in the reactor A121 to the required temperature ( 8.5 C) . Phase: acknowledged charge PotvPrid add 650 l of methanol default value into a reactor transfer class H1XXA121 adding 650 l of methanol actual value with the lot code 1548/8989 into the reactor A121. Security clearance request for the phase, acknowledged chargePotvPrid for the operator is also shown.

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Table 1 Comparison of our results with those of Love and Bunch 11. Methodology of Bunch, 1998 Lacks precise instructions for decomposition at physical model and procedural control model level Contains unnecessary and questionable rules Our methodology

Denes algorithms for decomposition at physical model and procedural control model level

Denes and uses the term phase as shared by two models Is not tied to SW Suitable for SW implementation implementation in InBatch Allows only sequential Allows use of SFCs and operations and phases parallel phases and operations Does not dene connections Uses the term connection between units dened within transfer class Denes and differentiates manual phases

This system of linking of the control recipe procedure to the equipment control remains formally the same both for simulation and for actual control manufacturing. After the process model and the recipes are simulated, and successfully tested and validated, the process model namely, its phases and their control/status tags can be connected to programmable logic controllers or to any other control system used to perform phase logic and/or interface functions with the manufacturing equipment, and the production can start. 7. Discussion The results of this work are compared to results published in Love and Bunch 11. The main advantages of our new methodology over the old one are described in Table 1. Aside from well measurable benets of introducing the new control system, such as lower manpower requirements, the system can cause other not precisely predictable effects. Among those non-tangible benets are Operator efciencya good measure of the workload on operators is to count the number of operator actions, which include, e.g., opening and closing valves, starting and

stopping pumps, and changing the setpoints of controllers. The number of such actions should decrease by 70% after the batch control system is implemented. Product quality improvementa reduction of operator-induced variability should occur. This improvement is also supported by easy and automated data acquisition, by better processing of the data, and by faster control interventions. Cycle time reduction and yield improvementsbased on our experience with implementation of these and similar control systems in real plants, there should appear at least some cycle time reduction. In a manually controlled process, there are many occasions where an operator does not execute a phase at the earliest possible time because of outside reasons e.g., he wants to drink his coffee rst. Through one batch, all of these delays can add up to a signicant amount of wasted time. Automation also usually results in yield improvements. Automatic recording of all events, actions, and time makes operators more precise and prompt. Flexibilitywhen the procedural control is separated from the equipment control, the process becomes much more exible. Most changes in the recipe procedure do not require either changes in physical model or code changes in PLCs. Reliabilityensuring that all necessary input and output parameters are within predened ranges is one of the most important benets. It is not possible to complete a phase, an operation, or a whole batch with wrong parameter values anymore, or to forget about the signature on the operation sheet. This is very important for FDA audits. Validationmany batch control systems based on InBatch have already been validated by the FDA, and this documents the suitability of this software. By designing the phase logic so that the phases are independent of one another, validation of the software whether built on InBatch or on other software is greatly simplied. Documentation and testing of each phases functionality need to be done only once. The recipe procedure is created and documented separately from the phase denitions and tested only to ensure that these phases are called upon in a proper sequence and with correct parameters. Consequently, changes to the recipe/

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procedure do not necessitate testing or documentation changes at the phase level. Data availabilitythis is enabled by automatic saving of both process and procedural data to prepared databases on the MS-SQL server. These data are available for other processing. The benets of such availability of data are not directly quantiable, but the effect on the optimization effort can be signicant. 8. Conclusions This paper shows how the models of the ISA S88 standard can be implemented in new batch control systems, with special attention to the pharmaceutical industry. The approach dened by us was described in the paper, and the new suggested decomposition methodology was also presented. Our case study and all other published papers prove that the S88 standard has large potential to signicantly improve the performance of the batch pharmaceutical industry. Software vendors who supply better packages for batch control systems compliant with the ISA standard, larger functionality, and higher reliability support this potential. References
1 FDA, 21 CFR 11, Electronic Records, Electronic Signatures, Final Rule, March 1997. EN ISO 9000-3, Quality management and quality standardsPart 3:

2 3 4 5

6 7 8 9 10 11 12

Guidelines for the application of ISO 9001:1994 to the development, supply, installation and maintenance of NI, Praha, computer software ISO 9000-3:1997, C 1998. ISAThe International Society for Measurement and Control, ANSI/ISA-S88.01, Batch Control, Part 1: Models and Terminology, ISA standard, 1995. Bastiaan, H.K., Process model and recipe structure, the conceptual design for a exible batch plant. ISA Trans. 36, 249255 1998. Crowl, T.E., S88.01 Concepts Streamline Control Software Application for Biotech Plant, ISA technical paper, 1998. , R. and Poz ivil, J., How to Apply S88 Models to Holy a Complex Manufacturing Process, Proceedings of the 12th International Conference on Process Control PC Matliare, Slovakia, 1999. 99, Tatranske Fleming, D.W. and Pillai, V., S88 Implementation Guide. McGraw-Hill, New York, 1998. Salazar, J., Batch standards enable computer validation. Pharm. Dev. Technol. 20, 46 52 1996. Webb, M., Computer system implementation, batch standards and validation. ISA Trans. 34, 379385 1995. Nelson, P.R. and Shull, R.S., Organizing for an initial implementation of S88. ISA Trans. 36, 189195 1997. Wonderware, InBatch Users Guide, Wonderware, Irvine, 1999. Love, J. and Bunch, M., Decomposition of requirement specications for batch process control. Trans. Inst. Chem. Eng., Part A 76, 973979 1998. Bunch, M., A Specication Methodology for Application Software for Batch Process Control Consistent with S88, PhD thesis, University of Leeds, 1998.