Добавить в избранное

Для содержимого этой страницы требуется более новая версия Adobe Flash Player.

Получить проигрыватель Adobe Flash Player

Optimizing the pharmaceutical supply chain by means of MES

Manufacturing Execution Systems to Optimize the Pharmaceutical Supply Chain
Rolf Blumenthal, Werum Software & Systems
Parsippany, NJ / Lueneburg, Germany
This article has originally been published in the German magazine
“Die pharmazeutische Industrie”.
Pharm. Ind. 66, Nr. 11a, 1414-1424 (2004) Editio Cantor Verlag, Aulendorf, Germany
ISSN 0031-711 X

Optimizing the pharmaceutical supply chain by means of MES page 2 of 28
Manufacturing Execution Systems (MES) enable the pharmaceutical industry to reduce production
costs and increase compliance with regulatory requirements significantly. This is due to the
capability of an MES to optimize business processes in the production supply chain, improve
product quality and ensure the safety of manufacturing processes.
This article provides practical advice on how to make the implementation of an MES solution a
success story. The article examines various production architectures and the associated process
workflows and states criteria to determine benefits and functional scope of an MES. The required
functions and interfaces are listed and implementation strategies are introduced. Finally case
studies describe successfully installed MES systems and document the benefits achieved for the
The author Rolf Blumenthal is Vice President International Consulting with Werum Software &
Systems America, Inc.
Rolf Blumenthal has been working with Werum since 1979 and is one of the 15 employees who
took over the company after the death of the company founder Wulf Werum in 1982. He has
gained outstanding expertise in the management of large-scale and international MES software
projects for Pharma and Biotech industries.
For more than five years Rolf Blumenthal has managed the product development for Werum's
MES software suite PAS-X. In this context, compliance with GMP and FDA requirements is of
prime importance. Since PAS-X is operated as an Electronic Batch Recording System in the
pharmaceutical industry the guidelines of the GAMP Community are of particular relevance for the
product development process.
Since Rolf Blumenthal is a renowned industry expert with hands-on experience and
comprehensive technical expertise he started international consulting activities in 2005. In this role
he advises PAS-X customers on the following major topics: IT architectural blueprints, system
integration, computer system validation, optimized use of PAS-X, and efficient creation of master
batch record libraries.
Rolf Blumenthal is a member of the GAMP D-A-CH Forum where he is actively participating as
editor and reviewer of new guidelines. Since 2002 he has been a member of the GAMP D-A-CH
Steering Committee and of the Special Interest Group “Validation of Small Manufacturing and
Weighing Devices”.

Optimizing the pharmaceutical supply chain by means of MES page 3 of 28
1 Introduction ...... 4
2 What are the Benefits of an MES System?........... 6
2.1 Objectives . 6
2.2 Various Production Architectures 7
2.2.1 Architectural Design of Biopharmaceutical Production....... 7
2.2.2 Architectural Design of the Production of Pharmaceutical Dosage
Forms 8
2.3 Classification and Assessment 10
3 Positioning within IT environment ... 11
3.1 Overview of Standards ISA S95.00.01/02/03................ 11
3.2 ISA-Compliant MES Integration 14
3.2.1 Integration with an ERP System........ 14
3.2.2 Equipment Integration ..... 15
4 Functional Packages ........ 17
4.1 Functions Required on MES Level .............. 19
5 Regulatory Requirements 21
6 Implementation Strategy .. 22
7 Case Studies... 23
7.1 Production of Pharmaceutical Solids - Bayer Health Care ........... 23
7.1.1 Purchased Software to Profit from the Experience of Other Users.... 23
7.1.2 A Focus on Flexible Processes ......... 24
7.1.3 The Reality of Electronic Documentation.......... 24
7.1.4 Integrated Systems .......... 24
7.1.5 Wrap-up............ 25
7.2 Biotechnical Production - Boehringer Ingelheim........ 25
7.2.1 Biotechnological Requirements ........ 25
7.2.2 Coordinating Complex Processes Safely.......... 26
7.2.3 Manual and Automatic Sequences Alternating. 26
7.2.4 Suitable to Meet Future Requirements .............. 27
8 Outlook............ 27

Optimizing the pharmaceutical supply chain by means of MES page 4 of 28
1 Introduction
As a production manager or having a similar position in the pharmaceutical industry you might be
familiar with a setting like this: Long rows of files with paper documents, some of them still partly
unprocessed; colleagues constantly asking you "What do I have to do next"; and not to forget the
permanent discussions with the sales department on which products are required urgently
Would you not prefer a situation like this: your personnel is equipped with RF hand-held terminals
and can inquire the activities next in line at any place and at any time; your operators thus execute
the required activities as specified. And on top: a complete, electronic documentation and a
statement about the performance and status of your production and packaging upon the click of a
A Manufacturing Execution System (MES) is at the core of such a scenario. An MES controls,
optimizes, and documents business processes executed on the shop floor in full compliance with
all the pharmaceutical requirements. It is the goal of an MES to increase security and reliability of
the manufacturing process and to improve product quality. MES solutions are suitable for different
processes including chemical or biochemical manufacturing of active pharmaceutical ingredients
as well as the subsequent processing of such APIs in solid and liquid pharmaceutical forms.
MES solutions are not isolated but a core component of the entire supply chain IT architecture. In
1998, AMR created the REPAC Model (Ready, Execute, Process Control, Analyze, Co-ordinate)
and thus laid the foundations for the basic understanding of the necessity to use an MES. An
autonomous MES enables the support and optimization of business processes by means of
software functions. To actually achieve such potentials and optimize the IT architecture on the long
run, it is necessary to standardize the functions and workflows in logical units. Typical examples of
such a view are Weighing & Dispensing, Electronic Batch Recording, Equipment Management,
Deviation Management with CAPA functions (Corrective Actions / Preventive Actions).

Optimizing the pharmaceutical supply chain by means of MES page 5 of 28
Figure 1: The REPAC model (Ready, Execute, Process Control, Analyze, Coordinate)
laid the foundations for an MES (source: AMR)
A Manufacturing Execution System is an electronic interface between personnel, equipment
automation, orders, logistics, equipment and processing instructions (batch records). Thus, the
MES is located between the company-wide Enterprise Resource Planning System (EPR) and the
process control systems (DCS). The MES mediates between business administration (covering
core functions such as sales and production planning or controlling) and the automation of the
production process.

Optimizing the pharmaceutical supply chain by means of MES page 6 of 28
2 What are the Benefits of an MES System?
The implementation of a complex MES solution involves large investments. Therefore, some
questions have to be answered to justify these costs. How can the user determine the necessity of
an MES and how does the user benefit from an MES? Only measurable and quantifiable
advantages can provide an economic investment justification.
In this context, a systematical procedural approach is essential. Objectives have to be defined and
typical characteristics of the examined plant and the involved business processes have to be
analyzed. The information obtained in such a matter is a solid basis for an objective assessment of
the benefits provided by an MES.
However, despite the importance of such a structured approach it cannot be denied that the
decision for or against the benefits of an MES system frequently involve factors that are not
measurable in economic terms.
2.1 Objectives
Typical goals to be achieved by the implementation of an MES system are:
• Optimizing of the entire supply chain with the MES system best suitable for controlling
workflows and procedures
• Improving process safety and reliability
• Recognition of deviations at an early stage
• Immediate documentation of process steps
• Improved data quality for assessing processes and products
• Visibility and transparency throughout the entire production process: only deviations are to be
analyzed, a detailed examination of the normal flow of operations is no longer required
• Reduction of storage costs due to reduced lead times (WIP)
• Reduction of administrative work for maintaining manufacturing documents
• Creating and approving master batch records
• Reducing the number of lost batches
• Reduction of operating costs due to a high level of integration and thus prevention of isolated
• Rapid access to current data: management based on up-to-the-minute information for all
critical business cases
• Complete 21 CFR Part 11 compliance also for lower-level systems

Optimizing the pharmaceutical supply chain by means of MES page 7 of 28
2.2 Various Production Architectures
In pharmaceutical production there are typical production structures for manufacturing active
pharmaceutical ingredients or dosage forms such as tablets, ointments or liquids. These structures
can be classified according to specific criteria. This classification can be used to define the
different benefits levels of an MES for a particular production architecture in detail and by degrees.
Moreover, such a classification also leads to different implementation concepts for an MES
system. It would be wrong to claim that there is one software solution to provide optimal support
for the respective type of production.
Obviously, such structures can only be regarded in a rather abstract way. Thus, in concrete cases
there may be deviations from the general patterns. For this reason, it is always advisable to
analyze a concrete example.
In this article, we only consider regulated production areas operating on the basis of master batch
records. The examples we use refer to the biopharmaceutical production of active pharmaceutical
ingredients and the production of solids. Similar structural descriptions could be established for the
production types we cannot regard in this paper.
2.2.1 Architectural Design of Biopharmaceutical Production
Biopharmaceutical production of active pharmaceutical ingredients is characterized by natural
fermentation processes of germs. Depending on the progress of the process the results of a
previous phase have to be distributed onto additional equipment that is getting larger with every

Optimizing the pharmaceutical supply chain by means of MES page 8 of 28
Figure 2: Biopharmaceutical API production – principle structure
Characteristic features of biopharmaceutical production:
• Highly automated production
• Sub recipe control by means of a DCS
• Few manual material transports
• The process is running "on rails" with just a few buffering possibilities
• Production requires a reliable verification of the cleaning status of all the different equipment
• Equipment management
2.2.2 Architectural Design of the Production of Pharmaceutical Dosage Forms
One of the characteristics of the production of pharmaceutical dosage forms is the material flow
using containers. The master batch records states fixed batch size limits related to the container
size. The input material quantities and the further operations are based on these limits.
Following the weighing/dispensing of material into a container it is transported from work centre to
work centre where it is processed according to specification. Sometimes the production workflow

Optimizing the pharmaceutical supply chain by means of MES page 9 of 28
in the building involves several floors. Some containers are transported in lifts and in some cases
the force of gravitation facilitates material transfer.
Figure 3: Production of pharmaceutical dosage forms – principle structure
Characteristic features of a manufacturing process for pharmaceutical dosage forms:
• A large number of work centers
– 5-10 granulators
– 20-40 tabletting machines
– 10-20 packaging lines
• The individual work centers are located in isolated workrooms with controlled access to ensure
• Many manual material transports in containers
(The process can be interrupted and WIP material can be held for further processes)
• Various, independent and few complex SCADA systems controlling individual machinery
• Material can be added and/or further processes be initiated on several production floors
• Vertical transports across the levels
(i.e. it is necessary to check that the correct containers are placed at the correct machines)

Optimizing the pharmaceutical supply chain by means of MES page 10 of 28
One of the major utilities for process acquisition and control are mobile RF terminals and barcode
scanners. They enable the identification of objects (such as containers, workroom or scale) at any
location, provided that these objects are equipped with a barcode label.
2.3 Classification and Assessment
It is possible to use a criteria catalogue to clarify in how far an MES solution in a production plant
provides benefits for the user or not. The checking of the criteria enables a judgment on the
concrete case. The following list states some of the criteria to be used for assessment.
• Type of process equipment
• Complexity of products
• Degree of automation in production
• Transports using containers
• Information about equipment status
• Work required to document production
• Material inventory in production (WIP)
• In-process control operations
One tendency is recognizable: the benefits in the supply chain increase from API production
towards packaging.
Figure 4: Significance and benefits of MES for various production structures

Optimizing the pharmaceutical supply chain by means of MES page 11 of 28
3 Positioning within IT environment
In the production supply chain it is the MES systems that substantially contribute to vertical
integration. All the individual systems of a company, the ERP system as well as the systems on
plant operations level down to the equipment merge into one overall system. In the context of
integration, the state of the art achieved by now provides good technical safety if adhering to
standards like ISO S95, ISO S88, or Namur NA 94. Solutions for individual industry segments are
developed, which require only reduced development efforts and implementation times.
How are the required functionalities to be distributed to the involved systems? This is a question
frequently discussed when an enterprise plans to implement an MES system. The distribution of
functions to various systems which support the individual task in the best possible way is a
common task and can be solved without major problems. However, it is not only necessary to
distribute the data but also to define which system is primarily managing the respective data. A
system has the sovereignty over data if it originally produces the data and transfers it to another
system for further processing. A material master, for instance, should originate in an ERP system
and should also be maintained and processed there. An MES, though, may add attributes and
data to make sure that pharmaceutical aspects are considered in the best possible way.
The ISA standard S95 focuses on the aspect of integration into IT environments. The descriptions
given in the standard provide a suitable basis for settling questions relating to task distribution and
3.1 Overview of Standards ISA S95.00.01/02/03
The standard ISA S95 consists of three individual parts:
• Part 1 defines models for describing the distribution of tasks between ERP and MES systems
(ISA-95.00.01) [1]
• Part 2 describes the associated data models (ISA-95.00.02) [2]
• Part 3 defines a catalogue of functions (ISA-95.00.03) [3]
The standard describes those areas on enterprise and plant operations level that deal with any
kind of activity required to manufacture a product and to control this process.
The first part of this standard with its description of the interface between ERP and MES may help
to position an MES system. In a first step, the standard divides the organizational structure into
four levels, with the ERP systems on level 4, the MES system on level 3 and the equipment
interfaces on levels 2 and 1.

Optimizing the pharmaceutical supply chain by means of MES page 12 of 28
Figure 5: ISA S95 level concept
An additional, more detailed model description illustrates the data flow between the functions for
production plants.

Optimizing the pharmaceutical supply chain by means of MES page 13 of 28
Figure 6: Scope of enterprise-control integration
The dotted lines define the interface between levels 3 and 4. The arrows show the flow of data
between the levels.

Optimizing the pharmaceutical supply chain by means of MES page 14 of 28
3.2 ISA-Compliant MES Integration
3.2.1 Integration with an ERP System
Following the specifications of ISA S95 the pharmaceutically relevant data are to be handled by
the MES system when the MES and EPR system are integrated:
For this reason, level 3 comprises the functions
• required to maintain “regulatory compliance”
• adding to the reliability of plant operations
• relating to the required equipment
• required to enable supervisor to control plant operations
Figure 7: ISA-compliant distribution of functions between ERP and MES system

Optimizing the pharmaceutical supply chain by means of MES page 15 of 28
3.2.2 Equipment Integration
Equipment interfacing by means of PLCs enables the MES system to use automatically acquired
data. Such data are more reliable than manually collected data, since errors during manual data
entry can be ruled out.
On the other hand, equipment interfacing involves some effort for integration and qualification.
Once such a system is running and validated, MES users can add originally acquired operating
data or rather sophisticated conversions to their batch records.
The MES collects such operating data in a production database (Historian Database) and places
relevant data available for the manufacturing report. The production database enables all kinds of
analysis which may also involve further data of the MES.
Operating data (such as temperature, pressure, or alarms) can be acquired by DCS systems for
process control as well as by SCADA systems for machine visualization, PLCs for machine
control, or by manual data input. Online queries are possible at each process step. Due to a time
stamp and the batch time frame (start/end of batch) the data are assigned to a produced batch.
The interface requires special attention if a DCS system is used to integrate equipment which at
the same time presents a recipe-driven batch system. In this case, pharmaceutical master batch
records and process recipes have to be harmonized. As both the master batch records as well
as the recipes are hierarchically structured descriptions, there should be a level on which the
descriptions can be mapped.
Also in this context the ISA standards S95 and S88 [4] [5] are a good help. On MES level, the
master batch records take into account the entire plant with all its workrooms and even the
individual machines (units). The process recipes, on the other hand, consider all phases and
technical functions of the machines and subsystems down to the individual acquisition values and
control elements.

Optimizing the pharmaceutical supply chain by means of MES page 16 of 28
Figure 8: MES and DCS system: Recipe integration

Optimizing the pharmaceutical supply chain by means of MES page 17 of 28
4 Functional Packages
On MES level 3, the standard S95 positions the complete functional package “Production
Operations” and parts of the functional packages “Material Inventory Control”, “Quality Assurance”,
and “Maintenance Management”. Considering the integration layers you get the following structure
for an MES system:
Figure 9: Components of an MES system
The component “Production Operations” comprises four main sets of functions defined for the
following tasks:
• Definition of production
• Management of resources
• Planning and execution of product manufacturing
• Acquisition, documentation, and analysis of production

Optimizing the pharmaceutical supply chain by means of MES page 18 of 28
Further detailing divides each functional package into a number of function groups:
Figure 10: Function groups of the package “Production Operations“

Optimizing the pharmaceutical supply chain by means of MES page 19 of 28
4.1 Functions Required on MES Level
Product definition management:
• Additional material master data
• Definition of master batch record
• Bill of material
• Operations
• Material flow in production
• Review and approval workflow
• Management of versions
Production resource management:
• Management of personnel and consideration of proper certification
• Equipment management, e.g. container, scales, tanks, setup parts, workrooms
• Management of material resources
• Coordination with maintenance management
• Management of future resource capabilities
• Equipment management, ensuring the right status for usage (like cleaned, in use, calibration
• Electronic logbooks
Detailed production scheduling:
• Allocation of shop floor orders to machines
• Comparison between actual and scheduled production
• Monitoring of work centers and resources
• Monitoring of order statuses

Optimizing the pharmaceutical supply chain by means of MES page 20 of 28
Production dispatching:
• Allocation of resources (personnel, equipment, material) to manufacturing orders -> shop floor
• Starting, stopping, interrupting and resuming of production order
• Batch record execution
• Performing assigned procedures and activities
• Reacting to deviations
• Throwing exceptions
• Taking samples
• Review and approval of batch record
Production data collection:
• Manual data acquisition
• Automated data acquisition
• Weighing and dispensing using scales
• Calculation of new values based on formulas
• Storing of production data in event or time context (trends)
• Acquisition of deviations, events and alarms
Production tracking:
• Electronic batch record report
• Batch genealogy
• Batch where-used list
• Deviation handling
• Tracking of all material movements
• Process analysis
• Statistical process control
• Production performance analysis (KPIs, e.g. cycle times, resource utilization, equipment

Optimizing the pharmaceutical supply chain by means of MES page 21 of 28
5 Regulatory Requirements
Depending on the country the products are delivered to, an MES system for the pharmaceutical
industry must functionally comply with the requirements of regulatory authorities in Europe and/or
in the United States:
• GMP requirements of FDA (21 CFR Part 210/211) [8]
• FDA requirements (21 CFR Part 11) for electronic records, electronic signatures [9]
These regulations for instance define the procedure for identifying a container (21 CFR Part
211.80 and 105) or the requirements electronic signatures have to meet (21 CFR Part 11.100-
Beyond this, there are a number of requirements and guidelines by regulatory authorities stating
the QA procedures relating to the Software Development Life Cycle in order to guarantee
software products of high quality. Examples are:
• GMP guidelines of EU [10] [11]
• GAMP 4 guidelines [12]
European and US laws may vary in details; what they have in common is the requirement for the
validation of computerized systems. The fundamental prerequisite that qualifies any system for
validation is that clearly defined QA policies have been observed throughout all project phases.
In this context, the GAMP V-model has become generally accepted in the pharmaceutical industry.
The V-model divides the production and maintenance of software systems into the phases Design
Qualification, Development Implementation, Factory and Site Acceptance Test, Installation
Qualification (IQ), Operational Qualification (OQ), Performance Qualification (PQ), and Ongoing
All these phases have to be concluded with a verification to prove that all the requirements for the
respective phase have been fulfilled. All the verifications have to be performed in a formal and
systematic way. Change management procedures have to be established to ensure an overall
consistency of the entire documentation across all phases.
The computer system must be developed and tested in accordance with a quality
management system. In the pharmaceutical industry software lacking appropriate proof of
such QM compliance is hardly acceptable.

Optimizing the pharmaceutical supply chain by means of MES page 22 of 28
6 Implementation Strategy
Since an MES system considerably affects production processes and their documentation,
detailed planning is required to make its installation a success. After all, established, reliable
procedures using paper are substituted by electronic procedures. Especially, if an MES system
entirely replaces the production documentation on paper by Electronic Batch Recording, all
possible risks have to be analyzed and ruled out. This is because one thing is for sure: a batch
without documentation cannot be sold.
In order to minimize the risks and gain the customer’s confidence by first installing a smaller
system of manageable proportions the following recommendations should be considered:
• Implementation in phases
The implementation should be carried out in phases. In a pilot phase an existing, operational
standard system (MES product) demonstrates the functions that are available or missing in the
implementation. The findings can then be considered as improvement in the next phase, the
implementation phase. Such improvements may not only concern the software but also the
workflows. The resulting system is already adjusted and suitable for productive operation in a
plant. In every-day use further requests for improvements may come up. An overall picture of
the customer’s standard system will finally turn out by including further requirements made by
other plants.
Such additional functions can be integrated in a roll-out version of the software product. During
the roll-out phase a proven, familiar system is available to the customer, which can also be
transferred to other sites with only little effort (saving up to 50 %).
• Integration of all key users
The best system will not be accepted if the users do not get the opportunity to get familiar with
the system before it is actually implemented. Unless key users get the necessary experience in
handling the new system and an understanding of the objectives to be achieved by installing
this system, the management will run the risk of loosing the users’ support. The implementation
would inevitably be doomed to failure.
For this reason, the key users should be integrated at a very early stage, for instance when
defining the system requirements or when analyzing the functionalities. As soon as the pilot
system is available, training courses should be held. In this phase, key users are just the
right persons to make crucial contributions to improving the system or supported
workflows. It is important to win the key users and make them advocates of "their" system.
They have to be convinced of the benefits the MES provides for them.
• Focusing on sophisticated system configuration and customization

Optimizing the pharmaceutical supply chain by means of MES page 23 of 28
As MES systems are supposed to be flexible enough to adjust to the most versatile workflows,
customization is necessary and wanted. This applies in particular to EBR functions since their
scope is strongly influenced by parameters set for the master batch record. It is to be noted
that depending on the complexity of procedures and the number of products to be
manufactured, customization activities lasting up to several months are not uncommon.
In general, master batch records exist on paper already and their contents are known. But
effective operation of an MES is related to the availability of well-structured master batch
records in the system. They are essential to profit from advantages as provided by predefined
building blocks. Reusable description elements are a core factor in reducing the effort for
creating master batch records considerably and consistently. The required restructuring of
data existing on paper represents an intellectual challenge that should not be underestimated.
The best way to solve the problem is to integrate process engineers, who are well-trained in
defining master batch records, right from the start phase of the project.
7 Case Studies
7.1 Production of Pharmaceutical Solids - Bayer Health Care
Bayer HealthCare, a subgroup of Bayer AG, is one of the world's leading companies in the health
care and medical products industry, combining the global activities of its Animal Health, Biological
Products, Consumer Care, Diagnostics and Pharmaceuticals divisions More than 34,000
employees work for Bayer HealthCare worldwide.
Bayer HealthCare's Pharmaceuticals Division develops innovative and highly effective drug
products. The research programs cover life-threatening conditions but also disorders that markedly
impair quality of life and life expectancy. The division has a promising early product pipeline, in
particular for the indications cancer, cardiovascular, metabolic disorders, and anti-invectives.
Each year several billions of tablets leave Bayer's manufacturing facilities for pharmaceutical
solids in Leverkusen. Such highly sophisticated production facilities demand software-based
support during all phases of production to ensure that patients get a drug of stable quality.
7.1.1 Purchased Software to Profit from the Experience of Other Users
Bayer started looking for a manufacturing execution system that offered the "customary comfort",
met today's and tomorrow's GMP compliance requirements and was apt to support optimal
material flow control, reliable user guidance and paperless production with electronic signatures.
At first, Bayer was not sure whether to use in-house development or purchase a market software
package. Based on the argument that with a purchased software package you can indirectly
benefit from the experience of other users they finally decided in favor of the MES system PAS-X

Optimizing the pharmaceutical supply chain by means of MES page 24 of 28
PHARMA by Werum Software & Systems.
7.1.2 A Focus on Flexible Processes
Bayer was looking for software that can be configured in a simple way, that enables them to create
recipes easily and which has a flexible structure. This is essential since the manufacturing of solid
pharmaceuticals is characterized by a large number of recipe variants. Several hundred recipes
are not uncommon. Thus, the administration and creation of Master Batch Records with all
relevant order and batch data is one the system's core functions.
With the objective to obtain high throughput and productivity the recipes are structured so that they
may be executed on different machines. It must be possible to switch between different equipment
without any problem.
A change of equipment required while the process is running is a real challenge, and fortunately
only happens rarely. Any modification of the batch record needs to be visible in the
documentation, but any impact on the Master Batch Record has to be avoided.
Also during "normal" batch record execution the collected data are continuously compared to the
stored recipe. The next step can only be initiated if all the data match. Such verifications are
automatically performed by the system. The entire workflow with all the associated deviations is
electronically documented, and then finally evaluated. This way safety procedures are integrated
into the process, and it is ensured that all the workflows are correct.
Transparency was also requested for the mapping and control of the complex material flow. It was
one of the primary goals to enable an easier and safe way of identifying the products across the
entire production process.
7.1.3 The Reality of Electronic Documentation
Meanwhile, a fourth partial goal has been achieved. Apart from a few forms, paper has completely
disappeared from production. All documents only exist in electronic form. Also all the signatures
required for the approval of individual production steps are performed electronically. It is ensured
that documentation and signatures are 21 CFR Part 11-compliant.
7.1.4 Integrated Systems
The Manufacturing Execution System is integrated into a comprehensive IT framework concept. At
the level above, there is a Unix-based system supporting materials planning, order creation and
the entire supervisory control planning. Below the MES, there is the machine level to which the
MES offers standard integration modules. A standard interface has been implemented to SAP. It
ensures that all pharmaceutically relevant data remain in the Manufacturing Execution System.
Material inventories are administered in SAP. Another important feature: the Manufacturing

Optimizing the pharmaceutical supply chain by means of MES page 25 of 28
Execution System provides an automatic master data interface to the SAP system. In case recipes
are changed in the MES the interface makes sure that the master data are automatically
reconciled between MES and SAP.
7.1.5 Wrap-up
Looking back on more than four years of practical experience with the Manufacturing Execution
System Bayer strikes a positive balance. Following an initial phase of familiarization, the user
satisfaction was complete. The use of mobile RF terminals has proven a real success. The
operators truly welcome the high degree of mobility and the safe guidance guaranteed during the
execution of orders.
In using the MES, Bayer has been able to further optimize pharmaceutical safety, to substantially
increase the transparency of the material flow, and to implement measures for boosting efficiency
of the manufacturing process.
7.2 Biotechnical Production - Boehringer Ingelheim
Boehringer Ingelheim is a research-driven group of companies dedicated to researching,
developing, manufacturing and marketing pharmaceuticals that improve health and quality of life.
With more than 34,000 employees and 152 affiliated companies spread all over the globe, the
company's two core businesses are Human Pharmaceuticals and Animal Health. The former is
made up of the business segments Prescription Medicines, Consumer Health Care and Industrial
Consumer, which includes Chemicals and Biopharmaceuticals.
At the locations in Biberach (Germany) and Vienna (Austria), Boehringer Ingelheim can provide
the entire biopharmaceutical process chain from genetic cell development to large-scale
commercial manufacturing.
7.2.1 Biotechnological Requirements
The demands in biopharmaceutical production of active pharmaceutical ingredients (API) are
particularly high. In the new API facility Boehringer Ingelheim will produce highly innovative
biopharmaceuticals. These advanced products are the result of many years of extensive
pharmaceutical research and, without a doubt, represent cutting-edge performance in
pharmaceutical production skills. A vital contribution to this process is the MES system by Werum,
which has been tailored to meet the very specific requirements of biotechnological production.
Over the last years, no other project in Europe's pharmaceutical industry has gained as much
notice as the new active ingredient plant of Boehringer Ingelheim in Biberach, Germany. As the
largest cell culture plant in Europe, it set a new record in development and construction, and
currently surpasses all others in terms of technology. In less than three years, more than Euro 255
million has been invested in this biotech complex. Just imagine: more than 18,000 cubic meters of

Optimizing the pharmaceutical supply chain by means of MES page 26 of 28
concrete, 2,700 tons of steel, 600 huge biotech apparatuses, 70 kilometers of piping, and about
800 kilometers of cable were used in the construction of the building.
7.2.2 Coordinating Complex Processes Safely
Without a Manufacturing Execution System that interfaces closely with the distributed control
system (DCS), it would not be possible to run the complex processes in such an optimal way. For
a smooth flow of production it is essential that the batch record is structured consistently to ensure
the manufacturing of products of constant form and stable quality.
The monitoring process in the active ingredient plant involves about 10,000 sensors and actuators
distributed over 150 pieces of equipment, supplying essential data or carrying out instructions.
With more than 1,000 processing operations executed in the Biberach plant, any action, i.e. every
touch of a button, every temperature reading, and every transfer, is executed according to precise
instructions and is subject to complete documentation. The MES system guides the operator
safely and step by step through each work segment and prevents errors in operation. The
importance of such a system for quality assurance can hardly be over-emphasized - being well
aware of this, Boehringer Ingelheim started the BIOMES project as early as May 1999.
7.2.3 Manual and Automatic Sequences Alternating
The main challenge that the MES has to face is that in biotechnological production, automated
workflows alternate with manual operations. For this reason, the automated sequences are first
filed in the DCS recipe system and transferred to the MES. The MES then links these automated
sub functions to the manual operations and consistency checks (e.g. batch or equipment status).
Finally, target values are assigned to these manufacturing specifications.
The MES handles all the manual sequences and triggers the automated procedures in the DCS.
On execution of automated sequences the DCS returns the result parameters to the MES. As the
controlling system, the MES continually displays the current status of all processes including DCS.
On completion of a manufacturing stage, the MES generates complete associated documentation.
The entire electronic process monitoring is designed to act as an early warning system. Trend
calculations are used to detect and report deviations even before they actually occur, so that the
operator has enough time to take corrective measures. On-line booking of every process step and
every material consumption makes it possible to follow the process flow directly.
Another essential task of the MES is the monitoring of cleaning and sterilization status, including
expiration dates for all related equipment, such as containers, pipe systems, and set-up parts. The
risk of contamination is minimized, since the system would, for instance, issue an alarm as soon
as an unsterilised pipe is to be used.

Optimizing the pharmaceutical supply chain by means of MES page 27 of 28
7.2.4 Suitable to Meet Future Requirements
Werum's PAS-X BIOTECH has made it possible for Boehringer Ingelheim to establish a central
electronic production management system. This system can be interfaced to all relevant
processes even outside the very area of production, such as laboratory information systems
(LIMS). The MES serves as a data "turntable" and ensures consistent data flow between SAP and
DCS environment.
8 Outlook
The cost-benefit ratio obtained by the implementation and operational use of an MES system
always depends on the capabilities provided by the basic technologies. Today's new technologies
show a trend towards open structures. In the field of basic software technologies J2EE is such an
open standard. There is no longer the need to stick to one particular supplier. Further examples
are XML and OPC interfaces, which facilitate a standardized data exchange. Currently, new
technologies are launched at rapid pace enabling many other optimizations at low costs. Among
these new trends are:
• Web-based functions: use of intranet/internet functions
• Mobile computing: use of mobile computers/handhelds
• PAT: analysis and intervention in realtime to avoid errors instead of analyzing them afterwards
• Modularization: use of J2EE, CORBA software architectures enabling an open system
environment (best of breed) with standardized interfaces.
Many attempts to create an all-embracing overall system have failed so far and will probably also
fail in the future. Some jobs have a rather universal character in all enterprises, such as the issuing
and processing of invoices. Other tasks are very specific and restricted to particular production
structures, such as the requirement to stage a given quantity of a material ensuring that all the
material belongs to the same batch. With the prospect of steadily growing market potential, it will
be one of the greatest challenges in the near future for IT and, thus, for MES applications, to
develop the optimum structure for IT components associated with production processes.

Optimizing the pharmaceutical supply chain by means of MES page 28 of 28
[1] ANSI/ISA 95.00.01-2000, Enterprise-Control System Integration Part 1: Models and
[2] ANSI/ISA 95.00.02-2001, Enterprise-Control System Integration Part 2: Object Model
[3] ANSI/ISA 95.00.02-2001, Enterprise-Control System Integration Part 3: Activity Models of
Manufacturing Operations Management
[4] ANSI/ISA-88.01-1995, Batch Control Part 1: Models and Terminology
[5] ANSI/ISA-88.00.02-2001, Batch Control Part 2: Data Structures and Guidelines for
[6] MESA: White paper 8, MESA’s next generation collaborative MES model
[7] Namur Worksheet NA 64, MES: Functions and Examples of operations control level
[8] 21 CFR Parts 210,211 cGMP for Finished Pharmaceuticals, FDA
[9] 21 CFR Parts 11 Electronic Records/ Electronic Signatures, FDA
[10] Annex 11 to the EU Guide to Good Manufacturing Practice, EUROPEAN COMMISSION
[11] Annex 15 to the EU Guide to Good Manufacturing Practice, EUROPEAN COMMISSION
[12] GAMP 4, GAMP Guide for Validation of Automated Systems, ISPE

Рейтинг@Mail.ru Rambler's Top100