The vision of IT-driven drug manufacturing, like that of the paperless office, is far from a reality for most companies today. In that vision, sophisticated computer programs, guided by design engineers and research chemists, would generate mounds of data that define new production plants. The data would flow seamlessly through each program as the plant is built, validated and commissioned. And when commercial production began, production data would flow in the reverse direction, matching plant capacity with production equipments, and meeting corporate regulatory, accounting and business goals.
The reality? Design and construction programs output paper documents that are handed over to a new plant's owner. A new data-gathering effort then begins to meet validation and production goals. Then, as production begins, more databases are created, each requiring constant attention. IT and automation budgets soar, time is wasted and regulators begin asking, "who's in charge here?"
The need to speed time to market is driving more corporate managers to move from the reality to the vision. Vendors of everything from design and engineering systems, to control systems, to corporate ERP, all propose solutions that combine program execution or calculation with a database for storing the program's data as well as the information flowing forward and backward across an organization. These products have traditionally come under the rubric of plant (or product) life cycle management (PLM) solutions, but are increasingly being referred to as "asset management" tools.
Whichever label you use, the idea of getting everything within such a system to talk to all its parts is a challenge. "Without going really crazy with the money, you could justify almost any level of IT costs to accomplish this, simply because you want to get to market fastest," says Drew Wildman, team leader, IT systems, at Eli Lilly & Co., Indianapolis.
Vendors may be leaping forward with product offerings, but they're encountering some resistance from pharmaceutical companies. Drug manufacturers have been slower to adopt new IT systems than other process industries, observers say, but the situation is changing.
"Being [part of] a regulated industry, pharmaceutical companies tend to be conservative," notes Mark Wheeler, a life sciences market manager at Aspen Technologies, Cambridge, Mass. He cites the current emphasis on modernization of facilities coming from FDA Commissioner Mark McClellan as one driver; another is the growing difficulty of meeting documentation and validation requirements without having modern IT tools.
But the trump card is time to market: "Passing clinical trials is still the controlling factor with new drugs, but once that happens, the problems in dealing with all the information to design and build a plant, and keeping all the paper and e-mails flying around in synch, becomes very difficult," Wheeler concludes.
It Starts With Design
Like their counterparts in other industries where chemical reactions are the source of products, pharmaceutical process designers work with process simulation tools. Unlike other process industries, however, most of the process design is batch-oriented, and"tends to be dominated by scheduling unit operations, rather than by the kinetics or reaction rates of the processes, according to Dimitri Petrides, president of Intellign, Inc., Scotch Plains, N.J.
Intelligen offers two tools, SuperPro and SuperSchedule, to model pharmaceutical processes. Petrides says that typically, a user would develop a flow diagram "based on the process recipe "in SuperPro, then shift the data to SchedulePro for scheduling and debottlenecking the process. Utilities, such as clean-in-place (CIP) skids, buffer solutions and the like, are often the bottleneck, especially when production is being scaled up. Most recently, Intelligen has developed an equipment database, based on Microsoft Access, to store asset information.
Aspen has a batch-oriented offering called Batch Plus. Following Aspen's acquisition of Hyprotech in 2002, the company is in the process of integrating components of Hyprotech's Batch Design Kit into Batch Plus. According to Aspen's Wheeler, Batch Plus is part of Aspen's Engineering Suite, which allows data-sharing between the recipe management of Batch Plus and the kinetics or distillation features of Aspen Plus.
In addition, Aspen has invested heavily in asset-management and supervisory process-control tools, such as its Electronic Batch Records System (EBRS), and Info Plus 21, to allow for data to move from one application to the next. "The idea here is to work collaboratively," Wheeler explains. "Years ago, manufacturing experts would not have been brought into the design process until a drug had passed Phase III trials. Now, process engineers and researchers can synchronize their workflows better." Besides "time to market," he stresses, companies need to plan for "time to volume" "the time it takes to ramp up production, especially during a crucial product launch.
Some of these activities could be seen in action at Merck kGa, a pharmaceutical intermediates and fine-chemicals producer in Darnstadt, Germany. There, according to Michael Grund, head of process development engineering, the largest multipurpose batch plant in Europe has been developed and built over the past several years.
Aspen's Batch Plus was used early in the design process to reduce the 250 distinct chemical reaction pathways into 12 design recipes that allow a range of products to be produced while sharing appropriate process equipment. Besides helping plan the batch scheduling, says Grund, Batch Plus provided the documentation necessary to win regulatory approvals. "When you can show all the mass balances accurately calculated and consistently presented, you speed up the review process," he says. "One wrong mass balance and the regulatory review stops."
Construction to Commissioning
Perhaps the most dramatic changes in how design data are handled is occurring with the computer-aided design (CAD) tools commonly used by engineering-consulting firms to design and build facilities. One of the biggest changes is a market-oriented one: more CAD software is being purchased by the pharmaceutical manufacturers (or, in engineering-consulting speak, the "owner-operators") than by the engineering firms that traditionally have used this software.
According to Daratech, a Cambridge, Mass.-based IT market-research firm, the market share of CAD systems purchased by engineering firms has dropped from 80% to 60% since 1998, while that purchased by owner-operators has risen from about 20% to 40%. (These owner-operators include all parts of the process industries, not just pharmaceuticals.)
The reason for this change: software vendors have converted their systems from "document-centric" ones, aimed primarily at producing blueprints and construction documents, to "data-centric" ones that produce a database of plant assets. An asset database, identifying the location, purpose and function of each piece of plant equipment, becomes the basis on which control systems can be constructed, and maintenance or operational-oriented systems for keeping the plant functioning in a validated manner over its life. Thus, the data-centric approach fits neatly into the PLM concept of design and information-management tools.
This shift is, of necessity, a gradual one. Engineering CAD systems are so elaborate, and so many work processes are tied to them, that an engineering company shies away from upgrading from one version of such a system to another during the life of one construction project. Intergraph, Huntsville, Ala., the market leader in overall industrial-construction CAD, initiated its new system design, called SmartPlant, several years ago, and only recently has introduced a three-dimensional (3D) version.
Intelligence Lets Users Retain And Use Critical Specs
As CAD systems have evolved, more and more intelligence, in the form of specifications beyond mere dimensions, have been built into the systems. "In the document-centric model of the past, this intelligence was lost when the handover occurred between the design firm and the owner-operator," explains Trisha Shaw, pharmaceutical marketing manager at Intergraph's U.K. office in Swindon. "This intelligence can assist in the validation process, in collaborative efforts between various manufacturing and quality departments. Owner-operators were losing this value; now they can retain it."
Examples of this intelligence are riddled throughout a modern CAD design: not just the dimensions of a piping system, but also the pressures of fluids flowing through them; tags for individual control points that can be linked to the tagging that goes on in configuring a control system; even attaching (electronically) the original-equipment-vendor's documentation.
"PLM techniques come to the fore when a new capital project is undertaken," says Shaw. "The time-to-market pressure focuses on the need to pull very diverse information about the facility together, and to share information even while it might be changing." Additionally, she says, at least 40% and as much as 70% of the information needed for product traceability in the event of a recall is contained within the design database.
Intergraph's product portfolio comprises SmartPlant Foundation, the central database for the design information, PDS 2D or 3D, the actual CAD software, InTools, used for designing control systems, and a variety of specialized products for piping analysis, structural design and related issues. Shaw says that PDS 3D will undergo trials with a select group of customers during this year; meanwhile, PDS 2D has left this trial phase and is now in general use.
One of the earliest switchers from a document- to data-centric approach was Houston-based CEA Technologies, whose Plant 4D products are now in use at CRB, Inc., Kansas City, Mo., a firm that specializes in pharmaceutical construction, as well as by pharmaceuticals giant Pfizer, Inc. CEA offers Plant 4D for doing design, and 4D Explorer, an asset-management tool.
Aveva Group PLC, Cambridge, England also offers its Vantage family of data-centric design tools for several years. Its longstanding flagship product, PDMS, has been transformed into Vantage Plant Engineering and Plant Design; there are also Vantage Project Resource Management (for materials management) and Vantage Enterprise Net (for collaboration and legacy applications). Aveva counts Jacobs Engineering (Pasadena, Calif.), a major contractor whose clients include Merck, Eli Lilly, GlaxoSmithKline and Pfizer, among its customers.
Classic Handover: A Thing Of The Past?
The classic "handover" of a project from engineering contractor to owner is becoming a thing of the past, says Ewan Botterill, a strategic programs manager at Aveva's Mississauga, Ont., office. With a powerful enough database in place, both the designers and the owners can look at and interact with the design database as it evolves. This collaboration can continue even after the construction is complete. "Why is it that many plants find it difficult to stay within operating parameters?" he asks. "Most plants forget the importance of the engineering data and do not keep it current; there should be an ongoing process of sharing engineering data with production and manufacturing" departments, which occurs easiest when these departments "and their databases "communicate."
Simultaneously with Intergraph announcing its PDS 3D offering, Aveva announced XmpLant, a data-translation system that enables users to convert PDS files into Vantage file formats, while preserving most if not all of the contained information. While an obvious competitive move, the action also highlights the needs of engineering contractors and owner-operators who may be trying to work with different CAD systems on the same project. For years, all of the major plant-CAD vendors have had utilities to translate or interact with what is still the most broadly used equipment-design program, Autodesk's AutoCAD.
Whose Database Is It Anyway?
When it comes to maintaining electronic records of actual production, data-storage needs can quickly mount into the terabytes. While design-systems vendors have made a persuasive argument for developing the initial asset database, their work tends to leave off, and the work of control-systems vendors tends to move to the fore. CAD vendors have developed tools specifically for instrumentation and control systems "and control vendors use them, even while offering their own databases for the ongoing data storage of operating data and equipment status.
Within the past several years, Emerson Process Management, Austin, Texas, has commercialized its Asset Management Suite, uniting several already-commercial products that can be accessed via a Web-based "Asset Portal." The products include packages for control devices, for machinery, for process equipment, and for real-time process optimization. In practice, a client might purchase Emerson's Delta V control system, then integrate parts or all of AMS with it. (AMS can be used with other vendors' systems as well, according to the company.) During validation and operational-qualification testing, AMS can be set up with tags to specific control or production equipment. As production gets under way, performance and monitoring data can be gathered and stored, all with the timestamps, electronic signatures and other features required by 21 CFR Part 11, FDA's rules on electronic recordkeeping.
In cases where self-monitoring devices like controllers or transmitters communicate via industry-standard protocols like Foundation Fieldbus or HART, the operational data-gathering can proceed automatically, says Krisi Bailey, sales support manager for AMS. "AMS is able to talk to these instruments, leveraging their intelligence, and avoiding the effort and potential error of manual inputs."
Non-intelligent devices, or non-control process equipment like tanks or heat exchangers, can have their operational records set up with configuration tools included in AMS. Bailey adds that the latest version of AMS includes templates designed specifically for testing and configuring pharmaceutical operations.
This year, ABB, Wickliffe, Ohio, rolled out the latest version of its Industrial IT control architecture : System 800xA. Included with this release is the Plant Asset Management (PAM) system, for storing and monitoring plant equipment conditions. ABB adds Profibus communication protocols to its list of supported protocols, which includes Foundation Fieldbus and others.
"Our strategy is to have a single interface, configured to the needs of each user," explains Jay Ruhe, batch production business manager. Behind this interface, "asset management, batch recipes, control-loop information "all are integrated, with a common representation that can be validated. Installation and operational qualification "IQ/OQ "are tightly coupled to this integrated data storage system." The result, he says, is the capability to present only relevant information to each user, whether an operator, a control engineer or a plant manager, and to streamline the process of validating or auditing operations.
PAM is set up to collect the data necessary to perform root cause analysis on equipment failure or process upsets, adds Jeorg Schubert, PAM product manager at ABB. "Normally, you'd have to look through manually written entries in a shift book to collect the information needed for root cause analysis," he says. "The ABB system can both collect information and provide predictive analysis of equipment performance."
Similar combinations of control technology and asset-management software are in place at Invensys Foxboro (which mates FoxBatch control software with the Avantis enterprise asset-management system) and Honeywell, with its PlantScape control software and Experion PKS information-management tools.
Measure Your Measurements
While keeping their eye on designing, configuring and installing control systems, control vendors must also pay attention to the maintenance of their own hardware through calibration services. Calibration is one of the final steps to commissioning the control system at a pharmaceutical plant, and the time-to-market pressure calls for an integrated solution that allows calibration data to be stored and retrieved easily.
Some vendors, notably Honeywell, offer a full-fledge calibration service, along with data-management tools and calibration devices. ABB announced an alliance this fall with Meriam Process Technologies (Cleveland, Ohio), a vendor of calibration hardware and software.
Meanwhile, pharmaceutical companies can call on numerous third-party suppliers of both calibration software and metrology services. Cybermetrics (Scottsdale, Ariz.) provides programs called GageTrak and FaciliWorks, the former specifically for calibration processes, and the latter for handling general maintenance schedules and workflows. "Pharmaceutical companies differ from our other industrial clients in that calibration is generally regarded as a subset of facility management, while in other manufacturing fields, the two are quite separate," notes Devin Ellis, technical services director. "Thus, we get numerous requests from pharmaceutical clients to add calibration features to FaciliWorks, but rarely the reverse."
Calibration Products Tend To Stand Alone
Ellis says that the delivery of calibration procedures and results from its programs into enterprise-level data systems (such as an ERP or a computerized maintenance-management system) has pluses and minuses. On the one hand, these enterprise tools tend to have fewer features than the quality-driven metrology manager would like. On the other hand, calibration processes tend to be site-specific. The end result is that calibration products like Cybermetrics' tend to be standalone applications, not tied into enterprise systems. "When a client requests it, we can customize some type of e-mail or messaging delivery," he concludes.
Similar third-party packages are available from Blue Mountain Quality Resources (State College, Pa.), Prime Technologies (West Chester, Pa.), Beamex (Marietta, Ga.). Prime Technologies touts its communication interfaces with Oracle's database systems, as well as maintenance-management systems. "Metrology tends not to be in very sharp focus in the pharmaceutical and biotech industries," comments Bob Nugent, operations director of Biotechnical Services (San Diego, Calif.), a calibration service provider. "Some companies just want to be able to put a sticker on their instruments attesting to its last maintenance check; at other companies, calibration is tightly linked to overall operations."
Similarly, some companies will be very aggressive about connecting calibration data to enterprise systems, and others less so. Perceiving a gap between the needs of biotech organizations, and their attentiveness to good manufacturing practices, Nugent is in the process of setting up a national partnership of maintenance and related service providers, to be called the Biotech Integrated Group.
Most observers see a gap between the capabilities of today's asset management tools and what pharmaceutical companies are doing with their assets. However, that gap is beginning to close. "We have a steering committee that looks at where our IT systems need to be, and where they are, and we've been concerned about falling behind our competitors," says Eli Lilly's Wildman. "On the other hand, we have the opportunity now to take advantage of the lessons learned from the early adoptions of this technology, and we can move faster."