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How can manufacturers improve efficiency and increase production while maintaining regulatory compliance? Process-automation solutions are one method.
Increasing competitive pressures have forced manufacturers to demand greater flexibility from production facilities. Production managers are being challenged to achieve the seemingly incompatible objectives of increasing output and reducing the risk of regulatory noncompliance while implementing cost-reduction initiatives. These pressures are driving the evolution of interoperability between distributed-control systems and enterprise-planning and information systems.
The deployment of modern process-automation solutions enables pharmaceutical manufacturers to increase production output and reduce manufacturing costs while ensuring and documenting regulatory compliance. This article will introduce the reader to current trends and possible applications of process-automation strategies for world-class pharmaceutical manufacturing.
Process automation: the basics
The most basic application of process automation is at the individual machine level. Process machinery used in the manufacture of pharmaceuticals may be installed with a programmable logic controller (PLC) embedded as part of the unit. Typically, this PLC also includes a basic panel display unit that provides limited operator information and interaction. The manufacturing transformation of the pharmaceutical material progresses from machine to machine with manual intervention by the operator. In this simplest scenario, the process automation is local to an individual machine and performs the sequencing and control of the specific process-equipment function. The coordination of equipment and production-record documentation are manual activities.
Figure 1: Batch-management software such as "System 800xA Production Management" provides the batch-context of material processing by providing markers to enable the automatic retrieval of the measured process values during batch processing.
A more commonly used approach to process automation is through the use of a process-control system. Other terms used to describe this method include process-control system (PCS), process-automation system, distributed-control system, open-control system, or supervisory control and data-acquisition system. A PCS typically includes multiple controllers, each responsible for one or more pieces of process equipment with one or more operator stations that enable the monitoring and control of the connected process equipment. New process-control systems such as ABB's "System 800xA Extended Automation" integrate plant systems and functions to include more than traditional process control. For example, such systems integrate production management, safety, smart instrumentation, smart drives and motor control, information management, asset optimization, documentation, and other areas into a single operations-and-engineering environment. This combination improves both the control and visibility of the production process.
The PCS also can be leveraged to provide programmed sequencing of the material through the production equipment. Most material processing in pharmaceutical manufacturing is done on a batch-by-batch basis. Batch-management software coordinates the manufacturing sequence as the material progresses through the processing equipment. A batch manager (or batch supervisor) promotes consistency throughout the manufacturing process. It ensures that each batch of material is sequenced in the same way and is not subject to subtle differences resulting from the working style of various operators or shift teams.
Figure 2: ABBs "Industrial IT Enterprise Connectivity" provides a framework for connecting enterprise resource planning systems such as SAP, Oracle, and PeopleSoft with process-control systems.
Deploying batch-management software also brings additional benefits to the manufacturing suites. It allows batch sequences to be programmed to monitor key measured process variables as processing step endpoints (commonly referred to as transitions) and immediately begin the subsequent processing steps. This software also removes some of the variability of the human element and should result in a more optimized processing time and lead to improved production throughput.
Increase product yield while maintaining batch consistency
Manufacturing plants with multiple production lines and those capable of processing several products use batch-management software to maximize product output. The material processing sequence equipment requirements, target process parameters, and the quantity and types of material to be used are all specified in a master recipe. A master recipe should exist for each type of material produced. A batch manager simultaneously supervises and sequences multiple instances of the same product master recipe (commonly referred to as a control recipe) on different production lines or a mix of different products across the production lines.
Batch traceability: meeting regulatory documentation requirements
The PCS system also can be used to fulfill production-recording requirements as specified by regulatory bodies such as the US Food and Drug Administration. Most systems include a continuous historian function, which provides a mechanism to sample and store measured process values on a regular, fixed interval. These historian functions supply data to be used as part of the production record. For example, they might document that a vessel temperature was within an allowable limit or confirm that the air pressure in a cleanroom-rated area was maintained above the minimum specified parameter.
In most cases, the record-keeping requirements to document fully each batch of material produced are more extensive than the simple examples described previously. A batch-production record (BPR) typically is created for each specific batch of material produced. In simple terms, the BPR includes all of the information about the processing of the batch that could have an effect on the final quality of the material produced. This record likely will include the specified master-recipe parameters, (e.g., target-process values and material ingredients to be added), the main processing steps and the results of their actual performance, and key process measured values that directly affect product quality.
Many of the regulations that specify the production record-keeping requirements were in effect before the widespread use of process-control systems in this sector. Pharmaceutical manufacturers implemented standard operating procedures (SOPs) to prepare and use manual BPRs required to fulfill the applicable regulations that governed the materials produced within the facility. Several of these facilities still use these manual-based SOPs to meet record-keeping requirements.
Electronic batch records streamline regulatory compliance
As facilities modernize, or as new production capacity comes on-line, electronic solutions for batch-production recordkeeping are becoming more mainstream. Regulatory agencies, especially FDA, have been actively working with industry to encourage the use of newer technologies to fulfill regulatory requirements. The PCS batch-management software, working in conjunction with the historian functions, can facilitate the maintenance of the BPRs electronically. As described previously, the basic PCS historian functions are designed to acquire and record measured process values at fixed intervals. The production-recording requirements, however, typically must record a process value during a specific step in the production sequence. Batch-management software provides the "batch context" of the material processing by providing "markers" for the batch to enable the automatic retrieval of the measured process values during the specific batch-processing duration.
Integrated batch and historian functionality: how it really works
A simple example can illustrate why batch and historian integration is useful. For example, a batch reactor includes a temperature probe and associated transmitter among its various process-control instruments. The PCS historian function is configured to acquire and record the value of the reactor temperature every 30 seconds. The typical batch recipe processes the material in the reactor for 90 minutes. Therefore, the BPR must include a trend of the reactor temperature, but only for the time during which the batch material is processed in that specific reactor. A properly configured PCS batch-management history strategy will associate the reactor temperature measured value with the portions of the batch recipe that are associated with the reactor. This eliminates the task of manually associating the batch-recipe processing times with the continuous historian trend data.
The batch-management software also transfers information to the BPR, including recipe parameter values, master-recipe version number, and the actual processing steps performed during that recipe's execution (control-recipe instance). The batch master recipe also may include specific processing steps that do not necessarily result in actual process-control actions on the equipment. These processing steps may include calculations performed within the batch-management software to confirm a quality-related attribute of the work-in-process material or the explicit recording of a total quantity of material added for inclusion in the batch-production record.
The PCS batch-management and historian functions can create a significant portion of the BPR. Depending upon the manufacturing methodology, it could even create the entire BPR. In some instances, all of the processing activities are not under the direct control of the integrated process-control system. There may be one or more manual processing activities, in-process sampling for quality evaluations, or processing in equipment that is not integrated into the PCS. The batch master recipe and the PCS can be developed to account for these activities to collect a complete electronic BPR. Leading-edge solutions access and integrate information from disparate systems and equipment from all parts of the process to create a complete batch history.
The master recipe includes processing steps to facilitate operating personnel's execution of manual processing activities. The batch-management software configures recipe steps that present context-based electronic work instructions to guide the operator through and facilitate the recording of the performance of manual processing activities. These work instructions also can be configured to accept operator keyboard input, including authentication actions that represent an electronic signature. Essentially all of the manual processing steps that were previously executed by means of an SOP and a manual batch record can be performed and recorded within the PCS. This functionality provides the possibility of using handheld barcode scanners for material or equipment confirmation and usage recording, which was not an option for a manually completed SOP or batch record.
As previously discussed, process machinery used in the manufacture of pharmaceuticals may be installed with a PLC embedded as part of the unit. The PLC, however, may not be a controller type native to the integrated PCS that controls the majority of the processing equipment. It is quite likely that the PLC can be connected to the PCS so that measured values can be acquired and supervisory commands can be transmitted to the PLC. In this manner, the batch-management software of the PCS also can include recipe steps for processing activities in the PLC-based equipment. The ability to acquire measured values enables these activities to be included in the consolidated BPR.
Industry standards foster a common approach among automation suppliers and manufacturers that deploy this technology. The ISA-88–IEC 61512 "Batch Control" standard defines common models, terminology, and data structures for batch control, batch recipes, and BPRs.
Reaping the productivity benefits
Why are various companies looking to deploy these types of solutions in the manufacturing environment?
Batch consistency. These solutions can drive consistency throughout the manufacturing process.
Required documentation. The solution also can document the successful completion of manufacturing activities as required by company policy and regulatory agencies.
Increased throughput with higher quality. Increased production quantities are one of the tangible financial results that can be realized by reducing the processing time and minimizing the production of out-of-specification material.
Reduced production delays, rework, and scrap. Using a batch manager to sequence the processing steps automatically helps eliminate processing delays while waiting for human intervention. Consistent processing should reduce the time spent on adjustments and reprocessing of out-of-specification material, leaving more time available for first-run product.
Expedited product release. Electronic BPRs typically reduce the amount of time required to review, approve, and release the finished product.
These solutions do not bring benefits in the full-scale commercial production environment alone. Using these solutions in a clinical-manufacturing or in a process-development and scale-up facility can add value and improve the bottom line. More complete electronic recording of clinical or scale-up production batches can facilitate more comprehensive analysis of the process, thus leading to quicker process improvement and optimization opportunities. It also may be possible to transfer significant portions of the PCS configuration and batch master recipes to the production environment, thereby enabling the faster introduction of new products into commercial production.
Some developing trends in additional applications of process automation in pharmaceutical manufacturing will provide more opportunities to improve efficiency. Facility and building automation, integration with business-level systems, and adoption of process analytical technology (PAT) are affecting how PCS is deployed.
Certain manufacturing facilities use the PCS for facility or building automation instead of a commercial-facility or building-automation system in critical process areas where the environmental conditions have an effect on product quality. In some processes, the environmental conditions (e.g., temperature, humidity, cleanliness) may have a significant effect on product quality and must be tightly controlled. These environmental conditions also must be collected, reported, and recorded as part of the BPR and are part of the quality criteria evaluated in the product-release decision.
Manufacturers that have adopted this approach have been motivated by various considerations. One factor is the ease of inclusion of these critical quality data in the consolidated BPR. Another is the ability to leverage the computer-system validation effort that must be undertaken for the process-control system.
The leading companies in this market sector are connecting the enterprise-level business systems (enterprise resource planning systems such as SAP, Oracle, and PeopleSoft) with the process-control systems. The deployment of the business-level systems has been completed in many companies, and now the focus has shifted to the systems and processes that consume and supply the information from these systems. A leading industry-analyst firm, ARC Advisory Group, recommends "a focus on work processes, connecting plant systems to business systems, and providing real-time access to information for better decisions. These are the keys to better performance" (1). A typical application includes transferring production-order information with material type and desired quantity to the PCS. The PCS subsequently would supply the enterprise resource-planning system with key information about the actual quantity produced associated with the production order. Similar to the batch-control standards, industry standards also have been developed in this area. ISA-95–IEC 62264 describes enterprise- and control-system integration. ABB's "Industrial IT Enterprise Connectivity," for example, provides a framework for deploying these integration scenarios.
FDA launched an initiative in August 2002 entitled "Pharmaceutical CGMP for the 21st Century: A Risk Based Approach." The agency issued subsequent guidance on the use of PAT in September 2004. A main goal of using PAT is to enhance the understanding and control of the manufacturing process. FDA hopes to promote innovative pharmaceutical development, manufacturing, and quality-assurance techniques. Some early adopters now use PAT in on-line process-control applications for manufacturing. As pharmaceutical and biotechnology manufacturers look to update, enhance, or introduce process-automation solutions, the ability of a PCS platform to implement or support process-control strategies that leverage PAT is an absolute must.
A wide variety of automation options exists for plant managers, manufacturing managers, and others responsible for the production of pharmaceutical products to consider. A spectrum of automation possibilities is available, from minimal through fully automated. It is important to carefully review the possible solutions available for the type of facility, the products produced there, and the overall goals that are desired or required by the management team.
The options, while giving a possible set of tangible benefits, have an associated cost. It is critical to evaluate carefully the likely costs of deployment against the target goals and the possible benefits resulting from the deployment of the solution. No two facilities or enterprises are alike. Typical benefits available may include a reduction in manufacturing cost because of the more efficient use of existing plant assets or the elimination of personnel, the elimination of costly errors resulting from data discrepancies between unconnected systems, a reduction in finished-goods inventory because of an expedited product-release process, or a reduction in the probability of noncompliance.
Patrick Martin is a product line manager at ABB Inc., 29801 Euclid Ave., Wickliffe, OH 44092, tel. 440.585.8180, fax 440.585.7071, firstname.lastname@example.org
1. G. Gorbach, "Why Manufacturers Are Investing in Plant Floor IT Systems," ARC Insight #2006-17EC, April 13, 2006.