The pressure on the life sciences industry as a whole has increased and continues to do so. With increasing regulatory requirements, R&D efforts and time to market have increased. Therapies tend to focus on smaller patient groups or have become personalized. Budgetary pressures in western countries have promoted the use of generic versus branded pharmaceuticals. In response, research-oriented, generic, and contract manufacturing organizations have emerged. This has increased the number of handovers and intercultural exchanges.
According to an international benchmarking study performed in 2007, even among research-oriented organizations, manufacturing remains the largest cost factor in the life sciences industry. The potential for reducing this cost is up to around 15 percent, when comparing the 10 percent best performing plants with the average. While these percentages may have changed a little in the interim, there is tremendous potential here to use manufacturing execution system (MES) technologies to capture and roll out optimized best practices (as opposed to simply automating average practices) and help integrate the design and operating environments.
As ARC Advisory Group learned in a recent briefing, Siemens uses SIMATIC IT eBR, a scalable, standards-based manufacturing solution, to help life sciences companies overcome a diverse range of challenges. The solution’s configurable environment can be easily adapted to clients’ specific requirements for new and existing applications. Standard functionality includes interoperability with design, business systems, and control systems; taking full advantage of digitalization. These elements lower the total cost of ownership for implementing and rolling out captured best practices.
SIMATIC IT eBR
SIMATIC IT eBR covers business processes and requirements for current good manufacturing processes (cGMP)-compliant paperless execution of life science manufacturing processes. Out of the box, the software is validation-ready and comes with a full documentation and validation package.
Master Batch Record
The user starts by defining materials and configuring the workflow and manufacturing process (including both manual and automated steps) to create a master batch record. The user configures and maintains these master batch records by creating and editing the process flow graphically and, subsequently, adding information for production or related to quality specifications. The user can structure the master batch record by using sub-records describing process sections. This helps make configuration flexible and efficient, because sections can be reused when they occur multiple times in the process. Additional efficiency can be obtained by standardizing workflow. Next, the user defines the electronic work instructions (eWIs) and standard operating procedures (SOPs) to be displayed and collected during process execution or lab operations. The workflow configuration provides an opportunity to implement quality by design (QbD), a type of workflow that helps ensure quality during production and avoids deviations and errors.
Work orders come in from the enterprise resource planning (ERP) system through a standard interface. These are then planned, dispatched, executed, and monitored for progress. To be executable, a work order is combined with a master batch record, specific equipment, personnel, and raw materials. During preparation, equipment parameters are downloaded to the automation layer, through native interfaces to Siemens PCS 7, or via OPC to other control systems.
Guided Manufacturing and Electronic Batch Recording
Electronic batch records (eBRs) are based on the master batch record template and populated with real-time data during the process. During execution, eWIs are displayed on the screen where the operation takes place to guide operators through the proper sequence of process steps. eWIs help ensure proper recipe execution and compliance with the SOPs. Real-time alerts warn the operator and supervisor when deviations occur. This enables corrective action that can bring the batch back on specification before the deviation becomes irreversible. The operator can activate conditional sections in the master recipe and modify the recipe when needed using compliant methods and producing compliant documentation.
Weighing and Dispensing
Weighing-and-dispensing (WD) functionality helps ensure accurate and consistent weighing for all types of materials. Instructions are displayed on user-friendly operator screens to help ensure compliance with cGMP procedures. Sixteen preconfigured, science-based calculations adjust target amounts to be weighed in for concentration, density, and potency of the ingredients. Built-in checks for equipment and plant “fitness for use” eliminate errors and reduce cycle times. A detailed predefined weighing report is available for each batch.
By making WD accurate, reliable, and reproducible, the module contributes considerably to “first-time-right” operations. Weighing errors could lead to lost batches, so the module can help reduce losses of material, time, and energy for processing.
SIMATIC IT eBR supports improved health safety and environment (HSE) performance using risk and safety phrases and pictograms in the operator instructions and on printed labels. These comply with the Globally Harmonized Systems (GSH) regulation.
All actions performed throughout the execution of the process are tracked by automated data acquisition or by time-stamped manual entry. This allows historical trends to be displayed, provides track-and-trace and genealogy, and an audit trail.
Paperless Batch Review and Release
While proactive quality management leads to fewer deviations, systematic quality control is needed to prove compliance. SIMATIC IT eBR guides operators and lab personnel in a paperless manner through the systematic quality control necessary to prove compliance.
The batch review and release process could delay products from reaching the market. This is because operators or material have to wait for lab results or validation of production steps. To reduce waiting, SIMATIC IT eBR makes lab results directly available from the LIMS, weighing, and eBR reports. The application helps perform alert validation and electronic batch review by exception, simplifying the process and speeding execution. By configuring appropriate authorization levels and signatures, only qualified personnel can review records. Batch record review tasks are visible in real time, allowing personnel to manage tasks based on priorities.
Integration with Automation
Siemens has invested significantly in recent years to increase integration with automation in both primary and secondary manufacturing.
When manufacturing drug substances, batch and process control systems execute a large number of production steps, while the operator remains in control by starting, stopping, interrupting or changing an operation when required and executing any manual steps. SIMATIC IT eBR provides an operator task list integrated with the automated process steps. This task list is visible in the main application as well as on the local HMI. Alerts and alarms of batch and control systems are also made visible to the SIMATIC IT eBR user, providing the opportunity for corrective action.
In secondary production, production is more highly automated, especially for larger batches. A recent trend is to have a fast line controller execute the orders from the MES. When used in conjunction with the SIMATIC WinCC line controller, SIMATIC IT eBR centralizes the information regarding batches to execute, and records execution data. The controller has built-in capabilities to interface with production equipment, including specific process execution and quality reporting control modules. This improves efficiency when implementing projects.
Baxter Healthcare uses SIMATIC IT eBR at multiple sites worldwide and has implemented paper-less manufacturing. The company uses the application to improve and roll out best practices. According to Baxter Healthcare, it increased its right-first-time production up to 99 percent, reduced risks and cost, improved compliance, and shortened time-to-market.
Shire (formerly Baxalta) uses SIMATIC IT eBR globally for weigh & dispense, eBR, and review by exception; as well to integrate with automation. The company reportedly increased process robustness and labor efficiency, reduced lost batches due to human error, and improved compliance.
At Sanofi Pasteur Vaccines, the goals for its MES were to reduce paperwork on the shop floor, provide closer operator guidance to reduce errors, and achieve GxP compliance at the lowest possible cost. The company, which believes that MES is an enabler for process excellence, deployed SIMATIC IT eBR at three sites in France and one in the US. According to the company, it increases operator flexibility and efficiency and helps guarantee target quality at the lowest possible cost.
In Ireland, Takeda wanted to improve productivity while optimizing costs by standardizing processes and reducing errors at all manufacturing stages of their work centers. The company achieved full traceability, reduced human error and batch re-runs, and accelerated batch release and time-to-market. The company reports a fast payback of its investment.
SIMATIC IT eBR appears to provide the full functionality needed to enable paper-less manufacturing. The review by exception functionality, in particular, reduces labor and time for the release of batches and has significant impact on working capital employed and customer service. The application integrates with control and batch execution systems, providing opportunities to correct deviations before they become irreversible to increase effective capacity and reduce production costs. IT eBR integrates with both quality systems and PLM and ERP systems to support new product introduction processes. Mandatory electronic batch records, produced in conjunction with material, energy consumption, and quality reports, are delivered directly to ERP systems.
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Keywords: Life Sciences, Electronic Batch Records, Recipe Management and Execution, Paper-less Manufacturing, Review by Exception, Quality by Design, ARC Advisory Group.