| Pharmaceutical and biopharmaceutical enterprises continue to face complex regulations and increased scrutiny from regulatory agencies related to the safety and efficacy of their products—from discovery and license approval through ongoing supply to the consuming public. These complexities and increased scrutiny can result in large fines and production shutdowns, making “top floor” executives more concerned with day-to-day “shop floor” operations. Although the initial push to focus on production control activities follows on the heels of unsettling events, many pharmaceutical and biopharmaceutical manufacturing executives are discovering that information systems are the key to providing reduced costs and increased competitiveness in the face of increasing regulatory pressure.
The lack of ability to communicate information/data between executives, operations personnel, facilities and regulatory agencies, however, is a source of growing concern as top managers become more involved in daily operational activities.
Managers and production personnel have historically worked in silos. Even when senior managers focus on operations, they are concerned with financial management, job management, production management and materials management. Production personnel, on the other hand, typically zero in on specific processes and product order fulfillment activities.
Additionally, the FDA and other regulatory agencies must oversee compliance to rules, practices and legislation governing drug production. Until recently, these agencies had to wade through mountains of paper to ensure a firm’s compliance.
Now, they use electronic documents, data and records to carry out their enforcement and compliance mission. So a successful information system must also bridge the information collection, reporting and management challenges that manufacturers and regulatory agencies face in trying to cooperate and communicate with one another.
With all this being said, it’s not surprising that information systems in pharmaceutical and biopharmaceutical manufacturing environments have struggled to integrate and exchange information and data. Managers rely on Enterprise Resource Planning systems (ERPs) to make business processes more efficient, while production personnel rely on automation control systems to streamline and control production processes. The two systems—like their users—are not primed to communicate and interact regularly.
It is only recently that the convergence of the Internet and open system communication protocols, extensible markup language (XML) and Web services have emerged to provide intra- and inter-system connectivity and communication. These technologies provide a means for integrating silos of information that stretch across the pharmaceutical and biopharmaceutical enterprise.
What’s needed in these manufacturing environments is technology that can help facilitate realtime communication between the top floor and the shop floor. Manufacturing Execution Systems (MES) sit between the two operational areas of the enterprise and act as a conduit—allowing data and information to be shared between the environments. By passing information between the two systems more frequently, an XML-based MES can pay off in huge benefits such as:
• increased compliance with good manufacturing practices;
• improved product quality;
• quicker product review and release;
• better labor utilization;
• improved equipment utilization; and
• decreased manufacturing cycle times.
Seizing the Opportunity To Share
For many years, pharmaceutical and biopharmaceutical manufacturers have been missing out on the benefits of networked information systems. ERP systems help corporate managers stay on top of manufacturing orders forecasting, production schedules, manufacturing standards, accounting, and financial and materials management. The automation control systems help production personnel control the drug manufacturing process by taking much of the human decision making out of the equipment control and production process.
Although each of these systems has been successful in its own domain, they operate in isolation and do not connect and share information with each other. Instead, information is merely passed back through manual data entry with significant time delays. As such, the systems (and more importantly, the respective systems’ users) often work with outdated or incorrect information.
Placing an XML-based MES application between the automation control system on the shop floor and the ERP system on the top floor allows the two systems to exchange information in real time. The automation control system can then share the following information through the MES layer and into the ERP system:
• expected start dates of manufacturing jobs;
• expected end dates of manufacturing jobs;
• resource and equipment status;
• labor status; and
• order status/completions.
At the same time, the ERP system can pass the following information through the MES layer to the automation control system:
• master recipe bill of material information;
• product demand requirements;
• routing/process specifications;
• labor characteristics;
• inventory and material status; and
• Standard Operating Procedure (SOP) references.
Increasing Compliance with GMPs
One of the most important advantages of using an XML-based MES to exchange information between automated control systems and ERP systems is increased compliance with good manufacturing practices 210 and 211.
In pharmaceutical and biopharmaceutical enterprises, evidence of regulatory compliance is achieved through the maintenance of records required by Subpart J (records and reports) in the current good manufacturing practices (cGMPs). Subpart J covers the following records: equipment cleaning and use logs; component and labeling records; master production and control records; batch production and control records (together with their review); laboratory records; distribution records; and complaint files. Compliance must be documented in all of these areas, as well as in areas not specifically mentioned by Subpart J but maintained as evidence of compliance with other sections of the regulations. These related sections include personnel training records; process and system validation records and reports; standard operating procedures; analytical methods and material specifications.
Achieving compliance for a certain lot of product involves developing a “batch record.” Such a record documents that pharmaceuticals are manufactured, tested and released pursuant to the requirements stated in the product and process specifications. Developing and controlling master product and process specifications on a product-by-product or process-by-process basis is considered a subset of the overall Master Batch Record, as defined in the cGMPs. Therefore, developing and controlling specifications is key to achieving compliance in pharmaceutical and biopharmaceutical manufacturing.
Automated control systems help manufacturers maintain compliance by providing for recipe execution and data archiving—ensuring that all processing occurs within previously validated ranges. Consider the use of process automation systems for maintaining recipe adherence. These systems are designed to ensure the processing of pre-programmed steps and control process parameter ranges.
During batch execution, these systems can also collect actual data from a process. This information is an important part of the final batch record because
it demonstrates process control and confirms that manufacturing was completed within validated ranges.
However, virtually all of these processes also require some manual intervention by a member of the operations staff, whether it’s verifying the use of materials and Resources or completing steps in the process that are not automated. As a result, most pharmaceutical and biopharmaceutical manufacturers also include a paper batch record for operators to record the completion of these manual steps, as well as any associated data.
For instance, a Master Batch Record for a product, authored in a word processor, might contain a bill of materials section. Once approved, this bill of materials must be manually entered into the ERP system so that manufacturing orders created for the product will have a correct record of the issued components. This redundancy can introduce specifications into the computer allocations that are not in compliance with the approved recipe—a potential disaster in cGMP manufacturing. This dual system can also lead to errors and omissions in manually documenting these steps.
However, placing an XML-based MES between the automated control system and ERP can prevent these errors and omissions. A document management application, which works in conjunction with the MES, provides guidance on how to manufacture the order. Via the document management application, the MES dictates to the automation control system the sequence of manual and automated functions to orchestrate the overall execution of the order. This additional level of automation increases compliance with good manufacturing practices by defining manual steps in the process automation recipe, plus acquired data from these steps is included in the final comprehensive batch record. As a result, pharmaceutical and biopharmaceutical manufacturers can produce a single batch record, thereby reducing duplication and raising the level of compliance with GMPs.
Although manufacturers do not increase revenues or save money by complying with GMPs, the cost of not complying can be substantial in terms of crippling fines from the FDA, lost products and eventual customer dissatisfaction.
Improving Quality Assurance
Sharing information between systems also results in improved overall quality while significantly reducing the labor hours required to verify this quality. An XML-based MES can help pharmaceutical and biopharmaceutical manufacturers monitor quality in real time, as opposed to conducting retrospective quality reviews. Instead of providing after-the-fact paper documentation, the MES can provide realtime assurance that manufactured products have met stated specifications by instantaneously sharing production information. In-line process control inspections can verify product characteristics such as fill weights and volumes, tablet characteristics, foreign matter detection, container and box counts, and labeling accuracy. When collected data is coupled with high-speed data historian and analysis packages, trends can be determined in real time to predict process degradation or future failures. As a result, when receiving this shop floor data, executive managers can proactively adjust process parameters to maintain finished product specifications, rather than attempting to remove failed products after the process is complete.
In addition, realtime information sharing helps to reduce errors by defining training, calibration and maintenance procedures, as well as adding application rules within the MES that require, allow or disallow operators to perform events on equipment. As such, not only is the need for manual log books eliminated, but the chances of using unsuitable equipment is reduced—providing higher levels of quality.
Errors are also reduced because shared information between systems results in a reduction of paperwork, which inherently lacks the control of an automated system. Document management applications that reside in the MES reduce errors by:
||replacing labor-intensive, time-consuming manual processes that are responsible for controlling and publishing paper documents, including manual copying distribution and maintenance of procedures and specification “books” common in pharmaceutical manufacturing;
||maintaining content fidelity and version control for documents;
||providing secure librarian functionality, categorization and organization of documents;
||supplying meta-tag data definitions; and
||managing electronic review, approval, publishing and change control processes for documents.
The reduction of errors and automated sharing of information pays off in reduced time spent on quality assurance activities. By using such a system, some manufacturers have reduced the time spent on investigations and deviations by almost 75%.
Reducing Order Release Time
Staying on top of what’s happening on the shop floor, in real time, can also help pharmaceutical and biopharmaceutical manufacturers improve order release. Since the MES provides realtime data from the automation control system to the ERP system, it is possible for managers to review data on the spot and immediately take any action that would be required to bring manufacturing processes into compliance.
When used for discrete processes, automated systems can provide around-the-clock assurance that manufactured products have met stated specifications. As a result of this realtime information exchange, quality management personnel can simply perform an exception-based review—looking for deviations in the electronic record received from the MES instead of reviewing a complete batch of paper records.
The electronic record also eliminates the 50% of batch records that are returned to manufacturing by the quality group because of data entry errors or omissions. All in all, this can reduce the product release time considerably, making it possible for manufacturers to quickly get their products out of production and into the market.
Maximizing Materials & Labor Utilization
There is no shortage of work on the shop floor at many pharmaceutical and biopharmaceutical manufacturing facilities, only a lack of coordination in deploying available factory resources (people, materials and tools) to manage the work. Because thousands of inter-related events and exceptions occur every day, expediting has become the standard way of doing business, while executing the planned schedule has become the exception. Often, hours are spent researching the current status of all jobs on the floor and developing a work schedule. Efforts are made more difficult because schedules often run a day or two behind what is really happening on the plant floor, meaning that executives are trapped between fast-paced demand and lagging information. 1
By using the realtime management capabilities of MES applications, operators can record when jobs start and stop, and track existing work flows through the entire process. Executives can use this information to apply techniques to manage the resources and work flow associated with the creation of value.
In turn, executives can then furnish operators with a continuously updated shop floor schedule and realtime dispatching of when and where events should occur. By managing execution, manufacturers gain control of the shop floor and have immediate visibility to any schedule variations.
Realtime information exchange afforded by the MES assures that an order will not go to the shop floor until all the materials to complete the job are in place. Thus, every released order will proceed through the production process as expediently as possible—significantly reducing non value-added activities. The exchange of information in real time prevents operators from using materials in a haphazard manner. For example, a manager typically might put needed materials on hold in an ERP, but shop floor operators might use the material anyway. With an MES sharing this information in real time, the production personnel would know that the material is earmarked for another order.
An XML-based MES also provides executives with realtime access to the production center’s capacity, making it easier to fully utilize labor resources. Executives can look for potential problems or bottlenecks before they occur and coordinate shop floor activities to execute work assignments as a synchronized operating unit. The improved workflow management creates a “pull” environment on the factory floor that dramatically improves lead time, productivity and inventory management.
There are many financial benefits accrued via realtime management of labor and resources. Cutting waste, lowering inventories and improving the order fulfillment cycle helps to reduce overall costs and the need for new plans and equipment. By reducing costs and being more responsive, manufacturers can also use their increased competitiveness to enter new markets. 2
Implementing One Step at a Time
Although pharmaceutical and biopharmaceutical manufacturers can potentially reap many benefits by using an MES to connect ERP systems to automation control systems, trying to do too much, too soon, could spell disaster. Since pharmaceutical and biopharmaceutical manufacturing facilities are typically set up to prevent change (in order to enhance uniform production), attempting to implement all MES applications simultaneously would require too much change and a labor-intensive validation effort.
In lieu of an all-at-once approach, manufacturers should tackle implementation of applications step-by-step. To this point, manufacturers could begin by managing equipment from top floor to shop floor; then move on to managing resources from top floor to shop floor; then move on to managing the integration of the recipe itself, and so on. Manufacturers should complete the implementation with the integration of the pharmaceutical recipe into the system.
One key to successful implementation is making sure that the MES mirrors manual processes. Typically, manual systems are driven by documents. However, many Manufacturing Execution Systems are data-centric. As a result, many implementations fail because they require too much change. When using a document-centric MES, managers and operations personnel are not required to adapt to a completely new paradigm. Instead they are able to operate more efficiently with electronic, "smart", XML based documents as they were previously familiar with in the manual, paper based operations method.
Worth the Effort
Developing a technology infrastructure that promotes the sharing of information from top floor to shop floor takes considerable effort, but the benefits can stretch far beyond simply increasing compliance and quality. The sharing of information can help pharmaceutical and biopharmaceutical manufacturers compete more successfully and operate more profitably. Reduced manufacturing costs, combined with increased capacity, utilization and efficiency, equals less pressure on earnings. In fact, running a highly automated and cost-efficient production facility could become the key to success, especially as new drug launches become less common and competition becomes more intense.
1. Execution-Driven Manufacturing Management for Competitive Advantage, Manufacturing Execution Systems Association White Paper #5, 1997