Merck Serono is among pharma firms deploying MES for process visibility and control.

As manufacturers seek to better understand processes toward the goal of operational excellence, manufacturing execution systems (MES) have emerged as a critical tool for increasing production efficiency and compliance.

An interface between machines and people on the shop floor and enterprise resource planning systems (ERP), MES integrates plant functions as processes and results are documented electronically.

“Customers have less and less time to do more and more work on the shop floor, while product quality is still paramount. They have told us, ‘We need a system that makes our work easier, more secure, and gives us confidence that we can produce the quality we need,’” says René Schwarz, manager of strategic business development, Rockwell Automation. (www.rockwellautomation.com).

“All of the top pharma and bio tech companies are introducing or planning MES implementations. As companies gain more experience with MES, the deployment costs go down,” Schwarz adds.

Paper-based processes are replaced as MES software manages master batch records and electronic batch recording (EBR). Companies have reported major reductions in process deviations and documentation errors.

Merck Serono, the pharma and biotech division of Merck KGaA, implemented Werum Software & Systems’ (www.werum-america.com) PAS-X MES solution this year at its pharma manufacturing plant in Naucalpan, Mexico. The Mexico launch—which takes Merck Serono (www.merckserono.com) one step further in rolling out PAS-X as a standard system globally—went live in January.

Merck Serono’s MES rollout is part of its focus to develop systems and processes that meet exacting standards of robustness and consistency, says Dr. Jörg Spörle, senior vice president, pharma manufacturing global market, Merck Serono.

“Operators completely document all production steps in the MES, so there is no more paper on the shop floor,” Spörle says.

The Naucalpan facility manufacturers’ solid dose products packaged in blisters and bottles, including Merck Serono brands Glucophage (metformin), Euthyrox (levothyroxine sodium), Concor (bisoprolol fumarate) and Neurobion. Sterile and non-sterile liquids are manufactured and packaged in bottles, prefilled syringes, and ampoules (Neurobion, Iliadin, and Nasivin).

The MES system covers the entire manufacturing process from product dispensing and weighing, tableting and filling of liquids, through to packaging. The facility is using core PAS-X modules for EBR, and management via electronic work flows of check weighing, materials, and inventory.

Standard Processes

PAS-X MES interfaces with Merck Serono’s global SAP ERP system for electronic execution of master batch records. Operators in product manufacturing, on the packaging line, or in receiving incoming goods, manually key in data to document batch processes and results following standard, rule-enforced dialogs.

During shop floor execution, EBR compares captured data to the target values set forth by the batch record. The EBR then summarizes the data in consolidated form, creating a separate report on deviations.

Deploying the MES solution required a comprehensive change management process, Spörle says.

•In a six-month phase, operators not familiar with using computers had to be trained from scratch.

•Master batch and instruction records were defined for more than 700 products, with maximum and minimum limits for production parameters.

•The Werum PAS-X is implemented initially as a “paper-on-glass” process that repeats the paper process electronically. QA personnel had to adjust to computer-based input and review.

“One of the major opportunities of MES is in quality assurance where the QA people do not have to review every page of batch records. The system is automatically comparing the values entered by the operators with the production parameter target values and upper and lower limits. Any deviations are automatically reported. In the ideal case, the QA person just has to press a button to release the batch,” Spörle says.

“The QA people had to be convinced they can trust the system. This mind set change was a major challenge,” he adds.

The rollout was accomplished in a year, about half the time required for implementing PAS-X at Merck Serono’s Darmstadt, Germany facility, which was the first site to deploy the MES solution last year. Problems were anticipated in workshops with Darmstadt participants.

“The master batch record and in-process controls were already designed from a group perspective. In the best case such as for identical products, the records just had to be translated from German into Spanish. As a global company, we want to harmonize processes. MES becomes a tool to trigger harmonization through standardized processes,” he says.

Merck Serono has harnessed significant OEE improvements before implementing MES, achieving increases from 27% to 50% to 70%. MES supports OEE in reducing documentation time and enabling faster batch closing. The electronic document system has improved OEE at the Mexico facility after just eight months, Spörle says.

“We have already realized a moderate 2% to 3% improvement in OEE. There is a significant potential to decrease manufacturing and packaging cycle times,” he adds.

After Merck’s acquisition of Serono in 2007, “we wanted one common system for the pharmaceutical and bio pharma production, but Werum couldn’t provide that at that time. So we are using two Werum subsystems globally, PAS-X for pharma and PAS-X for biopharma. In the future, we will reconsider a common pharma and biotech system which has since become available from Werum.”

PAS-X for biopharma is going live at Merck’s biopharma active ingredient production facility in Corsier-sur-Vevey, Switzerland, after PAS-X Bio was first implemented last year at the Aubonne, Swiss plant.

The company is reviewing packaging line track and trace alternatives, including Werum’s PAS-X track and trace, offered as a separate solution or as a business function integrated with PAS-X MES.

“We are considering several options for track and trace software. We have to figure out if it makes sense as a standalone system, such as for smaller production sites that are not initially in the scope of an MES implementation,” Spörle says.

Global Rollout

Merck Serono is rolling Werum MES out globally “at least to our most important production and packaging sites. It is a key element of operational excellence that helps us manage efficiently the complex logistics involved in a global production network and ensure the highest quality of our medicines for customers and patients. Because the added value of the system was demonstrated, we are now investigating the use of PAS X on the chemical production side as well,” Spörle says.

In implementing core MES functions across locations, companies are standardizing product manufacturing and packaging processes, says Marc Puich, senior vp sales & program management, Werum Software & Systems.

“With MES, for example Werum’s PAS-X, you are not only deploying a tool, but also the rules for compliance and guidance for efficiency that is loaded with the system. Once you transfer from paper, you are using a standard format for making a tablet or running a packaging line clearance, with standardized interfaces to the enterprise level and the shop floor. Companies can use this to compare performance on a global scale,” Puich says.

Data entries by operators on the shop floor or in the warehouse are rendered in a standard format, time-stamped, and verified with point-of-use checks, enabling right-the-first-time. Using standard formats with change management tracking for 21 CFR Part 11 reporting, plants can demonstrate the process is under control to FDA auditors.

Werum provides PAS-X MES in modules for functions including EBR for electronic execution of master batch records, data capture for weigh dispense management, and managing of inventory and materials. In a process quality control function, a dedicated overview shows deviations from specifications and provides early warnings. Quality personnel can intervene with a few mouse clicks for corrective actions on production processes when a negative trend is recorded.

A PAS-X Manufacturing Intelligence module supports data analysis, such as for comparing production data from lot to lot, line to line, shift to shift, and overarching plant to plant.

As MES software enables visibility into processes, companies can apply lean manufacturing initiatives for OEE improvements. The system follows quality system rules in executing the master batch record, electronically documenting if check weighers are trending out of tolerance, bottle caps are misapplied, or lines experience bottle necks or too many rejects.

Operators can use RF-capable mobile terminals and note pads with integrated scanners to check lines and materials following work instructions.

“PAS-X EBR tells you what to do and how to do it, then captures what has been done, how it’s been done, and what didn’t go well. This can be very helpful in line clearance where you want to ensure no foreign objects are in or near the line. Operators bring RF readers to tags around the line. The line clearance is not complete if every corner has not been visited,” says Jan-Henrik Dieckert, senior manager, sales and business consulting, Werum.

“You may not have to run a full line clearance if you are executing a batch with the same product in a different bottle size. PAS-X is checking the product and adjusting the clearance steps accordingly, enabling a faster set up,” Dieckert adds.

Data Collection

MES starts at the shop floor, and with machine manufacturers and integrators. Ultimately, standard interfaces between machines, SCADA/HMI, and MES promote real-time PAT applications across plant functions.

“Machines are being designed to be smarter (and even) . . . to slow down or speed up automatically when needed. This all creates a need for information exchange between a machine or line and an MES/production management system,” says John Blanchard, principal analyst, ARC Advisory Group.

“Some PAT initiatives and user requirement specifications (URS) address this in packaging operations. However, there is a huge installed base of less capable and expensive machines that won’t be replaced overnight,” he adds.

In plants with such a diversity of equipment, OPC architecture supports device interoperability and data reporting.

“When a customer specs our machines, they will often make mention of a machine control operating system to support OEE or serialization. The equipment has to interface with their client/server based OPC system,” says Walter Langosch, director, sales and marketing, ESS Technologies (www.esstechnologies.com).

“This doesn’t really change our design much because in most cases the OPC drivers are already built into our PLCs. Each machine is individually tracking count in/count out and down time, using input/output sensors and manually entered data. Fault tags are programmed into the software. If a magazine on a cartoner or case packer is at a low level, those faults are already identified and readily available, so you can prevent a machine stop. The details are communicated up through the OPC to an HMI,” Langosch says.

PAS-X MES supports real-time control of processes when data is automatically captured from machines and lines. Data is normally obtained from SCADA systems or intelligent PLCs, via OPC interface to PAS-X, Puich says.

“A process where you are automatically capturing production data in the MES is more favorable for a QbyD/PAT-type initiative. Manual data entry is a longer loop. We are vendor-independent for SCADA/OPC integration, so we can provide an out-of-the box solution for seamless integration with PAS-X,” he adds.

Uhlmann Packaging Systems (www.uhlmannpackaging.com) has partnered with Werum to develop Werum’s NetMaker 5.1 packaging line integration system, a solution that automatically downloads product and production data. The companies have jointly presented a track and trace solution in which Werum’s PAS-X integrates Uhlmann’s line-level track and trace system with companies’ ERP systems.

“Pharmaceutical companies are increasingly interested in having a superior hierarchy in place. In companies where MES has been adopted, communication with an Uhlmann packaging line is pretty much standard,” says Christoph Lehmann, director, Uhlmann.

“If a customer has an MES layer in place, they are managing the larger process in making dependencies transparent from ADI (active drug ingredient) through to warehousing. We can share the status of the packaging line as we record the data needed for EBR and 21 CFR Part 11 compliance. All the paper work can be significantly reduced and releases can happen faster because it is done electronically,” Lehmann says.

After the ERP sends the batch information to Werum’s MES, the PAS-X software downloads relevant recipe management data to the Uhlmann-managed line and manages the data reported from the line.

For firms without MES or with standalone packaging lines, Uhlmann directly controls the packaging line process. Uhlmann machines feature Touch Control, an industrial PC for capture and analysis of production data. For supervising a complete packaging line, Uhlmann offers a SCADA solution with integrated control, data acquisition, and monitoring, with the option of an OEE calculator for line OEE analysis. In applications without an MES layer, the Touch Control PC or SCADA system connect directly to the ERP level, typically via OPC architecture.

Packaging Line Supervision

“We generate batch recipe management, production status, number of products produced, current OEE—all the data needed to manage and supervise the packaging operation. This can all be stored locally or centrally,”
Lehmann says.

“Alternately, we can provide the data to Werum for the OEE calculation. If a customer is using MES, PAS-X pulls the information from the Uhlmann Data Base System (a Microsoft sequel server data base) for smart analysis of the data,” he says.

Companies are favoring globally standardized MES solutions for managing multiple lines and sites, with software interfaces to their enterprise levels. “Pharma companies will prefer Werum because they are certified to work with all the ERP providers,” Lehmann adds.

In serialized track and trace applications, Werum PAS-X can host the EPCIS data base for managing and communicating serial numbers with trading partners.

Uhlmann’s track and trace solution— used in over 100 instances globally—
provides line level control for data coding, aggregation of coded packaging levels, and exception handling and reporting. In helping Turkish contract manufacturer and packager Pharma-
Vision San. ve Tic. A.S. meet the country’s serialization requirement, Uhlmann provided plant-wide systems in equipping 15 lines for printing, inspecting, recording, and reporting.

The lines tie directly into PharmaVision San’s SAP ERP, receiving the serial numbers from SAP and reporting back a complete record when a lot is closed. Uhlmann also developed an interface for sending the serialized information directly to the Turkey Ministry of Health. “When we finish a batch, we clear the line of all data, store the data on a secure server in a government -approved format, send it via secure FTP line, and receive instant feedback from the Ministry, “ Lehmann says.

Uhlmann recently demonstrated a solution integrated with Werum PAS-X in which the packaging is coded at the primary blister and bottle, the requirement set forth this year in India’s serialization mandate. In the demo, PAS-X captured data from Uhlmann line level data bases on multiple lines.

The system supports in process control and trending analysis.

“Once you have coded the primary package, you can tie all the production-relevant data to that specific product, and pool the data at the MES layer for further analysis. You can now tackle outlier incidents scientifically,” Lehmann says.

“Even if you are only doing trending analysis, it becomes a powerful tool for understanding your process,” he adds.

Rockwell Automation has enhanced its MES solution for life sciences companies with the latest version of FactoryTalk Pharma Suite. The next generation of Rockwell’s RS PMX MES platform, Pharma Suite 3.0 features enhancements for easier use and flexible application development.

“Rather than completely rearchitect RS PMX, Pharma Suite is based on our proven multi-industry MES platform FactoryTalk Production Centre” with functions specific to pharma and bio tech industries, says Rockwell’s Schwarz.

Designers sought to enhance time-to-results based on the particular needs of different user roles such as recipe authors, shop floor operators, or batch record reviewers.

Making Work Easier

“Traditional MES screens are extremely crowded, often making it hard for operators to recognize what the system is telling them. For Pharma Suite, we have optimized how operators interact with the system. The information displayed is reduced to what is absolutely required,” he adds.

Pharma Suite applications are launched and run in a web browser with launch pads easily accessed by URL, obviating the need to install software on client stations. A Quality Dash board now supports on line batch review. Supervisors on the shop floor and QA personnel can review and handle exceptions in real time as manufacturing rules are enforced during batch recording. By investigating process deviations earlier, the amount of time spent on batch review after batch completion can be reduced.

IT technology helps reduce Pharma Suite implementation costs. Today systems can be tailored to customer’s requirements without the need to reprogram and revalidate source code, thanks to the built-in application development framework. A work flow engine, form designer, and scripting language tools enable extensions or changes by configuration instead of programming, Schwarz says.

“In traditional monolithic MES systems, you have to touch the code to change features. Pharma Suite is much easier to configure through its life cycles, so you are reducing total cost of ownership,” he adds.

MES can interface with a SCADA solution or machine PLCs connected through an OPC server, using various OPC standards for communicating data in real time.

“EBR helps ensure the batch documentation is correct and comprehensive, with all processes and specifications enforced. Manual entry is error prone and takes time. We provide the mechanisms for retrieving data from machines or line controllers into the batch record, which allows eliminating error and capturing more data,” Schwarz says.