Implementation of a Batch Tool in the

Pharmaceutical Industry
By Ronaldo Luis da Silva, Maintenance Engineer, Aché Laboratory; Moacyr Souza Júnior, Account Manager, Aquarius
Software; and Sidnei Kolano, Technical Manager, Link Automação

The original article in Portuguese appeared in InTech.

From the beginning of manufacturing operations to the pharmaceutical industry will be shown, as well as compliance Batch processes, in a comprehensive definition, are processes
present day, it is possible to notice a huge change. Regardless with the regulations required by competent bodies with the that combine continuous and discrete characteristics. We
of the segment, the market has demanded more than the implementation of the tool. find this type of process in the most diverse industrial sectors,
industries have produced, and the trend is that the demand such as pharmaceutical formulations, food recipes, chemical
for production will increase in line with the increase in the Types of Process plants or some paper and cellulose processes. This hybrid
population and its income. To be able to supply the market feature, combined with the need for flexibility through
and be competitive in their fields of activity, companies rely As previously mentioned, each process has characteristics parameterization, requires special attention when choosing
on the evolution of technology and the implementation of that differentiate them from each other. According to the the architecture of the automation and process data analysis
methodologies to be able to increase production. manufacturing method, the processes can be of three types: system.
discrete, continuous or batch.
It is important to consider that the manufacturing processes Batch processes lead to the production of finite amounts of
of one industry are not always valid for another. Because Discrete processes are those that, during the manufacturing material, subjecting input materials to a sequence of
each type of process, be it discrete, continuous or batch, has process, add independent parts and pieces, resulting in a final processing activities over a finite period and using one or
characteristics intrinsic to its manufacturing method, the product that can be a compressor, a car and even an airplane. more pieces of equipment. These processes have data with
methodologies developed for one product will not always be Regardless of the complexity and quantity of products continuous characteristics but separated by discrete intervals
functional for another. manufactured, it is easily classified and listed. that aggregate information by item. A typical example is a
reactor in a pharmaceutical industry, where we have all
In addition to the concern to serve the market, all industries Continuous processes are those in which we notice the process measurements (temperatures, pressures, etc.) stored
are studying ways to increase their profit. The first idea to be occurrence of transformation of raw material into product in in time series, related to quality data, such as batch approval,
raised is the increase of production lines or the installation of a continuous way and through physical-chemical reactions. separated by item.
more equipment. But there is not always the necessary Generally, the “ingredients” are inserted with their proper
physical space and investments planned to increase the size concentrations and proportions into an equipment that Because it combines the characteristics of continuous and
of the process. So, the question arises: how to increase receives them in operation. An example of this process would discrete processes, batch processes require specific tools to
production without changing the installed base? be the fractionation tower of a refinery, which always manage, store and analyze the data of the production
receives oil that results in various products such as kerosene, process.
In the case of the pharmaceutical segment, concerns go asphalt, etc. To add the raw material oil, it is not necessary to
beyond increasing production to serve the market. Because interrupt the operation of the tower, thus giving continuity of Standardization of a Batch System
the product contains elements that alter the health status of the production process and generating a large-scale product Configuration
consumers, the laboratories responsible for manufacturing volume. To assist in the standardization and communication of batch
the products must comply with manufacturing specifications systems when applied to highly complex processes, in the late
and methodologies established by the regulatory agencies This type of process has data with strongly temporal
1980s ISA published the first part of a standard called ISA-S88
and, if they do not meet these requirements, the product is characteristics, that is, to identify data in systems developed
[Ref. 1] (which was consolidated in the mid-90s), in order to
prevented from being marketed and is taken from pharmacy for these processes, it is enough to indicate the
standardize the terminology and modeling of these processes
shelves. measurement point (tag) and the moment of consultation
in software tools. These models helped in the development of
(time). For this data, trend analysis and correlation between
analytical and administrative tools that easily adapt to these
In this article, the characteristics of use and the benefits tags generate good results.
diverse industrial segments.
acquired with a batch process management solution in the
Segregated in parts that refer to equipment, procedures, For a better understanding, the figure below shows an defines the standard for controller programming. Within
process stages, data structure, recipe creation, etc., the example of the suitability of a process to the Procedural them, five programming languages are defined and one of
first part of the standard (S88.01), defines some types of model. these five is SFC.
models. Among them, we can highlight the physical model
or physical model, and the procedural model or procedural Basically, composed of three elements, the SFC allows to
model. create a graphic sequence of execution of procedures from a
typical procedural programming or a more elaborate
The idea of the physical model is to define the equipment procedural programming, with the possibility of executing
that participates in the production process. There are seven steps in parallel.
levels that are used to implement the hierarchy of each
control equipment within the company.

The scope of action of the ISA-S88 standard within the

physical model encompasses only the four most elementary The figure shows, in the first column on the left, the procedure
levels, which are: Process Cell, Unit, Equipment Module and (procedure) of how to make apple juice with vitamin C. The
Control Module (Process Cell, Unit, Equipment Module and procedure was segregated into two procedures that are
Control Module). These levels are detailed below. performed inside the units (unit procedure): “mixing the apple
juice” and “addition of vitamin C.” Within the unit procedure
• Process Cell: is the representation of a group of Units called "mixing apple juice" this general step was divided into
that participate in the production of a given product. three operations (operations): feeding, cooling and
• Unit: is the representation of a process unit, such as: transferring the solution. In the “feeding” stage, we arrive at
tank, reactor, etc. the elementary functions of the process (phases): “sugar and
apple juice solution” and “agitation.”
• Module Equipment Module: represents the control loop. The three elements that make up the SFC are: step, link and
Example: flow control, level, etc. This example clearly shows the purpose of programming transition. Based on the figure above, the steps are the gray
within S88: to divide a product's recipe into stages of rectangles. It describes the sequences and operations of the
• Control Module: is the level at which the final control process. Links (connections) are the vertical lines that
production until its most basic operation. This way, if there is
element of the mesh is suitable. Example: valves and connect the steps. There is no programming on the links,
a need to make the recipe for apple juice without vitamin C,
actuators. these are used only to indicate the sequence that the recipe
we would not need to program again. It would only be
The procedural model, on the other hand, tries to group the necessary to create a recipe disregarding the “adding vitamin should have. Finally, transitions are used to place a condition
tasks that are performed in the different stages of the C” procedure. in the transition from one step to another, that is, step 2 will
process. This model aims to transform a recipe down to the be performed only when the condition present in the
most basic levels of instruction to the controller. Unlike the The transformation of theory into the practice of the S88 transition is true.
physical model, four levels are used to define the grouping of concept is accomplished through a programming language
called SFC (Sequential Function Chart). The IEC (International The S88 standard is more used for batch processes because
tasks, and all are part of the scope of the standard. The levels
Electrotechnical Commission) created the IEC 61131-3 this process is more complex in the manufacture of the
are: Procedure, Unit Procedure, Operation and Phase
standard many years ago. This is the standard that defines product. In addition to combining characteristics of
(Procedure, Unit Procedure, Operation and Phase).
continuous and discrete processes, within the The way to reach the formula for a drug that does not exist on proving, through tests, that the implemented configurations
process cell (Process Cell) the product can pass the market or that is more effective, is not always simple, nor satisfy the required needs. Despite the simple definition,
through several devices arranged in sequence, which fast. Most of the research takes years, and there is not always validation is a process that is treated with great caution and
can have a fixed (single path), variable (multi path) or a guarantee that at the end the result will be a drug that can can take a long time, depending on the size and complexity of
network arrangement (network), as shown in the be commercialized. For laboratories, this entire research cycle the system. All necessary care must be taken with a system
figure below. is treated as an investment sponsored by a percentage of the that has already been validated, since any change in the
revenue from products already consolidated on the market. configuration that may affect or alter its operation may result
The increase in the production of existing drugs and the in the need to revalidate it.
optimization of the resources used in their manufacture can
generate a profit that can be directed to specific research and, To ensure the traceability and safety of changes made in the
consequently, accelerate the process of obtaining the results. process, there is a rule published by the FDA (Food and Drug
Administration) called 21 CFR Part 11 [Ref. 3]. This standard
To monitor the laboratories and establish manufacturing refers to electronic signatures and establishes that all
standards that ensure the health of consumers, there are electronic records must be inviolable, and their integrity must
regulatory bodies in each country or continent, responsible for be maintained in such a way that it is possible to identify who
organizing audits in production environments. In Brazil, performed an operation, at what time and what was the
ANVISA (National Health Surveillance Agency) is responsible alteration practiced.
for evaluating and monitoring the manufacturing processes of
the laboratories. However, if a Brazilian laboratory wants to Gathering all this important information and standards that
export its medicine, it must comply with regulations must be applied in the Brazilian market, ANVISA together
Regardless of the type of equipment arrangement at the with members of ISPE Brasil, created the document called the
established by agencies in other countries.
plant, they all allow batches to be produced in parallel, Computerized Systems Validation Guide [Ref. 4].
whether of the same or different products. To make the In order to facilitate the testing of the necessary
most of parallel runs, it is possible to connect the corporate functionalities of a manufacturing system, as well as its Implementation of a Batch System in the
system with the system that manages the dynamic adherence to industry regulations, a group of pharmacists Laboratory Aché
allocation of equipment in the process. Thus, it is possible from ISPE (International Society for Pharmaceutical
to scale the production capacity closer to reality and make Engineering) created a methodology with good practices Aché Laboratórios Farmacêuticos S.A. is a 100% national
production planning more efficient. called GAMP (Good Automated Manufacturing Practice) [Ref. capital company. Along its trajectory of more than four
2]. The GAMP provides guides on how to comply with good decades, Aché has consolidated itself as a dynamic company
Pharmaceutical Industry cleaning practices, good electronic data storage practices, by establishing strategic commercial partnerships, inside and
good control systems validation practices, among other outside the country, for its expertise in similar medicines,
In general, the pharmaceutical industry has a research and guides. management of a mature portfolio, knowledge of the Brazilian
development sector focused on innovation and the consumer market, and for the continuous development of
creation of new drugs that prevent the spread of epidemics There is a term widely used in the pharmaceutical segment products and services, in order to meet the needs of health
and / or help to improve the quality of life of the population. referred to as validation. Validation is nothing more than professionals and consumers, providing health and well-being
to the population.
With around 3.5 thousand employees, it has three industrial With an implementation date scheduled, the automation the documentation, testing and correction system a process
plants. The largest of them, located in the municipality of system of the liquid unit had the challenge of creating a capable of being accurately measured and with perfect
Guarulhos, in Greater São Paulo, also houses its standardized platform, based on international software adherence to regulations.
administrative headquarters. The second is installed on development standards and in compliance with the main
As the validation and qualification process in the
Avenida Nações Unidas, south of the city of São Paulo, and regulatory agencies of the pharmaceutical sector in the
pharmaceutical industry is rigorous and delicate, all settings
the third in Goiás, with the acquisition of 50% of the world.
must be documented with excellence in all stages. At this
pharmaceutical company Melcon, specialized in the
To overcome the challenge, it was necessary to obtain a stage of the project, if the software platform is not fully
production of female hormones.
software platform that was built under the norms of the compatible with the norms and good practices of the sector,
In its strategic direction, to operate as a complete solution pharmaceutical sector, facilitating the adaptation of the construction errors or problems of adaptation of the new
company, Aché operates in the three key segments of the production process and the personnel involved in the system to the production environment will be found,
pharmaceutical sector: Prescription, Generics and Non- production of medicines to the new system. condemning the computerized system to failure.
Prescription Drugs (MIP). It maintains a broad portfolio, with
In addition, the characteristic of being built under industry With the second step successfully completed, it was
more than 250 brands marketed in approximately 600
standards would facilitate the process of validation and necessary to create the recipe models (Procedures) that
presentations.
qualification of the new computerized system. would be used in the new computerized system and plan the
installation of the system.
Scenario Prior to the Implementation of the
Solution Adopted
System The creation of the solution based on the S88 standard
With the choice of the Proficy product line from GE Digital, allowed the system to use all the physical resources installed
Within the liquid unit of the Guarulhos plant, there were in the production unit, transferring these resources to the
through its distributor Aquarius Software and
numerous products to be manufactured and a great drug production recipes.
implementation by Link Automação, all the resources
variability in production times. All steps specified in the
available in the S88.0 construction standards, have earned
prescription of a drug were performed manually. With great At the same time as the recipes were created, another work
their reputation and, with the property of building libraries,
difficulty in stipulating a production delivery time for a given team performed the tests of the recipes already implemented,
the classes, phases and operations of the system, it was
batch, previous batches were analyzed, and a difference in validating the entire system in an almost parallel work format.
possible to implement a complex project, in a very short
execution times was found between the handlers responsible The programming and connectivity resources with databases
period of time and with great quality, eliminating the risk of
for producing batches of the same product. and objects provided by the software platform were
building errors.
fundamental for the success of the recipes to be achieved. In
In order to standardize the operating times until reaching the addition, the native Client / Server features and the ability to
The first step in implementing the system had already been
final product, a study was developed to verify the need to fully adapt to the operating system and the distributed
taken successfully, but the software platform needed to be
implement a tool capable of automatically managing the architecture, with different levels of security, allowed the
documented according to the requirements of good
batch production process. implementation to be carried out with several work teams at
manufacturing and documentation practices GAMP and FDA
21CFR part 11. different levels of the system. With electronic work messaging
After this analysis, it was found that with the reduction of
resources, the construction of product recipes reached the
manual interventions in the process, it would be possible to
As the platform was built under the guidelines of the highest quality standard and, at the same time, the operator's
achieve a forecast closer to reality regarding the delivery time
pharmaceutical market, the software adapted perfectly to proximity to the system, facilitating the development and
of a batch.
the resources requested by GAMP and 21CFR Part 11, making acceptance of the solution by the operation team.
In this stage of the project, the construction, documentation, Benefits with the Implementation of the Bibliographic References
testing and implementation steps had been successfully Management Tool
completed and the system needed to guarantee the return [1] ISA S88 – http://www.wbf.org/.
on investment and provide resources to optimize the With the implementation of this system, which is easy to
[2] GAMP (Good Automated Manufacturing Practice) –
process, through the analysis of the implemented revenue operate, where it is possible to monitor in real time all the
www.ispe.org.br/.
structure. resources that are being used and the products that are
being manufactured, there was a significant increase in [3] FDA (Food and Drug Administration) chamada 21 CFR Part
In order to resolve this issue, total compatibility with the S88
production capacity. 11 – http://www.fda.gov/RegulatoryInformation/Guidances/
standard was essential, because through a detailed study of
ucm125067.htm.
the recipe structure, it was possible to decrease the number The use of electronic signature in all interventions carried
of steps, reducing the software cycles and automatically out in the process with configuration of hierarchical levels [4] Guia de Validação de Sistemas Computadorizados – http://
shortening the production time for each product. ensures the registration of events and system actions, portal.anvisa.gov.br/wps/wcm/connect/d0dd6980474585
avoiding interventions by unauthorized people and ensuring 8b8f28df3fbc4c6735/Guia+VSC+ANVISA+FINAL+09_04_2010.
The recipes were created using the SFC (Sequential Function
that operations are being carried out consciously, with the pdf?MOD=AJPERES.
Chart) language, which facilitates the organization because it
user's confirmation and password. A typical example is the
graphically describes the sequential execution behavior,
release of recipes for production that are carried out only by
facilitating the visualization of the actions that will be
the Quality Assurance area.
performed and the transition conditions that will be
necessary for the next step to be initiated. With the reduction of human interventions, it is possible to
define the start and end times of production much more
The availability of the system was guaranteed with a solid
effectively, considering the product and the lot size,
hardware and software redundancy structure, which offers
guaranteeing precious information for an efficient and
the necessary security for the production process. With
dynamic management of the production process. In
redundant database servers and supervisory systems,
addition, the possibility of human error has decreased,
several process data recording locations, the system
ensuring standardization and execution of all steps in the
continues to operate even if many hardware items fail at the
same sequence and time interval.
same time.
Due to the system being based on the ISA-S88 standard, its
Currently, the data generated by the management system is
maintenance is easy to understand, saving time and
stored and traceability reports are consulted by the
technical resources, and ensuring a longer time of
supervisors of the production unit and quality assurance
availability for production.
department, to monitor the quality of the production.
The original article in Portuguese appeared in InTech.
Source: http://www.aquarius.com.br/wp-content/uploads/2018/05/InTech143-Batch.pdf

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