Batch Manufacturing in the Biopharmaceutical Environment

Transcription

1 Presented at the World Batch Forum North American Conference Chicago, IL May 16-19, Fox Valley Drive, Suite 204 Longwood, FL Fax: Batch Manufacturing in the Biopharmaceutical Environment Author Name: Torsten Winkler Title: Engineering Manager Company: Honeywell Inc. Address: Kaiserleistr. 39 City, State Postal Code: Offenbach Country: Germany Telephone Number: Fax Number: address: KEY WORDS Batch Automation, Biopharmaceuticals, MES-Integration ABSTRACT The operations and manufacture of biopharmaceuticals is a complex process combining the capabilities of multiple systems that extend the boundaries of batch processing. The Manufacturing Execution System (MES) receives information from the Enterprise Resource Planning (ERP) system and creates the necessary production orders, maintains material tracking/genealogy and coordinates key manual activities. The automated batch control system sequences the phases, controls the devices and captures the necessary history. These systems come together in the operation of Biopharmaceutical production plants, which require a very specific architecture that leverages standard batch products that are tightly integrated with MES capabilities. This is driven by the upstream and downstream processing specifications of such plants, the detailed compliance requirements and the benefits achieved in maximizing automated functionality. This paper explores the unique requirements of batch manufacturing in the biopharmaceutical environment. Copyright 2004 World Batch Forum. All rights reserved. Page 1

2 Introduction The successful sequencing of the human genome has opened the way to genomic-based methods for drug discovery. The demand for production of these drugs has increased substantially over the last few years. The most common production method for these biopharmaceuticals is the mammalian-based fermentation process, with the later separation and purification process. The process begins with the cell preparation. Following preparation, the fermentation process begins. The fermentation part of the production cycle is also called the upstream area. The aim is to grow the cell culture. This will be achieved by cascading the fermentation from smaller Fermenter to larger Fermenter. Depending on the production volume of the plant, multiple Fermenters may be cascaded in each of the fermentation steps. At the end of the upstream process comes the harvest of the product. The next step of the production is the separation of the product. There are several steps in this process including product concentration, purification, formulation and filtration. The Upstream and Downstream processes are supported with a utilities area. The utilities can be dedicated for the specific fermentation unit or there may be a centralized utilities system shared between the Fermenter. The utilities system provides water for injection, acid, base and cleaned water to these processes. The overall biopharmaceutical production process is a core batch oriented process. The only area where this plant has continuous processes is the utilities area. There are several key features of biopharmaceutical processing, which add unique complexities and are outlined below: Strong batch automation Regulatory compliance Long running batches vs. Short running batches Alarming and Equipment Management Skid mounted Equipment MES integration The quality of the product cannot be measured real-time Several of these features are explored in this paper. System Overview The overall system size for the facility is quite large with over 93 redundant controllers, 90 operator stations, control loops, 12 redundant servers and 1600 recipes. It has moveable skid mounted equipment used in the filtration and purification areas and a common utilities system that is shared throughout the facility. The system architecture is outlined below: Copyright 2004 World Batch Forum. All rights reserved. Page 2

3 Figure 1 System Architecture The batch control system manages all automated areas of the plant. By maximizing automation, the plant was able to reduce the total number of operators and increase the throughput of the facility. These are long running batches that may take weeks to complete, so early identification of product issues are critical. The operators / operator stations are located close to the equipment with no centralized control room. Life Cycle Management Validation is critical since the facility is regulated by the FDA. This results in the need to ensure each control loop, sequence, etc. follows the necessary life cycle stages for both initial validation and GMP operations. These stages include initial implementation, testing, technical release, pharma release, operation and retirement. The state transition diagram is defined by the site and enforced by the system. An example state transition diagram is included below: Copyright 2004 World Batch Forum. All rights reserved. Page 3

4 Develop ment Test Release Operate Figure 2 Life Cycle States Retire The system enforces the transitions where a normal cycle is included below: Development->Test->Release Technical-> Release Pharma->Operate->Retire Additionally, items can move from any stage back to the development stage or to the retirement stage. This allows individual items to be removed from service as necessary, but they are tracked and audited. Additionally, any item may be moved back into development stage if re-work is required. Each stage has the appropriate signatures to ensure only properly trained personnel are performing the actions and double signatures are used where applicable. When moving through the approval process, graphical comparisons provide the approver with detailed information on the specific changes so they can verify only specified functionality was implemented. This enforces the proper life cycle to ensure validation is maintained on the system with records available in an electronic format. System Management and Security With the large number of operators and stations to maintain, a centralized security management system is necessary. Domain based security is used to maintain over 400 operators and manage over 90 stations and provides site wide security management. This allows user groups, user/system maintenance and polices such as password expiration to be enforced from a centralized server. There are three groups of engineers: Standard, Process and Batch. Each level has permissions that allow them to perform only authorized actions. The Standard Engineer can implement changes, but cannot download those changes. The Process Engineer can both implement changes and download the changes. The Batch Engineer has the proper training to implement changes, download changes as well as perform changes to the operations. These policies and centralized administration result in better system management and enforcement of polices that support regulatory compliance. Additionally, all the control system accounts leverage the domain based security model and further reduce time and effort required for system maintenance while ensuring policies are applied uniformly across all stations. Copyright 2004 World Batch Forum. All rights reserved. Page 4

5 To further ensure user authentication, smart cards were implemented for user log-ins. The operator swipes their smart card when they begin a session. The control system tracks the user as identified through the smart card and appropriate access is provided. The smart card log-in provides continuous sessions in support of 21 CFR Part11 compliance. The system also supports single and double signatures as necessary depending on the operator actions. All signatures are recorded in the system and tracked. A typical single signature display is included below: Figure 3 Electronic Signatures Alarming and System Monitoring Since ownership of the batch is transitioned through multiple operators and alarms may have GMP impact, a key concern is the management of alarms and equipment throughout the batch execution. This results in the need for not only priorities of alarms provided to the operator, but separation of alarm/alert types that may need to be sent to maintenance personal or supervisors based on the criticality and type. Alarms are broken down into three types: Operator Alarms, GMP Alarms and Maintenance Alarms. If an operator alarm occurs, it falls within the operators normal process responsibilities and they are notified via the station displays. A second level of alarm is a GMP alarm. These are designated alarms that are critical to the process and may impact the quality of the batch such as exceeding the ph limits of a fermentation step. In addition to these alarms being sent to the operator via the station displays, an additional alert is sent to a site wide central location which is managed by the hot stand by operator and /paging notification is provided to necessary personnel. This centralized management of GMP level alarms results in improved response to critical alarms and reduced operations costs. Copyright 2004 World Batch Forum. All rights reserved. Page 5

6 The final alarm level is the maintenance notification. These are alerts provided to the maintenance department via that must be responded to in a specified period of time. Critical maintenance issues may also result in paging or cell phone notification. The management of alarms and alerts are critical to the site wide operations. In addition to alarms, there are monitoring activities that occur continuously on the system without normal operator interactions. These include items such as monitoring all the stations and servers to ensure free disk space is maintained. These monitoring activities are configured on the system and send automatic notification to the responsible system administrators in the event an issue is identified that needs to be addressed. These are not normal items the operator is monitoring and the system provides effective notification to ensure problems are pro-actively addressed and do not impact process operations. Skid mounted equipment Skid mounted equipment is used extensively in the filtration and purification areas of the process. These skids are moveable equipment that are shared across the system to reduce costs. There are multiple methods of handling skid mounted equipment and in this case, the I/O is included on the skid. This provided several benefits including flexible use of the skid with the controller loading the limits based on the attached skid. A unique identifier on the skid is passed to the controller when the I/O is connected since there are minor differences in the skids that must be tracked. The controller also detects the state of the skid when the I/O is connected. This provided a flexible use of the shared skids that ensured the equipment was in the correct state prior to using the skid. MES integration This site used an MES system in combination with the Batch Control System. The functions performed in the MES system were selected based on an analysis of the systems availability, failure scenarios and failure responses. Items that required high system availability where operations could not be interrupted were included in the batch control system. Items that could be performed via paper if necessary were included in the MES. This resulted in the MES managing production orders, electronic batch record (EBR) and equipment status. Automated functions were included in the batch control system. The interface to the MES requires different data to be exchanged in both directions. The data are as follow: Configuration data Batch data Continuous process data The data transfers between the MES and batch control system are illustrated below: Copyright 2004 World Batch Forum. All rights reserved. Page 6

7 Equipment Data Online Data MES Historical Data DCS Master Data Command Interface Table Batch Operations Unit Data & Crossreference List productspecific Recipe Parameter Interface Table for answering Signals Batch Data Base historical Data Base Notification Message Data Base OPC-Server DCS - Batch System Figure 4 Batch / MES Data Exchange This data exchange allows the MES to effectively manage the production order, schedule batches on the control system, manage equipment status and to maintain the EBR. It also allows the batch control system to receive batch execution requests from the MES production orders/schedules and execute the automated functionality to maximize throughput at the plant. Value of a Batch Historian Due to the long bath execution times and inability to directly measure product quality, early identification of process deviations based on measured variables is critical to batch operations. Throughout the process key variables including temperature, ph, O2 and CO2 are measured to provide early indications of process performance and quality. These variables are compared with golden batches to determine if corrective actions are necessary to bring the process back to normal conditions. Additionally, the comparison tools are used to optimize the process such as performing an analysis to identify the best method for controlling the differential pressure in the filtration step. An example comparison of deviation in batches is included below: Copyright 2004 World Batch Forum. All rights reserved. Page 7

8 Figure 5 Early Identification of Process Deviations and Process Optimization Summary Biopharamceutical processing is a batch centric process with batch times that may take weeks to complete. Centralized system management support is critical for large installations to effectively manage group policies and operators. MES integration can provide key benefits in production scheduling and managing the EBR, with the batch control system providing the highly available, automated processing. Leveraging features in the control system including life cycle management and security can reduce costs and assist in the initial validation process as well as maintaining validation throughout the life of the system. Due to the long cycle times and difficulty in directly measuring product quality, indirect measurement of key variables with comparison between batches and with golden batches can result in improved quality and profitability. The system features and implementation came together and resulted in the investment being recognized in record time. Copyright 2004 World Batch Forum. All rights reserved. Page 8