Single Use Systems in Biologics Manufacturing and their Impact on Manufacturing Execution System (MES)

Since their inception in production, single use systems (SUS) have evolved and improved thanks to the continuous relationship between vendors and biopharmaceutical manufacturers, accommodating a wide range of operational needs. From culture initiation in small volume bags, to large-scale production bioreactors, chemical solution preparation and product storage, the implementation of single use technologies is a key initiative that many biopharmaceutical companies are undertaking. Scale-ability, flexibility, lower utility costs, reduced capital investment and reduced risk of contamination are the key advantages offered by disposable systems.
Regardless of the type of equipment utilized, the success of manufacturing operations largely depends on the adoption of efficient business process combined with the appropriate operational technology, mainly plant automation, Manufacturing Execution Systems (MES), planning and scheduling applications, and data analytics.
The adoption of single use systems dictates that organizations rethink their existing practices as well as the user requirement specifications (URS) of all electronic systems involved in the manufacturing process, enabling optimal execution and achieving additional benefits. Amongst the key areas that require close examination and redefinition are: scheduling of new process steps that result from inspection and assembly of SUS; automation recipes to allow for pauses and manual activities; configuration and maintenance of master data in the Enterprise Resource Planning (ERP) tools; material management in MES; definition of realistic models to estimate the potential contribution of Leachables and Extractables (L/E) substances.

Master Batch Record Configuration
In the case of plants that utilize SUS, the successful implementation of MES depends on the detailed examination of the process steps and the documentation of new user requirements, prior to system configuration. The master batch record (MBR) design must include steps that address the availability of SUS station (bag tote, bag holder) and equipment selection as indicated in the Bill of Equipment (BOE). Additionally, the specific sequence for assembly and inspection of the SUS set up needs to be enforced. This is a critical requirement that is sufficiently mitigated by traditional MES functionality. The assembly steps can be performed under a specific “assembly MBR” that produces a configured system that is sometimes referred to as a “make-item”. This in turn becomes the input to the MBR that executes the actual operational steps.
In traditional facilities with stainless steel units, equipment use and clean status are tracked using paper logs or MES functionality offered by the equipment management module (EQM). This type of facility needs to explicitly design recipes for cleaning and steaming, as well as “hold times” that move a vessel into clean expiry if not used within a timeframe. These requirements add complexity to MES because there are multiple equipment states to be tracked, and the recipes to perform cleaning require not just the equipment itself, but also ancillary assets. In facilities with disposables, the equipment is treated as a raw material; therefore ‘Clean Status’ and ‘Use State’ become irrelevant. With disposables, there is less emphasis on EQM and more dependency on ERP genealogy features. The complex MES algorithms needed to represent equipment state become simpler; but a higher level of detail is required to fully capture the SUS characteristics in ERP and to obtain the full picture of SUS as part of batch genealogy. SU components must be incorporated in the Bill of Materials (BOM) which will enable full traceability and calculation of a realistic cost of consumables. As a result, the complexity of equipment management decreases, while the requirements for materials management increase.
The list of process orders and the associated BOM is communicated to MES from ERP via interface. It is typical in operations with SUS to have multiple options for the same disposable component. For example, tubing assemblies, bags and filters can have a primary option and alternatives (from the same or different supplier), that fulfills the same function. Since it is possible to select materials from multiple options, it is critical that the MBR design addresses this requirement and MES functionality allows the selection from multiple options during process execution. The system needs to correctly associate the consumed materials to the production batch number, and as a result, create the material genealogy of the production batch. During SUS assembly and inspection steps, the ability to select components amongst the approved, validated options is critical, since at times it is necessary to replace a damaged or defective item. In these situations, MES then, must have the ability to “return” the unused or non-conforming material to blocked inventory status in ERP and associate to the batch genealogy only the items that were actually used in the process.
The assembly of disposable systems requires the use of special equipment to perform tubing welds and seals, which also needs to be properly tracked as part of the equipment genealogy. This can become very relevant in future investigations and process troubleshooting scenarios.

Process Automation
MES triggers the initiation of the recipe in the process automation system. In the case of SUS facilities, there is heightened requirement for pauses to allow for manual intervention. In plants that use stainless steel, the automated process sequence typically relies on feedback from field devices such as proximity sensors and valve limit switches. This is not possible in SU equipment where components are pre-assembled by vendors and, for sterility purposes, are isolated with the use manual pinch clamps on tubing lines. Instead of relying on limit switches to detect valve positions, the pinch clamps need to be manually removed to allow liquid to flow. If pinch clamps are not removed, the peristaltic pumping of liquid could cause the tubing to burst. Technicians are required to “walk the line” and check the tubing runs to ensure that pinch valves are removed. This can take time, particularly when tubing runs can be 50-100 feet long, sometimes spanning multiple rooms. This scenario illustrates the impact to two systems: first, the process automation will now require pauses and perfect synchronization so that the “handshake” between systems occurs as the recipe and the electronic batch record execution progress. The second area of impact is to the process schedule, which will be discussed later.
Automation and eBR must contain adequate functionality to enable replacement of defective disposable components, which may be necessary during production execution, for example a fouled filter, bag failure during filling, or burst tubing. This is another scenario where pauses and resumes are required, as well as the perfect alignment of recipe and eBR. One key MES design requirement in these situations is the ability to document in the eBR the material ID, material batch number, quantity, and process step where the replacement material is used. The replacement material needs to be included in the production batch genealogy. This is a very critical user requirement for plants with SUS, because this scenario is guaranteed to occur during process. This functionality needs to be verified and documented during MES vendor selection to avoid major customizations, and needs to be validated during system implementation.
One typical use of disposable single-use bags is the storage of buffers, media, in-process intermediates and drug substance. In these cases it is also a requirement to capture the material ID, material lot and quantity of items used. Although these SU components are not part of the core assemblies or production systems, they are also part of the batch genealogy and need to be properly tracked by MES, since they are in direct contact with the product or intermediates, and this information will become relevant later for process monitoring activities.

End of Process and Review by Exception
When process execution is complete, a new eBR is initiated to account for the SUS breakdown and disassembly. This is done according to an enforced sequence and must account for additional batch information such as results of filter integrity testing post-use. Also, it is necessary to perform raw material reconciliation and account for scrap material and unused components that need to be returned to the warehouse and added back to inventory.
MES is a key system that has tremendous potential because it provides a global view of the manufacturing operation, raw material usage and equipment management. In addition to continuous process monitoring, more emphasis is been placed on key metrics such as ‘Right First Time’ and the management of process discrepancies and investigations. MES is key in this area because it can enable Review by Exception (RBE), which has the benefit of saving time and resources. In RBE, only departures from normal operations are highlighted and presented in a summary report for review and approval by Manufacturing and Quality functions. When this feature is enabled for processes with disposables, any material replacement or failure will be included as part of the exception report.

Finite Scheduling
The decision about using a stand-alone finite scheduling application or the scheduling module of MES is critical and requires upfront discussion and evaluation. In addition to ERP and MES modifications that result from the use of disposables, the scheduling of activities on the manufacturing shop floor is a topic that also needs examination, due to the unique complexities introduced by this technology. The selection and configuration of a finite scheduling application must take into account the flexibility required and the operator variability expected during the assembly of systems from kits. Also, there are inventory management requirements in cases where chemical solutions (buffer and media) are stored in disposable, mobile equipment. Regardless of the choice, stand-alone or as part of MES, finite scheduling needs to be evaluated independently.
Single use systems are characterized and managed as materials. As a result, production bills of materials (BOMs) tend to have a higher number of items as well as alternative substitutes that have to be picked, kitted and staged. This requires that warehouse personnel allocate more time to fulfilling the pick lists. Once staged, manufacturing technicians need time to confirm that the items in the kit are accurate prior to transporting them to the shop floor, where components are individually inspected for defects or damage that may have been caused by shipping and material handling.
Another activity that requires proper scheduling is system set up. In a manufacturing facility that uses traditional stainless steel systems, set up can be very predictable, usually requiring the connection of transfer panel jumpers, filters and other ancillary parts prior to performing validated, automated CIP and SIP cycles. In the case of plants with single use equipment, there are nuances that need to be accommodated in the schedule, with some activities becoming more efficient and others requiring additional time. For example, single use equipment is received sterilized from the vendor; therefore it would not require additional cleaning and sterilization to be performed by technicians prior to use. For single use cases, bags require set up and specific routing to be performed by trained technicians. Inlets, outlets, gas lines and ancillaries need to be connected by manual tubing welds or use of aseptic connection devices, which in turn, require careful inspection to ensure sterility. Technicians with varying degrees of experience perform these complex tasks, which result in a vast level of variability in the time (duration) it takes to set up a single use system such as a bioreactor.
Preparation of chemical solution (buffers and media) can be triggered using feedback from level transmitters in a stainless steel hold tank. When the plant scheduling application detects low level of inventory, a new batch order is automatically scheduled. This is standard practice today in companies that utilize stainless steel system in combination with the appropriate scheduling tool. This exact functionality cannot be enabled when solutions are stored in disposable bags held in mobile totes. With disposables, inventory management of buffer and media requires additional emphasis on ERP and MES, instead of the convenience of device-to- scheduling functionality.
System breakdown post use is another activity that requires planning and time allocation. Similar to system set-up, disconnection, decontamination and disposal are among the activities that need to be considered, and are also characterized by significant variability.

Process Data Analytics
In addition to compiling raw materials genealogy reports describing where each material was used, the potential effect of SUS on process and product needs to be evaluated to fulfill compliance requirements as part of continuous process monitoring programs and risk assessment efforts. Biopharmaceutical manufacturers are required to calculate the potential contribution of ‘Leachables and Extractables’ (L/E) substances that can become part of the product during process due to contact with polymeric materials of the SUS. MES is a very valuable tool that can enable this analysis by providing the data collected during the eBR execution, specifically the batch genealogy, and exporting these summaries to data analysis tools where each single use system is associated with their physical and chemical characteristics. Estimates of the total potential load of L/E can be calculated using representative models of the physical process. To develop accurate models it is necessary to consider the process environment including temperature, pH, and contact time (as indicated by the process step duration) between SU and product or intermediate.
MES contains the actual values for all these process conditions as part of the batch history, and it can be the most critical data source system for the evaluation of L/E in facilities with single use technologies.

Foundational Work
The benefits provided by MES in facilities with disposable systems are significant and will become more apparent as the adoption of SUS increases. However, the successful implementation and use of MES relies on a sound foundation that includes the clear definition of user requirements specific for the management of disposables, and the verification of functionality offered by vendors during the evaluation phase, which can only be accomplished through the adherence to detailed methodologies or front end studies. This practice includes a series of workshops, including material management, weigh and dispense, equipment management, quality and validation requirements, reporting and analytics, batch record configuration philosophy, interface definition, and extent of automation interface. Although these topics apply to the implementation of MES for traditional facilities (with stainless steel), they become critical in the case of SUS because of the particular details associated with the management and operation of disposables. This can only be accounted for and incorporated into the system design if the requirements have been documented in a front end study report. An added benefit is that through this analysis it is possible to accurately estimate the cost and extent of customizations that can result from the selection of a particular brand of MES.
In SU facilities there is more reliance on MES interfaces with ERP and the automation layer. Each ‘touch point’ needs to be clearly identified prior to configuration, and the messages across these interfaces need to be fully determined and documented. It is critical to rely on international standards, such as ISA-95 and ISA-88, and their applicable parts for the successful implementation of an integrated MES. Figure 1 shows a section of a process map with unit procedures, operations and phases for a hypothetical biopharmaceutical process.

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Although the creation of detailed process maps is tedious and resource consuming, it is definitely one of the most useful aspects of foundational work towards the implementation of integrated systems. At the Unit Procedure level, the map shows the context of a batch identified by the ID number assigned by ERP. The more detailed views of the map (Operations and Phases) show parallel activities that are typical of SU processes, for example, the set-up of multiple pieces of equipment occurring in two different rooms, by different operators. For process steps where manual activities are anticipated, process maps can provide the visual of the interfaces at the Phase level, making configuration and implementation of MES and process automation more straight forward and simpler.

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Summary and Conclusion
The benefits that biopharmaceutical companies obtain from MES implementation are numerous and well documented. For facilities with disposables technologies, the functionality provided by MES is fundamental for creation of batch records that include all the required functionality for proper material traceability, interface definition with ERP and process automation, data analytics and scheduling. The level of sophistication of MES, and therefore their suitability to properly manage operations with single use systems varies, which makes imperative that user companies dedicate sufficient effort to vendor selection and objective evaluation of MES functionality. Foundational work is critical to the success of complex projects, and proven methodologies (front end studies and process mapping) need to be completed to enable accurate design and to support the validation effort.
The fast pace of progress in information technology, for MES and data analytics, combined with advances in single use systems design will contribute to increased sophistication of biopharmaceutical manufacturing in years to come. But the success depends largely on collaborations between vendors of MES, disposable systems and users in the biopharma community for the ultimate benefit of patients that depend on life saving products manufactured more reliably and efficiently as companies adopt advanced technologies.

References
1. Configuring Manufacturing Operations Management Applications, Gloria Gadea-Lopez, Supplement to BioPharm International, Sept. 2014, http://www.biopharminternational.com/configuring-manufacturing-operation-management-applications-0
2. Data Management in Manufacturing, Jennifer Markarian, Pharmaceutical Technology, Vol. 38, Issue 5, May 2014
3. ISA, ISA95 Manufacturing Enterprise Systems Standards and User Resources, 3rd Edition (Research Triangle Park, NC, 2011)
4. Gadea-Lopez, G. and Korkmaz, B., “Successful Implementation of MES with ISA S88 and S95 Standards”, Presentation at MES 2013 8th Annual Forum on Manufacturing Execution Systems, Philadelphia, PA, USA, August 13-14, 2013

Author Biographies

Gloria Gadea-Lopez, Ph.D. is Director of Business Operations Management at the Shire Lexington, MA manufacturing site. She has over 15 years of experience implementing electronic applications for biopharmaceutical manufacturing and their associated compliance practices. She has led the deployment of integrated tools for data analytics, Manufacturing Execution Systems (MES), historians, machine vision and more recently, finite scheduling. She holds degrees in Chemical Engineering (BS), Food Science (MS) and a Ph.D. in Biosystems Engineering. Her team is responsible for business operations analysis and operations technology for the Lexington MA Biologics site. Of particular interest is the impact of single use systems (disposables) on MES, automation and data analytics.

John Maguire is the Associate Director of Manufacturing Systems at Shire’s Lexington, MA site. His main area of expertise is the application of process engineering and operational technology for life sciences. He has over 15 years of process engineering experience, including functional specification development and start-up of several drug substance manufacturing facilities in Ireland and the United States. John led the design and onboarding of single-use systems for Shire’s Lexington, MA manufacturing facility, which won an honorable mention for Facility of the Year in 2011. As a subject matter expert, John provides operations technology perspective for ERP and more recently to finite scheduling systems at Shire. John holds a Bachelor of Arts degree in Natural Science.



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