Manufacturing Execution Systems (MES) are designed to meet the industry's aspirations to go electronic. Susan Aldridge, PhD, and Volker Mensing of Werum report on their adoption based on views and advice given at a recent Werum organised user-forum in Ireland
The concept of MES is to integrate overall enterprise resource planning (ERP) and event/shop floor-based automation and control systems. Typically, MES cover aspects such as recipe management, material tracking, weighing and dispensing, deviation management, warehouse management, equipment management, and electronic batch recording (EBR) - all crucial aspects in modern pharmaceuticals manufacturing.
Liam O'Brien of Enterprise System Partners, a Cork-based consultancy, maintains the key advantages of MES are reduced labour and increased quality of operations through to the elimination of the generation, verification and management of paper batch records. It also makes compliance with regulatory demands, including 21 CFR Part 11, easier, he said.
Manufacturing execution systems have several additional features that can streamline workflows. For example, in terms of warehouse management, the main benefit is a significant reduction in labelling activity, while wireless devices and bar-coding decrease errors.
In the equipment and container management module, which works closely with material management, the functionality to define and enforce cleaning rules means that equipment can only be used if its status is correct.
Diarmuid Quinn, also of Enterprise System Partners, said a good System Master Plan is an essential starting point for the successful introduction of MES into a plant.
"This should ideally be a live document reviewed on an annual basis, looking five years ahead and considering the plant or corporation's needs," he said. After this, a Front End Study is needed, followed by vendor selection. The MES project team should be formed as early as possible - ideally playing some role in the Front End Study and vendor selection.
"This is probably the single biggest issue, for MES has impact across the whole organisation," said Quinn. The individuals on the team must have the power to make change and decisions, be IT system aware, and be fully committed to the long duration of the project. When it comes to MES implementation, a phased approach is desirable with prioritisation of the modules to be installed.
Quinn also offered a number of cautions, such as checking the maturity of vendors and their applications, being aware of the impact of MES on standard SOPs, as well as the regulatory impact and validation requirements.
"Training requirements must take into account of the existing level of PC awareness among staff, which can be low in the work environment, the complexity of the software, and the understanding of 21 CFR Part 11. For some staff, this will be the first time they have encountered an e-signature."
Simon Bragg, European research director, ARC Advisory Group, which advises upon manufacturing and supply chain issues, sees MES growing in importance as the production environment changes. Companies will no longer be relying on two or three blockbusters but will have portfolios of products with hundreds of different recipes and much smaller, almost personalised, batch sizes he notes. These trends will demand changes in manufacturing practices where there will be a leading role for Process Analytical Technology (PAT) and Collaborative Production Management (CPM). The pharmaceutical manufacturing will move from a supply chain to a value chain model, which will lead to a need to place CPM at the heart of the enterprise to improve productivity.
Graham Clarke, production manager of Nycomed's Carrigtohill site, near Cork, has had the experience of installing MES in a brand new plant. The site was designed as a back-up to one of the company's German sites and manufactures tablets for the proton pump inhibitor pantoprazole and a product currently in Phase III.
The tableting process involves the following operations: weighing, blending, granulating, blending (a complex step), compressing, coating and printing to give a finished product ready for shipping.
His advice to others is to include as many manufacturing personnel as possible in the qualification stages of MES. "This builds up local expertise on site," he said.
In Nycomed's case, plant start up - including tech transfer - and the MES project had to run in parallel. Getting MES to go "live" while at the same time going into commercial production presented Nycomed with a "huge challenge.
"The key thing is training of users," said Clarke. "The more [workers] involved in the early stages, the better." For, while the MES system is an excellent means of controlling material weighing, containers and scales, problems can occur if users are not completely familiar with all the required transactions.
Jim Lambe, IT manager of the Carrigtohill plant explained that his company decided to install an MES platform because it was seen as the best way forward in managing the manufacturing process in a compliant, safe, effective and efficient manner. Key benefits, he said, include a more predictable process with minimal risk of deviation, because material flows are so tightly controlled. MES also integrates with SAP, LIMS and other environments.
The following modules of the Werum PAS-X platform have been installed in the plant: MBR (Material Master Data), EBR (Electronic Batch Recording), WD (Weighing and Dispensing), WMS (Warehouse Management & Raw Material Sampling). The MES installation project began in February 2005 with the award of the purchase order to Werum and was finished by May 2006 with completion of the validation report.
Although Nycomed was using the EBR component, it currently still had some paper batch records as well. It had appointed a full time systems administrator. "We placed this post within IT because it is such a key focal area and its people are well known in the plant. Nycomed also developed a contingency plan. "We built the plant with two servers which are totally separate from one another, connected by two types of fibre optic cable. There is a massive amount of redundancy. If one server goes down, production can go on with data in real time - we monitor and test this on a regular basis."
Genzyme, one of the world's leading biotechnology companies, has also deployed Werum's MES PAS-X at its production site in Waterford, Ireland. This manufacturing facility is, among others, a primary tableting and bottling centre for the successful kidney dialysis drug Renagel.
Eamonn O'Mathuna, responsible for the MES at the Genzyme site in Waterford, said the vision of the genzyme Waterford Automation Program (gWAP) is to achieve paperless manufacturing in warehouse, oral dose, packaging, quality control, and fill finish. This involves the installation of the PAS-X system for the production management including electronic batch recording (EBR), material tracking and warehouse management, along with a Data Historian System, Product Data Management System and interfacing and integrating these with the existing ERP.
Genzyme was anticipating significant change and growth at Waterford which, according to O'Mathuna, would involve an increase of manual data entries from 750,000 in 2005 to 2.5 million in 2010 for batch records alone, with materials and quality data entries being additional to this. gWAP has proceeded, with tableting and packaging already being completely paperless since April.
Kevin Brady, OD manufacturing manager, explained that gWAP has realised benefits in the oral dose product, with 31 paper documents and 1,000 entries being eliminated per batch. There has also been an improvement in right-first-time results, with the target of over 93 % being realised and the need for a second signature has been all but eliminated.
Other benefits include real time update of information on batch status and improved container and equipment management. The phased implementation continues to expand. Therefore, production has reached new heights of 1.3 batches per eight-hour day, which is the highest output since the commencement of Renagel.
There have been many challenges along the way - over 263 SOPs have been updated and training has involved over 200 man-days. "It has been a challenge to change mind sets and let go of the paper," Brady said. "However, our future business is very much focused upon the electronic environment."
Looking to future developments, Christian Woelbeling, director of marketing and sales at Werum said the pharmaceutical MES market is growing at 10-15 % a year.
"To fully achieve operational excellence and lean manufacturing strategies in pharmaceutical production, you need independent, but integrated, MES," he said, adding that the company is committed to full integration of its products with SAP ERP which, after all, accounts for 90% of market share.
In Woelbeling's view, MES is a manufacturing excellence strategy and no longer merely a system. He cited the FDA paradigm shift to QbD (Quality by Design) and PAT calls for improved process understanding and control, as examples of new strategies that Werum's products are able to support. Accordingly, Werum is working towards real time release of eWorkflows. Woelbeling predicts that in 10 years time, every pharmaceutical company will be operating paperless, with EBR systems.